A Delicate Balance: Challenges in the Management of Primary Hyperparathyroidism and Congestive Heart Failure.

Primary hyperparathyroidism (PHPT) is an excessive parathyroid hormone (PTH) production disorder, causing increased calcium levels. Commonly, these cases are asymptomatic and detected incidentally on routine labs. These patients are usually conservatively managed and monitored periodically, including bone and kidney health evaluation. Medical management of severe hypercalcemia secondary to PHPT includes IV fluids, cinacalcet, bisphosphonates, and dialysis, while the surgical treatment is parathyroidectomy. Patients suffering from heart failure with reduced ejection fraction (HFrEF) on diuretics and PHPT require a delicate balance of their volume status to prevent exacerbation of either condition. In patients with these two comorbidities on the opposite ends of the volume spectrum, it can lead to challenges in managing these patients. We present a case of a woman with repeated hospitalizations due to poor volume status control.  An 82-year-old female with primary hyperparathyroidism (diagnosed 17 years ago), HFrEF due to non-ischemic cardiomyopathy, sick sinus syndrome with a pacemaker, and persistent atrial fibrillation presented to the emergency department with worsening bilateral lower limb swelling for several months. The remaining review of systems was largely negative. Her home medication regimen included carvedilol, losartan, and furosemide. Vitals were stable, and the physical exam revealed bilateral lower extremity pitting edema. Chest x-ray revealed cardiomegaly with mild pulmonary vascular congestion. Relevant labs were NT pro-BNP at 2190 pg/mL, calcium at 11.2 mg/dL, creatinine at 1.0 mg/dL, PTH at 143 pg/mL, and Vitamin D, 25-hydroxy at 48.6 ng/mL. The echocardiogram showed an ejection fraction (EF) of 39%, grade III diastolic dysfunction, severe pulmonary hypertension, and mitral and tricuspid regurgitation. The patient received IV diuretics and guideline-directed treatment for congestive heart failure exacerbation. She was managed conservatively for her hypercalcemia and advised to maintain hydration at home. Spironolactone and Dapagliflozin were added to her regimen, and the Furosemide dose was increased at discharge.  The patient was re-admitted three weeks later with fatigue and decreased fluid intake. Vitals were stable; however, the physical exam revealed dehydration. Pertinent labs were calcium at 13.4 mg/dL, potassium at 5.7 mmol/L, creatinine at 1.7 mg/dL (baseline 1.0), PTH at 204 pg/mL, and Vitamin D, 25-hydroxy at 54.1 ng/mL. Repeat ECHO showed an ejection fraction (EF) of 15%. She was started on gentle IV fluids to correct the hypercalcemia while preventing volume overload. Hypercalcemia and acute kidney injury improved with hydration. She was put on Cinacalcet 30 mg, and home medications were adjusted for better volume control at discharge. This case highlights the complications of balancing the volume status with primary hyperparathyroidism and CHF. Worsening HFrEF resulted in a higher diuretic requirement, thereby worsening her hypercalcemia. With emerging data on the correlation between PTH and cardiovascular risks, it is becoming necessary to assess the risks and benefits of conservative management in asymptomatic patients. Current research has also shown that various patient demographics and comorbidities prevent the surgical management of PHPT. Hence, in suitable candidates, parathyroidectomy must be considered early in patients with asymptomatic hyperparathyroidism.

Blockchain for COVID-19: a comprehensive review.

The rampant and sudden outbreak of the SARS-CoV-2 coronavirus also called COVID-19 and its uncontrollable spread have led to a global crisis. COVID-19 is a highly contagious disease and the only way to fight with it is to follow social distancing and Non-Pharmaceutical Interventions (NPIs). Moreover, this virus is increasing exponentially day-by-day and a huge amount of data from this disease is also generated at the fast pace. So, there is a need to store, manage, and analyze this huge amount of data efficiently to get meaningful insights from it, which further helps medical professionals to tackle this global pandemic situation. Moreover, this data is to be passed through an open channel, i.e., the Internet, which opens the doors for the intruders to perform some malicious activities. Blockchain (BC) emerges as a technology that can manage the data in an efficient, transparent manner and also preserve the privacy of all the stakeholders. It can also aid in transaction authorization and verification in the supply chain or payments. Motivated by these facts, in this paper, we present a comprehensive review on the adoption of BC to tackle COVID-19 situations. We also present a case study on BC-based digital vaccine passports and analyzed its complexity. Finally, we analyzed the research challenges and future directions in this emerging area.

The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis.

BACKGROUND & AIMS: We have previously reported that the mitochondrial dicarboxylate carrier (mDIC [SLC25A10]) is predominantly expressed in the white adipose tissue (WAT) and subject to regulation by metabolic cues. However, the specific physiological functions of mDIC and the reasons for its abundant presence in adipocytes are poorly understood. METHODS: To systemically investigate the impact of mDIC function in adipocytes in vivo, we generated loss- and gain-of-function mouse models, selectively eliminating or overexpressing mDIC in mature adipocytes, respectively. RESULTS: In in vitro differentiated white adipocytes, mDIC is responsible for succinate transport from the mitochondrial matrix to the cytosol, from where succinate can act on the succinate receptor SUCNR1 and inhibit lipolysis by dampening the cAMP- phosphorylated hormone-sensitive lipase (pHSL) pathway. We eliminated mDIC expression in adipocytes in a doxycycline (dox)-inducible manner (mDICiKO) and demonstrated that such a deletion results in enhanced adipocyte lipolysis and promotes high-fat diet (HFD)-induced adipocyte dysfunction, liver lipotoxicity, and systemic insulin resistance. Conversely, in a mouse model with dox-inducible, adipocyte-specific overexpression of mDIC (mDICiOE), we observed suppression of adipocyte lipolysis both in vivo and ex vivo. mDICiOE mice are potently protected from liver lipotoxicity upon HFD feeding. Furthermore, they show resistance to HFD-induced weight gain and adipose tissue expansion with concomitant improvements in glucose tolerance and insulin sensitivity. Beyond our data in rodents, we found that human WAT SLC25A10 mRNA levels are positively correlated with insulin sensitivity and negatively correlated with intrahepatic triglyceride levels, suggesting a critical role of mDIC in regulating overall metabolic homeostasis in humans as well. CONCLUSIONS: In summary, we highlight that mDIC plays an essential role in governing adipocyte lipolysis and preventing liver lipotoxicity in response to a HFD. LAY SUMMARY: Dysfunctional fat tissue plays an important role in the development of fatty liver disease and liver injury. Our present study identifies a mitochondrial transporter, mDIC, which tightly controls the release of free fatty acids from adipocytes to the liver through the export of succinate from mitochondria. We believe this mDIC-succinate axis could be targeted for the treatment of fatty liver disease.

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral-bacterial interactions.

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

Re-purposing 16S rRNA gene sequence data from within case paired tumor biopsy and tumor-adjacent biopsy or fecal samples to identify microbial markers for colorectal cancer.

Microbes colonizing colorectal cancer (CRC) tumors have the potential to affect disease, and vice-versa. The manner in which they differ from microbes in physically adjacent tissue or stool within the case in terms of both, taxonomy and biological activity remains unclear. In this study, we systematically analyzed previously published 16S rRNA sequence data from CRC patients with matched tumor:tumor-adjacent biopsies (n = 294 pairs, n = 588 biospecimens) and matched tumor biopsy:fecal pairs (n = 42 pairs, n = 84 biospecimens). Procrustes analyses, random effects regression, random forest (RF) modeling, and inferred functional pathway analyses were conducted to assess community similarity and microbial diversity across heterogeneous patient groups and studies. Our results corroborate previously reported association of increased Fusobacterium with tumor biopsies. Parvimonas and Streptococcus abundances were also elevated while Faecalibacterium and Ruminococcaceae abundances decreased in tumors relative to tumor-adjacent biopsies and stool samples from the same case. With the exception of these limited taxa, the majority of findings from individual studies were not confirmed by other 16S rRNA gene-based datasets. RF models comparing tumor and tumor-adjacent specimens yielded an area under curve (AUC) of 64.3%, and models of tumor biopsies versus fecal specimens exhibited an AUC of 82.5%. Although some taxa were shared between fecal and tumor samples, their relative abundances varied substantially. Inferred functional analysis identified potential differences in branched amino acid and lipid metabolism. Microbial markers that reliably occur in tumor tissue can have implications for microbiome based and microbiome targeting therapeutics for CRC.

Leveraging sequence-based faecal microbial community survey data to identify a composite biomarker for colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma-carcinoma sequence. Re-analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC. DESIGN: Raw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers. RESULTS: Definitive taxa, including Parvimonas micra ATCC 33270, Streptococcus anginosus and yet-to-be-cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP. CONCLUSIONS: Despite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC.

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

GLP-1 Cleavage Product Reverses Persistent ROS Generation After Transient Hyperglycemia by Disrupting an ROS-Generating Feedback Loop.

The assumption underlying current diabetes treatment is that lowering the level of time-averaged glucose concentrations, measured as HbA1c, prevents microvascular complications. However, 89% of variation in risk of retinopathy, microalbuminuria, or albuminuria is due to elements of glycemia not captured by mean HbA1c values. We show that transient exposure to high glucose activates a multicomponent feedback loop that causes a stable left shift of the glucose concentration-reactive oxygen species (ROS) dose-response curve. Feedback loop disruption by the GLP-1 cleavage product GLP-1(9-36)(amide) reverses the persistent left shift, thereby normalizing persistent overproduction of ROS and its pathophysiologic consequences. These data suggest that hyperglycemic spikes high enough to activate persistent ROS production during subsequent periods of normal glycemia but too brief to affect the HbA1c value are a major determinant of the 89% of diabetes complications risk not captured by HbA1c. The phenomenon and mechanism described in this study provide a basis for the development of both new biomarkers to complement HbA1c and novel therapeutic agents, including GLP-1(9-36)(amide), for the prevention and treatment of diabetes complications.

Joint prognostic effect of obesity and chronic systemic inflammation in patients with metastatic colorectal cancer.

BACKGROUND: Obesity is strongly linked with chronic systemic inflammation, and each has been linked with disease progression and survival in patients with colorectal cancer (CRC). The authors investigated the joint prognostic effects of obesity and circulating cytokines in patients with metastatic CRC (mCRC), an understudied patient group. METHODS: In 242 chemotherapy-naive patients with mCRC, the authors measured a multiplex cytokine panel and abstracted clinicopathological features, height, and weight from medical records. Overall survival (OS) was calculated from the date of mCRC diagnosis until the date of death from any cause and evaluated by Kaplan-Meier analysis and multivariable Cox proportional hazards regression models. Cut points for cytokines were determined by restricted cubic spline regression. RESULTS: In multivariable models, elevated interleukin (IL)-8, IL-2 receptor alpha, and lactate dehydrogenase (LDH) emerged as significant predictors of poor OS (hazard ratio [HR] and 95% confidence interval [95% CI] for above vs below the (referent) knot point: 2.5 [95% CI, 1.7-3.7], 1.9 [95% CI, 1.3-2.7], and 2.2 [95% CI, 1.6-3.1], respectively; all P<.001). Obesity (body mass index ≥30 kg/m(2) ) was not found to be associated with OS, but appeared to modify the relationships observed with IL-8 and LDH, which were associated with a significant 4-fold and 5-fold risk of death, respectively, in obese patients compared with a 2-fold risk of death in nonobese patients (P for interaction of .06 and .04, respectively). Similar results emerged from joint effects analysis, in which obese patients with high IL-8 (or LDH) experienced the highest risk of death. CONCLUSIONS: Although obesity itself was not found to be independently associated with survival in patients with mCRC, the adverse prognostic significance of LDH and IL-8 was found to be enhanced in obese patients.

Hepatoid adenocarcinoma of the peritoneal cavity: Prolonged survival after debulking surgery and 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) therapy.

Hepatoid adenocarcinoma is an alpha-fetoprotein producing adenocarcinoma arising in numerous extra-hepatic organs. The diagnosis may be difficult because of the varied presentation but immunohistochemistries help make the diagnosis. The prognosis is often poor but in this report, we present a young female with hepatoid carcinoma who is doing well more than three years after her diagnosis.

Application of a novel method for assessing cumulative risk burden by county.

The purpose of this study is to apply the Human Security Index (HSI) as a tool to detect social and economic cumulative risk burden at a county-level in the state of Texas. The HSI is an index comprising a network of three sub-components or "fabrics"; the Economic, Environmental, and Social Fabrics. We hypothesized that the HSI will be a useful instrument for identifying and analyzing socioeconomic conditions that contribute to cumulative risk burden in vulnerable counties. We expected to identify statistical associations between cumulative risk burden and (a) ethnic concentration and (b) geographic proximity to the Texas-Mexico border. Findings from this study indicate that the Texas-Mexico border region did not have consistently higher total or individual fabric scores as would be suggested by the high disease burden and low income in this region. While the Economic, Environmental, Social Fabrics (including the Health subfabric) were highly associated with Hispanic ethnic concentration, the overall HSI and the Crime subfabric were not. In addition, the Education, Health and Crime subfabrics were associated with African American racial composition, while Environment, Economic and Social Fabrics were not. Application of the HSI to Texas counties provides a fuller and more nuanced understanding of socioeconomic and environmental conditions, and increases awareness of the role played by environmental, economic, and social factors in observed health disparities by race/ethnicity and geographic region.

Pancreatic cancer and thrombosis. Highlights from the "2010 ASCO Annual Meeting". Chicago, IL, USA. June 4-8, 2010.

Although pancreatic cancer is recognized as a major risk factor for venous thromboembolism, the exact magnitude of the problem is not known. The incidence varies from 17% to 57% depending on different studies. The effect of venous thromboembolism on outcomes in not well defined and there is no known independent predictor of survival. This review is an update from the current American Society of Clinical Oncology (ASCO) Annual Meeting regarding the impact of thrombotic events on the clinical outcomes, the association of tissue factor and thrombotic events, and the primary prevention of venous thromboembolism in pancreatic cancer patients undergoing active treatment.

Medical professionalism in the new millennium: are there intercultural differences? Brief report and commentary.

We hypothesized that differences in premedical and medical indoctrination might lead to demonstrable differences in notions of medical professionalism among U.S. medical schoolgraduates (USMG) and international medical graduates (IMG). We used the previously validated Barry Challenges to Professionalism questionnaire to query applicants to our Medicine residency. Two hundred sixty-six of 1,476 applicants responded; 57 were USMG and 188 IMG were non-U.S. citizens. There were no significant differences in responses based on gender or medical school background (comparing USMG vs IMG). Graduates of U.S. and Canadian schools were more likely than those of Indian schools to answer correctly three of 10 questions. We use the results of this ostensibly "negative" study to comment on the foundations for the hypothesis and logistic difficulty of studying the question.

Fluoropyrimidine-associated cardiotoxicity: revisited.

BACKGROUND: The syndrome of 5-fluorouracil (5-FU)-associated cardiotoxicity remains poorly defined. PATIENTS AND METHODS: We performed a literature review (1969 - 2007) and compiled data derived from 377 evaluable cases out of 448 reported cases. RESULTS: Patient age ranged from 14 to 86 years. Of the patients 65% were 55 years old and the male:female ratio was 1.5:1. The most commonly treated tumors were gastrointestinal (60%), head and neck (22%) and breast (4%). Of the patients 14% had a history of heart disease whereas cardiac risk factors were found in 37%. Mode of administration included: continuous infusion (72%); bolus (22.5%); intermediate infusion (3%); oral (2%); and intraperitoneal (1 patient). The dosages of 5-FU used were < 750 mg/m(2)/day (36%), 751 - 999 (16%), 1,000 (26%), 1,001 - 1,499 (4%) and 1,500 (16%). Of the patients 54% received 5-FU in combination with other chemotherapeutic agents (cisplatin 44%) whereas 51% received 5-FU alone or with leucovorin. Only 4% patients had undergone previous or concomitant radiation therapy to the mediastinum. Of cardiac incidents that happened 69% were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of patients whereas myocardial infarction was seen in 22%, arrhythmias in 23, acute pulmonary edema in 5, cardiac arrest and pericarditis in 1.4 and heart failure in 2. Electro-cardiographic evidence of ischemia or ST-T changes were recorded in 69% of patients, but abnormal cardiac enzymes were found in only 12%. The cardiac symptoms were reproducible in 47%, including in one patient subsequently treated with 5-FU p.o. Symptoms were also elicited when the same patients were treated with lower doses or different schedules. Of the patients 68% responded to conservative anti-anginal therapy, although prophylactic coronary vasodilators had limited efficacy. Overall, 8% of patients showing cardiotoxicity on 5-FU administration died. Furthermore, 13% reexposed to 5-FU died. CONCLUSIONS: Our review suggests that 5-FU cardiotoxicity is an infrequent but real phenomenon that is independent of dose and may be related to a continuous infusion schedule. The presence of cardiac risk factors is not predictive. Patients should be observed closely and 5-FU administration discontinued if cardiac symptoms develop. A rechallenge with 5-FU should be reserved only for those patients in whom there is no reasonable alternative therapy and should be performed in the setting of aggressive prophylaxis and close monitoring.

K-ras mutations in colorectal cancer: a practice changing discovery.

Recent insights into the molecular pathogenesis of colorectal cancer have given rise to specific target-directed therapies, including monoclonal antibodies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These drugs have been approved as second and third line therapies for metastatic colorectal cancer (mCRC). Activating mutations of the K-Ras family of genes are the most common genetic events in tumorigenesis and have been implicated as a predictive factor in determining response to anti-EGFR drugs in pivotal studies. Phase II and III trials, conducted for investigating the role of K-Ras status on anti-EGFR treatment, revealed that patients with wild-type K-Ras had better clinical response in terms of prolonged median progression-free survival and overall response rates when compared to mutant K-Ras. In contrast, patients with mCRC benefit from anti-VEGF treatment irrespective of K-Ras status. Interestingly, a combination of anti-EGFR and anti-VEGF demonstrates no added value in these patients. The studies concluded that pretreatment testing of K-Ras in patients with mCRC offers valuable information in deciding treatment options. There are several molecular methods for mutation detection that seem practical enough to apply in clinical practice. Further confirmatory prospective studies are needed to evaluate the role of K-Ras mutation detections in tumor metastases, early stage CRC, and method of sampling specimens.

Recent advances in management of acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapeutically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to establish use of these newer molecules in pediatric populations.