COVID-19 and HIV/AIDS in a cohort study in Sao Paulo, Brazil: outcomes and disparities by race and schooling.

Studies describing characteristics and outcomes of COVID-19 among people living with HIV are currently limited, lacking detailed evaluation of the interplay among demographics, HIV-related variables, and comorbidities on COVID-19 outcomes. This retrospective cohort study describes mortality rates overall and according to demographic characteristics and explores predictors of admission to intensive care unit and death among 255 persons living with HIV with severe acute respiratory syndrome and confirmed SARS-CoV-2 infection in the State of Sao Paulo, Brazil. We found that the overall mortality rate was 4.1/1,000 person-days, with a case-fatality of 34%. Higher rates occurred among older adults, Black/Mixed skin color/race patients, and those with lower schooling. In a multivariable analysis adjusted for age, sex, CD4 count, viral load and number of comorbidities, skin color/race, and schooling remained significantly associated with higher mortality. Although tenofovir use was more frequent among survivors in the univariable analysis, we failed to find a statistically significant association between tenofovir use and survival in the multivariable analysis. Our findings suggest that social vulnerabilities related to both HIV and COVID-19 significantly impact the risk of death, overtaking traditional risk factors such as age, sex, CD4 count, and comorbidities.

Oropharyngeal microbial ecosystem perturbations influence the risk for acute respiratory infections in common variable immunodeficiency.

Background: The respiratory tract microbiome is essential for human health and well-being and is determined by genetic, lifestyle, and environmental factors. Patients with Common Variable Immunodeficiency (CVID) suffer from respiratory and intestinal tract infections, leading to chronic diseases and increased mortality rates. While CVID patients' gut microbiota have been analyzed, data on the respiratory microbiome ecosystem are limited. Objective: This study aims to analyze the bacterial composition of the oropharynx of adults with CVID and its link with clinical and immunological features and risk for respiratory acute infections. Methods: Oropharyngeal samples from 72 CVID adults and 26 controls were collected in a 12-month prospective study. The samples were analyzed by metagenomic bacterial 16S ribosomal RNA sequencing and processed using the Quantitative Insights Into Microbial Ecology (QIME) pipeline. Differentially abundant species were identified and used to build a dysbiosis index. A machine learning model trained on microbial abundance data was used to test the power of microbiome alterations to distinguish between healthy individuals and CVID patients. Results: Compared to controls, the oropharyngeal microbiome of CVID patients showed lower alpha- and beta-diversity, with a relatively increased abundance of the order Lactobacillales, including the family Streptococcaceae. Intra-CVID analysis identified age >45 years, COPD, lack of IgA, and low residual IgM as associated with a reduced alpha diversity. Expansion of Haemophilus and Streptococcus genera was observed in patients with undetectable IgA and COPD, independent from recent antibiotic use. Patients receiving azithromycin as antibiotic prophylaxis had a higher dysbiosis score. Expansion of Haemophilus and Anoxybacillus was associated with acute respiratory infections within six months. Conclusions: CVID patients showed a perturbed oropharynx microbiota enriched with potentially pathogenic bacteria and decreased protective species. Low residual levels of IgA/IgM, chronic lung damage, anti antibiotic prophylaxis contributed to respiratory dysbiosis.

Towards standardization of canine STRs: a proposed nomenclature for six markers from the ISAG comparison-test panel.

Eight short tandem repeat markers included in the International Society for Animal Genetics panel of 24 loci investigated in canine comparison tests were analysed in a sample of pure-breed dogs, with the purpose of defining an allele nomenclature based on the number of repeats. A regression analysis of the raw data produced by the sequencer, coupled with the direct sequencing of selected alleles, allowed us to propose a system of nomenclature for six of the eight loci (four di-nucleotidic: AHT121, AHTh137, REN169018 and REN64E19, and two tetra-nucleotidic: FH2001 and FH2328). The remaining two loci (INU055 and FH2848) showed a pattern of fragments that did not resolve in a simple allele series. This work may be useful to establish a basis for comparing data across different laboratories for a set of validated canine markers, which can be used in population genetics, forensics and other analyses.

Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome.

Leigh syndrome (LS) is a severe manifestation of mitochondrial disease in children and is currently incurable. The lack of effective models hampers our understanding of the mechanisms underlying the neuronal pathology of LS. Using patient-derived induced pluripotent stem cells and CRISPR/Cas9 engineering, we developed a human model of LS caused by mutations in the complex IV assembly gene SURF1. Single-cell RNA-sequencing and multi-omics analysis revealed compromised neuronal morphogenesis in mutant neural cultures and brain organoids. The defects emerged at the level of neural progenitor cells (NPCs), which retained a glycolytic proliferative state that failed to instruct neuronal morphogenesis. LS NPCs carrying mutations in the complex I gene NDUFS4 recapitulated morphogenesis defects. SURF1 gene augmentation and PGC1A induction via bezafibrate treatment supported the metabolic programming of LS NPCs, leading to restored neuronal morphogenesis. Our findings provide mechanistic insights and suggest potential interventional strategies for a rare mitochondrial disease.

The natural history of prehypertension. A 20-year follow-up.

OBJECTIVE: According to the JNC7 report, prehypertension category includes subjects with systolic blood pressure between 120 and 139 mmHg and/or diastolic blood pressure between 80 and 89 mmHg that would be at risk for developing hypertension and its untoward sequelae as myocardial infarction and cerebrovascular disease. Moreover, ambulatory blood pressure monitoring made it possible to detect subjects with masked hypertension, who are at risk of greater target organ damage than those with normal ambulatory or home blood pressure. The aim of this study was to evaluate the risk of cardiac, cerebral and vascular events in a group of prehypertensive subjects, with and without masked hypertension. PATIENTS AND METHODS: We studied 204 consecutive asymptomatic prehypertensive subjects without history and signs of cardiovascular disease or diabetes. All the subjects underwent clinical evaluation, electrocardiogram, routine laboratory tests and ambulatory blood pressure monitoring. They were followed-up for a maximum of 237 months or until a cardiovascular event occurred. RESULTS: Twenty-seven cardiovascular events (13.2%) occurred, including 4 abdominal aortic aneurysms. Age (p<0.0001), total cholesterol (p=0.004), smoking (p=0.03) and clinically overt hypertension development (p=0.011) were related to cardiovascular events. Prognosis was not related to masked hypertension. CONCLUSIONS: The results of this study suggest that, in subjects with prehypertension, followed for 20 years, traditional cardiovascular risk factors and development of clinically overt hypertension could be more relevant than ambulatory hypertension in the prediction of an adverse outcome.

Probing the topological arrangement of the N- and C-terminal residues of bradykinin for agonist activity at the B1 receptor.

The conformational features of H-Lys-Arg-Ado-Ser-Pro-Phe-OH (Ado = 12-aminododecanoic acid), a des-Arg(9) analogue of Lys-bradykinin, have been determined by high-resolution NMR in the presence of a zwitterionic lipid environment. The analogue is the most active member of a series of analogues designed to probe the topological arrangement of the N- and C-termini required for agonistic activity at the B1 kinin receptor. A novel computational procedure for the utilization of NOE constraints from cis and trans configurational isomers is illustrated. Only with this computational methodology could the structural features of the N-terminus of the peptide be determined. Using radical-induced relaxation of the (1)H NMR signals, we measured the topological orientation of the peptide with respect to the zwitterionic lipid interface. The results indicate that the long, alkyl chain of the Ado amino acid imbeds into the lipid surface. The structural features of the C-terminus of the B1-selective analogue consist of a well-defined turn. Although removed from a standard beta-turn, required for activity at the B2 kinin receptor, the topological orientation of the side chains of the des-Arg(9) compound are surprisingly similar to those previously observed for beta-turn-containing bradykinin analogues. Therefore, we attribute the high B1 receptor selectivity, observed upon removal of Arg(9) from bradykinin, solely to the loss of a charged amino acid and not to altered structural features.

A new class of pseudopeptide antagonists of the kinin B1 receptor containing alkyl spacers.

Four previously reported kinin receptor peptide antagonists, including the B1 receptor-selective peptides desArg10-HOE 140 (H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-OH) and B-9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH), have been modified by replacement of the central tetrapeptide Pro-Hyp-Gly-Xaa with linear alkyl spacers of variable length. The analogue of desArg10-HOE 140 containing the 11-aminoundecanoic acid as spacer, MEN 11575 [H-D-Arg-Arg-NH-(CH2)10-CO-Ser-D-Tic-Oic-OH], was found to be slightly more potent than the unmodified peptide (pA2 = 7.1) as a kinin B1 receptor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover, MEN 11575 is devoid of residual agonist activity at the kinin B1 receptor (rat ileum) and antagonist activity at the kinin B2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by the parent peptide desArg10-HOE 140. Therefore, despite its greatly simplified chemical structure, MEN 11575 shows an improved pharmacological profile in terms of both potency and selectivity, and it represents a good template for the development of new peptidomimetic kinin B1 receptor antagonists. We also report an attempt to investigate the conformational role of the flexible, linear spacer of MEN 11575 and to design more constrained analogues, possibly locked in the bioactive conformation, using semirigid spacers based on Calpha-tetrasubstituted alpha-amino acids of the family of 1-aminocycloalkane-1-carboxylic acids (Acnc).

Treatment of acute liver failure with hemodetoxification techniques.

The exact pathogenesis of hepatic coma is unknown and this fact has stimulated research in the field of hemodetoxification treatment. We studied 31 patients (19 M and 12 F) with acute hepatic failure and used different detoxification techniques such as hemodialysis, hemoperfusion, hemofiltration and plasmaferesis. We evaluated blood tests, degree of coma and serum levels of middle-molecular weight substances (by gel-chromatography) for each patient. Our results show that there was an improvement of consciousness and general clinical state in 40% of patients who underwent HD, in 50% of patients treated with HP, in 37.5% of those treated with PF and 78% of patients treated with HF. Unfortunately, the improvement did not last long. In conclusion we can say that artificial support improves hepatic coma and state of consciousness. This improvement could be due to the better regeneration possibilities of hepatic cells. For this reason hemodetoxification treatment should be started as soon as possible.

[Infected urachal cyst]. / Kyste de l'ouraque surinfecté.

There is a wide variety of pathologies associated with the presence of urachal remnants. We describe a case of infected urachal cyst in a young adult male, with classical symptoms of dysuria, lower abdominal pain, and fever. Ultrasound, cystography and CT are described, ultrasound being often the modality of choice. Differential diagnosis of acute abdominal and pelvic pain or a midline lower abdominal mass at this age should include infection of an urachal remnant.

Our experience with combined hemodialysis-hemoperfusion treatment in chronic uremia.

Hemodialysis can remove only substances that are highly diffusable, non protein bound and with small and middle-molecular weights. The combination of Hemodialysis-Hemoperfusion (HD-HF) takes advantage of both techniques. Uremic patient could reduce the number of weekly dialysis sessions. Fourteen uremic patients were submitted twice a week to a combined HD-HP treatment for 16 months. Polymethacrylate coated charcoal was inserted in the dialysis circuit before the dialyzer. The treatment resulted in improvement of: MNCV (30.5 + -6 to 38.7 + -5.6 m/sec.) subjective symptoms (disappearance of pruritus and insomnia) and hematological status (red blood cells 3.1 x 106 to 4.02 x 106; and hematocrits 28.3 to 36.1). Good control of serum biochemistries. Creatinine and urea clearances of 228 and 236 ml/min respectively. Significant removal of middle-molecules uremic toxins determinated by gel-filtration on Sephadex G15. In conclusion, we state that combined HD-HP improves the detoxication possibilities in chronic uremia.

Five-year trial of dialytic treatment for schizophrenia.

Thirty schizophrenic patients were treated with hemodialysis for 4-36 months. The clinical results were evaluated using two psychiatric scales: the Brief Psychiatric Rating Scale and the Inpatient Multidimensional Psychiatric Scale. In 13 schizophrenic patients psychiatric symptoms disappeared completely, and complete social reintegration followed. Eight patients showed no significant modification of schizophrenic disease after more than 30 dialysis sessions. Nine patients were not considered because their treatment was interrupted during the first month. Dialysis improved the psychotic attitude in one group of schizophrenic patients. The best results were obtained using polyacrylonitrile membranes.

Dialysis treatment in schizophrenia: two years experience.

The authors summarize two years trial of dialysis treatment of schizophrenia. Twenty-five schizophrenic patients were treated with hemodialysis using PAN membranes. The dialysis schedule was: dialyzer; RP 610; blood flow: 250 ml/min; dialysate flow: 500 ml/min; time: 3 hr; vascular access: arteriovenous fistula, femoral vein, antebrachial veins. Dialysis was first performed for three days, repeated after one week, two weeks, three weeks, and one month, and then performed once a month. The drug regimen was never modified or interrupted. The results were evaluated with the Overall and Lorr scale. Nine patients interrupted the treatment early and were not considered; nine patients showed disappearance of psychiatric symptomatology (Overall and Lorr index decreased to 21.8 at 2); non-significant modifications of the main schizophrenic symptoms were observed in seven patients. According to our trial, dialysis with polyacrylonitrile membranes can modify the psychotic attitude in a group of schizophrenic "dialysis responders".

HCV infection in hemodialyzed patients: incidence and correlation with dialytic age.

Hemodialyzed patients mean an high-risk population for hepatitis C infection. Our work was performed to evaluate the incidence of hepatitis C virus (HCV) infection in 51 hemodialyzed patients; the presence of anti-HCV antibodies was studied using the EIA and RIBA test of 1st and 2nd generation. 18 patients (35.29%) showed anti-HCV antibodies with the 1st test; 27 patients (52.94%) showed the presence of anti-HCV antibodies using 2nd generation test. The incidence of test positivity is not related to blood transfusions while it is strictly related with dialytic age. All HCV seropositive patients show antibodies against the c22-3 protein of "virus core". The presence in serum of anti-c22-3 antibodies means that in these patients, there is viral replication.

Absence of histological malignancy in a patient cohort with follicular lesions on fine-needle aspiration.

Follicular lesions account for 4-6% of all thyroid fine-needle aspiration (FNA) cytologies. To date, no cytological criteria exist to distinguish follicular adenoma from carcinoma. For this purpose, histological evaluation after surgical exeresis is required. From 1993 to 2000 we performed 1,238 US-assisted FNA biopsies in patients admitted to our unit for uni- or multi-nodular goiters. In the latter goiters, FNA was performed in the dominant nodule. Cytological examination revealed a follicular lesion in 71 patients (5.7%). All patients came from regions of Northern Italy with moderate iodine deficiency. In 48%, the lesion presented as a solitary nodule, while in the other 52% it occurred in the context of a multinodular goiter. Surgical exeresis of the neoplasm was recommended in all cases. Sixty-three patients (89%) underwent surgery (Group 1) while the other 8 patients (11%) opted for follow-up (Group 2). In Group 2, the mean nodule volume (3.2 +/- 0.5 ml) at baseline was slightly smaller (p = 0.08) than that found in Group 1 (5.4 +/- 0.7 ml). In Group 1, histological examination after surgery showed a follicular adenoma in 52 patients (83%) and a colloid goiter in the others (17%). No malignancy was detected. Group 2 underwent a median follow-up of 46 months (range 24-96 months) on L-thyroxine suppressive regimen (dose range 75-125 pg/day), with TSH levels ranging from 0.1 to 0.3 mlU/l. Throughout the follow-up, no patient developed clinical or ultrasonographic features that could be considered worrisome for malignancy; thus, no further biopsy was performed. However, an overall slight increase (median +5.2%) in nodular volume in respect to baseline was observed. Although institutional and cytological bias cannot be ruled out, our data do not confirm the reported incidence of malignancy in histological specimens of follicular lesions diagnosed on FNA cytology, and prompt us to suggest a less aggressive first-step approach (i.e. careful clinical and instrumental evaluation, and suppressive L-T4 therapy) for these lesions, unless anamnestic reports or clinical and ultrasonographic features of the nodules suggest malignancy.

Genetic alterations in hereditary breast cancer.

Genetic linkage studies have led to the identification of highly penetrant genes as the possible cause of inherited cancer risk in many cancer-prone families. Most women with a family history of breast/ovarian cancer have tumors characterized by alterations in particular genes, mainly BRCA1 and BRCA2, but also CHK2, ATM, STK11 and others. This paper examines the BRCA1 and BRCA2 genes, focusing on the Italian pattern of mutations. The function of these two genes, classified as tumor suppressors, is linked with key metabolic mechanisms such as DNA damage repair, regulation of gene expression and cell cycle control. The pathological BRCA allelic variants may cause alteration of protein function, transcriptional activity and DNA repair; accumulation of the defects leads to widespread chromosome instability that may be directly responsible for cancer formation. In fact, mutations in BRCA1 and BRCA2, conferring a highly increased susceptibility to breast and ovarian cancer, do not lead to cancer by themselves. The current consensus is that these are 'caretaker' genes, which, when inactivated, allow other genetic defects to accumulate. The nature of these other molecular events may define the pathway through which BRCA1 and BRCA2 act. The BRCA mutation spectrum is complex, and the significance of most nucleotide alterations is difficult to understand. Moreover, the mutation pattern seems to be related to ethnicity. The Italian Consortium of Hereditary Breast and Ovarian Cancer has reviewed 1758 families; 23% have been found to be carriers of pathogenetic mutations in BRCA1 or BRCA2. Founder mutations have been described in geographically restricted areas of Italy; a regional founder effect has been demonstrated in Italy for the mutations BRCA1 5083del19 and BRCA2 8765delAG, and a probable new founder mutation has been characterized in Tuscany. The presence of founder mutations has practical implications for genetic testing.