[Correlation between osteoporosis and types of fractures of the proximal femur: clinical and X-Ray study of 284 cases].
Proximal femoral fractures are the most severe medical and social consequence of osteoporosis. The bone loss in the proximal femur can be assessed with the Singh Index, which represents a cheap and reproducible method and which quantifies the osteoporosis on a 1-6 scale. The purpose of the study is to correlate the Singh Index with the anatomical forms of fracture (extra and intracapsular) in a series of patients. Three hundred consecutive patients over 60 years were operated for a proximal femur fracture. 284 radiological records were included in the study. They were classified in 4 age groups (60-69, 70-79, 80-89, 90 and more). The anatomic forms were classified following the AO scheme in extracapsular (A1, A2, A3) and respectively intracapsular fractures (B1, B2, B3). For each case the Singh Index was assessed twice on a standard AP view of the controlateral hip by a single examiner. There were 154 extracapsular fractures and 130 intracapsular fractures. The average Singh Index was 2.6/6. It decreases from 3.7/6 for males and 3.2/6 for females in age between 60-69 to 1.6 for males and 1.3 for females over 90. In all age groups females are more osteoporotic (0.3-0.5 of difference, p=0.003). The extracapsular fractures presented with a lower average Singh Index (2,34/6) compared to the intracapsular types 2,55/6 (excepting the impacted coxa-valga B1. This finding is seen in both male (2,50 vs 2,66) and female patients (2,33 vs 2,48). In this series patients with extracapsular proximal femur fractures show a lower Singh Index compared to the intracapsular types (p=0.03). The choice for the type of osteosynthesis or arthroplasty should take into account the mechanical solidity of the femur.


Endothelial cell aging detection by means of atomic force spectroscopy.
Endothelial cell aging is related to changes not only in cell phenotype, such as luminal changes, intimal and medial thickening, and increased vascular stiffness, but encompasses different cell responses to various substances including drugs or nanomaterials. In the present work, time- and dose-dependent elasticity changes evoked by silver nanoparticles in endothelial cells in early (below 15) passages were analyzed. Silver nanoparticle concentrations of 3, 3.6, and 16 μg/mL were selected for elasticity measurements for long incubation (24 hours) and of 1 and 3 μg/mL for monitoring dynamic elasticity changes of 1-, 3-, and 6-hour incubations. Surprisingly, a significant reduction in the cells elasticity modulus at lower number of passages exposed to silver nanoparticles used at 3 μg/mL for 24 hours was demonstrated. These results are in contrast to those obtained for endothelial cells in late (33-43) passages that may result from cellular aging in response to nanosilver. Furthermore, for short incubation times (1 and 3 hours), SNP-induced significant increase in the cell elasticity modulus was detected. In current work, we also attempted to answer the question whether the changes in cell elasticity were induced by the silver nanoparticles stabilized with polyvinyl pyrrolidone or by stabilizer itself. Elasticity measurements were supplemented by observations made with transmission electron microscopy and scanning electron microscopy, which confirmed the presence of silver nanoparticles inside the cells and on the cell membrane. Additionally, activation of reactive oxygen species was detected for cells exposed to SNPs for 1 and 3 hours, which was accompanied by increased cell elasticity modulus suggesting a possible mechanism of observed phenomenon.


Restless legs syndrome.
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is a common movement disorder characterised by an uncontrollable urge to move because of uncomfortable, sometimes painful sensations in the legs with a diurnal variation and a release with movement. The pathophysiology is only partially known and a genetic component together with dopaminergic and brain iron dysregulation plays an important role. Secondary causes for RLS need to be excluded. Treatment depends on the severity and frequency of RLS symptoms, comprises non-pharmacological (eg lifestyle changes) and pharmacological interventions (eg dopaminergic medication, alpha-2-delta calcium channel ligands, opioids) and relieves symptoms only. Augmentation is the main complication of long-term dopaminergic treatment of RLS. This article will provide a clinically useful overview of RLS with provision of diagnostic criteria, differential diagnoses, possible investigations and different treatment strategies with their associated complications.


[Mechanisms of growth of neuronal axons and dendrites].
Brain development is determined by neuronal differentiation including changes of cell polarity and asymetric growth of neuronal processes. Although, there are many unkown factors contributing to changes of lenght of neuronal cones, mounting experimental and review papers focus on changes of growth conus and role of axonal transport. In particular, mechanisms of actin/microtubule polymerisation and depolymerisation are important. Role of intracellular calcium is also significant. Normal and properly timed changes of lenght of axons and dendrites are dependent on interaction of neurons and glia. Moreover, regeneration of injured axons is dependent on growth factors secreted from glial cells. The aim of the present study is characterisation of the most important mechanisms underlying changes of lenght of neurites.


[Nuclear cardiology with new radiopharmaceuticals].
In the field of nuclear cardiology, 99mTc labeled myocardial perfusion agents such as MIBI, Tetrofosmin and Teboroxime, 111In-antimyosin for imaging of myocardial necrosis, 123I-betamethyl-iodophenylpentadecanoic acid (BMIPP) for imaging of myocardial fatty acid metabolism and 123I-metaiodobenzylguanidine (MIBG) for imaging of myocardial adrenergic function are introduced recently in Japan. Improved image quality and simultaneous evaluation of myocardial perfusion, function and wall motion can be obtained with use of 99mTc labeled myocardial perfusion agents. 111In-antimyosin enables specific imaging of myocardial necrosis which leads to the use for wide variety of heart diseases. Discrepancy of the myocardial perfusion and metabolism in case of stunned myocardium or cardiomyopathy can be evaluated by 123I-BMIPP in conjunction with perfusion agent. Recently wide variety of diseases which may have cardiac adrenergic abnormality are targeted for 123I-MIBG imaging. These new radiopharmaceuticals are expected to be powerful tool for evaluation of the pathophysiology including severity and prognosis and evaluation of the etiology of the various heart diseases.


Increased expression of myo-inositol oxygenase is involved in the tubulointerstitial injury of diabetic nephropathy.
Myo-inositol oxygenase (MIOX) catalyzes the oxidative cleavage of myo-inositol (MI) to give D-glucuronic acid, a committed step in MI catabolism. Previous studies have shown that increased mRNA and protein levels of MIOX in the cortex of the kidney in diabetic mice. The implication of MIOX expression in diabetic nephropathy, however, has not been revealed. In the present study, we demonstrate for the first time that the expression of MIOX was increased at both the mRNA and protein levels in the kidney of rats with diabetic nephropathy. In addition, alpha-smooth muscle actin (alpha-SMA) and fibronectin levels were increased and E-cadherin levels decreased in the same diabetic kidneys. In vitro, studies have shown that high concentrations of glucose significantly increased MIOX secretion in rat renal tubular epithelial cells NRK-52E in a dose-dependent manner, suggesting that hyperglycemia is a direct cause of the MIOX increase in the kidney. With respect to the function of MIOX, we have shown that overexpression of MIOX induces greater levels of alpha-SMA, increased fibronectin expression, and lower levels of E-cadherin expression relative to normal NRK-52E cells. The blockade of MIOX by antisense oligonucleotide (ODN) inhibits high glucose-induced production of alpha-SMA and fibronectin in normal NRK-52E cells. This suggests that increased expression of MIOX in diabetic kidneys may contribute to tubulointerstitial injury and the development of diabetic nephropathy.


Helium ion microscopy of graphene: beam damage, image quality and edge contrast.
A study to analyse beam damage, image quality and edge contrast in the helium ion microscope (HIM) has been undertaken. The sample investigated was graphene. Raman spectroscopy was used to quantify the disorder that can be introduced into the graphene as a function of helium ion dose. The effects of the dose on both freestanding and supported graphene were compared. These doses were then correlated directly to image quality by imaging graphene flakes at high magnification. It was found that a high magnification image with a good signal to noise ratio will introduce very significant sample damage. A safe imaging dose of the order of 10(13) He(+) cm(-2) was established, with both graphene samples becoming highly defective at doses over 5 × 10(14) He(+) cm(-2).The edge contrast of a freestanding graphene flake imaged in the HIM was then compared with the contrast of the same flake observed in a scanning electron microscope and a transmission electron microscope. Very strong edge sensitivity was observed in the HIM. This enhanced edge sensitivity over the other techniques investigated makes the HIM a powerful nanoscale dimensional metrology tool, with the capability of both fabricating and imaging features with sub-nanometre resolution.


Osteoclast regulation of osteoblasts via RANK‑RANKL reverse signal transduction in vitro.
The treatment of osteoporosis typically inhibits the activity of osteoclasts, which subsequently results in the suppression of bone formation and maintenance, however the underlying mechanism remains to be elucidated. The receptor activator of nuclear factor κ‑B ligand (RANKL)‑receptor activator of nuclear factor κ‑B (RANK) signaling axis is important in the osteoblast regulation of osteoclasts. RANKL surface‑bound molecules expressed on T cells stimulate a reverse signaling transduction in order to regulate the T cells, therefore the present study hypothesized that RANKL expressed on osteoblasts may transfer reverse signals to regulate osteoblasts. A series of experiments were designed to test the hypothesis, using MTT, stealth RNA interference, reverse transcription‑quantitative polymerase chain reaction, western blot analysis, alkaline phosphatase activity assay and alizarin red staining. The present study observed the role of RANK‑RANKL reverse signaling on osteoblasts, regulated by osteoclasts. Osteoblasts were treated with recombinant RANK proteins. The soluble RANK enhanced the mineralization of osteoblasts. When the RANKL was knocked down in the osteoblast, RANK demonstrated a weak osteogenic effect on the RANKL‑deficient osteoblast compared with the wild‑type osteoblast which served as a control. Addition of soluble RANK activated the p38 mitogen activated protein kinase (MAPK) signaling pathway in the osteoblast and blocking this same pathway in E1 cells reduced the effect of RANK. In the co‑culture system of osteoblasts and osteoclasts, p38 MAPK in E1 cells was phosphorylated a short time following co‑culture and the phosphorylation then blocked by abundant soluble RANKL. The findings suggested that RANKL expressed on osteoblasts transferred reverse signals from the exterior of the cell to the interior, which regulated the osteoblasts.


A Functional Network of Novel Barley MicroRNAs and Their Targets in Response to Drought.
The regulation of mRNA (messenger RNA) levels by microRNA-mediated activity is especially important in plant responses to environmental stresses. In this work, we report six novel barley microRNAs, including two processed from the same precursor that are severely downregulated under drought conditions. For all analyzed microRNAs, we found target genes that were upregulated under drought conditions and that were known to be involved in a plethora of processes from disease resistance to chromatin-protein complex formation and the regulation of transcription in mitochondria. Targets for novel barley microRNAs were confirmed through degradome data analysis and RT-qPCR using primers flanking microRNA-recognition site. Our results show a broad transcriptional response of barley to water deficiency conditions through microRNA-mediated gene regulation and facilitate further research on drought tolerance in crops.


Improved artificial neural networks in prediction of malignancy of lesions in contrast-enhanced MR-mammography.
The aim of this study was to evaluate the capability of improved artificial neural networks (ANN) and additional novel training methods in distinguishing between benign and malignant breast lesions in contrast-enhanced magnetic resonance-mammography (MRM). A total of 604 histologically proven cases of contrast-enhanced lesions of the female breast at MRI were analyzed. Morphological, dynamic and clinical parameters were collected and stored in a database. The data set was divided into several groups using random or experimental methods [Training & Testing (T&T) algorithm] to train and test different ANNs. An additional novel computer program for input variable selection was applied. Sensitivity and specificity were calculated and compared with a statistical method and an expert radiologist. After optimization of the distribution of cases among the training and testing sets by the T & T algorithm and the reduction of input variables by the Input Selection procedure a highly sophisticated ANN achieved a sensitivity of 93.6% and a specificity of 91.9% in predicting malignancy of lesions within an independent prediction sample set. The best statistical method reached a sensitivity of 90.5% and a specificity of 68.9%. An expert radiologist performed better than the statistical method but worse than the ANN (sensitivity 92.1%, specificity 85.6%). Features extracted out of dynamic contrast-enhanced MRM and additional clinical data can be successfully analyzed by advanced ANNs. The quality of the resulting network strongly depends on the training methods, which are improved by the use of novel training tools. The best results of an improved ANN outperform expert radiologists.


Psychosocial influences on suboptimal adjuvant breast cancer treatment adherence among African American women: implications for education and intervention.
Despite lower incidence, African American women are at increased risk of dying from breast cancer relative to their European American counterparts. Although there are key differences in both screening behavior and tumor characteristics, an additional part of this mortality difference may lie in the fact that African American women receive suboptimal adjuvant chemotherapy and may receive suboptimal hormonal therapy, therapies that are known to increase survival. The authors consider ethnic differences in the psychosocial factors that have been shown to relate to poor screening adherence and consider how they may influence adherence to breast cancer adjuvant treatment, thus the receipt of suboptimal adjuvant chemo or hormonal therapy. To this end, they review ethnic differences in cognitive, emotional, and social network variables. Psychosocial variables should be included in research designed to understand cancer disparities as well interventions that can be tailored to culturally diverse populations to improve treatment adherence.


Prokaryotic Argonautes - variations on the RNA interference theme.
The discovery of RNA interference (RNAi) has been a major scientific breakthrough. This RNA-guided RNA interference system plays a crucial role in a wide range of regulatory and defense mechanisms in eukaryotes. The key enzyme of the RNAi system is Argonaute (Ago), an endo-ribonuclease that uses a small RNA guide molecule to specifically target a complementary RNA transcript. Two functional classes of eukaryotic Ago have been described: catalytically active Ago that cleaves RNA targets complementary to its guide, and inactive Ago that uses its guide to bind target RNA to down-regulate translation efficiency. A recent comparative genomics study has revealed that Argonaute-like proteins are also encoded by prokaryotic genomes. Interestingly, there is a lot of variation among these prokaryotic Argonaute (pAgo) proteins with respect to domain architecture: some resemble the eukaryotic Ago (long pAgo) containing a complete or disrupted catalytic site, while others are truncated versions (short pAgo) that generally contain an incomplete catalytic site. Prokaryotic Agos with an incomplete catalytic site often co-occur with (predicted) nucleases. Based on this diversity, and on the fact that homologs of other RNAi-related protein components (such as Dicer nucleases) have never been identified in prokaryotes, it has been predicted that variations on the eukaryotic RNAi theme may occur in prokaryotes.


[A case of Listeria monocytogenes meningitis in an immunocompetent infant].
Listeria Monocytogenes meningitis is a rare affection after the neonatal period, but in immunocompromised patients. Listeria Monocytogenes is a Gram-positive, facultative intracellular bacterium frequently causing infection in pregnant women, in patients with cell-mediated immunity deficit and in the early and late stages of life. We present a case of Listeria Monocytogenes meningitis in an immunocompetent nomad 8-month-child, preceded by gastroenteritis. Although gastrointestinal symptoms may be due to intestinal infection by Listeria, the concomitant presence of other bacteric or viral enteric pathogens may have promoted bacterium intestinal translocation and generated disseminated disease. The main transmission route of infection after the neonatal period is ingestion of contaminated food. A diet history was taken after isolation of the bacterium in liquor and showed that the child was an eater of undercooked hot-dogs. Despite the frequency of clinical complication in such affection, the outcome in this patient was a complete recovery. Although the infection is extremely infrequent in healthy children, physicians should always consider Listeria as a possible etiologic agent of meningitis in pediatric patients, regardless of their age or immunological status, especially in patients living in precarious sanitary conditions, where weaning times and conditions are not respected and a suitable food cooking is not assured.


Anti-idiotype monoclonal antibody carrying the internal image of ganglioside GM3.
Murine anti-idiotype monoclonal antibodies were generated against a human IgM monoclonal antibody (L612) that recognizes ganglioside GM3 on human melanoma. Hybridomas secreting antibodies that bound specifically to L612 were selected by enzyme-linked immunosorbent assay using L612 and three negative control human IgMs, including monoclonal anti-GM2 and anti-GD2 antibodies, as well as purified serum IgM, as antigen sources. GM3-binding inhibition and cell-binding inhibition assays were used to identify seven anti-idiotype monoclonal antibodies that recognized determinants located within the antigen-combining sites of L612. To determine whether these anti-idiotype monoclonal antibodies possessed the internal image of the original antigen, we immunized syngeneic BALB/c mice with one of the anti-idiotype monoclonal antibodies, 4C10, coupled with keyhole limpet hemocyanin. Sera from the immunized mice reacted strongly with an antigen-positive M12 melanoma cell line and with purified GM3. Because L612 detects and kills melanoma tumor cells in vitro and in vivo in the presence of complement without affecting normal tissues, anti-idiotype monoclonal antibodies carrying the internal image of GM3 may be an effective tool for active specific immunotherapy in patients with melanoma.


Morphological & immunohistochemical spectrum in anorectal malignancies.
The morphological features of 62 anorectal malignancies diagnosed on sigmoidoscopic biopsy were studied. On haemotoxylin and eosin staining the tumours were diagnosed as adenocarcinomas (43), squamous cell carcinoma (12), malignant melanoma (3), carcinoid (2), clear cell carcinoma (1) and poorly differentiated carcinoma (1). PAS Alcian blue, Grimelius silver stain, AgNOR and immunohistochemical stain for carcinoembryonic antigen (CEA) and human papilloma virus (HPV) were done to further categorise these tumours. The ages of the patients varied from 18 to 77 yr (mean 43.7 yr) and the male: female ratio was 2:1. PAS Alcian blue staining was helpful in differentiating mucinous from non-mucinous adenocarcinomas and reclassifying one poorly differentiated carcinoma as mucin secreting adenocarcinoma. Also, it clearly identified pagetoid spread in two cases of adenocarcinomas. Grimelius silver stain was strongly positive in melanomas and neuroendocrine tumours. Basal silver staining was visualised in metaplastic foci but was absent in dysplastic epithelium. AgNOR counts may be considered useful in differentiating melanomas (high counts) from spindle cell variant of squamous carcinomas (low counts). High AgNOR counts and strong Grimelius positivity in clear cell carcinoma suggested its melanotic origin. Immunostaining for CEA and HPV were of limited value. CEA was positive in the majority of the adenocarcinomas while HPV could only be demonstrated in two squamous cell carcinomas.


Nurses' and physicians' perceptions of older people and attitudes towards older people: Ageism in a hospital in Turkey.
Abstract Nurses and physicians provide health care for a growing number of older people as a result of the rapid increase in the life expectancies of older people. Health professionals' negative attitudes towards older people affect the quality of health care offered to these individuals. The sample for this study included 110 nurses and 57 physicians working in the medical and surgical clinics of a university hospital. A questionnaire form and the Ageism Attitude Scale (AAS) were used to collect the data. A five-point Likert-type format was utilised for the AAS. The AAS total mean score was 80.02 ± 2.64 for nurses and 83.17 ± 9.09 for physicians. The difference between these mean scores was statistically significant (p < 0.05). For the AAS sub-dimension 'limiting the life of the older people,' the physicians' score (35.14 ± 6.22) was significantly higher than the nurses' score (33.22 ± 3.59). In this study, nurses' and physicians' attitudes, approaches, and considerations were found to be generally positive.


Soft and intermediate plaques in coronary arteries: how accurately can we measure CT attenuation using 64-MDCT?
The objective of this study was to validate the accuracy of 64-MDCT densitometry of soft and intermediate plaques. Acrylonitrile-butadiene-styrene resin (47 H) and acrylic (110 H) were used to simulate soft and intermediate plaques, respectively, in coronary artery models (diameters of 3 and 4 mm). The variable parameters were heart rate (50, 65, 80, and 95 beats per minute), reconstruction algorithm (half and segmentation), coronary artery enhancement (150, 250, 350, and 450 H), CT densitometry site (arterial lumen or center), shape of plaque (D-shaped, centric, and eccentric), and level of stenosis due to plaque (25%, 50%, and 75% of arterial diameter). Measured CT attenuation values of soft and intermediate plaques were compared for different combinations of parameters. Repeated measures analysis of variance, Wilcoxon's signed rank, Mann-Whitney U, and Kruskal-Wallis tests were used for statistical analyses. For measuring soft plaque, CT densitometry was accurate at low heart rates with the use of a half reconstruction algorithm (p < 0.01) on intracoronary artery enhancement of 250 H (p < 0.01). For both soft and intermediate plaques, the densitometry measurements near the arterial lumen were overestimated and higher than those at the center (p < 0.01). For plaques that were 50% or more of the arterial diameter, accurate CT densitometry was possible. Coronary artery enhancement has a significant impact on 64-MDCT densitometry measurements of coronary artery plaques, especially of soft plaques. A large plaque size, densitometry performed not near the arterial lumen but at the center of the plaque, intracoronary enhancement of 250 H, and a low heart rate increase the accuracy of plaque densitometry.


Correlations between clinical and placental histopathological and immunohistochemical features in women with and without hereditary thrombophilia.
The primary objective of this study was to correlate hereditary thrombophilia (high- or low-risk) with specific placental histopathological (HP) and∕or immunohistochemical (IHC) changes, for confirming∕ruling out a possible linkage between these two biological parameters. We present a 3-year prospective study conducted between 2016 and 2019 that enrolled 90 women registered in two Clinics of Obstetrics and Gynecology in Craiova, Romania, with personal thrombotic and/or pathological obstetrical history. The HP and IHC analysis of the placenta was performed using monoclonal anti-cluster of differentiation 34 (CD34) antibody, anti-hypoxia-inducible factor-1 alpha (HIF-1α) and anti-endothelial nitric oxide synthase (eNOS) antibody. There was a high incidence of all thrombophilia (TPh) mutations in Caucasian women with thrombotic and obstetrical complications. Among them, both HP and IHC examination revealed significant changes. These were more severe in the placentas of patients with homozygous Factor V Leiden (FVL) gene mutation and double heterozygous FVL∕PII gene mutation. Multiple placental infarctions with massive fibrinoid necrosis and an increase in syncytial knots are common findings. In the same group, we found by means of IHC examination - intense positive HIF-1α and eNOS immunoexpression, and low positive CD34 expression, especially in fibrinoid necrosis and thrombosis areas. We found no correlation between clinical, HP and IHC changes in patients with low-risk TPh or without TPh. Among patients with obstetric and thrombotic complications, there is a high prevalence of TPh. It appears that hypercoagulability reported in high-risk thrombophilia (HR-TPh) has major effects on placental tissue (fibrinoid necrosis, multiple thromboses, hypoxia and oxidative stress). Significant placental changes were found predominantly in women with HR-TPh. Strategies for TPh screening based on HP/IHC pattern would be, most probably, more cost-effective compared with the extended TPh testing offered in large populations. This way, a smaller number of patients will be tested and in this group a higher proportion of patients will be found as having HR-TPh mutations.


[Use of drugs in the hospital. Retrospective model study].
This study sets out to describe and evaluate antimicrobial therapy in the departments of surgery, medicine, gynecology and obstetrics of a 500-bed general hospital serving a mainly metropolitan population. About one third (605) of 2002 hospitalized patients received chemotherapy, 97 patients being treated for nosocomial infections. In 44% antimicrobials were given prophylactically, chiefly in the surgical department (in 60% of the drug courses) and the departments of gynecology (in 78%) and obstetrics (in 71%). Combinations (excluding sulphamethoxazole/ trimethoprim) were used on the medical wards in 5% and on the surgical wards in 15% of the drug courses. Gentamycin combined with beta-lactam antibiotics was most often used in medicine, while penicillin/streptomycin and ampicillin/cloxacillin in fixed ratios were the most frequent combinations in surgery. Finally, each therapy was evaluated by two experts as either rational, irrational or questionable. 61% of the 681 drug courses were considered rational, 16% questionable and 23% irrational. In the 155 irrational drug courses, one or more of the following criticisms were made: inappropriate chemoprophylaxis (101), wrong drug in chemoprophylaxis (66), inappropriate combination (30), wrong drug in symptomatic chemotherapy (28), no bacteriological diagnosis (26), sensitivity test not considered (17), use of antagonistic combinations (11) and wrong drug in therapeutic chemotherapy (5).


A randomized clinical trial of inpatient family intervention, III: Effects at 6-month and 18-month follow-ups.
This paper focuses on the follow-up results of a randomized clinical trial of inpatient family intervention (IFI) that emphasized psychoeducation. Results for the sample of 169 psychiatric patients suggested that adding family treatment to standard hospital treatment was effective; however, the statistical interactions indicated that this therapeutic effect was restricted to female patients with schizophrenia or major affective disorder. The effect of family treatment on male patients with these diagnoses was minimal or slightly negative. In a group of patients with other diagnoses, the Treatment by Sex effect was reversed: male patients did better with the family treatment.


Identification of acute ST-elevation myocardial infarction via remote implantable loop recorder monitor.
The indications for the use of implantable loop recorders include the evaluation of unexplained palpitations and syncope, embolic stroke of undetermined source, dizziness and lightheadedness presumed to be due to arrhythmogenic etiology, and for atrial fibrillation to guide antiarrhythmic drug therapy or catheter ablation efficacy. Long-term monitoring is especially beneficial if symptoms occur sporadically or are asymptomatic in nature. This is the first case to our knowledge of an acute ST-elevation myocardial infarction which was identified from remote monitoring of an implantable loop recorder through a device clinic.


Protein elasticity determined by pressure tuning of the tyrosine residue of ubiquitin.
We determined the isotropic, isothermal compressibility of ubiquitin by pressure tuning spectral holes burnt into the red edge of the absorption spectrum of the single tyrosine residue. The pressure shift is perfectly linear with burn frequency. From these data, a compressibility of 0.086 GPa(-1) in the local environment of the tyrosine residue could be determined. This value fits nicely into the range known for proteins. Although the elastic behavior at low temperatures does not show any unusual features, the pressure tuning behavior at room temperature is quite surprising: the pressure-induced spectral shift is close to zero, even up to very high pressure levels of 0.88 GPa, well beyond the denaturation point. The reason for this behavior is attributed to equally strong blue as well as red spectral pressure shifts resulting in an average pressure-induced solvent shift that is close to zero.


Tyrosine phosphorylation in peripheral lymphocytes from patients with systemic lupus erythematosus.
A comparative study of tyrosine phosphorylation was performed on peripheral blood lymphocytes from systemic lupus erythematosus (SLE) patients and from healthy donors. Freshly isolated SLE lymphocytes presented an elevated tyrosine phosphorylation level when compared to healthy donors lymphocytes (p = 0.005). Among all phosphorylated proteins, those called p120, p110, p80 and p55-p60 were more phosphorylated. The level of tyrosine phosphorylation of p120 and p110 proteins discriminated significantly (p = 0.0048, respectively, p = 0.02) between SLE patients and healthy donors. Lymphocytes form SLE patients and healthy donors were then stimulated by cross-linking T cell antigens (CD3, CD4, CD8) to further distinguish the signal transduction between normal and pathologic lymphocytes. No statistical differences in the tyrosine phosphorylation pattern, following CD4 or CD8 cross-linking, were observed between SLE patients and healthy donors lymphocytes. CD3 cross-linking induced an effect on tyrosine phosphorylation different in SLE patients versus healthy donors lymphocytes. Thus, the lymphocytes of SLE patients were refractile in anti-CD3 stimulation in comparison with the healthy donors lymphocytes. Chi-square analysis demonstrated that a significantly larger number of healthy donors responded to anti-CD3 stimulation compared to SLE patients (p = 0.03). The high frequency of tyrosine phosphorylation of p110 and p80 proteins, following CD3 stimulation, in normal versus SLE lymphocytes, suggested that these proteins could be involved in abnormal signal transduction in SLE cells.


Overnight orthokeratology-associated microbial keratitis.
This study was designed to report the clinical aspects, microbiologic findings, and treatment outcomes of overnight orthokeratology-associated microbial keratitis. Medical records of patients with overnight orthokeratology-associated microbial keratitis at National Taiwan University Hospital from August 2000 to October 2001were reviewed. The clinical and microbiologic characteristics and treatment outcomes were investigated. Nine patients (in total 10 eyes) from aged 8 to 17 (mean, 12.3 +/- 2.9) years were included in this study. Eight patients had a unilateral infection and one had a bilateral infection. The initial best corrected visual acuities ranged from hand motion to 20/20. The lesions were located at the central cornea in nine eyes (90%). Smears and cultures from corneal scrapings were obtained from all patients. Four eyes were culture-positive, which included nonfermentative Gram-negative bacillus, Pseudomonas aeruginosa and Acanthamoeba. Positive smears from another two eyes revealed Gram-negative bacilli and double-walled cyst. All patients were cured using antimicrobial medications with complete re-epithelization and disappearance of corneal infiltrates. Four eyes had a final best corrected visual acuity of 20/30 or worse after a mean follow-up of 9.4 months, including one eye that had visual acuity of hand motion only. Complications included corneal opacity in all eyes, glaucoma in one eye, and cataract in one eye. Overnight orthokeratology is an important risk factor of microbial keratitis, especially in school children. Acanthamoeba and Gram-negative bacilli, especially Pseudomonas aeruginosa, are the most common pathogens in our series. The risk of microbial keratitis after overnight orthokeratology should not be overlooked.


Thalamic involvement in paroxysmal kinesigenic dyskinesia: a combined structural and diffusion tensor MRI analysis.
Alteration of basal ganglia-thalamocortical circuit has been hypothesized to play a role in the pathophysiology underlying paroxysmal kinesigenic dyskinesia (PKD). We investigated macrostructural and microstructural changes in PKD patients using structural and diffusion tensor magnetic resonance imaging (MRI) analyses. Twenty-five patients with idiopathic PKD and 25 control subjects were prospectively studied on a 3T magnetic resonance (MR) scanner. Cortical thickness analysis was used to evaluate cortical gray matter (GM) changes, and automated volumetry and shape analysis were used to assess volume changes and shape deformation of the subcortical GM structures, respectively. Tract-based spatial statistics (TBSS) was used to evaluate white matter integrity changes in a whole-brain manner, and region-of-interest (ROI) analysis of diffusion tensor metrics was performed in subcortical GM structures. Compared to controls, PKD patients exhibited a reduction in volume of bilateral thalami and regional shape deformation mainly localized to the anterior and medial aspects of bilateral thalami. TBSS revealed an increase in fractional anisotropy (FA) of bilateral thalami and right anterior thalamic radiation in patients relative to controls. ROI analysis also showed an increase in FA of bilateral thalami in patients compared to controls. We have shown evidence for thalamic abnormalities of volume reduction, regional shape deformation, and increased FA in patients with PKD. Our novel findings of concomitant macrostructural and microstructural abnormalities in the thalamus lend further support to previous observations indicating causal relationship between a preferential lesion in the thalamus and development of PKD, thus providing neuroanatomical basis for the involvement of thalamus within the basal ganglia-thalamocortical pathway in PKD.


Influence of model assumptions about HIV disease progression after initiating or stopping treatment on estimates of infections and deaths averted by scaling up antiretroviral therapy.
Many mathematical models have investigated the population-level impact of expanding antiretroviral therapy (ART), using different assumptions about HIV disease progression on ART and among ART dropouts. We evaluated the influence of these assumptions on model projections of the number of infections and deaths prevented by expanded ART. A new dynamic model of HIV transmission among men who have sex with men (MSM) was developed, which incorporated each of four alternative assumptions about disease progression used in previous models: (A) ART slows disease progression; (B) ART halts disease progression; (C) ART reverses disease progression by increasing CD4 count; (D) ART reverses disease progression, but disease progresses rapidly once treatment is stopped. The model was independently calibrated to HIV prevalence and ART coverage data from the United States under each progression assumption in turn. New HIV infections and HIV-related deaths averted over 10 years were compared for fixed ART coverage increases. Little absolute difference (<7 percentage points (pp)) in HIV infections averted over 10 years was seen between progression assumptions for the same increases in ART coverage (varied between 33% and 90%) if ART dropouts reinitiated ART at the same rate as ART-naïve MSM. Larger differences in the predicted fraction of HIV-related deaths averted were observed (up to 15pp). However, if ART dropouts could only reinitiate ART at CD4<200 cells/μl, assumption C predicted substantially larger fractions of HIV infections and deaths averted than other assumptions (up to 20pp and 37pp larger, respectively). Different disease progression assumptions on and post-ART interruption did not affect the fraction of HIV infections averted with expanded ART, unless ART dropouts only re-initiated ART at low CD4 counts. Different disease progression assumptions had a larger influence on the fraction of HIV-related deaths averted with expanded ART.


Myocyte-specific enhancer binding factor 2A expression is downregulated during temporal lobe epilepsy.
Myocyte-specific enhancer binding factor 2A (MEF2A) is a multifunctional nuclear protein that regulates synaptogenesis, dendritic morphogenesis, and neuronal survival. This study aimed to investigate the expression pattern of MEF2A in epileptogenic processes. MEF2A expression was detected in 20 temporal neocortex tissue samples from patients with temporal lobe epilepsy (TLE) and 20 samples from trauma patients without epilepsy by real-time quantitative polymerase chain reaction, immunohistochemistry, double-label immunofluorescent staining, and western blot analysis. In addition, the expression patterns of MEF2A in the hippocampus and adjacent cortex of a lithium-pilocarpine-induced TLE rat model and control rats were examined. MEF2A was found to be expressed in the nuclei of neurons but not in the dendrites of neurons and astrocytes. MEF2A expression was significantly downregulated in temporal neocortex of humans and rats with TLE compared to the control groups. In addition, in the lithium-pilocarpine-induced TLE model, MEF2A expression dynamically decreased within 2 months. Taken together, these data suggest that MEF2A is involved in the pathogenesis of TLE.


Mutations of the adenomatous polyposis coli gene in the mutation cluster region: comparison of human pancreatic and colorectal cancers.
We analyzed the adenomatous polyposis coli (APC) tumor-suppressor gene as one of the possible genes mutated in human pancreatic carcinomas. DNAs from 39 surgical specimens were subjected to single-strand conformation polymorphism analysis of polymerase chain reaction products and the mutation cluster region (MCR) of the gene was examined. We also examined the same region of DNAs from 27 surgical specimens of sporadic colon carcinomas and detected mutations in 11 carcinomas (41%). This mutation frequency in colon carcinomas was similar to those reported previously. Using this system, we detected a mutated APC gene in one of 39 pancreatic carcinomas. The results indicated that mutation of the MCR in the APC gene is involved in genesis of some of human pancreatic carcinomas, but its frequency is much lower than in colorectal carcinomas.


Factors related to omalizumab resistance in chronic spontaneous urticaria.
Background: Omalizumab resistance (OmR) in chronic spontaneous urticaria (CSU) remains poorly understood. Objective: To identify clinical and laboratory attributes of patients that may be predictive of OmR in CSU. Methods: We conducted a retrospective observational study by using an electronic patient record data base of patients with severe CSU refractory to a fourfold H1-antihistamine dose, treated with omalizumab 300 mg every 4 weeks for at least 24 weeks. Complete response (CR) was defined as the reduction of baseline urticaria activity score by ≥ 90%, partial response (PR) by ≥ 30% to <90%, and OmR by <30% at 24 weeks. The patient characteristics of the CR, PR, and OmR groups were compared. Results: Sixty-three patients (58.9%) had a complete remission at 24 weeks of omalizumab therapy, and 16 patients (14.9%) had OmR. The patients who were OmR were characterized by a higher rate of arterial hypertension 7 (43.8%), higher mean ± standard deviation (SD) high-sensitivity C-reactive protein (hs-CRP) level (10.3 ± 8.2 mg/L), mean ± SD white blood cell (WBC) count (9.1 ± 2.8 × 10³ cells/mL), and higher mean ± SD C3 level (164.3 ± 45.4 mg/dL) at baseline than the patients with CR (arterial hypertension, 9 [13.1%], p = 0.009; mean ± SD hs-CRP, 3.4 ± 10.1, p = 0.014; mean ± SD WBC count, 6.5 ± 3.8 × 10³ cells/mL, p = 0.012; and mean ± SD C3 level, 121.8 ± 42.1 m/dL, p < 0.001). In multivariable analysis adjusted for age, sex, and body mass index, OmR was associated with an hs-CRP level of >3.0 mg/L (odds ratio 1.94 [95% confidence interval, 1.28-3.15], p = 0.009) and with C3 > 160 mg/dL (odds ratio 1.54 [95% confidence interval, 1.05-2.36], p = .017). Conclusion: Obesity, arterial hypertension, high plasma C3 level, and high-CRP level were associated with OmR in severe CSU.


Beak trimming of turkeys. 2. Effects of arc beak trimming on weight gain, feed intake, feed wastage, and feed conversion.
An experiment was conducted to study the effects of arc beak trimming on feed consumption, weight gain, and feed wastage in males and females from two large-bodied strains and one medium-bodied strain of turkeys. Birds were placed in wire-floored battery cages from 3 to 8 wk of age and feed intake, weight gains, and feed spilled into dropping pans were recorded for each of the 5 wk of each trial. Feed conversion was calculated as feed consumed divided by weight gained. Sex by beak trimming interactions were not found. Beak trimming reduced feed wastage of the two large-bodied strains, but did not affected feed wastage of the medium-bodied strain, which did not consume as much feed as the large-bodied strains. The results of this study support the hypothesis that beak trimming reduces feed wastage of large-bodied turkeys.


Selective Utilization of Benzimidazolyl-Norcobamides as Cofactors by the Tetrachloroethene Reductive Dehalogenase of Sulfurospirillum multivorans.
The organohalide-respiring bacterium Sulfurospirillum multivorans produces a unique cobamide, namely, norpseudo-B12, which serves as cofactor of the tetrachloroethene (PCE) reductive dehalogenase (PceA). As previously reported, a replacement of the adeninyl moiety, the lower base of the cofactor, by exogenously applied 5,6-dimethylbenzimidazole led to inactive PceA. To explore the general effect of benzimidazoles on the PCE metabolism, the susceptibility of the organism for guided biosynthesis of various singly substituted benzimidazolyl-norcobamides was investigated, and their use as cofactor by PceA was analyzed. Exogenously applied 5-methylbenzimidazole (5-MeBza), 5-hydroxybenzimidazole (5-OHBza), and 5-methoxybenzimidazole (5-OMeBza) were found to be efficiently incorporated as lower bases into norcobamides (NCbas). Structural analysis of the NCbas by nuclear magnetic resonance spectroscopy uncovered a regioselectivity in the utilization of these precursors for NCba biosynthesis. When 5-MeBza was added, a mixture of 5-MeBza-norcobamide and 6-MeBza-norcobamide was formed, and the PceA enzyme activity was affected. In the presence of 5-OHBza, almost exclusively 6-OHBza-norcobamide was produced, while in the presence of 5-OMeBza, predominantly 5-OMeBza-norcobamide was detected. Both NCbas were incorporated into PceA, and no negative effect on the PceA activity was observed. In crystal structures of PceA, both NCbas were bound in the base-off mode with the 6-OHBza and 5-OMeBza lower bases accommodated by the same solvent-exposed hydrophilic pocket that harbors the adenine as the lower base of authentic norpseudo-B12 In this study, a selective production of different norcobamide isomers containing singly substituted benzimidazoles as lower bases is shown, and unique structural insights into their utilization as cofactors by a cobamide-containing enzyme are provided.IMPORTANCE Guided biosynthesis of norcobamides containing singly substituted benzimidazoles as lower bases by the organohalide-respiring epsilonproteobacterium Sulfurospirillum multivorans is reported. An unprecedented specificity in the formation of norcobamide isomers containing hydroxylated or methoxylated benzimidazoles was observed that implicated a strict regioselectivity of the norcobamide biosynthesis in the organism. In contrast to 5,6-dimethylbenzimidazolyl-norcobamide, the incorporation of singly substituted benzimidazolyl-norcobamides as a cofactor into the tetrachloroethene reductive dehalogenase was not impaired. The enzyme was found to be functional with different isomers and not limited to the use of adeninyl-norcobamide. Structural analysis of the enzyme equipped with either adeninyl- or benzimidazolyl-norcobamide cofactors visualized for the first time structurally different cobamides bound in base-off conformation to the cofactor-binding site of a cobamide-containing enzyme.


Riluzole rescues cochlear sensory cells from acoustic trauma in the guinea-pig.
Acoustic trauma is the major cause of hearing loss in industrialised nations. We show in guinea-pigs that sound exposure (6 kHz, 120 dB sound pressure level for 30 min) leads to sensory cell death and subsequent permanent hearing loss. Ultrastructural analysis reveals that degeneration of the noise-damaged hair cells involved different mechanisms, including typical apoptosis, autolysis and, to a lesser extent, necrosis. Whatever the mechanisms, a common feature of noise damage to hair cells was mitochondrial alteration. Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is a neuroprotective agent that prevents apoptosis- and necrosis-induced cell death. Perfusion of riluzole into the cochlea via an osmotic minipump prevents mitochondrial damage and subsequent translocation of cytochrome c, DNA fragmentation, and hair cell degeneration. This was confirmed by functional tests showing a clear dose-dependent reduction (ED(50)=16.8 microM) of permanent hearing loss and complete protection at 100 microM. Although less efficient than intracochlear perfusion, intraperitoneal injection of riluzole rescues the cochlea within a therapeutic window of 24 h after acoustic trauma.These results show that riluzole is able to prevent and rescue the cochlea from acoustic trauma. It may thus be an interesting molecule for the treatment of inner ear injuries.


A rapid, sensitive myeloperoxidase stain using 4-chloro-1-naphthol.
The substitution of 4-chloro-1-naphthol for benzidine-containing compounds used in the myeloperoxidase stain for distinguishing granulocytes from lymphoid blood elements is described. 4-Chloro-1-naphthol is an acceptable substitute for benzidine compounds, which are considered to be carcinogenic. The feasibility of using this method on peripheral blood and bone-marrow films is discussed.


Impulse backscattering in granular beds: introducing a toy model.
Impulses efficiently propagate into nominally dry granular beds and backscatter from buried inclusions in such beds may be potentially exploited to image shallow buried objects (SBOs). However, reliable imaging of SBOs requires "cleaning up" of surface vibrations, and, in addition to three-dimensional (3D) particle dynamics simulations, a phenomenological model to parametrize the bed surface may be useful for field applications. We introduce a 1D mean-field-like toy model with two parameters, which allows one to model surface vibrations, is consistent with experiments in a granular bed, and can help estimate the approximate signal transmission properties of the bed.


Germline BRCA1/2 testing practices in ovarian cancer: Current state and opportunities for new directions.
Given the implications for clinical care and prevention in identifying a BRCA1/2 mutation, the objective of this study was to determine current BRCA1/2 testing practices in ovarian cancer and to identify future directions. Two parallel complementary web-based surveys were sent by email to representatives of Gynecologic Cancer InterGroup (GCIG) and to referral centers in countries with and without GCIG membership. Questions posed addressed indications of BRCA1/2 testing for ovarian cancer; the implication of genetic counseling; and prevention strategies employed. Among the GCIG, 22 collaborative groups from 19 countries answered the survey. For the complementary survey, 22 referral centers replied. Findings show criteria to offer germline BRCA1/2 testing are mixed; 55% of GCIG members based testing decisions on histology and, among all respondents the main testing criterion remains family history. Typically, genetic counseling is scheduled prior to the genetic testing; however, if negative, results may not be communicated by the genetic counselor. Time between testing and communicating results varies widely between the groups. Lastly, recommendations to relatives regarding risk reduction surgery are inconsistent. Our study highlights the need for collaborative efforts to devise international guidelines around BRCA1/2 testing in ovarian cancer to ensure consistent BRCA1/2 screening practices are adopted. Clinical practice is evolving rapidly and as BRCA1/2 testing is expected to become more widespread, new approaches are required. Coordinating BRCA1/2 testing practices is crucial in terms of care for the patient diagnosed with ovarian cancer but also towards cancer prevention for affected family members.


Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease.
Painful vaso-occlusive crisis (VOC), a complication of sickle cell disease (SCD), occurs when sickled red blood cells obstruct flow in the microvasculature. We postulated that exaggerated sympathetically mediated vasoconstriction, endothelial dysfunction and the synergistic interaction between these two factors act together to reduce microvascular flow, promoting regional vaso-occlusions, setting the stage for VOC. We previously found that SCD subjects had stronger vasoconstriction response to pulses of heat-induced pain compared to controls but the relative degrees to which autonomic dysregulation, peripheral vascular dysfunction and their interaction are present in SCD remain unknown. In the present study, we employed a mathematical model to decompose the total vasoconstriction response to pain into: 1) the neurogenic component, 2) the vascular response to blood pressure, 3) respiratory coupling and 4) neurogenic-vascular interaction. The model allowed us to quantify the contribution of each component to the total vasoconstriction response. The most salient features of the components were extracted to represent biophysical markers of autonomic and vascular impairment in SCD and controls. These markers provide a means of phenotyping severity of disease in sickle-cell anemia that is based more on underlying physiology than on genotype. The marker of the vascular component (BMv) showed stronger contribution to vasoconstriction in SCD than controls (p = 0.0409), suggesting a dominant myogenic response in the SCD subjects as a consequence of endothelial dysfunction. The marker of neurogenic-vascular interaction (BMn-v) revealed that the interaction reinforced vasoconstriction in SCD but produced vasodilatory response in controls (p = 0.0167). This marked difference in BMn-v suggests that it is the most sensitive marker for quantifying combined alterations in autonomic and vascular function in SCD in response to heat-induced pain.


[Influence of Coca-Cola on early erosion and surface microhardness of human enamel: an in situ study].
Assessed the effect of single dose attack of Coca-Cola on early erosion and surface microhardness of permanent human enamel, in order to provide diet instructions on minimum amount and frequency of carbonated beverage consumption. Eighty enamel slabs were prepared out of 10 extracted human mandibular third molars, and distributed into 8 groups with randomized block design(n=10). Ten generally healthy volunteers with normal saliva secretion wore acrylic palatal appliances containing 2 enamel slabs, with formation of a salivary pellicle 2 h ahead. The volunteers were instructed to drink 100 ml fresh Coca-Cola within 20 s. And then the alterations of the enamel slabs were measured using a Vicker's microhardness tester at 1, 2, 4, 6, 8, 10, 20 and 30 min after the consumption of Coca-Cola. For each volunteer, the experiment was carried out in four days, 2 samples were examined each time. Data were analyzed using Kruskal-Wallis and Wilcoxon tests(α =0.05). Significant decreases in surface microhardness(SMH)were observed in each time point(P<0.01). The percentages of surface microhardness changes on each exposure time were(12.2±3.9)%,(16.8±5.5)%,(16.7±5.6)%,(16.2±6.2)%,(16.6±9.0)%,(15.6±3.7)%,(13.8±4.8)% and(11.4±3.2)%, respectively. Significant differences were observed between G1 min and G2-8 min(P=0.029), G2-8 min and G30 min(P=0.008). Single intake of 100 ml Coca-Cola could lead to significant decrease of enamel microhardness and initiate erosion of enamel surface. Enamel surface microhardness decreased to the lowest points at 2-8 min, and began to recover after 10 min. The enamel surface microhardness could not fully recovered to the baseline level in 30 min if no intervention was performed.


Selection of odorants for memory tests on the basis of familiarity, perceived complexity, pleasantness, similarity and identification.
In a procedure for the selection of two equivalent sets of familiar and two equivalent sets of unfamiliar odours for use in odour memory studies, 24 naïve subjects were first asked to rate the familiarity, perceived complexity and pleasantness of 54 a priori unfamiliar odours and 57 a priori familiar odours and to identify the latter. After selection of the 40 most familiar and the 40 least familiar odours, the subjects sorted each of these two sets into groups of similar odours. Their results were analysed by multidimensional scaling and cluster analysis and each set was divided into two recognition sets that had the same degree of similarity between target and distractor odours and that had similar values of familiarity, pleasantness, perceived complexity (familiar and unfamiliar sets) and identifiability (familiar sets). Finally, recognition tasks were performed in order to check the equivalence in memory performance of both the two familiar and the two unfamiliar recognition sets.


The immunoexpression of EGFR, HER2 and HER3 in malignant serous ovarian tumors.
The expression of epidermal growth factor (EGF) receptors is common in human carcinomas and the proteins are used as therapeutics targets. In this study, we analyzed the immunoexpression of EGFR, HER2 (EGFR2) and HER3 (EGFR3) in 41 cases of serous borderline ovarian tumors and carcinomas, in relation to the degree of differentiation and tumor stage. The quantification of the results was done using the final staining score (FSS), which took into account the number of labeled cells and the intensity of immunoreactions. For all the receptors, the FSS values corresponding to the high-grade serous carcinomas were significantly superior compared with low-grade carcinomas and borderline tumors. Also, the FSS values associated with advanced stages ovarian tumors were significantly superior compared to those in the initial stages. In this study, we found positive linear correlations between the values associated with the expression of EGF receptors. The relation of EGFR, HER2 and HER3 immunoexpression with the lesion subtype, tumor grade and stage, designates the EGF receptors system as possible therapeutic target in ovarian serous tumors.


Methodologic differences and measurement of cup-disc ratio: an epidemiologic assessment.
A retrospective analysis was undertaken to estimate the effect on measurements of cup-disc ratio (CDR) that result from overall differences among examination methods used by experienced investigators. The findings suggest large inter-observer differences, that is, large differences in measurement attributable to differences in definitions and methods between one observer and another. Extreme caution is indicated before attaching wide clinical or investigative importance to a specific value of CDR. A value of CDR regarded as the dividing line between normalcy and suspicion by one observer may be a highly inappropriate cutoff for another observer. Similarly, if different observers record measurements on the same patient, it may be impossible to determine whether the cup of an individual patient changes with time. Interobserver differences also can cast doubt on conclusions drawn from the comparison of data collected by different investigators. There is a need for standardization of definitions and methods in such clinical or research situations.


Effects of increasing sound pressure level on lip and jaw movement parameters and consistency in young adults.
Examination of movement parameters and consistency has been used to infer underlying neural control of movement. However, there has been no systematic investigation of whether the way individuals are asked (or cued) to increase loudness alters articulation. This study examined whether different cues to elicit louder speech induce different lip and jaw movement parameters or consistency. Thirty healthy young adults produced two sentences (a) at comfortable loudness, (b) while targeting 10 dB SPL above comfortable loudness on a sound level meter, (c) at twice their perceived comfortable loudness, and (d) while multitalker noise was played in the background. Lip and jaw kinematics and acoustic measurements were taken. Each of the loud conditions resulted in a similar amount of SPL increase, about 10 dB. Speech rate was slower in the background noise condition. Changes to movement parameters and consistency (relative to comfortable) were different in the targeting condition as compared to the other loud conditions. The cues elicited different task demands, and therefore, different movement patterns were used by the speakers to achieve the target of increased loudness. Based on these results, cueing should be considered when eliciting increased vocal loudness in both clinical and research situations.


Haloperidol ameliorates androgen-induced behavioral deficits in developing male rats.
The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system.


Characteristics of microsatellites in the transcript sequences of the Laccaria bicolor genome.
In this paper, we analyzed the microsatellites in the transcript sequences of the whole Laccaria bicolor genome. Our results revealed that, apart from the triplet repeats, length diversification and richness of the detected microsatellites positively correlated with their repeat motif lengths, which were distinct from the variation trends observed for the transcriptional microsatellites in the genome of high plant. We also compare the microsatellites detected in the genic regions and in the non-genic regions of the L. bicolor genome. Subsequently, SSR primers were designed for the transcriptional microsatellites in the L. bicolor genome. These SSR primers provide desirable genetic resources to the ectomycorrhizae community and this study provides deep insight into the characteristics of the microsatellite sequences in the L. bicolor genome.


Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency.
Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin-like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin-1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin-proteasome and autophagocytosis systems and protein chaperones. The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.


Artificial Intelligence-Based Application Provides Accurate Medical Triage Advice When Compared to Consensus Decisions of Healthcare Providers.
Accurate medical triage is essential for improving patient outcomes and efficient healthcare delivery. Patients increasingly rely on artificial intelligence (AI)-based applications to access healthcare information, including medical triage advice. We assessed the accuracy of triage decisions provided by an AI-based application. We presented 50 clinical vignettes to the AI-based application, seven emergency medicine providers, and five internal medicine physicians. We compared the triage decisions of the AI-based application to those of the individual providers as well as their consensus decisions. When compared to the human clinicians' consensus triage decisions, the AI-based application performed equal or better than individual human clinicians.


Dalbavancin plasma concentrations in 133 patients: a PK/PD observational study.
Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study. Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible. One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L). Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.


Polyethylene Terephthalate Composite Films with Enhanced Flame Retardancy and Gas Barrier Properties via Self-Assembly Nanocoating.
The flammability and gas barrier properties are essential for package material. Herein, a highly-oriented self-assembly nanocoating composed of polyvinyl alcohol (PVA) and montmorillonite (MMT) was prepared for endowing polyethylene terephthalate (PET) films with excellent flame retardancy and gas barrier properties. The specific regular nanosheet structure of the PVA/MMT composite nanocoating was confirmed by Fourier transform infrared (FTIR) and X-ray diffraction (XRD). Thermogravimetric analysis (TGA) and the vertical burning test (VBT) suggested that the thermal stability and flame-retardancy of the coated PET films were considerably improved with more pick-up of the resulting nanocoating. When reaching 650 °C, there was still 22.6% char residual left for coated PET film, while only 6% char residual left for pristine PET film. During the vertical burning test, the flame did not spread through the whole PET film with the protection of PVA/MMT nanocoating, and no afterflame was observed. Scanning electron microscopy (SEM) is consistent with vertical burning test, proving that the thermal stability and flame retardancy of coated PET films were considerably enhanced with the increment of PVA/MMT. Thanks to the multi-layer structure, PVA/MMT nanocoating could effectively improve the gas barrier properties of PET films, and the oxygen vapor transmittance rate and water vapor transmittance rate of PET films were more than four hundred times lower and 30% lower than those of neat PET film. Our work demonstrates that bi-functional flame retardant and gas barrier materials could be gained via constructing inorganic/organic highly-oriented self-assembly nanocoating, which is promising in the area of packaging.


Plausibility and influence in selection models: A comment on Citkowicz and Vevea (2017).
I discuss how methods that adjust for publication selection involve implicit or explicit selection models. Such models describe the relation between the studies conducted and those actually observed. I argue that the evaluation of selection models should include an evaluation of the plausibility of the empirical implications of that model. This includes how many studies would have had to exist to yield the observed sample of studies. I also argue that the amount of influence that one or a small number of studies might have on the overall results is also important to understand. (PsycINFO Database Record


Activation of the Kynurenine Pathway and Production of Inflammatory Cytokines by Astrocytes and Microglia Infected With Neospora caninum.
In the central nervous system, astrocytes and microglia contribute to homeostasis, regulating the immune response to infectious agents. Neospora caninum is an obligate intracellular protozoan that infects different animal species and it is encysted in their nervous tissue while triggering an immune response modulated by glia. This study aimed to evaluate the infection of primary cultures of rat glial cells by N. caninum through the catabolites of tryptophan, the expression of inflammatory mediators and the integrity of neural tissue. Infection with this coccidium resulted in morphological and functional changes, particularly astrogliosis and microgliosis, and increased the expression of the inflammatory mediators TNF, IL1β, IL-10, and arginase, as well as mRNA for CCL5 and CCL2, molecules involved in the CNS chemotaxis. The infection with N. caninum in glial cells also triggered the activation of the tryptophan pathway, characterized by increased kynurenine 2,3 monooxygenase (KMO) mRNA expression, and by the production of the excitotoxin quinolinic acid (QUIN). Moreover, glia-neuron co-cultures, when exposed to the secretome derived from N. caninum infected glial cells, presented greater neurons distribution and formation of neurite extensions, associated to morphological changes in astrocytes compatible with neuro-preservation. Considering that the tryptophan catabolism is associated to immune response, these findings suggest that glial activation in N. caninum infection should be responsible for modulating the inflammatory status in an attempt to restore the nervous system homeostasis, since excessive inflammatory response can cause irreversible damage to tissue preservation.


A clinical study of PMCJ-9 (Bacillus Calmette-Guérin Connaught strain) treatment of superficial bladder cancer and carcinoma in situ of the bladder.
Intravesical Bacillus Calmette-Guérin (BCG) is now a standard treatment for Ta, T1 carcinoma and carcinoma in situ (CIS) of the urinary bladder. In Japan, however, only BCG Tokyo 172 strain is commercially available. We therefore designed a clinical study of PMCJ-9 (BCG Connaught strain) for obtaining approval from Japanese Ministry of Health, Labor and Welfare. In the phase I-II study, PMCJ-9 40.5, 81 (standard dose overseas) or 121.5 mg in saline was instilled into the bladder of patients with Ta, T1 or CIS once weekly for 8 weeks. The recommended dose was decided and similarly administered in the late phase II study. In the phase I-II study, 49 patients were evaluable for efficacy. The complete response (CR) rates were 60.0% (9/15), 68.2% (15/22) and 75.0% (9/12) in the 40.5, 81 and 121.5 mg groups. The incidence of adverse drug reactions (ADRs) was similar in all groups, but four 121.5 mg group patients developed severe ADRs. Thus, 81 mg was the recommended dose for the late phase II study. In that study, 39 patients were evaluable, showing CR rates of 71.8% (28/39) overall and 61.5% (16/26) and 92.3% (12/13) for the Ta, T1 and CIS cases. The safety was assessed in 42 patients and three (7.1%) were discontinued owing to ADRs. The recommended dose for the BCG Connaught strain was decided as 81 mg. PMCJ-9 administration at this dose level weekly for 8 weeks showed a clear antitumor effect and good safety profile against Ta, T1 and CIS transitional cell carcinoma of the bladder.


Intratracheal sensitization/challenge-induced biphasic asthmatic response and airway hyperresponsiveness in guinea pigs.
In most experimental model of asthma using guinea pigs, the animals are made to inhale an aerosolized antigen which passes through the nasal cavity. In the present study, we attempted to create an animal model of asthma showing a biphasic asthmatic response and airway hyperresponsiveness, in which the allergic responses are restricted to the lung. Guinea pigs were sensitized by the intratracheal instillation of ovalbumin (OVA)+Al(OH)₃ once a day for 7 d, and then intratracheally challenged with OVA 12 d after the last sensitization. The change in specific airway resistance (sRaw) and airway responsiveness to histamine were measured. Pranlukast (100 mg/kg), theophylline (50 mg/kg), and dexamethasone (10 mg/kg) were orally administered 18 and 2 h before the antigen challenge. The challenge caused a marked biphasic elevation of sRaw with peaks at 5 min and 4 h. At 24 h, airway hyperresponsiveness to histamine was observed. Pranlukast, theophylline, and dexamethasone suppressed the late asthmatic response and airway hyperresponsiveness. The early asthmatic response was inhibited by theophylline and dexamethasone. In conclusion, the intratracheal sensitization and challenge caused a biphasic asthmatic response and airway hyperresponsiveness in guinea pigs. This model may be useful for the evaluation of anti-asthma drugs.


HCV virus and lymphoid neoplasms.
Hepatitis C virus (HCV) is one of the viruses known to cause hepatic cancer. HCV is also believed to be involved in malignant lymphoma. In this paper, we investigated characteristics of malignant lymphoma cases that were anti-HCV antibody (HCV-Ab) positive. We were able to perform pathological examinations on 13 out of 14 HCV-positive cases. Of these, lymphoid tissues of 10 stained positive for HCV-Ab. There was no significant correlation between the degree of HCV staining and the rate of recurrence or resistance to treatment. However, there did appear to be a consistent decrease in the amount of HCV-RNA between pre- and posttreatment among HCV-Ab-positive cases; that is, treatment-resistant cases that exhibited resistance from the first treatment and recurrent cases more frequently had a higher HCV level at treatment termination compared to the pretreatment level. This suggests that the HCV virus either accelerates oncogenesis by direct interaction with B cells or indirectly affects lymphoma prognosis.


Removal of protein-bound, hydrophobic uremic toxins by a combined fractionated plasma separation and adsorption technique.
Protein-bound uremic toxins, such as phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate, contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, based on their protein binding, these hydrophobic uremic toxins are poorly cleared during conventional dialysis and thus accumulate in CKD-5D patients. Therefore, we investigated whether hydrophobic and cationic adsorbers are more effective for removal of protein-bound, hydrophobic uremic toxins than conventional high-flux hemodialyzer. Five CKD-5D patients were treated using the fractionated plasma separation, adsorption, and dialysis (FPAD) system for 5 h. A control group of five CKD patients was treated with conventional high-flux hemodialysis. Plasma concentrations of phenylacetic acid, indoxyl sulfate, and p-cresyl sulfate were measured. Removal rates of FPAD treatment in comparison to conventional high-flux hemodialysis were increased by 130% for phenylacetic acid, 187% for indoxyl sulfate, and 127% for p-cresol. FPAD treatment was tolerated well in terms of clinically relevant biochemical parameters. However, patients suffered from mild nausea 2 h after the start of the treatment, which persisted until the end of treatment. Due to the high impact of protein-bound, hydrophobic uremic toxins on progression of CKD and CVD in CKD-5D patients, the use of an adsorber in combination with dialysis membranes may be a new therapeutic option to increase the removal rate of these uremic toxins. However, larger, long-term prospective clinical trials are needed to demonstrate the impact on clinical outcome.


Effects of denervation on posterior cricoarytenoid muscle physiology and histochemistry.
The effects of chronic posterior cricoarytenoid muscle denervation were assessed at 3 and 7 months in 26 animals following resection of 10 cm of recurrent laryngeal nerve with stump ligation. The physiology of denervation was characterized by a decrease in contraction strength and an increase in contraction time. The reduction in contraction strength reflected the loss in muscle weight and atrophic changes in fiber density and diameter. A change in muscle composition occurred because of the increased susceptibility of fast-twitch (type 2) fibers to degeneration. However, the compositional change alone could not account for the slowing of muscle contraction. Muscle fibrosis was negligible at 3 months, but encompassed one third of the fiber population by 7 months. In view of the irreversible nature of fibrosis, this study suggested that clinical intervention to rescue denervated posterior cricoarytenoid muscle fibers should be delayed no longer than 7 months to improve the chances for full recovery.


A vicious partnership between AKT and PHLDA3 to facilitate neuroendocrine tumors.
Pancreatic neuroendocrine tumors (PanNET) are rare cancers that generally have a poor prognosis. Accurate diagnosis and proper treatment of these tumors requires a better understanding of the molecular mechanisms underlying the development of PanNET. It has been shown that the mTOR inhibitor everolimus can improve the progression-free survival of PanNET patients, suggesting that inhibition of the PI3K-Akt-mTOR pathway may suppress the progression of PanNET. PHLDA3 is a novel tumor suppressor protein that inhibits Akt activation by competition for binding to PIP3 . Our analysis of PanNET revealed frequent loss-of-heterozygosity and DNA methylation at the PHLDA3 locus, resulting in strong suppression of PHLDA3 transcription. Such alterations in the PHLDA3 gene were also frequently found in lung neuroendocrine tumors (NET), suggesting the possibility that various types of NET have in common the functional loss of the PHLDA3 gene.


Long-term results and functional outcome after cervical evisceration in patients with thyroid cancer.
Surgical strategy in patients with thyroid cancer (TC) infiltrating the aerodigestive system is controversial. This study was undertaken to examine the long-term results of cervical evisceration (CE). Since 1995, 14 consecutive patients with advanced TC underwent total laryngectomy (LE, n = 6) or esophagolaryngectomy (ELR, n = 8). Patients with unusual thyroid neoplasms or metastases to the thyroid (n = 3) were excluded. For esophageal reconstruction, free jejunal grafts (n = 6) and gastric tubes (n = 2) were used. Procedure-related morbidity and mortality were 42% and 14%, respectively. ELR was associated with a significant higher frequency of complications and reoperations compared with LE. Twelve-month and 30-month survival rates were 73% and 55%, respectively; 85% of the patients were satisfied with the surgical results. There were no long-term problems concerning food intake in the ELR patients. Two ELR patients were able to learn a substitutive voice. Cervical evisceration in patients with TC is associated with significant perioperative morbidity and mortality requiring careful patient selection. Regarding long-term survival, local tumor control, and patient's satisfaction, however, CE should be taken into account in suitable patients with advanced TC.


Stratification of enterochromaffin cells by single-cell expression analysis.
Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.


Experience of Treating Critically Ill COVID-19 Patients in Daegu, South Korea.
At the beginning of February 2020, Daegu faced a serious situation due to the rapid outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2. The healthcare system in Daegu Metropolitan City was ill-prepared for this sudden disaster situation. The COVID-19 pandemic is still ongoing in South Korea. Daegu has limited medical resources compared to the Seoul Metropolitan Area, and it is hypothesized that a review of the outbreak therein could provide information that will be valuable for dealing with future outbreaks. The likelihood of death due to COVID-19 depends on the capacity of the area for the treatment of critically ill patients. This report reviews the overall treatment process followed for critically ill patients in Daegu.


Transverse thoracic diameter in frontal chest radiographs of an adult Nigerian population.
Normal standards for thoracic dimensions that are available in our environment are often based on studies conducted on Caucasians. Application of such published data to a Nigerian population may lead to erroneous conclusions in terms of clinical implication. Our study aimed to establish age and sex specific transverse thoracic diameter (TD) for our environment. The TD of 303 males and females aged between 20 and 93 were obtained in a cross sectional study at a tertiary hospital. The mean values for the 20-39, 40-59 and the 3 60-year-old males were 29.6, 29.0, 27.8 cm respectively. The corresponding values for females were 26.3, 27.1 and 25.1 cm. Males had significantly larger thoracic diameter than females. The largest mean TD in males and females were in the 20-39 and 40-59 age groups respectively. The TD had a significant positive correlation with weight, height, body mass index and body surface area. The best correlations were with body surface area and weight. Nigerians have a smaller TD than Caucasians. Smaller TD in Nigerians is likely to be responsible for their high cardiothoracic ratios in comparison with Caucasians or Asians.


Glucocorticoid downregulates expression of IL-12 family cytokines in systemic lupus erythematosus patients.
This study aims to investigate expression of interleukin 12 (IL-12) family cytokines IL-12, IL-23, IL-27 and IL-35 in systemic lupus erythematosus (SLE) patients and the effect of glucocorticoid (GC) treatment on their expression. Plasma concentration of IL-12, IL-23, IL-27, IL-35, IL-6 and anti-double-stranded DNA (dsDNA) antibodies in 30 newly diagnosed severe SLE patients and 30 matched healthy subjects was measured by enzyme-linked immunosorbent assay. The correlation between the levels of IL-12 family cytokines and the levels of IL-6 or anti-dsDNA antibodies was analyzed by Spearman rank correlation. Significantly higher levels of plasma IL-12, IL-23, IL-27, IL-35, IL-6 and anti-dsDNA antibodies were observed in SLE patients compared with healthy controls (p < 0.05), and after prednisone treatment, the serum levels of IL-12 family cytokines decreased significantly. Moreover, serum levels of IL-12, IL-23, IL-27 and IL-35 were correlated with serum levels of IL-6 and anti-dsDNA antibodies in pre-treatment as well as post-treatment SLE patients. SLE patients have increased plasma levels of IL-12 family cytokines and GCs can downregulate the expression of them in SLE patients. Therefore, members of the IL-12 family may be involved in the pathophysiological process of SLE.


[F1000: a new medical literature evaluation and retrieval system].
This article introduced a new clinical research evaluating system, Faculty of 1000 Medicine (F1000M), in which articles are selected, rated, and evaluated by its faculty of over 10 000 expert scientists and clinical researchers engaging in more than 3 000 peer-reviewed journals. It is a kind of post-publication peer review. A few evaluated articles about Chinese medicine were selected and introduced. It is hoped that F1000 could inspire both traditional Chinese medicine researchers and Western medicine researchers to conduct good quality research and write good clinical research reports.


Detection of desmoplastic melanoma with dermoscopy and reflectance confocal microscopy.
Desmoplastic melanoma (DM) is frequently misdiagnosed clinically and often associated with melanoma in situ (MIS). To improve the detection of DM using dermoscopy and reflectance confocal microscopy (RCM). A descriptive analysis of DM dermoscopy features and a case-control study within a melanoma population for RCM feature evaluation was performed blindly, using data obtained between 2005 and 2015. After retrospectively identifying all DM cases with RCM data over the study period (n = 16), a control group of non-DM melanoma patients with RCM data, in a ratio of at least 3 : 1, was selected. The control group was matched by age and primary tumour site location, divided into non-DM invasive melanomas (n = 27) and MIS (n = 27). Invasive melanomas were selected according to the melanoma subtypes associated with the DM cases. The main outcomes were the frequency of melanoma-specific features on dermoscopy for DM; and the odds ratios of RCM features to distinguish DM from MIS and/or other invasive melanomas; or MIS from the combined invasive melanoma group. At least one of the 14 melanoma-specific features evaluated on dermoscopy was found in 100% of DMs (n = 15 DM with dermoscopy). Known RCM melanoma predictors were commonly found in the DMs, such as pagetoid cells (100%) and cell atypia (100%). The RCM feature of spindle cells in the superficial dermis was more common in DM compared with the entire melanoma control group (OR 3.82, 95% CI 1.01-14.90), and particularly compared to MIS (OR 5.48, 95% CI 1.11-32.36). Nucleated cells in the dermis and the RCM correlate of dermal inflammation were also significant RCM features favouring DM over MIS, as well as invasive melanoma over MIS. Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive melanomas. Larger studies are warranted.


Experimental perturbation of the development of sexual size dimorphism in the mouse skeleton.
BALB/c mice were raised for 30 days under nine treatment regimens to determine their effects on sexual dimorphism for size of the femur and of the body. Treatment groups were divided into three experiments: 1) burrowing in a high litter cage; eight times normal gravity for a total of one hour per day; a voluntary exercise control. 2) Unilateral femoral and sciatic nerve ablation; the opposite unoperated leg. 3) Swimming exercise; anabolic steroid; swimming and anabolic steroid; normal exercise control. Traits measured were body weight gain and thirteen femoral characters: moment at failure, length, cross-sectional area, anteroposterior and lateromedial diameters of the cross section, wall thickness for all four quadrants of the shaft, moments of inertia of the cross section in the anteroposterior and lateromedial directions, deflection of the shaft before failure, and total mineral content. Sexual dimorphism of the traits studied varied significantly with treatment. The greatest dimorphism was seen in the controls and the burrowing group. The least dimorphism was seen in the eight times gravity, the steroid, and the exercise and anabolic steroid groups. Reduction in the extent of sexual dimorphism was not correlated with a reduction in the loading regimen but rather seemed mediated by systemic changes in physiology brought on by several factors. Change in the amount of sexual dimorphism for size from the control reflects change in growth rates for males and females in response to different treatments. Change in growth rates of juvenile males and females will likely result in changes in the size of femoral characters and body weight in the adult. Change in the size of femoral characters affects the strength of the femur. In natural populations, a change in the body size of adult males and females could adversely affect reproductive success in groups that normally exhibit strong dimorphism, and hence, select against any conditions that reduce sexual dimorphism. Ordinarily, a significant change in sexual dimorphism--of the magnitude seen here--through natural selection, would take several generations.


Laparoscopic radical nephrectomy: morcellate or leave intact? Definitely morcellate!
Eleven years after the first laparoscopic radical nephrectomy (LRN), which was performed with morcellation, the best approach to the procedure remains controversial. Concerns include tumor seeding, recurrence, accuracy of staging, histopathological diagnosis, and longer surgery time. Enclosing the kidney in an impermeable sac prior to morcellation helps prevent seeding. Pathological review of morcellated LRN specimens has been shown to be as accurate as that of intact specimens. Ten-year survival data for LRN with morcellation are not available yet, but 5-year rates are as good as those for open nephrectomy. The utility of morcellation in LRN is supported by the results of clinical practice.


The influence of Cs/Cc correction in analytical imaging and spectroscopy in scanning and transmission electron microscopy.
Aberration correction in scanning/transmission electron microscopy (S/TEM) owes much to the efforts of a small dedicated group of innovators. Leading that frontier has been Prof. Harald Rose. To date his leadership and dynamic personality has spearheaded our ability to leave behind many of the limitations imposed by spherical aberration (Cs) in high resolution phase contrast imaging. Following shortly behind, has been the development of chromatic aberration correction (Cc) which augments those accomplishments. In this paper we will review and summarize how the combination of Cs/Cc technology enhances our ability to conduct hyperspectral imaging and spectroscopy in today's and future computationally mediated experiments in both thin as well as realistic specimens in vacuo and during in-situ/environmental experiments.


Factors predictive of regret in sex reassignment.
The objective of this study was to evaluate the features and calculate the frequency of sex-reassigned subjects who had applied for reversal to their biological sex, and to compare these with non-regretful subjects. An inception cohort was retrospectively identified consisting of all subjects with gender identity disorder who were approved for sex reassignment in Sweden during the period 1972-1992. The period of time that elapsed between the application and this evaluation ranged from 4 to 24 years. The total cohort consisted of 218 subjects. The results showed that 3.8% of the patients who were sex reassigned during 1972-1992 regretted the measures taken. The cohort was subdivided according to the presence or absence of regret of sex reassignment, and the two groups were compared. The results of logistic regression analysis indicated that two factors predicted regret of sex reassignment, namely lack of support from the patient's family, and the patient belonging to the non-core group of transsexuals. In conclusion, the results show that the outcome of sex reassignment has improved over the years. However, the identified risk factors indicate the need for substantial efforts to support the families and close friends of candidates for sex reassignment.


Electron tomography of early melanosomes: implications for melanogenesis and the generation of fibrillar amyloid sheets.
Melanosomes are lysosome-related organelles (LROs) in which melanins are synthesized and stored. Early stage melanosomes are characterized morphologically by intralumenal fibrils upon which melanins are deposited in later stages. The integral membrane protein Pmel17 is a component of the fibrils, can nucleate fibril formation in the absence of other pigment cell-specific proteins, and forms amyloid-like fibrils in vitro. Before fibril formation Pmel17 traffics through multivesicular endosomal compartments, but how these compartments participate in downstream events leading to fibril formation is not fully known. By using high-pressure freezing of MNT-1 melanoma cells and freeze substitution to optimize ultrastructural preservation followed by double tilt 3D electron tomography, we show that the amyloid-like fibrils begin to form in multivesicular compartments, where they radiate from the luminal side of intralumenal membrane vesicles. The fibrils in fully formed stage II premelanosomes organize into sheet-like arrays and exclude the remaining intralumenal vesicles, which are smaller and often in continuity with the limiting membrane. These observations indicate that premelanosome fibrils form in association with intralumenal endosomal membranes. We suggest that similar processes regulate amyloid formation in pathological models.


Sterile mutants in Caenorhabditis elegans: the synaptonemal complex as an indicator of the stage-specific effect of the mutation.
Two sterile mutants of Caenorhabditis elegans hermaphrodites have been examined using the electron microscope and serial section analysis. The F4 and F80 mutants were described previously ( Mounier and Brun , 1980), and they were shown to be blocked at the start of oogenesis. In the F4 mutant, normal sperm are produced and the pachytene nuclei contain tripartite synaptonemal complexes (SC) between the homologously paired chromosomes. In the F80 asynaptic mutant, only a few sperm are produced and they have abnormal morphology. Whereas SCs and SC associated structures (termed 'SC knobs') are present in the F4, these structures are absent from the F80 . The mutation in F80 affects gametogenesis prior to the pachytene stage of meiosis and pairing of homologous chromosomes apparently does not occur. The SC knobs may influence the regulation of the disjunction of the chromosomes. For that reason, these structures are now termed 'disjunction regulator regions'.


The Native Hawaiian Health Professions Scholarship program's impact on the community of Ko'olau Loa: a program report.
The Native Hawaiian Health Professions Scholarship was established as one component of the Native Hawaiian Health Care Act of 1988, which was later reauthorized as the Native Hawaiian Health Care Improvement Act of 1992. The Scholarship program was designed to develop Native Hawaiian primary health care professionals who would return to work in Native Hawaiian communities. To ensure this, scholarship recipients fulfill their scholarship agreement by working in medically unserved and underserved communities throughout Hawai'i. Since 1991, 121 scholarships have been awarded to Native Hawaiians training in different primary care professions including medicine, dentistry, nursing, midwifery, social work, and public health. Although the service obligation is attached to the scholarship as a means of "paying back," the intent is to provide an opportunity for graduates to establish a sense of social responsibility for the communities most in need. One of the communities benefiting from this program is Ko'olau Loa, a community that spans from Ka'a'awa to Pupukea on Windward O'ahu. Native Hawaiian Health Scholarship recipients, Kehau Santiago, Michele Shimizu, and Stephany Vaioleti live and continue to serve in the very community in which they fulfilled their service obligations. This article focuses on how the Native Hawaiian Health Scholarship Program--in particular, the three scholars--affected Ko'olau Loa.


Probability-based particle detection that enables threshold-free and robust in vivo single-molecule tracking.
Single-molecule detection in fluorescence nanoscopy has become a powerful tool in cell biology but can present vexing issues in image analysis, such as limited signal, unspecific background, empirically set thresholds, image filtering, and false-positive detection limiting overall detection efficiency. Here we present a framework in which expert knowledge and parameter tweaking are replaced with a probability-based hypothesis test. Our method delivers robust and threshold-free signal detection with a defined error estimate and improved detection of weaker signals. The probability value has consequences for downstream data analysis, such as weighing a series of detections and corresponding probabilities, Bayesian propagation of probability, or defining metrics in tracking applications. We show that the method outperforms all current approaches, yielding a detection efficiency of >70% and a false-positive detection rate of <5% under conditions down to 17 photons/pixel background and 180 photons/molecule signal, which is beneficial for any kind of photon-limited application. Examples include limited brightness and photostability, phototoxicity in live-cell single-molecule imaging, and use of new labels for nanoscopy. We present simulations, experimental data, and tracking of low-signal mRNAs in yeast cells.