Notch signalling is required for both dauer maintenance and recovery in C. elegans.
The Notch signalling pathway is conserved among higher metazoans and is used repeatedly throughout development to specify distinct cell fates among populations of equipotent cells. Mounting evidence suggests that Notch signalling may also be crucial in neuronal function in postmitotic, differentiated neurons. Here, we demonstrate a novel role for the canonical Notch signalling pathway in postmitotic neurons during a specialised ;diapause-like' post-embryonic developmental stage in C. elegans called dauer. Our data suggest that cell signalling downstream of the developmental decision to enter dauer leads to the activation of Notch-responding genes in postmitotic neurons. Consistent with this, we demonstrate that glp-1, one of the two C. elegans Notch receptors, and its ligand lag-2 are expressed in neurons during the dauer stage, and both genes are required to maintain this stage in a daf-7/TGFbeta dauer constitutive background. Our genetic data also suggest that a second Notch receptor, lin-12, functions upstream of, or in parallel with, insulin-like signalling components in response to replete growth conditions to promote dauer recovery. Based on our findings, cues associated with the onset of dauer ultimately trigger a glp-1-dependent Notch signalling cascade in neurons to maintain this developmental state. Then, as growth conditions improve, activation of the LIN-12 Notch receptor cooperates with the insulin-like signalling pathway to signal recovery from the dauer stage.


Maturation of phage T7 involves structural modification of both shell and inner core components.
The double-stranded DNA bacteriophages are good model systems to understand basic biological processes such as the macromolecular interactions that take place during the virus assembly and maturation, or the behavior of molecular motors that function during the DNA packaging process. Using cryoelectron microscopy and single-particle methodology, we have determined the structures of two phage T7 assemblies produced during its morphogenetic process, the DNA-free prohead and the mature virion. The first structure reveals a complex assembly in the interior of the capsid, which involves the scaffolding, and the core complex, which plays an important role in DNA packaging and is located in one of the phage vertices. The reconstruction of the mature virion reveals important changes in the shell, now much larger and thinner, the disappearance of the scaffolding structure, and important rearrangements of the core complex, which now protrudes the shell and interacts with the tail. Some of these changes must originate by the pressure exerted by the DNA in the interior of the head.


Effects of passive heat stress on human somatosensory processing.
Herein, we investigated the effects of passive heat stress on human somatosensory processing recorded by somatosensory-evoked potentials (SEPs). Fifteen healthy subjects received a median nerve stimulation at the left wrist under two thermal conditions: Heat Stress and normothermic Time Control. The latencies and amplitudes of P14, N20, P25, N35, P45, and N60 at C4' and P14, N18, P22, and N30 at Fz were evaluated. Under the Heat Stress condition, SEPs were recorded at normothermic baseline (1st), early in heat stress (2nd), when esophageal temperature had increased by ~1.0°C (3rd) and ~2.0°C (4th), and after heat stress (5th). In the Time Control condition, SEPs were measured at the same time intervals as those in the Heat Stress condition. The peak latencies and amplitudes of SEPs did not change early in heat stress. However, the latencies of P14, N20, and N60 at C4' and P14, N18, and P22 at Fz were significantly shorter in the 4th session than in the 1st session. Furthermore, the peak amplitudes of P25 and N60 at C4', and P22 and N30 at Fz decreased with increases in body temperature. On the other hand, under the Time Control condition, no significant differences were observed in the amplitudes or latencies of any component of SEPs. These results suggested that the conduction velocity of the ascending somatosensory input was accelerated by increases in body temperature, and hyperthermia impaired the neural activity of cortical somatosensory processing.


VIRULENCE OF ESCHERICHIA-SHIGELLA GENETIC HYBRIDS FOR THE GUINEA PIG.
Falkow, Stanley (Walter Reed Army Institute of Research, Washington, D.C.), H. Schneider, L. S. Baron, and S. B. Formal. Virulence of Escherichia-Shigella hybrids for the guinea pig. J. Bacteriol. 86:1251-1258. 1963.-Genetic recombination studies between donor Escherichia coli and recipient Shigella flexneri 2a strains were employed to examine alterations in the virulence of Shigella hybrids for guinea pigs. The genetic studies indicated that several chromosomal regions of E. coli and S. flexneri are grossly homologous. The frequency of recombination between E. coli and Shigella was decreased, however, in comparison with E. coli x E. coli matings. Moreover, the predominant Shigella hybrid classes acquired only the selected genetic marker, and extensive transfer of the Escherichia genome was detected only occasionally. The virulence studies made use of hybrids with well-defined single markers as well as those with overlapping chromosomal regions. Analysis of over one-half of the chromosome revealed only one chromosomal region, located between the rha(+) and xyl(+) genes, which was essential for virulence. However, hybrids which had received the E. coli pili antigen and fuc(+)-nic(+) determinants exhibited an intermediate virulence. Hybrids carrying a full complement of Shigella genes and the rha(+)-xyl(+)Escherichia region as a persistent exogenote (partial diploids) were of intermediate virulence. These partial diploids may return to complete virulence by elimination of the Escherichia chromosomal fragment or become avirulent by incorporation of this fragment.


Association between adaptive behaviour and age in adults with Down syndrome without dementia: examining the range and severity of adaptive behaviour problems.
Studies on adaptive behaviour and ageing in adults with Down syndrome (DS) (without dementia) have typically analysed age-related change in terms of the total item scores on questionnaires. This research extends the literature by investigating whether the age-related changes in adaptive abilities could be differentially attributed to changes in the number or severity (intensity) of behavioural questionnaire items endorsed. The Adaptive Behaviour Assessment System-II Adult (ABAS-II Adult) was completed by parents and caregivers of 53 adults with DS aged between 16 and 56 years. Twenty adults with DS and their parents/caregivers were a part of a longitudinal study, which provided two time points of data. In addition 33 adults with DS and their parents/caregivers from a cross-sectional study were included. Random effects regression analyses were used to examine the patterns in item scores associated with ageing. Increasing age was found to be significantly associated with lower adaptive behaviour abilities for all the adaptive behaviour composite scores, expect for the practical composite. These associations were entirely related to fewer ABAS-II Adult items being selected as present for the older participants, as opposed to the scores being attributable to lower item severity. This study provides evidence for a differential pattern of age-related change for various adaptive behaviour skills in terms of range, but not severity. Possible reasons for this pattern will be discussed. Overall, these findings suggest that adults with DS may benefit from additional support in terms of their social and conceptual abilities as they age.


[Thrombocytosis and neonatal subcutaneous adiponecrosis].
The authors report three newborns with subcutaneous fat necrosis, that appeared between the 4th and 21st day of life. The infants, full term of normal weight, presented severe perinatal hypoxia and needed primary resuscitation. Severity and duration of perinatal hypoxia were not related with the time of cutaneous lesion onset. Serum calcium levels were in the higher values of the neonatal normal range. Vitamin D levels were within the normal range and only one patient showed a transient elevation of PTH, suggesting a poor relevance of both these factors in determining serum calcium increase. All patients showed a marked increase of platelets number, before the onset of clinical manifestations. Thrombocytosis could play an important role in the pathogenesis of adipose tissue necrosis, causing lower blood perfusion with relative hypoxia and hypothermia.


Diet After Ileostomy Study: an observational study describing dietary intake and stoma-related symptoms in people with an ileostomy.
People with ileostomy are frequently advised to avoid specific foods and food groups, making it plausible that they are at risk of a range of nutrition-related adverse health consequences. Despite this there has been no recent study in the United Kingdom describing dietary intake, symptoms and food avoidance in people with ileostomy or post-reversal. A cross-sectional study was conducted at different time points in people with ileostomy and reversal. Participants were recruited at 6-10 weeks post-formation (n = 17) and ≥12 months with established ileostomy (n = 16) and with reversal (n = 20). In all participants, ileostomy/bowel-related symptoms in the previous week were assessed using a study-specific questionnaire. Dietary intake was assessed using three online diet recalls or 3-day dietary records. Food avoidance and reasons for food avoidance were assessed. Data were summarised using descriptive statistics. Participants reported a few ileostomy/bowel-related symptoms in the previous week. However, over 85% of participants reported avoiding foods, particularly fruits and vegetables. At 6-10 weeks the most common reason was being advised to do so (71%), although 53% avoided foods due to gas. At ≥12 months the most common reasons were foods visible in the bag (60%) or advised to do so (60%). Reported intakes of most nutrients were comparable to population medians, apart from lower fibre in people with ileostomy. Intakes of free sugars and saturated fats were above recommended levels in all groups, due to high consumption of cakes and biscuits and sugar-sweetened drinks. After the initial healing period, foods should not be automatically excluded unless found to be problematic after reintroduction. There may be a need for healthy eating advice for people with established ileostomies and post-reversal, targeting discretionary high-fat, high-sugar foods.


PTH[1-34] improves the effects of core decompression in early-stage steroid-associated osteonecrosis model by enhancing bone repair and revascularization.
Steroid-associated osteonecrosis (SAON) might induce bone collapse and subsequently lead to joint arthroplasty. Core decompression (CD) is regarded as an effective therapy for early-stage SAON, but the prognosis is unsatisfactory due to incomplete bone repair. Parathyroid hormone[1-34] (PTH[1-34]) has demonstrated positive efficacy in promoting bone formation. We therefore evaluated the effects of PTH on improving the effects of CD in Early-Stage SAON. Distal femoral CD was performed two weeks after osteonecrosis induction or vehicle injection, with ten of the ON-induced rabbits being subjected to six-week PTH[1-34] treatment and the others, including ON-induced and non-induced rabbits, being treated with vehicle. MRI confirmed that intermittent PTH administration improved SAON after CD therapy. Micro-CT showed increased bone formation within the tunnel. Bone repair was enhanced with decreased empty osteocyte lacunae and necrosis foci area, resulting in enhanced peak load and stiffness of the tunnel. Additionally, PTH enlarged the mean diameter of vessels in the marrow and increased the number of vessels within the tunnels, as well as elevated the expression of BMP-2, RUNX2, IGF-1, bFGF and VEGF, together with serum OCN and VEGF levels. Therefore, PTH[1-34] enhances the efficacy of CD on osteogenesis and neovascularization, thus promoting bone and blood vessels repair in the SAON model.


Fast-food consumption among US adults and children: dietary and nutrient intake profile.
To examine the dietary profile associated with fast-food use. To compare the dietary intake of individuals on the day that they ate fast food with the day that fast food was not eaten. Cross-sectional study design. The dietary intake of individuals who reported eating fast food on one or both survey days was compared with those who did not report eating fast food. Among the individuals who reported eating fast food, dietary intake on the day when fast food was eaten was compared with the day when fast food was not eaten. Weighted comparison of mean intakes and pairwise t-test were used in the statistical analysis. Subjects/setting Data from 17370 adults and children who participated in the 1994-1996 and 1998 Continuing Survey of Food Intakes by Individuals. Dietary intake data were collected by 2 non-consecutive 24-hour dietary recalls. Fast-food use was reported by 37% of the adults and 42% of the children. Adults and children who reported eating fast food had higher intake of energy, fat, saturated fat, sodium, carbonated soft drink, and lower intake of vitamins A and C, milk, fruits and vegetables than those who did not reported eating fast food (P<.001). Similar differences were observed among individuals between the day when fast food was eaten and the day when fast food was not eaten. Consumers should be aware that consumption of high-fat fast food may contribute to higher energy and fat intake, and lower intake of healthful nutrients.


Formulas for Calculated Osmolarity and Osmolal Gap: A Study of Diagnostic Accuracy.
The osmolal gap has been used for decades to screen for exposure to toxic alcohols. However, several issues may affect its reliability. We aimed to develop equations to calculate osmolarity with improved performance when used to screen for intoxication to toxic alcohols. Retrospective cohort study. 7,525 patients undergoing simultaneous measurements of osmolality, sodium, potassium, urea, glucose, and ethanol or undergoing similar measurements performed within 30 minutes of a measurement of toxic alcohol levels at a single tertiary-care center from April 2001 to June 2016. Patients with detectable toxic alcohols were excluded. Equations to calculate osmolarity using multiple linear regression. The performance of new equations compared with published equations developed to calculate osmolarity, and to diagnose toxic alcohol intoxications more accurately. We obtained 7,525 measurements, including 100 with undetectable toxic alcohols. Among them, 3,875 had undetectable and 3,650 had detectable ethanol levels. In the entire cohort, the best equation to calculate osmolarity was 2.006×Na + 1.228×Urea + 1.387×Glucose + 1.207×Ethanol (values in mmol/L, R2=0.96). A simplified equation, 2.0×Na + 1.2×Urea + 1.4×Glucose + 1.2×Ethanol, had a similar R2 with 95% of osmolal gap values between -10.9 and 13.8. In patients with undetectable ethanol concentrations, the range of 95% of osmolal gap values was narrower than previous published formulas, and in patients with detectable ethanol concentrations, the range was narrower or similar. We performed a subanalysis of 138 cases for which both the toxic alcohol concentration could be measured and the osmolal gap could be calculated. Our simplified equation had superior diagnostic accuracy for toxic alcohol exposure. Single center, no external validation, limited number of cases with detectable toxic alcohols. In a large cohort, coefficients from regression analyses estimating the contribution of glucose, urea, and ethanol were higher than 1.0. Our simplified formula to precisely calculate osmolarity yielded improved diagnostic accuracy for suspected toxic alcohol exposures than previously published formulas.


[Human fasciolasis and gastrointestinal compromise: study of 277 patients in the Cayetano Heredia National Hospital (1970-2002)].
This is a retrospective and descriptive review of 277 patients suffering fasciolasis. These patients were seen in Hospital Nacional Cayetano Heredia between 1970-2002; 240 (86.6%) developed the chronic phase and 37 (13.3%) the acute form. Group aged 20-29 years were the most affected (24%). The main places infected were the interandean valleys of Lima, Ancash and Junin. The 277 patients the main symptoms were: abdominal pain in 236, nausea/vomiting in 106 and diarrhea in 100. Hepatomegaly in 56, pallor in 44 and fever in 23 were the main physical findings. 47% (80/169) suffered eosinophilia, 46% (38/82) had an increase of alkaline phosphatase and 31% (52/169) anemia.


Tracheobronchial foreign body aspiration in children - diagnostic value of symptoms and signs.
Tracheobronchial foreign body (TFB) aspiration is a common cause of respiratory compromise in early childhood. Research indicates that a high number of children are missed with TFB aspiration. The aim of this study was to identify predictors of potential TFB aspiration. We analysed 370 endoscopic reports of children admitted to our emergency department who underwent explorative rigid bronchoscopy to exclude/remove a TFB (1989-2003). Patient characteristics, history, clinical, radiographic and bronchoscopic findings were noted. Sensitivities and specificities for TFB aspiration were calculated for patient history, clinical and radiographic findings. The median age was 1.8 years. In 59.7% of patients a TFB was found and removed. A group analysis was performed on children with symptoms less than 2 weeks (group A) and those more than 2 weeks (group B). The results showed that unilateral diminished breath sounds and unilateral overdistension on chest X-ray were the most sensitive (53-79%) and specific (68-88%) findings in both groups. The clinical triad of acute choking/coughing, wheezing and unilateral diminished breath sounds had a high specificity (96-98%) in both groups. In contrast, a positive history of acute choking/coughing in group A or a permanent cough in group B showed a low specificity (8-16%). In a paediatric respiratory compromise, the presence of unilateral diminished breath sounds, pathological chest X-ray or clinical triad is a powerful indicator for occurred TFB aspiration. Since no single or combined variables can predict TFB aspiration with full certainty, bronchoscopic exploration should be performed if TFB aspiration is suspected.


Efficacy of antibody response following the vaccination of SARS-CoV-2 infected and noninfected healthcare workers by two-dose inactive vaccine against COVID-19.
Sinovac is an inactive vaccine produced against Coronavirus Disease 2019 (COVID-19) for almost a year. No sufficient information is available concerning pro-vaccine immunogenicity. We investigated the efficacy of antibody response following vaccination of SARS-CoV-2-infected and noninfected healthcare workers by a two-dose inactive vaccine against COVID-19. The immunogenicity acquired on the 27th day and 42nd day after the first dose of vaccine (corresponding to Day 14 after the second dose) were compared by the demographics, immunosuppression, comorbidities, postvaccination reaction, and IgG levels of 120 subjects. The overall rate of second postvaccine seropositivity was 97.5% (n = 117) of all individuals, and 44 of these were seropositive after the first dose. The percentage of having a previous COVID-19 (59.1%) among seropositive individuals before 2nd vaccination was significantly higher than those of seropositive individuals (10.96%) after second vaccination (p < 0.0001). In our study, 35 healthcare workers stated that they had previously had a COVID-19 infection. Anti-SARS-CoV-2 antibody responses in people infected with SARS-CoV-2 follow a classical pattern, with a rapid increase within the first 3 weeks after the appearance of symptoms. Although the titers decreased thereafter, the ability to detect anti-SARS-CoV-2 IgG antibodies supports the view that the majority of subjects previously screened as positive for virus remain intact with confirmed neutralizing activity for up to 6 months.


Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers.
To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD). We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with (11)C-labeled Pittsburgh compound B (PiB) and (18)F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs). Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of Aβ(1-42), total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs. The lack of fibrillar β-amyloid (Aβ) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of Aβ(1-42) in CSF, that other forms of Aβ such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease.


[Sequential changes of the cardiomyopathy in Duchenne muscular dystrophy by 201Tl myocardial SPECT].
201Tl myocardial SPECT was performed to evaluate cardiomyopathy in Duchenne type of progressive muscular dystrophy (DMD). Follow up SPECT images of the same patients were also obtained about 1 year after the first scan. Cases subjected to study were 10 DMD. At the first study the hypoperfusion area of the left ventricular muscle was observed in 6 cases (60%) out of 10. At the second study the hypoperfusion areas became wider and lower in 4 out of 6 cases (66.7%). The new hypoperfusion area which was not demonstrated at the first study was observed at the second study in one case of these cases. These results suggested that the positive rate of cardiomyopathy in DMD by 201Tl myocardial SPECT was high, and 201Tl myocardial SPECT is a useful examination to detect the change of myocardial damage in DMD.


Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin.
The ClyA protein is a pore-forming cytotoxin expressed by Escherichia coli and some other enterobacteria. It confers cytotoxic activity toward mammalian cells, but it has remained unknown how ClyA is surface exposed and exported from bacterial cells. Outer-membrane vesicles (OMVs) released from the bacteria were shown to contain ClyA protein. ClyA formed oligomeric pore assemblies in the OMVs, and the cytotoxic activity toward mammalian cells was considerably higher than that of ClyA protein purified from the bacterial periplasm. The redox status of ClyA correlated with its ability to form the oligomeric pore assemblies. In bacterial cells with a defective periplasmic disulphide oxidoreductase system, the ClyA protein was phenotypically expressed in a constitutive manner. The results define a vesicle-mediated transport mechanism in bacteria, and our findings show that the localization of proteins to OMVs directly may contribute to the activation and delivery of pathogenic effector proteins.


Restoration of Glucose Counterregulation by Islet Transplantation in Long-standing Type 1 Diabetes.
Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ∼30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-(2)H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long-standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia.


Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.
Measurement of cortical gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. Study for association. Academic clinical research program. The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. The levels of occipital cortex GABA, glutamate, N-acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls (P =.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls (P<.001). Significant reductions in the percentage of solid tissue (P =.009) and the percentage of white matter (P =.04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD.


Multiferroic Two-Dimensional Materials.
The relation between unusual Mexican-hat band dispersion, ferromagnetism, and ferroelasticity is investigated using a combination of analytical, first-principles, and phenomenological methods. The class of material with Mexican-hat band edge is studied using the α-SnO monolayer as a prototype. Such a band edge causes a van Hove singularity diverging with 1/sqrt[E], and a charge doping in these bands can lead to time-reversal symmetry breaking. Herein, we show that a material with Mexican-hat band dispersion, α-SnO, can be ferroelastic or paraelastic depending on the number of layers. Also, an unexpected multiferroic phase is obtained in a range of hole density for which the material presents ferromagnetism and ferroelasticity simultaneously.


[Aphakia in a German Holstein calf].
Aphakia and further malformations of both eyes were diagnosed in a female German Holstein calf. Besides aphakia of the left eye, the calf exhibited microphthalmia, glaucoma and a hypoplastic uveoscleral tissue. Additional findings in the right eye were buphthalmus and glaucoma. Instead of aphakia, pathohistological and investigations revealed a very small (microphakia) and luxated lens. Neither the clinical nor the pathological examination revealed further malformations of other organs. A BVD infection could be excluded as cause for the ocular malformations observed. A deficiency or excess of vitamine A was unlikely because this would have also applied to all other calves born at the same time on the farm. An inbreeding coefficient of 3.168% for the malformed calf and the exclusion of environmental causes for these malformations of the eyes let us suppose a hereditary problem.


The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis.
Data from clinical research and our previous study have suggested the potential involvement of SENP1, the major protease of post-translational SUMOylation, in cardiovascular disorders. Here, we investigate the role of SENP1-mediated SUMOylation in graft arteriosclerosis (GA), the major cause of allograft failure. We observe an endothelial-specific induction of SENP1 and GATA2 in clinical graft rejection specimens that show endothelial activation-mediated vascular remodelling. In mouse aorta transplantation GA models, endothelial-specific SENP1 knockout grafts demonstrate limited neointima formation with attenuated leukocyte recruitment, resulting from diminished induction of adhesion molecules in the graft endothelium due to increased GATA2 SUMOylation. Mechanistically, inflammation-induced SENP1 promotes the deSUMOylation of GATA2 and IκBα in endothelial cells, resulting in increased GATA2 stability, promoter-binding capability and NF-κB activity, which leads to augmented endothelial activation and inflammation. Therefore, upon inflammation, endothelial SENP1-mediated SUMOylation drives GA by regulating the synergistic effect of GATA2 and NF-κB and consequent endothelial dysfunction.


Renal denervation and treatment of hypertension.
Cardiovascular diseases kill more people each year than any other diseases. In 2008, 7.3 million people died of ischaemic heart disease, 6.2 million from stroke or another form of cerebrovascular disease. Hypertension affects about 1 billion people worldwide and is a major risk factor for many cardiovascular diseases, including coronary heart disease and stroke. In contrast, our knowledge in regard to the underlying molecular mechanisms remains incomplete and, as a consequence, it is difficult if not impossible to efficiently treat the most affected patients. While the development and application of novel pharmacological agents in combination with lifestyle changes have been applied in Western developed countries to a large number of patients, a significant number of individuals fail to respond. Recently, several novel approaches have been developed including a minimally invasive catheter-based renal nerve ablation technique and some of the consequences will be highlighted in this brief review article. This will include the discussion of previous attempts to denervate the renal arteries as well as the significant improvements achieved when catheter-based interventions are applied.


Oogenesis in the leech Glossiphonia heteroclita (Annelida, Hirudinea, Glossiphonidae). I. Ovary structure and previtellogenic growth of oocytes.
Glossiphonia heteroclita has paired ovaries whose shape and dimensions change as oogenesis proceeds: during early previtellogenesis they are small and club-shaped, whereas during vitellogenesis they broaden and elongate considerably. During early oogenesis (previtellogenesis), each ovary is composed of an outer envelope (ovisac) that surrounds the ovary cavity and is filled with hemocoelomic fluid, in which a single and very convoluted ovary cord is bathed. The ovary cord consists of germline cells, including nurse cells and young oocytes surrounded by a layer of elongated follicle cells. Additionally, follicle cells with long cytoplasmic projections occur inside the ovary cord, where they separate germ cells from each other. The ovary cord contains thousands of nurse cells. Each nurse cell has one intercellular bridge, connecting it to a central anucleate cytoplasmic mass, the cytophore (rachis); it in turn is connected by one intercellular bridge with each growing oocyte. Numerous mitochondria, RER cisternae, ribosomes, and Golgi complexes are transported from the nurse cells, via the intercellular bridge and cytophore, to the growing oocytes. Oogenesis in G. heteroclita is synchronous with all oocytes in the ovary in the same stage of oogenesis. The youngest observed oocytes are slightly larger than nurse cells, and usually occupy the periphery of the ovary cord. As previtellogenesis proceeds, the oocytes gather a vast amount of cell organelles and become more voluminous. As a result, in late previtellogenesis the oocytes gradually protrude into the ovary cavity. Simultaneously with oocyte growth, the follicle cells differentiate into two subpopulations. The morphology of the follicle cells surrounding the nurse cells and penetrating the ovary cord does not change, whereas those enveloping the growing oocytes become more voluminous. Their plasma membrane invaginates deeply, forming numerous broad vesicles that eventually seem to form channels or conducts through which the hemocoelomic fluid can easily access the growing oocytes.


The economic burden of tuberous sclerosis complex in the UK: A retrospective cohort study in the Clinical Practice Research Datalink.
Tuberous sclerosis complex (TSC) is a multi-system genetic disorder characterized by the development of diverse clinical manifestations. The complexity of this disease is likely to result in substantial challenges and costs in disease management throughout the patient's lifetime. This retrospective database study aims to quantify healthcare resources utilized by TSC patients. TSC patients in the Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database were identified between January 1987 and June 2013. Analyses were conducted over the most recent 3-year period of data and stratified by pediatric (< 18) and adult patients. Prescriptions, procedures, diagnostic tests, and healthcare encounters were reported in comparison with a matched comparator cohort. Costs and key economic drivers by primary organ system manifestations were also examined. A total of 286 patients with TSC were identified and consistently reported 2-fold greater resource use than the matched presumably healthy controls. Despite this comparatively greater resource use, half of TSC patients did not record any procedures, and 20% of patients did not record any diagnostic tests; however, inpatient hospitalizations were greater for the TSC cohort (3.1 vs 1.3), but length of stay was comparable. TSC patients had costs totaling £12,681 per patient over the 3-year period, a figure 2.7-fold greater than the total costs in the comparator cohort (£4,777). Costs for patients with specific primary manifestations were even greater, with brain manifestations incurring £22,139 per affected patient. Kidney and nervous system manifestations were the main cost drivers. The economic burden of TSC and its impact on NHS healthcare resources is mostly attributable to the broad spectrum of manifestations that develop within multiple organ systems. TSC patients may benefit from co-ordinated care based on their requirement for high numbers of healthcare visits across specialties.


Evaluation of a community-based, family focused healthy weights initiative using the RE-AIM framework.
Childhood overweight and obesity is a major public health concern. Community-based interventions have the potential to reach caregivers and children. However, the overall health impact of these programs is rarely comprehensively assessed. This study evaluated a physical activity and healthy eating family program (Healthy Together; HT) using the RE-AIM framework. Ten sites implemented the 5-week program. Thirty-nine staff members and 277 program participants (126 caregivers [M age = 35.6] and 151 children [M age = 13]) participated in the evaluation. Each RE-AIM dimension was assessed independently using a mixed-methods approach. Sources of data included archival records, interviews and surveys. Effectiveness outcome variables were assessed at pre- and post-intervention and 6-month follow-up. Reach: HT participants were almost entirely recruited from existing programs within sites. Effectiveness: Caregivers' nutrition related efficacy beliefs increased following HT (ps < .03). Participation in HT was not associated with significant changes in physical activity or nutrition behaviour or perceived social support (ps > .05). Knowledge surrounding healthy diets and physical activity increased in children and caregivers (ps < .05). Adoption: Thirty-five percent of sites approached to implement HT expressed interest. The 10 sites selected recruited existing staff members to implement HT. Program objectives were met 72.8% of the time and 71 adaptations were made. HT was finance- and time-dependent. Maintenance: Two sites fully implemented HT in the follow-up year and 5 sites incorporated aspects of HT into other programs. Working alongside organizations that develop community programs to conduct comprehensive, arms-length evaluations can systematically highlight areas of success and challenges. Overall HT represents a feasible community-based intervention; however further support is required in order to ensure the program is effective at positively targeting the desired outcomes. As a result of this evaluation, modifications are currently being implemented to HT.


Real-time monitoring of the PDE2 activity of live cells: hormone-stimulated cAMP hydrolysis is faster than hormone-stimulated cAMP synthesis.
Cyclic nucleotide phosphodiesterases (PDEs) are the enzymes that catalyze the hydrolysis of cAMP and cGMP, thereby restricting the activity of these second messengers in cells. A unique ability to shape gradients of cyclic nucleotides and compartmentalize their signaling implies a high potency and a rapid action of PDEs. However, it has not been demonstrated how fast PDEs can hydrolyze cAMP in a living system. Here we perform a real-time monitoring of PDE2 activity in aldosterone-producing adrenal cells using a recently developed genetically encoded, fluorescent cAMP sensor, which reveals enormously rapid kinetics of cAMP degradation. Activation of PDE2 results in a rapid decrease of intracellular cAMP from high micromolar to the sub-micromolar range within a few seconds. Moreover, the kinetics of atrial natriuretic peptide-stimulated PDE2 activity (measured as decline of cAMP) are much faster than the speed of ACTH and isoprenaline-induced cAMP-synthesis (measured as cAMP accumulation) in the cells, revealing high catalytic activity and fast action of PDEs in regulating cAMP signaling in a physiological system.


Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer.
Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT). The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months. At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post-treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL. Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences.


[Experimental study of hyaluronic acid gel fillers biodegradation in orbit].
Recently, hyaluronic acid gel (HAG) fillers were proposed as an effective alternative treatment option for surgical orbital volume augmentation. Several authors reported about long-standing effect of the filler. To assess the features of HAG biodegradation after intraorbital injection in experimental environment. In the course of the experiment, 7 chinchilla rabbits (14 eyes) received a single 1ml intraorbital HAG injection (Restylane SubQ, Galderma, Sweden) using a cannula. The animals' orbits were examined by ultrasound scan after the injection and at 1, 3, 6, 9, 12 and 18 months. The animals were subsequently sacrificed for morphological study of orbital tissue containing the HAG filler. The HAG filler persisted in the orbit of experimental animals during the whole follow-up period. The volume of HAG depot and its density diminished gradually till the 18th month, after which the particles of HAG could still be detected with the morphological study and ultrasound. The HAG filler persisted in the orbit of experimental animals up to 18 months. Incomplete biodegradation explains the longstanding duration of the injection effect.


Generalized facilitated diffusion model for DNA-binding proteins with search and recognition states.
Transcription factors (TFs) such as the lac repressor find their target sequence on DNA at remarkably high rates. In the established Berg-von Hippel model for this search process, the TF alternates between three-dimensional diffusion in the bulk solution and one-dimensional sliding along the DNA chain. To overcome the so-called speed-stability paradox, in similar models the TF was considered as being present in two conformations (search state and recognition state) between which it switches stochastically. Combining both the facilitated diffusion model and alternating states, we obtain a generalized model. We explicitly treat bulk excursions for rodlike chains arranged in parallel and consider a simplified model for coiled DNA. Compared to previously considered facilitated diffusion models, corresponding to limiting cases of our generalized model, we surprisingly find a reduced target search rate. Moreover, at optimal conditions there is no longer an equipartition between the time spent by the protein on and off the DNA chain.


Novel nomogram for the prediction of seminal vesicle invasion including multiparametric magnetic resonance imaging.
To create a model that predicts side-specific seminal vesicle invasion using clinical, biopsy and multiparametric magnetic resonance imaging data. We analyzed data from 544 patients who underwent robot-assisted radical prostatectomy at a single institution. To develop a side-specific predictive model, we ultimately considered four variables: prostate-specific antigen, highest ipsilateral biopsy Gleason grade, highest ipsilateral percentage core involvement and seminal vesicle invasion on multiparametric magnetic resonance imaging. A binary multivariable logistic regression model was fitted to predict seminal vesicle invasion. A nomogram was then built based on the coefficients of the resulting logit function. The leave-one-out cross validation method was used for internal validation, and the decision curve analysis for the evaluation of the net clinical benefit. We relied on 804 side-specific cases after excluding negative biopsy observations (n = 284). Seminal vesicle invasion was reported on multiparametric magnetic resonance imaging in 41 (5%) cases, and on final pathology in 64 (8%) cases. All variables in the model emerged as predictors of seminal vesicle invasion (all P ≤ 0.001) and were subsequently considered to build a nomogram. The area under the curve of multiparametric magnetic resonance imaging alone in predicting seminal vesicle invasion was 59.1%; whereas one of the clinical variables only was 85.1%. The area under the curve of the nomogram resulting from their combination was 86.5%. After internal validation, this resulted in 84.7%. The model achieved good calibration and the decision curve analysis showed its clinical benefit, especially when compared with relying only on multiparametric magnetic resonance imaging prediction of seminal vesicle invasion. A nomogram based on clinical and multiparametric magnetic resonance imaging data can predict seminal vesicle invasion and serve as a tool to urologists for surgical planning.


[ERCC1 as a Marker of Ovarian Cancer Resistance to Platinum Drugs].
The review is concerned with the crucial marker of nucleotide excision repair ERCC1 and its contribution to platinum resistance of ovarian cancer. All the variants of the laboratory and clinical ERCC1 assessment in the ovarian cancer tissue (single nucleotide polymorphisms of the ERCC1 gene, levels of mRNA or protein) are considered. Data on the prognostic and predictive value of ERCC1 as a marker of the response to platinum-based therapy in ovarian cancer are systematized. The authors discuss the possible causes of heterogeneity of the results and emphasize the necessity of a unified and integrated approach to evaluation of ERCC1 in the tumor. The publications cited in the Search Engine Pub Med up to January 2015 were analyzed.


Estimate of the contemporary live-birth prevalence of recurrent 22q11.2 deletions: a cross-sectional analysis from population-based newborn screening.
Although pathogenic 22q11.2 deletions are an important cause of developmental delays and lifelong disease burden, their variable and complex clinical expression contributes to under-recognition, delayed molecular diagnosis and uncertainty about prevalence. We sought to estimate the contemporary live-birth prevalence of typical 22q11.2 deletions using a population-based newborn screening sample and to examine data available for associated clinical features. Using DNA available from an unbiased sample of about 12% of all dried blood spots collected for newborn screening in Ontario between January 2017 and September 2018, we prospectively screened for 22q11.2 deletions using multiplex quantitative polymerase chain reaction assays and conducted independent confirmatory studies. We used cross-sectional analyses to compare available clinical and T-cell receptor excision circle (TREC, used in newborn screening for severe combined immunodeficiency) data between samples with and without 22q11.2 deletions. The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10 000) live births (95% confidence interval [CI] 2.5 to 7.8 per 10 000), based on a total of 30 074 samples screened, with 14 having confirmed 22q11.2 deletions. Of term singletons, samples with 22q11.2 deletions had significantly younger median maternal age (25.5 v. 32.0 yr, difference -6.5 yr, 95% CI -7 to -2 yr), a greater proportion with small birth weight for gestational age (odds ratio 7.00, 95% CI 2.36 to 23.18) and lower median TREC levels (108.9 v. 602.5 copies/3 μL, p < 0.001). These results indicate that the 22q11.2 deletion syndrome is one of the most common of rare genetic conditions and may be associated with relatively younger maternal ages and with prenatal growth abnormalities. The findings support the public health importance of early - prenatal and neonatal - diagnosis that would enable prompt screening for and management of well-known actionable features associated with 22q11.2 deletions.


Differences in sexual attitudes and likeliness of sexual behaviors of black lower-socioeconomic father-present vs. father-absent female adolescents.
This study compared sexual permissiveness attitudes and likely behaviors of father-absent vs. father-present black, lower-socioeconomic female adolescents. Father-absent subjects were not found to be more sexually permissive in reported likely behavior or attitude than father-present subjects. However, the father-absent group was found to have significantly greater inconsistency between behavioral and attitudinal scores in which the reported behavior was more permissive than the reported attitude. Finally, within the father-absent group, those subjects whose fathers became absent before they were five years old, were found to have a significantly higher need for social approval than subjects whose fathers became absent after they were five years old. The implications of these results are discussed.


Removal of bacteria from blood by charcoal hemoperfusion.
E. coli bacteria were successfully removed from contaminated RBC/plasma by using a special matrix of micro-encapsulated albumin activated charcoal (ACAC). Efficacy of removing the bacteria was directly related to the amount of time the contaminated blood was in contact with the charcoal. The data indicated that the bacteria adhered to the ACAC, but that the charcoal was not bactericidal.


[Controversies on the treatment of early esophageal cancer].
Early cancer of the esophagus was defined as the mucosal and the submucosal cancer without any metastasis. The five-year-survival rate for early cancer cases was 61%. From our experience with nine cases of early mucosal cancer, not only no lymph node metastasis but also no vascular invasion was observed. So the diagnosis and the surgical treatment of mucosal carcinoma and further intraepithelial carcinoma must be important to obtain the long term survivals. The post operative combined treatments, such as the irradiation and the immunochemotherapy, were necessary for the early submucosal cancer with vascular invasion to improve the postoperative survivals.


Applicability of HLA-DQB oligonucleotide typing for the TA10 and 2B3 specificities in routine HLA typing.
Our group recently developed oligonucleotide probes associated to the TA10 and 2B3 specificities (1). Unambiguous typings were observed in a panel of homozygous typing cells and a family, using 32P-end labeled probes and PCR-amplified DNA (DQB exon 2). To investigate whether these TA10 and 2B3 associated oligonucleotides could be used in routine HLA-typing we extended the study to a panel of healthy, unrelated individuals. When TA10 and 2B3 typings by oligonucleotides were compared with those obtained in routine serology a complete correlation was observed for TA10. A discrepancy was seen for 2B3 typing in material obtained from DQw5- (and possibly DQw4)-positive individuals which could be explained by the CYNAP (cytotoxicity-negative, absorption-positive) phenomenon, using the IIB3 monoclonal antibody in routine tissue typing. Our results suggest that HLA-DQB oligonucleotide typing for TA10 and 2B3 is an accurate and reliable method and can be used effectively in routine HLA typing.


In silico studies toward the discovery of new anti-HIV nucleoside compounds through the use of TOPS-MODE and 2D/3D connectivity indices. 2. Purine derivatives.
The TOPological Substructural MOlecular DEsign (TOPS-MODE) approach has been used to predict the anti-HIV activity in MT-4 assays (Estrada et al., 2002) of a diverse range of purine-based nucleosides. A database of 206 nucleosides has been selected from the literature and a theoretical virtual screening model has been developed. The model is able of discriminating between compounds that have anti-HIV activity and those that do not, with a good classification level of 85% in the training and 82.8% in the cross-validation series. On the basis of the information generated by the model, the correct classification of practically 80% of compounds from an external prediction set has been achieved using the theoretical model. Furthermore, the contribution of a range of molecular fragments to the pharmacological action has been calculated and this could provide a powerful tool in the design of nucleoside analogues that show activity against the HIV. Finally, a QSAR model has been developed that allows quantitative data to be obtained regarding the pharmacological potency shown by this type of compound.


[Peroxisomal disorders].
Peroxisomes are multifunctional microorganelles that play a key role in numerous biochemical processes adapting dynamically to the current physiological requirements of the cell. The disturbance of the peroxisome structure due to mutations in different PEX and non-PEX genes coding functional peroxisomal proteins is the pathogenic basis of the peroxisomal disorders. The β-oxidation process of very long-chain fatty acids (VLCFA) is a unique metabolic pathway located exclusively in the peroxisome. This determines that VLCFA is the main biomarker for the diagnosis of peroxisomal diseases. Peroxisomal disorders present a broad spectrum of clinical symptoms from the neonatal, severe Zellweger syndrome with dysmorphia, multi-organ dysfunction to the late symptomatic adult form of X-linked adrenoleukodystrophy. Relatively common the use of highly specialized analytical techniques causes it is a still growing group of rare metabolic diseases.


Demonstration of the direct impact of ketamine on urothelium using a tissue engineered bladder model.
Ketamine is a common recreational drug. Severe lower urinary tract symptoms associated with its consumption have been reported, but little is known about the involved mechanisms. The effect of ketamine, which is excreted in urine, was evaluated by its application on an in vitro three-dimensional human tissue-engineered bladder model composed of an urothelium and a submucosa. Human urothelial cells were cultured with medium containing various concentrations of ketamine and harvested at different times to obtain growth curves. Using this model, specific activity of caspase-3 was measured to assess the level of apoptosis induced by ketamine. Finally, a human tissue-engineered bladder model was used. Urothelial cells were plated on a stromal layer made of dermal fibroblasts and incubated at the air/liquid interface to allow their differentiation. Ketamine was then put on the mature urothelium using paper or agarose vectors for 48 hours. The presence of ketamine increased cells' doubling times from 1.26 days for control to 1.38 days (p = 0.14) and 1.78 days (p < 0.01) for the 0.5 mM and 1.5 mM concentrations, respectively. 5 mM and 10 mM of ketamine led to decline in the major cell population. Exposure to 5 mM ketamine induced apoptosis, confirmed by a 2.5-fold increase in capase-3 specific activity from control (p = 0.03). The structure and cellular cohesion of the urothelium on the three-dimensional model, especially in the intermediate layers, were severely affected in a concentration dependant fashion with both vectors. The presence of ketamine in the bladder directly damages the urothelium through the induction of apoptosis.


Bonding of multiple noble-gas atoms to CUO in solid neon: CUO(Ng)n (Ng=Ar, Kr, Xe; n=1, 2, 3, 4) complexes and the singlet-triplet crossover point.
Laser-ablated U atoms co-deposited with CO in excess neon produce the novel CUO molecule, which forms distinct Ng complexes (Ng=Ar, Kr, Xe) with the heavier noble gases. The CUO(Ng) complexes are identified through CO isotopic and Ng reagent substitution and comparison to results of DFT frequency calculations. The U[bond]C and U[bond]O stretching frequencies of CUO(Ng) complexes are slightly red-shifted from neon matrix (1)Sigma(+) CUO values, which indicates a (1)A' ground state for the CUO(Ng) complexes. The CUO(Ng)(2) complexes in excess neon are likewise singlet molecules. However, the CUO(Ng)(3) and CUO(Ng)(4) complexes exhibit very different stretching frequencies and isotopic behaviors that are similar to those of CUO(Ar)(n) in a pure argon matrix, which has a (3)A" ground state based on DFT vibrational frequency calculations. This work suggests a coordination sphere model in which CUO in solid neon is initially solvated by four or more Ne atoms. Up to four heavier Ng atoms successively displace the Ne atoms leading ultimately to CUO(Ng)(4) complexes. The major changes in the CUO stretching frequencies from CUO(Ng)(2) to CUO(Ng)(3) provides evidence for the crossover from a singlet ground state to a triplet ground state.


Dislocation-induced local modulation of the surface states of Ag(111) thin films on Si(111) 7 x 7 substrates.
Local modulation of the Shockley-type surface state was studied around threading dislocations at the surfaces of ultrathin Ag(111) epitaxial films on Si(111) substrates. Scanning tunneling microscope (STM) observations indicated that the wavelength of the surface state electron was shortened around the dislocations in the electron standing wave pattern. Scanning tunneling spectroscopy (STS) revealed that the bottom of the local surface state (E0) shifts downward around the dislocation. The shift in E0 and the lattice displacement Delta u(z) have a linear relation, which indicates that the shift of the surface state is caused by local relaxation of the misfit strain around the dislocation.


The Influence of Tetrodotoxin (TTX) on the Distribution and Chemical Coding of Caudal Mesenteric Ganglion (CaMG) Neurons Supplying the Porcine Urinary Bladder.
The treatment of micturition disorders creates a serious problem for urologists. Recently, new therapeutic agents, such as neurotoxins, are being considered for the therapy of urological patients. The present study investigated the chemical coding of caudal mesenteric ganglion (CaMG) neurons supplying the porcine urinary bladder after intravesical instillation of tetrodotoxin (TTX). The CaMG neurons were visualized with retrograde tracer Fast blue (FB) and their chemical profile was disclosed with double-labeling immunohistochemistry using antibodies against tyrosine hydroxylase (TH), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), calbindin (CB), galanin (GAL) and neuronal nitric oxide synthase (nNOS). It was found that in both the control (n = 6) and TTX-treated pigs (n = 6), the vast majority (92.6% ± 3.4% and 88.8% ± 2%, respectively) of FB-positive (FB+) nerve cells were TH+. TTX instillation caused a decrease in the number of FB+/TH+ neurons immunopositive to NPY (88.9% ± 5.3% in the control animals vs. 10.6% ± 5.3% in TTX-treated pigs) or VIP (1.7% ± 0.6% vs. 0%), and an increase in the number of FB+/TH+ neurons immunoreactive to SOM (8.8% ± 1.6% vs. 39% ± 12.8%), CB (1.8% ± 0.7% vs. 12.6% ± 2.7%), GAL (1.7% ± 0.8% vs. 10.9% ± 2.6%) or nNOS (0% vs. 1.1% ± 0.3%). The present study is the first to suggest that TTX modifies the chemical coding of CaMG neurons supplying the porcine urinary bladder.


Potential uses for quality-of-life measures in childhood inflammatory bowel disease.
Health-related quality of life (HRQOL) in children with inflammatory bowel disease is clearly reduced in the physical as well as in the psychological and social functioning domains. However, very few studies of these children have been performed from a quality-of-life perspective. Multicenter studies on HRQOL are needed to answer questions about the impact of Crohn's disease and ulcerative colitis and their treatment and complications on HRQOL in children and adolescents and their association with outcome. This article describes perspectives from which quality of life studies may be performed, potential uses of HRQOL measures, and issues that should be accounted for in designing multicenter clinical studies on this topic.


Enteroviral RNA in dilated cardiomyopathy.
The exact cause of dilated cardiomyopathy (DCM) remains uncertain. However, a possibility of transition from coxsackievirus-infected myocarditis to DCM has been suspected. We investigated the role of enteroviral infection in the pathogenesis of DCM. The nested reverse transcriptase polymerase chain reaction (nRT-PCR) was used to detect enteroviral RNA in 45 endomyocardial biopsy tissues obtained from 35 patients with DCM and 10 patients (controls) with other non-infectious cardiac diseases. Enteroviral RNA was detected in 17 (49%) of the 35 patients with DCM. The progression to cardiac failure was rapid, usually within 12 months, and myocardial fibrosis and myocytic hypertrophy were marked in patients that were enteroviral RNA positive. Enteroviral RNA was not detected in any controls.


Resident murine alveolar and peritoneal macrophages differ in adhesion of apoptotic thymocytes.
Apoptotic cells must be cleared efficiently by macrophages (Mø) to prevent autoimmunity, yet their ingestion impairs Mø microbicidal function. The principal murine resident lung phagocyte, the alveolar Mø (AMø), is specifically deficient at apoptotic cell ingestion, both in vitro and in vivo, compared with resident peritoneal Mø (PMø). To further characterize this deficiency, we assayed static adhesion in vitro using apoptotic thymocytes and resident AMø and PMø from normal C57BL/6 mice. Adhesion of apoptotic thymocytes by both types of Mø was rapid, specific, and cold-sensitive. Antibody against the receptor tyrosine kinase MerTK (Tyro12) blocked phagocytosis but not adhesion in both types of Mø. Surfactant protein A increased adhesion and phagocytosis by AMø, but not to the levels seen using PMø. Adhesion was largely cation-independent for PMø and calcium-dependent for AMø. Adhesion was not inhibited in either Mø type by mAbs against beta1 or beta3 integrins or scavenger receptor I/II (CD204), but AMø adhesion was inhibited by specific mAbs against CD11c/CD18. Thus, resident murine tissue Mø from different tissues depend on qualitatively disparate receptor systems to bind apoptotic cells. The decreased capacity of murine AMø to ingest apoptotic cells is only partially explained by reduced initial adhesion.


Polyaniline-assisted synthesis of Si@C/RGO as anode material for rechargeable lithium-ion batteries.
A novel approach to fabricate Si@carbon/reduced graphene oxides composite (Si@C/RGO) assisted by polyaniline (PANI) is developed. Here, PANI not only serves as "glue" to combine Si nanoparticles with graphene oxides through electrostatic attraction but also can be pyrolyzed as carbon layer coated on Si particles during subsequent annealing treatment. The assembled composite delivers high reversible capacity of 1121 mAh g(-1) at a current density of 0.9 A g(-1) over 230 cycles with improved initial Coulombic efficiency of 81.1%, while the bare Si and Si@carbon only retain specific capacity of 50 and 495 mAh g(-1) at 0.3 A g(-1) after 50 cycles, respectively. The enhanced electrochemical performance of Si@C/RGO can be attributed to the dual protection of carbon layer and graphene sheets, which are synergistically capable of overcoming the drawbacks of inner Si particles such as huge volume change and low conductivity and providing protective and conductive matrix to buffer the volume variation, prevent the Si particles from aggregating, enhance the conductivity, and stabilize the solid-electrolyte interface membrane during cycling. Importantly, this method opens a novel, universal graphene coating strategy, which can be extended to other fascinating anode and cathode materials.


Diagnosis and treatment of idiopathic facial paralysis.
Bell's palsy is a diagnosis of exclusion; other causes of facial paralysis that might be confused with Bell's palsy should be considered in order that appropriate treatment for these conditions is not delayed. Diagnostic tests for Bell's palsy are presented. Prednisone is the recommended treatment for patients with complete facial paralysis; occasionally, selected patients may require surgical decompression.


Multiple sclerosis in Canada 2011 to 2031: results of a microsimulation modelling study of epidemiological and economic impacts.
The objective of our study was to present model-based estimates and projections on current and future health and economic impacts of multiple sclerosis (MS) in Canada over a 20-year time horizon (2011-2031). Using Statistics Canada's Population Health Microsimulation Model (POHEM) framework, specifically the population-based longitudinal, microsimulation model named POHEM-Neurological, we identified people with MS from health administrative data sources and derived incidence and mortality rate parameters from a British Columbia population-based cohort for future MS incidence and mortality projections. We also included a utility-based measure (Health Utilities Index Mark 3) reflecting states of functional health to allow projections of health-related quality of life. Finally, we estimated caregiving parameters and health care costs from Canadian national surveys and health administrative data and included them as model parameters to assess the health and economic impact of the neurological conditions. The number of incident MS cases is expected to rise slightly from 4051 cases in 2011 to 4794 cases per 100 000 population in 2031, and the number of Canadians affected by MS will increase from 98 385 in 2011 to 133 635 in 2031. The total per capita health care cost (excluding out-of-pocket expenses) for adults aged 20 and older in 2011 was about $16 800 for individuals with MS, and approximately $2500 for individuals without a neurological condition. Thus, after accounting for additional expenditures due to MS (excluding out-of-pocket expenses), total annual health sector costs for MS are expected to reach $2.0 billion by 2031. As well, the average out-of-pocket expenditure for people with MS was around $1300 annually throughout the projection period. MS is associated with a significant economic burden on society, since it usually affects young adults during prime career- and family-building years. Canada has a particularly high prevalence of MS, so research such as the present study is essential to provide a better understanding of the current and future negative impacts of MS on the Canadian population, so that health care system policymakers can best plan how to meet the needs of patients who are affected by MS. These findings also suggest that identifying strategies to prevent MS and more effectively treat the disease are needed to mitigate these future impacts.


Labial fusion: A rare cause of urinary retention in reproductive age woman and review of literature.
Labial fusion usually affects prepubertal girls and postmenopausal women, it may rarely occurs in reproductive years in the absence of predisposing factors such as vulvar infections, dermatitis, trauma, female circumcision and lichen sclerosis. Should be considered in differential diagnosis in the differential diagnosis of urinary retention even if the patient doesn't have history of sexual intercourse.


Plasma brain natriuretic peptide levels, right ventricular volume overload and exercise capacity in adolescents after surgical repair of tetralogy of Fallot.
Right ventricular (RV) volume overload secondary to pulmonary regurgitation contributes to long-term morbidities in patients after tetralogy of Fallot (TOF) repair. We tested the hypothesis that plasma brain natriuretic peptide (BNP) levels relate to RV volume overload, pulmonary regurgitation, and exercise capacity in adolescents after TOF repair. We assessed the RV function echocardiographically and plasma BNP levels in 32 postoperative TOF patients aged 14.7+/-3.1 years and 20 age-matched controls. Eighteen patients further underwent cardiovascular magnetic resonance imaging and 26 had exercise testing. Compared with controls, patients had significantly higher BNP levels (p=0.027), greater indexed RV end-diastolic dimension (p<0.001), increased RV myocardial performance index (p=0.005), and reduced tricuspid annular systolic velocity (p=0.008). Multivariate analysis identified indexed RV end-diastolic dimension as the only significant determinant of plasma BNP levels (beta=0.69, p<0.001). Plasma BNP levels correlated positively with indexed RV end-diastolic volume (r=0.6, p=0.009) and pulmonary regurgitant fraction (r=0.54, p=0.026), and negatively with exercise duration (r=-0.45, p=0.021), peak oxygen consumption (r=-0.43, p=0.03), and minute ventilation at maximal exercise (r=-0.52, p=0.006). Multivariate analysis demonstrated BNP levels (beta=-0.43, p=0.034) and body mass index (beta=-0.40, p=0.036) to be independent predictors of peak oxygen consumption. No relations were found between BNP levels and RV myocardial performance index, tricuspid annular velocities and RV ejection fraction. In adolescent patients after TOF repair, plasma BNP levels relate to RV volume overload, pulmonary regurgitation and exercise capacity.


Dried plum products as a substitute for phosphate in chicken marinade.
In order to address the growing demand for more natural poultry products, alkaline phosphates commonly used in chicken breast meat marinades were replaced with plum ingredients and evaluated. For initial sensory evaluation, 200 consumers of chicken were served a small portion of the chicken breast on a plate and were asked to evaluate the product for overall impression, flavor, and texture on a 9-point hedonic scale with 1 = "dislike extremely" and 9 = "like extremely." Also, a 5-point just-about-right (JAR) scale was used on questions about tenderness, juiciness, overall flavor, and saltiness. Both hedonic and JAR demonstrated that the marinades of plum concentrate and the blend of plum fiber and powder were not distinguishable from the control (P > 0.05). Using two different percentages of fiber/powder blend, two different percentages of concentrate, sodium tripolyphosphate (STPP), and no marinade, measurements were made for marinade per cent pickup, thaw loss, and cook loss. Plum concentrate at 1.1% was most similar to STPP in marinade per cent pickup, thaw loss, drip loss, and cook loss. These results show that plum ingredients can potentially be used as a substitute in standard phosphate marinades. Consumers are increasingly demanding more natural foods with less artificial additives. This research presents the results of experiments using dried plum ingredients as a substitute for phosphates commonly used in marinades for chicken. Results indicate that dried plum ingredients may be a suitable substitute for phosphates in marinades.


[Effect of body fat percentage on estimated propofol concentrations at awakening from anesthesia using target controlled infusion].
Target controlled infusion (TCI) for propofol allows anesthesiologists to target constant blood concentrations of propofol. However, the pharmacokinetic parameters in TCI system do not take account of the patient's age, make up and gender. We evaluated the relationship between body fat percentage and the estimated effect site propofol concentrations at awakening. Anesthesia was induced in 37 patients with fentanyl and propofol by TCI. Patients's percentage of fat was evaluated by measuring the thickness of the three parts of the skin fat with Skyndex (Caldwell Justiss, USA). After surgery and discontinuation of anesthesia, the estimated effect site propofol concentrations (EPEC) were determined when the patient could respond to verbal command. The EPECs at awakening were 1.5 +/- 0.2 micrograms.ml-1 in male and 1.5 +/- 0.3 micrograms.ml-1 in female. In male, the percentage of fat and body mass index (BMI) correlated significantly with EPEC (r = 0.79 and 0.49 respectively). In female, the percentage of fat and BMI did not correlate with EPEC. The estimated fentanyl effect site concentrations at awakening did not correlate with the EPEC. Male patients who have high percentage of fat have a tendency to delayed of awakening from propofol anesthesia. In female, however, no correlation was seen between percentage of fat and awakening time from propofol anesthesia. Measuring the percentage of fat might bring a new insight into pharmacokinetics of propofol.


Early cell loss after angioplasty results in a disproportionate decrease in percutaneous gene transfer to the vessel wall.
Acute cell loss has been documented following angioplasty of normal rat and rabbit arteries. Here we analyzed the effects of balloon injury intensity on early cellular loss in single- and double-injury models and how it influences the efficiency of percutaneous gene delivery to the vessel wall. Rabbits underwent bilateral iliac angioplasties (n = 52) with 2.5-mm (balloon-to-artery [B/A] ratio, 1.08 to 1.13) and 3.0-mm (B/A ratio, 1.29 to 1.34) balloons. In the single-injury model, the 3.0-mm balloon induced a 61% reduction in medial cellularity at 3 days postinjury (p < 0.001) while the 2.5-mm balloon did not produce significant cell loss. In the double-injury model, the effects were more pronounced, with 35% (p < 0.01) and 91% (p < 0.001) reductions in medial cellularity at 3 days with the 2.5- and 3.0-mm balloons, respectively, but neointimal cellularity was decreased only with the 3.0-mm balloon (37% reduction, p = 0.025). Adenovirus-mediated beta-galactosidase gene delivery with a channel balloon (n = 24) revealed that larger balloon-to-artery ratios decreased both absolute levels and relative frequencies of transgene expression in the vessel wall. In the single-injury model, gene transfer efficiency was 4.2+/-1.1 and 1.3+/-0.25% (p < 0.05) for the small and large balloons, respectively. In the double-injury model, gene transfer efficiency was 6.6+/-1.6 and 2.3+/-0.8% (p < 0.05) in the neointima and 4.1+/-1.2 and 2.6+/-1.2% (p = NS) in the media for the small and large balloon, respectively. We conclude that early cell loss is dependent on the intensity of the injury in both single- and double-injury models of balloon angioplasty, with greater frequencies of cell loss occurring in the media than in the neointima. In both models, larger balloon-to-artery ratios result in disproportionate reductions in percutaneous adenovirus-mediated gene delivery.


On the offensive.
The government has a target of halving the number of MRSA bacteraemias by 2008. A rapid review panel is investigating new equipment, materials and products to boost infection control.


Composite islet-endothelial cell grafts: a novel approach to counteract innate immunity in islet transplantation.
An instant blood-mediated inflammatory reaction (IBMIR) is elicited when islets come in contact with blood after intraportal transplantation. In contrast, endothelial cells (EC) readily tolerate contact with blood. A conceivable strategy to overcome IBMIR would be to create composite islet-EC grafts. Human islets were co-cultured with primary human aortic endothelial cells (HAEC) for 2-7 days to obtain 50-90% coverage. HAEC-coated islets were exposed to ABO-identical blood and analyzed with regard to clotting time, signs of inflammation and cell infiltration. Composite islet-HAEC graft survival was assessed after transplantation to athymic (nu/nu) nude mice. Exposed to blood, HAEC-coated islets induced less activation of coagulation and complement compared to control islets. Also, platelet and leukocyte consumption in blood was decreased. Clots with entrapped HAEC-coated islets showed less infiltration of CD11b+ cells. The extent of protection correlated to the level of HAEC coverage. Transplanted composite grafts stained positive for insulin and PECAM-1 demonstrating presence of both islets and HAEC within the islet graft 7 weeks after transplantation. Composite islet-HAEC grafts reduce all components of IBMIR. Refinement of the technique will allow introduction of composite islet-EC grafts in clinical islet transplantation, using autologous EC expanded in vitro and kept frozen until allogeneic islets become available for that specific recipient.


Hypercalciuria in school-aged children of Rasht: a single-center study.
Hypercalciuria is the most common identifiable metabolic cause of calcium kidney calculus disease. Idiopathic hypercalciuria is defined as hypercalciuria with normal serum electrolytes levels in the absence of any known underlying disease responsible for increased urinary calcium excretion. The aim of the present survey was to study the prevalence of urinary tract signs and symptoms of idiopathic hypercalciuria in a healthy group of primary school children living in Rasht, a city in north of Iran. The prevalence of idiopathic hypercalciuria in our study was estimated to be 5.6%. This is a first report of idiopathic hypercalciuria in Guilan province.


Two new species of Annulotrema (Monogenea: Dactylogyridae) from Hydrocynus vittatus (Characiformes: Alestidae) in Lake Kariba, Zimbabwe.
Two new and one known species of Annulotrema Paperna & Thurston, 1969 are reported from the gills of the tigerfish Hydrocynus vittatus Castelnau, 1861, collected in Lake Kariba, Zimbabwe. The new species, Annulotrema pseudonili n. sp. and A. bracteatum n. sp., are described and distinguished mainly on the basis of features of the male copulatory organ (MCO). Annulotrema pseudonili n. sp. most closely resembles A. nili Paperna, 1973, but differs from it by possessing a more delicate MCO with a thin-walled base without a fibrous distal part. Annulotrema bracteatum n. sp. is most similar to Annulotrema ruahae Paperna, 1973, from which it differs by having an MCO composed of a longer copulatory tube and a leaf-shaped accessory piece enveloping the distal part of the tube. The presence of Annulotrema pikoides Guégan, Lambert & Birgi, 1988 on H. vittatus in Zimbabwe represents a new locality record for this parasite.


The prefoldin bud27 mediates the assembly of the eukaryotic RNA polymerases in an rpb5-dependent manner.
The unconventional prefoldin URI/RMP, in humans, and its orthologue in yeast, Bud27, have been proposed to participate in the biogenesis of the RNA polymerases. However, this role of Bud27 has not been confirmed and is poorly elucidated. Our data help clarify the mechanisms governing biogenesis of the three eukaryotic RNA pols. We show evidence that Bud27 is the first example of a protein that participates in the biogenesis of the three eukaryotic RNA polymerases and the first example of a protein modulating their assembly instead of their nuclear transport. In addition we demonstrate that the role of Bud27 in RNA pols biogenesis depends on Rpb5. In fact, lack of BUD27 affects growth and leads to a substantial accumulation of the three RNA polymerases in the cytoplasm, defects offset by the overexpression of RPB5. Supporting this, our data demonstrate that the lack of Bud27 affects the correct assembly of Rpb5 and Rpb6 to the three RNA polymerases, suggesting that this process occurs in the cytoplasm and is a required step prior to nuclear import. Also, our data support the view that Rpb5 and Rpb6 assemble somewhat later than the rest of the complexes. Furthermore, Bud27 Rpb5-binding but not PFD-binding domain is necessary for RNA polymerases biogenesis. In agreement, we also demonstrate genetic interactions between BUD27, RPB5, and RPB6. Bud27 shuttles between the nucleus and the cytoplasm in an Xpo1-independent manner, and also independently of microtubule polarization and possibly independently of its association with the RNA pols. Our data also suggest that the role of Bud27 in RNA pols biogenesis is independent of the chaperone prefoldin (PFD) complex and of Iwr1. Finally, the role of URI seems to be conserved in humans, suggesting conserved mechanisms in RNA pols biogenesis.


Antitumoral activity of an immunomodulatory fraction of Nocardia opaca: mechanism of action.
Immunomodulatory substances have been used as antineoplastic agents in experimental and human systems. Many of these agents were derived from microorganisms. Several biologically active fractions have been isolated from Nocardia. These derivatives were shown to induce interferon production, to activate natural killer cells and macrophages and to exert an antitumoral effect. We attempted to examine the mechanism of the antitumoral activity of the Nocardia water-soluble mitogen (NWSM). The tumor tested was the Lewis lung carcinoma (3LL). Regular histological examination and identification of the cellular immune reaction by monoclonal antibodies against macrophages (Mac 1 antigen), B- (IgG expressing) and T-lymphocytes (anti-Lyt-1), analysed by flow cytometry, were performed on samples of the tumor site and of the spleen. Intratumoral administration of the immunomodulators resulted in a massive accumulation of inflammatory cells around the tumor in mice treated with NWSM. The thick rim of infiltrating cells consisted of macrophages and lymphocytes, while the nontreated tumor was found to provoke only a scanty lymphocyte infiltration. Macrophages were, therefore, present at the tumor site and were directly implicated in the antitumoral effect of the Nocardia immunomodulator. T-lymphocytes were also observed at the site of the tumor. The spleen reaction consisted of marked extramedullary hematopoiesis and enlarged follicles containing prominent germinal centres (assessed also by a FACS-demonstrated increase in B-lymphocytes). In view of the inefficiency of chemotherapy in the treatment of advanced cancer, it is of major importance to explore alternative cancer treatment modalities. Immunotherapy is a particularly interesting alternative since it can potentially affect metastatic disease.


The porcine dendritic cell family.
Considering the pivotal roles played by dendritic cells (DCs) in both innate and adaptive immune responses, advances in the field of porcine immunology DC biology have recently progressed rapidly. As with the more extensively studied murine and human DCs, porcine DC can be generated from bone marrow haematopoietic cells or monocytes, and have been analysed in various immunological and non-immunological tissues. Both conventional DC (cDC) and plasmacytoid DC (pDC) have been characterized. The function of porcine monocyte-derived DC has not only been characterized in terms of antigen presentation and lymphocyte activation, but also their response to various ligands of pattern recognition receptors. These have been characterized in terms of the induction of DC maturation and pro-inflammatory, Th1-like or Th2-like cytokines secretion. Porcine pDC most effectively sense virus infections and are characterized by their capacity to produce large quantities of IFN-alpha and the pro-inflammatory cytokines TNF-alpha, IL-6 and IL-12. As such, the DC family as a whole is a powerful ally in the host battle against pathogen attack. Nevertheless, DC in particular tissue environments or under particular stimuli can down-regulate immune response development. This is not only important for preventing over-activation of the immune system and also for ensuring tolerance against self or "friendly" substances including food components, but may also be used as a mechanism of pathogens to evade immune responses.


Drag Reduction in a Natural High-Frequency Swinging Micro-Articulation: Mouthparts of the Honey Bee.
Worker-bee mouthparts consist of the glossa, the galeae and the vestigial labial palp, and it is these structures that enable bees to feed themselves. The articulation joints, 60∼70 µm in diameter, are present on the tip of the labial palp and are covered with olfactory sensilla, allowing movements between the segments. Using a specially designed high-speed camera system, we discovered that the articulation joint could swing in the nectar at a frequency of ∼50 Hz, considerably higher than the usual motion frequency of mammalian joints. To understand the potential drag reduction in this tiny organ, we examined its microstructure and also its surface wettability. We found that chitinous semispherical protuberances (4∼6 µm in diameter) are uniformly scattered on the surface of the joint and, moreover, that the surface is hydrophobic. We proposed a hydrodynamic model and revealed that the specialized surface can effectively reduce the mean equivalent friction (Ff) by ∼10%, through the use of protuberances immersed in the liquid feed. Theoretical results indicated that the dimensions of such protuberances are the predominant factor in minimizing Ff, and that the natural dimensions of the protuberances are close to the theoretical optimum at which friction is at a minimum. These discoveries may inspire the design of high-frequency micro-joints for engineering applications, such as in micro-stirrers.


Effect of Insulin Analogs on Frequency of Non-Severe Hypoglycemia in Patients with Type 1 Diabetes Prone to Severe Hypoglycemia: Much Higher Rates Detected by Continuous Glucose Monitoring than by Self-Monitoring of Blood Glucose-The HypoAna Trial.
Hypoglycemia is an increasingly important endpoint in clinical diabetes trials. The assessment of hypoglycemia should therefore be as complete as possible. Blinded continuous glucose monitoring (CGM) provides an improved opportunity to capture asymptomatic and nocturnal events. Here we report results from the HypoAna trial comparing all-analog-insulin therapy (aspart/detemir) with all-human-insulin therapy (neutral protamine Hagedorn/regular) on non-severe hypoglycemia (symptomatic and asymptomatic hypoglycemia) as assessed by blinded CGM and compared with data obtained by self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes and recurrent severe hypoglycemia. Fifty-three patients completed a substudy of 4 × 3 days of blinded CGM. CGM traces were reviewed for hypoglycemic events lasting 15 min or longer. At the threshold ≤3.9 mmol/L, the per-protocol analysis demonstrated a 40% rate reduction (95% confidence interval [CI] 20%-60%; P = 0.002) in nocturnal non-severe hypoglycemia during analog treatment, mainly due to a 40% rate reduction (95% CI 0%-70%; P = 0.03) of nocturnal asymptomatic hypoglycemia. Similar nonsignificant trends were seen at the glucose threshold ≤3.0 mmol/L. Overall CGM-detected that nocturnal asymptomatic hypoglycemia ≤3.9 mmol/L was ∼17 times more frequent than SMBG-detected episodes (52 vs. 3 events/patient-year). This translates into a time needed to treat one patient with insulin analogs to prevent one episode that is 34 times shorter using CGM data than SMBG data (1.4 vs. 47 weeks). Capturing hypoglycemic events by the conventional method of SMBG in patients with impaired awareness reveals only a limited number of events. Blinded CGM can provide more complete data, particularly in terms of asymptomatic and nocturnal events.


Acromegaly incidence, prevalence, complications and long-term prognosis: a nationwide cohort study.
Valid data on acromegaly incidence, complications and mortality are scarce. The Danish Health Care System enables nationwide studies with complete follow-up and linkage among health-related databases to assess acromegaly incidence, prevalence, complications and mortality in a population-based cohort study. All incident cases of acromegaly in Denmark (1991-2010) were identified from health registries and validated by chart review. We estimated the annual incidence rate of acromegaly per 10(6) person-years (py) with 95% confidence intervals (95% CIs). For every patient, 10 persons were sampled from the general population as a comparison cohort. Cox regression and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were used. Mean age at diagnosis (48.7 years (CI: 95%: 47.2-50.1)) and annual incidence rate (3.8 cases/10(6) persons (95% CI: 3.6-4.1)) among the 405 cases remained stable. The prevalence in 2010 was 85 cases/10(6) persons. The patients were at increased risk of diabetes mellitus (HR: 4.0 (95% CI: 2.7-5.8)), heart failure (HR: 2.5 (95% CI: 1.4-4.5)), venous thromboembolism (HR: 2.3 (95% CI: 1.1-5.0)), sleep apnoea (HR: 11.7 (95% CI: 7.0-19.4)) and arthropathy (HR: 2.1 (95% CI: 1.6-2.6)). The complication risk was also increased before the diagnosis of acromegaly. Overall mortality risk was elevated (HR: 1.3 (95% CI: 1.0-1.7)) but uninfluenced by treatment modality. (i) The incidence rate and age at diagnosis of acromegaly have been stable over decades, and the prevalence is higher than previously reported. (ii) The risk of complications is very high even before the diagnosis. (iii) Mortality risk remains elevated but uninfluenced by mode of treatment.


Hungarian Isradipine Study (HIS): long-term (3-year) effects on blood pressure and plasma lipids.
These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.


[A child with a fever and rash].
A 1-year-old boy with flu-like symptoms and red papules, vesicles and macules around the mouth, on the extremities, on the palms of his hands and soles of the feet was seen at the outpatient clinic. He was diagnosed with an atypical form of hand, foot, and mouth disease, which can present itself in various forms.


Ontogenic development of autoantibody repertoires in spleen and peritoneal cavity of normal mice: examples of T cell-dependent and -independent reactivities.
The ontogenic development of B cell clonal precursors (BCP) reactive to bromelain-treated, syngeneic erythrocytes (BrMRC) and to single-stranded DNA has been studied by limiting dilution of both spleen and peritoneal cells. It was found that the frequency of anti-BrMRC BCP in the spleen is very low up to 4 weeks of age and slowly increases thereafter, to reach adult levels by 6-10 weeks. In the peritoneal cavity, no such BCP can be found before 2 weeks, but they occur at a very high frequency already by 3 weeks of age. Injection of adult, normal syngeneic T cells at birth has no apparent effect on the representation of anti-BrMRC BCP in the peritoneal cavity, but brings these to adult levels or even higher in the spleen already at 3 weeks of age. Accordingly, adult athymic (nude) mice contain normal frequencies of BrMRC-specific BCP in the peritoneal cavity but are devoid of such clones in the spleen. In contrast, the frequency of anti-DNA BCP is very high throughout postnatal development in both spleen and peritoneal cavity, of normal and athymic mice, in both resting and naturally activated splenic B cell compartments, and it is independent of T cell transfers into nude animals. These results indicate the role of T cells in the establishment of some clonal specificities in the adult, splenic autoreactive B cell repertoire.


Genome Wide Scan to Identify Potential Genomic Regions Associated With Milk Protein and Minerals in Vrindavani Cattle.
In this study, genome-wide association study (GWAS) was conducted for identifying significantly associated genomic regions/SNPs with milk protein and minerals in the 96 taurine-indicine crossbred (Vrindavani) cows using 50K SNP Chip. After quality control, a total of 41,427 SNPs were retained and were further analyzed using a single-SNP additive linear model. Lactation stage, parity, test day milk yield and proportion of exotic inheritance were included as fixed effects in GWAS model. Across all traits, 13 genome-wide significant (p < 1.20 x 10-06) and 49 suggestive significant (p < 2.41 x 10-05) SNPs were identified which were located on 18 different autosomes. The strongest association for protein percentage, calcium (Ca), phosphorus (P), copper (Cu), zinc (Zn), and iron (Fe) were found on BTA 18, 7, 2, 3, 14, and 2, respectively. No significant SNP was detected for manganese (Mn). Several significant SNPs identified were within or close proximity to CDH13, BHLHE40, EDIL3, HAPLN1, INHBB, USP24, ZFAT, and IKZF2 gene, respectively. Enrichment analysis of the identified candidate genes elucidated biological processes, cellular components, and molecular functions involved in metal ion binding, ion transportation, transmembrane protein, and signaling pathways. This study provided a groundwork to characterize the molecular mechanism for the phenotypic variation in milk protein percentage and minerals in crossbred cattle. Further work is required on a larger sample size with fine mapping of identified QTL to validate potential candidate regions.


Structural characterization of agonist and antagonist-bound acetylcholine-binding protein from Aplysia californica.
Nicotinic acetylcholine receptors (nAChRs) are well-characterized allosteric transmembrane proteins involved in the rapid gating of ions elicited by ACh. These receptors belong to the Cys-loop superfamily of ligand-gated ion channels, which also includes GABAA and GABAC, 5-HT3, and glycine receptors. The nAChRs are homo- or heteromeric pentamers of structurally related subunits that encompass an extracellular N-terminal ligand-binding domain, four transmembrane-spanning regions that form the ion channel, and an extended intracellular region between spans 3 and 4. Ligand binding triggers conformational changes that are transmitted to the transmembrane-spanning region, leading to gating and changes in membrane potential. The four transmembrane spans on each of the five subunits create a substantial region of hydrophobicity that precludes facile crystallization of this protein. However the freshwater snail, Lymnaea stagnalis, produces a soluble homopentameric protein, termed the ACh-binding protein (AChBP), which binds ACh (Smit et al., 2001). Its structure was determined recently (Brejc et al., 2001) at high resolution, revealing the structural scaffold for nAChR, and has become a functional and structural surrogate of the nAChR ligand-binding domain. We have characterized an AChBP from Aplysia californica and determined distinct ligand-binding properties when compared to those of L. stagnalis, including ligand specificity for the nAChR alpha7 subtype-specific alpha-conotoxin ImI (Hansen et al., 2004).


Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.
This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.


MicroRNA-1285 inhibits malignant biological behaviors of human pancreatic cancer cells by negative regulation of YAP1.
Pancreatic ductal adenocarcinoma is a most deadly malignancy, with a 5-year survival rate of ~7%. Chemotherapy is the main treatment strategy of this disease. However, the high rate of resistance to chemotherapeutic agent contributes to poor prognosis. MicroRNAs are essential for the initiation, progression and chemoresistance of human malignancies. Previous studies have shown that miRNA-1285 participates in renal cell carcinoma and hepatocellular carcinoma. However, its roles in pancreatic ductal adenocarcinoma are poorly understood. In this study, we confirmed that miR-1285 was significantly down-regulated in gemcitabine-resistant pancreatic cancer cell lines by qRT-PCR. We found that miR-1285 suppressed cell proliferation as well as increased the sensitivity of PDAC cells to gemcitabine by CCK8 assays in vitro. Results from transwell assay indicated that miR-1285 inhibited pancreatic cancer cell migration and invasion. Experiments using different cell lines got identical results. All those results demonstrated that miR-1285 act as tumor suppressor of pancreatic cancer. To our knowledge, this study is the first to elucidate the function of miR-1285 in pancreatic cancer. Western blotting analysis verified that miR-1285 negatively regulated YAP1 protein level, together with EGFR and β-catenin. YAP1 is a known oncoprotein of pancreatic cancer. As silencing of YAP1 activity might be beneficial in cancer prevention and treatment, our results suggest that miR-1285 might serve as a novel therapeutic target for miRNA-based therapy in pancreatic cancer. Further research elucidating the exact mechanisms of miRNA-1285 function and the correlation between miR-1285 levels in tissues or serum and clinical characteristics of pancreatic cancer is needed later.