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1.
PLoS One ; 13(1): e0191224, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29351342

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.


Assuntos
Biomarcadores Tumorais/genética , Síndrome de Fraser/genética , Mutação de Sentido Incorreto , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Animais Recém-Nascidos , Biomarcadores Tumorais/química , Criança , Consanguinidade , Sequência Conservada , Éxons , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Homozigoto , Humanos , Masculino , Camundongos , Modelos Animais , Modelos Moleculares , Linhagem , Homologia de Sequência de Aminoácidos , Sistema Urogenital/crescimento & desenvolvimento , Sistema Urogenital/metabolismo
2.
Pharmaceutics ; 9(3)2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28880210

RESUMO

This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90-91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.

3.
J Am Soc Nephrol ; 28(1): 69-75, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27151922

RESUMO

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.


Assuntos
Exoma/genética , Mutação , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Humanos , Fenótipo , Síndrome
4.
Artigo em Inglês | MEDLINE | ID: mdl-27978473

RESUMO

OBJECTIVES: Linezolid is the first approved oxazolidinone antibacterial agent, whereas PH027 is a novel compound of the same class that exhibits good in vitro antibacterial activity. The objective of this study was to develop an UPLC-MS/MS assay for the analysis of linezolid and PH027 in plasma and to apply the method for comparative pharmacokinetic and tissue distribution studies of both compounds. METHOD: Plasma samples and calibrators were extracted with diethyl ether after addition of the internal standard solution. After evaporation of the ether layer, the residue was reconstituted in mobile phase and injected into UPLC-MS/MS. The mobile phase consisted of 2mM ammonium acetate buffer solution and acetonitrile (70:30) at a flow rate of 0.2ml/min. Separation was achieved using UPLC BEH C18 column, and quantitative determination of the analytes was performed using multiple-reaction monitoring (MRM) scanning mode. The method was validated by analyzing quality control tissue homogenate samples, and was applied to analyze tissue homogenate samples obtained following IV injections of linezolid and PH027 in rabbits. RESULTS: The developed UPLC-MS/MS method was linear in the concentration range of 50-5000ng/ml. Validation of the method proved that the method's precision, selectivity and stability were all within the acceptable limits. Linezolid and PH027 concentrations were accurately determined in the quality control tissue homogenate samples, and analysis of samples obtained following IV administration of the two compounds showed that the tissue to plasma concentration ratio of PH027 was higher than that of linezolid probably due to its higher lipophilicity. CONCLUSIONS: The developed UPLC-MS/MS method for the analysis of linezolid and PH027 in rabbit's plasma can accurately determine the concentrations of these compounds in different tissues.


Assuntos
Antibacterianos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Linezolida/farmacocinética , Oxazolidinonas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Triazóis/farmacocinética , Animais , Antibacterianos/sangue , Monitoramento de Medicamentos/métodos , Limite de Detecção , Linezolida/sangue , Oxazolidinonas/sangue , Coelhos , Distribuição Tecidual , Triazóis/sangue
5.
Med Princ Pract ; 26(1): 30-34, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27648954

RESUMO

OBJECTIVES: The aim of this study was to describe the management protocol for intermittent testicular torsion (ITT) in adults and report the outcome of this clinical condition, which is commonly overlooked in adults. SUBJECTS AND METHODS: Sixty-three patients were included in the study. The inclusion criterion was the presence of sudden intermittent testicular pain over a duration of 3 months. All the patients underwent clinical examination, urine analysis, culture, and scrotal ultrasound with Doppler. The testicle was in an abnormal or in transverse lie and/or could easily be twisted. Scrotal support and analgesia were given for 1 month, then patients were offered orchidopexy or conservative treatment. Nineteen patients chose orchidopexy while 44 chose conservative treatment. Follow-up ranged from 3 months to 2 years. The improvement was assessed using a visual analog pain score. The outcome of the treatment was compared between the surgical and conservative groups using a χ2 test. RESULTS: The median age of the patients was 28 years (range: 17-50). Of the 19 patients who underwent orchidopexy, the pain resolved or visual analog pain scores improved (median 1/10) in 18 (94.7%) cases. On the other hand, 21 of the 44 (47.7%) cases that chose the conservative approach claimed their pain resolved or improved (visual analog pain scores: median 3/10) with a median of 13 months of follow-up. CONCLUSION: In this study, scrotal orchidopexy proved to be superior to conservative measures in cases of ITT in adults.


Assuntos
Analgésicos/uso terapêutico , Orquidopexia , Torção do Cordão Espermático/tratamento farmacológico , Torção do Cordão Espermático/cirurgia , Adolescente , Adulto , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dor/tratamento farmacológico , Dor/etiologia , Dor/cirurgia , Manejo da Dor/métodos , Torção do Cordão Espermático/complicações , Escala Visual Analógica , Adulto Jovem
6.
BMC Infect Dis ; 16(1): 506, 2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-27660027

RESUMO

BACKGROUND: Despite a worldwide common and progressive nature of benign prostate hyperplasia (BPH) in older men, no association has been observed between a causative pathogen and other etiology so far. METHODS: In this study, we investigated a causative association of Trichomonas vaginalis, a flagellate protozoan parasite, in 171 BPH cases presenting without symptoms of prostatitis at a surgical outpatient clinic in Kuwait. We detected T. vaginalis DNA by polymerase chain reaction (PCR) and T. vaginalis antigen by immunocytochemistry (ICC) in the prostate tissue of these cases. A total of 171 age-matched controls with no urinary tract symptoms were also included in the study. A detailed information regarding the sexual history and sexually transmitted infections (STIs) was enquired from all the enrolled subjects. RESULTS: We detected T. vaginalis DNA and T. vaginalis antigen in 42 (24.6 %) and 37 (21.6 %) of the 171 BPH cases respectively in their prostate tissue. Both these assays showed a very good agreement and statistically no significant difference in their sensitivities and specificities. A relatively higher seropositivity rate for antibodies to T. vaginalis was detected in BPH cases (53 of 171 cases, 31.0 %) than in the control group (26.9 %) [p: 0.19] and both were higher than in earlier reports but no significant association was observed between BPH and T. vaginalis serostatus. However, a greater proportion of seroreactive BPH cases had high IgG2 antibody absorbance score than in the control group (p:0.000). Furthermore, no significant association was observed between T. vaginalis seropositivity and presence of T. vaginalis DNA in the prostate tissue. CONCLUSIONS: Our study documents T. vaginalis DNA and T. vaginalis antigen in 24.6 and 21.6 % respectively in the prostate tissue of the BPH cases. We also detected a relatively higher seropositivity rate for antibodies to T. vaginalis both in the BPH cases and in normal control group, 31 and 26.9 % respectively but no significant association was observed between BPH and T. vaginalis serostatus or presence of T. vaginalis DNA in the prostate tissue. Further epidemiological and case-controlled studies are needed to focus on local response to chronic asymptomatic retention of T. vaginalis in prostate tissue in the development of benign prostate hyperplasia.

7.
J Orthop ; 13(2): 69-75, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27053836

RESUMO

BACKGROUND: The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. METHODS: Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. RESULTS: The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). CONCLUSION: We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

8.
Med Princ Pract ; 25(4): 336-42, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26954461

RESUMO

OBJECTIVE: The aim of this study is to investigate healing of fractures in patients with concomitant head injuries and to measure blood hormone levels to elucidate the mechanism of a possible accelerated osteogenesis. MATERIALS AND METHODS: One hundred and sixty-two patients were included in this study and divided into 3 cohorts: group A with head injuries only (n = 52); group B with head injuries as well as long-bone fractures (n = 50); group C with long-bone fractures only (n = 60). Fracture-healing parameters including time of appearance and thickness of the bridging callus, and blood hormonal assays were measured and compared using Student's t test. RESULTS: The mean time to healing was significantly lower in cohort B (6.9 ± 2.9 weeks) than C (22.4 ± 8.7 weeks; p = 0.001). The mean thickness of the healing callus was significantly higher in cohort B (26.3 ± 9.7 mm) than C (8.1 ± 5.9 mm; p = 0.002). The mean healing rate was also higher in cohort B (4.5 ± 2.3 mm/week) than C (0.38 ± 0.21 mm/week; p = 0.001). Blood hormonal assays in group B showed higher values of parathyroid hormone and growth hormone than in group C. However, adrenaline and noradrenaline values were lower in group B than in group C at all measured time intervals, and correspondingly leptin was lower in all groups (p = 0.001). Corticosteroid values were normal in group B compared to slightly higher values in group C, also at all measured time intervals. CONCLUSION: In this study, healing of fractures in patients with concomitant head injuries was accelerated, thereby indicating an involvement of a combined neurohormonal mechanism.


Assuntos
Traumatismos Craniocerebrais/epidemiologia , Traumatismos Craniocerebrais/fisiopatologia , Consolidação da Fratura/fisiologia , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/fisiopatologia , Corticosteroides/sangue , Adulto , Calo Ósseo/fisiopatologia , Diáfises/fisiopatologia , Feminino , Escala de Coma de Glasgow , Hormônio do Crescimento/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese/fisiologia , Hormônio Paratireóideo/análise , Fatores de Tempo , Adulto Jovem
9.
Nephrol Dial Transplant ; 31(8): 1280-3, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26908769

RESUMO

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney diseases in children and young adults, accounting for ∼50% of cases. These anomalies represent maldevelopment of the genitourinary system and can be genetically explained in only 10-16% of cases by mutations or by copy number variations in protein coding sequences. Knock-out mouse models, lacking components of the microRNA (miRNA) processing machinery (i.e. Dicer, Drosha, Dgcr8), exhibit kidney malformations resembling human CAKUT. METHODS: Given the Dicer-null mouse phenotype, which implicates a central role for miRNAs gene regulation during kidney development, we hypothesized that miRNAs expressed during kidney development may cause CAKUT in humans if mutated. To evaluate this possibility we carried out Next-Generation sequencing of 96 stem-loop regions of 73 renal developmental miRNA genes in 1248 individuals with non-syndromic CAKUT from 980 families. RESULTS: We sequenced 96 stem-loop regions encoded by 73 miRNA genes that are expressed during kidney development in humans, mice and rats. Overall, we identified in 31/1213 individuals from 26 families with 17 different single nucleotide variants. Two variants did not segregate with the disease and hence were not causative. Thirteen variants were likely benign variants because they occurred in control populations and/or they affected nucleotides of weak evolutionary conservation. Two out of 1213 unrelated individuals had potentially pathogenic variants with unknown biologic relevance affecting miRNAs MIR19B1 and MIR99A. CONCLUSIONS: Our results indicate that mutations affecting mature microRNAs in individuals with CAKUT are rare and thus most likely not a common cause of CAKUT in humans.


Assuntos
Rim/anormalidades , MicroRNAs/genética , Mutação , Sistema Urinário/anormalidades , Anormalidades Urogenitais/genética , Adolescente , Animais , Criança , Variações do Número de Cópias de DNA , Humanos , Camundongos , Camundongos Knockout , Fenótipo , Ratos , Adulto Jovem
10.
J Orthop ; 12(4): 217-21, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26566322

RESUMO

BACKGROUD/AIM: The aim of study was to test, for the presence of osteoblasts in the reaming debris of intramedullary nailing of femoral and tibial fracture in patients with and without severe head injury. METHODS: Two groups of patients were studied. Group A (n = 32) had long bone fractures in addition to having head injuries. Group B (n = 35) had only long bone fractures. The fractures in the 2 groups of patients was treated by inter medullary nailing. Osteoblasts in the debris of the inter medullary nailing was compared between the 2 groups of patients. RESULTS: The results demonstrated that histopathological specimens from reaming debris of fractured femur and tibia in patients with head injury showed osteoblasts in (82.9%) and in (27.5%) of patients with isolated long bone fractures (p < 0.001). CONCLUSION: Healing indicators in diaphyseal fractures and concomitant head injury confirm fast and adequate healing in these patients and the presence of plenty of osteoblasts in their reaming debris may reflect a proof of accelerated fracture healing environment.

11.
Am J Hum Genet ; 97(2): 291-301, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26235987

RESUMO

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Genes Dominantes/genética , Músculo Liso/embriologia , Mutação/genética , Proteínas com Domínio T/genética , Ureter/embriologia , Sistema Urinário/anormalidades , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Exoma/genética , Células HEK293 , Humanos , Imuno-Histoquímica , Imunoprecipitação , Microscopia de Fluorescência , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
12.
Hum Genet ; 134(8): 905-16, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26026792

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.


Assuntos
Proteínas Ativadoras de GTPase , Peptídeos e Proteínas de Sinalização Intercelular , Mutação , Proteínas do Tecido Nervoso , Receptores Imunológicos , Transdução de Sinais/genética , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Exoma , Proteínas Ativadoras de GTPase/biossíntese , Proteínas Ativadoras de GTPase/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mesoderma/metabolismo , Camundongos , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fatores de Risco , Anormalidades Urogenitais/embriologia , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/embriologia , Refluxo Vesicoureteral/genética
13.
BMC Nephrol ; 16: 26, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25880449

RESUMO

BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of Polycystic Kidney Disease (PKD) and occurs at a frequency of 1/800 to 1/1000 affecting all ethnic groups worldwide. ADPKD shows significant intrafamilial phenotypic variability in the rate of disease progression and extra-renal manifestations, which suggests the involvement of heritable modifier genes. Here we show that the PKD1 gene can act as a disease causing and a disease modifier gene in ADPKD patients. METHODS: Clinical evaluation of a family with ADPKD was performed to diagnose and assess disease progression in each individual. PKD1 was genotyped in each individual by targeted sequencing. RESULTS: Targeted screening analysis showed that the patients with ADPKD in the family had the PKD1: p.Q2243X nonsense mutation. A more severe disease phenotype, in terms of estimated Glomerular Filtration Rate (eGFR) and total kidney volume, was observed in two patients where in addition to the mutation, they carried a novel PKD1 variant (p.H1769Y). Other patients from the same family carrying only the (p.Q2243X) mutation showed milder disease manifestations. CONCLUSION: ADPKD shows significant intrafamilial phenotypic variability that is generally attributed to other modifier genes. In this rare case, we have shown that a variant at PKD1, in trans with the PKD1 mutation, can also act as a modifier gene in ADPKD patients. Understanding the molecular mechanism through which the gene exerts its disease modifying role may aid our understanding of the pathogenesis of ADPKD.


Assuntos
Predisposição Genética para Doença/epidemiologia , Mutação , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genética , Adulto , Estudos de Coortes , Feminino , Variação Genética , Heterozigoto , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Linhagem , Rim Policístico Autossômico Dominante/epidemiologia , Valor Preditivo dos Testes
14.
Indian J Urol ; 31(1): 57-64, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25624578

RESUMO

INTRODUCTION: The objective of this study is to investigate the molecular mechanisms underlying the effects of zinc deficiency on spermatogenesis in the Sprague-Dawley (SD) rat. MATERIALS AND METHODS: Three groups of eight adult male SD rats were maintained for 4 weeks on a normal diet as control, zinc deficient diet and zinc deficient diet with zinc supplementation of 28 mg zinc/kg body weight respectively. Using standard techniques, the following parameters were compared between the three groups of experimental animals at the end of 4 weeks: (a) Serum zinc, magnesium (Mg), copper (Cu), selenium (Se) and cadmium (Cd), (b) serum sex hormones, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPX), (c) interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), Bcl-2, Bax and caspase-3 expression in the testes, (d) assessment of apoptosis of testicular cells using electron microscopy and (e) testicular volume and histology using the orchidometer and Johnsen score, respectively. RESULTS: The zinc deficient group showed a reduction of testicular volume, serum concentrations of Zn, Cu, Se, Mg, SOD, GPX, IL-4, Bcl-2 and testosterone (P < 0.05), as well as increased levels of serum Cd, MDA and tissue TNF-α, Bax, caspase-3 and apoptosis of the germ cells (P < 0.05) compared with control and zinc supplementation groups. CONCLUSION: Zinc deficiency is associated with impaired spermatogenesis because of reduced testosterone production, increased oxidative stress and apoptosis. These findings suggest that zinc has a role in male reproduction.

15.
Int J Surg Case Rep ; 5(11): 811-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25308188

RESUMO

INTRODUCTION: Iatrogenic injuries to the urogenital tract are rare, with the bladder being the organ most affected. We describe a case of a vesical calculus that formed on non-absorbable sutures that were used to repair an inguinal hernia. PRESENTATION OF CASE: A 45-year-old male presented with frank haematuria and dysuria 2 years following an open left inguinal hernia repair. A CT urography showed a vesical calculus adherent to the left anterio-lateral wall of the bladder. Cystoscopy revealed that the calculus formed on non-absorbable sutures. Cystolapaxy was performed followed by cystoscopic excision of the sutures. The patient's post-operative course was uneventful. DISCUSSION: Foreign bodies in the urinary bladder always act as a nidus for formation of a calculus. Iatrogenic bladder injuries are common during hernia repair. It is however rare for sutures used to repair an inguinal hernia to involve the urinary bladder wall. The patient most likely had a full bladder at the time of hernia repair or the bladder was part of the contents of the hernia sac. CONCLUSION: This case illustrates the need to ensure that the bladder is empty prior to pelvic surgery and for surgeons to have a good understanding of inguinal anatomy to avoid injuring the contents of the hernia sac.

16.
J Am Soc Nephrol ; 25(9): 1917-22, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24700879

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, >90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in 574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study.


Assuntos
Proteínas de Transporte/genética , Proteínas da Matriz Extracelular/genética , Síndrome de Fraser/genética , Cadeias alfa de Integrinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/anormalidades , Mutação , Proteínas do Tecido Nervoso/genética , Receptores de Interleucina/genética , Sistema Urinário/anormalidades , Refluxo Vesicoureteral/genética , Animais , Anormalidades Congênitas/genética , Modelos Animais de Doenças , Feminino , Genes Recessivos , Humanos , Nefropatias/congênito , Nefropatias/genética , Masculino , Camundongos , Camundongos Mutantes , Anormalidades Urogenitais
17.
Kidney Int ; 85(6): 1429-33, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24429398

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease. CAKUT can be caused by monogenic mutations; however, data are lacking on their frequency. Genetic diagnosis has been hampered by genetic heterogeneity and lack of genotype-phenotype correlation. To determine the percentage of cases with CAKUT that can be explained by mutations in known CAKUT genes, we analyzed the coding exons of the 17 known dominant CAKUT-causing genes in a cohort of 749 individuals from 650 families with CAKUT. The most common phenotypes in this CAKUT cohort were vesicoureteral reflux in 288 patients, renal hypodysplasia in 120 patients, and unilateral renal agenesis in 90 patients. We identified 37 different heterozygous mutations (33 novel) in 12 of the 17 known genes in 47 patients from 41 of the 650 families (6.3%). These mutations include (number of families): BMP7 (1), CDC5L (1), CHD1L (5), EYA1 (3), GATA3 (2), HNF1B (6), PAX2 (5), RET (3), ROBO2 (4), SALL1 (9), SIX2 (1), and SIX5 (1). Furthermore, several mutations previously reported to be disease-causing are most likely benign variants. Thus, in a large cohort over 6% of families with isolated CAKUT are caused by a mutation in 12 of 17 dominant CAKUT genes. Our report represents one of the most in-depth diagnostic studies of monogenic causes of isolated CAKUT in children.


Assuntos
Genes Dominantes , Mutação , Refluxo Vesicoureteral/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Hereditariedade , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Anormalidades Urogenitais
18.
Urolithiasis ; 42(1): 67-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24057120

RESUMO

Textbooks describe three narrowest anatomic sites in the ureter as the most likely places for ureteral calculi to lodge, these are: the pelvi-ureteric junction (PUJ), the point where the ureters cross over the iliac vessels and the ureterovesical junction (UVJ). The purpose of this study is to determine whether calculi causing ureteric obstruction and requiring surgical treatment are found mostly at these three narrowest anatomic points of the ureter. Three hundred consecutive patients with impacted ureteric calculi who required surgical intervention were studied. The location of the impacted calculus on the day of surgical intervention was categorized according to nine predetermined levels outlined in a designed diagram based on findings on non-contrast CT of kidneys, ureters and bladder. Two peaks in stone distribution in the ureters were encountered; the first was above the ischial spine in the proximal part of the lower third ureter (84 patients, 28%), while the second was at the level between L3 and L4 lumbar vertebrae (66 patients, 22%). Overall, the location of impacted calculi was as follows, 53, 34, 10 and 3% in the lower third ureter, upper third ureter, PUJ and mid ureter, respectively. This study demonstrates two peaks of calculi distribution in the ureter where ureteric calculi become impacted: the upper ureter below the PUJ and a second in the lower ureter, more proximal than the UVJ. There was an absence of the peak in stone location over the iliac vessels, that is, the mid ureter.


Assuntos
Cálculos Ureterais/patologia , Cálculos Ureterais/cirurgia , Feminino , Humanos , Imagem Tridimensional , Litotripsia , Masculino , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Ureter/diagnóstico por imagem , Ureter/patologia , Ureter/cirurgia , Cálculos Ureterais/diagnóstico por imagem , Ureteroscopia
19.
Med Princ Pract ; 22 Suppl 1: 52-61, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24217224

RESUMO

The objective of this review article was to examine current and prospective developments in the scientific use of laboratory animals, and to find out whether or not there are still valid scientific benefits of and justification for animal experimentation. The PubMed and Web of Science databases were searched using the following key words: animal models, basic research, pharmaceutical research, toxicity testing, experimental surgery, surgical simulation, ethics, animal welfare, benign, malignant diseases. Important relevant reviews, original articles and references from 1970 to 2012 were reviewed for data on the use of experimental animals in the study of diseases. The use of laboratory animals in scientific research continues to generate intense public debate. Their use can be justified today in the following areas of research: basic scientific research, use of animals as models for human diseases, pharmaceutical research and development, toxicity testing and teaching of new surgical techniques. This is because there are inherent limitations in the use of alternatives such as in vitro studies, human clinical trials or computer simulation. However, there are problems of transferability of results obtained from animal research to humans. Efforts are on-going to find suitable alternatives to animal experimentation like cell and tissue culture and computer simulation. For the foreseeable future, it would appear that to enable scientists to have a more precise understanding of human disease, including its diagnosis, prognosis and therapeutic intervention, there will still be enough grounds to advocate animal experimentation. However, efforts must continue to minimize or eliminate the need for animal testing in scientific research as soon as possible.


Assuntos
Experimentação Animal/ética , Experimentação Animal/normas , Experimentação Animal/legislação & jurisprudência , Animais , Animais de Laboratório , Modelos Animais de Doenças , Indústria Farmacêutica/métodos , Educação Médica/métodos , Ratos , Testes de Toxicidade
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