Changes in admission to long-term care institutions in the Netherlands: comparing two cohorts over the period 1996-1999 and 2006-2009.
Using data from two cohorts, we examine to what extent a decline in institutional care in the Netherlands is associated with changes in the need for care and/or societal factors. We compared older adults, aged 65-89, who were admitted to a long-term care (LTC) institution in the period 1996-1999 and 2006-2009. Using the Andersen model, we tested per block of predisposing, enabling and need factors, which factors were significant predictors of admission to institutional care. With a Blinder-Oaxaca decomposition regression, we decomposed the difference in admission to an LTC institution between the period 1996-1999 and 2006-2009 into a part that is due to differences in health needs and other factors such as effect of policy, social values, and technology. Between 1996 and 2006, the percentage of co-residing partners and income increased and the average level of loneliness decreased significantly. The prevalence of disability, chronic diseases, however, increased. Whereas the care by partners declined, the formal care by professionals increased. Although the observed decline in the admission rate to institutional care was relatively small across the 10 years (from 5.3 % in 1996-1999 to 4.5 % in 2006-2009, a 15 % decrease), the probability of admission in 2006-2009 was relatively much lower when accounting for changes in the health and social conditions of the participants: the probability was 1.7-2.1 % point lower for adults in the period 2006-2009 compared to 1996-1999, a 32-40 % decrease. Our results show that the decline in the admission rate to LTC institutions is not the result of changes in need. The decline is suggested to be the combined effect of changes in policy, technological advances and changes in social norms.


miRNA-34c Overexpression Causes Dendritic Loss and Memory Decline.
Microribonucleic acids (miRNAs) play a pivotal role in numerous aspects of the nervous system and are increasingly recognized as key regulators in neurodegenerative diseases. This study hypothesized that miR-34c, a miRNA expressed in mammalian hippocampi whose expression level can alter the hippocampal dendritic spine density, could induce memory impairment akin to that of patients with Alzheimer's disease (AD) in mice. In this study, we showed that miR-34c overexpression in hippocampal neurons negatively regulated dendritic length and spine density. Hippocampal neurons transfected with miR-34c had shorter dendrites on average and fewer filopodia and spines than those not transfected with miR-34c (control mice). Because dendrites and synapses are key sites for signal transduction and fundamental structures for memory formation and storage, disrupted dendrites can contribute to AD. Therefore, we supposed that miR-34c, through its effects on dendritic spine density, influences synaptic plasticity and plays a key role in AD pathogenesis.


The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells.
A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from -1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, beta-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at -20 and -217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of beta-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the -20 and -217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.


Ion conducting polymer microelectrodes for interfacing with neural networks.
We have examined the stimulation and recording properties of conjugated polymer microelectrode arrays as interfaces with neural networks of dissociated cortical cells. In particular the stimulation properties were investigated as a means of supplying a neural network with information. The stimulation efficiency at low stimulation voltages was evaluated and referenced to bare indium tin oxide (ITO) electrodes. The polymer electrodes were electrochemically polymerized from a blend of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) and ethylenedioxythiophene (EDOT) onto ITO microelectrodes. Dissociated cortical cells were then plated on the electrodes and cultivated to form neural networks. Polymer electrode stimulation evoked a much greater response from the network than stimulation from ITO electrodes. Neural interfaces using polymer electrodes could be maintained for several months.


Fragmentation of brain apolipoprotein E (ApoE) and its relevance in Alzheimer's disease.
Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs) of neurons and senile plaques in the neuropil. After aging, the inheritance of the apolipoprotein E (ApoE) epsilon 4 (ε4) allele is the greatest risk factor for late-onset AD. The ApoE protein is the translated product of the ApoE gene. This protein undergoes proteolysis, and the resulting fragments colocalize with neurofibrillary tangles and amyloid plaques, and for that matter may be involved in AD onset and/or progression. Previous studies have reported the pathogenic potential of various ApoE fragments in AD pathophysiology. However, the pathways activated by the fragments are not fully understood. In this review, ApoE fragments obtained from post-mortem brains and body fluids, cerebrospinal fluid (CSF) and plasma, are discussed. Additionally, current knowledge about the process of fragmentation is summarized. Finally, the mechanisms by which these fragments are involved in AD pathogenesis and pathophysiology are discussed.


[Influence of bacterial infection during ovalbumin induced experimental asthma in guinea pigs].
The pathomechanism of bronchial asthma is not fully explained. The immunologic reactions in the bronchial epithelium may be better understood by an experimental approach in laboratory animals. Ovalbumin induced asthma in guinea pigs is widely accepted as an experimental model of bronchial asthma and was applied in this study. The bronchoconstriction, bronchial hypersensitivity and humoral immune response were measured after bronchial infection (intranasal Pseudomonas aeruginosa application). The increase of the bronchospastic reaction and bronchial hypersensitivity was observed after intranasal Pseudomonas aeruginosa application. Bacterial infection lead to the increase of the circulating immune complexes level and to the decrease of the haemolytic activity of the complement in serum.


Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.


Post-translational integration and oligomerization of connexin 26 in plasma membranes and evidence of formation of membrane pores: implications for the assembly of gap junctions.
Gap-junction channels provide a widespread intercellular signalling mechanism. They are constructed of a family of connexin membrane proteins that thread across the membrane four times and oligomerize to generate hexameric gap-junction hemichannels. Using an in vitro cell-free transcription/translation system, we demonstrate that connexin (Cx) 26, one of the smallest connexins, is integrated directly in a post-translational manner into plasma membranes. Protein-cleavage studies of Cx26 integrated into plasma membranes indicate a similar native transmembrane topography to that of Cx26 integrated co-translationally into microsomes. Cx26 integrated post-translationally into plasma membranes oligomerizes and, when incorporated into liposomes, provides permeability to ascorbic acid, suggesting that gap-junction hemichannels are generated. The results provide the basis of a novel alternative mechanism for spontaneous assembly in plasma membranes of Cx26 gap-junction hemichannels that occurs independently of the conventional biogenesis of gap junctions involving connexin trafficking and oligomerization via membrane components of the secretory pathway.


The Effect of Vitamin D Supplementation on Lipid Profiles: an Umbrella Review of Meta-Analyses.
According to published meta-analyses, vitamin D exerts different beneficial effects in preventing and controlling risk factors associated with noncommunicable chronic diseases; however, the results are still conflicting. The purpose of this umbrella meta-analysis was to investigate the effect of vitamin D supplementation on low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol (TC), and triglyceride (TG) as components of the lipid profile. PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews were systematically searched for meta-analyses of randomized controlled trials. The umbrella meta-analysis followed the PRISMA guidelines. The random-effects model was employed to estimate the overall effect size (ES). Overall, 25 meta-analyses were included. In the standardized mean difference analysis, vitamin D significantly decreased TG (ES: -0.15; 95% CI: -0.23, -0.08; P ≤ 0.001) and TC levels (ES: -0.17; 95% CI: -0.23, -0.11; P ≤ 0.001) and increased HDL levels (ES: 0.08; 95% CI: 0.01, 0.15; P = 0.025). In the weighted mean difference analysis, vitamin D significantly decreased only TG levels (ES: -4.63 mg/dL; 95% CI: -7.70, -1.57; P = 0.003). The present study supports that vitamin D supplementation could be considered a beneficial adjuvant therapy in managing lipid profile levels, especially in individuals with vitamin D deficiency. This systematic review was registered in PROSPERO as CRD42022306334.


Hypertension induced by nitric oxide synthase inhibitor increases responsiveness of ventricular myocardium and aorta of rat tissue to adrenomedullin stimulation in vitro.
In this work, we aimed to observe the changes in adrenomedullin (ADM) and its receptor-calcitonin receptor-like receptor (CL), receptor activity-modifying protein (RAMP) 1, RAMP2 and RAMP3-in cardiac ventricles and aortas of hypertensive rats, and the responsiveness of injured cardiovascular tissue to ADM, then to illustrate the protective mechanism of ADM on the cardiovascular system. Male SD rats were subjected to treatment with chronic N(G)-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. The ADM contents and cAMP production in myocardia and aortas were measured by RIA. The mRNA levels of ADM, CL, and RAMP1-3 were determined by RT-PCR. L-NNA induced severe hypertension and cardiomegaly. The ir-ADM content in plasma, ventricles and aortas in L-NNA-treated animals increased by 80%, 72% and 57% (all p<0.01), respectively. Furthermore, mRNA levels of ADM, CL, RAMP2 and RAMP3 were elevated by 91%, 33%, 50% and 72.5% (all p<0.01), respectively, in ventricles and by 95%, 177%, 74.7% and 85% (all p<0.01), respectively, in aortas. mRNA level of RAMP1 was elevated by 129% (p<0.01) in aortas but no significant difference in ventricles. The elevated mRNA levels of RAMP2 and RAMP3 were positively correlated with that of ADM in hypertrophic ventricles (r=0.633 and 0.828, p<0.01, respectively) and the elevated mRNA levels of CL, RAMP2 and RAMP3 were positively correlated with that of ADM in aortas (r=0.941, 0.943 and 0.736, all p<0.01, respectively). The response of ventricular myocardia and aortas to ADM administration potentiated, and the production of cAMP was increased by 41% and 68% (both p<0.01), respectively. ADM-stimulated cAMP generation in ventricular myocardia and aortas was blocked by administration of both ADM22-52, the specific antagonist of ADM receptor, and CGRP8-37, the antagonist of the CGRP1 receptor. The results showed an increased in cardiovascular ADM generation and an up-regulation of the gene expression of ADM and its receptor-CL, RAMP1-3 during hypertension, augmented responsiveness of ventricular myocardia and aortas of hypertensive rats to ADM, suggesting that these receptors may play a role in the cardiovascular adaptation in response to sub-chronic NO-inhibition.


Multidrug resistance and integron carriage in clinical isolates of Pseudomonas aeruginosa in Tehran, Iran.
Pseudomonas aeruginosa is the cause of 10% of hospital-acquired infections. The organisms are often multidrug- resistant, mediated mostly by antibiotic-resistant integrons. The aim of this research was to study integron carriage and its association with multidrug resistance in burn and nonburn clinical isolates of P. aeruginosa. A total of 112 P. aeruginosa clinical isolates were collected from the Motahari and Shohadaye Tajrish hospitals in Tehran between July and December 2011. Antibiotic susceptibility to 13 antibiotics was determined by disk diffusion. Detection of integron classes 1 and 2 and amplifications of internal variable regions (IVRs) of class 1 integrons were carried out by PCR and specific primers. Among the 112 isolates, 77 were from burn patients and 35 were nonburn isolates. Multidrug resistance and class 1 integron carriage were both significantly higher in the burn isolates compared to the nonburn strains (97.4% vs. 22.8% and 82.3% vs. 17.7%, respectively). Class 2 integron (2.7%) was only present in the burn isolates. Amplification of IVRs of class 1 integrons revealed 3 different fragment arrays. The significant association between multidrug resistance and integron carriage among P. aeruginosa burn isolates suggests a dissemination of resistance determinants by horizontal gene transfer.


Trunk Strength Characteristics of Elite Alpine Skiers - a Comparison with Physically Active Controls.
Core muscle imbalances and weak trunk strength are relevant for injury prevention and performance. Information regarding core strength requirements and ideal flexion/extension ratios in alpine skiing is limited. We aimed to compare trunk strength capacities in elite alpine skiers with those of a matched control group. The concentric maximal trunk flexion and extension of 109 elite skiers and 47 active controls were measured at 150°/s in a ballistic mode using the CON-TREX® TP 1000 test system. The relative flexion peak torque was higher in male ski racers (p = 0.003; 2.44 ± 0.30 Nm/kg) than in the controls (2.32 ± 0.42 Nm/kg). The relative peak torque for extension was 4.53 ± 0.65 Nm/kg in ski racers and 4.11 ± 0.52 Nm/kg in the controls (p = 0.001). Female athletes were significantly stronger in both, relative flexion force (p = 0.006; skiers 2.05 ± 0.22 Nm/kg; controls 1.74 ± 0.28 Nm/kg) and relative extension force (p = 0.001; skiers 3.55 ± 0.53 Nm/kg; controls 3.14 ± 0.48 Nm/kg). No significant differences were found in the ratios of flexion to extension forces in females and males. Ski racers are engaged in extensive strength training for both leg and trunk muscles, which explains the higher peak values. Both groups indicated a low ratio from 0.54-0.59, which represents high trunk extensor muscles strength relative to flexor muscles.


Chemotherapy for pulmonary large cell neuroendocrine carcinomas: does the regimen matter?
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is rare. Chemotherapy for metastatic LCNEC ranges from small cell lung carcinoma (SCLC) regimens to nonsmall cell lung carcinoma (NSCLC) chemotherapy regimens. We analysed outcomes of chemotherapy treatments for LCNEC.The Netherlands Cancer Registry and Netherlands Pathology Registry (PALGA) were searched for patients with stage IV chemotherapy-treated LCNEC (2003-2012). For 207 patients, histology slides were available for pathology panel review. First-line platinum-based combined chemotherapy was clustered as "NSCLC-t", comprising gemcitabine, docetaxel, paclitaxel or vinorelbine; "NSCLC-pt", with pemetrexed treatment only; and "SCLC-t", consisting of etoposide chemotherapy.A panel review diagnosis of LCNEC was established in 128 out of 207 patients. NSCLC-t chemotherapy was administered in 46% (n=60), NSCLC-pt in 16% (n=20) and SCLC-t in 38% (n=48) of the patients. The median (95% CI) overall survival for NSCLC-t chemotherapy was 8.5 (7.0-9.9) months, significantly longer than patients treated with NSCLC-pt, with a median survival of 5.9 (5.0-6.9) months (hazard ratio 2.51, 95% CI 1.39-4.52; p=0.002) and patients treated with SCLC-t chemotherapy, with a median survival of 6.7 (5.0-8.5) months (hazard ratio 1.66, 95% CI 1.08-2.56; p=0.020).In patients with LCNEC, NSCLC-t chemotherapy results in longer overall survival compared to NSCLC-pt and SCLC-t chemotherapy.


Delayed implantation in congenitally deaf children and adults.
To determine the efficacy of cochlear implants with current processing strategies in children and adults with long-term congenital deafness, and to determine whether the growth of auditory perceptual skills in these patients is similar to the data reported for patients who have undergone implantation with earlier devices and coding strategies. A prospective study of children and adults fulfilling the study inclusion criteria. University medical center. Thirty-five congenitally deaf children who received implants after the age of 8 years and 14 congenitally deaf adults who received implants as adults participated in this study. Length of device use ranged from 6 months to 3 years. Open set phoneme, word recognition tests, and sentence recognition tests were administered in quiet and noise auditory only conditions preoperatively and postoperatively. Changes in test scores were examined by paired t tests, and differences between groups were compared by Student's t tests. Spearman correlation coefficients were calculated to identify associations between scores and subject characteristics. A two-sided alpha of less than 0.05 was considered statistically significant. The results indicated significant improvement in open set speech perception skills in the children after implantation; the adults demonstrated improved mean scores on both word and sentence recognition. A shorter length of deafness correlated with better postoperative performance, but all subjects continued to improve over time. The improvement in test scores was similar between the devices, and no significant differences were detected between the different processing strategies. Children and adults with long-term congenital deafness can obtain considerable open set speech understanding after implantation. Length of deafness (age at implantation), length of device use, and mode of communication contribute to outcome.


Varying intensities of chronic stress induce inconsistent responses in weight and plasma metabolites in house sparrows (Passer domesticus).
One of the biggest unanswered questions in the field of stress physiology is whether variation in chronic stress intensity will produce proportional (a gradient or graded) physiological response. We were specifically interested in the timing of the entrance into homeostatic overload, or the start of chronic stress symptoms. To attempt to fill this knowledge gap we split 40 captive house sparrows (Passer domesticus) into four groups (high stress, medium stress, low stress, and a captivity-only control) and subjected them to six bouts of chronic stress over a 6-month period. We varied the number of stressors/day and the length of each individual bout with the goal of producing groups that would experience different magnitudes of wear-and-tear. To evaluate the impact of chronic stress, at the start and end of each stress bout we measured body weight and three plasma metabolites (glucose, ketones, and uric acid) in both a fasted and fed state. All metrics showed significant differences across treatment groups, with the high stress group most frequently showing the greatest changes. However, the changes did not produce a consistent profile that matched the different chronic stress intensities. We also took samples after a prolonged recovery period of 6 weeks after the chronic stressors ended. The only group difference that persisted after 6 weeks was weight-all differences across groups in metabolites recovered. The results indicate that common blood metabolites are sensitive to stressors and may show signs of wear-and-tear, but are not reliable indicators of the intensity of long-term chronic stress. Furthermore, regulatory mechanisms are robust enough to recover within 6 weeks post-stress.


The bidirectional association of nonalcoholic fatty liver disease with depression, bipolar disorder, and schizophrenia.
Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic-inflammatory disease associated with poor outcomes and decreased quality of life. NAFLD is overrepresented in patients with psychiatric disorders like depression, bipolar disorder, and schizophrenia; however, a comprehensive review on NAFLD and psychiatric disorders remains to be delineated. This review endeavors to investigate the association of NAFLD with psychiatric disorders, including shared pathogenesis and future clinical derivatives. Extant literature suggests that patients with psychiatric disorders (in particular, mood disorders) are more susceptible to the development of NAFLD due to multiple reasons, including but not limited to hypothalamic-pituitary-adrenal axis dysregulation, metabolic syndrome, and chronic perceived stress. Moreover, the clinical manifestations of mood disorders (e.g., anhedonia, psychomotor retardation, lifestyle modification, etc.), and potentially long-term treatment with weight-gaining agents, differentially affect these patients, making them more prone to NAFLD. Considering the increased morbidity associated with both mood disorders and NAFLD, our review recommends regular screenings for NAFLD in select patients with mood disorders exhibiting signs of increased risk (i.e., obesity, metabolic syndrome, diabetes, or family history of NAFLD) for better diagnosis and holistic care of both potentially interrelated conditions.


Formulation of Biopharmaceutical Dry Powder Inhaler Using the Void Forming Index (VFI) to Detect and Avoid Powder Caking in Dry Powder Inhaler Formulations.
It is mandatory to detect the powder cohesiveness of biopharmaceutical dry powder inhaler (Bio-DPI) formulations and their effect on their performance. Normally, Bio-DPI formulations consist of highly cohesive components with higher drug amounts than small molecules. Herein, a formulation study of a high-drug-ratio Bio-DPI was performed, detecting the risk of powder caking in DPI formulations. The Bio-DPI formulation was manufactured via the spray-dry method followed by mixing with excipients. Powder caking was detected through the void forming index (VFI), which was calculated using pressure drop measured by inverse gas chromatography (iGC). Since VFI can be used to evaluate the structural changes induced by powder caking over time with less than 1 g of sample, VFI is considered suitalbe to apply for DPI formulation screening. The risk of powder caking was detected in spray dryed particles at more than 45% relative humidity (RH) humidity condition, mannitol (as a carrier particle) and magnesium stearate (as a lubricant) were added to the formulations. With formulation screening, addition of more than 40% of mannitol was suggested to reduce the risk of powder caking. Selected DPI formulation remained higher emitted ratio (95.6%), than spray dried particle (52.5%) at 25 °C 65% RH condition for 1-month storage. In conclusion, VFI measurement is useful for selecting the DPI formulation by mitigating powder caking risk with limited samples.


Expression and muscarinic receptor coupling of Lyn kinase in cultured human airway smooth muscle cells.
Src family tyrosine kinases are signaling intermediates in a diverse array of cellular events including cell differentiation, motility, proliferation, and survival. In nonairway smooth muscle cells, muscarinic receptors directly interact with Src family tyrosine kinases. As little is known about the expression and signaling of these Src family tyrosine kinases in human airway smooth muscle cells, we determined the expression of Src family members and characterized the muscarinic receptor-mediated activation of Lyn kinase in these cells. RT-PCR revealed mRNA transcripts for FYN, c-SRC, YES, FRK, and LYN. Fyn, c-Src, Yes, and Lyn were identified in cultured airway smooth muscle cells by immunoblot analysis. In both nontransformed human cultured airway smooth muscle cells and cells transduced with wild-type human Lyn kinase, carbachol increased Lyn kinase activity. Pertussis toxin pretreatment failed to block carbachol activation of Lyn kinase but did attenuate the carbachol-induced increase in ERK/MAPK phosphorylation. Moreover, carbachol inhibited adenylyl cyclase but failed to increase total inositol phosphate synthesis in these cells. The present study shows that Lyn kinase is expressed in human cultured airway smooth muscle cells at both the mRNA and protein levels and that carbachol, an M2 muscarinic receptor agonist in these cells, activates Lyn kinase by a pertussis toxin-insensitive signaling pathway.


The Combination of Rituximab and Bendamustine as First-Line Treatment Is Highly Effective in the Eradicating Minimal Residual Disease in Follicular Lymphoma: An Italian Retrospective Study.
R-Bendamustine is an effective treatment for follicular lymphoma (FL). Previous large trials demonstrated the prognostic role of the molecular minimal residual disease (MRD) during the most frequently adopted chemotherapeutic regimens, but there are not yet conclusive data about the effect of combination of rituximab (R) and bendamustine in terms of MRD clearance. Thus, the aim of this retrospective study was to assess if and in what extent the combination of rituximab and bendamustine would exert a significant reduction of the molecular disease in 48 previously untreated FL patients. The molecular marker at baseline was found in the 62.5% of cases; no significant differences were observed between patients with or without the molecular marker in respect of the main clinical features. Moreover, the quantization of the baseline molecular tumor burden showed a great variability: the median value was 1.4 × 10-2 copies, ranging from 3 × 10-5 to 4 × 104. The initial molecular tumor burden did not correlate with clinical features and did not impact on the subsequent quality of response. After treatment, 93% of cases became MRD-negative; the median reduction of the BCL2/JH load was 4 logs. The 2-years PFS was 85%; it was significantly longer for patients in complete than for those in partial response (91 vs. 57%; p = 0.002), and for cases with lower FLIPI-2 score (88 vs. 60%; p = 0.004). On the contrary, PFS did not differ between patients with or without the molecular marker at baseline; a molecular tumor burden 15 times higher was observed in the relapsed subgroup in comparison to the relapse-free one, but this difference did not change the PFS length. The 2-years OS was 93.6%; the only variable that significantly impacted on it was the FLIPI-2 score; the presence of the molecular marker at baseline or its behavior after treatment did not impact on survival. This study, even if retrospective and conducted on a small series of patients, would represent a proof of concept that R-bendamustine is able to so efficaciously eradicate MRD that it could be able to by-pass the prognostic significance of MRD already demonstrated for other chemotherapeutic regimens in FL.


Abnormal immune responses in persons with previous extrapulmonary tuberculosis in an in vitro model that simulates in vivo infection with Mycobacterium tuberculosis.
Persons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4(+) lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related to Mycobacterium tuberculosis infection of macrophages have not been characterized. The objective of this study was to further characterize the in vitro immune responses to M. tuberculosis infection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n = 11), previous pulmonary tuberculosis (n = 21), latent M. tuberculosis infection (n = 19), and uninfected tuberculosis contacts (n = 20). Experimental conditions included M. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1β (IL-1β), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) were measured by multiplex cytokine array. When M. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-γ (P = 0.01), TNF-α (P = 0.04), IL-10 (P < 0.001), and IL-6 (P = 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latent M. tuberculosis infection. A similar pattern was observed with CXCL8 (P = 0.04), IL-10 (P = 0.02), and CCL2 (P = 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation with M. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response to M. tuberculosis infection.


Changing the balance of power in American medicine.
Representation and competition, as democratic and market strategies, have been of small consequence in producing significant improvement in medical care. Membership in an HMO is a greater source of consumer power than is representation in an HSA. Regulation and competition will continue to have limited--often ironic and incoherent--results in the absence of new institutional structures for reform.


Endophthalmitis caused by Moraxella osloensis.
To report the clinical presentation, antibiotic sensitivities, and treatment outcomes of endophthalmitis caused by Moraxella osloensis. retrospective review of the medical records of all patients treated for endophthalmitis at Bascom Palmer Eye Institute between 1 January 1991 and 31 December 2000. During the study interval, 757 eyes were treated for endophthalmitis. Moraxella osloensis was isolated from three eyes of two patients (3/757, or 0.39%). In all three eyes, the endophthalmitis was delayed-onset and bleb-associated; Moraxella osloensis was isolated on chocolate agar and 5% sheep's blood agar using a RapNH commercial Kit (by Remel) through an automated system (Vitek). Like most gram-negative organisms, Moraxella was sensitive to ceftazidime, ciprofloxacin, and the aminoglycosides. Although vision at presentation was poor, both patients regained baseline vision after treatment with pars plana vitrectomy and injection of intravitreal antibiotics. To our knowledge, this is the first report of endophthalmitis caused by Moraxella osloensis. Unlike most series of delayed-onset, bleb-associated endophthalmitis the visual prognosis following treatment for endophthalmitis caused by Moraxella osloensis appears to be generally favorable.


A method to evaluate the tensile strength and stress-strain relationship of carbon nanofibers, carbon nanotubes, and C-chains.
A method is introduced to assess the tensile strength of carbon nanofibers, carbon nanotubes (CNTs), and linear chains of carbon atoms (C-chains) obtained from thin amorphous carbon films by electron irradiation. Transmission electron microscopy images show that the nanofibers undergo a radiation-induced necking process, characterized by CNT formation and often followed by the formation of a C-chain. Simulations of the necking process are carried out to determine the tensile stress supported by the nanofiber and CNT neck.


Urinary tract infections in pregnant women with bacterial vaginosis.
Our purpose was to investigate the risk of urinary tract infections in pregnant women with bacterial vaginosis. In a cross-sectional study, 503 pregnant women were examined for bacterial vaginosis and urinary tract infections from July 1999 through April 2000. Nineteen (13.6%) of 140 women who had bacterial vaginosis had urinary tract infections compared with 24 (6.6%) of 363 women without it. Bacterial vaginosis in pregnancy was associated with an increased risk for urinary tract infections (odds ratio 2.21, 95% CI 1.16-4.18). Pregnant women with bacterial vaginosis are more likely to have urinary tract infections.


The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression.
T lymphocytes undergo apoptosis in response to cellular stress, including UV exposure and gamma irradiation. However, the mechanism by which stress stimuli induce apoptosis is not well understood. While stress stimuli induce the activation of the c-Jun N-terminal kinase (JNK) pathway, it is not clear whether the JNK cascade is activated as a result of cell death or whether the cascade participates in inducing apoptosis. Using a Jurkat T cell line transfected with dominant active (DA)-mitogen-activated protein kinase kinase kinase (MEKK1) in a tetracycline-regulated expression system, we found that expression of DA-MEKK1 results in the apoptosis of Jurkat cells in parallel with prolonged JNK activation. Moreover, DA-MEKK1 induced Fas ligand (FasL) cell surface and mRNA expression, as well as FasL promoter activation. Interference with Fas/FasL interaction prevented DA-MEKK1-mediated apoptosis. In comparing the effect of different stress stimuli to DA-MEKK1, we found that UV, gamma irradiation, and anisomycin prolonged JNK activation in parallel with FasL expression and onset of cell death. In addition, these stimuli also enhance cell surface expression of FasL. Interference with Fas/FasL interactions inhibited anisomycin but not UV- or gamma irradiation-induced apoptosis. Our data show that while the JNK pathway contributes to stress-induced apoptosis in T lymphocytes by regulating FasL expression, not all stress stimuli use the same cell death pathway.


Big Data-Driven Vocational Undergraduate Talent Training and Social Needs Adaptability Analysis and Collaborative Path Mining.
Aiming at the problem of mismatch between talent cultivation and social demand in the process of undergraduate education, this paper proposes a big data-driven method of adaptability analysis and collaborative path mining between vocational undergraduate talent cultivation and social demand. Starting from the big data-driven vocational undergraduate talent training and social needs, this paper points out the problems existing in the current social needs and puts forward the basic framework of vocational undergraduate talent training mode. Secondly, the clustering model of talent training and social demand is analyzed, and the clustering mining method is proposed. Finally, the big data-driven personnel training and social adaptation mining analysis, in their own ability and social needs adaptability analysis, the basic adaptation accounted for a higher proportion. Professional competence has a higher trust value in cluster analysis. Today's social employment situation is becoming more and more severe, and how to enhance the quality of profession undergraduate students has become one of the theoretical and practical issues worthy of attention in China's colleges at this stage. The talent training model of colleges and universities is closely in route with the demands of society, and the problem of student hire is prominent. Therefore, this paper proposes a student employability training program that combines the elements of student employability through social needs research.


Ant behavioral maturation is mediated by a stochastic transition between two fundamental states.
The remarkable ecological success of social insects is often attributed to their advanced division of labor, which is closely associated with temporal polyethism in which workers transition between different tasks as they age. Young nurses are typically found deep within the nest where they tend to the queen and the brood, whereas older foragers are found near the entrance and outside the nest.1-3 However, the individual-level maturation dynamics remain poorly understood because following individuals over relevant timescales is difficult; hence, previous experimental studies used same-age cohort designs.4-15 To address this, we used an automated tracking system to follow >500 individuals over >100 days and constructed networks of physical contacts to provide a continuous measure of worker social maturity. These analyses revealed that most workers occupied one of two steady states, namely a low-maturity nurse state and a high-maturity forager state, with the remaining workers rapidly transitioning between these states. There was considerable variation in the age at transition, and, surprisingly, the transition probability was age independent. This suggests that the transition is largely stochastic rather than a hard-wired age-dependent physiological change. Despite the variation in timing, the transition dynamics were highly stereotyped. Transitioning workers moved from the nurse to the forager state according to an S-shaped trajectory, and only began foraging after completing the transition. Stochastic switching, which occurs in many other biological systems, may provide ant colonies with robustness to extrinsic perturbations by allowing the colony to decouple its division of labor from its demography.


Analytical potential of fluorescein analogues for ultrasensitive determinations of phosphorus-containing amino acid herbicides by micellar electrokinetic chromatography with laser-induced fluorescence detection.
The analytical potential of three fluorescein analogues, fluorescein isothiocyanate isomer I (FITC), 5-(4,6-dichlorotriazinylamino) fluorescein (DTAF) and 5(6)-carboxyfluorescein N-succinimidyl ester (CFSE), as labelling reagents for the ultrasensitive determination of phosphorus-containing amino acid herbicides (glufosinate and glyphosate) and aminomethylphosphonic acid (the major metabolite of glyphosate) by nonionic surfactant micellar electrokinetic chromatography (MEKC) with laser-induced fluorescence (LIF) detection was investigated. Practical aspects related to label chemistry and MEKC separation showed that DTAF is the best choice for the determination of these herbicides; in addition, the most important features of these reagents for the derivatization of amino compounds are discussed. The optimum procedure includes a derivatization step of the herbicides at 40 degrees C with DTAF for 1 h and a 2-fold dilution prior to MEKC analysis, which is conducted within about 10 min using Brij-35 in the running buffer. This nonionic surfactant improves the selectivity and therefore the sensitivity of the method at low analyte concentrations by shifting the interfering peaks of the DTAF excess. The lowest detectable analyte concentration ranged from 0.06 to 0.16 microg/L with a precision of 2.1-3.2%. These results indicate that nonionic surfactant MEKC-LIF is useful as a selective, rapid and sensitive tool for the determination of these herbicides showing a great potential for their analysis in environmental samples without previous enrichment steps. The proposed method surpasses other chromatographic alternatives in terms of limit of detection and sample requirements for the analysis.


Seoul Virus Infection in Humans, France, 2014-2016.
We report detection of Seoul virus in 3 patients in France over a 2-year period. These patients accounted for 3 of the 4 Seoul virus infections among 434 hantavirus infections (1.7%) reported during this time. More attention should be given to this virus in Europe where surveillance has been focused mostly on Puumala and Dobrava-Belgrade hantaviruses.


Neuropsychological rehabilitation after closed head injury in young adults.
Cognitive and personality disturbances following severe closed head injury in young adults are associated with poor rehabilitation outcome. Yet systematic programmes for dealing with these disturbances have generally not appeared. The present report briefly describes the Neuropsychological Rehabilitation Program (NRP) at Presbyterian Hospital in Oklahoma City and the initial outcome data on eighteen closed head injury patients and seventeen untreated controls. Greater improvement in neuropsychological functioning occurred in the NRP patient group on selected variables, but generally the effects were modest. Emotional distress, however, substantially decreased in treated patients. Fifty percent of the NRP patients maintained productivity 75% of the time or more following rehabilitation, compared to 36% of the controls. Treatment successes showed less personality disturbances than treatment failures and better learning and memory scores post-treatment.


KOtBu-Mediated, Three-Component Coupling Reaction of Indoles, [60]Fullerene, and Haloalkanes: One-Pot, Transition-Metal-Free Synthesis of Various 1,4-(3-Indole)(organo)[60]fullerenes.
The KOtBu-mediated three-component coupling reaction of indoles, [60]fullerene, and haloalkane has been developed as a practical and efficient protocol for the one-pot synthesis of various 1,4-(3-indole)(organo)[60]fullerenes. The reaction exhibits high regioselectivity at the 3-position of indoles and the 1,4-position on the [60]fullerene core. Furthermore, this methodology features excellent functional group tolerance, such as chloro, ester, cyano, and nitro on indole.


Cation-cation interactions between NpO2(+) and UO2(2+) at different temperatures and ionic strengths.
Cation-cation interactions between NpO(2)(+) and UO(2)(2+) were studied at different temperatures (283.15 K to 358.15 K) and different ionic strengths (3-4.5 mol dm(-3)) by spectrophotometry and microcalorimetry. The cation-cation complex between NpO(2)(+) and UO(2)(2+) was weak and became stronger as the temperature was increased from 283.15 K to 358.15 K. The molar enthalpy of complexation was directly determined for the first time by microcalorimetry to be (4.2 ± 1.6) kJ mol(-1) at 298.15 K, in good agreement with the trend in the stability constant at different temperatures. The small and positive enthalpy and entropy of complexation support the argument that the cation-cation complex between NpO(2)(+) and UO(2)(2+) is of inner-sphere type. At each temperature, the stability constants of the cation-cation complex were found to increase as the ionic strength was increased. The specific ion interaction theory (SIT) was used to obtain the stability constants at infinite dilution and variable temperatures.


Manipulating the human embryo: cell cycle checkpoint controls.
Micromanipulation techniques are widely used in assisted human reproduction and it is logical to assume that successes with recent animal cloning will invariably raise the question of human cloning along with its related ethical problems. However, it is often overlooked that even in animals many complications are still associated with this technique. The purpose of our article is to highlight and discuss some of these problems in the context of the eventual use of nuclear and/or cytoplasmic transfer techniques in assisted human reproduction.


Emerging therapeutic targets in bladder cancer.
Treatment of muscle invasive urothelial bladder carcinoma (BCa) remains a major challenge. Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets. This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa. Small molecule pan-FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations. mTOR inhibitors for patients with TSC1 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K/AKT/mTOR pathway. Encouraging preclinical results with ado-trastuzumab emtansine (T-DM1) exemplifies a new potential treatment for HER2-positive BCa along with innovative bispecific antibodies. Inhibitors of cell cycle regulators (aurora kinase, polo-like kinase 1, and cyclin-dependent kinase 4) are being investigated in combination with chemotherapy. Early results of clinical studies with anti-CTLA4 and anti-PDL1 are propelling immune modulating drugs to the forefront of emerging treatments for BCa. Collectively, these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy.


[Value of the intraoperative neuromonitoring in surgery for thyroid cancer in identification and prognosis of function of the recurrent laryngeal nerves].
The aim of this study was both, to evaluate the usefulness of the method of neuromonitoring in intraoperative identification of the RLN and to estimate its value in the prognosis of postoperative RLN function in patients operated for TC. Among 109 patients undergoing surgery for TC between 12/2004 and 12/2005 the neuromonitoring method was used in 69 (63.3%) individuals (including 5 operations of completion total thyroidectomy). A Neurosign 100 equipment with laryngeal electrodes was employed in identification and assessment of total number of 134 RLN. Intraoperative results were compared to the postoperative results of the ENT-specialist examination of vocal cords mobility in indirect laryngoscopy, in each patient. Transient vs. permanent, unilateral RLN palsy was noted in 3 vs. 2 patients (2.2% vs. 1.4% of nerves at risk). The method of neuromonitoring facilitated identification of 123 (91.8%) RLN being not helpful in 11 (8.2%) cases. However, neuromonitoring was helpful in identification of the RLN, the value of the method in prognosis of posteoperative function of the RLN was limited. Results of indirect neurostimulation were more accurate than direct neurostimulation and were more accurate in prognosis of late rather than early RLN function after surgery (sensitivity 98.3%; specificity 100%; positive predictive value 100%; negative predictive value 50%, accuracy 98.4%). Application of intraoperative neuromonitoring facilitates identification of the RLN during surgery for TC. However, the method is of limited value in prognosis of postoperative RLN dysfunction in cases of missing signal after nerve stimulation.


Systemic Alterations of Immune Response-Related Proteins during Glaucoma Development in the Murine Model DBA/2J.
Animal models of glaucoma, a neurodegenerative disease affecting the retina, offer the opportunity to study candidate molecular biomarkers throughout the disease. In this work, the DBA/2J glaucomatous mouse has been used to study the systemic levels of several proteins previously identified as potential biomarkers of glaucoma, along the pre- to post-glaucomatous transition. Serum samples obtained from glaucomatous and control mice at 4, 10, and 14 months, were classified into different experimental groups according to the optic nerve damage at 14 months old. Quantifications of ten serum proteins were carried out by enzyme immunoassays. Changes in the levels of some of these proteins in the transition to glaucomatous stages were identified, highlighting the significative decrease in the concentration of complement C4a protein. Moreover, the five-protein panel consisting of complement C4a, complement factor H, ficolin-3, apolipoprotein A4, and transthyretin predicted the transition to glaucoma in 78% of cases, and to the advanced disease in 89%. Our data, although still preliminary, suggest that disease development in DBA/2J mice is associated with important molecular changes in immune response and complement system proteins and demonstrate the utility of this model in identifying, at systemic level, potential markers for the diagnosis of glaucoma.


[Pituitary diseases in elderly patients with chronic renal insufficiency].
Chronic renal failure (CRF) in the elderly is a cause of multiple endocrine dysfunctions. The three most common pituitary axes involved are the thyrotrope, lactotrope and gonadotrope axes. Thyroid dysfunction may be the consequence of thyroid or pituitary failure. Hyperprolactinemia results in gonadal failure and is present in 30% of patients. Early presentation of menopause and andropause are common in patients with CRF. Sexual hormonal replacement is controversial and must be individually tailored. We propose a systematic screening in the elderly with CRF: determination of TSH, TPO antibodies and cervical palpation, measures of PRL, LH, FSH and testosterone to explore lactotrope and gonadotrope axis.


Single Balloon Enteroscopy-Assisted Endoscopic Retrograde Cholangiopancreatography in Patients Who Underwent a Gastrectomy with Roux-en-Y Anastomosis: Six Cases from a Single Center.
Patients with altered anatomy such as a Roux-en-Y anastomosis often present with various pancreaticobiliary problems requiring therapeutic intervention. However, a conventional endoscopic approach to the papilla is very difficult owing to the long afferent limb and acute angle of a Roux-en-Y anastomosis. Balloon-assisted enteroscopy can be used for endoscopic retrograde cholangiopancreatography (ERCP) in patients with altered anatomy. We experienced six cases of Roux-en-Y anastomosis with biliary problems, and attempted ERCP using single balloon enteroscopy (SBE). SBE insertion followed by replacement with a conventional endoscope was attempted in five of six patients. The papilla was successfully approached using SBE in all cases. However, therapeutic intervention was completed in only three cases because of poor maneuverability caused by postoperative adhesion. We conclude that in patients with Roux-en-Y anastomosis, the ampulla can be readily accessed with SBE, but longer dedicated accessories are necessary to improve this therapeutic intervention.


Long-term increase in quality of nursing documentation: effects of a comprehensive intervention.
This study aimed to evaluate the longitudinal effects of a nursing-documentation intervention on the quantity and quality of the nursing documentation in a sample of patient records at a university hospital in Stockholm, Sweden. In this quasi-experimental longitudinal study, two hospital wards participated in a 2-year intervention and a third ward was used for comparison. The intervention consisted of organizational changes and education regarding nursing documentation in accordance with the VIPS model, a model designed to structure nursing documentation. To evaluate the effect, patient records were audited at three different time points: before the intervention, directly after the intervention and 3 years after the intervention. A total of 269 patient records were used. The findings showed a significant score increase in quantity as well as in quality of the nursing documentation, in the intervention wards directly after the intervention, as compared with those from the comparison ward. The results suggests that a comprehensive intervention based on the VIPS model and including organizational support for registered nurses (RN) may improve nursing documentation in an acute care hospital setting.


Angiotensin converting enzyme inhibitors. II. Clinical use.
Since their introduction in clinical practice in 1980, ACE inhibitors have been found useful in the treatment of hypertension and CHF. In hypertension, they are effective as monotherapy in 40% to 50% of the patients, and in combination with diuretics or calcium antagonists, they are effective in up to 85% of the patients. They are well tolerated, are not associated with depression, impotence, bronchospasm or metabolic derangements such as hypokalemia, hyperuricemia or hyperglycemia, and do not have adverse effects on the quality of life. As a result, they are preferred in hypertensive patients with CHF, left ventricular dysfunction, mental depression, older age, coronary artery disease, metabolic disorders, chronic destructive pulmonary disease, and peripheral vascular disease. In CHF they cause long-lasting hemodynamic and symptomatic improvement, improve exercise tolerance, and may lower mortality in certain patient subsets. Evolving new indications for ACE inhibitors include the diagnosis of renovascular hypertension, the prediction of surgical success, the treatment of scleroderma renal crisis, the reduction of proteinuria, renal protection, cardioprotection, the improvement of arterial compliance, in Bartter's syndrome and idiopathic edema, etc. ACE inhibitors are usually well tolerated but in some instances they may cause class-specific side effects such as hypotension; usually reversible azotemia or renal failure, especially in patients with renal artery stenosis or with CHF with low blood pressure; cough; angioedema; and hyperkalemia. Differences among ACE inhibitors are emerging and include chemical class (e.g., zinc ligand), biotransformation, potency, pharmacokinetics, prodrugs, tissue effects, additional pharmacologic properties, and drug interactions.


MicroRNA-219 is downregulated in non-small cell lung cancer and inhibits cell growth and metastasis by targeting HMGA2.
Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-associated mortality worldwide. Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer, and accounts for ~85% of all lung cancer cases. An increasing number of studies suggest that microRNAs (miRs) may be involved in the regulation of NSCLC carcinogenesis and progression. However, the expression and function of miRNA-219 in NSCLC, and its underlying mechanisms of action, remain unknown. In the present study, miR-219 expression in NSCLC tissues and cell lines was determined using reverse transcription-quantitative polymerase chain reaction. Following transfection with miR-219 mimics, the effects of miR-219 overexpression on NSCLC cell proliferation, migration and invasion were examined. Furthermore, the miR-219 target in NSCLC was investigated. miR-219 was observed to be downregulated in NSCLC tissues and NSCLC cell lines. In addition, miR-219 was demonstrated to function as a tumor suppressor in NSCLC, through inhibiting cell proliferation, migration and invasion in vitro. Furthermore, high mobility group AT-hook 2 (HMGA2) was identified to be a direct target of miR-219 in NSCLC, and downregulation of HMGA2 suppressed NSCLC cell proliferation, migration and invasion in vitro. HMGA2 expression was upregulated in NSCLC tissues, and was inversely correlated with miR-219 expression. In conclusion, miR-219 functions as a tumor suppressor and may be important in inhibiting the growth and metastasis of NSCLC cells via directly targeting HMGA2. Therefore, miR-219 may present a potential novel therapeutic target for NSCLC.


[The evolution and characteristics of social hygiene in modern Japan].
The purpose of this paper is the clarification of the theory of social hygiene and its conception in modern society. The theory of social hygiene in modern society was mainly formed by the influence of social democracy and the social reform movement. Social hygiene in modern Japan was presented by Germany in the middle Meiji era and prevailed in the Taisho era. Yoshie Fukuhara, Gito Terouka and Teido Kunisaki developed the mainstream of the theory about social hygiene in modern Japan. The principle of social hygiene in Japan was that the target group of social hygienic activities (such as laborers, poor people, consumers of medical service and so on) should establish the idea of self-government and autonomy of their lives. Social supports to the target group were recognized as combining with the idea of self-government and autonomy of lives. Some of those activities influenced by the principle were performed. Particularly, the work of Tetsuo Hoshino was unique in showing the relation between health and human culture. The work has shown that human health is reflected in human cultural activities. Social hygiene was important to the foundation of introduction and evolution of the thoughts of public health, health culture and medical insurance in modern Japan.


miR-96 suppresses renal cell carcinoma invasion via downregulation of Ezrin expression.
The present study examined the role of microRNA (miR)-96 in renal cell carcinoma (RCC) invasion. The expression of miR-96 was detected by quantitative reverse transcription-polymerase chain reaction in human RCC cell lines with high (Caki-1) and low (786-O) metastatic potential. Invasive ability and Ezrin expression were assessed in Caki-1 and 786-O cells transfected with a miR-96 mimic or inhibitor using wound healing assays, Transwell assays and western blotting. Expression of miR-96 and Ezrin was also examined in primary RCC samples from 17 patients with metastatic disease and 46 patients who maintained remission during a follow-up period of 37 months. miR-96 expression was significantly lower in Caki-1compared to786-O cells. The invasive ability of Caki-1 and 786-O cells increased following transfection of cells with miR-96 inhibitor, whereas it decreased following transfection with miR-96 mimic. Ezrin levels were negatively correlated with miR-96 in RCC, and inhibition of Ezrin expression suppressed the miR-96-induced change in invasive ability. The negative correlation between miR-96 and metastasis/Ezrin expression was also observed in human RCC specimens. These results suggest that miR-96 suppresses RCC invasion by modulating Ezrin expression.


Co-creating Environments: Empowering Elders and Strengthening Communities through Design.
Working with elders around the world has taught me that those living in grass huts in Africa with children at their feet are often happier than people in assisted-living homes with a chandelier over their heads. My work in design consultancy and in fifteen years of running a nonprofit, Ibasho, that aims to co-create socially integrated and sustainable communities that value their elders has allowed me to learn much about how architects and designers can contribute to helping people live a good life in late life. People often need supportive services or other adaptations as they age, but do they really need-or want-the luxury environment few are accustomed to? The challenge for architects and designers is not to create a built environment whose carefully curated facades hide lives of quiet desperation. It is to help elders access the support they need without upending their lives or severing virtually all ties to their communities.


Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach.
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39-1.95], P = 8.46 × 10(-9)) and was moderately heritable (h(2) = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34-2.11], P = 6.52 × 10(-6)) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27-2.75], P = 1 × 10(-3)). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.


Comorbidities and the quality of life in hypertensive patients.
An important factor influencing the perception of health‑related quality of life (HRQoL) is the presence of chronic diseases, especially polymorbidity. However, little is known about how concurrent chronic diseases influence the HRQoL of hypertensive patients. The primary aim of the study was to assess the relationship between comorbidities and different aspects of HRQoL in a large unselected cohort of patients undergoing treatment for hypertension. A questionnaire‑based study was conducted by 832 primary care physicians in a group of 12,525 unselected patients treated for hypertension for at least 3 months. HRQoL was evaluated using the Medical Outcomes Study 12‑item Short‑Form Health Survey (SF‑12). Coexisting diseases were reported in 7986 patients (63.8%). Significantly lower HRQoL values were associated with coexisting diseases, especially obstructive respiratory disease, degenerative disc disease, radiculopathy, coronary artery disease, heart failure, stroke, diabetes, epilepsy, neurotic disorders, and mood disorders. The HRQoL of hypertensive patients decreased significantly with age and duration of antihypertensive therapy (>2 years). HRQoL values were higher for men and participants with higher education and lower for participants who were obese or had visceral obesity. Antihypertensive therapy was effective in 25.4% of the participants. Chronic diseases concomitant with arterial hypertension negatively affect all dimensions of the HRQoL.


Evidence of successful recruitment of non-native pink salmon Oncorhynchus gorbuscha in Iceland.
In mid-May 2022, pink salmon Oncorhynchus gorbuscha smolts were caught in the rivers Botnsá, Grímsá, and Langá in Iceland. This observation provides the first evidence of successful spawning and the completion of the freshwater phase of the life cycle in Icelandic rivers. It is the most western record of O. gorbuscha smolts in Europe, further west than Russia, Norway, and the UK. Smolts originating from Iceland potentially support the recruitment of this species in the North Atlantic and may lead to the establishment of a self-sustaining population in Iceland.


Association between plasma angiopoietin-like protein 3 and arterial wall thickness in healthy subjects.
Angiopoietin-like protein 3 (ANGPTL3) is a liver-derived plasma protein that modulates plasma triglyceride clearance, angiogenesis and atherosclerosis in experimental models. So far, no study has examined its role in atherosclerosis in human subjects. We evaluated the possible association between plasma ANGPTL3 level and carotid artery intima-media thickness (CA-IMT) and femoral artery intima-media thickness (FA-IMT) in healthy human subjects. The subjects were 381 healthy volunteers. Plasma ANGPTL3 was determined by a specific ELISA. CA-IMT and FA-IMT were measured by high-resolution B-mode ultrasonography. The plasma ANGPTL3 level was 764 +/- 291 ng/ml (mean +/- SD). CA-IMT showed a significant positive correlation with plasma ANGPTL3 and other classical risk factors such as age, blood pressure, and plasma glucose and lipid levels. The positive association between ANGPTL3 and CA-IMT remained significant after adjustment for age, sex, smoking, body mass index, systolic blood pressure, plasma glucose, insulin resistance index, triglyceride, and high-density and low-density lipoprotein cholesterol levels. ANGPTL3 also showed a positive association with FA-IMT independent of these factors. These results demonstrate for the first time that ANGPTL3 is closely associated with arterial wall thickness in human subjects.


Monitoring programme on toxic metal in bluefish (Pomatomus saltatrix), anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) from Istanbul, Turkey: levels and estimated weekly intake.
Toxic metal (Hg, Cd, Pb, Cu and Zn) concentrations of small-medium bluefish, anchovy and sardine in Istanbul, Turkey, were determined using inductively coupled plasma-mass spectrometry (ICP-MS) throughout 1 year. The concentrations of pollutants were found to vary according to season and species. Estimates of weekly intake levels of the metals were calculated and compared to recommended safe limits for fish consumption by humans. The levels of Cd, Pb, Cu and Zn in the fillets of all species resulted in estimates of weekly intake levels that were lower than the recommended safe limits. The concentrations of Hg of small bluefish in September, of medium bluefish in June and September, of anchovy in March, and of sardine in August and September resulted in estimates of weekly intake levels that were higher than the recommended safe limits for human consumption.


Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma.
Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.


Promoting health in schools through a board game.
Primary prevention and health promotion have become salient topics in Canadian society and in nursing during the past two decades. The noncommunicable chronic diseases, such as heart disease and cancer, have been linked to specific lifestyle behaviors or habits, which often develop early in life. The success of public health efforts to improve the health status of all Canadians depends substantially on the success of educational programs directed toward children. Effective teaching strategies that seek to promote health and wellness in children need to be developed and empirically evaluated. Educational games may provide an efficient vehicle for carrying out developmentally specific nursing interventions in school settings. This article begins with a brief overview of the historical origins of games, along with their advantages and disadvantages as educational strategies. The results of a pretest-posttest control group design study that evaluated the effectiveness of a board game as a primary prevention teaching strategy with 23 sixth grade children in Winnipeg, Manitoba are presented. The experimental group had significant gains in knowledge related to anatomy and physiology, diet, and lifestyle risk factors associated with the development of heart disease and cancer.


Evaluation of an immunoassay procedure to measure 6-monoacetylmorphine.
Introduction: 6-Monoacetylmorphine (6-MAM) is a specific metabolite of heroin. Thus, the presence of 6-MAM in urine is a definitive indication of heroin intake. The possibility of having an immunoassay procedure to measure 6-MAM would be a diagnosis tool to discriminate, among opiates-positive, those patients who have consumed heroin and those who have not.Methods: EMIT® II Plus 6-Acetylmorphine Assay was used to measure 6-MAM in urine. The positive opiate screening results were confirmed at the Toxicology laboratory of our hospital by GC-MS.Results: This study includes 63 urine samples from subjects admitted to emergency department with suspicion of opiate consumption. Specificity was evaluated in the two groups of samples studied. In the first group all samples which resulted negative by opiate immunoassay (n = 33) were negative for 6-MAM immunoassay test. Thus, the specificity obtained for 6-MAM immunoassay in this group was 100%. Regarding the second specificity study, performed in positive samples by opiate immunoassay which were negative to 6 MAM by GC-MS, the specificity decreased down to 75%. In the study of sensitivity all samples confirmed as positive to 6-MAM by confirmatory method (GC-MS) resulted positive by the screening method, thus sensitivity obtained was 100%.Discussion: In this study no FN for 6-MAM was observed and therefore the new Emit® II Plus 6- Acetylmorphine Assay procedure has a high NPV, thus a negative result with 6-MAM immunoassay practically excludes heroine consume. The positive results to 6-MAM by immunoassay should be confirmed by a more analytically specific method, such as GCMS.


High school allied health students and their exposure to the profession of EMS.
Ensuring a stable Emergency Medical Services (EMS) workforce is a growing concern, and effective recruiting strategies are needed to expose young adults to the EMS profession. The objective of this study was to assess the exposure of high school allied health students to EMS as a career option, as well as measure their attitudes and beliefs about the EMS profession. Hypothesis Few high school allied health students are exposed to EMS educational and career opportunities. A convenience sample of allied health students in a rural high school system was surveyed about exposure to EMS, career intentions, factors impacting career decisions, and attitudes and beliefs about EMS. Descriptive statistics were calculated, and intention to pursue an EMS career was modeled using logistic regression. Of 171 students enrolled in allied health courses across six high schools, 135 (78.9%) agreed to participate; 85.2% were female. Almost all (92.6%) respondents intended to pursue a health career, but only 43.0% reported that their allied health course exposed them to EMS as a profession. Few participants (37.7%) were knowledgeable about EMS associate degree or baccalaureate degree (27.4%) programs. Only 20.7% of the respondents intended to pursue EMS as a career, although 46.0% wanted to learn more about the profession. Most (68.2%) students expressed interest in an emergency medical technician (EMT) course if one were offered, and 80.0% were interested in a ride-along program. Independent predictors of pursuing an EMS career included exposure to EMS outside of high school (OR = 7.4, 95% CI = 1.7-30.4); media influence on career choice (OR = 9.6, 95% CI = 1.8-50.1); and the belief that EMS was mentally challenging (OR = 15.9, 95% CI = 1.1-216.6). Negative predictors included the beliefs that an EMS career was stimulating (OR = 0.05, 95% CI = 0.00-0.53) and physically challenging (OR = 0.06, 95% CI = 0.00-0.63); as well as prior exposure to an EMS job advertisement (OR = 0.14, 0.03-0.53). Overall, there was a lack of exposure to career and educational options in EMS among allied health students in the school system studied, and few students intended to pursue an EMS career after graduation. However, the majority of students indicated they would like to learn more about EMS, and would enroll in an EMT course and ride-along program if available. These findings suggest that, with exposure to the profession, more allied health students could choose EMS as a career.


Malignant progression in pleomorphic xanthoastrocytoma: personal experience and review of the literature.
Pleomorphic xanthoastrocytoma (PXA) is a rare primary low-grade astrocytic tumor, recently classified as a neuroglial tumor. It generally occurs in children and young adults and shows benign behaviour (WHO II), although an anaplastic variant and malignant potential have been described. Pleomorphic xanthoastrocytomas with malignant transformation have been reported in three out of eight patients operated on for this type of tumor in our department in the last 15 years. The three patients were two adult women and a child, the primary tumors were located in the cortex of the right temporal lobe, and treatment consisted of complete surgical resection. Histological examination revealed simple PXA in two patients and a PXA with anaplastic foci in the other. Mean recurrence time was 5.7 years, with the original xanthoastrocytoma evolving to glioblastoma in two cases and anaplastic astrocytoma in the third. All three patients underwent a second operation, followed by adjuvant therapies. Two died from tumor progression and one from brain edema after intracerebral haemorrhage. A review of the available PXA literature dating back to 1979 revealed 16 cases of primary anaplastic astrocytoma and 21 cases of PXA with malignant transformation. Our experience adds three more cases of malignant transformations, outlining once again the potential malignancy of pleomorphic xanthoastrocytomas and the fact that prognosis in these cases is the same as for primary anaplastic astrocytoma and glioblastoma. Analysis of glioneuronal markers, Ki67 and p53 in all pleomorphic xanthoastrocytomas did not prove to be a discriminating factor to identify a subgroup of xanthoastrocytomas prone to malignancy. Accordingly, these tumors demand close long-term clinical and radiological follow-up.


Pd-catalyzed, Cu(I)-mediated cross-couplings of bisarylthiocyclobutenediones with boronic acids and organostannanes.
Bisarylthiocyclobutenedione 7 reacted smoothly with a variety of both organostannanes and (hetero)arylboronic acids in the presence of a catalytic amount of Pd and a stoichiometric amount of CuTC to produce symmetrical disubstituted cyclobutenediones in yields that range from 37 to 94% (18 examples).


Autoimmune retinopathy: A case report from India.
A first case report of autoimmune retinopathy (AIR) from India. A middle-aged female patient presented with subacute loss of vision in both eyes. Clinical examination revealed a near normal fundus in both the eyes. A presumed diagnosis of nonparaneoplastic AIR was made based on clinical features and suggestive investigations. Early detection and management with steroids or immunosuppression may be beneficial to patients with AIR.


Waiting in pain. Delays between referral and consultation in outpatient pain clinics.
Patients with chronic pain may benefit from referral to a pain specialist. This study describes the delay between referral and first appointment of 3386 new referrals seen in ten outpatient pain clinics between 1990 and 1992. We then assess the follow-up patterns of the pain clinics and how these relate to waiting times. Patients wait in pain for long periods before being seen in a pain clinic. In 1992 about half of patients waited more than 3 months for an appointment at a teaching hospital pain clinic; and half waited 9 weeks or longer to be seen at a district general hospital pain clinic. In many clinics the situation is worsening. Pain clinics differ widely in their patient follow-up, with patients averaging more than twice as many visits in some clinics than others. Clinic practice on reappointing patients largely determines the number of new referrals who can be accepted for management, and hence affects waiting lists. Thus our data suggest that pain clinics themselves can help reduce waiting times, by changing the extent and nature of patient follow-up. Ultimately, however, additional consultant sessions may be needed to enable pain clinics to meet the increasing demands placed on them.


A "turn-on" fluorescent chemosensor for aluminum ion and cell imaging application.
A simple and efficient fluorescent chemosensor for Al(3+) is reported in the paper. The chemosensor is obtained by dehydration reaction of 2-hydroxy-1-naphthaldehyde and 2-aminophenol. The chemosensor has high selectivity and sensitivity for Al(3+) and displays fluorescence "off-on" switch signal. The detection limit of the chemosensor for Al(3+) can reach 1.0×10(-7) M in DMSO/H2O (1:9, v/v) solution. The mass spectra and Job's plot analysis confirm the 1:1 stoichiometry between chemosensor and Al(3+). Potential utilization of the probe as an intracellular sensor of Al(3+) in human cancer (HiSa) cells is also examined by confocal fluorescence microscopy.


Prevalence of Hookah smoking in relation to religiosity and familial support in college students of Tabriz, northwest of Iran.
Hookah smoking has increased worldwide especially among youth and young adults and has been identified as an emerging threat to public health. The aim of the present study was to determine the prevalence of hookah use and related factors in a sample of Iranian college students. This study took place in Tabriz (northwest of Iran) in April and May 2011. The randomly selected sample consisted of 1837 college students. Data was collected in a survey. A self-administered questionnaire was used to measure religious belief, parental support and risk taking behaviors including hookah smoking. Logistic regression model was performed in data analysis. The prevalence of hookah smoking was 8.5% (CI95%: 7.3-9.9). After adjustment, being male (OR= 2.01), living in single house in comparison with living with parents (OR= 2.22), smoking (OR= 5.96) and ever drug abuse (OR= 3.02) were factors associated with students' hookah use. Our results showed a low prevalence of hookah smoking in Iranian college female students and revealed some of its associated factors. We demonstrated the co-occurrence of risky behaviors which emphasizes the importance of interventions aimed at reducing or preventing different high risk behaviors simultaneously.


Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma.
Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette-Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.


Imaging in Patients with Bisphosphonate-Associated Osteonecrosis of the Jaws (MRONJ).
Bisphosphonate-associated osteonecrosis of the jaws (MRONJ/BP-ONJ/BRONJ) is a commonly seen disease. During recent decades, major advances in diagnostics have occurred. Once the clinical picture shows typical MRONJ features, imaging is necessary to determine the size of the lesion. Exposed bone is not always painful, therefore a thorough clinical examination and radiological imaging are essential when MRONJ is suspected. In this paper we will present the latest clinical update on the imaging options in regard to MRONJ: X-ray/Panoramic Radiograph, Cone Beam Computed Tomography (CBCT) and Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Nuclear Imaging, Fluorescence-Guided Bone Resection. Which image modality is chosen depends not only on the surgeon's/practitioner's preference but also on the available imaging modalities. A three-dimensional imaging modality is desirable, and in severe cases necessary, for extended resections and planning of reconstruction.


[Computed tomographic images analysis of frontal recess anatomy based on three-dimension reconstruction].
To observe the CT three-dimensional imaging features of the frontal recess region with advanced three-dimensional reconstruction, and develop the real image of the important anatomical structures around the region to conduct surgery. Thirty patients were undergone spiral CT by 16 line high speed spiral CT, and multiplanar reconstruction images using standard three-dimensional reconstruction protocol on a computer workstation. The structure of the frontal recess, the agger nasi cell and adhere style of the uncinate process were observed. The parameter of the important anatomic structure of frontal recess was measured precisely. After the reconstruction, we get the three-dimensional model very close to the true state of the nasal cavity-sinuses cell, in which parts of the frontal recess can clearly identify the agger nasi cell, frontal cell and other important structures. In these patients, the height, width and depth of the agger nasi and frontal sinus were (9.45 ± 3.60)mm, (8.08 ± 3.37)mm, (26.98 ± 6.82)mm and (26.86 ± 9.45)mm, respectively. This study tried to develop the standardized techniques and measurements from three-dimensional reconstructed images of the frontal sinus and to ascertain the usefulness of the frontal sinus in identification of patients. The project results in better preoperative patient counselling and in predicting postoperative improvement in clinical status.


Racemose Neurocysticercosis: A Rare Cause of Rapidly Progressive Dementia-A Case Report.
This report describes the case of a 68-year-old woman with episodic memory impairment for 6 months. Brain magnetic resonance imaging detected multiple extra-axial variable-sized cystic lesions in the left medial temporal lobe, suprasellar cistern, and perimesencephalic cistern. The serum and cerebrospinal fluid tested positive for Taenia solium, confirming racemose neurocysticercosis. Albendazole and praziquantel were administered for 6 months and prednisolone for 1 month. After 3 months, her symptoms resolved. Despite its rarity, racemose neurocysticercosis should be considered in patients with rapidly progressive dementia and cystic brain lesions.


Diagnosis of Invasive Nonfunctional Pituitary Adenomas by Serum Extracellular Vesicles.
The invasiveness evaluation of nonfunctional pituitary adenoma (NFPAs) is crucial for the prediction of the malignant potential and for making surgical plans of NFPAs. Current invasiveness evaluation of NFPAs is based on neuroimaging, which can hardly predict the invasive potential and dynamically monitor disease progress. Here we used microbead-assisted flow cytometry to detect and analyze the serum extracellular vesicles (EVs) from 30 NFPAs patients (15 invasive and 15 noninvasive). Lower expressions of folate receptor 1 (FOLR1) and epithelial cell adhesion molecule (EpCAM) were found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones [area under the curve (AUC) of 0.94 for FOLR1 and 0.88 for EpCAM]. Meanwhile, increased mRNA expression of vimentin and N-cadherin, two mesenchymal markers, was found in serum EVs from the invasive NFPAs patients compared to the noninvasive ones. Consistent results were observed in the tumor tissue that invasive NFPAs have lower expression of the epithelial markers while higher expression of the mesenchymal markers. These results suggested the possible role of epithelial-mesenchymal transition (EMT) in the invasiveness of NFPAs. Pituitary tumor transforming gene 1 (PTTG1) mRNA in serum EVs was also found to be an indicator for invasive NFPAs and is related with EMT. These results provide a method for the blood-based diagnosis and invasiveness evaluation of NFPAs and would be beneficial to the diagnosis, prognosis prediction, and surgical risk evaluation of NFPAs.


Clinical significance of types of cerebellar amyloid plaques in human spongiform encephalopathies.
We report three patients with both spongiform encephalopathy and cerebellar amyloid plaques; one showed kuru-like plaques and was diagnosed as having Creutzfeldt-Jakob disease (CJD), and two had multicentric plaques and were diagnosed as having Gerstmann-Sträussler-Scheinker disease (GSSD). Evaluation of these cases and review of others previously reported suggests a clinicopathologic correlation between type of cerebellar plaque and neurologic clinical course. CJD patients who showed kuru-like plaques generally had disease with early onset (average age, 49.1 years) and long duration (average, 34 months), as compared with CJD patients without kuru-like plaques. GSSD patients usually had multicentric cerebellar plaques, and cases were usually familial, had early age of onset (average, 42.7 years), and were of long duration (average, 73 months). Myoclonus was infrequent in GSSD patients and pathologically spongiform change was minimal; spinal tract degeneration was common.


Relationship between β-Thalassemia minor and Helicobacter pylori infection.
Until now, no study has been reported investigating the association between β-thalassemia minor and Helicobacter pylori (H. pylori) infection. This study was designed to compare H. pylori infection rate between β-thalassemia minor patients and healthy controls. A number of 100 β-thalassemia minor patients (50 males, 50 females) and 100 gender-matched healthy controls were prospectively recruited in this study in a period of 3 months. The study population consisted of the people who referred to a health center in Babol, North of Iran, for premarital counseling. H. pylori status was assessed by measuring the anti-H. pylori IgG antibodies using enzyme-linked immunosorbent assay. Demographic information and informed consent were collected from all participants. The overall H. pylori infection rate was 43%. The infection was significantly more prevalent in thalassemia patients (53%) than in the controls (33%) in both univariate (OR=2.29, 95% CI: 1.3-4.06) and multivariable analyses (OR=2.05, 95% CI: 1.12-3.76). Age was the only significant factor which was positively correlated with the infection in β-thalassemia minor cases (OR=1.11, 95% CI: 1.02-1.2). Gender, blood groups, residency, and education level were not related to the infection. According to the results, it can be concluded that β-thalassemia minor patients are possibly more susceptible to H. pylori infection than healthy people. Further studies are needed to discover more about the exact mechanisms of increased susceptibility to H. pylori infection in β-thalassemia minor patients.


Unraveling mechanisms underlying partial agonism in 5-HT3A receptors.
Partial agonists have emerged as attractive therapeutic molecules. 2-Me-5HT and tryptamine have been defined as partial agonists of 5-HT3 receptors on the basis of macroscopic measurements. Because several mechanisms may limit maximal responses, we took advantage of the high-conductance form of the mouse serotonin type 3A (5-HT3A) receptor to understand their molecular actions. Individual 5-HT-bound receptors activate in long episodes of high open probability, consisting of groups of openings in quick succession. The activation pattern is similar for 2-Me-5HT only at very low concentrations since profound channel blockade takes place within the activating concentration range. In contrast, activation episodes are significantly briefer in the presence of tryptamine. Generation of a full activation scheme reveals that the fully occupied receptor overcomes transitions to closed preopen states (primed states) before opening. Reduced priming explains the partial agonism of tryptamine. In contrast, 2-Me-5HT is not a genuine partial agonist since priming is not dramatically affected and its low apparent efficacy is mainly due to channel blockade. The analysis also shows that the first priming step is the rate-limiting step and partial agonists require an increased number of priming steps for activation. Molecular docking suggests that interactions are similar for 5-HT and 2-Me-5HT but slightly different for tryptamine. Our study contributes to understanding 5-HT3A receptor activation, extends the novel concept of partial agonism within the Cys-loop family, reveals novel aspects of partial agonism, and unmasks molecular actions of classically defined partial agonists. Unraveling mechanisms underlying partial responses has implications in the design of therapeutic compounds.


Effect of the method of killing, interval between killing and neck cutting and blood vessels cut on blood loss in broilers.
1. Broiler chickens were killed using 90% argon in air, or 30% carbon dioxide and 60% argon in air or 120 mA per bird in a waterbath with a 50 Hz alternating electric current. Ventral or unilateral neck cutting was performed at 1, 3 or 5 min after killing. In addition, a group of broilers was stunned with 120 mA per bird in a waterbath using 1500 Hz alternating current and were bled out-with a ventral neck cut within 20 s from stunning. 2. Blood leaving the neck wound was collected in a bin placed on an electronic balance and a computer program calculated the cumulative blood loss up to 100 s after neck cutting. 3. Bleed-out was significantly affected by killing method and time of neck cutting. Broilers killed with the carbon dioxide-argon mixture bled-out less than those killed with argon or 50 Hz electric current. When compared with the 1 min neck cutting interval, a delay of 3-or 5 min resulted in a lower bleed-out. High frequency electrical stunning and ventral neck cutting within 20 s resulted in a slightly higher bleed-out than those recorded for the killing methods. However, within argon killing, a delay of 3 or 5 min in ventral or unilateral neck cutting had no significant effect on the bleed-out. In broilers killed with the carbon dioxide-argon mixture a 3 min delay in ventral neck cutting or a 5 min delay in unilateral neck cutting resulted in lower bleed-out. 4. Neck cutting of broilers within 5 min after argon killing or 3 min after killing with the carbon dioxide-argon mixture would result in a satisfactory bleed-out.


[Detection of monoclonality of gastric MALT lymphoma using PCR method and its clinicopathological application].
Twenty cases of H. pylori-related gastric lymphoproliferative disorders including 12 cases of MALT lymphoma (Grade 5 after Wotherspoon, et al), 6 of suspicious of MALT lymphoma (Grade 4), and 2 of active chronic gastritis (Grade 3) were studied. Using the nested PCR method, paraffin-embedded gastric biopsy specimens of these 20 cases were investigated whether or not monoclonal IgH rearrangement could be demonstrated in infiltrating lymphoid cells. Monoclonal IgH rearrangement was recognized in 6 of 12 MALT lymphomas, but in other 14 cases including 6 of MALT lymphomas the monoclonality was not recognized. The result showed the sensitivity was 50% and the specificity was 100% with this method. Follow-up study after eradication of H. pylori was performed on 6 cases of MALT lymphoma which had showed the monoclonality before, using the same method. The monoclonality disappeared in 5 of 6 and histology showed a complete remission. In the remaining one case the monoclonality was yet demonstrated and lymphoma cells were histologically recognized. Thus, this method is very useful to assess not only the histological diagnosis of MALT lymphoma but also the effectiveness after treatment.


Antimicrobial factors in saliva: ontogeny and relation to oral health.
Antimicrobial agents (antibody and non-antibody) present in human saliva protect oral tissues by a variety of mechanisms, such as prevention of bacterial adhesion, agglutination of micro-organisms, and inhibition of multiplication and metabolism. However, studies in which the concentrations of various salivary antimicrobial agents have been correlated to the presence and severity of oral diseases--of dental caries, in particular--have produced controversial data, and it seems evident, also on the basis of the present study, that no single salivary antimicrobial factor (except flow rate) affects oral health to a significant degree. In the present study, we report the levels of some selected salivary antimicrobial agents in predentate and dentate human infants, with a comparison to the levels found in young adults' saliva. Salivary lysozyme, peroxidase, and hypothiocyanite concentrations were already at the adult level at the time when the primary teeth erupt, whereas immunoglobulin (IgA, IgG, and IgM), lactoferrin, myeloperoxidase, and thiocyanate concentrations were significantly lower in children than in adults. Dentate children had more IgG, thiocyanate, and protein in whole saliva than did predentate children.


βCaMKII plays a nonenzymatic role in hippocampal synaptic plasticity and learning by targeting αCaMKII to synapses.
The calcium/calmodulin-dependent kinase type II (CaMKII) holoenzyme of the forebrain predominantly consists of heteromeric complexes of the αCaMKII and βCaMKII isoforms. Yet, in contrast to αCaMKII, the role of βCaMKII in hippocampal synaptic plasticity and learning has not been investigated. Here, we compare two targeted Camk2b mouse mutants to study the role of βCaMKII in hippocampal function. Using a Camk2b(-/-) mutant, in which βCaMKII is absent, we show that both hippocampal-dependent learning and Schaffer collateral-CA1 long-term potentiation (LTP) are highly dependent upon the presence of βCaMKII. We further show that βCaMKII is required for proper targeting of αCaMKII to the synapse, indicating that βCaMKII regulates the distribution of αCaMKII between the synaptic pool and the adjacent dendritic shaft. In contrast, localization of αCaMKII, hippocampal synaptic plasticity and learning were unaffected in the Camk2b(A303R) mutant, in which the calcium/calmodulin-dependent activation of βCaMKII is prevented, while the F-actin binding and bundling property is preserved. This indicates that the calcium/calmodulin-dependent kinase activity of βCaMKII is fully dispensable for hippocampal learning, LTP, and targeting of αCaMKII, but implies a critical role for the F-actin binding and bundling properties of βCaMKII in synaptic function. Together, our data provide compelling support for a model of CaMKII function in which αCaMKII and βCaMKII act in concert, but with distinct functions, to regulate hippocampal synaptic plasticity and learning.


Detection of Colistin Resistance in Salmonella enterica Using MALDIxin Test on the Routine MALDI Biotyper Sirius Mass Spectrometer.
Resistance to polymyxins in most Gram-negative bacteria arises from chemical modifications to the lipid A portion of their lipopolysaccharide (LPS) mediated by chromosomally encoded mutations or the recently discovered plasmid-encoded mcr genes that have further complicated the landscape of colistin resistance. Currently, minimal inhibitory concentration (MIC) determination by broth microdilution, the gold standard for the detection of polymyxin resistance, is time consuming (24 h) and challenging to perform in clinical and veterinary laboratories. Here we present the use of the MALDIxin to detect colistin resistant Salmonella enterica using the MALDxin test on the routine matrix-assisted laser desorption ionization (MALDI) Biotyper Sirius system.