Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.     

“Pulmonary tongue” a right ventricle phase abnormality in muga studies in patients with pulmonary hypertention

Pulmonary hypertension (PH) produces strain followed by hypertrophy and later dilatation of the right ventricle (RV) and pulmonary artery. The signs and symptoms are nonspecific. There is a need for a noninvasive sensitive way to diagnose PH. The purpose of this study is to evaluate phase abnormalities in radionuclide MUGA studies of patients with referred diagnosis of PH. In a retrospective analysis of 44 patients who had a radionuclide multigated study (MUGA) and contrast ventriculography (CV), 19 had high mean pulmonary pressure (over 20 mmHg) and a high pulmonary vascular resistance index (over 2.0). In 15 patients, a delayed phase segment in the RV corresponding to the pulmonary infundibulum and pulmonary conus was noted The Pulmonary Tongue sign (PT), 12 had PH (True positive) and 3 did not (false positive) on CV. No PT was seen in the remaining 29 patients, only 7 of them had PH (False negative). The sensitivity, specificity and accuracy of the PT sign in detecting PH was 80%, 72% and 77% respectively. The number of patients was too small to calculate the correlation of the grade of PT with the severity of PH. We conclude that The Pulmonary Tongue sign on a MUGA study is clinically useful in detecting PH.This project is supported by research project MLNO13 and funded by research Council, Kuwait University     

Toxicokinetics and molecular interaction of [14C]-formaldehyde in rats

The excretion, tissue distribution, and binding of [¹⁴C]-formaldehyde were studied at different time intervals in male rats following a single intraperitoneal injection of 72 mg CH₂O (14.7 Ci)/ kg body weight. Within 30 min, 10% of the total dose was recovered in expired air as¹⁴CO₂ and by the end of 72 hr, 41% of the administered dose was eliminated through expired air. The total elimination of¹⁴CH₂O activity in urine and feces in 72 hr was 15%. Erythrocytes retained significant amounts of radioactivity, even at the end of 72 hr. Substantial levels of radioactivity were detected in most tissues one hr after administration, indicating a fast absorption and rapid distribution. Subcellular fractionation of the tissues showed that the highest levels of relative percent binding was in the microsomal fraction, whereas cytosol fractions contained lowest levels of bound radioactivity. DNA, RNA, protein and lipid fractions of liver and spleen tissues showed significantly elevated levels of¹⁴C-incorporation as compared to other tissues. Thein vivo incorporation of¹⁴C-activity showed an increased association of¹⁴CH₂O with RNA in all the tissues. The maximum registration of radioactivity in RNA was at 48 hr after administration. Significantly higher amounts of¹⁴C-activity were registered in DNA of all tissues. The maximum registration of radiolabel in DNA of most tissues was at 12 hr after the¹⁴CH₂O administration. The liver DNA showed maximal levels at 3 hr with a second peak at 48 hr.Substantial amounts of bound radioactivity in nucleic acids of all the tissues were observed even 72 hr after dosing. The relationship between macromolecular association and formaldehyde toxicity has been discussed.     

Increased cancericidal activity of PTT.119; a new synthetic bis-(2-chloroethyl)amino-l-phenylalanine derivative with carrier amino acids

Summary A new synthetic tripeptide (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl), PTT.119, was demonstrated to have significant cancericidal activity against seven in vitro tumor cell lines of different origins and etiologies and against primary human AMML, ALL, and hairy cell leukemias. Viabilities of each murine tumor and rabbit, marmoset, and human leukemia and lymphoma line were significantly reduced by treatment with 1–50 g PTT.119 in media containing serum. Continuous 24-h exposure or pulse treatment as short as 15 and 30 min with the tripeptide resulted in irreversible damage to the tumor cells. Under identical treatment conditions, freshly isolated human leukemic cells, particularly ALL lymphoblasts, were even more susceptible to PTT.119 than any of the tested tumor cell models.Examination of the parameters of PTT.119 activity revealed that reductions of tumor cell survival were dependent on the concentration of the tripeptide. Prolongation of PTT.119 exposure from 15 min to 24 h increased the rates of tumor cell death but did not proportionally reduce the numbers of surviving cells. Assessment of tumor cell viabilities for 5 consecutive days following pulse exposure to PTT.119 demonstrated increasing reductions in tumor cell survival, which were greatest 5 days after treatment with the tripeptide.The cancericidal activity of PTT.119 was compared with its three parental components either as individual agents or as a mixture. Both the alkylator moiety, m-sarcolysin (m.L.SL) alone or together with p-fluoro-phenylalanine and l-methionine ethoxy HCl, and l-PAM (l-phenylalanine mustard), the p-isomer of m.L.SL, were 1.5- to 3-fold less cytotoxic to L1210 leukemia and MJY-alpha mammary tumor cells than PTT.119. Covalent linkage of the amino acid residues to m.L.SL yielded a molecule with greatly augmented cancericidal activity capable of acting against a broad spectrum of tumor cells.     

Immunomodulatory Effects of Dietary Polyphenols

Functional and nutraceutical foods provide an alternative way to improve immune function to aid in the management of various diseases. Traditionally, many medicinal products have been derived from natural compounds with healing properties. With the development of research into nutraceuticals, it is becoming apparent that many of the beneficial properties of these compounds are at least partly due to the presence of polyphenols. There is evidence that dietary polyphenols can influence dendritic cells, have an immunomodulatory effect on macrophages, increase proliferation of B cells, T cells and suppress Type 1 T helper (Th1), Th2, Th17 and Th9 cells. Polyphenols reduce inflammation by suppressing the pro-inflammatory cytokines in inflammatory bowel disease by inducing Treg cells in the intestine, inhibition of tumor necrosis factor-alpha (TNF-α) and induction of apoptosis, decreasing DNA damage. Polyphenols have a potential role in prevention/treatment of auto-immune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis by regulating signaling pathways, suppressing inflammation and limiting demyelination. In addition, polyphenols cause immunomodulatory effects against allergic reaction and autoimmune disease by inhibition of autoimmune T cell proliferation and downregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1, interferon-γ (IFN-γ)). Herein, we summarize the immunomodulatory effects of polyphenols and the underlying mechanisms involved in the stimulation of immune responses.     

Endocrine contribution to the sexual dysfunction in patients with advanced chronic kidney disease and the role of hyperprolactinemia

In this study, we investigated the prevalence of sexual dysfunction among males with advanced chronic kidney disease and the effect of treating hyperprolactinemia among these patients. In this prospective study, patients were assessed with history, physical examination, hormonal assessment, and two questionnaires, IIEF and AIPE. Patients with hyperprolactinemia received treatment with cabergoline 0.5 mg once per week for 6 months and were re-evaluated. A total of 102 patients were included in this study, 75 (73.53%) were on hemodialysis, 13 (12.75%) on peritoneal dialysis and 14 (13.73%) on medical treatment alone. Ninety (88.24%) patients had premature ejaculation, 85 (83.33%) had anything from mild-to-moderate-to-severe erectile dysfunction. The incidence of hypogonadism and hyperprolactinemia was 34.4%. Patients treated with cabergoline (n = 26) showed a significant increase in LH levels (p = .003) and a significant decrease in prolactin levels (p = .003). Testosterone levels and the incidence of erectile dysfunction or premature ejaculation did not improve significantly. There is a high incidence of sexual dysfunction among patients. Treatment of hyperprolactinemia is effective in correcting prolactin levels, but does not improve erectile dysfunction or premature ejaculation. Therefore, treating hyperprolactinemia is not an overall effective treatment for erectile dysfunction in these patients.     

Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS) training for emergency medicine and general surgery residents

BackgroundSuccessful trauma resuscitation relies on multi-disciplinary collaboration. In most academic programs, general surgery (GS) and emergency medicine (EM) residents rarely train together before functioning as a team.MethodsIn our Multi-Disciplinary Trauma Evaluation and Management Simulation (MD-TEAMS), EM and GS residents completed manikin-based trauma scenarios and were evaluated on resuscitation and communication skills. Residents were surveyed on confidence surrounding training objectives.ResultsResidents showed improved confidence running trauma scenarios in multi-disciplinary teams. Residents received lower communication scores from same-discipline vs cross-discipline faculty. EM residents scored higher in evaluation and planning domains; GS residents scored higher in action processes; groups scored equally in team management. Strong correlation existed between team leader communication and resuscitative skill completion.ConclusionMD-TEAMS demonstrated correlation between communication and resuscitation checklist item completion and communication differences by resident specialty. In the future, we plan to evaluate training-related resident behavior changes and specialty-specific communication differences by residents.     

Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression

BackgroundThere has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes.MethodsA systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality.ResultsAfter screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78–1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65–2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections.ConclusionMinimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume.