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Biomedical subjects

D Feldman

Publications and source records attributed to D Feldman.

At least 19 recordsLinked to original sources
PubMed2005

Concordance between childhood injury diagnoses from two sources: an injury surveillance system and a physician billing claims database.

OBJECTIVES: (1) To determine the concordance between injury diagnoses (head injury (HI), probable HI, or orthopedic injury) for children visiting an emergency department for an injury using two DATA SOURCES: an injury surveillance system (Canadian Hospitals Injury Research and Prevention Program, CHIRPP) and a physician billing claims database (Regie de l'assurance maladie de Quebec, RAMQ), and (2) to determine the sensitivity and specificity of diagnostic and procedure codes in billing claims for identifying HI and orthopedic injury among children. DESIGN: In this cross sectional cohort, data for 3049 children who sought care for an injury (2000-01) were obtained from both sources and linked using the child's personal health insurance number. METHODS: The physician recorded diagnostic codes from CHIRPP were used to categorize the children into three groups (HI, probable HI, and orthopedic), while an algorithm, using ICD-9-CM diagnostic and procedures codes from the RAMQ, was used to classify children into the same three groups. RESULTS: Concordance between the data sources was "substantial" (weighted Kappa 0.66; 95% CI 0.63 to 0.69). The sensitivity of diagnostic and procedure codes in the RAMQ database for identifying HI and for orthopedic injury were 0.61 (95% CI 0.57 to 0.64) and 0.97 (95% CI 0.96 to 0.98), respectively. The specificity for identifying HI and for orthopedic injury were 0.97 (95% CI 0.96 to 0.98) and 0.58 (95% CI 0.56 to 0.63), respectively. CONCLUSION: Combining diagnostic and procedures codes in a physician billing claims database (the RAMQ database) may be a valid method of estimating injury occurrence among children.

Adolescent↗
PubMed2005

Acute decompensated heart failure: best evidence and current practice.

Heart failure (HF) is one of the leading cardiovascular health problems in Europe and the United States. Acute decompensated HF remains a lethal diagnosis with a morbidity and mortality that often exceeds neoplastic or infective diseases. The incidence of HF continues to increase despite an intensive effort to increase education and delivery of healthcare to these affected patients. Yet, current guidelines in the United States do not address the management of acute decompensated HF, and focus predominantly on chronic stable systolic HF as well as patients with left ventricular dysfunction. Although the European Society of Cardiology has established some parameters for the management of acute HF, these guidelines are largely established by expert opinion, and are predominantly devoid of prospective randomized data in this cohort of patients. Current pharmacotherapies for acute decompensated HF include diuretics, neurohormonal antagonists, vasodilators, and inotropes. Regrettably, all of these drugs have their limitations in acute HF. Neurohormonal antagonists reduce morbidity and mortality, but may be inadequate to achieve and maintain the necessary hemodynamic relief required in advanced HF; while, bolus diuretics, a mainstay of initial symptomatic relief, may be maladaptive and up-regulate adverse neurohormonal regulatory mechanisms longterm with no positive impact on longterm mortality. Today, for those advanced HF patients who remain symptomatic despite optimal conventional therapy, limited treatments exist; but as newer therapies evolve, the options will expand to include more than palliative care, heart transplant and ventricular assist devices for these patients.

Acute Disease↗
PubMed2003

A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis.

OBJECTIVE: To evaluate and compare the efficacy and tolerability of etoricoxib and diclofenac in patients with osteoarthritis of the knee or hip. METHODS: In this 6-week double-blind, active comparator controlled, parallel-group study eligible osteoarthritis patients were randomised to receive either etoricoxib 60 mg once daily (n = 256) or diclofenac 50 mg three times daily (n = 260). The primary study endpoint was the Western Ontario McMaster osteoarthritis index (WOMAC) pain subscale. Other endpoints included were the WOMAC stiffness and physical function subscales, and the Patient's Global Assessment of Response to Therapy (PGART) questionnaire. Early efficacy was evaluated using WOMAC first question (pain walking on a flat surface) and PGART 4 h after the morning dose of each drug on days 1 and 2. Rescue medication (paracetamol) used was also recorded. The study was designed to show comparable efficacy between etoricoxib 60 mg once daily and diclofenac 50 mg three times daily with respect to the primary endpoint and was conducted outside the United States at 67 centres in 29 countries. RESULTS: Etoricoxib (60 mg once daily) was comparable in efficacy to diclofenac (150 mg daily) on all the above parameters. The one exception was in the assessment of early efficacy where etoricoxib demonstrated significantly greater benefit within 4 h of taking the first dose on the first day of therapy (p = 0.007) as evaluated by the percentage of patients with good or excellent (PGART) responses. The treatment effects of both drugs were similar by the time day 2 was reached and were sustained throughout the 6 weeks of therapy. Both treatments were generally well tolerated. CONCLUSIONS: Etoricoxib is clinically effective in the therapy of osteoarthritis providing a magnitude of effect comparable to that of the maximum recommended daily dose of diclofenac. The onset of clinical benefit with etoricoxib on day one is more rapid than that of diclofenac. Both drugs were generally well tolerated.

Adult↗
PubMed2003

The role of vitamin D and retinoids in controlling prostate cancer progression.

Prostate cancer is a leading cause of cancer-related deaths in many countries. Premalignant lesions and invasive cancer occur more frequently in the prostate than in any organ other than the skin. Yet, the incidence of clinically detected prostate cancer is much lower than the histopathological incidence. The slow growth of prostate cancer and the low incidence of clinically manifest disease in some geographical locations or racial/ethnic groups suggest that prostate cancer can be controlled, perhaps by dietary factors. Vitamin D and retinoids have emerged as leading candidates both to prevent and to treat prostate cancer. Many of the activities of these compounds, established from epidemiological studies, research with cell culture and animal models, and clinical trials, are consistent with tumor suppressor effects. However, retinoids may have additional tumor enhancer properties that balance or negate anti-cancer activity. This perhaps explains the overall lack of protective effects of vitamin A compounds against prostate cancer found in epidemiological studies, and the minimal efficacy of retinoids in clinical trials to treat prostate cancer. While current efforts focus on developing strategies to use vitamin D compounds to control prostate cancer, the possibility exists that prostate cancer cells may become resistant to tumor suppressor effects of vitamin D. Analyses of experimental model systems show that prostate cancer cells become less sensitive to vitamin D through loss of receptors or signaling molecules that mediate vitamin D's actions, or through changes in metabolic enzymes that synthesize or degrade vitamin D compounds. The potential promise of exploiting vitamin D to control prostate cancer is tempered by the possibility that prostate cancer, perhaps even at early stages, may develop mechanisms to escape tumor suppressor activities of vitamin D and/or retinoids.

Anticarcinogenic Agents↗
PubMed2002

Extensive polymorphism in the plasmodium vivax merozoite surface coat protein MSP-3alpha is limited to specific domains.

Plasmodium merozoites are covered by a complex coat of surface proteins. Several of the Merozoite Surface Proteins (MSPs) that make up this coat have been proposed as vaccine candidates although some of the MSPs are known to be highly polymorphic. We present here the first survey and analysis of the polymorphism in the recently characterized P. vivax surface protein PvMSP-3alpha. Full length or partial sequences were obtained for the Pvmsp-3alpha gene from isolates originating in Central and South America, Asia and the Pacific. The Pvmsp-3alpha sequence is remarkably diverse, but this extensive diversity is largely restricted to certain domains of the encoded protein. An acidic C-terminal domain and a smaller hydrophilic N-terminus are relatively conserved, while a central domain containing coiled-coil heptad repeats is highly polymorphic and in some isolates of P. vivax is partially deleted. Unlike other MSPs, there is no evidence of allelic families of PvMSP-3alpha gene sequences, and no evidence that certain patterns of polymorphism group within isolates of similar geographical origin. The distribution and nature of polymorphism suggest that there are functional restrictions on mutations in this gene, and have implications for inclusion of PvMSP-3alpha as a candidate in a P. vivax vaccine.

Amino Acid Sequence↗
PubMed2002

Identification and sequencing of HLA-B*0714 and B*2718 alleles and novel exon 1 sequences of B*0709 and B*2714 alleles in potential bone marrow donors.

Sequence specific oligonucleotide probe hybridization and sequence specific primer PCR typing of volunteer bone marrow donors suggested the presence of variants of known HLA-B alleles in two individuals. PCR products encompassing HLA-B locus exons 1, 2, and 3 were prepared, subcloned and sequenced. A Hispanic individual had a novel B*07 allele (B*0714) and a Chinese individual had a novel B*27 allele (B*2718). In two other individuals, a previously unknown sequence of exon 1 was determined for HLA-B*0709 (African American) and B*2714 (Native American). These findings further illustrate the substantial genetic variation present at the HLA-B locus within human populations. We discuss the structural variation in the protein sequence for these HLA-B alleles and its potential functional effects.

Asian People↗
PubMed2002

New HLA-B alleles identified and sequences extended in potential bone marrow donors: B*5804, B*4418, B*1558, and B*4805.

Nucleic acid-based methods for allele identification have revealed more than 470 polymorphic variants at the HLA-B locus. Screening of potential bone marrow donors with sequence specific primer polymerase chain reactions and sequence specific oligonucleotide probe hybridization assays revealed apparent variants within the B*58, *44, *15, and *48 allele groups. DNA sequencing of cloned DNA identified the new alleles B*5804, B*4418, and B*1558 within these groups and observed new sequence information for the previously reported allele B*4805. These findings further extend our knowledge of the substantial genetic variation present at the HLA-B locus within human populations.

Alleles↗
PubMed2001

Diaminoindanes as microsomal triglyceride transfer protein inhibitors.

The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC(50) values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.

Animals↗
PubMed2001

A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3).

Hereditary vitamin D-resistant rickets (HVDRR) is caused by heterogeneous inactivating mutations in the vitamin D receptor (VDR). Treatment of HVDRR patients with high doses of oral calcium and supraphysiologic doses of 1 alpha,25-dihydroxyvitamin D(3) (1,25D(3)) has had limited success. In this study we explored the use of vitamin D analogs as a potential therapy for this disorder. The rationale for the use of vitamin D analogs is that they bind the VDR at different amino acid residues than 1,25D(3), and their ability to modulate VDR functions differs from that of the natural hormone. In this report, we examined the VDR from three HVDRR patients with mutations in the ligand-binding domain of the VDR (histidine 305 to glutamine, arginine 274 to leucine, and phenylalanine 251 to cysteine) for their responses to two vitamin D analogs, 20-epi-1,25D(3) and 1 beta-hydroxymethyl-3-epi-16-ene-26a,27a-bishomo-25D(3) (JK-1626-2). Our results reveal that vitamin D analogs partially or completely restore the responsiveness of the mutated VDR. Analog treatment seemed to be more successful when the mutation affects the amino acids directly involved in ligand binding rather than amino acids that contribute to a functional VDR interface with dimerization partners or coactivators of transcription.

Amino Acid Substitution↗
PubMed2001

Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition.

Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)2D3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D3 [25(OH)D3], which is converted locally within the prostate to 1,25(OH)2D3 by 1alpha-hydroxylase. Quantification of 1alpha-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D3 inhibited growth of normal or BPH cells similarly to 1,25(OH)2D3. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2001

Typhlocolitis in NF-kappa B-deficient mice.

Activation of inflammatory gene expression by the transcription factor NF-kappaB is a central pathway in many inflammatory disorders, including colitis. Increased NF-kappaB activity has been linked with development of colitis in humans and animal models, thus it was unexpected when NF-kappaB-deficient mice developed spontaneous typhlocolitis. To further characterize this finding, we induced typhlocolitis in rederived NF-kappaB-deficient mice using intragastric infection with Helicobacter hepaticus. At 6 wk postinfection (PI), severe colitis with increased type 1 cytokine expression was seen in infected mice that lacked the p50 subunit of NF-kappaB and were also heterozygous for the p65 subunit of NF-kappaB(p50(-/-)p65(+/-)). Mice lacking the p50 subunit alone (p50(-/-)) were less severely affected, and wild-type mice and p65(+/-) mice were unaffected. T cell development in NF-kappaB-deficient mice was normal. These data indicate that p50 and p65 subunits of NF-kappaB have an unexpected role in inhibiting the development of colitis.

Animals↗
PubMed2001

Advancing paternal age and the risk of schizophrenia.

BACKGROUND: A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines. METHOD: We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry. RESULTS: Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age. CONCLUSIONS: These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.

Adult↗
PubMed2001

On mental events, disciplinary boundaries, and reductionism: a reply to Plaud.

Plaud's (2001) radical behavioral manifesto suggests that a psychological science based exclusively upon the study of environment-behavior functional contingencies would yield a discipline unencumbered by mentalism, vaguely delineated disciplinary boundaries, or inappropriate reductionism. In reply, we note that: (a) mental events-e.g., thoughts and feelings-are increasingly accessible to objective investigation, and provide an observable proximal causal mechanism for the environmental selection of behavior; (b) the call for pristine disciplinary boundaries is anachronistic, inasmuch as progress in the natural sciences has engendered disciplinary boundaries that are increasingly porous; (c) cognitive neuroscience facilitates a comprehensive understanding of complex human behavior by mapping out the relationship between such behavior and underlying brain events, thereby engaging in an appropriate form of reductionism (constitutive reductionism) that has become a hallmark of the natural sciences; and (d) ironically, it is radical behaviorism, in its disavowal of the informational level of complexity instantiated in brain events, that engages in inappropriate eliminative reductionism (i.e., reducing neural information to "nothing but" its underlying bring states).

Behaviorism↗
PubMed2001

The cognitive neuroscience paradigm: a unifying metatheoretical framework for the science and practice of clinical psychology.

The emerging discipline of cognitive neuroscience (CN) enjoins the efforts of cognitive psychologists, neuroscientists, computer scientists, clinical neurologists, neurophilosophers, and many others working collaboratively across traditional disciplinary boundaries to elucidate the manner in which the physical operations of the brain give rise to the vast panoply of human mental and behavioral events. The present article describes the foundational tenets of the CN metatheoretical framework and contends that the CN framework is capable of providing a coherent, unifying scientific paradigm for the discipline of clinical psychology. Clinical psychology's adoption of the CN paradigm would facilitate (a) its consilient linkage with the natural sciences, (b) resolution of long-standing internecine theoretical schisms, and (c) enhanced understanding and treatment of numerous forms of psychopathology. Nevertheless, psychology's historically influential radical behavioral (RB) perspective is not easily reconciled with the CN paradigm. However, unlike CN, RB (a) is not fully consilient with the natural sciences, (b) fails to articulate the proximal causal mechanisms that mediate environment-behavior relations, and (c) engages in "greedy reductionism" in its disavowal of informational levels of complexity in the patterning of neural activity. The article concludes with a discussion of the possibility of theoretical rapprochement between CN and RB.

Behaviorism↗
PubMed2001

A novel inborn error in the ligand-binding domain of the vitamin D receptor causes hereditary vitamin D-resistant rickets.

Mutations in the vitamin D receptor (VDR) cause hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease resulting in target organ resistance to 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. In this report, we describe the clinical case and molecular basis of HVDRR in an Asian boy exhibiting the typical clinical features of the disease including alopecia. Using cultured dermal fibroblasts from the patient, 1,25(OH)(2)D(3) resistance was demonstrated by a shift in the dose response required for 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) mRNA induction. Western blot showed that the cells express a normal size VDR but contained reduced levels of receptor compared to normal cells. At 24 degrees C, the affinity of the patient's VDR for [(3)H]1,25(OH)(2)D(3) was 50-fold lower than the VDR in normal fibroblasts. Sequence analysis identified a unique T to G missense mutation in exon 6 that changed phenylalanine to cysteine at amino acid 251 (F251C). The recreated F251C mutant VDR showed reduced transactivation activity using a 24-hydroxylase promoter-luciferase reporter. Maximal transactivation activity exhibited by the WT VDR was not achieved by the mutant VDR even when the cells were treated with up to 10(-6) M 1,25(OH)(2)D(3). However, the transactivation activity was partially rescued by addition of RXRalpha. In the yeast two-hybrid system and GST-pull-down assays, high concentrations of 1,25(OH)(2)D(3) were needed to promote F251C mutant VDR binding to RXRalpha, indicating defective heterodimerization. In conclusion, a novel mutation was identified in the VDR LBD that reduces VDR abundance and its affinity for 1,25(OH)(2)D(3) and interferes with RXRalpha heterodimerization resulting in the syndrome of HVDRR.

Animals↗
PubMed2001

Rationale for combination ketoconazole/ vitamin D treatment of prostate cancer.

The high rate of progression of prostate cancer after androgen deprivation therapy mandates that new strategies be developed. Adjuvant therapy combined with androgen deprivation may slow or prevent progression. Ketoconazole plus calcitriol therapy is an example of 1 such a combination with a mechanistic basis for synergistic activity. Ketoconazole is commonly used as a second-line androgen deprivation therapy. This imidazole derivative is an inhibitor of P-450 enzymes, including those involved in steroidogenesis. Other P-450 enzymes that are inhibited by ketoconazole include 1alpha-hydroxylase and 24-hydroxylase, which metabolize vitamin D. Growth inhibition of prostate cancer cells by vitamin D depends on levels of the active metabolite, 1,25-dihydroxyvitamin D(3) (calcitriol). The enzyme 24-hydroxylase converts calcitriol to less active products. The inhibition of 24-hydroxylase by ketoconazole maintains the magnitude and duration of response to calcitriol. Combined ketoconazole/calcitriol therapy might therefore potentiate the antitumor activity of calcitriol. Because androgen-independent prostate cancer cells often remain responsive to growth inhibition by calcitriol, it is also possible that calcitriol would slow or prevent development of androgen-independent cancer growth. Another consideration is that ketoconazole blocks 1alpha-hydroxylase activity, which is the key enzyme that creates calcitriol in the body. Therefore, patients receiving ketoconazole therapy are likely to be deficient in vitamin D. The detrimental consequences of vitamin D deficiency in these patients would also be alleviated by the addition of calcitriol to the therapeutic regimen.

Androgen Antagonists↗