Doença de Fabry : diagnóstico de uma doença rara

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid metabolism due to the deficiency of α-galactosidase A. The progressive accumulation of globotriaosylceramide (Gb3), particularly in the vascular endothelium, leads to renal, cardiac, and cerebrovascular manifestations and early death. Clinical manifestations include the onset of pain and paresthesias in extremities, angiokeratoma and hypohidrosis during childhood or adolescence. Proteinuria and lymphedema occur with increasing age. Severe renal impairment leads to hypertension and uremia. Death usually occurs due to renal failure or cardiac or cerebrovascular disease. Disease presentation may be subtle, and its signs and symptoms are often discounted as malingering or are mistakenly attributed to other disorders, such as rheumatic fever, neurosis, multiple sclerosis, lupus, or petechiae. We present a 46-year-old man who since adolescence has suffered from painful acroparesthesia, disseminated skin angiokeratomas, hypohidrosis and heat intolerance. He was submitted to a thorough investigation with different specialists, but never reached a diagnosis. He started hemodialysis 3 years ago and at the moment is in standby for kidney transplantation. He was enrolled in a Brazilian FD screening and a reduced serum activity of α-galactosidase A (0.0027 nmol/h/mL – reference value 4-22) confirmed the diagnosis of FD He has angiokeratoma at the bottom area, his echocardiogram demonstrated left ventricular hypertrophy and the family history is very rich, as the patient has 15 siblings. This case represents a very common story for FD patients. They usually spend most of their lives trying to find someone who could understand or explain their suffering. These results indicate that FD may be much more common among male dialysis patients than previously recognized. Subsequently, FD should be considered in every patient with unexplained renal disease, especially when cardiac or cerebral complications suggest an underlying multisystemic disorder. Early diagnosis of FD is important because it allows family studies to identify other affected relatives for genetic counseling and therapeutic intervention.A doença de Fabry (DF) é um erro inato do metabolismo dos glicoesfingolipídeos devido à deficiência da α-galactosidase A. O acúmulo progressivo de globotriaosilceramida (Gb3),particularmente no endotélio vascular, leva a manifestações renais, cardíacas e cerebrovasculares e morte precoce. As manifestações clínicas incluem o início, durante a infância ou adolescência, de episódios de dor e parestesias nas extremidades, angioqueratomas e hipohidrose. Com a idade, podem aparecer proteinúria e linfedema. Insuficiência renal grave leva à hipertensão e uremia. O óbito ocorre devido à insuficiência renal ou doença cardíaca ou cerebrovascular. A apresentação da doença pode ser sutil, e seus sinais e sintomas são erroneamente atribuídos a outras doenças, como febre reumática, neurose, esclerose múltipla, lúpus ou petéquias. Relatamos o caso de um paciente masculino com 46 anos que, desde a adolescência, sofre de acroparestesia, angioqueratomas disseminados, hipohidrose e intolerância ao calor. Ele foi submetido a extensa investigação com diferentes especialistas, mas nunca chegou a um diagnóstico. Iniciou hemodiálise há 3 anos e, no momento, está na lista de espera para transplante de rim. Participou de um programa brasileiro de triagem para DF, e uma atividade reduzida de α- galactosidase A (0,0027 nmol/h/mL – valor de referência 4-22) confirmou o diagnóstico de DF. O paciente apresenta angioqueratomas na área do calção, seu ecocardiograma demonstra hipertrofia ventricular esquerda e sua história familiar é rica, pois ele tem 15 irmãos. Este caso representa uma história muito comum entre pacientes com DF. Eles geralmente passam a maior parte de suas vidas tentando encontrar alguém que compreenda ou explique seu sofrimento. Estes resultados indicam que a DF pode ser muito mais comum entre homens que realizam hemodiálise do que antes previsto. Subseqüentemente, a DF deve ser considerada em todo paciente com doença renal sem causa aparente, principalmente quando complicações cardíacas ou cerebrovasculares sugerirem uma doença multissistêmica. O diagnóstico precoce da DF é importante, pois permite estudo familiar para identificar parentes afetados para aconselhamento genético e intervenção terapêutica

Elevated extracellular HSP72 and blunted heat shock response in severe covid-19 patients

Aims: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: (i) to measure the concentration of extracellular HSP72 (eHSP72) in patients with severe COVID-19 and in comparison with noninfected patients; (ii) to compare the HSR between critically ill patients with COVID-19 (with and without diabetes); and (iii) to compare the HSR in these patients with noninfected individuals. Methods: Sixty critically ill adults with acute respiratory failure with SARS-CoV-2, with or without diabetes, were selected. Noninfected subjects were included for comparison (healthy, n = 19 and patients with diabetes, n = 22). Blood samples were collected to measure metabolism (glucose and HbA1c); oxidative stress (lypoperoxidation and carbonyls); cytokine profile (IL-10 and TNF); eHSP72; and the HSR (in vitro). Results: Patients with severe COVID-19 presented higher plasma eHSP72 compared with healthy individuals and noninfected patients with diabetes. Despite the high level of plasma cytokines, no differences were found between critically ill patients with COVID-19 with or without diabetes. Critically ill patients, when compared to noninfected, presented a blunted HSR. Oxidative stress markers followed the same pattern. No differences in the HSR (extracellular/intracellular level) were found between critically ill patients, with or without diabetes. Conclusions: We demonstrated that patients with severe COVID-19 have elevated plasma eHSP72 and that their HSR is blunted, regardless of the presence of diabetes. These results might explain the uncontrolled inflammation and also provide insights on the increased risk in developing type 2 diabetes after SARS-CoV-2 infection

Integrating complex genomic datasets and tumour cell sensitivity profiles to address a 'simple' question: which patients should get this drug?

It is becoming increasingly apparent that cancer drug therapies can only reach their full potential through appropriate patient selection. Matching drugs and cancer patients has proven to be a complex challenge, due in large part to the substantial molecular heterogeneity inherent to human cancers. This is not only a major hurdle to the improvement of the use of current treatments but also for the development of novel therapies and the ability to steer them to the relevant clinical indications. In this commentary we discuss recent studies from Kuo et al., published this month in BMC Medicine, in which they used a panel of cancer cell lines as a model for capturing patient heterogeneity at the genomic and proteomic level in order to identify potential biomarkers for predicting the clinical activity of a novel candidate chemotherapeutic across a patient population. The findings highlight the ability of a 'systems approach' to develop a better understanding of the properties of novel candidate therapeutics and to guide clinical testing and application

Hibernation-like state induced by an opioid peptide protects against experimental stroke

BACKGROUND: Delta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system. RESULTS: Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. CONCLUSION: These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection

Syndromic Recognition of Influenza A Infection in a Low Prevalence Community Setting

BACKGROUND: With epidemics of influenza A virus infection, people and medical professionals are all concerned about symptoms or syndromes that may indicate the infection with influenza A virus. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was performed at a community clinic of a metropolitan area. Throat swab was sampled for 3-6 consecutive adult patients with new episode (<3 days) of respiratory tract infection every weekday from Dec. 8, 2005 to Mar. 31, 2006. Demographic data, relevant history, symptoms and signs were recorded. Samples were processed with multiplex real time PCR for 9 common respiratory tract pathogens and by virus culture. Throat swab samples were positive for Influenza A virus with multiplex real time PCR system in 12 of 240 patients. The 12 influenza A positive cases were with more clusters and chills than the other 228. Certain symptoms and syndromes increased the likelihood of influenza A virus infection. The syndrome of high fever plus chills plus cough, better with clustering of cases in household or workplace, is with the highest likelihood (positive likelihood ratio 95; 95% CI 12-750). Absence of both cluster and chills provides moderate evidence against the infection (negative likelihood ratio 0.51; 95% CI 0.29-0.90). CONCLUSIONS/SIGNIFICANCE: Syndromic recognition is not diagnostic but is useful for discriminating between influenza A infection and common cold. In addition to relevant travel history, confirmatory molecular test can be applied to subjects with high likelihood when the disease prevalence is low

Rapamycin Response in Tumorigenic and Non-Tumorigenic Hepatic Cell Lines

The mTOR inhibitor rapamycin has anti-tumor activity across a variety of human cancers, including hepatocellular carcinoma. However, resistance to its growth inhibitory effects is common. We hypothesized that hepatic cell lines with varying rapamycin responsiveness would show common characteristics accounting for resistance to the drug.We profiled a total of 13 cell lines for rapamycin-induced growth inhibition. The non-tumorigenic rat liver epithelial cell line WB-F344 was highly sensitive while the tumorigenic WB311 cell line, originally derived from the WB-F344 line, was highly resistant. The other 11 cell lines showed a wide range of sensitivities. Rapamycin induced inhibition of cyclin E-dependent kinase activity in some cell lines, but the ability to do so did not correlate with sensitivity. Inhibition of cyclin E-dependent kinase activity was related to incorporation of p27(Kip1) into cyclin E-containing complexes in some but not all cell lines. Similarly, sensitivity of global protein synthesis to rapamycin did not correlate with its anti-proliferative effect. However, rapamycin potently inhibited phosphorylation of two key substrates, ribosomal protein S6 and 4E-BP1, in all cases, indicating that the locus of rapamycin resistance was downstream from inhibition of mTOR Complex 1. Microarray analysis did not disclose a unifying mechanism for rapamycin resistance, although the glycolytic pathway was downregulated in all four cell lines studied.We conclude that the mechanisms of rapamycin resistance in hepatic cells involve alterations of signaling downstream from mTOR and that the mechanisms are highly heterogeneous, thus predicting that maintaining or promoting sensitivity will be highly challenging