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PubMed2004

Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data.

OBJECTIVE: The issue of thimerosal-containing vaccines as a possible cause of autistic spectrum disorders (ASD) and neurodevelopmental disorders (NDDs) has been a controversial topic since 1999. Although most practitioners are familiar with the controversy, many are not familiar with the type or quality of evidence in published articles that have addressed this issue. To assess the quality of evidence assessing a potential association between thimerosal-containing vaccines and autism and evaluate whether that evidence suggests accepting or rejecting the hypothesis, we systematically reviewed published articles that report original data pertinent to the potential association between thimerosal-containing vaccines and ASD/NDDs. METHODS: Articles for analysis were identified in the National Library of Medicine's Medline database using a PubMed search of the English-language literature for articles published between 1966 and 2004, using keywords thimerosal, thiomersal, mercury, methylmercury, or ethylmercury alone and combined with keywords autistic disorder, autistic spectrum disorder, and neurodevelopment. In addition, we used the "related links" option in PubMed and reviewed the reference sections in the identified articles. All original articles that evaluated an association between thimerosal-containing vaccines and ASD/NDDs or pharmacokinetics of ethylmercury in vaccines were included. RESULTS: Twelve publications that met the selection criteria were identified by the literature search: 10 epidemiologic studies and 2 pharmacokinetic studies of ethylmercury. The design and quality of the studies showed significant variation. The preponderance of epidemiologic evidence does not support an association between thimerosal-containing vaccines and ASD. Epidemiologic studies that support an association are of poor quality and cannot be interpreted. Pharmacokinetic studies suggest that the half-life of ethylmercury is significantly shorter when compared with methylmercury. CONCLUSIONS: Studies do not demonstrate a link between thimerosal-containing vaccines and ASD, and the pharmacokinetics of ethylmercury make such an association less likely. Epidemiologic studies that support a link demonstrated significant design flaws that invalidate their conclusions. Evidence does not support a change in the standard of practice with regard to administration of thimerosal-containing vaccines in areas of the world where they are used.

Autistic Disorder↗

PubMed2005

Microarray analysis of thioacetamide-treated type 1 diabetic rats.

It is well known that diabetes imparts high sensitivity to numerous hepatotoxicants. Previously, we have shown that a normally non-lethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats due to inhibited tissue repair allowing progression of liver injury. On the other hand, DB rats exposed to 30 mg TA/kg exhibit delayed tissue repair and delayed recovery from injury. The objective of this study was to investigate the mechanism of impaired tissue repair and progression of liver injury in TA-treated DB rats by using cDNA microarray. Gene expression pattern was examined at 0, 6, and 12 h after TA challenge, and selected mechanistic leads from microarray experiments were confirmed by real-time RT-PCR and further investigated at protein level over the time course of 0 to 36 h after TA treatment. Diabetic condition itself increased gene expression of proteases and decreased gene expression of protease inhibitors. Administration of 300 mg TA/kg to DB rats further elevated gene expression of proteases and suppressed gene expression of protease inhibitors, explaining progression of liver injury in DB rats after TA treatment. Inhibited expression of genes involved in cell division cycle (cyclin D1, IGFBP-1, ras, E2F) was observed after exposure of DB rats to 300 mg TA/kg, explaining inhibited tissue repair in these rats. On the other hand, DB rats receiving 30 mg TA/kg exhibit delayed expression of genes involved in cell division cycle, explaining delayed tissue repair in these rats. In conclusion, impaired cyclin D1 signaling along with increased proteases and decreased protease inhibitors may explain impaired tissue repair that leads to progression of liver injury initiated by TA in DB rats.

Animals↗

PubMed1988

Cloning of estrogen-regulated messenger ribonucleic acids from rat uterus.

A cDNA library prepared from the mRNA of uteri of estrogen-stimulated immature female rats was constructed in lambda gt10. Differential screening of the hybrid phages was performed using control and stimulated cDNAs as probes. Selected clones were then characterized by Northern and Southern blot hybridizations. In all, eight unique clones corresponding to estrogen-stimulated messages in rat uterus were identified. These clones hybridized to uterine mRNAs varying in size from 1.4-8.4 kilobases. Three of the clones were characterized as coding for three different types of collagen, and one as coding for smooth muscle actin. These are described in more detail elsewhere. The kinetics of increase in estrogen-regulated messages was examined. After a single injection of estradiol, five clones, including the three collagen mRNAs, showed two peaks of accumulation, at 4 and 24 h. Messages of two other clones were maximal at 12 h. The actin clone hybridized to mRNAs with peaks at 4 h for cytoskeletal actins and 8-12 h for smooth muscle actins. Sequential 24-h injections of the hormone produced multiple peaks of mRNA accumulation with a timing consistent with the kinetics found after a single injection of hormone. The multiple injections, however, did not result in enhanced mRNA accumulation for any of these clones. In fact, several messages showed suppressed accumulation with continued estradiol administration. Accumulated inhibitory factors in uterine cells may be responsible for this refractory condition. Except for the actin mRNA, the estradiol-stimulated mRNAs were expressed mainly in uterus and ovary. These clones may be useful in studies on the mechanism of action of estrogenic hormones and their tissue-specific regulation of gene expression.

Animals↗

PubMed2003

Periodontal host modulation with antiproteinase, anti-inflammatory, and bone-sparing agents. A systematic review.

BACKGROUND: The use of modulating agents, including inhibition of matrix metalloproteinases (MMPs) with antiproteinases, blocking production of proinflammatory cytokines and prostaglandins with anti-inflammatory drugs, and inhibiting activation of osteoclasts with bone-sparing agents, has been postulated to be of therapeutic value as an adjunctive therapy to the management of chronic periodontitis. RATIONALE: The objective of this systematic review of the literature was to assess the adjunctive efficacy of antiproteinase, anti-inflammatory, and bone-sparing host-modulating agents in the treatment of gingivitis, aggressive periodontitis, and chronic periodontitis. FOCUSED QUESTIONS: 1. In patients with periodontal diseases, what is the effect of host-modulation agents, alone or combined with conventional therapy, compared to conventional therapy alone as assessed by clinical, radiographic, adverse, and patient-centered outcomes? 2. In patients with dental implants, what is the effect of host-modulation agents on implant success assessed by clinical, radiographic, adverse, and patient-centered outcomes? SEARCH PROTOCOL: MEDLINE, Embase, and the Cochrane Library databases were searched without language restrictions through April 1, 2002 for studies that used tetracycline (TET)-related matrix metalloproteinase (MMP) inhibitors, or non-steroidal anti-inflammatory drugs (NSAIDs) and bisphosphonate anti-osteolytic agents. The investigation also included hand searching of journals and contacting authors and industry experts. SELECTION CRITERIA INCLUSION CRITERIA: Only human studies (randomized controlled clinical trials, cohort studies, case-control studies, cross-sectional studies, and case series) were selected. Studies were on subjects with gingivitis, aggressive or chronic periodontitis, or dental implants. Interventions included TET-related MMP inhibitors, NSAIDs, or bisphosphonate anti-osteolytic agents. EXCLUSION CRITERIA: Studies that used MMP tissue inhibitors as diagnostic or prognostic indicators of periodontal disease or that evaluated short-term systemic antibodies or locally delivered levels of drugs with antiproteinase activity were excluded. DATA COLLECTION AND ANALYSIS: The primary outcomes for assessment were changes in bone or clinical attachment levels (CAL); secondary outcomes included clinical measures of plaque, gingival inflammation, probing depth (PD), and mobility. Summary data appropriate for meta-analysis were pooled using a weighted average and analyzed using a standardized difference; the results were checked with both fixed-effects and random-effects models. MAIN RESULTS: 1. A meta-analysis done on the studies reporting changes in CAL and PD following administration of sub-antimicrobial doses of doxycycline (SDD) in conjunction with scaling and root planing (SRP) in patients with periodontitis showed a statistically significant beneficial adjunctive effect. 2. There were insufficient data to provide meta-analyses on periodontal patients treated with other host-modulating agents; descriptive tables are included. 3. NSAIDS show promise in their ability to slow periodontal disease. 4. Preliminary data on bisphosphonate agents indicate there is a potential role for these agents in periodontitis management. 5. There are a very limited number of studies on host-modulating agents and dental implants and no analyses were possible. 6. Because the treatment methodologies and clinical variables differed considerably among the studies, it is difficult to summarize the information and identify a reliable total patient population. REVIEWERS' CONCLUSIONS: 1. Large multi-center trials are needed to evaluate the role of host-modulating agents in the treatment of periodontitis. 2. NSAIDS and bisphosphonate drugs may have a potential adjunctive role in periodontal therapy. 3. The adjunctive use of SDD with SRP is statistically more effective than SRP alone in reducing PD and in achieving CAL gain.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1993

Chicken sterol carrier protein 2/sterol carrier protein x: cDNA cloning reveals evolutionary conservation of structure and regulated expression.

The chicken is a useful model for studies of lipid biochemistry because of the profound changes in lipid metabolism during development and the marked effects of estrogen on its lipids. Here we report the cloning of a cDNA encoding chicken sterol carrier protein 2 (SCP2)/sterol carrier protein x (SCPx), proteins that are believed to play key roles in intracellular lipid movement and metabolism. The 2.4-kb clone, isolated from a liver cDNA library by homology screening with a rat SCP2 cDNA, encodes a 58-kDa polypeptide, SCPx, which encompasses the sequence for SCP2 at its C-terminus. Comparison of the deduced amino acid sequence of the chicken protein with those of mammals revealed conservation of structure from an evolutionary standpoint. Like the other vertebrate SCPx proteins, the chicken protein contains a conserved Arg-Gly-Asp sequence and a cysteine residue in the N-terminus that aligns with the active site cysteine of Escherichia coli 3-ketoacyl-CoA thiolase, a protein that was previously shown to be homologous to vertebrate SCPx. Northern blot analysis of poly(A)+ RNA from different chicken tissues revealed two mRNA species, one of 2.5 kb, encoding SCPx, and one of 1.4 kb, presumably encoding SCP2. High levels of the 2.5 and 1.4-kb mRNAs were found in liver, intestine, and ovarian granulosa cells, consistent with a role for these proteins in lipid metabolism. There was no change in the 2.5-kb mRNA in chicken liver with development (Day 20 embryo to 4 weeks posthatch), but there was a 10-fold increase in the 1.4-kb mRNA by 1 week posthatch. Treatment of roosters with a single injection of estradiol (25 mg/kg) caused a twofold increase in the 2.5-kb mRNA in liver at 6 h after estradiol administration, reaching a maximum fourfold increase at 48 h, while the 1.4-kb mRNA increased twofold at 48 h. The two SCP2/SCPx mRNAs were most abundant in granulosa cells from small follicles. A reduction in SCP2/SCPx gene expression was observed with follicular maturation, correlating with falling estrogen production. In summary, we have documented (i) marked conservation of SCP2/SCPx structure across species and (ii) developmental and hormonal regulation of the mRNAs which encode proteins thought to be involved in lipid metabolism.

Amino Acid Sequence↗

PubMed1983

A cytochrome P-450 multigene family. Characterization of a gene activated by phenobarbital administration.

The capacity of the liver microsomal mixed function oxidase system to metabolize a great variety of exogenous as well as endogenous compounds is thought to reflect the participation of multiple forms of the terminal oxidase, cytochrome P-450, which have different broad, but overlapping, substrate specificities. Several of these isozymes accumulate in the liver after exposure of animals to specific inducing agents. In order to approach the questions of the genetic basis for the existence of multiple cytochrome P-450 isozymes and the molecular mechanisms of the induction process, we have used a cloned cDNA for a major phenobarbital-induced form of cytochrome P-450 to identify and characterize thirteen distinct rat genomic clones containing segments of six different genes. Only three clones, representing overlapping segments of a single gene, hybridized to the cloned cDNA or to phenobarbital-induced mRNA under conditions of high stringency. In vitro transcription studies with isolated rat liver nuclei indicated that only this gene, but not the genes represented by the other genomic clones, appears to be markedly activated by phenobarbital treatment of rats. Although there are a small number of differences, DNA sequence analysis of the eight exons of the gene present in these genomic clones indicates that they encode residues 58 to 491 (the COOH terminus) of cytochrome P-450e, a major phenobarbital-induced isozyme. It appears that the other cloned genes may contain only a small region of very strong homology to the cytochrome P-450e gene, a region which includes the exon encoding a tridecapeptide which is also present in two dissimilar forms of rabbit liver cytochrome P-450, one constitutive and one induced by phenobarbital. Southern blotting analysis of rat liver DNA indicates that the rat genome may contain two additional genes which are very closely related to the cytochrome P-450e gene but which we have not yet isolated from the genomic library. One of these genes is likely to encode cytochrome P-450b, the major phenobarbital induced form of cytochrome P-450 whose mRNA is greater than 95% homologous to that encoding cytochrome P-450e.

Animals↗

PubMed2006

Analgesics for pain after traumatic or orthopaedic surgery: what is the evidence--a systematic review.

OBJECTIVE: To assess analgesic drugs in the treatment of postoperative pain after traumatic and orthopaedic surgery (TOS). DESIGN: A systematic review of randomised clinical trials (RCTs). DATA SOURCES: Electronic PubMed, EMBASE, The Cochrane Library, and hand searches. STUDY SELECTION: RCTs of analgesics administered by oral, intramuscular, intravenous, subcutaneous or rectal route, were compared to other analgesics or placebo, in patients under TOS. Study design, characteristics of the study population, analgesic drugs tested, pain intensity and pain relief scores, and adverse effects were assessed. RESULTS: Ninety-two RCTs (9,596 patients) met our inclusion criteria. Forty-two (46%) were placebo-controlled, and 50 (54%) were direct comparisons between non-opioid, opioid, and/or combinations of both. Patients' mean age (SD) was 49 years (18). In most trials, gastrointestinal ulcer, liver and renal diseases were exclusion criteria. Only 30 trials (33%) were double-blind and reported standardised outcomes of pain intensity and pain relief; 19 of these were single-dose, and follow up of analgesic effects lasted no more than 12 h in 23 (77%). Globally, only nine trials (10%) were double blind, described dropouts or withdrawals, performed analysis by intention to treat, and reported the effects magnitude. CONCLUSION: Evidence from RCTs on the treatment of postoperative pain after TOS is inadequate for clinical decision making. Assessment of analgesics in pain after TOS should be based on agreed clinically relevant outcomes, in representative patients, and for longer observation periods. In addition, it should include direct comparisons between candidate drugs or their combinations and between various drug administration schedules.

Acetaminophen↗

PubMed1997

Opposite regulation of Gax homeobox expression by angiotensin II and C-type natriuretic peptide.

Growth arrest-specific homeobox (Gax) gene was isolated from rat aorta cDNA library and its expression was largely confined to the cardiovascular tissues. Gax gene was rapidly downregulated by platelet-derived growth factor in vascular smooth muscle cells (VSMCs) and overexpressed Gax was reported to reduce the neointimal thickening after balloon injury in vivo. We have demonstrated that angiotensin II (Ang II) stimulates vascular growth. In contrast, we also reported that C-type natriuretic peptide (CNP) is secreted from vascular endothelial cells to act as a novel endothelium-derived relaxing peptide and inhibits vascular growth via cGMP cascade. In the present study, we examined the effects of Ang II and CNP on Gax gene expression in VSMCs. In quiescent rat aortic VSMCs. Gax mRNA (2 3 kb) level became negligible 6 hours after the addition of Ang II (10(-6) mol/L). The inhibitory action of Ang II on Gax mRNA expression (ED50: 10(-11) mol/L) was almost completely blocked by an AT1R antagonist, CV11974. In contrast, CNP 10(-6) mol/L augmented Gax mRNA expression to exhibit 1.8-fold increase of the control 12 hours after the stimulation. This effect of CNP was mimicked by the addition of 8-bromoadenosine 3'-5'-cyclic monophosphate. The addition of C-ANF[4-23], an atrial natriuretic peptide-C receptor-specific agonist and devoid of stimulating cGMP production, exhibited no effect on Gax mRNA expression. Simultaneous administration of Ang II and CNP revealed that CNP (10(-6) mol/L) significantly attenuated the inhibitory action of Ang II (10(-10) mol/L) on Gax mRNA expression. These results suggest that Gax is a common transcription factor involved in the signaling pathway of vascular growth for Ang II and CNP and regulates the cell cycle and/or phenotype of VSMCs for vascular remodeling in hypertension and atherosclerosis.

Angiotensin II↗

PubMed2005

Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.

BACKGROUND: The proliferation of inhaler devices has resulted in a confusing number of choices for clinicians who are selecting a delivery device for aerosol therapy. There are advantages and disadvantages associated with each device category. Evidence-based guidelines for the selection of the appropriate aerosol delivery device in specific clinical settings are needed. AIM: (1) To compare the efficacy and adverse effects of treatment using nebulizers vs pressurized metered-dose inhalers (MDIs) with or without a spacer/holding chamber vs dry powder inhalers (DPIs) as delivery systems for beta-agonists, anticholinergic agents, and corticosteroids for several commonly encountered clinical settings and patient populations, and (2) to provide recommendations to clinicians to aid them in selecting a particular aerosol delivery device for their patients. METHODS: A systematic review of pertinent randomized, controlled clinical trials (RCTs) was undertaken using MEDLINE, EmBase, and the Cochrane Library databases. A broad search strategy was chosen, combining terms related to aerosol devices or drugs with the diseases of interest in various patient groups and clinical settings. Only RCTs in which the same drug was administered with different devices were included. RCTs (394 trials) assessing inhaled corticosteroid, beta2-agonist, and anticholinergic agents delivered by an MDI, an MDI with a spacer/holding chamber, a nebulizer, or a DPI were identified for the years 1982 to 2001. A total of 254 outcomes were tabulated. Of the 131 studies that met the eligibility criteria, only 59 (primarily those that tested beta2-agonists) proved to have useable data. RESULTS: None of the pooled metaanalyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings that was investigated. The adverse effects that were reported were minimal and were related to the increased drug dose that was delivered. Each of the delivery devices provided similar outcomes in patients using the correct technique for inhalation. CONCLUSIONS: Devices used for the delivery of bronchodilators and steroids can be equally efficacious. When selecting an aerosol delivery device for patients with asthma and COPD, the following should be considered: device/drug availability; clinical setting; patient age and the ability to use the selected device correctly; device use with multiple medications; cost and reimbursement; drug administration time; convenience in both outpatient and inpatient settings; and physician and patient preference.

Adrenergic beta-Agonists↗

PubMed1998

Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice.

To elucidate the role of neuropeptide Y (NPY)-Y1 receptor (Y1-R) in food intake, energy expenditure, and other possible functions, we have generated Y1-R-deficient mice (Y1-R-/-) by gene targeting. Contrary to our hypothesis that the lack of NPY signaling via Y1-R would result in impaired feeding and weight loss, Y1-R-/- mice showed a moderate obesity and mild hyperinsulinemia without hyperphagia. Although there was some variation between males and females, typical characteristics of Y1-R-/- mice include: greater body weight (females more than males), an increase in the weight of white adipose tissue (WAT) (approximately 4-fold in females), an elevated basal level of plasma insulin (approximately 2-fold), impaired insulin secretion in response to glucose administration, and a significant changes in mitochondrial uncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adipose tissue and down-regulation of UCP2 in WAT). These results suggest either that the Y1-R in the hypothalamus is not a key molecule in the leptin/NPY pathway, which controls feeding behavior, or that its deficiency is compensated by other receptors, such as NPY-Y5 receptor. We believe that the mild obesity found in Y1-R-/- mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studying the mechanism of mild obesity and abnormal insulin metabolism in noninsulin-dependent diabetes mellitus.

Animals↗

PubMed1987

Rat testosterone 7 alpha-hydroxylase. Isolation, sequence, and expression of cDNA and its developmental regulation and induction by 3-methylcholanthrene.

A P-450, designated P-450a, with high testosterone 7 alpha-hydroxylase activity was purified from rat liver microsomes. Specific polyclonal antibody against this P-450 was used to screen a lambda gt11 expression cDNA library and a 1687-base pair cDNA was isolated and sequenced. The deduced protein had 492 amino acids, a calculated Mr of 56,016, and it shared 51 and 45% amino acid similarities to P-450e and P-450f, respectively. Regions of similarity were distributed in distinct areas of high and low similarity along the P-450a primary sequence. P-450a cDNA was introduced into yeast cells using the expression vector pAAH5, and the resultant yeast microsomes contained both a protein of identical electrophoretic mobility to that of rat P-450a and testosterone 7 alpha-hydroxylase activity. These results confirm enzyme reconstitution data and antibody inhibition data that P-450a possesses testosterone 7 alpha-hydroxylase activity. The antibody and cDNA probes were used to examine the mechanism of regulation of P-450a by inducers and during development. P-450a and its mRNA were present at low level in newborn rats and increased to maximal level at 1 week of age in both males and females. At age 12 weeks, however, the P-450a level decreased in males but remained elevated in females. Concomitant with the decrease in P-450a in adult males was an increase in level of another immunologically related P-450. In adult male rats, P-450a was induced almost 5-fold by administration of 3-methylcholanthrene and this induction was the result of an increase in its mRNA. These results establish testosterone 7 alpha-hydroxylase as a member of the P-450e gene family that is developmentally regulated, sex-dependent, and markedly inducible by 3-methylcholanthrene.

Amino Acid Sequence↗

PubMedDate not supplied

LEC/chTNT-3 fusion protein for the immunotherapy of experimental solid tumors.

The human chemokine liver-expression chemokine (LEC) was originally found in an expressed sequence tag library, and later the LEC gene was located to chromosome 17q in the ML chemokine gene cluster. LEC has been shown to chemoattract monocytes, lymphocytes, and polymorphonuclear leukocytes (PMNs) by its binding to CCR1 and CCR8 chemokine receptors. Because of its potency as a chemoattractant for immune cells, LEC was used to genetically engineer a fusion protein with chTNT-3, a monoclonal antibody previously shown to target tumors by binding to DNA exposed in necrotic zones. Because the N-terminus of chemokines is important for their activity, the C-terminus of LEC was genetically linked to the chTNT-3 heavy chain variable region and, along with the light chain gene, cotransfected into NSO murine myeloma cells using the glutamine synthetase gene amplification system. The expressed LEC/chTNT-3 fusion protein was purified by tandem protein-A affinity and ion-exchange chromatography and chemotaxis and binding assays confirmed the bioactivity of the purified fusion protein. Pharmacokinetic and biodistribution studies in vivo showed that LEC/chTNT-3 had a biologic half-life of 3 hours and had good uptake in tumor (2.4% injected dose/g), which remained stable at 12 and 24 hours postinjection. Immunotherapy studies performed in three solid tumor models of the BALB/c mouse showed between 37% and 55% tumor reduction at 19 days post-implantation. Immunohistochemical studies using tumor sections obtained at different time points after the administration of control chTNT-3 and LEC/chTNT-3 showed heavy infiltration of CD4+ and CD8+ T cells, PMNs, B cells, and CD11c+CD11b+ dendritic cells in the LEC/chTNT-3 treated groups. The results of these studies demonstrate that this novel fusion protein has potent antitumor activity that is associated with the infiltration of different subpopulations of immune cells. The targeting of LEC to necrotic areas of tumors where the release of tumor antigens is prevalent may be a new approach for the immunotherapy of solid tumors.

Animals↗

PubMed1987

Growth hormone regulates expression of rat liver cytochrome P-450 15 beta at a pretranslational level.

Polyclonal antibodies to rat liver microsomal cytochrome P-450 15 beta-hydroxylase were used to screen a female rat liver cDNA expression library. Recombinant plasmid C-6, isolated from a positive colony, contained a cDNA of 1000 base pairs which hybridized to a single, 1.7 kilobase class of mRNA on Northern blot analysis. Semi-quantitative slot blots showed that the level of this mRNA was 17-fold lower in male rat liver than in females. Continuous infusion of human growth hormone to male rats caused them to express female levels of C-6 mRNA, while the same daily dose of hormone given intermittently had no effect. A high degree of correlation of the levels of C-6 mRNA with 15 beta-hydroxylase protein levels and catalytic activities was found, demonstrating that the sexually differentiated, growth hormone-dependent expression of the 15 beta-hydroxylase is regulated at a step preceding translation.

Animals↗

PubMed2002

Coding and billing for gastrointestinal endoscopy.

The complexities associated with the coding, billing, and reimbursement process seem to increase daily. Keeping abreast of the changes in this environment is, to say the least, a challenge. To succeed in today's billing environment the gastroenterologist should surround his or her practice with staff, resources, and education. Experienced skilled staff, preferably a certified professional coder should be employed. Certified coders bring advanced coding skills to ones practice, which allows increased proficiency with the coding and billing process. Provide the necessary resources for staff. Current coding material is crucial to the financial success of the practice. CPT-4, ICD-9, and Correct Coding Guide are the bare basics of the resource material available to staff. Maintaining a library of resource material (i.e., Medicare bulletins, managed care newsletters, and so forth) aids the staff with the necessary tools to carry out their duties. In addition, specific gastroenterology coding subscriptions are available to assist in staying ahead of the ever-changing billing and coding environment. Continuing education in the billing and coding process for both the physician and staff is essential. Numerous workshops are offered periodically. It is imperative that staff attends all Medicare-sponsored workshops in addition to gastroenterology-specific coding seminars. More and more physicians are now aware of their responsibility in the billing process and have begun to participate in the coding education along with their staff. This is a significant indicator of a physicians' intent to have a compliant and financially successful practice.

Cost-Benefit Analysis↗

PubMed2006

Interventions for trachoma trichiasis.

BACKGROUND: Trachoma is a leading cause of avoidable blindness. The World Health Organization recommends eliminating trachoma blindness by the SAFE strategy incorporating Surgery, Antibiotic treatment, Facial cleanliness and Environmental hygiene. OBJECTIVES: This review examined the evidence for the effectiveness of different interventions for trachoma trichiasis. SEARCH STRATEGY: We identified trials from the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (2005, Issue 3), MEDLINE (1966 to September 2005) PubMed (searched on 21-09-06; last 90 days), EMBASE (1980 to September 2005), LILACS (March 2004) and the reference lists of included studies. We also contacted authors for details of other relevant studies. SELECTION CRITERIA: We included randomised trials of any intervention intended to treat trachoma trichiasis and trials comparing different methods of delivering the same intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials. We contacted trial authors for missing data when necessary. MAIN RESULTS: Seven studies met the inclusion criteria. Three studies compared different surgical interventions. These trials suggest the most effective surgery is full-thickness incision of the tarsal plate and rotation of the terminal tarsal strip 180 degrees. One study showed that bilamellar rotation was more effective than unilamellar rotation but the other two studies did not. One trial found double-sided sticking plaster more effective than epilation for the immediate management of trichiasis but required frequent replacement (odds ratio (OR) 0.01, 95% confidence interval (CI) 0.00 to 0.22). Another trial found community-based surgery increased convenience for patients without increasing the risk of complications or recurrence when compared to health centres. One trial found no difference between trichiasis surgery performed by ophthalmologists and integrated eye workers (OR 1.32, 95% CI 0.83 to 2.11). A trial comparing trichiasis surgery with and without concurrent administration of azithromycin found no difference in success rates at one year (OR 0.99, 95% CI 0.67 to 1.46). AUTHORS' CONCLUSIONS: No trials show interventions for trichiasis prevent blindness. Certain interventions have been shown to be more effective at eliminating trichiasis. Full thickness incision of the tarsal plate and rotation of the lash-bearing lid margin through 180 degrees is probably the best technique and is preferably delivered in the community. The use of double-sided sticking plaster is more effective than epilation as a temporary measure. Surgery may be carried out by an ophthalmologist or a trained ophthalmic assistant. The addition of azithromycin treatment at the time of surgery does not appear to improve outcomes.

Anti-Bacterial Agents↗

PubMed2000

Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors.

Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

Administration, Oral↗

PubMed1996

Toxicological detection of the designer drug 3,4-methylenedioxyethylamphetamine (MDE, "Eve") and its metabolites in urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay.

Studies are presented on the toxicological detection of the designer drug methylenedioxyethylamphetamine [MDE, rac-N-ethyl-(3,4-methylenedioxyphenyl)-propane-2-amine] in urine after a single oral dose of 140 mg of MDE by GC-MS and fluorescence polarization immunoassay (FPIA). After acid hydrolysis, extraction and acetylation MDE and its metabolites could be detected by mass chromatography with the selected ions m/z 72, 86, 114, 150, 162 and 164, followed by identification of the peaks underlying full mass spectra by computer library search. The following metabolites could be detected: unchanged MDE and 3,4-dihydroxyethylamphetamine (DHE) for 33-62 h, 3,4-methylenedioxyamphetamine (MDA) for 32-36 h and 4-hydroxy-3-methoxyethylamphetamine (HME) for 7-8 days. 3,4-Dihydroxyamphetamine (DHA), 4-hydroxy-3-methoxyamphetamine (HMA), piperonyl acetone, 3,4-dihydroxyphenyl acetone and 4-hydroxy-3-methoxyphenyl acetone could only be detected in trace amounts within the first few hours. The Abbott TD x FPIA assay amphetamine/metamphetamine II gave positive results in urine for 33-62 h. Therefore, positive immunoassay results could be confirmed by the GC-MS procedure which also allowed the differentiation of MDE and its homologues 3,4-methylenedioxymethamphetamine (MDMA) and MDA as well as other amphetamine derivatives interfering with the TD x assay. Furthermore, this GC-MS procedure allowed the simultaneous detection of most of the toxicologically relevant drugs.

3,4-Methylenedioxyamphetamine↗

PubMed2006

Proton pump inhibitor treatment for acute peptic ulcer bleeding.

BACKGROUND: Randomised controlled trials (RCTs) evaluating the clinical effect of proton pump inhibitors (PPIs) in peptic ulcer (PU) bleeding yield conflicting results. OBJECTIVES: To evaluate the efficacy of PPIs in acute bleeding from PU using evidence from RCTs. SEARCH STRATEGY: We searched CENTRAL, The Cochrane Library (Issue 4, 2004), MEDLINE (1966 to November 2004), EMBASE (1980 to November 2004), proceedings of major meetings to November 2004, and reference lists of articles. We contacted pharmaceutical companies and experts in the field. SELECTION CRITERIA: RCTs of PPI treatment (oral or intravenous) compared with placebo or H(2)-receptor antagonist (H(2)RA) in acute bleeding from PU. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently, assessed study validity, summarised studies and undertook meta-analysis. The influence of study characteristics on the outcomes was examined by subgroup analyses and meta-regression. MAIN RESULTS: Twenty-four RCTs comprising 4373 participants in total were included. Statistical heterogeneity was found among trials for rebleeding (P = 0.04), but not for all-cause mortality (P = 0.24) or surgery (P = 0.45). There was no significant difference in all-cause mortality rates between PPI and control treatment; pooled rates were 3.9% on PPI versus 3.8% on control (odds ratio (OR) 1.01; 95% CI 0.74 to 1.40). PPIs significantly reduced rebleeding compared to control; pooled rates were 10.6% with PPI versus 17.3% with control treatment (OR 0.49; 95% CI 0.37 to 0.65). PPI treatment significantly reduced surgery compared with control; pooled rates were 6.1% on PPI versus 9.3% on control (OR 0.61; 95% CI 0.48 to 0.78). There was no evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. PPIs significantly reduced surgery compared with placebo but not when compared with H(2)RA. There was no evidence to suggest that study quality, route of PPI administration or application of initial endoscopic haemostatic treatment influenced results on surgery. PPI treatment appeared more efficacious in studies conducted in Asia compared to studies conducted elsewhere. All-cause mortality was reduced only in Asian studies; reductions in rebleeding and surgery were quantitatively greater in Asian studies. Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery. AUTHORS' CONCLUSIONS: PPI treatment in PU bleeding reduces rebleeding and surgery compared with placebo or H(2)RA, but there is no evidence of an overall effect on all-cause mortality.

Acute Disease↗