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29-year-old female presenting with an 8-year history of unexplained hypomagnesaemia, which was severe enough to warrant intermittent inpatient admission for intravenous magnesium. Urinary magnesium was inappropriately normal in the context of hypomagnesaemia indicating magnesium wasting. Ultrasound imaging demonstrated unilateral renal cysts and computed tomography of kidneys, ureters and bladder showed a bicornuate uterus. Referral to genetic services and subsequent testing revealed a de novo HNF1B deletion. LEARNING POINTS: HNF1B loss-of-function mutations are one of the most common monogenic causes of congenital anomalies of the kidney and urinary tract.Those with HNF1B mutations may have some of a constellation of features (renal and hepatic cysts, deranged liver function tests, maturity onset diabetes of the young type 5 (MODY5), bicornuate uterus, hyperparathyroidism, hyperuricaemic gout, but presenting features are highly heterogeneous amongst patients and no genotype/phenotype correlation exists. HNF1B mutations are inherited in an autosomal dominant pattern but up to 50% of cases are de novo.HNF1B mutations can be part of the Chr17q12 deletion syndrome, a contiguous gene deletion syndrome.Inorganic oral magnesium replacements are generally poorly tolerated with side effects of diarrhoea. Organic magnesium compounds, such as magnesium aspartate, are better absorbed oral replacement therapies.
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BACKGROUND: While many studies have shown associations between obesity and increased risk of morbidity and mortality, little comparable information is available on how body mass index (BMI) impacts health expectancy. We examined associations of BMI with healthy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of cohort studies in England, Finland, France and Sweden. BMI was categorized into four groups from normal weight (18.5-24.9 kg m-2) to obesity class II (⩾35 kg m-2). Health expectancy was estimated with two health indicators: sub-optimal self-rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years for each BMI category. RESULTS: The proportion of life spent in good perceived health between ages 50 and 75 progressively decreased with increasing BMI from 81% in normal weight men and women to 53% in men and women with class II obesity which corresponds to an average 7-year difference in absolute terms. The proportion of life between ages 50 and 75 years without chronic diseases decreased from 62 and 65% in normal weight men and women and to 29 and 36% in men and women with class II obesity, respectively. This corresponds to an average 9 more years without chronic diseases in normal weight men and 7 more years in normal weight women between ages 50 and 75 years compared to class II obese men and women. No consistent differences were observed between cohorts. CONCLUSIONS: Excess BMI is associated with substantially shorter healthy and chronic disease-free life expectancy, suggesting that tackling obesity would increase years lived in good health in populations.
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Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Inquéritos Epidemiológicos , Expectativa de Vida , Obesidade/epidemiologia , Idoso , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus/prevenção & controle , Inglaterra/epidemiologia , Feminino , Finlândia/epidemiologia , França/epidemiologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/prevenção & controle , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologiaRESUMO
Nitric oxide (NO) may modulate estrogen's anabolic effects on bone homeostasis by restraining osteoclast-mediated bone resorption and stimulation of osteoblast activity. Accordingly, NO donated by organic nitrates, including nitroglycerin, is thought to protect against bone loss associated with estrogen deficiency. In this study, we have explored this phenomenon. Thirty-two 12-week-old female Wistar rats were divided into four groups prior to bilateral ovariectomy or a sham operation. The ovariectomised rats received (1). vehicle control (OVX control), (2). 17-beta-estradiol (OVX+E2), or (3). transdermal nitroglycerin (OVX+NG) for 4 weeks. Femoral and tibial bone mineral density (BMD), serum alkaline phosphatase and urine deoxypyridinoline and NO metabolites were analysed at the end of the study period together with failure torque and torsional rigidity of the tibiae and cellular localisation of the NO-synthase (NOS) isoforms. In OVX+E2 group, proximal and distal femoral and proximal tibial BMD exceeded that of the Sham controls. Nitroglycerin prevented BMD loss at these three sites at levels comparable to that of the Sham controls. Deoxypyridinoline excretion did not change except in the OVX-E2 group that showed an expected reduction when compared to the Sham and OVX controls. There were no treatment-related differences in total alkaline phosphatase or urinary NO metabolites. Tibial failure torque was comparable between the groups but both OVX+E2 and OVX+NG groups showed decreased torsional rigidity compared with the OVX controls. Endothelial and inducible NOS were found in osteoblast-like cells associated with calcifying cartilage spicules in the distal femoral metaphysis. These data confirm previous findings and show that nitroglycerin counteracts the estrogen deficiency-induced osteopenia in the ovariectomised rat model. Organic nitrates may thus be beneficial in conditions where bone turnover is compromised such as in osteoporosis.
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Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Estrogênios/deficiência , Doadores de Óxido Nítrico/uso terapêutico , Nitroglicerina/uso terapêutico , Animais , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/prevenção & controle , Modelos Animais de Doenças , Feminino , Óxido Nítrico/biossíntese , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/farmacologia , Ovariectomia , Ratos , Ratos Wistar , Células Estromais/citologia , Células Estromais/metabolismoRESUMO
Previous studies have indicated that physiological levels of dynamic mechanical strain produce rapid increases in nitric oxide (NO) release from rat ulna explants and primary cultures of osteoblast-like cells and embryonic chick osteocytes derived from long bones. To establish the mechanism by which loading-induced NO production may be regulated, we have examined: nitric oxide synthase (NOS) isoform mRNA and protein expression, the effect of mechanical loading in vivo on NOS mRNA expression, and the effect of mechanical strain on NO production by bone cells in culture. Using Northern blot analyses, in situ hybridization, and immunocytochemistry we have established that the predominant NOS isoform expressed in rat long bone periosteal osteoblasts and in a distinct population of cortical bone osteocytes is the endothelial form of NOS (eNOS), with little or no expression of the inducible NOS or neuronal NOS isoforms. In contrast, in non-load-bearing calvariae there are no detectable levels of eNOS in osteocytes and little in osteoblasts. Consistent with these observations, ulnar explants release NO rapidly in response to loading in vitro, presumably through the activation of eNOS, whereas calvarial explants do not. The relative contribution of different bone cells to these rapid increases in strain-induced NO release was established by assessment of medium nitrite (stable NO metabolite) concentration, which showed that purified populations of osteocytes produce significantly greater quantities of NO per cell in response to mechanical strain than osteoblast-like cells derived from the same bones. Using Northern blot hybridization, we have also shown that neither a single nor five consecutive daily periods of in vivo mechanical loading produced any significant effect on different NOS isoform mRNA expression in rat ulnae. In conclusion, our results indicate that eNOS is the prevailing isoform expressed by cells of the osteoblast/osteocyte lineage and that strain produces increases in the activity of eNOS without apparently altering the levels of eNOS mRNA.
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Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/biossíntese , Osteoblastos/metabolismo , Animais , Animais Recém-Nascidos , Northern Blotting , Células Cultivadas , Embrião de Galinha , Técnicas de Cultura , Imuno-Histoquímica , Hibridização In Situ , Isoenzimas/biossíntese , Isoenzimas/metabolismo , Masculino , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo III , Osteócitos/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Crânio/metabolismo , Estresse Mecânico , Tíbia/metabolismo , Ulna/metabolismoRESUMO
Nitric oxide (NO) has been implicated in bone growth and remodeling by studies showing that inhibition of NO-synthase (NOS) activity retards normal gain in bone mineral density both during skeletal development and after sexual maturity. In the present study, we aimed to assess the level of expression and cellular localization of the three NOS isoforms during skeletal bone development from neonatal to sexual maturity in female Wistar rats. Reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the presence of NOS1 (neuronal), NOS2 (inducible), and NOS3 (endothelial) transcripts in femoral bone from neonatal, 4-, 8-, and 12-week-old rats. RT-PCR amplified NOS1, NOS2, and NOS3 transcripts of 472-, 807-, and 289-bp, respectively. There were no detectable differences in the levels of NOS1 mRNA between the groups; however, NOS2 mRNA was more abundant in the neonatal group compared with 4-, 8-, and 12-week groups. Expression of NOS1 protein could not be detected in bones by either Western blotting or immunocytochemistry in any of the age groups investigated. Western blots for NOS2 revealed expression in the neonatal group only and it was not detected in any of the older age groups. Immunostaining for NOS2 was also most evident in the neonatal group and was localized specifically to trabecular osteoblasts and osteoclasts. In all age groups studied, NOS3 mRNA and protein were found in bone-resorbing osteoclasts, cuboidal active osteoblasts, and osteocytes. Semiquantitative RT-PCR provided evidence of down-regulation of NOS3 transcripts during the skeletal development. This was confirmed using in situ hybridization, which showed higher expression in neonatal and 4-week groups than in other groups. Western blots and counting the ratio of trabecular osteoblasts that were NOS3 immunoreactive showed parallel down-regulation of NOS3 protein during skeletal development. Taken together, these data show that there is regulation of NOS2 and in particular NOS3 expression during skeletal development and this may be significant to trabecular bone growth and remodeling.
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Desenvolvimento Ósseo/fisiologia , Osso e Ossos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Isoenzimas/genética , Óxido Nítrico Sintase/genética , Animais , Animais Recém-Nascidos , Indução Enzimática , Feminino , Imuno-Histoquímica , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Nitric oxide is emerging as one of the most studied molecules in many aspects of human physiology and pathophysiology. Because of the inflammatory nature of aseptic loosening of total hip replacement, it is likely that nitric oxide plays a major role in this condition as well. Nitric oxide is known to interact with cyclooxygenase enzymes that produce prostanoids. Nitric oxide can stimulate synthesis and activity of the inducible, proinflammatory isoform of the enzyme, namely, cyclooxygenase 2. Interactions between the cytokine inducible nitric oxide synthase and cyclooxygenase 2 pathways serve to regulate bone cell viability such that cyclooxygenase 2 activity can protect against nitric oxide mediated programmed cell death. In the pseudomembrane these two pathways are coactivated in CD68 positive macrophages, fibroblasts, lining cells, and in vascular smooth muscles. Particle generation from wear of the prosthesis has a significant role as an inducer of nitric oxide synthase and cyclooxygenase 2; macrophages laden with small size particles and positive for inducible nitric oxide synthase and cyclooxygenase 2 are a frequent finding. Nitric oxide readily reacts with superoxide to form peroxynitrite, which is a strong oxidant species. In pseudosynovial interface membrane, detection of nitrotyrosine provides evidence for the formation and activity of peroxynitrite. These findings show evidence that nitric oxide, superoxide, and peroxynitrite mediated cellular damage is part of the pathophysiology of aseptic loosening of joint implants. These new findings suggest that antiinflammatory compounds can be useful to treat early aseptic loosening of joint implants.
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Reação a Corpo Estranho/etiologia , Prótese de Quadril , Óxido Nítrico , Falha de Prótese , Animais , Ciclo-Oxigenase 2 , Reação a Corpo Estranho/patologia , Humanos , Isoenzimas/metabolismo , Isoenzimas/fisiologia , Proteínas de Membrana , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico Sintase Tipo II , Peroxidases/metabolismo , Peroxidases/fisiologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandina-Endoperóxido Sintases/fisiologia , Superóxidos/metabolismoRESUMO
OBJECTIVE: To measure levels of salivary nitrite (NO2-) and to localize nitric oxide synthases (NOS) in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS). METHODS: NO2- was measured by the Griess reaction. LSGs were analyzed using NADPH-diaphorase histochemical and immunohistochemical studies to determine the constitutive NOS (neuronal [ncNOS] and endothelial [ecNOS]) and inducible NOS (iNOS) isoforms. RESULTS: The NO2- concentration (mean +/- SEM 307 +/- 51 microM versus 97 +/- 16 microM; P < 0.05) and output (166 +/- 46 nmoles/minute versus 37 +/- 7 nmoles/minute) were increased in SS patients compared with healthy control subjects. NADPH-diaphorase was found in some nerve fibers and endothelial cells, and, in SS, was found in myoepithelial, acinar, and ductal epithelial cells, but in only a few inflammatory cells. In SS, ncNOS-immunoreactive nerve fibers were sparse and ecNOS was found in a minority of the CD31-positive vascular endothelial cells and acinar cells, whereas iNOS was localized in myoepithelial, acinar, and ductal epithelial cells, often together with tumor necrosis factor alpha. CONCLUSION: Nitrite was found in normal human saliva. NO produced by ncNOS probably acts as a nonadrenergic, noncholinergic neurotransmitter, whereas that produced by ecNOS exerts a vasodilatory effect. SS patients had increased NO2- concentrations, with most of the superfluous salivary NO being produced not by the immigrant inflammatory cells, but rather, by the resident salivary gland cells. NO may contribute to inflammatory damage and acinar cell atrophy in SS.