Fever of unknown origin in a Mediterranean survey from a division of internal medicine: report of 91 cases during a 12-year-period (1991–2002)

Despite the availability of all advanced diagnostic tools, fever of unknown origin (FUO) remains a diagnostic challenge for physicians. The objective was to define, through a retrospective study, the categories of the diseases of Sicilian patients admitted at the Department of Clinical Medicine and Emerging Diseases, University of Palermo, Italy, for classical FUO. Using the registration system for patients admitted from 1991 to 2002, 508 charts of patients admitted because of fever were reviewed. Of these, only 91 patients fulfilled the criteria for classical FUO. The origin of FUO was diagnosed in 62 (68.1%) patients. Infection was the most common cause of FUO with 29 cases (31.8% of total of FUO), neoplasms accounted for 13 cases (14.2%), collagen vascular disease for 11 cases (12.0%), and miscellaneous for 9 cases (9.8%). Undiagnosed FUO were 29 (31.8%) and, of them, 22 cases were followed-up for 2 years. A definite diagnosis could be established only in 8 cases, 13 subjects completely recovered and 4 of them died. In the 73.4% of cases, the FUO have been the result of misleading factors in the diagnostic approaches as made by the physician. The results of our study are similar to those already reported by other authors in other populations, with infections as first, neoplasm as second, and collagen vascular diseases as third most important causes of FUO. In our study the prognosis for undiagnosed FUO cases was good, but a definite diagnosis could be established only in few cases. Therefore, further multicentric, prospective studies of good design are required.     

In vivo regulation of inducible no synthase in immune-mediated liver injury in mice

Inducible nitric oxide synthase (iNOS) has been shown to play an important role in the development of liver injury. iNOS deficiency protects mice from hemorrhage/resuscitation as well as from cytokine-mediated liver injury, for example, after administration of concanavalin A (con A). Here we investigated the in vivo effects of tumor necrosis factor (TNF)-alpha and/or interferon (IFN)-gamma, two mediators of con A-induced liver injury, the TNF receptor (TNFR) usage leading to iNOS expression, and its connection with nuclear factor kappaB (NF-kappaB) activation. In conclusion, iNOS expression in vivo is dependent on both TNF-alpha and IFN-gamma. Although con A-induced liver injury depends on both TNFR1 and TNFR2, TNF-dependent iNOS expression is mediated exclusively by TNFR1 and requires NF-kappaB activation.     

Determinants of cardiopulmonary functional improvement after transcatheter atrial septal defect closure in asymptomatic adults

OBJECTIVES: We sought to evaluate the course of cardiopulmonary function after transcatheter atrial septal defect (ASD) closure and to identify the physiopathologic mechanisms leading to this change. BACKGROUND: Conflicting reports exist on cardiopulmonary functional improvement in asymptomatic adults after transcatheter closure of a secundum ASD. METHODS: Thirty-two consecutive adults (13 males; age 42.6 +/- 16.7 years) underwent maximal cardiopulmonary exercise testing and transthoracic echocardiography both on the day before and six months after transcatheter ASD closure. Mean pulmonary artery pressure, pulmonary to systemic flow ratio (Qp/Qs), and ASD diameter were measured before closure. RESULTS: Peak oxygen uptake (Vo(2)) (p < 0.001), peak oxygen pulse (p = 0.0027), and vital capacity (p = 0.0086) improved after ASD closure, although peak heart rate did not. A significant correlation was found between peak Vo(2) improvements and Qp/Qs (p = 0.0013). Left ventricular ejection fraction (LVEF) (p < 0.0001) and left ventricular end-diastolic diameter (LVEDD) (p < 0.0001) significantly increased after six months, although left ventricular end-systolic diameter did not. Right ventricular long- and short-axis dimensions decreased (both p < 0.0001). Peak Vo(2) and of peak oxygen pulse improvements correlated to both LVEF (p = 0.0009 and 0.0019, respectively) and LVEDD (p < 0.0001 and 0.032, respectively) increments. The decrease of both long- and short-axis right ventricular dimensions positively correlated to both LVEF and LVEDD improvements. The improvement in LVEF correlated to Qp/Qs (p = 0.0026). CONCLUSIONS: Transcatheter ASD closure leads to a significant improvement in cardiopulmonary function within six months, via an increase in peak oxygen pulse. An increase in both left ventricular stroke volume and cardiac output due to a positive ventricular interaction is the mechanism leading to improved peak Vo(2).     

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Na(v)1.7, Na(v)1.8, and Na(v)1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Na(v)1.7 (PN1) in pain pathways. A global Na(v)1.7-null mutant was found to die shortly after birth. We therefore used the Cre-loxP system to generate nociceptor-specific knockouts. Na(v)1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na(v)1.8 locus to generate heterozygous mice expressing Cre recombinase in Na(v)1.8-positive sensory neurons. Crossing these animals with mice where Na(v)1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na(v)1.7 gene, SCN9A. Dominant Na(v)1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na(v)1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.     

Sex incidence of diabetes. An epidemiological study in the la spezia area

Summary The authors studied the relationship between age, year of onset of the disease and sex in 1,428 diabetic subjects. The whole population of the province of La Spezia was used for comparison. As for the M/F ratio, differences of homogeneousness were not observed between the diabetics examined and the population of the province. When the series was subdivided according to the year in which diabetes was diagnosed, it was found that from the five-year period 1950–1954 to the five-year period 1965–1969 the M/F ratio had changed from 0.47 to 0.96. Statistically, this is equivalent to an exponential function.     

Percepção Inadequada do Risco Cardiovascular e Baixo Conhecimento sobre Hipercolesterolemia Familiar em Indivíduos com Hipercolesterolemia Grave

BackgroundIndividuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH).ObjectivesTo assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program.MethodsFrom a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician.ResultsAlthough 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment.ConclusionsAn important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)     

Cognitive Impairment in Multiple Sclerosis: Clinical,Radiologic and Pathologic Insights

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have started to decipher the neuroanatomic substrate of MS‐related cognitive impairment and have shed light onto its pathogenesis. Where radiographic studies have been limited by inadequate resolution or non‐specificity, pathological studies have come to the fore. This review aims to provide an overview of the nature of cognitive impairment typically seen in MS and to explore the literature on imaging and pathological studies relevant to its evolution. In particular, the relative contributions of gray (ie, cerebral cortex, hippocampus, thalamus and basal ganglia) and white matter to MS‐related cognitive impairment will be discussed and the importance of interconnectivity between structures highlighted. The pressing need for longitudinal studies combining standardized neuropsychometric, paraclinical and radiographic outcomes obtained during life with post‐mortem tissue analysis after death is presented.     

Expanding the mutational spectrum of LZTR1 in schwannomatosis

Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.     

Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy

Aims Slow‐release morphine may represent a much‐needed new pharmacological treatment for opioid dependence. Design In a 14‐week randomized, double‐blind, double‐dummy, cross‐over study oral slow‐release morphine was compared with methadone as a treatment for opioid dependency. During two study periods, each consisting of a 1‐week titration and a 6‐week fixed‐dose treatment phase, medication was administered daily under supervised conditions. Setting The study was carried out at the Addiction Clinic, Department of Psychiatry, Medical University Vienna. Participants Sixty‐four subjects (56 males, eight females) with opioid dependence participated in the trial. Measurements Efficacy was evaluated on the basis of retention, use of illicit substances based on urinalysis, extent of drug cravings, withdrawal symptoms and general wellbeing. Safety was assessed on the basis of adverse events and clinical and physical examination. Demographic and baseline characteristics were assessed using the European Addiction Severity Index. Findings Fifty‐five patients (86%) completed the study, with a mean methadone dose of 85 mg and a mean slow‐release morphine dose of 680 mg. No significant differences in retention or use of illicit substances (opioids, benzodiazepines, cocaine) were observed, irrespective of treatment group or medication. However, patients receiving slow‐release morphine had significantly lower depression (P < 0.001) and anxiety scores (P = 0.008) and fewer physical complaints (P < 0.001). Conclusions Oral slow‐release morphine is as effective as methadone in the treatment of opioid dependency, with comparable safety and tolerability and a greater benefit on patient wellbeing. Greater pharmaceutical diversity represents a modern development in mainstream medicine. Slow‐release morphine might represent a future treatment option that will improve long‐term outcomes for this target group.     

Surface Chemistry of Amphiphilic Polysiloxane/Triethyleneglycol‐Modified Poly(pentafluorostyrene) Block Copolymer Films Before and After Water Immersion

New amphiphilic block copolymers Si‐EFSx composed of a poly(dimethyl siloxane) (Si) block and a poly(4‐(triethyleneglycol monomethyl ether)‐2,3,5,6‐tetrafluorostyrene) (EFS) block are synthesized by atom transfer radical polymerization (ATRP) starting from a bromo‐terminated Si macroinitiator. Similarly, new hydrophobic block copolymers Si‐FSy consisting of an Si block and a poly(pentafluorostyrene) (FS) block are prepared for comparison. X‐ray photoelectron spectroscopy (XPS) analysis on block copolymer films reveals that the Si block is concentrated at the polymer–air interface, while the EFS block is located in the layers underneath. The same polymer films undergo a marked surface reconstruction after immersion in water for 7 d, as probed by XPS. This phenomenon involves the exposure of the hydrophilic oxyethylenic chains to contact water. Such surface reconstruction is even more drastic when an amphiphilic block copolymer is dispersed in a cross‐linked poly(dimethyl siloxane) matrix film.