The purpose was to assess factors that may influence the use of IM modalities by ID physicians in their practice.In a 2010 national survey of 1000 practicing ID physicians, participants were asked to report the extent  to which the following considerations played a role in their recommendation/referral of IM modalities: (1) Knowledge of how and when to use them; (2) Amount of clinical research showing clear benefit; (3) Insurance; (4) Cost; (5) Reliable referral base; (6) Concern for professional reputation; (7) Fear of judgment from colleagues; (8) Insufficient regulatory oversight of supplements; and (9) Potential drug interactions with botanicals/supplements.A total of 311 (31%) ID physicians responded to the survey. The mean age was 49 and 64% of respondents were male. Their responses to the questions are listed below.For ID physicians, factors that were considered a major influence on the use of IM modalities included: potential drug interactions, clinical research, knowledge of IM modalities, and regulatory oversight. Factors that played a minor/no role in the use of IM modalities included fear of judgment and concern for professional reputation.


Objective: The immunochromatographic rapid tests facilitate the early diagnosis of dengue by providing evidence of the presence of virus specific proteins (antigens/ antibody) in human blood. Many products for rapid dengue diagnosis are available in the market; the performance of few selected products was evaluated and compared with enzyme linked immuno sorbent assays (ELISA).Methods: Sera from a large number of patients (n=184) admitted to National Institute of Blood Diseases & Bone Marrow Transplantation (NIBD) were used to determine the efficiency of non-structural (NS) 1, IgA, IgG and IgM based rapid test devices for dengue diagnosis.Results: The dengue NS1 antigen based device was least efficient while among the antibody based devices the dengue IgA rapid test (RDT) was comparatively better . This device could detect both primary and secondary dengue infection and was found to be the most sensitive device at all point of sample collection.Conclusion: The dengue IgA RDT could be a cost effective and efficient rapid test device for timely dengue diagnosis at all levels of healthcare settings. DHF is a vasculopathy characterized by capillary leakage and haematological deregulation; may result in fatal outcomes.8 An early and accurate diagnosis of dengue is important which assist not only in patient management by directing clinical attention but also in initiating community scale preventive measures for vector control to alleviate further dengue transmission. Commercial ELISA tests as well as immunochromatographic tests (RDT) that detect anti-dengue antibodies and the dengue NS1 antigen in plasma/sera have provided a new avenue for diagnosing dengue.9,10 In addition to this, the inexpensive and accurate dengue RDTs may also be useful in dengue epidemiological studies in resource limited countries. The primary and secondary dengue infections are diagnosed by the detection of either IgM or IgG or both in patient’s serum.8 These anti-dengue antibodies appear late in serum i.e. after 5-6 days of infection so NS 1 protein is detected in routine diagnosis during this period. The NS1 antigen appears in high concentration during the first few days of illness and it stays in serum after the infection subsides i.e. up to 14 days.10,11 Beside viral antigen detection a newer approach to dengue diagnosis is the use of anti-dengue IgA based RDT devices.12 IgA is the principal secretory antibody and human serum contains very low concentration of IgA1. During secondary dengue infection considerable increase in serum anti-dengue IgA is observed. The anti-dengue IgA is documented as the first antibody to appear in case of secondary dengue infection prior to IgG and IgM production while in case of primary infection it is produced after the anti-dengue IgM antibody due to class switching.13In the past few decades dengue has become a global health problem infecting millions of individuals annually.14 In this report three commercially available rapid diagnostic test devices were compared. Serological tests for dengue NS1 antigen, dengue IgA, dengue IgG/ IgM antibodies were carried out to demonstrate the potential application of these kits in early laboratory diagnosis of dengue infection with the special emphasis on utility of dengue IgA RDT as one of the new dengue diagnostic markers.12 The results were also compared with more specific and sensitive gold standard methods of dengue diagnosis i.e. IgG and IgM capture ELISAs.In Karachi, most of the clinical diagnostic facilities are using commercial immunochromatographic rapid tests (RDT) from international manufacturers relying only on the supporting literature on the efficiency of these devices. No local data on the efficacy and sensitivity of most of these tests is documented.Study design: A panel of 184 dengue disease suspected human serum samples was used for the evaluation of efficacy of dengue immunochromatographic tests (RDT).8 The study was conducted during the period of August to December 2010 at National Institute of Blood Diseases (NIBD). A signed informed consent form and detailed questionnaire were obtained from patients involved in this study following institutional review board (IRB) policies. Age range of the study population was 2-65 years.8 In the present study any sample positive for either dengue specific-antigen (NS1) or antibodies (IgM or IgG or IgA) by RDT screening was considered as positive dengue case. All samples were characterized using dengue acute diagnostics: NS1 Ag Rapid Test , ASSURE® dengue IgA Rapid Test  and dengue Duo Cassette . The efficiencies of all these devices were evaluated by comparing with dengue IgM capture ELISA  and dengue IgG capture ELISA . Complete blood count (CBC) was performed; after proper mixing by automated hematological analyzer; Sysmex XE-2100 ; to evaluate the clinical parameters of dengue diagnosis .A probable dengue case may be a patient with presentation of defined clinical symptoms and history of acute febrile illness of 2–7 days with or without haemorrohage.Dengue Antibodies ELISAs: Dengue IgM-Cap ELISA and IgG-Cap ELISA were used to detect dengue antibodies as per manufacturer’s instruction. Briefly, 100 µl/well of patient sera (diluted 1:100) and controls were added to the assay plate coated with either anti-human IgM or anti-human IgG to capture the IgM or IgG. Both plates were incubated for one hour at 37C. Then the plates were washed and 100 µl/well of enzyme conjugate was transferred to the assay plates except the blank wells. After 10 minutes, the reaction was stopped by addition of 100 µl/well 1 M phosphoric acid. The OD values were determined at 450 nm. A sample was defined as positive when ratio of sample absorbance and calculated cut-off value was > 1.Dengue NS1 Ag Rapid Test: Dengue NS1 Ag Rapid Test is a one-step chromatographic assay which uses murine monoclonal antibodies to capture dengue virus NS1 antigen in human serum or plasma and detected by NS1 antigen polyclonal antibodies conjugated with gold colloid. Assays were conducted and results were interpreted according to the instruction of manufacturers.Dengue IgA Rapid Test: ASSURE® Dengue IgA Rapid Test (WO 2009/139725 ) is a reverse flow technique (US Patent-6316205) immunochromatographic rapid test for the qualitative detection of anti-dengue IgA from patient’s biological samples . In this platform, test sample migrates upwards from the sample well and eventually form antibody-antigen complexes with dengue virus antigens in the test window. The bound antibody-antigen complexes is subsequently detected by goat anti-human IgA gold conjugate carried by chase buffer that flows downwards giving a pink-purplish color line in the test window. Control line which contains protein L captures human IgA from patient’s sample and binds with the anti-human IgA-gold conjugate, resulting in pink-purplish color line in the control window. The appearance of control line indicates the proper addition and migration of serum sample and chase buffer. The test was performed as per manufacturer’s instruction for use (IFU) and results were interpreted according to the intensity scale provided with the kit box without knowledge of the results of other tests.Dengue Duo IgM/IgG Cassette: Dengue Duo Cassette is a lateral flow based immunochromatographic rapid test for the qualitative detection of anti-dengue IgM and IgG from patient’s biological samples . The device is designed to detect IgM antibodies to dengue, as well as elevated IgG titers that are indicative of a secondary infection. The rapid tests were read and interpreted according to the manufacturers' instructions. The positivity of individual marker were calculated separately (IgM or IgG) as well as in combination (IgM and IgG).Statistical analysis: The quantitative variables were expressed as mean, standard deviation, confidence interval and minimum and maximum range. The qualitative variables were mentioned as percentages. The sensitivity and specificity of immunochromatographic tests were analyzed by 2x2 table using MedCalc statistical software, version-11.5 . Kappa value was used to test the efficiency and reliability of the rapid devices.Characteristics of the study population: The characteristics of the study population (n = 184 cases) that contributed acute sera to the test panel is shown in Sensitivity and specificity of dengue immunochromatographic tests versus reference dengue tests: The sensitivities and specificities of three RDTs against the reference tests i.e. dengue IgM-cap ELISA and IgG-cap ELISA are presented in Immunochromatographic tests sensitivity in primary or secondary infection: The detection of both dengue primary and secondary infected patients by dengue IgA RT was significantly higher than Panbio IgM/IgG Duo RDT and is presented in Sensitivity of Immunochromatographic tests by day of illness: The sensitivity of three RDTs was also evaluated based on the duration of onset of dengue fever, categorized into 6 groups  and 86.05% (80.95%) respectively. Additionally, the level of detection of infection at all stages of disease by IgA RDT was far better  false negative results. Dengue NS-1 antigen can be found in patient’s serum until the production of anti-NS-1 IgG or in some instances a few days after defervescence. The variable levels of NS-1 antigen in different phases of infection might be due to the immune-complex formation of NS1 antigen with anti-dengue IgG resulting in less sensitive dengue detection in acute-phase secondary infection as reported previously.21We conclude that the serological testing for early diagnosis of dengue infections could be accomplished by using IgA based RDT at all heath care settings during any stage of infection cycle. Moreover, it partially overcomes the limitations associated with ELISAs like handling of single sample without delay.


The cGMP-dependent protein kinase (PKG) is widely expressed in mammalian tissues and serves as an integral component of second messenger signaling in a number of biological contexts including vasodilation, motility and memory . PKG assHere we report the 2.5 Å crystal structure of a regulatory domain fragment containing both tandem cGMP binding sites of PKG Iα (amino acids 78-355). The overall domain topology of this structure shows a distinct and segregated architecture. The cGMP binding sites are separated by an extended central helix and offer limited interdomain communication. However, a previously uncharacterized helical domain (switch helix) promotes the assembly of a dimeric interface between PKG Iα78-355 protomers. Disruption of this interface by alanine scanning mutagenesis in full length PKG resulted in a marked reduction of activation constants.Our results offer new insight about PKG holoenzyme assembly as they provide the first detailed molecular view of tandem cGMP-binding domains and characterize the switch helix as a critical site of interchain communication between PKG protomers. The biological integrity of PKG appears to be mediated by this interface as it is necessary for the maintenance of kinetic fidelity. This structure highlights the critical importance of dimer communication in PKG biology and will likely serve as an improved platform for the strategic development of therapeutic agents aimed at treatment and prevention of cGMP-dependent pathologies.


This is a case report of a previously undescribed 20q chromosomal deletion (del(20q)) in marginal zone lymphoma (MZL). A 54-year-old Caucasian male presented with an enlarging neck mass and multiple violaceous skin nodules over his chest. Biopsy of the neck mass and cervical lymph nodes revealed MZL. Cytogenetic evaluation of both lymph node and bone marrow tissue revealed del(20q). This was an unexpected finding, as del(20q) is associated with myelodysplastic syndromes and myeloproliferative neoplasms and rarely seen in diffuse large B-cell lymphoma, follicular lymphoma, and T-cell lymphoma, but has not previously been described in MZL. We describe the case presentation and histologic findings and discuss the significance of this novel finding. Del, near 20q12 . There wNodal MZL is one of three subtypes of MZL and its incidence is relatively rare, comprising only 1.5% of all lymphomas , charactThe finding of a del(20q) in both the lymph node tissue and bone marrow samples was an unexpected finding in this case; a diagnosis of nodal MZL could confidently be made by lymph node histological features, IHC and flow cytometric immunophenotyping. The literature has not previously reported del(20q) in MZL. This finding may represent a specific cytogenetic abnormality in this nodal MZL with an aggressive morphology and high-stage disease. In conclusion, this case of nodal MZL with 20q deletion is a novel finding which can expand the breadth of knowledge of chromosomal abnormalities in MZL.


Salmonella enterica serovar Bovismorbificans from isolates associated with the 2011 hummus-borne multistate outbreak. All six genome sequences indicate the presence of two plasmids, one of which demonstrates similarity to the 93-kb pSLT2 IncF-type plasmid of Salmonella enterica serovar Typhimurium.We present six draft genome sequences of  Salmonella outbreak investigations [http://www.cdc.gov/salmonella/outbreaks.html]). In August through November of 2011, sesame seed paste (tahini) and hummus containing a rare serotype of Salmonella enterica caused illness in 23 people in 7 states and the District of Columbia   pattern that was distinctly different from those of other isolates of serovar Bovismorbificans recorded in the Pulse Net Database  from patient stool samples, two from hummus samples (SAL616 and 617) from the District of Columbia Public Health Laboratory, and one clinical isolate (SAL682) from the Michigan Department of Health.There are more than 40,000 cases of salmonellosis reported in the United States each year (see the CDC reports of de novo assembly of the paired-end reads to 100 contigs. The genomes were annotated by use of the RAST server (Genomic DNA from each strain was extracted from overnight cultures using QIAcube (Qiagen). The DNA library was constructed according to the Illumina recommended protocol for Nextera XT DNA sample prep and sequenced using Illumina Miseq . CLC bio software version 6.0.1  was used for the trimming and T server .S. enterica serovar Typhimurium. In addition to this virulence plasmid, an integration and conjugative element (ICE) similar to ICESb1 found in Salmonella bongori .The draft genome sequence accession numbers for these six


Massive fluid resuscitation followed by hypoperfusion abnormalities in the ICU is a risk factor for development of intra-abdominal hypertension (IAH). The aim of our study was to determine what influence would have the control of daily fluid balance on the incidence of IAH in patients after extensive abdominal surgery or after abdominal trauma.n = 22) or after abdominal surgery (n = 60). During first 7 days the fluid intake and balance was monitored and corrected at 6-hour intervals not to exceed 1,500 ml positivity over 24 hours . IAP was measured from admission twice daily . A sustained elevation of the IAP above 12 mmHg in two consecutive measurements was considered as IAH.A prospective observational study included a total of 82 adult patients , number of patients with intra-abdominal pressure (IAP) above 12 at admission: 23 (28%), admitted to a single ICU with the diagnosis of abdominal trauma (The incidence of IAH in relation to daily fluid intake and daily fluid balance is shown in Figure The incidence of IAH in patients after abdominal surgery or abdominal trauma may exceed the value of 40%, especially in situations associated with massive fluid resuscitation . We have


Migraine is 2-3 times more prevalent in women than in men, with frequent perimenstrual attacks. TRPV1 receptors on sensory nerve endings of the trigeminal track are important in mediating migraine attacks by releasing the vasodilator calcitonin gene-related peptide (CGRP). Variation in estrogen levels during the menstrual cycle may have an influence on the sensitivity of the TRPV1 receptor or on the amount of CGRP in perivascular nerve terminals and hence on CGRP release. Capsaicin, the active ingredient of hot chili peppers, stimulates the TRPV1 receptor and causes CGRP-dependent vasodilatation [


To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.10 copies/mL) was closely associated with HIV PVL  and HSV shedding  but not the presence of herpetic lesions .Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions . In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (logHIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility. Herpes simplex virus type-2 (HSV-2) infection is lifelong and a common cause of genital ulcers In vitro studies provide evidence of the effect of HSV-2 infection on HIV replication The frequency of recurrent episodes of clinical herpes and of subclinical viral shedding varies both between individuals and over time within the same individual The objectives of this study were to compare the presence and quantity of cervicovaginal HIV in HIV seropositive women living in Mbeya Region, Tanzania with clinical episodes of herpes, subclinical HSV-2 infection and without HSV-2 respectively; to examine the association between genital shedding of HIV and HSV-2; and to investigate factors influencing the quantity of HIV genital shedding.As part of a study of the determinants of HIV super-infection in Mbeya Region, Tanzania, an open cohort of 600 female barworkers aged 18 to 35 years was established in late 2000. Study procedures have been described previously Treponema pallidum particle agglutination assay  and the rapid plasma reagin test .A diagnostic algorithm including two different enzyme-linked immunosorbent assays  and a Western Blot assay  was used to determine HIV serostatus. Type-specific serological testing for HSV-2 was also performed by enzyme immune assay . Syphilis testing was carried out using the Serodia HIV-1 plasma viral load (PVL) was quantified by transcription polymerase chain reaction (PCR) , with a detection threshold of 50 HIV-RNA copies/ml.T pallidum, H ducreyi and HSV A single dry swab was taken from genital ulcers and multiplex PCR (M-PCR) was used for the detection of 6 cells for HIV-1 DNA. Cervicovaginal specimens were also tested for prostate specific antigen (PSA) using the VITROS immunodiagnostic product PSA reagent and calibrator packs on the automaton Ortho-Clinical Diagnostics VITROS Eci , and for traces of haemoglobin using Multistix 8 SG strips .Cervicovaginal secretions (CVS) were collected from all women at every study visit using standard vaginal lavage procedures Trichomonas vaginalis by direct microscopy of a wet mount preparation and Candida albicans by wet mount preparation and gram stain.Vaginal swabs were tested for CVS specimens collected from HIV seropositive women at 3-monthly study visits were excluded from analyses if (i) the woman had a genital lesion of non-herpetic origin (12 specimens were excluded for confirmed syphilis and 7 specimens excluded for chancroid), (ii) there were traces of haemoglobin in the specimen or (iii) the specimen was positive for PSA. Specimens from (i) were excluded as HSV shedding may have been influenced by other ulcerative STIs, and those from (ii) and (iii) were excluded as any HIV-RNA or HIV-DNA found in the genital tract may not have been attributable to genital shedding from the woman. Specimens were categorised into four study groups according to the woman’s HSV-2 serostatus and the presence or absence of confirmed herpetic genital lesions at the time of specimen collection. Women who experienced PCR-confirmed herpetic lesions at one or more study visits contributed to two study groups: Group 1  included CVS specimens collected in the presence of herpetic lesions; Group 2 , included specimens taken from the same women at follow-up examinations at least 6 months after or 6 months before the visits at which herpetic lesions were detected. In Group 3 (“never lesions”) a random sample of specimens were taken from HSV-2 seropositive women who never had herpetic genital lesions or a history of genital lesions at any of the study visits. Group 4 (“HSV-2 negative”) was randomly chosen from specimens taken from women not infected with HSV-2.10) transformations were applied to plasma and genital viral loads for HIV and HSV-2 to obtain approximately normal distributions, geometric means (GM), and 95% confidence intervals (95%CI). Differences in mean viral loads between groups were assessed using a random effects linear regression model to account for correlations within subjects. Correlations between viral loads  were assessed using Spearman’s rank correlation coefficient.Differences between study groups in proportions of CVS specimens with HIV-1 (RNA and DNA) and HSV DNA above the detection threshold were tested using random effects logistic regression modelling to account for correlations within subjects. Analyses of quantity of genital viral shedding were restricted to specimens with viral loads above the threshold of detection. Logarithmic .Initial analyses suggested that HSV shedding was a strong determinant of genital HIV shedding. We regrouped specimens of HSV-2 seropositive women in the subclinical and never lesions groups according to the presence of HSV shedding (asymptomatic HSV shedders) or absence of HSV shedding (HSV non-shedders). We then used random effects linear regression, accounting for multiple observations from the same individual, to examine the association of log-transformed HIV genital viral loads with HSV shedding status as well as other potential risk factors, including age, laboratory-diagnosed non-ulcerative sexually transmitted infections (STI), signs or symptoms of sexually transmitted diseases (STD), enlarged lymph nodes and HIV plasma viral load. In this analysis, specimens with HIV or HSV genital viral load below the threshold of detection were assigned a value of half the threshold.Analyses were performed using Stata 11.0 . The study was approved by the national ethics review committee of the National Institute for Medical Research of the United Republic of Tanzania and the LSHTM Ethics Committee . It was conducted within the framework of the Mbeya Medical Research Programme. All participants provided written, informed consent to participate in the study.Analyses were based on 221 eligible CVS samples from 131 HIV seropositive women. The four study groups comprised 57 women at 70 study visits with clinically manifest genital herpes (Group 1), 39 of the same women at 46 study visits when they did not have visible ulcers (Group 2), 55 HSV-2 seropositive women at 60 study visits who were never observed with herpetic lesions (Group 3), and 18 women at 45 study visits who were HSV-2 seronegative (Group 4) .Thirty-five women contributed to both Groups 1 and 2; four other women in Group 2 were not sampled at the time of clinical herpes. Three women were HSV-2 seronegative (Group 4) and later seroconverted, two with an episode of clinical herpes (Group 1) and one with no episode of clinical herpes (Group 3). Thirty-three women contributed more than one specimen to the same study group (up to 7 specimens from one HSV-2 seronegative woman).Mean age was around 28 years for HSV-2 positive women and 25 years for HSV-2 negative women. Slightly higher proportions of women were using hormonal contraception among those who had never had lesions, and those who were HSV-2 negative, but this difference was not statistically significant (p = 0.35).C Albicans was most common in the never lesions group (p = 0.08), but other STI or clinical signs of STD at the time of specimen collection did not differ significantly by study group  in samples from women uninfected with HSV-2 and highest  in samples from women with confirmed herpetic lesions. TPPA seropositivity, indicating past or current syphilis, was also lower in the HSV-2 uninfected group (p<0.001), and dy group .The prevalence of detectable genital HIV RNA was lowest in the HSV-2 negative group (73%) and highest in the clinical herpes group (94%) . The gen6 cells) and the lowest in the never lesions group (GM = 141 copies per 106 cells) . The pattern was less clear than for HIV RNA, but the highest viral load was seen in the clinical herpes group (GM = 252 copies per 106 cells) .All women with detectable genital HIV RNA also had detectable plasma HIV RNA. Among women with detectable genital HIV RNA, quantities of plasma and genital HIV RNA were significantly correlated .As expected, the prevalence of detectable genital HSV DNA varied substantially between the three study groups of HSV-2 positive women, with a much higher prevalence among women with clinical herpes (77%) than in the subclinical herpes (20%) and never lesions (12%) groups (p<0.001). HSV DNA viral load showed a similar, though non-significant trend .Of the 35 women who had specimens taken during clinical episodes of herpes and also at visits when they were asymptomatic, 30 (86%) had detectable HIV RNA on both occasions, while all 29 women with paired specimens analysed for HIV DNA were positive on both occasions. There was no evidence of a difference in the quantity of genital HIV shed between clinical and subclinical phases of herpes . AlthougTo explore whether signs of clinical herpes or HSV-2 viral shedding were more important determinants of HIV shedding, we re-categorised the specimens into four new groups: clinical herpes, HSV-2 seropositive with detectable genital HSV DNA shedding (asymptomatic HSV shedders), HSV-2 seropositive without detectable genital HSV shedding (HSV non-shedders at that visit), and HSV-2 seronegative. In all four groups, the majority of specimens had detectable HIV RNA and HIV DNA, and the prevalence was highest in samples taken during clinical or subclinical shedding episodes . OverallAmong specimens with HSV DNA shedding (with or without lesions), the genital viral loads of HIV RNA and HSV DNA were positively correlated . The correlation of genital HIV DNA and HSV DNA was weaker , as was the correlation between plasma HIV RNA and genital HSV DNA . A positive correlation between genital and plasma viral loads of HIV was seen in all women . While tGenital HIV RNA viral load increased with quantity of HIV PVL (p<0.001) and presence and quantity of genital HSV DNA . AlthougSimilarly, genital HIV DNA viral load increased with both HIV PVL (p<0.001) and genital HSV DNA viral load . AlthougIn this study we determined the frequency and quantity of cervicovaginal HIV and HSV using specimens collected from 131 HIV infected women who were followed up every three months for up to 30 months. The prevalence of detectable genital HSV DNA in asymptomatic HIV positive women was similar to studies from elsewhere in Africa The main objective of our study was to determine whether genital shedding of HIV occurred more frequently in the presence of genital herpetic lesions. A strength of the study was the long follow-up period, providing an opportunity to observe women both during and between clinical episodes of herpes. Clinical herpes was associated with higher levels of genital HIV shedding, but only partially as there were episodes of herpetic ulceration where HSV genital shedding was not recorded, and conversely episodes of HSV genital shedding in asymptomatic women. In the multivariate analysis, we clearly saw that herpetic ulcers were not independently associated with genital shedding of HIV RNA , whereas there remained a clear association between HSV genital shedding and genital shedding of HIV RNA , suggesting that this increase was related to the quantity of genital HSV and the HIV plasma viral load rather than to the presence or absence of herpetic lesions. In paired specimens taken from women with clinical herpes and from other study visits when they were asymptomatic, no difference was seen in HIV genital shedding at the two visits. When the original study groups were rearranged to examine the effect of genital HSV shedding, there was a clear difference in HIV genital shedding between HSV shedders and non-shedders, but no additional increase in HIV shedding in those with clinical herpes. Similarly, when risk factors for HIV genital shedding were examined in a multivariate regression analysis, the quantity of genital HIV RNA or DNA was significantly associated with HIV plasma viral load and HSV shedding, but after adjustment for these factors was not associated with clinical herpes.Our findings are consistent with results from a study carried out in Bangui, Central African Republic, where among HIV positive women shedding HSV, there was a significant correlation between genital HIV RNA shedding and genital shedding of HSV The observational design of these studies limits inferences about causality, but stronger evidence concerning the effect of herpes on HIV infectivity comes from seven recently completed randomised controlled trials of herpes suppressive therapy. Four trials, using valacyclovir or high dose acyclovir (800 mg b.i.d.), found significant reductions in PVL as well as significant reductions in rectal and cervicovaginal HIV-1 RNA concentrations Our results are consistent with previous reports of an association between HSV-2 shedding and HIV PVL, and suggest that clinical and subclinical herpetic reactivations might increase genital HIV shedding not only through a direct viral interaction at the genital level, but also through their systemic effect on plasma HIV viral load In this study we used cervicovaginal specimens as a marker of genital shedding, and did not find evidence of increased HIV shedding in the presence of genital lesions. However, HIV shedding may also occur directly from a herpetic lesion, and we cannot exclude the possibility that overall HIV infectivity is increased in the presence of lesions, particularly as 64% of herpetic lesions seen in this study were found on the vulva T pallidum or H ducreyi) were excluded from this analysis, as were specimens with traces of blood or semen, although we cannot rule out the possibility that some HIV or HSV detected in CVS originated from infected sexual partners. Some CVS were collected from women with non-ulcerative STI, and this may have led to underestimation of the association between herpetic lesions and HIV shedding, as cervicovaginal secretion of HIV-1 has been associated with the presence of non-ulcerative STI such as gonorrhoea and Chlamydia and found to decrease after effective treatment Genital specimens from women with ulcers of other confirmed aetiology (Increased genital HIV-1 viral load has been shown to be associated with immunosuppression in some studies In conclusion, this study adds to the accumulating evidence that HSV-2 infection increases genital shedding of HIV, and may therefore increase the infectivity of HIV infected individuals to their sexual partners. Our data suggest that the increase in HIV shedding is related to the quantity of HSV shedding rather than to the presence of clinical lesions of herpes. These findings emphasise the importance of developing and evaluating effective interventions to control herpes in populations where HSV-2 may account for a substantial proportion of HIV transmission.


Energy therapies in the hospital setting are met with various levels of acceptance due to questions of efficacy and evidence base. This prospective randomized controlled study quantifies the impact of one form of energy therapy on post-operative anxiety and pain in the lumbar spine surgery population.After meeting inclusion and exclusion criteria, patients that consented to participate in the study were randomized into standard post operative care (Control), standard post operative care plus a Healing Touch therapy intervention (Treatment), and standard post operative care plus an attention-control intervention (Sham). Patients were asked to complete the Visual Analog Anxiety Scale, Visual Analog Pain Scale, and Hospital Anxiety Depression Scale (HADS) both prior to and after receiving four consecutive sessions of Healing Touch intervention, attention-controlled intervention, or the standard of care. Baseline data were compared among the three groups using the chi-square test. The Sham and Treatment group were compared in terms of average change  in HADS, anxiety and pain scores using the t-test.A total of 75 patients were included: 25 in the Control group (33%), 24 (32%) and 26 (35%) in the Sham and Treatment groups, respectively. The three groups were similar in terms of baseline factors (p>0.05). Results from comparing the Sham and Treatment group in terms of the change in anxiety and pain scores showed marginally statistically significant differences in anxiety scores in session 2, statistically significant differences in anxiety in session 3, and statistically significant differences in pain scores measured in sessions 2, 3 and 4. No differences were observed between the two groups in terms of the change in HADS (p>0.05).Healing Touch demonstrated a statistically significant reduction in post-operative pain and is a viable adjunct in the care of patients undergoing lumbar spine surgery.


To develop a tool for self-assessment of HH resources, practice and promotion in healthcare facilities (HCF), based on the key components of the WHO Multimodal Hand Hygiene (HH) Improvement Strategy (MHHIS).A task force (TF) of HH experts developed the tool and identified the following desired features: 1) to reflect the 5 components of the WHO MHHIS; 2) to include measurable indicators based on scientific evidence and expert consensus; 3) to be in the format of a user-friendly questionnaire; 4) to be associated with a score; 5) to be usable repetitively over time. Tool development steps were: 1) identification of indicators, score and format; 2) usability and reliability pilot testing; 3) review and finalization.The tool was named HH Self-Assessment Framework (HHSAF) and structured in 5 sections corresponding to the WHO MHHIS components . 27 indicators were included and points assigned according to available evidence and importance attributed by experts. WHO implementation tools suited to the improvement of each indicator were referred to within the HHSAF. A score of maximum 100 points was established per each HHSAF section. According to the overall score, 4 HH situation levels were identified: inadequate; basic; intermediate; advanced. Additional leadership criteria for HH reference centres were included. The draft was finalized according to results of usability and reliability tests.Through a thorough development process, all desired features identified for an optimal HH self-assessment tool at HCF level were successfully fed into the HHSAF.None declared.


Human species and guinea pigs have to obtain vitamin C (VC) from food because they are unable to synthesize ascorbic acid due to the absence of the gene that encodes L-gulonolactone oxidase (Gulo). The spontaneous bone fracture (sfx) mouse is a mouse model which is deficient in the synthesis of VC because of the deletion in Gulo gene. Because muscle forces are a strong determinant of bone structure, particularly during the process of growth and development, we examined the gene expression of muscle in sfx mice.In order to identify the genes that regulate muscle development through Vitamin C (VC) pathway, we analyzed the gene expression profile in mouse muscle from femur. For microarray analysis, muscle from three age-matched, wild-type +/+ Balb/By, inbred strain mice (WT) and 3 female and 3 male homozygous sfx/sfx mice were used.Our results indicated that 1) The expression of Myogenic factor 6 (Myf6) gene in sfx mice is increased in both female and male mice, while the increase in male mice is much higher than that in female mice. 2) Some of dystrophin relevant genes are also affected in the sfx mice. The expressions of adenylate kinase (Ak1), creatine kinase sarcomeric mitochondrial (Ckmt2), and calcium-and integrin-binding protein 2 (Cib2) are decreased. The expression of creatine kinase muscle type (Ckb) and Cdc42 binding protein kinase beta (Cdc42bpb), on the other hand, although at a low level are increased in both sfx and wild type mice. Pathological analysis suggests that the diameters of male and female of sfx mice are smaller than that of Wt mice.Suggesting a deficiency in muscle development and potentially function.There is a significant difference in myopathy and gene regulations in muscle of sfx mice between female and male mice.


The most significant SNP, rs7952106 , was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene . Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5’ CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10 Sickle cell disease (SCD) is an inherited hemoglobin disorder affecting approximately 1 in 600 individuals of African American ancestry in the United States  and contStudies of familial aggregation provide significant evidence that blood pressure is a highly heritable trait ; howeverThis study includes two unrelated admixed African American ancestry SCD cohorts. Study protocols of both cohorts were approved by the Institutional Review Board (IRB) of Johns Hopkins University and Boston Medical Center. Additionally, IRB approval was acquired from all of the participating sites for subject enrollment and conducted in accordance with institutional guidelines.http://sitstudy.wustl.edu/) . These studies suggest that the DRD2 locus is plausibly involved in the regulation of SBP. Our results support these findings and the suggestive association from the DRD2 region SNPs may represents a true signal associated with SBP in SCD patients.) have reactive oxygen species (ROS)-dependent hypertension [44]. In addition, the pression  and showRecently, several large and well powered studies from European ancestry populations have identified 29 genomic loci associated with blood pressure -23. We sCACNB2 (5’) locus showed the consistent nominal significance for both SBP and SCI .A quantile-quantile (Q-Q) plot showing the distribution of observed χThe black diagonal line indicates expected results under the null hypothesis.(TIFF)Click here for additional data file.Figure S2Comparison of the effect size of variants from the reported regions associated with SBP in the ICBP meta-analysis and SCD cohort.(TIFF)Click here for additional data file.Figure S3Power calculation to detect genome-wide significant SNPs  for systolic blood pressure in the combined SIT Trial and CSSCD cohort, utilizing 1617 SCD samples.The authors thank the staff, clinicians and patients for their participation in the Silent Infarct Transfusion (SIT) Trial study. Genotyping services for the SIT Trial were provided by the Center for Inherited Disease Research (CIDR) at Johns Hopkins University and the Division of Blood Disorders at the Centers for Disease Control and Prevention (CDC). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.(TIFF)Click here for additional data file.


The consistent retention of habitat variables in our predictive models supports the area of refuge hypothesis which posits reduced extinction rates in the Coral Triangle. This does not preclude support for a center of origin hypothesis that suggests increased speciation in the region may contribute to species richness. In addition, consistent retention of sea surface temperatures in models suggests that available kinetic energy may also be an important factor in shaping patterns of marine species richness. Kinetic energy may hasten rates of both extinction and speciation. The position of the Indo-Pacific Warm Pool to the east of the Coral Triangle in central Oceania and a pattern of increasing species richness from this region into the central and northern parts of the Coral Triangle suggests peripheral speciation with enhanced survival in the cooler parts of the Coral Triangle that also have highly concentrated available habitat. These results indicate that conservation of habitat availability and heterogeneity is important to reduce extinction of marine species and that changes in sea surface temperatures may influence the evolutionary potential of the region.Range overlap patterns were observed in a dataset of 10,446 expert-derived marine species distribution maps, including 8,295 coastal fishes, 1,212 invertebrates (crustaceans and molluscs), 820 reef-building corals, 50 seagrasses, and 69 mangroves. Distributions of tropical Indo-Pacific shore fishes revealed a concentration of species richness in the northern apex and central region of the Coral Triangle epicenter of marine biodiversity. This pattern was supported by distributions of invertebrates and habitat-forming primary producers. Habitat availability, heterogeneity, and sea surface temperatures were highly correlated with species richness across spatial grains ranging from 23,000 to 5,100,000 km Persistent questions remain regarding the origins of the uneven distribution of marine species richness across the tropical Indo-Pacific The tropical Indian and Pacific Oceans encompass about two thirds of the earth’s equatorial circumference and include two distinct marine zoogeographic regions The observation that peaks in marine species richness throughout geologic time follow changing concentrations of available habitat is an extension of the area of refuge hypothesis, one of the numerous hypotheses invoked to explain the current epicenter of marine biodiversity in the Coral Triangle In addition to area of refuge, other hypotheses used to explain the current epicenter of marine biodiversity can be summarized as: 1) center of origin A neutral hypothesis has also been tested relating to the mid-domain effect The area of refuge hypothesis was primarily formulated as an alternative to the well-established center of origin hypothesis which heavily relies on assumptions about dispersal One component of the area of refuge hypothesis is habitat heterogeneity, which has long been considered important in shaping species diversity patterns It has long been established that there are latitudinal gradients in species richness with highest species richness in the tropics linked to multiple potential factors A number of different methods have been used to examine causes of the uneven distribution of marine species across the Indo-Pacific The study range covers the entire Indian Ocean (including Red Sea and Persian Gulf) and the entire Pacific Ocean between 30°N and 30°S. All data layers were projected onto the World Cylindrical Equal Area coordinate system centered at 130° longitude.2/grid cell, except for the grids located along upper and lower edges of the study area which cover less area. To compare the effect of area distortion, we used, five different equal area grids: small , medium , large , extra large , and largest . The use of different grid sizes was not to test for the best possible grain but to test at which grain the predictors are likely to operate The study area was divided into equal grids of different horizontal resolutions  and the commonly-used Universal Transverse Mercator (UTM) grid to test the grid choice effects on relationships between predictors and species richness. Different orientations of centroid location were tested and found to have minimal effects , S2 so tThe aim of this study was to test for effects of available nearshore habitat on species diversity, and therefore, relates to pelagic, benthic, or demersal species found primarily over continental or island shelves. The total number of species maps produced in this study was 10,446  of which2) from a 200 m bathymetry layer processed from ETOPO1  raster data Using a Geographic Information System (GIS), we calculated the amount of continental shelf or shallow water area (SW)  for each habitat and N = total habitat area .The SST layer was developed from the monthly long-term SST data derived from the National Oceanic and Atmospheric Administration Optimum Interpolation dataset. This product was constructed from two intermediate climatologies to produce a 1° resolution dataset with a 1961–1990 base period y is fitted as a Poisson variable. Using the log of y we fit the GLM as below:o, β1β, 2β, 3β, and 4β are the parameter estimates. For SLM, we used maximum likelihood estimation of spatial simultaneous autoregressive error model in the form:Range overlap maps and environmental layers were combined to form grid matrices with the corresponding values of species richness, habitat availability , two habitat heterogeneity indices , SST and NPP in each cell. Statistical analyses were performed to test the relationship between the environmental variables versus four different species richness subgroups: combined all species, all fish species, all habitat-forming species , and all invertebrate species. We modeled the influences of habitat area and heterogeneity to each subgroup using both a generalized linear model (GLM) and a spatial linear model (SLM) to account for spatial autocorrelation β is the vector of coefficient for intercept and explanatory variable X; λ is the spatial autoregression coefficient; W is the spatial weights; μ is the spatially-dependent error term; and ε is the error vector. Likewise, the Poisson response variable y was also fitted as a log function.2R values were used as a guide to model selection by evaluating the amount of variation explained. Since an equivalent 2R does not exist in spatial analysis with a logistic regression, we used pseudo-2RIWe performed SLM with spatial distance weights derived from five nearest-neighbor cells. We used five and not eight nearest neighbors since most of the cells  are isolated creating coastal and island effects. The presence of isolated cells will create a bias in spatial weight distance calculation. To normalize the data, all variables (dependent and independent) were log-transformed. Pearson correlation coefficients were generated for all between-variable comparisons. We tested individual habitat predictors versus each subgroup using single-predictor models. Then we used multiple-predictors model to test the effects of the combination of different habitats in each subgroup. The effects of multiple predictors were further explained by identifying the minimal-adequate model using backwards elimination method. Model fit was assessed using t-values (GLM) and z-values (SLM) for both single and multiple-predictor relationships. In GLM, adjusted Species richness across the Indo-Pacific showed the expected pattern of highest richness in the Coral Triangle . The cenGreatest shallow water area (SW) and longest coastline (CL) per unit area , 3A wereAverage SST values were highest (over approximately 29°C) around and east of the Solomon Islands and northern Australia and were also high (over approximately 28°C) in eastern central Indonesia, western Sumatra and northwestern Madagascar . SpeciesPredictor variables were consistently highly correlated with one another at all scales, with some notable exceptions . SW and Species richness of all taxonomic sets was significantly correlated with most environmental variables at all scales in single predictor GLM and SLM with the exception of insignificant correlations with SST at the smallest grid sizes, insignificant correlations with NPP at nearly all grid sizes, and HDIa and some other variables at the larger grain sizes . CL mostI indicated significant autocorrelation at all grains sizes except the largest grain size. As expected with increasing grains size and decreasing sample sizes, R2 and pseudo-R2 increased (less variation to explain) and AIC values decreased with larger grain sizes (less entropy to account for). However, when comparing equal grain sizes between GLM and SLM the correction for significant autocorrelation always improved the model (higher pseudo-R2 versus R2 and lower AIC). CL was consistently retained in all SLM for all taxonomic sets at all grain sizes except in the largest grain size. In SLM across all taxa most consistently retained were SW at smallest and largest grain sizes, HDIa at smallest grain size and variably in large grain sizes, HDIn and SST mostly at all grain sizes except small and medium, and NPP negatively correlated and variably retained at larger grain sizes.Multiple regression results were similar to single predictor results in that many environmental variables were significant and retained in models . GLM andRange overlap  of 10,44The pattern of species richness in this study  is dominThe high correlation among our predictor variables  and the I test shows significant effects of autocorrelation in our data (R2 than R2) and more entropy removed from the model (lower AIC). When comparing models based on the same grid size, correction for autocorrelation resulted in a lower AIC, and therefore, SLM is the preferred model The choice of best predictors for species richness  is influour data  similar our data  consisteR2 values increase with increasing grid size over the same area since there is less variation to explain with smaller sample sizes  is not statistically defensible le sizes . Similar2 a habitat heterogeneity index similar to HDIn may suffice in addition to CL as a proxy for habitat availability. Differences in how the different habitat complexity indices behave in models are a result of the form of complexity they emphasize. Our HDIa index is based on the relative proportion of area for our different habitat types  in a grid. Heterogeneity is negatively correlated with shallow water area  and the available kinetic energy predictor variable (SST) are consistently retained as positive significant predicator variables across species groups and grid sizes, accounting for autocorrelation . Coastliter area  because ter area . HDIn ister area . FurtherThe position of the Indo-Pacific Warm Pool appears to be a primary reason that available kinetic energy, as exemplified by SST, is most consistently retained in models with autocorrelation considered . LatitudOur results suggest that kinetic energy, habitat availability, and habitat complexity are all important in shaping species richness patterns across the Indo-Pacific but the relationship of these variables to area of refuge, area of accumulation, and center of origin hypotheses is not straightforward. The striking pattern of diminishing species richness away from the epicenter in the Coral Triangle was a factor in formation of both the center of origin and area of accumulation hypotheses, both mediated primarily by dispersal out of or into the Coral Triangle An alternative explanation for the pattern of increasing species richness into the Coral Triangle from the east and the correlation of SST with species richness is that the position of the Indo-Pacific Warm Pool is only a coincidence and does not influence speciation and extinction rates. If speciation within the Coral Triangle is the dominant factor then dispersal out of the Coral Triangle would rely on stepping stones of available habitat counter to prevailing currents over geologic time periods. There is some evidence for gene direction out of the Coral Triangle Habitat availability is central to both the center of origin and area of accumulation hypotheses but also to the neutral and eclectic hypotheses as well. The observed correlations among species richness, habitat availability, and habitat heterogeneity may simply be a function of the well-known species-area relationship This complex view of the area of refuge hypothesis supports the concept that both area of available habitat and complexity of available habitat are potentially important in models seeking to predict and conserve tropical marine species diversity. Shallow water area, as a measure of available habitat, is a significant component in shaping species richness in the region across different taxonomic groups. However, the largest shallow water area (the Sunda and Arafura shelves), does not coincide with the location of highest species richness . Available habitat in terms of shallow water area alone is not the optimal explanation for variation in species richness because coastline length and habitat heterogeneity are significant explanations for variation in species richness . BellwooAnother factor that may profoundly influence the role that available shallow water area plays in shaping biodiversity in the Coral Triangle is local extinction from glacial maxima and concomitant sea level lows. Marine life was extirpated on the extensive tropical sea floor represented by the Sunda and Arafura shelves several times during the Pleistocene Tittensor et al. (2010) th century Our findings further support previous studies based largely on different distribution databases Available habitat and habitat complexity both significantly explain variation in species richness, and therefore, the loss of these attributes may reduce diversity. Advances in our understanding of the different components of area of refuge may help more clearly define distinctions between available habitat and complexity of habitat. For example, more accurate mapping of presumptive keystone structures such as seagrass beds, mangrove areas, and coral reefs may improve the accuracy of habitat diversity indices. Testing additional types of habitat indices may also improve our understanding. Finding a practical alternative to grid-based spatial analyses may also improve resolution of the degree to which habitat availability components and factors such as SST explain variation in species richness. It is clear that habitat-based conservation efforts targeted at preserving biodiversity should aim to preserve both area and complexity of habitats. This effort is most crucial in the Coral Triangle where species richness is at its peak but it may also be very important in preserving the evolutionary potential of isolated islands, particularly those in the Indo-Pacific Warm Pool. Habitat destruction is a key factor linked to species threats in the Coral Triangle but fortunately, destruction is less intense at present in the islands of Oceania Figure S1Distribution pattern of shallow water extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the amount of shallow water area recorded in each cell such that cells in red have the largest amount of shallow water area, and cells in blue have the lowest amount of shallow water area. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S2Distribution pattern of coastal length extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S3Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S4Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S5Distribution pattern of the mean sea surface temperature in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S6Distribution pattern of the mean net primary productivity in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S7Combined adjacent cells (red color) against the regular sized cells (yellow color). (A) Small grid, (B) Medium grid, (C) Large grid, (D) UTM, (E) UTM shifted north/south, (F) UTM shifted east/west, (G) UTM shifted northeast/southwest. There are no adjacent cells that were combined in extra large and largest grids.(PDF)Click here for additional data file.Figure S8The two types of basemaps used in this study. (A) Visualization basemap consisting of 200 m depth and 100 km buffer, (B) Bathymetry basemap showing the 200 m depth used in analyses of species richness versus independent variables.(PDF)Click here for additional data file.Figure S9Distribution pattern of coastal length extent in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S10Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S11Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S12Distribution pattern of the mean sea surface temperature in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S13Distribution pattern of the mean net primary productivity in the Indo-Pacific at different grid scales. The grids were classified  into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Table S1Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). UTM NS = centroid shifted on a North-South plane, UTM EW = centroid shifted on an East-West plane and UTM NE = centroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R  value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Table S2Multiple predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001). UTM NS = centroid shifted on a North-South plane, UTM EW = centroid shifted on an East-West plane and UTM NE = centroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. 2R values are for GLM results, while pseudo-2R (p–2R) values are for SLM results.(PDF)Click here for additional data file.Table S3List of families with the number of species distribution maps used in this study.(PDF)Click here for additional data file.Table S4Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) complete results at different grid sizes. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R  value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Text S1Methods and results for UTM grids shifted to different centroid orientation.(PDF)Click here for additional data file.Text S2Sources for species range used in producing the distribution maps.(PDF)Click here for additional data file.


Fever is a common observation during critical illness ,2 and maAn online scenario-based questionnaire survey was distributed to medical and nursing members of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) and their intensive care colleagues. Main outcome measures: the choice of drug and preferred threshold temperature for intervention with antipyretics in clinical practice and in a clinical trial.There were 588 email invitations distributed through the ANZICS-CTG and Research Coordinator mailing list. Four hundred and forty-seven responses were received from 308 nurses (69%), 137 doctors (31%), and two others (0.5%). The majority of respondents having more than 8 years of experience 62%) worked in mixed medical and surgical units (84%) in a metropolitan or tertiary hospital setting (77%). The primary findings of our survey suggest that fever management is highly variable. Most clinicians administer an intervention to reduce temperature at or below 39°C (Figure % worked This survey suggests there is considerable clinical variability in fever management in patients with sepsis and without neurological injury or hyperthermic syndromes. At present, no particular management strategy is known to be superior to any other and it remains possible that current practice may be harming substantial numbers of patients. A temperature threshold of up to 40°C may be acceptable to clinicians for the design of a future randomized controlled trial. Further observational data may be informative for the design of such clinical trials.


Time-series data collected over a four-year period were used to characterize patterns of abundance for pelagic fishes in the northern Gulf of Mexico (GoM) before (2007–2009) and after (2010) the Deepwater Horizon oil spill. Four numerically dominant pelagic species  were included in our assessment, and larval density of each species was lower in 2010 than any of the three years prior to the oil spill, although larval abundance in 2010 was often statistically similar to other years surveyed. To assess potential overlap between suitable habitat of pelagic fish larvae and surface oil, generalized additive models (GAMs) were developed to evaluate the influence of ocean conditions on the abundance of larvae from 2007–2009. Explanatory variables from GAMs were then linked to environmental data from 2010 to predict the probability of occurrence for each species. The spatial extent of surface oil overlapped with early life habitat of each species, possibly indicating that the availability of high quality habitat was affected by the DH oil spill. Shifts in the distribution of spawning adults is another factor known to influence the abundance of larvae, and the spatial occurrence of a model pelagic predator (blue marlin) was characterized over the same four-year period using electronic tags. The spatial extent of oil coincided with areas used by adult blue marlin from 2007–2009, and the occurrence of blue marlin in areas impacted by the DH oil spill was lower in 2010 relative to pre-spill years. Pelagic fishes that frequent open oceans are valuable economically and influence the structure and resilience of offshore ecosystems 6 (±20%) barrels of oil into the northern Gulf of Mexico (GoM) [9). Oil trajectory models predicted that surface or near surface oil covered a large region of the continental shelf and slope In April 2010, the Deepwater Horizon [DH) oil spill resulted in the release of approximately 4.4×10Thunnus atlanticus), blue marlin (Makaira nigricans), dolphinfish (Coryphaena hippurus), and sailfish (Istiophorus platypterus). We first explored temporal variability during early life by contrasting larval abundances of each species before (2007–2009) and after (2010) the DH event. Next, generalized additive models (GAMs) were developed from 2007–2009 data to assess habitat associations, and then to predict the probability of occurrence the following year (2010) in relation to surface oil . Finally, patterns of occurrence for a model pelagic predator (blue marlin) over the same four-year period were examined using pop-up archival transmitting (PAT) tags, and light-based geo-locations from tags were used to compare the distribution of adults before and after the DH oil spill. Our working hypothesis was that the distribution and abundance of pelagic fishes in our study area, both early life and adult stages, may have changed in 2010 due to changes in habitat condition or other activities related to the DH oil spill. We fully recognize that natural environmental variability is known to influence the distribution and abundance of pelagic fishes in the northern GoM The aim of the present study was to assess possible impacts of the DH oil spill on four pelagic fishes that commonly inhabit outer shelf and slope waters of the northern GoM: blackfin tuna  and the oceanographic factors that influence the abundance of larvae, inter-annual variability was investigated with separate models for June and July. In June surveys, a significant year effect was observed for all four species: blackfin tuna (p = 0.030), blue marlin (p = 0.001), dolphinfish (p = <0.001), and sailfish (p = 0.006). Despite the fact that the mean density of each species was lower in June 2010 than any of the other June surveys , this yea concentration, depth, distance to feature, feature classification, salinity, sea surface temperature, sea surface height anomaly) on the occurrence of larvae varied across species and within species when contrasting June and July models  and 44.3% (July). Final GAMs for dolphinfish  retained three explanatory variables in the June model and four in the July model, with depth being the only variable common between the two models. Percent deviance explained for dolphinfish GAMs was 13.2% (June) and 13.5% (July). Final GAMs for sailfish  included three common explanatory variables in June and July models , and percent deviance explained was 20.3% (June) and 15.3% (July).GAMs based on presence/absence data developed for each species indicated that the influence of 7 oceanographic factors  varied markedly among species . The spaectively . High qu2 in both June and July.The spatial extent of surface oil from the DH event was viewed in relation to the total available area of high quality habitat predicted with GAMs to determine whether suitable habitat of each species was exposed to oil contamination. In June 2010, the estimated overlap between high quality habitat and surface oil was relatively low for blue marlin (0%) and sailfish (4.5%). Conversely, percent overlap for blackfin tuna and dolphinfish was considerably higher, with 15.3% and 13.9% of the predicted high quality habitat exposed to surface oil in the northern GoM. Species-specific patterns for July 2010 were similar, and again the percentage of high quality habitat exposed to surface oil was considerably lower for blue marlin (0.2%) and sailfish (7.2%) when compared to blackfin tuna (19.4%) or dolphinfish (11.4%). Given the predicted overlap observed for blackfin tuna, it is not surprising that the areal coverage of high quality habitat exposed to surface oil was relatively large, exceeding 60,000 km2 (9.3%) of the core use area in 2007–2009 was exposed to surface oil in 2010. Based on daily mean positions, we also observed that use of a region subsequently closed to fishing in 2010 by the National Oceanic and Atmospheric Administration  and after (2010) the DH oil spill . From 20Both the abundance and percent occurrence of fish larvae for selected pelagic fishes declined in 2010 relative to the three years prior to the DH oil spill, suggesting that changes in environmental conditions, possibly linked to the presence of oil and dispersants, may have contributed to observed inter-annual variability. Previous studies have demonstrated a clear relationship between these contaminants and the demographics of a wide range of marine organisms including invertebrates, fishes, birds, and mammals Although results from this study suggest a possible connection between reduced abundance of pelagic fish larvae in 2010 and the DH oil spill, inter-annual variability is relatively common for cohorts of pelagic larvae in the GoM Variability in mesoscale circulation has been shown to influence the spatial distribution of larvae in the GoM Determining the primary cause of annual fluctuations in the abundance of pelagic fish larvae is challenging, and establishing a direct link between the abundance of larvae and the DH oil spill is not possible given the data available. However, our estimates of overlap between surface oil and high quality habitat of billfish, dolphinfish, and tuna larvae, support the premise that highly suitable nursery areas (or spawning areas) of these taxa were impacted by the DH oil spill. Oil contamination occurred across several hundred thousand square kilometers of suitable habitat of pelagic fish larvae, accounting for approximately 10–20% of the available high quality habitat for blackfin tuna and dolphinfish in the northern GoM. Estimates of percent overlap were lower for billfish larvae , and suitable habitat for these taxa appeared to be more limited in coverage and farther offshore , possibly out of reach of significant oil contamination from the DH oil spill. While the presence of surface oil may have impacted larval survival within a restricted area, the majority of the high quality habitat for each species occurred in areas of the northern GoM unaffected by the oil spill. Therefore, anticipated effects of the DH oil spill on early life survival or reduced larval abundance are expected to be relatively modest, which interestingly is in accord with observed annual patterns of abundance.Apart from early life processes that directly impact the dispersal and survival of larvae, differences in the demographics (age structure) and abundance (spawning stock biomass) of spawning adults can also influence the abundance of larvae within a given area The influence of direct  and/or indirect  effects of the DH oil spill on the abundance and distribution pelagic fishes is currently unresolved, and caution must be exercised when interpreting time-series data that are limited in scope and duration. While larval abundances of all four species examined were lower in 2010 relative to the three-year baseline sample, abundance in 2010 was statistically similar to at least one of the other years surveyed, suggesting that observed declines are within the bounds of expected natural variability. Despite the fact that we cannot explicitly link observed inter-annual trends in the abundance of larvae to the DH oil spill, we can conclude that large areas of high quality habitat of pelagic fishes were exposed to oil contamination. In turn, oil contamination may have contributed to observed temporal patterns of abundance, but the main driver  of observed temporal patterns is unknown.Ichthyoplankton surveys were conducted over a four-year period (2007–2010) from approximately 26.5 to 28.0°N latitude and 87.5 to 92.0°W longitude in the northern GoM. Summer surveys were conducted each year during the same two months , which corresponds to the primary spawning periods of many pelagic fishes in the GoM Thunnus atlanticus (family Scombridae), blue marlin Makaira nigricans and sailfish Istiophorus platypterus (family Istiophoridae), and dolphinfish Coryphaena hippurus (family Coryphaenidae). Density at each station was determined by combining numbers of individuals in both 500 and 1200 µm mesh nets and adjusted to reflect a sampling depth of 0.75 m. Average volume of water sampled with both nets at each station was approximately 3500 m3. Percent occurrence at the species level was also determined and based on the number of stations where selected taxa were present divided by the total number of stations sampled.Fish larvae were sorted in the laboratory, and density and occurrence were determined for blackfin tuna Thunnus) to species was based on sequence variability of mitochondrial DNA [41) and High Resolution Melting (HRM) assays based on fixed nucleotide differences among species Thunnus larvae to determine the abundance of blackfin tuna (T. atlanticus) in our collections. Two congeners were also present in our collections , and blackfin tuna accounted for nearly 90% of the Thunnus larvae collected.Fish larvae were identified visually to family level based on anatomical and morphometric features Temporal differences in the densities of larvae collected over the four-year period were compared with a Kruskal-Wallis (rank sums) one-way analysis of variance (ANOVA). This non-parametric method does not assume a normal distribution, which was required due to the large number of zero values in our data set (skewed distribution). Species-specific models were developed for each species in both June and July to investigate temporal differences in larval density for all four species. Non-parametric multiple comparison tests (Wilcoxon method) were run to determine which factor levels or years differed from others. Statistical significance for all tests was based on α = 0.05.a, depth), and parameters related to mesoscale oceanographic features   were used to investigate the influence of environmental conditions on the occurrence of each species. Presence/absence models were fit with a binomial distribution using a logit link function in R software feature) . MesoscaA manual backwards stepwise procedure based on minimizing the Akaike Information Criterion  tags were deployed opportunistically on blue marlin from sport fishing vessels in the GoM from 2007–2010, following methods previously described Daily mean position estimates from the primary spawning season of blue marlin (May–July) were compared before (2007–2009) and after (2010) the DH oil spill. PAT tag data from deployments prior to the DH oil spill (n = 13) ranged from 60 to 365 days. Daily mean positions of adult blue marlin after the spill were based on geo-location estimates generated from 1-year tag deployments on blue marlin (n = 4). These fish were tagged in summer/fall 2009 and the tags released from fish during or after July 2010. Our analysis is based on the assumption that individuals return to the same general spawning area the following year, which is supported by long-term tag deployments on blue marlin and white marlin before or after 2010 . GriddedFigure S1Spatial and temporal variability in the density of pelagic fish larvae collected from 2007 to 2010 for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus). June (red) and July (blue) survey shown and colored lines represent the observed margin of the Loop Current during each sampling trip (coded by color). Density (larvae. 1000 m−3) denoted by circle size.(TIF)Click here for additional data file.Figure S2Response plots from final presence/absence generalized additive models (GAMs) based on June data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S3Response plots from final presence/absence generalized additive models (GAMs) based on July data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S4Map showing the region closed to fishing on June 21, 2010 by the National Oceanic and Atmospheric Administration due to the Deepwater Horizon oil spill.(TIF)Click here for additional data file.Figure S5Long-term tracks (ca. 1 year) of individual A) white marlin  and B) blue marlin (Makaira nigricans) from pop-up archival transmitting (PAT) tags deployed in the Gulf of Mexico. Blue shading depicts kernel density (95% volume of utilization distribution shown) based on daily mean positions the first month of the deployment (dark blue) and the same month the next year (light blue). Colored symbols represent quarterly geo-location estimates for each individual over the deployment period and all geo-location data were generated using state-space models that implemented the Kalman filter algorithm from light-based location data generated from PAT tags. Estimated weights of white marlin (ID: WM-09-01) and blue marlin (ID BM-10-02) shown here were 30 and 120 kg, respectively.(TIF)Click here for additional data file.Table S1(DOCX)Click here for additional data file.


Although postsynaptic and transmembrane currents over local neuronal populations are considered the main factors for shaping local field potential (LFP) and current source density (CSD) fluctuations , high-frFirstly, we employ a spiking network model of the CA3 and CA1 hippocampal areas that reproduces key features of SWRs based on synchronous CA3 population bursts and strong, fast-decaying CA1 recurrent inhibition . The emein vivo, from multiple locations in areas CA3 and CA1 of the rat hippocampus while animals run on a linear track with resting areas at both ends. The spiking activity of detected place cells, firing in sequence during the running sessions, is replayed in either forward or reverse order during SWRs occurring at the resting areas [Next, we apply our analysis to a set of LFPs and unit activity, recorded ng areas . We tracThis work provides a deeper understanding of the nature of extracellular fields and offers a new approach to the decoding of ongoing cell assemblies based on extracellular current flows. Differences in the emerging SWR field activity may play an important role in information processing during memory consolidation.


Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions. Cardiovascular disease is the number one cause of death worldwide and remains a burdensome health problem. Understanding the underlying molecular mechanisms of cardiovascular disease will provide valuable information for the design of novel drugs for pharmacological therapies.As a central player of the canonical NO-sGC-cGMP pathway, sGC controls important physiological functions such as smooth muscle relaxation, platelet aggregation, and hemostasis   NO is formed via two primary pathways. NO is generated when endothelial nitric oxide synthase (eNOS) is activated by Cain vitro and cell lysates  further mediates membrane localization of sGC in cardiomyocytes . Riociguat raises the potency of sGC activation by NO and has been approved for the treatment of pulmonary arterial hypertension   mice but not in CD36−/− mice  that putatively inactivated/inhibited sGC through phosphorylation at a yet to be determined residue  signaling  and cystathionine γ-lyase (CSE)   and hydrogen peroxide (H2O2) that in turn modify proteins and adversely alter their function . TSP1 is a more potent stimulator of ROS compared to the classic activators phorbol myristate acetate and angiotensin II. The CD47 targeting peptide 7N3 that contains the Val-Val-Met sequence also increased VSMC O·−2 production -mediated activation of sGC and subsequent dephosphorylation of myosin light chain 2 (the kinase responsible for vasoconstriction) while increasing immuno-reactive F-actin in cultured VSMC  TSP1−/− mice maintained a more normal cardiovascular profile compared to wild type animals with less change in right ventricular systolic pressure, less right ventricular hypertrophy and less pulmonary vascular smooth muscle cell hyperplasia. This observation was further associated with less pulmonary ROS production  10SDG2600345 (Elsa D. Garcin), 13PRE17000045 (Franziska Seeger) and 13POST14520003 (Natasha M. Rogers) and by the Intramural Research Program of the NIH/NCI (David D. Roberts). This work was further supported by the Institute for Transfusion Medicine, the Hemophilia Center of Western Pennsylvania and the Vascular Medicine Institute (Jeffrey S. Isenberg).Jeffrey S. Isenberg is Chair of the Scientific Advisory Boards of Vasculox, Inc.  and Radiation Control Technologies, Inc.  and holds equity interest in the same. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The female genital tract is an important site of HIV acquisition, but the epithelial and submucosal tissue factors associated with HIV susceptibility have not been defined.Ectocervical biopsies were obtained from HIV-exposed seronegative (HESN) women (n=20) and HIV-seronegative lower risk controls (n=20). Epithelial thickness and tissue distribution of immunological markers were assessed in situ by immunohistochemistry and measurement of mRNA expression was performed by quantitative PCR.The thickness of the ectocervical epithelium was significantly higher in HESN vs. lower risk subjects. CD4 and DC-SIGN mRNA expression was significantly lower in HESN than lower risk women, and in situ immunohistochemical analysis confirmed the reduced CD4 expression in HESN participants. In addition, immunohistochemistry demonstrated lower CCR5 and higher Langerin expression in the HESN subjects.A thicker epithelial barrier and altered expression of HIV binding receptors in the ectocervix of HESN women may contribute to protection against HIV transmission.


NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis.Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both  The identification of genes that participate in oncogenesis has facilitated recent development of molecular targeted therapies against cancer (reviewed in -3). In tThe SNF1/AMP-activated protein kinase (AMPK) family functions to control the balance of cellular metabolisms, and is activated by the cellular AMP:ATP ratio that is regulated by metabolic stresses such as hypoxia and glucose deprivation , 18. AMPRecent tenacious efforts by investigators have accelerated the elucidation of genomic alterations in melanoma cells. The first step to decipher enigmas in complex genomic alterations in melanoma cells had started by taking advantage of techniques that had been utilized to elucidate chromosomal abnormalities in hematopoietic malignancies -39. ThosAcral melanomas occur on nailbeds and plantar regions such as the palms of the hands and soles of the feet . The hisCGH combined with analyses of clinical parameters are a powerful approach to identify genomic loci that have significant impact on the clinical outcome of melanoma patients. Both the classical cytogenetic approach and the CGH approach share the same implication that the long arm of chromosome 1 and the short arm of chromosome 6 may have a profound effect on the tumorigenesis of melanomas since both chromosomal regions have a significant impact on the clinical outcome of patient survival Fig. 50, 61], 6150, 6NUAK2 is the fourth member of the AMPK family of kinases and shares a similar catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. The NUAK2 gene resides at 1q32 and encodes 630 amino acid residues that are translated into a protein of approximately 76 kDa . In geneCaenorhabditis elegans, participates in maintaining the integrity of components of myosin filaments. Disruption of unc-82 by mutations causes defects in cytoskeleton reorganization during embryogenesis [The amount of knowledge about the regulation and function(s) of NUAK2 is quite limited compared to AMPK-α1 and AMPK-α2. However, several important functions related to myosin filaments and cytoskeleton organization have been revealed. Myosin phosphatase target subunit 1 (MYPT1) was identified as a specific substrate for NUAK2. MYPT1 is phosphorylated by NUAK2 at sites other than Thr696 and The853, which are known as Rho-kinase (ROCK) phosphorylation sites . Furtherogenesis . Anotherogenesis . As the ogenesis , 81. Musin vitro and tumor growth in vivo in melanomas, and the extent of those reductions of cell proliferation varies depending on the different genomic aberrations of melanoma cells [in vivo from the profile of the proliferating cell population [Disruption of the normal regulation and function(s) of NUAK2 may lead to the dysregulation of proliferation and migration in cancer cells. However, the exact effects and mechanisms participating in tumorigenesis remain to be elucidated due to the lack of sufficient molecular studies of NUAK2. Several conflicting results on tumorigenesis including cell proliferation, apoptosis and migration have been reported. The knockdown of NUAK2 using siRNA or shRNA reduces cell proliferation ma cells . Anotherpulation . Over-expulation . This fupulation , 84. Howpulation . NUAK2 apulation . CD95 stP = 0.0036), and multivariate analysis using multiple Cox regression analysis also showed the impact of NUAK2 on relapse-free survival . Interestingly, those impacts of NUAK2 on melanoma patient survival are significant at relapse-free survival of acral melanomas compared to weak significances at Non-CSD melanomas and overall survival. Those observations lead to the speculation that NUAK2 has more profound effects on cell migration resulting in worsening relapse-free survival of acral melanoma patients as suggested by both a migration assay and a wound healing assay [UV irradiation is one of the major causes of cutaneous melanomas, but acral and mucosal melanomas are protected from exposure to UV irradiation due to their anatomical locations. Thus, the molecular pathogenesis of acral and mucosal melanomas should be different from that of cutaneous melanomas arising from sun-exposed areas such as Non-CSD melanomas, and causes other than UV irradiation, such as reactive oxygen species (ROS), may play an important role in the melanomagenesis of acral and/or mucosal melanomas. The HGF/SF transgenic mouse model is prone to develop cutaneous melanomas following UV irradiation . In thatng assay .The recent identification of KIT mutations in acral, mucosal and CSD melanomas led to the development of therapeutic modalities using imatinib mesylate to target KIT activation. Although initial studies achieved only poor responses using imatinib mesylate against melanomas, the stratification and appropriate selection of patients based on KIT activation by mutations and amplifications have improved responses of melanoma patients to imatinib mesylate , 98. As