Utilizing a TLR5-Adjuvanted Cytomegalovirus as a Lentiviral Vaccine in the Nonhuman Primate Model for AIDS.
Despite tremendous progress in our understanding of human immunodeficiency virus (HIV) natural history and advances in HIV treatment, there is neither an approved vaccine nor a cure for infection. Here, we describe the development and characterization of a novel replicating vaccine vector utilizing Cytomegalovirus (CMV) and a TLR5 adjuvant. After partial truncation of the central, immunodominant hypervariable domain, flagellin (fliC) from Salmonella was cloned downstream of a codon optimized gag gene from simian immunodeficiency virus (SIV) and transiently expressed in telomerized rhesus fibroblast (TeloRF) cells in culture. Lysates generated from these transfected cells induced the tumor necrosis factor alpha (TNF-α), in a mouse macrophage cell line, in a TLR5-dependent manner. The Gag/FliC expression construct was cloned into a bacterial artificial chromosome encoding the rhesus CMV (RhCMV) genome, and infectious RhCMV was generated following transfection of TeloRF cells. This virus stably expressed an SIV Gag/FliC fusion protein through four serial passages. Lysates generated from infected cells induced TNF-α in a TLR5-dependent manner. Western blot analysis of infected cell lysates verified expression of a Gag/FliC fusion protein using a SIV p27 capsid monoclonal antibody. Lastly, rhesus macaques inoculated with this novel RhCMV virus demonstrated increased inflammatory responses at the site of inoculation seven days post-infection when compared to the parental RhCMV. These results demonstrate that an artificially constructed replicating RhCMV expressing an SIV Gag/FliC fusion protein is capable of activating TLR5 in a macrophage cell line in vitro and induction of an altered inflammatory response in vivo. Ongoing animals studies are aimed at determining vaccine efficacy, including subsequent challenge with pathogenic SIV.


Bargaining and trust: the effects of 36-h total sleep deprivation on socially interactive decisions.
Although it is well known that sleep loss results in poor judgement and decisions, little is known about the influence of social context in these processes. Sixteen healthy young adults underwent three games involving bargaining ('Ultimatum' and 'Dictator') and trust, following total sleep deprivation (TSD) and during rested wakefulness (RW), in a repeated-measures, counterbalanced design. To control for repeatability, a second group (n = 16) was tested twice under RW conditions. Paired anonymously with another individual, participants made their simple social interaction decisions facing real monetary incentives. For bargaining, following TSD participants were more likely to reject unequal-split offers made by their partner, despite the rejection resulting in a zero monetary payoff for both participants. For the trust game, participants were less likely to place full trust in their anonymous partner. Overall, we provide novel evidence that following TSD, the conflict between personal financial gain and payoff equality is focused upon avoidance of unfavourable inequality (i.e. unfairness). This results in the rejection of unfair offers at personal monetary cost, and the lack of full trust which would expose one to being exploited in the interaction. As such, we suggest that within a social domain decisions may be more influenced by emotion following TSD, which has fundamental consequences for real-world decision-making involving social exchange.


The gut and oral microbiome in HIV disease: a workshop report.
Recent years have seen a massive expansion in our understanding of how we interact with our microbial colonists. The development of new, rapid sequencing techniques such as pyrosequencing and other next-generation sequencing systems have enabled us to begin to characterise the constituents of our diverse microbial communities, revealing the astonishing genetic richness that is our microbiome. Despite this, our ignorance of how these communities change over the course of an HIV infection is profound. Whilst some steps have been made to characterise the HIV microbiome at selected sites, these reports are still limited and much remains to be done. It has become apparent, however, that host-microbiota interactions are perturbed during HIV infections, with microbial translocation of potential pathogens linked to a variety of different HIV complications, including more rapid progression of disease. The use of probiotics and prebiotics has been investigated as treatments to alleviate symptoms for a variety of conditions, and is now being proposed for the treatment of symptoms associated with HIV. However, this is a new area of investigations and many questions remain unanswered. What we know about both of these topics is a drop in the ocean compared with what we need to know. In this article, we report on a workshop where these two major under-investigated research areas were presented, and future directions explored and discussed.


Rehabilitation interventions for improving physical and psychosocial functioning after hip fracture in older people.
Social and psychological factors such as fear of falling, self-efficacy and coping strategies are thought to be important in the recovery from hip fracture in older people. To evaluate the effects of interventions aimed at improving physical and psychosocial functioning after hip fracture. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (September 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE and EMBASE (to December 2008), other databases and reference lists of related articles. Randomised and quasi-randomised trials of rehabilitation interventions applied in inpatient or ambulatory settings to improve physical or psychosocial functioning in older adults with hip fracture. Primary outcomes were physical and psychosocial function and 'poor outcome' (composite of mortality, failure to return to independent living and/or readmission). Two authors independently selected trials based on pre-defined inclusion criteria, extracted data and assessed risk of bias. Disagreements were moderated by a third author. Nine small heterogeneous trials (involving 1400 participants) were included. The trials had differing interventions, including 'usual care' comparators, providers, settings and outcome assessment. Although most trials appeared well conducted, poor reporting hindered assessment of their risk of bias.Three trials testing interventions (reorientation measures, intensive occupational therapy, cognitive behavioural therapy) delivered in inpatient settings found no significant differences in outcomes. Two trials tested specialist-nurse led care, which was predominantly post-discharge but included discharge planning in one trial: this trial found some benefits at three months but the other trial found no differences at 12 months. Coaching (educational and motivational interventions) was examined in two very different trials: one trial found no effect on function at six months; and the other showed coaching improved self-efficacy expectations at six months, although not when combined with exercise. Two trials testing interventions (home rehabilitation; group learning program) started several weeks after hip fracture found no significant differences in outcomes at 12 months. Some outcomes may be amenable to psychosocial treatments; however, there is insufficient evidence to recommend practice changes. Further research on interventions described in this review is required, including attention to timing, duration, setting and administering discipline(s), as well as treatment across care settings. To facilitate future evaluations, a core outcome set, including patient-reported outcomes such as quality of life and compliance, should be established for hip fracture trials.


Comparison of Clinical Characteristics and Prognosis in Patients with Right- and Left-sided Infective Endocarditis.
Right-sided endocarditis (RSE) accounts for 5%-10% of all cases of infective endocarditis (IE) and frequently has different etiological, pathogenetic, and clinical presentations compared with left-sided endocarditis (LSE). The aims of this study were to evaluate the epidemiologic and clinical characteristics and prognosis of RSE patients and to compare them with those of LSE patients. This study's importance relates to the local understanding of RSE and LSE, since Israeli demographics are different compared to the Unites States and Europe with regard to intravenous drug abuse and rheumatic valvular disease prevalence. A retrospective cohort study of 215 patients with infective endocarditis was performed. The primary outcome was in-hospital mortality. The secondary outcomes were duration of hospitalization, recurrent hospitalization, recurrent infective endocarditis, and one-year mortality. Of the 215 patients in the study, 176 had LSE and 39 had RSE. The RSE patients were younger than the LSE patients (48.1±18.9 years versus 61.8±17.0 years, P<0.001). The most common pathogen in both groups was Staphylococcus aureus, which occurred more in the RSE group (51%) versus the LSE group (19%). In-hospital mortality was lower among patients with RSE (2.6% versus 17%, P<0.037). Our study demonstrated an increasing percentage of RSE compared to LSE among patients with IE. Pacemaker lead infection has become the leading cause of RSE in intravenous drug users (IVDU), although less common in Southern Israel. The etiological and clinical differences between RSE and LSE are noteworthy. Patients with RSE have a better prognosis than those with LSE.


The effect of formoterol on the late asthmatic phenomena in guinea pigs.
We investigated the effects of formoterol, a new, long-acting, selective beta 2-adrenoceptor agonist, on the antigen-induced late asthmatic response (LAR) and airway inflammation in guinea pigs. Animals were sensitized by exposure to aerosolized ovalbumin (2% in saline). After antigen challenge, preceded by administration of an H1-receptor antagonist, specific airway conductance was measured with a two-chambered whole-body plethysmograph. An aerosolized solution of formoterol, isoproterenol, or saline was inhaled 15 minutes before challenge. Bronchoalveolar lavage (BAL) was performed 24 hours after challenge. The provocative concentrations of histamine required to decrease specific airway conductance by 50% were obtained before challenge, at 24 hours, and at 72 hours after challenge. The LAR (52.7% +/- 7.7% of the baseline; p less than 0.02) was observed 6 to 8 hours after antigen challenge. An increased cellular influx in BAL (mainly eosinophils and macrophages) and an increased bronchial responsiveness to histamine occurred 24 hours after antigen challenge. Formoterol completely inhibited the LAR and the cellular increase in BAL; however, isoproterenol failed to prevent either the cellular infiltration or the LAR. Formoterol also decreased the antigen-induced increase in bronchial reactivity. These findings suggest that formoterol has inhibitory effects on the underlying inflammatory processes in antigen-induced asthma in addition to prolonged bronchodilation.


Hexane fraction of adlay (Coix lachryma-jobi L.) testa ethanolic extract inhibits human uterine sarcoma cancer cells growth and chemosensitizes human uterine sarcoma cells to doxorubicin.
Cancer has remained among the top ten causes of death in Taiwan since 1982. Uterine sarcoma is a rare gynecologic cancer, and chemotherapy is one type of cancer treatment. Doxorubicin (Dox) is widely used for treating several cancers, including uterine sarcoma, however, multidrug resistance (MDR) is a major clinical problem and a critical cause of treatment failure. The ethanolic extracts of adlay testa (ATE) exhibited significant anticancer activities against many cancer types. In this study we investigated the antitumor effects of the hexane fraction of the adlay testa ethanolic extracts (ATE-Hex) on the human uterine sarcoma cancer cell line MES-SA, as well as on the multidrug-resistant human uterine sarcoma cancer cell line MES-SA/Dx5. The MTT assay was performed to assess the effects of the extracts of different parts of the adlay on the proliferation of human uterine sarcoma cells (MES-SA and MES-SA/Dx5) and human uterine smooth muscle cells (HUtSMCs). To determine whether ATE-Hex has a chemosensitizing effect on drug-resistant uterine sarcoma cells, the MTT assay was performed to examine the synergistic effects of ATE-Hex, the chemotherapeutic drug Dox alone, and in combination. Rhodamine accumulation was analyzed using fluorescence detection. Apoptotic cells were analyzed via flow cytometry. In addition, employing a flame ionization detector (GC/FID) gas chromatography was also developed as the analysis platform for ATE-Hex. The results demonstrated that ATE-Hex exhibited the best effects of inhibition on MES-SA and MES-SA/Dx5 cells. Co-treatment of ATE-Hex and Dox could synergistically inhibit the proliferation of cancer cells. ATE-Hex reduced the rhodamine efflux in MES-SA/Dx5 cells, indicating that ATE-Hex could reduce the expression of P-gp. In addition, our results showed that treatment with ATE-Hex alone or in combination with Dox significantly inhibited the growth of cancer cells and induced apoptosis by increasing the sub-G1 phase and poly(ADP-ribose) polymerase (PARP) being cleaved. Flow cytometry revealed that ATE-Hex induced apoptosis. These results suggest that ATE-Hex can inhibit human uterine sarcoma cancer cells by inducing apoptosis and increasing the chemosensitivity of the multidrug-resistant human uterine sarcoma cancer cell MES-SA/Dx5 to Dox. Furthermore, the combination of ATE-Hex and Dox could decrease MDR and increase the synergistic effect.


Video-based coping skills to reduce health risk and improve psychological and physical well-being in Alzheimer's disease family caregivers.
To determine whether video-based coping skills (VCS) training with telephone coaching reduces psychosocial and biological markers of distress in primary caregivers of a relative with Alzheimer's disease or related dementia (ADRD). A controlled clinical trial was conducted with 116 ADRD caregivers who were assigned, alternately as they qualified for the study, to a Wait List control condition or the VCS training arm in which they viewed two modules/week of a version of the Williams LifeSkills Video adapted for ADRD family care contexts, did the exercises and homework for each module presented in an accompanying Workbook, and received one telephone coaching call per week for 5 weeks on each week's two modules. Questionnaire-assessed depressive symptoms, state and trait anger and anxiety, perceived stress, hostility, caregiver self-efficacy, salivary cortisol across the day and before and after a stress protocol, and blood pressure and heart rate during a stress protocol were assessed before VCS training, 7 weeks after training was completed, and at 3 months' and 6 months' follow-up. Compared with controls, participants who received VCS training plus telephone coaching showed significantly greater improvements in depressive symptoms, trait anxiety, perceived stress, and average systolic and diastolic blood pressures that were maintained over the 6-month follow-up period. VCS training augmented by telephone coaching reduced psychosocial and biological indicators of distress in ADRD caregivers. Future studies should determine the long-term benefits to mental and physical health from this intervention. http://www.clinicaltrials.gov; #NCT00396825.


Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury.
Following a mild traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial blow to the head consists of excitotoxicity, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after mild TBI. In this study, male mice were treated with either placebo or resveratrol (100 mg/kg) at 5 minutes and 12 hours after mild TBI. The mice were injured using the controlled cortical impact device. In this closed-head model, a midline incision was made to access the skull and the impactor tip was aligned on the sagittal suture midway between the bregma and lambda sutures. The mice were injured at a depth of 2.0 mm, velocity of 4 m/s, and a delay time of 100 milliseconds. At 72 hours following injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for microglial activation (Iba1). In addition, using the enzyme-linked immunosorbent assay, tissue levels of interleukin 6 (IL-6) and IL-12 were measured in the cerebral cortex and hippocampus. In this study, we found that in the placebo treatment group, there was a significant increase in Iba1 staining in the brain. The levels of microglial activation was reduced by resveratrol in the cerebral cortex (p < 0.001), corpus callosum (p < 0.001), and dentate gyrus (p < 0.005) brain regions after mild TBI. In addition to Iba1, resveratrol decreased the brain levels of IL-6 (p < 0.0001) and IL-12 (p < 0.004), which were observed in the hippocampus of the placebo group. In our model, no increase of IL-6 or IL-12 was observed in the cerebral cortex following TBI. Resveratrol given acutely after TBI results in a decrease in neuroinflammation. These results suggest that resveratrol may be beneficial in reducing secondary brain injury after experiencing a mild TBI.


The GUDMAP database--an online resource for genitourinary research.
The GenitoUrinary Development Molecular Anatomy Project (GUDMAP) is an international consortium working to generate gene expression data and transgenic mice. GUDMAP includes data from large-scale in situ hybridisation screens (wholemount and section) and microarray gene expression data of microdissected, laser-captured and FACS-sorted components of the developing mouse genitourinary (GU) system. These expression data are annotated using a high-resolution anatomy ontology specific to the developing murine GU system. GUDMAP data are freely accessible at www.gudmap.org via easy-to-use interfaces. This curated, high-resolution dataset serves as a powerful resource for biologists, clinicians and bioinformaticians interested in the developing urogenital system. This paper gives examples of how the data have been used to address problems in developmental biology and provides a primer for those wishing to use the database in their own research.


Fitness test results of Hungarian and international-level soccer referees and assistants.
The aim of our research was primarily to compare the conditional abilities of European countries' Fédération Internationale de Football Association (FIFA) referees with those of Hungarian national and county referees and, secondly, to investigate whether the stop tests of FIFA and the Union of European Football Associations (UEFA) provide reliable discrimination criteria between the different levels of referees. The main focuses of our research were speed and endurance, which were measured by the stop tests of FIFA and UEFA-namely, 50- and 200-m sprint runs and a 12-minute run, respectively (Cooper test). In our study, the test results of 2459 soccer referees were analyzed; they include the results of the total Hungarian population of referees and the results from 17 different European countries. Referees were classified into 6 different levels according to their qualifications. The results show that in the 12-minute run, FIFA referees covered the longest distance (3043 +/- 127 m), followed by the Hungarian elite referees (2939 +/- 136 m); less distance was covered by county III-level referees (2522 +/- 270 m). Differences between groups in the endurance event were significant (p < 0.05) in all cases. In the sprint runs, there was no difference between FIFA and Hungarian elite referees. In both sprints, FIFA-level and Hungarian elite referees performed the fastest times, and county III-level referees had the slowest times. It can be concluded that the aerobic fitness level demonstrated in the 12-minute run provides the most adequate criteria for discrimination between different competitive levels. Hungarian elite referees, on the basis of their fitness test results, are comparable with international-level referees. The major quality step in a referee's career can be located at the third-division competition level.


Predictors of social leisure activities in older Europeans with and without multimorbidity.
Older people spend much time participating in leisure activities, such as taking part in organized activities and going out, but the extent of participation may differ according to both individual and environmental resources available. Chronic health problems become more prevalent at higher ages and likely necessitate tapping different resources to maintain social participation. This paper compares predictors of participation in social leisure activities between older people with and those without multimorbidity. The European Project on Osteoarthritis (EPOSA) was conducted in Germany, UK, Italy, The Netherlands, Spain and Sweden (N = 2942, mean age 74.2 (5.2)). Multivariate regression was used to predict social leisure participation and degree of participation in people with and without multimorbidity. Fewer older people with multimorbidity participated in social leisure activities (90.6 %), compared to those without multimorbidity (93.9 %). The frequency of participation was also lower compared to people without multimorbidity. Higher socioeconomic status, widowhood, a larger network of friends, volunteering, transportation possibilities and having fewer depressive symptoms were important for (the degree of) social leisure participation. Statistically significant differences between the multimorbidity groups were observed for volunteering and driving a car, which were more important predictors of participation in those with multimorbidity. In contrast, self-reported income appeared more important for those without multimorbidity, compared to those who had multimorbidity. Policies focusing on social (network of friends), physical (physical performance) and psychological factors (depressive symptoms) and on transportation possibilities are recommended to enable all older people to participate in social leisure activities.


The Virome of Acute Respiratory Diseases in Individuals at Risk of Zoonotic Infections.
The ongoing coronavirus disease 2019 (COVID-19) pandemic emphasizes the need to actively study the virome of unexplained respiratory diseases. We performed viral metagenomic next-generation sequencing (mNGS) analysis of 91 nasal-throat swabs from individuals working with animals and with acute respiratory diseases. Fifteen virus RT-PCR-positive samples were included as controls, while the other 76 samples were RT-PCR negative for a wide panel of respiratory pathogens. Eukaryotic viruses detected by mNGS were then screened by PCR (using primers based on mNGS-derived contigs) in all samples to compare viral detection by mNGS versus PCR and assess the utility of mNGS in routine diagnostics. mNGS identified expected human rhinoviruses, enteroviruses, influenza A virus, coronavirus OC43, and respiratory syncytial virus (RSV) A in 13 of 15 (86.7%) positive control samples. Additionally, rotavirus, torque teno virus, human papillomavirus, human betaherpesvirus 7, cyclovirus, vientovirus, gemycircularvirus, and statovirus were identified through mNGS. Notably, complete genomes of novel cyclovirus, gemycircularvirus, and statovirus were genetically characterized. Using PCR screening, the novel cyclovirus was additionally detected in 5 and the novel gemycircularvirus in 12 of the remaining samples included for mNGS analysis. Our studies therefore provide pioneering data of the virome of acute-respiratory diseases from individuals at risk of zoonotic infections. The mNGS protocol/pipeline applied here is sensitive for the detection of a variety of viruses, including novel ones. More frequent detections of the novel viruses by PCR than by mNGS on the same samples suggests that PCR remains the most sensitive diagnostic test for viruses whose genomes are known. The detection of novel viruses expands our understanding of the respiratory virome of animal-exposed humans and warrant further studies.


Identification and pathogenomic analysis of an Escherichia coli strain producing a novel Shiga toxin 2 subtype.
Shiga toxin (Stx) is the key virulent factor in Shiga toxin-producing Escherichia coli (STEC). To date, three Stx1 subtypes and seven Stx2 subtypes have been described in E. coli, which differed in receptor preference and toxin potency. Here, we identified a novel Stx2 subtype designated Stx2h in E. coli strains isolated from wild marmots in the Qinghai-Tibetan plateau, China. Stx2h shares 91.9% nucleic acid sequence identity and 92.9% amino acid identity to the nearest Stx2 subtype. The expression of Stx2h in type strain STEC299 was inducible by mitomycin C, and culture supernatant from STEC299 was cytotoxic to Vero cells. The Stx2h converting prophage was unique in terms of insertion site and genetic composition. Whole genome-based phylo- and patho-genomic analysis revealed STEC299 was closer to other pathotypes of E. coli than STEC, and possesses virulence factors from other pathotypes. Our finding enlarges the pool of Stx2 subtypes and highlights the extraordinary genomic plasticity of E. coli strains. As the emergence of new Shiga toxin genotypes and new Stx-producing pathotypes pose a great threat to the public health, Stx2h should be further included in E. coli molecular typing, and in epidemiological surveillance of E. coli infections.


The SV40 late protein VP4 is a viroporin that forms pores to disrupt membranes for viral release.
Nonenveloped viruses are generally released by the timely lysis of the host cell by a poorly understood process. For the nonenveloped virus SV40, virions assemble in the nucleus and then must be released from the host cell without being encapsulated by cellular membranes. This process appears to involve the well-controlled insertion of viral proteins into host cellular membranes rendering them permeable to large molecules. VP4 is a newly identified SV40 gene product that is expressed at late times during the viral life cycle that corresponds to the time of cell lysis. To investigate the role of this late expressed protein in viral release, water-soluble VP4 was expressed and purified as a GST fusion protein from bacteria. Purified VP4 was found to efficiently bind biological membranes and support their disruption. VP4 perforated membranes by directly interacting with the membrane bilayer as demonstrated by flotation assays and the release of fluorescent markers encapsulated into large unilamellar vesicles or liposomes. The central hydrophobic domain of VP4 was essential for membrane binding and disruption. VP4 displayed a preference for membranes comprised of lipids that replicated the composition of the plasma membranes over that of nuclear membranes. Phosphatidylethanolamine, a lipid found at high levels in bacterial membranes, was inhibitory against the membrane perforation activity of VP4. The disruption of membranes by VP4 involved the formation of pores of ∼3 nm inner diameter in mammalian cells including permissive SV40 host cells. Altogether, these results support a central role of VP4 acting as a viroporin in the perforation of cellular membranes to trigger SV40 viral release.


The Trypanosoma brucei MitoCarta and its regulation and splicing pattern during development.
It has long been known that trypanosomes regulate mitochondrial biogenesis during the life cycle of the parasite; however, the mitochondrial protein inventory (MitoCarta) and its regulation remain unknown. We present a novel computational method for genome-wide prediction of mitochondrial proteins using a support vector machine-based classifier with ∼90% prediction accuracy. Using this method, we predicted the mitochondrial localization of 468 proteins with high confidence and have experimentally verified the localization of a subset of these proteins. We then applied a recently developed parallel sequencing technology to determine the expression profiles and the splicing patterns of a total of 1065 predicted MitoCarta transcripts during the development of the parasite, and showed that 435 of the transcripts significantly changed their expressions while 630 remain unchanged in any of the three life stages analyzed. Furthermore, we identified 298 alternatively splicing events, a small subset of which could lead to dual localization of the corresponding proteins.


Adjusting ante-natal clinic data for improved estimates of HIV prevalence among women in sub-Saharan Africa.
To find a simple and robust method for adjusting ante-natal clinic data on HIV prevalence to represent prevalence in the general female population in the same age range, allowing for fertility differences by HIV status. HIV prevalence comparisons for pregnant women and women in the general community show that prevalence in the latter is significantly higher than in the former. An adjustment procedure is needed that is specific for the demographic and epidemiological circumstances of a particular population, making maximum use of data that can easily be collected in ante-natal clinics or are widely available from secondary sources. Birth interval length data are used to allow for subfertility among HIV-positive women. To allow for infertility, relative HIV prevalence ratios for fertile and infertile women obtained in community surveys in populations with similar levels of contraception use are applied to demographic survey data that describe the structure of the population not at risk of child-bearing. For populations with low contraception use, the procedure yields estimates of general female HIV prevalence of 35-65% higher than the observed ante-natal prevalence, depending on population structure. Results were verified using general population prevalence data collected in Kisesa (Tanzania) and Masaka (Uganda). For high contraception use populations, adjusted values range from 15% higher to 5% lower, but only limited verification has been possible so far. The procedure is suitable for estimating general female HIV prevalence in low contraception use populations, but the high contraception variant needs further testing before it can be applied widely.


The national heart failure audit for England and Wales 2008-2009.
To obtain national data on the clinical characteristics, investigation, management and outcome of patients hospitalised with a diagnosis of heart failure. A survey was carried out of the first 10 patients hospitalised with a primary diagnosis of heart failure each month in 86 hospitals providing services for acute medical admissions in England and Wales from April 2008 until March 2009. The main outcome measures were rates of investigations, treatments and specialist management, length of hospital stay and mortality. The 86 hospitals enrolled 6170 patients with a median age of 78 years (IQR 70-85 years), including 2639 (43%) women. At admission, only 30% of patients were breathless at rest, while 43% had peripheral oedema. Echocardiograms were recorded in 75% of patients and left ventricular ejection fraction (LVEF) was ≤40% in 78%. Natriuretic peptides were rarely measured. Allowing for missing data, >90% of patients were treated with loop diuretics at discharge, 80% with ACE inhibitors or angiotensin receptor blockers, 50% with β-blockers and 30% with aldosterone antagonists. Patients with an LVEF <40% were more likely to receive these agents. Median hospital stay was 9 days (IQR 5-17) and in-patient mortality was 12%. Patients admitted to general medicine rather than cardiology wards were more likely to die (HR=2.5, 95% CI 2.0 to 3.3, p<0.001) even after adjusting for differences (HR=1.9, 95% CI 1.5 to 2.5, p<0.001). Projected 1-year mortality below and above age 75 years was 26% and 56%, with higher rates if managed on general medicine rather than cardiology wards (HR=1.4, 95% CI 1.2 to 1.6, p<0.001). The prognosis of patients hospitalised with heart failure remains poor and investigation and treatment suboptimal. Specialist services are associated with higher rates of investigation and treatment and improved outcome.


Apocalmodulin itself promotes ion channel opening and Ca(2+) regulation.
The Ca(2+)-free form of calmodulin (apoCaM) often appears inert, modulating target molecules only upon conversion to its Ca(2+)-bound form. This schema has appeared to govern voltage-gated Ca(2+) channels, where apoCaM has been considered a dormant Ca(2+) sensor, associated with channels but awaiting the binding of Ca(2+) ions before inhibiting channel opening to provide vital feedback inhibition. Using single-molecule measurements of channels and chemical dimerization to elevate apoCaM, we find that apoCaM binding on its own markedly upregulates opening, rivaling the strongest forms of modulation. Upon Ca(2+) binding to this CaM, inhibition may simply reverse the initial upregulation. As RNA-edited and -spliced channel variants show different affinities for apoCaM, the apoCaM-dependent control mechanisms may underlie the functional diversity of these variants and explain an elongation of neuronal action potentials by apoCaM. More broadly, voltage-gated Na channels adopt this same modulatory principle. ApoCaM thus imparts potent and pervasive ion-channel regulation. PAPERCLIP:


Reduced disability and mortality among aging runners: a 21-year longitudinal study.
Exercise has been shown to improve many health outcomes and well-being of people of all ages. Long-term studies in older adults are needed to confirm disability and survival benefits of exercise. Annual self-administered questionnaires were sent to 538 members of a nationwide running club and 423 healthy controls from northern California who were 50 years and older beginning in 1984. Data included running and exercise frequency, body mass index, and disability assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI; scored from 0 [no difficulty] to 3 [unable to perform]) through 2005. A total of 284 runners and 156 controls completed the 21-year follow-up. Causes of death through 2003 were ascertained using the National Death Index. Multivariate regression techniques compared groups on disability and mortality. At baseline, runners were younger, leaner, and less likely to smoke compared with controls. The mean (SD) HAQ-DI score was higher for controls than for runners at all time points and increased with age in both groups, but to a lesser degree in runners (0.17 [0.34]) than in controls (0.36 [0.55]) (P < .001). Multivariate analyses showed that runners had a significantly lower risk of an HAQ-DI score of 0.5 (hazard ratio, 0.62; 95% confidence interval, 0.46-0.84). At 19 years, 15% of runners had died compared with 34% of controls. After adjustment for covariates, runners demonstrated a survival benefit (hazard ratio, 0.61; 95% confidence interval, 0.45-0.82). Disability and survival curves continued to diverge between groups after the 21-year follow-up as participants approached their ninth decade of life. Vigorous exercise (running) at middle and older ages is associated with reduced disability in later life and a notable survival advantage.


Projective risk variables in early adolescence and subsequent disinhibitory psychopathology.
The objective was to examine early adolescent projective risk indicators for the development of antisocial behaviour as related to adult personality traits, psychopathy, and violent behaviour over the life span. Assessment data included Rorschach (Rr) ratings (at age 11-14 years), personality inventories (EPQ-I and KSP scales), and a shortened Psychopathy Check List (PCL) (administered at age 32-40 years), obtained from a group of 199 male subjects; and smoking habits (at age 36-44 years) obtained from 125 of those subjects. Results, controlled for intelligence, indicated that the high and very high risk groups, as determined by level of total Rr risk scores, were (1) significantly higher on self-rated IVE Impulsiveness, the anxiety-related KSP Muscular Tension, and nonconformity traits, as compared to the low Rr risk group--the very high risk group also scoring significantly higher on the EPQ Psychoticism scale, related to aggressiveness and cruelty; (2) higher on clinically rated PCL total sum and factor scores; and (3) they were overrepresented among Ss with subsequent violent offence, and Ss with heavy smoking habits. The results are discussed in terms of the possible usefulness of psychodynamic oriented cognitive-emotional indicators in the search for underlying mechanisms in the development of disinhibitory psychopathology.


Propagation properties of Airy-Gaussian vortex beams through the gradient-index medium.
Propagation of Airy-Gaussian vortex (AiGV) beams through the gradient-index medium is investigated analytically and numerically with the transfer matrix method. Deriving the analytic expression of the AiGV beams based on the Huygens diffraction integral formula, we obtain the propagate path, intensity and phase distributions, and the Poynting vector of the first- and second-order AiGV beams, which propagate through the paraxial ABCD system. The ballistic trajectory is no longer conventional parabolic but trigonometric shapes in the gradient-index medium. Especially, the AiGV beams represent the singular behavior at the propagation path and the light intensity distribution. The phase distribution and the Poynting vector exhibit in reverse when the AiGV beams through the singularity. As the order increases, the main lobe of the AiGV beams is gradually overlapped by the vortex core. Further, the sidelobe weakens when the AiGV beams propagate nearly to the singularity. Additionally, the figure of the Poynting vector of the AiGV beams proves the direction of energy flow corresponding to the intensity distribution. The vortex of the second-order AiGV beams is larger, and the propagation velocity is faster than that of the first order.


Successful Co-Lactation by a Queer Couple: A Case Study.
With cultural and social evolution and improvements in reproductive technology, an increasing number of babies are born to lesbian, gay, bisexual, transgender, intersex, queer and/or questioning, and asexual and/or ally parents. As parental roles and gender expression become more expansive, the role of breastfeeding a baby must naturally also expand to include the option of sharing of breastfeeding among parents, called co-lactation (Bamberger & Farrow, 2021). In most cases, co-lactation involves a gestational parent and a non-gestational parent. If a non-gestational parent desires to produce milk for the purpose of breastfeeding, they do so by inducing lactation. While interest in and research about induced lactation are developing quickly, little information is currently available about co-lactation. A couple identifying as queer presented with concerns about inducing lactation in the non-gestational parent, as well as seeking assistance in managing a successful sharing of the breastfeeding relationship. Breast massage, milk expression, acupuncture, hormone therapy, and galactagogues, including domperidone, goat's rue, and malunggay (moringa oleifera) were used to initiate and establish lactation by the non-gestational parent. Parents shared the breastfeeding relationship equally and carefully managed milk expression when the other parent was breastfeeding to maintain or increase lactation. With professional lactation support, commitment to a lactation plan, responsive parenting, and strong communication and cooperation between parents, two parents were able to successfully co-lactate for more than a year. Breastfeeding was shared equally and supplementation of breastfeeds was rarely needed.


Stem cell factor inhibits erythroid differentiation by modulating the activity of G1-cyclin-dependent kinase complexes: a role for p27 in erythroid differentiation coupled G1 arrest.
Terminal erythroid differentiation is accompanied by decreased expression of c-Kit and decreased proliferation of erythroid progenitor cells. Using a newly established erythroleukemia cell line HB60-5, which proliferates in response to erythropoietin (Epo) and stem cell factor (SCF) and differentiates when stimulated with Epo alone, we characterized several events associated with the cell cycle during erythroid differentiation. Forty-eight h after SCF withdrawal and Epo stimulation, there was strong inhibition of cyclin-dependent kinase (cdk) 4 and cdk6 activities, associated with an increase in the binding of p27 and p15 to cdk6. A significant increase in the binding of p27 to cyclin E- and cyclin A-associated cdk2 correlated with the inhibition of these kinases. In addition, the expression of c-Myc and its downstream transcriptional target Cdc25A were found to be down-regulated during Epo-induced terminal differentiation of HB60-5 cells. The loss of Cdc25A was associated with an increase in the phosphotyrosylation of cyclin E-associated cdk2, which may contribute to cell cycle arrest during differentiation. Although overexpression of p27 in HB60-5 cells caused G1 arrest, it did not promote terminal erythroid differentiation. Thus, the cell cycle arrest that involves p27 is part of a broader molecular program during HB60-5 erythroid differentiation. Moreover, we suggest that SCF stimulation of erythroblasts, in addition to inhibiting erythroid differentiation, activates parallel or sequential signals responsible for maintaining cyclin/cdk activity.


Studies on N5-methyltetrahydrofolate-homocystein methyltransferase in normal and leukemia leukocytes.
A cobalamin-dependent N5-methyltetra-hydrofolate-homocysteine methyltransferase (methyl-transferase) was demonstrated in unfractioned extracts of human normal and leukemia leukocytes. Activity was substantially reduced in the absence of an added cobalamin derivative. Presumably, this residual activity reflects the endogeneous level of holoenzyme. Enzyme activity was notably higher in lymphoid cells than in myeloid cells. Thus, mean specific activities (+/-SD) were: chronic lymphocytic leukemia lymphocytes, 2.15+/-1.16; normal lymphocytes, 0.91+/-0.59; normal mature granulocytes, 0.15+/-0.10; chronic myelocytic leukemia granulocytes, barely detectable activity. Properties of leukocytes enzymes resembled those of methyltransferases previously studied in bacteria and other animal cells. Granulocytes and chronic myelocytic leukemia cells contain a factor or factors that inhibits Escherichia coli enzyme. The data suggest that the prominence of this cobalamin-dependent enzyme in lymphocytes and other mononuclear cell types may be related to their potential for cell division.


Humanitarian Needs in Government Controlled Areas of Syria.
Five years of conflict in Syria have led to 13.5 million people in need of humanitarian assistance and 6.6 million internally displaced people. Humanitarian needs are ever-increasing as an inability to maintain humanitarian corridors and ceasefires continue. In light of the protracted nature of the conflict, immense needs, and dearth of large-scale data, we undertook this assessment to inform humanitarian response. A survey of accessible areas, which were largely urban and government controlled, was undertaken from April - June 2016 to identify unmet needs and assistance priorities. A cluster design with probability sampling was used to attain a final sample of 2,405 households from ten of fourteen governorates; 31 of 65 (47.7%) districts were included that are home to 38.1% of people in need (PiN). Overall 45% of households received assistance in the preceding month; receipt of aid was lowest in al-Hasakeh (17%). Shelter was a concern, with 48% of households having shelter need(s); the unmet shelter needs were highest in the West Coast, Rif Damascus and al-Hasakeh. Food security was a major concern where 64% had unmet food needs and 65% at least one indicator of concern; food insecurity was most severe in Rif Damascus and the West Coast. Water was also a concern with 36% of households reporting inconsistent access and 48% no access to water for several day periods; water needs were highest in Aleppo. This assessment included accessible populations in predominantly urban and government controlled areas, which are likely to have better access to services and fewer needs than populations in rural locations or areas not controlled by the government. The humanitarian situation in inaccessible and non-government controlled areas is likely to be considerably worse, thus findings should not be generalized. An expanded humanitarian response is desperately needed for Syrians to better endure the conflict.


Monitoring the reproductive activity in captive bred female ball pythons (P. regius) by ultrasound evaluation and noninvasive analysis of faecal reproductive hormone (progesterone and 17β-estradiol) metabolites trends.
The royal python (Python regius) is commonly bred in captivity. To have a successful breeding season, accurate monitoring of the reproductive activity is necessary. The use of non-invasive monitoring methods in exotics is important in order to minimize stress. For this purpose ultrasound has been anecdotally used to monitor royal python reproductive activity. However, there is limited information regarding the reproductive cycle of this species. The aim of the present study is to monitor the female reproductive cycle of the royal python using ultrasonography and gonadal steroid metabolite measurements in the faeces. The reproductive activity of one hundred twenty-nine adult female P. regius was examined during two consecutive years. We performed brief scans on non-anaesthetized snakes using a portable ultrasound system and a 10-12 MHz linear array transducer (MyLab™ 30 Gold, Esaote). Ultrasound features, dimension and echogenicity of the reproductive structures were determined. During the second reproductive cycle, the hormonal profiles of 30 animals were also evaluated, with a monthly collection of faecal samples. These samples were classified according to reproductive stage, as identified by ultrasonographic examination, and the mean faecal progesterone and 17β-estradiol levels were calculated using the results from an enzyme-linked immunosorbent assay (ELISA). Progesterone levels increased during the reproductive cycle. Estradiol levels showed greater variability, although they appeared to increase before coupling when compared to the levels between coupling and egg laying. The present study suggests that it is possible to identify different phases in the female royal python reproductive cycle: anovulatory phase, transition, folliculogenesis and embryogenesis. Ultrasound is also useful for identifying follicular regression or slugs. Gonadal steroid metabolite measurements from the faeces could help integrate reproductive information. The use of ultrasonography in addition to the steroid metabolite measurement in the faeces gives an accurate picture of ovarian activity in captive adult female royal pythons.


Inhalational anthrax: epidemiology, diagnosis, and management.
Anthrax, a disease of great historical interest, is once again making headlines as an agent of biological warfare. Bacillus anthracis, a rod-shaped, spore-forming bacterium, primarily infects herbivores. Humans can acquire anthrax by agricultural or industrial exposure to infected animals or animal products. More recently, the potential for intentional release of anthrax spores in the environment has caused much concern. The common clinical manifestations of anthrax are cutaneous disease, pulmonary disease from inhalation of anthrax spores, and GI disease. The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure. A rapid decline, culminating in septic shock, respiratory distress, and death within 24 h is not uncommon. The high mortality seen in inhalational anthrax is in part due to delays in diagnosis. Classic findings on the chest radiograph include widening of the mediastinum as well as pleural effusions. Pneumonia is less common; key pathologic manifestations include severe hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, and edema. Diagnosis requires a high index of suspicion. Treatment involves supportive care in an intensive care facility and high doses of penicillin. Resistance to third-generation cephalosporins has been noted. Vaccines are currently available and have been shown to be effective against aerosolized exposure in animal studies.


Modulating Mitophagy in Mitochondrial Disease.
Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.


A case of metastatic breast cancer with HER2 gene amplification that responded completely to single agent trastuzumab.
An 80-year-old woman visited our hospital with a massive ulcerated tumor in the upper lateral quadrant of the right breast. Her performance status was 2. Histopathologically, a mass consisting of a huge primary tumor and metastatic axillary lymph nodes was seen and invasive ductal carcinoma was diagnosed. Both estrogen and progesterone receptors were negative. Herceptest (DakoCytomation, Glostrup, Denmark) showed 2 + staining and HER2 amplification was detected by fluorescent in situ hybridization. CT revealed multiple lung metastases. Her old age and performance status of 2 made aggressive chemotherapy difficult. After receiving 5'-DFUR 600 mg/day as the first line treatment for two months, the tumors progressed. As second-line treatment, single agent therapy with a loading dose, a trastuzumab 4 mg/kg followed by 2 mg/kg weekly was recommended. The patient also received 60 Gy radiotherapy. Six months after the second line treatment, the breast tumor disappeared and only a scar remained on the chest wall and axilla. CT showed no lung tumors. During the trastuzumab treatment, no adverse effect was observed. Her performance status improved to zero, and she is alive and free from the disease 24 months after the disappearance of the tumor.


Ultrafast convergent power-balance model for Raman random fiber laser with half-open cavity.
The power-relevant features of Raman random fiber laser (RRFL), such as lasing threshold, slope efficiency, and power distribution, are among the most critical parameters to characterize its operation status. In this work, focusing on the power features of the half-open cavity RRFL, an ultrafast convergent power-balance model is proposed, which highlights the physical essence of the most common RRFL type and sharply reduces the computation workload. By transforming the time-consuming serial calculation to a parallel one, the calculation efficiency can be improved by more than 100 times. Particularly, for different point-mirror reflectivities and different fiber lengths, the input-output power curves and power distribution curves calculated by the present model match nicely with those of the conventional model, as well as with the experimental data. Moreover, through the present model the relationship between point-mirror reflectivity and laser threshold is analytically derived, and the way for improving RRFL's slope efficiency is also provided with a lucid theoretical explanation.


Epidemiology of feline infectious peritonitis among cats examined at veterinary medical teaching hospitals.
To determine proportions of cats in which feline infectious peritonitis (FIP) was diagnosed on an annual, monthly, and regional basis and identify unique characteristics of cats with FIP. Case-control study. Records of all feline accessions to veterinary medical teaching hospitals (VMTH) recorded in the Veterinary Medical Data Base between January 1986 and December 1995 and of all feline accessions for necropsy or histologic examination at 4 veterinary diagnostic laboratories. Proportions of total and new feline accessions for which a diagnosis of FIP was recorded were calculated. To identify characteristics of cats with FIP, cats with FIP were compared with the next cat examined at the same institution (control cats). Approximately 1 of every 200 new feline and 1 of every 300 total feline accessions at VMTH in North America and approximately 1 of every 100 accessions at the diagnostic laboratories represented cats with FIP. Cats with FIP were significantly more likely to be young, purebred, and sexually intact males and significantly less likely to be spayed females and discharged alive than were control cats. The proportion of new accessions for which a diagnosis of FIP was recorded did not vary significantly among years, months, or regions of the country. Results indicated that FIP continues to be a clinically important disease in North America and that sexually intact male cats may be at increased risk, and spayed females at reduced risk, for FIP. The high prevalence of FIP and lack of effective treatment emphasizes the importance of preventive programs, especially in catteries.


Pt(II) mono-carbonyl complexes of a cyclometallating 2-(2'-thienyl)-(pyridinato-C,3N') ligand: nature and dynamics of the lowest excited state of the chloro- and thiolato-complexes.
The synthesis of a cyclometallated Pt(II) thiolate carbonyl complex Pt(thpy)(CO)(mts), (thpy = 2-(2'-thienyl)-pyridinate, mts = methylthiosalicylate) is reported. A combination of emission and time-resolved infrared (TRIR) techniques revealed for both Pt(thpy)(CO)(mts) and its chloride analogue Pt(thpy)(CO)Cl the predominant intra 2-(2'-thienyl)-pyridinate 3pi pi* character of the lowest electronic excited state. The unusually short lifetime (780 ps) of the intraligand 3pi pi* lowest excited state of Pt(thpy)(CO)(mts) indicates that this electronic state is influenced by another close-lying excited state, probably charge-transfer in origin.


Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.


Wavefront reconstruction by spatial-phase-shift imaging interferometry.
Common-path imaging interferometers offer some advantages over other interferometers, such as insensitivity to vibrations and the ability to be attached to any optical system to analyze an imaged wavefront. We introduce the spatial-phase-shift imaging interferometry technique for surface measurements and wavefront analysis in which different parts of the wavefront undergo certain manipulations in a certain plane along the optical axis. These manipulations replace the reference-beam phase shifting of existing interferometry methods. We present the mathematical algorithm for reconstructing the wavefront from the interference patterns and detail the optical considerations for implementing the optical system. We implemented the spatial phase shift into a working system and used it to measure a variety of objects. Measurement results and comparison with other measurement methods indicate that this approach improves measurement accuracy with respect to existing quantitative phase-measurement methods.


Depression predicts all-cause mortality: epidemiological evaluation from the ACCORD HRQL substudy.
Depression affects up to 20-25% of adults with type 2 diabetes and may increase all-cause mortality, but few well-designed studies have examined the effects of depression on the full range of cardiovascular disease outcomes in type 2 diabetes. A total of 2,053 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Health-Related Quality of Life substudy completed the Patient Health Questionnaire (PHQ)-9 measure of depression symptoms at baseline and 12, 36, and 48 months. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% CI) for the time-varying impact of depression on protocol-defined clinical outcomes with and without adjustment for demographic, trial-related, clinical, and behavioral variables. In fully adjusted models, depression was not significantly related to the ACCORD primary composite outcome (cardiovascular death, nonfatal heart attack, or stroke) (HR 1.53 [95% CI 0.85-2.73]) or to the ACCORD microvascular composite outcome (0.93 [0.53-1.62]), but all-cause mortality was significantly increased both in those with PHQ-assessed probable major depression (2.24 [1.24-4.06]) and PHQ score of ≥ 10 (1.84 [1.17-2.89]). The effect of depression on all-cause mortality was not related to previous cardiovascular events or to assignment to intensive or standard glycemia control. Probable major depression (by PHQ-9) had a borderline impact on the ACCORD macrovascular end point (1.42 [0.99-2.04]). Depression increases the risk of all-cause mortality and may increase the risk of macrovascular events among adults with type 2 diabetes at high risk for cardiovascular events.


The development and meiotic behavior of asymmetrical isochromosomes in wheat.
To determine which segments of a chromosome arm are responsible for the initiation of chiasmate pairing in meiosis, a series of novel isochromosomes was developed in hexaploid wheat (Triticum aestivum L.). These isochromosomes are deficient for different terminal segments in the two arms. It is proposed to call them "asymmetrical." Meiotic metaphase I pairing of these asymmetrical isochromosomes was observed in plants with various doses of normal and deficient arms. The two arms of an asymmetrical isochromosome were bound by a chiasma in only two of the 1134 pollen mother cells analyzed. Pairing was between arms of identical length whenever such were available; otherwise, there was no pairing. However, two arms deficient for the same segment paired with a frequency similar to that of normal arms, indicating that the deficient arms retained normal capacity for pairing. Pairing of arms of different length was prevented not by the deficiency itself, but rather, by the heterozygosity for the deficiency. Whether two arms were connected via a centromere in an isochromosome or were present in two different chromosomes had no effect on pairing. This demonstrates that in the absence of homology in the distal regions of chromosome arms, even if relatively short, very long homologous segments may remain unrecognized in meiosis and will not be involved in chiasmate pairing.


An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins.
DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.


Magnetic resonance imaging abnormalities in the shoulder and wrist joints of asymptomatic elite athletes.
To characterize abnormalities on magnetic resonance images (MRI) in the shoulder and wrist joints of asymptomatic elite athletes to better define the range of "normal" findings in this population. Cohort study. Academic medical center. Division IA collegiate volleyball players (n=12), swimmers (n=6), and gymnasts (n=15) with no history of injury or pain and normal physical examination results. None. Grade of severity of MRI changes of the shoulder and wrist joints. A 3- to 4-year follow-up questionnaire was administered to determine the clinical significance of the asymptomatic findings. All athletes demonstrated at least mild imaging abnormalities in the joints evaluated. Shoulder: Volleyball players had moderate and severe changes primarily in the labrum (50% moderate, 8% severe), rotator cuff (25% moderate, 17% severe), bony structures (33% moderate), and tendon/muscle (25% moderate, 8% severe). Swimmers had moderate changes primarily in the labrum (83% moderate) and ligament (67% moderate). Wrist: All gymnasts had changes in the wrist ligaments (40% mild, 60% moderate), tendons (53% mild, 47% moderate), and cartilage (60% mild, 33% moderate, 7% severe). Most gymnasts exhibited bony changes (20% normal, 47% mild, 26% moderate, 7% severe), the presence of cysts/fluid collections (80%), and carpal tunnel changes (53%). Swimmers had no wrist abnormalities. At follow-up interview, only 1 swimmer and 1 volleyball player reported shoulder problems during the study. Additionally, only 1 gymnast reported a wrist injury during their career. Asymptomatic elite athletes demonstrate MRI changes of the shoulder (swimmers and volleyball players) and wrist (gymnasts) similar to those associated with abnormalities for which medical treatment and sometimes surgery are advised. Given the somewhat high frequency of these asymptomatic findings, care must be taken to correlate clinical history and physical examination with MRI findings in these patients with symptoms.


Growth hormone receptor (GHR) exon 3 polymorphism status detection by dual-enzyme-linked immunosorbent assay (ELISA).
GH receptor (GHR) exon 3-deleted/full-length (d3/fl) polymorphism has been proposed to affect the responsiveness to GH therapy. Conventional multiplex PCR genotyping method for this polymorphism detection requires DNA samples, which may be difficult to obtain due to ethical and procedural issues and may limit further studies into the role of this polymorphism in health and disease. The objective of the study was to develop a simple genotyping-alternative method for GHRd3 identification by directly measuring serum levels of total GH binding protein (tGHBP) and exon 3-positive GHBP[(E3(+)GHBP] by immunoassay and thereby assess the GHRd3 status. The GHRd3 genotype was determined by PCR, and tGHBP and E3(+)GHBP levels were measured in serum of 88 healthy adults. The GHRd3 chemotype by ELISA was compared with the genotype by conventional PCR. The concordance rate of GHR exon 3 status identification between PCR genotyping and ELISA chemotyping was shown to be 100%. There were negligible detectable serum levels of E3(+)GHBP in d3/d3 subjects. The ratio of serum levels E3(+)GHBP vs. tGHBP in fl/fl and d3/fl subjects was (mean ± SD) 96.6 ± 5.1 and 57.1 ± 8.4%, respectively (P < 0.0001). Interestingly, we observed that d3/d3 subjects had significantly lower serum levels of tGHBP compared with fl/fl and d3/fl genotypes. This dual ELISA against tGHBP and E3(+)GHBP can be used as an alternative method for determining GHRd3 polymorphism status. The implications of differences in serum levels of tGHBP among different genotypes and responsiveness to GH therapy need to be further investigated.


Investigation of dietary factors and endometrial cancer risk using a nutrient-wide association study approach in the EPIC and Nurses' Health Study (NHS) and NHSII.
Data on the role of dietary factors in endometrial cancer development are limited and inconsistent. We applied a "nutrient-wide association study" approach to systematically evaluate dietary risk associations for endometrial cancer while controlling for multiple hypothesis tests using the false discovery rate (FDR) and validating the results in an independent cohort. We evaluated endometrial cancer risk associations for dietary intake of 84 foods and nutrients based on dietary questionnaires in three prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC; N = 1,303 cases) followed by validation of nine foods/nutrients (FDR ≤ 0.10) in the Nurses' Health Studies (NHS/NHSII; N = 1,531 cases). Cox regression models were used to estimate HRs and 95% confidence intervals (CI). In multivariate adjusted comparisons of the extreme categories of intake at baseline, coffee was inversely associated with endometrial cancer risk (EPIC, median intake 750 g/day vs. 8.6; HR, 0.81; 95% CI, 0.68-0.97, Ptrend = 0.09; NHS/NHSII, median intake 1067 g/day vs. none; HR, 0.82; 95% CI, 0.70-0.96, Ptrend = 0.04). Eight other dietary factors that were associated with endometrial cancer risk in the EPIC study (total fat, monounsaturated fat, carbohydrates, phosphorus, butter, yogurt, cheese, and potatoes) were not confirmed in the NHS/NHSII. Our findings suggest that coffee intake may be inversely associated with endometrial cancer risk. Further data are needed to confirm these findings and to examine the mechanisms linking coffee intake to endometrial cancer risk to develop improved prevention strategies.


SU-E-T-172: Ion Recombination Correction Factor in Medium Dose Rate for Advanced Markus Ionization Chamber.
To determine the ion recombination correction factor using different methods in medium dose per pulse electron beams for Advance Markus ionization chamber (AMC) Methods: Two different methods were applied to obtain ion recombination correction factor. Conventional Boag's two voltage analysis (TVA) recommended in IAEA TRS-398 dosimetry protocol and recently modified Boag's TVA expressions which consider the effect of free electron contribution on ks value. High energy electron beams of a dedicated linear accelerator, NOCAC7 (NRT, Italy), for intraoperative radiation therapy were applied. Dose per pulse in medium range of 4 to 41 mGy/pulse was investigated. Radiochromic films (ISP Gafchromic EBT2, USA) have been exploited as reference dose rate independent method. Dose measurement was performed by AMC in a small water phantom (IBA Dosimetry, Germany). At reference conditions (9 MeV, 100 mm applicator, SSD 80 cm (27 mGy/pulse)), ks values derived from IAEA TRS- 398 dosimetry protocols deviates 0.3% from reference value. From 4-35 mGy/pulse TVA yielded acceptable result (in average 1.0% deviation). For dose rate more that 35 mGy/pulse, conventional two voltage analysis (TVA) might be applied with caution (4.2% deviation at 41 mGy/pulse). In this range first model in the new modified Boag's expressions yielded acceptable accordance (average deviation 1.3%) in comparison with dose rate independent reference dosimeter (EBT2, Gafchromic film). The deviation in ks value among Boag's modified expressions increased when the dose rate raised. Authors concluded that AMC could be employed for absorbed dose determination of medium dose per pulse electron beams. The accuracy of TVA which is recommended currently in dosimetry protocol IAEA-TRS-398 is dependent on the range of applied dose rate. It is proper to be used for dose rate less than 35 mGy/pulse. First expression in Boag's modified formulas is proper for ks determination in high dose rate values (> 35 mGy/pulse).


Automated recommendation for cervical cancer screening and surveillance.
Because of the complexity of cervical cancer prevention guidelines, clinicians often fail to follow best-practice recommendations. Moreover, existing clinical decision support (CDS) systems generally recommend a cervical cytology every three years for all female patients, which is inappropriate for patients with abnormal findings that require surveillance at shorter intervals. To address this problem, we developed a decision tree-based CDS system that integrates national guidelines to provide comprehensive guidance to clinicians. Validation was performed in several iterations by comparing recommendations generated by the system with those of clinicians for 333 patients. The CDS system extracted relevant patient information from the electronic health record and applied the guideline model with an overall accuracy of 87%. Providers without CDS assistance needed an average of 1 minute 39 seconds to decide on recommendations for management of abnormal findings. Overall, our work demonstrates the feasibility and potential utility of automated recommendation system for cervical cancer screening and surveillance.


Weight loss on a low-fat diet: consequence of the imprecision of the control of food intake in humans.
This study examined the degree to which humans compensate for a reduction in dietary fat by increasing energy intake. Thirteen females were randomly assigned to either a low-fat diet (20-25% of calories as fat) or a control diet (35-40% fat) for 11 wk. After a 7-wk washout period, the conditions were reversed for another 11 wk. Energy intake on the low-fat diet gradually increased by 0.092 kJ/wk resulting in a total caloric compensation of 35% by the end of the 11-wk treatment period. This failure to compensate calorically on the low-fat diet resulted in a deficit of 1.22 kJ/d and a weight loss of 2.5 kg in 11 wk, twice the amount of weight lost on the control diet. These results demonstrate that body weight can be lost merely by reducing the fat content of the diet without the need to voluntarily restrict food intake.


The importance of water quality and haemodialysis fluid composition.
Treatment of renal failure by haemodialysis uses dialysis fluid to facilitate the normalization of electrolyte and acid base abnormalities and the removal of low molecular weight uraemic compounds present in the plasma such as urea. The dialysis fluid is a continuously produced blend of treated tap water and a concentrated solution containing electrolytes, buffer, and glucose. The water used originates as drinking water but undergoes additional treatment. Recent surveys have indicated that the chemical and microbiological content of such water frequently fails to meet the requirements of established standards, and its bacterial content arising from the presence of a biofilm in the water distribution network or the hydraulic circuit of the dialysis machine is a contributory factor to the chronic inflammatory state in patients undergoing regular dialysis. The composition of the dialysis fluid plays an important role in the modulation of complications associated with end-stage renal disease, as well as those associated with the treatment itself. The avoidance of complications arising from water contaminants requires a constant and vigorous attention to water quality, whilst with the composition of electrolytes and buffer there is a trend towards greater individualization to provide a high degree of treatment tolerance.


α-SNAP is expressed in mouse ovarian granulosa cells and plays a key role in folliculogenesis and female fertility.
The balance between ovarian folliculogenesis and follicular atresia is critical for female fertility and is strictly regulated by a complex network of neuroendocrine and intra-ovarian signals. Despite the numerous functions executed by granulosa cells (GCs) in ovarian physiology, the role of multifunctional proteins able to simultaneously coordinate/modulate several cellular pathways is unclear. Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (α-SNAP) is a multifunctional protein that participates in SNARE-mediated membrane fusion events. In addition, it regulates cell-to-cell adhesion, AMPK signaling, autophagy and apoptosis in different cell types. In this study we examined the expression pattern of α-SNAP in ovarian tissue and the consequences of α-SNAP (M105I) mutation (hyh mutation) in folliculogenesis and female fertility. Our results showed that α-SNAP protein is highly expressed in GCs and its expression is modulated by gonadotropin stimuli. On the other hand, α-SNAP-mutant mice show a reduction in α-SNAP protein levels. Moreover, increased apoptosis of GCs and follicular atresia, reduced ovulation rate, and a dramatic decline in fertility is observed in α-SNAP-mutant females. In conclusion, α-SNAP plays a critical role in the balance between follicular development and atresia. Consequently, a reduction in its expression/function (M105I mutation) causes early depletion of ovarian follicles and female subfertility.


Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus.
Cognitive impairment is present in 80% of patients with systemic lupus erythematosus (SLE) 10 years after diagnosis. The natural history of cognitive dysfunction in newly diagnosed SLE is unknown. We examined the association of depression and cognitive performance in newly diagnosed SLE. A multicenter cohort of 111 patients newly diagnosed (within 9 months) with SLE underwent cognitive function testing using an automated battery [Automated Neuropsychological Assessment Metrics (ANAM)] with 9 subtests. Depression was measured using the Calgary Depression Scale (CDS). The patient cohort was 97.3% female, 55.9% white, 15.3% African American, 20.7% Hispanic, mean age 37.8 years, mean education 15.2 years. CDS score ranged from 0 to 18 (mean 5.0 ± 4.6). CDS score did not differ by age, sex, ethnicity, or prednisone dose. Higher Krupp Fatigue Severity Scale scores and presence of fibromyalgia were significantly associated with higher CDS score (p < 0.001; p = 0.006, respectively). Depressed patients, defined by a CDS score > 6, had significantly poorer performance on 5 ANAM throughput measures: code substitution (p = 0.03), continuous performance (p = 0.02), matching-to-sample (p = 0.04), simple reaction time (p = 0.02), and the Sternberg memory test (p = 0.04). Adjusting for age, sex, ethnicity, education, and prednisone dose, a higher CDS score remained significantly associated with poorer performance on 3 measures, but the association was slightly attenuated for code substitution and matching-to-sample. Depression was not associated with mathematical or spatial processing. Depression, a modifiable risk factor, is associated with significantly poorer function in several cognitive domains in patients newly diagnosed with SLE. Treatment of depression when the CDS score is greater than 6 may improve cognitive functioning and should be further studied.


The effect of maternal age and planned place of birth on intrapartum outcomes in healthy women with straightforward pregnancies: secondary analysis of the Birthplace national prospective cohort study.
To describe the relationship between maternal age and intrapartum outcomes in 'low-risk' women; and to evaluate whether the relationship between maternal age and intrapartum interventions and adverse outcomes differs by planned place of birth. Prospective cohort study. Obstetric units (OUs), midwifery units and planned home births in England. 63 371 women aged over 16 without known medical or obstetric risk factors, with singleton pregnancies, planning vaginal birth. Log Poisson regression was used to evaluate the association between maternal age, modelled as a continuous and categorical variable, and risk of intrapartum interventions and adverse maternal and perinatal outcomes. Intrapartum caesarean section, instrumental delivery, syntocinon augmentation and a composite measure of maternal interventions/adverse outcomes requiring obstetric care encompassing augmentation, instrumental delivery, intrapartum caesarean section, general anaesthesia, blood transfusion, third-degree/fourth-degree tear, maternal admission; adverse perinatal outcome (encompassing neonatal unit admission or perinatal death). Interventions and adverse maternal outcomes requiring obstetric care generally increased with age, particularly in nulliparous women. For nulliparous women aged 16-40, the risk of experiencing an intervention or adverse outcome requiring obstetric care increased more steeply with age in planned non-OU births than in planned OU births (adjusted RR 1.21 per 5-year increase in age, 95% CI 1.18 to 1.25 vs adjusted RR 1.12, 95% CI 1.10 to 1.15) but absolute risks were lower in planned non-OU births at all ages. The risk of neonatal unit admission or perinatal death was significantly raised in nulliparous women aged 40+ relative to women aged 25-29 (adjusted RR 2.29, 95% CI 1.28 to 4.09). At all ages, 'low-risk' women who plan birth in a non-OU setting tend to experience lower intervention rates than comparable women who plan birth in an OU. Younger nulliparous women appear to benefit more from this reduction than older nulliparous women.


Location of the Popliteal Artery in Knee Extension on Magnetic Resonance Imaging.
The goal of this study was to define the course of the popliteal artery (PA) and determine any variability among different patient demographics; by identifying risk factors for injury, surgeons can decrease patient morbidity and mortality. Ninety-four adult magnetic resonance imaging studies of the knee were reviewed. In extension, the artery is at most 7.87 mm posterior and 4.83 mm lateral to the midline below the tibial plateau. Proximally, the artery is more anterior and midline. With increasing body mass indexes, the artery is more posterior at any level. At the femur, 1 cm above the distal articular surface, the artery was more posterior in younger patients; 1 cm below the joint line, it was more posterior in elder patients. Attention should be given during total knee arthroplasty, revision surgery, lateral meniscal repair, posterior cruciate ligament reconstruction, high tibial osteotomy, and fixation of tibial tubercle fractures. Proximally, the PA is more anterior and midline, placing it at significant risk during these procedures. (Journal of Surgical Orthopaedic Advances 27(4):325-328, 2018).


Implementing Tobacco Control Assistance in Pediatric Departments of Chinese Hospitals: A Feasibility Study.
Evidence-based tobacco control strategies delivered through pediatric settings could encourage parental smoking cessation and reduce children's exposure to second hand smoke (SHS) in the United States. The extent to which these tobacco control strategies could be routinely implemented in the pediatric setting of a developing country is not known. We tested the feasibility and efficacy of implementing an evidence-based intervention, the Clinical Effort Against Secondhand Smoke Exposure (CEASE), in a Chinese hospital to address the second hand smoke exposure of children in the home and car and to address parental smoking. We conducted a quasi-experimental trial of CEASE implementation in the pediatric inpatient departments of 2 Chinese hospitals, 1 assigned as the intervention hospital and another assigned as the control hospital. Data were collected through pre- and postsurveys of parents and clinicians, implementation process surveys, and chart review. In the intervention hospital, pediatricians' rates of delivering different types of tobacco control assistance to smoking parents were all significantly (P < .0001) higher during the post-CEASE implementation period than in the pre-CEASE implementation period. During the post-CEASE implementation period, pediatricians' rates of delivery for all aspects of tobacco control assistance were significantly higher (all P < .0001) in the intervention hospital than in the control hospital, whereas there was no difference during the pre-CEASE period. The findings of this study suggest that it is feasible to implement a system-level intervention of CEASE in the pediatric inpatient department of a major hospital in southern China. A large-scale trial incorporating measures to increase quit rates and including a long-term follow-up is needed to examine the effectiveness of CEASE implementation in China.


Adaptation, Validation, Reliability and Factorial Equivalence of the Rosenberg Self-Esteem Scale in Colombian and Spanish Population.
The Rosenberg Self-Esteem Scale is the most widely used instrument to assess self-esteem. In light of the absence of adaptations in Colombia, this study seeks to validate and adapt this scale in the Colombian population, and perform factorial equivalence with the Spanish version. A total of 1,139 seniors (633 Colombians and 506 Spaniards) were evaluated; the individuals answered the Rosenberg Self-Esteem Scale and sexual self-esteem scale. The average score of the items was similar to the questionnaire's theoretical average, and standard deviations were close to one. The psychometric properties of the items are generally adequate with alphas of .83 and .86 and significant (CI = .95) and correlations with the sexual self-esteem scale ranging from .31 and .41. Factorial equivalence was confirmed by means of a structural equation model (CFI = .912 and RMSEA = .079), thus showing a strong level of invariance.


Cold air plasma to decontaminate inanimate surfaces of the hospital environment.
The hospital environment harbors bacteria that may cause health care-associated infections. Microorganisms, such as multiresistant bacteria, can spread around the patient's inanimate environment. Some recently introduced biodecontamination approaches in hospitals have significant limitations due to the toxic nature of the gases and the length of time required for aeration. This study evaluated the in vitro use of cold air plasma as an efficient alternative to traditional methods of biodecontamination of hospital surfaces. Cultures of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli, and Acinetobacter baumannii were applied to different materials similar to those found in the hospital environment. Artificially contaminated sections of marmoleum, mattress, polypropylene, powder-coated mild steel, and stainless steel were then exposed to a cold air pressure plasma single jet for 30 s, 60 s, and 90 s, operating at approximately 25 W and 12 liters/min flow rate. Direct plasma exposure successfully reduced the bacterial load by log 3 for MRSA, log 2.7 for VRE, log 2 for ESBL-producing E. coli, and log 1.7 for A. baumannii. The present report confirms the efficient antibacterial activity of a cold air plasma single-jet plume on nosocomial bacterially contaminated surfaces over a short period of time and highlights its potential for routine biodecontamination in the clinical environment.


House sparrows (Passer domesticus) increase protein catabolism in response to water restriction.
Birds primarily rely on fat for energy during fasting and to fuel energetically demanding activities. Proteins are catabolized supplemental to fat, the function of which in birds remains poorly understood. It has been proposed that birds may increase the catabolism of body protein under dehydrating conditions as a means to maintain water balance, because catabolism of wet protein yields more total metabolic and bound water (0.155·H(2)O(-1)·kJ(-1)) than wet lipids (0.029 g·H(2)O(-1)·kJ(-1)). On the other hand, protein sparing should be important to maintain function of muscles and organs. We used quantitative magnetic resonance body composition analysis and hygrometry to investigate the effect of water restriction on fat and lean mass catabolism during short-term fasting at rest and in response to a metabolic challenge (4-h shivering) in house sparrows (Passer domesticus). Water loss at rest and during shivering was compared with water gains from the catabolism of tissue. At rest, water-restricted birds had significantly greater lean mass loss, higher plasma uric acid concentration, and plasma osmolality than control birds. Endogenous water gains from lean mass catabolism offset losses over the resting period. Water restriction had no effect on lean mass catabolism during shivering, as water gains from fat oxidation appeared sufficient to maintain water balance. These data provide direct evidence supporting the hypothesis that water stress can increase protein catabolism at rest, possibly as a metabolic strategy to offset high rates of evaporative water loss.


HLA-DR restriction-fragment-length polymorphisms in narcolepsy.
Seventeen white patients from the Stanford Sleep Disorders Clinic complaining of excessive daytime somnolence (EDS) were selected for restriction-fragment-length polymorphism (RFLP) studies. Fourteen of the patients with clinically diagnosed narcolepsy were seropositive for DR2. RFLP analysis of these patients compared with a homozygous DR2-Dw2 cell line failed to reveal any polymorphism when digested with six restriction endonucleases and hybridized with three different cDNA probes. None of the three patients with central nervous system hypersomnia, a syndrome similar to narcolepsy, were DR2-positive. We conclude that any polymorphism of the DR beta, DQ alpha, or DQ beta genes of DR2 narcoleptics that might distinguish them from DR2 normals cannot be resolved through RFLP analysis.


Hepatocyte growth factor activator: a possible regulator of morphogenesis during fetal development of the rat gastrointestinal tract.
The role played by the hepatocyte growth factor activator (HGFA) during morphogenesis of the gastrointestinal tract was investigated in fetal rats between days 16 and 21 of gestation. By our recently established method using chelation and dissecting microscope, samples could be separated into epithelium and mesenchyme, essentially without cross-contamination. The expression of the gene for HGFA together with those for hepatocyte growth factor (HGF) and its receptor, c-met, was investigated in each tissue element by RT-PCR. In the fetal rat gastrointestinal tract, mRNA signals for the HGFA gene were observed only in epithelia expressing c-met mRNA. In contrast, expression of HGF mRNA was limited to the mesenchymal elements, indicating the presence of a local HGF system in the gastrointestinal tract; an inactive form of HGF (proHGF) is secreted from the mesenchyme and then cleaved into the active form by HGFA secreted by the target epithelia. During the period of morphogenesis and histodifferentiation in the gastrointestinal tract, enhanced expression of the genes for HGF and its receptor/c-met was evident, with elevated HGFA mRNA level observed throughout the gastrointestinal tract except in the forestomach, where mRNA expression was barely detectable. These results strongly suggest the possibility that morphogenesis of the gastrointestinal tract is regulated not only by a local increase in production of HGF, but also by enhanced proteolytic activation of proHGF. Thus, it is probable that locally synthesized HGFA plays a significant role as a regulator of the morphogenic action of HGF during gastrointestinal tract development.


Retrospective Analysis of Motor Development in Infants at High and Low Risk for Autism Spectrum Disorder.
To measure upper-extremity and gross motor skill development in infants with and without risk factors for autism spectrum disorder (ASD). Data were coded retrospectively from 39 infants who participated in longitudinal structured early developmental assessments. Twenty-five infants were at high risk for ASD, and the remaining 14 infants were classified as low risk. Upper-extremity and motor skill development were coded at ages 2, 4, and 6 mo. Five infants went on to receive an ASD diagnosis at age 2-4 yr. Infants at high risk for ASD demonstrated fewer midline behaviors with the upper extremities and delayed motor skill development than the low-risk group. Differences in motor skills were most apparent at age 4 mo. Early monitoring for motor delay in infants at high risk for ASD is warranted. Midline control and play with the upper extremities and overall motor skill development are possible assessment and therapeutic targets.


Low frontal assessment battery score as a risk factor for falling in patients with Hoehn-Yahr Stage III Parkinson's disease: a 2-year prospective study.
Recently, we evaluated factors responsible for falling, including walking speed evaluated with the use of originally designed, suddenly narrowed paths, in patients with Hoehn-Yahr stage III PD. We prospectively studied the same cohort of patients with PD who were followed up for 2 years, to determine predictors of future falls. We performed clinical assessments and evaluated balance in 26 patients. A total of 19 variables including PD-related independent variables, balance investigation-related independent variables and gait independent-related variables were evaluated. The Frontal Assessment Battery (FAB) score (p = 0.002), Tinetti balance (p = 0.009), and gait velocity (p = 0.001) were higher in fallers than in non-fallers. On multiple logistic regression analysis, the FAB score was related to falling (odds ratio = 3.328, p = 0.033, 95% confidence interval = 1.104-10.03). On the FAB, the scores of 'inhibitory control' and 'sensitivity to interference' were significantly lower in fallers than in non-fallers. The use of the originally designed, suddenly narrowed path was the primary reason for demonstrating for the first time that a low FAB score is a risk factor for future falls. Calculation of the FAB score may be useful for predicting the risk of future falls.


Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer's disease.
Defects in p21-activated kinase (PAK) lead to dendritic spine abnormalities and are sufficient to cause cognition impairment. The decrease in PAK in the brain of Alzheimer's disease (AD) patients is suspected to underlie synaptic and dendritic disturbances associated with its clinical expression, particularly with symptoms related to frontal cortex dysfunction. To investigate the role of PAK combined with Aβ and tau pathologies (3xTg-AD mice) in the frontal cortex, we generated a transgenic model of AD with a deficit in PAK activity (3xTg-AD-dnPAK mice). PAK inactivation had no effect on Aβ40 and Aβ42 levels, but increased the phosphorylation ratio of tau in detergent-insoluble protein fractions in the frontal cortex of 18-month-old heterozygous 3xTg-AD mice. Morphometric analyses of layer II/III pyramidal neurons in the frontal cortex showed that 3xTg-AD-dnPAK neurons exhibited significant dendritic attrition, lower spine density and longer spines compared to NonTg and 3xTg-AD mice. Finally, behavioral assessments revealed that 3xTg-AD-dnPAK mice exhibited pronounced anxious traits and disturbances in social behaviors, reminiscent of fronto-dependent symptoms observed in AD. Our results substantiate a critical role for PAK in the genesis of neuronal abnormalities in the frontal cortex underlying the emergence of psychiatric-like symptoms in AD.


Stem cell therapy: A novel treatment approach for oral mucosal lesions.
Stem cells have enormous potential to alleviate sufferings of many diseases that currently have no effective therapy. The research in this field is growing at an exponential rate. Stem cells are master cells that have specialized capability for self-renewal, potency and capability to differentiate to many cell types. At present, the adult mesenchymal stem cells are being used in the head and neck region for orofacial regeneration (including enamel, dentin, pulp and alveolar bone) in lieu of their proliferative and regenerative properties, their use in the treatment of oral mucosal lesions is still in budding stages. Moreover, there is scanty literature available regarding role of stem cell therapy in the treatment of commonly seen oral mucosal lesions like oral submucous fibrosis, oral lichen planus, oral ulcers and oral mucositis. The present review will focus on the current knowledge about the role of stem cell therapies in oral mucosal lesions and could facilitate new advancements in this area (articles were obtained from electronic media like PubMed, EBSCO, Cochrane and Medline etc., from year 2000 to 2014 to review the role of stem cell therapy in oral mucosal lesions).


Cardiac mitochondrial matrix and respiratory complex protein phosphorylation.
It has become appreciated over the last several years that protein phosphorylation within the cardiac mitochondrial matrix and respiratory complexes is extensive. Given the importance of oxidative phosphorylation and the balance of energy metabolism in the heart, the potential regulatory effect of these classical signaling events on mitochondrial function is of interest. However, the functional impact of protein phosphorylation and the kinase/phosphatase system responsible for it are relatively unknown. Exceptions include the well-characterized pyruvate dehydrogenase and branched chain α-ketoacid dehydrogenase regulatory system. The first task of this review is to update the current status of protein phosphorylation detection primarily in the matrix and evaluate evidence linking these events with enzymatic function or protein processing. To manage the scope of this effort, we have focused on the pathways involved in energy metabolism. The high sensitivity of modern methods of detecting protein phosphorylation and the low specificity of many kinases suggests that detection of protein phosphorylation sites without information on the mole fraction of phosphorylation is difficult to interpret, especially in metabolic enzymes, and is likely irrelevant to function. However, several systems including protein translocation, adenine nucleotide translocase, cytochrome c, and complex IV protein phosphorylation have been well correlated with enzymatic function along with the classical dehydrogenase systems. The second task is to review the current understanding of the kinase/phosphatase system within the matrix. Though it is clear that protein phosphorylation occurs within the matrix, based on (32)P incorporation and quantitative mass spectrometry measures, the kinase/phosphatase system responsible for this process is ill-defined. An argument is presented that remnants of the much more labile bacterial protein phosphoryl transfer system may be present in the matrix and that the evaluation of this possibility will require the application of approaches developed for bacterial cell signaling to the mitochondria.