bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypokalemia as a Surrogate Marker of Severity in COVID 19 Infection
Authors: Bhatnagar Mohit 
Published: May 2021

Abstract
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 &lt;3 mmol/L), hypokalemia (plasma potassium 3-3.5 mmol/L), and normokalemia (plasma potassium &gt;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 &gt; 24/min OR spO2 &lt;94% in room air) and severe (respiratory distress requiring mechanical ventilation- NIV or invasive, respiratory rate &gt; 30/min Or SpO2 &lt;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

Abstract
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 &lt; .001) which was maintained at T2 (38.2 kg/m2 ± 5.9, p &lt; .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 &lt; .001) and T2 (38.6 ng/nl ± 16.0, p &lt; .01), just like insulin which was significantly decreased at T1 (123 pmol/l ± 65, p &lt; .05) and T2 (128 pmol/l ± 64, p &lt; .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 &lt; .01) compared to T1. T0-T2 BMI decrease correlated positively with T0-T2 decreases in leptin (r = .667, p &lt; .001), insulin (rho = .535, p &lt; .001) and increases of adiponectin (r = .412, p &lt; .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

Abstract
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

Abstract
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

Abstract
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.
Circulating LEAP-2 Levels in Adult Growth Hormone Deficiency and Their Relationship With IGF-1
Authors: Vergani Edoardo , Bruno Carmine , Gavotti Cesare , Capobianco Emmanuel , Currò Diego , Mancini Antonio 
Published: May 2021

Abstract
Liver enriched antimicrobial peptide-2 (LEAP-2) is an endogenous antagonist of ghrelin, which acts as an allosteric modulator of growth hormone secretagogue receptors. It is expressed predominantly in liver, followed by kidney, jejunum, duodenum and stomach. Its expression in conditions of metabolic impairment, obesity for instance, may be upregulated, usually pairing with a concomitant reduction in ghrelin secretion. Weight gain and hyperglycaemia seem to be the main trigger factors for LEAP-2 production. Adult growth hormone deficiency (aGHD) is known as a pathological condition characterized by metabolic impairment (insulin resistance, weight gain, increased fat mass, decreased lean mass). To the best of our knowledge, no study in literature deals with the problem of circulating LEAP-2 levels in GHD. Therefore, the primary endpoint of this cross-sectional observational study was to evaluate circulating LEAP-2 levels in GHD in comparison to healthy controls whether the secondary endpoint was to evaluate any possible correlation with IGF-1 and metabolic parameters in such condition.
30 patients were included in the study. Group A included adult GHD: 15 patients, 7 females and 8 males, mean±standard error of the mean (SEM) age 54.6±3.51 years, BMI 29,95±1.63 kg/m2). The etiologies of GHD were empty sella (n=6), idiopathic (n=6), post-surgical hypopituitarism (n=2), pineal cyst (n=1). Group B was formed by controls: 15 patients, 11 females and 4 males, mean±SEM age 40.33±2.61 years, BMI 24.19±1.33 kg/m2. They were evaluated for: serum glucose and insulin, HOMA-index, QUICKI-index, Total/LDL/HDL cholesterol, triglycerides, IGF-1 and LEAP-2 (measured using Human LEAP-2 ELISA kit, Phoenix Pharmaceuticals Inc, according to manufacturer’s instructions).
Circulating LEAP-2 is significantly higher in GHD than in control group (26.98±3.12 vs 18.7±1.9 ng/ml, p=0.03). LEAP-2 levels in our cohort was not influenced by BMI, while a significant direct correlation between LEAP-2 and age was detected in aGHD group. A strong significative inverse correlation between LEAP-2 and IGF-1 was evidenced in aGHD (r2=0.5). Finally, in this group, LEAP-2 inversely correlates with total cholesterol (r2=0.45).
As expected circulating LEAP-2 levels, in a condition of metabolic impairment such as GHD, were higher than controls even if no correlation with BMI was evidenced in our cohort. The inverse correlation between LEAP-2 and IGF-1 in GHD patients may suggest a body adjustment in a worse clinical condition. LEAP-2 may act as a brake for ghrelin production, thus preventing further weight gain and fat mass increase, although losing its secretagogue effect.
Renal (Pro)renin Receptor Contributes to High Fat Diet-Induced Obesity
Authors: Culver Silas Allen , Siragy Helmy M 
Published: May 2021

Abstract
Recently we reported that (Pro)renin receptor (PRR) expression increases in the renal nephron during high fat diet intake. This study evaluated the role of renal PRR in the development of obesity. Eight-week old male mice with inducible nephron specific PRR knockout (KO) and wild type littermate (control) were fed either normal diet (ND, 12%kcal fat) or high fat diet (HFD, 45%kcal fat) for 6 months. KO Mice underwent induction of PRR KO with oral doxycycline 2mg/mL in 2% sucrose water for 12 days prior to starting diet. Compared to ND, HFD increased body weight by 40% (p&lt;0.05) in control mice. In contrast, compared to control mice fed HFD, body weight of induced PRR KO on HFD was reduced by 56% (p&lt;0.05). Total body fat increased by 179% (p&lt;0.05) with HFD compared to ND control mice while it did not increase in PRR KO mice fed HFD. Twenty-four-hour caloric intake was not reduced in KO mice compared to controls while there were significant increases in nocturnal VO2 by 31% and respiratory exchange by 10% (p&lt;0.05) in HFD PRR KO mice compared to HFD fed controls. Unexpectedly, urine glucose excretion significantly increased in PRR KO mice on both ND and HFD. Our results demonstrate that nephron specific PRR KO reduced diet induced obesity and adiposity, while increasing energy expenditure. Future investigations are warranted to elucidate the mechanisms by which renal PRR contributes to the development of obesity.
Polyciliation of GnRH Neurons in Vivo and in Vitro
Authors: Brewer Kathryn M , Bansal Ruchi , Engle Staci E , Antonellis Patrick J , Cummins Theodore R , Berbari Nicolas F 
Published: May 2021

Abstract
Puberty and reproduction are initiated and controlled through the hypothalamic-pituitary-gonadal (HPG) axis. A critical surge of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are released from the anterior pituitary upon release of gonadotrophins from gonadotrophin releasing hormone (GnRH) neurons. Thus, GnRH neurons are key regulators of the HPG axis. GnRH neurons become active when kisspeptin (Kiss1) neuropeptides are released from neurons in the arcuate nucleus. Kiss1 binds to the Kiss1 receptor (Kiss1R), a G-protein coupled receptor (GPCR) which localizes to the primary cilia of GnRH neurons. Loss-of-function mutations of Kiss1R cause hypogonadism in mouse and human models while gain-of-function mutations are associated with precocious puberty. Interestingly, the subset of GnRH neurons that express Kiss1R are observed to be polyciliated, possessing more than one primary cilia, an uncommon property as most neurons only possess a single, primary cilium. The mechanism and conditions leading to GnRH neuron polyciliation are unknown. It is also unclear if multiple cilia impact Kiss1R or other GPCR signaling in these neurons. Here, we utilize cultured mouse primary hypothalamic neurons to begin addressing some of these questions. We have confirmed with qPCR that the ligands GnRH and Kiss1, as well as Kiss1R, are all expressed in these cultures. Surprisingly, when treated with Kiss1 and GnRH ligands we observed a small subset of polyciliated neurons compared to vehicle treated neurons. These observations mirror what is seen during sexual maturation in vivo and suggest that our model system may help elucidate fundamental questions about how ciliary localization of Kiss1r and other GPCRs participate in initiation of puberty and regulation of reproduction. Future studies will focus on the mechanisms of polyciliation and the conditions needed to induce the formation of new cilia in GnRH neurons. Investigating neuronal polyciliation could provide insights into new signaling paradigm in hypogonadism and HPG signaling.
Sex and Genotype Dependent Effects of a Restricted Access Diet in Ghrelin-Deficient Mice
Authors: Prins Karina , Delhanty Patric J , Huisman Martin , Mies Rosinda , McLuskey Anke , Visser Jenny A 
Published: May 2021

Abstract
Ghrelin, a peptide hormone secreted by the stomach, stimulates both appetite and reward signalling. Its deletion in mice results in poor recovery from metabolic challenges, like starvation, but does not affect food intake or body weight. While sex differences in appetite and feeding behavior have been reported, little is known about the role of ghrelin herein. To investigate this, we used a metabolic cage system to continuously monitor responses of ghrelin-deficient (GKO) and wildtype (WT) mice to three different diets. Male and female mice (5 weeks old) were housed individually in a Promethion system (Sable Systems, USA) and provided one of three diets for 9 weeks: RA, continuous chow with restricted access to a Western-style diet (WD; 2h access, 3d/week) in the light phase; CA, continuous access to both diets; CC, continuous chow. Glucose tolerance was assessed at week 7 by IPGTT; food intake (kcal/g bodyweight), energy expenditure and locomotor activity at week 8; body weight and body composition (EchoMRI, USA) at week 9. On access days, RA mice ate up to 60% of their 24h intake during the WD access period. Following WD access GKO RA mice ate less chow than WT RA mice. Intriguingly, this compensatory reduction in food intake by GKO mice occurred at different times for males and females. GKO RA males ate 45% less chow in the dark phase immediately after WD access (p &lt; 0.001). In contrast, this reduction in food intake (30% less) did not occur until the following, non-access, day in GKO RA females (genotype-sex: p &lt; 0.05). Depending on diet, GKO mice showed differential regulation of energy expenditure in the light phase. Energy expenditure was 6–17% higher in GKO than WT mice in the RA group on access days and in the CA group. On non-access days, however, GKO mice in the RA group expended 13% less energy than WT RA mice (p &lt; 0.005). Regardless of diet, locomotor activity in females was greater than in males (p &lt; 0.001). However, GKO females in the RA and CC groups showed a marked 30% reduction in locomotor activity compared to WTs (genotype-sex: p &lt; 0.05). After nine weeks, neither sex nor genotype effects were seen in body weight gain and composition of RA animals. CA females gained 17% more body weight and had a 6.1% higher fat percentage than CA males (both p &lt; 0.001). In the CC group body weight gain did not differ, but GKO females had 3.1% more fat than WT females (genotype-sex: p &lt; 0.01). Glucose tolerance (AUC) was similar in all groups. In conclusion, we demonstrated that ghrelin deficiency changes the response to the three diets in a sex-dependent manner. Especially, restricted access to WD differentially affected food intake timing and locomotor activity of male and female GKO mice. These results add to the growing body of evidence that ghrelin signalling is sexually dimorphic.