Repetitive transcranial magnetic stimulation in the treatment of depression in adolescents: an open-label study

OBJECTIVE: This open-label pilot study examined repetitive transcranial magnetic stimulation as a possible treatment of adolescent resistant depression. METHOD: Nine adolescents (aged 16-18 years) with severe resistant depression (determined by SCID) were recruited, and their depression, suicidality, and cognitive functions were evaluated before, during, and after a course of twenty 10-Hz, 2-second trains (intertrain intervals of 58 seconds) given over 20 min/d over 14 working days. RESULTS: Lower levels of depression with progression in therapy were recorded by both the Beck Depression Inventory and Child Depression Rating Scale measures (F1.7,14.01 = 4.52, P < 0.05; F4,32 = 6.645, P < 0.01, respectively). Three patients reached the primary outcome measure of less than 30% reduction in their Child Depression Rating Scale. The effect on suicidality was not significant. Side effects were considered mild. CONCLUSIONS: Repetitive transcranial magnetic stimulation might be a possible therapy for adolescent depression. Our preliminary findings warrant double-blind, controlled studies.     

GnRH-agonist triggering for final oocyte maturation in GnRH-antagonist IVF cycles induces decreased LH pulse rate and amplitude in early luteal phase: a possible luteolysis mechanism

The use of GnRH agonist to trigger final oocyte maturation in GnRH-antagonist in vitro fertilization (IVF) cycles has been shown to significantly reduce or even eliminate the risk of ovarian hyperstimulation syndrome (OHSS) by inducing rapid luteolysis early in the luteal phase. The exact mechanism of this early luteolysis is still widely unknown. Since luteinizing hormone (LH) has a major role in corpus luteum support, we sought to explore the pattern of LH secretion early in the luteal phase. Ten high risk patients for developing OHSS and triggered with GnRH agonist were included. Frequent blood sampling (every 20?min for 6?h) to measure LH, estradiol and progesterone was done on the day of oocyte collection (n?=?5, Group 1) and on the day of embryo transfer, 48?h after oocyte collection (n?=?5, Group 2). We found that the mean LH concentration and its secretion rate decreased significantly in Group 2 compared to Group 1. Both groups had similar number of LH pulses characterized by very small amplitude. In Group 2, there was a steady significant decrease in estradiol and progesterone over time. The results of this study show that LH secretion deviates significantly from normal physiologic pattern, which can explain, at least in part, the post-GnRH-agonist trigger early luteolysis mechanism.     

Respiratory syncytial virus(RSV)-induced allergy may be controlled by IL-4 and CX3C fractalkine antagonists and CpG ODN as adjuvant: hypothesis and implications for treatment

Based on the hypothesis that respiratory syncytial virus (RSV) sG protein causes allergy in patients, it is suggested that treatment of RSV patients with antagonists of IL-4 and FKN early in infection will prevent the increased level of IL-4 in the serum. Together with CpG ODNs that induce Toll-like receptor 9⁺ (TLR9⁺) plasmacytoid dendritic cells to release type I IFN-α and -β will reactivate the inhibited Th1 cells and the antiviral cytotoxic T leukocytes. In addition, binding of CpG ODNs to TLR9⁺ B cells will stop IgE synthesis and antiviral IgG and IgA will continue. Together, the IL-4 and FKN antagonists and CpG ODNs reactivate the adaptive immune response to clear the virus and protect the patient from a second RSV infection. It is also suggested that the less-pathogenic RSV strain Long may be a candidate for vaccine development after deletion of the FKN and superantigen domains from the G gene.     

Alternative pathways of disulfide bond formation yield secretion-competent, stable and functional immunoglobulins

Disulfide bonds within and between proteins are responsible for stabilizing folding and covalent assembly. They are thought to form by an obligatory pathway that leads to a single native structure compatible with secretion. We have previously demonstrated that the intradomain disulfide in the C(H)1 domain of the Ig gamma2b heavy chains was dispensable for secretion [Elkabetz, Y., Argon, Y., Bar-Nun, S., 2005. Cysteines in C(H)1 underlie retention of unassembled Ig heavy chains. J. Biol. Chem. 280, 14402-14412]. Here we show that the heavy chain-light chain interchain disulfide is also dispensable. gamma2b with mutated Cys128, which normally disulfide bonds with the light chain, still assembled with lambdaI light chain into a secretion-competent, tetrameric IgG2b. This assembly comprised of a covalent homo-dimer of mutant heavy chains (C128S(2)) accompanied non-covalently by a covalent homo-dimer of light chains (lambda(2)). The lambda(2) homo-dimer formed only upon association with C128S(2), through disulfide bonding of the two "orphan" heavy chain-interacting Cys214 in lambdaI. The unique Ig tetramer was secreted efficiently as a functional antibody whose antigen-binding capacity resembled that of normal IgG2b. Therefore, disulfide bonding of Ig manifests considerable plasticity and can generate more than one functional structure that is considered native by the cellular quality control system.     

Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients

BACKGROUND: Tenofovir disoproxil fumarate (DF) has been studied in combination with efavirenz in healthy volunteers and no interaction was found. No data are available on the possible interaction of tenofovir DF with nevirapine and efavirenz in HIV-infected patients. In this study the combination of nevirapine 200 mg twice daily with tenofovir DF 300 mg once daily and nevirapine 400 mg once daily with tenofovir DF 300 mg once daily were compared with nevirapine twice daily or once daily without tenofovir DF in HIV-infected patients. Furthermore, the combination of efavirenz 600 mg and tenofovir DF 300 mg once daily was compared with use of efavirenz 600 mg once daily only. METHODS: Data were retrospectively collected from routine therapeutic drug monitoring plasma samples. Nevirapine, efavirenz, and tenofovir plasma levels and tenofovir concentration ratios were analyzed. The concentration ratio represents the measured plasma concentration compared with the time-adjusted average concentration, as measured in a reference population. Six different groups were studied: 200 mg nevirapine twice daily, 400 mg nevirapine once daily, 600 mg efavirenz once daily, all without tenofovir DF (groups 1, 2, and 3, respectively), and the same groups with the drugs combined with tenofovir 300 mg once daily (groups 4, 5, and 6, respectively). RESULTS: Plasma samples were evaluable for 272, 18, 126, 32, 94, and 118 patients in the groups 1-6, respectively. No differences were found in plasma levels for tenofovir, nevirapine, and efavirenz for either of the combinations studied. Addition of tenofovir DF to efavirenz or nevirapine in HIV-infected patients does not influence the plasma levels of nevirapine or efavirenz. Furthermore, nevirapine and efavirenz have no effect on tenofovir plasma levels or tenofovir concentration ratios. CONCLUSION: Efavirenz or nevirapine can be coadministered with tenofovir DF in HIV-infected patients without dose modifications.     

Training in survey and research methods within a Master of Public Health program

Sound decision-making and practice in public health, as in other disciplines, is contingent upon information that is properly collected, analyzed, and interpreted. We describe the content and teaching methods of a graduate course in investigative methods in public health taught within the framework of a Master of Public Health (MPH) program. Following the progressive steps of carrying out research, we highlight the main concepts and skills that a student of public health should be exposed to. This includes the formulation of the study purpose and objectives, basic study designs, definition and selection of the study population and study variables, issues related to the actual collection of data in the field including the reliability and validity of the information, and preparing the data for analysis. We describe the teaching methods that are employed including frontal lectures, individual and group-based exercises, and the use of simulated data to develop skills in the critical reading of published literature and data analysis. The integration of the learned concepts and tools into course workshops and dissertation work is also addressed. Together with training in epidemiology, statistics and other quantitative and qualitative methodologies, this course provides a solid basis for MPH graduates to tackle the public health challenges that await them.     

Dengue fever virus and Japanese encephalitis virus synthetic peptides,with motifs to fit HLA class I haplotypes prevalent in human populations in endemic regions,can be used for application to skin Langerhans cells to prime antiviral CD8+ cytotoxic T cells (CTLs)—A novel approach to the protection of humans

Flaviviruses were reported to induce CD8⁺ cytotoxic T cells in infected individuals, indicating that nonapeptides, proteolytic cleavage products of the viral precursor protein, enter the endoplasmic reticulum in infected cells and interact with HLA class I molecules. The assembled HLA class I molecules are transported to the plasma membrane and prime CD8⁺ T cells. Current knowledge of the interaction of viral peptides with HLA molecules is reviewed. Based on this review, an idea is presented to use synthetic flavivirus peptides with an amino acid motif to fit with the HLA class I peptide binding group of HLA haplotypes prevalent in a given population in an endemic area. These synthetic viral peptides may be introduced into the human skin using a lotion containing the peptides (Peplotion) together with substances capable of enhancing the penetration of these peptides into the skin to reach Langerhans cells. The peptide-treated Langerhans cells, professional antigen-presenting cells, may bind the synthetic viral peptides by their HLA class I peptide-binding grooves. Antigens carrying Langerhans cells are able to migrate and induce the cellular immune response in the lymph nodes. This approach to the priming of antiviral CD8⁺ cytotoxic T cells may provide cellular immune protection from flavivirus infection without inducing the humoral immune response, which can lead to the shock syndrome in Dengue fever patients. To be able to develop anti-Dengue virus synthetic peptides for populations with different HLA class I haplotypes, it is necessary to develop computational studies to design HLA class I Dengue virus synthetic peptides with motifs to fit the HLA haplotypes of the population living in an endemic region for Dengue fever. Experiments to study Dengue virus and Japanese encephalitis peptides vaccines and their effectiveness in protection against Dengue fever and Japanese encephalitis are needed. The development of human antiviral vaccines for application of viral peptides in a lotion to human skin (Peplotion) may be useful and affordable for populations of developing countries.     

Computer analysis of the amino acid sequences in gp41 of apathogenic African green monkey (AGM) virus,less pathogenic HIV-2 and highly pathogenic SIV and HIV-1 lentiviruses

The bestfit computer program was used to compare the amino acid sequence of the gp160 envelope glycoprotein of an apathogenic AGM and the pathogenic SIV_AGM monkey lentiviruses. It was found that the gp120 envelope glycoproteins of these viruses resembled each other in their functional domains. However, an insert of 40 amino acids was found in the gp41 envelope glycoproteins of the pathogenic SIV_AGM virus in the amino acid sequence between the membrane anchoring sequence and the carboxyterminus. The insert introduced a new RRIR proteolytic cleavage signal into gp41. Comparing HIV-1 gp41 to that of the pathogenic SIV_AGM virus revealed that the HIV-1 sequence contains an RR sequence that also serves as a signal for proteolytic cleavage. Comparing HIV-2 gp41 to the apathogenic and pathogenic simian immunodeficiency viruses revealed that HIV-2 gp41 lacks the above proteolytic cleavage signal. It is hypothesized that the pathogenic human and simian immunodeficiency lentiviruses can be proteolytically cleaved at the carboxyterminus of gp41, releasing two peptides: a) an immunodeficiency 58 amino acid peptide and b) an IL-2-like peptide. The apathogenic AGM virus and the less pathogenic HIV-2 lack one proteolytic cleavage signal in the gp41 amino acid sequence and therefore can release only the IL-2-like peptide but not the immunodeficiency peptide. If indeed the pathogenic SIV_AGM and HIV-1 do release an immunodeficiency peptide, then such a peptide can be regarded as a toxin. Immunization of healthy individuals or HIV-1 patients against the toxic effect of the viral gp41 toxic peptide might prevent damage to the immune system when the virus reactivation leads to ARC and AIDS in infected individuals. Synthetic peptides modeled according to the immunodeficiency peptide (the toxin) can be used to produce anti-toxin antibodies in healthy HIV-1 infected individuals. Such anti-toxin antibodies can be used for passive immunization of AIDS patients or for active immunization of HIV-1 positive individuals prior to ARC or AIDS.