Improved Survival for Patients with Systemic Sclerosis-associated Pulmonary Arterial Hypertension: The Johns Hopkins Registry.

Rationale: To date, it remains unclear whether recent changes in the management of patients with systemic sclerosis-associated pulmonary hypertension (SSc-PH) have improved survival. Objectives: To describe a cohort of patients with SSc-PH and compare their characteristics and survival between the last two decades. Methods: Patients with SSc-PH prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Center Registry were grouped into two cohorts based on the date of diagnostic right heart catheterization: cohort A included patients whose disease was diagnosed between 1999 and 2010, and cohort B included those whose disease was diagnosed between 2010 and 2021. Patients' characteristics were compared between the two cohorts. Measurements and Main Results: Of 504 patients with SSc-PH distributed almost equally between the two cohorts, 308 (61%) had World Symposium on Pulmonary Hypertension group 1, 43 (9%) had group 2, and 151 (30%) had group 3 disease. Patients with group 1 disease in cohort B had significantly better clinical and hemodynamic characteristics at diagnosis, were more likely to receive upfront combination pulmonary arterial hypertension therapy, and had a nearly 4-year increase in median transplant-free survival in univariable analysis than those in cohort A (P < 0.01). Improved transplant-free survival was still observed after adjusting for patients' baseline characteristics. In contrast, for group 2 or 3 patients with SSc-PH, there were no differences in baseline clinical, hemodynamic, or survival characteristics between the two cohorts. Conclusions: This is the largest single-center study that compares clinical characteristics of patients with SSc-PH between the last two decades. Transplant-free survival has improved significantly for those with group 1 disease over the last decade, possibly secondary to earlier detection and better therapeutic management. Conversely, those with group 2 or 3 disease continue to have dismal prognosis.

A journey into the regulatory secrets of the de novo purine nucleotide biosynthesis.

De novo purine nucleotide biosynthesis (DNPNB) consists of sequential reactions that are majorly conserved in living organisms. Several regulation events take place to maintain physiological concentrations of adenylate and guanylate nucleotides in cells and to fine-tune the production of purine nucleotides in response to changing cellular demands. Recent years have seen a renewed interest in the DNPNB enzymes, with some being highlighted as promising targets for therapeutic molecules. Herein, a review of two newly revealed modes of regulation of the DNPNB pathway has been carried out: i) the unprecedent allosteric regulation of one of the limiting enzymes of the pathway named inosine 5'-monophosphate dehydrogenase (IMPDH), and ii) the supramolecular assembly of DNPNB enzymes. Moreover, recent advances that revealed the therapeutic potential of DNPNB enzymes in bacteria could open the road for the pharmacological development of novel antibiotics.

Challenges Facing Viral Hepatitis C Elimination in Lebanon.

Hepatitis C is a hepatotropic virus that causes progressive liver inflammation, eventually leading to cirrhosis and hepatocellular carcinoma if left untreated. All infected patients can achieve a cure if treated early. Unfortunately, many patients remain asymptomatic and tend to present late with hepatic complications. Given the economic and health burdens of chronic hepatitis C infection, the World Health Organization (WHO) has proposed a strategy to eliminate hepatitis C by 2030. This article describes the epidemiology of hepatitis C in Lebanon and highlights the challenges hindering its elimination. An extensive search was conducted using PubMed, Medline, Cochrane, and the Lebanese Ministry of Public Health-Epidemiologic Surveillance Unit website. Obtained data were analyzed and discussed in light of the current WHO recommendations. It was found that Lebanon has a low prevalence of hepatitis C. Incidence is higher among males and Mount Lebanon residents. A wide variety of hepatitis C genotypes exists among various risk groups, with genotype 1 being the most predominant. In Lebanon, many barriers prevent successful hepatitis C elimination, including the absence of a comprehensive screening policy, stigma, neglect among high-risk groups, economic collapse, and a lack of proper care and surveillance among the refugees. Appropriate screening schemes and early linkage to care among the general and high-risk populations are essential for successful hepatitis C elimination in Lebanon.

Interaction network among de novo purine nucleotide biosynthesis enzymes in Escherichia coli.

In human cells, de novo purine nucleotide biosynthesis is known to be regulated through the formation of a metabolon called purinosome. Here, we employed a bacterial two-hybrid approach to characterize the protein-protein interactions network among the corresponding enzymes of Escherichia coli. Our study revealed a dense network of binary interactions that connect most purine nucleotide biosynthesis enzymes. Notably, PurK, an exclusive prokaryotic enzyme, appears as one of the central hubs of this network. We further showed that modifications in PurK, which disrupted several interactions in the network, affected the purine nucleotide pools and altered the bacterial fitness. Our data suggest that the bacterial de novo purine nucleotide biosynthesis enzymes can assemble in a supramolecular complex and that proper interactions among the components of this complex can contribute to bacterial fitness.

Insight into the role of the Bateman domain at the molecular and physiological levels through engineered IMP dehydrogenases.

Inosine 5'-monophosphate (IMP) dehydrogenase (IMPDH) is an ubiquitous enzyme that catalyzes the NAD+ -dependent oxidation of inosine 5'-monophosphate into xanthosine 5'-monophosphate. This enzyme is formed of two distinct domains, a core domain where the catalytic reaction occurs, and a less-conserved Bateman domain. Our previous studies gave rise to the classification of bacterial IMPDHs into two classes, according to their oligomeric and kinetic properties. MgATP is a common effector but cause to different effects when it binds within the Bateman domain: it is either an allosteric activator for Class I IMPDHs or a modulator of the oligomeric state for Class II IMPDHs. To get insight into the role of the Bateman domain in the dissimilar properties of the two classes, deleted variants of the Bateman domain and chimeras issued from the interchange of the Bateman domain between the three selected IMPDHs have been generated and characterized using an integrative structural biology approach. Biochemical, biophysical, structural, and physiological studies of these variants unveil the Bateman domain as being the carrier of the molecular behaviors of both classes.

Serum Cadmium Levels and Risk of Metabolic Syndrome: A Cross-Sectional Study.

The increase in the prevalence of metabolic disorders globally is becoming a public health concern. Previous studies have reported an association between environmental exposures to hazardous substances, including various heavy metals, and the risk for metabolic syndrome. However, reports on the contributions of cadmium (Cd) to the risk for obesity and diabetes remain inconsistent. This study aims to investigate an association between serum Cd levels (SCL) and diabesity and dyslipidemia risk scores. A total of 140 subjects were identified from a public academic institution in Lebanon. Socio-demographic information, diabesity, and obesity risk scores were determined using an interview-based adapted FINDRISC questionnaire and analysis of an acquired blood sample. SCL was quantified using inductively coupled plasma mass spectrometry (ICP-MS). The statistical analysis relied on a chi-squared test and multivariate logistic regression models, along with checks for confounders and effect modifiers. Our results showed a Cd geometric mean of 4.04 µg/L (± 2.5). High SCL was significantly associated with higher dyslipidemia risk (OR: 3.05 [95% CI: 1.19-7.86], P = 0.02), even after adjusting for confounders. However, SCL did not show a statistically significant association with diabetes and obesity outcomes. Elevated SCL increases the risk of dyslipidemia and alters the blood lipid profile. In addition, our findings do not support a role for Cd in diabesity.