A prospective study comparing the accuracy of the clinical diagnosis of meniscus tear with magnetic resonance imaging and its effect on clinical outcome.
A prospective, single-blind study of 57 consecutive knees with an initial clinical diagnosis of a torn meniscus was completed to test the hypothesis that a routine preoperative magnetic resonance imaging (MRI) scan could improve accuracy over clinical diagnosis alone. The overall accuracy for the clinical diagnosis of meniscal tear was 80.7% and the corresponding accuracy for MRI was 73.7%. Surgical pathology was found in all knees at arthroscopy. Relying blindly on MRI to determine surgical intervention would have resulted in inappropriate treatment in 35.1% of the knees. A surgeon can safely rely on the clinical diagnosis of meniscal tear alone and will find surgical pathology in almost all cases. Relying on MRI alone without using clinical judgment may lead to inappropriate treatment in a high percentage of cases. Clinical examination alone is at least as accurate as MRI. MRI did not prevent "unnecessary surgery" in any case. MRI should be reserved for confusing or special cases.


Applications of the CuBr vapor laser as an image-brightness amplifier in high-speed photography and photomicrography.
A CuBr vapor laser with an output power of ~1 W has been used as a brightness amplifier, for the first time to our knowledge, in high-speed photography and photomicrography.


Role of the pineal gland in male rats chronically exposed to increased temperature.
The effects of the pineal gland on endocrine function (especially those of the gonads) were investigated in male rats chronically exposed to increased temperature. Weanling male rats were either pinealectomized (Px) or sham-operated (Sh). Following one week of recovery, animals were assigned to either control temperature of 21 +/- 1 degree C (PxC and ShC) or a temperature of 35 +/- 1 degrees C (PxH and ShH). The animals were kept at their respective temperature for at least 30 days. In both groups (PxH and ShH) exposure to increased temperature resulted in a significant reduction in body and hypophysial weights, and in serum LH and testosterone levels as compared with the respective controls (PxC and ShC). Rectal temperature and serum corticosterone were also significantly increased. No changes were found in pineal hydroxyindole-O-methyltransferase activity of sham-operated rats kept in increased temperature (ShH vs. ShC). Pinealectomy alone (PxC vs. ShC) did not alter any of the measured parameters, except for increased pituitary LH content. Increased temperature plus pinealectomy (PxH vs. PxC; and PxH vs. ShH) caused a significant reduction in pituitary LH content and further accentuated (PxH vs. ShH) the diminished serum LH and testosterone levels evoked by exposure to high temperature. The results suggest that in male rats the pineal gland may play a role in moderating the changes in the reproductive processes that are induced by increased temperature.


[Antiplatelet therapy in women: A gender-specificity?]
Women is a fragile and complex substet of patients, under-represented in clinical trials, but experiencing growing cardiovascular events, with higher mortality, delayed presentation, higher bleeding complications and undertreatment with antithrombotic therapies, compared to their male counterparts. Female gender has been associated with enhanced basal platelet reactivity, high residual on-treatment platelet reactivity and various responses to antiplatelet agents. Growing concern on gender-specificity has emerged, including potential difference in women compared with men on the benefits and risks of antiplatelet therapy in primary or secondary prevention and according the antiplatelet agent used. We provide here a review of available data on antiplatelet therapy in women.


Development of indications and results during 10 years of orthotopic liver transplantation.
Liver transplantation has rapidly emerged in recent years from an uncommon experimental procedure, limited to a few centers, to become a major international effort to support patients with advancing and decompensating liver disease. The excellent results which can be achieved with optimal timing and expert clinical management are now no longer in doubt. The greatest emphasis now must be on obtaining suitable high quality donors at the right time to give the patient the best opportunity to make a full and complete recovery.


Inhibitory effect of hexamethylene bisacetamide on replication of human cytomegalovirus.
The effect of hexamethylane bisacetamide (HMBA), a hybrid polar compound, on gene expression and replication of human cytomegalovirus (HCMV) was studied. When HCMV-infected human thyroid papillary carcinoma (TPC-1) and human embryonic lung (HEL) fibroblast cells were maintained with medium containing 2.5 and 5 mM HMBA for 10 days, there was a greater than 2- to 3-log reduction in virus yield compared to that in untreated cells. Infection of TPC-1 cells with HCMV resulted in an establishment of persistent infection and the cells continuously produced virus with titer of over 10(5) PFU/ml, whereas HMBA prevented the infected cells from entering into the persistent infection. Moreover, treatment of the persistently infected cultures with HMBA reduced production of infectious HCMV more efficiently than did ganciclovir, and eventually ceased HCMV production. Western blotting analysis revealed that HMBA blocks accumulation of the immediate early 2 (IE2) protein in TPC-1 cells and delays synthesis of this protein in HEL cells, but has little effect on the level of the IE1 protein during the early times after infection. Synthesis of the viral early and late proteins in both cells was also substantially blocked by HMBA. The results indicate that the inhibition or the delay of the critical IE2 protein synthesis in the presence of HMBA would actually be a process that fails to proceed beyond the IE stages in HCMV replication cycle.


Cytologic diagnosis of atypical squamous cells of undetermined significance in perimenopausal and postmenopausal women: lessons learned from human Papillomavirus DNA testing.
The authors have noted that in cervical cytology specimens from perimenopausal and postmenopausal women, the diagnosis of atypical squamous cells of undetermined significance (ASC-US), as defined in the Bethesda system, is often not associated with a clinically evident lesion on follow-up. Reflex human papillomavirus (HPV) testing provides an opportunity to distinguish cytologic features of significance from those within the spectrum of benign cellular change in this age group. Liquid-based preparations that were diagnosed as ASC-US between January 2003 and July 2005 at Emory University Hospital were identified from the computer files. The results of HPV-DNA testing were recorded. Two hundred four Papanicolaou tests from perimenopausal women (n = 81, 40-49 years) and postmenopausal women (n = 123, >50 years) were reviewed in a blinded fashion. HPV-DNA results were available for 903 of 1044 patients diagnosed as ASC-US. Overall, 323 results (35.8%) were positive, 510 results (56.6%) were negative, and 70 results (7.8%) were indeterminate. In addition, 73% of ASC-US specimens in patients aged > or =40 years were negative for HPV DNA. The HPV-DNA detection rate dropped from 60% in the group ages 10 to 19 years to approximately 18% in the group aged >50 years. A review of HPV-negative cases in the group aged >40 years showed squamous cells with random nuclear enlargement and slight hyperchromasia that likely were interpreted as ASC-US (based on the cells that were dotted by the original reviewer). Nuclear grooves were frequent in these nuclei; and cytoplasmic halos, when present, usually were perinuclear. HPV-DNA detection in cervical cytology specimens has an inverse relation to patient age. A diagnosis of ASC-US in perimenopausal and postmenopausal women is likely to result in a negative HPV-DNA test in a significant proportion of patients. Enlarged nuclei with nuclear grooves and slight hyperchromasia are possibly the cause of ASC-US overdiagnosis in this age group.


On the Bending and Stretching of Liquid Metal Receive Coils for Magnetic Resonance Imaging.
The eGaIn coil on neoprene demonstrated in this paper presents a stretchable radio frequency receive coil for magnetic resonance imaging (MRI). The coil with dimensions [Formula: see text] is tuned to resonate at 128 MHz for 3 T MRI. We investigate the effect of stretching (up to 40% strain) and bending (50 mm radius of curvature) of the coil on the coil's resistance and resonance frequency. Measurements and simulations show a decrease in resonance frequency of 2.5 MHz per 10% strain. The higher resistivity of liquid metal compared to copper reduces the SNR of MRI scans by 34%; therefore, a tradeoff between flexibility and performance remains. Nevertheless, we have successfully performed MRI scans with the liquid metal coil.


CRISPR/Cas9-mediated genome editing of splicing mutation causing congenital hearing loss.
Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has ushered in a new era of gene therapy. In this study, we aimed to demonstrate precise CRISPR/Cas9-mediated genome editing of the splicing mutation c.919-2A > G in intron 7 of the SLC26A4 gene, which is the second most common causative gene of congenital hearing loss. We designed candidate single-guide RNAs (sgRNAs) aimed to direct the targeting of Staphylococcus aureus Cas9 to either exon 7 or exon 8 of SLC26A4. Several of the designed sgRNAs showed targeting activity, with average indel efficiencies ranging from approximately 14% to 25%. The usage of dual sgRNAs delivered both into Neuro2a cells and primary mouse embryonic fibroblasts resulted in the successful removal of large genomic fragments within the target locus. We subsequently evaluated genome editing in the presence of artificial donor templates to induce precise target modification via homology-directed repair. Using this approach, two different donor plasmids successfully introduced silent mutations within the c.919-2A region of Slc26a4 without evident off-target activities. Overall, these results indicate that CRISPR/Cas9-mediated correction of mutations in the Slc26a4 gene is a feasible therapeutic option for restoration of hearing loss.


Comparison of 980- and 1064-nm wavelengths for interstitial laser thermotherapy of the liver.
Interstitial laser thermotherapy (ILT) of liver tumors is generally performed using neodyium yttrium-aluminium-garnet (Nd-YAG) lasers. More versatile diode units, developed predominantly for other clinical applications, may be equally suitable for ILT. This study compares the efficacy of diode and Nd-YAG lasers in achieving maximum tissue necrosis, at low power, in a murine model. Thermal ablation was induced in the liver of CBA strain mice by diode (980-nm wavelength) and Nd-YAG (1064-nm wavelength) lasers using 400-microm diameter bare fibers. Treatment time prior to tissue charring was determined for both lasers at a power output of 2 W. Tissue temperature was recorded upon completion of therapy 3 mm from the fiber insertion site. The maximum diameter of necrosis was accurately assessed by nicotinamide adenine dinucleotide (NADH) diaphorase tissue staining. Maximum diameter of tissue necrosis prior to charring occurred at 20 s (40 J) with the diode laser compared to 50 s (100 J) with the Nd-YAG laser. The maximum diameter of necrosis (mean [SEM]) produced by the diode laser, 5.9 mm (0.14), was equivalent to the necrosis induced by the Nd-YAG laser, 5.9 mm (0.14) (p = 0.963). Tissue temperature 3 mm from the fiber application site immediately following ILT in the diode laser group, 40.8 degrees C (0.93), was not statistically different than that of the Nd-YAG laser group, 39.0 degrees C (0.86) (p = 0.452). Tissue charring consistently prevented treatment beyond 20 s at 2W by the diode laser. Low power ILT with diode and Nd-YAG lasers achieves equivalent maximal necrosis when applied to the liver by a bare fiber. Treatment time to produce maximal necrosis is however significantly shorter with the diode laser.


Emergence of West Nile virus lineage 2 belonging to the Eastern European subclade, Greece.
West Nile virus (WNV) emerged in Greece in 2010 and since then human outbreaks occurred every year except 2015 and 2016. An early start and prolonged WNV transmission season was observed in 2018 with a record number of 316 reported cases and 47 fatalities. The Greek WNV strains detected during 2010-2018 clustered within the central European subclade of lineage 2. A novel WNV genetic variant was detected in August 2018 in one human case in the north-eastern region of Greece, at the land cross-border with Turkey and Bulgaria. The strain belongs to the Eastern European subclade of lineage 2 suggesting a new virus introduction in the country and the continuously changing epidemiology of the disease.


Exploration of Phytoconstituents from Mussaenda roxburghii and Studies of Their Antibiofilm Effect.
In the context of ethno botanical importance with no phytochemical investigations, Mussaenda roxburghii have been investigated to explore it's phytoconstituents and studies of their antibiofilm activity. Four compounds have been isolated from the aerial parts of this plant and were characterized as 2α,3β,19α,23-tetrahydroxyurs-12-en-28-oic acid (1), β-sitosterol glucoside (4), lupeol palmitate (5), and myoinositol (6). All these compounds were tested for antibacterial and antibiofilm activity against Pseudomonas aeruginosa. Compound 1 exhibited three times more antibiofilm activity with minimum inhibitory concentration (MIC) at 0.74 mm compared to that of streptomycin. Molecular docking studies exhibited a very high binding affinity of 1 with P. aeruginosa quorum sensing proteins and motility associated proteins viz. LasR and PilB, PilY1, PilT, respectively. Compound 1 was also found to be non-cytotoxic against sheep RBC and murine peritoneal macrophages at selected sub-MIC doses.


Combined therapy in the treatment of auricular keloids.
Management of earlobe keloids is still controversial. Many different treatment modalities have been employed; however, no single approach has been completely successful. We used combination therapy that included compression therapy, laser excision, and serial steroid injection, which has improved our therapeutic outcomes for earlobe keloids.


Intrinsic motivation towards sports in Singaporean students: the role of sport ability beliefs.
This study investigated determinants of active lifestyles in Singaporean university students. Using confirmatory factor analysis, a measure of lay beliefs concerning athletic ability was confirmed. Other results confirmed hypotheses that beliefs reflecting that athletic ability can be developed over time (incremental beliefs) predict an achievement task (self-referenced) orientation, while beliefs reflecting that athletic ability is relatively stable (entity beliefs) predict an ego (other-person, comparative) orientation. Goal orientations directly affect perceived competence which, in turn, influence intrinsic motivation to be physically active. A task orientation had a direct link to intrinsic motivation. Results suggest that intrinsic motivation towards sport and physical activity might be enhanced through interventions that focus on self-referenced and self-improvement notions of ability as well as perceived competence.


Percutaneous radiofrequency ablation of renal tumors: technique, complications, and outcomes.
To report the safety, technical success, and effectiveness of percutaneous radiofrequency (RF) ablation for renal tumors. The authors retrospectively reviewed the medical records and imaging studies of 29 consecutive patients (18 men, 11 women; mean age, 65 +/- 2.62 years) with 30 renal tumors (mean diameter, 3.5 +/- 0.24 cm) who underwent percutaneous RF ablation at their institution from September 2001 to March 2004. All procedures were performed with computed tomography guidance with general anesthesia, and all patients were admitted to the hospital for overnight observation. Technical success, complications, and their management were recorded. Technique effectiveness was assessed by imaging and clinical follow up. Overall, 88 overlapping ablations were performed (mean, 2.6 +/- 0.16 ablations per tumor per session) in 34 sessions. There were four major complications (12%). Three patients had gross hematuria and urinary obstruction, all were successfully treated. One patient had persistent anterior abdominal wall weakness. There were also two minor complications (6%) without significant clinical sequelae. One patient had gross hematuria which resolved spontaneously, another patient had transient paresthesia of the anterior abdominal wall. There were no significant changes in renal function after RF ablation. The intent of RF ablation was eradication of the primary tumor in 27 patients and treatment of gross hematuria in the other two. Technical success was achieved in all cases. Follow-up images were available for 26 patients. The primary tumor was completely ablated in 23 of 24 patients (96%) in whom eradication of the primary tumor was attempted (follow up period: mean, 10 months, median 7 months). The two patients treated for hematuria remained asymptomatic for 6 and 27 months each. Percutaneous RF ablation for renal tumors is safe and well tolerated. High technical success rates are expected. Early reports of the technique's effectiveness are promising.


Meta-analysis comparing the efficacy and adverse events of biologics and thiopurines for Crohn's Disease after surgery for ulcerative colitis.
Long-term inflammatory complications of IPAA include Crohn's Disease (CD) or "CD-like" (CDL) condition. We performed a meta-analysis to evaluate the efficacy of anti-tumor necrosis factor (anti-TNF) with or without immunomodulator (IM) therapy in this group of patients. Literature databases were searched from inception to October 4, 2017. Further searches using references from papers of interest were conducted and, abstracts from major GI conferences were searched. The primary endpoint was: complete clinical response in the two arms. Out of 9 identified studies 4 were included for quantitative analysis. 48% (84/175) were female and mean age was 30.7 years. There was no significant difference in complete clinical response rates, RR 0.58 (95%CI 0.13-2.54, p = 0.5) or partial clinical response rates of RR 0.98 (95%CI 0.52-1.83, p = 0.94). All patients achieved endoscopic and deep remission in the only study reporting these outcomes comparatively in the two arms. There was a trend towards higher risk of major [RR 3.89, (95%C 0.92-16.45 p = 0.09)], and minor adverse events [RR 3.07 (95%CI 0.7-13.52 p = 0.28)] when using anti-TNF therapy compared to anti-TNF with IM. We found no difference in outcomes with anti-TNF monotherapy compared to concurrent anti-TNF therapy with IM. Additional studies are needed to define the optimal therapy for CD after IPAA.


Effect of fluoroacetate on the inhibitory action of ketone bodies and fatty acids on renal ammoniagenesis.
Renal cortical slices from acidotic dogs (NH4CL) were incubated at pH 7.0 with L-glutamine (1 and 5 mM) or L-glutamate (5 mM) with or without DL-beta-hydroxyburyrate 1 mM, acetoacetate 0.5 mM, as well as oleate, palmitate, octanoate, and crotonate 0.5 mM and in the presence or absence of fluoroacetate 0.05 mM. Fluoroacetate alone increased glutamine or glutamate uptake and ammoniagenesis whereas gluconeogenesis rose only when glutamine 5 mM or glutamate were used. Alanine production also rose by 30% when glutamine but not glutamate was used as substrate in the presence of fluoroacetate. Efficient blocking of the Krebs cycle at the aconitase level by fluoroacetate was evidenced by the release of citrate in the incubation medium and by a slight but significant decrease in oxygen consumption (10-20%). The marked decrease in glutamine uptake, ammoniagenesis, and gluconeogenesis induced by ketone bodies and fatty acids was completely corrected by addition of fluoroacetate. The present studies demonstrate that ketone bodies and fatty acids inhibit renal ammoniagenesis and gluconeogenesis in vitro through their oxidation in the mitochondria. They also suggest that direct transamination of glutamine into alanine (glutaminase II pathway) may be significant when oxidation of pyruvate is inhibited by fluoroacetate.


The nurse-patient relationship as a caring relationship.
Studies regarding healthcare professionals and patient relationships were found to be few in the review completed by this author. Moreover, there are fewer still that analyze the role of nurse professionals as agents in the relationship. The author of this column approaches the nurse-patient relationship from the framework of the general systems theory and shows the need to further study and clarify the function of different elements in the nurse-patient relationship as it occurs in daily practice, and in patients' expectations.


Experimental hut trials of permethrin-impregnated mosquito nets and eave curtains against malaria vectors in Tanzania.
Permethrin impregnated netting was tested against Tanzanian populations of Anopheles arabiensis Patton, An.gambiae Giles and An.funestus Giles in experimental huts fitted with traps to catch samples of the mosquitoes existing during the night. Treated bednets killed some mosquitoes and increased the tendency of survivors to exit during the night. Treated cotton did not perform so well as treated nylon bednets. An impregnated bednet in which holes had been cut, to simulate a torn net, reduced the number of mosquitoes which fed and survived approximately as well as an intact untreated net. Treated curtains around the eaves of experimental huts did not perform so well as bednets but caused considerable reductions in the number of mosquitoes which fed and survived. However, there was no such effect when treated netting was placed around the eaves of a dwelling house. When one child slept under a treated net and another slept outside the net in the same hut, the number of bites on the latter child was less than if neither child had been under a net. Various aspects of the applicability of permethrin impregnated nets on a community basis are discussed.


Antidepressants for depression in medical illness.
To determine whether antidepressants are clinically effective and acceptable for the treatment of depression in people who also have a physical illness. Medline, Cochrane Library Trials Register and Cochrane Depression and Neurosis Group Trials Register were all systematically searched, supplemented by hand searches of two journals and reference searching. All relevant randomised trials comparing any antidepressant drug (as defined in the British National Formulary) with placebo or no treatment, in patients of either sex over 16, who have been diagnosed as depressed by any criterion, and have a specified physical disorder (for example cancer, myocardial infarction). "Functional" disorders where there is no generally agreed physical pathology (e.g. irritable bowel syndrome) were excluded. The main outcome measures are numbers of individuals who recover/improve at the end of the trial and, as a proxy for treatment acceptability, numbers who complete treatment. Data was extracted independently by the reviewers onto data collection forms and differences settled by discussion. 18 studies were included, covering 838 patients with a range of physical diseases (cancer 2, diabetes 1, head injury 1, heart 1, HIV 5, lung 1, multiple sclerosis 1, renal 1, stroke 3, mixed 2). Depression was diagnosed clinically in 3 studies, otherwise by structured interview or checklist. Only 5 studies described how they performed randomisation. 1 study compared drug with no treatment, and the rest with placebo: all of the latter said they were double blind. 6 studies used SSRIs, 3 atypical antidepressants, and the remainder tricyclics. Patients treated with antidepressants were significantly more likely to improve than those given placebo (13 studies, OR 0.37, 95% CI 0.27-0.51) or no treatment (1 study, OR 3.45, 95% CI 11.1-1.10). About 4 patients would need to be treated with antidepressants to produce one recovery from depression which would not have occurred had they been given placebo (NNT 4.2, 95% CI 3.2-6.4). Most antidepressants (tricyclics and SSRIs together, 15 trials ) produced a small but significant increase in dropout (OR 1.66, 95% CI 1.14-2.40. NNH 9.8, 95% CI 5.4-42.9). The "atypical" antidepressant mianserinproduced significantly less dropout than placebo. Only 2 studies used numerical scales designed to measure effects on function and quality of life; in HIV (Karnofsky scale), drug was better than no treatment; in lung disease (Sickness Impact Profile), drug was not significantly different from placebo. Only 7 studies reported looking for changes in the physical disease. Antidepressants produced no change in immune function in HIV relative to placebo (2 studies) or no treatment (1 study). Relative to placebo, antidepressants produced no change in cardiovascular function in heart disease, in respiratory function in lung disease, or in vital signs or laboratory tests in cancer (1 study each). Nortriptyline produced worse control in diabetes. Trends towards tricyclics being more effective than SSRIs, but also more likely to produce dropout were noted, but these are based on non-randomised comparisons between trials. The review provides evidence that antidepressants, significantly more frequently than either placebo or no treament, cause improvement in depression in patients with a wide range of physical diseases. About 4 patients would need to be treated with antidepressants to produce one recovery from depression which would not have occurred had they been given placebo (NNT 4.2, 95% CI 3.2-6.4). Antidepressants seem reasonably acceptable to patients, in that about 10 patients would need to be treated with antidepressants to produce one dropout from treatment which would not have occurred had they been given placebo (NNH 9.8, 95% CI 5.4-42.9). The evidence is consistent across the trials, apart from 2 trials in cancer, where the "atypical" antidepressant mianserin produced significantly less dropout than placebo. Trends towards tricyclics being more effective than SSRIs, but also more likely to produce dropout were noted, but these are based on non-randomised comparisons between trials. Problems with the evidence include most of the trials' use of observers, rather than patients, to decide on improvement, and concentration mainly on symptoms rather than function and quality of life. There is also a possibility of undetected negative trials. Nevertheless, the review provides evidence that use of antidepressants should at least be considered in those with both physical illness and depression. Regarding diagnosis, the existence of a cheap and readily available treatment for depression should encourage detailed assessment of persistent low mood in the physically ill.


Influence of cutting time on brush response: implications for herbivory in linear (transportation) corridors.
An experiment was conducted to determine the influence the time of brush-cutting can have on plant regrowth and attractiveness to herbivores that browse in linear corridors. The influence of cutting time on leaf flush and senescence, shoot morphometry, and biomass was measured for 3 consecutive years after initial brush-cutting. Results indicate that morphological and phenological attributes of three woody deciduous plants were influenced by the timing of brush-cutting for up to 3 years after initial cutting. Brush-cutting generally stimulated plants to produce larger than normal shoots and delay leaf senescence. The degree to which plants were affected, however, varied with the timing of initial cutting and the species in question. Generally, plants cut later in the year resprouted more vigorously and were taller in the third year after cutting but produced less overall biomass than when cut earlier. In the years following brush-cutting, plants cut earlier flushed leaves earlier in the spring but delayed leaf senescence in the fall when compared to uncut controls. Results of these trials suggest that brush-cutting time influences plant response and several plant attributes known to influence plant attractiveness to moose and other herbivores. We therefore recommend that roadside and railside vegetation management plans consider the influence of cutting time on plant regrowth. Such considerations can ensure that brush is cut to reduce the attractiveness of plant regrowth in these linear corridors, reduce the utilization of such brush by herbivores, and, as such, mitigate collision risk between motorists and herbivores such as moose.


[First results of a national hearing screening program in Switzerlans].
A Swiss study group was formed in summer 1998 with the aim of establishing a universal hearing screening programme in newborns following the recommendations of the "European Consensus Statement on Neonatal Hearing Screening" (Milan 1998). The aim of the group was to standardise and to introduce universal hearing screening in all infants born in Switzerland. Starting in June 1999, several hospitals in Switzerland began the screening programme using commercially available equipment for easy and highly automated measurement of transient evoked otoacoustic emissions. Up to March 2000, 6262 children were born in these hospitals and 5656 (90%) underwent neonatal hearing screening. 88 children of the 5656 did not pass the screening test. The measurement of otoacoustic emissions was repeated in a follow-up examination within 6 weeks. If otoacoustic emissions were again absent, evoked auditory brainstem potentials were measured. 48 children were found to have hearing within normal limits at the follow-up examination, 24 children have not been examined yet, 11 children were examined in other clinics or the follow-up examination was refused by the parents. 5 children were found to have bilateral hearing dysfunction and were referred to rehabilitation within the first 6 months of life.


First molecular evidence of Coxiella burnetii infecting ticks in Cuba.
Coxiella burnetii is the causative agent of Q fever. In order to explore the occurrence of C. burnetii in ticks, samples were collected from horses, dogs and humans living in a Cuban occidental community. The species most commonly recovered were Amblyomma mixtum (67%), Rhipicephalus sanguineus s.l. (27%) and Dermacentor nitens (6%). Specific IS1111 PCR and amplicon sequencing allowed the identification of C. burnetii DNA in A. mixtum collected from a domestic horse. These findings, for first time in Cuba, indicate the need for an in-depth assessment of the C. burnetii occurrence in hosts and humans at risk of infection.


[Bilateral cancer of the kidney and cancer of a solitary kidney].
The analysis of a series of 31 cases of bilateral renal cancers and cancers of solitary kidneys revealed the following findings: 1) conservative in situ surgery with clamping of the renal pedicle and dopamine, when it is possible, appears to be by far the most logical and simplest solution (17 cases); 2) ex-vivo surgery with auto-grafting represents an extreme solution (2 cases); 3) cases of technical impossibility, in the absence of distant metastases, require radical nephrectomy followed by dialysis (3 cases); 4) in advanced forms, surgical abstention followed by hormone therapy (8 cases) or highly selective embolisation (1 case) sometimes provides surprising survivals.


Pseuderanthemum palatiferum leaf extract inhibits the proinflammatory cytokines, TNF-α and IL-6 expression in LPS-activated macrophages.
The anti-inflammatory potential and underlying mechanisms of an ethanol extract of Pseuderanthemum palatiferum (EEP) leaves was investigated using LPS-activated macrophages. Our results show EEP produced a concentration-dependent suppression of TNF-α and IL-6 secretion by LPS-activated mouse peritoneal macrophages. EEP also suppressed LPS-induced TNF-α and IL-6 protein and mRNA levels in mouse-derived myeloid cell line RAW264.7. To further elucidate the molecular mechanisms responsible for impaired TNF-α and IL-6 regulation by EEP, the activation of transcription factors, NF-κB, C/EBP, and AP-1, was monitored using electrophoretic mobility shift assays. EEP suppressed LPS-induced NF-κB DNA binding activity within both the TNF-α and IL-6 promoters in RAW264.7 cells with impairment being more pronounced in the IL-6 promoter. In addition, EEP exhibited a concentration-dependent suppression of C/EBP and AP-1 DNA binding activity within the IL-6 promoter. Concordantly, IL-6 luciferase promoter reporter activity was also suppressed by EEP in transiently transfected RAW264.7 cells, upon LPS activation. EEP analysis by GC-MS and HPLC DAD-MSD revealed the presence of β-sitosterol and various polyphenols, respectively, which are known to possess anti-inflammatory activity. Collectively, these results suggest that the anti-inflammatory effects of EEP are mediated, at least in part, by modulating TNF-α and IL-6 expression through impairment of NF-κB, C/EBP, and AP-1 activity.


Vector competence of Simulium oyapockense s.l. and S. incrustatum for Onchocerca volvulus: Implications for ivermectin-based control in the Amazonian focus of human onchocerciasis, a multi-vector-host system.
Although it is now well established that in the Amazonian onchocerciasis focus, straddling between Venezuela and Brazil, the main vectors in the highland (hyperendemic) and lowland (hypoendemic) areas, are respectively Simulium guianense sensu lato Wise and S. oyapockense s.l. Floch and Abonnenc, investigation of the vectorial role of a third anthropophagic species, Simulium incrustatum Lutz has remained inconclusive. Here we compare the vector competence of S. incrustatum with that of S. oyapockense s.l. by conducting, in the Venezuelan part of the focus, a series of feeding experiments designed to analyze their relative: (a) microfilarial intakes when fed upon the same skin load; (b) proportions of microfilariae (mf) surviving damage inflicted by the cibarial armature (present in both species); and (c) infective (L3) larval outputs. Although the ability of S. oyapockense s.l. to ingest mf, for a given microfilaridermia, was markedly higher than that of S. incrustatum, the (density-dependent) proportions of those ingested mf that were damaged by the armature were also consistently higher, with the resulting output of L3 larvae being significantly lower in S. oyapockense s.l. than in S. incrustatum. These results indicate that S. incrustatum plays a more important role in onchocerciasis transmission in the Amazonian focus than previously realized. We discuss the implications of our findings for the control and elimination of onchocerciasis with mass administration of ivermectin in this focus, where the three main anthropophagic species often co-occur.


Transient glucose and amino acid deprivation induces delayed preconditioning in cultured rat cortical neurons.
Several studies have demonstrated that glucose deprivation, combined either with anoxia or with the inhibition of oxidative phosphorylation, leads to the development of ischemic tolerance in neurons. The aim of our experiments was to investigate whether similar effects could be achieved by transient energy deprivation without either anoxia or the inhibition of the electron transfer chain. Preconditioning was carried out by incubating primary rat cortical neuronal cultures for 3, 6 or 9 h in a glucose- and amino acid-free balanced salt solution supplemented with B27 in normoxic conditions. After 24 h, neuronal cultures were exposed to oxygen-glucose deprivation, glutamate or hydrogen peroxide. Cell viability was measured 24 h after the lethal insults. Potential mechanisms that can influence free radical production were also examined. Energy deprivation protected neuronal cells against lethal stimuli (e.g. cell survival after oxygen-glucose deprivation was 33.1 +/- 0.52% in the untreated group and 80.1 +/- 1.27% in the 9-h energy deprivation group), reduced mitochondrial membrane potential, decreased free radical formation, attenuated the intracellular free calcium surge upon glutamate receptor stimulation, and resulted in an elevated level of GSH. Our findings show that transient energy deprivation induces delayed preconditioning and prevents oxidative injuries and neuronal cell death.


Physical therapy management of peripheral vestibular dysfunction: two clinical case reports.
We describe the treatment of two patients with peripheral vestibular dysfunction using a novel, staged exercise program. Response to treatment was documented. The first patient, a 62-year-old woman with unilateral vestibular dysfunction (UVD) and a 6-month history of disequilibrium following herpes zoster oticus resulting in damage to the right inner ear, was treated with an 8-week course of vestibular physical therapy. During the 8 weeks, the patient attended weekly physical therapy sessions and was trained to perform vestibular adaptation exercises on a daily basis at home. The second patient, a 53-year-old woman with progressive disequilibrium secondary to profound bilateral vestibular hypofunction (BVH), was treated with a 16-week course of vestibular physical therapy. During the first 8 weeks, the patient attended weekly physical therapy sessions and was trained to perform vestibular adaptation and substitution exercises on a daily basis at home. During the second 8 weeks, the patient continued performing vestibular physical therapy exercises at home independently. Vestibular function (sinusoidal vertical axis rotation testing), postural control (clinical tests and posturography), stability during the performance of selected activities of daily living (ADLs), and self-perception of symptoms and handicap were measured prior to and at the conclusion of treatment for both patients and at the midpoint of treatment for the patient with BVH. After 8 weeks of treatment, both patients reported improvements in self-perception of symptoms and handicap and demonstrated objective improvements in clinical balance tests, posturography, and several kinematic indicators of stability during the performance of selected ADLs. Further improvements were noted in the patient with BVH after 16 weeks of treatment. Improvements in postural control were noted after 8 weeks of treatment for the patient with UVD and after 16 weeks for the patient with BVH. Vestibular function improved during the course of treatment for the patient with UVD only. These case reports describe two different individualized treatment programs and document self-reported and laboratory-measured functional improvements in two patients with vestibular deficients--one with unilateral damage and one with bilateral damage.


Pressure-Induced Emission Enhancement of Carbazole: The Restriction of Intramolecular Vibration.
Pressure-induced emission enhancement (PIEE), a novel phenomenon in the enhancement of the solid-state emission efficiency of fluorophores, has been arousing wide attention in recent years. However, research on PIEE is still in the early stage. To further pursue more enhanced efficiency, discovering and designing more PIEE systems would be urgently desirable and of great importance. In this Letter, we found that carbazole presented a conspicuous emission enhancement under high pressure up to 1.0 GPa. In situ high-pressure infrared spectroscopy and angle-dispersive X-ray diffraction analysis combined with Hirshfeld surface theory calculation indicated that the PIEE of carbazole was attributed to the decrease of the nonradiation vibration process. This phenomenon mainly resulted from restriction of the N-H stretching vibration by increased N-H···π interactions under high pressure. Our study puts forward a mechanism of PIEE related to the restriction of intramolecular vibration, which provided deep insight into the essential role of intermolecular interaction in fluorescence emission properties.


Enzymatic conversion of all-trans-beta-carotene to retinal.
Enzymatic conversion of all-trans-beta-carotene to retinal by a partially purified enzyme from rabbit, rat, and human neonatal intestinal mucosa has been demonstrated. The enzymatic product was characterized based on the following evidence. First, the product gave rise to its O-ethyl oxime by treatment with O-ethylhydroxylamine with an absorption maximum at 363 nm in ethanol characteristic of authentic retinal (O-ethyl) oxime. High-performance liquid chromatography of this derivative yielded a sharp peak with a retention time of 7.99 min, corresponding to the authentic compound. The enzyme blank and boiled enzyme blank failed to show any significant HPLC peaks corresponding to retinal (O-ethyl) oxime or retinal or retinol. Second, the mass spectrum of the O-ethyl oxime of the enzymatic product was identical to that of authentic retinal (O-ethyl) oxime (m/z 327, 45%; m+ and m/z 282, 100%, methoxy). Third, the 14C radioactivity persisted to constant specific activity even after repeated crystallization of the retinal (O-ethyl) oxime isolated from the enzyme reaction with purified beta-[14C]carotene. Fourth, the enzymatic product exhibited an absorption maximum at 370 nm in light petroleum characteristic of authentic retinal. Furthermore, it was reduced by horse liver alcohol dehydrogenase to retinol with an absorption maximum at 326 nm in light petroleum. This retinol was enzymatically esterified to retinyl palmitate by rat pancreatic esterase with a retention time of 10 min on HPLC, corresponding to authentic retinyl palmitate. Thus, the enzymatic product of beta-carotene cleavage by the partially purified intestinal enzyme has been unequivocally confirmed to be retinal. Similarly, enzymatic conversion of all-trans-beta-carotene to retinal by an intestinal mucosal enzyme from autopsy samples of human neonates has also been demonstrated. Based on the observed activities among intestinal samples from 12 premature infants, the BCC enzyme activity ranged from 3.3 to 1210 pmol/mg mucosal protein/hr. However, the observed activities in the human autopsy samples may be markedly underestimated, presumably because of marked loss of enzyme activity from the time of death to the time of assay. Therefore, the true activity of the enzyme can be assessed only after the extent of the loss of its activity on storage of the human samples can be accurately measured. Nonetheless, the demonstration of BCC enzyme activity in human neonates shows that beta-carotene may be an important source of vitamin A nutrition during gestation.


Functional interplay between intrinsic B and T cell defects leads to amplification of autoimmune disease in New Zealand black chromosome 1 congenic mice.
Genetic loci on New Zealand Black (NZB) chromosome 1 play an important role in the development of lupus-like autoimmune disease. We have shown previously that C57BL/6 mice with an introgressed NZB chromosome 1 interval extending from approximately 35 to 106 cM have significantly more severe autoimmunity than mice with a shorter interval extending from approximately 82 to 106 cM. Comparison of the cellular phenotype in these mice revealed that both mouse strains had evidence of increased T cell activation; however, activation was more pronounced in mice with the longer interval. Mice with the longer interval also had increased B cell activation, leading us to hypothesize that there were at least two independent lupus susceptibility loci on chromosome 1. In this study, we have used mixed hemopoietic radiation chimeras to demonstrate that autoimmunity in these mice arises from intrinsic B and T cell functional defects. We further show that a T cell defect, localized to the shorter interval, leads to spontaneous activation of T cells specific for nucleosome histone components. Despite activation of self-reactive T cells in mixed chimeric mice, only chromosome 1 congenic B cells produce anti-nuclear Abs and undergo class switching, indicating impaired B cell tolerance mechanisms. In mice with the longer chromosome 1 interval, an additional susceptibility locus exacerbates autoimmune disease by producing a positive feedback loop between T and B cell activation. Thus, T and B cell defects act in concert to produce and amplify the autoimmune phenotype.


Optimization, characterization, and biological activity of polysaccharides from Berberis dasystachya Maxim.
In this study, the extraction of water-soluble polysaccharides (BDPs) from Berberis dasystachya Maxim using dynamic microwave-assisted extraction (DMAE) was discussed. A Box-Behnken design combined with response surface methodology has been employed to optimize extraction parameters of DMAE. The BDPs have been analyzed in order to identify a variety of chemical properties. Antioxidant and anti-tumor activities in vitro have been studied by DPPH, ABTS, reducing power assay, and MTT assay, respectively. The results obtained showed that the optimal extraction conditions were as follows: ratio of water to raw material (X1) 25.84 mg/L, extraction power (X2) 433.13W, extraction time (X3) 35.18 min, and the maximum yield of extraction was 6.472 ± 0.384%, which was in good agreement with the predicted value. The physicochemical tests demonstrated that the BDPs mainly consist of rhamnose, arabinose, xylose, mannose, glucose and lactose in a molar ratio of 1:17.3:1.33:7:2.33:1.78; the average molecular weight of the BDPs was estimated to be from 2.95×10(5) and 1.52×10(3)Da, respectively. Furthermore, the BDPs exhibited effective antioxidant and anti-proliferative properties in vitro. Such pharmaceutical activities could prove useful for potential future applications involving the berries of B. dasystachya Maxim.


Role of photodynamic therapy and intraductal radiofrequency ablation in cholangiocarcinoma.
Cholangiocarcinoma comprises 3% of all gastrointestinal malignancies. Prognosis is poor as the disease is locally advanced at the time of its presentation. Biliary endoprosthesis are widely used for biliary decompression, however, they only provides temporary relief. Photodynamic therapy and Radiofrequency ablation are two innovative approaches performed endoscopically to locally destruct the malignant tissue. This chapter focuses on their application and appropriate use along with their benefits and complications.


Time-resolved diffuse reflectance using small source-detector separation and fast single-photon gating.
We demonstrate the feasibility of time-resolved diffuse reflectance measurements at small source-detector separations using a single-photon avalanche diode operated in time-gated mode. Photon time distributions at an interfiber distance of 2 mm were obtained on a homogeneous tissue phantom with a dynamic range of 10(6) and collecting photons at arrival times up to 4 ns. Moreover, we were able to detect a local inhomogeneity deeply buried within a diffusive medium with better spatial resolution, higher signal intensity, and same contrast of a larger (20 mm) interfiber distance. Finally, the proposed approach proved valuable to detect in vivo a task-related brain activation.


Accuracy of SenseWear Pro2 Armband to predict resting energy expenditure in childhood obesity.
The accuracy of the SenseWear Pro2 Armband (SWA) in estimating resting energy expenditure (REE) in children and adolescents with obesity, using indirect calorimetry (IC) as a reference was evaluated. REE was assessed using both the SWA and IC in 40 obese subjects (26 M/14 F, age 11.5 ± 2.57 years, z-score BMI 3.14 ± 0.53). The agreement between methods was assessed by the Bland-Altman procedure. The relationship between REE assessments and patients' characteristics was also analyzed. SWA- and IC-derived estimates of REE showed a significant correlation (r = 0.614; P < 0.001), but the SWA overestimated mean REE by 13% (P < 0.001). Age and kilogram of fat-free mass (kg-FFM) were significantly correlated with both REE estimation by SWA (r = 0.434 and r = 0.564, respectively) and IC (r = 0.401 and r = 0.518, respectively). Only kg-FFM was demonstrated to be the main predictor factor of REE variability (r(2) 79% SWA; 75% IC). The SWA overestimated mean REE in childhood obesity, suggesting that the SWA and IC are not yet interchangeable methods. This would require improving the SWA by developing better algorithms for predicting REE and, probably, bias in each individual REE could be reduced by an adjustment for subjects' kg-FFM.


Factors underlying anxiety in HIV testing: risk perceptions, stigma, and the patient-provider power dynamic.
Client anxiety is often associated with diagnostic testing. In this study, the authors used a grounded theory approach to examine the situational and social factors underlying anxiety associated with HIV testing, analyzing transcripts from semistructured interviews with 39 HIV test recipients in Ontario, Canada (selected based on HIV serostatus, risk experience, geographic region, gender, and number of HIV tests), then integrating emergent themes with existing research literature. Analysis revealed four themes: perceptions of risk and responsibility for health, stigma associated with HIV, the patient-provider power dynamic, and techniques used by test recipients to enhance control in their interactions with providers. Service implications include modifications to information provision during the test session, attention to privacy and anonymity, and sensitivity to patient-provider interactions.


Influence of voltage rise time on operation frequency in magnetically insulated transmission line oscillator.
In the experiments of a magnetically insulated transmission line oscillator (MILO), the initiatory microwave frequency is slightly higher than the stable microwave frequency. This paper investigates the influence of the front edge of the voltage on microwave frequency. The theoretical analysis shows that the MILO operates at the 2π mode in the initiatory stage; therefore, the microwave frequency is determined by the single slow wave structure (SWS) cavity. During the stable operation, the MILO works at the π mode and the microwave frequency is decided by the structure parameters of the resonant cavity chain. It is a fact that the resonant frequency of a single SWS cavity is higher than that of the resonant cavity chain, so the reason why the initiatory microwave frequency is slightly higher than the stable microwave frequency can be explained. The simulation results agree with the theoretical results.


Thermal heterogeneity mediates the effects of pulsed subsidies across a landscape.
Spatial and temporal heterogeneity interact to make the foraging rates of individuals more variable than expected from models assuming that spatial and temporal dimensions of habitat conditions operate independently. For example, trophic resource pulses produce temporal patches of prey superabundance, yet little is known about how spatial heterogeneity in habitat conditions mediates the ability of consumers to exploit these high-quality foraging opportunities. We studied how spatial variation in water temperature regulates the potential for juvenile coho salmon to exploit a seasonal pulsed subsidy of eggs produced by anadromous sockeye salmon. Streams within the Wood River watershed, southwestern Alaska, USA, ranged in mean summer temperature from 3.6 degrees to 14.5 degrees C. Growth of juvenile coho prior to the arrival of the seasonal egg subsidy was positively related to water temperature among streams. An in situ experiment combined with field samples of diets revealed a size threshold for egg consumption; only individuals longer than approximately 70 mm could consume eggs due to gape limitation of smaller individuals. A bioenergetics simulation demonstrated that water temperature regulated whether age-0 coho salmon could grow large enough to exceed the size threshold for egg consumption. Coho salmon that consumed eggs had energy rations that were five times higher than fish that did not consume eggs, resulting in a positive feedback of water temperature on their integrated seasonal growth. Across this landscape, heterogeneity in water temperature mediates individual- and population-level responses to seasonally available resource pulses. Our study illustrates that ecological mechanisms, such as size-based foraging asymmetries, can magnify the effects of climate change compared to predictions based on physiology alone.


Zonal rotor purification and characterization of "mannosomes": a tubular membrane system in gastropod mollusc digestive gland.
Mannitol oxidase (manox) is an H2O2-generating oxidase apparently unique to molluscs and especially abundant in alimentary tissues. In the digestive gland it is localized to an organelle ("mannosome") that forms an unusual tubular membrane system. We have developed a novel centrifugation procedure for >100-fold purification of these membranes in 20% yield from approximately 30 g of digestive gland of the slug Arion ater. Mannosomes from several other gastropod species are also substantially purified by the procedure. Four successive density gradient separations are employed which minimize structural damage by exploiting near isosmotic conditions early on and by completely avoiding traumatic pelleting and resuspension. Plasma membrane contamination is reduced by digitonin-induced density perturbation. The purified preparation is characterized by a predominant 68-kDa integral membrane protein and retains the in situ appearance of hexagonally arranged tubules with an enveloping outer membrane.


[Serum cytokine levels in children with newly diagnosed active systemic juvenile idiopathic arthritis].
To study the changes in serum cytokines levels in children with newly diagnosed active systemic juvenile idiopathic arthritis (SJIA) and to explore the role of cytokines in the development and progression of SJIA. Seventy-four pediatric patients with active SJIA between January 2010 and December 2013 were included in the study. Serum levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukine-10 (IL-10), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) were measured by flow cytometry in these patients. The levels of cytokines were also determined in 202 healthy children as the control group. Routine laboratory parameters including white blood cell (WBC) count, percentage of neutrophils, hemoglobin level, platelet count, hypersensitive C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR) were monitored in the patient group. The WBC count, percentage of neutrophils, hs-CRP, and ESR in 74 cases of SJIA were significantly above the normal range, their platelet counts were within the normal range, whereas hemoglobin levels were below the normal range. Compared with the control group, the patient group showed a significantly increased level of IL-6 (P<0.01) and significantly reduced levels of IL-4, IL-10, and TNF (P<0.01). However, there were no significant changes in serum levels of IL-2 and IFN-γ in the patient group (P>0.05). In SJIA children, IL-6 level, which was significantly elevated, was negatively correlated with hemoglobin level, which was significantly reduced (r=-0.244, P<0.05). Serum level of IL-6 is significantly increased in children with SJIA, and it has a negative correlation with anemia.


Variations in the use of cesarean delivery for dystocia: lessons about the source of care.
Aggregate data show variations in the use of cesarean delivery according to the source of care, which suggests that rising cesarean rates are at least in part attributable to nonmedical factors. In the research presented here, the likelihood of cesarean delivery is examined for low-risk, primiparous women with physicians who practice in a single hospital but are from three practice organizations--a health maintenance organization (HMO), private practice, and a hospital clinic--while controlling for a wide spectrum of clinical factors. Maternal age was found to be a dominant factor in determining the decision for a cesarean delivery, independent of clinical risk and physicians' practice organization. Only among women in their optimal childbearing years (25 to 29 years) was having an HMO physician associated with a lower likelihood of cesarean delivery. The authors conclude that lowering the primary cesarean rate in the 1990's may require more reeducation and clinical policy formulation, with particular attention being paid to maternal age, and less reorganization of services than the aggregate data suggests.


Sphenoid wing meningioma causing a proptosis in a child. Case report.
A sphenoid wing meningioma causing a progressive painless proptosis is reported in a 5-year-old boy. The diagnostic evaluation and surgical management of this case are reported. A review of the literature indicates this is the youngest patient with sphenoid wing meningioma.


Expression, purification, and isotope labeling of a gp120 V3 peptide and production of a Fab from a HIV-1 neutralizing antibody for NMR studies.
Most human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies in infected individuals and in immunized animals are directed against the third variable loop (V3) of the envelope glycoprotein (gp120) of the virus. This loop plays a crucial role in phenotypic determination, cytopathicity (syncytium induction), and coreceptor usage of HIV-1. The human monoclonal antibody 447-52D was found to neutralize a broad spectrum of HIV-1 strains. In order to solve the solution structure of the V3MN peptide bound to the 447-52D Fab fragment by NMR, large quantities of labeled peptide and a protocol for the purification of the Fab fragment were needed. An expression plasmid coding for the 23-residue V3 peptide of the HIV-1MN strain (V3MN peptide, YNKRKRIHIGPGRAFYTTKNIIG) linked to a derivative of the RNA-binding domain of hnRNCP1 was constructed. The fusion protein attached to the V3 peptide prevents its degradation. Using this system, U-15N, U-13C,15N, and U-13C,15N, 50% 2H labeled fusion protein molecules were expressed in Escherichia coli grown on rich Celtone medium with yields of about 240 mg/liter. The V3MN peptide was released by CNBr cleavage and purified by RP-HPLC, giving final yields of 6-13 mg/liter. This expression system is generally applicable for biosynthesis of V3-related peptides and was also used to prepare the V3JR-FL. The 447-52D Fab fragment was obtained by a short enzymatic papain cleavage of the whole antibody. Preliminary NMR spectra demonstrate that full structural analysis of the V3MN complexed to the 447-52D Fab is feasible. This system enables studies of the same epitope bound to different HIV-1 neutralizing antibodies.


Biochemical and biological aspects of the plasminogen activation system.
Plasminogen activators (PAs) are specific proteolytic enzymes which convert the inactive proenzyme plasminogen to plasmin. The plasmin formed is a potent and nonspecific protease which cleaves blood fibrin clots and several other extracellular proteins. In addition to their primary role in the initiation of fibrinolysis, PAs are implicated in a variety of basic biological processes, such as, degradation of the extracellular matrix, tumor invasiveness, tissue remodelling, and cellular differentiation. This review describes recent observations on the biochemical and biophysical characteristics of the different components of the plasminogen activation system. This complex system includes: the proenzymes of tissue type PA (tPA) and urokinase type PA (uPA); the active enzymes tPA, uPA and plasmin; the substrate plasminogen; several natural inhibitors of PA and plasmin activity; and the cellular receptors that bind the proenzymes, enzymes, and inhibitor-enzyme complexes. Through the coordinated interactions of these components, the location, timing, and extent of potent proteolytic activity is controlled. Recent findings on the structure, properties, biological functions, and regulation of the different components of the plasminogen activation cascade are reviewed. Current methods for assay of the amount and activity of the enzymes, inhibitors, and receptors are described. Observations implying specific functions of the system in health and disease, and its potential utilization for diagnosis are examined. Specifically, the potential application of PAs as laboratory markers of neoplasia, as diagnostic tools in diseases of the blood clotting system, their use for monitoring of thrombolytic therapy, and their possible relevance in certain disease states are described.


Videodensitometrical study of the alveolar bone crest in periodontal disease.
The relative mineral content per unit volume of bone in the alveolar bone crest was determined in 81 bone crests from 25 human autopsy cases by means of contact microradiography and videodensitometry of 100 microns thick sections. Each bone crest was divided in 4 areas: crestal, mesial, distal, and trabecular; and the relative mineral content was determined for each area. The data were analyzed statistically and it was found that the crestal area had a significantly lower mineral content than the other 3 areas. Histologically, the crestal area had a reduced number of Sharpey's fibers and it was speculated that these features lower the probability of restoring the natural crestal shape and the fiber reattachment, increasing the risk of bone loss. No correlation was found between relative mineral content and age or extent of inflammatory infiltration of the periodontal tissues.


HL-A 27 and ankylosing spondylitis in B.C. Indians.
HL-A antigens were determined in Haida and Bella Coola native Indians, two communities known to have a high prevalence of ankylosing spondylitis. Tests were conducted on those with x-ray evidence of sacroiliitis and on a sample of the community at large. Sacroiliitis was found to prevail in approximately 10% of adult Haida males and in over 2% of Bella Coola adult males. Of 20 Haidas with sacroiliitis. 17 were HL-A 27 positive. Fifty percent of the Haida community at large were HL-A 27 positive. Three Bella Coolas known to have sacroiliitis were all HL-A 27 positive, while 25% of the community sampled at large were HL-A 27 positive. About one in five adult Haida males who were HL-A 27 positive showed evidence of sacroiliitis, a proportion close to that ascertained in Caucasian communities. It would appear, therefore that the risk of disease in HL-A 27 positive Bella Coola males is considerably lower.


Prenatal findings of omphalocele-exstrophy of the bladder-imperforate anus-spinal defects (OEIS) complex.
Omphalocele-exstrophy of the bladder (cloaca)-imperforate anus-spinal defects (OEIS) complex describes a rare grouping of more commonly occurring component malformations. We report two cases of OEIS complex diagnosed prenatally by ultrasound and magnetic resonance imaging (MRI). In both cases, OEIS complex was suspected by conventional sonography in the second trimester, and fetal MRI was performed at 27 and 32 weeks of gestation. Conventional sonography revealed low abdominal wall mass, spina bifida, absent bladder and ambiguous genitalia, but those findings were inconclusive. Using fetal MRI, we were able to detect omphalocele, imfraumbilical mass connected to gut tract, absent bladder, ambiguous external genitalia and spinal defect. Our findings suggest that fetal MRI is a useful tool for prenatal diagnosis of OEIS complex. MRI helps prenatal counseling and planning of postnatal early treatment strategy.


Passive stent coatings in the drug-eluting era.
Advances in coronary stent technology, both in terms of stent design and function, have significantly improved the safety and efficacy of percutaneous coronary intervention, including marked reduction in restenosis. This has led to its use in increasingly challenging clinical and lesional subsets, with potential for increased risk of stent-associated thrombosis. In this article we outline the development of passive stent coatings, and evaluate the ongoing role of such coatings in the contemporary era of antiproliferative drug-eluting stents.


Can a diagnosis be made in retrospect? The case of Desiderius Erasmus.
Review of data in very old charts sometimes brings new insights and perspectives, and suggests new hypothesis for illnesses of patients long deceased. Such applications can be made if enough information is available, e.g., autobiographical letters, skeletal remains, pictorial representations. Finally the process must be discussed in the context of the major disease processes occurring at that time. When such an approach was applied to Erasmus (Rotterdam c 1466--Basle 1536), the differential diagnosis included gout, syphilitic arthritis and enteric rheumatism.


Embryonic donor age and dissection influences striatal graft development and functional integration in a rodent model of Huntington's disease.
The method of embryonic dissection and the age of the donor material remain areas of controversy in the preparation of striatal tissue for intrastriatal implantation. This study explores the relationship between these two parameters with respect to the morphology, function, and physiological integration of the resultant grafts. Tissue derived from embryos of 14 and 16 days of gestation (CRL 10-11 and 14-15 mm, respectively) was prepared as whole, lateral, and medial ganglionic eminence suspensions (WGE, LGE, and MGE, respectively). The embryonic material was implanted into the excitotoxically lesioned striatum of host rats. Grafts derived from E14 LGE attenuated drug-induced rotational bias whereas grafts from E14 MGE ameliorated contralateral deficits in paw reaching. Six months after grafting retrograde tracing of graft projections to the globus pallidus was performed followed by electrical excitation of cortical afferent fibers. Grafts derived from E14 WGE had the largest volume of striatum-like tissue and more striatal neurons compared to LGE from the same donor age. These results suggest that MGE tissue as well as LGE plays a role in the structural and functional integration of striatal grafts.


Effect of phosphatidyl-L-serine and vinculin on actin polymerization.
The effects of phosphatidyl-L-serine (PS) and/or vinculin on actin polymerization are examined by spectrophotometry, viscometry and electrophoresis. Actin polymerization is inhibited by PS alone and stimulated by PS and vinculin. The results suggest that actin does not directly adhere to cell membrane and that vinculin is a protein which is involved in structures connecting actin microfilaments to cell membranes.


Silver enhancement of quantum dots resulting from (1) metabolism of toxic metals in animals and humans, (2) in vivo, in vitro and immersion created zinc-sulphur/zinc-selenium nanocrystals, (3) metal ions liberated from metal implants and particles.
Autometallographic (AMG) silver enhancement is a potent histochemical tool for tracing a variety of metal containing nanocrystals, e.g. pure gold and silver nanoclusters and quantum dots of silver, mercury, bismuth or zinc, with sulphur and/or selenium. These nanocrystals can be created in many different ways, e.g. (1) by manufacturing colloidal gold or silver particles, (2) by treating an organism in vivo with sulphide or selenide ions, (3) as the result of a metabolic decomposition of bismuth-, mercury- or silver-containing macromolecules in cell organelles, or (4) as the end product of histochemical processing of tissue sections. Such nano-sized AMG nanocrystals can then be silver-amplified several times of magnitude by being exposed to an AMG developer, i.e. a normal photographic developer enriched with silver ions. The present monograph attempts to provide a review of the autometallographic silver amplification techniques known today and their use in biology. After achieving a stronghold in histochemistry by Timm's introduction of the "silver-sulphide staining" in 1958, the AMG technique has evolved and expanded into several different areas of research, including immunocytochemistry, tracing of enzymes at LM and EM levels, blot staining, retrograde axonal tracing of zinc-enriched (ZEN) neurons, counterstaining of semithin sections, enhancement of histochemical reaction products, marking of phagocytotic cells, staining of myelin, tracing of gold ions released from gold implants, and visualization of capillaries. General technical comments, protocols for the current AMG methods and a summary of the most significant scientific results obtained by this wide variety of AMG histochemical approaches are included in the present article.


[A commercial available kit for semiquanititative determination of plasmatic and urinary aminoacids by thin layer chromatography (author's transl)].
A commercially available kit (Amino-acid TLC kit-Sibar, Perugia, Italy) for screening of plasma aminoacids inborn errors has been used as routine method for plasma newborn examinations in a mid-size clinical Laboratory. Good results were obtained by this inexpensive and simple kit.


Lipidomic changes in the rat hippocampus following cocaine conditioning, extinction, and reinstatement of drug-seeking.
Cocaine dependence affects millions of individuals worldwide; however, there are no pharmacotherapeutic and/or diagnostic solutions. Recent evidence suggests a role for lipid signaling in the development and maintenance of addiction, highlighting the need to understand how lipid remodeling mediates neuroadaptation after cocaine exposure. This study utilized shotgun lipidomics to assess cocaine-induced lipid remodeling in rats using a novel behavioral regimen that incorporated multiple sessions of extinction training and reinstatement testing. Mass spectrometric imaging demonstrated widespread decreases in phospholipid (PL) abundance throughout the brain, and high-spatial resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry indicated hippocampus-specific PL alterations following cocaine exposure. We analyzed the expression of genes involved in hippocampal lipid metabolism and observed region-specific regulation. In addition, we found that cocaine exposure differentially regulates mitochondrial biogenesis in the brain. This work presents a comprehensive lipidomic assessment of cocaine-induced lipid remodeling in the rat brain. Further, these findings indicate a potential interplay between CNS energetics and differential lipid regulation and suggest a role for cocaine in the maintenance of energy homeostasis.


[Research advance of influenza B viruses].
Influenza B virus (IBV) is a segmented negative-strand RNA virus, which often causes local outbreak or seasonal epidemic along with influenza A virus (IAV) in the world. It is pathogenic to children, teenagers and elderly people and has a higher mortality rate in children and adolescents, so it poses a serious threat to public health and health. IBV is more likely to cause complications than IAV and the disease burden of IBV even exceeds IAV in the epidemic season. Recently, especially after winter of 2017, IBV has become the dominant strain in many areas of our country and seriously affects people's health. In view of this, this article reviews the structure, epidemiology, immunology and prevention of IBV, aiming at enhancing public's perceptions of the virus and providing reference for making strategies for prevention and control of influenza B.


The Association Between Gender Inequality and Sexual Violence in the U.S.
Few societal-level factors are established as risk or protective factors for sexual violence. Traditional gender norms and gender inequality are linked to sexual violence, but much of this research was conducted internationally or is becoming outdated and may not reflect current norms in the U.S. This study expands on previously published research by examining gender inequality's association with state-level sexual violence. Using state-level prevalence estimates published in the National Intimate Partner and Sexual Violence Survey 2010-2012 State Report and the Gender Inequality Index, Pearson correlations were examined to investigate the relationship between state-level gender inequality and lifetime victimization for various types of sexual violence among U.S. female and male adults. The analysis was conducted in 2019. Findings indicate that states with a high degree of gender inequality also report higher prevalence estimates among women for rape using physical force. Gender inequality was also negatively correlated with noncontact unwanted sexual experiences among women and men. In addition, an exploratory analysis of the relationship between individual indicators of gender inequality and violence outcomes suggest that the adolescent birth rate, female government representation, and labor force participation demonstrate an association with certain state-level violence outcomes, although the patterns were inconsistent. Although this study relied on cross-sectional data, collectively, these findings suggest that gender inequality may represent an important societal-level factor associated with sexual violence among women and men. However, this relationship appears complex and requires further research. These findings have potential to inform population-level violence prevention approaches.


Evaluation of an outbreak of West Nile virus infection in horses: 569 cases (2002).
To characterize an outbreak of West Nile virus (WNV) infection in horses in North Dakota in 2002, evaluate vaccine effectiveness, and determine horse characteristics and clinical signs associated with infection. Retrospective study. 569 horses. Data were obtained from veterinary laboratory records, and a questionnaire was mailed to veterinarians of affected horses. Affected horses were defined as horses with typical clinical signs and seroconversion or positive results of virus isolation; affected horses were detected in 52 of the 53 counties and concentrated in the eastern and northeastern regions of the state. Among affected horses, 27% (n = 152) were vaccinated against WNV, 54% (309) were not, and 19% (108) had unknown vaccination status; 61 % (345) recovered, 22% (126) died, and 17% (98) had unknown outcome. The odds of death among nonvaccinated horses were 3 and 16 times the odds among horses that received only 1 or 2 doses of vaccine and horses that were vaccinated according to manufacturer's recommendations, respectively. Horses with recumbency, caudal paresis, and age > 5 years had higher odds of death, whereas horses with incoordination had lower odds of death, compared with affected horses without these characteristics. Vaccination appears to have beneficial effects regarding infection and death caused by WNV.


Motor Performance in South African Children with Cystic Fibrosis.
Aims: This study aimed to investigate motor performance in children with cystic fibrosis (CF) and the relationship with respiratory and anthropometric outcome measures. Methods: A cross-sectional exploratory study investigated 12 children with CF, mean (SD) age 6.17 (0.67) years, using the Movement Assessment Battery for Children 2nd edition (MABC-2), spirometry, body weight, height, body mass index, and age-related anthropomorphic z-scores. Results: MABC-2 total scores indicated 9/12 (75%) children performed below average (<50th percentile), of which 4/12 children (33.3%) had motor delay and 2/12 (16.7%) were at risk for motor delay. The balance subscale showed the lowest scores, with 5/12 (41.7%) participants performing at or below the 5th percentile and a median (IQR) percentile score of 9.00 (5.00-62.50). A significant negative correlation was found between the manual dexterity subscale and both height and height for age z-scores (p = 0.017 and p = 0.019, respectively), as well as peak expiratory flow in liter (p = 0.027). The balance subscale scores were positively correlated with forced expiratory volume in %predicted (p = 0.048). No other significant correlations were found. Conclusion: Children with CF may be at risk for delayed motor development, particularly their balance skills. Poor lung function might affect motor development but further research is recommended.


Follow-up of small, postmenopausal ovarian cysts using vaginal ultrasound and CA-125 antigen.
To determine the natural history of small, simple ovarian cysts in postmenopausal women, 51 postmenopausal patients with small (< 5 cm), smooth, aseptate, hypoechogenic ovarian cysts, without ascites, were followed by vaginal ultrasound examinations every 3 months for an average period of 2.5 years. In 34, CA-125 antigen was measured and found to be within normal limits. None of the cysts showed changes in texture, nor did ascites appear. The CA-125 antigen serum levels remained low. The mean size of the cysts decreased with time. There was no statistically significant correlation between the initial size of the cyst, its tendency to grow or shrink, and the absolute CA-125 serum level. Our findings support the option of a conservative follow-up by repeated ultrasonic and CA-125 antigen examinations of small, simple cysts in postmenopausal women.


Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure.
Sevelamer, or more precisely 'sevelamer hydrochloride', is a weakly basic anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of patients with end-stage renal failure, usually those on long-term haemodialysis. The rationale for this therapy was that sevelamer would sequester phosphate within the gastrointestinal tract, so preventing its absorption and enhancing its faecal excretion. Over the succeeding years, large numbers of patients have been treated with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure. However, it is only one of many anion-exchange resins that could be used for this purpose, some of which are currently available for clinical use and are much less costly than sevelamer. Theoretical considerations suggest that some of these other resins might be at least as efficient as sevelamer in sequestering phosphate in the gastrointestinal tract. Neither sevelamer, nor any of these other agents, has been submitted to a proper metabolic balance study to measure the amount of phosphate sequestered by the resin in the bowel, and without this information it is impossible to judge which is the ideal resin for this purpose.


Forward and backward recall: Different visuospatial processes when you know what's coming.
In an immediate memory task, when participants are asked to recall list items in reverse order, benchmark memory phenomena found with more typical forward recall are not consistently reproduced. These inconsistencies have been attributed to the greater involvement of visuospatial representations in backward than in forward recall at the point of retrieval. In the present study, we tested this hypothesis with a dual-task paradigm in which manual-spatial tapping and dynamic visual noise were used as the interfering tasks. The interference task was performed during list presentation or at recall. In the first four experiments, recall direction was only communicated at the point of recall. In Experiments 1 and 2, fewer words were recalled with manual tapping than in the control condition. However, the detrimental effect of manual tapping did not vary as a function of recall direction or processing stage. In Experiment 3, dynamic visual noise did not influence recall performance. In Experiment 4, articulatory suppression was performed on all trials and manual tapping was added on half of them. As in the first two experiments, manual tapping disputed forward and backward recall to the same extent. In Experiment 5, recall direction was known before list presentation. As predicted by the visuospatial hypothesis, when manual tapping was performed during recall, its detrimental effect was limited to backward recall. Overall, results can be explained by calling upon a modified version of the visuospatial hypothesis.


Directed evolution of protein inhibitors of DNA-nucleases by in vitro compartmentalization (IVC) and nano-droplet delivery.
In vitro compartmentalization (IVC) uses water-in-oil emulsions to create artificial cell-like compartments in which genes can be individually transcribed and translated. Here, we present a new application of IVC for the selection of DNA-nuclease inhibitors. We developed a nano-droplets delivery system that allows the transport of various solutes, including metal ions, into the emulsion droplets. This transport mechanism was used to regulate the activity of colicin nucleases that were co-compartmentalized with the genes, so that the nucleases were activated by nickel or cobalt ions only after the potential inhibitor genes have been translated. Thus, genes encoding nuclease inhibitors survived the digestion and were subsequently amplified and isolated. Selection is therefore directly for inhibition, and not for binding of the nuclease. The stringency of selection can be easily modulated to give high enrichments (100-500-fold) and recoveries. We demonstrated its utility by selecting libraries of the gene encoding the cognate inhibitor of colicin E9 (immunity protein 9, or Im9) for inhibition of another colicin (ColE7). The in vitro evolved inhibitors show significant inhibition of ColE7 both in vitro and in vivo. These Im9 variants carry mutations into residues that determine the selectivity of the natural counterpart (Im7) while completely retaining the residues that are conserved throughout the family of immunity protein inhibitors. The in vitro evolution process confirms earlier hypotheses regarding the "dual recognition" binding mechanism and the way in which new colicin-immunity pairs diverged from existing ones.


[Fulminant acne in Klinefelter syndrome treated with testosterone. A side effect of anti-tallness therapy].
Acne lesions usually do not occur in patients with Klinefelter's syndrome (47 XXXY). But a 19 year old patient with Klinefelter's syndrome, under therapy with testosteronenantat (500 mg every two weeks over a period of 18 months) for treatment of excessively tall stature developed acne fulminans. Following discontinuation of testosterone treatment and isotretinoin therapy over 16 weeks skin lesions healed almost completely although with severe scars. In conclusion, high doses testosterone-treatment in excessively tall boys needs the additional care of dermatologist when mostly after a 7 months period acne begins to develop under this treatment.


[Immunohistochemical distribution and fine localization of atrial natriuretic peptides in the stria vascularis of normal guinea pigs].
The paper presents the distribution and fine localization of the atrial natriuretic peptides (ANP) in the stria vascularis of normal guinea pig by using immunohistochemical technique (ABC method) and immunoelectronic microscopy. ANP-IR was found in stria vascularis in all turns of the lateral walls of cochlea, but no positive products were found in the spiral ligament. The positive immunoreactive products were seen more distinct in the liber surface than that of basilaris. A large of spherical bodies whose diameters are 250-350nm were seen in cytoplasm of marginal cells and intermediate cells in stria vascularis; spheroid is less in the cytoplasm of basal cells and vascular endothelial cells. The study suggests that the stria vascularis can secrete ANP. ANP morphological distribution and its possible meaning in the stria vascularis are discussed.


The treatment of congenital hip dysplasia.
The authors take into consideration the different phases of the treatment of congenital hip dysplasia (CHD) as it is related to age and natural development. Within the first year of age three objectives must be aimed at: reduction of the epiphysis, its retention and immobilization, maturation of the hip. After three years of age, once the epiphysis has been reduced, reconstructive and stabilizing surgery must be performed (acetabuloplasty and femoral osteotomy) in order to correct the modified joint parameters. After ten years of age and until the end of growth the degree of dysplasia influences treatment, as intervention is justified (preferably with biological reconstruction of the acetabulum) in forms of severe dysplasia caused by the definite occurrence of pain at an early age. We emphasize the importance of adapting treatment to the specific phase of evolution of the hip understood to be dynamic reality.


Activation and alteration of lysosomes in multiple system atrophy.
Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder. Its histopathological features include glial cytoplasmic inclusions that contain α-synuclein as the main component. Recently, multiple lines of evidence have suggested a role for lysosomes in the pathogenesis of many neurodegenerative diseases. To elucidate whether lysosomes are also implicated in the pathology of MSA, we carried out an immunohistochemical study using antibodies against lysosomal proteins in the brains of patients with MSA and in control brains. A robust increase in the expression and an alteration in the morphology and distribution of lysosomal-protein-positive structures were observed in MSA brains. Double immunohistochemistry demonstrated that lysosomal markers did not colocalize mainly with glial cytoplasmic inclusions, but colocalized with a microglial marker. These immunohistochemical signatures suggest that lysosomes are activated in microglia during the disease process, and play a pivotal role in the pathology of MSA.


Hypothyroidism minimizes the effects of acute hepatic failure caused by endoplasmic reticulum stress and redox environment alterations in rats.
The aim of this study was to investigate if a protective effect from hypothyroidism in acute liver failure resulted from reduced endoplasmic reticulum stress and changes to the redox environment. Twenty male Sprague-Dawley rats were divided in four groups: (1) euthyroid (sham surgery), (2) hypothyroid, (3) euthyroid (sham surgery)+thioacetamide and (4) hypothyroid+thioacetamide. Hypothyroidism was confirmed two weeks after thyroidectomy, and thioacetamide (TAA) (400mg/kg, ip) was administrated to the appropriate groups for three days with supportive therapy. Grades of encephalopathy in all animals were determined using behavioral tests. Animals were decapitated and their blood was obtained to assess liver function. The liver was dissected: the left lobe was used for histology and the right lobe was frozen for biochemical assays. Body weight, rectal temperature and T4 concentration were lower in hypothyroid groups. When measurements of oxidative stress markers, redox environment, γ-glutamylcysteine synthetase and glutathione-S-transferase were determined, we observed that hypothyroid animals with TAA compensated better with oxidative damage than euthyroid animals treated with TAA. Furthermore, we measured reduced expressions of GADD34, caspase-12 and GRP78 and subsequently less hypothyroidism-induced cellular damage in hypothyroid animals. We conclude that hypothyroidism protects against hepatic damage caused by TAA because it reduces endoplasmic reticulum stress and changes to the redox environment.


Combination chemotherapy with methotrexate, etoposide, and actinomycin D for high-risk gestational trophoblastic tumors.
The goal of this study was to evaluate the efficacy, toxicity, and survival of patients with high-risk gestational trophoblastic tumors (GTTs) treated with a methotrexate-etoposide-actinomycin D (MEA) regimen without cyclosphosphamide or vincristine. Thirty-nine consecutive patients with high-risk GTTs (28 were defined high risk by WHO criteria) were treated with primarily the MEA regimen. Among them, 27 patients had received no prior chemotherapy and 12 had received prior chemotherapy. Survival, causes of treatment failure, and toxicity were analyzed retrospectively. After treatment with the MEA regimen, 29 of 39 patients achieved primary remission (74.4%), 8 developed resistance (20.5%), and 2 died of widespread metastases and chemotherapy-related toxicity. All 8 patients who developed resistance were treated with high-dose 5-fluorouracil and actinomycin D (FA); 6 were salvaged and 2 died of refractory disease. Three patients relapsed; 2 were controlled with FA or cisplatin-based chemotherapy and 1 who refused further treatment died. The disease-free survival rate was 87%. WHO grade 4 leukocytopenia and thrombocytopenia with the MEA regimen occurred in 5.3 and 6.4%, respectively, of the cycles; other toxic effects were acceptable and manageable. At present, MEA chemotherapy (without cyclophosphamide or vincristine) is our treatment of choice for patients with high-risk GTT. Its toxicity is predictable and manageable. For patients who become resistant to MEA, new salvage chemotherapy regimens are needed.


Synthesis and structure-activity relationship of mono-indole-, bis-indole-, and tris-indole-based sulfonamides as potential anticancer agents.
A series of arylsulfonyl mono-indoles (10-15), bis-indoles (16-27), and tris-indoles (28-32) have been synthesized and evaluated for their cytotoxicity toward four human cancer cell lines including HuCCA-1 (cholangiocarcinoma), HepG2 (hepatocellular carcinoma), A-549 (lung carcinoma), and MOLT-3 (lymphoblastic leukemia). Most of the synthesized indoles displayed cytotoxicity against the MOLT-3 cell line except for analogs 16, 17, and 32. Significantly, the [Formula: see text]-sulfonylphenolic bis-indole series (18-27) and the [Formula: see text]-chlorobenzenesulfonyl tris-indole (30) showed higher antiproliferative activity against HepG2 cell than the reference drug, etoposide. Promisingly, the [Formula: see text]-chlorobenzenesulfonyl bis-indole (20) and tris-indole (30) provided 3-fold and 2-fold stronger activity, respectively, against HepG2 cell than etoposide. Moreover, the phenolic bis-indole (20) was also shown to be the most potent cytotoxic agent against HuCCA-1 and A-549 cell lines with [Formula: see text] values of 7.75 and [Formula: see text], respectively. The tris-indole analogs 28, 29, and 31 also exhibited selectivity against MOLT-3 cell. The findings disclosed that [Formula: see text]-arylsulfonyl bis-indoles-bearing phenolic groups are potentially interesting lead pharmacophores of anticancer agents that should be further investigated in more detail.


Interleukin 2-induced activation of Ras requires two domains of interleukin 2 receptor beta subunit, the essential region for growth stimulation and Lck-binding domain.
Interleukin 2 (IL-2) can stimulate the proliferation of various kinds of T-cell lines. The receptor for IL-2 is composed of at least two subunits (alpha and beta), of which beta subunit plays the major role in transducing growth signals into the cells. A nonreceptor-type tyrosine kinase, Lck, is associated with IL-2 receptor beta subunit, and the binding of IL-2 to its receptor induces the activation of Lck. On the other hand, it has been shown that stimulation of T-cells with IL-2 causes rapid activation of Ras protein. In this paper, we describe that both of the two regions in IL-2 receptor beta subunit, the indispensable region for the induction of cell growth (serine-rich region) and the binding region of Lck protein (acidic region), are required for the activation of Ras. These two regions are also required for tyrosine phosphorylation of an 85-kDa cellular protein (p85) and the accumulation of fos and jun mRNAs. This observation suggests also that the activation of a receptor-associated tyrosine kinase in response to IL-2-stimulation is primarily responsible for subsequent activation of the pathway through Ras to Fos and Jun.


A study of phospholipid interactions between high-density lipoproteins and small unilamellar vesicles.
Previous observations on serum-induced leakage of liposome contents from egg phosphatidylcholine liposomes (Allen, T.M. and Cleland, L.G. (1980) Biochim. Biophys, Acta 597, 418--426) have been extended in order to examine the role of the phase transition and phospholipid backbone in leakage. The high-density lipoprotein (HDL) fraction has been purified from human serum and the rate of transfer of radioactively labelled phospholipids from sonicated liposomes to high-density lipoproteins has been examined. Results obtained from the calcein dequenching method for serum-induced leakage of liposome contents showed that as the proportion of solid phospholipid (distearoyl phosphatidylcholine, Tc = 56 degrees C) increased, relative to the proportion of egg phosphatidylcholine, the half-time for retention of liposome contents at 37 degrees C in the presence of serum also increased. Including increasing amounts of bovine brain sphingomyelin (Tc = 30 degrees C) in egg phosphatidylcholine liposomes also substantially decreased leakage from liposomes in the presence of serum at 37 degrees C. 14C-labelled egg phosphatidylcholine was found to transfer readily from liposomes to purified HDL, as did 14C-labelled dioleoyl phosphatidylcholine. Including cholesterol in egg phosphatidylcholine liposomes decreased the rate of transfer of phospholipid to HDL. 14C-labelled distearoyl phosphatidylcholine did not exchange readily with HDL. These results are consistent with the interpretation that tightening bilayer packing prevents the apolipoprotein-mediated transfer of phospholipid to HDL and slows the leakage of liposome contents associated with this transfer. [14C]Sphingomyelin also did not exchange readily with HDL. This does not appear to be a phase transition effect as the majority of sphingomyelin is above its phase transition at 37 degrees C. The failure of sphingomyelin to exchange readily with HDL is interpreted as being due to intermolecular hydrogen bonding between the sphingosine backbones of the sphingomyelin molecule.


Retention of dopamine 2 receptor mRNA and absence of the protein in craniospinal and extracranial metastasis of a malignant prolactinoma: a case report.
The case presented here describes the clinical evolution of a malignant prolactinoma with occurrence of intra- and extra-cranial metastases. In this case, the presence of dopamine 2 receptor (D2R) was studied at the mRNA and protein level, in order to understand the pathological background of the resistance to treatment with different dopamine agonists. Together with an extensive description of the clinical history of this case, a combination of in vitro and in vivo techniques was performed to provide the basis of the dopamine resistance developed in the course of the disease. A comparison of the D2R was performed in specimens obtained at presentation of the disease compared with autoptic specimens derived from local invasion and metastasis using in situ hybridization and immunohistochemical techniques. Intact D2R mRNA was found in the primitive tumor and metastatic tissues, whereas protein for the same receptor was present only in the tissues derived from neurosurgical operations and not in the metastases obtained post-mortem. This is the first report of the absence of D2R protein despite the retention of the transcript in an advanced stage of a malignant prolactinoma. The findings of this single case suggest the hypothesis that postranscriptional mechanisms may contribute to the development of dopamine resistance in prolactinomas.


Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension).
This study was designed to test the safety and efficacy of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PA hypertension (IPAH) not responding optimally to medical therapy. Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main PA. We previously demonstrated that PADN completely abolished the experimentally elevated PA pressure responses to occlusion of the left interlobar PA. Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group. PADN was performed at the bifurcation of the main PA, and at the ostial right and left PA. Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed. The primary endpoints were the change of PA pressure (PAP), tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up. Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001). We report for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy. Further randomized study is required to confirm the efficacy of PADN. (First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension [PADN-1] study; chiCTR-ONC-12002085).


[Levels of prolactin in atherosclerotic subjects before and after HCG tests].
Among the researches concerning the therapeutic mechanism of HCG in the arteriosclerotic disease, in this work the Authors report the values of prolactin before and after a stimulus with HCG in a group of 10 arteriosclerotic patients. The prolactin values are not modified by HCG and would not confirm the eventual direct or indirect mediation of the hypophysis in the above mentioned therapeutic action.