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Document: Charles D. Drake
No full textExtract from speech of Charles D. Drake, chairman of Committee of Seventy, delivered at St. Louis, October 17, 186
Preeclampsia risk, maternal 25-hydroxyvitamin D concentration, and variation in vitamin D metabolism pathway genes
No full textOBJECTIVE: Our objectives were to study the relationships between 25-hydroxyvitamin D (25(OH)D) and preeclampsia risk, maternal genetic variation in 3 vitamin D metabolism genes (GC, CYP27B1, VDR) and preeclampsia risk, and variation in the same genes and 25(OH)D. METHODS: We used two racially diverse pregnancy cohorts (EVITA and Collaborative Perinatal Project (CPP)) to achieve these objectives. We estimated the association between log-transformed 25(OH)D and preeclampsia risk in EVITA by using log-binomial regression with restricted cubic splines. In EVITA and CPP, we used multivariable logistic and linear regression models to estimate the associations between allelic variation and preeclampsia risk, and genotype and log-transformed 25(OH)D, respectively. Meta-analyses were conducted to calculate estimates of association between and within cohorts. RESULTS: Dose-response associations of 25(OH)D were observed for both severe and mild preeclampsia. Trends of associations were observed in genetic variation and preeclampsia risk. Compared with major allele carriers, Black mothers in EVITA who carried the minor allele for rs11732451 GC single nucleotide polymorphism (SNP) and 2 VDR SNPs (rs4340112, rs10459217) had increased odds of preeclampsia, while the odds were lowered for those who carried the minor allele for 1 GC SNP (rs1099028) and 2 VDR SNPs(rs757344, rs12721364). In the meta-analysis, two VDR SNPs (rs886441 and rs2853561) had trends of decreased odds of preeclampsia for all Black mothers. For the 25(OH)D analysis, statistically significant associations were observed. Compared with those with major allele genotypes, mothers with minor allele genotypes of rs1844885 (GC) and rs11168275 (VDR) had increased 25(OH)D and of rs11732451 (GC) had lowered 25(OH)D. In the meta-analysis on all Black mothers, rs1844885 (GC) was associated with increased 25(OH)D while there was a trend of decreased 25(OH)D for rs10877016 (CYP27B1). CONCLUSIONS: Low 25(OH)D may be enough to reduce risk of preeclampsia. If our findings are confirmed in a replication study, genetic variation may be an independent risk factor for maternal 25(OH)D, making the findings of this research relevant to public health
Characterization of a Mycobacterium Smegmatis Mutant that is Simultaneously Resistant to D-Cycloserine and Vancomycin.
No full textA mutant of Mycobacterium smegmatis has been isolated that is simultaneously resistant to both D-cycloserine (D-CS) and vancomycin. Genetic complementation with a PBP4 homolog restores sensitivity to both drugs. Resistance to D-CS and vancomycin in this mutant is most likely due to a novel mechanism involving peptidoglycan assembly at the cell surface
Evaluating the effectiveness of state R&D tax credits
No full textThis paper aimed to analyze the effectiveness of state R&D tax credit programs in the context of R&D-relevant policies and regional economic development policies. Although there were extensive theoretical recommendations for promoting private R&D, and state R&D tax credit programs have been one of the most popular regional economic development programs, only few evaluations of state R&D tax credit programs have been conducted. Inspired by this lack of previous study, this study provided an empirical finding for the effectiveness of these programs by applying a quasi-experimental approach, which means conducting experiments without randomness, for comparing states with tax credits and states with no credits.For dealing with the embedded non-randomness, plausible other explanations that weaken the causal relationship between the programs and the effects were examined and ruled out as much as possible. Rival hypotheses were selected using different tax and government policies, overall business and R&D-specific environments, and firm characteristics. They were eliminated by constructing valid control groups, using the difference-in-differences and matching methods, selecting covariates and matching variables as observable variables, and absorbing year-specific fixed effects and cross-sectional-fixed effects as unobservable variables. The decision was made based on multiple estimates and multiple datasets. The research analyzed two sets of industries: the all industry group and high-technology industy. The major findings are : 1) state R&D tax credits positively affect the increase in R&D spending and increase in employment; 2) positive effects on R&D spending are widespread across the all industry group while positive effects on employment are limited to high-technology industry overall; 3) positive effects on R&D spending are also spread out to different sized firms in both the all industry group and high-technology industry; and 4) positive effects on employment are found mainly in large firms in both the all industry group and high-technology industry.The above findings support the utilization of state R&D tax credits. As an indirect intervention, state R&D tax credit programs can increase productivity and encourage innovation by generating additional private R&D activities. State R&D tax credit programs can also make a positive contribution to regional economic growth through the growth of R&D-relevant and high-technology industries
Vitamin D: to test or not to test
No full textVitamin D deficiency has recently been linked to many chronic diseases such as MS (multiple sclerosis), cancer, rheumatoid arthritis, and diabetes. It has been a topic of debate among healthcare providers on whether or not it is beneficial to test and treat patients who have vitamin D deficiency. This paper looks at the potential mechanism of vitamin D in these disease processes and evaluates the various studies in the literature focusing on vitamin D levels and chronic diseases. This paper concludes by recommending that physicians in Allegheny County, PA, test all their adult patients for vitamin D deficiency, especially during the winter months. Vitamin D deficiency and the link to chronic disease have vast significance in the field of public health both in Allegheny County, PA, and nationwide
The Role of the Sympathetic Nervous System in the Hypothermic Effect of d-Fenfluramine
No full textExperiments in this dissertation were conducted to characterize the effects of d-fenfluramine on body temperature and the mechanisms by which d-fenfluramine alter body temperature. The experiments were conducted in conscious male Sprague-Dawley rats. Body temperature was measured in all animals using telemetry. The results of the experiments indicated that d-fenfluramine altered body temperature in animals kept 28, 22, 16 and 4 degrees Centigrade. D-fenfluramine produced hyperthermia in animals kept at 28 degrees Centigrade and varying degrees hypothermia at normal and cooler ambient temperatures. Further experiments were conducted to explore the effects of d-fenfluramine on brown adipose tissue (BAT) thermogenesis, cutaneous vascular tone and whole body oxygen consumption. In animals kept at 22 and 4 degrees Centigrade, we found that d-fenfluramine activated BAT, as indicated by a decrease in BAT norepinephrine content, to the same magnitude. Thus, the hypothermia seen at normal and cooler ambient temperature was not due to lack of BAT activation. Also, activation of BAT by d-fenfluramine was mediated through the sympathetic nervous system and through release of central serotonin, since ganglionic blocker pentolinium and serotonin reuptake inhibitor fluoxetine blocked d-fenfluramine-mediated BAT activation. In animals kept at 16 degrees Centigrade, d-fenfluramine increased tail-skin temperature (Tsk), an index of cutaneous vascular tone, indicating that d-fenfluramine produced cutaneous vasodilation. d-fenfluramine-induced increase in Tsk was mediated through withdrawal of the sympathetic vasoconstrictor tone to the tail, since pentolinium blocks this effect. In animals kept at 28 degrees Centigrade, d-fenfluramine produced a decrease in Tsk, indicating vasoconstriction. The effects of d-fenfluramine on the Tsk were mediated through release of serotonin, since fluoxetine blocked these effects. D-fenfluramine increased whole body oxygen consumption, an index of metabolic activity and the increase was due to BAT activation, since pentolinium prevented the increase. Thus, although d-fenfluramine increased metabolic activity through BAT activation, the increase was insufficient to make up for the heat loss produced by cutaneous vasodilation and thus produces hypothermia. The hyperthermia seen at 28oC is due to activation of BAT and the subsequent inability of the animal to lose the excess heat due to cutaneous vasoconstriction produced by d-fenfluramine at 28 degrees Centigrade
MEDIATION OF CHEMOTHERAPY-INDUCED APOPTOSIS BY THE LYSOSOMAL PROTEASE CATHEPSIN D
No full textOne of the most common hallmarks of cancer is dysregulation of cellular apoptotic processes. A comprehensive knowledge of the underlying mechanisms of the apoptotic machinery is vital for the identification of new drug targets and the development of innovative agents that stimulate the cell death process in cancer cells. Studies have shown that the lysosomal protease cathepsin D is important in the extrinsic apoptotic pathway stimulated by the death receptor ligands for TNFR1 and FAS, as well as by oxidative stress and the protein kinase C inhibitor staurosporine. To date, the role of cathepsin D in the chemotherapy-induced apoptotic pathway has not been characterized. This project examined the role of the lysosomal protease cathepsin D in chemotherapy-induced apoptosis of HeLa and U937 cells. The data demonstrated that following stimulation of U937 cells with the chemotherapy drug VP-16, cathepsin D was released into the cytosol approximately 4 hours after drug treatment. This release was selective for cathepsin D, as cathepsin B and the lysosomal markers LAMP and â-hexosaminidase were not released into the cytosol following VP-16 treatment. Inhibitors of caspases andcathepsin D had no effect on cathepsin D release, demonstrating that cathepsin D release occurred independently of caspase and cathepsin D activities. Downregulation of cathepsin D expression in U937 and Hela cells using siRNA was found to inhibit cell death resulting from a variety of stimuli, including death receptor ligands, oxidative stress, PKC inhibitors, and importantly, chemotherapy drugs. In addition, U937 and HeLa cells expressing cathepsin D siRNA exhibited delayed cytochrome c release and caspase-3 activation following VP-16 treatment. Moreover, isolated mitochondria from wild-type U937 cells released cytochrome c in response to cytosolic extracts that were treated with cathepsin D, suggesting that cathepsin D acts on a cytosolic factor to induce cytochrome c release. Inhibition of caspases had no impact on cytochrome c release provoked by cathepsin D-cleaved cytosolic extract, demonstrating that caspases are not mediators of cathepsin D-induced cytochrome c release. Taken together, these results demonstrate that cathepsin D is an important component of the apoptotic pathway and that it acts via an intermediary cytosolic factor to promote cytochrome c release and caspase activation during chemotherapy-induced apoptosis
Tubular proteinuria and vitamin D deficiency in sickle cell disease
No full textKidney disease is a significant complication of sickle cell disease (SCD) with great public health concern, causing over 18% of total patient mortality. Proximal tubule (PT) dysfunction, including tubular proteinuria, is a common early symptom of kidney disease in SCD patients and can lead to chronic kidney disease. Although not well understood, PT dysfunction in SCD is thought to be caused by exposure to higher cell-free hemoglobin (Hb) concentrations from increased red blood cell hemolysis. Hb is filtered by the glomerulus to enter the tubule lumen, where it is reabsorbed by PT cells upon binding to multiligand receptors megalin and cubilin. Megalin and cubilin bind to numerous proteins in the kidney filtrate, including albumin, vitamin D binding protein (DBP), and retinol binding protein (RBP), and are important for maintaining vitamin homeostasis and a protein-free urine.
To better understand PT dysfunction at the cellular level, we treated PT cells with physiologic levels of Hb estimated in SCD and measured protein endocytosis and toxicity/oxidative stress. We found that Hb inhibited albumin, DBP, and RBP uptake by PT cells to variable degrees. Hb inhibition occurred in the absence of a cytotoxic response and appeared to be due to direct competition for megalin/cubilin binding. These results suggest that binding competition between Hb and normally filtered proteins may be the primary cause of tubular proteinuria in SCD patients. Additionally, Hb inhibition appeared to be selective for highly alpha helical proteins. Understanding the selectivity of Hb binding competition could help to identify biomarkers and therapeutic compounds to detect and treat tubular proteinuria in SCD patients prior to the onset of kidney disease.
Inhibition of DBP uptake by PT cells could contribute to vitamin D deficiency commonly observed in SCD patients. We also found prolonged Hb exposure created an increased cytotoxic response and alteration of vitamin D hydroxylase expression in PT cells, indicating Hb-induced toxicity may affect vitamin D metabolism. Finally, we observed selective changes in protein reabsorption by PT cells with variation of active vitamin D availability, suggesting further possible complications in protein reabsorption and vitamin D homeostasis in SCD patients with low vitamin D status
The Association Between Serum Vitamin D Concentration and Nueromuscular Function in Patients with Crohn's Disease
No full textSerum vitamin D concentrations are not typically assessed in patients with Crohn's disease, even though neuromuscular complaints are one of the most common complaints observed. Crohn's patients, especially with small bowel resections, are at risk for hypovitaminosis D and fatigue. Purpose: To determine if Crohn's disease patients have low serum 25(OH)D concentrations and to determine the association between 25(OH)D and measures of neuromuscular function, such as muscle strength, muscle fatigue, nerve function, and quality of health. Methods: Nineteen Crohn's patients (9 male and 10 female), with at least one small bowel resection were tested. Isometric muscle strength at 45� of knee extension and flexion, EMG fatigue rates of the rectus femoris (RF) and vastus lateralis (VL), and the total physical score (PCS) and total mental score (MCS) from the SF-36 were collected. Statistics: Pearson correlations were calculated to determine the association between vitamin D and the measures of neuromuscular function. Results: The mean 25(OH)D was 32ng/ml. The Crohn's patients tested were 43.16 + 10.26 years with an average of 1.79 resections and 17.79 years with the disease. The mean peak torque (Nm) for knee extension was 75.24 + 45.39, and 28.94 + 12.76 for flexion. The mean average peak torque (Nm) for knee extension was 55.91 + 35.55, and 20.96 + 9.80 for flexion. The mean fatigue rates (Hz/sec) were -0.07 + 0.05 for RF and -0.03 + 0.04 for VL. Peroneal nerve latency mean was 4.28 + 1.75 ms and the mean amplitude was 2.26 + 2.03 mV. No significant differences at the � = 0.05 level for muscle strength, fatigue rates, nerve function, and the MCS were found. A significant (p = 0.02) positive correlation existed for the PCS (r = 0.55) of the SF-36. Conclusions: The average vitamin D concentrations were sufficient and vitamin D was not correlated to muscle strength, fatigue, or nerve function. The serum vitamin D concentrations were found to explain 30% of the variability of the PCS of their quality of health. Further studies are required to identify the exact mechanisms of the decreased strength and fatigue experience by Crohn's patients
Vitamin D, Tissue Resistance, Bone Mineral Density and Breast Cancer Risk
No full textEtiologic factors such as vitamin D and estrogen are potentially related to breast cancer development, although details of their mechanisms are not completely understood. We prospectively investigated correlates of breast cancer risk among postmenopausal women in the Study of Osteoporotic Fractures (SOF). First, we undertook a case-cohort study to test the hypothesis that low serum 25-hydroxyvitamin D [25(OH)D] will be associated with an increased risk of ER+ breast cancer (N=502). Low 25(OH)D levels were not associated with an increased risk of breast cancer and do not support an association between 25(OH)D and ER+ breast cancer development. Second, we utilized fractional calcium absorption (FCA) as a marker of tissue resistance to vitamin D to test the hypothesis that low FCA will be associated with an increased risk of breast cancer (N=5035). To the contrary, over a mean 9.6 years, increasing rates of FCA were associated with a higher risk of invasive breast cancer. A stronger positive relationship was noted among women with low dietary calcium intake. The findings support a modestly increased risk of breast cancer with higher FCA rates particularly among those who have low calcium intake. Finally, we examined the long-term association of an initial bone mineral density (BMD) measure and change in BMD (annual percent change assessed 3.5 years later) on breast cancer risk (N=5385). Furthermore, we tested the hypothesis that the risk associated with an initial BMD measure would be strengthened by the addition of the change variable. Over a mean 9.5 years, there was no association between increasing levels of BMD, change in BMD, or a combined model and breast cancer. The effect of BMD was found to be dependent upon family history of breast cancer. Among women with a positive family history, high BMD was associated with a 3-fold higher risk of breast cancer compared to low BMD. Through our investigations of two etiologic factors and their association with breast cancer development, we have enhanced our knowledge regarding the interdependence of vitamin D, calcium, and estrogen. These findings may lead to improved opportunities for prevention and early detection and are of significant public health relevance
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