Γ-secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment.
γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-β (Aβ) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aβ production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aβ over the baseline after a transient reduction (known as Aβ-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aβ-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and β-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aβ-rebound, possibly because of the lack of accumulation of β-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aβ-rebound.


Use of generalized linear mixed models in analyzing mutant frequency data from the transgenic mouse assay.
The transgenic mouse assay is now widely used for the study of mutagenesis in diverse rodent tissues and to test chemicals for genotoxic potential. This kind of assay generally involves nested observations at several levels of sampling, e.g., animals, packaging reactions, and plates. Due to the common origin, the mutant frequency (MF) in tissues from the same animal are likely to be positively correlated, inducing extra variation relative to the common binomial variation. In this article, a generalized linear mixed model is used to analyze the overdispersed binomial data on mutant frequency from the transgenic mouse assay, with a random effect for each level of the sampling hierarchy. This is a comprehensive framework within which different sources of variation in the data can be evaluated in nested factorial experiments and treatment effects can be assessed simultaneously. It avoids the current practice of repeated testing for excess binomial variability at each level of the sampling hierarchy and aggregating data up the levels, but fits the data with one single model. Parameters associated with the fixed effects, particularly dose, and the variance components for the random effects (e.g., animals, packages, and plates) can be estimated and tested for significance. Data previously reported in the literature involving the lacl gene from the Big Blue mouse are used to illustrate the proposed method.


Biogenesis of E. coli Pap pili: papH, a minor pilin subunit involved in cell anchoring and length modulation.
The biogenesis of Escherichia coli Pap pili, encoded by the pap gene cluster, was studied. A novel gene, papH, was identified and found to encode a weakly expressed pilin-like protein. PapH was dispensable for digalactoside-specific binding and for formation of Pap pili. However, in papH deletion mutants 50%-70% of total pilus antigen was found free of the cells. We present evidence showing coregulation of papH and the adjacent gene, papA, which encodes the major pilin subunit. A decrease in the PapA to PapH ratio resulted in a large fraction of cells producing shortened pili, whereas overproduction of PapA relative to PapH resulted in cells with lengthened pili. The data show that PapH has roles in anchoring the pilus to the cell and in modulating pilus length.


Federalism, the economic-industrial health care complex and high-cost pharmaceutical assistance in Brazil.
Brazil has a relevant, although relatively unknown, special medicines programme that distributes high-cost products, such as drugs needed for cancer treatments. In 2009, the purchase of these medicines became the responsibility of the Brazilian Federal Government. Until then, there were no clear norms regarding the responsibilities, in terms of the management/financing of these medicines, of the Brazilian Federal Government and of the states themselves. This qualitative study analyses the policy process needed to transfer this programme to the central government. The study examines the reports of the Tripartite Commission between 2000 and 2012, and in-depth interviews with eleven key informants were conducted. The study demonstrates that throughout the last decade, institutional changes have been made in regard to the federal management of these programmes (such as recentralisation of the purchasing of medicines). It concludes that these changes can be explained because of the efficiency of the coordinating mechanisms of the Federal Government. These findings reinforce the idea that the Ministry of Health is the main driver of public health policies, and it has opted for the recentralisation of activities as a result of the development project implicit in the agenda of the Industrial and Economic Heal.


Dietary salt intake is related to inflammation and albuminuria in primary hypertensive patients.
In this study, we hypothesized that dietary salt intake may be related with inflammation and albuminuria independently from blood pressure (BP) in non-diabetic hypertensive patients. A total of 224 patients with primary hypertension were included in the study. Serum C-reactive protein (CRP) levels, 24-h urine sodium and albumin excretion were measured in all patients. The subjects were divided into tertiles according to the level of 24-h urinary sodium excretion: low-salt-intake group (n = 76, mean urine sodium: 111.7 ± 29.1 mmol/24 h), medium-salt-intake group (n = 77, mean urine sodium: 166.1 ± 16.3 mmol/24 h) and high-salt-intake group (n = 71, mean urine sodium: 263.6 ± 68.3 mmol/24 h). Systolic and diastolic BP measurements of patients were similar in the three salt-intake groups. CRP and urinary albumin levels were significantly higher in high-salt-intake group compared with medium- and low-salt-intake groups (P = 0.0003 and P = 0.001, respectively). CRP was positively correlated with 24-h urinary sodium excretion (r = 0.28, P = 0.0008) and albuminuria, whereas albuminuria was positively correlated with 24-h urinary sodium excretion (r = 0.21, P = 0.0002). Multiple regression analysis revealed that urinary sodium excretion was an independent predictor of both CRP and albuminuria. These findings suggest that high salt intake is associated with enhanced inflammation and target organ damage reflected by increased albuminuria in treated hypertensive patients independent of any BP effect.


Unusual Patterns of Mitochondrial Inheritance in the Brown Alga Ectocarpus.
Most eukaryotes inherit their mitochondria from only one of their parents. When there are different sexes, it is almost always the maternal mitochondria that are transmitted. Indeed, maternal uniparental inheritance has been reported for the brown alga Ectocarpus but we show in this study that different strains of Ectocarpus can exhibit different patterns of inheritance: Ectocarpus siliculosus strains showed maternal uniparental inheritance, as expected, but crosses using different Ectocarpus species 7 strains exhibited either paternal uniparental inheritance or an unusual pattern of transmission where progeny inherited either maternal or paternal mitochondria, but not both. A possible correlation between the pattern of mitochondrial inheritance and male gamete parthenogenesis was investigated. Moreover, in contrast to observations in the green lineage, we did not detect any change in the pattern of mitochondrial inheritance in mutant strains affected in life cycle progression. Finally, an analysis of field-isolated strains provided evidence of mitochondrial genome recombination in both Ectocarpus species.


[Laparoscopic extirpation of retroperitoneal bronchogenic cyst].
The retroperitoneal bronchogenic cyst is an extremely rare anomaly. During the examination of an 18-year-old female patient due to her extreme thinness, the abdominal ultrasound and later the CT indicated as an accidental finding--a left side adrenal/suprarenal adenoma, which turned out to be hormonally inactive. But while we were doing a laparoscopic surgical intervention we found a 6-8-cm cyst in the retroperitoneum, between the greater curvature and the spleen. It contained light grey, mucinous liquid. The left suprarenal gland had normal size and appearance. During the microscopic examination the removed terime showed cystic structures, which were covered inside with multilayer ciliated columnar epithelium, mucous excretory glands, a whole layer of connective/interstitial and smooth muscle tissue. Neither cartilage, nor gastrointestinal epithelium was found. Only a few publications have reported about retroperitoneal bronchogenic cyst so far. These lesions occur very rarely at the greater curvature. Although this alteration is really unusual, bronchogenic cysts have to be expected in the differential diagnostics of the retroperitoneal tumors.


Suitability of several naphthalene metabolites for their application in biomonitoring studies.
Naphthalene occurs together with polycyclic aromatic hydrocarbons (PAHs) at industrial workplaces and is ubiquitous in the environment. For biological monitoring of naphthalene exposures, up to now mainly 1- and 2-naphthol in urine have been used. Recently, we proposed 1,2-dihydroxynaphthalene (1,2-DHN) and the 1- and 2-naphthylmercapturic acid (1- and 2-NMA) as new urinary biomarkers to characterise a naphthalene exposure. In this study, in a collective of nine occupationally exposed workers handling with creosote the naphthalene metabolites 1,2-DHN, 1- and 2-NMA as well as 1- and 2-naphthol were analysed in order to evaluate the suitability of the different parameters for their application in biomonitoring studies. Additionally, air sampling was conducted to characterise the exposure in task related exposure situations at different workplaces. In the analysed 51 urine samples, 1,2-DHN was the main metabolite with concentrations ranging from 2.3 to 886 μg/g creatinine (crea) (median 34 μg/g crea). For the sum of 1- and 2-naphthol, concentrations in the range of 2.6-174 μg/g crea (median 15 μg/g crea) were observed. 1-NMA concentrations were in the range of < LOD-2.4 μg/g crea (61% > LOD), while 2-NMA was not detected in the analysed urine samples. The biomarkers 1,2-DHN, 1- and 2-naphthol as well as 1-NMA showed significant correlations, which pointed out to naphthalene as the common exposure source. The poor correlations between naphthalene in the air and the biomarkers in urine may be a result of the varying exposure situations and may indicate not solely inhalative, but additional dermal uptake. 1,2-DHN was the most sensitive and, together with 1-NMA, the most specific parameter of the biological monitoring of naphthalene exposure at workplaces. Further studies with this parameter are needed for individuals at different workplaces as well as for persons of the general population without occupational PAH exposure to characterise 1,2-DHN levels as well as to establish their relationship with the naphthalene exposure.


Female form of persistent müllerian duct syndrome: MDCT findings.
Persistent müllerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism. Two anatomic forms are described in this syndrome, the male and the female one; the second one is usually associated with bilateral cryptorchidism. About 150 cases are reported in literature; most of them are focused on anatomical, genetic, and surgical aspects. Radiological imaging features, important for diagnosis and therapy planification, are rarely reported. We describe a case of a female type of PMDS studied with multidetector computed tomography.


An evaluation of the darkroom prone provocative test in family members of primary angle closure glaucoma patients.
To compare ocular biometric parameters with darkroom prone provocative test (DRPPT) in family members of primary angle closure glaucoma (PACG) patients. One hundred and forty-nine family members of 46 PACG patients underwent ocular examination included slit lamp biomicroscopy, gonioscopy, fundus examination using +90 D lens, Goldmann applanation tonometry, darkroom prone provocative test, perimetry on Humphrey's field analyzer II and optic disc evaluation using HRT II. Ultrasonic ocular biometry and the DRPPT were then performed. IOP>or=8 mmHg rise from baseline with iridocorneal touch was considered as a positive test. Of the 149 family members examined, 55 (36.9%) were found to have PACG. Forty (72.7%) of these had subacute PACG and 15 (27.3%) were found to have chronic PACG. Thirty-nine (70.3%) of the affected members showed a positive DRPPT. Mean anterior chamber depth (ACD) was 2.03+/-0.3, 2.3+/-0.4, 2.7+/-0.3 mm (P=0.0001) and mean lens thickness was 4.41+/-0.39, 3.99+/-0.5, 3.93+/-0.4 mm (P=0.0001) in DRPPT positives, borderlines and negatives respectively. ROC curve (ACD) plotted showed cutoff value of 2.07 mm (sensitivity 88.57%) for screening. Anterior chamber is shallowest, lens is thickest and axial length is shortest in affected and DRPPT positive, family members of PACG patients.


Block of neuronal Ca++ influx by the anti-ischemic agent TA3090.
We examined the effect of the novel anti-ischemic drug, TA3090 on Ca++ entry into peripheral and central neurons. TA3090 inhibited voltage-dependent Ca++ entry into rat dorsal root ganglion (DRG) and sympathetic neurons. The degree of inhibition produced by the drug was voltage-dependent. TA3090 also inhibited Ca++ entry into DRG cells elicited by trains of action potentials. TA3090 inhibited Ca++ influx into neurons from the hippocampus. As in peripheral neurons, TA3090 blocked Ca++ influx associated with a Ca++ current in voltage-clamped cells or elicited by trains of action potentials. Furthermore, TA3090 blocked Ca++ influx stimulated by glutamate or N-methyl-D-aspartate. In addition, TA3090 blocked excitatory glutamate-mediated synaptic transmission between hippocampal pyramidal neurons. These data indicate that the protective effects of TA3090 in the brain under ischemic conditions may be partly or completely due to its ability to inhibit neuronal Ca++ influx.


Storing parenteral medication at home.
The storage requirements for parenteral products vary with the characteristics of the medication in the product. Temperature, light, moisture, pH, composition of the container, type of infusion fluid, and exposure to other chemical substances are the major determinants of the stability of parenteral medication stored in the patient's home.


Effect of ethanol on function of the rat heart and skeletal muscles.
The present study was undertaken to evaluate the acute effects of ethanol on responses of the rat heart and skeletal muscles both in vivo and in vitro. In the anesthetized rat, intravenous infusion of ethanol at 0.1-0.5 g/kg body weight (33-167 mM) decreased the breathing rate by 8-83%, heart rate by 4-52%, and QRS amplitude by 5-27%, and increased the P-R interval by 1-49%. In the anterior tibialis muscle subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, ethanol at 0.1 g/kg increased the amplitude of the muscle action potential (AP) by 7%, whereas at 0.5 g/kg it decreased the muscle AP by 32%. The nerve-evoked tetanic tension was reduced by 7-34% at 0.1-0.5 g/kg ethanol. In the isolated rat heart, perfusion of ethanol at 0.1-3.0% (22-651 mM) decreased the heart rate by 8-48% and QRS amplitude by 10-39%, and increased the P-R interval by 5-61%. Left ventricular pressure was increased by 10% at 0.1% ethanol, and decreased by 80% at 3.0% ethanol. In the isolated rat phrenic nerve-diaphragm muscle preparation subjected to repetitive nerve stimulation at 100 Hz for 0.5 sec, 0.1-3.0% ethanol decreased the amplitude of the nerve AP by 5-89%, nerve-evoked muscle AP by 2-96%, and peak tetanic tension by 1-87%. On repetitive direct muscle stimulation at 100 Hz for 0.5 sec, 0.1-3.0% ethanol decreased the amplitude of the muscle-evoked muscle AP by 8-65%, and muscle-evoked tetanic tension by 2-65%. These studies indicate that ethanol causes smaller reduction in responses of the heart and skeletal muscles at clinical concentrations, but marked reduction in these responses at higher concentrations due to direct action on excitability of these tissues. At higher concentrations, ethanol causes greater reduction in excitability of the skeletal muscle than of the heart.


International pharmaceutical expenditure differentials: why?
The following questions facilitate further thought on the issue of reimportation: POLICY ISSUES: Who should pay for drug development? Do NCEs provide value for money invested? What is the most efficient means of developing new drugs? What is the proper balance between societal benefit and intellectual property protection? REGULATORY QUESTIONS: If reimportation or importation is permitted, how can the provenance of a product be protected? How is reimportation defined? Can a product be transported from the United States to Europe to Canada and then be sent back to the United States? Or, is reimportation a single-step process (e.g., United States to Canada and vice versa)? If reimportation is limited to Canada, can we expect that other countries would want to be included (or excluded) from our reimportation policy? Will state pharmacy practice acts be applicable to reimportation? Does reimportation alter the balance between state and federal regulations? If legal action occurs because of alleged harm from a reimported product, who is liable? MARKET ISSUES: Will U.S. prices rise in protected markets to compensate for losses due to reimports? Will Canadians be allowed to import prescription drugs from the United States?


Expression of Pseudomonas stutzeri Zobell cytochrome c-551 and its H47A variant in Escherichia coli.
The nirM gene encoding cytochrome c-551 from Pseudomonas stutzeri Zobell (PZ) has been expressed in Escherichia coli at levels higher than those previously reported but only under strict anaerobic growth conditions. Expression yields for wild-type cytochrome in this study typically reached 0.6 micromol per liter of saturated E. coli culture (5.5mg/L). Culture conditions investigated are compared to obtained c-551 expression levels; the results may lead to a greater understanding of the challenges encountered when expressing c-type hemoproteins in E. coli. The nirM gene was mutated to produce a histidine-47-alanine mutation of c-551 that been heterologously expressed in E. coli using optimum culture conditions and had its physiochemical properties compared to those of the wild-type protein. In PZ, the histidine-47 residue is part of a conserved hydrogen-bonding network located at the bottom of the heme crevice that also involves tryptophan-56 and a heme propionate. Ionization events within this network are experimentally demonstrated to modulate c-551 oxidation-reduction potential and its observed dependence on pH around neutrality. The redox potential of the mutant cytochrome still displays pH-dependence; however, the midpoint potential is approximately 25mV lower with respect to wild-type c-551 at neutral pH while the pK at which the heme propionate (HP-17) ionizes is lowered by 1.3 pH units. Temperature and chemical denaturant studies also show that loss of the hydrogen-bond-donating imidazole leads to a large decrease in c-551 tertiary stability.


Soluble adhesion molecules in middle ear effusions from patients with chronic otitis media with effusion.
Soluble forms of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been identified in the peripheral blood and other body fluids. These soluble adhesion molecules have been reported to reflect the upregulation of cell surface ICAM-1 and VCAM-1 expression in inflammatory diseases. The levels of soluble ICAM-1 and soluble VCAM-1 in 37 middle ear effusions from 37 patients with chronic otitis media with effusion (OME) were quantitatively determined with enzyme-linked immunosorbent assays. The levels of soluble ICAM-1 in mucoid effusions were significantly higher than those in serous effusions, but the levels of soluble VCAM-1 did not differ significantly between the two types of effusion. The levels of soluble VCAM-1 in effusions from atopic patients were significantly higher than those from non-atopic patients, whereas the levels of soluble ICAM-1 in samples from atopic patients were significantly lower than those from non-atopic patients. Therefore, our data suggest that an increase in soluble VCAM-1 plays a more important role in the pathogenesis of OME in atopic patients than in non-atopic patients. In addition, soluble ICAM-1 is likely to play a more important role in the pathogenesis of OME in nonatopic patients than soluble VCAM-1.


Induction of HSP70 mRNA after transient ischemia in gerbil brain.
Heat shock protein (HSP) plays an important role in stress responses of cells. Inductions of HSP70 mRNA, amyloid precursor protein (APP) mRNA, and tubulin mRNA within hippocampal CA1 and parietal cortex in gerbil brains were examined at 1 h to 7 days after 10 min of bilateral common carotid artery occlusion using Northern blot analyses. In contrast to the induction of HSP70 mRNA, no induction was observed in APP mRNA or tubulin mRNA. Regional differences in the induction of HSP70 mRNA were found. CA1 cells produced less amount of HSP70 mRNA than cortical cells at 8 h after the transient ischemia. Transient global ischemia is known to result in the selective neuronal death of hippocampal CA1 cells days after reperfusion. Our results suggest that the regional difference in the induction of HSP70 mRNA may relate to the regional difference of the vulnerability of neuronal cells after transient ischemia.


Seroprevalence of tularemia in rural Azerbaijan.
A representative, two-stage probability sampling design was used to select 40 villages in northern Azerbaijan with populations of <500 people to screen for evidence of prior infection with Francisella tularensis. Informed consent was provided, and samples were obtained from 796 volunteers and tested for the presence of immunoglobulin G antibodies using enzyme-linked immunosorbent assay. F. tularensis seropositivity was prevalent (15.5% of volunteers), but there was minimal reporting of signs and symptoms consistent with clinical tularemia, suggesting that mild or asymptomatic infection commonly occurs. Frequently seeing rodents around the home was a risk factor for seropositivity (POR = 1.6, p = 0.03), controlling for age and gender. Geospatial analysis identified associations between village-level tularemia prevalence and suitable tick habitats, annual rainfall, precipitation in the driest quarter, and altitude. This study contributes to the growing understanding of the geographic distribution of tularemia and provides further information on the climatic and landscape conditions that increased the potential for exposure to this pathogen. The potential occurrence of asymptomatic or mild F. tularensis infection warrants further study.


SP-PLP-EPR study of chain-length-dependent termination in free-radical polymerization of n-dodecyl methacrylate, cyclohexyl methacrylate, and benzyl methacrylate: evidence of "composite" behavior.
The chain-length dependence of the termination rate coefficient in n-dodecyl methacrylate (DMA), cyclohexyl methacrylate (CHMA), and benzyl methacrylate (BzMA) bulk free-radical homopolymerizations at ambient pressure and at temperatures from -20 to 0 degrees C is deduced using the recently developed technique of SP-PLP-EPR: pulsed-laser polymerization (PLP) in which time-resolved EPR measurement of radical concentration, cR, is made following each single pulse (SP) of an excimer laser. The decay of cR results from termination of radicals of almost identical size. Their chain length, i, increases linearly with time, t, after applying a SP. The rate coefficient, kt(i,i), for termination of two radicals of size i is determined by fitting the experimental cR vs t data. This process demonstrates that (at least) two power-law exponents are necessary to describe kt(i,i) over the extended chain-length range of i = 1 to 1000. This is consistent with the so-called "composite model" , which uses power-law exponents alpha(S) and alpha(L) to describe termination of radicals either shorter or longer, respectively, than a crossover chain length, ic. The fourth parameter obtained from fitting the SP-PLP-EPR data with this model is kt(1,1), the termination rate coefficient for two radicals of degree of polymerization 1. Previous DMA experiments are reanalyzed while new experimental results are reported and analyzed for CHMA and BzMA. The parameter values for CHMA and BzMA termination at 0 degrees C are almost identical-kt(1,1) approximately 3 x 10(7) L mol(-1) s(-1), alpha(S) approximately 0.50, ic approximately 90, and alpha(L) approximately 0.21-and they are close to those for DMA at 0 degrees C: kt(1,1) approximately 1 x 10(7) L mol(-1) s(-1), alpha(S) approximately 0.64, ic approximately 50, and alpha(L) approximately 0.18. The results fully support the composite model in that the chain-length dependence is more pronounced for shorter than for longer radicals, i.e., alpha(S) > alpha(L). Moreover, the power-law exponent that characterizes termination of long-chain radicals is close to the theoretical value of alpha(L) = 0.16. In fact all parameter values-including the small differences between DMA and CHMA/BzMA-are more-or-less in accord with expectations based on polymer dynamics. Furthermore, our results suggest that termination of methacrylate radicals with large cyclic or long n-alkyl substituents may be affected by steric shielding of the radical functionality.


Insulin-mediated tyrosine phosphorylation of myosin heavy chain and concomitant enhanced association of C-terminal SRC kinase during skeletal muscle differentiation.
In this study, we present for the first time: (1) evidence regarding tyrosine phosphorylation of myosin heavy chain, (2) evidence that insulin can phosphorylate myosin, (3) association of myosin with Csk, a signalling molecule, (4) modulation of this association by insulin, and (5) evidence that these interactions are associated with skeletal muscle differentiation.


Haemodynamic response to peripheral venous congestion in patients with unexplained recurrent syncope.
In patients with recurrent unexplained syncope, exaggerated peripheral venous pooling and impaired circulatory adjustment is thought to contribute to the outcome of a head-up tilt (HUT) test. The present study investigated the role of leg volume changes during venous congestion in the haemodynamic response of patients with recurrent unexplained syncope and the ability to predict the outcome of a HUT test. Changes in calf volume (strain gauge plethysmography), heart rate and arterial blood pressure were recorded in 60 patients with history of unexplained syncope (without postural tachycardia symptom) during venous congestion provoked by pneumatic thigh cuffs while supine at rest and during the initial 10 min of a 45 min 70 degrees HUT test. Twenty-seven patients [age (mean+/-S.D.), 39+/-16 years] exhibited symptoms [HUT(+)] and 33 patients (45+/-14 years) were asymptomatic [HUT(-)]. During venous congestion, mean+/-S.E.M. calf volume increased in both groups [HUT(-), 4.5+/-0.2; HUT(+), 4.8+/-0.4 ml x 100 ml(-1), not significant), but significantly less during head-upright tilt [HUT(-), 3.3+/-0.2, P <0.01; HUT(+), 2.6+/-0.3 ml x 100 ml(-1), P <0.001] without differences between the groups. During venous congestion, arterial pressure increased significantly in asymptomatic HUT(-) patients, but not in the HUT(+) patients. Calf volume changes did not correlate with a symptomatic outcome to a 70 degrees HUT. The lack of exaggerated venous pooling during venous congestion and the inability of calf volume changes to predict a positive HUT suggest that excessive venous pooling does not contribute to the outcome of HUT. Attenuated changes in arterial pressure during venous congestion while supine suggest impaired adjustment of peripheral resistance to leg venous occlusion.


Establishing therapeutic contact with schizophrenics: a supervisory approach.
The beginning resident in psychiatry often finds schizophrenic inpatients to be noncompliant with the standard therapeutic approaches. This can present a significant supervisory challenge. An approach that views the schizophrenic as deficient of "good" objects and emphasizes the resident's capacity to form ordinary human relationships is discussed as a means of establishing therapeutic contact.


Repair and de novo replication of rat lung DNA following instillation of 3-methylcholanthrene.
Structural analysis of rat lung DNA was made by stepwise elution of the nucleic acid from benzoylated--DEAE-cellulose with 1.0 M NaCl and 30% formamide solutions respectively, the DNA content of collected fractions being determined by absorbance. The proportion of the minor fraction, which was eluted with formamide and thought to contain DNA having single-stranded regions, was increased by intratracheal instillation of 3-methylcholanthrene prior to death of the animal. Maximum initial increase was observed 14 h after treatment. Analysed up to 10 days after treatment, there was a biphasic response, the early maxima being dose dependent and the second apparently independent of the amount of hydrocarbon administered. The data implicate DNA repair processes and cellular proliferation stimulated by 3-methylcholanthrene as being involved in recovery of the lung from this potentially carcinogenic insult.


Influence of lunar phases on suicide: the end of a myth? A population-based study.
The hypothesis of lunar influence on suicide remains widespread, despite the fact that little scientific evidence to substantiate it. We conducted a population-based study to assess the influence of the lunar phases on suicides according to age, sex, and chosen method. The study included all suicides in Middle Franconia between 1998 and 2003. From a population-based sample of 3351 events, the files of 3054 suicides (1949 males and 1105 females) were complete for the study variables. Data were categorized by lunar phase, sex, age, and chosen method-"violent" vs. "non-violent" acts. No significant relationship was detected between the full, absent, and moon's interphases and suicide incidence. Nevertheless, there was a weak association between the absent moon and choice of a non-violent suicide method in men aged less than the median of 40.2 yrs. There was no evidence of a relationship between suicide and lunar phase. Some explanations for this phenomenon are discussed.


Apatite-coated collagen scaffold for bone morphogenetic protein-2 delivery.
Bone morphogenetic proteins (BMPs) are the most potent osteoinductive growth factors. BMP-2 is clinically used for spine fusion and bone fracture healing. Commercially available BMP-2 uses a type I collagen scaffold as a carrier, but it only releases BMP-2 for a short period of time, which may release the bone formation efficacy. In the present study, we hypothesize that apatite coating of a collagen scaffold increases the release period as well as the osteogenic efficacy of BMP-2. Apatite coating was achieved by incubating collagen scaffolds in simulated body fluids (SBFs). Apatite coating on collagen scaffolds was confirmed by X-ray diffraction, electron spectroscopy for chemical analysis, attenuated total reflectance-Fourier transform infrared spectroscopy, and scanning electron microscopy. The rate and period of BMP-2 release from apatite-coated collagen scaffolds varied depending on the concentration of SBFs used. The 5× and 10× SBF apatite-coated collagen scaffolds released 91.8%±11.5% and 82.2%±13.1% of their loaded BMP-2 over 13 days in vitro, respectively, whereas noncoated collagen scaffold released 98.3%±2.2% over the initial one day. BMP-2 released from apatite-coated collagen scaffold significantly increased the alkaline phosphatase activity of cultured osteoblasts, compared with BMP-2 released from noncoated collagen scaffold. Computed tomography and histomorphometry showed that BMP-2 delivery using apatite-coated collagen scaffolds resulted in 2.5-fold higher bone formation volume and 4.0-fold higher bone formation area than BMP-2 delivery using noncoated collagen scaffolds. This study shows that simple apatite coating of a collagen scaffold results in a BMP-2 carrier that renders long-term release of BMP-2 and dramatically enhances osteogenic efficacy.


Atypical streptococcal infection of gingiva associated with chronic mouth breathing.
Streptococcal infections of oral tissues are mainly seen in young children who experience a variety of upper respiratory tract infections. The disease is characterized by fever, lymphadenopathy, and ulcers on the gingiva, lips, and tonsils. This case report presents an atypical streptococcal infection of the gingiva in an 18-year-old man. The patient was referred to the periodontology department complaining of a 2-month history of gingival enlargement. He had persistent fever (39.5 degrees C) and general malaise for 2 weeks. Intraoral examination revealed extremely inflamed and enlarged gingiva with spontaneous bleeding and suppuration. Based on the otolaryngologic consultation and the hematologic, immunologic, and microbiologic tests, the final diagnosis was an atypical streptococcal gingivitis with chronic adenoid-related mouth breathing and oral hygiene neglect as contributing factors. Treatment consisted of a broad-spectrum antibiotic regimen, supragingival and subgingival debridement, adenoidectomy, and scaling and root planing. A good response to nonsurgical therapy was achieved despite poor patient compliance, and no recurrence of gingival enlargement was observed after 1 year. Streptococcal gingivitis should be included in the differential diagnosis of suppurative gingival enlargements. Furthermore, chronic mouth breathing may initiate and/or contribute to this disease.


M(mu-CN)Fe(mu-CN)M' chains with phthalocyanine iron centers: preparation, structures, and isomerization.
The molecular building blocks Fe(II)Pc (Pc = phthalocyaninato2-), Fe(III)Pc, ZnPc, Cp(dppe)Fe, and Cp(PPh3)2Ru were combined in the cyanide-bridged dinuclear reference compounds with M-CN-ZnPc and M-CN-FePc-CN arrays containing Fe(II)Pc and Fe(III)Pc. The linear trinuclear species with the M(mu-CN)Fe(mu-CN)M' backbone were prepared for both Fe(II)Pc and Fe(III)Pc centers, for terminal Fe/Fe, Fe/Ru, and Ru/Ru combinations and for all three possible cyanide orientations (M-CN-Fe-NC-M', M-CN-Fe-CN-M', and M-NC-Fe-CN-M'). The 15 complexes obtained were identified from their IR spectra and six structure determinations. The preferred orientation of the cyanide bridges could be established starting from the [Fe-NC-Fe(III)Pc-CN-Fe]+ complex, which is labile in solution and isomerizes to the corresponding [Fe-CN-Fe(III)Pc-NC-Fe]+ complex. A kinetic analysis of this isomerization has yielded an activation barrier of roughly 110 kJ/mol.


Mucosal Malignant Melanoma of Nasal Cavity Recurring a Year After Radiotherapy.
Sinonasal mucosal malignant melanoma is a rare entity. In this report we present a nasal mucosal malignant melanoma case with its histopathological and clinical features. An 88-year-old female patient presented with epistaxis a month ago. Examination revealed a polypoid mass lesion of right nasal cavity originating from the middle concha. Her medical history revealed that she had been found to have a mass lesion in the right nasal cavity 15 months ago. She then underwent a punch biopsy from that lesion. A definitive histopathological diagnosis was not made but it was declared that the lesion had been a malignant epithelial tumor. The patient then had radiotherapy and the lesion showed complete regression. One year after completion of radiotherapy, the lesion recurred. Her last PET-CT showed multiple metastatic foci. Endoscopic excisional biopsy was performed for her recurrent lesion. Fragmented tumoral tissues were measured as 3,6x3x0,5 cm. Macroscopically the tumor was brownish in color. Histopathologically the tumor consisted of spindled and epitheloid cells. Immunohistochemically the tumor cells displayed positivity for S-100, HMB-45 and Melan-A. Findings were consistent with malignant melanoma. Mucosal malignant melanomas have a poor prognosis despite chemotherapy and radiotherapy. Five-year survival for sinonasal melanoma is reported to be lower than 35%. Sinonasal melanomas show a high recurrence rate. The immunohistochemical markers showing high specificity for malignant melanoma such as S-100, HMB-45 and Melan-A are used in order to reach a correct diagnosis. In our case the tumor showed recurrence and multiple metastases 1 year after completion of radiotherapy. For this recurrent tumor, chemotherapy and radiotherapy have been planned.


A focus of human infection by Haplorchis taichui (Trematoda: Heterophyidae) in the southern Philippines.
We report an exceptionally high rate of infection by Haplorchis taichui (Nishigori, 1924) in human populations on Mindanao Island, southern Philippines. This intestinal fluke is seldom encountered, and this is the first report of high prevalence of infection (36%) in humans by H. taichui in the Philippines. The likely source of haplorchine infection has been linked to consumption of raw or undercooked freshwater fish containing infective metacercariae. The most common clinical symptoms appeared as upper abdominal discomfort or pain and borborygmi. Praziquantel (75 mg/kg divided in 3 doses in 1 day) was a well-tolerated and effective treatment for infection by H. taichui.


Novel retinoic acid receptor alpha agonists: syntheses and evaluation of pyrazole derivatives.
We have designed and synthesized a series of pyrazole derivatives as candidate retinoic acid receptor (RAR) agonists. One of them, 4-[5-(1, 5-diisopropyl-1H-3-pyrazolyl)-1H-2-pyrrolyl]benzoic acid (11b), which possesses a 2,5-disubstituted pyrrole moiety, showed selective transactivation activity for the RAR alpha receptor, and had highly potent cell-differentiating activity on HL-60 cells.


[Substituted 16alpha,17alpha-cyclohexanopregnanes: the anionic oxy-Cope rearrangement of 3beta-tert-butyldimethylsilyloxy-19-hydroxy-19-vinyl-16alpha,17alpha-cyclohexapregn-5-en-20-one].
(19R)- and (19S)-tert-Butyldimethylsilyl (TBS) ethers of 19-hydroxy-19-vinyl-16alpha,17alpha-cyclohexanopregn-5-en-20-ones were synthesized. These compounds containing the 1,5-oxydienoic motif were subjected to the anionic oxy-Cope rearrangement to obtain 3beta-TBS ether of 6beta-(3-oxopropyl)-16alpha,17alpha-cyclohexano-19-nor-pregn-5(10)-en-20-one. The structures of the compounds synthesized were confirmed by the analysis of their H and 13C NMR spectra.


[New aspects of the diagnosis and therapy of microangioma].
Microangioma means a clinical entity of different arterio-venous vascular malformations. Often so called atypical intracerebral hemorrhage or a symptomatic epilepsy are caused by these malformations. Nowerdays diagnosis is much more easier by the new imaging devices like CT and MRI. Especially MRI allows to interpretate the dignity and exact localisation of these malformations. Therefore microsurgical extirpation without postoperative morbidity becomes possible.


[Determining the size of myocardial necrosis by a time-related biochemical method].
A mathematical procedure is proposed for quantitative assessment of necrosis weight, which is based on the processing of serial measurements of peripheral MB CPK activity in patients who died of acute myocardial infarction. The method is based on statistical treatment of biochemical findings and the results of postmortem determination of necrosis weight. A formula is derived for the biochemical equivalent of necrosis weight, which can be used a real-time intravital test.


[Policies encouraging price competition in the generic drug market: Lessons from the European experience].
To describe alternative policies aimed at encouraging price competition in generic drug markets in countries with strict price regulation, and to present some case studies drawn from the European experience. Systematic literature review of articles and technical reports published after 1999. The shortcomings in consumer price competition observed in some European generic markets, including Spain, may be reduced through three types of public reimbursement or financing reforms: policies aimed at improving the design of current maximum reimbursement level policies; policies aimed at monitoring competitive prices in order to reimburse real acquisition cost to pharmacies; and, more radical and market-oriented policies such as competitive tendering of public drug purchases. The experience of recent reforms adopted in Germany, Belgium, Holland, Norway, and Sweden offers a useful guide for highly price-regulated European countries, such as Spain, currently characterized by limited consumer price competition and the high discounts offered to pharmacy purchases. Direct price regulation and/or the generic reference pricing systems used to reduce generic drug prices in many European countries can be successfully reformed by adopting measures more closely aimed at encouraging consumer price competition in generic drug markets.


Collisional versus collisionless resonant and autoresonant heating in laser-cluster interaction.
When a hot cluster expands, a transient matching between the plasma frequency and the laser frequency has been predicted, observed, and analyzed recently. The associate energy transfer to the electrons has been described as an enhanced collisional absorption. However, for hot plasmas the collision frequency is small and a collisionless resonant heating is more efficient. We set up and solve the problem of resonant collisional and collisionless cluster heating taking into account cluster expansion, laser pulse duration and pulse chirping. Moreover, we identify an efficient autoresonant mechanism of collisionless heating with a chirped laser pulse when the crossing between the plasmon frequency and the laser frequency is degenerate and the time derivatives of these two frequencies are equal at the crossing time. Transition between collisional regime of cluster heating and collisionless one is discussed.


Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs?
In the last decade Toll-like receptor (TLR) research has led to new insights in the pathogenesis of many rheumatic diseases. In autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis TLR signaling is likely to be involved in tolerance breakthrough and chronic inflammation via combined Fc gamma receptors and TLR recognition of immune complexes. Furthermore, inflammatory diseases like psoriatic arthritis and gout also show more and more evidence for TLR involvement. In this review we will discuss the involvement of TLR signaling in several rheumatic diseases and stress their similarities and differences based on recent findings.


Tumor necrosis factor α knockout increases fertility of mice.
Tumor necrosis factor α (TNFα) acts through two receptors, TNFα receptor| (TNFR|) and TNFα‖ (TNFR‖). Tumor necrosis factor α receptor| knockout mice had early senescence and poor fertility, whereas TNFR‖ knockout mice had reproductive performance not different from wild type (WT) mice. In the present study, TNFα knockout mice were used to study the roles of TNFα in female reproduction. The TNFα-/- mice had similar vaginal opening time (PD 27.6 ± 1.8 vs PD 27.7 ± 1.9, respectively, P > 0.05) and exogenous gonadotropin primed TNFα-/- mice shed more ova (28.9 ± 3.75 vs 9.8 ± 0.51, respectively, P = 0.001) compared with WT controls. At 2 mo of age, in 21 d, TNFα-/- mice had more estrous cycles than WT counterparts (6.0 ± 0.25 vs 4.0 ± 0.28, respectively, P < 0.05). Tumor necrosis factor α mutation also influenced ovarian follicular development; TNFα-/- mice had approximately a two-fold larger follicle pool in the early neonatal period (6087 ± 508.15 vs 3440 ± 261.91, respectively, P = 0.004), whereas TNFα knockout affected growth of primordial follicles to the antral stage as well. Moreover, TNFα-/- mice gave birth to 21% more pups than control mice during a 12 mo breeding period (37.38 ± 3.69 vs 22.38 ± 3.53, respectively, P = 0.03). At 1 y of age, the follicular reserve in TNFα-/- mice was more than that in WT mice. These physiological differences in TNFα-/- mice were associated with increased proliferation of granulosa cells and decreased apoptosis of oocytes. This was apparently the first demonstration that in the TNFα-/- mouse model, multiple parameters of ovarian function were altered, and that lack of TNFα increased fertility in mice.


Coping with failure: relationship with self-concept discrepancy and attributional style.
In the relationship of attributional style and self-concept discrepancy with coping behavior among 10th-grade Hong Kong Chinese students, 3 significant canonical variate pairs were identified. The total criterion redundancy showed that self-concept discrepancy and attributional style predicted about 20% of the variance of coping behavior. The 1st variate pair indicated that students with small self-concept discrepancy and low-depressive attributional style tended to cope with failure by planful problem solving and by positive reappraisal. The 2nd variate pair showed that students, particularly girls, with small self-concept discrepancy in verbal ability and same-sex peer relations tended to cope with failure by seeking social support. The last variate pair showed that students with great self-concept discrepancy in same-sex peer relations and parent relations tended to cope with failure by avoiding or escaping. The 3 canonical variate pairs also suggested a new taxonomy for coping behavior: mobilization of internal coping resources, mobilization of external coping resources, and the inability to mobilize any coping resources.


[Massive intestinal hemorrhage caused by leiomyoma of the jejunum. Report of a case].
Small-bowel leiomyoma is a rare tumour. The authors report a case complicated by severe bleeding. Esophagus-gastro-duodenal endoscopy was not decisive enough, while TC was the most reliable instrumental investigation. Because of dimensions basic than 10 cm, the presence of a pseudocapsule end the absence of cariokinetic figures, the histopathologic test supports the hypothesis that it was a benign disease. One year follow-up, negative for relapse, confirm that the lesion is benign.


[Morphological and functional characteristics of the heart in untreated hypertension].
To better define the different forms of hypertensive heart disease, we performed 2D guided M mode echo recording of the left ventricle (LV) and Doppler assessment of LV filling in 118 newly recognised (less than 1 year) and untreated hypertensive patients (mean age +/- SD: 49 +/- 10 years, 80 males, 38 females). All recordings were read "blindly". 86 patients underwent also 24 hours BP monitoring during daily routine. 1) The relative wall thickness (h/r) shows a normal distribution: mean = 0.39; SD = 0.08; 1st quartile = 0.33; 3rd = 0.43; 2) The septal/posterior wall ratio (ST/PWT) shows also a normal distribution: mean = 1.14; SD = 0.24; 1st quartile = 1; 3rd = 1.3; 3) Among patients with LVH (Devereux's criteria, n = 65) the 6 patients with h/r less than or equal to 0.33 are significantly different from the 18 patients with h/r greater than or equal to 0.43 for age (44 +/- 8 vs 51 +/- 10; p less than 0.03), casual (146 +/- 7 vs 166 +/- 13 mmHg; p less than 0.05) and ambulatory SBP (135 +/- 19 vs 146 +/- 16 mmHg; p less than 0.05), peak systolic stress (280 +/- 15 vs 187 +/- 31 Dynes/cm2; p less than 0.001) and E/A ratio (1.17 +/- 0.01 vs 0.94 +/- 0.27; p less than 0.05) but not for ponderal excess. 4) Patients with asymmetric LVH(ST/PWT greater than 1.3 in 22; greater than 1.5 in 10) are significantly different from patients with symmetric LVH for age (54 +/- 10 vs 47 +/- 10; p less than 0.03), diastolic diameter (51 +/- 5 vs 53 +/- 5 mm; p less than 0.02), ST (13.2 +/- 2.9 vs 10 +/- 1.9 mm; p less than 0.001) and PWT (8.9 +/- 1.5 vs 9.7 +/- 1.5 mm; p less than 0.02) but not for BP fractional shortening and LV filling. eccentric LVH may be found in young hypertensive patients with normal systolic function and LV filling despite high parietal stress; asymmetric LVH is more frequent in older patients in which LVH seems to develop rather on the septum than on free wall, independently of BP and without consequences on LV function.


Reliability and validity of a tool to measure the severity of tongue thrust in children: the Tongue Thrust Rating Scale.
This study aimed to develop a scale called Tongue Thrust Rating Scale (TTRS), which categorised tongue thrust in children in terms of its severity during swallowing, and to investigate its validity and reliability. The study describes the developmental phase of the TTRS and presented its content and criterion-based validity and interobserver and intra-observer reliability. For content validation, seven experts assessed the steps in the scale over two Delphi rounds. Two physical therapists evaluated videos of 50 children with cerebral palsy (mean age, 57·9 ± 16·8 months), using the TTRS to test criterion-based validity, interobserver and intra-observer reliability. The Karaduman Chewing Performance Scale (KCPS) and Drooling Severity and Frequency Scale (DSFS) were used for criterion-based validity. All the TTRS steps were deemed necessary. The content validity index was 0·857. A very strong positive correlation was found between two examinations by one physical therapist, which indicated intra-observer reliability (r = 0·938, P < 0·001). A very strong positive correlation was also found between the TTRS scores of two physical therapists, indicating interobserver reliability (r = 0·892, P < 0·001). There was also a strong positive correlation between the TTRS and KCPS (r = 0·724, P < 0·001) and a very strong positive correlation between the TTRS scores and DSFS (r = 0·822 and r = 0·755; P < 0·001). These results demonstrated the criterion-based validity of the TTRS. The TTRS is a valid, reliable and clinically easy-to-use functional instrument to document the severity of tongue thrust in children.


Differential mRNA expression of TACR1 after ischemic peritoneal trauma: a pilot animal study.
Experimental trial in an in vivo animal model in the laboratory facilities of a university department of obstetrics and gynecology and a microarray facility using seventeen female Wistar rats to investigate the regional expression level of TACR1 at specific locations in the peritoneum in a rodent animal model of post-operative adhesions. Peritoneal adhesions were induced by the placement of three unilateral ischemic lesions. A time course experiment was performed to identify when adhesions form in this model to determine the optimal time for tissue harvesting. To this effect, second look analysis for adhesion scoring occurred after day 1, 3 and 5. Eighteen tissue samples from the adhesiogenic lesions and the contralateral non-adhesiogenic peritoneum were harvested from n = 3 animals at day 3 for quantitative real-time PCR analysis. After 1 day, no adhesions were macroscopically detectable. After 3 days, adhesions were detectable which could be separated easily by gravity. After 5 days, all animals had formed adhesions and strong traction was required for adhesiolysis. The adhesions always formed to the ischemic part of the lesions. Quantitative PCR analysis after 3 days demonstrated down-regulation of TACR1 mRNA in the adhesiogenic peritoneum of the lesions compared to non-adhesiogenic peritoneum on the contralateral side. This difference was statistically highly significant (p < 0.01). In the ischemic lesion model of adhesiogenesis, TACR1 is differentially expressed between adhesiogenic peritoneum and non-adhesiogenic peritoneum at the time-point of adhesion formation.


Effect of alkaline pretreatment on mesophilic and thermophilic anaerobic digestion of a submerged macrophyte: Inhibition and recovery against dissolved lignin during semi-continuous operation.
The long-term effect of alkaline pretreatment on semi-continuous anaerobic digestion (AD) of the lignin-rich submerged macrophyte Potamogeton maackianus was investigated using mesophilic and thermophilic conditions. In pretreated reactors, dissolved lignin accumulated to high levels. CH4 production under the pretreated condition was higher than that of the untreated condition, but decreased from Days 22 (mesophilic) and 42 (thermophilic). However, CH4 production subsequently recovered, although dissolved lignin accumulated. Further, the change in the microbial community was observed between conditions. These results suggest that dissolved lignin temporarily inhibited AD, although acclimatization to dissolved lignin occurred during long-term operation. During the steady state period, mesophilic conditions achieved a 42% increase in the CH4 yield using pretreatment, while thermophilic conditions yielded an 8% increment. Because volatile fatty acids accumulated even after acclimatization during the thermophilic pretreated condition and was discharged with the effluent, improvement of the methanogenic step would enable enhanced CH4 recovery.


A recombinant X chromosome in a short statured girl resulting from a maternal pericentric inversion.
A 7 3/4-year-old girl with short stature was found to have a recombinant (X),dup q chromosome resulting from an apparently unique pericentric inversion (X)(p11.2q26) present in her mother and maternal grandmother. The recombinant X chromosome was shown to be late replicating and the inversion X chromosome to be randomly inactivated. This appears to be only the eighth report (7 female, 1 male) of a recombinant resulting from an X pericentric inversion despite all diagnosed females having mild clinical abnormalities. Reasons for the rarity of such recombinant X chromosomes in man are examined.


Towards large scale preparation of graphene in molten salts and its use in the fabrication of highly toughened alumina ceramics.
Highly crystalline graphene nanosheets were reproducibly generated by the electrochemical exfoliation of graphite electrodes in molten LiCl containing protons. The graphene product has been successfully applied in several applications. This paper discusses the effect of molten salt produced graphene on the microstructures and mechanical properties of alumina articles produced by slip casting and pressureless sintering, which is one of the most convenient methods for the commercial production of alumina ceramics. In addition to graphene, graphite powder and multi-walled carbon nanotubes (CNTs) were also used to prepare alumina articles for comparative purposes. A graphene strengthening effect was realized through microstructural refinement and by influencing the formation of alumina nanorods during the sintering of α-Al2O3 articles. The fracture toughness of the sintered alumina articles increased to an impressive value of 6.98 MPa m(1/2) by adding 0.5 wt% graphene nanosheets. This was attributed to the unique microstructure obtained, comprised of micrometer sized alumina grains separated by alumina nanorods.


Pediatric circulatory support.
Mechanical circulatory support in infants and small children is still a crucial issue. Until recently technological advances have been limited to the adult population. Between February 1994 and December 1996, 553 infants or children underwent operation at our institution. Ten of them were treated with cardiac assist systems. Their ages ranged from 4 days to 8 years (median 5 months). In 8 patients we used a pulsatile circulatory support system available in 6 sizes (9, 10, 22.5, 25, 54, and 60 mL). A centrifugal pump was used in 2 additional infants. In 3 children cardiac assist was considered as a bridge to transplantation; in the remaining patients postcardiotomy failure or cardiogenic shock led to mechanical support. Median duration of assist was 4 days (range 8 hours to 17 days). In all cases we could observe recovery of renal, hepatic, and cardiac function in the immediate postimplantation period. Six patients survived and could be discharged either after successful transplantation or after myocardial recovery from postcardiotomy failure. The cause of death in 4 cases was bleeding and multiorgan failure. No technical failures occurred with either system. The pulsatile circulatory support system seems to be feasible and effective for pediatric extracorporeal support. If the anatomic situation does not permit implantation, centrifugal pumps are an alternative.


TNFRSF11B: A potential plasma biomarker for diagnosis of obstructive sleep apnea.
Obstructive sleep apnea (OSA) was characterized by chronic intermittent hypoxia, which was an independent risk factor for endothelial dysfunction. Circulating TNFRSF11B might play an important role in promoting endothelial cells dysfunction. We explored the role of plasma TNFRSF11B as a potential mechanism of endothelial dysfunction in OSA patients. The study population consisted of 120 patients with varying severity of OSA and 40 control subjects. Plasma TNFRSF11B levels were measured using human Magnetic Luminex assay. Our data showed that plasma TNFRSF11B levels were significantly higher in patients with OSA. After adjusting confounding factors, plasma TNFRSF11B levels were independently associated with the presence of OSA (Beta:0.434, 95% CI: 664.096 to 1076.247; P < 0.001) and plasma TNFRSF11B levels were positively associated with the apnea-hypopnea index (Beta:0.486, 95% CI: 0.007 to 0.017; P < 0.001). Furthermore, plasma TNFRSF11B showed higher discriminatory accuracy in predicting the presence of OSA (AUC:0.964). Plasma TNFRSF11B levels were significantly associated with the presence of OSA and its severity. TNFRSF11B could be a plasma biomarker with a positive diagnostic value for premature vascular endothelial dysfunction in patients with OSA.


Pathogenic bacteria in an orthopaedic hospital in India.
The problem of changes in pathogenic microbiological flora and the emergence of bacterial resistance has created major problems in the management of orthopaedic diseases and fractures. Due to the use of implants for open reduction and internal fixation, which are foreign bodies to the body, orthopaedic trauma surgery is at grave risk of microbiological contamination and infection. With new microbiological agents in vogue, we have conducted a retrospective study to determine the pattern of bacterial infection, sensitivity to various antimicrobial agents, and their relations to various orthopaedic illnesses and procedures. Gram negative (E. coli and Pseudomonas spp.) infections have emerged as the major threat (74.37%) in orthopaedic cases in contrast to Staphylococcus aureus (23.31%). These bacteria infected patients with open fractures (34.3%), spinal instrumentation with bedsores (23.31%), osteomyelitis of bone (24.42%) and guillotine amputation stumps (14.43%). Cefaperazone and ceftriaxone were found to be the most effective antibiotics against gram negative bacteria while cefaperazone was equally effective against S. aureus. Emerging resistance was found against amoxicillin, ampicillin and the aminoglycoside: amikacin.


Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G.
The urokinase receptor (CD87) participates to the pericellular proteolytic potential of migrating cells and to the recruitment of leukocytes during inflammation. It consists of three structurally homologous domains, with the C-terminal domain D3 attached to cell membranes through a GPI anchor. CD87 is susceptible to an endoproteolytic processing removing the N-terminal domain D1 and generating truncated D2D3 membrane species, thus modulating CD87-associated functions. Full-length or truncated CD87 can be also released from cells via juxtamembrane cleavage by phospholipases and/or by yet unidentified proteinases. Using a recombinant CD87 and the CD87-positive monocytic U937 cell line and isolated blood monocytes, we show by protein immunoblotting and flow immunocytometry that the human neutrophil serine-proteinases elastase and cathepsin G cleave CD87 within the D1-D2 linker sequence, while in addition cathepsin G is highly efficient in cleaving the C terminus of D3. The combination of cathepsin G and elastase provided by degranulated neutrophils results in enzymatic cooperation leading to the release from monocytic cells of a truncated D2D3 species resembling that previously described in pathological body fluids. Using mass spectrometry analysis, the proteolytic fragmentation of synthetic peptides mapping the D1-D2 linker and D3 C-terminal domains identifies potential cleavage sites for each enzyme and suggests the existence of a mechanism regulating the CD87(D1-D2)-associated chemotactic activity. Finally, isolated or combined elastase and cathepsin G drastically reduce the capacity of cells to bind urokinase. Secretable leukocyte serine-proteinases are thus endowed with high potential for the regulation of CD87 expression and function on inflammatory cells.


Longitudinal follow-up of 100 patients at risk of intrauterine growth retardation: comparison of diagnosis in two periods.
The concept of low birth weight includes two different entities: prematurity and intrauterine growth retardation. Both of them are major public health problems, because they increase perinatal morbidity and mortality Early diagnosis of IUGR leads to adequate decisions, making possible a reduction in perinatal morbidity and mortality. In order to make an early diagnosis of IUGR, clinical methods have proven to be insufficient. Ultrasonography is an important aid to this diagnosis, introducing the measurement of fetal diameters and perimeters. This study, designed to compare both methods, was carried out in at the Antoine Béclère Hospital, Clamart, France. Data processing was done in CLAP-PAHO/WHO. In the first period, retrospective analyses of 116 clinical histories with IUGR were performed. In this study, only fetal diameters were used and the accuracy of clinical and ultrasonographic diagnosis was evaluated. In the second period a prospective longitudinal follow-up study of 100 pregnant women at risk of developing IUGR was carried out. Clinical diagnosis was also evaluated, and compared to the ultrasonographic approach. The parameters used were the fetal diameters and perimeters (head and abdominal perimeters, and their relationship). Sensitivity, specificity and predictive values of the ultrasonic parameters were calculated (table I). The clinical and ultrasonographic diagnosis of both periods were compared with the purpose to analyze the effect of the measurement of fetal perimeters in the diagnostic accuracy. Newborns of the 100 patients in the prospective study were classified into two groups according to birth weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Carcinoembryonic antigen (CEA) and alkaline phosphatase in progressive colorectal cancer with special reference to patient survival.
The prognostic value of serial CEA tests was evaluated in 175 consecutive patients with progressive colorectal cancer who subsequently died of their disease. The upper normal plasma CEA limit was determined to be 8 ng/ml from serial CEA determinations in 31 patients radically operated on for colorectal cancer and observed in median 40 months without evidence of recurrence. A CEA value of greater than 8 ng/ml was highly suggestive of residual disease or recurrence, even when no clinical evidence was present. Approximately 90% of the patients dying from colorectal cancer showed an increase in CEA to greater than 8 ng/ml during the course of the disease. In 63% of the patients CEA increase preceded clinical progression or relapse, with a median time period of 4 months. Sixty-eight per cent of the patients had rising CEA values over an extended time period of many months, 14% had a preterminal increase, 13% had constantly normal and 5% constantly elevated CEA. As 6/9 patients developed a drop in CEA in relation to initiation of chemotherapy without clinical response, it is concluded that CEA is not a reliable indicator of clinical response to chemotherapy. Patients with liver metastases had higher CEA and alkaline phosphatase levels than patients with only localized disease. However, no good statistical correlation between CEA and serum alkaline phosphatase was found in patients with liver metastases (coefficient of correlation r = 0.35). An increase in CEA from normal to above 8 ng/ml predicted a decrease in survival time of median 60% counted from the time of diagnosis. The numerical CEA value was predictive of shortening of survival only when greater than 3000 ng/ml. Such high values were observed only in a minority of the patients (12%). Greater than 1000 U/l (27% of the patients) alkaline phosphatase predicted an extremely poor prognosis, with a median survival of 1 month (range 0.5-4 months). It is concluded that a rise in CEA to greater than 8 ng/ml indicates with high degree of certainty relapse or disease progression in colorectal cancer patients. CEA is not a reliable indicator of clinical response to chemotherapy, and an increase in the CEA level is of little prognostic value concerning survival. Alkaline phosphatase seems to be a more valuable predictor of a worsening of prognosis.


Lactic acid production from cellulosic material by synergetic hydrolysis and fermentation.
The hydrolysis process on corncob residue was catalyzed synergetically by the cellulase from Trichoderma reesei and the immobilized cellobiase. The feedback inhibition to cellulase reaction caused by the accumulation of cellobiose was eliminated efficiently. The hydrolysis yield of corncob residue was 82.5%, and the percentage of glucose in the reducing sugar reached 88.2%. The glucose in the cellulosic hydrolysate could be converted into lactic acid effectively by the immobilized cells of Lactobacillus delbrueckii. When the enzymatic hydrolysis of cellulose and the fermentation of lactic acid were coupled together, no glucose was accumulated in the reaction system, and the feedback inhibition caused by glucose was also eliminated. Under the batch process of synergetic hydrolysis and lactic acid fermentation with 100 g/L of cellulosic substrate, the conversion efficiency of lactic acid from cellulose and the productivity of lactic acid reached 92.4% and 0.938 g/ (L.h), respectively. By using a fed-batch technique, the total concentration of cellulosic substrate and lactic acid in the synergetic process increased to 200 and 107.5 g/L, respectively, whereas the dosage of cellulase reduced from 20 to 15 IU/g of substrate in the batch process. The results of the bioconversion of renewable cellulosic resources were significant.


Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47.
We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas. Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adenocarcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium. In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma-associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers.


The role of guilt sensitivity in OCD symptom dimensions.
Although some studies have found that guilt may precede, motivate, or be a consequence of obsessive-compulsive disorder (OCD), the relationship between guilt and OCD has been under investigated. The studies that explored the role of trait guilt (guilt propensity) in OCD reported inconsistent findings and failed to support its predictive role. Since it has been suggested that OCD patients perceive guilt in a more threatening manner, it might also be relevant to test to what extent they negatively evaluate the experience of guilt (i.e., guilt sensitivity; GS). Study 1 investigated the psychometric properties of a new 10-item Italian measure developed to assess GS-named Guilt Sensitivity Questionnaire-in a nonclinical sample (N = 473). Results from exploratory factor analyses supported the unidimensionality of the scale. It also showed excellent internal consistency and good discriminant validity. Study 2 investigated the role of GS in OCD symptoms, in particular with regard to responsibility for harm obsessions and checking compulsions, using a heterogeneous OCD sample (N = 61) and a control group of patients with anxiety disorders (N = 47). GS was the unique significant predictor of checking related OCD symptoms independent of negative mood states and obsessive beliefs. Guilt Sensitivity Questionnaire scores of patients with responsibility for harm concerns were significantly higher than those of patients with other kinds of obsessive concerns and with anxiety disorders. Findings supported the hypothesis that GS plays a relevant role in OCD symptoms when checking rituals are primarily involved. Implications for current cognitive behavioral models are discussed. Guilt sensitivity may play a role in checking-related OCD symptoms. We developed a psychometrically sound unidimensional 10-item scale to assess guilt sensitivity. Guilt sensitivity was a unique predictor of checking-related OCD symptoms. Targeting beliefs about the intolerability/dangerousness of experiencing guilt may be useful. Acceptance-based approaches may be helpful as they promote the acceptance of guilt.


Therapeutic efficacy of a polysaccharide isolated from Cordyceps sinensis on hypertensive rats.
This study was aimed to investigate the antihypertensive effect of a polysaccharide fraction from Cordyceps sinensis on spontaneously hypertensive rats (SHR). The CSP1, one component of Cordyceps sinensis polysaccharides (CSP), was obtained after water extraction, deproteinization, de-colorization and purification with DEAE-cellulose 52. And a more homogeneous component CSP1-2 was obtained using Sepharose CL-6B chromatography. CSP1-2 mainly consisted of mannose, glucose and galactose in a molar ratio of about 2:2:1 and its average molecular weight was approximately 2.70×10(4)Da. Pharmacological tests showed that CSP1, in which the CSP1-2 was its main component, had antihypertensive effect by stimulating the secretion of vasodilator NO, decreasing the level of ET-1, epinephrine, noradrenaline and angiotensin II, inhibiting the increase of transforming growth factor β1 (TGF-β1) and lowering the level of inflammatory mediator of C-reactive protein (CRP). These results suggested that CSP1 may possess high potential in treating hypertension.


[Diagnosis and treatment of verrucous laryngeal cancer--a case report].
A male patient of 71 years old was admitted due to repeated hoarseness for two years which got worse accompanied with dyspnea so that to receive tracheotomy in another hospital more than one month ago. The two vocal cord biopsies carried out in the other hospital before showed vocal keratosis and squamous cell hyperplasia. Electronic laryngoscopy result showed normal epiglottis. a lot of saliva at hypopharynx, and rough arytenoid mucosa. The supraglottic area was remarkably swollen and the glottal area can not be observed clearly. The biopsy of throat was unable to conduct. Barium swallow examination revealed no obvious space-occupying lesion in piri form fossa or esophagus. Larynx CT scan showed a space-occupying lesion in the laryngeal cavity on the right side of the neck involving the thyroid cartilage. The patient was finally treated by total laryngectomy. cervical infected tissue resection. grafting transposition with pectoralis major flap and tracheostomy. The postoperative pathology showed laryngeal verrucous carcinoma.


3-T proton magnetic spectroscopy in unmedicated first episode psychosis: a focus on creatine.
Different lines of evidence suggest an abnormal cerebral energy metabolism as being critical to the pathophysiology of schizophrenia. However, it is unknown as to whether levels of creatine (Cr) would be involved in these anomalies. The study involved 33 unmedicated first episode psychosis patients and 41 healthy controls. Proton magnetic resonance spectroscopy ((1) H-MRS) was performed at 3 T using a long TE (TE/TM/TR of 240/27/3000 ms) such that within the total phosphocreatine (PCr) plus Cr signal (tCr(240)), mainly Cr was detectable. The target region was an 18 cm(3) prefrontal volume. A negative association was found between age of patients and tCr(240) levels referenced to internal water, with 20% of the variance in tCr(240) accounted for by Age. A secondary finding revealed 16% reduction of tCr(240) levels in patients, solely when comparing participants older than the median age of patients. No association existed between tCr(240) levels and clinical variables. These findings support previous data reporting abnormalities in brain creatine kinase isoenzymes involved with the maintenance of energy pools in schizophrenia. The implications of using a long TE are discussed in terms of the relative proportions of Cr and PCr within the tCr(240) signal, and of potential group differences in T(2) times.


[Effects of low-molecular-weight heparin on proliferative glomerulonephritis].
To investigate the effects of LMWH on proliferative nephritis, we randomized 41 patients who had obvious mesangial cell proliferation testified by renal biopsy into 2 groups according to age, course, clinical manifestations and the pathological lesions. The patients in the control group were given steroid, cyclophosphamide and bennazipril, and the patients in the treated group LMWH (fraxiparin) with the dosage of 60 anti Xa IU.kg-1.day-1 besides the medicine used in the control group. We observed a significant decrease in proteinuria and increase in serum albumin in the treated group compared with those in the control group after 4 weeks of treatment (P < 0.05). The improvement of creatinine clearance in the treated group was significant after 8 and 12 weeks treatment compared with that in the control group (P < 0.05). Our data indicated that LMWH can decrease the proteinuria in the patients who have intraglomerular coagulation and proliferative nephritis with various degrees of sclerosis, and it is helpful to relieve nephrotic syndrome. Because the less risk of hemorrhage, LMWH can be used for long-term treatment to prevent glomerulosclerosis and the process of renal function loss without special mornitoring.


Expression of E-selectin messenger RNA and protein in rheumatoid arthritis.
To examine the de novo synthesis and cellular distribution of the E-selectin adhesion molecule in synovial tissues obtained from patients with rheumatoid arthritis (RA). Immunohistochemistry techniques combined with in situ hybridization were used to examine RA synovium. There were numerous endothelial cells positive for E-selectin and E-selectin messenger RNA in the RA synovial membranes. Moreover, E-selectin expression appeared to correlate with inflammatory activity. The strong vascular expression of E-selectin indicates an activation of endothelial cells in the recruitment of cells associated with the chronic inflammation of RA.


A new method of predicting US and state-level cancer mortality counts for the current calendar year.
Every January for more than 40 years, the American Cancer Society (ACS) has estimated the total number of cancer deaths that are expected to occur in the United States and individual states in the upcoming year. In a collaborative effort to improve the accuracy of the predictions, investigators from the National Cancer Institute and the ACS have developed and tested a new prediction method. The new method was used to create the mortality predictions for the first time in Cancer Statistics, 2004 and Cancer Facts & Figures 2004. The authors present a conceptual overview of the previous ACS method and the new state-space method (SSM), and they review the results of rigorous testing to determine which method provides more accurate predictions of the observed number of cancer deaths from the years 1997 to 1999. The accuracy of the methods was compared using squared deviations (the square of the predicted minus observed values) for each of the cancer sites for which predictions are published as well as for all cancer sites combined. At the national level, the squared deviations were not consistently lower for every cancer site for either method, but the average squared deviations (averaged across cancer sites, years, and sex) was substantially lower for the SSM than for the ACS method. During the period 1997 to 1999, the ACS estimates of deaths were usually greater than the observed numbers for all cancer sites combined and for several major individual cancer sites, probably because the ACS method was less sensitive to recent changes in cancer mortality rates (and associated counts) that occurred for several major cancer sites in the early and mid 1990s. The improved accuracy of the new method was particularly evident for prostate cancer, for which mortality rates changed dramatically in the late 1980s and early 1990s. At the state level, the accuracy of the two methods was comparable. Based on these results, the ACS has elected to use the new method for the annual prediction of the number of cancer deaths at the national and state levels.


N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor.
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. AZD0530 displays excellent pharmacokinetic parameters in animal preclinically and in man (t(1/2) = 40 h). AZD0530 is a potent inhibitor of tumor growth in a c-Src-transfected 3T3-fibroblast xenograft model in vivo and led to a significant increase in survival in a highly aggressive, orthotopic model of human pancreatic cancer when dosed orally once daily. AZD0530 is currently undergoing clinical evaluation in man.


Peritoneal dialysis in the critically ill patient.
The use of peritoneal dialysis on an acute basis is increasing each year. Peritoneal dialysis pulls waste products and excess water out of the blood stream and into dialysate solution in the peritoneal cavity. When patients are unstable hemodynamically, have severe cardiovascular disease, already require peritoneal dialysis, or are small children, peritoneal dialysis is the preferred treatment. Patients may be dialyzed using either a cycler or manual peritoneal dialysis. Patients should be monitored carefully for volume status, bowel status, and infection. Potential complications include problems with access, infection, pain, respiratory status, fluid imbalance, and potassium imbalance. Special consideration should be given to nutritional status because critically ill patients often need increased intake. Drug therapy needs modification because excretion of drugs by the kidney is delayed. Patient and family support is important because of decreased ability to understand, anxiety, loss of control, and change in body image. Treatment termination also may be an issue.


The pharmacokinetics of antiviral therapy in paediatric patients.
Effective treatment requires administration of optimal drug dose. In paediatric patients this may be difficult to achieve due to lack of pharmacokinetic studies, administration of small doses, changes in body composition, continuous growth, and development and maturation of organs and systems. This article reviews the factors and misconceptions associated with determining optimal drug dose and route of administration in different paediatric populations. The pharmacokinetics, appropriate doses and preferred routes of administration for aciclovir, ganciclovir, famciclovir, foscarnet and cidofovir, for treating herpesvirus infections in the paediatric population, are discussed.


Comparison of intradermal injection with iontophoresis of abobotulinum toxin A for the treatment of primary axillary hyperhidrosis: a randomized, controlled trial.
Botulinum neurotoxin type A (BTX-A) injection is the treatment of choice for idiopathic axillary hyperhidrosis (IAH) refractory to conventional treatments. This study compared the efficacy of BTX-A injection and iontophoresis for treatment of IAH in a randomized controlled trial. In eleven patients with the diagnosis of IAH, one axilla was randomly treated with injections of 1.5 mL (250 MU) of BTX-A, and the other side was treated with BTX-A administered by iontophoresis. The amount of sweating, skin hydration, transepidermal water loss, pain, and patient satisfaction on both axilla were compared with baseline levels, and also between both sides 1 week, 1 month, and 6 months after treatment. The injection side had significantly less sweat production than the iontophoresis side 1 week, 1 month, and 6 months after treatment (84%, 76%, and 50% vs. 73%, 22%, and 32%, respectively). The response to iontophoresis was more stable than that to injection. Participants' pain perception during the procedure score was significantly less on the iontophoresis side compared with the injection side (15.0 vs. 20.0, p < 0.05). This study has shown that injection is a more effective method for the administration of BTX-A, though iontophoresis can also be considered a non-invasive and painless method in some patients.


Non-high-density lipoprotein cholesterol concentration is associated with the metabolic syndrome among US youth aged 12-19 years.
To test the hypothesis that the concentration of non-high-density lipoprotein cholesterol (non-HDL-C) is associated with the metabolic syndrome (MetS) in youth. Data on children and adolescents aged 12-19 years (n = 2734) from the cross-sectional National Health and Nutrition Examination Survey 1999-2004 were analyzed. Depending on the definition of MetS used, the mean non-HDL-C concentration among youth with MetS ranged from 144.2 to 155.8 mg/dL, compared with 108.8-109.1 mg/dL in those without MetS (all P < .001). The MetS prevalence ranged from 6.9% to 11.7% in youth with a non-HDL-C concentration of 120-144 mg/dL and from 21.5% to 23.4% in those with a concentration ≥ 145 mg/dL-both significantly higher than the prevalence of 1.9%-3.4% in youth with a concentration <120 mg/dL (all P < .001). After adjustment for potential confounders, youth with a non-HDL-C concentration ≥ 120 mg/dL or ≥ 145 mg/dL were about 3 or 4 times more likely to have MetS compared with those with a non-HDL-C <120 mg/dL or <145 mg/dL (all P < .001). Fasting non-HDL-C concentration was strongly associated with MetS in US youth. Our results support the use of non-HDL-C thresholds of 120 mg/dL and 145 mg/dL to indicate borderline and high MetS risk, respectively.


Development and evaluation of a whole virus-based enzyme-linked immunosorbent assay for the detection of human metapneumovirus antibodies in human sera.
To apply serological testing for human metapneumovirus (hMPV) to large-scale sera samples, an enzyme-linked immunosorbent assay (ELISA) was developed in which purified virions were used as the antigen. The ELISA was evaluated using 102 human sera specimens from patients aged 0-59 years. There was a positive association between the ELISA results and neutralization test titers, with the correlation coefficients being greater in children <6 years old (rho=0.899, P<0.0001), which is consistent with a primary infection, than in persons >or=6 years old (rho=0.523, P<0.0001). Fifty sera samples were subjected to radioimmunoprecipitation to measure the quantity of antibodies to the fusion protein (RIP-F) and the nucleoprotein (RIP-N). The results showed significant associations between the ELISA titers and the amount of RIP-F as determined by radioimmunoprecipitation in children <6 years old (rho=0.804, P=0.0083) and in persons >or=6 years old (rho=0.577, P=0.0009). The correlation between the ELISA titer and the amount of RIP-N determined by radioimmunoprecipitation was not significant in persons >or=6 years old (rho=0.417, P=0.0829), although this correlation was significant in children <6 years old (rho=0.764, P=0.0137). The ELISA titer correlated with the amount of antibodies to the F protein, but not to the N protein. This whole virus-based ELISA will be useful for the diagnosis of hMPV infection in clinical laboratories and is also useful for the large-scale investigations, such as seroprevalence among residents of a particular region.


Modularity in rehabilitation of working memory: a single-case study.
The objective of the present study was to assess the specificity of rehabilitation on different subdomains of working memory. A 38-year-old female with chronic (4 years) stroke suffered from an impairment of the three subdomains of working memory (modality-specific storage systems for verbal and visuo-spatial information and the central executive). She was given an experimental rehabilitation programme, using a multiple-baseline across behaviour design. After two baseline measures three months apart, the first training stage focused on the phonological loop, the second on the visuo-spatial sketchpad, and the third on central executive functions. Verbal aspects of working memory improved significantly after the first training stage, while visuo-spatial tests improved after the second training stage. Central executive functions improved mainly after the third training stage. Modularity effects were not as pronounced for less specific ecological outcome measures, such as the Working Memory Questionnaire, which improved throughout the trial, irrespective of the training condition. This case study suggests that there are both domain-specific and generalisation effects in rehabilitation of working memory, and that rehabilitation should be adapted and tailored to each individual patient's impairments.


Potential impact of self-perceived prodromal symptoms on the early diagnosis of Parkinson's disease.
The detection of Parkinson's disease (PD) at stages earlier than current diagnostic criteria allow for may increase the efficacy of disease-modifying therapies. Here we studied the relationship between retrospectively reported prodromal non-motor and motor features of PD, their pre-diagnostic presentation to physicians, and the extrapolated potential of an earlier diagnosis of PD considering early diagnostic markers detected at presence. One hundred and fifteen PD patients (41 women; age 63.2 ± 8.6 years) underwent a structured face-to-face interview on 22 prediagnostic symptoms. Present olfactory function, motor symptoms, and substantia nigra hyperechogenicity (SN-h) were assessed using standardized tools. Most frequently self-perceived symptoms in the early and very early prediagnostic phase (>2, >7 years prior to diagnosis) were hyposmia (23, 10 %), musculoskeletal pain (21, 9 %), and depression/anxiety (14, 11 %). In the late prediagnostic phase (≤ 2 years) mild motor signs, especially asymmetric bradykinesia and rest tremor, increasingly dominated the self-perception. In the prediagnostic phase, 99 % of patients consulted a physician because of motor symptoms but only 36 % with non-motor symptoms, mostly pain (20 %), depression/anxiety (9 %), constipation, bladder urgency, insomnia, REM sleep behaviour disorder, sexual dysfunction, and malignant melanoma (each, <6 %). Assuming the potential detectability of present hyposmia, asymmetric motor slowing and SN-h, a triad highly specific for PD, as early as 5 years prior to diagnosis, up to 84 (73 %) patients could have been identified in the prediagnostic phase using their or their physicians' awareness of early symptoms. We conclude that educating the general population and physicians on the importance of distinct prodromal features and applying symptom-specific diagnostic programs can improve the early detection of PD.


[Regularities of hemopoietic development in bone marrow erythroblastic islands during early ontogenesis].
Erythroblastic islands (EIs) of the bone marrow are multicellular associations of erythroid and macrophage cells. EIs serve as morpho-functional units of erythropoiesis. Erythropoiesis was studied in the rat liver, spleen, and bone marrow on days 1, 3, 7, 10, 15, and 30 after birth. Changes in the number of EIs and in their composition were simultaneously examined. After birth, erythropoiesis was shown to decrease in the liver and spleen, but it became more active in the bone marrow. There were islands of nondifferentiated hemopoietic cells on day 1 after birth, mixed hemopoietic islands on day 3, and a drastic increase in bone marrow EIs on day 7. On day 30, the levels of EIs were the same as in adult rats. There was a close relationship between the number of EIs and that of erythroid cells in the bone marrow, as well as the count of red blood cells. The age-specific dynamics of quantitative and qualitative changes in EIs and erythropoiesis is presented.


[Toxicology of tobacco].
Tobacco is one of the major toxic agents in our civilization. The extent and severity of the current smoking epidemics are due to the use of industrial cigarettes: their smoke, less irritant than that of cigars and pipe, can be inhaled intensively with rapid absorption of all toxic compounds. Tobacco smoke is composed of a gas phase (CO2, CO, CNH, etc.) and a particle phase (a very fine aerosol) in which more than 4000 substances have been identified. The main toxic compounds in tobacco are Co, nicotine and tars. CO binds to haemoglobin to form COHb, a major factor of hypoxia and vascular accidents. Within a few seconds, nicotine reaches the brain where it binds to specific receptors, which explains its psycho-active effects (psychological dependence) and the induction of physical dependence. This dual dependence is responsible for the failures and relapses observed in attempted withdrawals. Furthermore, nicotine stimulates the sympathetic system with hypersecretion of catecholamines resulting in vascular complications. Tars contain carcinogenic substances, such as aromatic hydrocarbons, which exert local effects on the respiratory tract and systemic effects since they are absorbed by the lungs; this explains the remote neoplasias such as cancer of the bladder. Tars also contain irritant agents (acrolein, formaldehyde, etc.) and oxidative substances responsible for chronic bronchitis and emphysema. Thus, all organs and tissues can be damaged by the toxic compounds that are present in tobacco and, in particular, in tobacco smoke.


[A case of squamous cell carcinoma of the lung associated with acanthosis nigricans and solitary bronchial papilloma].
A 58-year-old man diagnosed as having acanthosis nigricans symmetrically distributed on the face, neck, hands, navel and external genitals, was admitted to our department for further investigation of abnormal chest films. Bronchoscopy revealed squamous cell carcinoma of left S6 and solitary bronchial papilloma of left S3. After left pneumonectomy, facial hyperpigmentation improved slightly. About half of the reported cases of acanthosis nigricans are accompanied by various kinds of malignant neoplasms, mostly adenocarcinomas of the digestive system. The association with squamous cell carcinoma of the lung in our case appears to be unique. Only 16 cases of solitary bronchial papilloma, including our case which had the smallest diameter of 2 mm, have been reported in Japan. While it is suggested that malignant neoplasms contribute to abnormal epidermal growth such as acanthosis nigricans, a causal relationship between squamous cell carcinoma of the lung and bronchial papilloma cannot be established.


Human hypertrophic scar-like nude mouse model: characterization of the molecular and cellular biology of the scar process.
Hypertrophic scar (HTS) following thermal injury and other forms of trauma is a dermal fibroproliferative disorder that leads to considerable morbidity. Because of the lack of an ideal animal model, research is difficult. We have established an HTS model that involves transplanting human split-thickness skin graft (STSG) or full-thickness skin graft (FTSG) onto the backs of nude mice. The animals developed raised, firm, and reddish scars 2 months following transplantation. Histology and micromeasurement indicate raised, thickened engrafted skin with STSG and FTSG. In contrast, thickening was not observed with full-thickness rat skin grafts used as controls. Masson's trichrome staining demonstrates increased accumulations of collagen fibrils in the dermis in both scars grafted with STSG and FTSG. Staining cells with toludine blue and an antibody for F4/80 showed an increase in the infiltration of mast cells and macrophages. Quantification of fibrocytes reveals increased fibrocytes. Moreover, STSG grafted skin had significantly more macrophages, mast cells, and fibrocytes than FTSG. Real-time polymerase chain reaction analysis showed significantly elevated mRNA levels for type I collagen, transforming growth factor-β, connective tissue growth factor and heat shock protein 47 in both types of engrafted skin. These data demonstrate that human skin grafted onto nude mice develops red raised and thickened scars having intrinsic properties that closely resemble HTS formation as seen in humans. Interestingly, STSG developed more scar than FTSG. Furthermore, inflammatory cells and bone marrow-derived fibrocytes may play a critical role in HTS development in this animal model.


Spatial discrimination learning of electrocutaneous stimuli.
The present study investigates whether the spatial discrimination of somatosensory stimuli can be improved with training when sets of 1, 2, 3, or 4 simultaneously stimulated electrodes (so called patterns) have to be discriminated. Healthy human subjects were trained over a period of 5 days to discriminate 23 different somatosensory stimulus patterns. Somatosensory stimulation was based on electrical stimuli applied through an array of eight electrodes attached with a cuff to the skin of the left upper arm. Daily sessions consisted of a pretest, a training phase, and a posttest. Pre- and posttests revealed subject's discrimination ability. Performance of a treatment group receiving sensory real training was compared to performance of a control group receiving sham training. Results revealed (1) improvements of discrimination ability in both groups, and (2) a significantly greater discrimination performance throughout the training period in the treatment group as compared to the control group. The present study demonstrates that discrimination of electrocutaneous stimuli can be improved through training. Results illustrate that electrocutaneous stimuli are a possible and easy-to-apply tool for biofeedback settings.


The utility of renal venous renin studies in selection of patients with renal artery stenosis for angioplasty: a retrospective study.
Recent studies of renal artery stenosis (RAS) failed to demonstrate greater benefit from angioplasty in terms of blood pressure (BP) lowering than medical treatment. Not all RAS are haemodynamically significant and identification of patients likely to benefit from angioplasty remains essential. We examined whether performing renal venous renin studies under stringent conditions might predict BP improvement. Patients with at least 60% RAS who underwent renal venous renin measurements in 2008-2013 were identified. Renal venous renin lateralization ratios (RVRRs) were calculated by dividing venous renin from the stenotic kidney with contralateral levels before and after stimulation with enalaprilat or captopril. Benefit was defined as BP less than 140/90 mmHg without medication, 10% decreased mean BP without increased daily defined doses (DDDs) or decreased DDD without a significant increase of mean BP. Twenty-eight patients were treated medically and 42 with angioplasty (median age 60.1 years, 41% male, 29% chronic kidney disease, 50% resistant hypertension). At 11.4 ± 3.3 months, 69% of patients treated with angioplasty had BP benefit compared with 25% with medical treatment (P < 0.001). Logistic regression identified resistant hypertension [odds ratio (OR) 0.18, 95% confidence interval (95% CI) 0.04-0.82, P = 0.03] and baseline DDD (OR 0.69, 95% CI 0.48-0.98, P = 0.04) as being negatively associated, and positive stimulated RVRR (OR 21.6, 95% CI 3.50-133.3, P = 0.001) positively associated with benefit from angioplasty. On multivariate logistic regression, only stimulated RVRR positivity predicted BP benefit (OR 20.5, 95% CI 2.9-145.0, P = 0.003). These findings suggest that a positive stimulated RVRR measured under optimal conditions may help to identify patients with RAS likely to improve from angioplasty.