Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation

We present the clinical, biochemical, and molecular findings of three Greek patients with tyrosine hydroxylase (TH) deficiency. All patients presented with a severe clinical phenotype characterized by prominent motor delay, infantile parkinsonism, oculogyric crises, and signs of autonomic dysfunction. Cerebrospinal fluid analysis disclosed reduced dopamine metabolites and normal pterins. Response to levodopa was favorable though not dramatic. All patients were homozygous for a previously reported mutation (p.L236P). SNP haplotype analysis was consistent with a common ancestral mutation, thus indicating a founder effect in Greek patients with TH deficiency. © 2010 Movement Disorder Society     

The Relationships Between IGF-1 and CRP, NO, Leptin, and Adiponectin During Weight Loss in the Morbidly Obese

Background

The relationship between C-reactive protein (CRP), nitric oxide (NO), leptin, adiponectin, and insulin growth factor 1 (IGF-1) is poorly defined in morbidly obese patients before and after gastric bypass and, in some cases, is controversial.

Methods

We examined the plasma of 34 morbidly obese patients before and 1, 6, and 12 months after Roux-en-Y gastric bypass surgery.

Results

Obese people had more CRP (21.3?±?1.8 μg/ml) and leptin (36.9?±?4.0 ng/ml) than those in the control group (nonobese people: CRP?= 6.9?±?0.9 μg/ml, p?<?0.0001; leptin?= 7.5?±?0.4 ng/ml, p?<?0.0001). However, they had less NO (30.4?±?2.7 nmol/ml), IGF-1 (77.5?±?6.6 ng/ml), and adiponectin (11.1?±?1.0 μg/ml) than those in the control group (NO?= 45.8?±?3.9 nmol/ml, p?=?0.0059; IGF-1?= 202.0?±?12.0 ng/ml, p?<?0.0001; adiponectin?= 18.0?±?2.0 μg/ml, p?<?0.0001). During weight loss, the amount of CRP and leptin decreased until they reached the nonobese values, but the level of NO remained lower than in nonobese people, even 1 year after surgery. The linear regression slopes were negative and very significant for leptin (p?=?0.0005) and CRP (p?=?0.0018) but were less significant for NO (p?=?0.0221). IGF-1 displayed a very good linear regression (both negative and significant) with some anthropometric parameters, including body mass index (p?=?0.0025), total fat (p?=?0.0177), and the percentage of fat (p?<?0.0001).

Conclusion

For the first time, we report the relationship between IGF-1 and CRP, NO, leptin, and adiponectin. For all these parameters, the best and most widely demonstrated improvements in comorbidities before and during weight loss in morbid obesity were associated with CRP and leptin.     

Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish Cohort

Osteoporosis is a complex disease involving many putative genetic factors. Association analysis of functional SNPs in candidate genes is an important tool for their identification. However, this approach is affected by limited power, population stratification, and other drawbacks that lead to discordant results. Replication in independent cohorts is essential. We performed association analyses of three functional polymorphisms previously associated with bone phenotypes—namely, Ala222Val in MTHFR, Ile1062Val in LRP6, and −13910C>T in LCT—in a cohort of 944 postmenopausal Spanish women, all of them with lumbar spine (LS) bone mineral density (BMD) data and most with femoral neck (FN) BMD and fracture data. We found significant differences between genotypes only for the MTHFR polymorphism and vertebral factures, with an OR of 2.27 (95% CI 1.17–4.38) for the TT vs. CC/CT genotypes, P = 0.018. We present genotype and allele frequency data for LCT −13910C>T for a Spanish population, where the T allele (conferring lactase persistence) has a frequency of 38.6%. Genotype frequencies were consistent with observed clines in Europe and with the prevalence of lactase nonpersistence. The LCT −13910C>T polymorphism was significantly associated with height and weight, such that T allele carriers were 0.88 cm taller (95% CI 0.08–1.59 cm, P = 0.032, adjusted by age) than CC individuals and TT homozygotes were 1.91 kg heavier than CC/CT individuals (95% CI 0.11–3.71 kg, P = 0.038, adjusted by age). In conclusion, no significant association was observed between the studied polymorphisms and LS BMD or FN BMD in postmenopausal Spanish women, and only MTHFR Ala222Val was associated with vertebral fractures.     

Analysis of the expectations of elderly patients before undergoing total knee replacement

The opinion of patients expressed in terms of satisfaction is extremely important in any evaluation of total knee arthroplasty (TKA) results. The primary endpoint of this study was to determine the quantitative and qualitative expectations of elderly patients before undergoing TKA. Cross-sectional study of 497 patients over 65 years was performed before TKA. Main variables collected: demographic, functioning, pain, comorbidity, depression and expectations assessed with the Hospital for Special Knee Replacement Expectation Survey. Statistical tests used were: Student's t-test, analysis of variance, Spearman's ρ and multivariate regression analysis. The means of the total and maximum expectations were 12.3 ± 1.63 and 9.5 ± 1.78 (±S.D.), respectively. Between 90 and 100% of patients referred expectations to improvement regarding pain, basic functional activities (walking, climbing stairs, knee mobility, general mobility) and general well being. There were statistically significant correlations with age (r = −0.321), pain before operation (r = −0.206), expected pain at 6 months (r = −0.206), depressive symptoms (r = −0.180) and the Barthel index (BI) (r = 0.154). One can conclude, that the expectations of improvement among patients before TKA are high and may be classified as expectations of improvement of pain, basic functional activities and general well being. Age, pain intensity and presence of depression correlate inversely with the amount of expectations.     

Effects of dopamine on LC3-II activation as a marker of autophagy in a neuroblastoma cell model

Dopamine at 100–500 μM has toxic effects on human SH-SY5Y neuroblastoma cells, manifested as apoptotic cell loss and strong autophagy. The molecular mechanisms and types of dopamine-induced cell death are not yet well known. Their identification is important in the study of neurodegenerative diseases that specifically involve dopaminergic neurons. We looked for changes in expression and content of proteins involved in apoptosis and autophagy after dopamine treatment. All the changes found were prevented by avoiding dopamine oxidation with N-acetylcysteine, indicating a key role for the products of dopamine oxidation in dopamine toxicity. As early as 1–2 h after treatment we found an increase in hypoxia-inducible factor-1α (HIF-1α) and an accumulation of ubiquitinated proteins. Proteins regulated by HIF-1α and involved in apoptosis and/or autophagy, such as p53, Puma and Bnip3, were subsequently increased. However, apoptotic parameters (caspase-3, caspase-7, PARP) were only activated after 12 h of 500 μM dopamine treatment. Autophagy, monitored by the LC3-II increase after LC3-I linkage to autophagic vacuoles, was evident after 6 h of treatment with both 100 and 500 μM dopamine. The mTOR pathway was inhibited by dopamine, probably due to the intracellular redox changes and energy depletion leading to AMPK activation. However, this mechanism is not sufficient to explain the high LC3-II activation caused by dopamine: the LC3-II increase was not reversed by IGF-1, which prevented this effect when caused by the mTOR inhibitor rapamycin. Our results suggest that the aggregation of ubiquitinated non-degraded proteins may be the main cause of LC3-II activation and autophagy. As we have reported previously, cytosolic dopamine may cause damage by autophagy in neuroblastoma cells (and presumably in dopaminergic neurons), which develops to apoptosis and leads to cell degeneration.