The Patient Rejection Scale in an Israeli sample: correlations with relapse and physician's assessment.

The Patient Rejection Scale (PRS), which was developed to assess the feelings of rejection that relatives experience toward mental patients, was administered to a sample of 50 family members living with schizophrenic outpatients in Jerusalem, Israel. PRS response distribution was similar to that reported for a New York City sample. Total rejection scores were significantly correlated with a number of demographic variables and with the treating physician's assessment of the degree of rejection, hostility and criticism of the respective family members. Physician's rating of emotional over-involvement did not correlate with PRS scores. Both PRS and treating physician's ratings correlated significantly with course of illness parameters. The findings and their implications are discussed in the context of expressed emotion (EE) research.     

IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients

Intravenous immunoglobulin (IVIg) is used to treat a number of immune-deficiencies and autoimmune diseases. It has been shown that IVIg contains anti-idiotypic antibodies, which explains its immunomodulatory action.In murine models, recent investigations have demonstrated that IVIg can prevent and reduce the affliction by systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and scleroderma. Relevant disease-specific fractions of IVIg were able to reproduce and even enhance the therapeutic effect in a murine model.IVIg treatment before tumor resection in rodents inoculated with melanoma and sarcoma cells dramatically improved the cure rate (50%) in comparison to the control group (0%).In patients affected by SLE, several clinical manifestations responded to IVIg treatment including serositis, hematological manifestations, treatment-resistant nephritis and central nervous system involvement. Similarly, in women with recurrent fetal loss due to APS, IVIg was able to diminish the abortion rate. Vasculitides such as Churg-Strauss' and Wegener's and skin fibrosis in patients affected by scleroderma improved after IVIg treatment. In agreement with in vitro investigations, prolonged survival has been noted in cancer patients treated with IVIg.We suggest that in the presence of a steroid and immunosuppressive-resistant autoimmune disease, IVIg is a rational and safe choice.     

A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

Metal Ions and Chemical Modification Reagents Inhibit the Enzymatic Activity of Lecithin-Dependent Hemolysin from Vibrio parahaemolyticus

Lecithin-dependent thermolabile hemolysin (LDH) is a virulence factor excreted by Vibrio parahaemolyticus, a marine bacterium that causes important losses in shrimp farming. In this study, the function of LDH was investigated through its inhibition by metal ions (Mg²⁺, Ca²⁺, Mn²⁺, Co²⁺, Ni²⁺ and Cu²⁺) and chemical modification reagents: β-mercaptoethanol (βME), phenylmethylsulfonyl fluoride (PMSF) and diethyl pyrocarbonate (DEPC). LDH was expressed in the Escherichia coli strain BL-21, purified under denaturing conditions, and the enzymatic activity was evaluated. Cu²⁺, Ni²⁺, Co²⁺ and Ca²⁺ at 1 mmol/L inhibited the LDH esterase activity by 20–95%, while Mg²⁺ and Mn²⁺ slightly increased its activity. Additionally, PMSF and DEPC at 1 mmol/L inhibited the enzymatic activity by 40% and 80%, respectively. Dose-response analysis showed that DEPC was the best-evaluated inhibitor (IC₅₀ = 0.082 mmol/L), followed by Cu²⁺ > Co²⁺ > Ni²⁺ and PMSF (IC₅₀ = 0.146–1.5 mmol/L). Multiple sequence alignment of LDH of V. parahaemolyticus against other Vibrio species showed that LDH has well-conserved GDSL and SGNH motifs, characteristic of the hydrolase/esterase superfamily. Additionally, the homology model showed that the conserved catalytic triad His-Ser-Asp was in the LDH active site. Our results showed that the enzymatic activity of LDH from V. parahaemolyticus was modulated by metal ions and chemical modification, which could be related to the interaction with catalytic amino acid residues such as Ser153 and/or His 393.     

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.     

Effect of Acute β-blocker Withholding on Ventilatory Efficiency in Patients With Advanced Chronic Heart Failure

BackgroundThis is the first study to examine the effect of acute (24-hour) β-blocker withholding on ventilatory efficiency in patients with advanced chronic heart failure (CHF) during maximal incremental treadmill cardiopulmonary exercise test.Methods and ResultsSeventeen CHF patients were studied either 3 hours after administration of β-blocker (BB_ON) or 27 hours after the last β-blocker ingestion (BB_OFF). The ventilatory efficiency was measured via the slope of the linear relationship between ventilation (V′_E) and carbon dioxide production (V′CO₂) (ie, V′_E/V′CO₂ slope). Measurements were also made at rest, anaerobic threshold (AT), maximal end-tidal pressure for carbon dioxide (P_ETCO_2max), respiratory compensation point (RC), and peak exercise. Compared with BB_ON, the V′_E/V′CO₂ slope was significantly increased during BB_OFF (30.8 ± 7.4 vs. 29.1 ± 5.4, P = .04). At peak exercise, oxygen uptake (V′O₂, 16.0 ± 2.7 vs. 15.6 ± 2.8 mL·kg·min) and V′CO₂ (1458 ± 459 vs. 1414 ± 429 mL/min) were not different between the 2 conditions, whereas V′_E was higher during BB_OFF (49.5 ± 10.7 vs. 46.1 ± 9.6 L/min, P = .04). No differences were noted at AT and RC in V′O₂, V′CO₂, V′_E, V′_E/V′O₂, and V′_E/V′CO₂ ratios during the 2 conditions. At P_ETCO_2max, used to noninvasively estimate the CO₂ set point, V′_E was higher (33.9 ± 7.6 vs. 31.7 ± 7.3 L/min, P = .002) and P_ETCO₂ was lower (37.4 ± 4.8 vs. 38.5 ± 4.0 mm Hg, P = .03), whereas V′CO₂ was unchanged (1079 ± 340 vs. 1050 ± 322 mL/min) during BB_OFF.ConclusionAcute β-blocker withholding resulted in decreased ventilatory efficiency mostly from an increase of V′CO₂-independent regulation of V′_E and less likely from a change in ventilation/perfusion mismatching.     

Echocardiographic Changes in Patients Implanted With a Fully Magnetically Levitated Left Ventricular Assist Device (Heartmate 3)

Background

The Heartmate 3 (HM3) is a Conformiteé Européenne mark–approved left ventricular (LV) assist device (LVAD) with fully magnetically levitated rotor and features consisting of a wide range operational speeds, wide flow paths, and artificial pulse. We performed a hemodynamic-echocardiographic speed optimization evaluation in HM3-implanted patients to achieve optimal LV- and right ventricular (RV) shape.