Patentees research and development expenditure in Canada.
Many industries are affected by the stale global economy recently. However, the innovative pharmaceutical and biotechnology industry seems to be relentlessly producing a wealth of newer therapeutic products to meet the increasing demand of the aging population. These companies" abilities to produce safer and more effective products are the results of research and development (R&D) spending. Clearly, by investigating R&D expenditures of patentees, one can paint a better picture of the condition in this sector of the Canadian economy. To track patentees R&D expenditures, the Patented Medicine Prices Review Board (PMPRB) annual reports have become the primary sources of data. Furthermore, the financial market and the Therapeutic Directorate Annual Drug Submission Performance Report have also been used to address some of the patterns that are seen in PMPRB data. Most of the data suggest excellent growth in the innovative pharmaceutical and biotechnology sector in Canada. Despite this growth, it still lags behind the demand of newer therapeutic products. Nevertheless, the industry can weather a volatile economy well. Patentees R&D expenditure is a good indicator of the health in the industry. It provides a perspective not only within Canada itself, but also globally.


Rho-kinase inhibitor and nicotinamide adenine dinucleotide phosphate oxidase inhibitor prevent impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats.
We previously reported that acute cigarette smoking can cause a dysfunction of endothelium-dependent vasodilation in cerebral vessels, and that blocking the angiotensin II (Ang II) type 1 (AT1) receptor with valsartan prevented this impairment. Our aim was to investigate the effects of a Rho-kinase inhibitor (fasudil) and a Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase inhibitor (apocynin) on smoking-induced endothelial dysfunction in cerebral arterioles. In Sprague-Dawley rats, we used a closed cranial window preparation to measure changes in pial vessel diameters following topical acetylcholine (ACh) before smoking. After one-minute smoking, we again examined the arteriolar responses to ACh. Finally, after intravenous fasudil or apocynin pre-treatment we re-examined the vasodilator responses to topical ACh (before and after cigarette smoking). Under control conditions, cerebral arterioles were dose-dependently dilated by topical ACh (10(-6) M and 10(-5) M). One hour after a one-minute smoking (1 mg-nicotine cigarette), 10(-5) M ACh constricted cerebral arterioles. However, one hour after a one-minute smoking, 10(-5) M ACh dilated cerebral pial arteries both in the fasudil pre-treatment and the apocynin pre-treatment groups, responses that were significantly different from those obtained without fasudil or apocynin pre-treatment. Thus, inhibition of Rho-kinase and NADPH oxidase activities may prevent the above smoking-induced impairment of endothelium-dependent vasodilation.


Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis.
Long non-coding RNAs (lncRNAs) are regarded as crucial regulators for cancer initiation and progression. Heart and Neural Crest Derivatives Expressed 2 antisense RNA 1 (HAND2-AS1) was recently proposed to function as tumor suppressor in several human cancers. However, its role in gastric cancer (GC) remains unclear. HAND2-AS1 expression in GC tissues and normal tissues was analyzed at GEPIA (a web server for gene expression profiling analysis). Moreover, RT-qPCR method was utilized to explore HAND2-AS1 expression in GC cells and normal cell. In vitro experiments were carried out using cell counting kit-8 assay, colony formation assay, and flow cytometry assay, respectively. Bioinformatic analysis and luciferase activity reporter assay were performed to identify the downstream targets of HAND2-AS1. We found HAND2-AS1 has decreased expression in both GC tissues and cells. Overexpression of HAND2-AS1 was able to inhibit GC cell proliferation, colony formation, but promote apoptosis. On the contrary, knockdown of HAND2-AS1 could cause the opposite effects on GC cells. Furthermore, HAND2-AS1 was shown to function as a competitive RNA that binds with microRNA-590-3p (miR-590-3p) to affect the expression of potassium sodium-activated channel subfamily T member 2 (KCNT2). Our results indicated the tumor suppressive role of HAND2-AS1 in GC. Also, the newly identified HAND2-AS1/miR-590-3p/KCNT2 axis will help us to understand the role of HAND2-AS1 in cancer.


Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin.
Cutaneous vasoconstriction (VC) is the initial thermoregulatory response to cold exposure and can be elicited through either whole body or localized skin cooling. However, the mechanisms governing local cold-induced VC are not well understood. We tested the hypothesis that Rho kinase participates in local cold-induced cutaneous VC. In seven men and women (20-27 yr of age), up to four ventral forearm skin sites were instrumented with intradermal microdialysis fibers for localized drug delivery during cooling. Skin blood flow was monitored at each site with laser-Doppler flowmetry while local skin temperature was decreased and maintained at 24 degrees C for 40 min. Cutaneous vascular conductance (CVC; laser-Doppler flowmetry/mean arterial pressure) was expressed as percent change from 34 degrees C baseline. During the first 5 min of cooling, CVC decreased at control sites (lactated Ringer solution) to -45 +/- 6% (P < 0.001), increased at adrenoceptor-antagonized sites (yohimbine + propranolol) to 15 +/- 14% (P = 0.002), and remained unchanged at both Rho kinase-inhibited (fasudil) and adrenoceptor-antagonized + Rho kinase-inhibited sites (yohimbine + propranolol + fasudil) (-9 +/- 1%, P = 0.4 and -6 +/- 2%, P = 0.4, respectively). During the last 5 min of cooling, CVC further decreased at all sites when compared with baseline values (control, -77 +/- 4%, P < 0.001; adrenoceptor antagonized, -61 +/- 3%, P < 0.001; Rho kinase inhibited, -34 +/- 7%, P < 0.001; and adrenoceptor antagonized + Rho kinase inhibited sites, -35 +/- 3%, P < 0.001). Rho kinase-inhibited and combined treatment sites were significantly attenuated when compared with both adrenoceptor-antagonized (P < 0.01) and control sites (P < 0.0001). Rho kinase mediates both early- and late-phase cold-induced VC, supporting in vitro findings and providing a putative mechanism through which both adrenergic and nonadrenergic cold-induced VC occurs in an in vivo human thermoregulatory model.


The carbon/nitrogen regulator ARABIDOPSIS TOXICOS EN LEVADURA31 controls papilla formation in response to powdery mildew fungi penetration by interacting with SYNTAXIN OF PLANTS121 in Arabidopsis.
The carbon/nitrogen (C/N) balance of plants is not only required for growth and development but also plays an important role in basal immunity. However, the mechanisms that link C/N regulation and basal immunity are poorly understood. We previously demonstrated that the Arabidopsis (Arabidopsis thaliana) Arabidopsis Tóxicos en Levadura31 (ATL31) ubiquitin ligase, a regulator of the C/N response, positively regulates the defense response against bacterial pathogens. In this study, we identified the plasma membrane-localized soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor SYNTAXIN OF PLANTS121 (SYP121) as a novel ATL31 interactor. The syp121-1 loss-of-function mutant showed similar hypersensitivity to C/N stress conditions as the atl31 atl6 double mutant. SYP121 is essential for resistance to penetration by powdery mildew fungus and positively regulates the formation of cell wall appositions (papillae) at fungal entry sites. Microscopic analysis demonstrated that ATL31 was specifically localized around papillae. In addition, ATL31 overexpressors showed accelerated papilla formation, enhancing their resistance to penetration by powdery mildew fungus. Together, these data indicate that ATL31 plays an important role in connecting the C/N response with basal immunity by promoting papilla formation through its association with SYP121.


Dimethylsulfoniopropionate decorated cryogels as synthetic spatially structured habitats of marine bacterial communities.
In microbial consortia bacteria often settle on other organisms that provide nutrients and organic material for their growth. This is true for the plankton where microalgae perform photosynthesis and exude metabolites that feed associated bacteria. The investigation of such processes is difficult since algae provide bacteria with a spatially structured environment with a gradient of released organic material that is hard to mimic. Here we introduce the design and synthesis of a cryogel-based microstructured habitat for bacteria that provides dimethylsulfoniopropionate (DMSP) as a carbon and sulfur source for growth. DMSP, a widely distributed metabolite released by algae, is thereby made available for bacteria in a biomimetic manner. Based on a novel DMSP derived building block (DMSP-HEMA), we synthesized cryogels providing structured surfaces for settlement and delivering the organic material fueling bacterial growth. By monitoring bacterial settlement and performance we show that the cryogels represent microbial arenas mimicking the ecological situation in the plankton.


The fibroblast growth factor binding protein is a novel interaction partner of FGF-7, FGF-10 and FGF-22 and regulates FGF activity: implications for epithelial repair.
The fibroblast growth factor-binding protein (FGF-BP) binds and activates FGF-1 and FGF-2, thereby contributing to tumor angiogenesis. In this study, we identified novel binding partners of FGF-BP, and we provide evidence for a role of this protein in epithelial repair processes. We show that expression of FGF-BP increases after injury to murine and human skin, in particular in keratinocytes. This upregulation is most likely achieved by major keratinocyte mitogens present at the wound site. Most importantly, we demonstrate that FGF-BP interacts with FGF-7, FGF-10, and with the recently identified FGF-22, and enhances the activity of low concentrations of ligand. Due to the important functions of FGF-7 and FGF-10 for repair of injured epithelia, our findings suggest that upregulation of FGF-BP expression after injury stimulates FGF activity at the wound site, thus enhancing the process of epithelial repair.


A Probabilistic Graphical Model for Ab Initio Folding.
Despite significant progress in recent years, ab initio folding is still one of the most challenging problems in structural biology. This paper presents a probabilistic graphical model for ab initio folding, which employs Conditional Random Fields (CRFs) and directional statistics to model the relationship between the primary sequence of a protein and its three-dimensional structure. Different from the widely-used fragment assembly method and the lattice model for protein folding, our graphical model can explore protein conformations in a continuous space according to their probability. The probability of a protein conformation reflects its stability and is estimated from PSI-BLAST sequence profile and predicted secondary structure. Experimental results indicate that this new method compares favorably with the fragment assembly method and the lattice model.


The inhibition of accumulation of [1-14C]glycine and its incorporation into protein of Ehrlich ascites-carcinoma cells by DL-methionine.
1. By incubation of Ehrlich ascites-carcinoma cells in vitro with [1-(14)C]glycine the relation between the uptake of glycine and its incorporation into protein was examined. 2. With dl-methionine as a competitive inhibitor, there was not only a decrease in uptake of this amino acid, but also inhibition of its incorporation into protein. 3. It is only in its initial stage that the increase in incorporation is accompanied by increase in intracellular concentration of free glycine. Further increase in the amino acid pool has no effect on protein synthesis. 4. Even with a high cell concentration of glycine, methionine produces a decrease both in the uptake and its incorporation. This suggests that the inhibition of incorporation of glycine by methionine is due, not only to decrease in its intracellular concentration, but also to changes in other processes responsible for protein synthesis.


DLK1-DIO3 imprinted locus deregulation in development, respiratory disease, and cancer.
The imprinted DLK1-DIO3 locus at 14q32.1-32.31 holds biological significance in fetal development, whereby imprinting errors are causal to developmental disorders. Emerging evidence has implicated this locus in other diseases including cancer, highlighting the biological parallels between fetal organ and tumour development. Areas covered: Controlled regulation of gene expression from the imprinted DLK1-DIO3 locus at 14q32.1-32.31 is crucial for proper fetal development. Deregulation of locus gene expression due to imprinting errors has been mechanistically linked to the developmental disorders Kagami-Ogata Syndrome and Temple Syndrome. In adult tissues, deregulation of locus genes has been associated with multiple malignancies although the causal genetic mechanisms remain largely uncharacterised. Here, we summarize the genetic mechanisms underlying the developmental disorders that arise as a result of improper locus imprinting and the resulting developmental phenotypes, emphasizing both the coding and noncoding components of the locus. We further highlight biological parallels common to both fetal development and disease, with a specific focus on lung development, respiratory disease, and lung cancer. Expert commentary: Many commonalities between respiratory and developmental defects have emerged with respect to the 14q32 locus, emphasizing the importance of studying the effects of imprinting on gene regulation patterns at this locus in both biological settings.


[Unusual removal of a Küntscher nail after 35 years].
A 68 year old patient with persistent feeling of sickness and increasing pain in the left forearm was seen. A complex both bone fracture of the distal forearm shaft had been stabilized with Küntscher nails in radius and ulna 35 years ago. The loose ulna nail had been removed after ten weeks. Reosteosynthesis twelve months later with a Küntscher nail and cerclages had led to osteomyelitis and persistent bone defect, possibly caused by galvanic reaction between the different alloyies. A lymphocyte transformation test with nickel sulphate confirmed an allergic reaction and supported the indication to late implant removal. After exposure of the nail's end by a short approach a sufficient take over of power to the implant was reached by a coupling pole. Extraction was stopped after two centimetres by a blockage of the nail. Widening the entry of nail and drilling its whole notch by means of a Kirschner wire using the radiolucent ruler and by the repeated extraction and reinsertion led finally to the complete removal of the nail. Whereas local pain is disappeared three month after removal presenting bland local findings the general condition is improved slowly. Already Küntscher described the blockage of his nail after a short distance extraction. In addition to a number of not always successful means of extraction this method is described for the first time.


Anticancer effects of metformin on neuroendocrine tumor cells in vitro.
Metformin is a widely used oral antidiabetic drug with good tolerability. Recent studies suggest that it also possesses adjuvant potent anticancer properties in a variety of tumors. Neuroendocrine tumors (NETs) of the gastro-entero-pancreatic system (GEP) comprise a heterogeneous group of tumors with increasing incidence and limited effective therapeutic options. Here we report the antiproliferative effects of metformin in neuroendocrine tumor cells in vitro. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727, and midgut GOT1 neuroendocrine tumor cells with increasing concentrations of metformin (0.1-10 mM) dose-dependently suppressed cell viability and cell counts. Metformin induced AMPK phosphorylation in pancreatic BON1 and midgut GOT1 but suppressed AMPK activity in bronchopulmonary NCI-H727. Thus, AMPK-dependent and AMPK-independent properties may be operative in NETs of different origin. Metformin suppressed mTORC1 signaling in all three tumor cell types, evidenced by suppression of 4EBP1, pP70S6K, and S6 phosphorylation, and was associated with compensatory AKT activity. We observed induction of ERK phosphorylation in BON1 and NCI-H727 and inhibition of ERK in midgut GOT1 cells, while all three tumor cell types responded with induction of GSK3 phosphorylation. This suggests a central role for GSK3 in metformin-mediated signal transduction. Inhibition of cell proliferation by metformin was associated with apoptosis induction only in midgut GOT1, evidenced by increased subG0/1 fraction and PARP cleavage. These results suggest a potential role of metformin as a (adjuvant) therapeutic for patients with NETs.


Nemaline Myopathy: A Case Report.
Generalized weakness in the pediatric and adolescent population is caused by many disorders that affect the neuromuscular axis. As next-generation sequencing (NGS) is becoming of high yield in replacing more invasive procedures, that is, muscle and nerve biopsy, more previously undiagnosed diseases of the muscles are now labeled with specific pathogenicity. A 16-year-old-girl diagnosed with nemaline myopathy but previously was misdiagnosed with congenital myasthenia and put-on unnecessary medications. Clinicians should be aware of congenital diseases that affect the muscles and know the importance of the NGS in reaching the correct diagnosis more so when there is a history of consanguinity.


Oxidized low-density lipoproteins activate CD4+ T cell apoptosis in patients with end-stage renal disease through Fas engagement.
Oxidized LDL (oxLDL) are cytotoxic to vascular cells, but their possible toxic action on T cells from patients with ESRD has not been evaluated. oxLDL concentrations were measured and compared in patients who were on long-term hemodialysis (HD), in patients who had ESRD and were on continuous ambulatory peritoneal dialysis, in nondialyzed patients with chronic kidney disease, and in age- and gender-matched control subjects. In parallel, the proliferative capacity of CD69+/CD4+ T cells and their rate of apoptosis, IL-2 expression, and intracellular expression of Bcl-2 and Bax were determined in vitro. The oxLDL concentrations were significantly higher in HD patients (all P = 0.001). Upon phytohemagglutinin stimulation, CD69+/CD4+ T cells from HD patients proliferated significantly less than those from the other patients' group (both P < 0.001). oxLDL but not the native LDL were led to CD69+/CD4+ T cells' program cell death in a dosage- and time-dependent manner through Fas pathway (P = 0.001). Cell surface Fas expression was followed by DNA fragmentation when CD69+/CD4+ T cells from HD patients or control subjects were cultured with oxLDL (200 microg/ml; 31 +/- 3 versus 25 +/- 3%; P = 0.001). In the presence of oxLDL, CD69+/CD4+ T cells from HD patients expressed significantly lower IL-2 levels, which strongly correlated with a decrease in the antiapoptotic Bcl-2 and conversely with an increase in the proapoptotic Bax expression. In conclusion, these data suggest that, in HD patients, exposure of activated CD4+ T cells to oxLDL leads to Fas-mediated apoptosis in association with inhibition of IL-2 expression. Subsequently, this may favor activation of mitochondria-dependent apoptotic pathways, leading to activated CD4+ T cell dysfunction.


Patient-reported health outcomes after total hip and knee surgery in a Dutch University Hospital Setting: results of twenty years clinical registry.
Patient-Reported Outcome (PRO) measurement is a method for measuring perceptions of patients on their health and quality of life. The aim of this paper is to present the results of PRO measurements in total hip and knee replacement as routinely collected during 20 years of surgery in a university hospital setting. Data of consecutive patients between 1993 and 2014 were collected. Health outcomes were measured pre-surgery and at 3, 6, and 12 months post-surgery. Outcomes for hip replacement were measured with the Harris Hip Score (HHS) and Oxford Hip Score (OHS). Outcomes for knee replacement were measured with the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Knee Society Score (KSS). A Visual Analog Scale (VAS) for pain was used. Absolute and relative Minimal Clinically Important Differences (MCID) were estimated. Generalized estimating equation analysis was used for estimating mean outcomes. Trends over time were analyzed. The database contained 2,089 patients with hip replacement, and 704 patients with knee replacement. Mean HHS and OHS scores in primary hip replacement at 12 months post-surgery were 86.7 (SD: 14.5) and 41.1 (SD: 7.5) respectively. Improvements on the HHS based on absolute MCID was lower for revisions compared to primary hip replacements, with 72.4% and 87.0% respectively. Mean WOMAC and KSS scores in knee replacement at 12 months post-surgery were 21.5 (SD: 18.2) and 67.0 (SD: 26.4) respectively. Improvements based on absolute MCID were lowest for the KSS (62.6%) and highest for VAS pain (85.6%). Trend analysis showed a difference in 1 out of 24 comparisons in hip replacement and in 2 out of 9 comparisons in knee replacement. The functional status of a large cohort of patients significantly improved after hip and knee replacement based on routine data collection. Our study shows the feasibility of the routine collection of PRO data in patients with total hip and knee replacement. The use of PRO data provides opportunities for continuous quality improvement.


Understanding definitions of minimally verbal across instruments: evidence for subgroups within minimally verbal children and adolescents with autism spectrum disorder.
Minimally verbal (MV) children with autism spectrum disorder (ASD) are often assumed to be profoundly cognitively impaired and excluded from analyses due to challenges completing standardized testing protocols. A literature aimed at increasing understanding of this subgroup is emerging; however, the many methods used to define MV status make it difficult to compare studies. Understanding how different instruments and definitions used to identify MV children affect sample composition is critical to advance research on this understudied clinical population. The MV status of 1,470 school-aged children was defined using five instruments commonly used in ASD research. MV sample composition was compared across instruments. Analyses examined the proportion of overlap across MV subgroups and the extent to which child characteristics varied across MV subgroups defined using different definitions or combinations of measures. A total of 257 children were classified as MV on at least one instrument. Proportion of overlap between definitions ranged from 3% to 100%. The stringency of definition (i.e. few-to-no vs. some words) was associated with differences in cognitive and adaptive functioning; more stringent definitions yielded greater consistency of MV status across instruments. Cognitive abilities ranged from profoundly impaired to average intelligence; 16% had NVIQ ≥ 70. Approximately half exhibited verbal skills commensurate with nonverbal cognitive ability, whereas half had verbal abilities significantly lower than their estimated NVIQ. Future studies of MV children must carefully consider the methods used to identify their sample, acknowledging that definitions including children with 'some words' may yield larger samples with a wider range of language and cognitive abilities. Broadly defined MV samples may be particularly important to delineate factors interfering with language development in the subgroup of children whose expressive impairments are considerably below their estimated nonverbal cognitive abilities.


Anterior insula GABA levels correlate with emotional aspects of empathy: a proton magnetic resonance spectroscopy study.
Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated. Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI). Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p<0.05) and the personal distress score (r = 0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores. Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities.


Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice.
Extensive tau-immunoreactive neurons and glial cells associated with chronic traumatic encephalopathy (CTE) have been documented in the brains of some professional athletes and others with a history of repetitive mild traumatic brain injury (r-mTBI). The neuropathology and tau involvement in mTBI have not been extensively studied in animal models, particularly in aged animals. We investigated the effects of single mTBI (s-mTBI) and r-mTBI in 18-month-old hTau mice, which express wild-type human tau isoforms on a null murine tau background (n = 3-5 per group). At this age, hTau mice already demonstrate tau pathology, but there was a significant increase in phospho-tau immunoreactivity in response to r-mTBI, but not to s-mTBI,as determined using multiple phospho-tau-specific antibodies. Repetitive mTBI also resulted in a marked increase in astrocyte/microglia activation notably in the superficial layer of the motor/somatosensory cortex and the corpus callosum. We did not observe the perivascular tau pathology, neuritic threads, or astrocytic tangles that are commonly found in human CTE. The increase in phospho-tau in the r-mTBI mice suggests that this may be a useful model for investigating further the link between mTBI, particularly r-mTBI, and tau pathobiology in CTE and in understanding responses of the aged brain to mTBI.


[Enhanced antibody production by lung lymphocytes after oral immunization with Bordetella pertussis surface antigens].
The purpose of our study was to evaluate the effect of oral vaccination with Bordetella pertussis surface antigens on the immune response at the site of antigen application. We orally immunized female BALB/c mice on five consecutive days and repeated this procedure after a free interval of 10 days. Lymphocytes of the lung (LL), Peyer's patches (PPL) and lamina propria of the gut (LPL) were isolated and the immunoglobulin secretion rate was measured with time-resolved immunofluorescence. Oral immunization was found to enhance the IgA secretion rate by 69.9% in LL compared to unimmunized animals. The IgG synthesis in LL was increased by 28.1% and the IgM synthesis by 14.1%. In addition, an improvement of 47.8% was observed for the IgG secretion in LPL and PPL. Thus, our results demonstrate a strong local immune response after oral immunization with Bordetella pertussis.


Glycine receptor subunits expression in the developing rat retina.
Glycine receptor (GlyR) consists of two α (1-4) and three β subunits. Considerable evidence indicates that the adult retina expresses the four types of α subunits; however, the proportion of these subunits in adult and immature retina is almost unknown. In this report we have studied mRNA and the protein expression of GlyR subunits in the retina during postnatal rat development by Real-Time qRT-PCR and western blot. mRNA and protein expression indicated a gradual increase of the α1, α3, α4 and β GlyR subunits during postnatal ages tested. The mRNA β subunit showed higher expression levels (∼3 fold) than those observed for the α1 and α3 subunits. Very interestingly, the α2 GlyR subunit had the highest expression in the retina, even in the adult. These results revealed the expression of GlyR at early postnatal ages, supporting its role in retina development. In addition, our results indicated that the adult retina expressed a high proportion of the α2 subunit, suggesting the expression of monomeric and/or heteromeric receptors. A variety of studies are needed to further characterize the role of the specific subunits in both adult and immature retina.


Examination of clinical factors affecting intrauterine microbiota.
Following reports of an increase in implantation and pregnancy continuation rates by a higher percentage of Lactobacillus in the intrauterine microbiota, it has received attention in infertility treatment. This study aimed to examine Japanese women for intrauterine microbiota. The clinical background factors in women that influence the abundance of Lactobacillus in the bacterial microbiota were examined. We included 147 patients (31 and 116 in the follicular and luteal phase, respectively), from June 2018 to June 2020, who underwent their first intrauterine microbiota test and had not used antibiotics for at least 4 weeks before the test. In the luteal phase, we compared the background factors of women in cases with 90% or more and less than 90% of Lactobacillus. Differences in the intrauterine microbiota were examined during the follicular and luteal phases. The proportion of Lactobacillus tended to be low among women aged 36 years and older with a history of childbirth (P = 0.0631). Some bacteria were only detected during the follicular and luteal phases, and the bacterial microbiota may change during the menstrual cycle. Bacterial microbiota in the uterus may differ between the follicular and luteal phases. Furthermore, it was shown that the rate of Lactobacillus may be lower in women (older than 36 years) who had given birth, indicating that intrauterine microbiological testing may be considered for these women in clinical practice. Good implantation and pregnancy continuation rates have been reported when the proportion of the bacteria Lactobacillus is high in the uterus (intrauterine) bacterial population (microbiota). In this study, we assessed whether the clinical background of Japanese women (age, history of pregnancy and childbirth, and presence of gynecological or hormonal disorders) affect the proportion of intrauterine microbiota. Intrauterine samples were collected and sequenced to evaluate the intrauterine microbiota and the composition ratio of each bacterium. Comparing the percentage of Lactobacillus in the latter phase of the menstrual cycle with the clinical background, it was found that the percentage tended to be lower in women with a history of childbirth. We compared the intrauterine microbiota between the first phase and latter phase of the menstrual cycle and revealed that it may differ between the two phases. Advances in the development of criteria for assessing intrauterine microbiota are expected.


Using machine learning and big data for the prediction of venous thromboembolic events after spine surgery: A single-center retrospective analysis of multiple models on a cohort of 6869 patients.
Venous thromboembolic event (VTE) after spine surgery is a rare but potentially devastating complication. With the advent of machine learning, an opportunity exists for more accurate prediction of such events to aid in prevention and treatment. Seven models were screened using 108 database variables and 62 preoperative variables. These models included deep neural network (DNN), DNN with synthetic minority oversampling technique (SMOTE), logistic regression, ridge regression, lasso regression, simple linear regression, and gradient boosting classifier. Relevant metrics were compared between each model. The top four models were selected based on area under the receiver operator curve; these models included DNN with SMOTE, linear regression, lasso regression, and ridge regression. Separate random sampling of each model was performed 1000 additional independent times using a randomly generated training/testing distribution. Variable weights and magnitudes were analyzed after sampling. Using all patient-related variables, DNN using SMOTE was the top-performing model in predicting postoperative VTE after spinal surgery (area under the curve [AUC] =0.904), followed by lasso regression (AUC = 0.894), ridge regression (AUC = 0.873), and linear regression (AUC = 0.864). When analyzing a subset of only preoperative variables, the top-performing models were lasso regression (AUC = 0.865) and DNN with SMOTE (AUC = 0.864), both of which outperform any currently published models. Main model contributions relied heavily on variables associated with history of thromboembolic events, length of surgical/anesthetic time, and use of postoperative chemoprophylaxis. The current study provides promise toward machine learning methods geared toward predicting postoperative complications after spine surgery. Further study is needed in order to best quantify and model real-world risk for such events.


Paracervical block with etidocaine for out-patient abortion.
Paracervical block using etidocaine 0.5 % and 1.0 % without adrenaline proved to be an effective anaesthetic procedure for first trimester abortion performed by surgical dilatation of the cervix and subsequent vacuum suction. Three blocks out of 24 were inadequate, probably due to inaccurate deposition of the local anaesthetic. There were two adverse reactions, possibly as a result of inadvertant intravascular injection. The need for long-acting agents for the present indication is questioned.


Phylogenetic analysis of oryx species using partial sequences of mitochondrial rRNA genes.
We conducted a comparative evaluation of 12S rRNA and 16S rRNA genes of the mitochondrial genome for molecular differentiation among three oryx species (Oryx leucoryx, Oryx dammah and Oryx gazella) with respect to two closely related outgroups, addax and roan. Our findings showed the failure of 12S rRNA gene to differentiate between the genus Oryx and addax, whereas a 342-bp partial sequence of 16S rRNA accurately grouped all five taxa studied, suggesting the utility of 16S rRNA segment for molecular phylogeny of oryx at the genus and possibly species levels.


[A rare cause of sudden death in young adults with "normal" heart: the Brugada syndrome].
Brugada syndrome is a rare condition causing sudden death in young adults due to unexpected sudden-onset ventricular fibrillation. Diagnosis is based on the presence of an ST depression in the anteroseptal territory and a right branch block. No underlying dysrhythmic condition or arrhythmogenic heart disease can be detected. A 15-year old boy with an uneventful past history experienced cardiocirculatory failure due to ventricular fibrillation during a sports competition. Cardiac arrest developed and resuscitation was initially successful but death ensued due to cerebral anoxia. Characteristic electrocardiographic signs and the presence of similar anomalies in a brother and an aunt led to the diagnosis of Brugada syndrome. Brugada syndrome is a recently discovered hereditary condition with a probably underestimated prevalence. Systematic family studies have demonstrated autosomal dominant inheritance. The characteristic electrocardiographic anomalies can be transitory and may be unmasked by sensitivization tests. The only currently effective treatment is the implantable defibrillator programmed to prevent sudden death by ventricular fibrillation.


[Diagnostic and therapeutic standards for rheumatic diseases in children].
The rheumatic diseases constitute a significant group of chronic illnesses affecting children of all ages, including adolescence. This chapter provides an overview of rheumatic diseases and medical treatment options. The author describes in detail diagnostic and therapeutic standards proceedings in rheumatic fever, juvenile chronic arthritis, systemic lupus erythematosus and Kawasaki disease. The article contains the newest data from literature about new therapy trials in above mentioned diseases.


Misconceptions about traumatic brain injury among correctional health care professionals.
This study explored the prevalence of misconceptions of traumatic brain injury (TBI) among a sample of correctional health care professionals. Prior research has identified a high prevalence of TBI among criminal offenders, and misconceptions about TBI exist among laypersons and nonexpert professionals. Participants (N = 155) completed a 25-item survey about the sequelae of TBI. Results were compared with previous studies. This sample performed significantly better than laypersons and commensurable to other nonexpert professionals. Misconceptions were higher on items related to loss of consciousness, memory, and recovery. Gender, prior familiarity to someone with a history of TBI, and prior training in TBI accounted for statistically fewer misconceptions. The findings support the need for continued training and increased awareness about TBI among inmates.


Spontaneous phase transition of hexagonal wurtzite CoO: application to electrochemical and photoelectrochemical water splitting.
The addition of water initiates the phase transition of hexagonal CoO to Co(OH)2 nanocrystals. Inducing the phase transition of h-CoO on various substrates results in efficient chemical bonding between Co(OH)2 and the substrate. The efficient deposition of Co(OH)2 is widely applicable for electrochemical and photoelectrochemical water oxidation reactions.


HLA-A, -B and -DR allele and haplotype frequencies in Malays.
One thousand four hundreds and forty-five Malays registered with the Malaysian Marrow Donor Registry were typed for HLA-A, HLA-B and HLA-DR. Fifteen HLA-A, twenty nine HLA-B and fourteen HLA-DR alleles were detected. The most common HLA-A alleles and their frequencies were HLA-A24 (0.35), HLA-A11 (0.21) and HLA-A2 (0.15). The most common HLA-B alleles were HLA-B15 (0.26), HLA-B35 (0.11) and HLA-B18 (0.10) while the most common HLA-DR alleles were HLA-DR15 (0.28), HLA-DR12 (0.27) and HLA-DR7 (0.10). A24-B15-DR12 (0.047), A24-B15-DR15 (0.03) and the A24-B35-DR12 (0.03) were the most frequent haplotypes. This data may be useful in determining the probability of finding a matched donor and for estimating the incidence of HLA associated diseases.


Design and control of system for elbow rehabilitation: Preliminary findings.
The use of an exoskeleton elbow is considered an effective treatment in several pathologies, including post-stroke complications, traumatic brain injury (TBI) and spinal cord injury (SCI), as well as in patients with neurodegenerative disorders. The effectiveness of rehabilitation is closely linked to a suitably chosen therapy. The treatment can be performed only by specialized personnel, significantly supported by the use of automated devices. The aim of this study was to present a novel exoskeleton for elbow rehabilitation without a complicated control system. Single-degree-of-freedom (SDOF) solution in constructing the prototype of an elbow exoskeleton for rehabilitation purposes has been applied. The simplicity of the actuation mechanism was set as one of the priorities in the design; thus, a single-axis stepper motor with a controller was found to be adequate for providing a reliable and precise source of motion for the exoskeleton. Technological development may provide novel solutions, such as an exoskeleton - a wearable, external structure which supports or (in selected applications) even replaces the muscle actuation in the patient. The reported advantages of the proposed exoskeleton reflect current state-of-the-art. The proposed control strategy relies on closed-loop position control, performance, low manufacturing cost, and predicted performance in a rehabilitation scenario. All these factors play an important role in establishing the directions for further research, e.g., an integrated force sensor in the device, measurements of torque interactions on the elbow joint, and assessment and response to an overload of articulation. This study suggests not only the clinical but also the possible economic and logistical advantages offered by the portability of the system, and its effective support for therapists applying an elbow exoskeleton.


Self-assembling peptides as immunomodulatory biomaterials.
Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.


Tolerance of Orthotopic Ileal Neobladders to Radiotherapy: A Multi-institutional Retrospective Study.
The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy. A multi-institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale. A total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3-pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade ≥ 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula. The use of moderate doses of pelvic RT (range, 45-50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated.


An Evolutionary Analysis of Learned Attention.
Humans and many other species selectively attend to stimuli or stimulus dimensions-but why should an animal constrain information input in this way? To investigate the adaptive functions of attention, we used a genetic algorithm to evolve simple connectionist networks that had to make categorization decisions in a variety of environmental structures. The results of these simulations show that while learned attention is not universally adaptive, its benefit is not restricted to the reduction of input complexity in order to keep it within an organism's processing capacity limitations. Instead, being able to shift attention provides adaptive benefit by allowing faster learning with fewer errors in a range of ecologically plausible environments.


Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity.
Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-alpha is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (-308 G/A) of the TNF-alpha gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. Obese, non-diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p < 0.001), higher HOMA scores (10.2 vs. 5.3; p < 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p = 0.02), and lower high-density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p = 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r = -0.710; p < 0.001) occurred in subjects with the A allele only. The -308 G/A TNF-alpha gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.


Sensitivity of two enzyme-linked immunosorbent assay tests in relation to western blot in detecting human T-cell lymphotropic virus types I and II infection among HIV-1 infected patients from São Paulo, Brazil.
We investigated the presence of human T-cell lymphotropic virus types I and II (HTLV-I and HTLV-II) infections, first searching for specific antibodies in 553 serum samples obtained from HIV-1-infected patients from São Paulo, Brazil. Sera were screened using two enzyme-linked immunosorbent assays (ELISAs): the ELISA-EM (ELISA HTLV-I/II, EMBRABIO, BR), which contains HTLV-I and HTLV-II lysates, and the ELISA-DB [ELISA HTLV-I/II, Diagnostic Biotechnology (DB), Singapore], which contains HTLV-I lysate, and HTLV-I and HTLV-II recombinant env proteins (MTA-1 and K55, respectively). Serum samples showing two positive and/or borderline results were confirmed by Western blot (WB 2.3, DB), which discriminates HTLV-I from HTLV-II. WB analyses disclosed 22 cases (4.0%) of HTLV-I and 34 (6.1%) of HTLV-II seroreactivity; 24 sera had indeterminate antibody profile (4.3%) and 2 specimens showed reactivity to both MTA-1 and K55 env proteins. Using stringent WB criteria and analyzing the population according to risk factors, the prevalence rates of HTLV-I and HTLV-II infections were 11.2% and 16.8% in i.v. drug users, 3.4% and 5.5% in heterosexual individuals, and 1.4% and 2.2% in homosexual/bisexual men, respectively. A comparison of ELISA and WB results disclosed that both ELISAs were highly sensitive in detecting HTLV-I antibodies, whereas the ELISA-DB showed 82% sensitivity and the ELISA-EM 100% sensitivity in detecting HTLV-II antibodies. PCR analyses conducted on 37 representative cells samples confirmed the presence of HTLV proviral DNA in the majority of concordant serological cases, except in one, which was HTLV-I infected and seroreacted with K55 protein of HTLV-II. Indeed, after PCR, one case of HTLV-I infection and HTLV-II coinfection, and 30% of WB-seroindeterminate or inconclusive cases infected with HTLV-II could be detected. Our data stress high prevalences of both HTLV-I and HTLV-II infections in HIV-1 coinfected i.v. drug users from São Paulo, and suggests that ELISA kits containing only K55 protein as the HTLV-II-specific antigen, may not have the appropriate sensitivity for the detection of HTLV-II infection in this geographic region, pointing out the need of improved screening tests to be used in Brazil.


Development of spontaneous seizures after experimental status epilepticus: implications for understanding epileptogenesis.
This report examines several concepts concerning the latent period to the first convulsive seizure, subsequent increases in seizure frequency, and possible mechanisms of epileptogenesis after kainate-induced status epilepticus. Previous data concerning the latent period and seizure progression from intermittent and continuous behavioral monitoring are compared, and hypothetical mechanisms of acquired epilepsy are discussed. Data involving electrographic recordings with tethered animals or with radiotelemetry are assessed in terms of their potential for addressing different hypotheses concerning the latent period and progressive changes in seizure frequency. Experimental analyses of the time course of occurrence of spontaneous seizures are interpreted in terms of possible cellular mechanisms underlying epileptogenesis.


Detection of antibody to group B adult diarrhea rotaviruses in humans.
Group B rotaviruses have been responsible for annual epidemics of severe diarrhea affecting both adults and children in China. We developed a specific and sensitive enzyme-linked immunosorbent blocking assay to detect antibody to group B rotaviruses that will be useful to assess the role of group B rotavirus infections as a cause of human gastroenteritis. We tested 219 human sera and 18 immunoglobulin pools collected from eight countries for antibodies to both group A and group B rotaviruses. Overall, a low proportion (10 of 237 or 4.2%) of sera contained antibody to group B rotaviruses. Antibody to group B rotavirus was detected in only 1 of 155 serum samples from healthy or hospitalized individuals in the United States, including patients with the chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis. No antibody was detected in 15 serum samples from Australia and from an outbreak of gastroenteritis on a cruise ship or in nine immunoglobulin pools from Japan and the United Kingdom. Antibody to group B rotaviruses was detected in 8 convalescent-(but not acute-)phase serum samples from Chinese patients with group B gastroenteritis, in five immunoglobulin pools from China, in 1 of 6 serum samples from Chinese students in the United States, and in 1 each of 10 serum samples from Kenya, 20 from Thailand, and 15 from Canada. In contrast, most of these samples (226 of 237 or 95.4%) had antibody to group A rotaviruses. These results indicate that human infection with group B rotavirus has not been widespread in areas outside China. Seroconversion observed between the acute-and convalescent-phase serum samples from China also suggests that infections with this virus are primary infections. Continued surveillance for this new group of rotaviruses should determine whether the many susceptible people become infected of whether other factors influence the severe pathogenicity of human infections with these viruses in China.


Local anesthetic improves individuals affected with herpes simplex type 1 labialis.
Infections caused by the herpes simplex virus 1 (HSV-1), commonly called herpes simplex labialis (HSL), are a public health problem, reaching around 40% of the world's population. Thus, the search for effective therapeutic alternatives in the control of the limitations caused by this virus during the stages of evolution of the disease, is necessary, since they have a direct impact on the quality of life of the patients. The aim of the present study was to evaluate the efficacy of the in situ film precursor semisolid composition in the treatment of herpes simplex lesions in human HSV-1. Ninety-eight (n = 98) patients with HSV-1 were used for this study. The initial exclusion criteria left 81 patients to be considered in the present study. Three applications were performed, the first at time zero (T0) and the other two at 8 and 16 hours, after initial application (T8 and T16). Photographs were taken in the first appointment and 24 and 72 hours after the last application. After the three periods, each patient received a total amount of 90 mg of anesthetic and the prognosis of the patients was followed for 6 months and 1 year after the application. Frequency analysis showed that 40.3% of patients had remission of symptoms 24 hours after the last application. For the present study, the film presented a positive therapeutic potential and an esthetic benefit that is absent in the current products (ointments and gels). The invent presents dosage convenience (only three applications in a 24-hour period) and a low production cost, with a much shorter healing time than that reported using topical antiretrovirals.


Optoelectronic memory using two-dimensional materials.
An atomically thin optoelectronic memory array for image sensing is demonstrated with layered CuIn7Se11 and extended to InSe and MoS2 atomic layers. Photogenerated charge carriers are trapped and subsequently retrieved from the potential well formed by gating a 2D material with Schottky barriers. The atomically thin layered optoelectronic memory can accumulate photon-generated charges during light exposure, and the charges can be read out later for data processing and permanent storage. An array of atomically thin image memory pixels was built to illustrate the potential of fabricating large-scale 2D material-based image sensors for image capture and storage.


Singular tori as attractors of four-wave-interaction systems.
We study the spatiotemporal dynamics of the Hamiltonian four-wave interaction in its counterpropagating configuration. The numerical simulations reveal that, under rather general conditions, the four-wave system exhibits a relaxation process toward a stationary state. Considering the Hamiltonian system associated to the stationary state, we provide a global geometrical view of all the stationary solutions of the system. The analysis reveals that the stationary state converges exponentially toward a pinched torus of the Hamiltonian system in the limit of an infinite nonlinear medium. The singular torus thus plays the role of an attractor for the spatiotemporal wave system. The topological properties of the singular torus confer a robust character to the stationary solution when the boundary conditions or the length of the nonlinear medium are modified. Furthermore, an adiabatic approach of the boundary conditions reveals that singular tori also play a major role for the description of the spatiotemporal dynamics of the wave system.


[The infrahyoid musculocutaneous flap. Anatomic bases and the results of a preliminary experience in cervicofacial oncology].
The infrahyoid myocutaneous flap has been described by Wang in 1986. Its blood supply comes from the superior thyroid artery. This flap consists of sternohyoid muscle, sternothyroid muscle, superior belly of omohyoid muscle and a skin pad from the medial infrahyoid area. Thanks to its arc of rotation, this flap is appropriate for the repair of mucosal defects of the tongue, floor of the mouth, retromolar region, interior side of cheek, oropharynx, hypopharynx and in the face, skin defects of the exterior side of cheek, parotid region and lower lip. The infrahyoid myocutaneous flap has obvious interest in head and neck reconstruction surgery given its versatility and the quality of its cosmetic results.


[Prevention of thromboembolic risk in spinal cord injury: results of a questionnaire concerning short- and long-term treatment].
The use of medications to prevent thromboembolic risk is recommended in spinal cord injury patients during the early phase, but there is no consensus on treatment duration and modalities. Differences in practice include choice of medication (heparin, low molecular weight heparin, inhibitors of platelet aggregation), treatment duration (three to six months or more), and criteria for discontinuation of treatment. To determine usual practice modalities for prophylaxis of deep vein thrombosis in spinal cord injury patients, and to identify determinant criteria. Postal survey of physiatrists taking care of spinal cord injury patients. The questionnaire asks the physician about his usual practice modalities (choice of treatments, paraclinical tests, use of compressive stockings, during and after the first six months and criteria for discontinuation of treatments). Forty-two questionnaires were suitable for analysis. Results show that usual practice modalities combine venous doppler testing only in the setting of suggestive clinical signs, treatment with low molecular weight heparin during three to six months, and combination with compressive stockings. Despite the absence of consensus on this question, our results are consistent with data from the literature, which identify acute spinal cord lesions as a factor of high risk for deep vein thrombosis. The risk decreases during the chronic phase. Adjuvant techniques include mobilisation, elastic compression, and standing. A study of long-term treatment modalities after deep vein thrombosis would be needed.


Extracorporeal shock wave lithotripsy for vesical lithiasis: initial experience.
The classical treatment for vesical lithiasis consists of surgery or endoscopic transurethral disintegration. These procedures require anaesthesia and hospitalisation. We report our experience with the Siemens Lithostar in 18 male patients with bladder stones. Complete fragmentation was achieved after a single session in 14 patients and 4 required 2 sessions. A 3-way Foley catheter with saline irrigation was used during treatment. Patients were treated in the prone position followed by immediate evacuation of stone fragments in 9 cases. Morbidity was minimal. Two patients developed impacted fragments and required stone retrieval. Extracorporeal shock wave lithotripsy (ESWL) for vesical lithiasis appears to be a simple, well tolerated and effective form of treatment.


Inhibition of Pref-1 (preadipocyte factor 1) by oestradiol in adolescent girls with anorexia nervosa is associated with improvement in lumbar bone mineral density.
Adolescents with anorexia nervosa (AN) are amenorrheic and have decreased bone mass accrual and low bone mineral density (BMD). The regulation of mesenchymal stem cell differentiation is an important factor governing bone formation. Preadipocyte factor 1 (Pref-1), an inhibitor of adipocyte and osteoblast differentiation, is elevated in states of oestrogen deficiency. In this study, we aim to (i) investigate effects of transdermal oestradiol on Pref-1 in adolescent girls with AN, and (ii) examine associations of changes in Pref-1 with changes in lumbar BMD and bone turnover markers. Adolescent girls with AN and normal-weight controls were studied cross-sectionally. Girls with AN were examined longitudinally in a double-blind study and received transdermal oestradiol (plus cyclic medroxyprogesterone) or placebo for 12 months. Sixty-nine girls (44 with AN, 25 normal-weight controls) 13-18 years were studied at baseline; 22 AN girls were followed prospectively. Pref-1 levels, bone formation and resorption markers, and BMD. Pref-1 levels decreased in girls with AN after treatment with transdermal oestradiol compared with placebo (-0·015 ± 0·016 vs 0·060±0·026 ng/ml, P = 0·01), although at baseline, levels did not differ in AN vs controls (0·246 ± 0·015 vs 0·267 ± 0·022 ng/ml). Changes in Pref-1 over 12 months correlated inversely with changes in lumbar BMD (r = -0·48, P = 0·02) and positively with changes in CTX (r = 0·73, P = 0·006). For the first time, we show that Pref-1 is negatively regulated by oestradiol in adolescent girls with AN. Inhibition of Pref-1 may mediate the beneficial effects of transdermal oestradiol replacement on BMD in girls with AN.


Cartilage-free areas in the elbow joint of young golden retrievers.
The present study describes cartilage-free areas on the ulnar trochlear notch and the humeral condyle of eight very young golden retrievers with otherwise healthy elbow joints. Remarkably, the youngest dog with full-thickness cartilage-free areas was only 8 weeks old. The younger dogs showed no macroscopic abnormalities on the locations that were affected in the older dogs. Two kinds of cartilage modifications were found. Cartilage-free areas at the edges of the articular cartilage layer were present on the humeral capitulum and on two locations of the ulna, (the medial and lateral at the base of the anconeal process, and the trochlear notch near the lateral coronoid process, which was fractured in two cases). Histological examination showed that these cartilage-free areas were filled with dense supportive tissue. Synovial cells covered this tissue as well as the surrounding hyaline cartilage. The synovial membrane covering the areas was macroscopically enlarged, but histological examination revealed no signs of inflammation. The second type of modification consisted of discoloration of the articular surface at the humeral trochlea. Histological examination revealed that in this area the articular surface was composed of fibrocartilage instead of hyaline cartilage. Apparently, there are locations within the elbow joint in which articular cartilage is not necessary for normal joint functioning. The presence of fibrocartilage on the articular surface of the humeral condyle is a surprising finding, for which no explanation has yet been found.


Okadaic acid inhibits the trichostatin A-mediated increase of human CYP46A1 neuronal expression in a ERK1/2-Sp3-dependent pathway.
The CYP46A1 gene codes for the cholesterol 24-hydroxylase, a cytochrome P450 specifically expressed in neurons and responsible for the majority of cholesterol turnover in the central nervous system. Previously, we have demonstrated the critical participation of Sp transcription factors in the CYP46A1 response to histone deacetylase (HDAC) inhibitors, and in this study we investigated the involvement of intracellular signaling pathways in the trichostatin A (TSA) effect. Our results show that pretreatment of neuroblastoma cells with chemical inhibitors of mitogen-activated kinase kinase (MEK)1 significantly potentiates the TSA-dependent induction of cholesterol 24-hydroxylase, whereas inhibition of protein phosphatases by okadaic acid (OA) or overexpression of MEK1 partially impairs the TSA effect without affecting histone hyperacetylation at the promoter. Immunoblotting revealed that TSA treatment decreases ERK1/2 phosphorylation concomitantly with a decrease in Sp3 binding activity, which are both reversed by pretreatment with OA. Chromatin immunoprecipitation analysis demonstrated that TSA induces the release of p-ERK1/2 from the CYP46A1 proximal promoter, whereas pretreatment with OA restores the co-occupancy of Sp3-ERK1/2 in the same promoter fragments. We demonstrate for the first time the participation of MEK-ERK1/2 signaling pathway in HDAC inhibitor-dependent induction of cytochrome P450 gene expression, underlying the importance of this regulatory signaling mechanism in the control of brain cholesterol elimination.


Strong ultraviolet luminescence of ZnO thin films with nanowall-network structures.
ZnO thin films with three different types of surface structures, smooth, large nanowall-networks, and small nanowall-networks, were grown by a vapor phase transport process. The XRD patterns of these samples showed a high c-axis orientation. Photoluminescence spectra of these samples showed that the intensities of ultraviolet (UV) emission from ZnO thin films having a surface with nanowall-network structures were enhanced by 1-2 orders of magnitude, the linewidths of UV emission were reduced, and the peak positions blueshifted significantly compared with the ZnO film having a smooth surface. The greatly enhanced UV emission was attributed to high crystalline quality with the oriented growth, and whispering gallery mode resonance in the nanowall-formed cavities.


[Diagnosis and therapy of benign tumors of the esophagogastric junction].
Benign tumors of the esophagogastric junction are rare and mostly found incidentally during endoscopic or radiological procedures which are often performed for unrelated reasons. Epithelial lesions must be distinguished from subepithelial findings, where the latter are far more common and mostly represent benign leiomyomas, especially in the esophagus. Some benign tumors, such as small gastrointestinal stromal tumors, have malignant potential and must therefore be distinguished from completely benign lesions. Epithelial tumors can be diagnosed by standard endoscopic biopsies, whereas tissue acquisition of subepithelial lesions is more challenging. For this purpose endosonography is a valuable tool even before tissue acquisition or resection is performed. Endosonography can identify the gastrointestinal wall layer from which the lesion arises and gives additional information by identification of characteristic echographic features. Endoscopic resection techniques are used to remove those tumors that originate from the mucosa or submucosa. Some authors have even described resection of tumors originating from the deep muscle layer, but these techniques have a significant risk of perforation. Several surgical techniques are available for complete resection ranging from laparoscopic enucleation to combined endoscopic laparoscopic (rendezvous) techniques and abdominothoracic approaches. The current diagnostic and therapeutic challenges regarding benign tumors of the esophagogastric junction are outlined in this review article.


An elective course on the basic and clinical sciences aspects of vitamins and minerals.
Objective. To develop and implement an elective course on vitamins and minerals and their usefulness as dietary supplements. Design. A 2-credit-hour elective course designed to provide students with the most up-to-date basic and clinical science information on vitamins and minerals was developed and implemented in the doctor of pharmacy (PharmD) curriculum. In addition to classroom lectures, an active-learning component was incorporated in the course in the form of group discussion. Assessment. Student learning was demonstrated by examination scores. Performance on pre- and post-course surveys administered in 2011 demonstrated a significant increase in students' knowledge of the basic and clinical science aspects of vitamins and minerals, with average scores increasing from 61% to 86%. At the end of the semester, students completed a standard course evaluation. Conclusion. An elective course on vitamin and mineral supplements was well received by pharmacy students and helped them to acquire knowledge and competence in patient counseling regarding safe, appropriate, effective, and economical use of these products.


[Synovial cyst of the hip: a misleading strangulated crural hernia diagnosis].
We report a case of crural tumefaction becoming rapidly painful revealing a synovial cyst of the hip. Literature data concerning differential diagnosis, pathogenesis, clinical varieties, diagnosis and treatments of this rare pathology are emphasized.


Prediction of the mechanical properties of hydroxyapatite/polymethyl methacrylate/carbon nanotubes nanocomposite.
In this work carbon nanotubes (CNTs) were used to increase the strength and toughness of the hydroxyapatite (HA) and consequently to reduce its brittleness. The combination of CNT, HA and polymethyl methacrylate (PMMA) has led to a new composite material, which has mechanical properties superior to those of conventional HA/PMMA for biomedical scaffold in tissue engineering. PMMA is a well known bone cement which is highly compatible with HA and also it can act as a functionalizing/linking material with HA. The mechanical properties of the new nanocomposite were predicted with a self-consistent computational model taking into account the structure morphology and the orientation of the CNTs. CNT reinforced HA composite is shown to be a promising coating material for high-load-bearing metal implants. The development of this new nanocomposite based on HA/PMMA and CNTs, may significantly contribute to the bond strength of the HA/PMMA metal interface and the overall mechanical properties of the HA/PMMA coating.


Main bronchial reconstruction with sparing of pulmonary parenchyma for benign diseases.
Main bronchial reconstruction is anatomically suitable for benign main bronchial stenosis. But, it has been hardly recommended for operative mortality and morbidity. This study was aimed at providing validity and the proper clinical information of bronchoplasty for benign main bronchial stenosis by reviewing the results we obtained over the last ten years for main bronchial reconstruction operations. We retrospectively reviewed admission and office records. Twenty eight consecutive patients who underwent main bronchoplasty were included. Enrolled patients underwent main bronchial reconstruction for benign disease (tuberculosis in 21, trauma in 4, endobronchial mass in 3). Concomitant procedures with main stem bronchoplasty were performed in 19 patients. There were no incidences of postoperative mortality and significant morbidity. There were 2 cases of retained secretions, and these problems were resolved by bronchoscopy or intubation. All of the patients are still alive without obstructive airway problem. Bronchoplasty should be considered as one of the primary treatment modalities, if it is anatomically feasible.


[The Expanded Program on Immunization in the WHO African region: current situation and implementation constraints].
The expanded Programme on Immunization in the African region was launched in 1978 and by the mid-eighties, all countries had established national immunization programmes. A mid decade evaluation, conducted in 1985, indicates that the regional immunization coverage was still under 20% for all antigens. For this reason, member states agreed to accelerate the programme. They adopted a resolution declaring 1986 the "African Immunization Year" and pursued implementation of various accelerated efforts until 1990. During the acceleration phase, the political commitment was strong, with the involvement of top national officials and First Ladies in launching the immunization campaign in many countries. The resources required were supplied mainly from external funding agencies. As a result, sixteen countries reached the 80% immunization coverage rates for antigens administered to the infants and remarkable progress has been achieved in the control of the EPI priority diseases. Concerning polio eradication, at least fourteen countries, representing 20% of the regional population have reported zero incidence of poliomyelitis for two consecutive years, during the period 1991-1993. In five of these countries independent teams of international and national experts assessed the quality of the epidemiological surveillance and confirmed that polio cases may have been eliminated. This suggests that a polio-free zone has emerged in the southern part of Africa, where most of these countries are located. In the meantime, an outbreak of poliomyelitis (with 28 cases confirmed by isolation of type 1 poliovirus) was reported from one country (Namibia) where no cases had been reported for the last few years. It is still unclear whether poliovirus was imported or the virus continued to circulate without causing paralytic cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis of Euglena gracilis plastid-targeted proteins reveals different classes of transit sequences.
The plastid of Euglena gracilis was acquired secondarily through an endosymbiotic event with a eukaryotic green alga, and as a result, it is surrounded by a third membrane. This membrane complexity raises the question of how the plastid proteins are targeted to and imported into the organelle. To further explore plastid protein targeting in Euglena, we screened a total of 9,461 expressed sequence tag (EST) clusters (derived from 19,013 individual ESTs) for full-length proteins that are plastid localized to characterize their targeting sequences and to infer potential modes of translocation. Of the 117 proteins identified as being potentially plastid localized whose N-terminal targeting sequences could be inferred, 83 were unique and could be classified into two major groups. Class I proteins have tripartite targeting sequences, comprising (in order) an N-terminal signal sequence, a plastid transit peptide domain, and a predicted stop-transfer sequence. Within this class of proteins are the lumen-targeted proteins (class IB), which have an additional hydrophobic domain similar to a signal sequence and required for further targeting across the thylakoid membrane. Class II proteins lack the putative stop-transfer sequence and possess only a signal sequence at the N terminus, followed by what, in amino acid composition, resembles a plastid transit peptide. Unexpectedly, a few unrelated plastid-targeted proteins exhibit highly similar transit sequences, implying either a recent swapping of these domains or a conserved function. This work represents the most comprehensive description to date of transit peptides in Euglena and hints at the complex routes of plastid targeting that must exist in this organism.


An evaluation of serological tests in the diagnosis of bovine brucellosis in naturally infected cattle in KwaZulu-Natal province in South Africa.
The diagnostic sensitivity (DSe) of the Rose Bengal test (RBT), the complement fixation test (CFT), the serum agglutination test (SAT), the competitive enzyme-linked immunosorbent assay (cELISA) and the indirect ELISA (iELISA) were determined in naturally infected cattle in KwaZulu-Natal province of South Africa with known infectious status from culture (gold standard). Natural brucellosis infection status of animals was determined by culturing and identification of Brucella abortus biovar 1 from abomasal fluid, milk, hygroma fluid, lymph nodes or uterine discharges samples. The diagnostic specificity (DSp) of the tests mentioned above was determined using samples from known negative herds. There was no statistically significant difference between the tests in their ability to diagnose brucellosis. The RBT and iELISA had the highest DSe of 95.8%, whereas RBT and CFT had the highest DSp of 100%. In South African laboratories, the RBT and CFT serological tests are used, because of the cost efficacy of CFT when compared to the less labour intensive but more expensive iELISA.


Heterogeneity of biomaterial-induced multinucleated giant cells: Possible importance for the regeneration process?
Biomaterial-associated multinucleated giant cells (BMGCs) have been found within the implantation beds of many different biomaterials. However, their exact differentiation and their involvement in the inflammatory and healing events of the foreign body response still remain mostly unclear. Silk fibroin (SF) scaffolds, which induces a tissue reaction involving both macrophages and BMGCs, was implanted in the subcutaneous connective tissue of four CD-1 mice for 15 days using an established subcutaneous implantation model. Analysis of macrophage polarization and BMGCs was performed by immunohistochemcial detection of pro- (cyclooxygenase-2 (COX-2), C-C chemokine receptor type 7 (CCR7), nuclear factor "kappa-light-chain-enhancer" (NF-κB)) and anti-(heme oxygenase-1 (HO-1) and mannose receptor (MR, also known as CD206)). Furthermore, histochemical detection of tartrate-resistant acid phosphatase (TRAP) was conducted to test its predictive efficiency for the pro-inflammatory differentiation of cells. An established system for histomorphometrical analysis was used for counting of BMGCs expressing these molecules. The results show that BMGCs express both pro- and anti-inflammatory molecules within the implantation beds of SF scaffolds in comparable numbers, while only statistically significantly lower numbers of TRAP-positive BMGCs were measured in comparison to the BMGCs expressing the above-mentioned molecules. As these data substantiate the heterogeneity of BMGCs, the question arises to what extent BMGCs can "support" the process of tissue regeneration. Furthermore, the data prompt the question to what extent TRAP-expression within a biomaterial implantation bed can be seen as a predictive marker for an inflammatory condition, as in this study no obvious correlation between TRAP-expression and other pro-inflammatory markers could be observed.


Effects of lead on the somatic growth of children.
Studies on the effects of lead on the somatic growth of children are limited and contradictory. The authors investigated the adverse effects of blood lead concentration on the somatic growth of primary-school-age children. In this study, there was a total of 522 children, aged 6-9 y, who resided in three areas of Greece (i.e., Loutraki, Lavrion, and Elefsina). The medical evaluation included medical history; physical examination; and measurements of height, head circumference, and chest circumference. The authors also evaluated dietary information, socioeconomic status, and height of parents. The authors conducted laboratory tests for hematological parameters and blood lead levels. The mean blood lead level was 12.3 microg/dl (standard deviation = 8.9 microg/dl), and levels ranged from 1.3 microg/dl to 51.2 microg/dl. There were negative monotonic relationships between growth parameters and blood lead levels, even after the authors allowed for confounding effects. An increase in blood lead level of 10 microg/dl was associated with a decrease of (a) 0.33 cm in head circumference (95% confidence interval = 0.12, 0.55; p = .002); (b) 0.86 cm in height (95% confidence interval = 0.14, 1.16; p = .020); and (c) 0.40 cm in chest circumference (95% confidence interval = -0.22, 1.02; p = .207). These findings led the authors to conclude that a decrease in growth in children may be associated with blood lead concentrations.


Suspect Screening, Prioritization, and Confirmation of Environmental Chemicals in Maternal-Newborn Pairs from San Francisco.
Our proof-of-concept study develops a suspect screening workflow to identify and prioritize potentially ubiquitous chemical exposures in matched maternal/cord blood samples, a critical period of development for future health risks. We applied liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF/MS) to perform suspect screening for ∼3500 industrial chemicals on pilot data from 30 paired maternal and cord serum samples (n = 60). We matched 662 suspect features in positive ionization mode and 788 in negative ionization mode (557 unique formulas overall) to compounds in our database, and selected 208 of these for fragmentation analysis based on detection frequency, correlation in feature intensity between maternal and cord samples, and peak area differences by demographic characteristics. We tentatively identified 73 suspects through fragmentation spectra matching and confirmed 17 chemical features (15 unique compounds) using analytical standards. We tentatively identified 55 compounds not previously reported in the literature, the majority which have limited to no information about their sources or uses. Examples include (i) 1-(1-acetyl-2,2,6,6-tetramethylpiperidin-4-yl)-3-dodecylpyrrolidine-2,5-dione (known high production volume chemical) (ii) methyl perfluoroundecanoate and 2-perfluorooctyl ethanoic acid (two PFAS compounds); and (iii) Sumilizer GA 80 (plasticizer). Thus, our workflow demonstrates an approach to evaluating the chemical exposome to identify and prioritize chemical exposures during a critical period of development.


Computed tomography chest findings in post-acute COVID-19 lung disease at a South African regional hospital - a descriptive study.
whilst many studies have focused on acute and chronic complications of COVID-19, few studies have been performed on the immediate post-acute COVID-19 phase complications. The objective of the study was to describe computed tomography (CT) imaging findings in patients from a South African (SA) cohort during the post-acute COVID-19 phase. To describe the findings using existing CT description systems and, if present, pulmonary imaging findings unique to our cohort. a review of CT chest examinations performed over the second wave of COVID-19 in SA for post-acute COVID-19 cardiorespiratory complaints at Worcester Hospital. The CT findings were described using a modified semi-quantitative tabulation method. eight males and 12 females met the inclusion criteria with a mean age of 56 years. Half had hypertension, 11 had diabetes, two had human immunodeficiency virus (HIV), half had raised D-dimers and six had pre-existing lung disease. The predominant parenchymal pattern was mixed ground glass and reticular changes in a diffuse/peripheral multilobar distribution with relative sparing of the left upper lobe. Four cases demonstrated pulmonary emboli, 50% pulmonary hypertension, three pleural effusions and nine lymphadenopathy. None of the cases had evidence of active pulmonary tuberculosis. CT lung findings appear to mirror global findings with expected evolutionary differences. An interesting observation was the relative sparing of the left upper lobe. Reporting using the modified table proved efficient. Real-world extrapolation of our findings is limited by low-case numbers.


Application Research on Optimization Algorithm of sEMG Gesture Recognition Based on Light CNN+LSTM Model.
The deep learning gesture recognition based on surface electromyography plays an increasingly important role in human-computer interaction. In order to ensure the high accuracy of deep learning in multistate muscle action recognition and ensure that the training model can be applied in the embedded chip with small storage space, this paper presents a feature model construction and optimization method based on multichannel sEMG amplification unit. The feature model is established by using multidimensional sequential sEMG images by combining convolutional neural network and long-term memory network to solve the problem of multistate sEMG signal recognition. The experimental results show that under the same network structure, the sEMG signal with fast Fourier transform and root mean square as feature data processing has a good recognition rate, and the recognition accuracy of complex gestures is 91.40%, with the size of 1 MB. The model can still control the artificial hand accurately when the model is small and the precision is high.


Polydopamine regulated hydroxyapatite microspheres grown in the three-dimensional honeycomb-like mollusk shell-derived organic template for osteogenesis.
Layered osteochondral composite scaffolds are considered as a promising strategy for the treatment of osteochondral defects. However, the insufficient osseous support and integration of the subchondral bone layer frequently result in the failure of osteochondral repair. Therefore, it is essentially important to explore new subchondral bone constructs tailored to support bone integration and healing. In this study, a novel three-dimensional porous biomimetic construct (HA/pDA-OTMS) was successfully developed by polydopamine (pDA) regulating hydroxyapatite (HA) microspheres grown in the honeycomb-like mollusk shell-derived organic template (OTMS). The biomimetic OTMS had good mechanical properties, high toughness, biodegradability and excellent biocompatibility. Moreover, the long-range ordered cavity structure of OTMS allowed the smallest material to create the largest and most stable geometric space, endowing it high HA loading capacity. The modification of pDA on OTMS surface effectively promoted the mineral nucleation of HA in the micro-nano cavities of OTMS. The compression mechanical tests showed that the combination of inorganic HA and organic pDA-OTMS greatly improved the mechanical properties of the construct. Additionally, the HA/pDA-OTMS composite provided adequate 3-D support for osteoblast cell attachment, proliferation and differentiation, as well as significantly up-regulated the expression of osteogenesis-related genes. These results demonstrated that as-prepared HA/pDA-OTMS constructs with combined mechanical strength and excellent osteogenic activity show great application prospects in subchondral bone regeneration.


Specific staining of sialic acid components on sodium dodecyl sulfate polyacrylamide gel.
Specific staining of sialic acid components after sodium dodecyl sulfate polyacrylamide gel electrophoresis can be carried out as follows: 1) extract glycoprotein of erythrocyte membranes or serum by the phenol-saline method, 2) electrophorese the extract on 5% polyacrylamide gel containing 0.1% sodium dodecyl sulfate at constant current, 3) treat the gel with chilled 0.04 M HIO4 for 45 minutes, 4) replace the periodic acid solution with one containing resorcinol 0.6 g, conc. HCl 50 ml, 0.1 M CuSO4 0.5 ml and H2O 50 ml, 5) warm the container in boiling water until blue violet sialic acid bands become clear, 6) replace the staining solution with a mixture of equal parts water and concentrated HCl and observe at once.


Role of dopamine in the diuresis caused by stimulation of atrial receptors.
The diuretic response to stimulation of left atrial receptors, by distending balloons located either at the pulmonary vein-left atrial junctions or in the body of the left atrium was studied during blockade of dopamine receptors using a continuous infusion o sulpiride in doses ranging from 0.632 to 5.153 mumol . kg-1 . min-1, in anaesthetized dogs. A diuretic response was obtained in each experiment of distension of the balloons: the response was similar to that observed in dogs without blockade of dopamine receptors and was not significantly related to the dose os sulpiride used. It is concluded that the diuretic response to stimulation of atrial receptors, known to be mediated by a blood-borne agent, is unlikely to be caused by dopamine.


A Study of the Information Embedding Method into Raster Image Based on Interpolation.
This article is devoted to the study of the improved neighbor mean interpolation (INMI) steganographic method. To date, no steganalysis of such a method of information embedding has been carried out. We implemented the INMI method of embedding messages in raster files and conducted a stegoanalysis on a set of 800 images of 225 × 225 size. Experimentally, we found that with this embedding method, the maximum container capacity is 21% and that it depends on the contents of the container. It is established that only 60 files out of 800 actually have the maximum capacity. We presented the calculation of the Type I error and the percentage of information detection in the obtained containers by the regular-singular (RS) method. The results showed that the considered steganographic algorithm is resistant to RS steganalysis and is comparable to the stegosystem of the permutation method investigated in one of our previous articles.


Variant detection and runs of homozygosity in next generation sequencing data elucidate the genetic background of Lundehund syndrome.
The Lundehund is a highly specialized breed characterized by a unique flexibility of the joints and polydactyly in all four limbs. The extremely small population size and high inbreeding has promoted a high frequency of diseased dogs affected by the Lundehund syndrome (LS), a severe gastro-enteropathic disease. Comprehensive analysis of bead chip and whole-genome sequencing data for LS in the Lundehund resulted in a genome-wide association signal on CFA 34 and LS-specific runs of homozygosity (ROH) in this region. Filtering analysis for variants with predicted high or moderate effects revealed a missense mutation in LEPREL1 1.2 Mb proximal to the region of the genome-wide association, which was shown to be significantly associated with LS. LS-affected Lundehund harbored the mutant LEPREL1:g.139212C>G genotype A/A whereas all controls of other breeds showed the C/C wild type. In addition, ROH analysis for the Lundehund indicated a high enrichment of genes in potential signatures of selection affecting protein activation and immunoregulatory processes like NOD1 potentially involved in LS breed disposition. Sequencing results for Lundehund specific traits reveal a potential causative mutation for LS in the neuropeptide operating gene LEPREL1 and suggests it as a precursor of the inflammatory process. Analyses of ROH regions give an insight into the genetic background of characteristic traits in the Lundehund that remain to be elucidated in the future.


Ethanol Modulates the Spontaneous Complex Spike Waveform of Cerebellar Purkinje Cells Recorded in vivo in Mice.
Cerebellar Purkinje cells (PCs) are sensitive to ethanol, but the effect of ethanol on spontaneous complex spike (CS) activity in these cells in vivo is currently unknown. Here, we investigated the effect of ethanol on spontaneous CS activity in PCs in urethane-anesthetized mice using in vivo patch-clamp recordings and pharmacological manipulation. Ethanol (300 mM) induced a decrease in the CS-evoked pause in simple spike (SS) firing and in the amplitude of the afterhyperpolarization (AHP) under current clamp conditions. Under voltage-clamp conditions, ethanol significantly decreased the area under the curve (AUC) and the number of CS spikelets, without changing the spontaneous frequency of the CSs or the instantaneous frequency of the CS spikelets. Ethanol-induced a decrease in the AUC of spontaneous CSs was concentration dependent. The EC50 of ethanol for decreasing the AUC of spontaneous CSs was 168.5 mM. Blocking N-methyl-D-aspartate receptors (NMDARs) failed to prevent the ethanol-induced decreases in the CS waveform parameters. However, blockade of cannabinoid receptor 1 (CB1) significantly suppressed the ethanol-induced effects on the CS-evoked pause in SS firing, amplitude of the AHP, spikelet number and the AUC of CSs. Moreover, a CB1 receptor agonist not only reduced the number of spikelets and the AUC of CSs, but also prevented the ethanol-induced inhibition of CS activity. Our results indicate that ethanol inhibits CS activity via activation of the CB1 receptor in vivo in mice, suggesting that excessive ethanol intake inhibits climbing fiber (CF)-PC synaptic transmission by modulating CB1 receptors in the cerebellar cortex.


Gross and histopathological evaluation of umbilical outpouchings in pigs.
Clinical presentations of umbilical outpouchings (UOs) in pigs cover a variety of pathological manifestations. Pigs with UOs often do not reach the abattoir as they die due to complications or are euthanized for welfare concerns. The primary objective was to characterize the gross appearance of UOs in pigs with respect to the different types of pathological manifestations. Also the association between the pathological manifestation and presence of a wound on the UO was evaluated. Pigs (in different age groups, n = 444) with an UO were sampled in Denmark from different locations (two herds and at an abattoir) and examined post mortem. Tissue samples from animals with an enterocystoma or internal umbilical proliferations were collected for histological and immunohistochemical characterization. Hernia umbilicalis was the most frequent cause (72%, n = 320) of the UOs. It was the only diagnosis in 57% (n = 254) of the pigs, and in 15% (n = 66) of the pigs the hernia appeared in combination with other manifestations. Thus, 28% (n = 124) of the pigs were diagnosed with an enterocystoma, internal umbilical proliferations, subcutaneous abscess/ fibrosis or another diagnosis, presented alone or in combination. The distribution of diagnoses varied in the different age groups. Overall, 38% (110/291) of the pigs presented a wound on the UOs post mortem. The age of the pigs confounded the relation between the pathological manifestation and the presence of a wound. The odds that an UO had a wound were lower among pigs with a subcutaneous abscess/ fibrosis compared to pigs diagnosed with an umbilical hernia or enterocystoma (OR, 0.3; 95% Cl, 0.1-0.7). The odds of wounds were higher among weaners (OR, 4.3; 95% Cl 2.3-8.3) and finishers (OR, 6.5; 95% Cl, 3.4-12.7) compared with piglets from the farrowing unit. The area of wounds ranged from 0.03 to 78.5 cm2 and increased with age (P < 0.001). Histologically and immunohistochemically the enterocystomas and internal umbilical proliferations seemed to be lined with mesothelial cells and both had a content comparable with mesenchymal embryonic connective tissue. However, only the cavities of the enterocystomas were also lined with mesothelial cells. In conclusion, UOs in pigs are caused by complex pathological conditions with hernia umbilicalis as the dominating diagnosis. Knowledge clarifying the different pathological manifestations causing an UO and the presence of wounds on the UOs is essential for future prevention strategies.


A computational and perceptual account of motion lines.
To indicate motion in a static drawing, artists often include lines trailing a moving object. The use of these motion lines is notable because they do not seem to be related to anything in the optic array. The dynamic behavior of a neural-network model for contour detection is analyzed and it is shown that it generates trails of oriented responses behind moving stimuli. The properties of the oriented response trails are shown to correspond to motion lines. The model generates trails of different orientations depending on the speed and length of the movement, and thereby predicts different uses of two types of motion lines. The model further predicts that motion lines should bias real motion in some situations. An experiment relating motion lines to ambiguous motion percepts demonstrates that motion lines contribute to motion percepts.


[A man with a painful hand after punching a wall].
A 23-year-old man had a painful right hand after punching a wall. The base of the second metacarpal was swollen and painful. The base of the second metacarpal is difficult to assess radiologically, due to overlying structures. After a trauma, additional slight oblique X-rays may help to make a diagnosis.


Patients' views on optimal visit length in primary care.
Visit length (VL) has been decreasing over the last decades. Patients and physicians alike hold that this may have adverse affects on quality of care and patient-doctor rapport. Our aim was to study the optimal VL as viewed by the patients as well as possible related factors such as demographicparameters and patient satisfaction. By using surveys, we determined that patient satisfaction was highly correlated with VL and satisfaction from VL. Optimal VL as viewed by the patients was 15.4 minutes on average with considerable variation. Longer expected VL was associated with longer visits. Patient satisfaction from the visit was significantly decreased when expressed optimal VL exceeded the estimated duration of the visit. The surveys demonstrated that in young adults, satisfaction is highly correlated with VL. When asked, patients expect attainable VLs, which are on average only somewhat longer then the scheduled duration. We believe that patients should take part in decisions regarding visit scheduling. We suggest that individualization may contribute to the cost-effectiveness of physicians' time.


Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation.
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)-ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid-liquid phase separation under acute hyperosmotic stress.


Prevalence of HTLV-I-associated myelopathy among HTLV-I carriers in Saga, Japan.
Surveying the disease by sending questionnaires to all physicians of the Saga Medical Association, we tabulated 19 definite cases of HTLV-I-associated myelopathy (7 males and 12 females) as of January 31, 1988. The population at risk of HTLV-I carriers was estimated by applying sex- and age-specific anti-HTLV-I antibody-positive rates among blood donors at the Saga Red Cross Blood Center in the fiscal year of 1986 to the population of Saga Prefecture in 1982. The crude prevalence rates among HTLV-I carriers from 20 to 69 years of age per 100,000 were 65.7 for males and 86.9 for females, respectively. The summary prevalence rates with 95% confidence intervals were 46.5 (14.3-97.3) for males and 74.9 (35.3-129.2) for females. There was no remarkable difference in the age-specific prevalence rates in either sex. The crude and summary rates among females were higher than those among males, but the difference was not statistically significant.


Synchronous breast cancer and lymphoma: a case series and a review of the literature.
Four patients with synchronous breast cancer and lymphoma are described. In all cases, the lymphoma was an unexpected finding in the histopathology of the axillary lymph-node dissection. The diagnosis of synchronous malignancies poses challenges for both the diagnosing pathologist and the treating clinician.