Open versus endoscopic great saphenous vein harvest for lower extremity revascularization of critical limb ischemia.
This study determined wound complication rates, intervention rates, failure mechanisms, patency, limb salvage, and overall survival after lower extremity revascularization using open vein harvest (OVH) vs endoscopic vein harvest (EVH) for critical limb ischemia. A single-institution review was conducted of consecutive patients who underwent infrainguinal bypass with a single-segment reversed great saphenous vein between 2005 and 2012. A total of 251 patients with critical limb ischemia underwent revascularization, comprising 153 with OVH and 98 with EVH. The OVH group had a lower mean body mass index (26.7 vs 29.9 kg/m(2); P = .001). There were no other differences in demographics, comorbidities, medications, smoking, or in the proximal or distal anastomotic site. Median operative times were 249 minutes (OVH) vs 316 minutes (EVH; P < .001). Median postoperative hospital length of stay was 7 days (OVH) vs 5 days (EVH; P < .001). Median follow-up was 295 days (OVH) vs 313 days (EVH; P = .416). During follow-up, 21 OVH grafts (14%) and 27 EVH grafts (28%) underwent an intervention (P = .048). There were a similar number of surgical interventions: 50% (OVH) vs 61% (EVH; P = .449). Failed grafts had a mean of 1.2 stenoses per graft, regardless of harvest method. Median stenosis length was 2.1 cm (OVH) vs 2.5 cm (EVH; P = .402). At 1 and 3 years, the primary patency was 71% and 52% (OVH) vs 58% and 41% (EVH; P = .010), and secondary patency was 88% and 71% (OVH) vs 88% and 64% (EVH; P = .266). A secondary patency Cox proportional hazard model showed EVH had a hazard ratio of 2.93 (95% confidence interval, 1.03-8.33; P = .044). Overall and harvest-related wound complications were 44% and 29% (OVH) vs 37% and 12% (EVH; P = .226 and P = .002). At 5 years, amputation-free survival was 48% (OVH) vs 54% (EVH; P = .305), and limb salvage was 89% (OVH) and 91% (EVH; P = .615). OVH and EVH have similar failure mechanisms, limb salvage, amputation-free survival, and overall survival. EVH is associated with impaired patency, increased need for intervention, longer operative times, shorter hospital stays, and decreased vein harvest site wound complications. OVH of the great saphenous vein may provide optimal patency but was not necessarily associated with better patient-centered outcomes. Similar limb salvage rates and amputation-free survival may justify the use of EVH, despite inferior patency, to capture shorter hospital stays and decreased wound complications.


Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5 weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5 weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture.


Aminoalkylpyridines (AAPs), triazoline metabolite analogues, as anticonvulsants highly effective in the MES test.
Elucidation of the metabolism and pharmacology of 1,2,3-triazolines (TRs) led to the identification of the triazoline pharmacophore and the evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the sigma(1) receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA/PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the sigma selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP leads, indicated that the 4-pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C1(2) substitution on the N-phenyl group, afforded the most active compounds. Amino group modification by acylation did not improve activity. The hydrazone compounds were the most active. Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet tests, which would imply a role for both Glu and GABA, is a prerequisite for antiischemic activity.


The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas.
CDX2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestines. Based on recent studies, CDX2 expression is immunohistochemically detectable in normal colonic enterocytes and is retained in most, but not all, colorectal adenocarcinomas. CDX2 expression has also been documented in a subset of adenocarcinomas arising in the stomach, esophagus and ovary. In this study, we examined CDX2 expression in a series of large tissue microarrays representing 4652 samples of normal and neoplastic tissues. Strong nuclear staining for CDX2 was observed in 97.9% of 140 colonic adenomas, 85.7% of 1109 colonic adenocarcinomas overall and 81.8% of 55 mucinous variants. There was no significant difference in the staining of well-differentiated (96%) and moderately differentiated tumors (90.8%, P=0.18), but poorly differentiated tumors showed reduced overall expression (56.0%, P<0.000001). Correspondingly, there was an inverse correlation between CDX2 expression and tumor stage, with a significant decrease in staining between pT2 and pT3 tumors (95.8 vs 89.0%, P<0.012), and between pT3 and pT4 tumors (89.0 vs 79.8%, P<0.016). Analysis of 140 locally advanced, CDX2-positive colorectal adenocarcinomas coarrayed with their matching lymph node metastases revealed that expression of this marker was retained in 82.1% of the metastases. Consistent with previous reports, CDX2 staining was observed in gastric adenocarcinomas (n=71), more commonly in the intestinal-type than the diffuse-type (28.9 vs 11.5%, P<0.05). Occasional ovarian carcinomas were positive for CDX2, including mucinous (10.5%), endometrioid (9.3%) and serous variants (2%), but expression was either very rare or absent in primary carcinomas of the lung, breast, thyroid, pancreas, liver, gallbladder, kidney, endometrium and urinary bladder. A low frequency of CDX2 expression in pancreatic and biliary carcinomas observed on the microarrays was pursued further by comparing these tumors with ampullary adenocarcinomas on conventional sections. Ampullary adenocarcinomas were more commonly positive for CDX2 (19/24, 79%) than cholangiocarcinomas (1/11, 9%) and pancreatic carcinomas (3/20, 15%). In summary, CDX2 is a sensitive and specific marker for colorectal adenocarcinoma, although its expression is decreased among higher grade and stage tumors, and it is not invariably present in metastases from positive primaries. CDX2 may also be helpful in distinguishing adenocarcinomas of the ampulla from those arising in the pancreas and biliary tree.


Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development.
Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8 A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8 A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440-480 ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide-selective sequencing (OS-Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome.


Flocculus Purkinje cell signals in mouse Cacna1a calcium channel mutants of escalating severity: an investigation of the role of firing irregularity in ataxia.
Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25-1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125-1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture.


Werner syndrome: clinical evaluation of two cases and a novel mutation.
Werner syndrome (WS) is a premature aging disorder, inherited in an autosomal recessive pattern and caused by the mutation in the WRN gene. In this report we describe two male patients with negative family history who demonstrate characteristic findings of WS, with different mutations, including one novel mutation. The first case was a 47-year-old man who had been suffering from large, ischemic ulcers on both legs for 7 years. Physical examination revealed a thin and short man with severe wasting of all extremities. He had a high-pitched voice, hoarseness, a characteristic bird-like facies, bilateral cataracts, generalized osteoporosis, hypotrichosis, atrophic and poikilodermic skin, flexion contractures of hands, feet and knees, and soft tissue calcifications. Laboratory investigations revealed anemia, high erythrocyte sedimentation rate, low creatinine clearance, and high liver enzymes. Genetic analysis showed a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2, which has not been described before. The second case was a 23-year-old man who was referred for large callosities on both feet, present for 7 years. He complained of weakness, weight loss, wasting of muscles, and early graying of hair. The entire skin was thin, wrinkled and dry. Generalized hypotrichosis, scattered ephelid-like macules, sclerotic fingers, calcinosis cutis on ears, hyperpigmentation on elbows were the other alterations of skin. Skeletal survey revealed osteoporosis. Genetic analysis showed a homozygous known pathogenic splice site mutation c.3460-2A>G, causing skipping of Exon 30 in WRN.


Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir.
Several nucleoside analogues (penciclovir, lobucavir, dioxalane guanine [DXG], 1-beta-2,6-diaminopurine dioxalane [DAPD], L-FMAU, lamivudine) and acyclic nucleoside phosphonate analogues (adefovir, tenofovir) that are in clinical use, in clinical trials or under preclinical development for the treatment of hepatitis B virus (HBV) infections, were evaluated for their inhibitory effect on the replication of a la- mivudine-resistant HBV variant containing the methionine --> valine substitution (M550V) in the polymerase nucleoside-binding domain. The antiviral activity was determined in the tetracycline-responsive HepAD38 and HepAD79 cells, which are stably transfected with either a cDNA copy of the wild-type pregenomic RNA or with cDNA containing the M550V mutation. As expected, lamivudine was much less ( approximately 200-fold) effective at inhibiting replication of the M550V mutant virus than the wild-type virus. In contrast, adefovir, tenofovir, lobucavir, L-FMAU, DXG and DAPD proved almost equally effective against both viruses. A second objective of this study was to directly compare the antiviral potency of the anti-HBV agents in HepG2 2.2.15 cells (which are routinely used for anti-HBV drug-screening purposes) with that in HepAD38 cells. HepAD38 cells produce much larger quantities of HBV than HepG2 2.2.15 cells, and thus allow drug screening in a multiwell plate format. All compounds were found to be almost equally effective at inhibiting HBV replication in HepAD38 cells (as in HepG2 2.2.15 cells), except for penciclovir, which was clearly less effective in HepAD38 cells.


Four Corners States Biomonitoring Consortium: Lessons Learned During Implementation.
Building on a history of collaboration in environmental public health and biomonitoring activities, laboratory and environmental epidemiology leaders in Arizona, Colorado, New Mexico, and Utah created the Four Corners States Biomonitoring Consortium, which is now in its third year of activities. In this article, we briefly highlight some lessons learned during the implementation phases of the consortium, including the processes of collaborating to identify common environmental exposure concerns, prioritizing those concerns, identifying cohorts and communities with potential risks of excessive exposure, developing a model for conducting exposure investigations, and the challenges presented during the implementation phases and early fieldwork activities. Detailed information on these topics can be found at www.4csbc.org. The advantages of collaborating with, and leveraging the resources of, state Environmental Public Health Tracking Networks and Public Health Emergency Preparedness programs are discussed. Using one example from the early stages of this work, we also discuss the potential of biomonitoring as a vehicle for empowering the public to make informed choices to control their exposures and to influence public health decisions, support science-based environmental health policy and program development, and respond to emerging environmental exposure concerns.


Perspectives of survivors, families and researchers on key outcomes for research in acute respiratory failure.
There is heterogeneity among the outcomes evaluated in studies of survivors of acute respiratory failure (ARF). To evaluate the importance of specific outcome domains to acute respiratory distress syndrome (ARDS) survivors, their family members and clinical researchers. Nineteen outcome domains were identified from the National Institutes of Health's Patient Reported Outcomes Measurement Information System; WHO's International Classification of Functioning, Disability, and Health; Society of Critical Care Medicine's Post-Intensive Care Syndrome (PICS); as well as patient, clinician and researcher input. We surveyed ARDS survivors, family members and critical care researchers, 279 respondents in total, using a 5-point scale (strongly disagree, disagree, neutral, agree and strongly agree) to rate the importance of measuring each domain in studies of ARF survivors' postdischarge outcomes. At least 80% of patients and family members supported (ie, rated 'agree' or 'strongly agree') that 15 of the 19 domains should be measured in all future studies. Among researchers, 6 of 19 domains were supported, with researchers less supportive for all domains, except survival (95% vs 72% support). Overall, four domains were supported by all groups: physical function, cognitive function, return to work or prior activities and mental health. Patient, family and researcher groups supported inclusion of outcome domains that fit within the PICS framework. Patients and family members also supported many additional domains, emphasising the importance of including patients/family, along with researchers, in consensus processes to select core outcome domains for future research studies.


Cognitive ability and personality as predictors of participation in a national colorectal cancer screening programme: the English Longitudinal Study of Ageing.
The English NHS Bowel Cancer Screening Programme has offered biennial faecal occult blood testing to people aged 60-69 years since 2006, and to those aged 60-74 years since 2010. Analysis of the first 2.6 million screening invitations found that 54% of eligible people took up the invitation. The reasons for this low uptake are unclear. We investigated whether participation in screening varies according to cognitive ability and personality. Participants were members of The English Longitudinal Study of Ageing. In 2010-2011, respondents were asked about participation in bowel cancer screening, and cognitive ability and the 'Big Five' personality traits were assessed. Logistic regression was used to examine the cross-sectional relationships between cognitive ability and personality and screening participation in 2681 people aged 60-75 years who were eligible to have been invited to take part in the UK national screening programme for bowel cancer. In age-adjusted and sex-adjusted analyses, better cognition and higher conscientiousness were associated with increased participation in cancer screening. ORs (95% CIs) per SD increase were 1.10 (1.03 to 1.18) for cognitive ability and 1.10 (1.01 to 1.19) for conscientiousness. After further adjustment for household wealth and health literacy-shown previously to be associated with participation-these associations were attenuated (ORs were 1.07 (1.00 to 1.15) and 1.07 (0.97 to 1.18), respectively). We found some indication that better cognitive function and greater conscientiousness may be linked with a slightly increased likelihood of participation in bowel cancer screening. These relationships need investigation in other cohorts of older people.


Adaptive Scheme for Detecting Induction Motor Incipient Broken Bar Faults at Various Load and Inertia Conditions.
This paper introduces a novel online adaptive protection scheme to detect and diagnose broken bar faults (BBFs) in induction motors during steady-state conditions based on an analytical approach. The proposed scheme can detect precisely adjacent and non-adjacent BBFs in their incipient phases under different inertia, variable loading conditions, and noisy environments. The main idea of the proposed scheme is monitoring the variation in the phase angle of the main sideband frequency components by applying Fast Fourier Transform to only one phase of the stator current. The scheme does not need any predetermined settings but only one of the stator current signals during the commissioning phase. The threshold value is calculated adaptively to discriminate between healthy and faulty cases. Besides, an index is proposed to designate the fault severity. The performance of this scheme is verified using two simulated motors with different designs by applying the finite element method in addition to a real experimental dataset. The results show that the proposed scheme can effectively detect half, one, two, or three broken bars in adjacent/non-adjacent versions and also estimate their severity under different operating conditions and in a noisy environment, with accuracy reaching 100% independently from motor parameters.


Plasma cholesterol-lowering activity of gingerol- and shogaol-enriched extract is mediated by increasing sterol excretion.
The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7α-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up-regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP.


A shift from exploitation to interference competition with increasing density affects population and community dynamics.
Intraspecific competition influences population and community dynamics and occurs via two mechanisms. Exploitative competition is an indirect effect that occurs through use of a shared resource and depends on resource availability. Interference competition occurs by obstructing access to a resource and may not depend on resource availability. Our study tested whether the strength of interference competition changes with protozoa population density. We grew experimental microcosms of protozoa and bacteria under different combinations of protozoan density and basal resource availability. We then solved a dynamic predator-prey model for parameters of the functional response using population growth rates measured in our experiment. As population density increased, competition shifted from exploitation to interference, and competition was less dependent on resource levels. Surprisingly, the effect of resources was weakest when competition was the most intense. We found that at low population densities, competition was largely exploitative and resource availability had a large effect on population growth rates, but the effect of resources was much weaker at high densities. This shift in competitive mechanism could have implications for interspecific competition, trophic interactions, community diversity, and natural selection. We also tested whether this shift in the mechanism of competition with protozoa density affected the structure of the bacterial prey community. We found that both resources and protozoa density affected the structure of the bacterial prey community, suggesting that competitive mechanism may also affect trophic interactions.


Emerging Functions of Natural IgM and Its Fc Receptor FCMR in Immune Homeostasis.
Most natural IgM antibodies are encoded by germline Ig sequences and are produced in large quantities by both mice and humans in the absence of intentional immunization. Natural IgM are reactive with many conserved epitopes, including those shared by microorganisms and autoantigens. As a result, these antibodies play important roles in clearing intruding pathogens, as well as apoptotic/necrotic cells and otherwise damaged tissues. While natural IgM binds to target structures with low affinity due to a lack of significant selection by somatic hypermutation, its pentameric structure with 10 antigen-binding sites enables these antibodies to bind multivalent target antigens with high avidity. Opsonization of antigen complexed with IgM is mediated by cell surface Fc receptors. While the existence of Fc alpha/mu receptor has been known for some time, only recently has the Fc receptor specific for IgM (FCMR) been identified. In this review, we focus on our current understandings of how natural IgM and FCMR regulate the immune system and maintain homeostasis under physiological and pathological conditions.


A squamous metaplasia in a gastric ulcer scar of the antrum.
An 81-year-old man presented with epigastric pain and weight loss for one month. He had a past history of pulmonary tuberculosis, 10 years ago. We performed a gastroscopy, which showed a linear depressed whitish gastric ulcer scar (0.8 cm in length) in the posterior wall of the prepyloric antrum. The result of biopsy was reported as squamous epithelium. Immunohistochemical staining using an antibody to high molecular weight cytokeratin (HMC) revealed positive staining in the squamous epithelium. Two years later, the lesion was followed up. The lesion remained at same site endoscopically, but no squamous epithelium could be seen microscopically.


Peer-Centered Versus Standard Physician-Centered Video Counseling for Midurethral Sling Surgery: A Randomized Controlled Trial.
Peer counseling may improve upon provider counseling and enhance patient preparedness for midurethral sling (MUS) surgery. We aimed to compare the impact of peer-centered versus standard preoperative video counseling by assessing patient preparedness for MUS surgery. Women undergoing MUS were randomized to view either a peer-centered (PEER) or standard physician preoperative counseling video (PHYS). The PEER video featured a woman who had undergone MUS surgery and included the standard risks and benefits as well as additional information identified in prior work as important to patients. The PHYS video featured a surgeon discussing risks and benefits. Patients viewed either video at their preoperative visit and completed the Patient Preparedness Questionnaire (PPQ), Surgical Decision Satisfaction, Decisional Regret Scale, and the Urogenital Distress Inventory Short Form. Patients then underwent standard in-person surgeon counseling. Sessions were timed and compared with historical timed sessions. Our primary outcome was between-group differences in 6-week postoperative PPQ scores. Patient Preparedness Questionnaire scores did not differ between groups (postoperative PPQ scores: median [interquartile range], 95 [84, 100] vs 92 [80, 100]; P=0.50). The PEER group reported higher decisional regret (15 [0, 28.75] vs 0 [0, 10], P=0.02) and less symptom improvement on Urogenital Distress Inventory Short Form change scores compared with the PHYS group (47.2 [37.2, 62.5] vs 36.1 [16.5, 50], P=0.03); secondary outcomes were not different between groups. In-person counseling times decreased after watching either video compared with the institution's historical standard (8:27 minutes [08:56, 17:14] vs 11:34 minutes [5:22, 13:07]; P < 0.005). Patient preparedness did not differ between groups. Decision regret did not differ between groups once adjusted for urinary symptoms.


Astaxanthin Inhibits Oxidative Stress-Induced Ku Protein Degradation and Apoptosis in Gastric Epithelial Cells.
Oxidative stress induces DNA damage which can be repaired by DNA repair proteins, such as Ku70/80. Excess reactive oxygen species (ROS) stimulate the activation of caspase-3, which degrades Ku 70/80. Cells with decreased Ku protein levels undergo apoptosis. Astaxanthin exerts antioxidant activity by inducing the expression of catalase, an antioxidant enzyme, in gastric epithelial cells. Therefore, astaxanthin may inhibit oxidative stress-induced DNA damage by preventing Ku protein degradation and thereby suppressing apoptosis. Ku proteins can be degraded via ubiquitination and neddylation which adds ubiquitin-like protein to substrate proteins. We aimed to determine whether oxidative stress decreases Ku70/80 expression through the ubiquitin-proteasome pathway to induce apoptosis and whether astaxanthin inhibits oxidative stress-induced changes in gastric epithelial AGS cells. We induced oxidative stress caused by the treatment of β-D-glucose (G) and glucose oxidase (GO) in the cells. As a result, the G/GO treatment increased ROS levels, decreased nuclear Ku protein levels and Ku-DNA-binding activity, and induced the ubiquitination of Ku80. G/GO increased the DNA damage marker levels (γ-H2AX; DNA fragmentation) and apoptosis marker annexin V-positive cells and cell death. Astaxanthin inhibited G/GO-induced alterations, including Ku degradation in AGS cells. MLN4924, a neddylation inhibitor, and MG132, a proteasome inhibitor, suppressed G/GO-mediated DNA fragmentation and decreased cell viability. These results indicated that G/GO-induced oxidative stress causes Ku protein loss through the ubiquitin-proteasome pathway, resulting in DNA fragmentation and apoptotic cell death. Astaxanthin inhibited oxidative stress-mediated apoptosis via the reduction of ROS levels and inhibition of Ku protein degradation. In conclusion, dietary astaxanthin supplementation or astaxanthin-rich food consumption may be effective for preventing or delaying oxidative stress-mediated cell damage by suppressing Ku protein loss and apoptosis in gastric epithelial cells.


The Bvg virulence control system regulates biofilm formation in Bordetella bronchiseptica.
Bordetella species utilize the BvgAS (Bordetella virulence gene) two-component signal transduction system to sense the environment and regulate gene expression among at least three phases: a virulent Bvg+ phase, a nonvirulent Bvg- phase, and an intermediate Bvgi phase. Genes expressed in the Bvg+ phase encode known virulence factors, including adhesins such as filamentous hemagglutinin (FHA) and fimbriae, as well as toxins such as the bifunctional adenylate cyclase/hemolysin (ACY). Previous studies showed that in the Bvgi phase, FHA and fimbriae continue to be expressed, but ACY expression is significantly downregulated. In this report, we determine that Bordetella bronchiseptica can form biofilms in vitro and that the generation of biofilm is maximal in the Bvgi phase. We show that FHA is required for maximal biofilm formation and that fimbriae may also contribute to this phenotype. However, expression of ACY inhibits biofilm formation, most likely via interactions with FHA. Therefore, the coordinated regulation of adhesins and ACY expression leads to maximal biofilm formation in the Bvgi phase in B. bronchiseptica.


Glutamine and glutamate kinetics in humans.
To study glutamate and glutamine kinetics, 4-h unprimed intravenous infusions of L-[15N]glutamate, L-[2-15N]glutamine, and L-[5-15N]-glutamine were administered to healthy young adult male subjects in the postabsorptive state. Arterialized-venous blood samples were drawn and analyzed for glutamate and glutamine 15N enrichments. The fractional turnover rates of the tracer-miscible glutamate and glutamine pools were fast, 8.0 and 2.8% min-1, respectively. The glutamate tracer-miscible pool accounted for less than one-tenth the estimated free glutamate pool in the body. The plasma glutamate amino N, glutamine amino N and glutamine amide N rates of appearance were 83 +/- 22 (means +/- SD), 348 +/- 33, and 283 +/- 31 mumol X kg-1 X h-1, respectively. The glutamine amide N appearance rate was 20% slower than the amino N appearance rate, indicating that glutamine transaminase is an active pathway in human glutamine metabolism. From measurement of transfer of tracer 15N, we found that only 5% of the glutamine synthesized in cells and released into plasma was derived from intracellular glutamate that had mixed with plasma. These data demonstrate that intravenously administered tracers of glutamate or glutamine do not mix thoroughly with the intracellular pools, and their measured kinetics reflect transport rates through plasma rather than whole-body fluxes.


[Pathogenic effect of the parasite nematode Strelkovimermmis spiculatus (Nematoda Mermithidae) in larvae of mosquito Culex quinquesfasciatus (Diptera Culicidae) under laboratory conditions in Cuba].
The infective capacity of Strelkovimermis spiculatus Poinar and Camino, 1986, was evaluated under laboratory conditions for the first time in Cuba in order to introduce it as a new agent of biological control of mosquitoes of medical and epidemiological importance. The second stage larvae of Culex quinquefasciatus Say, 1823, were used and exposed to the infective juvenile parasites at different doses. It was observed a rise in the mean values of infestation and in the mortality percentage with the dose increase. Culex quinquefasciatus Say proved to be a good host and a dose of 7:1 will be optimum to attain high percentages of mortality and to obtain this parasite massively for its further evaluation under field conditions.


A study of phage- and ribotype patterns of Staphylococcus aureus isolated from bovine mastitis in the Nordic countries.
This study was conducted to investigate the geographical distribution of phage and ribotypes of Staphylococcus aureus causing bovine mastitis in the 5 Nordic countries. A total of 403 isolates of S. aureus was isolated from 403 different dairy herds. One hundred five strains were isolated in Denmark, 81 in Finland, 17 in Iceland, 96 in Norway and 104 in Sweden. The isolates were phage typed and characterized for their EcoRI restriction fragment length polymorphisms of the genes encoding ribosomal RNA (ribotyping). A total of 351 (87%) of the 403 isolates could be typed by phages assigning them to 25 different phage types. Two to 3 different phage types predominated within each country. One type (29/52) accounted for 36% of all the isolates and was found in 4 of the countries. A total of 87 different ribotypes was found among the isolates investigated. As for phage typing 2 to 3 different types predominated within countries. However, except for one type (ribotype 1), which was commonly found in Denmark, Sweden and Finland, different ribotypes predominated within each country. The combination of phage and ribotyping assigned the isolates to 178 different types. Ninety-six percent of the isolates of ribotype 1 belonged to phage type 29/52. This combined type accounted for 17% of all the 403 isolates. These findings show that a large number of different types of S. aureus can be isolated from cases of bovine mastitis. However, few types predominate within different countries. These predominating types seem to be specific in each country, however, a single type was common for both Denmark, Sweden and Finland. This could suggest differences in the virulence or in modes of transmission of predominating and rare types of S. aureus associated with bovine mastitis.


Production of monoclonal antibodies against human hepatocellular carcinoma by immunisation with a cell membrane preparation.
Monoclonal antibodies that bound to 3 human hepatocellular carcinoma cell lines (PLC/PRF/5, SK-SF and Mahlavu) and snap-frozen sections of a patient's tumour were raised by immunising mice with PLC/PRF/5 membrane preparations. The monoclonals designated RF-HCC 1 and RF-HCC 2 were of IgG1 and IgM subclasses respectively. Binding of the antibodies to surface epitopes present on Mahlavu cells in vitro took place in a biphasic fashion, with initial rapid binding of each antibody during the first 15 minutes of incubation followed by a plateau after this period. It was found that the commercially available MOPC 21 myeloma IgG1 (Sigma) monoclonal antibody used a control also bound to a surface antigenic determinant expressed on Mahlavu cells.


Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons.
A molecular basis of survival from neuronal injury is essential for the development of therapeutic strategy to remedy neurodegenerative disorders. In this study, we demonstrate that an EF-hand Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1), one of the key proteins for various neuronal functions, also acts as an important survival factor. Overexpression of NCS-1 rendered cultured neurons more tolerant to cell death caused by several kinds of stressors, whereas the dominant-negative mutant (E120Q) accelerated it. In addition, NCS-1 proteins increased upon treatment with glial cell line-derived neurotrophic factor (GDNF) and mediated GDNF survival signal in an Akt (but not MAPK)-dependent manner. Furthermore, NCS-1 is significantly up-regulated in response to axotomy-induced injury in the dorsal motor nucleus of the vagus neurons of adult rats in vivo, and adenoviral overexpression of E120Q resulted in a significant loss of surviving neurons, suggesting that NCS-1 is involved in an antiapoptotic mechanism in adult motor neurons. We propose that NCS-1 is a novel survival-promoting factor up-regulated in injured neurons that mediates the GDNF survival signal via the phosphatidylinositol 3-kinase-Akt pathway.


Noncommutative control in the rotational vestibuloocular reflex.
To investigate the role of noncommutative computations in the oculomotor system, three-dimensional (3D) eye movements were measured in seven healthy subjects using a memory-contingent vestibulooculomotor paradigm. Subjects had to fixate a luminous point target that appeared briefly at an eccentricity of 20 degrees in one of four diagonal directions in otherwise complete darkness. After a fixation period of approximately 1 s, the subject was moved through a sequence of two rotations about mutually orthogonal axes in one of two orders (30 degrees yaw followed by 30 degrees pitch and vice versa in upright and 30 degrees yaw followed by 20 degrees roll and vice versa in both upright and supine orientations). We found that the change in ocular torsion induced by consecutive rotations about the yaw and the pitch axis depended on the order of rotations as predicted by 3D rotation kinematics. Similarly, after rotations about the yaw and roll axis, torsion depended on the order of rotations but now due to the change in final head orientation relative to gravity. Quantitative analyses of these ocular responses revealed that the rotational vestibuloocular reflexes (VORs) in far vision closely matched the predictions of 3D rotation kinematics. We conclude that the brain uses an optimal VOR strategy with the restriction of a reduced torsional position gain. This restriction implies a limited oculomotor range in torsion and systematic tilts of the angular eye velocity as a function of gaze direction.


The relationship between self-reported borderline personality features and prospective illness course in bipolar disorder.
Although bipolar disorder (BD) and borderline personality disorder (BPD) share clinical characteristics and frequently co-occur, their interrelationship is controversial. Especially, the differentiation of rapid cycling BD and BPD can be troublesome. This study investigates the relationship between borderline personality features (BPF) and prospective illness course in patients with BD, and explores the effects of current mood state on self-reported BPF profiles. The study included 375 patients who participated in the former Stanley Foundation Bipolar Network. All patients met DSM-IV criteria for bipolar-I disorder (n = 294), bipolar-II disorder (n = 72) or bipolar disorder NOS (n = 9). BPF were assessed with the self-rated Personality Diagnostic Questionnaire. Illness course was based on 1-year clinician rated prospective daily mood ratings with the life chart methodology. Regression analyses were used to estimate the relationships among these variables. Although correlations were weak, results showed that having more BPF at baseline is associated with a higher episode frequency during subsequent 1-year follow-up. Of the nine BPF, affective instability, impulsivity, and self-mutilation/suicidality showed a relationship to full-duration as well as brief episode frequency. In contrast all other BPF were not related to episode frequency. Having more BPF was associated with an unfavorable illness course of BD. Affective instability, impulsivity, and self-mutilation/suicidality are associated with both rapid cycling BD and BPD. Still, many core features of BPD show no relationship to rapid cycling BD and can help in the differential diagnosis.


Phytochemistry: ibuprofen-like activity in extra-virgin olive oil.
Newly pressed extra-virgin olive oil contains oleocanthal--a compound whose pungency induces a strong stinging sensation in the throat, not unlike that caused by solutions of the non-steroidal anti-inflammatory drug ibuprofen. We show here that this similar perception seems to be an indicator of a shared pharmacological activity, with oleocanthal acting as a natural anti-inflammatory compound that has a potency and profile strikingly similar to that of ibuprofen. Although structurally dissimilar, both these molecules inhibit the same cyclooxygenase enzymes in the prostaglandin-biosynthesis pathway.


COVID-19 Vaccination Gap in Admitted Trauma Patients: A Critical Opportunity.
Coronavirus disease 2019 (COVID-19) vaccination is the core strategy for pandemic management. We hypothesized that a vaccination gap might exist between emergency department (ED) patients admitted for trauma and other ED patients. This was an observational quality improvement study using electronic health record data at an academic level-1 trauma center. Participants were all patients presenting to the adult ED with a Tennessee home address between January 1 and June 1, 2021. We measured the proportional difference in vaccination between admitted trauma patients and other ED patients over time (by week) and association via Spearman's rank correlation coefficient. Binary logistic regression facilitated covariate analysis to account for age, sex, race, home county, and ethnicity without and then with interaction between trauma admission and time. Geographic visual analysis compared county-level vaccination rates with odds of trauma admission by home county using a bivariate chloropleth map. The proportional difference in vaccination between trauma-admitted and other ED patients increased over time (Spearman's = 0.699). Adjusting for age, sex, race, home county, and ethnicity, there was a statistically significant vaccination difference between trauma-admitted and other ED patients (odds ratio = 0.53, 95% CI 0.43-0.65, p < 0.0001). Geographic analysis revealed increased trauma admission odds and lower vaccination rates in surrounding counties compared with Davidson County. We observed a widening COVID-19 vaccination gap between trauma-admitted and other ED patients. Vaccine outreach during trauma admission may provide a valuable point of contact for unvaccinated patients.


Multivariate-$t$ nonlinear mixed models with application to censored multi-outcome AIDS studies.
In multivariate longitudinal HIV/AIDS studies, multi-outcome repeated measures on each patient over time may contain outliers, and the viral loads are often subject to a upper or lower limit of detection depending on the quantification assays. In this article, we consider an extension of the multivariate nonlinear mixed-effects model by adopting a joint multivariate-$t$ distribution for random effects and within-subject errors and taking the censoring information of multiple responses into account. The proposed model is called the multivariate-$t$ nonlinear mixed-effects model with censored responses (MtNLMMC), allowing for analyzing multi-outcome longitudinal data exhibiting nonlinear growth patterns with censorship and fat-tailed behavior. Utilizing the Taylor-series linearization method, a pseudo-data version of expectation conditional maximization either (ECME) algorithm is developed for iteratively carrying out maximum likelihood estimation. We illustrate our techniques with two data examples from HIV/AIDS studies. Experimental results signify that the MtNLMMC performs favorably compared to its Gaussian analogue and some existing approaches.


Evaluation of Pain Assessment Techniques and Analgesia Efficacy in a Female Guinea Pig (Cavia porcellus) Model of Surgical Pain.
Guinea pigs (Cavia porcellus) are a frequently used species in research, often involving potentially painful procedures. Therefore, evidence-based recommendations regarding analgesia are critically needed to optimize their wellbeing. Our laboratory examined the efficacy of carprofen and extended-release (ER) buprenorphine, alone and as a multimodal combination, for relieving postsurgical pain in guinea pigs. Animals were assessed by using evoked (mechanical hypersensitivity), nonevoked (video ethogram, cageside ethogram, time-to-consumption test), and clinical (weight loss) measurements for 96 h during baseline, anesthesia-analgesia, and hysterectomy conditions. In addition, ER buprenorphine was evaluated pharmacologically. Guinea pigs treated with a single analgesic showed increased mechanical sensitivity for at least 96 h and indices of pain according to the video ethogram for as long as 8 h, compared with levels recorded during anesthesia-analgesia. In contrast, animals given both analgesics demonstrated increased mechanical sensitivity and behavioral evidence of pain for only 2 h after surgery compared with anesthesia-analgesia. The cageside ethogram and time-to-consumption tests failed to identify differences between conditions or treatment groups, highlighting the difficulty of identifying pain in guinea pigs without remote observation. Guinea pigs treated with multimodal analgesia or ER buprenorphine lost at least 10% of their baseline weights, whereas weight loss in carprofen animals was significantly lower (3%). Plasma levels for ER buprenorphine exceeded 0.9 ng/mL from 8 to 96 h after injection. Of the 3 analgesia regimens evaluated, multimodal analgesia provided the most effective pain control in guinea pigs. However the weight loss in the ER buprenorphine-treated animals may need to be considered during analgesia selection.


Spontaneous acetylcholine release in mammalian neuromuscular junctions.
Spontaneous secretion of the neurotransmitter acetylcholine in mammalian neuromuscular synapsis depends on the Ca2+ content of nerve terminals. The Ca2+ electrochemical gradient favors the entry of this cation. We investigated the possible involvement of three voltage-dependent Ca2+ channels (VDCC) (L-, N-, and P/Q-types) on spontaneous transmitter, release at the rat neuromuscular junction. Miniature end-plate potential (MEPP) frequency was clearly reduced by 5 microM nifedipine, a blocker of the L-type VDCC, and to a lesser extent by the N-type VDCC blocker, omega-conotoxin GVIA (omega-CgTx, 5 microM). On the other hand, nifedipine and omega-CgTx had no effect on K(+)-induced transmitter secretion. omega-Agatoxin IVA (100 nM), a P/Q-type VDCC blocker, prevents acetylcholine release induced by K+ depolarization but failed to affect MEPP frequency in basal conditions. These results suggest that in the mammalian neuromuscular junction Ca2+ enters nerve terminals through at least three different channels, two of them (L- and N-types) mainly related to spontaneous acetylcholine release and the other (P/Q-type) mostly involved in depolarization-induced neurotransmitter release. Ca(2+)-binding molecule-related spontaneous release apparently binds Ca2+ very rapidly and would probably be located very close to Ca2+ channels, since the fast Ca2+ chelator (BAPTA-AM) significantly reduced MEPP frequency, whereas EGTA-AM, exhibiting slower kinetics, had a lower effect. The increase in MEPP frequency induced by exposing the preparation to hypertonic solutions was affected by neither external Ca2+ concentration nor L-, N-, and P/Q-type VDCC blockers, indicating that extracellular Ca2+ is not necessary to produce hyperosmotic neurosecretion. On the other hand, MEPP frequency was diminished by BAPTA-AM and EGTA-AM to the same extent, supporting the view that hypertonic response is promoted by "bulk" intracellular Ca2+ concentration increases.


Aspects of asthma.
Dr H Blair outlines the etiology of asthma inchildren and discusses investigation, treatmentand prevention with special reference to theelimination of external allergens.


Recombination between chromosomal IS200 elements supports frequent duplication formation in Salmonella typhimurium.
Spontaneous tandem chromosomal duplications are common in populations of Escherichia coli and Salmonella typhimurium. They range in frequency for a given locus from 10(-2) to 10(-4) and probably form by RecA-dependent unequal sister strand exchanges between repetitive sequences in direct order. Certain duplications have been observed previously to confer a growth advantage under specific selective conditions. Tandem chromosomal duplications are unstable and are lost at high frequencies, representing a readily reversible source of genomic variation. Six copies of a small mobile genetic element IS200 are evenly distributed around the chromosome of S. typhimurium strain LT2. A survey of 120 independent chromosomal duplications (20 for each of six loci) revealed that recombination between IS200 elements accounted for the majority of the duplications isolated for three of the loci tested. Duplications of the his operon were almost exclusively due to recombination between repeated IS200 elements. These data add further support to the idea that mobile genetic elements provide sequence repeats that play an important role in recombinational chromosome rearrangements, which may contribute to adaptation of bacteria to stressful conditions.


Effectiveness of sucrose analgesia in newborns undergoing painful medical procedures.
Sucrose is widely used to manage procedural pain in term newborns despite a lack of evidence of its effectiveness for different procedures and infant populations. Our objectives were to evaluate the effectiveness and safety of sucrose in newborns undergoing various medical procedures within 2 days of birth. We performed a double-blind, randomized controlled trial. We included newborns (>or= 36 weeks gestation) of diabetic mothers and nondiabetic mothers. Each newborn received 2 mL of a 24%-sucrose or placebo solution before all procedures. We used the Premature Infant Pain Profile to assess pain during intramuscular injection of vitamin K, venipuncture for the newborn screening test and the first 3 heel lances for glucose monitoring (newborns of diabetic mothers only). Scores ranged from from 0 (no pain) to 18 (maximum pain). We included 240 newborns (120 from diabetic mothers, 120 from nondiabetic mothers). The overall mean pain score was lower among newborns who received sucrose than among those who received a placebo (mean difference -1.3, 95% confidence interval [CI] -2.0 to -0.6). We found that pain scores during intramuscular injection did not differ significantly between the sucrose and placebo groups for newborns of diabetic or nondiabetic mothers (newborns of nondiabetic mothers: mean difference -1.1, 95% CI -2.4 to 0.2; newborns of diabetic mothers: mean difference -1.0, 95% CI -2.4 to 0.4). During venipuncture, newborns who received sucrose had lower pain scores compared with those who received a placebo (newborns of nondiabetic mothers: mean difference -3.2, 95% CI -4.6 to -1.8; newborns of diabetic mothers: mean difference -2.4, 95% CI -3.8 to -1.0). Among newborns of diabetic mothers, there was no difference in pain during the first 3 heel lances or mean glucose levels between the sucrose and placebo groups (p = 0.94 and p = 0.29 respectively). We found a modest reduction of pain in newborns of both diabetic and nondiabetic mothers when sucrose was used for all medical procedures performed in the first 2 days after birth. However, when each procedure was analyzed separately, we found that the effectiveness of sucrose was limited to venipuncture for the newborn screening test. (http://Clinicaltrials.gov trial register no. NCT00213213.).


Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes.
Early clinical trials, mostly in the setting of melanoma, have shown that dendritic cells (DCs) expressing tumor antigens induce some immune responses and some clinical responses. A major difficulty is the extension to other tumors, such as breast carcinoma, for which few defined tumor-associated antigens are available. We have demonstrated, using both prostate carcinoma and melanoma as model systems, that DCs loaded with killed allogeneic tumor cell lines can induce CD8+ T cells to differentiate into cytotoxic T lymphocytes (CTLs) specific for shared tumor antigens. The present study was designed to determine whether DCs would capture killed breast cancer cells and present their antigens to autologous CD4+ and CD8+ T cells. We show that killed breast cancer cells are captured by immature DCs that, after induced maturation, can efficiently present MHC class I and class II peptides to CD8+ and CD4+ T lymphocytes. The elicited CTLs are able to kill the target cells without a need for pretreatment with interferon gamma. CTLs can be obtained by culturing the DCs loaded with killed breast cancer cells with unseparated peripheral blood lymphocytes, indicating that the DCs can overcome any potential inhibitory effects of breast cancer cells. Loading DCs with killed breast cancer cells may be considered a novel approach to breast cancer immunotherapy and to identification of shared breast cancer antigens.


Efficacy of a program of prevention and control for methicillin-resistant Staphylococcus aureus infections in an intensive-care unit.
Methicillin-resistant Staphylococcus aureus (MRSA) is endemic in most Brazilian Hospitals, and there are few studies which show the efficacy of control measures in such situations. This study evaluated intensive care unit (ICU) patients, in two years divided in control, intervention and post-intervention group. Intervention measures: hands-on educational programs for healthcare workers; early identification of MRSA infected or colonized patients, labeled with a bed-identification tag for contact isolation; nasal carriers, patients, and healthcare professionals treated with topical mupirocin for five days. The hospital infection rates in the control period were compared to the ones in the post-intervention period. Hospital infection rates were found by means of the NNISS methodology The incidence coefficients of MRSA hospital infection (monthly average of 1,000 pts/day) in the control, intervention and post-intervention groups were respectively: 10.2, 5.1 and 2.5/1,000 pts/day (p<0.001) and MRSA-originated bloodstream infections were 3.6, 0.9 and 1.8/1,000 central venous catheter/day (p=0.281). Nasal colonization in both intervention and post-intervention periods was of 30.9% and 22.1% among the hospitalized patients, respectively 54.4% and 46.1% of whom were already MRSA-positive when admitted to the unit. In the intervention period, most of those MRSA infected patients (76.2%) were nasal carrier. Mortality rates were, respectively 26.6%; 27.3% and 21.0% (p<0.001). Nasal carriers, both patients (93.7%) and healthcare professionals (88.2%), were successfully treated with topical mupirocin. Intervention measures for the prevention and control of MRSA infections in ICUs, have been efficient in the reduction of the bloodstream and MRSA-originated hospital infections incidence, and reduced the overall mortality rate significantly.


Influence of a sexism and sexual harassment prevention course on medical students' perceptions of and responses to problematic situations.
Issues of sexism and sexual harassment within the medical field are widespread. The aim of his study was to describe the influence of a training course on the prevention of sexism and sexual harassment on medical students' perceptions and responses to problematic situations in the workplace. We performed a secondary analysis of the transcripts of 16 medical students' interviews. The data were initially gathered as part of an external evaluation of the course. We decided to further explore these with a focus on potential changes about sexism and sexual harassment awareness induced by the course. Data were analyzed using qualitative thematic analysis. Most medical students were aware of the existence of sexism and sexual harassment in the medical environment before the course but were not always able to delineate what could be considered as such or not. The course allowed them to broaden their ability to identify problematic situations, that were somewhat "trivialized" before, and to set a lower cut-off when judging what constitutes sexism or sexual harassment. It also provided them with tools on how to react when confronted to these situations, as well as resources to seek help. However, students stressed the importance of such courses also being offered to medical staff higher up in the hierarchy, as they are the ones in a position of power. The course helped students to better identify and react to sexism and sexual harassment. However, given students' lack of power within the hierarchy, efforts to prevent sexism and sexual harassment must be undertaken at an institutional level to allow for change in the system as a whole.


Help! I Need a Remote Guide in My Mixed Reality Collaborative Environment.
The help of a remote expert in performing a maintenance task can be useful in many situations, and can save time as well as money. In this context, augmented reality (AR) technologies can improve remote guidance thanks to the direct overlay of 3D information onto the real world. Furthermore, virtual reality (VR) enables a remote expert to virtually share the place in which the physical maintenance is being carried out. In a traditional local collaboration, collaborators are face-to-face and are observing the same artifact, while being able to communicate verbally and use body language, such as gaze direction or facial expression. These interpersonal communication cues are usually limited in remote collaborative maintenance scenarios, in which the agent uses an AR setup while the remote expert uses VR. Providing users with adapted interaction and awareness features to compensate for the lack of essential communication signals is therefore a real challenge for remote MR collaboration. However, this context offers new opportunities for augmenting collaborative abilities, such as sharing an identical point of view, which is not possible in real life. Based on the current task of the maintenance procedure, such as navigation to the correct location or physical manipulation, the remote expert may choose to freely control his/her own viewpoint of the distant workspace, or instead may need to share the viewpoint of the agent in order to better understand the current situation. In this work, we first focus on the navigation task, which is essential to complete the diagnostic phase and to begin the maintenance task in the correct location. We then present a novel interaction paradigm, implemented in an early prototype, in which the guide can show the operator the manipulation gestures required to achieve a physical task that is necessary to perform the maintenance procedure. These concepts are evaluated, allowing us to provide guidelines for future systems targeting efficient remote collaboration in MR environments.


Information-seeking trends of medical professionals and students from middle-income countries: a focus on the Philippines.
Increased emphasis has been given to the practice of evidence-based medicine (EBM) worldwide. Access to quality health information is essential to the practice of EBM in developing countries. To understand the information needs and sources of information of physicians from low- and middle-income countries (LMICs). Medical doctors and students participated in an 18-question online or paper study. Of the 156 respondents from six LMICs, 146 (94%) came from the Philippines. Eighty-eight per cent encountered at least one clinical question daily, while 58% were very likely to search for answers. A basic mobile phone was the most used device at home (94%) and at work (82%). More than half had Internet connectivity at home (62%) and just under half at work (46%). In decreasing order, short messaging services (SMS), email, instant messaging and multimedia messaging services (MMS) were the most commonly used messaging tools at home and at work. The primary source for medication questions was a formulary, but for diagnostic dilemmas, colleagues were consulted first. PubMed use was high for therapy and management questions. The use of health information from the Internet through mobile devices may be increasing. Access to health information was higher at home than at work. These results may be useful when planning resources for healthcare givers in resource-poor settings.


Smooth muscle membrane vesicle orientation: a study on intactness and sidedness of rat myometrium plasma membrane vesicles.
Plasma membrane vesicles of rat myometrium were prepared in media containing 240 mM sucrose. The vesicles were exposed to isotonic, hypertonic, and hypotonic sucrose concentrations, fixed, sectioned, and studied using the electron microscope. The vesicles fixed in isotonic media were circular in appearance. Vesicles fixed in hypertonic media were distorted and showed a reduced volume to surface ratio consistent with the hypothesis that greater than 80% of the vesicles were osmotically active to sucrose. Cationized ferritin binding studies and Ca binding and release studies were also consistent with this finding. Exposure to hypotonic media also yielded membranes with distorted profiles indicating that they had been ruptured. [3H]Sucrose trapping experiments revealed that the vesicles had an internal volume of 1.20-1.44 mL/g protein. Hypotonic shock treatment reduced this intravesicular volume to 0.20-0.28 mL/g protein. The hypotonic shock treatment also led to enhanced galactose oxidase catalyzed Na3B3H4 labelling of the membranes and to increased K+-activated ouabain-sensitive p-nitrophenyl phosphatase activity. The enhancement was the same (55 +/- 10%) in the various membrane preparations for both the parameters. The data are interpreted to conclude that the rat myometrium plasma membrane vesicles consisted of 20% broken vesicles and equal proportions of intact vesicles of inside-out and rightside-out orientations.


Beyond the waves: Unraveling pandemic outcomes with genomic insights and immunity analysis - Evidence from 14 countries.
Although the World Health Organization and many governments have recategorized COVID-19 as a generally mild to moderately severe disease, consecutive pandemic waves driven by immune escape variants have underscored the need for timely and accurate prediction of the next outbreak. Nevertheless, little attention has been paid to translating genomic data and infection- and vaccine-induced immunity into direct estimates. We retrieved epidemiologic and genomic data shortly before pandemic waves across 14 developed countries from late 2021 to mid-2022 and examined associations between early-stage variant competition, infection- and vaccine-induced immunity, and the time intervals between wave peaks. We applied regression analysis and the generalized estimating equation method to construct an inferential model. Each per cent increase in the proportion of a new variant was associated with a 1.0% reduction in interpeak intervals on average. Curvilinear associations between vaccine-induced immunity and outcome variables were observed, suggesting that reaching a critical vaccine distribution rate may decrease the caseload of the upcoming wave. By leveraging readily accessible pre-outbreak genomic and epidemiologic data, our results not only substantiate the predictive potential of early variant fractions but also propose that immunity acquired through infection alone may not sufficiently mitigate transmission. Conversely, a rapid and widespread vaccination initiative appears to be correlated with a decrease in disease incidence.


FOXF1 Regulates Alveolar Epithelial Morphogenesis through Transcriptional Activation of Mesenchymal WNT5A.
Mutations in the FOXF1 (forkhead box F1) gene, encoding the mesenchymal FOX (forkhead box) transcription factor, are linked to alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with the loss of alveolar capillaries and lung hypoplasia. Although proangiogenic functions of FOXF1 have been extensively studied, the role of FOXF1 in mesenchymal-epithelial signaling during lung development remains uncharacterized. Herein, we used murine lung organoids to demonstrate that the S52F FOXF1 mutation (found in patients with ACDMPV) stimulates canonical WNT/β-catenin signaling in type 2 alveolar epithelial cells (AEC2s), leading to increased proliferation of AEC2s and decreased differentiation of AEC2s into type 1 alveolar epithelial cells (AEC1s). Alveolar organoids containing Foxf1WT/S52F lung fibroblasts and wild-type epithelial cells grew faster on Matrigel and exhibited AEC2 hyperplasia. AEC2 hyperplasia and loss of AEC1s were found in the lungs of Foxf1WT/S52F embryos, a mouse model of ACDMPV. Activation of canonical WNT/β-catenin signaling in AEC2s of lung organoids and Foxf1WT/S52F mice was associated with decreased expression of noncanonical WNT5A (Wnt family member 5A) ligand in lung fibroblasts. Mechanistically, FOXF1 directly activates the Wnt5a gene transcription through an evolutionarily conserved +6320/+6326 region located in the first intron of the Wnt5a gene. Site-directed mutagenesis of the +6320/+6326 region prevented the transcriptional activation of the Wnt5a enhancer by FOXF1. Treatment with exogenous WNT5A ligand inhibited the effects of the S52F FOXF1 mutation on canonical WNT/β-catenin signaling in alveolar organoids, preventing aberrant AEC2 expansion and restoring differentiation of AEC1s. Activation of either FOXF1 or WNT5A may provide an attractive strategy to improve lung function in patients with ACDMPV.


Improving fluid balance monitoring on the wards.
Clinical experience and nursing metrics have consistently identified poor documentation of fluid balance monitoring at Milton Keynes University Hospital, compromising patient safety and quality of care. This project aimed to increase the percentage of fluid balance charts correctly completed on the wards. Three areas for improvement were identified: understanding the importance of good fluid balance monitoring, correct identification of patients requiring monitoring, and ease of completion of fluid balance charts. Three interventions were deployed on two acute medical awards in consecutive cycles; 1) small group education for staff, 2) creation of board magnets to aid the multidisciplinary team to identify patients requiring monitoring, 3) modification of the current fluid balance chart. Questionnaires were utilised to highlight improvements with current charts and measured staff awareness pre and post education. Each intervention was implemented for one week followed by daily surveys for four days to monitor compliance. Initial results showed a range of 6-12 charts used daily per ward. Of these 0-45% of them were correctly filled. Post education there was a reduced number of inappropriate charts. Introduction of board magnets improved correlation between doctors and nurses in identification of patients (52% before, 77% after magnets). Following modification there was a subjective improvement in the quality of chart completion. This study highlighted that understanding and use of fluid balance monitoring can be improved for nurses, health care assistants (HCAs), and doctors. These improvements allow better documentation and safer patient care. As a result, Milton Keynes University Hospital is investing in magnets and modified charts for a Trust-wide pilot.


Adolescent health in rural Ghana: A cross-sectional study on the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors.
In sub-Saharan Africa, infectious diseases and malnutrition constitute the main health problems in children, while adolescents and adults are increasingly facing cardio-metabolic conditions. Among adolescents as the largest population group in this region, we investigated the co-occurrence of infectious diseases, malnutrition and cardio-metabolic risk factors (CRFs), and evaluated demographic, socio-economic and medical risk factors for these entities. In a cross-sectional study among 188 adolescents in rural Ghana, malarial infection, common infectious diseases and Body Mass Index were assessed. We measured ferritin, C-reactive protein, retinol, fasting glucose and blood pressure. Socio-demographic data were documented. We analyzed the proportions (95% confidence interval, CI) and the co-occurrence of infectious diseases (malaria, other common diseases), malnutrition (underweight, stunting, iron deficiency, vitamin A deficiency [VAD]), and CRFs (overweight, obesity, impaired fasting glucose, hypertension). In logistic regression, odds ratios (OR) and 95% CIs were calculated for the associations with socio-demographic factors. In this Ghanaian population (age range, 14.4-15.5 years; males, 50%), the proportions were for infectious diseases 45% (95% CI: 38-52%), for malnutrition 50% (43-57%) and for CRFs 16% (11-21%). Infectious diseases and malnutrition frequently co-existed (28%; 21-34%). Specifically, VAD increased the odds of non-malarial infectious diseases 3-fold (95% CI: 1.03, 10.19). Overlap of CRFs with infectious diseases (6%; 2-9%) or with malnutrition (7%; 3-11%) was also present. Male gender and low socio-economic status increased the odds of infectious diseases and malnutrition, respectively. Malarial infection, chronic malnutrition and VAD remain the predominant health problems among these Ghanaian adolescents. Investigating the relationships with evolving CRFs is warranted.


Impact of Roux-en-Y gastric bypass surgery on rat intestinal glucose transport.
Roux-en-Y gastric bypass (RYGB) has become the gold-standard bariatric procedure, partly because of the rapid resolution of accompanying diabetes. There is increasing evidence this is mediated by duodenal exclusion. We hypothesize that duodenal exclusion suppresses intestinal Na(+)/glucose cotransporter SGLT1-mediated glucose transport, improving glucose handling, and aimed to test this in a rodent RYGB model. Sprague-Dawley rats underwent sham procedure or duodenal exclusion by RYGB (10 cm Roux, 16 cm biliopancreatic limbs). Animals were maintained for 3 wk on a Western diet, before harvest at 10 AM, 4 PM, and 10 PM. Sections were taken from each limb for hematoxylin and eosin staining, and morphological assessment was performed. Functional glucose uptake studies, along with Western blotting and quantitative PCR, were performed on Roux limb. Histology showed morphometric changes in Roux and common limbs, with increase in villus height and crypt depth compared with BP and sham jejunum. Despite this, glucose transport was reduced by up to 68% (P < 0.001) in the Roux limb compared with sham jejunum. Normal diurnal rhythms in glucose uptake were ablated. This occurred at a posttranscriptional level, with little change in message but appearance of different weight species of Sglt1 on Western blotting. We have shown duodenal exclusion significantly influences both intestinal structure and glucose transport function, with glucose absorptive capacity reduced after RYGB. This provides a novel mechanistic explanation for some of the antidiabetic effects of RYGB.


Chromosome 6p22 locus associated with clinically aggressive neuroblastoma.
Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known. We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations. We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01). A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.


Remodeling potential of phalangeal distal condylar malunions in children.
Distal condylar phalangeal (DCP) fractures in children are uncommon, but their periarticular location makes them problematic. Malunions are particularly difficult to treat. These fractures are generally thought to have a poor remodeling potential because their location is far from the phalangeal physis. We present 8 cases of DCP malunion in children with a mean 5-year follow-up demonstrating consistent remodeling. In this study, DCP fractures were defined as those occurring at or distal to the collateral ligament recess of the proximal or middle phalanx in skeletally immature patients. Radiographic parameters examined at the time of established malunion and at final follow-up included coronal and sagittal plane deformity and translational malalignment of the distal fragment in relation to the proximal shaft. Range of motion was measured, and a brief questionnaire was implemented to establish patient satisfaction. We examined 8 patients with a minimum 1-year follow-up (mean, 5.3 y). Average age at injury was 8.8 years (range, 2-14 y). In the sagittal plane, fractures remodeled from an initial mean deformity of 30.9° to 0.0°; in the coronal plane, from 10.5° to 3.9°. Fracture translation in the sagittal plane corrected, as well, from a mean 57.5% at injury to 0.0% at final follow-up. There was no functionally limiting loss of motion of the digit in any patient. Subjectively, only 2 patients complained of cosmetic deformity, both of which were coronal plane deformities of the small finger. In this case series, DCP malunions in children remodeled significantly and completely in the sagittal plane, and all patients had good final range of motion. Furthermore, patients were satisfied with nonsurgical treatment at long-term follow-up. This series describes the remodeling potential of DCP fractures in children, lending support to the previously reported cases. These findings support treating late-presenting pediatric DCP malunions nonsurgically. Therapeutic IV.


Intravenous prednisolone in chronic bronchial asthma.
A single injection of 40 mg prednisolone phosphate was given to 10 patients with chronic bronchial asthma. Changes in pulmonary function were followed over a 30-hour period. Statistically significant changes occurred in the tests employed one hour after the injection of prednisolone. The maximum change for the group as a whole was seen to occur after eight hours. This time course of response is very similar to that obtained in previous studies on similar groups of patients with oral prednisolone where the peak effect occurred nine hours after the drug had been given. Intravenous hydrocortisone produces a much earlier peak effect, at five hours, when it is administered to chronic asthmatic patients.


Type 2 iodothyronine deiodinase is essential for thyroid hormone-dependent embryonic development and pigmentation in zebrafish.
Despite the known importance of thyroid hormones (THs) in vertebrate growth and development, the role of tissue-specific TH activation in early embryogenesis remains unclear. We therefore examined the function of type 2 iodothyronine deiodinase (D2), one of the two tissue-specific enzymes catalyzing the conversion of T4 to T3, in developing zebrafish embryos (Danio rerio). Microinjection of early embryos with antisense oligonucleotides targeting either the D2 translation start site or the splice junction between the first exon and intron induced delays in development and pigmentation, as determined through the measurement of otic vesicle length, head-trunk angle, and pigmentation index at 31 h after fertilization. The antisense-induced delays in developmental progression and pigmentation were reversible through treatment with T3, suggesting that these phenotypic effects may be due to the depletion of intracellular T3 levels. Additional evidence for this hypothesis was provided by quantitative RT-PCR analysis of TH receptor-beta expression in D2 knockdown embryos, revealing a significant down-regulation of this T3-induced transcript that could be reversed by T3 treatment. Tyrosinase expression was also down-regulated in D2 knockdown embryos to a greater degree than could be predicted by the observed delay in developmental progression, suggesting that reduced D2 activity and resultant low intracellular T3 availability may directly influence pigmentation in zebrafish. These data indicate that TH activation by D2 is essential for embryonic development and pigmentation in zebrafish.


Topological defects in moiré fringes with spiral zone plates.
We present a study of spatial structures created by superposition of spiral zone plates used for generating optical beams with phase singularities. Moiré fringes are observed that show topological defects similar to those appearing in interference patterns of optical vortices. A brief theoretical discussion is included that supports the similarities between the two phenomena. Our results may lead to interesting applications to digital information processing by optical means.


Comparison between the gold standard DXA with calcaneal quantitative ultrasound based-strategy (QUS) to detect osteoporosis in an HIV infected cohort.
Osteoporosis represents one of the most frequent comorbidity among HIV patients. The current standard method for osteoporosis diagnosis is dual-energy X-ray absorptiometry. Calcaneal quantitative ultrasound can provide information about bone quality. The aims of this study are to compare these two methods and to evaluate their ability to screen for vertebral fracture. This cross-sectional study was conducted in HIV patients attending the Clinic of Infectious and Tropical Diseases of Brescia during 2014 and who underwent lumbar/femoral dual-energy X-ray absorptiometry, vertebral fracture assessment and calcaneal quantitative ultrasound. The assessment of osteoporosis diagnostic accuracy was performed for calcaneal quantitative ultrasound and for vertebral fracture comparing them with dual-energy X-ray absorptiometry. We enrolled 73 patients and almost 48% of them had osteoporosis with at least one of the method used. Vertebral fracture were present in 27.4%. Among patients with normal bone measurements, we found vertebral fracture in proportion between 10% and 30%. If we used calcaneal quantitative ultrasound method and/or X-ray as screening, the percentages of possible savable dual-energy X-ray absorptiometry ranged from 12% to 89% and misclassification rates ranged from 0 to 24.6%. A combined strategy, calcaneal quantitative ultrasound and X-Ray, identified 67% of patients with low risk of osteoporosis, but 16.4% of patients were misclassified. We observed that patients with osteoporosis determined by calcaneal quantitative ultrasound and/or dual-energy X-ray absorptiometry have higher probability to undergo vertebral fracture, but neither of them can be used for predicting vertebral fracture. Use of calcaneal quantitative ultrasound for screening is a reasonable alternative of dual-energy X-ray absorptiometry since our study confirm that none strategy is clearly superior, but both screen tools must be always completed with X-ray.


Changes in the expression of the Alzheimer's disease-associated presenilin gene in drosophila heart leads to cardiac dysfunction.
Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer's disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.


Application and challenges of olfactory ensheathing cells in clinical trials of spinal cord injury.
Spinal cord injury (SCI) can lead to severe motor, sensory and autonomic nervous dysfunction, cause serious psychosomatic injury to patients. There is no effective treatment for SCI at present. In recent years, exciting evidence has been obtained in the application of cell-based therapy in basic research. These studies have revealed the fact that cells transplanted into the host can exert the pharmacological properties of treating and repairing SCI. Olfactory ensheathing cells (OECs) are a kind of special glial cells. The application value of OECs in the study of SCI lies in their unique biological characteristics, that is, they can survive and renew for life, give full play to neuroprotection, immune regulation, promoting axonal regeneration and myelination formation. The function of producing secretory group and improving microenvironment. This provides an irreplaceable treatment strategy for the repair of SCI. At present, some researchers have explored the possibility of treatment of OECs in clinical trials of SCI. Although OECs transplantation shows excellent safety and effectiveness in animal models, there is still lack of sufficient evidence to prove the effectiveness of their clinical application in clinical trials. There has been an obvious stagnation in the transformation of OECs transplantation into routine clinical practice, and clinical trials of cell therapy in this field are still facing major challenges and many problems that need to be solved. Therefore, this paper summarized and analyzed the clinical trials of OECs transplantation in the treatment of SCI, and discussed the problems and challenges of OECs transplantation in clinical trials.


How I treat indolent lymphoma.
Despite advances in treatment, there was little evidence until recently that this led to improvement in the survival of patients with indolent lymphoma, with patients continuing to have an unremitting course of relapse of disease. There appears to have been a change in the natural history of these diseases with the introduction of chemoimmunotherapy that may finally result in improvements in survival. With so many agents available for the treatment of indolent lymphomas, questions that have to be addressed include the following: is there still a role for a "watch-and-wait" approach in asymptomatic patients or should they be treated at diagnosis, what are the optimal first-line and salvage treatments, what is the role of maintenance therapy, and is there any role for stem cell transplantation in these diseases? No established treatment of choice has yet emerged, and many of these questions remain unresolved. It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released and that improvement in outcome will result from identification of therapies that target the underlying pathophysiology of the diseases.


Bordetella pertussis: an underreported pathogen in pediatric respiratory infections, a prospective cohort study.
The incidence of pertussis has been increasing worldwide. In the Netherlands, the seroprevalence has risen higher than the reported cases, suggesting that laboratory tests for pertussis are considered infrequently and that even more pertussis cases are missed. The objective of our study was to determine the frequency of pertussis in clinically unsuspect cases compared to suspect cases with the intention of finding clinical predictors. The present prospective cohort study was part of a controlled clinical trial evaluating the impact of molecular diagnostics on clinical decision making in pediatric respiratory infections, performed during 2 winter seasons. For this study, in the first season pertussis was only tested in case of clinical suspicion, in the second season, pertussis was also tested without clinical suspicion. Multivariate and univariate analysis were performed using SPSS 18 and Statistical software 'R'. In the two seasons respectively 22/209 (10,5%) and 49/373 (13,1%) cases were clinically suspected of pertussis. Bordetella pertussis was detected by real time RT-PCR in respectively 2/22 (9,1%) and 7/49 (14,3%) cases. In the second season an additional 7 cases of pertussis were found in clinically unsuspected cases (7/257 = 2,7%). These additional cases didn't differ in clinical presentation from children without a positive test for pertussis with respect to respiratory symptoms. Pertussis in children sometimes mimics viral respiratory tract infections. If pertussis diagnostics are based on clinical suspicion alone, about 1 in 5 cases (19%) is missed. Despite widely accepted clinical criteria, paroxysmal cough is not a good predictor of pertussis. To prevent spreading, physicians should include B. pertussis in routine diagnostics in respiratory tract infections.


Diagnostic capability of dynamic ultrasound evaluation of supination-external rotation ankle injuries: a cadaveric study.
Ankle syndesmosis injuries are common and range in severity from subclinical to grossly unstable. Definitive diagnosis of these injuries can be made with plain film radiographs, but are often missed when severity or image quality is low. Computed tomography (CT) and magnetic resonance imaging (MRI) can provide definitive diagnosis, but are costly and introduce the patient to radiation when CT is used. Ultrasonography may circumvent many of these disadvantages by being inexpensive, efficient, and able to detect injuries without radiation exposure. The purpose of this study was to evaluate the ability of ultrasonography to detect early stage supination-external rotation (SER) ankle syndesmosis injuries with a dynamic external rotational stress test. Nine, all male, fresh frozen specimens were secured to an ankle rig and stress tested to 10 Nm of external rotational torque with ultrasonography at the tibiofibular clear space. The ankles were subjected to syndesmosis ligament sectioning and repeat stress measurements of the tibiofibular clear space at peak torque. Stress tests and measurements were repeated three times and averaged and analyzed using a repeated one-way analysis of variance (ANOVA). There were six ankle injury states examined including: Intact State, 75% of AITFL Cut, 100% of AITFL Cut, Fibula FX - Cut 8 cm proximal, 75% PITFL Cut, and 100% PITFL Cut. Dynamic external rotation stress evaluation using ultrasonography was able to detect a significant difference between the uninjured ankle with a tibiofibular clear space of 4.5 mm and the stage 1 complete injured ankle with a clear space of 6.0 mm (P < .02). Additionally, this method was able to detect significant differences between the uninjured ankle and the stage 2-4 injury states. Dynamic external rotational stress evaluation using ultrasonography was able to detect stage 1 Lauge-Hansen SER injuries with statistical significance and corroborates criteria for diagnosing a syndesmosis injury at ≥6.0 mm of tibiofibular clear space widening.


Therapeutic Targeting of TGFβ Ligands in Glioblastoma Using Novel Antisense Oligonucleotides Reduces the Growth of Experimental Gliomas.
Transforming growth factor (TGF)-β is expressed at high levels by glioma cells and contributes to the malignant phenotype of glioblastoma. However, its therapeutic targeting remains challenging. Here, we examined an alternative therapeutic approach of TGFβ inhibition using two novel phosphorothioate-locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, ISTH1047 and ISTH0047, which specifically target TGFβ1 and TGFβ2. We characterized the effects of ISTH1047 and ISTH0047 on TGFβ1/2 expression, downstream signaling and growth of human LN-308, LN-229, and ZH-161 cells as well as murine SMA-560 glioma cells in vitro. Furthermore, we assessed their target inhibition and effects on survival in orthotopic xenogeneic and syngeneic rodent glioma models in vivo. Both antisense oligonucleotides specifically silenced their corresponding target and abrogated SMAD2 phosphorylation in several glioma cell lines. Moreover, inhibition of TGFβ1 or TGFβ2 expression by ISTH1047 or ISTH0047 reduced the migration and invasiveness of LN-308 and SMA-560 glioma cells. Systemic antisense oligonucleotide administration to glioma-bearing mice suppressed TGFβ1 or TGFβ2 mRNA expression as well as the expression of the downstream target PAI-1 in orthotopic gliomas. Glioma-bearing mice had significantly prolonged survival upon systemic treatment with ISTH1047 or ISTH0047, which was associated with a reduction of intratumoral SMAD2 phosphorylation and, in a fully immunocompetent model, with increased immune cell infiltration. Targeting TGFβ expression with the novel LNA antisense oligonucleotides ISTH1047 or ISTH0047 results in strong antiglioma activity in vitro and in vivo, which may represent a promising approach to be examined in human patients with glioma.


[Osteocytic bone remodeling: history of the problem, morphological markers].
On the basis of the authors' own results and the analysis of the literature, the morphological markers of resorptive and synthetic phases of osteocytic bone remodeling under physiological conditions, are discussed. Their application by different authors is considered taking into account the history of the research of the osteocyte role in bone matrix metabolism (synthesis and resorption). Currently, there arose an urgent need for the quantitative assessment of osteocyte remodeling by combining routine histological methods of the osseous tissue study with the possibilities of modern image analysis systems.


Relationship Between Intracellular Free Calcium Concentration and NMDA-induced Cerebellar Granule Cell Survival In Vitro.
The survival of cerebellar granule cells in culture is stimulated by activation of the N-methyl-d-aspartate (NMDA) class of glutamate receptors. Activation of these receptors at the key period for cell survival in vitro (3 days; 3DIV) resulted in a sustained elevation of intracellular free calcium concentration [Ca2+]i over the same concentration range of NMDA that led to granule cell survival. Agents that release Ca2+ from intracellular stores led to only small, transient elevations of [Ca2+]i and were unable to stimulate granule cell survival. Addition of the Ca2+ ionophore ionomycin to granule cell cultures at 3DIV resulted in increased granule cell number at 7DIV. The ability of ionomycin to stimulate granule cell survival was related to the [Ca2+]i elicited, indicating that a rise in [Ca2+]i is sufficient to activate the processes leading to granule cell survival and that the extent of the elevation in [Ca2+]i is crucially important in determining granule cell fate.


Sequence properties of the 1,2-diacylglycerol 3-glucosyltransferase from Acholeplasma laidlawii membranes. Recognition of a large group of lipid glycosyltransferases in eubacteria and archaea.
Synthesis of the nonbilayer-prone alpha-monoglucosyldiacylglycerol (MGlcDAG) is crucial for bilayer packing properties and the lipid surface charge density in the membrane of Acholeplasma laidlawii. The gene for the responsible, membrane-bound glucosyltransferase (alMGS) (EC ) was sequenced and functionally cloned in Escherichia coli, yielding MGlcDAG in the recombinants. Similar amino acid sequences were encoded in the genomes of several Gram-positive bacteria (especially pathogens), thermophiles, archaea, and a few eukaryotes. All of these contained the typical EX(7)E catalytic motif of the CAZy family 4 of alpha-glycosyltransferases. The synthesis of MGlcDAG by a close sequence analog from Streptococcus pneumoniae (spMGS) was verified by polymerase chain reaction cloning, corroborating a connection between sequence and functional similarity for these proteins. However, alMGS and spMGS varied in dependence on anionic phospholipid activators phosphatidylglycerol and cardiolipin, suggesting certain regulatory differences. Fold predictions strongly indicated a similarity for alMGS (and spMGS) with the two-domain structure of the E. coli MurG cell envelope glycosyltransferase and several amphipathic membrane-binding segments in various proteins. On the basis of this structure, the alMGS sequence charge distribution, and anionic phospholipid dependence, a model for the bilayer surface binding and activity is proposed for this regulatory enzyme.