Background:As well as its role in the regulation of calcium metabolism, vitamin D is an immunoregulatory hormone. Epidemiological evidence also suggests a link between vitamin D deficiency and ...tuberculosis (TB). A study was undertaken to examine serum vitamin D concentrations before treatment in patients with active TB and their contacts from the same ethnic and social background and to investigate the relative contributions of diet and sunlight exposure.Methods:Serum vitamin D concentrations were measured before treatment in 178 patients with active TB and 130 healthy contacts. The prevalence of vitamin D deficiency and its relation to skin colour, month of estimation and TB diagnosis were determined. 35 patients and 35 frequency-matched contacts completed dietary and sun exposure questionnaires to determine the relative contribution of these to serum vitamin D concentrations.Results:There was a statistically significant difference in serum vitamin D concentrations between patients and contacts (20.1 vs 30.8 nmol/l, 95% CI 7.1 to 14.3; p<0.001) and significantly more patients had severely deficient concentrations (<21 nmol/l) than controls (114/178 (64%) vs 40/130 (31%), p<0.001). There was no association between serum concentrations of vitamin D and skin pigmentation. The healthy contacts showed a predictable seasonal pattern, rising to peak concentrations in the summer months, but this response was absent in patients with TB. Dietary intake was the same in both patients with TB and contacts matched for age, sex and skin colour, but patients with TB displayed a stronger correlation between serum vitamin D concentrations and dietary intake (r = 0.42, p = 0.016) than controls (r = 0.13, p>0.1). There was no difference in sunlight exposure between the groups.Conclusions:Patients with active TB have lower serum vitamin D concentrations than contacts from similar ethnic and social backgrounds and with comparable dietary intake and sun exposure, and do not show the expected seasonal variation. These observations indicate that other factors are contributing to vitamin D deficiency in patients with TB and suggest abnormal handling of this vitamin.
Vitamin D was used to treat tuberculosis in the pre-antibiotic era, and its metabolites induce antimycobacterial immunity in vitro. Clinical trials investigating the effect of adjunctive vitamin D on ...sputum culture conversion are absent.
We undertook a multicentre randomised controlled trial of adjunctive vitamin D in adults with sputum smear-positive pulmonary tuberculosis in London, UK. 146 patients were allocated to receive 2·5 mg vitamin D
3 or placebo at baseline and 14, 28, and 42 days after starting standard tuberculosis treatment. The primary endpoint was time from initiation of antimicrobial treatment to sputum culture conversion. Patients were genotyped for
TaqI and
FokI polymorphisms of the vitamin D receptor, and interaction analyses were done to assess the influence of the vitamin D receptor genotype on response to vitamin D
3. This trial is registered with
ClinicalTrials.gov number
NCT00419068.
126 patients were included in the primary efficacy analysis (62 assigned to intervention, 64 assigned to placebo). Median time to sputum culture conversion was 36·0 days in the intervention group and 43·5 days in the placebo group (adjusted hazard ratio 1·39, 95% CI 0·90–2·16; p=0.14).
TaqI genotype modified the effect of vitamin D supplementation on time to sputum culture conversion (p
interaction=0·03), with enhanced response seen only in patients with the
tt genotype (8·09, 95% CI 1·36–48·01; p=0·02).
FokI genotype did not modify the effect of vitamin D supplementation (p
interaction=0·85). Mean serum 25-hydroxyvitamin D concentration at 56 days was 101·4 nmol/L in the intervention group and 22·8 nmol/L in the placebo group (95% CI for difference 68·6–88·2; p<0·0001).
Administration of four doses of 2·5 mg vitamin D
3 increased serum 25-hydroxyvitamin D concentrations in patients receiving intensive-phase treatment for pulmonary tuberculosis. Vitamin D did not significantly affect time to sputum culture conversion in the whole study population, but it did significantly hasten sputum culture conversion in participants with the
tt genotype of the
TaqI vitamin D receptor polymorphism.
British Lung Foundation.
BACKGROUND
Previous Commission on Cancer data from the National Cancer Data Base (NCDB) have examined time trends in stage of disease, treatment patterns, and survival for selected cancers. The most ...current (1993) data are described here.
METHODS
Five calls for data have yielded a total of 3,700,000 cases for the years 1985 through 1993, including 477,679 cases for 1988, and 608,593 cases for 1993, from hospital cancer registries across the U.S.
RESULTS
The most recent call for data for 1993 comprised 52% of the estimated new cases of cancer in the U.S. The country was comprised of 6 regions, with the Mountain and Southeast regions having the highest regional reporting of new cases of cancer (69% and 55%, respectively) and the Northeast and Pacific regions having the lowest (47% each). Approximately 96% of patients received their treatment at the reporting hospital. The 4 most common carcinomas were breast (15.7%), lung (14.6%), prostate (14.2%), and colon (7.5%) and comprised the majority of new cases. Trends in patterns of care for breast carcinoma were analyzed for possible bias in the 1988 and 1993 periods. When hospitals reporting only in 1988 or in 1993 were compared with hospitals reporting at both time points, the only differences were small differences in ethnic participation. These differences were less than 1.5% in the proportion of African Americans reported in the different time periods. There were no significant differences in the downstaging of breast carcinoma, or the role of conservative surgery or adjuvant radiation therapy.
CONCLUSIONS
The NCDB is a cancer management and outcomes data base for health care organizations that presently comprises 52% of the estimated new cases in the U.S. This will increase to 80% as the approved hospitals of the Commission on Cancer are required to report to the NCDB. Comparison of breast carcinoma findings at two time periods appeared similar regardless of hospital reporting set (i.e., set of hospitals reporting for one period versus both periods). Cancer 1996;78:1829‐37.
The year 2019 featured extensive debates on transforming the United States multipayer health care system into a single-payer system. At a time when reimbursement structures are in flux and potential ...changes in government may affect health care, it is important for neuroradiologists to remain informed on how emerging policies may impact their practices. The purpose of this article is to examine potential ramifications for neuroradiologist reimbursement with the Medicare for All legislative proposals. An institution-specific analysis is presented to illustrate general Medicare for All principles in discussing issues applicable to practices nationwide.
Background: The diagnosis of spinal tuberculosis (ST) is difficult and it commonly presents at an advanced stage. The management and follow up is complicated by a lack of guidance on the appropriate ...use and interpretation of spinal magnetic resonance studies (MR). Aims: A retrospective study was performed at a UK centre to identify the demographic and presenting features of a spinal TB population, their response to treatment, and the value of follow up MR studies. Patients and Results: Twenty one patients were identified with mean symptom duration of 11 (1.5–36) months having been assessed by a health practitioner on 3.2 (0–10) occasions before referral for investigation for ST. Twenty were born outside the UK. Their mean duration of residence in the UK was 6.67 (0.75–20) years, and six (32%) were resident for more than 10 years. Most (85.7%) did not have a medical history and one was HIV positive. Back pain, neurological, and constitutional symptoms were found in 100%, 29%, and 38% respectively. Musculoskeletal and neurological signs were found in 29% and 19% respectively. Spinal MR performed between 6 and 12 months suggests that six months of chemotherapy (for a fully sensitive organism) may not be sufficient to achieve disease resolution. Conclusions: Awareness of the demographic, clinical, and laboratory features of an ST population may facilitate earlier diagnosis. Guidance is required on the appropriate use and interpretation of MRI in the follow up of these patients.
Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a variety of cellular processes. We describe a family of potent PDE4 inhibitors discovered using an ...efficient method for scaffold-based drug design. This method involves an iterative approach starting with low-affinity screening of compounds followed by high-throughput cocrystallography to reveal the molecular basis underlying the activity of the newly identified compounds. Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates.
Cyclic nucleotides are second messengers that are essential in vision, muscle contraction, neurotransmission, exocytosis, cell growth, and differentiation. These molecules are degraded by a family of ...enzymes known as phosphodiesterases, which serve a critical function by regulating the intracellular concentration of cyclic nucleotides. We have determined the three-dimensional structure of the catalytic domain of phosphodiesterase 4B2B to 1.77 angstrom resolution. The active site has been identified and contains a cluster of two metal atoms. The structure suggests the mechanism of action and basis for specificity and will provide a framework for structure-assisted drug design for members of the phosphodiesterase family.
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of ...the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.
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