Cutaneous Reactions after COVID-19 Vaccines: Analysis of the Clinical and Histopathological Spectrum-Case Series and Review of the Literature.

(1) Background: Various cutaneous adverse drug reactions (ADRs) are observed with the implementation of mRNA COVID-19 vaccines. To gain insight into the clinicopathologic features, we analyzed the correlation of histological and clinical data in 48 patients with these ADRs. (2) Methods: Single-center retrospective study in patients with ADRs after mRNA COVID-19 vaccination (mRNA-1273 and BNT162b2 vaccines).

Diffuse Dermal Angiomatosis of the Breast: A Distinct Entity in the Spectrum of Cutaneous Reactive Angiomatoses - Clinicopathologic Study of Two Cases and Comprehensive Review of the Literature.

Diffuse dermal angiomatosis (DDA) is a rare reactive angioproliferation in the skin and considered to be a subtype in the group of cutaneous reactive angiomatoses. DDA is clinically characterized by livedoid patches and plaques with tender ulceration. Its histologic features are a reactive diffuse proliferation of bland endothelial cells and pericytes within the dermis, forming small capillary vessels.

Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu) receptor negative allosteric modulators.

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck.

Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications.

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore.

4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors: From HTS hit to development candidate.

High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability.

NMR and mass spectrometric characterization of vinblastine, vincristine and some new related impurities--part II.

In the course of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC at the production site. Repeated attempts to isolate and purify these unknown impurities by preparative liquid chromatography yielded small amounts of materials whose main components were the unknown impurities, but were still contaminated with other VLB/VCR-related compounds. In spite of these difficulties, by using a combination of high-resolution (LC-)MS/MS and off-line 1D and 2D ultra high-field NMR techniques and leaning on the relevant spectroscopic data for VLB and VCR as discussed in Part 1 [1], we could unambiguously solve the structures of, and could give a complete spectral characterization for, the trace impurities.

First observation of intrabeam stripping of negative hydrogen in a superconducting linear accelerator.

We report on an experiment in which a negative hydrogen ion beam in the Spallation Neutron Source (SNS) linear accelerator was replaced with a beam of protons with similar size and dynamics. Fractional beam loss in the superconducting part of the SNS accelerator was measured to be at least 2×10(-5) for the H(-) beam, and it was an order of magnitude lower for the protons. Also beam loss has a stronger dependence on intensity with H(-) than with proton beams.

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile.

Buschke-Ollendorff syndrome in a three-generation family: influence of a novel LEMD3 mutation to tropoelastin expression.

Buschke-Ollendorff syndrome refers to the concomitant occurrence of connective tissue nevi, composed of elastic fibers in most cases, with osteopoikilosis. This autosomal dominant inherited disorder is caused by mutations in the gene LEMD3 on chromosome 12q14, which induces a rather heterogeneous clinical phenotype. Here, we report on the most proximal germline mutation found to date in the LEMD3 gene, p.

Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists.

Hit-to-lead optimization of a HTS hit led to new carbamoyloxime derivatives. After identification of an advanced hit (8d) the CYP enzyme inhibitory activity of this class of compounds was successfully eliminated. Systematic exploration of different parts of the advanced hit led us to some promising lead compounds with mGluR5 affinities comparable to that of MPEP.

Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile.

A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.

[Synthesis and NMR structure elucidation of bromocryptine stereoisomers].

We describe for the first time the synthesis and NMR structural characterization of two important but so far ignored diasteroisomers of bromokryptine. During this work we have made some interesting insights regarding the conformational and epimerizational behaviour of these molecules.

Effects of resonances on halo formation in high-intensity storage rings.

Numerical calculations for the Spallation Neutron Source accumulator ring indicate that lattice resonances excited by the space-charge potential can increase a mismatch significantly by deforming the beam distribution in phase space. Hence increased mismatch leads to enhanced envelope oscillations that are driving the 2:1 parametric resonance leading to halo formation, even for initially matched beams. We have observed this behavior for the 2 nu(x) - 2 nu(y) = 0 resonance and for the 4 nu(y) = 23 resonance.

A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function.

The present studies were designed to provide careful measures of effects of oxandrolone, an anabolic steroid, intravenous nutritional supplementation, and the combination of these two treatments on liver functions, metabolic balances, nitrogen metabolism, and nutritional status in patients with moderate to severe alcoholic hepatitis. Of 43 patients originally recruited, 39 (19 men, 20 women) with typical clinical and laboratory features of alcoholic hepatitis (11 Child's-Pugh class B; 28 class C) were admitted to a metabolic unit and completed a 35-day three-phase protocol. Phase I was a 10-day baseline period of observation, during which routine and special quantitative tests of liver function (galactose and antipyrine metabolism), a 7-day elemental balance study, and a 15N, 13C-leucine metabolism study were done.

Prevalence and prediction of osteopenia in chronic liver disease.

To obtain information on the prevalence and clinical and laboratory correlates of osteopenia in patients with chronic liver disease, we measured bone densities and 30 selected laboratory variables in 133 subjects (70 men, 63 women) with liver disease. Thirty-two had alcoholic liver disease, 18 had primary biliary cirrhosis, 16 had primary sclerosing cholangitis, 48 had other forms of cirrhosis (cryptogenic, posthepatic) and 19 had chronic hepatitis or fibrosis without cirrhosis. Bone densities of the lumbar spine and three sites of the proximal femur (neck, Ward's triangle, greater trochanter) were estimated by dual-photon absorptiometry.

Evaluation of patients with portal hypertension.

In order to select the most suitable management of portal hypertension, a full evaluation of the patient is desirable. The aspects studied should include the possible causes of portal hypertension and the disease and function of the liver, as well as the psychosocial aspects of this condition. The usual reason to investigate the presence and causes of portal hypertension is the detection of gastroesophageal varices.

Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. A prospective, randomized trial.

Study Objective: To define the roles of endoscopic variceal sclerosis and distal splenorenal shunt in the prevention of recurrent variceal bleeding in patients with cirrhosis.

Design: A prospective, randomized clinical trial with crossover for those failing therapy. The median follow-up was 61 months.

Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease.

The major biological functions of S-adenosyl-L-methionine (SAMe) include methylation of various molecules (transmethylation) and synthesis of cysteine (trans-sulphuration). A stable double salt of SAMe has been found to be effective in intrahepatic cholestasis. The mechanism of its therapeutic effect is not fully understood but presumably involves methylation of phospholipids.

Ethanol: relative fuel value and metabolic effects in vivo.

A nasogastric formula infusion method was used to evaluate the steady-state fuel value of ethanol relative to that of glucose in eight chronically alcoholic men undergoing a 4- or 5-week balance experiment. Each subject received a maintenance infusion of the formula diet throughout the study. When control formula glucose (week 1) was isocalorically replaced with ethanol [week 2, 30% of kcal; week 3 or 4 (5-week experiment) 40% to 60% of kcal], the following was observed: weight loss; zero energy balance and reduced or negative balances of N, K, P, Mg, and Na; increased urinary urea N and 3-methylhistidine; lowered urinary C-peptide; no change in indirectly or directly measured thermal energy losses; and a blood level related rise in breath and urinary ethanol losses.

Sclerosing cholangitis: palliation with percutaneous cholangioplasty.

Fourteen patients with sclerosing cholangitis underwent percutaneous cholangioplasty and stent placement with balloon-angioplasty and biliary-drainage catheters. There was initial clinical improvement in 13 of the 14 patients; one patient did not improve and died 1 month after the procedure. One of the 13 survivors developed encephalopathy and received a liver transplant 9 months after cholangioplasty; during the 9 months before transplantation, serum bilirubin and alkaline phosphatase levels returned to normal, and pruritus decreased.

A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis.

We performed a controlled trial of peripheral hyperalimentation in moderate and severe alcoholic hepatitis to determine whether improvement in survival and liver function could be obtained. Twelve patients with moderate and 22 with severe alcoholic hepatitis were randomized to 28 days of peripheral parenteral nutrition (PPN) or standard therapy (ST). In the moderate group, six were treated with each therapy.