Selective acquired long QT syndrome (saLQTS) upon risperidone treatment.

ABSTRACT: BACKGROUND: Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially. CASE PRESENTATION: We report here a case of aLQTS in response to small doses of risperidone that was confirmed at three independent drug challenges in the absence of other QT-prolonging drugs. On the other hand, the patient did not respond with QT prolongation to some other antipsychotics. In particular, the administration of clozapine, known to be associated with higher QT-prolongation risk than risperidone, had no effect on QT-length. A detailed genetic analysis revealed no mutations or polymorphisms in KCNH2, KCNE1, KCNE2, SCN5A and KCNQ1 genes. CONCLUSIONS: Our observation suggests that some patients may display a selective aLQTS to a single antipsychotic, without a potassium channel-related genetic substrate. Contrasting with the idea of a common target of the aLQTS-triggerring drugs, our data suggests existence of an alternative target protein, which unlike the KCNH2 would be drug-selective.

Selection on age at first and at last reproduction in the long-lived Alpine Swift Apus melba

The way an organism spreads its reproduction over time is defined as a life-history trait, and selection is expected to favour life-history traits associated with the highest fitness return. We use a long-term dataset of 277 life histories to investigate the shape and strength of selection acting on the age at first reproduction and at last reproduction in the long-lived Alpine Swift. Both traits were under strong directional selection, but in opposite directions, with selection favouring birds starting their reproductive career early and being able to reproduce for longer. There was also evidence for stabilising selection acting on both traits, suggesting that individuals should nonetheless refrain from reproducing in their first 2 years of life (i.e. when inexperienced), and that reproducing after 7 years of age had little effect on lifetime fitness, probably due to senescence.

Molecular epidemiology reveals long-term changes in HIV type 1 subtype B transmission in Switzerland.

BACKGROUND: Sequence data from resistance testing offer unique opportunities to characterize the structure of human immunodeficiency virus (HIV) infection epidemics. METHODS: We analyzed a representative set of HIV type 1 (HIV-1) subtype B pol sequences from 5700 patients enrolled in the Swiss HIV Cohort Study. We pooled these sequences with the same number of sequences from foreign epidemics, inferred a phylogeny, and identified Swiss transmission clusters as clades having a minimal size of 10 and containing >or=80% Swiss sequences. RESULTS: More than one-half of Swiss patients were included within 60 transmission clusters. Most transmission clusters were significantly dominated by specific transmission routes, which were used to identify the following patient groups: men having sex with men (MSM) (38 transmission clusters; average cluster size, 29 patients) or patients acquiring HIV through heterosexual contact (HETs) and injection drug users (IDUs) (12 transmission clusters; average cluster size, 144 patients). Interestingly, there were no transmission clusters dominated by sequences from HETs only. Although 44% of all HETs who were infected between 1983 and 1986 clustered with injection drug users, this percentage decreased to 18% for 2003-2006 (P<.001), indicating a diminishing role of injection drug users in transmission among HETs over time. CONCLUSIONS: Our analysis suggests (1) the absence of a self-sustaining epidemic of HIV-1 subtype B in HETs in Switzerland and (2) a temporally decreasing clustering of HIV infections in HETs and IDUs.

Anti-TNF therapy in acute sciatica reduces the long-term need for surgery: A three-year follow-up of a randomized double blind placebo controlled trial

Introduction: Two subcutaneous injections of adalimumab in severeacute sciatica have demonstrated a significant benefit on the numberof back surgeries in a short-term randomized controlled clinical trial[1]. This 3-year follow-up study aimed to determine whether theshort-term benefit was sustained over a longer period of time.Methods: Information on surgery was retrieved in 56/61 patients(93%). We used a Cox proportional hazard models to determinefactors predisposing to surgery.Results: Twenty-three (41%) patients had back surgery within 3 years,8/29 (28%) in the adalimumab group and 15/ 27 (56%) in the placebogroup, p = 0.038. Adalimumab injections reduced the need for backsurgery by 61% (Hazard Ratio (HR): 0.39 (95% CI: 0.17-0.92). In amultivariate model, treatment with a TNF-α antagonist remained thestrongest protective factor (HR 0.17, p = 0.002). Other significantpredictors of surgery were a good correlation between symptomsand MRI findings (HR = 11.6, p = 0.04), baseline intensity of leg pain(HR = 1.3, p = 0.06), intensity of back pain (HR = 1.4, p = 0.03)and duration of sickness leave (HR = 1.01 per day, p = 0.03).Conclusion: A short course of adalimumab in patients with severeacute sciatica significantly reduces the need for back surgery.

The long and painful path towards arthroplasty: A qualitative study

Hip or knee arthroplasty is proposed after osteoarthritis or an accident. It is decided after a long path of pain and decrease in the quality of life. This research explores the period of illness until surgery. Twenty-four semi-structured interviews were conducted one month before surgery and a thematic discourse analysis performed. The diversity and complexity of the patient experience, in a commonly performed surgical intervention underlines important topics, requiring attention in order to improve patient preparations and information prior to arthroplasty: information adapted to individual concerns, needs and representations. Psychological and physical acceptance is necessary for integration of the prosthesis.

An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses

The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon gamma enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/10(6) mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of epitopes was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen

Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance.

Thanks to decades of research, gait analysis has become an efficient tool. However, mainly due to the price of the motion capture systems, standard gait laboratories have the capability to measure only a few consecutive steps of ground walking. Recently, wearable systems were proposed to measure human motion without volume limitation. Although accurate, these systems are incompatible with most of existing calibration procedures and several years of research will be necessary for their validation. A new approach consisting of using a stationary system with a small capture volume for the calibration procedure and then to measure gait using a wearable system could be very advantageous. It could benefit from the knowledge related to stationary systems, allow long distance monitoring and provide new descriptive parameters. The aim of this study was to demonstrate the potential of this approach. Thus, a combined system was proposed to measure the 3D lower body joints angles and segmental angular velocities. It was then assessed in terms of reliability towards the calibration procedure, repeatability and concurrent validity. The dispersion of the joint angles across calibrations was comparable to those of stationary systems and good reliability was obtained for the angular velocities. The repeatability results confirmed that mean cycle kinematics of long distance walks could be used for subjects' comparison and pointed out an interest for the variability between cycles. Finally, kinematics differences were observed between participants with different ankle conditions. In conclusion, this study demonstrated the potential of a mixed approach for human movement analysis.

Pulmonary Sarcoid-like Granulomatosis after Multiple Vaccinations of a Long-term Surviving Patient with Metastatic Melanoma.

Autoimmune side effects are frequent in patients with cancer treated with immune checkpoint-targeting antibodies, but are rare with cancer vaccines. Here, we present a case report on a patient with metastatic melanoma who developed pulmonary sarcoid-like granulomatosis following repetitive vaccinations with peptides and CpG. Despite multiple metastases, including one lesion in the brain, the patient is alive and well more than 13 years after the diagnosis of metastatic disease. The strongly activated tumor-specific CD8(+) T cells showed robust long-term memory and effector functions. It is possible that long-term survival and adverse autoimmune events may become more common for vaccines inducing robust anticancer immune responses as were present in this patient. Cancer Immunol Res; 2(12); 1148-53. ©2014 AACR.

Long-term follow-up of follicular lymphoma (FL) patients receiving single agent rituximab at two different schedules in trial SAKK 35/98

Background: In FL, Rituximab as a single agent delivered in the standard schedule (4 times weekly) may induce a response rate of 50−70% with an event-free survival (EFS) of 1−3 years according to patients' characteristics. Prolonged Rituximab exposure seems to improve EFS at least in responding patients and to increase the rate of longterm responders. Here we report long-term results of a clinical trial comparing single agent Rituximab delivered in the standard schedule versus prolonged exposure, with focus on the proportion of long-term responders and their characteristics. Material and Methods: Between 1998 and 2002, chemotherapy na¨ıve (n = 64) or pre-treated (n = 138) FL patients received Rituximab in the standard schedule. Those responding or with stable disease were randomized to no further treatment (observation, n = 78) or 4 additional doses of Rituximab given at 2-month intervals (prolonged exposure, n = 73). EFS was calculated from the first dose of standard schedule until progression, relapse, second tumor or death. Results: At a median follow up of 9.4 years and with all living patients having been followed for at least 5 years, the median EFS is 13 months for the observation and 24 months for the prolonged exposure arm (p = 0.0007). In the observation arm 13% had no event at 5-years and only 4% at 8 years, while in the prolonged exposure arm it was 27% at 5 years and remained 21% at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was the prolonged Rituximab schedule (hazard ratio 0.58, CI 0.39−0.86, p = 0.007), whereas being chemotherapy na¨ıve, presenting with stage

Reproductive allocation strategies: a long-term study on proximate factors and temporal adjustments in a viviparous lizard.

Optimisation of reproductive investment is crucial for Darwinian fitness, and detailed long-term studies are especially suited to unravel reproductive allocation strategies. Allocation strategies depend on the timing of resource acquisition, the timing of resource allocation, and trade-offs between different life-history traits. A distinction can be made between capital breeders that fuel reproduction with stored resources and income breeders that use recently acquired resources. In capital breeders, but not in income breeders, energy allocation may be decoupled from energy acquisition. Here, we tested the influence of extrinsic (weather conditions) and intrinsic (female characteristics) factors during energy storage, vitellogenesis and early gestation on reproductive investment, including litter mass, litter size, offspring mass and the litter size and offspring mass trade-off. We used data from a long-term study of the viviparous lizard, Lacerta (Zootoca) vivipara. In terms of extrinsic factors, rainfall during vitellogenesis was positively correlated with litter size and mass, but temperature did not affect reproductive investment. With respect to intrinsic factors, litter size and mass were positively correlated with current body size and postpartum body condition of the previous year, but negatively with parturition date of the previous year. Offspring mass was negatively correlated with litter size, and the strength of this trade-off decreased with the degree of individual variation in resource acquisition, which confirms theoretical predictions. The combined effects of past intrinsic factors and current weather conditions suggest that common lizards combine both recently acquired and stored resources to fuel reproduction. The effect of past energy store points out a trade-off between current and future reproduction.

Long circulating half-life and high tumor selectivity of the photosensitizer meta-tetrahydroxyphenylchlorin conjugated to polyethylene glycol in nude mice grafted with a human colon carcinoma.

In a mode of nude mice bearing a human colon carcinoma xenograft, the biodistribution and tumor localization of metatetrahydroxyphenylchlorin (m-THPC) coupled to polyethylene glycol (PEG) were compared with those of the free form of this photosensitizer used in photodynamic therapy (PDT). At different times after i.v. injection of both forms of 125I-labeled photosensitizer, m-THPC-PEG gave on average a 2-fold higher tumor uptake than free m-THPC. In addition, at early times after injection, m-THPC-PEG showed a 2-fold longer blood circulating half-life and a 4-fold lower liver uptake than free m-THPC. The tumor to normal tissue ratios of radioactivity concentrations were always higher for m-THPC-PEG than for free m-THPC at any time point studied from 2 to 96 hr post-injection. Significant coefficients of correlation between direct fluorescence measurements and radioactivity counting were obtained within each organ tested. Fluorescence microscopy studies showed that m-THPC-PEG was preferentially localized near the tumor vessels, whereas m-THPC was more diffusely distributed inside the tumor tissue. To verify whether m-THPC-PEG conjugate remained phototoxic in vivo, PDT experiments were performed 72 hr after injection and showed that m-THPC-PEG was as potent as free m-THPC in the induction of tumor regression provided that the irradiation does for m-THPC-PEG conjugate was adapted to a well-tolerated 2-fold higher level. The overall results demonstrate first the possibility of improving the in vivo tumor localization of a hydrophobic dye used for PDT by coupling it to PEG and second that a photosensitizer conjugated to a macromolecule can remain phototoxic in vivo.

Evaluation of two long synthetic merozoite surface protein 2 peptides as malaria vaccine candidates.

Merozoite surface protein 2 (MSP2) is a promising vaccine candidate against Plasmodium falciparum blood stages. A recombinant 3D7 form of MSP2 was a subunit of Combination B, a blood stage vaccine tested in the field in Papua New Guinea. A selective effect in favour of the allelic family not represented by the vaccine argued for a MSP2 vaccine consisting of both dimorphic variants. An alternative approach to recombinant manufacture of vaccines is the production of long synthetic peptides (LSP). LSP exceeding a length of well over 100 amino acids can now be routinely synthesized. Synthetic production of vaccine antigens cuts the often time-consuming steps of protein expression and purification short. This considerably reduces the time for a candidate to reach the phase of clinical trials. Here we present the evaluation of two long synthetic peptides representing both allelic families of MSP2 as potential vaccine candidates. The constructs were well recognized by human immune sera from different locations and different age groups. Furthermore, peptide-specific antibodies in human immune sera were associated with protection from clinical malaria. The synthetic fragments share major antigenic properties with native MSP2. Immunization of mice with these antigens yielded high titre antibody responses and monoclonal antibodies recognized parasite-derived MSP2. Our results justify taking these candidate poly-peptides into further vaccine development.