Tardive dyskinesia on clozapine treatment

Antipsychotic-induced tardive dyskinesia is a potentially irremediable and debilitating condition with the onset most commonly associated with the use of first-generation antipsychotics. The development of tardive dyskinesia on clozapine, a second-generation antipsychotic, is uncommon, and the drug is therefore a treatment option for those patients who develop the syndrome following treatment with first-generation agents. I report on the case of a 27-year-old man who developed severe tardive dyskinesia following initiation of clozapine treatment. To the best of my knowledge, this is the first case of tardive dyskinesia associated with clozapine use reported in South Africa

Family therapy for schizophrenia: cultural challenges and implementation barriers in the South African context

Family therapy is an effective, evidence based intervention for schizophrenia. This literature review explores the impact of culture on family therapy as a treatment model for schizophrenia and examines how cultural beliefs impact on access to care. Although there is a good deal of evidence to suggest that certain principles of family therapy such as empathy and psycho-education are universal, there is a paucity of literature about the role of culture in designing family interventions for people living with schizophrenia in a culturally diverse setting such as South Africa. It is well acknowledged that cultural ideologies influence families’ belief systems of schizophrenia, expected expressed emotion, and levels of stigma in relation to mental illness. Additionally, in adapting models designed for first-world settings, consideration needs to be given to aspects such as language, educational level and accessibility of mental health care facilities. Family therapists are increasingly recognising the need for the study and implementation of evidence based culture-relevant and culture-responsive therapeutic techniques. These techniques need to be cost-effective and will require training, supervision, staff support, and management input in order to become generally available.Keywords: Schizophrenia; Family therapy; South Africa; Cultur

Investigating the association between diabetes mellitus, depression and psychological distress in a cohort of South African teachers

Background. Diabetes mellitus (DM) may increase the risk of depression as a result of a sense of threat of debilitating complications or because of associated lifestyle changes. Depression may increase the risk of type 2 diabetes as a result of poor health behaviours.Objective. To determine the association between diabetes mellitus, depression and psychological  distress in a cohort of South African (SA) teachers.Methods. Teachers from 111 public schools in the Metro South District of the Cape Metropolitan area,  SA, were invited to participate in this study. The Center for Epidemiologic Studies Depression Scale  (CES-D) and the Kessler Psychological Distress Scale (K10) were used to assess depression and psychological distress, respectively. A professional nurse completed a physical examination and  collected blood for measurement of glucose, cholesterol and serum creatinine.Results. Of the 388 teachers who completed the questionnaires, 67.5% were female and the average age  was 46.2 years (standard deviation 8.7). Psychological distress was identified in 28.1% of the cohort and depression in 15.5%, and 7.7% were found to fulfil criteria for DM. A diagnosis of DM was associated with an increased risk of depression (adjusted odds ratio (AOR) 3.90; 95% confidence interval (CI) 1.33 - 11.37) and psychological distress (AOR 3.62; 95% CI 1.31 - 10.00).Conclusion. The high prevalence of obesity and DM in this cohort of SA teachers is of concern. A  diagnosis of DM was strongly associated with an increased risk of depression and psychological distress

An audit of operating theatre utilisation and day-of-surgery cancellations at a regional hospital in the Durban metropole

Background. Operating theatres account for a significant proportion of hospital costs. There is a paucity of data evaluating utilisation of South African (SA) state operating theatres.Objectives. To measure operating theatre utilisation and the rate of day-of-surgery cancellations (DOSCs) in a state hospital theatre complex.Methods. A prospective audit of a state operating theatre complex at a Durban regional hospital was performed between 26 February and 26 April 2018. Times were collected for each theatre case from the entry of the patient into theatre to their departure to the post-anaesthetic care unit. This was done on weekdays between 08h00 and 16h00. The factors causing any delays and DOSCs were identified and recorded.Results. Over the study period, 125 220 operative minutes were available for both elective and emergency operating theatres; 655 elective cases and 359 emergency cases were performed. Overall theatre utilisation was 55.2%, with actual operating time comprising only 36.9% of all available time. Non-operative time occupied 63.1% of all available time, split between late starts (9.3%), early list finishes (16.1%), changeover times (19.4%) and anaesthetic time (18.3%). The DOSC rate was 26.2%, with 232 cases cancelled on the day of surgery. Just under half of the DOSCs were avoidable. The most common reason for cancellation was lack of operative time.Conclusions. Measured theatre utilisation was higher than previously quoted figures for SA state hospitals, but below international benchmarks. A significant amount of time was wasted as a result of delayed first-case starts, prolonged changeovers and early terminations of lists, all of which contributed to a high DOSC rate. Before more theatre time can be made available, theatre users must first optimise use of currently available time. Further studies quantifying the effect of staff shortages in state operating theatres on inefficient use of time are required.

Inhibition of HCV by the serpin antithrombin III

Background: Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection, interferon-α based therapy remains challenging for certain populations, including those with unfavorable IL28B genotypes, psychiatric co-morbidity, HIV co-infection, and decompensated liver disease. We have recently shown that ATIII, a serine protease inhibitor (serpin), has broad antiviral properties. Results: We now show that ATIII is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations. At a mechanistic level using gene-expression arrays, we found that ATIII treatment down-regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma, including Jun, Myc and BMP2. Using a protein interactive network analysis we found that changes in gene-expression caused by ATIII were dependent on three nodes previously implicated in HCV disease progression or HCV replication: NFκB, P38 MAPK, and ERK1/2. Conclusions: Our findings suggest that ATIII stimulates a novel innate antiviral host cell defense different from current treatment options

In Vivo Anti-HIV Activity of the Heparin-Activated Serine Protease Inhibitor Antithrombin III Encapsulated in Lymph-Targeting Immunoliposomes

Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log10 reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention

A Signature in HIV-1 Envelope Leader Peptide Associated with Transition from Acute to Chronic Infection Impacts Envelope Processing and Infectivity

Mucosal transmission of the human immunodeficiency virus (HIV) results in a bottleneck in viral genetic diversity. Gnanakaran and colleagues used a computational strategy to identify signature amino acids at particular positions in Envelope that were associated either with transmitted sequences sampled very early in infection, or sequences sampled during chronic infection. Among the strongest signatures observed was an enrichment for the stable presence of histidine at position 12 at transmission and in early infection, and a recurrent loss of histidine at position 12 in chronic infection. This amino acid lies within the leader peptide of Envelope, a region of the protein that has been shown to influence envelope glycoprotein expression and virion infectivity. We show a strong association between a positively charged amino acid like histidine at position 12 in transmitted/founder viruses with more efficient trafficking of the nascent envelope polypeptide to the endoplasmic reticulum and higher steady-state glycoprotein expression compared to viruses that have a non-basic position 12 residue, a substitution that was enriched among viruses sampled from chronically infected individuals. When expressed in the context of other viral proteins, transmitted envelopes with a basic amino acid position 12 were incorporated at higher density into the virus and exhibited higher infectious titers than did non-signature envelopes. These results support the potential utility of using a computational approach to examine large viral sequence data sets for functional signatures and indicate the importance of Envelope expression levels for efficient HIV transmission

lentiglobin gene therapy for transfusion dependent β thalassemia outcomes from the phase 1 2 northstar and phase 3 northstar 2 studies

Introduction Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by anemia, iron overload and serious comorbidities for which gene therapy may be an effective treatment option. LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. Objective Evaluate the efficacy and safety of LentiGlobin in patients with TDT in the phase 1/2 Northstar (HGB-204; NCT01745120) and phase 3 Northstar-2 (HGB-207; NCT02906202) studies. Methods Patients with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) received G-CSF and plerixafor for mobilization and HSCs were transduced with the BB305 LVV. Patients underwent single agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for engraftment, safety, and efficacy. Statistics are presented as median (min – max). Results As of March 7, 2018, 18 patients (12 – 35 yrs) were treated in Northstar (follow-up 32.1 [23.1 – 41.9] months) and as of May 15, 2018, 11 patients (12 – 24 yrs) were treated in Northstar-2 (follow-up 8.5 [0.3 – 16.2] months). Patients received a median cell dose of 8.0 (5.0 – 19.4) CD34+ cells × 106/kg in both studies. The median time to neutrophil and platelet engraftment in both studies was 19 (14 – 30) days and 44 (19 – 191) days, respectively; 1 patient in Northstar-2 (0.3 months follow-up) had not engrafted at time of analysis. Of 6 patients with platelet engraftment ≥ Day 60, 4 had non-serious bleeding events prior to engraftment. All 6 had intact spleens and 3/6 received G-CSF between Days 0 – 21. Both factors appeared associated with time to platelet engraftment. In Northstar, 8/10 patients with non-β0/β0 genotypes and 2/8 patients with β0/β0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Median Hb during TI was 10.0 (9.3 – 13.1) g/dL. In Northstar-2, 7/8 patients with non-β0/β0 genotypes and ≥ 6 months follow-up stopped RBC transfusions with Hb of 11.1 – 13.3 g/dL at last visit; the first patient treated achieved TI. Non-hematologic grade ≥ 3 adverse events post-infusion in ≥ 5/29 (15%) patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Veno-occlusive liver disease attributed to busulfan occurred in 4/29 patients (Table 1). There was no transplant-related mortality, vector-mediated replication competent lentivirus, or clonal dominance. Conclusion In Northstar, 80% of patients with non-β0/β0 genotypes achieved TI and early Northstar-2 data suggest that patients can achieve near-normal Hb without transfusions. The safety profile of LentiGlobin is consistent with myeloablative busulfan conditioning. Longer time to platelet engraftment was observed in few patients, but no graft failure or deaths were reported

Factors moderating the relationship between childhood trauma and premorbid adjustment in first-episode schizophrenia

CITATION: Kilian, S. et al. 2017. Factors moderating the relationship between childhood trauma and premorbid adjustment in first-episode schizophrenia. PLoS ONE, 12(1):e0170178, doi:10.1371/journal.pone.0170178.The original publication is available at http://journals.plos.org/plosoneChildhood trauma is a recognised risk factor for schizophrenia. It has been proposed that childhood trauma interferes with normal neurodevelopment, thereby establishing a biological vulnerability to schizophrenia. Poor premorbid adjustment is frequently a precursor to schizophrenia, and may be a manifestation of neurodevelopmental compromise. We investigated the relationship between childhood trauma and premorbid adjustment in 77 patients with first-episode schizophrenia spectrum disorders. We also investigated possible mediating roles for other selected risk factors in the relationship. We found several significant correlations between different trauma types and both social and academic premorbid adjustment from childhood to late adolescence. There were no significant moderating effects for family history of schizophrenia or family history of psychiatric disorder. History of obstetric complications, substance abuse and poor motor coordination weakened some of the associations between childhood trauma and premorbid adjustment, while poor sequencing of motor acts strengthened the association. Our results confirm previous studies indicating an association between childhood trauma and premorbid adjustment. Results indicate a general rather than specific association, apparent with different types of trauma, and affecting both social and academic components of premorbid adjustment across childhood, early and late adolescence. Further, our results suggest a complex interplay of various risk factors, supporting the notion of different pathways to psychosis.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170178Publisher's versio

Serpin Induced Antiviral Activity of Prostaglandin Synthetase-2 against HIV-1 Replication

The serine protease inhibitors (serpins) are anti-inflammatory proteins that have various functions. By screening a diverse panel of viruses, we demonstrate that the serpin antithrombin III (ATIII) has a broad-spectrum anti-viral activity for HIV-1, HCV and HSV. To investigate the mechanism of action in more detail we investigated the HIV-1 inhibition. Using gene-expression arrays we found that multiple host cell signal transduction pathways were activated by ATIII in HIV-1 infected cells but not in uninfected controls. Moreover, the signal pathways initiated by ATIII treatment, were more than 200-fold increased by the use of heparin-activated ATIII. The most up-regulated transcript in HIV-1 infected cells was prostaglandin synthetase-2 (PTGS2). Furthermore, we found that over-expression of PTGS2 reduced levels of HIV-1 replication in human PBMC. These findings suggest a central role for serpins in the host innate anti-viral response. Host factors such as PTGS2 elicited by ATIII treatment could be exploited in the development of novel anti-viral interventions