Leber hereditary optic neuropathy—new insights and old challenges

Graefe's Archive for Clinical and Experimental Ophthalmology - Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of...     

The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis

OBJECTIVE: To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis. METHODS: In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF. RESULTS: Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer. CONCLUSIONS: The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.     

Sialoglycan recognition is a common connection linking acidosis,zinc, and HMGB1 in sepsis

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.

The pH of body fluids in healthy individuals spans a very broad range in different tissue types and organs, ranging from pH 1.5 (stomach contents) to 8.0 (urine). Human cells in tissue culture can also tolerate a wide range of pH values. In contrast, blood pH is tightly regulated between 7.35 and 7.45 (1), and departure out of this range (acidosis or alkalosis) can be very detrimental. For example, in the recent COVID-19 pandemic, 30% of nonsurvivors had acidosis, compared to 1% among survivors (2). Acidosis in sepsis is partly due to lactic acid release from anoxic tissues, which overwhelms the buffering capacity of circulating blood (3). A “cytokine storm” of proinflammatory mediators in sepsis triggers a cascade of destructive outcomes such as multiple organ failure (4–8) as currently seen in severe cases of COVID-19 infection (9). The mechanisms underlying lethality associated with low blood pH are not clear but include low zinc levels and release from apoptotic or necrotic cells of High mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) defined as one of the late mediators of sepsis, further up-regulating many other proinflammatory cytokines (10–12). Importantly, a recent study indicates that HMGB1 levels are strongly associated with mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (13). Here we show that sialylated plasma glycoproteins bind HMGB1 to suppress its ability to promote inflammatory responses in a zinc- and pH-dependent manner. Besides providing an explanation for the very tight regulation of blood pH, these findings provide an avenue for developing a new therapeutic strategy for treating sepsis.     

Participatory patient-physician communication and morbidity in patients with systemic lupus erythematosus

OBJECTIVE: To examine associations between active patient-physician communication and measures of morbidity in patients with systemic lupus erythematosus (SLE). METHODS: Audiotapes of routine visits between 79 women with SLE and their rheumatologists were coded for active patient participation and the degree of patient-centered communication of the physician, using a validated coding scheme. Measures of SLE activity, functional disability, and permanent organ damage were recorded at the same visit. Permanent organ damage was reassessed in 68 patients after a median of 4.7 years. RESULTS: Patients who participated more actively in their visits had less permanent organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and tended to accrue less organ damage over time. There were no associations between either active patient participation or physicians' patient-centered communication scores and measures of SLE activity or functional disability. CONCLUSIONS: Patients with SLE who participated more actively in their visits had less permanent organ damage, suggesting that involving patients more in their care may decrease morbidity.     

Left Paraduodenal Hernia Causing Small Bowel Obstruction

A case of small bowel obstruction secondary to a left paraduodenal hernia is illustrated together with its radiological features and intra-operative appearance. Paraduodenal hernias are rare congenital causes of small bowel obstruction, and various approaches to surgical treatment are available including conventional open and minimally invasive laparoscopic techniques. This case presents one possible option for surgical management and briefly reviews the literature for the various surgical techniques and strategies available to the surgeon when faced with a left paraduodenal hernia.     

Association between a marker in the UCP-2/UCP-3 gene cluster and genetic susceptibility to anorexia nervosa

Anorexia nervosa (AN) is an enigmatic syndrome affecting approximately 0.1% of the at risk population in the UK which equates to approximately 70000 sufferers. Data from a number of studies have demonstrated the heritability of this disorder, however it is only in the last few years that studies have begun to determine the involvement of particular candidate genes in this genetic predisposition. In the current study we have used classical case-control association analysis to determine whether two highly polymorphic microsatellite markers, located within a 3-cM region of the UCP-2/UCP-3 locus, show involvement of this region of the human genome in the predisposition to AN. Analysis of a cohort of 170 female Caucasian anorexia nervosa sufferers and 150 normal female controls shows evidence of association with the marker D11S911 but not D11S916. Allele 13 of the marker D11S911 is significantly over represented in the anorexia nervosa population suggesting that a mutation in linkage disequilibrium with this locus may form part of the genetic component of AN. Further work is now required to try to reproduce these data in a second independent cohort and to further characterise this region of the human genome.     

Comparative Evaluation of Canal Isthmus Debridement Efficacy of Modified EndoVac Technique with Different Irrigation Systems

Introduction

The purpose of this study was to evaluate the canal isthmus debridement efficacy of a new modified EndoVac (Discus Dental, Culver City, CA) irrigation protocol in comparison with EndoVac, passive ultrasonic irrigation (PUI), and conventional needle irrigation in mesial roots of mandibular molars.

Methods

The mesial roots of 64 extracted mandibular molars mounted in resin using Kuttler's endodontic cube, sectioned at 2 and 4 mm from the working length, were randomly divided into 4 groups (n = 16): group 1: Max-I-Probe (Dentsply Tulsa Dental, York, PA), group 2: EndoVac (EVI), group 3: modified EndoVac, and group 4: PUI. The specimens were reassembled and instrumented. A standard irrigation protocol was used during cleaning and shaping and final irrigation with the 4 irrigation/agitation techniques. Images of the isthmus region were taken before and after cleaning and shaping and after final irrigation. The percentage reduction of debris in the isthmus region was calculated by using the software program Image J (v1.43; National Institutes of Health, Bethesda, MD). Intergroup analysis was performed using the Kruskal Wallis and Mann-Whitney U tests. Intragroup analysis was performed using Friedman and Wilcoxon signed rank tests. The level of significance was set at P < .05.

Results

Intragroup analysis revealed a statistically significant difference in the percentage reduction of debris after cleaning and shaping and after final irrigation protocol in all the groups (P < .001). The final irrigation protocol produced significantly cleaner canal isthmuses in all the groups (P < .001). On intergroup analysis, the modified EVI group performed significantly better than the other groups. The EVI and PUI groups performed better than the Max-I-Probe group. There was no statistical significance between the EVI and PUI groups.

Conclusions

Canal isthmuses were significantly cleaner with the modified EndoVac irrigation technique when compared with the cleanliness seen with the other irrigation systems.