Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases.

Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Podocytopathies associated with familial partial lipodystrophy due to LMNA variants: report of two cases

SUMMARY Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephrotic-range proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and to nephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Photobiomodulation for Preventive Therapy of Recurrent Herpes Labialis: A 2-Year In Vivo Randomized Controlled Study.

Objective: The present study aimed to evaluate the effectiveness of the application of photobiomodulation therapy (PBMT) in the prevention of recurrent herpes labialis (RHL) through a randomized controlled clinical trial. Background data: RHL is a lifelong infection that effects patients' quality of life. In the literature PBMT has shown positive results preventing RHL, decreasing recurrences and severity of lesions. Despite the good results reported, there are still few controlled clinical studies published on the subject. Methods: For this study, 158 volunteers were recruited and were randomly divided into three study groups: Laser 1-1 J/point (L1J): n = 61, Laser 2-2 J/point (L2J): n = 50, and placebo-0 J/point: n = 47. The treatment consisted of a protocol of 15 sessions throughout 6 months and 2 years of follow-up posttreatment. Results: The results showed that L1J presented the most satisfactory results concerning the reduction of the number of lesions per year and less severity of recurrences in the long-term evaluation when compared with L2J. Both Laser Groups (L1J and L2J) were statistically more efficient than placebo in all aspects analyzed. All patients who received laser treatment (L1J and L2J) and presented recurrences had significant improvement in frequency and/or severity of lesions. No patient had side effects from treatment. Conclusions: PBMT can be effective in the reduction of the frequency of recurrences of RHL and in the severity of postirradiation lesions that may appear.

Chikungunya virus as a trigger for different renal disorders: an exploratory study.

INTRODUCTION: Chikungunya virus was detected in cases of acute chikungunya fever in renal tissue. However, chikungunya virus-related kidney injury still lacks characterization, and it is unknown whether the kidneys are reservoirs for the virus. We sought to detect histopathological changes and viral antigens in renal tissue, and to evaluate kidney injury markers in different phases of chikungunya fever. METHODS: Two groups were evaluated in this exploratory study: patients with biopsy-proven kidney injury established after chikungunya fever, and patients with post-chikungunya fever chronic joint manifestations without known kidney injury, in whom we actively searched for kidney injury markers. RESULTS: In the first group, 15 patients had kidney injury 0.5-24 months after chikungunya fever. The most frequent histopathological diagnoses were glomerular lesions. No viral antigens were detected in renal tissue. High-risk genotypes were detected in patients with atypical hemolytic uremic syndrome and focal and segmental glomerulosclerosis. In the second group, 114 patients had post-chikungunya fever joint manifestations on average for 35.6 months. Mean creatinine and proteinuria were 0.9 mg/dl and 71.5 mg/day, respectively. One patient had isolated hematuria. There was no indication for renal biopsy in this group. CONCLUSIONS: Several histopathological features were found after chikungunya fever, without virus detection in renal tissue. These findings suggest that chikungunya virus may trigger kidney lesions with varying degrees of severity at different stages of infection. However, the probability that this virus replicates in the renal tissue seems unlikely.

Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America.

BACKGROUND: Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E. LPG mainly affects Asian individuals, however occasional cases have also been described in Americans and Europeans. Herein we report two unrelated Brazilian patients with LPG in whom genetic analyses revealed the APOE-Osaka/Kurashiki variant. CASE PRESENTATION - CASE 1: A 29-year-old Caucasian male sought medical attention with complaints of face swelling and foamy urine for the last 3 months. He denied a family history of kidney disease, consanguinity, or Asian ancestry. His tests showed proteinuria of 12.5 g/24 h, hematuria, serum creatinine 0.94 mg/dL, albumin 2.3 g/dl, total cholesterol 284 mg/dL, LDL 200 mg/dL, triglycerides 175 mg/dL, and negative screening for secondary causes of glomerulopathy. A kidney biopsy revealed intraluminal, laminated deposits of hyaline material in glomerular capillaries consistent with lipoprotein thrombi. These findings were confirmed by electron microscopy, establishing the diagnosis of LPG. His apolipoprotein E serum level was 72 mg/dL and genetic analysis revealed the APOE pathogenic variant c.527G > C, p.Arg176Pro in heterozygosis, known as the Osaka/Kurashiki mutation and positioned nearby the LDL receptor binding site. CASE 2: A 34-year-old Caucasian man sought medical assessment for renal dysfunction and hypertension. He reported intermittent episodes of lower-limb edema for 3 years and a family history of kidney disease, but denied Asian ancestry. Laboratorial tests showed BUN 99 mg/dL, creatinine 10.7 mg/dL, total cholesterol 155 mg/dL, LDL 79 mg/dL, triglycerides 277 mg/dL, albumin 3.1 g/dL, proteinuria 2.7 g/24 h, and negative screening for secondary causes of glomerulopathy. His kidney biopsy was consistent with advanced chronic nephropathy secondary to LPG. A genetic analysis also revealed the Osaka/Kurashiki variant. He was transplanted a year ago, displaying no signs of disease relapse. CONCLUSION: We report two unrelated cases of Brazilian patients with a diagnosis of lipoprotein glomerulopathy whose genetic assessment identified the APOE-Osaka/Kurashiki pathogenic variant, previously only described in eastern Asians. While this is the second report of LPG in Latin America, the identification of two unrelated cases by our medical team raises the possibility that LPG may be less rare in this part of the world than currently thought, and should definitely be considered when nephrotic syndrome is associated with suggestive kidney biopsy findings.

The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures.

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

APOL1 in an ethnically diverse pediatric population with nephrotic syndrome: implications in focal segmental glomerulosclerosis and other diagnoses.

BACKGROUND: APOL1 high-risk genotypes (HRG) are associated with increased risk of kidney disease in individuals of African ancestry. We analyzed the effects of APOL1 risk variants on an ethnically diverse Brazilian pediatric nephrotic syndrome (NS) cohort. METHODS: Multicenter study including 318 NS patients, categorized as progressors to advanced CKD [estimated glomerular filtration rate (eGFR)] < 30 mL/min/1.73 m2] and slow/non-progressors (eGFR > 30 mL/min/1.73 m2 through the study). We employed Cox regression with progression time as the outcome and APOL1 genotype as the independent variable. We tested this association in the entire cohort and three subgroups; (1) focal segmental glomerulosclerosis (FSGS), (2) steroid-resistant NS (SRNS), and (3) those who underwent kidney biopsy. RESULTS: Nineteen patients (6%) had an HRG. Of these, 47% were self-reported White. Patients with HRG manifested NS at older ages and presented higher frequencies of FSGS and SRNS. HRG patients progressed to advanced CKD more often than low-risk-genotype (LRG) children in the whole NS cohort (p = 0.001) and the three subgroups. In SRNS and biopsied patients, a single risk variant was associated with trends of higher CKD progression risk. CONCLUSIONS: Novel discoveries include a substantial prevalence of HRG among patients self-reported White, worse kidney outcomes in HRG versus LRG children in the FSGS subgroup, and a trend of higher CKD progression risk associated with a single risk variant in the SRNS cohort. These findings suggest APOL1-associated NS extends beyond patients self-reported non-White, the HRG effect is independent of FSGS, and a single risk variant may have a detrimental impact in children with NS.

A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease.

Background: Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods: Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results: Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively). Conclusions: Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.

Brazilian Consortium for the Study on Renal Diseases Associated With COVID-19: A Multicentric Effort to Understand SARS-CoV-2-Related Nephropathy.

Kidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Serviços Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2.

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo.

OBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela.

Cardiac structural and functional findings in Persian cats with autosomal dominant polycystic kidney disease / Achados estruturais e funcionais cardíacos em gatos persas com doença renal policística autossômica dominante

ABAutosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n=12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.(AU)

A doença renal policística autossômica dominante (DRPAD) tem sido relacionada a anormalidades estruturais e funcionais de ventrículo esquerdo em pacientes humanos. O objetivo do presente estudo foi avaliar os achados estruturais e funcionais cardíacos em gatos persas com DRPAD. Gatos persas pertencentes à clientes com DRPAD (n=12) e sem DRPAD (n=12) foram envolvidos neste trabalho. Os animais foram submetidos aos exames de eco e eletrocardiografia (ECG) e foram obtidas medições não-invasivas da pressão arterial sistólica (PAS). Ambos os grupos apresentaram valores semelhantes em relação aos parâmetros hematológicos e bioquímicos, incluindo contagem de glóbulos brancos e níveis séricos de ureia, creatinina, proteína total e tiroxina. Não houve diferença em relação aos parâmetros do ECG entre os gatos com ou sem DRPAD. A hipertrofia ventricular esquerda foi demonstrada em 6/12 (50%) dos gatos normotensos com DRPAD e função renal preservada. Não houve diferenças entre os grupos em relação aos parâmetros ecocardiográficos, incluindo fração de ejeção e fração de encurtamento do ventrículo esquerdo, entretanto a espessura septal interventricular basal na diástole na via de saída do ventrículo esquerdo e a velocidade do fluxo da artéria aórtica mostraram valores ligeiramente elevados em gatos com DRPAD. Nosso estudo revelou que gatos persas com DRPAD não reproduzem o fenótipo cardíaco funcional e estrutural encontrado em pacientes humanos. No entanto, estudos de coorte em larga escala são necessários para distinguir as possibilidades de uma verdadeira ligação entre a hipertrofia ventricular do miocárdio e a DRPAD nesta raça.(AU)

KLOTHO polymorphisms and age-related outcomes in community-dwelling older subjects: The São Paulo Ageing & Health (SPAH) Study.

Defective KLOTHO gene expression in mice led to a syndrome resembling human ageing. This study evaluated three KLOTHO polymorphisms, namely G395A, C1818T, and C370S, in an elderly population (mean age of 73 years) and their associations with ageing-related outcomes (cardiovascular events, kidney function, osteoporosis, sarcopenia) and mortality. Estimated glomerular filtration rates (eGFR) was lower in subjects with 1818TT (P = 0.047) and 370SS (P = 0.046) genotypes. The 1818TT genotype (P = 0.006) and 1818T allele were associated with higher frequency of myocardial infarction (MI) (CC:1.7% vs. CT + TT:7.0%; P = 0.002). The 370SS genotype was associated with lower stroke frequency (P = 0.001). MI (OR 3.35 [95% CI: 1.29-8.74]) and stroke (OR 3.64 [95% CI: 1.48-8.97]) were associated with mortality. Regarding MI, logistic regression showed 1818T allele was a risk factor for death-related MI (OR 4.29 [95% CI: 1.60-11.52]; P = 0.003), while 370C was protective (OR 0.03 [95% CI: 0.01-0.08]; P < 0.001). Regarding stroke, the 395A and 370C alleles were protective factors (respectively: OR 0.28 [95% CI: 0.20-0.80]; P = 0.018; OR 0.10 [95% CI: 0.05-0.18]; P < 0.001). This is the first study to determine potential associations between common ageing-related outcomes/mortality and KLOTHO polymorphisms. The 1818T allele was a risk factor for MI-related death. The 395A and 370C alleles were protective factors for stroke-related death in elderly from community.

Cardiac structural and functional findings in Persian cats with autosomal dominant polycystic kidney disease / Achados estruturais e funcionais cardíacos em gatos persas com doença renal policística autossômica dominante

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n=12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.

RESUMO: A doença renal policística autossômica dominante (DRPAD) tem sido relacionada a anormalidades estruturais e funcionais de ventrículo esquerdo em pacientes humanos. O objetivo do presente estudo foi avaliar os achados estruturais e funcionais cardíacos em gatos persas com DRPAD. Gatos persas pertencentes à clientes com DRPAD (n=12) e sem DRPAD (n=12) foram envolvidos neste trabalho. Os animais foram submetidos aos exames de eco e eletrocardiografia (ECG) e foram obtidas medições não-invasivas da pressão arterial sistólica (PAS). Ambos os grupos apresentaram valores semelhantes em relação aos parâmetros hematológicos e bioquímicos, incluindo contagem de glóbulos brancos e níveis séricos de ureia, creatinina, proteína total e tiroxina. Não houve diferença em relação aos parâmetros do ECG entre os gatos com ou sem DRPAD. A hipertrofia ventricular esquerda foi demonstrada em 6/12 (50%) dos gatos normotensos com DRPAD e função renal preservada. Não houve diferenças entre os grupos em relação aos parâmetros ecocardiográficos, incluindo fração de ejeção e fração de encurtamento do ventrículo esquerdo, entretanto a espessura septal interventricular basal na diástole na via de saída do ventrículo esquerdo e a velocidade do fluxo da artéria aórtica mostraram valores ligeiramente elevados em gatos com DRPAD. Nosso estudo revelou que gatos persas com DRPAD não reproduzem o fenótipo cardíaco funcional e estrutural encontrado em pacientes humanos. No entanto, estudos de coorte em larga escala são necessários para distinguir as possibilidades de uma verdadeira ligação entre a hipertrofia ventricular do miocárdio e a DRPAD nesta raça.

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

OBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela

Two cases of fungal cyst infection in ADPKD: is this really a rare complication?

BACKGROUND: Cyst infection is a prevalent complication in autosomal dominant polycystic kidney disease (ADPKD) patients, however therapeutic and diagnostic approaches towards this condition remain unclear. The confirmation of a likely episode of cyst infection by isolating the pathogenic microorganism in a clinical scenario is possible only in the minority of cases. The available antimicrobial treatment guidelines, therefore, might not be appropriate to some patients. CASE PRESENTATION: We describe two unique cases of kidney cyst infection by Candida albicans, a condition that has not been previously described in literature. Both cases presented clear risk factors for Candida spp. infection. However, since there was no initial indication of cyst aspiration and culture, antifungal therapy was not immediately started and empirical treatment was initiated as recommended by the current guidelines. Antifungal treatment was instituted in both cases along the clinical course, according to their specificities. CONCLUSION: Our report highlights the possibility of Candida spp. cyst infection. Failure of clinical improvement with antibiotics should raise the suspicion of a fungal infection. Identification of infected cysts should be pursued in such cases, particularly with PET-CT, and when technically possible followed by cyst aspiration and culture to guide treatment. Risk factors for this condition, such as Candida spp. colonization, previous antimicrobial therapy, hemodialysis, necrotizing pancreatitis, gastrointestinal/hepatobiliary surgical procedure, central venous catheter, total parenteral nutrition, diabetes mellitus and immunodeficiency (neutropenia < 500 neutrophils/mL, hematologic malignancy, chemotherapy, immunosuppressant drugs), should be also considered accepted criteria for empirical antifungal therapy.

Influence of androgenic blockade with flutamide on pain behaviour and expression of the genes that encode the NaV1.7 and NaV1.8 voltage-dependent sodium channels in a rat model of postoperative pain.

BACKGROUND: Experimental studies suggest that testosterone reduces the nociceptive response after inflammatory and neuropathic stimuli, however the underlying mechanisms have not been fully elucidated. The aims of this study were to evaluate the effect of peripheral blockade of testosterone on pain behaviour and on expression levels of the genes that encode the NaV1.7 and NaV1.8 channels, in dorsal root ganglia in an acute postoperative pain model, as well as the influence of androgen blockade on the expression of these genes. METHODS: Postoperative pain was induced by a plantar incision and the study group received flutamide to block testosterone receptor. The animals were submitted to behavioural evaluation preoperatively, 2 h after incision, and on the 1st, 2nd, 3rd and 7th postoperative days. Von Frey test was used to evaluate paw withdrawal threshold after mechanical stimuli and the guarding pain test to assess spontaneous pain. The expression of the genes encoding the sodium channels at the dorsal root ganglia was determined by real time quantitative polymerase chain reaction. RESULTS: Animals treated with flutamide presented lower paw withdrawal threshold at the 1st, 2nd, 3rd, and 7th postoperative days. The guarding pain test showed significant decrease in the flutamide group at 2 h and on the 3rd and 7th postoperative days. No difference was detected between the study and control groups for the gene expression. CONCLUSIONS: Our data suggest an antinociceptive effect of androgens following plantar incision. The expression of genes that encode voltage-gated sodium channels was not influenced by androgen blockade.

A novel single amino acid deletion impairs fibronectin function and causes familial glomerulopathy with fibronectin deposits: case report of a family.

BACKGROUND: Glomerulopathy with fibronectin deposits is an autosomal dominant disease associated with proteinuria, hematuria, hypertension and renal function decline. Forty percent of the cases are caused by mutations in FN1, the gene that encodes fibronectin. CASE PRESENTATION: This report describes two cases of Glomerulopathy with fibronectin deposits, involving a 47-year-old father and a 14-year-old son. The renal biopsies showed glomeruli with endocapillary hypercellularity and large amounts of mesangial and subendothelial eosinophilic deposits. Immunohistochemistry for fibronectin was markedly positive. Whole exome sequencing identified a novel FN1 mutation that leads to an amino-acid deletion in both patients (Ile1988del), a variant that required primary amino-acid sequence analysis for assessment of pathogenicity. Our primary sequence analyses revealed that Ile1988 is very highly conserved among relative sequences and is positioned in a C-terminal FN3 domain containing heparin- and fibulin-1-binding sites. This mutation was predicted as deleterious and molecular mechanics simulations support that it can change the tertiary structure and affect the complex folding and its molecular functionality. CONCLUSION: The current report not only documents the occurrence of two GFND cases in an affected family and deeply characterizes its anatomopathological features but also identifies a novel pathogenic mutation in FN1, analyzes its structural and functional implications, and supports its pathogenicity.