Interaction between RGS7 and polycystin

Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase activity of certain Gα subunits and thereby modulate a number of G protein-dependent signaling cascades. Currently, little is known about the regulation of RGS proteins themselves. We identified a short-lived RGS protein, RGS7, that is rapidly degraded through the proteasome pathway. The degradation of RGS7 is inhibited by interaction with a C-terminal domain of polycystin, the protein encoded by PKD1, a gene involved in autosomal-dominant polycystic kidney disease. Furthermore, membranous expression of C-terminal polycystin relocalized RGS7. Our results indicate that rapid degradation and interaction with integral membrane proteins are potential means of regulating RGS proteins.

Polaris, a Protein Involved in Left-Right Axis Patterning, Localizes to Basal Bodies and Cilia

Mutations in Tg737 cause a wide spectrum of phenotypes, including random left-right axis specification, polycystic kidney disease, liver and pancreatic defects, hydrocephalus, and skeletal patterning abnormalities. To further assess the biological function of Tg737 and its role in the mutant pathology, we identified the cell population expressing Tg737 and determined the subcellular localization of its protein product called Polaris. Tg737 expression is associated with cells possessing either motile or immotile cilia and sperm. Similarly, Polaris concentrated just below the apical membrane in the region of the basal bodies and within the cilia or flagellar axoneme. The data suggest that Polaris functions in a ciliogenic pathway or in cilia maintenance, a role supported by the loss of cilia on the ependymal cell layer in ventricles of Tg737orpk brains and by the lack of node cilia in Tg737Δ2-3βGal mutants.

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by ≈50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G1 and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.

Fragilidade e qualidade de vida de idosos com doença renal crônica

Introdução: A expectativa de vida dos brasileiros cresce a cada ano; com isso, os idosos vivem mais, e fatores como, Hipertensão Arterial Sistêmica, Diabetes mellitus e o próprio processo de envelhecimento os tornam suscetíveis à doença renal crônica (DRC). Com a DRC, esses idosos têm maiores chances de desenvolverem a fragilidade e terem consequências desfavoráveis na Qualidade de Vida (QV). Objetivo geral: Analisar a relação entre as variáveis independentes (fragilidade, características sociodemográficas e clínicas) e a variável desfecho (QV) de idosos com DRC em tratamento conservador, hemodiálise (HD) e diálise peritoneal (DP). Material e método: Trata-se de uma pesquisa quantitativa, descritiva e transversal. Participaram idosos com 60 anos ou mais, com DRC em tratamento conservador, HD ou DP, que estavam, no mínimo, há seis meses em tratamento e em acompanhamento em um hospital público de Ribeirão Preto-SP. A coleta de dados ocorreu de outubro/14 a março/15, utilizando-se os seguintes instrumentos: de caracterização sociodemográfica, econômica e clínica adaptado; para avaliar a fragilidade, a Edmonton Frail Scale (EFS); para avaliar a QV, o WHOQOL-BREF e WHOQOL-OLD; para avaliar a cognição, o Mini-Exame do Estado Mental (MEEM). Foram realizadas análises estatísticas descritivas, teste de correlação de Spearman e análise de variância multivariada (MANOVA) para as variáveis de interesse. O nível de significância adotado foi de 5%. O projeto foi aprovado por um Comitê de Ética em Pesquisa com seres humanos com CAAE número 34923214.0.0000.5393; seguiu-se as recomendações da Resolução CNS 466/2012. Resultados: Participaram 77 idosos, sendo 35 em tratamento conservador, 14 em DP e 28 em HD. A maioria era homem (41; 53,2%) e tinha companheiro(a) (51; 66,2%). A média dos escores de fragilidade entre os tratamentos foi: tratamento conservador (7,71±3,10); DP (6,79±2,72) e HD (7,36±2,92). No WHOQOL-BREF, os domínios relações sociais e físico obtiveram maior e menor escores médios, respectivamente, (68,93±17,48) e (55,44±14,11). O WHOQOL-OLD apresentou a maior média na faceta Intimidade (68,67±16,45) e menor média na faceta Morte e morrer (37,66±22,76). Foram encontradas correlações inversas entre a idade e o escore do MEEM (p=0,001) e entre anos de estudo e fragilidade (p=0,016); por outro lado, houve correlações positivas entre os escores do MEEM e anos de estudo (p<0,001), entre número de complicações da DRC e fragilidade (p<0,001) e número de comorbidades e fragilidade (p<0,001). Em relação à QV, houve correlação positiva entre o escore global do WHOQOL-BREF e o escore da faceta global do WHOQOL-OLD, bem como correlação inversa entre os escores globais desses instrumentos com os escores de fragilidade (p<0,00; p=0,023). Na MANOVA, o tipo de tratamento e o número de complicações não influenciaram a QV, porém a fragilidade apresentou relação com o constructo, sendo que, para o aumento de um ponto na escala da fragilidade, a QV apresentou redução média de 1,38 no escore global do WHOQOL-BREF e 0,82 no escore global do WHOQOL-OLD, considerando pertencer ao mesmo tipo de tratamento. Conclusão: os pacientes com DRC apresentaram piores escores médios de QV mediante a maiores escores de fragilidade, independentemente do tipo de tratamento e considerando-se a mesma média de complicações

Student notes from medical lectures by Benjamin Rush, undated

The volumes contain student notes on a course of medical lectures given by Dr. Benjamin Rush (1746-1813) while he was Professor of the Institutes of Medicine and Clinical Practice at the University of Pennsylvania Medical School, likely in circa 1800-1813. The notes indicate Rush often referenced the works or teachings of contemporaries such as Scottish physicians William Cullen, John Brown, John Gregory, and Robert Whytt, and Dutch physician Herman Boerhaave. He frequently included anecdotes and case histories of his own patients, as well as those of other doctors, to illustrate his lecture topics. He also advised students to take notes on the lectures after they ended to allow them to focus on what they were hearing. Volume 1 includes notes on: physician conduct during visits to patients; human and animal physiology; voice and speech; the nervous system; the five senses; and faculties of the mind. Volume 2 includes notes on: food, the sources of appetite and thirst, and digestion; the lymphatic system; secretions; excretions; theories of nutrition; differences in the minds and bodies of women and men; reproduction; pathology; a table outlining the stages of disease production; “disease and the origin of moral and natural evil”; contagions; the role of food, drink, and clothing in producing disease; worms; hereditary diseases; predisposition to diseases; proximate causes of diseases; and pulmonary conditions. Volume 3 includes notes on: the pulse; therapeutics, such as emetics, sedatives, and digitalis, and treatment of various illnesses like pulmonary consumption, kidney disease, palsy, and rheumatism; diagnosis and prognosis of fever; treatment of intermitting fever; and epidemics including plague, smallpox, and yellow fever, with an emphasis on the yellow fever outbreaks in Philadelphia in 1793 and 1797.

Cistatina C : um marcador de função renal promissor em doentes com lúpus eritematoso sistémico?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Hiperparatiroidismo secundário e compromisso neurológico, que relação? : apresentação de um caso de osteodistrofia renal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Transferrina e colagénio tipo IV : novos marcadores glomerulares de lesão renal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Tratamento conservador da doença renal crónica estadio V : uma abordagem a implementar

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate homeostasis. Circulating FGF23 is elevated in chronic kidney disease (CKD) and independently associated with poor renal and cardiovascular outcomes and mortality. Because the study of FGF23 in individuals with normal renal function has received little attention, we examined in a large, population based study of 1128 participants the associations of FGF23 with markers of mineral metabolism and renal function. The median estimated glomerular filtration rate (eGFR) of the cohort was 105 ml/min per 1.73 m2, and the median plasma FGF23 was 78.5 RU/ml. FGF23 increased and plasma 1,25-dihydroxyvitamin D3 decreased significantly below an eGFR threshold of 102 and 99 ml/min per 1.73 m2, respectively. In contrast, plasma parathyroid hormone increased continuously with decreasing eGFR and was first significantly elevated at an eGFR of 126 ml/min per 1.73 m2. On multivariable analysis adjusting for sex, age, body mass index, and GFR, FGF23 was negatively associated with 1,25-dihydroxyvitamin D3, and urinary absolute and fractional calcium excretion but not with serum calcium or parathyroid hormone. We found a positive association of FGF23 with plasma phosphate, but no association with urinary absolute or fractional phosphate excretion and, unexpectedly, a positive association with tubular maximum phosphate reabsorption/GFR. Thus, in the absence of CKD, parathyroid hormone increases earlier than FGF23 when the eGFR decreases. The increase in FGF23 occurs at a higher eGFR threshold than previously reported and is closely associated with a decrease in 1,25-dihydroxyvitamin D3. We speculate that the main demonstrable effect of FGF23 in the setting of preserved renal function is suppression of 1,25-dihydroxyvitamin D3 rather than stimulation of renal phosphate excretion.

Impact of a Potassium-enriched, Chloride-depleted 5% Glucose Solution on Gastrointestinal Function after Major Abdominopelvic Surgery: Results of a Randomized Controlled Trial.

BACKGROUND Gastrointestinal (GI) complications often delay recovery after radical cystectomy with urinary diversion. The authors investigated if perioperative administration of a potassium-enriched, chloride-depleted 5% glucose solution (G5K) accelerates recovery of GI function. METHODS This randomized, parallel-group, single-center double-blind trial included 44 consecutive patients undergoing radical cystectomy and pelvic lymph node dissection with urinary diversion. Patients were randomized to receive either a G5K (G5K group) solution or a Ringer's maleate solution (control group). Fluid management aimed for a zero fluid balance. Primary endpoint was time to first defecation. Secondary endpoints were time to normal GI function, need for electrolyte substitution, and renal dysfunction. RESULTS Time to first defecation was not significantly different between groups (G5K group, 93 h [19 to 168 h] and control group, 120 h [43 to 241 h]); estimator of the group difference, -16 (95% CI, -38 to 6); P = 0.173. Return of normal GI function occurred faster in the G5K group than in the control group (median, 138 h [range, 54 to 262 h] vs. 169 h [108 to 318 h]); estimator of the group difference, -38 (95% CI, -74 to -12); P = 0.004. Potassium and magnesium were less frequently substituted in the G5K group (13.6 vs. 54.5% [P = 0.010] and 18.2 vs. 77.3% [P < 0.001]), respectively. The incidence of renal dysfunction (Risk, Injury, Failure, Loss and End-stage kidney disease stage "risk") at discharge was 9.1% in the G5K group and 4.5% in the control group; P = 1.000. CONCLUSIONS Perioperative administration of a G5K did not enhance first defecation, but may accelerate recovery of normal GI function, and reduces potassium and magnesium substitution after radical cystectomy and urinary diversion.

Using a problem detection study (PDS) to identify and compare health care provider and consumer views of antihypertensive therapy

The objectives of this study were to ascertain consumer knowledge and behaviour about hypertension and treatment and to compare these with health care providers' perceptions (of 'most' consumers). The design for the study was a problem detection study (PDS): focus groups and then survey. Focus groups and survey participants were convenience samples of consumers, doctors, nurses and pharmacists. The main outcome measures were agreement on a 5-point Likert scale with statements about consumers' knowledge and behaviour about high blood pressure and medication. The survey identified areas of consensus and disagreement between consumers and health providers. While general knowledge and concordance with antihypertensive therapy among consumers was good, consequences such as eye and kidney disease, interactions with herbal medicines, and how to deal with missing a dose were less well known. Side effects were a problem for over one-quarter of participants, and cost was a problem in continuing therapy. Half the consumers had not received sufficient written information. Providers overall disagreed that most consumers have an adequate understanding of the condition. They agreed that most consumers adhere to therapy and can manage medicines; and about their own profession's role in information provision and condition management. Consumers confirmed positive provider behaviour, suggesting opportunities for greater communication between providers about actions taken with their consumers. In conclusion, the PDS methodology was useful in identifying consumer opinions. Differences between consumer and provider responses were marked, with consumers generally rating their knowledge and behaviour above providers' ratings of 'most' consumers. There are clear gaps to be targeted to improve the outcomes of hypertension therapy.

Identifying the molecular phenotype of renal progenitor cells

Although many of the molecular interactions in kidney development are now well understood, the molecules involved in the specification of the metanephric mesenchyme from surrounding intermediate mesoderm and, hence, the formation of the renal progenitor population are poorly characterized. In this study, cDNA microarrays were used to identify genes enriched in the murine embryonic day 10.5 (E10.5) uninduced metanephric mesenchyme, the renal progenitor population, in comparison with more rostral derivatives of the intermediate mesoderm. Microarray data were analyzed using R statistical software to determine accurately genes differentially expressed between these populations. Microarray outliers were biologically verified, and the spatial expression pattern of these genes at E10.5 and subsequent stages of early kidney development was determined by RNA in situ hybridization. This approach identified 21 genes preferentially expressed by the E10.5 metanephric mesenchyme, including Ewing sarcoma homolog, 14-3-3 theta, retinoic acid receptor-alpha, stearoyl-CoA desaturase 2, CD24, and cadherin-11, that may be important in formation of renal progenitor cells. Cell surface proteins such as CD24 and cadherin-11 that were strongly and specifically expressed in the uninduced metanephric mesenchyme and mark the renal progenitor population may prove useful in the purification of renal progenitor cells by FACS. These findings may assist in the isolation and characterization of potential renal stem cells for use in cellular therapies for kidney disease.

Echocardiographic parameters in 14 healthy English Bull Terriers

Objective To determine the range of various cardiac parameters using echocardiography in apparently normal, healthy English Bull Terriers. Design Fourteen English Bull Terriers were selected for study. Cardiac auscultation of the parents of these dogs was normal. Echocardiographic examination of one parent of each animal showed: no mitral or aortic valve abnormalities; no myocardial lesions; no two dimensional evidence of fixed or dynamic left ventricular outflow tract obstruction; and no systolic aortic or left ventricular outflow tract turbulence on colour flow Doppler examination. The 14 selected dogs did not have arrhythmias or murmurs, and on echocardiographic examination had similar findings to their parents. Systolic blood pressure was measured in all dogs and they had no clinical evidence of Bull Terrier polycystic kidney disease or Bull Terrier hereditary nephritis. Procedure All dogs were auscultated and subjected to a sequential global echocardiographic assessment of the heart, including two dimensional long and short axis, and colour flow Doppler interrogation of the mitral and aortic valves. Dimensional measurements, including those from the left atrium, aortic annulus and left ventricle, were taken from a right parasternal window, and derived values such as fractional shortening, stroke volume and left atrial to aortic annulus ratio were calculated. Peak systolic aortic velocity was measured from the left parasternal window using two dimensional-guided pulsed wave Doppler with angle correction. Systolic blood pressure was measured using a Doppler monitor. The absence of Bull Terrier polycystic kidney disease was determined using renal ultrasonography, and of Bull Terrier hereditary nephritis using urinary protein to creatinine ratio. Results These 14 dogs had greater left ventricular wall thickness and smaller aortic root diameters than those reported as normal for other breeds of comparable body size. Left atrial dimensions were also larger, however this may have been due to the maximising method of measurement. These apparently normal English Bull Terriers also had higher aortic velocities than those reported for other breeds, possibly due to a smaller aortic root diameter or other anatomic substrate of the left ventricular outflow tract, lower systemic vascular resistance, or breed-specific normal left ventricular hypertrophy. While these dogs were selected to be as close to normal as possible, the breed may have a particular anatomy that produces abnormal left ventricular echocardiographic parameters. Conclusion These echocardiographic parameters may be used to diagnose left ventricular outflow tract obstruction and left ventricular hypertrophy, and inaccurate diagnoses may result if breed-specific values are not used.

Lessons in ethnonephrology

Only recently has the nephrology community moved beyond a fairly singular focus on terminal kidney failure to embrace population-based studies of earlier stages of disease, its markers and risk factors, and of interventions. Observations in developing countries, and in minority, migrant, and disadvantaged groups in westernized countries, have promoted these developments. We are only beginning to interpret renal disease in the context of public health history, social and health transitions, changing population demography, and competing mortality. Its intimate relationships to other health issues are being progressively exposed. Perspectives on the multideterminant etiology of most disease and the pedestrian nature of most risk factors are maturing. We are challenged to reconcile epidemiologic patterns with morphology in diseased renal tissue, and to consider structural markers, such as nephron number and glomerular size, as determinants of disease susceptibility. New work force models are mandated for population-based studies and intervention programs. Intervention programs need to be integrated with other chronic disease initiatives and nested in a matrix of systematic primary care, and although flexible to changing needs, must be sustained over the long term. Cross-disciplinary collaboration is essential in designing those programs, and in promoting them to health-care funders. Substantial expansion and restructuring of the discipline is needed for the nephrology community to participate effectively in those processes.