Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. ...Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.
•Aspects of the current knowledge of the role of the SSADH enzyme are summarized.•Pathological and polymorphic variations are responsible for SSADH enzyme variability.•Integrated genomics and metabolomic approaches for treatment of SSADHD patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We hypothesized that blood levels of γ-aminobutyric acid (GABA) and γ-hydroxybutyric acid (GHB), biomarkers of succinic semialdehyde dehydrogenase deficiency (SSADHD), would correlate with age. GABA ...and GHB were quantified in plasma and red blood cells (RBCs) from 18 patients (age range 5–41 years; median 8). Both metabolites negatively correlated with age (
P
< 0.05). Plasma and RBC GHB declined with age, reaching a nadir and approximate steady state by 10 years. Declining plasma GABA achieved this approximate steady state at 30–40 years of age. These biomarker relationships may reflect further GABA- and GHB-ergic neurotransmission imbalances that correlate with the onset of adolescent/adulthood neuropsychiatric morbidity and epilepsy in SSADHD.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Objectives To test the antimicrobial activity and evaluate the risk of systemic toxicity of novel catheters coated with silver nanoparticles. Methods Catheters were coated with silver using AgNO3, a ...surfactant and N,N,N ′,N ′-tetramethylethylenediamine as a reducing agent. Particle size was determined by electron microscopy. Silver release from the catheters was determined in vitro and in vivo using radioactive silver (110mAg+). Activity on microbial growth and biofilm formation was evaluated against pathogens most commonly involved in catheter-related infections, and the risk for systemic toxicity was estimated by measuring silver biodistribution in mice implanted subcutaneously with 110mAg+-coated catheters. Results The coating method yielded a thin (∼100 nm) layer of nanoparticles of silver on the surface of the catheters. Variations in AgNO3 concentration translated into proportional changes in silver coating (from 0.1 to 30 µg/cm2). Sustained release of silver was demonstrated over a period of 10 days. Coated catheters showed significant in vitro antimicrobial activity and prevented biofilm formation using Escherichia coli, Enterococcus, Staphylococcus aureus, coagulase-negative staphylococci, Pseudomonas aeruginosa and Candida albicans. Approximately 15% of the coated silver eluted from the catheters in 10 days in vivo, with predominant excretion in faeces (8%), accumulation at the implantation site (3%) and no organ accumulation (≤ 0.1%). Conclusions A method to coat plastic catheters with bioactive silver nanoparticles was developed. These catheters are non-toxic and are capable of targeted and sustained release of silver at the implantation site. Because of their demonstrated antimicrobial properties, they may be useful in reducing the risk of infectious complications in patients with indwelling catheters.
We report the in vitro assessment of pharmacotoxicity for the high-affinity GHB receptor ligand, NCS-382, using neuronal stem cells derived from mice with a targeted deletion of the aldehyde ...dehydrogenase 5a1 gene (succinic semialdehyde dehydrogenase(SSADH)-deficient mice). These animals represent a phenocopy of the human disorder of GABA metabolism, SSADH deficiency, that metabolically features accumulation of both GABA and the GABA-analog γ-hydroxybutyric acid in conjunction with a nonspecific neurological phenotype. We demonstrate for the first time using MDCK cells that NCS-382 is actively transported and capable of inhibiting GHB transport. Following these in vitro assays with in vivo studies in aldh5a1−/− mice, we found the ratio of brain/liver GHB to be unaffected by chronic NCS-382 administration (300mg/kg; 7 consecutive days). Employing a variety of cellular parameters (reactive oxygen and superoxide species, ATP production and decay, mitochondrial and lysosomal number, cellular viability and necrosis), we demonstrate that up to 1mM NCS-382 shows minimal evidence of pharmacotoxicity. As well, studies at the molecular level indicate that the effects of NCS-382 at 0.5mM are minimally toxic as evaluated using gene expression assay. The cumulative data provides increasing confidence that NCS-382 could eventually be considered in the therapeutic armament for heritable SSADH deficiency.
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•NCS-382 pharmacotoxicity was evaluated in SSADH-deficient neural stem cells.•NCS-382 is actively transported and inhibits GHB transport in epithelial MDCK cells.•NCS-382 showed minimal toxicity in parameters of cellular oxidative stress.•NCS-382 minimally impacted cell organelle number, viability, and gene expression.•NCS-382 holds promise for treating SSADH deficiency, a disorder of GABA metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy.
This multicenter phase 3 study enrolled patients with ...positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes.
T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 only for medial/central or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival.
In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Gamma-hydroxybutyrate (GHB) is a drug of abuse, an approved therapeutic for narcolepsy, an agent employed for facilitation of sexual assault, as well as a biomarker of succinic semialdehyde ...dehydrogenase deficiency (SSADHD). Our laboratory seeks to identify surrogate biomarkers in SSADHD that can shed light on the developmental course of this neurometabolic disease. Since GHB may be quantified in hair as a potential surrogate to identify victims of drug-related assault, we have opted to examine its level in SSADHD. We quantified GHB in hair derived from ten patients with SSADHD, and documented a significant negative age correlation. These findings are consistent with recent results in patient biological fluids, including plasma and red blood cells. These findings may provide additional insight into the developmental course of SSADHD (Jansen et al., J Inherit Metab Dis 39:795–800, 2016).
HEALTHY was a 3-year middle school-based primary prevention trial to reduce modifiable risk factors for type 2 diabetes in youth. The study was conducted at seven centers across the country. This ...paper describes the recruitment and retention activities employed in the study. Schools and students were the focus of recruitment and retention. Each center was responsible for the recruitment of six schools; eligibility was based on ability to enroll a sufficient number of predominately minority and lower socioeconomic status students. Study staff met with district superintendents and school principals to verify the eligibility of schools, and to ascertain how appropriate the school would be for conducting the trial. Sixth grade students were recruited employing a variety of techniques; students and their parents did not know whether their school was randomized to the intervention or control arm. This cohort was followed through sixth, seventh and eighth grades. In the eighth grade, an additional sample of students who were not originally enrolled in the study was recruited in a similar manner to participate in data collection to allow for cross-sectional and dose-response secondary analyses. Parents signed informed consent forms and children signed informed assent forms, as per the needs of the local Institutional Review Board. Parents received a letter describing the results of the health screening for their children after data collection in sixth and eighth grades. Retention of schools and students was critical for the success of the study and was encouraged through the use of financial incentives and other strategies. To a large extent, student withdrawal due to out-migration (transfer and geographical relocation) was beyond the ability of the study to control. A multi-level approach that proactively addressed school and parent concerns was crucial for the success of recruitment and retention in the HEALTHY study.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic ...semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear. Pharmacological antagonism of GHB binding may have multiple instances of therapeutic relevance. The high affinity GHB receptor antagonist, NCS-382 (6,7,8,9-tetrahydro-5-hydroxy-5H-benzo-cyclohept-6-ylideneacetic acid) has not been piloted in humans. To address the potential clinical utility of NCS-382, we have piloted initial studies of its toxicology in HepG2 and primary hepatocyte cells. At high dose (0.5mM), NCS-382 showed no capacity for inhibition of microsomal CYPs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) and minimal potential for activation of xenobiotic nuclear receptors. Additional cellular integrity and functional assays (viability, oxidative stress, apoptosis, ATP production) revealed little evidence for cytotoxicity, and a low degree of dysregulation of >370 genes actively engaged in the mediation of cellular toxicity. In vitro testing indicates a low probability of cellular toxicity associated with NCS-382.
•NCS-382 did not inhibit multiple human microsomal cytochrome P450s•NCS-382 did not significantly induce xenobiotic nuclear receptors•NCS-382 did not provide evidence of cell toxicity•NCS-382 did not dysregulate multiple genes implicated in toxicological processes•NCS-382 appears to have a good safety profile.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The recently identified transient receptor potential (TRP) channel family member, TRPV4 (formerly known as OTRPC4, VR-OAC, TRP12, and VRL-2) is activated by hypotonicity. It is highly expressed in ...the kidney as well as blood-brain barrier-deficient hypothalamic nuclei responsible for systemic osmosensing. Apart from its gating by hypotonicity, little is known about TRPV4 regulation. We observed that hypotonic stress resulted in rapid tyrosine phosphorylation of TRPV4 in a heterologous expression model and in native murine distal convoluted tubule cells in culture. This tyrosine phosphorylation was sensitive to the inhibitor of Src family tyrosine kinases, PP1, in a dose-dependent fashion. TRPV4 associated with Src family kinases by co-immunoprecipitation studies and confocal immunofluorescence microscopy, and this interaction required an intact Src family kinase SH2 domain. One of these kinases, Lyn, was activated by hypotonic stress and phosphorylated TRPV4 in an immune complex kinase assay and an in vitro kinase assay using recombinant Lyn and TRPV4. Transfection of wild-type Lyn dramatically potentiated hypotonicity-dependent TRPV4 tyrosine phosphorylation whereas dominant negative-acting Lyn modestly inhibited it. Through mutagenesis studies, the site of tonicity-dependent tyrosine phosphorylation was mapped to Tyr-253, which is conserved across all species from which TRPV4 has been cloned. Importantly, point mutation of Tyr-253 abolished hypotonicity-dependent channel activity. In aggregate, these data indicate that hypotonic stress results in Src family tyrosine kinase-dependent tyrosine phosphorylation of the tonicity sensor TRPV4 at residue Tyr-253 and that this residue is essential for channel function in this context. This is the first example of direct regulation of TRP channel function through tyrosine phosphorylation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A School-Based Intervention for Diabetes Risk Reduction Foster, Gary D; Linder, Barbara; Baranowski, Tom ...
New England journal of medicine/The New England journal of medicine,
07/2010, Volume:
363, Issue:
5
Journal Article
Peer reviewed
Open access
This school-based study involved children whose race or ethnic group and socioeconomic status placed them at high risk for obesity and type 2 diabetes. Schools were randomly assigned to either a ...multicomponent school-based intervention or assessment only (control). The combined prevalence of overweight and obesity decreased in both study groups, although the comprehensive school-based intervention was associated with greater decreases in indicators of adiposity and insulin levels.
Recent data indicate that 16% of children 6 to 19 years of age in the United States are overweight, and 19% are obese.
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Rates are even higher in economically disadvantaged ethnic minority groups.
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Of all the consequences of childhood obesity,
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the most serious is the development of type 2 diabetes. Children in whom type 2 diabetes develops are at risk for complications from the disease, including retinopathy, neuropathy, and cardiovascular and renal disease, that can be manifested when they are adults, if not earlier. Schools present opportunities for reducing the risk of diabetes, since no other institution has as . . .
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