Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population

Dear Sir, We read the recent article by Franklin and Kutteh (2002), concerningthe pregnancy outcomes of recurrent pregnancy loss (RPL) patientswho had normal obstetrical evaluations with the exception ofpositive antiphospholipid antibodies (aPL) findings. In theirreport distinctions were made between two groups of aPL positiveRPL patients with reference to their aPL specificities. Group1 patients had ‘the common’ aPL, anticardiolipin(aCL), or antiphosphatidylserine antibodies (aPS) and/or a lupusanticoagulant (LAC). For comparisons,     

LPS-Induced NF-kappaB activation and TNF-alpha release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is an important mediator of septic shock. Endotoxin (LPS) signal transduction in human monocytes leads to activation of nuclear factor-kappa B (NF-kappaB) and TNF-alpha release. Previous studies have implicated activation of both protein kinase C (PKC) and protein tyrosine kinases (PTK) in LPS-induced NF-kappaB activation and TNF-alpha production. We hypothesized that inhibition of either PKC or PTK would decrease LPS-induced NF-kappaB DNA binding and TNF-alpha release in human monocytes. MATERIALS AND METHODS: Human monocytes were stimulated with PMA (50 ng/ml) alone or LPS (100 ng/ml) with and without a nonspecific serine/threonine protein kinase inhibitor staurosporine (Stauro), a specific pan-PKC inhibitor bisindolylmaleimide (Bis), or an inhibitor of PTK genistein (Gen). TNF-alpha release in culture supernatants was measured by an ELISA. NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay. RESULTS: LPS increased NF-kappaB DNA binding and TNF-alpha release in human monocytes. Nonspecific protein kinase inhibition inhibited NF-kappaB activation and TNF-alpha release, while specific PKC inhibition with Bis had no effect on LPS-induced NF-kappaB DNA binding or TNF-alpha release. PTK inhibition with Gen attenuated both LPS-induced NF-kappaB DNA binding and TNF-alpha production in human monocytes. Direct activation of PKC with PMA induced both NF-kappaB activation and TNF-alpha production by human monocytes. CONCLUSIONS: These results suggest that LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes are independent of PKC activity. Furthermore, our results provide evidence that PTK plays a role in LPS-induced NF-kappaB activation and TNF-alpha release in human monocytes and thus could be a potential therapeutic target in inflammatory states.     

Population Size Estimation From Capture-Recapture Studies Using shinyrecap: Design and Implementation of a Web-Based Graphical User Interface

BackgroundPopulation size estimates (PSE) provide critical information in determining resource allocation for HIV services geared toward those at high risk of HIV, including female sex workers, men who have sex with men, and people who inject drugs. Capture-recapture (CRC) is often used to estimate the size of these often-hidden populations. Compared with the commonly used 2-source CRC, CRC relying on 3 (or more) samples (3S-CRC) can provide more robust PSE but involve far more complex statistical analysis.ObjectiveThis study aims to design and describe the Shiny application (shinyrecap), a user-friendly interface that can be used by field epidemiologists to produce PSE.Methodsshinyrecap is built on the Shiny web application framework for R. This allows it to seamlessly integrate with the sophisticated CRC statistical packages (eg, Rcapture, dga, LCMCR). Additionally, the application may be accessed online or run locally on the user’s machine.ResultsThe application enables users to engage in sample size calculation based on a simulation framework. It assists in the proper formatting of collected data by providing a tool to convert commonly used formats to that used by the analysis software. A wide variety of methodologies are supported by the analysis tool, including log-linear, Bayesian model averaging, and Bayesian latent class models. For each methodology, diagnostics and model checking interfaces are provided.ConclusionsThrough a use case, we demonstrated the broad utility of this powerful tool with 3S-CRC data to produce PSE for female sex workers in a subnational unit of a country in sub-Saharan Africa.     

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.     

Combination therapy with diltiazem and propranolol: precipitation of congestive heart failure

Although congestive heart failure has been reported with the combination of a beta blocker and either verapamil or nifedipine, it has not previously been reported for combination therapy that includes diltiazem. The following case documents the occurrence of clinical congestive failure in a patient with baseline left ventricular dysfunction and severe angina pectoris. Although the patients had tolerated propranolol therapy for years without difficulty, and high-dose diltiazem monotherapy with an excellent clinical response, the combination of diltiazem and propranolol resulted in the development of congestive heart failure. Thus, although generally well tolerated, given the suitable scenario of reduced left ventricular function, the combination of diltiazem and a beta blocker may adversely affect left ventricular performance.