Selective integration of diverse taste inputs within a single taste modality.

A fundamental question in sensory processing is how different channels of sensory input are processed to regulate behavior. Different input channels may converge onto common downstream pathways to drive the same behaviors, or they may activate separate pathways to regulate distinct behaviors. We investigated this question in the Drosophila bitter taste system, which contains diverse bitter-sensing cells residing in different taste organs. First, we optogenetically activated subsets of bitter neurons within each organ. These subsets elicited broad and highly overlapping behavioral effects, suggesting that they converge onto common downstream pathways, but we also observed behavioral differences that argue for biased convergence. Consistent with these results, transsynaptic tracing revealed that bitter neurons in different organs connect to overlapping downstream pathways with biased connectivity. We investigated taste processing in one type of downstream bitter neuron that projects to the higher brain. These neurons integrate input from multiple organs and regulate specific taste-related behaviors. We then traced downstream circuits, providing the first glimpse into taste processing in the higher brain. Together, these results reveal that different bitter inputs are selectively integrated early in the circuit, enabling the pooling of information, while the circuit then diverges into multiple pathways that may have different roles.

Scrotal testis size in unilateral non-palpable cryptorchidism, what it can and cannot tell: Study of a Middle Eastern population.

BACKGROUND: Predicting the fate of a unilateral non-palpable testis based on its scrotal counterpart has been recommended by some, yet disputed by others, and the question remains open. OBJECTIVE: To investigate the accuracy of contralateral testis hypertrophy in predicting the absence of a unilateral non-palpable testis in a Middle Eastern population. STUDY DESIGN: This retrospective study included all patients referred to the present institution with unilateral non-palpable testis between June 2010 and August 2014, who had undergone laparoscopy. The scrotal testis was examined by sonography for size and volume, and diagnostic laparoscopy was utilized to determine the state of the cryptorchid testis. RESULTS: Of the 135 referred patients, 64 were aged ≤8 years, 29 were 9-18 years, and 42 were >18 years old. Diagnostic laparoscopy revealed 63 intra-abdominal testes, 20 small intra-inguinal testes, 32 vanished testes, and 20 nubbins or aplasia (Summary fig.). Scrotal testis volume was only a modest predictor for absence of the contralateral gonad in adult patients in whom a 22 ml cut-off yielded 64.3% sensitivity and 92.9% specificity. For those aged <18 years, overall accuracy was poor and dropped below 60%. Relative enlargement of contralateral testis in decreasing order of size was observed in patients with primary monorchism, followed by those with secondarily atrophic or nubbin testis, and then those with normal sized inguinal or abdominal testis. DISCUSSION: Unlike some previous series, which based their conclusions upon open exploration and mostly studied pre-pubertal subjects, the present results exclusively from laparoscopic exploration suggested that contralateral testis volume is a poor and inconsistent predictor of monorchism in children, and marginally predictive for young adults with unilateral non-palpable testis. This study comprised a reasonably large overall sample size compared with preceding reports; however, the number of patients within in each age group was limited. Greater numbers could allow for statistical comparison stratified by age group, for which this study was not powered. CONCLUSION: Contralateral testis volume predicts, with modest accuracy, monorchism in adults with unilateral non-palpable testis. In younger patients, the overall predictive accuracy of scrotal testis size is poor and not consistently dependable.

The status on non-communicable disease prevention and control in the Philippines: A systematic review

OBJECTIVE: This paper aims to provide concise background information regarding the state of noncommunicable diseases (NCDs) and their risk factors as well as the existing efforts to address them in the Philippines in the last 25 years. METHODS: A desk review of documents and literature review as well as analyses of available statistical data and several consultations with involved government agencies have been made to come up with summary figures and tables.RESULTS: NCDs as well as metabolic conditions that can potentially lead to NCDs are on the rise in the last score of years. The Philippines, through the Department of Health, has been visionary in leading various projects and activities to fight NCDs over the last two decades, and its efforts are slowly paying off: the prevalence of tobacco use and that of hypertension have decreased over the last 5 years. NCD mortality (including premature deaths) and prevalence of behavioral risk factors, however, generally remain high, and the Philippines needs to accelerate whole-of-society and whole-of-government actions to sustain the gains and attain its NCD targets in the next 10 years or so. CONCLUSION: The need to strengthen health system interventions and promote accountability of various sectors in addressing NCDs and its risk factors in the country arises. The development of a multisectoral action plan on NCD prevention and control is needed to halt the rise of NCDs in the country.

Heparin brand is associated with postsurgical outcomes in children undergoing cardiac surgery.

BACKGROUND: We sought to determine whether the use of specific unfractionated heparin brands during cardiopulmonary bypass for pediatric cardiac surgery was associated with differences in postoperative outcomes, especially regarding the incidence of bleeding and thromboembolic complications. METHODS: We compared postoperative outcomes for pediatric cardiac surgeries performed with Hepalean (Organon Teknika) to those performed with PPC heparin (Pharmaceutical Partners of Canada). Differences in clinical outcomes were determined in multivariable logistic and linear regression models adjusted for patients and surgery characteristics. RESULTS: In all, 903 operations were reviewed, 289 (32%) using Hepalean and 614 (68%) using PPC heparin. Patient demographics and surgical variables were comparable between groups. In multivariable regression models, adjusted for patients' characteristics, heparin use and choice of antifibrinolytic agents, the use of PPC heparin was associated with greater use of red blood cell transfusions in the first 48 postoperative hours (estimates +1.6 mL/kg, p<0.001), increased odds of bleeding complications (odds ratio 3.8, p=0.04), thromboembolic complications (odds ratio 4.7, p=0.01), early unplanned reoperation (odds ratio 6.9, p=0.03), longer postoperative intensive care unit stay (estimate +3.2 days, p<0.001), and longer hospital stay (estimate +3.6 days, p<0.001). CONCLUSIONS: Brand of unfractionated heparin used during cardiopulmonary bypass for pediatric cardiac surgery was associated with bleeding complications and clinical outcomes. Different brands of unfractionated heparin should not be considered equivalent without proper validation in formal trials.

Feasibility of very-high resolution ultrasound to assess elastic and muscular arterial wall morphology in adolescents attending an outpatient clinic for obesity and lipid abnormalities.

OBJECTIVE: Atherosclerosis begins during early life and is accelerated in individuals with cardiovascular risk factors. We hypothesized that very-high resolution ultrasound (VHRU, 25-55 MHz) could feasibly detect early arterial changes in adolescents with risk factors. METHODS: We prospectively imaged the carotid, brachial and radial arterial morphology (far wall intima-media thickness, IMT; adventitia thickness, AT) by VHRU in 58 youths (age 14 ± 2 years) attending a Pediatric Preventive Cardiology Clinic for assessment and management of cardiovascular risk factors and compared the findings to those from an age-matched group of 67 controls. RESULTS: Brachial and radial imaging was successful for all subjects. The carotid far wall could not be imaged in 7% of the patients due to limitations in penetration. VHRU image quality was related to body size and imaging depth. Imaging and analysis time were 12 ± 3 and 18 ± 3 min, respectively. Carotid IMT was increased in patients (0.42 ± 0.05 vs. 0.40 ± 0.06 mm, p = 0.05). No differences were found in brachial or radial IMT or AT vs. controls. Age, male gender, body mass index, systolic blood pressure (BP), but not lipid levels, were associated with arterial IMT in regression analyses. CONCLUSION: VHRU is feasible in imaging carotid and peripheral muscular artery IMT in adolescents. The arterial IMT is associated with age, gender, adiposity and systolic BP, but not lipid levels, in this adolescent population. Further studies including patients with manifest clinical atherosclerosis are needed to assess if VHRU has applications in atherosclerosis research.

The 'Golden Keys' to health - a healthy lifestyle intervention with randomized individual mentorship for overweight and obesity in adolescents.

OBJECTIVE: To conduct a pilot study designed to measure the impact of a healthy lifestyle intervention with or without individualized mentorship on adiposity, metabolic profile, nutrition and physical activity in overweight teens. METHODS: A total of 38 overweight adolescents (body mass index above the 85th percentile) 12 to 16 years of age, who were enrolled in a healthy lifestyle intervention program for six months, were randomly assigned to a nonmentored or individualized mentored intervention. RESULTS: For the entire cohort (final n=32), there was a nonstatistically significant reduction in mean (± SD) body mass index z score (2.08±0.38 to 2.01±0.47, P=0.07) and waist circumference (98±10 cm to 96±11 cm, P=0.08), and significant improvements in high-density lipoprotein level (1.08±0.24 mmol/L to 1.20±0.26 mmol/L, P<0.001), and low-density lipoprotein/high-density lipoprotein ratio (2.55±0.84 to 2.26±0.87, P<0.001) from baseline to the end of the intervention. Subjects consumed fewer high-calorie foods (3.9±1.9 to 3.0±1.5 servings/day, P=0.01) and snacks (9.7±5.5 to 6.8±4.0 servings/day, P=0.02), made fewer fast food restaurant visits (1.4±1.3 to 0.8±0.9 visits/week, P=0.02), and had less screen time (8.3±3.8 to 6.9±3.6 h/day, P=0.01). In addition, mentorship was found to be a feasible approach to supporting weight management in obese teens. Our study was underpowered to determine treatment effect, but promising modifications to lifestyle were observed despite the absence of statistically significant improvements in outcomes. CONCLUSIONS: The healthy lifestyle intervention improved subjects' lifestyles and lipid profiles, and the addition of mentorship in this context is feasible. A larger study with a longer intervention time is required to determine whether behavioural changes are associated with clinical improvement and to determine the role of mentorship in promoting lifestyle change.

Varicella-zoster virus neurotropism in SCID mouse-human dorsal root ganglia xenografts.

Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus and the causative agent of varicella and herpes zoster. VZV reactivation from latency in sensory nerve ganglia is a direct consequence of VZV neurotropism. Investigation of VZV neuropathogenesis by infection of human dorsal root ganglion xenografts in immunocompromised (SCID) mice has provided a novel system in which to examine VZV neurotropism. Experimental infection with recombinant VZV mutants with targeted deletions or mutations of specific genes or regulatory elements provides an opportunity to assess gene candidates that may mediate neurotropism and neurovirulence. The SCID mouse-human DRG xenograft model may aid in the development of clinical strategies in the management of herpes zoster as well as in the development of "second generation" neuroattenuated vaccines.

Frostbite: incidence and predisposing factors in mountaineers.

BACKGROUND: Frostbite, the most common cold injury, occurs in mountaineers, a major group at risk, more often than in the general population. OBJECTIVES: To describe the incidence of frostbite and the situations associated with it in mountaineering, emphasising factors that can be modified to decrease its frequency and severity. METHODS: In this cross sectional, questionnaire based study, 637 mountaineers were asked if they had suffered any frostbite injuries during the preceding two years and to provide the personal and circumstantial details. RESULTS: The mean incidence was 366/1000 population per year. Grade 1 injury (83.0%) and hands (26.4%) and feet (24.1%) involvement were most common. There was a significant relation between lack of proper equipment (odds ratio 14.3) or guide (p<0.001) and the injury. Inappropriate clothing, lack or incorrect use of equipment, and lack of knowledge of how to deal with cold and severe weather were claimed to be the main reasons for the injury. CONCLUSIONS: In high altitude and winter expeditions, mountaineers should wear appropriate clothing, have the necessary equipment such as quality boots and mittens, use a competent guide, and have training on how to tackle cold weather. They should also avoid wet clothing, windy terrains, and should never remain in the same position for long periods to reduce the risk of cold injuries.

Antimicrobial activity of crude methanolic extract of Satureja khuzistanica.

The methanolic extract of the aerial parts of Satureja khuzistanica was investigated for its antimicrobial activity. The maximum antibacterial and antifungal activities were observed against Staphylococcus aureus and Candida albicans.

Immune responses to measles and mumps vaccination of infants at 6, 9, and 12 months.

Immunizing infants against measles at the youngest age possible has the potential to reduce morbidity and mortality. The ability of infants at 6, 9, or 12 months to respond to measles and mumps vaccines was evaluated by measuring T cell proliferation, interferon-gamma production, and neutralizing antibody titers before and after vaccination. Infants in all age groups had equivalent cellular immune responses to measles or mumps viruses, with or without passive antibodies when immunized. In contrast, 6-month-old infants without passive antibodies had low geometric mean titers of antibody to measles or mumps viruses and low seroconversion rates. Geometric mean titers of antibody to measles virus increased if infants were revaccinated at 12 months. Six-month-old infants had limited humoral responses to paramyxovirus vaccines, whereas cellular immunity was equivalent to that of older infants. T cell responses can be established by immunization with these live attenuated virus vaccines during the first year, despite the presence of passive antibodies.

Varicella-zoster virus: molecular virology and virus-host interactions.

Cosmid-based mutagenesis and methods to examine varicella-zoster virus (VZV) tropism for differentiated human cells in vivo provide new information about molecular mechanisms of VZV infection. How specific VZV gene products contribute to viral replication has been further defined, and effects of VZV on expression of cellular genes have been demonstrated.

Mutational analysis of the repeated open reading frames, ORFs 63 and 70 and ORFs 64 and 69, of varicella-zoster virus.

Varicella-zoster virus (VZV) open reading frame 63 (ORF63), located between nucleotides 110581 and 111417 in the internal repeat region, encodes a nuclear phosphoprotein which is homologous to herpes simplex virus type 1 (HSV-1) ICP22 and is duplicated in the terminal repeat region as ORF70 (nucleotides 118480 to 119316). We evaluated the role of ORFs 63 and 70 in VZV replication, using recombinant VZV cosmids and PCR-based mutagenesis to make single and dual deletions of these ORFs. VZV was recovered within 8 to 10 days when cosmids with single deletions were transfected into melanoma cells along with the three intact VZV cosmids. In contrast, VZV was not detected in transfections carried out with a dual deletion cosmid. Infectious virus was recovered when ORF63 was cloned into a nonnative AvrII site in this cosmid, confirming that failure to generate virus was due to the dual ORF63/70 deletion and that replication required at least one gene copy. This requirement may be related to our observation that ORF63 interacts directly with ORF62, the major immediate-early transactivating protein of VZV. ORF64 is located within the inverted repeat region between nucleotides 111565 and 112107; it has some homology to the HSV-1 Us10 gene and is duplicated as ORF69 (nucleotides 117790 to 118332). ORF64 and ORF69 were deleted individually or simultaneously using the VZV cosmid system. Single deletions of ORF64 or ORF69 yielded viral plaques with the same kinetics and morphology as viruses generated with the parental cosmids. The dual deletion of ORF64 and ORF69 was associated with an abnormal plaque phenotype characterized by very large, multinucleated syncytia. Finally, all of the deletion mutants that yielded recombinants retained infectivity for human T cells in vitro and replicated efficiently in human skin in the SCIDhu mouse model of VZV pathogenesis.

Natural history of neonatal herpes simplex virus infections in the acyclovir era.

OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.

OBJECTIVE: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed. PARTICIPANTS: Infants who were

Granulysin blocks replication of varicella-zoster virus and triggers apoptosis of infected cells.

Granulysin, a lytic protein present in cytolytic granules of human natural killer and cytotoxic T cells, entered cells infected with varicella-zoster virus (VZV). Exposure to granulysin accelerated death of infected cells as assessed by apoptosis markers. The functional domain of granulysin that mediated its antiviral effects was amino acid 23-51; this domain also mediates the additional antitumor cell effects of granulysin. Because granulysin is a product of natural killer cells and T lymphocytes, it is possible that its antiviral activity may act as a mediator of innate and adaptive immune mechanisms.

Immune evasion mechanisms of varicella-zoster virus.

Varicella-zoster virus can to modulate the expression of class I and class II major histocompatibility (MHC) molecules. MHC class I expression is downregulated in VZV-infected T cells as well as in fibroblasts. VZV-infected cells do not respond to exposure to interferon-gamma (IFN-gamma) by upregulation of MHC class II expression. However, MHC class II expression is induced when cells are treated with IFN-gamma before VZV infection. These effects on MHC class I and class II expression can be expected to interfere transiently with adaptive immune responses of the host, mediated by CD4 and CD8 T cells, ensuring that the virus has sufficient opportunity for transmission to susceptible contracts.

Varicella-zoster virus retains major histocompatibility complex class I proteins in the Golgi compartment of infected cells.

We sought to examine the effects of varicella-zoster virus (VZV) infection on the expression of major histocompatibility complex class I (MHC I) molecules by human fibroblasts and T lymphocytes. By flow cytometry, VZV infection reduced the cell surface expression of MHC I molecules on fibroblasts significantly, yet the expression of transferrin receptor was not affected. Importantly, when human fetal thymus/liver implants in SCID-hu mice were inoculated with VZV, cell surface MHC I expression was downregulated specifically on VZV-infected human CD3+ T lymphocytes, a prominent target that sustains VZV viremia. The stage in the MHC I assembly process that was disrupted by VZV in fibroblasts was examined in pulse-chase and immunoprecipitation experiments in the presence of endoglycosidase H. MHC I complexes continued to be assembled in VZV-infected cells and were not retained in the endoplasmic reticulum. In contrast, immunofluorescence and confocal microscopy showed that VZV infection resulted in an accumulation of MHC I molecules which colocalized to the Golgi compartment. Inhibition of late viral gene expression by treatment of infected fibroblasts with phosphonoacetic acid did not influence the modulation of MHC I expression, nor did transfection of cells with plasmids expressing immediate early viral proteins. However, cells transfected with a plasmid carrying the early gene ORF66 did result in a significant downregulation of MHC I expression, suggesting that this gene encodes a protein with an immunomodulatory function. Thus, VZV downregulates MHC I expression by impairing the transport of MHC I molecules from the Golgi compartment to the cell surface; this effect may enable the virus to evade CD8+ T-cell immune recognition during VZV pathogenesis, including the critical phase of T-lymphocyte-associated viremia.

Immune evasion as a pathogenic mechanism of varicella zoster virus.

Varicella zoster virus (VZV) is a human herpesvirus that causes varicella (chickenpox) during primary infection, establishes latency in dorsal root ganglia and may reactivate years later, producing herpes zoster. VZV must evade antiviral immunity during three important stages of viral pathogenesis, including the cell-associated viremia characteristic of primary infection, persistence in dorsal root ganglia during latency and the initial period of VZV reactivation. Our observations about the immunomodulatory effects of VZV document its capacity to interfere with adaptive immunity mediated by CD4 as well as CD8 T cells, ensuring the survival of the virus in the human population from generation to generation.