Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk

Background: The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.

Research design and methods: Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.

Results: Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R² = 0.239, p = 0.018; R² = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R² = 0.347, p = 0.026, R² = 0.513, p = 0.009).

Conclusions: The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.     

Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic adenocarcinoma: implications for adjuvant radiotherapy

Background

Adjuvant chemoradiotherapy (CRT) in the treatment of pancreatic ductal adenocarcinoma (PDA) is controversial. Minimal data exists regarding the clinical significance of margin clearance distance and lymph node (LN) parameters, such as extent of dissection and LN ratio. We assessed the impact of these variables on clinical outcomes to more clearly define the subset of patients who may benefit from adjuvant radiotherapy (RT).

Methods

We identified 106 patients with resected stage 1-3 PDA from 2007-2013. Resection margins were categorized as positive (tumor at ink), ≤1, or >1 mm. LN evaluation included total number examined (NE), number of positive nodes (NP), ratio of NP to NE (NR), extent of dissection, and positive periportal LNs. The impact of these variables was assessed on disease-free survival (DFS) and overall survival (OS) using multivariate cox proportional hazards modeling.

Results

In patients receiving adjuvant chemotherapy (CT) alone, greater margin clearance led to improved DFS (P=0.0412, HR =0.51). Range of NE was 4-37, with a mean of 19. NE was not associated with DFS or OS, yet absolute NP of 5 or more was associated with a significantly worse DFS (P=0.005). Whereas periportal lymphadenectomy did not result in improved DFS or OS, patients with positive periportal LN had worse clinical outcomes (DFS, P=0.0052; OS, P=0.023). The use of adjuvant CRT was associated with improved OS (P=0.049; HR=0.29).

Conclusions

In patients receiving adjuvant CT alone, there was a clinically significant benefit to clearing the surgical margin beyond tumor at ink. Having ≥5 NP and positive periportal LN led to significantly worse clinical outcomes. The addition of adjuvant RT to CT in resected PDA improved OS. A comprehensive evaluation of resection margin distance and LN parameters may identify more patients at risk for locoregional failure who may benefit from adjuvant CRT.     

Inhibition of TCR triggering by a spectrum of altered peptide ligands suggests the mechanism for TCR antagonism

Understanding the parameters involved in T cell activation has been complicated by the discovery of partial T cell agonists. Altered peptide ligands (APL) have recently shown that different subsets of T cell responses can be selectively activated by certain peptides, which define a hierarchy of T cell activation. For cytotoxic T cells, this hierarchy ranges from sensitizing target cells for lysis through proliferation to effector cell induction. The degree of TCR down-regulation mediated by APL-MHC interactions correlates well with the induction of specific T cell effector functions. This suggests that the potential agonist response induced by a given peptide occurs at different triggering thresholds. To examine the relative agonist and antagonist functions of different peptides, we have investigated the ability of lymphocytic choriomeningitis virus glycoprotein-derived APL to induce or inhibit a range of effector functions in naive CD8⁺ T cells. By this, we have defined a hierarchy of peptides that display a range of properties from strong agonist to no agonist function. At each level, peptides that were ranked lower in this hierarchy were able to interfere or antagonize the induction of effector functions by higher ranking peptides. We have therefore shown that this spectrum of peptides ranging from strong to no agonist function has an inverse gradient from strong antagonist to no antagonist function. Moreover, the ability of the different peptides to inhibit TCR internalization correlated with their ranking within the hierarchy. These findings support the model that antagonists are effectively preventing TCR oligomerization and functional TCR triggering.     

Genetic variants of the inflammatory C-reactive protein and schizophrenia in Armenian population: a pilot study

C-reactive protein (CRP) is an inflammation marker implicated in the pathogenesis of schizophrenia. To investigate association of the CRP rs1417938, rs1800947, rs1205 variants with susceptibility to schizophrenia 208 unrelated Armenians (103 patients and 105 healthy controls) were genotyped. In this pilot study, none of studied variants was associated with schizophrenia.     

Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS

BackgroundThere is no consensual first-line chemotherapy for elderly patients with mantle cell lymphoma (MCL). The GOELAMS (Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang) group previously developed the (R)VAD+C regimen (rituximab, vincristine, doxorubicin, dexamethasone and chlorambucil), which appeared as efficient as R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, prednisone) while less toxic. Based on this protocol, we now added bortezomib (RiPAD+C: rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil) given its efficacy in relapsed/refractory MCL patients. The goal of the current phase II trial was to evaluate the feasibility and efficacy of the RiPAD+C regimen as frontline therapy for elderly patients with MCL.Patients and methodsPatients between 65 and 80 years of age with newly diagnosed MCL received up to six cycles of RiPAD+C.ResultsThirty-nine patients were enrolled. Median age was 72 years (65–80). After four cycles of RiPAD+C, the overall response rate was 79%, including 51% complete responses (CRs). After six cycles, CR rate increased up to 59%. After a 27-month follow-up, median progression-free survival (PFS) is 26 months and median overall survival has not been reached. Four patients (10%) discontinued the treatment because of a severe toxicity and seven patients (18%) experienced grade 3 neurotoxicity.ConclusionThe bortezomib-containing RiPAD+C regimen results in high CR rates and prolonged PFS with predictable and manageable toxic effects in elderly patients with MCL.     

Sleep-disordered breathing and stroke: A relation to be considered

Stroke is a leading cause of death and disability. Despite expensive and elaborative research in finding out mechanisms of interrelation between sleep-disordered breathing (SDB) and stroke, there is yet much attention to be given in stroke units worldwide to the prompt diagnosis and treatment of SDB in order to improve morbidity and mortality rates related with stroke. The preventive diagnosis and treatment of SDB reduce stroke rate and improves penumbra area in case of ischemic stroke. Stroke itself predispose to SDB, making the interrelationship more complicated. The review by Parra O and Arboix A reflects the results from carefully selected reviews reported in the literature so far. This review of the literature and presentation of the original study of the Authors based on their patients’ data, enhances the conviction that there exists a direct relation between SDB and stroke. Diagnosis of SDB in new stroke cases should be sought and treated carefully whenever present.     

Relationship between intraocular pressure and obesity in children

PURPOSE: To establish the relationship between intraocular pressure (IOP) and obesity in children. METHODS: Seventy-two obese children (body mass index in the 95th percentile or greater) were compared with 72 age-matched and sex-matched controls (body mass index <95th percentile). Both groups underwent Goldmann applanation tonometry (3 times), blood pressure measurement (3 times), and Hertel exophthalmometry. Paired and unpaired t tests and the Cochran-Mantel-Haenzel statistics were used for statistical analysis. RESULTS: The mean IOP between the obese children and controls were significantly different (P<0.0001), even after adjusting for systolic and diastolic blood pressure (P<0.001). Diurnal variation of IOP was higher in obese children (P<0.001). Obese children had higher Hertel values (P<0.001). Sex did not significantly effect IOP in either group (P>0.05). CONCLUSIONS: In addition to its indirect effect on IOP via blood pressure change, obesity is also an independent risk factor for increased IOP.     

Social determinants of psychological distress in Sierra Leone

Purpose

Growing evidence demonstrates that daily stressors such as family violence, unemployment, and living conditions play an important part in causing psychological distress. This paper investigates the impact of distressing events and day-to-day living conditions on psychological distress in the fragile context of Sierra Leone.

Methods

A cross-sectional survey was conducted with 904 adults (454 men, 450 women) in 5 districts of Sierra Leone. The survey questionnaire comprised the Sierra Leone Psychological Distress scale and measures of demographic variables and personal characteristics, current life circumstances and potentially distressing events.

Results

Multiple regression results identified three factors to be the greatest contributors to psychological distress: family conflict (β = 0.185, p < 0.001) and inability to afford basic needs (β = 0.175, p < 0.001). Gender differences were evident: factors predicting men’s psychological distress included severe sickness or injury (β = 0.203, p < 0.001) and being unable to afford basic needs (β = 0.190, p < 0.001); for women, predicting factors were family conflict (β = 0.212, p < 0.001), perceived poor health (β = 0.192, p < 0.001) and inability to afford basic needs (β = 0.190, p < 0.001).

Conclusion

Initiatives to promote good mental health and psychosocial wellbeing in Sierra Leone should focus on enhancing income-generating and employment opportunities, promoting access to education, and strengthening family relationships.