A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2-/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age.     

Comparative studies on effects of three chitin synthesis inhibitors on common malaria mosquito (Diptera: Culicidae)

Toxicities of three chitin synthesis inhibitors (diflubenzuron, nikkomycin Z and polyoxin D) were evaluated using second instars of the common malaria mosquito, Anopheles quadrimaculatus Say (Diptera: Culicidae). Neither nikkomycin Z nor polyoxin D at 50 microg/liter caused significant larval mortality, although they reduced the body weight of the survivors by 20.5 and 33.8%, respectively, in 48 h. In contrast, exposures of the larvae to diflubenzuron at 12.5 microg/liter for 48 h resulted in 86.7% larval mortality and reduced the body weight of the survivors by 29.1%. Exposure of the pupae (<12 h old) to diflubenzuron at 100 microg/liter for 48 h caused 18.9% pupal mortality and consequently reduced the adult emergence by 24.7% from the surviving pupae. Furthermore, exposure of third instars to diflubenzuron at 4, 20, 100, and 500 microg/liter for 24 h resulted in the reduction of larval chitin contents by 4.25, 33.2, 35.2, and 57.7%, respectively. Such an effect seemed to be associated with only cuticular chitin synthesis because the same exposures did not significantly affect chitin contents in the guts. Our results indicated that diflubenzuron was highly toxic to second instars by not only causing high larval mortality but also by affecting their growth. Diflubenzuron was also fairly toxic to pupae by not only causing pupal mortality but also affecting the adult emergence. Our results suggest that diflubenzuron might affect only chitin synthesis in the cuticle but not in the peritrophic matrix, which is probably due to diflubenzuron's direct contact to mosquito larvae in water, slow distribution in insect body, rapid degradation in the insect gut, or a combination.     

Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series

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Evaluation of Opportunities and Limitations of Mid-Infrared Skin Spectroscopy for Noninvasive Blood Glucose Monitoring

Background:A wide range of optical techniques has recently been presented for the development of noninvasive methods for blood glucose sensing based on multivariate skin spectrum analysis, and most recent studies are reviewed in short by us. The vibrational spectral fingerprints of glucose, as especially found in the mid-infrared or Raman spectrum, have been suggested for achieving largest selectivity for the development of noninvasive blood glucose methods.Methods:Here, the different aspects on integral skin measurements are presented, which are much dependent on the absorption characteristics of water as the main skin constituent. In particular, different mid-infrared measurement techniques as realized recently are discussed. The limitations of the use of the attenuated total reflection technique in particular are elaborated, and confounding skin or saliva spectral features are illustrated and discussed in the light of recently published works, claiming that the attenuated total reflection technique can be utilized for noninvasive measurements.Results:It will be shown that the penetration depth of the infrared radiation with wavelengths around 10 µm is the essential parameter, which can be modulated by different measurement techniques as with photothermal or diffuse reflection. However, the law of physics is limiting the option of using the attenuated total reflection technique with waveguides from diamond or similar optical materials.Conclusions:There are confounding features from mucosa, stratum corneum, or saliva, which have been misinterpreted for glucose measurements. Results of an earlier study with multivariate evaluation based on glucose fingerprint features are again referred to as a negative experimental proof.     

Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects

OBJECTIVES: We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND: Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS: Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS: The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS: Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infant's myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group.     

A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811

The goal of this phase II multicenter clinical trial was to evaluate a new intensive chemotherapy program for adults with untreated acute lymphoblastic leukemia (ALL) and to examine prospectively the impact of clinical and biologic characteristics on the outcome. One hundred ninety-seven eligible and evaluable patients (16 to 80 years of age; median, 32 years of age) received cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase; 167 patients (85%) achieved a complete remission (CR), 13 (7%) had refractory disease, and 17 (9%) died during induction. A higher CR rate was observed in younger patients (94% for those < 30 years old, 85% for those 30 to 59 years old, and 39% for those > or = 60 years old, P < .001) and in those who had a mediastinal mass (100%) or blasts with a T-cell immunophenotype. Eighty percent of B-lineage and 97% of T-cell ALL patients achieved a CR (P = .01). The coexpression of myeloid antigens did not affect the response rate or duration. Seventy percent of those with cytogenetic or molecular evidence of the Philadelphia (Ph) chromosome and 84% of those without such evidence achieved a CR (P = .11). Patients in remission received multiagent consolidation treatment, central nervous system prophylaxis, late intensification, and maintenance chemotherapy for a total of 24 months. After a median follow-up time of 43 months, the median survival for all 197 patients is 36 months; the median remission duration for the 167 CR patients is 29 months. Favorable pretreatment characteristics relative to remission duration or survival are younger age, the presence of a mediastinal mass or lymphadenopathy, a white blood cell count (WBC) less than 30,000/microL, L1 morphology, T or TMy immunophenotype, and the absence of the Ph chromosome. The estimates of the proportion surviving at 3 years are 69% for patients less than 30 years old, 39% for those 30 to 59 years old, 89% for those who had a mediastinal mass, 59% with WBC less than 30,000/microL, 63% with L1 morphology, 69% for T or TMy antigen expression, and 62% for those who lack the Ph chromosome. Fifteen patients (8%) had no unfavorable prognostic factors and have an estimated probability of survival at 5 years of 100% (95% confidence interval, 77% to 100%). This intensive chemotherapy regimen produces a high remission rate and a high proportion of durable remissions in adults with ALL.     

Community Mobilization and Empowerment of Female Sex Workers in Karnataka State,South India: Associations With HIV and Sexually Transmitted Infection Risk

Objectives. We examined the impact of community mobilization (CM) on the empowerment, risk behaviors, and prevalence of HIV and sexually transmitted infection in female sex workers (FSWs) in Karnataka, India.Methods. We conducted behavioral–biological surveys in 2008 and 2011 in 4 districts of Karnataka, India. We defined exposure to CM as low, medium (attended nongovernmental organization meeting or drop-in centre), or high (member of collective or peer group). We used regression analyses to explore whether exposure to CM was associated with the preceding outcomes. Pathway analyses explored the degree to which effects could be attributable to CM.Results. By the final survey, FSWs with high CM exposure were more likely to have been tested for HIV (adjusted odd ratio [AOR] = 25.13; 95% confidence interval [CI] = 13.07, 48.34) and to have used a condom at last sex with occasional clients (AOR = 4.74; 95% CI =  2.17, 10.37), repeat clients (AOR = 4.29; 95% CI = 2.24, 8.20), and regular partners (AOR = 2.80; 95% CI = 1.43, 5.45) than FSWs with low CM exposure. They were also less likely to be infected with gonorrhea or chlamydia (AOR = 0.53; 95% CI = 0.31, 0.87). Pathway analyses suggested CM acted above and beyond peer education; reduction in gonorrhea or chlamydia was attributable to CM.Conclusions. CM is a central part of HIV prevention programming among FSWs, empowering them to better negotiate condom use and access services, as well as address other concerns in their lives.HIV prevention strategies with female sex workers (FSWs) have traditionally relied on individual behavior change, involving peer educators, condom promotion, and provision of sexual health services.1,2 Over the past decade, there has been a growing recognition that HIV epidemics are “socially and culturally produced,”3 and that psychosocial and community-level processes underlie an individual’s ability to adopt safer sexual behaviors. This has influenced approaches to HIV prevention, with more attention being paid to structural and social factors (such as violence, stigma, and poverty) that shape individual-level risk behaviors (e.g., condom use) and interventions that are targeted toward contextual factors in the HIV risk environment.4–8Among FSW populations, community mobilization (CM) has been endorsed as one of the structural interventions that improve the risk environment, with it''s effectiveness in addressing health and social issues of poor and marginalized populations largely explained through “empowerment.”9–12 Such programs have been recognized in the Joint United Nations Programme on HIV/AIDS investment framework, which includes CM as a critical enabler to core programs.13 In contrast to peer education, which usually involves peers meeting FSWs in the field, talking to them about the program, about difficulties they are facing in their lives, about the importance of condom use, and about the clinics and drop-in centers and other program activities, CM involves bringing together FSWs of various typologies who are scattered and hidden across rural areas and towns through mobilization, participation, and empowerment processes, to provide them with the space and the opportunity to act together, to fight injustices against them, and to campaign for their rights. Thus, whereas peer education can be a fairly “top down” approach, CM is designed to be an inclusive process that is initiated and sustained by the community to bring about the changes they desire (e.g., reduction in violence) through the process of empowerment. Empowerment can be defined as “the processes by which those who have been denied the ability to make choices (disempowered) acquire such an ability.”14^(p437) Most empowerment approaches recognize a dynamic interplay between gaining internal skills and overcoming external barriers, often drawing upon a conceptual framework that distinguishes “power within” (for example, self-confidence or critical thinking skills that contribute to individual agency), “power to” (for example, the ability to make individual decisions that determine and demonstrate such agency), and “power with” (communal decisions, such as group solidarity or collective action, which acknowledge that positive change may often be effected by individuals working together, rather than alone).9,15,16 In the context of sex work, the principles of social solidarity and CM seek to shift the burden of safer sex negotiation from being solely that of an individual FSW to a concept that is collectively shared and owned by the SW community, by acknowledging the dynamics and inequalities between a FSW and her client and the owners, pimps, and madams of sex establishments where sex workers work.17The Sonagachi program in Kolkata in east India provided one of the first examples of a rights-based HIV prevention program for FSWs, focusing on the mobilization and empowerment of brothel-based sex workers, as well as engagement with power structures,12,18–20 with data suggesting that HIV prevalence remained much lower in this setting compared with FSWs elsewhere in India.19 More recently, a growing body of evidence has suggested that organizing FSWs into support groups and community-based organizations can help the community to collectively challenge factors contributing to their vulnerability, such as stigma, discrimination, poverty, housing instability, violence, and harassment.21–31 However, although studies have reported strong associations between CM and collective power, uptake of sexually transmitted infection (STI) services, and consistent condom use with clients,11,17,32–35 there remains a paucity of data examining the impact of CM on biological (HIV or STI) outcomes.India has an estimated 2.4 million people living with HIV.36 Karnataka state in south India has the fourth highest HIV prevalence in the country. HIV is predominantly transmitted heterosexually, with the prevalence of HIV previously exceeding 1% in the general population, and a prevalence of more than 30% among FSWs in some districts.37,38 Before 2003, there was little HIV prevention programming in Karnataka. The Karnataka Health Promotion Trust was established in 2003 as part of the India Avahan initiative, funded by the Bill & Melinda Gates foundation.39,40 The program aimed to slow the HIV epidemic by rapidly scaling up targeted HIV prevention programs, reaching more than 60 000 FSWs and 20 000 men who have sex with men and transgenders in 20 of the 30 districts in the state.Community mobilization and the empowerment of FSWs formed a core part of HIV prevention programming in Karnataka (Figure 1).21,29–31 The process of mobilization and empowerment was gradual, with later phases of the program building on previous phases, and each activity contributing to the mobilization of SWs. For example, in the early phase of the project, peer educators were recruited from the FSW community. FSWs were brought together, and safe drop-in centers were created to respond to FSWs’ need for somewhere safe to rest, dress up, and meet friends. The program organized events and meetings for FSWs together with clinical services in these drop-in centers. These services included the provision of the “gray pack,” which was supplied every 3 to 6 months for the periodic presumptive treatment of gonorrhea and Chlamydia (containing 1 g azithromycin and 400 mg cefixime). These drop-in centers, in turn, helped attract more SWs, which resulted in the centers becoming a space where FSWs could meet each other and share their experiences, which helped create a sense of solidarity. The program then worked to support and develop critical thinking among the FSW community, providing a forum where FSWs could discuss the difficulties in their lives and reflect on how they could work together to address the challenges they faced.Open in a separate windowFIGURE 1—Community mobilization activities of Karnataka Health Promotion Trust: Karnataka, India, 2003–2014.Note. DIC = drop-in center; FSW = female sex worker; STI = sexually transmitted infection.In the intensive phases of the program (2006–2008), FSWs built on their sense of solidarity and started to undertake collective action, working with policymakers, the police, government officials, human rights lawyers, and the media to address issues of stigma, discrimination, violence, and social inequity.21,31 This, in turn, gave birth to collectivization and the formation of community-based institutions, such as peer groups or collectives. In the maintenance phase (2008–2013), FSW community-based organizations were formed to enable the process of handing over ownership of the Avahan program to FSWs and to the state government by 2013, which is now complete.41A detailed analysis of the impact of Avahan on HIV and risk behavior has been conducted, and suggests that the combination HIV program had a significant impact on HIV prevalence in Karnataka.42 However, a key policy debate, especially given current resource constraints, has been whether it is necessary to include CM, collectivization, and empowerment components in FSW HIV prevention programming, which can be costly and time-consuming. Therefore, we examined the impact of CM on HIV and STI prevalence, HIV risk behaviors, and collective and individual power among FSWs in Karnataka, using secondary analyses of data from 2 rounds of behavioral–biological surveys conducted with FSWs in 2008 and 2011.     

New Clamp-PID Algorithm for Automated Glucose Clamps Improves Clamp Quality

Background:In automated glucose clamp experiments, blood glucose (BG) concentrations are kept close to a predefined target level using variable glucose infusion rates (GIRs) determined by implemented algorithms. Clamp quality (ie, the ability to keep BG close to target) highly depends on the quality of these algorithms. We developed a new Clamp algorithm based on the proportional-integral-derivative (PID) approach and compared clamp quality between this and the established Biostator (BS) algorithm.Methods:In numerical simulations, the PID-based algorithm was optimized in silico. The optimized Clamp-PID algorithm was tested in in vitro experiments and finally validated in vivo in a small (n = 5) clinical study.Results:In silico, in vitro, and in vivo experiments showed better clamp quality for the new Clamp-PID algorithm compared with the BS algorithm: precision and absolute control deviation (ACD) decreased from 3.7% to 1.1% and from 2.9 mg/dL to 0.6 mg/dL, respectively, in the numerical simulation. The in vitro validation demonstrated reductions in precision (from 3.3% ± 0.1% (mean ± SD) to 1.4% ± 0.4%) and in ACD (from 2.3 mg/dL ± 0.4 mg/dL to 0.8 mg/dL ± 0.2 mg/dL), respectively. In the clinical study, precision and ACD improved from 6.5% ± 1.3% to 4.0% ± 1.1% and from 3.6 mg/dL ± 0.9 mg/dL to 2.2 mg/dl ± 0.6 mg/dl, respectively. The quality parameter utility did not change.Conclusions:The new Clamp-PID algorithm improves the clamp quality parameters precision and ACD versus the BS algorithm.