Identification of a novel circulating recombinant form (CRF) 36_cpx in Cameroon that combines two CRFs (01_AE and 02_AG) with ancestral lineages of subtypes A and G

An array of CRFs have been identified in Cameroon, the most notable being CRF02_AG. HIV-1 in the East Province of Cameroon is particularly diverse: in a recent study, we found a high proportion of unique recombinant forms (URFs). Herein we describe the analysis of the full-length sequences of two of these URFs, which, after preliminary analysis of gag, pol, and env fragments, appeared to be a novel CRF. This novel strain, CRF36_cpx, contains fragments that can be assigned to the CRF01_AE, CRF02_AG, and subtype A and G radiations. Forty percent of the genome can be classified as CRF02_AG, including regions in gag, pol, env, and the accessory genes. Twenty-seven percent is CRF01_AE, comprising the majority of gag, the beginning of env, and the end of env into the 3' LTR. Twenty percent of the genome can be assigned to subtype A, with segments in pol and env. The remaining 13% of the sequence is classifiable as subtype G, in pol and vpu. The subtype A and G lineages formed by the CRF36_cpx sequences are unique and appear ancestral in nature. CRF36_cpx is both the first to combine more than one CRF and the first to include fragments of CRF02_AG. The ancestral sequences present in CRF36_cpx represent a link to extinct strains, and, potentially, insight into the evolution of HIV-1.     

Analysis of Gene Polymorphisms Associated with K+ Ion Circulation in the Inner Ear of Patients Susceptible and Resistant to Noise-induced Hearing Loss

Noise-induced hearing loss (NIHL) is one of the leading occupational health risks in industrialized countries. It results from an interaction between environmental and genetic factors, however the nature of the genetic factors contributing to NIHL has not yet been clarified. Here, we investigated whether genetic variations in 10 genes putatively involved in the potassium recycling pathway in the inner ear may influence susceptibility to noise. 99 SNPs were genotyped in Polish noise-exposed workers, categorized into susceptible and resistant subjects. The most interesting results were obtained for KCNE1 and KCNQ4 as we replicated associations that were previously reported in a Swedish sample set, hence confirming that they are NIHL susceptibility genes. Additionally we report significant associations in GJB1 , GJB2 , GJB4 , KCNJ10 and KCNQ1 , however due to the lack of replication in the Swedish sample set, these results should be seen as suggestive.     

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study

Background

Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.

Methods

Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.

Results

The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.

Conclusion

Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.     

Assessment of stroke volumeindex with three different bioimpedance algorithms: lack of agreement compared to thermodilution

Objective The accuracy of bioimpedance stroke volumeindex (SVI) is questionable as studies report inconsistent results. It remains unclear whether the algorithms alone are responsible for these findings. We analyzed the raw impedance data with three algorithms and compared bioimpedance SVI to transpulmonary thermodilution (SVI_TD). Design and setting Prospective observational clinical study in a university hospital. Patients Twenty adult patients scheduled for coronary artery bypass grafting (CABG). Interventions SVI_TD and bioimpedance parameters were simultaneously obtained before surgery (t ₁), after bypass (t ₂), after sternal closure (t ₃), at the intensive care unit (t ₄), at normothermia (t ₅), after extubation (t ₆) and before discharge (t ₇). Bioimpedance data were analyzed off-line using cylinder (Kubicek: SVI_K; Wang: SVI_W) and truncated cone based algorithms (Sramek–Bernstein: SVI_SB). Measurements and results Bias and precision between the SVI_TD and SVI_K, SVI_SB, and SVI_W was 1.0 ± 10.8, 9.8 ± 11.4, and −15.7 ± 8.2 ml/m² respectively, while the mean error was abundantly above 30%. Analysis of data per time moment resulted in a mean error above 30%, except for SVI_W at t ₂ (28%). Conclusions Estimation of SVI by cylinder or truncated cone based algorithms is not reliable for clinical decision making in patients undergoing CABG surgery. A more robust approach for estimating bioimpedance based SVI may exclude inconsistencies in the underlying algorithms in existing thoracic bioimpedance cardiography devices. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This study was supported solely by institutional grants. W. B. was a member of the Medical Advisory Board from Pulsion Medical Systems, the manufacturer of the PiCCO System, and has received honoraria for lectures from Pulsion Medical Systems     

Value of proton spin tomography in the diagnosis of intra-articular pathological disorders of the knee]

Magnetic resonance imaging (MRI) of the knee was performed in 50 patients with unilateral knee problems with clinical suspicion of a meniscal tear or degeneration of the cartilage. The findings of the MRI examination were compared with previously performed arthrography and the diagnosis was subsequent confirmed arthroscopically. MRI detected degenerative changes in 69 out of 100 menisci and signs of a meniscal tear in 31 of the menisci. The diagnostic accuracy of MRI for a tear in the medial or the lateral meniscus was 91%. MRI was accurate in the detection of 8/11 ruptures of the anterior cruciate ligament and in 6/13 cases with degenerative changes of the patella.     

Simulation of minimally invasive vascular interventions for training purposes.

OBJECTIVE: To master the skills required to perform minimally invasive vascular interventions, proper training is essential. A computer simulation environment has been developed to provide such training. The simulation is based on an algorithm specifically developed to simulate the motion of a guide wire--the main instrument used during these interventions--in the human vasculature. In this paper, the design and model of the computer simulation environment is described and first results obtained with phantom and patient data are presented. MATERIALS AND METHODS: To simulate minimally invasive vascular interventions, a discrete representation of a guide wire is used which allows modeling of guide wires with different physical properties. An algorithm for simulating the propagation of a guide wire within a vascular system, on the basis of the principle of minimization of energy, has been developed. Both longitudinal translation and rotation are incorporated as possibilities for manipulating the guide wire. The simulation is based on quasi-static mechanics. Two types of energy are introduced: internal energy related to the bending of the guide wire, and external energy resulting from the elastic deformation of the vessel wall. RESULTS: A series of experiments were performed on phantom and patient data. Simulation results are qualitatively compared with 3D rotational angiography data. CONCLUSIONS: The results indicate plausible behavior of the simulation.     

Predicting outcome in older patients with cancer: Comprehensive geriatric assessment and clinical judgment

ObjectivesComprehensive Geriatric Assessment (CGA) has been incorporated into geriatric oncology to prevent unfavorable outcome from anticancer treatment. This study determined the value of CGA and medical oncologist's clinical judgment in predicting unfavorable outcome and explored whether treatment decisions can be based on CGA.Patients and MethodsIn this prospective cohort study, a multidomain CGA was performed by a geriatric nurse and geriatrician in 110 consecutive patients aged ≥70 years, newly referred to a multidisciplinary oncology clinic. CGA domains included comorbidity, polypharmacy, mood, cognition, nutrition, functionality and physical performance. Medical oncologist's clinical judgment on expected tolerance of standard treatment was noted (N = 62). Unfavorable outcome was defined as any ≥grade three chemotherapy toxicity, dose reduction, postponement of treatment, death before start of treatment and early progression before first evaluation of treatment (N = 80).ResultsCGA identified multidomain problems in 77 out of 110 patients (70.0%) and the medical oncologist had doubts about standard treatment tolerance in 30 out of 62 patients (48.4%). Unfavorable outcome occurred in 48 out of 80 patients (60%) who received anticancer treatment but could not be predicted by CGA, medical oncologists' clinical judgment or their combination. There was discrepancy between CGA and clinical judgment in 24 out of 62 patients (38.7%).ConclusionNeither CGA, medical oncologist's clinical judgment or a combination could predict unfavorable outcome in our heterogeneous sample. CGA and clinical judgment did not align in more than one-third of patients.     

Visualization of a peripheral stalk in V-type ATPase: Evidence for the stator structure essential to rotational catalysis

F- and V-type ATPases are central enzymes in energy metabolism that couple synthesis or hydrolysis of ATP to the translocation of H⁺ or Na⁺ across biological membranes. They consist of a soluble headpiece that contains the catalytic sites and an integral membrane-bound part that conducts the ion flow. Energy coupling is thought to occur through the physical rotation of a stalk that connects the two parts of the enzyme complex. This mechanism implies that a stator-like structure prevents the rotation of the headpiece relative to the membrane-bound part. Such a structure has not been observed to date. Here, we report the projected structure of the V-type Na⁺-ATPase of Clostridium fervidus as determined by electron microscopy. Besides the central stalk, a second stalk of 130 Å in length is observed that connects the headpiece and membrane-bound part in the periphery of the complex. This additional stalk is likely to be the stator.