Effect of sodium-glucose co-transporter-2 inhibitors on coronary blood flow in patients with type 2 diabetes mellitus.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is known to be associated with endothelial dysfunction (ED). Reducing ED can attenuate the occurrence of cardiovascular diseases. One of the indicators of ED is decreased coronary blood flow (CBF). Sodium-glucose co-transporter 2 inhibitors (SGLT-2is) are known to directly improve ED in both euglycemic and hyperglycemic conditions and have been shown to decrease the incidence of major cardiovascular events. We aimed to investigate whether SGLT-2is improves CBF in patients with T2DM, who have angiographically normal or nearly normal coronary arteries. PATIENTS AND METHODS: In this single-center retrospective study, all patients who underwent coronary angiography between January 2017 and September 2022 were screened. We designed the study by dividing the patients into two groups - those who used conventional antidiabetic medications (CAM) together with SGLT-2is (patients using an SGLT-2 inhibitor for at least 3 months) and those who used only conventional antidiabetic medications. Of the 18,205 patients who underwent coronary angiography, 5,040 patients had T2DM. After exclusion, 288 patients were divided into two groups - those who used CAM together with SGLT-2is and those who used only CAM. CBF was assessed by thrombolysis in myocardial infarction (TIMI) frame counting. RESULTS: Two hundred eighty-eight patients who had T2DM and met the inclusion criteria were included in our study. The patients were divided into two groups - those who used CAM together with SGLT-2is (n = 75) and those who used only CAM (n = 213). The median age in the group that used CAM together with SGLT-2is was 55 (51-64), where 52 (69.3%) patients were female. The mean TIMI frame count (TFC) was 23.5 in the group using CAM + SGLT-2is and 27.5 in the group using only CAM. In the multivariable linear regression analysis, the mean TFC was significantly lower in the group using CAM together with SGLT-2is compared to the group using only CAM [ß-coefficient = -12.766, 95% Cl: -5.304; -3.887, p < 0.001]. Moreover, there was a statistically significant correlation between an increase in BMI and hemoglobin with an increase in the mean TFC [ß-coefficient = 3.018, 95% Cl 0.037-0.175, p = 0.003 and ß-coefficient = 2.316, 95% Cl 0.033-0.405, p = 0.021, respectively]. CONCLUSIONS: We have demonstrated that the use of SGLT-2is improves coronary artery blood flow in patients with T2DM who have normal or nearly normal coronary angiography.

Evaluation of the effect of bun/albumin ratio on in-hospital mortality in hypertensive COVID-19 patients.

OBJECTIVE: The impact of COVID-19 infection still continues all over the world and is an important cause of mortality. The mortality rate due to infection varies between 1-5%. The mortality rate is higher in those with cardiovascular risk factors, especially in cases with hypertension. Some studies have shown that blood urea nitrogen (BUN) and albumin levels are associated with worse prognosis in patients with COVID-19. In our study, we aimed to investigate whether the BUN/albumin (BAR) ratio has an effect on in-hospital mortality in hypertensive COVID-19 patients. PATIENTS AND METHODS: A total of 800 hypertensive COVID-19 patients, (618 of whom were alive and 182 died) were included in our study. Patients with a history of heart failure, malignancy, acute coronary syndrome, and myocarditis were excluded. RESULTS: The median age of the study population was 69 (60-77 IQR) years, and 305 (38%) of these patients were men. There was no statistically significant difference between the patients who died during follow-up and cases that remained alive in terms of comorbidities except chronic obstructive pulmonary disease (COPD) which was significantly lower in surviving group (p=0.014). Multivariable logistic regression analysis revealed that age [OR: 1.04, CI (1.01-1.06); p=0.002], male gender [OR: 1.85, CI (1.13-3.02); p=0.010], lymphocyte count [OR: 0.63, CI (0.40-0.98); p=0.038], SaO2 [OR: 0.82, CI (0.79-0.85); p<0.001] and BAR level [OR: 1.09, CI (1.04-1.16); p=0.001] were independent predictors of in-hospital mortality. ROC analysis yielded that BAR is a better predictor of in-hospital mortality compared to albumin and BUN alone. CONCLUSIONS: BUN, albumin, and BAR levels were found to be reliable predictors of in-hospital mortality in COVID-19 patients, and BAR was also found to be a more reliable predictor than BUN and albumin levels. Hypertension is one of the major risk factors for morbidity and mortality in COVID-19 and, BAR presents additional prognostic data in hypertensive COVID-19 patients that may direct physicians for treatment intensification.

GII.4 human norovirus and G8P[1] bovine-like rotavirus in oysters (Crassostrea gigas) from Argentina.

Bivalve mollusks have been widely recognized as an important source of foodborne virus. The aim of this work was to determine the presence of norovirus (NoV) and rotavirus (RVA) in Pacific cupped oyster (Crassostrea gigas) from Buenos Aires, Argentina. A total of 88 oyster were processed. 7% of pooled samples resulted positive for NoV GII by RT-qPCR. The nucleotide analysis showed that it was closely related to GII.4/Sydney. Regarding RVA, 21% were positive by RT-qPCR targeting the NSP3 gene. RVA from one pool was isolated in cell culture and infective viral particles were evidenced by immunofluorescence. The genotype constellation of RVA/Oyster-wt/Crassostrea gigas_BA/2015/G8P[1] isolated strain was G8-P[1]-I2-R2-C2-M2-A3-N2-T6-E2-H3, which has a bovine-like genome backbone. Notably, RVA possesses an E2 genotype which is different from the characteristic E12 genotype of RVA circulating in animal species from South America. Our findings evidence not only the presence of enteric viruses in oysters from Argentina, but most important the viability of RVA. This result pose the need to implement surveillance programs to prevent potential foodborne viral outbreaks due to the consumption of contaminated shellfish.

Identification of the gamma irradiation dose applied to ground beef that reduces Shiga toxin producing Escherichia coli but has no impact on consumer acceptance.

The aims of the present study were: a) to estimate the minimal dose of gamma irradiation required to reduce 5 log CFU/g of native O157 and non-O157 Shiga toxin-producing Escherichia coli population in ground beef samples inoculated with high inoculum; b) to assess its effectiveness in samples with low inoculum and 3) to evaluate consumer acceptance. Based on the results, 1 kGy was estimated as the minimal dose of gamma irradiation required to reduce 5 log CFU/g of STEC in ground beef. However, when samples with low inoculum level were subjected to 1 kGy, 3.9% of the samples were positive for stx and eae genes after an enrichment step. Consumer acceptance analysis was carried out with samples subjected to 2.5 kGy and no significant differences were found between irradiated and control samples. Therefore, 2.5 kGy was identified as the gama irradiation dose that reduces STEC but has no impact on consumer acceptance of ground beef.

Food allergy phenotypes: The key to personalized therapy.

Food allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non-IgE-mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE-mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies.

Nineteen-year-old female with idiopathic thrombosis of the internal jugular vein.

Internal jugular vein thrombosis is a rarely seen condition which may be due to infection or neoplastic, thrombophilic, traumatic or iatrogenic causes. If the thrombosis in the jugular vein leads to pulmonary embolism, septic emboli or atrial or dural sinus thrombosis, it may be life-threatening. We report a successfully treated case of a 19-year-old female patient presenting with swelling and neck pain who was diagnosed with a stepwise approach of this rare condition.

A clinical trial on absorption and N-acetylation of oral and rectal mesalazine.

BACKGROUND: Mesalazine (5-ASA) is a standard treatment for ulcerative colitis. Extent of absorption and N-acetylation determine systemic exposure to 5-ASA, and are thereby relevant for the safety of the treatment. The aim of the study was to compare absorption and N-acetylation of 5-ASA following rectal or oral drug administration. Healthy subjects were compared to patients with ulcerative colitis to evaluate the impact of chronic inflammation of colorectal mucosa on disposition of 5-ASA. MATERIALS AND METHODS: First, 12 healthy adults were randomized to receive 2 g of 5-ASA by each of four different formulations: oral delayed release granules, 30 mL enema, 60 mL rectal foam, and 120 mL rectal foam. Second, 12 patients with active ulcerative colitis received 60 mL rectal foam. Pharmacokinetic analysis was performed by determination of 5-ASA and its acetylated, pharmacologically inactive metabolite (Ac-5-ASA) in plasma and urine. RESULTS: First, systemic exposure to 5-ASA was markedly lower after rectal drug administration as compared to oral dosing (P < 0.001; e.g. median relative bioavailability of 60 mL rectal foam: 36%). Second, N-acetylation of rectal 5-ASA was lower in patients than in healthy subjects [area under the curve (AUC) ratio Ac-5-ASA/5-ASA: 1.6 +/- 0.5 vs. 2.3 +/- 0.4, mean +/- SD, P < 0.01]. High peak plasma concentrations of 5-ASA were correlated with high microscopic disease activity (r = 0.67, P < 0.05). CONCLUSIONS: Rectal delivery of 5-ASA results in low systemic drug exposure with potentially reduced toxicity in comparison with oral drug administration. Chronic inflammation of colorectal mucosa might be a relevant source of variability in pharmacokinetics of 5-ASA.

Arylpropanolamines: selective beta3 agonists arising from strategies to mitigate phase I metabolic transformations.

Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.

BMS-201620: a selective beta 3 agonist.

A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.

Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)

BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

Relation of vascular oxidative stress, alpha-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters.

A model of early atherosclerosis in hamsters with moderate hypercholesterolemia (217 to 271 mg/dL) was established that was highly responsive to exogenous antioxidants. A key feature of this model was elevation of vascular oxidative stress by use of a diet deficient in nutritional antioxidants and supplemented with corn oil (10%) and cholesterol (0.2%, 0.4%, or 0.8%). After 10 weeks on the 0.4% cholesterol diet, mean plasma alpha-tocopherol levels declined from 5.68 +/- 0.30 to 1.27 +/- 0.15 micrograms/mL, while monocyte-macrophage foam cell lesions in the aortic arch, as assayed by video microscopy/image analysis of oil red O-stained histological specimens, increased from undetectable at week 0 to 60,900 +/- 5400 microns 2 per specimen at week 10 (mean +/- SEM, n = 36). alpha-Tocopherol or probucol administered for 10 weeks markedly suppressed LDL oxidation ex vivo and profoundly inhibited aortic foam cell formation. However, the effects of antioxidants on aortic lesions were attenuated at higher plasma cholesterol levels, although LDL oxidation ex vivo was effectively inhibited. With a plasma cholesterol level at approximately 250 mg/dL, the maximum effect of alpha-tocopherol on lesion size reached approximately 36% of control value, and the dose for half-maximal effect was approximately 10 mg.kg-1.d-1, which resulted in a plasma alpha-tocopherol value of approximately 20 micrograms/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma alpha-tocopherol concentration was observed (n = 68, r = -0.581, P < .001). The data demonstrate that LDL oxidation is a significant component of early atherogenesis in this model but suggest that hyperlipidemia can outweigh the therapeutic effectiveness of antioxidants. The high sensitivity of aortic lesion initiation to alpha-tocopherol in hamsters maintained on moderately hypercholesterolemic diets depleted of endogenous antioxidants demonstrates that vascular oxidative stress can be isolated from other causative factors in an in vivo model of atherosclerosis.