Knowledge, attitudes, and practice of female genital mutilation and cutting: an observational cross-sectional study in English primary care (FGM/C Study).
Female genital mutilation and cutting (FGM/C) describes procedures involving partial or total removal of the external female genitalia or other injury to the female genital organs for non-medical reasons. Increasing migration means many communities living in the UK originate from countries where FGM/C is practised. Consequently, clinicians in the UK are increasingly exposed to women and children who have experienced FGM/C. To explore the knowledge, attitudes, and practice of primary care GPs and practice nurses (PNs) regarding FGM/C. An observational cross-sectional study with GPs and PNs working in primary care in the West Midlands, UK. An online survey was circulated to GPs and PNs between September 2019 and December 2019. A total of 137 survey responses were received. Study participants were predominantly female (81.8%) and GPs (59.9%), with a mean age of 47.3 years (standard deviation [SD] 9.1). The survey found 19.7% of responders reported seeing >1 patient with FGM/C in the past 12 months. It also found 91.3% of responders had received some form of FGM/C training; however, the format and frequency of training varied and 34.3% felt they had received inadequate training to manage treatment of FGM/C. The results have suggested varying degrees of competence and confidence associated with recognising and managing patients with FGM/C in primary care in the West Midlands. Given that patients with FGM/C typically present in primary care, it is important that clinicians can provide appropriate support underpinned by up-to-date training.


The Sleep of the Ring: Comparison of the ŌURA Sleep Tracker Against Polysomnography.
Objective/Background: To evaluate the performance of a multisensor sleep-tracker (ŌURA ring) against polysomnography (PSG) in measuring sleep and sleep stages. Participants: Forty-one healthy adolescents and young adults (13 females; Age: 17.2 ± 2.4 years). Methods: Sleep data were recorded using the ŌURA ring and standard PSG on a single laboratory overnight. Metrics were compared using Bland-Altman plots and epoch-by-epoch (EBE) analysis. Results: Summary variables for sleep onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) were not different between ŌURA ring and PSG. PSG-ŌURA discrepancies for WASO were greater in participants with more PSG-defined WASO (p < .001). Compared with PSG, ŌURA ring underestimated PSG N3 (~20 min) and overestimated PSG REM (~17 min; p < .05). PSG-ŌURA differences for TST and WASO lay within the ≤ 30 min a-priori-set clinically satisfactory ranges for 87.8% and 85.4% of the sample, respectively. From EBE analysis, ŌURA ring had a 96% sensitivity to detect sleep, and agreement of 65%, 51%, and 61%, in detecting "light sleep" (N1), "deep sleep" (N2 + N3), and REM sleep, respectively. Specificity in detecting wake was 48%. Similarly to PSG-N3 (p < .001), "deep sleep" detected with the ŌURA ring was negatively correlated with advancing age (p = .001). ŌURA ring correctly categorized 90.9%, 81.3%, and 92.9% into PSG-defined TST ranges of < 6 hr, 6-7 hr, > 7 hr, respectively. Conclusions: Multisensor sleep trackers, such as the ŌURA ring have the potential for detecting outcomes beyond binary sleep-wake using sources of information in addition to motion. While these first results could be viewed as promising, future development and validation are needed.


Elevated pro alpha 2(I) collagen mRNA levels in cultured scleroderma fibroblasts result from an increased transcription rate of the corresponding gene.
Fibroblasts cultured from affected and unaffected skin sites of three scleroderma patients were studied for the activation of type I collagen gene expression. Dot blot hybridizations with pro alpha 2(I) collagen specific cDNA probe revealed 2.9-4.8-fold increases in pro alpha 2(I) mRNA levels in the affected fibroblasts over the unaffected control cells. Transcription rate of the pro alpha 2(I) gene in the nuclei isolated from the same cells was 2.0-3.7-fold higher in the scleroderma fibroblasts than in the controls. The results show that scleroderma fibroblasts have undergone activation of collagen gene expression at the transcriptional level, which subsequently results in elevated procollagen mRNA levels, overproduction of collagen, and development of dermal fibrosis.


Aggressive behavior of adult meadow voles (Microtus pennsylvanicus) towards young.
Field evidence indicates that adult microtines, especially females, may be a major cause of poor juvenile survival and this may be instrumental in their population regulation. This suggests that males and females behave differently towards young animals. To examine how adult males, nonlactating females, and lactating females behave towards strange young, I introduced young animals into the home cage of the adults. Lactating females were most aggressive towards young; most males investigated them; most nonlactating females ignored them. However, discriminant function analysis indicated a great deal of overlap in the behavior of the classes. None of the classes behaved differently towards young of either sex. Females did not vary their behavior during lactation. Behavior varied among lactating females, with 55% showing little aggression and 20% showing a great deal. Most lactating females showed similar behavior in each of their bouts: docile females remained docile, aggressive females remained aggressive. I conclude that lactating females are most aggressive towards strange young. These results are consistent with the field evidence, which suggests that adult females depress juvenile survival and recruitment and that the main culprits are breeding females.


Bayesian deep learning for error estimation in the analysis of anomalous diffusion.
Modern single-particle-tracking techniques produce extensive time-series of diffusive motion in a wide variety of systems, from single-molecule motion in living-cells to movement ecology. The quest is to decipher the physical mechanisms encoded in the data and thus to better understand the probed systems. We here augment recently proposed machine-learning techniques for decoding anomalous-diffusion data to include an uncertainty estimate in addition to the predicted output. To avoid the Black-Box-Problem a Bayesian-Deep-Learning technique named Stochastic-Weight-Averaging-Gaussian is used to train models for both the classification of the diffusion model and the regression of the anomalous diffusion exponent of single-particle-trajectories. Evaluating their performance, we find that these models can achieve a well-calibrated error estimate while maintaining high prediction accuracies. In the analysis of the output uncertainty predictions we relate these to properties of the underlying diffusion models, thus providing insights into the learning process of the machine and the relevance of the output.


Albumin gene expression in adenocarcinomas with hepatoid differentiation.
Two cases of hepatoid adenocarcinomas were studied with an in situ hybridization technique (ISH) using a RNA probe for human albumin mRNA. In case 1 the urinary bladder of a 67-year-old woman was affected; in case 2 the tumour was located in the gastric antrum of an 80-year-old woman. In neither case had alpha fetoprotein (AFP) been determined preoperatively. Histologically these cases showed adenocarcinomatous features intermingled with hepatoid areas. These latter areas were characterized by cords of polygonal cells, each with an oval nucleus and prominent nucleoli, separated by a fine network of sinusoids. In the hepatoid areas the immunohistochemical profile was similar to that observed in hepatocellular carcinomas, in that the tumour cells were positive with AFP, alpha-1-antitrypsin (A1AAT) and albumin antisera and there was a canalicular type of reactivity with polyclonal anti-CEA (pCEA) antibody. ISH revealed albumin mRNA in virtually all hepatoid cells in case 1, and in about 50% of those in case 2. In addition, in case 2 occasional cells in the adenocarcinomatous areas showed albumin transcripts of ISH. Our findings confirm that ISH for albumin mRNA probe is a valuable method of establishing hepatocellular differentiation, and that hepatoid adenocarcinomas are tumours with true extrahepatic hepatocellular differentiation.


Heart rate variability is altered following spinal cord injury.
Spinal cord injury (SCI) patients are known to suffer from autonomic failure as a result of their injury. The magnitude of the dysautonomia resulting from such an injury is difficult to predict or characterize and, in varying degree, it impedes the recovery of physiological homeostasis. This study is intended to investigate the effectiveness of heart rate variability (HRV) analysis as a method of quantifying and characterizing autonomic function in patients with traumatic spinal myelopathy. HRV analysis was carried out in 13 male SCI patients (six tetraplegic, seven paraplegic) and 13 age-matched, able-bodied controls. Twenty-four hour ambulatory and sleep ECG tracings were obtained. Time domain, amplitude, and power spectral analyses were used to study HRV and autonomic function. Both tetraplegic (20+/-12 ms, mean+/-SD) and paraplegic (22+/-8 ms) subjects demonstrated significant loss of low frequency 24-hour HRV compared to able-bodied controls (36+/-14 ms, p < 0.05) and during sleep. This was interpreted as being consistent with predominantly sympathetic denervation uninfluenced by degree of physical activity. There were no significant differences between groups in parasympathetically mediated high frequency HRV. We conclude that HRV analysis is capable of distinguishing between SCI or able-bodied humans and among tetraplegic and paraplegic patients. Patterns of altered HRV may be useful in more completely characterizing or stratifying changes in physiology associated with injury level and may have diagnostic, prognostic, or therapeutic significance.


Intracellular free calcium concentration in lymphocytes of patients with muscular dystrophies.
Intracellular free calcium concentration [( Ca2+]i) of human peripheral blood lymphocytes was determined by fluorescence spectroscopic measurements with quin2 in patients with different types of muscular dystrophy and in controls. The [Ca2+]i level in lymphocytes showed a significant increase in adult type (facioscapulohumeral and limb-girdle) muscular dystrophies, while it showed a decrease in Duchenne dystrophy as compared to the values of age- and sex-matched controls. The data obtained suggest an alteration in the effectiveness of the calcium pump in lymphocytes and may represent a sign of generalized membrane damage in these hereditary muscle diseases.


Rab11 is essential for lgl mediated JNK-Dpp signaling in dorsal closure and epithelial morphogenesis in Drosophila.
Dorsal closure during Drosophila embryogenesis provides a robust genetic platform to study the basic cellular mechanisms that govern epithelial wound healing and morphogenesis. As dorsal closure proceeds, the lateral epithelial tissue (LE) adjacent to the dorsal opening advance contra-laterally, with a simultaneous retraction of the amnioserosa. The process involves a fair degree of coordinated cell shape changes in the dorsal most epithelial (DME) cells as well as a few penultimate rows of lateral epithelial (LE) cells (collectively referred here as Dorsolateral Epithelial (DLE) cells), lining the periphery of the amnioserosa, which in due course of time extend contra-laterally and ultimately fuse over the dorsal hole, giving rise to a dorsal epithelial continuum. The JNK-Dpp signaling in the dorsolateral epidermis, plays an instrumental role in guiding their fate during this process. A large array of genes have been reported to be involved in the regulation of this core signaling pathway, yet the mechanisms by which they do so is hitherto unclear, which forms the objective of our present study. Here we show a probable mechanism via which lgl, a conserved tumour suppressor gene, regulates the JNK-Dpp pathway during dorsal closure and epithelial morphogenesis. A conditional/targeted knock-down of lgl in the dorsolateral epithelium of embryos results in failure of dorsal closure. Interestingly, we also observed a similar phenotype in a Rab11 knockdown condition. Our experiment suggests Rab11 to be interacting with lgl as they seem to synergize in order to regulate the core JNK-Dpp signaling pathway during dorsal closure and also during adult thorax closure process.


Comparative immunohistochemical demonstration of peptide F- and other enkephalin-containing neurons in the enteric nervous system of the rat.
The immunohistochemical localization of peptide F and the related enkephalins met5-enkephalin (met-enk), leu5-enkephalin (leu-enk), met5-enkephalin-arg6-phe7 (met-enk-arg-phe), and met5-enkephalin-arg6-gly7-leu8 (met-enk-arg-gly-leu) was investigated by means of the indirect immunofluorescence technique in the enteric nervous system of the rat. Peptide F-like immunoreactivity was widely distributed within neuronal structures throughout the gastrointestinal (GI) tract of the rat. Peptide F-containing nerve cell bodies were mainly located in the myenteric plexus, and only rarely were seen in the submucosal plexus. Peptide F-immunoreactive nerve fibers were principally present in the myenteric plexus and circular muscle layer; few were found in the submucosal plexus, longitudinal muscle layer, muscularis mucosa, and mucosa. No peptide F-containing fibers were found associated with blood vessels in the gut. By comparing the distribution of immunoreactive peptide F with other related enkephalins met-enk, leu-enk, met-enk-arg-phe, and met-enk-arg-gly-leu, we observed that there was a remarkable similarity in the distribution of peptide F and other enkephalins in the GI tract. These data, combined with our previous studies, indicate that peptide F may coexist with other related enkephalins in the same neurons of the enteric nervous system. The results suggest that peptide F, a product of the proenkephalin A gene, may play a physiological role within the enteric nervous system.


[Preparation and identification of monoclonal antibody against human GCRG213].
To prepare and characterize the monoclonal antibody against human GCRG213. The HIS-GCRG213 fusion protein was expressed in E.coli. Mice were immunized with the purified HIS-GCRG213 protein. Hybridoma cell lines secreting monoclonal antibodies against GCRG213 were screened by regular cell fusion and subcloning approach. The titer and specificity of the antibody was characterized by ELISA and Western blot, respectively. The expression of GCRG213 was determined using immunohistochemistry technique on paraffin-embedded tissue sections from normal gastric mucosal tissues and advanced gastric cancer. The HIS-GCRG213 fusion protein with relative molecular mass of 20 800 was over expressed in E.coli. Two hybridoma cell lines which secreted monoclonal antibody specifically against human GCRG213 fusion protein were successfully obtained. The ascite titers of this monoclonal antibody reached 1:10(6);. Western blot analysis showed that the monoclonal antibody could bind to the recombinant HIS-GCRG213 protein specifically.The immunohistochemistry showed that GCRG213 were expressed higher in gastric cancer tissues than in normal ones. The monoclonal antibody against human GCRG213 with high titer and specificity has been successfully prepared, which could be utilized as a useful reagent for further studying the biological function of the GCRG213.


Two Distinct Tumorigenic Processes in Endometrial Endometrioid Adenocarcinoma.
Endometrial endometrioid adenocarcinoma (EEA) is conventionally considered to be a single pathologic entity that develops through a hyperplasia-carcinoma sequence under the influence of estrogen. Previously, another EEA subtype was described and proposed to arise directly from normal endometrium. These conventional and de novo subtypes are designated groups 1 and 2, respectively. To identify the molecular mechanisms of these distinct tumorigenic processes, we conducted comprehensive integrated analyses of genomic data with hormonal status for group 1 paired carcinoma and hyperplasia and group 2 carcinoma samples. Although group 1 carcinomas mostly exhibited genomically stable characteristics and the activation of estrogen signaling, group 2 EEAs showed enriched hypermutator and CpG island methylator phenotypes. Pairwise comparisons of hyperplasia and carcinoma, along with time-course analyses of the hyperplasia-carcinoma sequence, revealed the acquisition of driver mutations in the evolutionary process of hyperplasia but not in the transition from hyperplasia to carcinoma. The current study confirms the existence of two different histopathologic programs during EEA development that harbor distinct molecular bases and demonstrates the biological relevance of these differential tumorigenic processes.


Building specificity with nonspecific RNA-binding proteins.
Specificity is key to biological regulation. Two families of RNA binding proteins, heterogeneous nuclear ribonucleoproteins and serine-arginine-rich proteins, were initially thought to have redundant or nonspecific biochemical functions. Recently, members of these families have been found as components of distinct regulatory complexes with highly specific and essential roles in mRNA metabolism. Here we discuss the basis for their functional specificity and the mechanisms of action of some of their characteristic protein domains.


1H-MRS in vivo predicts the early treatment outcome of postoperative radiotherapy for malignant gliomas.
To analyze prospectively the prognostic significance of 1H magnetic resonance spectroscopy (MRS) in vivo recorded from the tumor bed of patients after surgery for malignant glioma. Fifty-one patients aged 20-68 years were examined using a MRI/MRS system (Elscint 2T Prestige). Of the 51 patients, 33 had Grade 3 gliomas and 18 had glioblastomas. MRI-localized 1HMR spectra were acquired using a single-voxel, double-spin-echo sequence. Relative intensities of the signals (choline, creatine [Cr] N-acetyl aspartate [NAA], myo-inositol, lactate, and lipids) were obtained by numeric integration of fitted signals. Two voxels were examined, one located at the tumor bed and the second distant to the tumor bed. All patients were irradiated to 60 Gy using three-dimensional conformal noncoplanar techniques to 60 Gy. MRS in vivo in patients after brain tumor surgery revealed a statistically significant decrease in the NAA/Cr ratio and increases in the choline/creatine (Cr), choline/NAA, and myo-inosytol/Cr ratios. The intensive signals of lactate and lipids appeared in spectrum. Survival correlated strongly with tumor grade and patient age but the strongest prognostic factor was the lactate/NAA ratio. For lactate/NAA values >2.0 (intensive lactate signal) the 1-year survival rate was 20%, and for lactate/NAA values <2.0, the 1-year survival rate was 85%. A new diagnostic tool demonstrated ability to distinguish between patients with a favorable prognosis and those who will die within 1 year.


Neurotoxic and other side effects of high-dose interferon in amyotrophic lateral sclerosis.
6 patients with amyotrophic lateral sclerosis were treated with intravenous infusion of 100-200 million IU per day of human leukocyte interferon. Side effects of treatment included fever, chills, malaise, nausea, marked leukopenia, mild anemia, and thrombocytopenia. Tiredness, confusion, papilledema, and overall signs of acute encephalitis were observed. Tendon reflexes and muscle force decreased. EEG activity was slowed, and evoked potentials showed significant slowing of conduction times. Neuropsychological tests revealed congitive dysfunction. The syndrome of inappropriate antidiuretic hormone secretion developed in all patients. All side effects were reversible with cessation of interferon treatment.


"I don't want to introduce it into new places in my life": The marketing and consumption of no and low alcohol drinks.
Recent years have seen an expanding 'no and low alcohol' (NoLo) drinks market in the United Kingdom and other high-income countries. With the UK government pledging to increase the availability of NoLos and encourage their consumption, further research is required to underpin policy and explore the potential for NoLos to ease - or exacerbate - alcohol-related harm. This paper draws on original primary research on NoLo marketing and consumption in the UK; analysis of two NoLo marketing campaigns and semi-structured interviews with both drinkers and non-drinkers who consume NoLos. Addition marketing was identified in the promotion of NoLo products, encouraging consumers to incorporate NoLo consumption into new spatial and temporal contexts on top of their typical weekly drinking patterns. However, there was resistance towards these practices from consumers, who stressed they were more likely to drink NoLos in place of alcohol and incorporate them into their existing drinking routines. This paper expands a currently very limited evidence base and contributes directly to ongoing debates around 'addition' versus 'substitution' (i.e. whether NoLo products are being used on top of or in place of alcohol). Findings highlight both some of the challenges and opportunities of the expanding market, pointing towards the problematic presence of 'addition marketing' but also highlighting the ways consumers might challenge this and use NoLos flexibly to reduce consumption. As a result, NoLo promotion could function as one tool amongst many to help at least some consumers drink in moderation, alongside a broader package of measures such as education and wider social change.


Activation of vitamin D receptor inhibits Tau phosphorylation is associated with reduction of iron accumulation in APP/PS1 transgenic mice.
Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes β-amyloid (Aβ) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aβ production via promoting the lysosomal degradation of β-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3β phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3β activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.


Microvessel density and expression of vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived endothelial growth factor in oral squamous cell carcinomas.
Angiogenesis, the growth of capillary vessels, plays an important role in the metabolic functions of malignant tissues. Tumor growth and malignant transformation are considered to be dominated by uncontrolled angiogenesis. To understand the mechanism of increased vascularity associated with malignant tissues, we immunohistochemically evaluated microvessel density (MVD) and the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived endothelial growth factor (PDGF) in oral cancers. Microvessel density did not differ significantly between normal oral mucosa and epithelial dysplasia, but was significantly increased in tumor tissues. Expression of angiogenic factors was not found in normal oral mucosa, but increased in association with increasing vascularity in OSCC tissue. In tumor tissue, angiogenic factor expression correlated with MVD. MVD in OSCC was related to T stage, tumor differentiation, and stage of invasion. VEGF expression also correlated with tumor differentiation and the stage of invasion. These findings suggest that VEGF might play an important role in tumor angiogenesis of OSCC.


[A study on sarcosaphagous insects species variety with seasons in Chengdu].
To study the species of sarcosaphagous insects. Rabbits were killed and placed outdoors from March to November. Flies that appeared the cadavers were observed and identified. There are five main flies, i.e., Muscadomesticauicina, Lucilia sericata, C. Megacephala, S. fuscicauda, Aldrichiragrahormi. From midtime of April to the beginning of October, Muscadomesticauicina could be seen on the cadvers, however, Aldrichiragrahormi only could be seen before the beginning of May. Otherwise, Lucilia sericata, C. Megacephala, S. fuscicauda could be seen on the cadvers from March to the end of October. After the midtime of November, none of sarcosaphagous flies could be seen on the cadvers. On the other hand, maggots of sarcosaphagous flies could be seen often on the cadvers after adults of sarcosaphagous flies intruding 1 to 4 days, relating to temperature of environment. If these flies history of life be studied. it is useful for estimating postmortem interval in Chengdu.


Characterization of PET/CT images using texture analysis: the past, the present… any future?
After seminal papers over the period 2009 - 2011, the use of texture analysis of PET/CT images for quantification of intratumour uptake heterogeneity has received increasing attention in the last 4 years. Results are difficult to compare due to the heterogeneity of studies and lack of standardization. There are also numerous challenges to address. In this review we provide critical insights into the recent development of texture analysis for quantifying the heterogeneity in PET/CT images, identify issues and challenges, and offer recommendations for the use of texture analysis in clinical research. Numerous potentially confounding issues have been identified, related to the complex workflow for the calculation of textural features, and the dependency of features on various factors such as acquisition, image reconstruction, preprocessing, functional volume segmentation, and methods of establishing and quantifying correspondences with genomic and clinical metrics of interest. A lack of understanding of what the features may represent in terms of the underlying pathophysiological processes and the variability of technical implementation practices makes comparing results in the literature challenging, if not impossible. Since progress as a field requires pooling results, there is an urgent need for standardization and recommendations/guidelines to enable the field to move forward. We provide a list of correct formulae for usual features and recommendations regarding implementation. Studies on larger cohorts with robust statistical analysis and machine learning approaches are promising directions to evaluate the potential of this approach.


Health-related quality of life in adult survivors after paediatric allo-SCT.
Fifty-three adults who had received SCT as children responded to questionnaires on health-related quality of life (HRQoL) (Swedish HRQoL survey (SWED-QUAL)), sense of coherence (SOC), anxiety and depression (HAD) and a health and symptom inventory. Late effects were classified following the Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0. HRQoL was below norm in 9 of 13 SWED-QUAL domains. Poorest domains (P<0.001) were satisfaction with physical health, general health, partner relations and sexual function, whereas emotional wellbeing and satisfaction with family life were on par with the norm. Older age, time elapsed post-SCT and fewer self-reported symptoms correlated with better HRQoL. Unfavourable late effect scores had no or limited impact, whereas age at SCT or TBI did not adversely affect HRQoL. Most subjects were well subjectively and objectively, whereas 24% had more complicated late effects. The median Karnofsky score was 90, 13% of subjects having scores below 80. In total, 53% reported pain, whereas 42.5% had memory and concentration problems. Anxiety and/or depression, reported by 35%, were associated with lower HRQoL and SOC ratings. Overall, 55% reported infertility and expressed difficulty with this. To conclude, childhood SCT did not negatively affect overall health for most of these adult long-term survivors, although poorer HRQoL with psychological and cognitive problems are common.


Size transformation of Au nanoclusters for enhanced photocatalytic hydrogen generation: Interaction behavior at nanocluster/semiconductor interface.
Recently, atomically precise metal nanoclusters (NCs) become a new class of photosensitizer for light energy conversion in metal-cluster-sensitized semiconductor (MCSS) system. However, fundamental understanding for the suitable combination of NCs and semiconductor is still unclear. Aside from aspects of light harvesting, energy level alignment and catalytic activity, interfacial interaction behavior at NCs/semiconductor interface is also crucial due to its important influence in charge transportation. In this work, the interface interaction between Au NCs and TiO2 is examined by precise transformation of Au NCs from Au22(SG)18 to Au18(SG)14, as well as its effect on photocatalytic hydrogen production activity. From the optical, charge transport and solid-states spectroscopy analyses, it is able to display that precisely tuning the number of core atoms from Au22(SG)18 to Au18(SG)14 results in the strong interface interaction between Au NCs and TiO2, reflecting in high difference of work function and modified surface band bending of TiO2, therefore promoting the injection of electrons from NCs to TiO2 and reducing interfacial charges recombination. As a result, Au18(SG)14/TiO2 shows higher hydrogen generation rate than Au22(SG)18/TiO2 under light irradiation. This work would provide new insights into rational combination of metal NCs with semiconductor and highlights the overlooked effect of interfacial interaction behavior on light energy conversion.


Device for quantitating tremor activity in mice: antitremor activity of atropine versus soman- and oxotremorine-induced tremors.
A tremor monitor was constructed and tested that quantitates soman- and oxotremorine-induced tremors. The device consisted of a force transducer, from which was suspended a plastic beaker containing a mouse. The signal from the force transducer was fed into a tremor monitor, which was essentially a low-pass filter, and quantitated using the Applecounter from Columbus Instruments (Columbus, Ohio) with the data stored on floppy diskette in a personal computer or on a magnetic tape cassette. The tremor monitor demonstrated a dose response relationship to both soman- and oxotremorine-induced tremors and the antagonism of these tremors by various doses of atropine. In addition, the duration of action of a dose of atropine (17.4 mg/kg, ip) normally used in the therapy of organophosphate poisoning was assessed using the atropine antagonism of oxotremorine-induced tremors as an indicator. This device permits the unbiased determination of the tremor activity of a drug and allows the use of statistical analysis on the data produced.


Nitric oxide formation and plasma L-arginine levels in pulmonary hypertensive rats.
The elevation of plasma L-arginine levels stimulates nitric oxide (NO) synthesis, but the underlying mechanisms are not yet understood. We examined the role of physiological changes in pulmonary arteries on endogenous NO production. Male Wistar rats were divided into following groups: (1) control rats receiving normal water orally, (2) ARG rats receiving L-arginine water orally, (3) MCT rats injected with monocrotaline (MCT) on day 0 and receiving normal water orally, and (4) MCT+ARG rats injected with MCT on day 0 and receiving L-arginine water orally. The rats were studied after 23 days of dietary intervention. In MCT+ARG rats, supplemental L-arginine exhibited a significant pulmonary vasodilatory effect, as shown by a decreased pulmonary arterial pressure (PAP) (P<0.001), decreased right ventricular hypertrophy (P<0.01), and improved endothelium-dependent relaxation (P<0.01). Also L-arginine inhibited the elevation of plasma endothelin-1 (P<0.01). Oral L-arginine administration increased plasma L-arginine levels about twofold, but in only MCT+ARG rats (i.e., not in ARG rats) did the urinary nitrate excretion significantly increase (P<0.05), which is an indicator of endogenous NO formation. Oral administration of L-arginine is effective against pulmonary vascular remodeling. The data also suggest that the initial elevation of PAP is important for the induction of endogenous NO synthesis.


Gastroesophageal Reflux Disease and the Patient with Obesity.
Patients with obesity who present with gastroesophageal reflux disease (GERD) require a nuanced approach. Those with lower body mass index (BMI) (less than 33) can be counseled on weight loss, and if successful may be approached with laparoscopic fundoplication. Those who are unable to achieve weight loss or those who present with a BMI greater than or equal to 35 should proceed with laparoscopic Roux-en-Y gastric bypass (LRYGB). Conversion to LRYGB from sleeve gastrectomy is a safe and effective way to manage GERD after sleeve gastrectomy.


The treatment of pemphigus vulgaris. Experience with 48 patients seen over an 11-year period.
We present a retrospective analysis of 48 patients with pemphigus vulgaris (PV) who were seen between 1978 and 1988. They were divided into three treatment groups: 25 (group A) received 40-100 mg of oral prednisone daily; eight (group B) received > 100 mg of prednisone daily; 15 (group C) received 40 mg of oral prednisone every other day and azathioprine 100 mg daily. A second immunosuppressive agent was subsequently added to the treatment regimen of three patients in group A and eight patients in group B. By 1989, 10% of the patients had been able to discontinue all therapy, and were in complete remission. Sixty-five per cent of patients were on maintenance therapy, but in clinical remission. Twenty-five per cent of the patients had died [eight in group A (31%) and four in group B (50%)] either as a consequence of the disease or its treatment. None of the patients in group C had died. Most of the deaths occurred during the first 2-3 months of therapy. Morbidity and mortality were related to the severity of the disease, to the maximum dose of prednisone required to induce remission, and to the presence of other diseases. Patients needing a total of 5 g or more of prednisone to induce a remission during the acute stage had a high mortality rate.


The Efficacy of Wearable Cueing Devices on Gait and Motor Function in Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
To summarize the efficacy of wearable cueing devices for improving gait and motor function of patients with Parkinson disease (PWP). PubMed, Embase, and Cochrane CENTRAL databases were searched for papers published in English, from inception to October 23, 2022. Randomized controlled trials focusing on the effects of wearable cueing devices on gait and motor function in PWP were included. Two reviewers independently selected articles and extracted the data. The Cochrane Bias Risk Assessment Tool was used to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the quality of evidence. Seven randomized controlled trials with 167 PWP were included in the meta-analysis. Significant effect of wearable cueing devices on walking speed (mean difference [MD]=0.07 m/s, 95% confidence interval [CI]: [0.05, 0.09], P<.00001) was detected; however, after sensitivity analysis, no significant overall effect on walking speed was noted (MD=0.04 m/s, 95% CI: [-0.03, 0.12], P=.25). No significant improvements were found in stride length (MD=0.06 m, 95% CI: [0.00, 0.13], P=.05), the Unified Parkinson's Disease Rating Scale-III score (MD=-0.61, 95% CI: [-4.10, 2.88], P=.73), Freezing of Gait Questionnaire score (MD=-0.83, 95% CI: [-2.98, 1.33], P=.45), or double support time (MD=-0.91, 95% CI: [-3.09, 1.26], P=.41). Evidence was evaluated as low quality. Wearable cueing devices may result in an immediate improvement on walking speed; however, there is no evidence that their use results in a significant improvement in other gait or motor functions.


Endoscopic esophageal substitution for pure esophageal atresia and wide gap esophageal atresia: A report of five cases with minimum follow-up of twelve months.
The aim of the study is to report feasibility and safety of endoscopic esophageal substitution in infants with pure esophageal atresia and wide gap tracheoesophageal fistula with a minimum one year follow-up. This prospective study was conducted from January 2012 for twenty four consecutive months at Apollo Hospital, New Delhi. All babies either followed up or referred for esophageal substitution without any history of mediastinitis or associated major congenital anomaly and weighing greater than 6kg were to be included in the study. The indication, intraoperative details, operative approach, conversion to open, esophageal substitute, postoperative ventilation, ICU and hospital stay, time to solid foods, morbidity and mortality were recorded. Informed consent was obtained from all the parents and ethical clearance was obtained for the study from the hospital ethical committee. Postoperatively babies were followed up monthly for first six months, 3 monthly for next six months and annually thereafter. Between January 2012 and December 2013, in the two year period six infants were admitted for laparoscopic gastric transposition. In five patients the procedure was completed by the laparoscopic approach and one required conversion to open surgery owing to dense adhesions. The age range at the time of surgery was from 8months to 12months with a mean age of 10months. Four patients had pure esophageal atresia (type A) and two had wide gap esophageal atresia with distal tracheoesophageal atresia (type C). Five had primary esophagostomy and gastrostomy as a newborn, the sixth had postoperative anastomotic leak and required subsequent diversion. The mean operating time was 194minutes (range 170-210minutes). The mean stay in ICU was 7days with a range of 4-12days. All patients were ventilated in the postoperative period for an average of 5days with a range of 4-7days. One patient had prolonged gastric ileus which delayed the oral feeds by 14days. The mean time to start the oral feeds was 8days with a range of 6-14days. The mean hospital stay was 19.6days (range 16-23days). Early complications were pneumonia and pleural effusion in one patient. One patient developed anastomotic stricture which was amenable to dilatation. One patient had leak from esophagogastric anastomosis which healed spontaneously. All children are now orally fed, swallow without difficulty, and parents report an excellent cosmetic outcome. The follow-up ranges from 12 to 36months. The initial results of endoscopic esophageal substitution are encouraging and easily comparable to the outcome of open surgery with all the attendant benefits of minimally invasive approach.


Adults' preferences between Picture Communication Symbols (PCSs) and Gus Communication Symbols (GCSs) used in AAC.
The purpose of the study was to determine whether significantly different preference exists in typical adults between Picture Communication Symbols (PCSs) and Gus Communication Symbols (GCSs) frequently displayed on their AAC. A total of 56 participants participated in the study, including 15 participants in ages 20-35; 14 participants in ages 36-50; 13 participants in ages 51-60; and 14 participants in ages 66-80. Two tasks, an identification task and a preference task, were administered sequentially and individually. The results of this study suggest: (1) typical adults' preference between PCSs and GCSs did not show any significant difference; (2) the effect of age groups of typical adults did not have any significant effect on their preference between PCSs and GCSs. However, except the group of ages 51-65, the other three groups did consciously show their preferences for PCSs. Limitations and clinical implications of the current study have been concluded.


Prevention of cadmium accumulation in retinal pigment epithelium with manganese and zinc.
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly. Risk factors include old age, female gender, obesity, smoking, low dietary intakes of antioxidants and increased exposure to the toxic metal cadmium (Cd(2+)). Supplementation with high-dose zinc (80 mg) provides some protection, but the mechanism(s) underlying such protection has not been fully elucidated. The present study had a focus on the human retinal pigment epithelial (RPE) cell line ARPE-19 in an attempt to demonstrate a reduction in intracellular Cd(2+) effect associated with heme oxygenase-1 (HO-1) expression by co-exposure with zinc (Zn(2+)) or manganese (Mn(2+)), which is known to be a more potent inhibitor of Cd(2+) uptake than Zn(2+). Our results indicated that co-exposure of 10 microM Cd(2+) with 5 microM Mn(2+) reduced the intracellular Cd(2+) effect by 50-60%, possibly by limiting the amounts of Cd(2+) entering cells through Mn(2+) transporter protein (ZIP8). A similar reduction in a Cd(2+) effect was achieved by co-exposure with 20 microM Zn(2+) while co-exposure with 5 and 10 microM Zn(2+) ions was ineffective. Mn(2+) ions as low as 2.5 microM were found to cause an increase in HO-1 mRNA expression levels in ARPE-19 cells, demonstrating for the first time that Mn(2+) is an inducer of HO-1. Mn(2+) ions at 1 microM induced HO-1 mRNA expression in the HEK293 human embryonic kidney cells. In contrast, Zn(2+) in 5, 10 or 20 microM concentrations did not induce expression of HO-1 in ARPE-19 cells or any other cells tested. These data suggest the superiority of Mn(2+) over Zn(2+) in preventing Cd(2+) uptake and accumulation in RPE to toxic levels. Further, induction of HO-1 by Mn(2+) could provide RPE with some resistance to enhanced oxidative stress arising from Cd(2+) accumulation in RPE as HO-1 is one of the frontline cellular antioxidant defense mechanisms.


Stratified risk of pregnancy loss for women with a viable singleton pregnancy in the first trimester.
Calculate the risk of miscarriage in women with a viable (defined as presence of fetal heart rate on ultrasound) first trimester singleton pregnancy and to create a model for stratified risk-assessment for pregnancy loss based on significant risk factors. Retrospective cohort study of unselected women with singleton pregnancies in a large obstetrical practice who presented for prenatal care prior to 14 weeks over a three-year period. All women underwent a formal first-trimester ultrasound, and we only included women with viable pregnancies with fetal heart activity seen on that ultrasound. Our primary outcome was pregnancy loss prior to 20 weeks. Statistical modeling was used to create a risk-assessment tool from adjusted likelihood ratios of pregnancy loss based on risk factors independently associated with this outcome. From January 2015-December 2017, 2,446 women met the inclusion criteria for the study and 132 (5.4%) had a pregnancy loss <20 weeks. On regression analysis, the independent risk factors for pregnancy loss were earlier gestational age (aOR 0.72, 95% CI 0.65-0.80) and increasing number of prior miscarriages (aOR 1.56, 95% CI 1.32-1.83). Using these risk factors, we calculated the stratified risk of pregnancy loss, which ranged from 0.8% in women at 13 weeks of gestation with no prior miscarriages to 33.7% in women at six weeks of gestation with three or more prior miscarriages. In first trimester singleton pregnancies, the overall risk of pregnancy loss <20 weeks after confirmation of fetal heart activity is 5.4%, but can be stratified for each woman and ranges from 0.8% to 33.7% based on the gestational age and number of prior pregnancy losses.


Mid- to long-term results after bipolar radial head arthroplasty.
Radial head arthroplasty is considered the treatment of choice for unreconstructable radial head fractures in the acute fracture situation. Although short-term results in the current literature are promising, replacement of the radial head remains controversial as long-term results are still missing. We report our 8.8-year results after treatment with a bipolar radial head prosthesis by Judet. In our department, 19 patients were treated with bipolar radial head arthroplasty between 1997 and 2001. Seventeen of these patients-14 men and 3 women-were examined retrospectively after 106 months (range, 78-139). Of these, 9 patients were treated primarily, 7 patients secondarily, and 1 because of a tumor. On the Mayo Elbow Performance Score, 6 patients achieved excellent results, 10 good, and one fair. The mean DASH score was 9.8 (range, 0-34). No differences were seen between primary and secondary implantation. Flexion averaged 124° (range, 110-150°), the extension deficit was 21° (range, 0-40°), pronation 64° (range, 30-90°), and supination 64° (range, 30-90°). The following complications were seen: 2 dislocations and 8 cases of degenerative changes of the capitellum, 1 with severe erosion. Signs of ulnohumeral arthrosis were found in 12 patients. No evidence of loosening, radiolucencies, or proximal bone resorption was detected. Despite major primary complications and high incidence of radiographic signs of degenerative changes after 8.8 years, mainly good clinical results were achieved with Judet's bipolar prosthesis.


Q-aTc interval as a clinical indicator of hypercalcemia.
The charts were reviewed of more than 200 patients discharged from the hospital between 1972 and 1977 with a diagnosis implying abnormal calcium metabolism. When all other variables known to affect the Q-T interval were eliminated, serum calcium concentrations on 65 occasions in 39 patients were found to correlate significantly (P less than 0.001 or better) with the following electrocardiographic intervals: Q-aTc (beginning of QRS complex to apex of T wave), Q-oTc (beginning of QRS complex to onset of T wave) and Q-Tc (beginning of QRS complex to end of T wave). Of these, the Q-aTc interval was the more easily and precisely measured at elevated calcium levels and exhibited the strongest correlation (P less than 0.0001) over the range of calcium levels measured. The relation was linear and could be used to estimate serum calcium levels from measured Q-aTc intervals. For a Q-aTc interval of 0.29 second or less (range 0.23 to 0.29) the serum calcium was estimated to +/- 1.9 mg/dl with 95 percent confidence. For a Q-aTc interval of 0.27 second or less, the correspondence with hypercalcemia in the study series was 90 percent or better. When all other factors known to affect the Q-T interval are ruled out, the shortening of the Q-aTc interval appears to be a useful clinical indicator of hypercalcemia.


Histologic assessment of lymph nodes in mycosis fungoides/Sézary syndrome (cutaneous T-cell lymphoma): clinical correlations and prognostic import of a new classification system.
Mycosis fungoides and the Sézary syndrome share common cutaneous histopathologic features, and this spectrum of malignant disease is referred to here as cutaneous T-cell lymphoma (CTCL). A method (LN classification) for describing the histopathologic features of lymph nodes in CTCL is presented. In this system, lymph node biopsy specimens are scored according to the number of atypical lymphoid cells in T-cell-dependent paracortical zones and the preservation or distortion of the lymph node architecture. Lymph node architecture is preserved in lymph nodes scored LN1 to LN3, and these nodes may have coexistent dermatopathic change. LN1 nodes have single infrequent atypical lymphocytes in paracortical T-cell regions. LN2 nodes have small clusters of paracortical atypical cells. LN3 nodes have large clusters of atypical cells. LN4 nodes are partially or totally effaced by atypical cells. This system was used to classify 96 lymph node biopsy specimens obtained within six months of the initial diagnosis of CTCL; no LN1 nodes, 37 LN2, 44 LN3, and 15 LN4 nodes were found. The LN class was significantly correlated with the extent of skin, blood, and visceral involvement, as well as with survival. Patients with LN2 lymph nodes have an estimated five-year survival of 70 per cent, while patients with LN3 and LN4 nodes have estimated five-year survivals of 30 and 15 per cent, respectively. The survival differences between the LN subgroups were all significant (P less than 0.05). The LN classification system was clearly shown to be reproducible among experienced pathologists. The LN system for the histopathologic classification of lymph nodes in CTCL is of prognostic value and should be used to assess lymph node biopsies in patients with CTCL.


Acute hypokalemic myopathy in alcoholism. A clinical entity.
Two cases of an acute myopathy without muscle pain, tenderness, or swelling are described in alcoholic patients. Both were associated with severe hypokalemia and were largely reversible with potassium repletion. Hypokalemia may be the cause of some cases of acute myopathy in alcoholism, particularly those in which muscle cramps are absent.


Regulation of Arf activation occurs via distinct mechanisms at early and late Golgi compartments.
At the Golgi complex, the biosynthetic sorting center of the cell, the Arf GTPases are responsible for coordinating vesicle formation. The Arf-GEFs activate Arf GTPases and are therefore the key molecular decision-makers for trafficking from the Golgi. In Saccharomyces cerevisiae, three conserved Arf-GEFs function at the Golgi: Sec7, Gea1, and Gea2. Our group has described the regulation of Sec7, the trans-Golgi Arf-GEF, through autoinhibition, positive feedback, dimerization, and interactions with a suite of small GTPases. However, we lack a clear understanding of the regulation of the early Golgi Arf-GEFs Gea1 and Gea2. Here we demonstrate that Gea1 and Gea2 prefer neutral over anionic membrane surfaces in vitro, consistent with their localization to the early Golgi. We illustrate a requirement for a critical mass of either Gea1 or Gea2 for cell growth under stress conditions. We show that the C-terminal domains of Gea1 and Gea2 toggle roles in the cytosol and at the membrane surface, preventing membrane binding in the absence of a recruiting interaction but promoting maximum catalytic activity once recruited. We also identify the small GTPase Ypt1 as a recruiter for Gea1 and Gea2. Our findings illuminate core regulatory mechanisms unique to the early Golgi Arf-GEFs.


Targeting HER2-positive breast cancer: advances and future directions.
The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.


Host competence of Algerian Gerbillus amoenus for Leishmania major.
Cutaneous leishmaniasis (CL) is the most important neglected disease reported in North Africa, Algeria ranks second in the world with more than 5000 cases per year. In Algeria, two rodent species Psammomys obesus and Meriones shawi, are so far known as proven reservoirs of Leishmania major, however, they are absent in several endemic localities. In this study, we experimentally infected Gerbillus rodents trapped around human dwellings in Illizi, Algeria to assess their susceptibility to L. major. Seven gerbils, morphologically and molecularly identified as Gerbillus amoenus, were intradermally inoculated with 104 parasites derived from culture, monitored for six months and their infectiousness for sand flies was tested by xenodiagnosis. The study revealed that G. amoenus was susceptible to L. major and was able to maintain and transmit the parasites to sand flies tested six months after infection, suggesting the role of this gerbil as a potential reservoir for L. major.


Management of status dystonicus in children. Cases report and review.
Status dystonicus (SD) is a medical emergency weighed by a relevant morbidity and mortality. It mainly affects patients with primary or secondary dystonia and is often triggered by events such as fever, infections, exposure medications or their abrupt cessation. We report on three patients presenting with SD. Two of them were affected by a static encephalopathy and the other one by a neurodegenerative disorder such as megalencephalic leukoencephalopathy with subcortical cysts (MLC). To our knowledge this is the first patient affected by MLC presenting with SD. All our patients underwent continuous infusion of midazolam, in association with pimozide and trihexyphenidyl, which led to complete resolution of muscular spasms in two patients. In the other one a complete cessation of dystonic spasms was obtained after intrathecal baclofen. From a therapeutic point of view there are no evidence-based management guidelines in SD. The approach is empiric and based on very limited anecdotal reports. On the basis of our observations and an extensive review of the literature we delineated a possible therapeutic strategy of SD in children.


Multiple sclerosis, the microbiome, TLR2, and the hygiene hypothesis.
The pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) involves a complex interaction between genetic and environmental factors. Studies of monozygotic twins suggest a significant role for environmental factors in susceptibility to MS. Numerous studies, driven by the "Hygiene Hypothesis," have focused on the role of environmental factors in allergic and autoimmune diseases. The hygiene hypothesis postulates that individuals living in environments that are too "clean" lack the requisite exposure to "immune-tolerizing" microbial products, resulting in poorly regulated immune systems and increased immune-mediated diseases. Interestingly, few studies have linked MS with the hygiene hypothesis. Similarly, although numerous studies have examined the role of the microbiome in autoimmune diseases, there has been no consistent documentation of disease-specific alterations in the MS microbiome. In this review, we present evidence that integrating the hygiene hypothesis and the microbiome allows for the identification of novel pathophysiologic mechanisms in MS. Our central hypothesis is that the microbiome in MS represents a "defective environment" that fails to provide normal levels of "TLR2-tolerizing" bacterial products to the systemic immune system. Consistent with the hygiene hypothesis, we posit that this defective microbiome function results in abnormally regulated systemic innate immune TLR2 responses that play a critical role in both the inflammatory and defective remyelinative aspects of MS. We have completed proof of concept studies that support the inflammatory, remyelinating, and human immune response components of this paradigm. Our studies suggest that induction of TLR2 tolerance may represent a novel approach to treating MS, inhibiting autoimmune inflammation while simultaneously facilitating remyelination.


[Management of a case of iatrogenic treatment of anterior teeth].
A case with unusual iatrogenia due to dental attention is introduced, as well as the first steps made to solve the situation. Some conclusions obtained from the treatment are also summarized.


Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity.
We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.


[Research strategies towards a holistic characterization of rheumatoid arthritis--a systems biology approach].
Genome-wide screening methods used in functional genomics (genome, transcriptome, proteome and metabolom analysis) have increasingly been conducted in integrative research platforms to enable a comprehensive holistic characterization of multifactorial polygenic diseases. First results of this research strategy demonstrate that extended data sets are compiled whose quality is ensured by the application of standard operating procedures (SOPs) and the integration of specific laboratory information management systems (LIMS). Experimental data derived from this technology and methodology platform are obtained by applying standardized sampling procedures followed by comprehensive experimental validation and bioinformatic comparisons with the world knowledge publicly available. This research strategy should finally lead to a holistic understanding of the pathogenesis presented in rheumatoid arthritis by identifying disease-associated regulatory networks (pathways) and assigning them to cell populations involved in the disease mechanisms. In addition, it has to be investigated to what extent genetic as well as epigenetic factors direct disease initiation and progression in potential conjunction with environmental impacts (infections, smoking, etc.).


Calculation, knowledge, and identity: Dimensions of trust when making COVID-19 vaccination choices in China.
Vaccine hesitancy threatens the response to the COVID-19 pandemic and to other infectious disease outbreaks globally. Fostering trust has been highlighted as a critical factor in addressing vaccine hesitancy and expanding vaccine coverage, but qualitative exploration of trust in the context of vaccination remains limited. We contribute to filling this gap by providing a comprehensive qualitative analysis of trust in the context of COVID-19 vaccination in China. We conducted 40 in-depth interviews with Chinese adults in December 2020. During data collection, trust emerged as a highly salient topic. Interviews were audio-recorded, transcribed verbatim, translated into English, and analyzed with a combination of inductive and deductive coding. Following established trust literature, we differentiate between three types of trust - calculation-based trust, knowledge-based trust, and identity-based trust - which we grouped across components of the health system, as informed by the WHO's building blocks. Our results highlight how participants attributed their level of trust in COVID-19 vaccines to their trust in the medical technology itself (based on assessing risks and benefits or previous vaccination experiences), the service delivery and health workforce (informed by past experiences with health providers and their role throughout the pandemic), and leadership and governance (drawing on notions of government performance and patriotism). Reducing negative impact from past vaccine controversies, increasing the credibility of pharmaceutical companies, and fostering clear communication are identified as important channels for facilitating trust. Our findings emphasize a strong need for comprehensive information on COVID-19 vaccines and increased promotion of vaccination by credible figures.


TLRs Go Linear - On the Ubiquitin Edge.
Toll-like receptors (TLRs) are crucial in protecting the host from pathogens. However, their exact role in disease remains incompletely understood. TLR signaling is tightly controlled because too little or too much TLR activation can result in immunodeficiency or autoinflammation, respectively. There is increasing evidence that linear ubiquitination, mediated by the linear ubiquitin chain assembly complex (LUBAC), plays a pivotal role in the regulation of TLR signaling. Recent advances have identified an intricate interaction between LUBAC and TLRs, with immunological consequences for infection and the development of autoinflammation in the host. We propose that defective linear ubiquitination contributes to TLR-mediated disease pathogenesis and that perturbed TLR signaling contributes to the phenotype observed in inherited LUBAC deficiency in humans and mice.


Freeze-dried human serum albumin improves the adherence and proliferation of mesenchymal stem cells on mineralized human bone allografts.
Mineralized scaffolds are widely used as bone grafts with the assumption that bone marrow derived cells colonize and remodel them. This process is slow and often unreliable so we aimed to improve the biocompatibility of bone grafts by pre-seeding them with human mesenchymal stem cells from either bone marrow or dental pulp. Under standard cell culture conditions very low number of seeded cells remained on the surface of freeze-dried human or bovine bone graft or hydroxyapatite. Coating the scaffolds with fibronectin or collagen improved seeding efficiency but the cells failed to grow on the surface until the 18th day. In contrast, human albumin was a very potent facilitator of both seeding and proliferation on allografts which was further improved by culturing in a rotating bioreactor. Electron microscopy revealed that cells do not form a monolayer but span the pores, emphasizing the importance of pore size and microstructure. Albumin coated bone chips were able to unite a rat femoral segmental defect, while uncoated ones did not. Micro-hardness measurements confirmed that albumin coating does not influence the physical characteristics of the scaffold, so it is possible to introduce albumin coating into the manufacturing process of lyophilized bone allografts.


Immune Response of A Novel ATR-AP205-001 Conjugate Anti-hypertensive Vaccine.
We developed a virus-like particle (VLP)-based therapeutic vaccine against angiotensin II receptor type 1, ATR-AP205-001, which could significantly reduce the blood pressure and protect target organs of hypertensive animals. In this study, we focused on the immunological effect and safety of the VLP-based vaccine. By comparing to the depolymerized dimeric vaccine ATR-Dimer-001, we found that ATR-AP205-001 reached subcapsular sinus of lymph node shortly after administration, followed by accumulation on follicle dendritic cells via follicle B cell transportation, while ATR-Dimer-001 vaccine showed no association with FDCs. ATR-AP205-001 vaccine strongly activated dendritic cells, which promoted T cells differentiation to follicular helper T cells. ATR-AP205-001 vaccine induced powerful germinal center reaction, which was translated to a boost of specific antibody production and long-lasting B cell memory, far superior to ATR-Dimer-001 vaccine. Moreover, neither cytotoxic T cells, nor Th1/Th17 cell-mediated inflammation was observed in ATR-AP205-001 vaccine, similar to ATR-Dimer-001 vaccine. We concluded that ATR-AP205-001 vaccine quickly induced potent humoral immunity through collaboration of B cells, follicular dendritic cells and follicular helper T cells, providing an effective and safe intervention for hypertension in the future clinical application.


Diapause in a tropical species, Cothonaspis boulardi (Parasitic hymenoptera).
The strain of Cothonaspis boulardi originating from a field collection at Guadeloupe (16° lat. N-West Indies) exhibits a facultative diapause that occurs at the final larval instar. The diapause was induced by low temperature (17.5° C) and was inhibited at 25° C. Diapause was independent of photoperiod. The termination of diapause was hastened in about 10 days by exposing larvae to a temperature of 25° C. Although a succession of sufficient cold days for diapause occurs only rarely in the collection area (Petit-Bourg), at higher elevations within 20 km of Petit-Bourg conditions that could induce diapause occur annually.


Gene cloning and complete nucleotide sequence of philippine Schistosoma japonicum paramyosin.
The development of an effective vaccine is recognised as a necessary adjunct to the control of schistosomiasis japonica, a disease affecting several million people in China and the Philippines. Currently, recombinant Schistosoma japonicum molecules are considered most suitable for large scale vaccine production and a number of genes encoding vaccine candidate polypeptides have been cloned and expressed (see Waine et al., 1993a). One of the molecules providing most promise as a vaccine target is paramyosin (Butterworth, 1992), a major structural protein of thick filaments in the muscle of most invertebrates; paramyosin genes have now been cloned from a range of parasitic helminths, including schistosomes (Limberger and McReynolds, 1990; Laclette et al., 1991; Dahmen et al., 1993; Landa et al., 1993; Mühlschlegel et al., 1993, Nara et al., 1994). The cloning and nucleotide sequence of S. Japonicum paramyosin is described.


Sesquiterpenoids from Atractylodes macrocephala act as farnesoid X receptor and progesterone receptor modulators.
Two sesquiterpenoids, atractylenolide II and III, were isolated and identified from Atractylodes macrocephala (Asteraceae) to be subsequently evaluated for their activity against farnesoid X receptor (FXR) and progesterone receptor (PR) by transient transfection reporter assays. These sesquiterpenoids did not exert significant agonistic effect but antagonized the activity of chenodeoxycholic acid (CDCA), an endogenous FXR agonist, for FXR driven SHP promoter transactivation. Additionally, they transactivated CYP7A1 gene promoter activity by antagonizing FXR. Apart from acting as a FXR antagonist, atractylenolide III also showed agonistic activity against PR. All these results demonstrated that atractylenolide II and III are the active components of Atractylodes macrocephala to exert specific pharmacologic effects.


A diagnostic conundrum: two siblings with features overlapping the Kabuki and Malpuech syndromes. A new MCA syndrome?
We report two siblings, a boy and a girl, with a constellation of anomalies that overlap the phenotypes of Kabuki and Malpuech syndromes. Both patients had a facial appearance suggestive of Kabuki syndrome, sagittal vertebral clefts, and short fifth fingers. In addition, the girl had brachydactyly of the index finger, and the boy, cleft lip and palate, mild postnatal growth deficiency, coarctation of the aorta, ventricular septal defect, patent ductus arteriosus, and a caudal appendage. The fact that this pattern of anomaly occurred in siblings, together with the presence of sparse eyebrows medially, rather than laterally, in both patients and a caudal appendage in the boy, militates against the diagnosis of Kabuki syndrome. Furthermore, the presence of a caudal appendage in a child with cleft lip and cleft palate and renal abnormalities is suggestive of Malpuech syndrome. The normal growth pattern and psychomotor development observed in both children, however, is inconsistent with this diagnosis, although they may represent a milder end of the phenotypic spectrum for Malpuech syndrome. Alternatively, we conclude that the condition may represent a distinct multiple congenital anomaly (MCA) syndrome. The occurrence of a pattern of MCA in two siblings with phenotypically normal parents and normal cytogenetic studies, including high-resolution banding and subtelomeric probes, points toward an autosomal recessive mode of inheritance. However, germinal mosaicism and other types of non-traditional inheritance, such as a defect in genomic imprinting or uniparental disomy, should also be considered.


The Gracilis Free Flap.
The gracilis free flap is the ideal modality of emotive and spontaneous facial reanimation in patients with a viable contralateral facial nerve. A 2-stage procedure with a cross-face nerve graft followed by gracilis free flap inset is advocated. In this article, the anatomy of the gracilis muscle, alternative neural sources (including the masseteric nerve), and technical aspects of the procedure are discussed. The literature regarding outcomes and complications is reviewed.


Posterior reversible encephalopathy syndrome due to immunosuppressant after living-donor lobar lung transplantation: report of a case.
Living-donor lobar lung transplantation was performed in a 10-year-old boy with bronchiolitis obliterans after bone marrow transplantation for recurrent acute myeloid leukemia. He developed posterior reversible encephalopathy syndrome (PRES) due to calcineurin inhibitor (CNI) postoperatively, which was recovered with suspension of CNI. PRES should be considered one of the important morbidity after lung transplantation.


Quantitative observations of the effect of sex-steroids on the postnatal development of LH-cells. An immunohistochemical study.
The effects of sex-steroids on the LH-cell development in neonatal rats were studied. The cells were stained immunohistochemically by applying anti-HCG serum. On the second day after birth some of the animals of both sexes were gonadectomized and simultaneously injected with testosterone or estradiol (50 or 200 microgram). The remaining animals were either gonadectomized or injected with either one of the sex-steroids. The LH-cell numbers in each group were determined on the 12th day of age from serially cut histological sections of the pituitary. In castrated males the number of LH-cells was about twice that of the intact animals. In the so-called sex-zone, LH-cells tended to be hypertrophied in castrates. These alterations in the appearance of LH-cells did not occur after ovariectomy. In gonadectomized animals injected with sex-steroids (200 microgram), the cells were markedly reduced in number and size, both in males and females. Testosterone injection (50 microgram) into intact newborn animals also suppressed the numerical development of LH-cells, especially in females. These alterations were particularly evident in the sex-zone in both sexes. Thus the present findings show that sex-steroids may be involved in sexual differences in morphological development of LH-cells in newborn rats.


Efficacy and Safety of Induction Therapy With Calcineurin Inhibitors in Combination With Vedolizumab in Patients With Refractory Ulcerative Colitis.
Vedolizumab is used to treat patients with ulcerative colitis (UC), although there is a delay before it is effective. Induction therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) in combination with vedolizumab as maintenance therapy could be an option for patients with an active steroid-refractory UC. We assessed the efficacy and safety of this combination. We performed a retrospective observational study, collecting data from 12 referral centers in France that were included in the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif. We collected information on 39 patients with an active steroid-refractory UC (31 with active severe UC and 36 failed by treatment with a tumor necrosis factor antagonist) who received a calcineurin inhibitor as induction therapy along with vedolizumab as maintenance therapy. Inclusion date was the first vedolizumab infusion. The outcomes were survival without colectomy, survival without vedolizumab discontinuation, and safety. After a median follow-up period of 11 months, 11 patients (28%) underwent colectomy. At 12 months, 68% of the patients survived without colectomy (95% CI, 53%-84%) and 44% survived without vedolizumab discontinuation (95% CI, 27%-61%). No deaths occurred and 4 severe adverse events were observed. In a retrospective analysis of 39 patients with an active steroid-refractory UC (most refractory to a tumor necrosis factor antagonist), we found that initial treatment with a calcineurin inhibitor in combination with vedolizumab allowed more than two thirds of patients to avoid colectomy. Further studies are needed to assess the safety of this strategy.


[Resection margins in conservative breast cancer surgery].
Conservative breast cancer surgery is facing a new problem: the potential tumour involvement of resection margins. This eventuality has been closely and negatively associated with disease-free survival. Various factors may influence the likelihood of margins being affected, mostly related to the characteristics of the tumour, patient or surgical technique. In the last decade, many studies have attempted to find predictive factors for margin involvement. However, it is currently the new techniques used in the study of margins and tumour localisation that are significantly reducing reoperations in conservative breast cancer surgery.


Influence of different base thicknesses on maxillary complete denture processing: linear and angular graphic analysis on the movement of artificial teeth.
The purpose of this study was to compare the dental movement that occurs during the processing of maxillary complete dentures with 3 different base thicknesses, using 2 investment methods, and microwave polymerization. A sample of 42 denture models was randomly divided into 6 groups (n = 7), with base thicknesses of 1.25, 2.50, and 3.75 mm and gypsum or silicone flask investment. Points were demarcated on the distal surface of the second molars and on the back of the gypsum cast at the alveolar ridge level to allow linear and angular measurement using AutoCAD software. The data were subjected to analysis of variance with double factor, Tukey test and Fisher (post hoc). Angular analysis of the varying methods and their interactions generated a statistical difference (P = 0.023) when the magnitudes of molar inclination were compared. Tooth movement was greater for thin-based prostheses, 1.25 mm (-0.234), versus thick 3.75 mm (0.2395), with antagonistic behavior. Prosthesis investment with silicone (0.053) showed greater vertical change compared with the gypsum investment (0.032). There was a difference between the point of analysis, demonstrating that the changes were not symmetric. All groups evaluated showed change in the position of artificial teeth after processing. The complete denture with a thin base (1.25 mm) and silicone investment showed the worst results, whereas intermediate thickness (2.50 mm) was demonstrated to be ideal for the denture base.


A microsomal exoribonuclease from rat liver.
A exoribonuclease has been purified from the microsomes of rat liver. The enzyme had an apparent molecular weight of 80 000-83 000 and produced, via a processive mechanism, 5'-AMP as the only product from poly(A). The degradation was found to proceed in the 3' to 5' direction. The relative rates of breakdown of synthetic polynucleotides by the enzyme under standard conditions were in the order poly(A) equal to poly(U) greater than poly(C). In addition to Mg2+, K+ was required for maximum activity. The enzymic activity was inhibited by p-chloromercuribenzoate and poly(G), but not by a rate liver RNAase inhibitor. The effect of spermine on the breakdown of synthetic polynucleotides by the enzyme has been studied. In the absence of K+, the breakdown of poly(C) was stimulated and that of poly(A) was stimulated slightly. However, the breakdown of poly(U) was inhibited slightly by spermine.


A new method based on ICBM152 head surface for probe placement in multichannel fNIRS.
We propose a new probe placement method for multichannel functional Near Infrared Spectroscopy (fNIRS) based on the ICBM152 template, the most commonly used reference brain for neuroimaging. Our method is based on the use of a physical model of the ICBM152 head surface as reference scalp and its validity is supported by previous investigations of cranio-cerebral correlation. The method, intended for fNIRS group studies, dispenses with the use of individual MRI scan and digitizing procedure for each participant. The present approach offers a fast, simple, reproducible and straightforward method to place the probes on the head surface according to the MNI coordinates of the regions of interest with an average measurement error similar to those of previous methods. This ensures that fNIRS results can be readily compared within the neuroimaging community, both across studies and techniques.


[Not Available].
Due to infections with moulds already in the vineyards, the formation of mycotoxins is possible under certain circumstances during the process of red wine making. At this, metabolites ofPenicillium spp. are of major importance, as this species are to be found frequently on grapes. Beside the nephrotoxic citrinin, which is often co-occurring with ochratoxin A, the occurrence of mycophenolic acid (MPA), a substance of immunosuppressive action, was investigated since it is formed by a great number of Penicillium-species. The detection of these compounds was carried out by means of ELISA and LC-MS. As testing material 44 red wine samples of different provenience and vintages were used. Mycophenolic acid could be detected in 91 % of the samples. The maximum content amounted to 130 ng/ml, yet most of the samples resulted in much lower concentrations of between 3 and 20 ng/ml. The extent of contamination seems to depend rather on the origin of the wine than on the vintage. In particular samples from Southern Europe were most contaminated. This could be due to different practises in wine-making. Citrinin was not detectable in any sample (< 0,2 ng/ml). Regarding the detected concentrations of MPA and citrinin, there is probably no concern for consumers' health. However, the degree of contamination of wine with MPA may well serve as an indicator for hygiene in production.


SIX5-activated LINC01468 promotes lung adenocarcinoma progression by recruiting SERBP1 to regulate SERPINE1 mRNA stability and recruiting USP5 to facilitate PAI1 protein deubiquitylation.
Increasing research has uncovered the involvement of long noncoding RNAs (lncRNAs) in the progression of multiple cancers including lung adenocarcinoma (LUAD). RT-qPCR and western blot were done to measure RNAs and proteins. Functional assays assessed LUAD cell biological behaviors under knockdown or overexpression of LINC01468, SIX5, SERBP1 or SERPINE1, and the specific function of those genes in regulating LUAD progression was evaluated via animal experiments. Supported by bioinformatics analysis, the interaction among genes was verified via mechanism assays. Upregulation of LINC01468 in LUAD tissues and cells as well as its association with poor clinical outcome was predicted. LINC01468, transcriptionally activated by SIX5, could strengthen proliferative, migratory and invasive abilities of LUAD cells. The oncogenic role of LINC01468 was further validated via animal experiments. SIX5 was a positive transcription regulator of LINC01468 and could exacerbate LUAD cell malignant behaviors. LINC01468 could recruit SERBP1 to enhance SERPINE1 mRNA stability and interact with USP5 to affect PAI1 protein ubiquitination. The oncogenic role of SERBP1 and SERPINE1 was also confirmed. Rescue experiments finally verified LINC01468 modulated proliferation, migration and invasion of LUAD cells via upregulation of SERPINE1. Our observations could contribute to deeper understanding of LUAD.


Simultaneous abdominal wall defect repair and Tenckhoff catheter placement in candidates for peritoneal dialysis.
The presence of pre-existing abdominal wall defect (AWD) could represent a potential contraindication for peritoneal dialysis (PD) treatment. We report the results of our 6-year experience involving simultaneous repair of pre-existing AWD and catheter insertion for PD. Patients with estimated glomerular filtration rate (e-GFR) 7-10 ml/min attending a single nephrology clinic between January 2008 and December 2014 were evaluated. Simultaneous AWD repair and catheter placement was performed. For inguinal (IH) or umbilical hernia (UH), a prolene mesh repair technique was adopted. Except for one case of total anaesthesia, the surgical procedure was performed under either spinal or local anaesthesia. Ceftazidime alone or in association with quinolones was administered 1 h before surgery in a single dose. Patients were discharged 2 days after surgery, and returned to the clinic twice during the 1st week for peritoneum washing (first volume of peritoneal dialysis solution: 300 ml). From week 3, volume (2000 ml) and dwells were personalized according to the patient's clinical condition; options were: incremental PD, standard PD, or continuous cycling PD. Surgical follow-up was planned at 1, 6, and 12 months. Peritoneal catheters were inserted in 170 patients. IH, UH and incisional hernia were found in 18, 2 and 1 patients, respectively. IH was bilateral in 4 patients; concomitant IH and UH occurred in 1 patient. There were no deaths, nor intra-operative complications apart from scrotal haematoma in 1 patient. Over a mean follow-up of 551 days (range 342-1274) no hernia recurrence was registered and the peritoneal catheter continued functioning without problems. Simultaneous AWD repair and peritoneal catheter placement seems a reliable and safe surgical procedure that allows patients with AWD to benefit from PD treatment.


Site-directed mutagenesis of the cell-binding domain of human fibronectin: separable, synergistic sites mediate adhesive function.
Polypeptide sequences required for function of the cell-binding domain of human fibronectin were analyzed by site-directed mutagenesis. Site-specific deletion of the putative recognition sequence Arg-Gly-Asp-Ser or an Asp-to-Glu mutation decreased the adhesive activity of fibronectin fusion proteins expressed in E. coli by greater than or equal to 97%. A second functional site over 0.5 kb away was identified by deletion mutagenesis. These mutants also showed a greater than or equal to 96% loss of activity, indicating cooperativity between sites. The two classes of mutant protein displayed synergism of activity in a trans complementation assay. Effective actin microfilament bundle organization was also dependent on the combined function of both sites. Thus, fibroblast adhesion and intracellular response to the fibronectin cell-binding domain involve two synergistic sites, each of major quantitative importance.


ROS-responsive nanoparticles for oral delivery of luteolin and targeted therapy of ulcerative colitis by regulating pathological microenvironment.
Oxidative stress, caused by excessive production of reactive oxygen species (ROS), plays a crucial role in the occurrence and development of ulcerative colitis (UC). We developed ROS-responsive nanoparticles (NPs) as an efficacious nanomedicine against UC with oral administration. The NPs were fabricated with a d-α-tocopherol polyethylene glycol succinate-b-poly(β-thioester) copolymer (TPGS-PBTE) for ROS cleavage via the colitis-targeted delivery of luteolin (LUT), a natural flavonoid with good anti-inflammation and radical-scavenging activity. Owing to the thioether bond in the polymer main chain, the TPGS-PBTE NPs exhibited an ROS-responsive size change and drug release, which benefited the ROS-scavenging and selective accumulation of LUT in the inflamed colon. In a dextran sulfate sodium-induced acute colitis murine model, LUT@TPGS-PBTE NPs alleviated body weight loss, colon length shortening, and damage to the colonic tissues due to the suppression of ROS and proinflammatory cytokines (e.g., IL-17A, IL-6, interferon-γ, tumor necrosis factor-α), as well as upregulation of glutathione and anti-inflammatory factors (e.g., IL-10, IL-4). More importantly, LUT@TPGS-PBTE NPs regulated the inflammatory microenvironment by modulating the T helper (Th)1/Th2 and Th17/regulatory T cell (Treg) balance (i.e., increased numbers of Tregs and Th2 cells and decreased numbers of Th1 and Th17 cells), thus resolving inflammation and accelerating the healing of the intestinal mucosa. Additionally, the LUT@TPGS-PBTE NPs formulation enabled the reduction of the effective dose of LUT and showed excellent biosafety in the mouse model, demonstrating its potential as a targeted UC therapeutic oral preparation.


Human farnesyl pyrophosphate synthase inhibition by nitrogen bisphosphonates: a 3D-QSAR study.
We report the results of a comparative molecular field analysis and comparative molecular similarity index analysis of the human farnesyl pyrophosphate synthase (FPPS) inhibition by nitrogen bisphosphonates (NBPs) taking into account their time-dependent inhibition efficacies. The 3D-QSAR models obtained provide steric, electrostatic and hydrophobic contour maps consistent with the interactions into the active site of human FPPS observed in available crystallographic structures. Furthermore, the 3D-QSAR models obtained provide accurately IC50 values of the NBPs of the training set. The predictive ability of these 3D-QSAR models was found to rely on the choice of biologically active conformations of the target molecules and on a careful examination of the protonation status of the NBPs in the training set. The best models obtained can be useful to predict biological values of a high number of NBPs that have been used for the treatment of different diseases as potential inhibitors of the activity of the FPPS enzyme.


Presence of a sexual problem may not affect women's satisfaction from their sexual function.
It has been proposed that women's sexual problems/dysfunctions, in the absence of personal and interpersonal distress, may have little clinical importance, as they may not necessarily affect women's sexual satisfaction. However, data are missing to support such interpretation. The objective of the present study was to examine whether the presence of a sexual problem necessary affects women's satisfaction with sexual function. The study included 164 women who visited a general hospital because of symptoms not related to their sexual function and were asked to complete voluntarily and anonymously demographic data and two questionnaires. Women completed the Female Sexual Function Index (FSFI)--an instrument which evaluates women sexual function--and the Symptom Checklist of Sexual Function-women version (SCSF-w), a screening tool of women's self-perception of sexual function. Mean patients' age was 43 +/- 12.6 (18-72) years. According to the FSFI, 48.8% of the participants had a sexual dysfunction. However, based on their self-perception of sexual function (SCSF), 80.5% of the sample declared to be satisfied with their sexual function, despite the fact that 69.5% of them reported at least one sexual problem. Of all women, only 26.2% would like to talk about their sexual problem(s) with a doctor (57.4% of those who are "bothered" by their sexual symptoms). Logistic regression analysis revealed no association between any sexual dysfunction and women's satisfaction from their sexual function. Despite the presence of sexual problem(s), women may be satisfied with their sexual function, but half of those who are bothered would like to talk about it with their doctor. The presence of a sexual problem or its severity is not a determinant of women's help-seeking behavior. Such data strongly support current definitions of women's sexual dysfunction, where the presence of personal distress has been included as a crucial dimension.


Heme oxygenase-1 induction by the ROS-JNK pathway plays a role in aluminum-induced anemia.
Aluminum (Al) overload is correlated with hypochromic anemia. It is possible that Al impedes heme biosynthesis and degradation by affecting the activity of biosynthetic enzymes. However, the molecular mechanisms by which Al affects these enzymes are unknown. Here, we show that long-term exposure of Sprague-Dawley rats to Al decreased hemoglobin concentration and the hematocrit level. In addition, the activity of aminolevulinic acid dehydratase (ALA-D) in rat liver was reduced, but heme oxygenase (HO) activity was enhanced, suggesting an impairment of heme homeostasis. The increase in HO activity was due to up-regulation of mRNA and protein of an inducible HO isozyme, HO-1. Furthermore, we found that reactive oxygen species (ROS)-mediated activation of c-Jun N-terminal kinase (JNK) was critical for HO-1 induction by Al, because ROS scavengers and JNK inhibitors abrogated enhancement of HO-1 by Al in rat hepatocytes. Thus, Al enhances HO-1 expression through the ROS-JNK pathway, which may enhance HO activity and accelerate degradation of heme, leading to hypochromic anemia.


Tribological Performance of Microhole-Textured Carbide Tool Filled with CaF₂.
To enhance the friction and wear performance of cemented carbide, textured microholes were machined on micro Electron Discharge Machining (EDM) on the tool rake face, and Calcium Fluoride (CaF₂) powders were burnished into the microholes. The friction and wear characteristics of the microhole-textured tool filled with CaF₂ were investigated using sliding friction tests and dry cutting tests. Results exhibited that the working temperature could affect the tribological performance of the microhole-textured tool filled with CaF₂ due to the temperature-sensitive nature of CaF₂. There is no obvious lubrication effect for the textured tool filled with CaF₂ at room temperature, while it was shown to be more effective in improving tribological property at a cutting speed of higher than 100 m/min with a corresponding to cutting temperature of 450 °C. The possible mechanisms for the microhole-textured tool filled with CaF₂ were discussed and established.


Review of robust multivariate statistical methods in high dimension.
General ideas of robust statistics, and specifically robust statistical methods for calibration and dimension reduction are discussed. The emphasis is on analyzing high-dimensional data. The discussed methods are applied using the packages chemometrics and rrcov of the statistical software environment R. It is demonstrated how the functions can be applied to real high-dimensional data from chemometrics, and how the results can be interpreted.


Risk factors for hospital death of patients with end-stage renal disease without previous diagnosis of severe chronic renal failure arriving in an emergency situation at the hospital.
Many end stage renal disease (ESRD) patients get their first nephrologic care under critical clinical conditions and without previous diagnosis of chronic renal failure (CRF), a situation even worse than the late referral of CRF patients for nephrologic treatment. Data on these "nonreferred" patients are scarce. The objectives of this study were to assess clinical and laboratory features, the reasons for coming to the hospital and the factors associated with death in nonreferred ESRD patients first seen by a nephrologist in an emergency situation. Retrospective study (April 1996-March 2000) using the medical records of patients diagnosed with ESRD at the nephrologic emergency visit in a university tertiary hospital. Clinical and laboratory parameters were reviewed. Patients were divided into two groups according to hospital outcome: survivors or nonsurvivors. There were 414 patients (12% of all nephrologic emergency visits), aged 49 +/- 17 years, 266 males (64%) and 208 (55%) hypertensive. Mortality rate was 13.7% (54/393). When compared to nonsurvivors were older, used mechanical ventilation and vasoactive drugs more frequently, presented higher infection rate, and showed lower plasma creatinine. Multivariate logistic regression showed as factors independently associated with death: first nephrologic visit at intensive care unit, infection as cause for seeking medical care, and increasing age. Plasma creatinine above 10 mg/dL was a protective factor for death. ESRD patients reaching dialysis in a nephrologic emergency situation presented high hospital mortality, which was mostly associated with their poor clinical condition at admission.


Combined surgery and chemotherapy for the treatment of primary gastrointestinal intermediate- or high-grade non-Hodgkin's lymphomas.
Fifty-five consecutive patients with primary gastrointestinal intermediate or high grade non-Hodgkin's lymphoma were analysed to assess the efficacy of chemotherapy following surgical tumour resection. Histological subtypes were high grade (n = 18), intermediate grade (n = 36) and unclassified (n = 1). The majority of patients had gastric presentation (71%) and localised disease (84%). Surgery consisted of radical resection in 25 patients (45%) and partial or palliative excision in the remaining cases (22 and 8 respectively). Four subjects died within 3 months of surgery, two patients refused adjuvant chemotherapy and 49 completed the postoperative chemotherapeutic programme. Chemotherapy included either Fi2/74 (adriamycin + vincristine + bleomycin + cyclophosphamide + prednisone) or Fi3/74 (adriamycin + VM26 + bleomycin + cyclophosphamide + prednisone). Excluding the group who underwent radical tumour resection, postoperative chemotherapy induced complete remission in 81% of the remaining 30 patients. The 10-year cause-specific survival for the 53 treated patients was 76% (median follow-up 58 months) with a stable curve plateau after 80 months. Proportional-hazard multivariate statistics showed that survival was influenced by type of surgical resection (P less than 0.05) and stage (P less than 0.05), whereas age, sex and histological subtype were not influential. Our data indicate that chemotherapy following surgical resection of gastrointestinal lesion induces long-term remission in primary gastrointestinal lymphomas.


Uridine triphosphate-sensitive pathway of Ca2+ release from the sarcoplasmic reticulum of rat skeletal muscle fibers.
The pyrimidine nucleotide, uridine triphosphate (UTP), was tested with skinned skeletal muscle fibers in order to investigate the UTP-sensitive pathway of Ca2+ release from the sarcoplasmic reticulum. The presence of ryanodine (200 microM), ruthenium red (10 microM) or heparin (2.5 mg/ml) did not affect the tension elicited in the presence of UTP, demonstrating that the UTP-induced Ca2+ release involved neither ryanodine nor inositol triphosphate-sensitive channels. Drugs such as compound 48/80 or cyclopiazonic acid used to inhibit Ca2+-ATPase in its reverse function appeared to be, respectively, non-specific or without any inhibitory effect on the tension induced by UTP. Finally, the UTP-induced tension as well as the trifluoperazine-induced tension were abolished in the presence of spermidine (50 mM), supporting the hypothesis that the UTP-sensitive pathway of the SR Ca2+ release might occur through the uncoupled calcium ATPase.


Relief of oxidative stress by ascorbic acid delays cellular senescence of normal human and Werner syndrome fibroblast cells.
Primary human cells have a definite life span and enter into cellular senescence before ceasing cell growth. Oxidative stress produced by aerobic metabolism has been shown to accelerate cellular senescence. Here, we demonstrated that ascorbic acid, used as an antioxygenic reagent, delayed cellular senescence in a continuous culture of normal human embryonic cells, human adult skin fibroblast cells, and Werner syndrome (WS) cells. The results using human embryonic cells showed that treatment with ascorbic acid phospholic ester magnesium salt (APM) decreased the level of oxidative stress, and extended the replicative life span. The effect of APM to extend the replicative life span was also shown in normal human adult cells and WS cells. To understand the mechanism of extension of cellular life span, we determined the telomere lengths of human embryonic cells, both with and without APM treatment, and demonstrated that APM treatment reduced the rate of telomere shortening. The present results indicate that constitutive oxidative stress plays a role in determining the replicative life span and that suppression of oxidative stress by an antioxidative agent, APM, extends the replicative life span by reducing the rate of telomere shortening.


'In vivo' time course of plasma myeloperoxidase levels after granulocyte colony-stimulating factor-induced stem cell mobilization.
Administration of granulocyte colony-stimulating factor (G-CSF) is widely used for harvesting an adequate number of CD34+ stem cells by leukapheresis in normal donors. G-CSF is the most established agent for the mobilization of stem cells in current clinical practice, because it has been proven to be superior to any other agent tested to date in terms of not only mobilization capacity, but also of tolerance. However, although regulatory and accrediting agencies have provided guidelines to protect donors, the short- and long-term side effects of G-CSF need to be further studied. In this study, we evaluated the time course of plasma myeloperoxidase (MPO) levels measured in a group of donors given recombinant human G-CSF (rHuG-CSF) at different intervals: (i) before starting rHuG-CSF administration, (ii) on day 5 of rHuG-CSF administration, (iii) on the same day soon after the end of the first leukapheresis procedure and (iv) 1 week after rHuG-CSF withdrawal. Plasma MPO levels significantly increased in the donors after 5 days of rHuG-CSF treatment, returning to the baseline values within 7 days following rHuG-CSF withdrawal. These findings may contribute to a better understanding of G-CSF safety profile in stem cell donors.


Clinically induced hypothermia with cardiopulmonary support in a high-risk patient undergoing carotid endarterectomy.
Contralateral carotid occlusion increases the risk of stroke by hypoperfusion in patients undergoing carotid surgery. We present the case of a high-risk patient with crescendo cerebral ischemic events, for whom clinically induced hypothermia controlled by cardiopulmonary bypass was applied as a protective measure during carotid endarterectomy.