Predictive performance of CHA2DS2-VASc-HS score and Framingham risk scores for coronary disease severity in ischemic heart disease patients with invasive coronary angiography.

OBJECTIVE: The objective of this study was to determine the predictive performance and compatibility of CHA2DS2-VASc-HS scores and Framingham risk scores (FRS) in patients with coronary angiography. PATIENTS AND METHODS: This cross-sectional analysis study enrolled 98 patients with ischemic heart disease who were indicated for invasive coronary angiography. Sensitivity and specificity were determined using the cut-off values of the ROC curve. The Gensini score was used to evaluate the correlation. RESULTS: The cut-off value of the Congestive heart failure, hypertension, age 75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category - hyperlipidemia, smoking (CHA2DS2-VASc-HS) score was 2.5, and for FRS, it was 14.5. The area under the curve (95% CI) for the CHA2DS2-VASc-HS score and FRS were 0.76 (0.66, 0.85) and 0.80 (0.71, 0.85), respectively. For every 1-point increase in the CHA2DS2-VASc-HS score, the Gensini score increased by 0.44 (r = 0.56; R2 = 0.19, Beta = 0.44, p < 0.01), and the number of stenosis coronary branches increased by 0.55 (r = 0.56; R2 = 0.30, Beta = 0.55, p < 0.01). For every 10-point increase in FRS, the Gensini score increased by 3.8 (r = 0.57; R2 = 0.14, Beta = 0.38, p < 0.01), and the number of stenosis coronary branches increased by 5 (r = 0.53; R2 = 0.25, Beta = 0.5, p < 0.01). CONCLUSIONS: Our study demonstrated a high predictive performance of coronary artery injury using the CHA2DS2-VASc-HS score and Framingham risk scores. These scores could be applied in predicting ischemic heart disease in non-symptomatic cases where invasive coronary angiography is not indicated.

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

The culture of HaCaT cells on liquid substrates is mediated by a mechanically strong liquid-liquid interface.

The mechanical properties of naturally-derived matrices and biomaterials are thought to play an important role in directing cell adhesion, spreading, motility, proliferation and differentiation. However, recent reports have indicated that cells may respond to local nanoscale physical cues, rather than bulk mechanical properties. We had previously reported that primary keratinocytes and mesenchymal stem cells did not seem to respond to the bulk mechanical properties of poly(dimethyl siloxane) (PDMS) substrates. In this study, we examine the mechanical properties of weakly crosslinked PDMS substrates and observe a liquid-like behaviour, with complete stress relaxation. We then report the observation that HaCaT cells, an epidermal cell line, proliferate readily at the surface of uncrosslinked liquid PDMS, as well as on low viscosity (0.77 cSt) fluorinated oil. These results are surprising, considering current views in the field of mechanotransduction on the importance of bulk mechanical properties, but we find that strong mechanical interfaces, presumably resulting from protein assembly, are formed at liquid-liquid interfaces for which cell adhesion and proliferation are observed. Hence our results suggest that cells sense the nanoscale mechanical properties of liquid-liquid interfaces and that such physical cues are sufficient to sustain the proliferation of adherent cells.

Can acclimation of thermal tolerance, in adults and across generations, act as a buffer against climate change in tropical marine ectotherms?

Thermal acclimation capacity was investigated in adults of three tropical marine invertebrates, the subtidal barnacle Striatobalanus amaryllis, the intertidal gastropod Volegalea cochlidium and the intertidal barnacle Amphibalanus amphitrite. To test the relative importance of transgenerational acclimation, the developmental acclimation capacity of A. amphitrite was investigated in F1 and F2 generations reared at a subset of the same incubation temperatures. The increase in CTmax (measured through loss of key behavioural metrics) of F0 adults across the incubation temperature range 25.4-33.4°C was low: 0.00°C (V. cochlidium), 0.05°C (S. amaryllis) and 0.06°C (A. amphitrite) per 1°C increase in incubation temperature (the acclimation response ratio; ARR). Although the effect of generation was not significant, across the incubation temperature range of 29.4-33.4°C, the increase in CTmax in the F1 (0.30°C) and F2 (0.15°C) generations of A. amphitrite was greater than in the F0 (0.10°C). These correspond to ARR's of 0.03°C (F0), 0.08°C (F1) and 0.04°C (F2), respectively. The variability in CTmax between individuals in each treatment was maintained across generations, despite the high mortality of progeny. Further research is required to investigate the potential for transgenerational acclimation to provide an extra buffer for tropical marine species facing climate warming.

High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance.

The development of obesity-associated insulin resistance is associated with B-lymphocyte accumulation in visceral adipose tissue (VAT) and is prevented by B-cell ablation. To characterize potentially pathogenic B-cell repertoires in this disorder, we performed high-throughput immunoglobulin (Ig) sequencing from multiple tissues of mice fed high-fat diet (HFD) and regular diet (RD). HFD significantly changed the biochemical properties of Ig heavy-chain complementarity-determining region-3 (CDRH3) sequences, selecting for IgA antibodies with shorter and more hydrophobic CDRH3 in multiple tissues. A set of convergent antibodies of highly similar sequences found in the VAT of HFD mice but not RD mice showed significant somatic mutation, suggesting a response shared between mice to a common antigen or antigens. These findings indicate that a simple high-fat dietary intervention has a major impact on mouse B-cell repertoires, particularly in adipose tissues.

Involvement of GABA(A) receptors in myoclonus.

Alterations in multiple neurochemical systems have been reported in animal and human studies of posthypoxic myoclonus. It is impossible, however, to establish causative relationships between the observed changes and the myoclonic movements from these studies. Therefore, to establish causative links between neurochemical changes and myoclonus, ligands that target neurotransmitter systems that are altered in posthypoxic myoclonus were microinjected into the lateral ventricles of normal rats to identify the changes that can produce myoclonus. Of the ligands that were tested, only the GABA(A) antagonists produced myoclonus after intracerebroventricular administration, suggesting the importance of disinhibition of GABAergic systems in myoclonus. To further examine the role of GABA in myoclonus, GABAergic antagonists were microinjected into the nucleus reticularis of the thalamus (NRT), an area of the brain in which extensive pathologic changes are seen in posthypoxic animals. GABA(A), but not GABA(B), antagonists produced myoclonus after microinjection into the NRT. Earlier investigators have further reported the ability of GABA(A) antagonists to produce myoclonus after microinjection into the caudate. The data therefore suggest that disruption of activity at GABA(A) receptors at any one of a number of levels in the neural axis can produce myoclonus.

Evaluation of the postoperative meniscus of the knee: a study comparing conventional arthrography, conventional MR imaging, MR arthrography with iodinated contrast material, and MR arthrography with gadolinium-based contrast material.

OBJECTIVE: To compare four imaging methods in the evaluation of the postoperative meniscus: conventional arthrography, conventional MR imaging, MR arthrography with iodinated contrast material, and MR arthrography with gadolinium-based contrast material. DESIGN AND PATIENTS: Thirty-three patients referred for knee MR examinations with a history of meniscal surgery were studied prospectively. At the first patient visit, conventional MR examination was followed by an MR arthrogram with gadolinium-based contrast material. At the second visit, a conventional arthrogram with iodinated contrast material was followed immediately by an MR examination. Imaging examinations were interpreted by a masked reader, and then compared with the results of repeat arthroscopic surgery in 12 patients. RESULTS: The correct evaluation of the status of postoperative menisci was allowed in 12 of 13 patients (92%) by MR arthrography using gadolinium-based contrast agent, 10 of 13 patients (77%) by conventional MR examination, 9 of 12 patients (75%) by MR arthrography, and 7 of 12 patients (58%) by conventional arthrography. CONCLUSION: Intra-articular fluid is advantageous in the evaluation of patients with a suspected meniscal retear. MR arthrography with gadolinium-based contrast material is the most accurate imaging method for the diagnosis of meniscal retears.

Long-term brimonidine therapy in glaucoma patients with apraclonidine allergy.

PURPOSE: To report the use of brimonidine in patients with a documented ocular allergy to apraclonidine. METHODS: We conducted a prospective, open-label study on the use of long-term brimonidine therapy in 57 patients with chronic glaucoma with documented allergy to apraclonidine. The study patients were placed on brimonidine tartrate 0.2%, 1 drop three times daily in one or both eyes, either as additive therapy to a medical regimen devoid of apraclonidine for further lowering of intraocular pressure (25 patients) or as a replacement for apraclonidine at the time of diagnosis of apraclonidine ocular allergy for maintenance of intraocular pressure control (32 patients). Clinical symptoms and signs of ocular allergy to brimonidine were monitored for up to 18 months. RESULTS: During the treatment period of up to 18 months, six (10.5%) of 57 patients developed slit-lamp biomicroscopic findings and subjective symptoms of an ocular allergic reaction that led to discontinuation of brimonidine treatment. All six patients developed ocular allergy to topical brimonidine 0.2% during the first 4 months of therapy. The addition of brimonidine 0.2% topical medication or the replacement of apraclonidine with brimonidine resulted in a significant decrease in mean intraocular pressure from 20.5+/-5.3 to 16.5+/-4.2 mm Hg (P < .0001) at the mean treatment period of 10.6+/-4.6 months (range, 0.5 to 18.0 months in all 57 patients: 5 to 18 months in the 51 patients without brimonidine allergy and 0.5 to 3.8 months in the six patients who developed brimonidine allergy. CONCLUSIONS: The incidence of ocular allergy after the use of brimonidine 0.2% topical medication for up to 18 months was 10.5% in patients with a documented history of apraclonidine allergy. Therefore, it is generally safe as well as efficacious to administer brimonidine to patients with an ocular allergy to apraclonidine.

Transcriptional control of human Tenon's capsule fibroblast collagen synthesis in vitro by gamma-interferon.

PURPOSE: Gamma-interferon (gamma-IFN) has been shown to be a potent inhibitor of collagenous protein production independent of its effects on noncollagenous protein production and cell proliferation in vitro. To understand further the processes controlling tissue fibrosis and the potential use of gamma-IFN as an antifibrotic treatment after glaucoma filtering surgery, the in vitro effects of recombinant gamma-IFN on procollagen mRNA production were studied. METHODS: Subconfluent human Tenon's capsule fibroblast cultures were exposed to 10, 50, 500, and 1000 U/ml of human recombinant gamma-IFN for 48 hours and to 500 U/ml for 12, 24, and 72 hours. After the incubation period, polyA+ mRNAs were isolated by oligo (dT) cellulose columns, separated according to size by electrophoresis through a denaturing agarose gel, and transferred to an activated nylon membrane for Northern blot analysis. The levels of type III (alpha 1) procollagen, type I (alpha 1) procollagen, and fibronectin (noncollagenous protein) mRNA were determined by hybridization with radiolabeled cDNA probes specific for these components followed by autoradiography. RESULTS: Densitometric analysis showed gamma-IFN selectively inhibited type III and type I procollagen mRNA synthesis from 24% (10 U/ml) to 99% (1000 U/ml) while leaving fibronectin mRNA synthesis unaffected. The degree of inhibition was also time dependent; more inhibition occurred with increasing incubation time. CONCLUSIONS: These results indicate that gamma-IFN is able to regulate collagen synthesis at the transcriptional level and that its inhibition is relatively specific. Gamma-interferon's specific inhibitory effects may offer advantages over current therapies in modulating the fibrotic response after glaucoma filtering surgery.

Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye.

PURPOSE: To investigate the use of topically applied FK506, a new immunosuppressive compound, systemic and ocular absorption was determined in serum and various ocular tissues. METHODS: Two drops of 20 microliters FK506 were applied using oil dissolved (OD-FK506) or liposome-bound (LIP-FK506) drug. FK506 concentrations were measured at intervals of 30, 60, and 120 minutes by immunoassay. RESULTS: After application of OD-FK506, the highest concentrations of FK506 were found in the cornea and the conjunctiva (200-1200 ng/g) with substantial drug also present in anterior and posterior sclera. Relatively low concentrations were measured in the aqueous and vitreous humors (0.2-1.0 ng/g) of these animals. Using the same treatment regimen, LIP-FK506 was effective in delivering significantly higher drug concentrations (P < 0.05) to all ocular tissues and particularly aqueous humor (5-28 ng/g) and vitreous humor (12-22 ng/g) at all time points. During the observation period drug concentrations produced by LIP-FK506 remained well above the therapeutic range. FK506 levels were not detectable in serum (< 0.2 ng/ml) with either drug formulation. CONCLUSION: These findings indicate that liposomes may be a promising formulation for topical use of FK506 in ocular immune-mediated diseases.

In vitro evaluation of antiproliferative potential of topical cyclooxygenase inhibitors in human Tenon's fibroblasts.

Pharmacologic agents which inhibit fibroblast proliferation and scar formation may improve the success of glaucoma filtration surgery. To evaluate the potential use of nonsteroidal anti-inflammatory drugs as an antifibrotic treatment following glaucoma filtration surgery, the time and dose-related effects of four commonly used topical cyclo-oxygenase inhibitors--diclofenac, flurbiprofen, piroxicam, and suprofen--on human Tenon's fibroblast attachment and proliferation were studied. Fibroblasts were incubated with different concentrations of a drug and analysed for dose response 1, 3, and 8 days following drug addition. The cell density was quantified by Coulter counting, hexosaminidase assay, and [3H]thymidine uptake into the DNA. All four drugs inhibited fibroblast attachment at the highest concentrations. Diclofenac was the most effective agent in inhibiting fibroblast proliferation, with inhibition occurring at a range of concentrations above 10(-3)-10(-4) mmol l-1. Flurbiprofen, piroxicam, and suprofen were comparable to each other in their antiproliferative activities, with inhibition occurring at a range of concentrations above 10(-1)-10(-2) mmol l-1. These results suggest a potential role for the commonly used topical nonsteroidal anti-inflammatory drugs in preventing excessive fibroblast proliferation following GFS, but further clinical studies are indicated to assess their activity as anti-inflammatory and antiproliferative agents in preventing bleb failure.

Effect of steroids and nonsteroidal antiinflammatory agents on human ocular fibroblast.

5-fluorouracil and steroids have been used to suppress excessive scar formation after glaucoma filtering surgery (GFS). Steroidal and nonsteroidal antiinflammatory drugs (NSAIDs), which are inhibitors of arachidonic acid (AA) pathway, both limit fibroblast activity and reduce inflammation. In this experiment, the ability of corticosteroid (dexamethasone sodium phosphate), cyclooxygenase inhibitor (piroxicam), lipoxygenase inhibitor (ferulic acid), and dual cyclo/lipoxygenase inhibitor (phenidone) to inhibit human Tenon's fibroblast proliferation was evaluated in culture. After human Tenon's fibroblast cell lines were established, a complete dose-response curve was done for the representative compounds for 8 days. Fibroblast attachment and proliferation were quantified by Coulter counter, hexosaminidase, and tritiated thymidine uptake assays. All four drugs inhibited attachment and proliferation at high concentrations. Phenidone was the most effective, with inhibition occurring within the 0.001-0.1 mmol/l range. It also was the only drug that showed inhibition at the antiinflammatory range in vivo. Dexamethasone, piroxicam, and ferulic acid did not inhibit fibroblast attachment and proliferation until doses well above those required to inhibit AA biosynthesis were attained. Only dexamethasone showed increased potency with incubation time. Overall, the NSAIDs showed antiproliferative activity comparable to or better than that of the steroids. Because the potency of steroids increases over time, these drugs may be more beneficial if given prior to initiation of inflammation. These results suggest that NSAIDs may be useful as both antiinflammatory and antiproliferative agents in preventing bleb failure after GFS.

Effects of timolol, betaxolol, and levobunolol on human tenon's fibroblasts in tissue culture.

Evidence has been found suggesting that long-term therapy with topical antiglaucoma medications may decrease the success of glaucoma filtering surgery. To investigate this question further, the antiproliferative effects of the preservative benzalkonium chloride and three pure and commercially available beta-adrenergic antagonist preparations (timolol, betaxolol, and levobunolol) were studied on tissue cultures of human Tenon's capsule fibroblasts. Each drug preparation was tested on three different cell lines. Fibroblast growth was measured with tritiated thymidine uptake and hexosaminidase assays. Trypan blue uptake was used to assess cell viability microscopically. The commercially available preparations containing benzalkonium chloride and those of betaxolol and levobunolol without the preservative had similar inhibitory doses for 50% of cells. The timolol preparation without preservative was significantly less toxic than its commercially available one. The three tested beta-adrenergic blockers did not stimulate fibroblast proliferation directly in this in vitro model. Even when the cultures were washed free of the drugs, growth continued to be suppressed, suggesting that the inhibition was not reversible. An increase in fibroblasts and inflammatory cells after long-term antiglaucoma medical therapy thus may be caused not by a direct stimulation of cell proliferation but by chronic inflammation from the irritating effects of antiglaucoma medications and/or their preservatives.

Artificial nerve graft using glycolide trimethylene carbonate as a nerve conduit filled with collagen compared to sutured autograft in a rat model.

A study was conducted to compare the regeneration of rat peroneal nerves across 0.5 cm gaps repaired with artificial nerve grafts (ANG) versus sutured autografts (SAG). The ANG model is composed of a synthetic biodegradable passive conduit made of glycolide trimethylene carbonate (GTMC) filled with a collagen matrix (predominantly Type I collagen, derived from calf skin, and with the telopeptide ends left intact). Axonal regeneration was studied in 11 long-term animals (two at 6 months and nine at 9 months). The nerves were studied by qualitative and quantitative histological, electrophysiological, and functional assays. Axonal regeneration with the ANG was equal to SAGs as measured by axonal diameters, physiological, and functional methods, although the SAG demonstrated statistically higher axonal counts.

Unusual feature of soft-tissue calcification in chronic renal failure: tumoral calcification.

Two cases of massive calcification in dialysed patients are described with computerized tomography correlation: one in the abdominal/pelvic cavity, which is a rare location, and the other in the abdominal wall. The cause of these calcified deposits is multifactorial and complex. Usually painless, they may cause restriction of joint movement by virtue of their bulky size.

The artificial nerve graft: a comparison of blended elastomer-hydrogel with polyglycolic acid conduits.

A study was undertaken to compare the regeneration of rat peroneal nerves across a 0.5-cm gap repaired with either a permanent, porous or a resorbable, non-porous artificial nerve graft. The resorbable, impermeable artificial nerve graft was a synthetic passive conduit made from polyglycolic acid (PGA). The permanent, porous artificial nerve graft conduit was manufactured from a hydrophilic elastomeric biopolymer (HEB), and four variations were tested. Qualitative histology on short-term animals revealed similar inflammatory reactions to HEB and PGA. Axonal regeneration was evaluated in longer-term animals after three, four, and six months by qualitative and quantitative histology. Qualitative histology on longer-term animals demonstrated both artificial nerve grafts to be anti-immunogenic. All PGA-artificial nerve graft repairs among three-, four-, and six-month rats contained myelinated axons, as did all HEB-1 repairs. However, three other HEB-graft varieties accounted for a 25 percent failed regeneration rate. Quantitative histologic comparison of repair-site cross-sections in viable PGA and HEB matched pairs demonstrated statistically equivalent myelinated axon counts but larger average myelinated fiber diameters in HEB repairs, with p = .001.