The clinical characteristics and outcomes of patients with pulmonary hypertension in association with hyperthyroid state: A systematic review.

BACKGROUND: Pulmonary hypertension (PHTN) may occur in thyroid disorders, especially in hypothyroidism. However, there is increasing evidence of PHTN in hyperthyroidism (HTH). The etiology, clinical course, management, and factors associated with outcomes of PHTN in the setting of HTH are unascertained. This systematic review consolidates available evidence on patients with HTH who developed PHTN. METHODS: We conducted a systematic review on English articles from PubMed, Scopus, and Google Scholar reporting PHTN in patients with hyperthyroidism. Data were analyzed and reported in Microsoft Excel 2020, SPSS version 26, and Jamovi version 1.2. RESULTS: We identified 589 patients with PHTN in the setting of HTH. Etiologies included Grave disease 66.7%), toxic multinodular goiter (TMNG) (16.8%), drug-induced HTH (0.3%), thyroiditis(0.8%), and toxic adenoma(0.1%). Most patients did not receive any specific management for PHTN and were managed by antithyroid treatment (97.4%). Outcomes of PHTN were reported in 181 patients, with a 94% recovery rate. Pulmonary artery pressures (PAP) before and after HTH management ranged from 22.5 to 75 mm Hg and from 24 to 50 mm Hg, respectively. Outcome analysis performed on data from case reports and series with individually identifiable data revealed a 67.6% female preponderance. An estimated 73.5% of the patients had PHTN at the initial presentation of HTH, which was associated with a better resolution rate of PHTN(OR: 12, P-value: 0.048). TRAB was positive in 47% patients with no clinical difference in outcomes. antiTG AB was reported positive in 29.4%, all of whom had an improvement, compared to an 83.3% improvement rate in those with negative antiTG AB. Various etiologies and treatments did not have any significant differences in the outcome of PHTN. CONCLUSIONS: PHTN can be present at the initial diagnosis of HTH, which is associated with better outcomes of PHTN. There is a clear female preponderance in the development of PHTN. However, resolution rates seem to be better in males. Although TRAB is associated with the development of PHTN, it does not seem to affect the outcomes. PHTN in patients with HTH does not need any specific management, with >90% resolution with antithyroid therapy. Whether any specific antithyroid therapy has a better outcome in PHTN needs to be explored prospectively.

The effect of black seed (Nigella sativa) extract on lipid metabolism in HepG2 cells.

Black seed extract stimulates apolipoprotein A-I (apo A-I) gene expression in hepatocytes and intestinal cells in part by elevating peroxisome proliferator-activated receptor α (PPARα) and retinoid X receptor α (RXRα) levels. To explore potential ramifications of these observations, we examined the effects of black seed extract on hepatocyte lipid content and expression of key transcriptional regulators of fatty acid ß-oxidation and lipogenesis in HepG2 cells. PPARα, peroxisome proliferator-activated receptor γ (PPARγ), RXRα, thyroid hormone receptor ß (TRß), sterol-responsive element binding protein 1 (SREBP1), and sterol-responsive element binding protein 2 (SREBP2) levels were measured in black seed extract treated liver-derived HepG2 cells. Black seed extract treatment increased PPARα and RXRα expression and decreased intracellular neutral lipid content. Black seed extract treatment increased TRß expression and activity, and PPARα activity. In contrast, PPARγ, SREBP1 and SREBP2 levels were decreased in black seed extract treated cells. Black seed extract treatment also increased acyl-CoA synthetase long chain family member 5 (ACSL5), peroxisomal acyl-CoA oxidase 1 (ACOX1), and carnitine palmitoyl transferase 1A (CPT-1A) expression, three PPARα-dependent rate-limiting genes that facilitate fatty acid oxidation, similar to fenofibrate. PPARα knockdown reversed the effects of fenofibrate and blackseed on ACSL5, ACOX1, and CPT-1A expression. In conclusion, black seed extract-mediated lipid lowering in HepG2 cells is associated with increased expression of fatty acid oxidation enzymes and PPARα and reduced lipogenic signaling. Thus black seed extract may be potentially beneficial in metabolic diseases such as diabetes, cardiovascular disease, and metabolic syndrome.

Successful use of the sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with renal transplant and diabetes: a case series and literature review.

Management of patients with diabetes and renal transplant could be challenging. Transplant patients use multiple immune suppressants that can worsen or even trigger hyperglycemia. There are no data about the use of the new class of sodium-glucose co-transporter-2 (SGLT-2) inhibitor dapagliflozin in patients with renal transplant and diabetes. CASE SERIES: Four patients, with diabetes, who are attending the diabetes clinic at our institution, are presented here. They were all counseled to be started on dapagliflozin 10 mg to improve diabetes control as they were on multiple agents and not achieving targets. All four patients showed significant improvement in hemoglobin A1c, with no adverse effects on renal parameters and had favorable effect on weight and blood pressure (BP). CONCLUSION: Use of the SGLT-2 inhibitor dapagliflozin in the standard dose of 10 mg helped to achieve satisfactory control with favorable effects on BP and weight with no adverse effects on renal function.

Pregnancy outcomes of early detected gestational diabetes: a retrospective comparison cohort study, Qatar.

OBJECTIVE: To compare pregnancy outcomes in patients with early versus usual gestational diabetes mellitus (GDM). DESIGN: A retrospective cohort study. SETTINGS: The Women's Hospital, Hamad Medical Corporation, Qatar. PARTICIPANTS: GDM women who attended and delivered in the Women's Hospital, between January and December 2016. GDM was diagnosed based on the 2013-WHO criteria. The study included 801 patients; of which, 273 E-GDM and 528 U-GDM. Early GDM (E-GDM) and usual GDM (U-GDM) were defined as GDM detected before and after 24 weeks' gestation, respectively. OUTCOMES: Maternal and neonatal outcomes and the impact of timing of GDM-diagnosis on pregnancy outcomes. RESULTS: At conception, E-GDM women were older (mean age 33.5±5.4 vs 32.0±5.4 years, p<0.001) and had higher body mass index (33.0±6.3 vs 31.7±6.1 kg/m2, p=0.0059) compared with U-GDM. The mean fasting, and 1-hour blood glucose levels were significantly higher in E-GDM vs U-GDM, respectively (5.3±0.7 vs 4.0±0.7 mmol/L, p<0.001 and 10.6±1.7 vs 10.3±1.6 mmol/L, p<0.001). More patients in the U-GDM were managed on diet alone compared with E-GDM (53.6% vs 27.5%, p<0.001). E-GDM subjects gained less weight per week compared with U-GDM (0.02±0.03 vs 0.12±0.03 kg/week, p=0.0274). Maternal outcomes were similar between the two groups apart from a higher incidence of preterm labour (25.5% vs 14.4%; p<0.001) and caesarean section (52.4% vs 42.8%; p=0.01) in E-GDM vs U-GDM, respectively. After correction for covariates; gestational age at which GDM was diagnosed was associated with increased risk of macrosomia (OR 1.06, 95% CI 1.00 to 1.11; p<0.05) and neonatal hypoglycaemia (OR 1.05, 95% CI 1.00 to 1.11; p<0.05). CONCLUSION: Our data support the concept of early screening and treatment of GDM in high-risk patients. More data are needed to examine the optimal time for screening.

Outcomes of type 1 diabetes mellitus in pregnancy; effect of excessive gestational weight gain and hyperglycaemia on fetal growth.

AIMS: To study pregnancy outcomes in patients with type 1 diabetes mellitus (T1DM) and the factors associated with poor outcomes. METHODS: A retrospective study of 110 patients with T2DM who attended our diabetes in pregnancy clinic at the Women's Wellness and Research centre, Doha, between March 2015 and December 2016 and 1419 normoglycaemic controls. RESULTS: There was no difference in age, weight, and BMI between the two groups. The incidence of macrosomia, shoulder dystocia and stillbirth were similar in the two groups while that of pre-term labour, pre-eclampsia, Caesarean section (CS), large for gestational age (LGA), neonatal ICU (NICU) admission and neonatal hypoglycaemia were significantly higher in the T1DM than in the control group. From a multivariate regression analysis, excessive gestational weight gain was associated with increased risk of LGA (OR 4.53; 95% CI [1.42-14.25]). Last trimester HBA1c was associated with increased risk for macrosomia [OR 2.46, 95% CI [1.03-5.86)]; LGA [ OR 3.25, 95% CI [1.65-6.40)]; increased risk for C-section (OR 1.96, 95% CI [1.12-3.45]), and increased risk of NICU admission (OR 2.46, 95% CI [1.04-5.86]). The changes in HBA1C between the first and last trimester HBA1c was associated with a reduction in the risk of LGA [OR 0.46, 95% CI [(0.28-0.75)] CONCLUSION: T1DM in pregnancy is associated with adverse pregnancy outcomes compared to the general population. Reducing gestational weight gain and improving glycaemic control might improve pregnancy outcomes.

A CASE OF HYPERPARATHYROIDISM TREATED WITH CINACALCET DURING PREGNANCY.

OBJECTIVE: Hyperparathyroidism during pregnancy is associated with increased maternal and neonatal complications. Cinacalcet is a calcimimetic medication that is used in the treatment of hyperparathyroidism; its use in pregnancy is limited to a few case reports. METHODS: Case report and literature review. RESULTS: We are reporting on a 37-year-old patient who was admitted to the hospital with dyspnea at 24 weeks gestation. A routine blood test revealed hypercalcemia; corrected calcium level was 3.17 mmol/L, and parathyroid hormone was elevated at 168 pg/mL. The patient was asymptomatic. Following her last delivery 10 years previously, her newborn developed severe tetany and needed treatment with intravenous (IV) calcium. Neck ultrasound was normal. Due to obesity and history of recurrent deep venous thrombosis, neck exploration was not favored. Initial treatment included calcitonin and IV fluids. The aim was to keep her calcium level as normal as possible to avoid any fetal complications. She was started on cinacalcet 15 mg once per day, which was increased later to 15 mg twice daily. By 36 weeks gestation, corrected calcium levels were down to <2.60 mmol/L. The patient was scheduled to deliver via elective cesarean section at 38 weeks, but she presented at 37 weeks in labor pain and delivered via emergency cesarean section. Postdelivery, the neonate calcium levels remained normal. CONCLUSION: During pregnancy, parathyroid surgery is the recommended treatment. Cinacalcet could be one of the options in severe cases of hypercalcemia if surgery cannot be performed. Further studies are needed to examine the safety of cinacalcet in pregnancy.

A pilot study using flash continuous glucose monitoring in patients with type-2 diabetes on multiple anti-diabetic agents during Ramadan.

BACKGROUND: This study aims to examine the incidence of hypoglycaemia, based on activity, during Ramadan in patients with type 2 diabetes mellitus who were on were on three or more anti-diabetic medications. METHODS: Type 2 diabetes patients who fasted during Ramadan and were on three or more anti-diabetic medications were studied for two weeks using flash glucose monitoring. The patients were asked to document all episodes of hypoglycaemia and were classified as active or sedentary according to their daytime activity. RESULTS: The study included 16 patients of whom 10 were active and 6 were sedentary. There were 13 males and 3 females; mean age was 53.4 ±â€¯6.4 years; mean diabetes duration was 15 ±â€¯5.9 years, and mean HbA1C was 7.9 ±â€¯1.3%. Over the two weeks; there were 7.9 episodes of hypoglycaemia recorded per patient; 50% of which were asymptomatic. There was no difference at baseline in age, BMI, HBA1C, diabetes duration, and anti-diabetic medications between the active and sedentary groups. The active group had better glucose control; median blood glucose was (7.1 (5.1-8.5) vs 10.6 (9.6-11.5) mmol p < 0.01), mean estimated HBA1C was (6.2 ±â€¯1.2% vs 8.3 ±â€¯1.0%; p = 0.047). The active group had more episodes of hypoglycaemia compared to the sedentary group (11.6 vs 1.8 hypo episode per patient/two weeks; p = 0.019); most of which were asymptomatic. CONCLUSION: Patients with type 2 diabetes mellitus who are on three or more anti-diabetic medications should be warned about the increased risk of asymptomatic hypoglycaemia during Ramadan. Anti-diabetic medication adjustments during Ramadan should take into account the degree of activity. Flash glucose monitoring system can help patients to fast safely during Ramadan and detect asymptomatic hypoglycaemia.

MicroRNA-122 as a Novel Non-Invasive Marker of Liver Fibrosis in Hepatitis C Virus Patients.

BACKGROUND: Noninvasive evaluation of hepatic fibrosis is a growing scientific effort in medicine and is of particular interest as early diagnosis is important for the timely prevention and treatment of liver fibrosis and cirrhosis. Non-invasive markers of liver fibrosis have recently been developed as an alternative to liver biopsy. Aim of the work: The aim of this study was to assess the diagnostic value of serum microRNA 122 in Egyptian chronic hepatitis C virus infected patients. This may be a useful tool as a non invasive diagnostic test to detect early stages of fibrosis in comparison to 4 non invasive indexes (APRI, Forns, FIB-4, and FI) vs. control and their ability to differentiate between mild and moderate fibrosis stages. METHODS: This study was conducted on 40 chronic hepatitis C patients diagnosed by liver biopsy and PCR and 20 apparently healthy volunteers who served as control group (III). Liver fibrosis was staged according to the METAVIR scoring system and consequently patients were classified in two groups of liver fibrosis: mild fibrosis (I) and moderate fibrosis (II). RESULTS: The mean expression level of microRNA-122 was significantly higher in both patient groups (I and II) as compared to the control group (III) (p < 0.001 for each). While there was no statistically significant difference in serum miR-122 expression level between group I compared to group II, microRNA 122 and 4 non invasive indexes (APRI, Forns, FIB-4, and FI) were statistically significant for prediction of fibrosis. MicroRNA 122 had the best performing ROC curve for prediction of fibrosis followed by APRI, FI, Forns, and FIB-4. The AUROCs ranged from 0.912 for FIB-4 to 1 for microRNA 122. While FIB-4 and Forns were statistically significant in differentiating mild and moderate fibrosis, FIB-4 had a better AUROC than Forns (0.75 and 0.71, respectively). CONCLUSIONS: The study concluded that there was increased expression of mcroiRNA-122 in Egyptian chronic hepatitis C virus (CHCV) infected patients. MicroRNA 122 has a strong potential to serve as one of the novel noninvasive markers of early liver fibrosis.

Induction of apolipoprotein A-I gene expression by black seed (Nigella sativa) extracts.

CONTEXT: Black seed [Nigella sativa L. (Ranunculaceae)] has been shown in animal models to lower serum cholesterol levels. OBJECTIVES: In order to determine if extracts from black seed have any effects on high-density lipoprotein (HDL), we characterized the effects of black seed extract on apolipoprotein A-I (apo A-I) gene expression, the primary protein component of HDL. MATERIALS AND METHODS: Hepatocytes (HepG2) and intestinal cells (Caco-2) were treated with black seed extracts, and Apo A-I, peroxisome proliferator-activated receptor α (PPARα), and retinoid-x-receptor α (RXRα) were measured by Western blot analysis. Apo A-I mRNA levels were measured by quantitative real-time polymerase chain reaction and apo A-I gene transcription was measured by transient transfection of apo A-I reporter plasmids. RESULTS: Extracts from black seeds significantly increased hepatic and intestinal apo A-I secretion, as well as apo A-I mRNA and gene promoter activity. This effect required a PPARα binding site in the apo A-I gene promoter. Treatment of the extract with either heat or trypsin had no effect on its ability to induce apo A-I secretion. Treatment with black seed extract induced PPARα expression 9-fold and RXRα expression 2.5-fold. Furthermore, the addition of PPARα siRNA but not a control siRNA prevented some but not all the positive effects of black seed on apo A-I secretion. DISCUSSION: Black seed extract is a potent inducer of apo A-I gene expression, presumably by enhancing PPARα/RXRα expression. CONCLUSIONS: We conclude that black seed may have beneficial effects in treating dyslipidemia and coronary heart disease.

The effect of black seed (Nigella sativa) extract on FOXO3 expression in HepG2 cells.

Black seed extracts are known to alter cellular metabolism through multiple signaling pathways. Since Forkhead box transcription factor 3 (FOXO3) has a significant role in regulating cellular metabolism, the effect of lipid extracts of black seed (Sativa nigella) on FOXO3 levels and AKT and 5-AMP activated protein kinase α (AMPKα) signaling was measured in HepG2 hepatoma cells. FOXO3 levels, phosphorylation, and nuclear exclusion were measured by Western blot, as were AKT and AMPK expression and activity using phosphorylation-specific antibodies. Apolipoprotein A-I expression, a black seed-responsive gene, was measured by Western blot. Treatment with black seed extract increased FOXO3 phosphorylation and decreased its expression. In contrast to control cells where FOXO3 was located primarily in the nucleus, in black seed-treated HepG2 cells, FOXO3 was localized primarily to the cytoplasm. These changes in FOXO3 phosphorylation, expression, and localization were accompanied by increased AKT activity. Black seed also decreased AMPKα activity but increased AMPKα expression. Lipid extracts from black seeds inhibit FOXO3 activity and thereby modulate the expression of FOXO3-dependent genes.

Endoplasmic reticulum stress in HepG2 cells inhibits apolipoprotein A-I secretion.

AIMS: Endoplasmic reticulum (ER) stress modulates gene expression and has been implicated in causing dyslipidemias. To determine if ER stress may contribute to hypoalphalipoproteinemia through suppression of apo A-I gene expression, human hepatoma cell line Hep G2 was treated with ER stress inducers and the changes in apo A-I gene expression were compared to albumin gene expression. MAIN METHODS: HepG2 cells were treated with tunicamycin (TM) and thapsigargin (TG), two potent inducers of ER stress, and apo A-I and albumin protein levels, mRNA levels, and promoter activity were measured. ER stress was measured using the ER stress-responsive alkaline phosphatase assay and by Western blot quantitation of ER stress markers such as glucose-regulated protein-78 (GRP-78), phosphorylated Jun N-terminal kinase (phospho-JNK), total JNK, phosphorylated eukaryotic initiation factor 2 alpha (phospho eIF2α), and total eIF2α. KEY FINDINGS: TM and TG induced ER stress in HepG2 cells and reduced apo A-I and albumin secretion in a dose-dependent manner. Intracellular albumin levels increased in cells treated with TM and TG while intracellular apo A-I levels decreased. Albumin mRNA and albumin gene promoter activity were reduced in proportion to the decrease in albumin secreted while changes in the apo A-I mRNA levels and promoter activity were modest and did not account for the reduction in apo A-I secretion. SIGNIFICANCE: These results indicate that apo A-I secretion is inhibited by ER stress possibly by affecting cellular degradation pathways. However, ER stress does not affect apo A-I secretion by regulating gene expression.

Induction of apolipoprotein A-I gene expression by glucagon-like peptide-1 and exendin-4 in hepatocytes but not intestinal cells.

OBJECTIVE: Diabetic dyslipidemia is an important risk factor for the development of macrovascular complications. Recent clinical trials suggest that diabetics treated with glucagon-like peptide-1 (GLP-1) have normalized lipid levels, including an increase in plasma high-density lipoprotein cholesterol (HDLc) levels. METHODS: To determine if GLP-1 (7-36 amide) and the GLP-1-like insulinotropic peptide exendin-4 regulate expression of apolipoprotein A-I (apo A-I), the primary anti-atherogenic component of high-density lipoprotein (HDL), HepG2 hepatocytes and Caco-2 intestinal cells, representative of tissues that express the majority of apo A-I, were treated with increasing amounts of each peptide and apo A-I gene expression was measured in the conditioned medium. RESULTS: Apo A-I secretion increased in both GLP-1 and exendin-4-treated HepG2, but not Caco-2 cells, and this was accompanied by similar changes in apo A-I mRNA levels and apo A-I promoter activity. Induction of apo A-I promoter activity by GLP-1 and exendin-4 required an SP1-responsive element. Hepatic ATP binding cassette protein A1 (ABCA1) expression, but not scavenger receptor class B type1 receptor expression was also induced by GLP-1 and exendin-4. CONCLUSIONS: These results suggest that GLP-1- and exendin-4-mediated changes in HDLc are likely due to changes in hepatic expression of apo A-I and ABCA1.

Inhibition of apolipoprotein A-I gene by the aryl hydrocarbon receptor: a potential mechanism for smoking-associated hypoalphalipoproteinemia.

AIMS: Smokers have lower plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) compared with nonsmokers. To determine the molecular basis of this observation, the effect of activation of the aryl hydrocarbon receptor (AhR) on apo A-I gene expression was examined. MAIN METHODS: HepG2 cells were treated with AhR receptor agonists benzo(a)pyrene (BaP) and CAY10465, and AhR receptor antagonist CAY10464 and apo A-I protein, mRNA levels and promoter activity were measured. The effect of nicotine on apo A-I protein secretion was also tested. Using a series or apo A-I gene promoter deletion constructs, a xenobiotic response element (XRE) was identified. KEY FINDINGS: Treatment of HepG2 cells with the AhR receptor agonists BaP and CAY10465, inhibited apo A-I protein synthesis while nicotine, which does not bind AhR had no effect. Benzo(a)pyrene treatment also suppressed apo A-I mRNA and gene promoter activity. Treatment of HepG2 cells with the AhR receptor antagonist CAY10464 reversed the suppressive effect of BaP on apo A-I gene expression. A putative xenobiotic response element (XRE) was identified between nucleotides -325 and -186 (relative to the transcriptional start site, +1). SIGNIFICANCE: These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR.

Effects of resveratrol on acoustic trauma.

OBJECTIVE: The purpose of the study is to test the ability of resveratrol to protect the auditory system from reactive oxygen species (ROS)-mediated noise damage. Oxidative stress is mediated by ROS, which are known to cause cellular and molecular damage. Interfering with this process, using ROS inhibitors/scavengers such as antioxidants has shown promise in protecting specific systems from oxidative damage. Among the antioxidants receiving recent attention is resveratrol, an active component in red wine. Study design and setting Ten Fischer rats were used for this study. The experimental group (n = 5) received 7 weeks of resveratrol treatment (430/microg/kg/day), by gavage, and the control group (n = 5) received normal saline solution by gavage. Baseline auditory brainstem responses (3, 6, 9, 12 and 18 kHz) were determined for both groups. After 21 days, animals were exposed to noise (105 dB, 4500 to 9000 Hz for 24 hours). Postnoise auditory brainstem responses were assessed at 4 recovery time points: immediate, at 3 days, 7 days, and 4 weeks after noise exposure. RESULTS: Results demonstrate that the resveratrol group showed reduced threshold shifts compared with the control group after noise exposure. These shifts were significantly different between groups at 6 and 9 kHz (P < 0.05), corresponding to the region most represented by the frequency of the traumatic noise.Conclusion/significance Initial studies in our laboratory as well as other investigators have shown the importance of specific antioxidant therapy in the prevention of ischemic, noise, and age related hearing loss. The current study demonstrates a protective effect of resveratrol on noise-induced hearing loss.