Functional and psychosocial impact of COVID-19 pandemic on rheumatic patients’ quality of life in Saudi Arabia

Quality of Life Research - The COVID-19 pandemic might add to the stressors experienced by people living with rheumatic diseases. This study aimed to examine rheumatic patients’ functional...     

Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion.

Naltrexone (NTX) is a potent opioid antagonist used in the treatment of alcohol dependence and heroin abuse. Compared with naloxone, NTX has a longer duration of action largely attributed to its major active metabolite, 6-beta-naltrexol. The purpose of this study was to increase the delivery of 6-beta-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-beta-naltrexol linked to hydroxybupropion was synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The drug melting points, solubilities, chemical stability, and skin disposition were determined. The carbonate codrug was hydrolyzed on passing through skin and appeared as a combination of intact codrug and parent drugs, 6-beta-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p<0.05) higher 6-beta-naltrexol flux across human skin than 6-beta-naltrexol base. The extent of parent drug regeneration in the skin ranged from 56 to 86%. A higher stratum corneum partition coefficient and rapid bioconversion of the carbonate codrug in the skin correlated with increased 6-beta-naltrexol delivery rates.     

Retinal arteriovenous communication in retinitis pigmentosa with Refsum's disease-like findings

In this report we describe, herewith, a patient with primary pigmentary dystrophy of the retina (retinitis pigmentosa) associated with unilateral retinal arteriovenous communication and exudative retinal detachment. The patient had complete resolution of the retinal detachment following laser photocoagulation treatment. Such association has not been previously reported.     

Analysis of UV-induced damage and repair in young and senescent human dermal fibroblasts using the comet assay

A major cause of ageing is thought to be the accumulation of damage to macromolecules. Accumulation to DNA damage in cells therefore presupposes that aged cells are unable to repair this damage. We have used the in vitro model of cellular ageing to test the idea that senescent cells are deficient in some aspect of DNA repair. Using the alkaline single cell gel electrophoresis assay (comet assay), we have determined the responses of young and senescent human dermal fibroblasts to DNA damage caused by exposure to UVC light. At low doses of UVC, senescent cells generate smaller comets than young cells whilst at medium doses the situation is reversed. At high doses, young and senescent cells respond similarly to one another. Time course experiments revealing repair of DNA damage show that senescent cells generate larger comets than young cells at early stages of repair suggesting that either senescent cells bear more damage per genome than do young cells or that senescent cells are more efficient at excising bulky adducts from DNA. Cells maintained in low levels of serum irrespective of age are less able to repair DNA damage compared with cells maintained in high levels of serum, and furthermore young and senescent cells maintained in high levels of serum are equally able to repair DNA damage. Our data, therefore, reveal both age-dependent and age-independent responses to UV-induced DNA damage. Use of the comet assay highlights the heterogeneity of cellular responses to genotoxic stress.     

Antigen-induced T cell death is regulated by CD4 expression

Activation induced cell death (AICD) is a major physiologic pathway that regulates T cell homeostasis. In CD4 T cells, AICD is mediated mainly through Fas/FasL interactions. Although TCR occupancy triggers AICD, the contribution of its tightly associated CD4 coreceptor to the process that leads to AICD is not known. Here we show that CD4 molecule plays an essential regulatory role of TCR dependent AICD. Loss of CD4 rendered activated 5kc T cell hybridoma resistant to AICD. The resistance of CD4 negative 5kc T cells to AICD was due to selective inhibition of FasL expression and it could be reversed by addition of recombinant FasL. Furthermore, a direct functional link between CD4 and FasL was demonstrated by induction of FasL upon CD4 crosslinking in a TCR independent fashion. The importance of CD4 interaction with MHC/peptide complex in mediating AICD was also evident in normal T cells that could survive chronic stimulation with anti-CD3 but died after short period of proliferation after stimulation with MHC/peptide. Thus it appears that AICD is controlled by the CD4 molecule via regulation of FasL expression. These findings have important implications for our understanding of mechanisms of peripheral tolerance as well as pathogenesis of autoimmune diseases.     

ASO Visual Abstract: Will It Play in Peoria? A Pilot Study of a Robotic Skills Curriculum for Surgical Oncology Fellows

Annals of Surgical Oncology -     

Methimazole in the Treatment of Melasma: A Clinical and Dermascopic Study

BACKGROUND: Melasma is a chronic hypermelanotic disorder that is challenging to treat; no single effective therapeutic agent for it has been discovered. Methimazole, an oral antithyroid drug, has a skin depigmenting effect when used topically. OBJECTIVE: We sought to evaluate the efficacy and safety of methimazole, applied during microneedling sessions and additional topical use in between sessions, for the treatment of melasma. METHODS: This split-face study included 30 Egyptian patients with melasma, each of whom received 12 microneedling sessions once per week for 12 weeks followed by topical methimazole on the right side of face and placebo on the left side. In between the sessions, topical methimazole 5% cream was applied twice per day on the right side and placebo on the left side. Assessments were performed using the Hemi-melasma Area and Severity Index (hemi-MASI) percentage of improvement, patient satisfaction, dermoscopy, and thyroid-stimulating hormone (TSH) serum levels. RESULTS: There were significant clinical and dermoscopic improvements; hemi-MASI scores on the methimazole-treated right sides were decreased (p<0.001). The percent of hemi-MASI score improvement was significantly associated with the malar pattern (p=0.031) and epidermal type (p=0.04) of melasma. About 70 percent of our studied patients reported being satisfied with their treatment response (7% excellent, 33% good, 30% fair). No significant local or systemic side effects were observed. Pre- and posttreatment serum TSH levels were within the normal range in all treated cases. CONCLUSIONS: Methimazole has the potential to be a safe and promising therapeutic agent for the treatment of melasma via dermapen-delivered microneedling sessions with topical use in between sessions.     

Desensitization of guanylyl cyclases in cultured human airway smooth-muscle cells

We previously showed that cultured human airway smooth-muscle cells (HASMC) contain soluble and particulate guanylyl cyclases (GCs). We studied the desensitization of soluble and particulate GCs in HASMC. Homologous desensitization of soluble GC occurred after incubation with S-nitroso-N-acetyl pencillamine (SNAP). SNAP-dependent desensitization was blocked by hemoglobin, a nitric oxide (NO) scavenger, suggesting that it was due to NO release. Cross-desensitization between SNAP and sodium nitroprusside (SNP) and the lack of thiol reduction after SNAP or SNP treatment suggested that thiol depletion was not involved. Assays for soluble GC activity and experiments using protein synthesis inhibitors suggested that SNAP-dependent desensitization was due to reduced soluble GC. Homologous desensitization of particulate GC occurred after pretreatment with atrial natriuretic peptide (ANP) accompanied by reduced particulate GC activity. Recovery required protein synthesis, suggesting that it was due to reduction in particulate GC. Homologous desensitization to either SNAP or ANP was not altered by phosphodiesterase (PDE) inhibitors, suggesting that increased PDE activity was not involved. Cross-desensitization experiments using SNAP and ANP and experiments using zaprinast to elevate cyclic guanosine monophosphate showed no evidence of heterologous desensitization. Our results suggest that pretreatment of HASMC with SNAP or ANP causes homologous, but not heterologous, desensitization of soluble and particulate GCs, respectively.     

GENDER AND AGE DIFFERENCES IN ANEMIA PREVALENCE DURING THE LIFECYCLE IN KUWAIT

Anemia remains a significant worldwide public health problem. Most studies of anemia and iron deficiency, the major cause of anemia, have targeted small children and reproductive age women. Much less is known about anemia in other lifecycle groups, especially preschool age children, prepubertal boys and girls, or in older adults. Yet recent studies indicate that anemia may increase the risk for chronic diseases and accelerate declining function in older adults. We examined anemia throughout the lifecycle in Kuwait by analyzing data from the 2002 Kuwait Nutrition Surveillance Program. Over 13,000 individuals of both sexes representing all ages were studied. The prevalence of anemia was higher in females than males between 6 months and 3 years. From age 4 to 14 years, there was a reversal with males having a higher rate of anemia. Older females had a lower prevalence of anemia than younger females. These results imply certain policy options.     

Antibacterial macrolides: a drug class with a complex pharmacological profile.

Macrolides are widely used antibacterial agents. Although generally well tolerated, they have a number of important additional pharmacological effects, which can sometimes result in significant adverse reactions. This review focuses on three of these side effects: the prokinetic action associated with stimulation of motilin receptors, the proarrhythmic effect due to prolongation of the QT interval of the electrocardiogram and the potential for drug interactions due to inhibition of drug metabolising enzymes. For macrolides that have obtained marketing authorisation in Italy, United Kingdom or United States of America, we also considered whether these actions are properly reported in the approved summaries of the product characteristics and tried to provide strategies to identify patients at risk of significant side effects when macrolides are administered.