Longitudinal trajectories of neurocognitive test performance among individuals with perinatal HIV-infection and -exposure: adolescence through young adulthood.

There are an estimated 2.1 million youth less than 15 years of age living with HIV globally (the majority perinatally HIV-infected [PHIV]) and millions more perinatally HIV-exposed uninfected (PHEU) youth who are expected to survive through adolescence and into adulthood. Transitioning from adolescence to young adulthood requires adaptation to more demanding social interactions, academic pressures, and individual responsibilities which place distinct demands on neurocognitive functions. This study examined longitudinal trajectories of neurocognitive test performance in the domains of processing speed (PS), working memory (WM), and executive functioning (EF) among PHIV and demographically similar PHEU from adolescence through young adulthood. Data for this paper come from four time points, spanning approximately 10 years, within the Child and Adolescent Self-Awareness and Health Study (CASAH). Youth age ranged from 15 to 29 years. Longitudinal linear mixed effect models were computed for each test. Few differences in performance were found on tests of EF and WM between PHIV and PHEU youth as they aged, though PHEU youth showed significantly better PS as they aged than PHIV youth. Future research is needed to understand these vulnerable youth's neurocognitive trajectories as a function of HIV infection and -exposure, biological functions and psychosocial stressors.

A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial.

OBJECTIVE: Research has suggested that subanesthetic doses of ketamine may work to improve cocaine-related vulnerabilities and facilitate efforts at behavioral modification. The purpose of this trial was to test whether a single ketamine infusion improved treatment outcomes in cocaine-dependent adults engaged in mindfulness-based relapse prevention. METHODS: Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute intravenous infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay, during which they also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). RESULTS: Overall, 48.2% of individuals in the ketamine group maintained abstinence over the last 2 weeks of the trial, compared with 10.7% in the midazolam group (intent-to-treat analysis). The ketamine group was 53% less likely (hazard ratio=0.47; 95% CI=0.24, 0.92) to relapse (dropout or use cocaine) compared with the midazolam group, and craving scores were 58.1% lower in the ketamine group throughout the trial (95% CI=18.6, 78.6); both differences were statistically significant. Infusions were well tolerated, and no participants were removed from the study as a result of adverse events. CONCLUSIONS: A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing risk of relapse. Further research is needed to replicate these promising results in a larger sample.

Effects of aerobic conditioning on cardiovascular sympathetic response to and recovery from challenge.

Exercise has widely documented cardioprotective effects, but the mechanisms behind these effects are still poorly understood. Here, we test the hypothesis that aerobic training lowers cardiovascular sympathetic responses to and speeds recovery from challenge. We conducted a randomized, controlled trial contrasting aerobic versus strength training on indices of cardiac (pre-ejection period, PEP) and vascular (low-frequency blood pressure variability, LF-BPV) sympathetic responses to and recovery from psychological and orthostatic challenge in 149 young, healthy, sedentary adults. Aerobic and strength training did not alter PEP or LF-BPV reactivity to or recovery from challenge. These findings, from a large randomized, controlled trial using an intent-to-treat design, show that moderate aerobic exercise training has no effect on PEP and LF-BPV reactivity to or recovery from psychological or orthostatic challenge. In healthy young adults, the cardioprotective effects of exercise training are unlikely to be mediated by changes in sympathetic activity.

New types of metacaspases in phytoplankton reveal diverse origins of cell death proteases.

Metacaspases are evolutionarily distant homologs of caspases that are found outside the metazoan and are known to have key roles in programmed cell death (PCD). Two types of metacaspases (types I and II) have been defined in plants based on their domain structures; these have similarities to metazoan 'initiator' and 'executioner' caspases. However, we know little about metacaspases in unicellular organisms and even less about their roles in cell death. We identified a novel group of metacaspases in sequenced phytoplanktonic protists that show domain architectures distinct from either type I or II enzymes; we designate them as type III. Type III metacaspases exhibit a rearrangement of domain structures between N- and C-terminus. In addition, we found a group of metacaspase-like proteases in phytoplankton that show sequence homology with other metacaspases, but defy classification in conventional schemes. These metacaspase-like proteases exist in bacteria alongside a variant of type I metacaspases and we propose these bacterial metacaspases are the origins of eukaryotic metacaspases. Type II and III metacaspases were not detected in bacteria and they might be variants of bacterial type I metacaspases that evolved in plants and phytoplanktonic protists, respectively, during the establishment of plastids through the primary and secondary endosymbiotic events. A complete absence of metacaspases in protists that lost plastids, such as oömycetes and ciliates indicates the gene loss during the plastid-to-nucleus gene transfer. Taken together, our findings suggest endosymbiotic gene transfer (EGT) is a key mechanism resulting in the evolutionary diversity of cell death proteases.

Tacrolimus ointment in the treatment of chronic cutaneous graft-vs-host disease: a case series of 18 patients.

BACKGROUND: Tacrolimus (formerly FK 506) is an immunosuppressive drug that works by inhibiting calcineurin, a calcium-dependent protein phosphatase required for immune function. Tacrolimus has been shown to be effective topically in atopic dermatitis and systemically in psoriasis and graft-vs-host disease (GVHD). However, its efficacy in treating cutaneous GVHD when applied topically has not been reported. OBJECTIVE: To assess the therapeutic efficacy of 0.1% tacrolimus ointment on chronic cutaneous GVHD in patients with symptoms refractory to systemic corticosteroid therapy. RESULTS: Tacrolimus ointment effectively treated pruritus and/or erythema in 13 (72%) of 18 patients with chronic GVHD. Responding patients had a rapid effect within several hours to days. Effectiveness was measured by means of patient report, results of physical examination, side-by-side comparisons of tacrolimus vs a vehicle control, and temporal flares of the cutaneous symptoms of the disease in the context of stopping tacrolimus ointment therapy. Because of the progression of GVHD and in 2 cases, loss of drug efficacy, all patients eventually went on to receive more aggressive treatment, including increases in steroid dosage, psoralen-UV-A therapy, and extracorporeal photopheresis. CONCLUSIONS: This case series suggests that tacrolimus ointment has efficacy in treating the erythema and pruritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus ointment may provide a useful therapeutic bridge to systemic therapies that have slower onset, such as psoralen-UV-A therapy or extracorporeal photopheresis.

Quantum confinement in amorphous silicon quantum dots embedded in silicon nitride.

Amorphous silicon quantum dots (a-Si QDs) were grown in a silicon nitride film by plasma enhanced chemical vapor deposition. Transmission electron micrographs clearly demonstrated that a-Si QDs were formed in the silicon nitride. Photoluminescence and optical absorption energy measurement of a-Si QDs with various sizes revealed that tuning of the photoluminescence emission from 2.0 to 2.76 eV is possible by controlling the size of the a-Si QD. Analysis also showed that the photoluminescence peak energy E was related to the size of the a-Si QD, a (nm) by E(eV) = 1.56+2.40/a(2), which is a clear evidence for the quantum confinement effect in a-Si QDs.

Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase.

Receptor tyrosine kinases regulate cell behavior by activating specific signal transduction cascades. Epidermal growth factor (EGF) receptor tyrosine kinases include ErbB1, ErbB2, ErbB3 and ErbB4. ErbB4 is a tyrosine kinase receptor that binds neuregulins (NRG) and several other EGF family members. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis identified two isoforms of ErbB4 that differed in their cytoplasmic domain sequences. Specifically, RT-PCR using primers flanking the putative phosphatidyl inositol 3-kinase (PI3-K) binding site of ErbB4 generated two specific bands when human and mouse heart and kidney tissues were analysed. Cloning and sequencing of these RT-PCR products revealed that one of the ErbB4 isoforms (ErbB4 CYT-2) lacked a 16 amino acid sequence including a putative PI3-K binding site, that was present in the other isoform (ErbB4 CYT-1). RT-PCR analysis of mouse tissues suggested that the expression of ErbB4 CYT-1 and ErbB4 CYT-2 was tissue-specific. Heart, breast and abdominal aorta expressed predominantly ErbB4 CYT-1 whereas neural tissues and kidney expressed predominantly ErbB4 CYT-2. To ascertain whether the absence of the putative PI3-K binding site in ErbB4 CYT-2 also resulted in the loss of PI3-K activity, NIH3T3 cell lines overexpressing ErbB4 CYT-1 or ErbB4 CYT-2 were produced. NRG-1 bound to and stimulated equivalent tyrosine phosphorylation of both isoforms. However, unlike ErbB4 CYT-1, the ErbB4 CYT-2 isoform was unable to bind the p85 subunit of PI3-K and to stimulate PI3-K activity in these cells. Furthermore, tyrosine phosphorylation of p85 or association of PI3-K activity with phosphotyrosine was not induced in NRG-1 treated cells expressing ErbB4 CYT-2, indicating that this isoform was incapable of activating PI3-K even indirectly. It was concluded that a novel naturally occurring ErbB4 isoform exists with a deletion of the cytoplasmic domain sequence required for the activation of the PI3-K intracellular signal transduction pathway and that this is the only PI3-K binding site in ErbB4.

A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester.

Human epidermal growth factor receptor 4 (HER4) is a member of the epidermal growth factor (EGF) receptor subfamily of receptor tyrosine kinases that is activated by neuregulins (NRG), betacellulin (BTC), and heparin-binding EGF-like growth factor. Sequencing of full-length human HER4 cDNAs revealed the existence of two HER4 isoforms that differed by insertion of either 23 or 13 alternative amino acids in the extracellular juxtamembrane (JM) region. The 23-amino acid form (HER4 JM-a) and the 13-amino acid form (HER4 JM-b) were expressed in a tissue-specific manner, as demonstrated by reverse transcriptase-polymerase chain reaction analysis of mouse and human tissues. Both isoforms were expressed in neural tissues such as cerebellum, whereas kidney expressed HER4 JM-a only and heart HER4 JM-b only. In situ hybridization using specific oligonucleotides demonstrated transcription of both JM-a and JM-b isoforms in the mouse cerebellum. Tyrosine phosphorylation analysis indicated that both receptor isoforms were activated to the same extent by NRG-beta1 and BTC, and to a lesser extent by NRG-alpha1 and heparin-binding EGF-like growth factor. A functional difference was found, however, in response to phorbol ester treatment. Stimulation of cells with phorbol ester resulted in a loss of 125I-NRG-beta1 binding and in a reduction of total cell-associated HER4 protein in HER4 JM-a transfectants but not in HER4 JM-b transfectants. It was concluded that novel alternatively spliced isoforms of HER4 exist, that they are distributed differentially in vivo in mouse and human tissues, that they are both activated by HER4 ligands, and that they may represent cleavable and noncleavable forms of HER4.

A simple noninvasive measurement of stenotic mitral valve area: an alternative approach using M-mode and Doppler echocardiography.

Doppler echocardiography is a widely used noninvasive technique to examine the mitral valve area (MVA) by obtaining mitral pressure half-time (PHT) and to assess the severity of the stenosis. However, several hemodynamic factors influence the PHT and may render the PHT data inaccurate in any measurement of MVA under certain conditions. Using a simple echo-Doppler (E-D) method, we assessed the MVA in a physiological equation. The mitral flow volume (MFV) is represented by MVA x transmitral mean flow velocity (mV) x diastolic filling time (DFT). Thus, the formula can be restated as MVA (cm2) = MFV (cm3)/mV (cm/sec) x DFT (sec). We measured MFV by M-mode, and mV and DFT by continuous wave Doppler echocardiography. This formula was tested in 43 patients with isolated mitral stenosis. MVA was obtained by the PHT and E-D methods, and the data obtained were validated against the results of cardiac catheterization. The results obtained using the E-D method showed much better correlation (r = 0.82) with those of catheterization than those with the PHT method (r = 0.52). The inter- and intraobserver variabilities were checked. The results obtained with the E-D method were found to be reproducible. To further validate the accuracy of the E-D method, MVA was measured by both methods at different R-R intervals after exercise and the results were compared. The MVA obtained by the PHT method showed marked variations; whereas, that obtained by the E-D method remained nearly constant. Similarly, in a patient with atrial fibrillation, the MVA assessed by the PHT method varied from beat to beat; whereas, the fluctuations in MVA were minimal using the E-D method. We concluded that the E-D method can be reliable and clinically easily applicable for the accurate assessment of MVA.