DIABETIC MICROVASCULAR COMPLICATIONS

People with diabetes have an increased risk of developing microvascular complications, diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, which, if undetected or left untreated, can have a devastating impact on quality of life and place a significant burden on health care costs. In addition, diabetic microvascular complications can reduce life expectancy. The strongest risk factors are glycaemic control and diabetes duration; however, other modifiable risk factors such as hypertension, hyperlipidaemia and smoking, and unmodifiable risk factors including age at onset of diabetes and genetic factors may all play a part. Along with the presence of external risk factors, some associations have also been noted between diabetic microvascular complications themselves. There is evidence that diabetic retinopathy in association with increased blood pressure is an important risk factor for diabetic nephropathy progression. Significant correlations have also been shown between the presence of diabetic peripheral neuropathy and the presence of background or proliferative diabetic retinopathy. Clinical trials are currently in progress looking at a number of approaches to designing treatments to prevent the adverse effects of hyperglycaemia. It is essential however, that risk factors associated with the progression and development of diabetic microvascular complications are detected and treated at an early stage in order to further reduce morbidity and mortality. Considering all three complications as interrelated may well facilitate early detection of microvascular disease. Despite good long-term glycaemic and blood pressure control, diabetes remains a major cause of blindness, renal failure and amputations. As the incidence of diabetes continues to rise, the burden of diabetic microvascular complications will increase in future, hence the need for early detection. Considering the microvascular complications of diabetes as related, and enquiring proactively about complications, may well facilitate early detection of microvascular disease

Distribution of ozone and its precursors over Bay of Bengal during winter 2009: role of meteorology

Measurements of ozone and NO₂ were carried out in the marine environment of the Bay of Bengal (BoB) during the winter months, December 2008–January 2009, as part of the second Integrated Campaign for Aerosols, gases and Radiation Budget conducted under the Geosphere Biosphere Programme of the Indian Space Research Organization. The ozone mixing ratio was found to be high in the head and the southeast BoB with a mean value of 61 ± 7 ppb and 53 ± 6 ppb, respectively. The mixing ratios of NO₂ and CO were also relatively high in these regions. The spatial patterns were examined in the light of airflow patterns, air mass back trajectories and other meteorological conditions and satellite retrieved maps of tropospheric ozone, NO₂, CO, and fire count in and around the region. The distribution of these gases was strongly associated with the transport from the adjoining land mass. The anthropogenic activities and forest fires/biomass burning over the Indo Gangetic Plains and other East Asian regions contribute to ozone and its precursors over the BoB. Similarity in the spatial pattern suggests that their source regions could be more or less the same. Most of the diurnal patterns showed decrease of the ozone mixing ratio during noon/afternoon followed by a nighttime increase and a morning high. Over this oceanic region, photochemical production of ozone involving NO₂ was not very active. Water vapour played a major role in controlling the variation of ozone. An attempt is made to simulate ozone level over the north and south BoB using the photochemical box model (NCAR-MM). The present observed features were compared with those measured during the earlier cruises conducted in different seasons

Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes.

Background: vitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. Methods: we conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity. Results: overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain--all self-reported--or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26). Conclusions: intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.)

SUMOylation of Syntaxin1A regulates presynaptic endocytosis

Neurotransmitter release from the presynaptic terminal is under very precise spatial and temporal control. Following neurotransmitter release, synaptic vesicles are recycled by endocytosis and refilled with neurotransmitter. During the exocytosis event leading to release, SNARE proteins provide most of the mechanical force for membrane fusion. Here, we show one of these proteins, Syntaxin1A, is SUMOylated near its C-terminal transmembrane domain in an activity-dependent manner. Preventing SUMOylation of Syntaxin1A reduces its interaction with other SNARE proteins and disrupts the balance of synaptic vesicle endo/exocytosis, resulting in an increase in endocytosis. These results indicate that SUMOylation regulates the emerging role of Syntaxin1A in vesicle endocytosis, which in turn, modulates neurotransmitter release and synaptic function

Phosphorylation of Syntaxin‐1a by casein kinase 2α (CK2α) regulates presynaptic vesicle exocytosis from the reserve pool

The t-soluble NSF-attachment protein receptor protein Syntaxin-1a (Stx-1a) is abundantly expressed at pre-synaptic terminals where it plays a critical role in the exocytosis of neurotransmitter-containing synaptic vesicles. Stx-1a is phosphorylated by Casein kinase 2α (CK2α) at Ser14, which has been proposed to regulate the interaction of Stx-1a and Munc-18 to control of synaptic vesicle priming. However, the role of CK2α in synaptic vesicle dynamics remains unclear. Here, we show that CK2α over-expression reduces evoked synaptic vesicle release. Furthermore, shRNA-mediated knockdown of CK2α in primary hippocampal neurons strongly enhanced vesicle exocytosis from the reserve pool, with no effect on the readily releasable pool of primed vesicles. In neurons in which endogenous Stx-1a was knocked down and replaced with a CK2α phosphorylation-deficient mutant, Stx-1a(D17A), vesicle exocytosis was also increased. These results reveal a previously unsuspected role of CK2α phosphorylation in specifically regulating the reserve synaptic vesicle pool, without changing the kinetics of release from the readily releasable pool

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development

Predicting Diabetic Nephropathy Using a Multifactorial Genetic Model

AIMS: The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. METHODS: Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random "training" (75%) and "test" (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. RESULTS: The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672) better than a model based on conventional variables only (C = 0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (χ(2) = 17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (χ(2) = 3.2673, p = 0.07). CONCLUSION: In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for use across multiple ethnic groups or if population-specific models are required

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Ethnobotany in the Nepal Himalaya

<p>Abstract</p> <p>Background</p> <p>Indigenous knowledge has become recognized worldwide not only because of its intrinsic value but also because it has a potential instrumental value to science and conservation. In Nepal, the indigenous knowledge of useful and medicinal plants has roots in the remote past.</p> <p>Methods</p> <p>The present study reviews the indigenous knowledge and use of plant resources of the Nepal Himalayas along the altitudinal and longitudinal gradient. A total of 264 studies focusing on ethnobotany, ethnomedicine and diversity of medicinal and aromatic plants, carried out between 1979 and 2006 were consulted for the present analysis. In order to cross check and verify the data, seven districts of west Nepal were visited in four field campaigns.</p> <p>Results</p> <p>In contrast to an average of 21–28% ethnobotanically/ethnomedicinally important plants reported for Nepal, the present study found that up to about 55% of the flora of the study region had medicinal value. This indicates a vast amount of undocumented knowledge about important plant species that needs to be explored and documented. The richness of medicinal plants decreased with increasing altitude but the percentage of plants used as medicine steadily increased with increasing altitude. This was due to preferences given to herbal remedies in high altitude areas and a combination of having no alternative choices, poverty and trust in the effectiveness of folklore herbal remedies.</p> <p>Conclusion</p> <p>Indigenous knowledge systems are culturally valued and scientifically important. Strengthening the wise use and conservation of indigenous knowledge of useful plants may benefit and improve the living standard of poor people.</p

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice