The presence and origin of autoantibodies against α4 and α7 nicotinic acetylcholine receptors in the human blood: possible relevance to Alzheimer's pathology

Alzheimer's disease (AD) is characterized by a loss of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) in the brain and severe memory impairments. Previously, we found that antibodies elicited against extracellular domain of α7 nAChR subunit decreased the number of α7 nAChRs in the brains of mice and impaired episodic memory. Here we show that antibodies capable to bind α7(1-208) are present in the blood of both healthy humans and AD patients. In healthy individuals, their capacity to compete with [(125)-I]-α-bungarotoxin for the binding to α7(1-208) increased with age. The level of such antibodies was significantly elevated in children with severe form of obstructive bronchitis and in mice injected with Lewis lung carcinoma cells expressing both α4β2 and α7 nAChRs. Elevated antibody levels were accompanied with decreased surface nAChRs on the blood lymphocytes of children and of mice immunized with α7(1-208). Among AD patients, the level of α7 nAChR-specific antibodies was significantly larger in people 62.5 ± 1.5 years old with moderate or severe AD stages (15.2 ± 1.3 MMSE scores) compared to those of 76 ± 1.5 years old with the mild (22.7 ± 0.1 MMSE scores) AD stage. We concluded that α7(1-208) nAChR-specific antibodies found in the human blood are formed as a result of common infections accompanied with the destruction of respiratory epithelium. Elevated blood plasma levels of α7(1-208) nAChR-specific antibodies are characteristic for the early-onset AD and, therefore, are suggested as one of the risk factors for the development of this form of the disease.     

Migraine preventive drugs differentially affect cortical spreading depression in rat

Cortical spreading depression (CSD) is the most likely cause of the migraine aura. Drugs with distinct pharmacological properties are effective in the preventive treatment of migraine. To test the hypothesis that their common denominator might be suppression of CSD we studied in rats the effect of three drugs used in migraine prevention: lamotrigine which is selectively effective on the aura but not on the headache, valproate and riboflavin which have a non-selective effect. Rats received for 4 weeks daily intraperitoneal injections of one of the three drugs. For valproate and riboflavin we used saline as control, for lamotrigine its vehicle dimethyl sulfoxide. After treatment, cortical spreading depressions were elicited for 2h by occipital KCl application. We measured CSD frequency, its propagation between a posterior (parieto-occipital) and an anterior (frontal) electrode, and number of Fos-immunoreactive nuclei in frontal cortex. Lamotrigine suppressed CSDs by 37% and 60% at posterior and anterior electrodes. Valproate had no effect on posterior CSDs, but reduced anterior ones by 32% and slowed propagation velocity. Riboflavin had no significant effect at neither recording site. Frontal Fos expression was decreased after lamotrigine and valproate, but not after riboflavin. Serum levels of administered drugs were within the range of those usually effective in patients. Our study shows that preventive anti-migraine drugs have differential effects on CSD. Lamotrigine has a marked suppressive effect which correlates with its rather selective action on the migraine aura. Valproate and riboflavin have no effect on the triggering of CSD, although they are effective in migraine without aura. Taken together, these results are compatible with a causal role of CSD in migraine with aura, but not in migraine without aura.     

Combined treatment of L1CAM antibodies and cytostatic drugs improve the therapeutic response of pancreatic and ovarian carcinoma

The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and represents a novel marker for various tumor entities including pancreatic and ovarian carcinoma. Recently, we showed that L1CAM inhibition increases the apoptotic response of tumor cells towards cytostatic drugs pointing to the potential of L1CAM to serve as a chemosensitizer in anti-cancer therapy. Thus, the present study evaluated the therapeutic potential of combined treatment with L1CAM antibodies and chemotherapeutic drugs in pancreatic and ovarian carcinoma model systems in vivo. Two L1CAM-specific antibodies (L1-14.10 and L1-9.3/2a) exhibiting high binding affinity to the L1CAM expressing pancreatic adenocarcinoma cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment. The combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of subcutaneously grown Colo357 or SKOV3ip tumors more efficiently than treatment with the cytostatic drug alone or in combination with control IgG. This was accompanied by an increased number of apoptotic tumor cells along with an elevated procaspase-8 expression. Furthermore, a lowered activation of NF-κB along with a reduced expression of VEGF and a diminished number of CD31-positive blood vessels were observed in tumors after combined therapy compared to control treatments, while the infiltration of F4/80-positive macrophages increased. Overall, these data provide new insights into the mechanism of the anti-cancer activity of L1CAM-blocking antibodies in vivo and support the suitability of L1CAM as a target for chemosensitization and of L1CAM-interfering antibodies as an appropriate tool to increase the therapeutic response of pancreatic and ovarian carcinoma.     

Primary trabeculectomy with mitomycin C: safety and efficacy at 2 years

Purpose: To examine the rates of intermediate‐term intraocular pressure (IOP) control after trabeculectomy with adjunctive mitomycin C (MMC) and assess for associated complications. Methods: Medical records of patients undergoing primary trabeculectomy with MMC at Concord Repatriation Hospital, Sydney between January 1997 and December 2005 were reviewed. All eyes with a minimum of 2‐year follow up were included. Follow‐up data were collected in a standardized form on postoperative IOP, bleb‐related and other complications. Success was measured as IOP ≤ 18 mmHg and ≥6 mmHg (criteria 1) with (qualified success) or without (absolute success) the use of glaucoma medications. A secondary outcome measure was an IOP reduction of greater than 20% from baseline (criteria 2). Eyes with preoperative IOP of 18 mmHg or less were included, but also analysed separately to those eyes with preoperative IOP above 18 mmHg. Results: Sixty eyes from 42 patients were included in the study, with 3‐year follow up on 48 eyes. Mean preoperative IOP was 25.3 mmHg (range 8–45) and mean postoperative IOP was 14.0 mmHg at 1‐ and 2‐year follow up, and 14.7 mmHg at 3 years (ranges: 3–31, 4–30 and 8–45 mmHg respectively). Cumulative success for criteria 1 was 85.0% at 2 years and 83.3% at 3 years, and for criteria 2 it was 80.0% and 79.2%, respectively. The number of eyes on glaucoma medications was reduced from 51 preoperatively to 30 at 3 years. Complications were infrequent. There was one eye with a shallow anterior chamber beyond the immediate postoperative period. One eye required cataract surgery at 1‐year follow up. Subgroup analysis was performed using the first operated eye only, and results did not differ significantly from overall results. Conclusion: MMC‐augmented trabeculectomy can significantly reduce IOP in the short and intermediate term, with a favourable safety profile.     

Exploring the promises of intersectionality for advancing women's health research

Women's health research strives to make change. It seeks to produce knowledge that promotes action on the variety of factors that affect women's lives and their health. As part of this general movement, important strides have been made to raise awareness of the health effects of sex and gender. The resultant base of knowledge has been used to inform health research, policy, and practice. Increasingly, however, the need to pay better attention to the inequities among women that are caused by racism, colonialism, ethnocentrism, heterosexism, and able-bodism, is confronting feminist health researchers and activists. Researchers are seeking new conceptual frameworks that can transform the design of research to produce knowledge that captures how systems of discrimination or subordination overlap and "articulate" with one another. An emerging paradigm for women's health research is intersectionality. Intersectionality places an explicit focus on differences among groups and seeks to illuminate various interacting social factors that affect human lives, including social locations, health status, and quality of life. This paper will draw on recently emerging intersectionality research in the Canadian women's health context in order to explore the promises and practical challenges of the processes involved in applying an intersectionality paradigm. We begin with a brief overview of why the need for an intersectionality approach has emerged within the context of women's health research and introduce current thinking about how intersectionality can inform and transform health research more broadly. We then highlight novel Canadian research that is grappling with the challenges in addressing issues of difference and diversity. In the analysis of these examples, we focus on a largely uninvestigated aspect of intersectionality research - the challenges involved in the process of initiating and developing such projects and, in particular, the meaning and significance of social locations for researchers and participants who utilize an intersectionality approach. The examples highlighted in the paper represent important shifts in the health field, demonstrating the potential of intersectionality for examining the social context of women's lives, as well as developing methods which elucidate power, create new knowledge, and have the potential to inform appropriate action to bring about positive social change.     

Correlates of HIV and Inconsistent Condom Use Among Female Sex Workers in Ukraine

While female sex workers (FSWs) carry one of the highest risks of HIV transmission, little is known about predictors of HIV and risky behavior of FSWs in Ukraine. In this study of 4806 Ukrainian FSWs, the prevalence of HIV was 5.6 %. FSWs had higher odds to be HIV infected if they had lower income, were older, injected drugs, experienced violence, and solicited clients on highways. Inconsistent condom use with clients was reported by 34.5 % of FSWs. FSWs who solicited clients at railway stations, via media, through previous clients and other FSWs, and on highways reported lower consistency of condom use. Furthermore, inconsistent condom use was related to younger age, alcohol use, having fewer clients, not being covered with HIV prevention, and experiences of violence. The present study expands on the rather limited knowledge of correlates of the HIV and inconsistent condom use among FSWs in Ukraine.     

Progressive pulmonary calcification in a child after orthotopic liver transplantation

We present a case of progressive pulmonary calcification associated with prolonged respiratory insufficiency in a 2-year-old boy with a history of orthotopic liver transplantation. This case demonstrates the potentially progressive nature of pulmonary calcification and that it can present with respiratory insufficiency at a later period after transplantation than previously thought. We describe radiological findings and discuss established as well as plausible pathological mechanisms contributing to the development of calcifications in these patients.     

Identification of Nordic Berries with Beneficial Effects on Cognitive Outcomes and Gut Microbiota in High-Fat-Fed Middle-Aged C57BL/6J Mice

High-fat diets are associated with neuronal and memory dysfunction. Berries may be useful in improving age-related memory deficits in humans, as well as in mice receiving high-fat diets. Emerging research has also demonstrated that brain health and cognitive function may be related to the dynamic changes in the gut microbiota. In this study, the impact of Nordic berries on the brain and the gut microbiota was investigated in middle-aged C57BL/6J mice. The mice were fed high-fat diets (60%E fat) supplemented with freeze-dried powder (6% dwb) of bilberry, lingonberry, cloudberry, blueberry, blackcurrant, and sea buckthorn for 4 months. The results suggest that supplementation with bilberry, blackcurrant, blueberry, lingonberry, and (to some extent) cloudberry has beneficial effects on spatial cognition, as seen by the enhanced performance following the T-maze alternation test, as well as a greater proportion of DCX-expressing cells with prolongation in hippocampus. Furthermore, the proportion of the mucosa-associated symbiotic bacteria Akkermansia muciniphila increased by 4–14 times in the cecal microbiota of mice fed diets supplemented with lingonberry, bilberry, sea buckthorn, and blueberry. These findings demonstrate the potential of Nordic berries to preserve memory and cognitive function, and to induce alterations of the gut microbiota composition.     

Rheumatologists’ perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets

Clinical Rheumatology - The ongoing pandemic coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a matter of global concern....