Calcium balance in drug-induced osteomalacia: response to vitamin D.
The effect of oral vitamin D3 therapy on calcium balance was compared in 18 institutionalized subjects with drug-induced osteomalacia and in 18 similar subjects without osteomalacia. The subjects with osteomalacia were receiving standard doses of phenytoin and phenobarbital. Diagnosis of osteomalacia was based on low serum calcium and phosphorus, elevated alkaline phosphatase, and appropriate roentgenographic bone changes. The study group achieved positive calcium balance at approximately 975 IU of vitamin D3 per day, while the control group achieved positive calcium balance at approximately 380 IU of vitamin D3 per day. The difference is highly significant (p less than 0.001). These data support previous observations that the osteomalacia of patients receiving anticonvulsant drugs is related to the drugs and that these patients require supplemental doses of vitamin D.


Clinical integration across multiple hospitals: the agony, the ecstasy.
The author shares one system's experience with the clinical integration of multiple facilities over several years. This inside view relates the good, the bad, and the ugly; the difficulties and the successes; and the agonies and the ecstasies. The author arrives at the conclusion that all the pain and anguish are worth the rewards of an integrated system that is well positioned in the marketplace to meet the mission and vision of a community health care system committed to thriving in the 21st century.


Shark fin: a new sign of thermal injury.
Three cases are described in which a curvilinear lucency in the corneal stroma signified a surgical thermal injury. The "shark fin" appearance represents focal shrinkage of tissue within the incisional tunnel.


Cerebral blood flow autoregulation during hypobaric hypotension assessed by laser Doppler scanning.
Hypobaric hypotension was used to reduce systemic blood pressure in rats below the lower threshold of CBF autoregulation to evaluate a new laser Doppler (LD) "scanning" technique. Spontaneously breathing male Wistar Kyoto rats (n = 8) were anesthetized with chloral hydrate and the head fixed in a stereotaxic head holder. A cranial window with intact dura mater was introduced to assess local CBF (lCBF) by LD. One stationary probe served to detect rapid flow changes, whereas the second probe was used to sample lCBF recordings from many cortical locations by means of a stepping motor-controlled micromanipulator to obtain lCBF frequency histograms. Advantages are an improved spatial resolution together with the easy detection of low-flow areas and a better comparison of data from individual experiments. Arterial blood pressure was stepwise reduced by exposing the lower body portions to subatmospheric pressures (hypobaric hypotension), thus avoiding the use of drugs or heparinization. The lower threshold of CBF autoregulation was detected by "scanning" at arterial pressures between 50 and 46 mm Hg, with low-flow spots occurring immediately. The data suggest LD scanning as a method suited particularly for studies where lCBF inhomogeneities are expected, e.g., the ischemic penumbra or sinus vein thrombosis.


Caveolin internalization by heat shock or hyperosmotic shock.
We investigated the cellular localization of caveolin, a landmark protein of caveolae, by indirect immunofluorescence after heat shock or hyperosmotic shock. Caveolin was internalized to the perinucleus by heat shock (43 degrees C) and relocalized in the plasma membrane after recovery of NIH3T3 cells at 37 degrees C for 4 h. The caveolin internalization was also observed after cells were exposed to hyperosmotic shock. Caveolin disappeared from detergent-insoluble complexes in the heat-shocked cells, but alkaline phosphatase was still there, suggesting that their responses to heat shock are quite different even though both of them were enriched in detergent-insoluble complexes of normal cells. Caveolin was internalized by the actin depolymerizer cytochalasin D, but not by the tubulin depolymerizer nocodazole. In addition, cellular exposure to hydrogen peroxide caused caveolin internalization along with disintegrated microfilaments and intact microtubules. Since cellular exposure to heat shock showed disintegrated microfilaments but intact microtubules, caveolin internalization might be due to depolymerized microfilaments. When cells were exposed to heat shock and allowed to recover for 4 h, actin depolymerization and caveolin internalization were not induced by a second heat shock, suggesting that some heat shock protein(s) might prevent actin depolymerization and caveolin internalization.


Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of N,N'-bis[2-oxo-2H-benzopyran]-3-carboxamides.
A novel series of N,N'-bis[2-oxo-2H-1-benzopyran]-3-carboxamide derivatives have been synthesized and investigated for the ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO). Some of the synthesized compounds show good selective inhibitory activity against the MAO-A isoform. Both the MAO-A and -B isoforms, deposited in the Protein Data Bank as the 2BXR and 1GOS models, respectively, were considered in a computational study performed with docking techniques on the most active and selective inhibitors.


[An integrated model for the evaluation and risk management of tuberculosis infection and active tuberculosis in homeless people in the city of Rome (Italy)].
In this article we describe an integrated model for the evaluation and risk management of tuberculosis (TB) infection and active TB in socially disadvantaged populations in the city of Rome. We describe and discuss the clinical evaluation procedures performed and the data collection forms used; these tools are useful for the epidemiologic surveillance and clinical management of patients, particularly high risk patients such as the homeless.


Chimeric CYP11B2/CYP11B1 causing 11β-hydroxylase deficiency in Chinese patients with congenital adrenal hyperplasia.
CYP11B1 and CYP11B2 are highly homologous genes that can form chimera following unequal crossing-over during meiosis. A chimeric CYP11B1/CYP11B2 gene causes glucocorticoid-remediable aldosteronism (GRA), while the rare CYP11B2/CYP11B1 chimeric gene leads to 11β-hydroxylase deficiency (11-OHD). The aim of the study was to find the underlying genetic causes of three distinct Chinese pedigrees with 11-OHD. The family history, clinical data, laboratory findings and alterations in the CYP11B1 gene sequence were analyzed in all patients. We found that patient 1 and patient 2 harbored novel homozygotic chimeric CYP11B2/CYP11B1 genes consisting of the promoter, exons 1-6 of CYP11B2, and exons 7-9 of CYP11B1. Patient 3 had compound heterozygotic mutation with one allele containing the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1, and the other allele comprising novel, previously undescribed p.W56X (c.168G>A) mutation in exon 1 of CYP11B1. The breakpoints to form Chimeric CYP11B2/CYP11B1 were not the same for the three patients. Rare chimeric CYP11B2/CYP11B1 gene mutations are the underlying cause of disease in three patients with 11-OHD. We hypothesize that the lack expression of CYP11B1 under the control of the CYP11B2 promoter in zona fasciculata may contribute to a cortisol defect as well as the resultant 11-OHD.


Demographic factors and playing variables in online computer gaming.
Despite the growing popularity of online game playing, there has been no primary survey of its players. Therefore, an online questionnaire survey was used to examine basic demographic factors of online computer game players who played the popular online game Everquest (i.e., gender, age, marital status, nationality, education level, occupation). The survey also examined playing frequency (i.e., amount of time spent playing the game a week), playing history (i.e., how long they had been playing the game, who they played the game with, whether they had ever gender swapped their game character), the favorite and least favorite aspects of playing the game, and what they sacrifice (if anything) to play the game. Results showed that 81% of online game players were male, and that the mean age of players was 27.9 years of age. For many players, the social aspects of the game were the most important factor in playing. A small minority of players appear to play excessively (over 80 h a week), and results suggest that a small minority sacrifice important activities in order to play (e.g., sleep, time with family and/or partner, work, or schooling).


Patterning sub-10 nm line patterns from a block copolymer hybrid.
We report the formation and directed self-assembly of sub-10 nm half-pitch line patterns from lamellar microdomains of a block copolymer hybrid. The hybrid, which is a mixture of poly(styrene-b-ethylene oxide) (PS-b-PEO) and a low molecular weight organosilicate (OS), shows strong segregation between two phases (i.e. PS and PEO+OS) and forms lamellar microdomains of down to approximately 7 nm in half-pitch. Patterns applicable to multifinger device layouts are created by self-assembling the hybrid on topographic pre-patterns with a chemically non-selective surface. With careful design of the guiding topographic pattern geometry, well-controlled lateral placement including bent structures of lamellar microdomains can be obtained by this approach.


Ag/CdS Nanocomposite: An Efficient Recyclable Catalyst for the Synthesis of Novel 8-Aryl-8H-[1,3]dioxolo[4,5-g]chromene-6-carboxylic Acids under Mild Reaction Conditions.
Chromene derivatives are privileged heterocyclic systems that exhibit various types of biological properties such as antioxidant, anticancer, antimicrobial, hypotensive, and local anesthetic. Cadmium sulfide nanoparticles (CdS NPs) as an efficient heterogeneous catalyst is used in various organic transformations because of its certain unique and unusual physico-chemical properties. The effectiveness of catalytic activity of CdS NPs can be improved due to the combined effect of Ag particles. Ag/CdS nanocomposite is a readily available, recyclable, and non-toxic catalyst used for the highly efficient synthesis of novel 8-aryl-8H-[1,3]dioxolo[4,5-g]chromrne-6-carboxylic acids. This reaction is conveniently performed under mild reaction conditions. All synthesized compounds were well characterized by their satisfactory elemental analyses, IR, 1H and 13C NMR spectroscopy. The synthesized catalyst was fully characterized by XRD, SEM, and EDX techniques. The present methodology focuses on the condensation reaction of arylmethylidenepyruvic acids with 3,4-methylenedioxyphenol, using a catalytic amount of Ag/CdS nanocomposite (15 mol%) in aqueous media at room temperature to afford 8-aryl-8H-[1,3]dioxolo [4,5-g]chromrne-6-carboxylic acids in high yields (90-97%) within short reaction times (2-4 h). The Ag/CdS nanocomposite was also prepared by an ultrasonic-assisted sol-gel method. In conclusion, we have successfully synthesized novel 8-aryl-8H-[1,3]dioxolo[4,5- g]chromrne-6-carboxylic acid derivatives by the Ag/CdS nanocomposite catalyzed cyclocondensation reaction of arylmethylidenepyruvic acids with 3,4-methylenedioxyphenol under mild reaction conditions. Environmentally benign procedure, high to excellent yields of products, simplicity of operation, and use of readily available and recyclable catalyst are the advantages of this new practical reaction.


The best strategy for RAS wild-type metastatic colorectal cancer patients in first-line treatment: A classic and Bayesian meta-analysis.
At present, there is uncertainty on the best systemic treatment in first-line setting for RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. Indeed, several chemotherapy and biologics combinations showed an improvement on survival. We performed a systematic review with a pair-wise and bayesan meta-analysis to rank the best strategy for these patients. A systematic literature search through March 2017 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity rate (TR) in RAS WT mCRC patients. Data were extracted from studies and pooled using the random-effect model for pair-wise meta-analyses and bayesan model for network meta-analysis (NMA). Eight studies with a total of 2518 individuals were included in the meta-analyses. Pooled analyses for subgroups stratified by type of schedule and tumor location demonstrated that anti-EGFR + doublet had the best OS when compared to doublet ± bevacizumab (0.767; 95%CI, 0.695-0.846; P < 0.0001). This benefit is limited to LSCC when compared to a doublet-based schedule and doublet + bevacizumab (HRs, 0.692; 95%CI, 0.596-0.804; P < 0.001; 0.706; 95%CI, 0.584-0.854; P < 0.001; respectively). No significant differences are detected in PFS, whereas the cetuximab-based regimens showed the highest ORR and TR. In NMA our ranking showed the best performance for FOLFOX + panitumumab. Our study indicates that FOLFOX + panitumumab has the major probability to provide an improvement of survival with a good safety profile in patients with RAS WT mCRC with an added value from selection based on sidedness.


Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study.
Previous studies have shown a sex-specific increased risk of Alzheimer disease (AD) in women older than 80 years. Basic neuroscience findings suggest that hormone replacement therapy (HRT) could reduce a woman's risk of AD. Epidemiologic findings on AD and HRT are mixed. To examine the relationship between use of HRT and risk of AD among elderly women. Prospective study of incident dementia among 1357 men (mean age, 73.2 years) and 1889 women (mean age, 74.5 years) residing in a single county in Utah. Participants were first assessed in 1995-1997, with follow-up conducted in 1998-2000. History of women's current and former use of HRT, as well as of calcium and multivitamin supplements, was ascertained at the initial contact. Diagnosis of incident AD. Thirty-five men (2.6%) and 88 women (4.7%) developed AD between the initial interview and time of the follow-up (3 years). Incidence among women increased after age 80 years and exceeded the risk among men of similar age (adjusted hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.22-3.86). Women who used HRT had a reduced risk of AD (26 cases among 1066 women) compared with non-HRT users (58 cases among 800 women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied with duration of HRT use, so that a woman's sex-specific increase in risk disappeared entirely with more than 10 years of treatment (7 cases among 427 women). Adjusted HRs were 0.41 (95% CI, 0.17-0.86) for HRT users compared with nonusers and 0.77 (95% CI, 0.31-1.67) compared with men. No similar effect was seen with calcium or multivitamin use. Almost all of the HRT-related reduction in incidence reflected former use of HRT (9 cases among 490 women; adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect with current HRT use (17 cases among 576 women; adjusted HR, 1.08 [95% CI, 0.59-1.91]) unless duration of treatment exceeded 10 years (6 cases among 344 women; adjusted HR, 0.55 [95% CI, 0.21-1.23]). Prior HRT use is associated with reduced risk of AD, but there is no apparent benefit with current HRT use unless such use has exceeded 10 years.


Behavioral dopamine signals.
Lesioning and psychopharmacological studies suggest a wide range of behavioral functions for ascending midbrain dopaminergic systems. However, electrophysiological and neurochemical studies during specific behavioral tasks demonstrate a more restricted spectrum of dopamine-mediated changes. Substantial increases in dopamine-mediated activity, as measured by electrophysiology or voltammetry, are related to rewards and reward-predicting stimuli. A somewhat slower, distinct electrophysiological response encodes the uncertainty associated with rewards. Aversive events produce different, mostly slower, electrophysiological dopamine responses that consist predominantly of depressions. Additionally, more modest dopamine concentration fluctuations, related to punishment and movement, are seen at 200-18,000 times longer time courses using voltammetry and microdialysis in vivo. Using these responses, dopamine neurotransmission provides differential and heterogeneous information to subcortical and cortical brain structures about essential outcome components for approach behavior, learning and economic decision-making.


In search of benzene-like Sn6(6-): synthesis of Na4CaSn6 with interconnected cyclohexane-like Sn6(6-).
The title compound was synthesized in an attempt to produce stacked benzene-like Sn6(6-) rings separated by alkaline-earth cations in analogy with the recently reported stacks of aromatic cyclopentadienyl-like Sn5(6-) in Na8BaSn6 (in addition to isolated Sn4- anions). The resulting compound, synthesized from a stoichiometric mixture of the elements at high temperature, has the "correct" stoichiometry with six tin atoms and six positive charges. However, the rings of Sn6(6-) are puckered into chair-type cyclohexanes that are interconnected into isolated cylindrical tubes stuffed with Ca2+ between the rings. Such tubes, if fused to each other, form the hexagonal diamond structure. The new compound is electronically balanced according to magnetic and four-probe resistivity measurements. Reported are also the synthesis and properties of Na10EuSn12 and Na10YbSn12 which are isostructural with the known Na10CaSn12.


Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura.
The aim of this study was to explore the profile and function of CD4(+)CD25(+) regulatory T cells (Treg cells) in idiopathic thrombocytopenic purpura (ITP) patients. Treg cell numbers were analyzed by flow cytometric analysis in peripheral blood mononuclear cells collected from healthy donors or patients with ITP. Quantification of cell proliferation was assayed by an enzyme-linked immunosorbent assay kit, based on the measurement of BrdU incorporation during DNA synthesis. The percentage of Treg cells was significantly decreased in ITP patients in active and non-remission state(5.79 +/- 1.22%) when compared with the patients in remission(11.63 +/- 4.56%) and to healthy subjects(12.68 +/- 3.59%). The suppressive activity of Treg cells in ITP patients was also found to be impaired. These results suggest that decreased number and function of Treg cells might be one of mechanisms that cause immune regulation dysfunction in ITP.


[Anti-hypoxia protective role of the effective component extracted from angelia injection].
To investigate anti-hypoxia protective roles of the effective component extracted from angelia injection using hypoxia injury model in mice and ECV304 cells separately. The survival time of mice was observed separately under normobaric and hypobaric hypoxia. The activity of ECV304 cells was tested by MTT assay, and the mortality rate was examined by Trypan blue exclusion assay to evaluate the pharmacodynamic effects. After exposed to hypoxia the survival time of mice was increased in medicine groups,compared with the control groups (P < 0.05). The cell survival rate was decreased and the cell mortality rate was increased after cells were exposed to hypoxia,while the cell survival rate was significantly increased (P < 0.01), and the cell mortality rate was significantly decreased (P < 0.1) in the medicine groups compared with the control groups. The effective component extracted from angelia injection can protect against the injury induced by hypoxia.


[Histochemical diagnosis of short segment Barrett's esophagus].
Recently, we have many chances of findings of Barrett's esophagus in routine endoscopic examination. It is also reported that we have few frequent findings of typical Barrett's esophagus, long segment Barrett's esophagus (LSBE) which is seen predominantly in Europe and United States, however the frequency of finding of short segment Barrett's esophagus (SSBE) and adenocarcinoma derived from SSBE is gradually increasing in Japan. So it is thought that precise diagnosis of SSBE and the evaluation of potential malignancy of SSBE are needed in the present medical management. The present study has shown the differences of characteristics of mucinous contents and malignant potentials between in SSBE and LSBE by use of biopsy specimen taken by endoscopic procedure. It is well known that Barrett's epithelium is categorized gastric fundic type, junctional type and specialized columnar epithelium, especially Barrett's mucosa is characterized by specialized columnar epithelium, e. g. incomplete epithelial type of intestinal metaplasia. We have set up two characteristic groups, gastric mucin dominant and intestinal mucin dominant by using specific mucin staining for MUC2, MUC5AC, Con A and CD10. In results, we confirmed that 80% of specialized columnar epithelia revealed intestinal mucin dominant in LSBE and 77% revealed gastric mucin dominant as compared with 23%, intestinal mucin dominant. Moreover, we have examined the ability of cell proliferation using Ki67-immunostaining in Barrett's epithelia. It was demonstrated that positive immunoactivity of Ki67 in proliferative zone was shown in 37.5% of gastric mucin dominant and 76.5% of intestinal mucin dominant. The results described above suggested that specialized columnar epithelia with intestinal mucin dominant have a higher potential of malignant transformation. We concluded that the evaluation of characteristics of mucinous contents in specialized columnar epithelia plays an important role in determination of high risk group of carcinogenesis in the case of SSBE.


Visual Performance of a New Extended Depth-of-Focus Intraocular Lens Compared to a Distance-Dominant Diffractive Multifocal Intraocular Lens.
To investigate the clinical performance of a new extended depth-of-focus (EDOF) intraocular lens (IOL) and compare it to that of a distance-dominant diffractive multifocal IOL. Patients implanted with an EDOF IOL (Mini Well; SIFI, Catania, Italy) inducing spherical aberration and with a multifocal IOL (ReSTOR SV25T; Alcon Laboratories, Inc., Fort Worth, TX) were analyzed. The following monocular parameters were investigated: corrected distance visual acuity (CDVA), distance-corrected near visual acuity (DCNVA), reading speed, defocus curve, contrast sensitivity, and halos and glare as quantified by a simulator (Halo & Glare Simulator; Eyeland-Design Network GmbH, Vreden, Germany) and questionnaire. Twenty patients with the EDOF IOL and 37 with the multifocal IOL were enrolled. No statistically significant difference was observed for CDVA. The defocus curve of the EDOF IOL revealed no gaps for the intermediate range. Statistically significant differences were observed at -1.00 diopter (D) (EDOF IOL: 0.08 ± 0.09 logMAR; multifocal IOL: 0.21 ± 0.12 logMAR; P < .0001) and -1.50 D defocus (EDOF IOL: 0.15 ± 0.11 logMAR; multifocal IOL: 0.24 ± 0.13 logMAR; P = .0122). The reading speed at 40 cm was similar at all print sizes. The mean DCNVA was the same (EDOF IOL: 0.35 ± 0.14 logRAD, multifocal IOL: 0.35 ± 0.13 logRAD). No differences in contrast sensitivity were detected. According to the simulator, halos had a smaller mean size (P = .0439) and a lower mean intensity (P = .0222) with the EDOF IOL. No statistically significant differences were detected for glare size. The new EDOF IOL performed similarly to a multifocal IOL at distance and near but was superior at intermediate distances. [J Refract Surg. 2018;34(4):228-235.].


Expression of the catalase and superoxide dismutase genes in mature pollen in maize.
The expression of the Cat and Sod genes encoding the multiple catalases and superoxide dismutases in maize has been studied in maize pollen at anther dehiscence. Pollen from three catalase activity variant inbred lines was examined. Zymorgram analysis, immunoassays, and RNA blots show that, in the lines used, only the CAT-1 catalase isozyme is expressed in mature pollen; the CAT-2 and CAT-3 isozymes are not. The data presented further demonstrate that the Cat1 gene is transcribed and translated after tetrad formation. The relative protein levels of the various superoxide dismutase (SOD) isozymes appear to be similar in pollen and scutella, and correspond to the relatively low levels observed for the different Sod transcripts in these tissues. The presence of "double" transcripts for Sod3 and Sod4A is discussed.


Biotransformation of alprenolol in dog, guinea-pig and rat liver microsomes.
1. Metabolites of alprenolol were isolated and identified in dog, guinea-pig and rat liver microsomes by means of g.l.c.-mass spectrometry and comparison with synthetic reference compounds. 2. The compounds were chromatographed as n-butylboronate derivatives, giving a series of diagnostic ions in the mass spectral fragmentation, which was elucidated by using stable isotopes. 3. Alprenolol was metabolized by aromatic ring hydroxylation, oxidation of the allylic function, and degradation of the isopropylaminopropanol side-chain. Alprenolol and four metabolites were quantified by h.p.l.c. and batch extraction techniques based on radioactivity measurements. 4. Five metabolites were detected in rat and guinea-pig liver microsomes and four in the dog. A species variation in the biotransformation of the allyl function in alprenolol was observed. The metabolite formed by oxidation of the allyl double bond was detected in significant amounts in the guinea-pig, and was also formed in the rat but could not be detected in dog liver microsomes.


Geriatric dentistry content in the curriculum of the dental schools in Chile.
The purpose of this study was to identify the status of pre-doctoral geriatric dentistry education among all Chilean dental schools. Chile is one of the most rapidly ageing countries in Latin America. Consequently, specific knowledge and training on the needs of elderly populations need to be emphasised in dental schools. The current extent and methods of teaching geriatric dentistry among the dental schools in Chile are unknown. A web-based questionnaire was developed and sent to all 19 Chilean dental schools to identify which schools had a formal programme on geriatric dentistry and ask about their format, content and type of training of the faculty who taught in the programmes. Data were analysed, and a comparison was made among the schools. Sixteen (84%) of the participant schools reported teaching at least some aspects of geriatric dentistry, using various methodologies, but only 7 (37%) had specific courses. Of those schools reporting a didactic content on geriatric dentistry, 71% included clinical training, either in the school's dental clinics or in an extramural service. Contents mostly included demographics of ageing, theories of ageing and medical conditions. More than half of the faculty (57%) stated that they had formal training in geriatric dentistry, 43% were trained in prosthodontics, public health or other areas. Although most dental schools taught geriatric dentistry, only some had a specific course. Most schools with formal courses followed the international curriculum guidelines for geriatric dentistry.


Evidence for two phylogenetic clusters within hepatitis C virus (HCV) genotype 2 inferred from analysis of complete coding sequences of 15 HCV strains.
The aim of this study was to gain further insight into the evolution and classification of hepatitis C virus (HCV) by assessing the subtype distribution of 273 genotype 2 strains isolated from French blood donors from 1990 to 2010 and by determining complete coding sequences in subtype 2 strains. These classified into 7 of the established subtypes and into 15 additional lineages not yet assigned to a known subtype. Phylogenetic tree construction showed two well-supported clusters. Cluster 1 included most subtype 2 strains while cluster 2 included subtype 2l and one unassigned subtype 2. Full genome sequencing was performed on 15 genotype 2 strains belonging to both clusters, that is, one subtype 2b, two subtype 2c, three subtype 2i, two subtype 2j, one subtype 2k, two subtype 2l, and four unassigned strains. Genomes included a 9042- to 9108-nucleic acid open reading frame coding for a polyprotein comprising 3014-3036 amino acids. Mean nucleotide distances between subtypes belonging to the first cluster was 20.2 ± 1.4% while the mean distance between the two clusters was 25.9 ± 0.3%. Analysis indicated that the bifurcation between subtype 2l and other subtype 2 strains occurred early in the evolutionary process. Subtype 2l retained a genomic feature characteristic of non-genotype 2, that is, absence of the 60-nucleotide insertion in the NS5A region. This finding suggests that appearance and fixation of this insertion occurred late in the evolutionary history of HCV type 2 and that its absence is an ancestral feature of HCV.


Demonstration of a class of porphyrin-containing cells in the pars intermedia of the rat hypophysis.
Cells emitting orange-red autofluorescence have been found in the pars intermedia of aging rats. The fluorescence maximum of the emission is localized in an area of the spectrum where the most intense band maxima of porphyrins are located. The fluorescence fades when the excitation wavelength is about 400 nm, which is specific (Soret band) for the absorption spectra of porphyrins. The fluorescence is emitted by coarse inclusions in the cytoplasm of a few cells. These inclusions are also stainable with paraldehyde-fuchsin and exhibit a high endogenous peroxidase activity. The inclusions observed have morphologic features similar to those of porphyrin-containing astrocytes from the periventricular area of the hypothalamus. The inclusion-bearing cells of the pars intermedia also contain debris that might be due to the phagocytic activity of these cells.


A randomised study of tailored toxicity-based dosage of fluorouracil-epirubicin-cyclophosphamide chemotherapy for early breast cancer (SBG 2000-1).
Retrospective studies have demonstrated a worse outcome in breast cancer patients not developing leukopenia during adjuvant chemotherapy. The SBG 2000-1 is the first randomised trial designed to compare individually dosed chemotherapy without G-CSF support based on grade of toxicity to standard-dosed chemotherapy based on body surface area (BSA). Patients with early breast cancer were included and received the first cycle of standard FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2). Patients with nadir leukopenia grade 0-2 after first cycle were randomised between either 6 additional courses of tailored FEC with increased doses (E 75-90 mg/m2, C 900-1200 mg/m2) or fixed treatment with 6 standard FEC. Patients with grade 3-4 leukopenia were registered and treated with 6 standard FEC. Primary end-point was distant disease-free survival (DDFS). The study enrolled 1535 patients, of which 1052 patients were randomised to tailored FEC (N = 524) or standard FEC (N = 528), whereas 401 patients with leukopenia grade 3-4 continued standard FEC and formed the registered cohort. Dose escalation did not statistically significantly improve 10-year DDFS (79% and 77%, HR 0.87, CI 0.67-1.14, P = 0.32) or OS (82% and 78%, respectively, HR 0.89, CI 0.57-1.16, P = 0.38). Corresponding estimates for the registered group of patients were DDFS 79% and OS 82%, respectively. The SBG 2000-1 study failed to show a statistically significant improvement of escalated and tailored-dosed chemotherapy compared with standard BSA-based chemotherapy in patients with low haematological toxicity, although all efficacy parameters showed a numerical advantage for tailored treatment.


Does GH replacement therapy in adult GH-deficient patients result in recurrence or increase in size of pituitary tumours?
Hypopituitary GH-deficient patients have an increased cardiovascular mortality and GH replacement in this population has resulted in considerable therapeutic benefit. GH replacement involves administration of a potentially mitogenic substance to patients with a previous or residual pituitary tumour. Our objective was to evaluate whether GH replacement results in an increase in the size of pituitary tumours. This was a non-randomised observational study on patients recruited from the endocrine clinic. All subjects had GH deficiency, proven on an insulin tolerance test and were divided into those who were or were not receiving long-term GH replacement. Comparison of change in pituitary size was made with interval radiological imaging of the pituitary. Seventy-five patients (40 men and 35 women) were in the study, 47 were on long-term GH replacement and there were 28 controls. The average length of treatment for the treated group was 3.6 patient years. Thirty-nine patients in the treated group had at least 2 years of GH treatment between imaging studies of the pituitary. Two patients in the treated group had an increase in pituitary size (non-functioning adenomas) and two in the control group (one functioning and one non-functioning adenoma adenoma). None of these four patients required further treatment. There was no statistically significant difference between the two groups. Using a representative cohort of hypopituitary patients attending an endocrine clinic, GH replacement was not associated with an increased pituitary tumour recurrence rate. Although the results are not conclusive, in the period of observation GH had little adverse effect but longer studies are required to be certain.


[Soft palate transnasal retractor].
An anterior transoral approach allows the surgeon to access the lower portion of the clivus; to the first, second or third thoracic vertebra. It is indispensible that the teeth, lips, cheeks and tongue be retracted to avoid interposition on the surgical field. This retraction is carried out by means of a Dingman separator. Nevertheless, generally the soft palate is elevated with sutures through the nasal fossa. Because this invasive method could damage soft tissues, we have designed a basket to separate the soft palate from the surgical field, thus allowing the surgeon to maneuver with comfort and without damaging structures. A 30-cm segment of 22 gauge wire is passed through each end of a thin sheet of silicon (4 x 3 x 1.5 cm) forming a basket. With the patient under general anesthesia, both free ends of the wire are introduced into the buccal cavity in the same manner nasal packing is used to control epistaxis. Each end of the wire is slid from the mouth through the nasal fossa to bring them outside the face. Traction is placed on both ends of the wire allowing the intraoral band of silicon to elevate and hold the soft palate. We present the case of a 64-year-old woman with spastic quadriparesis and hyperreflexia predominantly of the upper extremities, in addition to trophic changes due to arthritis of long duration. Imaging studies demonstrated nonreducible subluxation of the atlantoaxial joint with ventral compression of the bulbomedullar union by the odontoid apophysis. Resection of the anterior arch of the atlas and apophyses was made via the transoral route, where retraction of the soft palate by means of the described basket was employed. The patient did not experience significant sequelae as a result of the technique utilized.


Combined Monte Carlo and quantum mechanics study of the solvatochromism of phenol in water. The origin of the blue shift of the lowest pi-pi* transition.
A combined and sequential use of Monte Carlo simulations and quantum mechanical calculations is made to analyze the spectral shift of the lowest pi-pi* transition of phenol in water. The solute polarization is included using electrostatic embedded calculations at the MP2/aug-cc-pVDZ level giving a dipole moment of 2.25 D, corresponding to an increase of 76% compared to the calculated gas-phase value. Using statistically uncorrelated configurations sampled from the MC simulation, first-principle size-extensive calculations are performed to obtain the solvatochromic shift. Analysis is then made of the origin of the blue shift. Results both at the optimized geometry and in room-temperature liquid water show that hydrogen bonds of water with phenol promote a red shift when phenol is the proton-donor and a blue shift when phenol is the proton-acceptor. In the case of the optimized clusters the calculated shifts are in very good agreement with results obtained from mass-selected free jet expansion experiments. In the liquid case the contribution of the solute-solvent hydrogen bonds partially cancels and the total shift obtained is dominated by the contribution of the outer solvent water molecules. Our best result, including both inner and outer water molecules, is 570 +/- 35 cm(-1), in very good agreement with the small experimental shift of 460 cm(-1) for the absorption maximum.


An investigation of classical swine fever virus seroprevalence and risk factors in pigs in East Nusa Tenggara, eastern Indonesia.
Classical swine fever virus (CSFV) is a highly infectious disease of pigs. It has had significant impacts on East Nusa Tenggara, eastern Indonesia since its introduction in 1997. In spite of its importance to this region, little is known about its seroprevalence and distribution, and pig-level and farmer-level factors that may have an impact on the serological status of an individual pig. To address this knowledge deficit, a cross-sectional seroprevalence survey was conducted in 2010 involving 2160 pigs and 805 farmers from four islands in the region. Farmer questionnaires and pig record forms were used to collect data about the farmers and pigs surveyed. Blood was collected from each pig to determine its CSFV serological status. Apparent and true prevalence were calculated for each island, district, subdistrict, and village surveyed. CSFV serological status was used as an outcome variable in mixed effects logistic regression analyses. Overall true CSFV seroprevalence was estimated at 17.5% (lower CI 16.0%; upper CI 19.5%). Seroprevalence estimates varied widely across the islands, districts, subdistricts, and villages. Manggarai Barat, a district on the western end of Flores Island, contained pigs that were positive for antibody to CSFV. This result was unexpected, as no clinical cases had been reported in this area. Older pigs and pigs that had been vaccinated for CSFV were more likely to test positive for antibody to CSFV. The final multivariable model accounted for a large amount of variation in the data, however much of this variation was explained by the random effects with less than 2% of the variation explained by pig age and pig CSFV vaccination status. In this study we documented the seroprevalence of CSFV across four islands in East Nusa Tenggara, eastern Indonesia. We also identified risk factors for the presence of antibody to CSFV. Further investigation is needed to understand why clinical CSFV has not been reported on the western end of Flores Island, and to identify additional risk factors that explain CSFV serological status to inform disease control strategies.


Identifying dietary differences between Scotland and England: a rapid review of the literature.
Rates of premature mortality have been higher in Scotland than in England since the 1970s. Given the known association of diet with chronic disease, the study objective was to identify and synthesise evidence on current and historical differences in food and nutrient intakes in Scotland and England. A rapid review of the peer-reviewed and grey literature was carried out. After an initial scoping search, Medline, CINAHL, Embase and Web of Science were searched. Relevant grey literature was also included. Inclusion criteria were: any date; measures of dietary intake; representative populations; cross-sectional or observational cohort studies; and English-language publications. Study quality was assessed using the Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. A narrative synthesis of extracted information was conducted. Fifty publications and reports were included in the review. Results indicated that children and adults in Scotland had lower intakes of vegetables and vitamins compared with those living in England. Higher intakes of salt in Scotland were also identified. Data were limited by small Scottish samples, difficulty in finding England-level data, lack of statistical testing and adjustment for key confounders. Further investigation of adequately powered and analysed surveys is required to examine more fully dietary differences between Scotland and England. This would provide greater insight into potential causes of excess mortality in Scotland compared with England and suitable policy recommendations to address these inequalities.


Injury to the infrapatellar branch of the saphenous nerve in ACL reconstruction with the hamstrings technique: clinical and electrophysiological study.
The incidence of IBSN injury to the infrapatellar branch of the saphenous nerve (IBSN) in ACL surgery using the hamstrings technique has been reported to be between 30 and 59%. The purpose of this study was to evaluate the incidence of IBSN injury in ACL surgery with the hamstrings technique through clinical and electrophysiological evaluation, and also to evaluate potential risk factors of IBSN injury related to the surgical incision. Between November 2003-September 2004, 21 consecutive patients (22 knees) with an acute ACL rupture suitable for reconstruction were included. Patients with previous surgeries or scars around the knee and those with any degree of osteoarthritis were excluded. Clinical and electrophysiological evaluations were performed in all the cases. Hypoesthesia of the IBSN territory was found in 17 knees (77%) with an average area of 36 cm(2) (1-120 cm(2)). Injury to the IBSN was electrophysiologically detected in 15 knees (68%). Two patients also had an injury to the saphenous nerve (9%). The presence of sensory loss associated with damage to the IBSN did not correlate with the size of the incision or the distance to the tibial tubercle. This injury probably occurs during tendon harvesting as found by an injury to the saphenous nerve in two of our patients. However the sensory loss does not impair normal daily activities in these patients.


Liver transplantation for HCV-related cirrhosis in a patient with gastric mucosa-associated lymphoma (MALToma) pretreated with rituximab.
End-stage liver disease due to chronic hepatitis C virus (HCV) infection is now the most frequent indication for liver transplantation. HCV infection is associated with extrahepatic disease including cryoglobulinemia and lymphoma. The number of patients requiring liver transplantation (LT) for cirrhosis secondary to HCV infection has increased over the past 10 years; consequently, associated extrahepatic manifestations (in particular hematological malignancies) will be more commonly observed in this patient group. The management of patients with both end-stage liver disease and significant HCV-related extrahepatic disease is undefined. We report a 59-year-old man in whom extranodal marginal-zone B-cell lymphoma arising in gastric mucosa-associated lymphoid tissue (MALToma) was successfully eradicated by rituximab administration and gastrectomy at LT for HCV-related cirrhosis. Our experience with rituximab in this patient suggests that it can be used safely in the setting of severe liver disease due to HCV infection. Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible.


Submental flap as an alternative to microsurgical flap in intraoral post-oncological reconstruction in the elderly.
Oral and oropharyngeal squamous cell carcinoma (Scc) occur most commonly in middle-aged and elderly individuals. Free flaps are commonly used for reconstruction of extensive tumor resection defects in the oral cavity. Age alone is not an independent variable for increased risk in microvascular reconstruction; however operative time and ASA risk score correlated with medical complications but not with surgical complications. The submental island flap has proven to be a reliable alternative in reconstruction of composite oral cavity defects for its thinness, pliability and versatility in design, shared by the radial forearm free flap, and its advantageous donor site. The submental flap can be easily raised and involves shorter operative time and hospital stay compared to the free-flap procedure. It can be an excellent choice in patients with a high ASA risk score, moreover in elderly patients, where the potential complications linked to microsurgical procedures are avoided.


[Can modern infusion solutions cause serious disruption of inner environment of an organism?].
The article brings a description of a patient case when an application of mineral balanced infusion solutions led to a disruption of inner environment, beginning of a combined failure of the acid-base balance with a serious metabolic acidosis. Patient J. was artificially respirated after a CPR. During the therapy the patient was given basically without any changes a combination of mineral solution Plasma-Lyte 148, amino-acid and 20% glucose. During 8 days a serious metabolic alkalosis had developed (caused by a lack of chlorides, phosphates and other reasons), combined with respirational acidosis. Hydrogencarbonate level was increased to 47.2 mmo/l (at norm of 24 mmol/l), base excess level to 21.4 mmol/l (at norm of 0 mmol/l). Metabolic acidosis led to reduction of sensibility of the respiratory centers and therefore it was not possible to restore spontaneous respiration. After the therapy change and reduction of metabolic acidosis the state of the patient got better. Application of acidifying solutions, supplementation of phosphate and potassium levels and replenishment of actual losses of phosphates led to regulation of the inner environment. Together with the application of sufficient amount of basic nutrients was the improvement of acid-base balance the key factor which enabled the restoration of spontaneous respiration and disconnection of the patient from the ventilator. In short summary you can see reasons which cause different effect of identical infusions to acid-base balance of the inmates in different situations. The article points to a necessity of controlling groovy medical procedures according to actual patient's needs.


Prevention of transplantable tumors by adoptive transfer of spleen cells from immunized rats.
Fischer 344 rats were specifically hyperimmunized with allogeneic, nonvirus-producing [Kirsten murine sarcoma virus (KiMSV)] or syngeneic, virus-producing [KiMSV (Rasheed)] rat tumors. Spleen cells taken from these rats adoptively transferred protection against a 100 to 1,000 X rat tumor dose50 cell challenge with several different transplantable rat tumors. Protection was obtained with spleen cells after removal of adherent cells and macrophages but not peritoneal cells. The spleen cells were not directly cytotoxic but required more than 3 days residence in the recipient before protecting the recipient against challenge. No protection against tumor cell challenge was observed when spleen cells were lethally x-ray irradiated before injection into nontreated rats. Spleen cells taken from rats immunized with normal histocompatibility antigens did not protect in this test system.


Precursor Ion Scan Mode-Based Strategy for Fast Screening of Polyether Ionophores by Copper-Induced Gas-Phase Radical Fragmentation Reactions.
The potential of copper(II) to induce gas-phase fragmentation reactions in macrotetrolides, a class of polyether ionophores produced by Streptomyces species, was investigated by accurate-mass electrospray tandem mass spectrometry (ESI-MS/MS). Copper(II)/copper(I) transition directly induced production of diagnostic acylium ions with m/z 199, 185, 181, and 167 from α-cleavages of [macrotetrolides + Cu]2+. A UPLC-ESI-MS/MS methodology based on the precursor ion scan of these acylium ions was developed and successfully used to identify isodinactin (1), trinactin (2), and tetranactin (3) in a crude extract of Streptomyces sp. AMC 23 in the precursor ion scan mode. In addition, copper(II) was also used to induce radical fragmentation reactions in the carboxylic acid polyether ionophore nigericin. The resulting product ions with m/z 755 and 585 helped to identify nigericin in a crude extract of Streptomyces sp. Eucal-26 by means of precursor ion scan experiments, demonstrating that copper-induced fragmentation reactions can potentially identify different classes of polyether ionophores rapidly and selectively.


The critical need for defining preclinical biomarkers in Alzheimer's disease.
The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.


Synthesis, radiosynthesis, and in vitro evaluation of [131I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl]-2-methoxy-benzamide as a potential tumor imaging agent.
This work reports the synthesis, radiolabeling and preliminary in vitro evaluation of [(131)I]-5-iodo-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl)-ethyl]-2-methoxy-benzamide. The tributylstannylprecursor was synthesized with a yield of 38%. Radiolabeling was performed using an electrophilic iododestannylation. Tracer yield was 94%, radiochemical purity was >95%. The tracer showed high uptake in MCF-7 breast cancer cell line and therefore will be evaluated further.


Anomalous head posture with early-onset homonymous hemianopia.
We have noted the frequent finding of an ipsilateral head turn in children with early-onset homonymous hemianopia. We report a series of patients with these findings and propose a theory to explain this association. Ten patients with early-onset homonymous hemianopia and anomalous head posture were examined. Head computed tomography and magnetic resonance imaging confirmed a cerebral lesion as the cause of the hemianopia in all patients. All patients had onset of central nervous system disease prenatally or before age 18 months. A head turn toward the visual field defect with a gaze preference contralateral to the visual field defect was present in all patients. Early-onset homonymous hemianopia should be included in the differential diagnosis of anomalous head posture.


Use of live and inactivated Salmonella enteritidis phage type 4 vaccines to immunise laying hens against experimental infection.
Four groups of Dekalb Delta commercial layer hens (8 hens per group) were reared individually in cages in an isolation unit. At the age of 8 weeks, groups 1 and 2 were vaccinated with 9R Salmonella gallinarum live (9R live) vaccine. At the age of 18 weeks, group 1 was re-vaccinated with 9R live S. enteritidis vaccine, while groups 2 and 3 were vaccinated with S. enteritidis bacterin. At the age of 22 weeks, groups 2 and 3 were re-vaccinated with S. enteritidis bacterin. Group 4 was not vaccinated and was kept as a control group. At 24, 27 and 30 weeks of age, the four groups were challenged using various concentrations of S. enteritidis phage type 4 and various routes of inoculation. Eggs, cloacal swabs and blood were collected weekly for bacteriological and serological examination. Isolation of the challenge organism from the eggshells and egg contents of the vaccinated groups was significantly lower than with the control group. There was no correlation between humoral antibodies and the shedding of the challenge organism in eggs or cloacal swabs. A combined vaccination programme of 9R live S. enteritidis vaccine and S. enteritidis bacterin provided better protection to laying hens than either vaccine administered alone. Vaccination should never be performed alone but in conjunction with other measures related to veterinary hygiene and good management.


Compression plate arthrodesis of the elbow.
We reviewed 15 patients with an arthrodesis of the elbow using an AO compression-plate technique, after an average follow-up of 24 months. The most common indication was an open, infected high-energy injury with associated bone loss. Arthrodesis was successful in all but one patient in whom severe deep infection necessitated amputation. Eight patients were treated with the metal partly exposed in an infected wound. After removal of the metal, all wounds healed secondarily and none had clinical or radiographic signs of sepsis at latest review. Compression-plate arthrodesis of the elbow is a generally applicable method that can be used even in cases of severe bone loss. There appears to be greater certainty of union than with other techniques, and no increased risk of subsequent fracture.


[Topical treatment of persistent cutaneous leishmaniasis with paromomycin].
Cutaneous leishmaniasis is an infectious disease with increasing prevalence in Germany. Diagnosis and therapy may be difficult due to the variability of the clinical and histomorphological picture and resistance to therapy. In this case study we report on a female patient with a persistent cutaneous leishmaniasis successfully treated with topical administration of paromomycin.


Intracerebroventricular administration of cholecystokinin-8 elevates plasma pancreatic polypeptide levels in awake dogs.
The effect of intracerebroventricular (ICV) administration of cholecystokinin-8 (CCK-8) (0.5, 1.0, 2.0, 4.0 micrograms) on plasma levels of pancreatic polypeptide (PP) was studied in conscious dogs. ICV administration of CCK-8 (1.0, 2.0, 4.0 micrograms) produced a rapid and transient elevation in plasma concentrations of PP. Peripheral muscarinic receptor blockade with atropine or truncal vagotomy abolished PP secretion induced by ICV CCK-8. Pretreatment with ICV atropine also prevented the elevation in plasma PP induced by CCK-8. Plasma levels of CCK-33/39, CCK-8, and gastrin were not affected by ICV CCK-8. Our results indicate that central administration of CCK-8 selectively elevated plasma PP concentration. Since the effect of CCK-8 on plasma PP was abolished by central and peripheral atropine pretreatment, as well as by vagotomy, central and peripheral vagal cholinergic mechanisms appear to participate in release of PP that is induced by CCK-8 given by ICV injection.


Localisation of nonspecific esterases in mouse lymphoid leukemia L 1210 cells.
It was found that diazo dye used for histochemical reaction of nonspecific esterases may influence on the localisation of the reaction product.


Development of an unsupported arm exercise test in patients with chronic obstructive pulmonary disease.
Unsupported arm exercise tests have been used to evaluate the effects of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD), but the reliability and validity of these tests are not established. We evaluated the test-retest reliability and validity of a 6-minute pegboard and ring test (PBRT) in 27 outpatients with COPD and 30 age-matched controls. We evaluated a 6-minute PBRT, subject demographics, pulmonary function and disease-specific quality of life questionnaire, and the Pulmonary Functional Status Dyspnea Questionnaire-Modified version in 27 patients with COPD. Highly significant correlation coefficients (r = .91, P < .001) were found between test and retest of PBRT scores. Statistically significant correlation coefficients were found between PBRT scores and pulmonary function tests such as FEV1% pred and FVC% pred, and activity domain and subdomain of Pulmonary Functional Status Dyspnea Questionnaire-Modified (P <or= .045). In addition, PBRT scores of healthy subjects were significantly higher than those of COPD subjects (P < .001), and were inversely related to age (P = .031). The FEV1% predicted and gender together accounted for 50% of the variance in the PBRT scores of patients with COPD. PBRT is a reliable and valid method to assess unsupported arm exercise endurance in patients with COPD.


Erythrocyte pyruvate kinase deficiency: a kinetic method for differentiation between heterozygosity and compound-heterozygosity.
The goal of the present study was to search for criteria that allow one to distinguish between normal individuals and heterozygotes as well as compound heterozygotes for pyruvate kinase (PK) deficiency. As the residual activity of PK with heterozygotes was between 35% and 110% of the normal activity, it was necessary to find other methods to prove heterozygosity. The PK in the hemolysates of 23 patients suffering from PK deficiency, 36 paternal and maternal enzymes as well as the enzymes of five heterozygous and four normal siblings together with those of 20 normal individuals, were studied according to the recommendations of the International Committee for Standardization in Haematology. The following hematological and enzyme kinetic parameters can serve to identify heterozygotes for PK deficiency: 1) a slight reticulocytosis, 2) an up-to-twofold increase of the intracellular concentrations of glucose-6-phosphate in the erythrocyte, 3) a mixed cooperativity of the phosphoenolpyruvate (PEP)-binding process of PK, 4) a decreased nucleotide specificity with guanosine diphosphate and uridine diphosphate, and 5) a lowered affinity for adenosine diphosphate. The most significant criterium found with all heterozygotes was a mixed cooperativity of the PEP-binding process caused by the presence of a mixture of normal and mutant PK.


[Left ventricular outflow tract obstruction after mitral valve plasty; report of a case].
A 65-year-old female was admitted to our hospital with mitral regurgitation (MR). Transthoracic echocardiography showed severe mitral valve prolapse and subaortic septal hypertrophy with no pressure gradient. Mitral valve plasty consisted of artificial chorda implantation and ring annuloplasty was performed. During intensive care unit( ICU) stay after operation, systolic murmur and low cardiac output syndrome were noted and echocardiography revealed left ventricular outflow tract obstruction (LVOTO) without systolic anterior motion and MR. Cessation of catecholamine, volume administration, beta-blocker and negative inotropic drug like cibenzoline rapidly reduced LVOTO and the hemodynamic condition was improved. Even in a case of subaortic septal hypertrophy with no pressure gradient, emergence of LVOTO should be considered when new systolic murmur and low cardiac output syndrome appeared.


Evaluating Multi-Dimensional Visualizations for Understanding Fuzzy Clusters.
Fuzzy clustering assigns a probability of membership for a datum to a cluster, which veritably reflects real-world clustering scenarios but significantly increases the complexity of understanding fuzzy clusters. Many studies have demonstrated that visualization techniques for multi-dimensional data are beneficial to understand fuzzy clusters. However, no empirical evidence exists on the effectiveness and efficiency of these visualization techniques in solving analytical tasks featured by fuzzy clusters. In this paper, we conduct a controlled experiment to evaluate the ability of fuzzy clusters analysis to use four multi-dimensional visualization techniques, namely, parallel coordinate plot, scatterplot matrix, principal component analysis, and Radviz. First, we define the analytical tasks and their representative questions specific to fuzzy clusters analysis. Then, we design objective questionnaires to compare the accuracy, time, and satisfaction in using the four techniques to solve the questions. We also design subjective questionnaires to collect the experience of the volunteers with the four techniques in terms of ease of use, informativeness, and helpfulness. With a complete experiment process and a detailed result analysis, we test against four hypotheses that are formulated on the basis of our experience, and provide instructive guidance for analysts in selecting appropriate and efficient visualization techniques to analyze fuzzy clusters.


Perioperative ultrasonography of lymph nodes in patients with gynaecological malignancy.
To examine the accuracy of perioperative ultrasonography in detecting pelvic and para-aortic lymph nodes, and to compare the ultrasonographic findings with those observed in histology. Forty women with gynaecological malignancy were examined by ultrasonography during their operations before surgical exploration of the lymph nodes; 182 specimens were taken for histological analysis. Ultrasonographic findings were compared with histological diagnoses of lymph node biopsies. Suspicious lymph nodes (diameter > 5 mm) were found in 31 lymph node regions. Seventeen histologically malignant lymph nodes were found. The sensitivity, specificity, and accuracy of finding metastatic lymph nodes by ultrasonography were 71%, 88%, and 87%, respectively. The frequency of false negative ultrasonographic findings was 29%. Perioperative ultrasonographic examination can be of use in localising pelvic and paraaortic lymph nodes, especially in laparoscopic operations, where tactile palpation of the retroperitoneal space is not possible. The negative predictive value of the method is high, but the relatively poor sensitivity limits its diagnostic value.


Production of live offspring with predicted genotypes using PCR-RFLP analysis of polar bodies from mouse oocytes.
Accurate identification of genotypes in gametes and early embryos could facilitate the efficient production of offspring with desirable traits. This study demonstrates the feasibility of producing offspring with predictable genotypes from micromanipulated mouse oocytes. The Polymerase Chain Reaction (PCR) was used to amplify genes in the IA subregion of the major histocompatibility complex of the mouse. The validity of the approach was demonstrated in experiment 1 with IA haplotypes of unfertilized mouse ova amplified via PCR and distinguished by restriction fragment length polymorphism (RFLP) analysis. In experiment 2, fertilized oocytes were micromanipulated to remove the first and second polar bodies, which were then genotyped by validated PCR-RFLP procedures. Primary oocytes of heterozygous females contain two copies of each of the different alleles. Following meiosis I and II, the genotype of the ovum was predicted by subtracting the alleles observed in micromanipulated polar body samples. Sixty-two fertilized ova were micromanipulated and transferred to recipient females resulting in 27 live offspring (44%). The correct maternal contribution to the embryonic genotype was predicted in 19 of 27 (71%) offspring as confirmed by PCR-RFLP analysis of DNA from pup tails. Predicted genotypes of two pups were not confirmed (7%), whereas no prediction could be made in six cases (22%).


Noradrenergic mechanisms and the cardiovascular actions of nitroglycerin.
In this article we review noradrenergic activities of nitroglycerin in the central and peripheral nervous systems. Nitroglycerin may cause paradoxical bradycardia and occasional life threatening hypotension in patients. Intracisternal injections and microinjections of nitroglycerin into nucleus tractus solitarii produce hypotension and bradycardia, effects which mimic the baroreflex and may involve central noradrenergic mechanisms. The drug also triggers an alpha 2-adrenoceptor-mediated sympatho-inhibition reflex through vagal afferents. Nitroglycerin mimics biological responses associated with sympathetic neuronal activity, e.g., increase in outflow of norepinephrine and its metabolites from perfused guinea pig atria, medulla-pons tissue and cerebrospinal fluid. The sympathomimetic effects of nitroglycerin are antagonized by pre-treatment with yohimbine or rauwolscine. Clinical studies and animal experiments show that hemodynamics of nitroglycerin and sodium nitroprusside are different. Nitroglycerin is lipophilic and the compounds readily enters cells to form nitric oxide, but sodium nitroprusside is very hydrophilic and the compound has difficulty crossing membranes. Thus, intravenous nitroglycerin-induced increases in central noradrenergic activation and inhibitory reflexes may account for at least some of the therapeutic actions and side effects of the drug. In contrast, minimal central responses are produced by intravenous administration of sodium nitroprusside.


Skin graft meshing, over-meshing and cross-meshing.
Split skin grafts (SSGs) are often meshed to increase their size and allow exudate to escape. We investigated the expansion obtained with meshing, and the possibility of re-meshing skin that has already been meshed ("overmeshing"). Both useful and inadvisable permutations are illustrated. Thin porcine SSGs were sideways meshed, or meshed with ratios of 1.5:1 and 3:1. Subsequently samples were over-meshed in a variety of ratios and directions. All grafts were maximally expanded and their areas calculated. Meshed skin did not expand as much as suggested by the ratios displayed on dermacarriers. A 1:1.5 dermacarrier produced an area expansion of 1.36×, and a 1:3 meshing apparatus produced only a 1.80×area expansion. Several combinations of twice-meshed SSGs maintained integrity as long as over-meshing was done in the axis of initial meshing. Up to 2.3×expansion was obtained, by following a 1:1.5 mesh with a 1:3 mesh. We term this procedure as "overmeshing". Re-meshing in a direction orthogonal to initial meshing (cross meshing) cut the skin into small pieces. Over-meshing a SSG can allow considerable further expansion, facilitating overgrafting of donor sites or simply increasing the area that can be covered with the existing harvested skin.


Community capacity as means to improved health practices and an end in itself: evidence from a multi-stage study.
This three-phase study characterized, validated, and applied community capacity domains in a health communication project evaluation in Zambia. Phase I explored community capacity domains from community members' perspectives (16 focus groups, 14 in-depth interviews, 4 sites. These were validated in Phase II with 720 randomly selected adults. The validated domains were incorporated into a program evaluation survey (2,462 adult women, 2,354 adult men; October 2009). The results indicated that the intervention had direct effects on community capacity; enhanced capacity was then associated with having taken community action for health. Finally, community capacity mediated by community action and controlling for confounders, had a significant effect on women's contraceptive use, children's bed net use, and HIV testing. The results indicate that building community capacity served as a means to an end-improved health behaviors and reported collective action for health-and an end-in-itself, both of which are essential to overall wellbeing.


Children with unilateral sensorineural hearing loss: cognitive, academic, and social development.
Children with unilateral loss have been considered to have few, if any, communication or academic difficulties. This study was designed to evaluate the academic achievement, cognitive ability, psycholinguistic, and social skills of a group of 25 monaurally hearing-impaired compared with 25 nonhearing-impaired children. Results indicated no significant differences between the two groups on cognitive or self-concept measures. However, the unilateral group had significantly lower scores on academic tests of word recognition, spelling, and language. The unilateral group was more likely to have repeated a grade, needed special education resource help, or additional tutoring in school. Within the unilateral group, children with severe-to-profound hearing loss had significantly lower WISC-R full scale I.Q.s as compared to the group with mild-to-moderate hearing loss. The results of this study suggest that monaural deafness, especially when severe to profound, may be associated with cognitive and academic deficits, as well as secondary behavioral adjustment problems.


The effect of changing the gaseous diffusion coefficient on the mass loss pattern of Hyalophora cecropia pupae.
The importance of gas phase diffusion in insect gas exchange remains unclear. The role of diffusion in gas exchange of developing Hyalophora cecropia pupae was examined by altering the gaseous diffusion coefficient in the breathing mixture. Gaseous diffusion coefficients were manipulated by substituting helium or sulfur hexafluoride for the nitrogen usually present in air. Sensitive mass loss recordings were employed to monitor gas exchange activity. Mass loss recordings showed a two-phase cycle, open and closed-flutter. Mass loss rates during the open and closed-flutter periods were not altered in proportion to the changes induced in the rate of diffusion. Open-phase duration was inversely and proportionally related to the diffusion coefficient. These results are consistent with changes in spiracle resistance or convective flow during the open period in response to a change in the diffusion coefficient. In addition, they indicate a significant gas phase diffusive resistance within the pupal tracheal system. This previously unreported gas phase resistance appears to be a major determinant of the duration of the open period and thus of overall water loss rates in these pupae.


Novel extended in vitro-in vivo correlation model for the development of extended-release formulations for baclofen: From formulation composition to in vivo pharmacokinetics.
In vitro-in vivo correlation (IVIVC), a predictive mathematical model between the in vitro dissolution and the in vivo pharmacokinetics has been utilized for the development of new extended release (ER) formulations. The aim of the present study was to extend the IVIVC approach, which correlates among the formulation composition, the in vitro dissolution, and the plasma drug concentration, to predict plasma drug concentrations from a given composition of the formulation, and vice versa, using baclofen as a model drug. Baclofen ER tablets with different dissolution rates were prepared by varying the composition of hydroxypropyl methylcellulose (HPMC). First, the HPMC compositions and the corresponding in vitro dissolutions parameters were correlated, and then the in vitro dissolution parameters were correlated with the in vivo dissolution parameters extracted from the pharmacokinetic profiles of the baclofen ER formulations via population pharmacokinetic modeling. The final extended IVIVC model linked the composition of the formulation, the in vitro dissolution, and the in vivo plasma concentration profile and was successfully applied for the prediction of in vivo pharmacokinetics from the amount of HPMC in baclofen ER formulations. The present approach holds great promise for designing optimal compositions of ER formulations to present desired plasma concentration profile.


Preventing falls in hospitalized elderly: design and validation of a team intervention.
The objective of the present study was the design and validation, by a panel of experts, of a team intervention to manage the risk of falls in the hospitalized elderly. The method used was a quanti-qualitative approach, using the Delphi method. The study was developed in two phases: in the first, five researchers designed the intervention; in the second, 13 professionals validated it. The analysis of the content of the intervention designed by the participants in the first phase of the study allowed assignment of the indicators to the following previously defined categories: team formation; communication; leadership; monitoring; and mutual support. After two rounds, all the indicators obtained a consensus higher than 80%. The present study allowed validation of a team intervention by a panel of experts, so that teams can manage the risk of falls in hospitalized elderly. The reliability test results ensure that the intervention can be used safely in clinics and for research.


Julio Cortázar quotes on normal and abnormal movements: magical realism or reality?
Together with Mario Vargas Llosa and Gabriel García Márquez, Julio Cortázar was one of the most representative authors of the Latin American magical realism genre. Within his extensive body of work, many descriptions of characters suffering physical disabilities, as well as situations suggesting such medical conditions, can be extracted. In this review, two short stories by Cortázar are presented. In the first one, the main character could easily be a man suffering from corticobasal degeneration; in the second, an old woman with symptoms suggestive of progressive supranuclear palsy is clearly depicted. Despite the fact that one of the main ingredients in Cortázar's magical realism is fiction, cases described here fit real medical conditions quite well, making it hard to believe that they represent purely fantastic descriptions rather than the product of Cortázar's inquisitive observation and the description of real patients.


Revision total hip arthroplasty using a Kerboull-type acetabular reinforcement device with bone allograft: minimum 4.5-year follow-up results and mechanical analysis.
We retrospectively reviewed 40 hips in 36 patients who had undergone acetabular reconstruction using a titanium Kerboull-type acetabular reinforcement device with bone allografts between May 2001 and April 2006. Impacted bone allografts were used for the management of American Academy of Orthopaedic Surgeons Type II defects in 17 hips, and bulk bone allografts together with impacted allografts were used for the management of Type III defects in 23 hips. A total of five hips showed radiological failure at a mean follow-up of 6.7 years (4.5 to 9.3), two of which were infected. The mean pre-operative Merle d'Aubigné score was 10 (5 to 15) vs 13.6 (9 to 18) at the latest follow-up. The Kaplan-Meier survival rate at ten years, calculated using radiological failure or revision of the acetabular component for any reason as the endpoint, was 87% (95% confidence interval 76.3 to 97.7). A separate experimental analysis of the mechanical properties of the device and the load-displacement properties of bone grafts showed that a structurally hard allograft resected from femoral heads of patients with osteoarthritis should be preferentially used in any type of defect. If impacted bone allografts were used, a bone graft thickness of < 25 mm was acceptable in Type II defects. This clinical study indicates that revision total hip replacement using the Kerboull-type acetabular reinforcement device with bone allografts yielded satisfactory mid-term results.


Change of the host immune response during the early phase of interferon therapy correlates with its long-term efficacy for chronic hepatitis C.
Host immunomodulation through T cell action may play a pivotal role in determining the response to interferon (IFN) therapy for chronic hepatitis C. We examined whether the early changes in the host immune response were helpful in predicting the final effect in 31 patients with chronic hepatitis C receiving IFN. IFN treatment significantly reduced the serum levels of intercellular adhesion molecule-1 (ICAM-1) and E-selectin, and significantly increased those of vascular cell adhesion molecule-1 (VCAM-1) and interleukin-2 receptor alpha (IL-2Ralpha) in the first 7-10 days. Serum levels of these immunological parameters did not correlate with serum alanine aminotransferase (ALT) when evaluated with either absolute values or relative values (over pre-treatment value), implying that our results are not just secondary to improvement in hepatic inflammation. The relative changes (Delta) in these parameters reflected the long-term response to IFN therapy, i.e. the lower the change, the more effective the therapy was. Among these serum parameters, DeltaIL-2Ralpha within the first 7-10 days of IFN treatment was the most useful parameter in predicting the response to therapy. In conclusion, a dynamic immunomodulation during the early phase of IFN therapy may determine the subsequent long-term response to IFN therapy.


Hearing non-signers use their gestures to predict iconic form-meaning mappings at first exposure to signs.
The sign languages of deaf communities and the gestures produced by hearing people are communicative systems that exploit the manual-visual modality as means of expression. Despite their striking differences they share the property of iconicity, understood as the direct relationship between a symbol and its referent. Here we investigate whether non-signing hearing adults exploit their implicit knowledge of gestures to bootstrap accurate understanding of the meaning of iconic signs they have never seen before. In Study 1 we show that for some concepts gestures exhibit systematic forms across participants, and share different degrees of form overlap with the signs for the same concepts (full, partial, and no overlap). In Study 2 we found that signs with stronger resemblance with signs are more accurately guessed and are assigned higher iconicity ratings by non-signers than signs with low overlap. In addition, when more people produced a systematic gesture resembling a sign, they assigned higher iconicity ratings to that sign. Furthermore, participants had a bias to assume that signs represent actions and not objects. The similarities between some signs and gestures could be explained by deaf signers and hearing gesturers sharing a conceptual substrate that is rooted in our embodied experiences with the world. The finding that gestural knowledge can ease the interpretation of the meaning of novel signs and predicts iconicity ratings is in line with embodied accounts of cognition and the influence of prior knowledge to acquire new schemas. Through these mechanisms we propose that iconic gestures that overlap in form with signs may serve as some type of 'manual cognates' that help non-signing adults to break into a new language at first exposure.


Does the established cause of chronic cough depend on diagnostic approach?
The objective of the present study was to evaluate the prevalence of chronic cough causes and to compare the efficacy of two diagnostic approaches used in ambulatory vs. hospitalized setting. Eighty patients with chronic cough, 40 in each group, were enrolled into the study. The etiology of cough was determined on medical history and on either basic (in out-patients) or detailed (in in-patients) investigations on most common causes of chronic cough. We diagnosed etiology of cough in all subjects. The most frequent causes of cough were gastroesophageal reflux disease (GERD) and upper airway cough syndrome (UACS). Nonasthmatic eosinophilic bronchitis (NAEB) and multiple cough causes were recognized more often in hospitalized patients (P<0.05). We conclude that the main causes of chronic cough were GERD and UACS. An extensive diagnostic approach allows recognizing NEAB more frequently and reveals the complex nature of chronic cough.


Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.
We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.


Infectious complications of advanced cancer.
We present a retrospective study of the frequency, pattern, and management of infections in advanced cancer. Three hundred ninety-three patients were admitted to an acute care palliative medicine unit in an 8-month period for evaluation and palliation of cancer-related symptoms and complications. One hundred fifteen had at least one positive bacteriological culture, and 100 of these patients were evaluable. One hundred fifty-two infections and 192 isolates were identified. Sixty-eight patients had polymicrobial infections. Sixty-six patients had urinary tract infections. Forty-one were found to have multisystemic infections. Eighty-one had invasive devices; 32 had more than one invasive device. Fifty-three were taking corticosteroids at the time of infection. Only 3 were neutropenic. Urinary tract infections were significantly more common in those taking corticosteroids. The median duration of antibiotic treatment was 11 days and the median hospital stay, 14 days. Twenty-eight patients died in the hospital; 10 of those who died had lung cancer, which was a statistically significant observation. In conclusion, infections are an underrecognized but common complication in nonneutropenic hospitalized patients with advanced solid tumors. Urinary tract infections appear to be associated with the use of corticosteroids. Lung cancer patients are at greater risk for fatal infections. Infections increase morbidity in debilitated patients with solid tumors, are a frequent cause of hospital admission, and are associated with significant mortality.


Submicrostructure and typing of female genital condylomata.
Thirty biopsies from female genital condylomata were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study structural characteristics and typing of condylomata. It was found that cytoplasmic clearing was marked in acuminate condylomata, diffuse interstitial and epithelial proliferation in nodular condylomata (flat condylomata), and invagination of the lesions into the interstitial tissue or glandular ducts in endophytic condylomata. In nodular condylomata, SEM also showed some structural features similar to those of intra-epithelial neoplasia. Microridges on the surface of squamous cells had villiform of granular changes. On the surface of a percentage of squamous or columnar cells, there were holes with a diameter of about 3 to 5 microns. A number of giant cells were seen among other cells. The cervical squamatization zone contained groups of special cells covered with dense microvilli. TEM of nodular condylomata revealed some pictures resembling active proliferation of tumor cells, such as enlarged or irregular nuclei (large N/C ratio), evaginated or invaginated nuclear membranes, condensed chromatin attached to the inner part of the nuclear membrane, transparent nucleoplasm, and frequent nucleosomes and karyokinesis. Virus particles with the morphological characteristics of HPV (naked hexagon-like particles with an average diameter of 45-50 nm) were seen in some nuclei with markedly condensed chromatin. It is suggested that HPV-induced genital condylomata, especially nodular one (flat condylomata), entail a potential progression to malignancy.


A comparative I-123 IMP SPECT study in Binswanger's disease and Alzheimer's disease.
The regional cerebral blood flow in 31 patients was semiquantitatively measured with SPECT using N-isopropyl iodo-amphetamine (I-123 IMP). Of the 31 patients, 9 had Binswanger's disease (BD) (mean age: 64.2 years), 10 had Alzheimer's disease (AD) (mean age: 66.8 years), and 12 were neurologically normal (mean age: 67.8 years). Tracer activity was determined in 7 pairs of cerebellar, cortical, and subcortical regions and was expressed as two ratios: the activity in each region of interest (ROI) compared to the mean count in the cerebellar region (ROI/CER ratio) and compared to the mean count in the occipital cortex (ROI/OCC ratio). Patients with BD showed a reduction of the ROI/CER ratio in the temporal cortex, thalamus, and basal ganglia compared to normal subjects. However, the ROI/CER ratio for the occipital region was higher than that of normal controls, suggesting that cerebellar blood flow was reduced in patients with BD. AD patients showed a decreased ROI/CER ratio in the frontal, temporal, and parietal cortices. Both BD and AD patients showed decreased ROI/OCC ratios in all the cortical and subcortical regions compared to the neurologically normal patients. In BD patients, the most marked reduction of both ratios was found in the thalamus, while for AD patients the most prominent reduction was seen in the parietal cortex. Our results indicate that these two types of dementia show characteristic regional cerebral blood flow patterns, which may be associated with their clinical features.


Follistatin Expression in Human Invasive Breast Tumors: Pathologic and Clinical Associations.
Follistatin is a potent native activin antagonist that is expressed in the normal mammary gland and in different breast proliferative diseases. Despite experimental evidence that follistatin can modulate the breast cancer cell cycle, the clinical significance of follistatin expression in these tumors is unknown. The aim of this study was to correlate the intensity of follistatin expression in invasive breast cancer with some of its clinical and pathologic features, such as the disease stage and the hormonal receptor status. Paraffin blocks of tumor samples that had been fixed in buffered formalin were obtained from 154 women subjected to surgery for breast cancer between 2008 and 2012. Sections from all paraffin blocks were cut and processed together by immunohistochemistry using a commercial monoclonal antibody to human follistatin. The intensity of follistatin staining was unrelated to the menopausal status, the disease stage, the grade, progesterone receptor expression, and local or systemic recurrence. However, follistatin immunoreactivity was significantly stronger in estrogen receptor (ER)-negative tumors than in ER-positive tumors. These findings suggest that follistatin expression in invasive breast cancer is unrelated to the disease severity and the risk of recurrence, but is more intense in ER-negative tumors.


Possible involvement of GTP-binding proteins in the deactivation of an inwardly rectifying K+ current in enterocytes isolated from guinea-pig small intestine.
The possible regulation of guinea pig enterocyte ion channels by GTP-binding proteins has been investigated by using the whole-cell recording mode of the patch-clamp technique and non-hydrolysable analogues of GTP. The main K+ currents in these cells are mediated by inwardly-rectifying K+ channels. Intracellular dialysis with hydrolysis-resistant GTP analogues leads to the deactivation of the inward K+ currents. Non-hydrolysable analogues of ATP or GDP were without effect. The effect occurs after a lag phase of 2 to 7 min, suggesting a multistep mechanism. Cl currents were not affected by any of the nucleotide analogues. It is suggested that inwardly-rectifying K+ currents are deactivated by a G-protein-dependent process.


Mannose 6-phosphate-independent Lysosomal Sorting of LIMP-2.
The lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) has been described as a mannose 6-phosphate (M6P)-independent trafficking receptor for β-glucocerebrosidase (GC). Recently, a putative M6P residue in a crystal structure of a recombinantly expressed LIMP-2 ectodomain has been reported. Based on surface plasmon resonance and fluorescence lifetime imaging analyses, it was suggested that the interaction of soluble LIMP-2 with the cation-independent M6P receptor (MPR) results in M6P-dependent targeting of LIMP-2 to lysosomes. As the physiological relevance of this observation was not addressed, we investigated M6P-dependent delivery of LIMP-2 to lysosomes in murine liver and mouse embryonic fibroblasts. We demonstrate that LIMP-2 and GC reach lysosomes independent of the M6P pathway. In fibroblasts lacking either MPRs or the M6P-forming N-acetylglucosamine (GlcNAc)-1-phosphotransferase, LIMP-2 still localizes to lysosomes. Immunoblot analyses also revealed comparable LIMP-2 levels within lysosomes purified from liver of wild-type (wt) and GlcNAc-1-phosphotransferase-defective mice. Heterologous expression of the luminal domain of LIMP-2 in wild-type, LIMP-2-deficient and GlcNAc-1-phosphotransferase-defective cells further established that the M6P modification is dispensable for lysosomal sorting of LIMP-2. Finally, cathepsin Z, a known GlcNAc-1-phosphotransferase substrate, but not LIMP-2, could be precipitated with M6P-specific antibodies. These data prove M6P-independent lysosomal sorting of LIMP-2 and subsequently GC in vivo.


Condensed State of Heavy Vectorlike Neutrinos.
Some extensions of the standard model suggest the existence of vectorlike fermions whose mass M can be larger by up to several orders of magnitude than the electroweak scale v, and with the Higgs mechanism providing only a small part m of this mass that is a fraction of v. It is shown that in a certain range of the parameters m and M, there exist stable globules of degenerate fermionic matter made from the lighter of the neutral vectorlike leptons (superheavy neutrinos) with a number density much larger than m(h)v(2), with m(h) being the Higgs boson mass. The stability is due to the deformation of the Higgs field inside the globule to values greatly exceeding v. The globules are absolutely stable if the lighter of the vectorlike neutrinos is stable and can be (a part of) the dark matter.


[The effect of combined treatment methods on the dynamics of the evoked potentials of the brain in disseminated sclerosis patients].
Data are reported of an investigation of somatosensory evoked potentials in patients with multiple sclerosis in the course of treatment with three drug complexes including tactivin, prodigiosan, pyrogenal. Evoked potentials showed a positive dynamics in patients treated with tactivin and prodigiosan while only minor positive changes were observed with pyrogenal treatment. Side effects due to pyrogenal treatment are characterized by inhibition or the evoked activity of the brain.


The effect of post-core and ferrule on the fracture resistance of endodontically treated maxillary central incisors.
To evaluate the effect of post reinforcement, post type and ferrule on the fracture resistance of endodontically treated maxillary central incisors. Sixty central incisor teeth were selected and grouped into six groups, viz. A, B, C, D, E, and F, each consisting of 10 specimens. Group A specimens were not subjected to any restorative treatment. Group B specimens were endodontically treated and crowned. Specimens of groups C and D were restored with custom cast post and core. Specimens of groups E and F were treated with prefabricated titanium post and composite core. Specimens of groups C and E were restored with porcelain-fused metal (PFM) crown having 2 mm ferrule. Specimens of groups D and F were restored with PFM crown having no ferrule. All the specimens were subjected to load (newton, N) on the lingual surface at a 135 degree angle to the long axis with a universal testing machine until it fractured. The fracture load and mode of fracture of each specimen were noted. One-way analysis of variance with Tukey honestly significant difference procedure was employed to identify the significant difference among the groups at 5% level (P < 0.05). There were significant differences among the six groups studied (P < 0.0001). The highest fracture strength was recorded with specimen of group C (1376.7 N). There were significant differences between groups A and D versus groups B, E, and F. There were no significant differences between groups B, E, and F. Cervical root fracture was the predominant mode of failure in all the groups except group A. The results showed that endodontically treated teeth restored with custom cast post core were as strong as the untreated group. Teeth restored with custom cast post core were better resistant to fracture than teeth restored with prefabricated titanium post and composite core. Ferrule is more important in custom cast post core than in prefabricated post and composite core.


Control of crystal growth during enamel maturation.
Attempts to promote crystal growth in maturation stage enamel from rat incisors were carried out by incubation in saturated solutions of calcium phosphate. Resulting crystallites were visualised in the TEM and the dimensions of their profiles measured. No crystal growth was observed unless the maturation stage enamel was first pretreated with either 8M urea or sodium hypochlorite to remove residual protein matrix. The results suggest that the protein matrix plays an important role in the control of crystal growth in vivo.


Dissociation of brain ERP topographies for tonal and phonetic oddball tasks.
ERP topographies for 30 scalp electrodes were examined in 26 healthy right-handed volunteers during oddball tasks (20% targets) using binaurally presented consonant-vowel syllables or complex tones. Response hand was counterbalanced across participants. Both window averages and a principal components analysis (PCA) with Varimax rotation revealed task-related (tonal/phonetic) hemispheric asymmetries for N2, early P3, and particularly for N2-P3 amplitude. In the tonal task, N2 was maximal over right lateral-temporal regions, and early P3 over right medial-parietal regions. For the phonetic task, N2 was maximal over the left lateral-parietal regions, and late P3/N3 over left medial-parietal regions. A response-related frontal negativity (N3) interacted with task-related asymmetries in an unbalanced fashion. The distinct, asymmetric N2 and P3 topographies for tonal and phonetic tasks presumably reflect differential involvement of cortical structures in pitch (right frontotemporal) and phoneme (left parietotemporal) discrimination.


The power of relativistic jets is larger than the luminosity of their accretion disks.
Theoretical models for the production of relativistic jets from active galactic nuclei predict that jet power arises from the spin and mass of the central supermassive black hole, as well as from the magnetic field near the event horizon. The physical mechanism underlying the contribution from the magnetic field is the torque exerted on the rotating black hole by the field amplified by the accreting material. If the squared magnetic field is proportional to the accretion rate, then there will be a correlation between jet power and accretion luminosity. There is evidence for such a correlation, but inadequate knowledge of the accretion luminosity of the limited and inhomogeneous samples used prevented a firm conclusion. Here we report an analysis of archival observations of a sample of blazars (quasars whose jets point towards Earth) that overcomes previous limitations. We find a clear correlation between jet power, as measured through the γ-ray luminosity, and accretion luminosity, as measured by the broad emission lines, with the jet power dominating the disk luminosity, in agreement with numerical simulations. This implies that the magnetic field threading the black hole horizon reaches the maximum value sustainable by the accreting matter.


Undercarboxylation of recombinant prothrombin revealed by analysis of gamma-carboxyglutamic acid using capillary electrophoresis and laser-induced fluorescence.
The gamma-carboxyglutamic acid (Gla) content of several variants of human prothrombin has been measured by using capillary electrophoresis and laser-induced fluorescence (CE-LIF). Both plasma-derived prothrombin and recombinant prothrombin contain ten residues of Gla per molecule of protein. In contrast, a variant of human prothrombin (containing the second kringle domain of bovine prothrombin) was separated into two populations that differed in their Gla content. Direct measurement of the Gla content showed an association with the presence or absence of the calcium-dependent conformational change that is required for prothombinase function. Thus, the CE-LIF assay is useful in determining the carboxylation status of recombinant proteins.


Frequency of ST-segment depression produced by mental stress in stable angina pectoris from coronary artery disease.
Physical exertion is a well-documented trigger of transient myocardial ischemia in patients with coronary disease. More recently, studies have shown that mental stress may also be a cause of myocardial ischemia. The purpose of this study was to examine the relationship of physical activities and perceived mental states to myocardial ischemia while patients were going about their normal daily activities. Twenty-eight patients with documented coronary artery disease underwent ambulatory monitoring of the electrocardiogram. Physical activity and perceived mental status were recorded by patients in a diary which was then graded according to intensity of the activity. Analyses of the continuous electrocardiographic recordings were done separately from the analysis of the diaries. The time of each episode of ischemia, the duration of each episode in minutes and the number of episodes in each 24-hour period were calculated. A total of 372 episodes of ST-segment depression occurred in 912 hours of monitoring. Ischemic events occurring during usual physical and usual mental activities were most frequent (36%). Twenty-six percent of ischemic episodes occurred during increased physical activity, but usual mental activities. Interestingly, 22% of the ischemic events occurred at high levels of mental stress, but low physical activity. Ten percent of episodes occurred during sleep. Although the majority of events occurred during usual daily activities, when duration of ischemia was normalized for time spent in each category, increasing physical or mental activity was associated with an increasing duration of ischemia per unit (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)