bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Visceral Fat and Its Correlation With Changes in Metabolic Variables After Bariatric Surgery
Authors: Doval Eduardo , Lopez Susana Reyes , Albarran Alejandra , Sosa Ernesto , Ramirez Claudia , Ferreira Aldo , Espinosa Etual
Published: May 2021

Obesity is a health problem. There is a relationship between visceral adipose tissue (VAT) and various metabolic components. So far the most effective treatment for weight reduction and control of comorbidities is bariatric surgery. After bariatric surgery there is a reduction in VAT and a correlation with better control of metabolic variables would be expected. Objective: To determine the decrease in VAT, calculated by bioimpedance at 3 and 6 months after bariatric surgery and its correlation with changes in metabolic parameters (fasting glucose, HOMA, HbA1c, lipid profile). MATERIAL AND Methods: Patients belonging to the HECMNSXXI Obesity Clinic undergoing bariatric surgery during 2020 who agreed to participate in the study were included. VAT volume was determined before surgery and at 3 and 6 months after the procedure by bioimpedance using the SECA mBCA525 body analyzer. At the same time, biochemical metabolic markers were determined (fasting glucose, HOMA, HbA1c, CT, HDL, LDL, and triglycerides). The results were reported using descriptive statistics. A Pearson or Spearman correlation was carried out according to the distribution of the variables. P <0.05 was taken as significant. Results: Eleven patients with a mean age of 49 ± 7 years were included, 73% of them were women. Their average initial BMI was 42 ± 4 kg/m2. VAT prior to surgery had a mean of 10.6 ± 2.5L for men and 6.4 ± 2.4L for women. Eighty-two percent of the patients fulfilled harmonized criteria for metabolic syndrome. There was a statistically significant decrease in VAT at 3 and 6 months after surgery in both men and women (Baseline 7.5 ± 3L, 3 months 3.8 ± 2.8 L (p <0.001), 6 months 2.5 ± 2 L (p = 0.001). An average decrease in visceral adipose tissue of 57 ± 24% in women and 34 ± 18% in men (p = 0.18) was found 3 months after surgery and 70 ± 22% in women and 60 ± 21% in men (p = 0.53) 6 months after surgery. Laparoscopic one-anastomosis gastric bypass (OAGB) was the type of surgery with the highest percentage of VAT loss at 3 and 6 months, however, this was not statistically significant when compared with Y-Roux Gastric bypass (YRGB). A statistically significant decrease in HbA1c, HOMA, total cholesterol, LDL, and triglycerides levels were found at 3 and 6 months after surgery. However, when correlating the proportion of VAT lost with the metabolic variables, only a significant correlation was found with the HbA1c levels. The higher the proportion of VAT lost, the lower the HbA1c levels (R2 -0.72 p = 0.01). Conclusions: Bariatric surgery produces a statistically significant reduction in visceral adipose tissue from 3 months after surgery. In this study, an inversely proportional correlation was found between the proportion of VAT lost and HbA1c levels.
Diabetes and Insulin Resistance Show Association With Femoral Instead of Abdominal Adipocyte Size in Asian Indians
Authors: Sahlot Rahul , Kumar Anshul , Tiwari Pradeep , Mathur Nitish , Sharma Himanshu , Purwar Naincy , Mathur Sandeep Kumar
Published: May 2021

Objectives: Energy intake exceeding expenditure results in adipogenesis, which consists of adipocyte hyperplasia and hypertrophy. Adipocyte hypertrophy is the pathological hallmark of ‘sick fat’ responsible for the development of insulin resistance and diabetes mellitus. In Asian Indians, who show a thin, fat phenotype, the association of adipocyte hypertrophy in various fat depots with insulin resistance and diabetes is not precisely known. The objective of this study is to find an association between adipocyte size of abdominal and thigh fat depot and certain parameters of diabetes mellitus. Material & Methods: In this cross-sectional analytical study, 172 patients were recruited. Abdominal subcutaneous and visceral fat samples were available of 100 patients (Non-diabetics: 56; Diabetics: 44), whereas thigh fat was analyzed in 72 patients (Non-diabetics: 40; Diabetics: 32). All participants had a BMI of less than 30 kg/m2 to negate the effect of obesity on adipocyte size. Fasting glucose, insulin, HbA1c, lipid profile including triglycerides, and total cholesterol were measured in all participants, and HOMA-IR was calculated. Adipocyte size in biopsied tissue after fixation was measured with the help of Motic Panthera Moticam 5 trinocular microscope (BA210LED) and Adobe Photoshop CC image analysis tool. Results: Mean adipocyte size in abdominal visceral compartment in diabetics and non-diabetics were 16610.3 ± 889.5 um2 and 16129.8 ± 878.5 um2 respectively. Whereas, mean adipocyte size in abdominal subcutaneous fat in diabetics and non-diabetics were 15071.0 ± 1261.1 um2 and 14356.8 ± 1004.7 um2 respectively. Adipocyte size difference of both the abdominal compartments between diabetic and non-diabetic group was statistically non-significant (p= 0.70 & 0.65 in omental and abdominal subcutaneous compartments respectively). Mean adipocyte size of thigh in diabetics and non-diabetics were 13070.2 ± 1416.2 um2 and 9020.1 ± 811.1 um2 respectively and difference between adipocyte size between both groups was statistically significant (p = 0.01). Thigh Adipocyte size in diabetic subgroup was positively correlated with HOMA -IR (r = 0.4, p = 0.02), triglycerides (r= 0.4, p = 0.03), waist circumference (r = 0.32, p = 0.03). On multivariate linear regression analysis HOMA-IR (β= 0.45, p=0.00), triglycerides (β=0.38, p=0.01) and waist circumference (β=0.35, p=0.02) are predictor of increased adipocyte size. Conclusion: We found that thigh adipocyte size was significantly larger in diabetics in comparison to non-diabetics, whereas no such difference was found in the abdominal fat compartment. In diabetic patients’ thigh, adipocyte size was positively correlated with HOMA-IR, waist circumference, and triglyceride levels, underlining the role of peripheral fat depots in the pathogenesis of diabetes type 2.
Effect of Time-Restricted Feeding on Body Weight and Cardiometabolic Risks: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Ruanpeng Darin , Upala Sikarin , Sanguankeo Anawin
Published: May 2021

Introduction: Time-restricted eating (TRE) or time-restricted feeding (TRF), a form of intermittent fasting (IF) when food consumption is restricted to a 4–12 hour window, poses unique possible health benefits that allow the nutrient to work in harmony with circadian rhythm. Whether TRF is effective in weight loss and cardiometabolic profile compare to usual diet is controversial. We conducted a meta-analysis of randomized control trials to investigate the weight and metabolic effects of TRF in humans.

Methods: The systematic review was conducted according to the PRISMA guidelines. The literature search was conducted in MEDLINE, EMBASE, and CENTRAL from database inception to November 30, 2020. The search terms included time restricting feeding, time-restricted eating, periodic fasting, intermittent fasting, and periodic fasting. The eligibility criteria included a randomized controlled trial (RCT) comparing the effect of TRF as an intervention and control diet on weight and cardiometabolic risks in individuals with overweight (BMI 23–26.9 kg/m2 in Asian and 25–29.9 kg/m2 in others) or obesity (BMI≥27 kg/m2 in Asian and ≥30 kg/m2 in others) with study duration of at least 8 weeks. The primary outcome is the change in body weight between preintervention and postintervention. The secondary outcome is the change in total fat mass and lean mass, HDL, LDL, and triglycerides. Pool mean differences (MD) with 95% confidence interval (CI) were calculated for each outcome.

Results: Four articles met the inclusion criteria and were included in this systematic review and meta-analysis. There were 511 participants with BMI 24 kg/m2 and above and aged between 18 and 65. TRF was defined as a 4–8 hours ad-lib unrestricted eating in 24 hours. The control diet was defined as ad-lib eating per usual habits. There was a significant improvement in weight and body composition in the TRF group. The mean weight loss was -2.08 kg (95% CI: -3.49 to -0.68) greater among TRF group. There was a significant total fat mass and lean mass loss in the TRF group with the MD of -1.29 kg (95% CI: -2.04 to -0.54) and -0.59 kg (95% CI: -1.15 to -0.03), respectively. There was no significant change in HDL, LDL, or triglycerides comparing between TRF and control diet.

Conclusion: This systematic review and meta-analysis of RCT showed that TRF with no calories restriction resulted in significant decreased in weight, fat mass, and a slight decreased in total lean mass compared with control diet. Our findings support TRF as an effective lifestyle intervention for weight loss.
Endocrine and Metabolic Comorbidities in Hospitalized Psoriasis Patients in the United States
Authors: Edigin Ehizogie , Eseaton Precious , Shaka Hafeez , Akuna Emmanuel , Asemota Iriagbonse , Asotibe Jennifer Chiagoziem , Williams Dimeji , Velazquez Genaro
Published: May 2021

Introduction: Psoriasis is a chronic immune-mediated, genetic disease manifesting in the skin or joints or both. Studies have shown an association between psoriasis and metabolic syndrome [1]. However, there is a scarcity of studies on metabolic and endocrine co-morbidities of hospitalized psoriasis patients. This study aims to compare the prevalence of metabolic and endocrine co-morbidities in hospitalized psoriasis patients to hospitalized non-psoriasis patients.

Methods: Data were abstracted from the National Inpatient Sample (NIS) 2016 and 2017 Database. NIS is the largest inpatient hospitalization database in the United States. The NIS was searched for hospitalizations for adult patients aged 18 years or above with a principal or secondary diagnosis of psoriasis and those without any diagnosis of psoriasis. Chi-square test was used to compare the prevalence of common metabolic and endocrine comorbidities between psoriasis and non-psoriasis hospitalized patients. Co-morbidities were obtained from secondary diagnoses. We used ICD-10 codes to obtain psoriasis hospitalizations and co-morbidities. STATA, version 16 was used for analysis.

Results: There were over 71 million discharges in the combined 2016 and 2017 NIS database. Out of this, 323,405 hospitalizations had a diagnosis of psoriasis. Psoriasis hospitalizations had a higher prevalence of dyslipidemia (41.8% vs 31.8%, p<0.0001), hypothyroidism (15.6% vs 12.0%, p<0.0001), hyperthyroidism (0.6% vs 0.5%, p=0.0133), type 2 diabetes mellitus (31.1% vs 24.5%, p<0.0001), obesity (24.4% vs 14.3%, p<0.0001), Non-alcoholic fatty liver disease (0.9% vs 0.3%, p<0.0001) and similar prevalence of type 1 diabetes mellitus (0.9% vs 0.9%, p=0.1567) compared to non-psoriasis hospitalizations.

Conclusion: Hospitalized psoriasis patients have a higher prevalence of dyslipidemia, hypothyroidism, hyperthyroidism, type 2 diabetes mellitus, obesity and non-alcoholic fatty liver disease compared to non-psoriasis hospitalized patients. Endocrinology consultation during hospitalization will be helpful in managing these comorbidities in psoriasis patients.

References 1. Gisondi P, Fostini AC, Fossà I, Girolomoni G, Targher G. Psoriasis and the metabolic syndrome. Clin Dermatol. 2018;36(1):21–28. doi:10.1016/j.clindermatol.2017.09.005
Greater Adherence to Treatment After Bariatric Surgery by the Implementation of a Standardized Protocol for Delivering Care
Authors: Maraschin Clara K , Blume Carina A , Telo Gabriela H , Schaan Beatriz D
Published: May 2021

Bariatric surgery reference centers adopt different protocols of postoperative care including vitamins and minerals supplementation, since there is no consensus in the literature supporting the best approach. We sought to assess the impact of implementing a standardized postoperative care protocol on the adherence to a multidisciplinary team follow-up and the use of vitamin and mineral supplementation for one year after bariatric surgery in a tertiary care public hospital. This study compared a retrospective cohort of patients [n=70; usual care (UC)] who had undergone Roux-en-Y gastric bypass (RYGB) between April 2017 and April 2018 with a prospective cohort of patients [n=64; standardized postoperative protocol (SPP)] who had undergone RYGB between May 2018 and May 2019. The protocol included (1) a pre-scheduled calendar for one-year appointments with surgeons, nutritionists, and endocrinologists, (2) a systematic follow-up trough phone calls by a trained nurse, (3) a standardized vitamins/minerals supplementation during one year, and (4) pre-scheduled laboratory assessment. The initial approach started in the day after the surgery, when the nurse explained post-operative procedures and delivered printed material with the information and schedules. Patients received a standard supplementation free of charge (daily multivitamins with minerals, calcium carbonate 1,500 mg/day, vitramin D 20,000 IU/week, and 5,000 µg of intramuscular vitamin B12 if serum levels were lower than 400 pg/mL). This study was approved by the local Ethics Committee (2018-0183). Among the 134 patients, 86.7% were women, 42.4 ± 10.1 years-old, with preoperative body mass index of 48.5 ± 8.2 kg/m². Adherence to the postoperative care (multidisciplinary team follow-up and laboratory analyses) was 96.9% in the SPP and 81.7% in the UC (p = .003). The SPP attended a greater number of appointments (11 ± 2 vs. 7 ± 2, p <.001), showed a lower prevalence of suboptimal vitamin B12 at 3 months (18.7% vs. 39.5%, p = .03), and had a higher serum vitamin D levels at 3, 6, and 12 months (p <.001). Prevalence of vitamin D deficiency (lower than 20 ng/mL) one year after surgery was 1.6% vs. 24.3% (p <.001) in the SPP and UC, respectively. Only 18.3%, 26.8% and 41% of patients were using vitamin D supplements in the UC after 3, 6 and 12 months, respectively. We conclude that the proposed standardized protocol led to a greater adherence to the postoperative bariatric surgery care, adding attendance to appointments and reducing the incidence of vitamin deficiencies. Further cost-effectivity analysis may be needed to evaluate properly the implementation feasibility of the protocol in other centers. Financial support: CNPq, CAPES, FIPE (HCPA)
Impact of Morbid Obesity on Patients With Hypertriglyceridemia Induced Acute Pancreatitis
Authors: Pudasaini Garima , Shaka Hafeez , Ikechukwu Achebe , Asotibe Jennifer Chiagoziem , Tejeda Emmanuel Palomera , Warraich Muhammad Sheharyar , Rashad Essam
Published: May 2021

Introduction: Obesity is reportedly associated with worse outcome in patients with acute pancreatitis (AP). However, AP has varying etiologies. Hypertriglyceridemia induced acute pancreatitis (HTGP) has sociodemographic variations compared to AP from biliary stones or alcohol. This study aimed to determine the impact of obesity on outcomes of patients with HTGP. Methods: This was a retrospective cohort study of the combined Nationwide Inpatient Sample database for 2016 and 2017. Hospital discharges of patients 18 years and over with HTGP were included. This cohort was divided based on presence of comorbid obesity into three groups- patients without obesity, mild-moderate obesity (MMO) (BMI: 30.0 - 39.9) and morbid obesity (MO) (BMI >=40.0). Primary outcome was inpatient mortality. Secondary outcomes included length of hospital stay (LOS), total hospital charges (THC), discharge diagnoses of hypocalcemia, sepsis, septic shock, acute renal failure (AKI) and acute respiratory failure (ARF). Multivariate regression analysis was used to adjust for patients’ sociodemographic factors, Charlson comorbidity index as well as hospital characteristics as confounders. Results: A total of 104,465 hospitalizations were principally for HTGP, accounting for 18.2% of patients with acute pancreatitis during the study period. Of the patients with HTGP, 13.7% and 10.9% of these patients classified as having MMO and MO respectively. Patients with obesity were significantly younger than patients without obesity.

In patients with MO, there was higher odds of mortality (aOR=1.83, 95% CI: 1.090 – 3.083, p=0.022), while there was no difference in mortality in patients with MMO (aOR 1.09 95% CI: 0.609 – 1.940, p=0.777), both compared with patients without obesity. Patients with MO had increased mean LOS of 0.5 days (95% CI: 0.3 – 0.7, p<0.001) as well as increased THC of $3977 (95% CI: 1467 – 6487, p=0.002) compared to those without obesity. There was no difference in mortality, THC and LOS in patients with MMO. Morbidly obese patients also had increased odds of septic shock (aOR=2.27, 95% CI: 1.297 – 3.972, p=0.007), AKI (aOR=1.28, 95% CI: 1.120 – 1.459, p<0.001), and ARF (aOR=1.94, 95% CI: 1.491 – 2.524, p<0.001). Conclusion: Morbid obesity is associated with higher mortality and poor outcomes in patient with hypertriglyceridemia induced pancreatitis.
Insulin Resistance Shows Stronger Correlation With Ectopic Liver Fat Instead of Visceral Fat in Asian Indians
Authors: Garg Umesh Kumar , Mathur Sandeep Kumar , Mathur Nitish , Purwar Naincy , Kumar Anshul , Tiwari Pradeep , Saxena Aditya
Published: May 2021

Introduction: Insulin resistance (IR) is associated with abdominal obesity. Asian Indians have higher insulin resistance at lower abdominal obesity levels as compared to the western population. However, the relative association of various compartments of abdominal fat, i.e., Subcutaneous Fat (SCAT), Visceral fat (VAT), and ectopic Liver Fat, is not very clear. Our study’s objective was to look for the association of abdominal fat composition in Asian Indians with IR level and gender and diabetes status. Methodology: Our study is an analytical cross-sectional study conducted from 2018–2020 at SMS Hospital located in northwest India. 91 subjects were studied during the study period and underwent MRI for SCAT, VAT, and Liver fat estimation. We divided subjects into tertile groups, based on HOMA-IR levels, and statistical analysis for SCAT, VAT, and Lipid fat in each tertile and as a whole group carried out. Similarly, we analysed data in male and female and diabetic and non-diabetic groups, as tertiles and as a whole. Results: Of the recruited subjects 49 were diabetics (M: F=23:26) and 42 were non-diabetic (M: F=12:30). In the overall group, HOMA-IR has a weak positive association with VAT and Liver Fat and a weak negative association with SCAT (R=0.28,0.38 and -0.11, respectively). From tertile1 to tertile3, there was a consistent increase in VAT and Liver fat (119.3, 121.1, 156.6 cm2 and 8.18, 10.02, 10.89% respectively), so that R value increases from -0.24 to 0.21 for VAT and -0.195 to 0.58 for Liver Fat. On the other hand, the SCAT levels were not different and correlation with IR declined from -0.299 to -0.39. On Sex wise analysis negative correlation of SCAT with IR become substantial from tertile1 to tertile3 in both males and females but strong correlation was seen in females (-0.189 to -0.515) though amount of SCAT was not different among tertiles. Both VAT and Liver Fat increased with tertile1 to terrtile3; IR was very strongly correlated with Liver Fat in both the sexes at higher tertiles (0.91 for males and 0.71 for females). In the diabetic group, liver fat was significantly associated with IR at higher tertile (R=0.9). The SCAT was negatively associated with IR, and a further decline in correlation coefficient with each tertile, became significant at 3rd tertile (-0.41) with a weak correlation of IR with VAT. These relations have similar SCAT and Liver fat trends but a strong correlation not seen in the non-diabetic group. Conclusion: Insulin resistance strongly correlated with ectopic liver fat in Asian Indians including diabetics with no gender disparity which became significant at higher tertile. As compared to ectopic liver fat, VAT has only a minor role in development of IR. SCAT has a protective role against IR in both diabetics and non-diabetics.
Severe Hyperlipidemia With LDL Cholesterol of 393 Milligrams per Decilitre After 7 Months of High Fat Ketogenic Diet: A Rare Case Report
Authors: Swaid Bakr
Published: May 2021

Introduction: Ketogenic diet (KD) is now a popular weight-loss diet with other proclaimed health benefits. KD is largely safe in the short-term especially if done under medical supervision to monitor for well-described side effects like hyperlipidemia among others. We report a case of KD-induced drastic elevation in LDL cholesterol.

Clinical Case: An otherwise healthy 41-year-old male with obesity and a BMI of 35.8 kg/m2 followed KD to help with weight loss. His lipid panel 18 months prior to initiation of KD showed total cholesterol (TC) 171 mg/dL (reference <200 preferred), HDL cholesterol (HDL-C) 49 mg/dL (reference >60 preferred), LDL cholesterol (LDL-C) 99 mg/dL (reference <100 optimal), and a triglyceride (TG) 145 mg/dL (reference <200). During his KD journey, he lost 40 pounds and his BMI became 29.5 kg/m2 after seven months. While on KD, he reported more mental clarity, improved sleep quality, higher energy level, and complete resolution of chronic cystic acne. Seven months after starting KD, his lipid panel showed TC 488.7 mg/dL, HDL-C 54.4 mg/dL, LDL-C 393 mg/dL, VLDL-C 41.5 mg/dL, and triglyceride 207.5 mg/dL. Lipid panel was repeated in 2 days to exclude a possible laboratory error but it confirmed the previous result and repeat LDL-C was 380 mg/dL. Fasting plasma glucose (FPG) was 91 mg/dL. HbA1c was normal at 5.0%. Uric acid was elevated at 8.9 mg/dL (reference 3.4–7.0). High sensitivity C-reactive protein was not elevated at 0.13 mg/dL (reference <0.5). Total 25 hydroxy-vitamin D level was normal at 43.9 ng/mL (reference 30–100). CBC, renal function, and liver function tests were all normal. Since the patient declined statin therapy, he was counseled to decrease saturated fat (e.g. animal-based) intake and to liberalize his carbohydrate intake (i.e. 30% of total calorie intake instead of his baseline of 5–10%). Two weeks after doing so, lipid panel was remarkable for TC 371.2 mg/dL, HDL-C 49.7 mg/dL, LDL-C 279.0 mg/dL, VLDL-C 42.26 mg/dL and TG 211.3 mg/dL. Six weeks from the initial lipid panel, repeat testing showed TC 266.2 mg/dL, HDL-C 54.4 mg/dL, LDL-C 190.0 mg/dL, VLDL-C 21.64 mg/dL and TG 108.2 mg/dL. The patient remained without any major symptoms, namely no symptoms of cardiovascular disease.

Conclusion: To the best of our knowledge, our patient had the highest reported KD-induced increase in LDL-C (297% increase) despite normal baseline and no history of familial hypercholesterolemia. Dietary modification alone resulted in 29% decrease in 2 weeks and 52% decrease in six weeks. A limitation to this case report is the lack of lipid panel subfractionation as previous studies showed KD to result in a decrease in small LDL particles (atherogenic) and an increase in large LDL particles (non-atherogenic). More research is needed on the long-term health consequences of KD. Despite guidelines on how to manage KD-induced hyperlipidemia are greatly needed, they are lacking.
Untangling the Heterogeneity of Acquired Generalized Lipodystrophy
Authors: Cavdar Umit , Akinci Baris , Foss de Freitas Maria Cristina , Conjeevaram Hari , Fox David , Fontana Robert , Tayeh Marwan , Frame David , Innis Jeffrey , Walkovich Kelly , Oral Elif A
Published: May 2021

Acquired generalized lipodystrophy (AGL) is characterized by extensive adipose tissue loss, subsequent development of metabolic disease with severe insulin resistance and hypertriglyceridemia and a varying spectrum of autoimmune or immune-dysregulatory features. We recently evaluated twelve patients (8 females, 4 males; age range: 14 - 54 years). The reported onset of fat loss varies from age 2 to 31 years of age but most patients presenting between age 3 and 19 years. The age of diagnosis varies from 4 to 53 years. Clinical panniculitis was reported in 4 patients. Although adipose tissue loss occurred in a generalized fashion, several patients had measured body fat as high as 35 percent on DEXA scans with leptinemia also covering a spectrum from undetectable levels to as high as 6.2 ng/ml. All patients had insulin resistance. Eight patients had diabetes (4 had type 1 diabetes). Dyslipidemia was diagnosed in 11 patients. Hepatic steatosis and/or elevated liver function tests were detected in all subjects. The liver disease was varied and had distinctive characteristics of episodic increases in liver tests in 4 with development of portal hypertension and splenomegaly. These patients had periportal lymphocytic and eosinophilic infiltration on liver biopsies when undertaken during transaminitis and developed portal hypertension, splenomegaly and biliary obstruction while preserving synthetic liver function over time, suggesting that their clinical course may be consistent with nodular regenerative hyperplasia (NRH). Patients also developed a wide range of immune-dysregulatory features including IgA deficiency, common variable immunodeficiency, autoimmune hives, angioedema, eczematous dermatitis, autoimmune hypothyroidism, Graves’ disease, atrophic gastritis, juvenile dermatomyositis, rheumatoid arthritis, polyarthritis, immune thrombocytopenia, cutaneous morphea, lentigo, peripheral T cell lymphoma, graft versus host disease, hemophagocytic syndrome, interstitial lung disease, autoimmune hemolytic anemia, autoimmune colitis, Crohn disease, and periodic fevers. Low complement 4 levels were detected in 5 patients, and 3 had low complement 3 levels. Genetic workup revealed CTLA-4 haploinsufﬁciency in one case and variants of uncertain significance in P4HA3, TTN, TNFRSF13B, and NLRP3 genes in several others. One distinctive patient was heterozygous for a pathogenic LRBA variant. The exact etiology of AGL is unknown and heterogeneity creates a diagnostic challenge. While panniculitis is a distinct initial presentation in some cases, immune dysregulation affecting multiple organs with accompanying NRH may constitute a new subgroup of AGL. Immune check-point perturbation via gremlin mutation may also lead to AGL. Collective review of cases with predetermined clinical and laboratory evaluation criteria may be helpful to describe subgroups of AGL.
Adipocyte-Derived Lactate Potentiates Obesity-Evoked Adipose Macrophage Inflammation
Authors: Hui Xiaoyan Hannah , Feng Tianshi
Published: May 2021

Introduction: Obesity is characterized by mobilization of macrophage inflammation, which represents the major events of obesity-associated adipose tissue inflammation. . On the other hand, lactate accumulation in adipose tissue long been observed. However, whether elevation of lactate plays an essential role in adipose inflammation is not known. In this study, we sought to examine the intermediary role of lactate in macrophage polarization and adipose inflammation upon obesity. Method: Lactate level and activity of lactate dehydrogense (LDH), the key enzyme of lactate production, were measured by biochemical assays. Adipocyte- and macrophage- specific Ldha knock out mice were constructed by cre-LoxP system to study the physiological role of lactate in diet induced obesity. Macrophage polarization and inflammation were examined by western blotting and Q-PCR. Results: Lactate and LDH activity were selectively upregulated in adipose tissues of obese mice. Adipocyte-, but not macrophage-selective deletion of LDHA, led to a significant improvement of adipose inflammation and metabolic dysfunctions. In vitro experiments showed that the lactate promoted M1 polarization through direct interation and inhibition of the PHD2, which subsequently stabilizes HIF-1alpha. In addition, a positive correlation between adipose lactate level and adipose tissue inflammation was found in obese patients. Conclusion: In obese condition, increased production of lactate from adipocytes enhances adipose tissue inflammation by promoting the proinflammatory polarization of adipose macrophages.
Fatty Acids Modify the MicroRNA Content of Exosomes Released by Hypothalamic Astrocytes and the Response of POMC Neurons to These Exosomes
Authors: Collado-Pérez Roberto , García-Piqueres Jorge , Jiménez-Hernaiz María , Argente Jesús , Belsham Denise D , Frago Laura M , Chowen Julie A
Published: May 2021

It is now clear that hypothalamic astrocytes participate in maintaining metabolic homeostasis. Both nutrients and metabolic hormones can directly impact on these glial cells to modify their release of gliotransmitters, metabolic factors, growth factors, etc, as well as their physical interaction with neighboring neurons. Another mechanism by which astrocytes could communicate with neurons is through their release of exosomes. We have previously shown (by RNAseq analysis) that exposure to palmitic acid (PA) dramatically modifies the miRNA content of exosomes released by hypothalamic astrocytes. Here our objectives were: 1) To determine if the miRNA changes in hypothalamic astrocyte-derived exosomes in response to oleic acid (OA) differ from those seen in response to PA and 2) Analyze the response of POMC neurons to exosomes derived from astrocytes exposed to either PA or OA. Primary hypothalamic astrocyte cultures were treated with PA (0.5 mM), OA (0.5 mM) or vehicle (V) for 24 hours. Exosomes were purified from the media and used for miRNA analysis and to treat a POMC neuronal cell line (mHypoA-POMC/GFP-1). Both OA and PA modified miRNA levels in exosomes compared to those detected in V exosomes, but these modifications differed between the two fatty acids. Furthermore, the response of POMC neurons to exosomes from vehicle (E-V), OA (E-OA) and PA (E-PA) treated astrocytes for 24 hours differed significantly. The expression of POMC mRNA was significantly decreased in response to E-V and increased in response to both E-OA and E-PA, although the increase in POMC mRNA was significantly greater in E-PA treated neurons. These results suggest that hypothalamic astrocytes can directly communicate with neurons involved in metabolic control through exosomes and that the messages contained within these exosomes are modulated by the nutrient environment.
Identification of Key Genes and Pathways for Childhood Obesity Using System Biology Approach Based on Comprehensive Gene Information
Authors: Crispim Daisy , Pellenz Felipe Mateus , Assmann Tais Silveira
Published: May 2021

Introduction: Childhood obesity is one of the most important public health issues of the 21st century. Epidemiological studies have suggested that obesity during childhood increases the risk of developing comorbidities, such as type 2 diabetes, later in life. Childhood obesity is a complex disease whose molecular mechanisms are not completely elucidated. In this context, a system biology approach could contribute to the scientific knowledge regarding genetic factors related to childhood obesity onset. Aim: To identify molecular mechanisms involved in childhood obesity by implementing a system biology approach. Methods: Experimentally validated and computationally predicted genes related to Pediatric Obesity (C2362324) were downloaded from the DisGeNET v7.0 database. The protein-protein interaction (PPI) network was constructed using the STRING v11.0 database and analyzed using NetworkAnalyst v3.0 and Cytoscape v3.8.1. The relevance of each node for the network structure and functionality was assessed using the degree method to define hub genes. Functional and pathway enrichment analyses were performed based on Gene Ontology (GO) terms and KEGG Pathways. Results: The search on the DisGeNET database retrieved 191 childhood obesity-related genes. The PPI network of these genes showed 19 hub genes (STAT3, SIRT1, BCL2, IRS1, PPARG, SOCS3, TGFB1, HDAC4, DNMT1, ADCY3, PPARA, NEDD4L, ACACB, NR0B2, VEGFA, APOA1, GHR, CALR, and MKKS). These hub genes were involved in biological processes of lipid storage / kinase activity, regulation of fatty-acid metabolic processes, regulation of pri-miRNA transcription by RNA polymerase II, and negative regulation of small molecules and carbohydrate metabolic processes. In terms of molecular functions, repressing of transcription factors biding was found enriched. Regarding KEGG Pathways, the hub genes are involved with adipocytokine signaling, insulin resistance, longevity regulation, and cytokine signaling pathways. Conclusion: Our approach identified 19 hub genes, which are highly connected and probably have a key role in childhood obesity. Moreover, functional enrichment analyses demonstrated they are enriched in several biological processes and pathways related to the underlying molecular mechanisms of obesity. These findings provide a more comprehensive information regarding genetic and molecular factors behind childhood obesity pathogenesis. Further experimental investigation of our findings may shed light on the pathophysiology of this disease and contribute to the identification of new therapeutic targets.
Hypokalemia as a Surrogate Marker of Severity in COVID 19 Infection
Authors: Bhatnagar Mohit
Published: May 2021

Introduction: Patients with COVID-19 infection present with a variety of clinical symptoms such as fever, diarrhea, dyspnea, anosmia and various electrolyte abnormalities. Hypokalemia is an important electrolyte abnormality associated with infection due to SARS-CoV-2 as it may be associated with life threatening cardiac abnormalities

Objective: To investigate the prevalence and clinical implications of of hypokalemia and its association with disease severity and various laboratory markers of inflammation.

Materials and methods-design, setting and participants: This retrospective study was conducted at Peerless Hospital, Kolkata, West Bengal, India, from March 15, 2020, to September 30, 2020. Participants included patients who received a diagnosis of COVID-19 after testing positive by RT-PCR test and were admitted to the hospital. The patients were classified as having severe hypokalemia (plasma potassium <3 mmol/L), hypokalemia (plasma potassium 3-3.5 mmol/L), and normokalemia (plasma potassium >3.5 mmol/L). We categorized patients into 3 groups of disease severity- mild (fever/uncomplicated upper respiratory tract infection without hypoxemia), moderate (pneumonia with no signs of severe disease, respiratory rate > 24/min OR spO2 <94% in room air) and severe (respiratory distress requiring mechanical ventilation- NIV or invasive, respiratory rate > 30/min Or SpO2 <90% in room air). The clinical features, lab and ECG abnormalities, were compared between the 3 groups. Data analysis was conducted in October 2020.

Interventions: The patients were given general support and antiviral therapy. Their epidemiological and clinical features were collected.

Results: 122 patients(38.4%) had hypokalemia and 58 patients(18.2%) had severe hypokalemia. There was significant association between disease severity and hypokalemia. Fever had significant association with hypokalemia and severe hypokalemia. There was also significant association between dyspnea, anosmia, decreased oxygen saturation, ECG abnormalities and mortality with hypokalemic patients. Also there was significant association between degree of hypokalemia and markers of systemic inflammation such as IL-6 and CRP.

Conclusions: The high prevalence of hypokalemia among patients with coronavirus disease 2019 suggests the presence of disordered rennin angiotensin system activity, which is increased as a result of the reduced counteractivity of angiotensin converting enzyme 2, which is bound by severe acute respiratory syndrome coronavirus. The study also indicates the need to monitor this group of patients for cardiac rhythm disturbances, especially when drugs like hydroxychloroquine and azithromycin, which are known to prolong the QTc interval and are known to reduce the rate of cardiac conduction and cause arrythmias, are used off-label to treat COVID-19.
Improvements in Long-Term Appetite-Regulating Hormones in Response to a Combined Lifestyle Intervention for Obesity
Authors: Kuckuck Susanne
Published: May 2021

Altered levels of hormonal appetite regulators have been observed in obesity (BMI ≥ 30.0 kg/m2), most prominently increases of insulin and leptin (indicating resistance) as well as decreases of adiponectin - all of which are long-term energy regulators and adiposity signals. Disrupted signaling of these hormones may have detrimental effects on metabolism, but may also promote weight gain. Weight loss is often accompanied by normalizations of long-term adiposity signals, but findings concerning short-term appetite regulators after weight loss vary across interventions (e.g. very low calorie diets vs. exercise). Moreover, it is debated whether such weight-loss-induced hormonal changes may reflect a disposition for weight regain. Here, we investigated changes of long- and short-term appetite signals in response to an intensive 75-week combined lifestyle intervention (CLI) comprising a normocaloric healthy diet, physical activity and psychotherapy to promote improved long-term weight management. For 39 patients, data on fasting serum levels of appetite-regulating hormones (leptin, insulin, adiponectin, GIP, PP, PYY, CCK, FGF21) were available. Hormone levels were correlated to BMI at baseline (T0) and compared across three time points: T0, T1 (after 10 weeks; initial weight loss) and T2 (after 75 weeks; weight loss maintenance). T0-T1 hormone changes were correlated to BMI changes between T1 and T2 to investigate whether hormonal alterations during initial weight loss are associated with weight regain. At T0, hormone levels were not associated with BMI. BMI decreased significantly from T0 (40.13 kg/m2 ± 5.7) to T1 (38.2 ± 5.4, p < .001) which was maintained at T2 (38.2 kg/m2 ± 5.9, p < .001). There were no significant changes in GIP, PP, PYY, CCK and FGF21. Leptin decreased from T0 (44.9 ng/nl ± 15.3) to T1 (33 ng/nl ± 14.8, p < .001) and T2 (38.6 ng/nl ± 16.0, p < .01), just like insulin which was significantly decreased at T1 (123 pmol/l ± 65, p < .05) and T2 (128 pmol/l ± 64, p < .05) compared to T0 (160 pmol/l ± 80). Adiponectin did not change between T0 (3.36 ug/ml ± 2.1) and T1 (3.2 ug/ml ± 2.1), but was increased at T2 (3.7 ug/ml ± 2.9, p < .01) compared to T1. T0-T2 BMI decrease correlated positively with T0-T2 decreases in leptin (r = .667, p < .001), insulin (rho = .535, p < .001) and increases of adiponectin (r = .412, p < .01), but no other hormone. T0-T1 hormone changes did not predict T1-T2 BMI changes. Thus, a 75-week CLI was associated with beneficial changes in the long-term energy regulators adiponectin, leptin and insulin, but no changes in short-term appetite-regulating hormones were observed despite significant weight loss. Initial changes in appetite-regulating hormones were not associated with subsequent weight regain. Overall, our data suggest that a CLI does not lead to adverse changes in appetite regulation, but rather long-term improvements such as e.g. increased leptin and insulin sensitivity.
Single-Cell Gene Expression Analysis Reveals Gene Regulatory Networks Driving Proliferation in Pituitary Stem and Endocrine Cells
Authors: Cheung Leonard , Daly Alexandre , Brinkmeier Michelle , Camper Sally Ann
Published: May 2021

A fundamental question for pituitary development and disease is to understand the mechanisms that regulate proliferation, quiescence, and differentiation of stem cells and endocrine lineage-committed precursor cells. Pituitary stem cells, marked by expression of SOX2, are highly proliferative during development and the early postnatal period. This pool becomes quiescent over time, but stem cells retain the ability to re-enter the cell cycle and differentiate into nascent endocrine cells of all lineages in response to physiological demands. The rodent pituitary gland undergoes substantial growth in the postnatal period, and much of this increase in size is due to proliferation of committed progenitors, such as Pou1f1-expressing cells. We performed single-cell RNA transcriptomics analyses of over 8,000 male and female 4-day-old mouse pituitary cells in order to assess stem cell heterogeneity and to identify novel pituitary stem cell biomarkers. We identified a number of factors enriched in pituitary stem cells relative to differentiating cells, including the transcription factors TGIF1 and NR4A3 as well as several members of the nuclear factor I family (NFIA, NFIB, NFIX). We also detected stem cell-specific expression of the cortisol synthesizing enzyme HSD11B1 and folate receptor FOLR1, suggesting novel roles for these pathways in pituitary stem cells. There were few transcriptomic differences between proliferating and non-proliferating stem cells. However, proliferating stem cells and proliferating committed progenitors shared expression of cell-cycle associated genes and novel transcription factors such as BRCA1 and E2F1. Furthermore, single-cell gene network inference and clustering (SCENIC) analyses demonstrated activation of common gene regulatory networks in both proliferating stem and proliferating endocrine populations, including both the E2f1 and Brca1 regulons. RNA velocity, trajectory, and phylogenetic analyses and find that proliferating stem and endocrine cells are likely independent cellular states. Instead, they support the idea that proliferating stem cells become quiescent and transition to committed progenitors that re-enter the cell cycle and then subsequently activate hormone gene expression. In conclusion, our single-cell gene expression analyses of early postnatal pituitary cells have shed light on the developmental trajectory from proliferating stem cell to quiescent differentiated hormone-producing cells.
A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment of Cushing’s Disease
Authors: Paes Ticiana , Van der Pas Rob , Bisschop Peter H , Hofland Leo J , Feelders Richard Abraham
Published: May 2021

Context: The lack of efficacy of octreotide in the medical treatment of Cushing’s disease (CD) may result from suppressive effects of hypercortisolism on somatostatin receptor subtype 2 (SST2) expression by corticotroph adenomas. We previously demonstrated that SST2 mRNA expression levels in corticotroph tumor cells from patients preoperatively treated with cortisol-lowering therapy are significantly higher compared to those from patients with uncontrolled CD at time of surgery. It may be hypothesized that control of cortisol production induced by steroidogenesis inhibitors may reverse SST2 expression and increase efficacy of tumor-directed therapy with octreotide. Objective: To evaluate the efficacy of a sequential strategy of initiation treatment with ketoconazole (KTC) to reduce cortisol levels, followed by octreotide as maintenance therapy in patients with CD. Patients and Design: 14 adult patients with CD were prospectively enrolled. All patients started on KTC (600-800 mg/day), and once cortisol levels were normalized, octreotide 20 mg/4 weeks was initiated which could eventually be increased to 30 mg/4 weeks. After two months of combined therapy, patients were maintained on octreotide monotherapy until the end of the study period (9 months). Treatment success was assessed by the mean of 2 collections of urinary free cortisol (UFC) levels. Results: The mean age of our study population (14 patients) was 48.6 years, 64% (n=8) were female, 85% (n=12) were newly diagnosed and naïve in treatment. Ketoconazole was able to normalize UFC level in 11 (79%) patients. Subsequently, octreotide effectively sustained normal UFC levels in 3 patients (27%) (responders). Four (36%) other patients showed a partial response to octreotide. In 3 patients, normal UFC levels were sustained for one- or two-months following discontinuation of KTC and in the other partial responder, the UFC levels at follow-up decreased by at least 50% of the baseline levels. The remaining 4 (36%) patients developed hypercortisolism as soon as ketoconazole was stopped (non-responders). Responders to octreotide had lower UFC levels at baseline when compared to partial and non-responders (1.40 ± 0.06 vs. 2.05 ± 0.20 ULN, p=0.08). Two of three responders showed improvement in weight, waist circumference, and systolic and diastolic blood pressure during the treatment period. In terms of side effects, one patient discontinued KTC because of gastrointestinal intolerance and 5 patients had a transient increase in liver enzymes. Conclusions: This proof-of-concept study shows that the sequential treatment with ketoconazole to lower cortisol levels followed by octreotide to maintain normal cortisol production seems effective in a subset of patients with mild CD. Ongoing studies aim to evaluate whether this is the result from increased SST2 expression in corticotroph adenomas.
Prevalence of the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in Patients With Brucellosis: A Meta-Analysis
Authors: Mohamed Mouhand F H , Habib Mhd Baraa , Alsaud Arwa , Ahmed Ashraf O
Published: May 2021

Background: Hyponatremia is prevalent amongst hospitalized patients and is associated with adverse outcomes. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. In our experience in a middle eastern country, we observed a relationship between brucellosis and SIADH associated hyponatremia. Nonetheless, there is limited literature describing this association. Thus, we aimed to systematically review the literature and pool the prevalence of SIADH in patients with brucellosis. Methods: We comprehensively searched PubMed, EMBASE, and Google scholar (first 100 hits) for observational studies ascertaining the prevalence of SIADH in brucellosis patients. We had no age, language, or date limitations. We used a proportion meta-analysis utilizing the random-effects model with double arcsine transformation. I2 was used to ascertain heterogeneity. We used MetaXl software for statistical analysis. The protocol was preregistered at PROSPERO. Results: Our search in PubMed and EMBASE retrieved 107 articles, of which only four observational studies were relevant. Aysha et al. conducted the first analysis of 58 brucellosis patients in which 24% had sodium levels of less than 130 mmol/L. We excluded this study from our quantitative synthesis as the SIADH prevalence could not be accurately ascertained. Finally, the quantitative synthesis comprised three studies encompassing 306 patients and revealed a pooled SIADH prevalence of 20% (95% CI 0-52%, I2 96%). The quality assessment revealed low to moderate quality of included studies. Conclusion: The reported prevalence of SIADH in individual studies included in our analysis ranged from 3-56%. The results were heterogeneous, as depicted by a high I2. This varying prevalence is perhaps due to the varying age of included participants, definitions used by the primary studies, and the included data’s observational nature. Nonetheless, our meta-analysis revealed a relatively high prevalence of SIADH of 20% in patients with brucellosis. Hence, hyponatremia in patients with chronic fever should prompt a workup for SIADH and brucellosis, especially in endemic areas for brucellosis. Larger prospective studies are needed to ascertain the exact prevalence of SIADH in this patient cohort and its impact on the overall prognosis.