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1.
Artículo en Inglés | MEDLINE | ID: mdl-39113278

RESUMEN

OBJECTIVE: There is limited information on population-specific norms of trabecular-bone-score (TBS) and its associated factors. Here, we provide norms of TBS in Asian-Indians and its relationship with serum 25-hydroxyvitamin D [25(OH)D] and intact-parathyroid hormone (iPTH). PARTICIPANTS AND MEASUREMENTS: TBS, bone-mineral-density (BMD), and vertebral-fractures (VFs) were assessed using dual-energy X-ray absorptiometry in 923 healthy Asian-Indians (aged 20-60 years). Serum 25(OH)D, iPTH, T4/TSH,, glycosylated-haemoglobin (HbA1c) were measured and associations with TBS assessed using multivariable linear regression. Subjects with BMD Z-score ≤ -2.0 or ≥2.0 at any sites, VFs, TSH > 10.0 or <0.05 µIU/ml, blood-glucose >11.1 mmol/L or HbA1c > 8.0% were excluded for generating Asian-Indian norms. RESULTS: TBS norms were generated in 744 healthy Asian-Indians (M:F,389:385). The cut-offs generated for 'normal', 'partially-degraded', and 'degraded' TBS were >1.305, 1.204-1.305 and <1.204, respectively. Mean TBS was lower in females than males (p < .001). There was 75% congruency in TBS categories between Asian-Indian and existing norms. Specificity (97.8 vs. 77.9%, p < .001) and diagnostic-accuracy (97.8% vs. 78.4%, p < .001) of TBS to detect osteoporosis were higher with Asian-Indian norms. The sensitivity of 'partially-degraded' TBS to diagnose osteopenia was also higher with Asian-Indian norms. In multivariable regression, gender, body-mass-index (BMI), BMD-L1-L4, serum PTH, daily dietary-calorie intake and calcium intake were associated with TBS. Though 25(OH)D inversely correlated with PTH, 25(OH)D was not associated with TBS. CONCLUSION: This study provides norms for TBS in Asian-Indians with gender-specific differences. Increasing age and higher BMI were associated with lower TBS. Associations of TBS with circulating PTH and/or 25(OH)D need confirmation in further studies.

2.
Clin Endocrinol (Oxf) ; 98(4): 505-515, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36567495

RESUMEN

OBJECTIVE: Patients with chronic hypoparathyroidism (cHypoPT) are prone to intracranial-calcification, cataract and nephrocalcinosis. In this study, we systematically investigated the possibility of increased coronary artery calcification (CAC) and coronary artery disease (CAD) in them. DESIGN: Cross-sectional. PATIENTS AND MEASUREMENTS: Ninety-four nonsurgical cHypoPT (M:F = 50:44; age = 45 ± 15 years) with 18.6 ± 9.3 years of illness were assessed. Those with dyspnoea, angina, syncope, abnormal electrocardiogram, echocardiography or significant CAC underwent coronary angiography or myocardial-perfusion-stress imaging. Their lipid parameters and high-sensitivity C-reactive protein (hsCRP) were compared with age-matched healthy controls (Group A, n = 101). The prevalence of CAC in cHypoPT was compared with that of subjects referred from cardiology-clinics (Group B, n = 148, age = 52 ± 11 years). RESULTS: One of 94 cHypoPT had known CAD. On screening, 17 cHypoPT required evaluation for CAD. Two of 17 had severe coronary stenosis, and 12 showed subclinical CAD. CAC and aortic-valve calcification occurred in 21.5% and 11.8%. Clinical and subclinical CAD, CAC and aortic-valve calcification in cHypoPT ≥50 years of age was 8.1%, 27.0%, 52.8% and 27.8%, respectively. Frequency of age-adjusted CAC was comparable between cHypoPT and control Group B (30.2% vs. 30.7%, p = .93). Elevated hsCRP was higher in cHypoPT than in controls A (52% vs. 32%, p < .01). Factors associated with CAD in cHypoPT were CAC and hypertension. However, CAD and CAC showed no association with long-term calcemic or phosphatemic control and intracranial-calcification in cHypoPT. CONCLUSIONS: Clinical and subclinical CAD was observed in 3.2% and 12.8% of cHypoPT patients. The increased prevalence of CAD, CAC and aortic-valve calcification in cHypoPT above 50 years of age suggested their careful cardiac evaluation during follow-up.


Asunto(s)
Enfermedad de la Arteria Coronaria , Calcificación Vascular , Humanos , Adulto , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/epidemiología , Estudios Transversales , Proteína C-Reactiva , Tomografía Computarizada por Rayos X , Angiografía Coronaria , Calcificación Vascular/complicaciones , Factores de Riesgo
3.
Mol Cell Biochem ; 478(10): 2351-2359, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36703095

RESUMEN

Primary hyperparathyroidism is a common endocrine disorder. Interestingly, the majority (75%) of parathyroid tumors are localized to the inferior parathyroid glands. To date, the reason for this natural bias has not been investigated. We assessed the global gene expression profile of superior and inferior glands obtained from forensic autopsies. The genes with significant differential expression between superior and inferior parathyroids were further assessed by RT-PCR in 19 pairs. As an iterative approach, additional genes with an established role in parathyroid disorders, i.e., CASR, MAFB, PAX9, TBCE, TBX1, VDR, MEN1, CCND1, and CDC73 were also evaluated by RT-PCR in all 19 pairs of superior and inferior parathyroid glands. Seven homeobox genes, namely HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, and one encoding for ALDH1A2 showed a lower expression in the inferior parathyroid glands than in the superior. Conversely, SLC6A1 showed a higher expression in the inferior glands. Of the nine genes with significant differential mRNA expression among superior and inferior glands HOXB9, HOXB4 and IRX1 could be detected by western blotting/mass spectrometry. The study is the first to show the differential expression of nine genes HOXA4, HOXA5, HOXBAS3, HOXB4, HOXB6, HOXB9, IRX1, ALDH1A2, and SLC6A1 in inferior versus the superior parathyroid glands. This could have potential implications for the preferential localization of parathyroid tumors to the inferior parathyroid glands as observed in patients with primary hyperparathyroidism.


Asunto(s)
Hiperparatiroidismo Primario , Neoplasias de las Paratiroides , Humanos , Glándulas Paratiroides/química , Glándulas Paratiroides/metabolismo , Glándulas Paratiroides/patología , Neoplasias de las Paratiroides/genética , Neoplasias de las Paratiroides/metabolismo , Neoplasias de las Paratiroides/patología , Hiperparatiroidismo Primario/metabolismo , Hiperparatiroidismo Primario/patología , Western Blotting , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo
4.
Phys Chem Chem Phys ; 26(1): 463-476, 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38078459

RESUMEN

Multi-exponential waiting-time distribution and randomness parameter greater than unity ascribe dynamic disorder in single-enzyme catalysis corroborated to the interplay of transforming conformers [English et al., Nat. Chem. Biol., 2006, 2, 87]. The associated multi-state model of enzymatic turnovers with statically heterogeneous catalytic rates misdescribes the non-linear uprising of the randomness parameter from unity in relation to the attributes of the fall-offs of the waiting-time distribution at different substrate concentrations. To resolve this crucial issue, we first employ a comprehensive stochastic reaction scenario and further rationalize and work out the minimal indispensable dynamic-disorder model that ensures the foregoing relationship upon comparison with the data. We elucidate that specific disregard for the transition rate coefficients in the multi-state model on account of the especially slow conformational transitions is the underlying reason for not achieving interrelation between the observables.


Asunto(s)
Catálisis , Conformación Molecular , Cinética
5.
Alcohol Alcohol ; 57(5): 552-558, 2022 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-34935031

RESUMEN

AIM: To investigate abnormalities in bone mineral density, trabecular bone score and vertebral fractures in male patients with alcohol use disorder to understand the impact on bone health. METHODS: The study subjects included 134 male patients. Controls were 134 age matched healthy males. Assessments were made of the bone mineral density (BMD), trabecular bone score (TBS) and vertebral morphometry (VFA) for vertebral fractures. Biochemical measurements included serum total T4, thyroid stimulating hormone (TSH), parathyroid hormone (PTH) and 25- Hydroxyvitamin D 25(OH) D. RESULTS: The mean BMD at total forearm, proximal forearm (or distal 1/3) and mid forearm was significantly higher in the alcohol use disorders (AUD) group than the controls (P < 0.01). Around 15% of patients with AUD had VFs compared with 9.0% of the healthy controls (P = 0.19). For each kg/m2 gain in body mass index (BMI), lumbar spine and total hip BMD increased by 0.009 and 0.014 g/cm2, respectively. Lumbar and hip BMD decreased by 0.002 and 0.003 g/cm2 per year increase in duration of alcohol used. For every 5 years increase in age of the patients the odds of having VFs increased by 39% (odds ratio 1.393 [95% confidence interval = 1.031-1.881, P = 0.03]). CONCLUSION: The findings of the current study suggest that persons with AUD in third and fourth decades of life, with BMI in normal range and with alcohol use disorder duration of around one decade might have no major alteration in BMD and TBS. Impact of alcohol use in this population was manifest by marginal increase in the prevalence of mild grade of vertebral fractures, mostly in the thoracic region.


Asunto(s)
Alcoholismo , Fracturas de la Columna Vertebral , Alcoholismo/complicaciones , Alcoholismo/diagnóstico por imagen , Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Humanos , Vértebras Lumbares/diagnóstico por imagen , Masculino , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología
6.
Clin Endocrinol (Oxf) ; 91(2): 356-362, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31087795

RESUMEN

BACKGROUND: There is reservation about accepting the notion of widespread vitamin D deficiency (VDD) in sunny countries because information base is largely urban indoors, and the cut-off serum 25(OH)D > 75.0 nmol/L to define sufficiency is perceived as high. OBJECTIVE: We assessed the vitamin D status of subjects engaged in six types of outdoor jobs with freedom to seek shade, when needed. DESIGN: Descriptive observational study. SUBJECTS AND METHODS: A total of 573 outdoors, (hawkers, n = 144; auto-rickshaw drivers, n = 113; manual rickshaw pullers, n = 49; fuel-station attendants, n = 84; gardeners, n = 96; traffic police personnel, n = 87) were assessed for serum 25(OH)D, iPTH and total calcium during summer and winter. Bank employees were indoor controls (n = 72). Serum 25(OH)D was defined as sufficient if ≥50.0 nmol/L and deficient when <30.0 nmol/L, as per 'Institute of Medicine'. RESULTS: Mean serum 25(OH)D of 573 outdoors was 44.8 ± 19.6 nmol/L and showed a physiological inverse relation with iPTH (P < 0.001). 77.5% of the outdoors did not have VDD. Hawkers, gardeners, fuel-station attendants and rickshaw pullers had sufficient or near sufficient serum 25(OH)D. The mean serum 25(OH)D (30.6 ± 23.2 nmol/L) of indoors though lower by 12.7 nmol/L than outdoors was above the cut-off of VDD. Proportions with supranormal iPTH were comparable between outdoors and indoors (14.0% vs 20.8%). Despite winter dip, the mean serum 25(OH)D (31.2 ± 14.3 nmol/l) of outdoors was not deficient. CONCLUSIONS: Vitamin D deficiency is not universal. Most urban outdoor workers do not have VDD.


Asunto(s)
Ocupaciones , Luz Solar , Deficiencia de Vitamina D/epidemiología , Vitamina D/análogos & derivados , Vitamina D/biosíntesis , Adulto , Humanos , India , Masculino , Persona de Mediana Edad , Estaciones del Año , Vitamina D/sangre
7.
Clin Endocrinol (Oxf) ; 88(2): 217-226, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29095521

RESUMEN

BACKGROUND: Cholecalciferol and/or calcium supplementation might increase skeletal muscle strength and serum testosterone in young adult males. OBJECTIVE: We performed a randomized control trial assessing the effect of cholecalciferol/calcium on skeletal muscle strength and serum testosterone in vitamin D deficient young males. DESIGN: Two-by-two factorial RCT. SUBJECT AND INTERVENTION: Two-hundred and twenty-eight young males were block-randomized to (i) double-placebo, (ii) calcium/placebo, (iii) cholecalciferol/placebo and (iv) cholecalciferol/calcium. Doses for cholecalciferol were 60 000 IU/wk for 8 weeks followed by 60 000 IU/fortnightly, and doses for elemental calcium were 500 mg/twice daily for 6 months. A total of 180 subjects completed the study protocol. Their  ean age, body mass index and baseline 25(OH)D were 20.2 ± 2.2 years, 23.0 ± 3.6 kg/m2 and 21.5 ± 9.5 nmol/L, respectively. MEASUREMENTS: Handgrip (primary outcome), pinch-grip strength, distance walked in 6 minutes, dyspnoea-score, quality of life by Short Form 36, serum 25(OH)D, 1,25(OH)2 D, iPTH, total testosterone and free androgen index (FAI). RESULTS: After intervention, mean serum 25(OH)D was >75.0 nmol/L in cholecalciferol groups. However, the handgrip strength (29.7 ± 4.4, 29.3 ± 4.6, 30.6 ± 5.0 and 28.8 ± 4.3 kg, P = .28) was comparable in the 4 groups. Subgroups analysis among subjects with baseline serum 25OH)D < 25.0 and <12.0 nmol/L showed similar results. The mean serum testosterone decreased significantly at 6 months; however, delta change was similar in 4 groups. Change in handgrip strength and other outcomes was similar in 4 groups with and without adjustment for delta testosterone and FAI. CONCLUSIONS: Six months of cholecalciferol/calcium supplementation had no significant effect on skeletal muscle strength and serum testosterone in young adult males.


Asunto(s)
Calcio/uso terapéutico , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Testosterona/sangre , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/tratamiento farmacológico , Vitamina D/uso terapéutico , Adolescente , Adulto , Humanos , Masculino , Deficiencia de Vitamina D/fisiopatología , Adulto Joven
8.
J Bone Miner Metab ; 35(2): 177-184, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26832389

RESUMEN

Urban Asian Indians generally have low serum 25(OH)D. Information on serum bioavailable 25(OH)D and the effect of prolonged sun-exposure in them is not known. We assessed serum 25(OH)D and bioavailable 25(OH)D in males with varying durations of sun-exposure in Delhi during August-September. Serum 25(OH)D, vitamin D-binding protein (DBP), bioavailable 25(OH)D, free 25(OH)D index, iPTH, ionized calcium and sun-index were assessed in outdoor, mixed outdoor-indoor and indoor workers (n = 88, 32 and 74, respectively). The mean sun-index (12.0 ± 6.25, 4.3 ± 2.20 and 0.7 ± 0.62, respectively; P < 0.001) was highest outdoors and lowest indoors. Serum 25(OH)D (29.0 ± 8.61, 19.1 ± 5.73 and 10.9 ± 4.19 ng/ml, respectively; P < 0.001), bioavailable 25(OH)D and free 25(OH)D index were maximum in outdoor workers followed by mixed-exposure and indoor workers. Their mean serum DBP levels (241.2 ± 88.77, 239.3 ± 83.40 and 216.6 ± 63.93 µg/ml, respectively; P = 0.12) were comparable. Mean serum iPTH was significantly lower in outdoor than indoor workers and showed inverse correlations with serum 25(OH)D, bioavailable 25(OH)D and free 25(OH)D index (r = -0.401, -0.269 and -0.236, respectively; P < 0.001 in all). Daily dietary-calorie intake was higher and calcium lower in outdoor than indoor workers. On regression analysis, sun-exposure was the only significant variable, increasing serum 25(OH)D by 2.03 ng/ml per hour of sun-exposure (95 % confidence interval 1.77-2.28; P < 0.001). Outdoor workers with prolonged sun-exposure were vitamin D-sufficient, with higher serum bioavailable 25(OH)D than the indoor workers during summer. Use of serum DBP levels did not affect the interpretation of their vitamin D status.


Asunto(s)
Luz Solar , Proteína de Unión a Vitamina D/sangre , Vitamina D/sangre , Lugar de Trabajo , Adulto , Calcio de la Dieta/administración & dosificación , Humanos , India , Masculino , Hormona Paratiroidea/sangre , Estaciones del Año , Población Blanca , Adulto Joven
9.
J Bone Miner Metab ; 35(4): 405-411, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27465913

RESUMEN

Cataract is a cardinal manifestation of hypoparathyroidism. Although patients with hypoparathyroidism require cataract surgery at a younger age than individuals without hypoparathyroidism, there is limited information on the outcome of this surgery. We assessed long-term complications of cataract surgery in patients with idiopathic hypoparathyroidism (IH) and its relationship with their clinical and biochemical parameters. Twenty-seven patients with IH and 25 nonhypoparathyroid controls with a minimum follow-up of 2 years after cataract surgery were assessed for visual acuity, intraocular pressure, lens centricity, Nd:YAG laser capsulotomy, and the severity of posterior capsular opacification (PCO) and anterior capsular opacification. High-resolution optical slit-lamp images were analyzed by an ophthalmologist. Patients with IH had cataract surgery at a younger age than controls (34.0 ± 16.4 years vs 58.0 ± 11.2 years, P < 0.001). A higher proportion of IH patients had dense white PCO (75.0 % vs 39.4 %, P = 0.004), Nd:YAG laser capsulotomy (44.2 % vs 10.0 %, P = 0.001), anterior capsular opacification (97.7 % vs 84.2 %, P = 0.03), and a decentric lens (28.3% vs 2.6 %, P = 0.001) at a comparable time after surgery (8.6 ± 6.1 years vs 8.7 ± 6.8 years, P = 0.85). On regression analysis, the severity of PCO in IH correlated only with male sex and not with other factors, including serum total calcium and inorganic phosphorus levels at the baseline and during follow-up. To conclude, patients with IH are likelier than individuals without IH to develop PCO and to require Nd:YAG laser capsulotomy after cataract surgery. Proper precautions should be taken during surgery to minimize this complication in IH.


Asunto(s)
Extracción de Catarata , Hipercalcemia/complicaciones , Hipoparatiroidismo/complicaciones , Adulto , Estudios de Casos y Controles , Catarata/complicaciones , Catarata/patología , Extracción de Catarata/efectos adversos , Femenino , Humanos , Cápsula del Cristalino/patología , Cápsula del Cristalino/cirugía , Masculino , Análisis Multivariante , Complicaciones Posoperatorias/etiología , Análisis de Regresión , Lámpara de Hendidura , Factores de Tiempo , Resultado del Tratamiento
10.
Clin Endocrinol (Oxf) ; 84(4): 578-86, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26147910

RESUMEN

BACKGROUND: Patients with idiopathic hypoparathyroidism (IH) require variable doses of calcium and 1-α-(OH)D. The reasons for such variability are not clear. As autoimmune mechanisms may play a role in IH, there is a possibility of coexistent coeliac disease with calcium/vitamin D malabsorption. OBJECTIVE: We assessed the prevalence of coeliac disease and antitissue transglutaminase autoantibodies (anti-tTGAbs) in IH and analysed the effect of a gluten-free diet on calcaemic control. METHOD: A total of 171 patients with IH and 126 healthy controls were screened for anti-tTGAb. IH patients with anti-tTGAb >20 RU/ml underwent duodenoscopy and intestinal biopsy; those with biopsy-proven coeliac disease were followed up on a gluten-free diet. RESULTS: Eleven of 171 (6·4%) patients with IH and seven of 126 (5·6%) controls had anti-tTGAb (P = 0·81). There was no difference in the clinical and biochemical parameters at diagnosis and during long-term follow-up of 7·2 ± 4·8 year (mean serum total calcium = 1·88 ± 0·16 vs 1·82 ± 0·36 mmol/l, P = 0·52; phosphorus = 1·81 ± 0·17 vs 1·87 ± 0·36 mmol/l, P = 0·53) in IH patients with and without anti-tTGAb. Although CaSRAb positivity was comparable in the two groups, IH patients with anti-tTGAb had higher TPOAb positivity (45·5% vs 12·8%, P = 0·02). Coeliac disease was diagnosed in only 2/9 patients with IH on biopsy, both of whom showed improved calcaemic control with a gluten-free diet. CONCLUSION: The prevalence of coeliac autoimmunity (6·4%) and coeliac disease (1·2%) in patients with IH seems to be similar to that in the general population. Notwithstanding this modest prevalence, it is important to be aware of the potential occurrence of coeliac disease with IH and the beneficial effect of a gluten-free diet on calcium control.


Asunto(s)
Enfermedad Celíaca/inmunología , Dieta Sin Gluten , Hipercalcemia/dietoterapia , Hipoparatiroidismo/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Biopsia , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Comorbilidad , Duodenoscopía , Femenino , Estudios de Seguimiento , Humanos , Hipercalcemia/embriología , Hipoparatiroidismo/epidemiología , India/epidemiología , Intestinos/patología , Masculino , Persona de Mediana Edad , Prevalencia , Transglutaminasas/inmunología , Adulto Joven
11.
Mol Cell Biochem ; 417(1-2): 49-56, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27160934

RESUMEN

Selection of appropriate housekeeping-genes as reference is important in mRNA expression-related experiments. It is more important in diabetes since hyperglycemia per se can influence expression of housekeeping-genes. RNA expression of Glyceraldehyde-3-phosphate-dehydrogenase, ß-actin and 18S-ribosomal-RNA, Hypoxanthine-phosphoribosyl-transferase (HPRT), Tyrosine-3-monooxygenase/tryptophan (YHWAZ), ß2-microglobin (ß2M), TATA-binding-protein (TBP), and Ubiquitin C and cytochrome1 (CYC1) assessed in circulating-lymphocytes-(PBMC) of patients with type-1-diabetes and healthy controls. The stability ('M' value <1.02) and number of housekeeping-genes required for normalization in qRT-PCR were determined by 'ge-norm software.' Vitamin-D-receptor (VDR) was used as a target gene. All the nine genes tested had sufficient 'M' value in diabetes and healthy controls. However, housekeeping-genes indicated a relatively higher stability of expression in healthy controls in comparison to diabetes. Use of single housekeeping-genes brought gross variation in the calculation of VDR-mRNA copies. The ge-norm software suggested geometric mean of five housekeeping-genes for ideal normalization in diabetes (CYC1, ß-actin, YHWAZ, HPRT, and ß2M) and only three in controls (CYC1, ß-actin, and TBP). HbA1c did not correlate with expression of any of the nine housekeeping-genes. Thus, geometric mean of CYC1, ß-actin, YHWAZ, HPRT, and ß2M needs to be used for ideal normalization of mRNA in type-1-diabetes. Similar studies are required in other population.


Asunto(s)
Diabetes Mellitus Tipo 1 , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genes Esenciales , ARN Mensajero , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adolescente , Adulto , Niño , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Perfilación de la Expresión Génica/normas , Humanos , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normas
12.
BMC Endocr Disord ; 14: 28, 2014 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-24655472

RESUMEN

BACKGROUND: Some of the patients with idiopathic hypoparathyroidism (IHP) report symptoms of hypocalcemia during menstruation. There is limited data on this observation. METHODS: Twenty six menstruating women with IHP and 26 healthy controls were questioned regarding symptoms suggestive of hypocalcemia during menstruation. Twelve patients and eight controls were asked to prospectively monitor symptoms suggestive of hypocalcemia and premenstrual syndrome (PMS) if any, over two consecutive menstrual cycles. Serum ionized calcium (SiCa++), total and albumin adjusted calcium and intact paratharmone (iPTH) were measured at eight points covering menstrual, immediate post-menstrual, mid-cycle and premenstrual phase. RESULTS: Twelve of the 26 (46.2%) patients with IHP reported hypocalcemic symptoms during menstruation as compared to none of the controls. During prospective monitoring, there was no specific trend of hypocalcemic symptoms with respect to the phase of menstrual cycle. The mean SiCa++, serum total and albumin-adjusted calcium, iPTH and inorganic-phosphorus measured over two menstrual cycles were not significantly different in either of the two study groups. None of the subjects had PMS. CONCLUSION: Women with IHP do not show any trend of hypocalcemic symptoms or fluctuations in serum calcium over different phases of menstrual cycles. Therefore, patients with hypoparathyroidism linking hypocalcemic symptoms with menstruation should be reassured regarding lack of this association.

13.
World J Microbiol Biotechnol ; 30(5): 1575-82, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24337707

RESUMEN

Cells of Azotobacter chroococcum MAL-201 (MTCC 3853) are capable of accumulating the intracellular poly(3-hydroxybutyric acid) [P(3HB)], accounting for 65-71 % of its cell dry weight and also capable of synthesizing the enzyme alkaline phosphatase (APase), when grown in glucose and tricalcium phosphate containing nitrogen-free modified Stockdale medium. The concentration of insoluble phosphate in broth medium was optimized as 0.25 % (w/v) for growth and biosynthesis of APase. However, the suboptimal concentration of phosphate (0.1 %, w/v) appeared as the best suited for accumulation of P(3HB) by the strain. The significant differences were observed in biosynthesis of polymer and APase enzyme under variable phosphate concentrations. Glucose, 3.0 % (w/v) was recorded as the optimum concentration for all of the three parameters. The continuation of APase biosynthesis was observed during the period of significant decline in the cellular content of the polymer in the late phase of growth. In order to study the role of P(3HB), the rate of autodigestion of biopolymer and phosphate solubilization rate (k, mineralization constant) were determined in carbon-free medium under batch cultivation process and the parameters were found to be positively correlated. The maximum phosphate solubilization rate (k = 0.0154) by the strain MAL-201 timed at the 10th hour of incubation when the rate of polymer degradation concomitantly attained its peak corresponding to 87 mg/l/h and then declined gradually. Only a negligible amount of residual polymer remained undigested. These data strongly support the functional role of P(3HB) in response to multinutritional stress condition.


Asunto(s)
Fosfatasa Alcalina/metabolismo , Azotobacter/crecimiento & desarrollo , Proteínas Bacterianas/metabolismo , Fosfatos de Calcio/metabolismo , Hidroxibutiratos/metabolismo , Poliésteres/metabolismo , Azotobacter/clasificación , Azotobacter/enzimología , Carbono/metabolismo , Medios de Cultivo/metabolismo , Cinética , Nitrógeno/metabolismo
14.
Artículo en Inglés | MEDLINE | ID: mdl-38758961

RESUMEN

CONTEXT: Hypocalcemia predisposes patients with chronic hypoparathyroidism (cHypoPT) to an increased risk of QTc prolongation and life-threatening arrhythmias. Information on clinical and biochemical correlates of QTc in cHypoPT is limited. DESIGN AND SETTING: Observational cohort study at tertiary-care-center. SUBJECTS AND METHODS: Eighty-eight non-surgical cHypoPT (mean age 44.1 ± 15.4 years, 45 males) were assessed for QTc interval and its possible correlates including arrhythmic symptoms (palpitation/giddiness/syncope), serum total-calcium, phosphate, 25(OH)D and iPTH. RESULTS: The mean QTc in HypoPT cohort was 428 ± 34 ms with 13.6% having prolonged QTc. There was a significant inverse correlation between QTc interval and serum total-calcium measured on the same day (r = -0.43, p < 0.001). The mean serum total-calcium was significantly lower in patients with prolonged QTc (7.05 ± 1.94 vs. 8.49 ± 1.01 mg/dL, p = 0.02). 21.6% of cHypoPT patients had arrhythmic symptoms. They had significantly higher mean QTc (p = 0.02) and also tended to have lower mean serum total-calcium during follow-up (p = 0.06). In multivariable regression, female gender, higher current-age, higher BMI, and low serum total-calcium showed significant association with prolonged QTc. For every mg/dL decrease in serum total-calcium, QTc increased by 13 ms. Receiver-operating-characteristic analysis revealed serum total-calcium at cut-off of 8.3 mg/dL discriminated prolonged QTc with area-under-curve being 0.72 [95% CI: 0.51,0.93]. CONCLUSION: One-fifth of cHypoPT had arrhythmic symptoms and a significant proportion had prolonged QTc. This highlights the need for close monitoring of cHypoPT patients for arrhythmic symptoms and QTc prolongation. The serum total-calcium should be maintained to at least 8.3 mg/dL to minimize the risk of potentially life-threatening arrhythmia in cHypoPT.

15.
J Phys Chem A ; 117(33): 7661-9, 2013 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-23879409

RESUMEN

Lindemann, almost a century ago, proposed a schematic mechanism for unimolecular gas-phase reactions. Here, we present a new semiempirical method to calculate the effective rate constant in unimolecular gas-phase kinetics through a stochastic reformulation of Lindemann kinetics. Considering the rate constants for excitation and de-excitation steps in the Lindemann mechanism as temperature dependent empirical parameters, we construct and solve a chemical master equation for unimolecular gas-phase kinetics. The effective rate constant thus obtained shows excellent agreement with experimental data in the entire concentration range in which it is reported. The extrapolated values of the effective rate constant for very low and very high concentrations of inert gas molecules are in close agreement with values obtained using the Troe semiempirical method. Stochastic Lindemann kinetics, thus, provides a simple method to construct the full falloff curves and can be used as an alternative to the Troe semiempirical method of kinetic data analysis for unimolecular gas-phase reactions.

16.
J Chem Phys ; 137(4): 045102, 2012 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-22852658

RESUMEN

Recent studies in single-molecule enzyme kinetics reveal that the turnover statistics of a single enzyme is governed by the waiting time distribution that decays as mono-exponential at low substrate concentration and multi-exponential at high substrate concentration. The multi-exponentiality arises due to protein conformational fluctuations, which act on the time scale longer than or comparable to the catalytic reaction step, thereby inducing temporal fluctuations in the catalytic rate resulting in dynamic disorder. In this work, we study the turnover statistics of a single enzyme in the presence of inhibitors to show that the multi-exponentiality in the waiting time distribution can arise even when protein conformational fluctuations do not influence the catalytic rate. From the Michaelis-Menten mechanism of inhibited enzymes, we derive exact expressions for the waiting time distribution for competitive, uncompetitive, and mixed inhibitions to quantitatively show that the presence of inhibitors can induce dynamic disorder in all three modes of inhibitions resulting in temporal fluctuations in the reaction rate. In the presence of inhibitors, dynamic disorder arises due to transitions between active and inhibited states of enzymes, which occur on time scale longer than or comparable to the catalytic step. In this limit, the randomness parameter (dimensionless variance) is greater than unity indicating the presence of dynamic disorder in all three modes of inhibitions. In the opposite limit, when the time scale of the catalytic step is longer than the time scale of transitions between active and inhibited enzymatic states, the randomness parameter is unity, implying no dynamic disorder in the reaction pathway.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Enzimas/metabolismo , Inhibidores Enzimáticos/química , Enzimas/química , Cinética
17.
Phys Rev Lett ; 107(21): 218301, 2011 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-22181931

RESUMEN

Recent fluorescence spectroscopy measurements of single-enzyme kinetics have shown that enzymatic turnovers form a renewal stochastic process in which the inverse of the mean waiting time between turnovers follows the Michaelis-Menten equation. We study enzyme kinetics at physiologically relevant mesoscopic concentrations using a master equation. From the exact solution of the master equation we find that the waiting times are neither independent nor identically distributed, implying that enzymatic turnovers form a nonrenewal stochastic process. The inverse of the mean waiting time shows strong departure from the Michaelis-Menten equation. The waiting times between consecutive turnovers are anticorrelated, where short intervals are more likely to be followed by long intervals and vice versa. Correlations persist beyond consecutive turnovers indicating that multiscale fluctuations govern enzyme kinetics.


Asunto(s)
Biocatálisis , Enzimas/química , Enzimas/metabolismo , Modelos Químicos , Probabilidad , Procesos Estocásticos , Termodinámica
18.
J Clin Endocrinol Metab ; 106(7): 2092-2102, 2021 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-33616655

RESUMEN

CONTEXT: Alfacalcidol and calcitriol are commonly used for managing hypoparathyroidism. Their relative merits have not been systematically assessed. OBJECTIVE: We compared the effect of alfacalcidol and calcitriol on phosphatemic control, hypercalciuria, and associated factors in idiopathic-hypoparathyroidism (IH). DESIGN AND SETTING: Open-label randomized controlled trial, tertiary care center. SUBJECTS AND METHODS: IH patients with optimal calcemic control on alfacalcidol were continued on the same (n = 20) or switched to calcitriol (n = 25) at half of the ongoing alfacalcidol dose. The dose was adjusted during follow-up to maintain serum total calcium between 8.0 and 9.5 mg/dL. Serum calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 24-h urine calcium-to-creatinine ratio, and fractional excretion of phosphorus (FEPh) were measured at baseline and 6 months. Plasma intact-FGF23 was measured at final follow-up. RESULT: Patients receiving alfacalcidol and calcitriol had comparable serum calcium at 6 months (8.7 ±â€…0.4 vs 8.9 ±â€…0.4 mg/dL, P = 0.13). Their median [interquartile range (IQR)] dose at 6 months was 2.0 (1.0-2.5) and 0.75 (0.5-1.0) µg/d, respectively. Serum 1,25(OH)2D levels were physiological in both (35.3 ±â€…11.6 and 32.3 ±â€…16.9 pg/mL). Serum phosphate and calcium excretion were comparable in 2 arms. A majority had hyperphosphatemia (75% vs 76%), hypercalciuria (75% vs 72%), and elevated FGF23 (116 ±â€…68 and 113 ±â€…57 pg/mL). Age showed significant independent association with plasma FGF23 (ß = 1.9, P = 0.001). Average FEPh was low despite high FGF23. CONCLUSION: At optimal calcium control, both alfacalcidol and calcitriol lead to comparable but high serum phosphate levels, hypercalciuria, physiological circulating 1,25(OH)2D, and elevated FGF23. Further studies are required to systematically investigate other treatment options.


Asunto(s)
Calcitriol/uso terapéutico , Hormonas y Agentes Reguladores de Calcio/uso terapéutico , Hidroxicolecalciferoles/uso terapéutico , Hipoparatiroidismo/tratamiento farmacológico , Adulto , Calcio/sangre , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hipercalciuria/inducido químicamente , Hiperfosfatemia/inducido químicamente , Hipoparatiroidismo/sangre , Masculino , Hormona Paratiroidea/sangre , Fosfatos/sangre , Resultado del Tratamiento , Vitamina D/análogos & derivados , Vitamina D/sangre
19.
J Phys Chem B ; 125(29): 8010-8020, 2021 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-34270240

RESUMEN

Single-molecule experiments on ß-galactosidase from Escherichia coli that catalyzes the hydrolysis of resorufin-ß-d-galactopyranoside revealed important observations like fluctuating catalytic rate, memory effects arising from temporal correlations between the enzymatic turnovers and nonexponential waiting time distributions. The root cause of the observed results is intrinsic fluctuations among the different conformers of the active species, during the course of the reaction, thereby imparting dynamic disorder in the system under investigation. Originally, a multistate stochastic kinetic theory was employed that, despite satisfying the measured waiting time distributions and the mean waiting times at different substrate concentrations, yields a constant estimate of the randomness parameter. Inevitably, this manifests a strong disagreement with the substrate-concentration-dependent time variations of the said distribution, which at the same time misinterprets the measured magnitudes of the randomness parameter at lower concentrations. Here, we suggest a dual approach to the single-enzyme reaction, independently, making important improvements over the parent study and the recently suggested two-state stochastic analyses followed by quantitative rationalization of the experimental data. In the first case, an off-pathway mechanism satisfied the Michaelis-Menten equation under the circumstance of prevailing disorder while tested against the single-molecule data. However, recovery of randomness data in the lower-concentration regime, albeit primarily marks a significant refinement, a qualitative agreement at the growing concentrations seems to be reasoned by an account of switching among the limited numbers of discrete conformers. Consequently, in the second case, we circumvented the conventional way of approaching the enzyme catalysis and mapped the dynamics of structural transitions of the biocatalyst with the temporal fluctuations of the spatial distance between the different locations along a coarse-grained polymer chain. Exploiting a general mechanism for dynamic disorder, a reaction-diffusion formalism yielded an analytical expression for the waiting time distribution of the enzymatic turnovers, from which the mean waiting time and the randomness parameter were readily determined. Application of our results to the findings of the experiment on single ß-galactosidase shows a quantitative agreement in each case. This soundly validates the usefulness of accounting for a more rigorous microscopic description pertinent to the conformational multiplicity in rationalizing the real-time data over the routine state-based sketch of the reaction system.


Asunto(s)
Escherichia coli , Catálisis , Difusión , Escherichia coli/metabolismo , Cinética , beta-Galactosidasa/metabolismo
20.
Endocrinology ; 162(4)2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33539507

RESUMEN

CONTEXT: Basal-ganglia calcification (BGC) is common (70%) in patients with chronic hypoparathyroidism. Interestingly, cortical gray matter is spared from calcification. The mechanism of BGC, role of hyperphosphatemia, and modulation of osteogenic molecules by parathyroid hormone (PTH) in its pathogenesis is not clear. OBJECTIVE: We assessed the expression of a large repertoire of molecules with proosteogenic or antiosteogenic effects, including neuroprogenitor cells in caudate, dentate, and cortical gray matter from normal autopsy tissues. The effect of high phosphate and PTH was assessed in an ex vivo model of BGC using striatum tissue culture of the Sprague-Dawley rat. METHODS: The messenger RNA and protein expression of 39 molecules involved in multiple osteogenic pathways were assessed in 25 autopsy tissues using reverse-transcriptase polymerase chain reaction, Western blot, and immunofluorescence. The striatal culture was maintained in a hypoparathyroid milieu for 24 days with and without (a) high phosphate (10-mm ß-glycerophosphate) and (b) PTH(1-34) (50 ng/mL Dulbecco's modified Eagle's medium-F12 media) for their effect on striatal calcification and osteogenic molecules. RESULTS: Procalcification molecules (osteonectin, ß-catenin, klotho, FZD4, NT5E, LRP5, WNT3A, collagen-1α, and SOX2-positive neuroprogenitor stem cells) had significantly higher expression in the caudate than gray matter. Caudate nuclei also had higher expression of antiosteogenic molecules (osteopontin, carbonic anhydrase-II [CA-II], MGP, sclerostin, ISG15, ENPP1, and USP18). In an ex vivo model, striatum culture showed an increased propensity for calcified nodules with mineral deposition similar to that of bone tissue on Fourier-transformed infrared spectroscopy, alizarin, and von Kossa stain. Mineralization in striatal culture was enhanced by high phosphate and decreased by exogenous PTH through increased expression of CA-II. CONCLUSION: This study provides a conceptual advance on the molecular mechanisms of BGC and the possibility of PTH therapy to prevent this complication in a hypoparathyroid milieu.


Asunto(s)
Ganglios Basales/fisiopatología , Hipoparatiroidismo/fisiopatología , Osteogénesis , Animales , Ganglios Basales/metabolismo , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Calcinosis , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , Núcleo Caudado/metabolismo , Marcadores Genéticos/genética , Sustancia Gris/metabolismo , Humanos , Hipoparatiroidismo/genética , Hipoparatiroidismo/metabolismo , Técnicas In Vitro , Masculino , Osteonectina/genética , Osteonectina/metabolismo , Hormona Paratiroidea/metabolismo , Fosfatos/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Ratas , Ratas Sprague-Dawley
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