Showing papers by "Mahidol University published in 2013"

Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study

Abstract: Purpose Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. Patients and Methods Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. Results The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for ...

The associations of parity and maternal age with small-for-gestational-age, preterm, and neonatal and infant mortality: a meta-analysis

Abstract: Previous studies have reported on adverse neonatal outcomes associated with parity and maternal age. Many of these studies have relied on cross-sectional data, from which drawing causal inference is complex. We explore the associations between parity/maternal age and adverse neonatal outcomes using data from cohort studies conducted in low- and middle-income countries (LMIC). Data from 14 cohort studies were included. Parity (nulliparous, parity 1-2, parity ≥3) and maternal age (<18 years, 18-<35 years, ≥35 years) categories were matched with each other to create exposure categories, with those who are parity 1-2 and age 18-<35 years as the reference. Outcomes included small-for-gestational-age (SGA), preterm, neonatal and infant mortality. Adjusted odds ratios (aOR) were calculated per study and meta-analyzed. Nulliparous, age <18 year women, compared with women who were parity 1-2 and age 18-<35 years had the highest odds of SGA (pooled adjusted OR: 1.80), preterm (pooled aOR: 1.52), neonatal mortality (pooled aOR: 2.07), and infant mortality (pooled aOR: 1.49). Increased odds were also noted for SGA and neonatal mortality for nulliparous/age 18-<35 years, preterm, neonatal, and infant mortality for parity ≥3/age 18-<35 years, and preterm and neonatal mortality for parity ≥3/≥35 years. Nulliparous women <18 years of age have the highest odds of adverse neonatal outcomes. Family planning has traditionally been the least successful in addressing young age as a risk factor; a renewed focus must be placed on finding effective interventions that delay age at first birth. Higher odds of adverse outcomes are also seen among parity ≥3 / age ≥35 mothers, suggesting that reproductive health interventions need to address the entirety of a woman’s reproductive period. Funding was provided by the Bill & Melinda Gates Foundation (810-2054) by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group.

Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

Abstract: We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist in its elimination.

Single-molecule analysis of fluorescently labeled G-protein–coupled receptors reveals complexes with distinct dynamics and organization

Abstract: G-protein–coupled receptors (GPCRs) constitute the largest family of receptors and major pharmacological targets. Whereas many GPCRs have been shown to form di-/oligomers, the size and stability of such complexes under physiological conditions are largely unknown. Here, we used direct receptor labeling with SNAP-tags and total internal reflection fluorescence microscopy to dynamically monitor single receptors on intact cells and thus compare the spatial arrangement, mobility, and supramolecular organization of three prototypical GPCRs: the β1-adrenergic receptor (β1AR), the β2-adrenergic receptor (β2AR), and the γ-aminobutyric acid (GABAB) receptor. These GPCRs showed very different degrees of di-/oligomerization, lowest for β1ARs (monomers/dimers) and highest for GABAB receptors (prevalently dimers/tetramers of heterodimers). The size of receptor complexes increased with receptor density as a result of transient receptor–receptor interactions. Whereas β1-/β2ARs were apparently freely diffusing on the cell surface, GABAB receptors were prevalently organized into ordered arrays, via interaction with the actin cytoskeleton. Agonist stimulation did not alter receptor di-/oligomerization, but increased the mobility of GABAB receptor complexes. These data provide a spatiotemporal characterization of β1-/β2ARs and GABAB receptors at single-molecule resolution. The results suggest that GPCRs are present on the cell surface in a dynamic equilibrium, with constant formation and dissociation of new receptor complexes that can be targeted, in a ligand-regulated manner, to different cell-surface microdomains.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis

Abstract: Background Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. Objectives To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. Search methods We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. Selection criteria We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). Data collection and analysis Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. Main results Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001). We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06) It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials. It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). Authors' conclusions The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX. There was a clincally important significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a clincally important significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance. This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG

Abstract: Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody-dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env-specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine-induced immunity by diminishing ADCC effector function.

8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications

Abstract: Metal ions play an important role in biological processes and in metal homeostasis. Metal imbalance is the leading cause for many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. 8-Hydroxyquinoline (8HQ) is a small planar molecule with a lipophilic effect and a metal chelating ability. As a result, 8HQ and its derivatives hold medicinal properties such as antineurodegenerative, anticancer, antioxidant, antimicrobial, anti-inflammatory, and antidiabetic activities. Herein, diverse bioactivities of 8HQ and newly synthesized 8HQ-based compounds are discussed together with their mechanisms of actions and structure-activity relationships.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Abstract: The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.

Human rabies: neuropathogenesis, diagnosis, and management

Abstract: Rabies is an almost invariably fatal disease that can present as classic furious rabies or paralytic rabies. Recovery has been reported in only a few patients, most of whom were infected with bat rabies virus variants, and has been associated with promptness of host immune response and spontaneous (immune) virus clearance. Viral mechanisms that have evolved to minimise damage to the CNS but enable the virus to spread might explain why survivors have overall good functional recovery. The shorter survival of patients with furious rabies compared with those with paralytic rabies closely corresponds to the greater amount of virus and lower immune response in the CNS of patients with the furious form. Rabies virus is present in the CNS long before symptom onset: subclinical anterior horn cell dysfunction and abnormal brain MRI in patients with furious rabies are evident days before brain symptoms develop. How the virus produces its devastating effects and how it selectively impairs behaviour in patients with furious rabies and the peripheral nerves of patients with paralytic rabies is beginning to be understood. However, to develop a pragmatic treatment strategy, a thorough understanding of the neuropathogenetic mechanisms is needed.

Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia

Abstract: The declining efficacy of artemisinin derivatives against Plasmodium falciparum in western Cambodia is a major concern. The knowledge gap in the understanding of the mechanisms involved hampers designing monitoring tools. Here, we culture-adapted 20 isolates from Pailin and Ratanakiri (areas of artemisinin resistance and susceptibility in western and eastern Cambodia, respectively) and studied their in vitro response to dihydroartemisinin. No significant difference between the two sets of isolates was observed in the classical isotopic test. However, a 6-h pulse exposure to 700 nM dihydroartemisinin (ring-stage survival assay -RSA]) revealed a clear-cut geographic dichotomy. The survival rate of exposed ring-stage parasites (ring stages) was 17-fold higher in isolates from Pailin (median, 13.5%) than in those from Ratanakiri (median, 0.8%), while exposed mature stages were equally and highly susceptible (0.6% and 0.7%, respectively). Ring stages survived drug exposure by cell cycle arrest and resumed growth upon drug withdrawal. The reduced susceptibility to artemisinin in Pailin appears to be associated with an altered in vitro phenotype of ring stages from Pailin in the RSA.

Unresolved problems related to scrub typhus: a seriously neglected life-threatening disease.

Abstract: Ecology and epidemiology. Scrub typhus is a life-threatening infectious disease that presents as an acute undifferentiated febrile illness. Its agent,Orientia tsutsugamushi, is an obligately intracytosolic bacterium that is transmitted by feeding larval trombiculid mites, which are the reservoir of the agent and the only life stage that feeds on a vertebrate host. Nymphal and adult trombiculid mites live in the soil and feed on the eggs of insects. Mites maintain the organisms by transovarian transmission as well as transtadial transmission through the mite’s lifecycle. Although mites transmit O. tsutsugamushi to vertebrate hosts such as rodents, only a small proportion of uninfected mites acquire Orientia during feeding on infected animals, and the ingested Orientia do not establish disseminated infection in the mites and are not transmitted transovarially to the next generation. It seems that chigger cofeeding on rodents is more relevant for effective mouseto-mite transmission of Orientia than feeding on rickettsemic hosts. Thus, the true role of rodents as reservoirs requires additional investigation, because there may be marked genetic variability in chiggers with respect to the ability to acquire rickettsiae by feeding. Also, rodents may be better considered as dead-end hosts just as humans are rather than a reservoir. However, the evolutionary selection of tremendous antigenic diversity of the immunodominant major 56 kDa surface protein presents an enigma if immune variation plays no role in survival of O. tsutsugamushi. The potential immunomodulatory effects of the saliva of larval mites on the pathogenesis of and immunity to infection with O. tsutsugamushi remain undetermined. One million cases of scrub typhus occur each year with an estimated 10% case fatality rate unless treated appropriately, very likely resulting in more deaths than dengue. Currently, scrub typhus has predominantly been reported from an area extending from the Russian Far East and Korea in the north to northern Australia in the south and Afghanistan in the west, and it includes islands of the western Pacific and Indian Oceans, including Japan, Taiwan, Philippines, Papua New Guinea, Indonesia, and Sri Lanka. This geographical range may be an underrepresentation, because case reports have been published from Africa and South America. The recent isolation of a novel species O. chuto acquired by a patient in Dubai, the detection of another divergentOrientia transmitted to a patient in Chile, and serologic diagnoses of scrub typhus acquired in Africa indicate that a wider geographic distribution and genetic diversity of the genus should be investigated. The burden of disease in rural areas of Asia is large, with studies showing scrub typhus causing up to 20% of febrile hospital admissions, an incidence of infections of greater than 3% of the population monthly, seroprevalence over 50% of the population, despite a significant annual rate of reversion to seronegativity of 50% of cases, and a seroconversion rate of 484 per 1,000 person-years. In 1999, the World Health Organization (WHO) stated, “Scrub typhus is probably one of the most underdiagnosed and underreported febrile illnesses requiring hospitalization in the region.” This opinion remains valid today and could justifiably be adjusted to scrub typhus is probably the single most prevalent, under-recognized, neglected, and severe but easily treatable disease in the world. This ancient disease is currently undergoing increased awareness both because of re-emergence and rising incidence in previously unrecognized areas and improved diagnostic testing. It is apparent that scrub typhus has been recognized to occur frequently now in places where the illness was nearly forgotten, including India, Sri Lanka, the Maldives, and Micronesia. However, scrub typhus has also emerged in regions north of the Yangtse River in China, where it was not known previously. The emergence of scrub typhus should also take into consideration the expansion of farmlands that have generated ideal habitats for trombiculid mites. The potential relationship with global climate change is unclear. Greater recognition in some countries, such as Thailand, Laos, Taiwan, and Japan, may reflect increased medical investigations and application of new diagnostic methods. The critical unresolved issues regarding epidemiology emphasize the need to determine the reasons for emergence and re-emergence and the true incidence of this neglected disease, for which calculated days of disability-adjusted years of life lost (DALYs) have not been determined and to which appropriate attention has not been paid (Table 1). Clinical manifestations. Scrub typhus ranges from a mild to a fatal illness. The early clinical manifestations are an eschar, representing localized cutaneous necrosis at the site of mite feeding (which is not always present), and regional lymphadenopathy followed subsequently by fever, headache, myalgia, generalized lymphadenopathy, cough, gastrointestinal symptoms, transient hearing loss, and rash. Progression of severe scrub typhus may manifest as acute respiratory distress, meningoencephalitis, gastrointestinal bleeding, acute renal failure, hypotensive shock, and coagulopathy. Unresolved clinical issues include the reason for the wide range of occurrence of eschars (7–97%), the reason for rash and severity of illness, and the need for characterization and determination of the mechanisms of the coagulopathy, hemorrhages, interstitial pneumonia, and meningoencephalitis. There is currently no unified approach to assess and stratify *Address correspondence to David H. Walker, Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0609. E-mail: dwalker@utmb.edu

Plasma IgG to Linear Epitopes in the V2 and V3 Regions of HIV-1 gp120 Correlate with a Reduced Risk of Infection in the RV144 Vaccine Efficacy Trial

Abstract: Neutralizing and non-neutralizing antibodies to linear epitopes on HIV-1 envelope glycoproteins have potential to mediate antiviral effector functions that could be beneficial to vaccine-induced protection. Here, plasma IgG responses were assessed in three HIV-1 gp120 vaccine efficacy trials (RV144, Vax003, Vax004) and in HIV-1-infected individuals by using arrays of overlapping peptides spanning the entire consensus gp160 of all major genetic subtypes and circulating recombinant forms (CRFs) of the virus. In RV144, where 31.2% efficacy against HIV-1 infection was seen, dominant responses targeted the C1, V2, V3 and C5 regions of gp120. An analysis of RV144 case-control samples showed that IgG to V2 CRF01_AE significantly inversely correlated with infection risk (OR= 0.54, p=0.0042), as did the response to other V2 subtypes (OR=0.60-0.63, p=0.016-0.025). The response to V3 CRF01_AE also inversely correlated with infection risk but only in vaccine recipients who had lower levels of other antibodies, especially Env-specific plasma IgA (OR=0.49, p=0.007) and neutralizing antibodies (OR=0.5, p=0.008). Responses to C1 and C5 showed no significant correlation with infection risk. In Vax003 and Vax004, where no significant protection was seen, serum IgG responses targeted the same epitopes as in RV144 with the exception of an additional C1 reactivity in Vax003 and infrequent V2 reactivity in Vax004. In HIV-1 infected subjects, dominant responses targeted the V3 and C5 regions of gp120, as well as the immunodominant domain, heptad repeat 1 (HR-1) and membrane proximal external region (MPER) of gp41. These results highlight the presence of several dominant linear B cell epitopes on the HIV-1 envelope glycoproteins. They also generate the hypothesis that IgG to linear epitopes in the V2 and V3 regions of gp120 are part of a complex interplay of immune responses that contributed to protection in RV144.

The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study

Abstract: During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses.

Reduced Susceptibility of Plasmodium falciparum to Artesunate in Southern Myanmar

Abstract: Background Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.

Asia–Pacific consensus recommendations for endoscopic and interventional management of hilar cholangiocarcinoma

Abstract: Hilar cholangiocarcinoma (HCCA) is one of the most common types of hepatobiliary cancers reported in the world including Asia-Pacific region. Early HCCA may be completely asymptomatic. When significant hilar obstruction develops, the patient presents with jaundice, pale stools, dark urine, pruritus, abdominal pain, and sometimes fever. Because no single test can establish the definite diagnosis then, a combination of many investigations such as tumor markers, tissue acquisition, computed tomography scan, magnetic resonance imaging/magnetic resonance cholangiopancreatography, endoscopic ultrasonography/intraductal ultrasonography, and advanced cholangioscopy is required. Surgery is the only curative treatment. Unfortunately, the majority of HCCA has a poor prognosis due to their advanced stage on presentation. Although there is no survival advantage, inoperable HCCA managed by palliative drainage may benefit from symptomatic improvement. Currently, there are three techniques of biliary drainage which include endoscopic, percutaneous, and surgical approaches. For nonsurgical approaches, stent is the most preferred device and there are two types of stents i.e. plastic and metal. Type of stent and number of stent for HCCA biliary drainage are subjected to debate because the decision is made under many grounds i.e. volume of liver drainage, life expectancy, expertise of the facility, etc. Recently, radio-frequency ablation and photodynamic therapy are promising techniques that may extend drainage patency. Through a review in the literature and regional data, the Asia-Pacific Working Group for hepatobiliary cancers has developed statements to assist clinicians in diagnosing and managing of HCCA. After voting anonymously using modified Delphi method, all final statements were determined for the level of evidence quality and strength of recommendation.

Strongyloides stercoralis infection

Abstract: #### Summary points Strongyloides stercoralis is an intestinal helminth that infects humans through contact with soil containing the larvae. Between 30 and 100 million people are infected worldwide.1 In the United Kingdom, strongyloidiasis is seen predominantly in migrants and returning travellers from endemic areas in the tropics and subtropics. Strongyloidiasis may present with cutaneous or gastrointestinal symptoms but is asymptomatic in over 60% of cases and only indicated by a raised blood eosinophil count.2 Diagnosis is important as the infection may persist for decades.3 Immunosuppressed patients with chronic strongyloidiasis are at high risk of developing strongyloides hyperinfection syndrome, a life threatening complication whereby larval proliferation leads to systemic sepsis and multiorgan failure. If strongyloidiasis is diagnosed early, however, it is easily treatable with oral antihelmintic drugs. In this article we review the epidemiology and common symptoms of strongyloidiasis and strongyloides hyperinfection syndrome, discuss the appropriate investigations, and summarise the evidence on treatment. #### Sources and selection criteria We performed a search of PubMed using the search term “ Strongyloides stercoralis ”, and included English language studies only. There is a paucity of randomised controlled trails investigating the treatment of strongyloides infection, and no Cochrane reviews have been published. Likewise there are no national or globally recognised guidelines for the investigation …

Anti–GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis

Abstract: Cryptococcal meningitis has been described in immunocompromised patients, as well as in those for whom no immune defect has been identified. GM-CSF regulates the function of phagocytes and pulmonary alveolar macrophages, critical elements in cryptococcal control. We performed clinical histories, immunological evaluation, and anticytokine autoantibody screening in four current patients with cryptococcal meningitis and identified and tested 103 archived plasma/cerebrospinal fluid samples from patients with cryptococcal meningitis. We assessed the ability of anti-GM-CSF autoantibody-containing plasmas to inhibit GM-CSF signaling. We recognized anti-GM-CSF autoantibodies in an otherwise healthy female with cryptococcal meningitis who later developed pulmonary alveolar proteinosis (PAP). Her diagnosis prompted screening of patients with cryptococcal meningitis for anticytokine autoantibodies. We identified seven HIV-negative patients with cryptococcal meningitis who tested positive for high-titer anti-GM-CSF autoantibodies. Two of the seven later developed evidence of PAP. Plasma from all patients prevented GM-CSF-induced STAT5 phosphorylation and MIP-1α production in normal PBMCs. This effect was limited to their IgG fraction. Anti-GM-CSF autoantibodies are associated with some cases of cryptococcal meningitis in otherwise immunocompetent patients. These cases need not have associated PAP.

Janus Colloidal Particles: Preparation, Properties, and Biomedical Applications

Abstract: Janus or anisotropic colloidal particles comprising of at least two components of different chemistry, functionality, and/or polarity have attracted attentions in a wide range of applications, e.g., in optics, magnetics, plasmonics, colloidal chemistry, and biomedicine. The interesting features of Janus colloidal particles are attributed to their tunable and controllable asymmetric structure, which allows controlling their physicochemical properties, down to the nanoscale. Moreover, their synergistic potential for multiplexing, multilevel targeting, and combination therapies make them particularly attractive for biomedical applications. However, the synthesis of Janus colloidal particles must be well-adapted to get particles with precise control of their various structural/physical/chemical properties. Nowadays, the advance in new fabrication processes is a strong need for fabricating compact composite particles with spatially separated functionalities, uniform size, tunable composition, and effective res...

Physiologic Uterine Inflammation and Labor Onset: Integration of Endocrine and Mechanical Signals

Abstract: The mechanisms underlying the preparation of the uterus for labor are not fully understood. Our previous studies have shown that during pregnancy, the uterine muscle (myometrium) undergoes dramatic phenotypic modulation culminating in term labor. The current review will discuss the cellular mechanisms involved in the regulation of myometrial activity and its modulation by endocrine signals and by mechanical stimulation of the uterus by the growing fetus. In particular, the contribution of uterine inflammation to the onset of labor will be described. We provide evidence that increased production of cytokines/chemokines in pregnant myometrium is associated with uterine occupancy and regulated by progesterone, suggesting the integration of mechanical and endocrine signals. Myometrial cells can actively participate in the inflammatory process in the uterus through the release of multiple proinflammatory cytokines and chemokines, providing a strong signal for activation of immune cells, their subsequent infiltration into pregnant uterus, and the initiation of labor.

A prospective randomised controlled study of patient-specific cutting guides compared with conventional instrumentation in total knee replacement

Abstract: Patient-specific cutting guides (PSCGs) are designed to improve the accuracy of alignment of total knee replacement (TKR). We compared the accuracy of limb alignment and component positioning after TKR performed using PSCGs or conventional instrumentation. A total of 80 patients were randomised to undergo TKR with either of the different forms of instrumentation, and radiological outcomes and peri-operative factors such as operating time were assessed. No significant difference was observed between the groups in terms of tibiofemoral angle or femoral component alignment. Although the tibial component in the PSCGs group was measurably closer to neutral alignment than in the conventional group, the size of the difference was very small (89.8° (sd 1.2) vs 90.5° (sd 1.6); p = 0.030). This new technology slightly shortened the bone-cutting time by a mean of 3.6 minutes (p < 0.001) and the operating time by a mean 5.1 minutes (p = 0.019), without tangible differences in post-operative blood loss (p = 0.528) or need for blood transfusion (p = 0.789). This study demonstrated that both PSCGs and conventional instrumentation restore limb alignment and place the components with the similar accuracy. The minimal advantages of PSCGs in terms of consistency of alignment or operative time are unlikely to be clinically relevant.