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PubMed2004

Day care versus in-patient surgery for age-related cataract.

BACKGROUND: Age-related cataract accounts for more than 40% of cases of blindness in the world with the majority of people who are blind from cataract found in the developing world. With the increased number of people with cataract there is an urgent need for cataract surgery to be made available as a day-care procedure. OBJECTIVES: The objective of this review is to provide reliable evidence regarding the safety, feasibility, effectiveness and cost-effectiveness of cataract extraction performed as day-care versus in-patient procedure. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register) on The Cochrane Library (Issue 4 2002), MEDLINE (1966 to November 2002), EMBASE (1980 to November 2002) and LILACS (November 2002). SELECTION CRITERIA: This review includes randomised controlled trials comparing day-care and in-patient surgery for age-related cataract. The primary outcome was the achievement of a satisfactory visual acuity six weeks after the operation. DATA COLLECTION AND ANALYSIS: Although two trials are included in the review, adequate data were available for only one trial and therefore pooling of data from studies was not attempted. A descriptive summary is presented. MAIN RESULTS: Two trials, involving a total of 1284 people, are included in this review. One trial reported statistically significant differences in early postoperative complication rates in the day-care group, with an increased risk of increased intraocular pressure, which had no clinical relevance to visual outcomes four months postoperatively. The mean change in visual acuity (Snellen lines) of the operated eye four months postoperatively was 4.1 (standard deviation (SD) 2.3) for the day-care group and 4.1 (SD 2.2) for the in-patient group and not statistically significant. The four-month postoperative mean change in quality of life score measured using the VF14 showed minimal differences between the two groups. Costs were 20% more for the in-patient group and this was attributed to higher costs for overnight stay. One study only reported hotel costs for the non-hospitalised participants making aggregation of data on costs impossible. REVIEWER'S CONCLUSIONS: This review provides some evidence that there is a cost saving but no significant difference in outcome or risk of postoperative complications between day-care and in-patient cataract surgery. This is based on one detailed and methodologically sound trial conducted in the developed world. The success, safety and cost-effectiveness of cataract surgery as a day-care procedure appears to be acceptable but additional well-designed trials are required to confirm these perceptions.

Ambulatory Surgical Procedures↗

PubMed2006

Estimates of the cost and length of stay changes that can be attributed to one-week increases in gestational age for premature infants.

OBJECTIVE: To estimate the potential savings, both in terms of costs and lengths of stay, of one-week increases in gestational age for premature infants. The purpose is to provide population-based data that can be used to assess the potential savings of interventions that delay premature delivery. DATA: Cohort data for all births in California in 1998-2000 that linked vital records data with those from hospital discharge abstracts, including those of neonatal transport. All infants with a gestational age between 24 and 37 weeks were included. There were 193,167 infants in the sample after deleting cases with incomplete data or gestational age that was inconsistent with birth weight. METHODS: Hospital costs were estimated by adjusting charges by hospital-specific costs-to-charges ratios. Data were aggregated across transport into episodes of care. Mean and median potential savings were calculated for increasing gestational age, in one-week intervals. The 25th and 75th percentiles were used to estimate ranges. RESULTS: The results are presented in matrix format, for starting gestational ages of 24-34 weeks, with ending gestational ages of 25 to 37 weeks. Costs and lengths of stay decreased with gestational age from a median of $216,814 (92 days) at 24 weeks to $591 (2 days) at 37 weeks. The potential savings from delaying premature labor are quite large; the median savings for a 2 week increase in gestational age were between $28,870 and $64,021 for gestational ages below 33 weeks, with larger savings for longer delays in delivery. Delaying deliveries <29 weeks to term (37 weeks) resulted in savings of over $122,000 per case, with the savings being over $206,000 for deliveries <26 weeks. CONCLUSIONS: These results provide population-based data that can be applied to clinical trials data to assess the impacts on costs and lengths of stay of interventions that delay premature labor. They show that the potential savings of delaying premature labor are quite large, especially for extremely premature deliveries.

California↗

PubMed1975

Prothrombin complex proteins as cofactors in platelet aggregation. I. Inhibition of aggregation by antiserum.

Data are presented to support the concept that the vitamin K-dependent coagulation factors are adsorbed onto the platelet membrane and that these make up part of the "plasma atmosphere" necessary for the aggregation of platelets by various agents. Together with evidence that other coagulation factors also are part of the plasma atmosphere, it is suggested that the aggregation reaction is part of the coagulation sequence. The immunologic approach to demonstrating constituents of the platelet membrane promises to be a highly specific technique for studying further the constituents of the platelet membrane and their reactions in hemostasis.

Blood Coagulation Factors↗

PubMed1995

Three-dimensional quantitative autoradiography by disparity analysis: theory and application to image averaging of local cerebral glucose utilization.

Traditional autoradiographic image analysis has been restricted to the two-dimensional assessment of local cerebral glucose utilization (LCMRglc) or blood flow in individual brains. It is advantageous, however, to generate an entire three-dimensional (3D) data set and to develop the ability to map replicate images derived from multiple studies into the same 3D space, so as to generate average and standard deviation images for the entire series. We have developed a novel method, termed "disparity analysis," for the alignment and mapping of autoradiographic images. We present the theory of this method, which is based upon a linear affine model, to analyze point-to-point disparities in two images. The method is a direct one that estimates scaling, translation, and rotation parameters simultaneously. Disparity analysis is general and flexible and deals well with damaged or asymmetric sections. We applied this method to study LCMRglc in nine awake male Wistar rats by the [14C]2-deoxyglucose method. Brains were physically aligned in the anteroposterior axis and were sectioned subserially at 100-microns intervals. For each brain, coronal sections were aligned by disparity analysis. The nine brains were then registered in the z-axis with respect to a common coronal reference level (bregma + 0.7 mm). Eight of the nine brains were mapped into the remaining brain, which was designated the "template," and aggregate 3D data sets were generated of the mean and standard deviation for the entire series. The averaged images retained the major anatomic features apparent in individual brains but with some defocusing. Internal anatomic features of the averaged brain were smooth, continuous, and readily identifiable on sections through the 3D stack. The fidelity of the internal architecture of the averaged brain was compared with that of individual brains by analysis of line scans at four representative levels. Line scan comparisons between corresponding sections and their template showed a high degree of correlation, as did similar comparisons performed on entire sections. Fourier analysis of line scan data showed retention of low-frequency information with the expected attenuation of high-frequency components produced by averaging. Region-of-interest (ROI) analysis of the averaged brain yielded LCMRglc values virtually identical to those derived from measurements and subsequent averaging of data from individual brains.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1972

Regulation of the tryptophan synthetic enzymes in Clostridium butyricum.

Experiments concerned with the regulation of the tryptophan synthetic enzymes in anaerobes were carried out with a strain of Clostridium butyricum. Enzyme activities for four of the five synthetic reactions were readily detected in wild-type cells grown in minimal medium. The enzymes mediating reactions 3, 4, and 5 were derepressed 4- to 20-fold, and the data suggest that these enzymes are coordinately controlled in this anaerobe. The first enzyme of the pathway, anthranilate synthetase, could be derepressed approximately 90-fold under these conditions, suggesting that this enzyme is semicoordinately controlled. Mutants resistant to 5-methyl tryptophan were isolated, and two of these were selected for further analysis. Both mutants retained high constitutive levels of the tryptophan synthetic enzymes even in the presence of repressing concentrations of tryptophan. The anthranilate synthetase from one mutant was more sensitive to feedback inhibition by tryptophan than the enzyme from wild-type cells. The enzyme from the second mutant was comparatively resistant to feedback inhibition by tryptophan. Neither strain excreted tryptophan into the culture fluid. Tryptophan inhibits anthranilate synthetase from wild-type cells noncompetitively with respect to chorismate and uncompetitively with respect to glutamine. The Michaelis constants calculated for chorismate and glutamine are 7.6 x 10(-5)m and 6.7 x 10(-5)m, respectively. The molecular weights of the enzymes estimated by zonal centrifugation in sucrose and by gel filtration ranged from 24,000 to 89,000. With the possible exception of a tryptophan synthetase complex, there was no evidence for the existence of other enzyme aggregates. The data indicate that tryptophan synthesis is regulated by repression control of the relevant enzymes and by feedback inhibition of anthranilate synthetase. That this enzyme system more closely resembles that found in Bacillus than that found in enteric bacteria is discussed.

Aldehyde-Lyases↗

PubMed2000

YD-3, a novel inhibitor of protease-induced platelet activation.

1. In the present study, the antiplatelet effects and mechanisms of a new synthetic compound YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole] were examined. 2. YD-3 inhibited the aggregation of washed rabbit platelets caused by thrombin (IC(50)=28.3 microM), but had no or little inhibitory effect on that induced by arachidonic acid, collagen, platelet-activating factor (PAF) or U46619. YD-3 also suppressed generation of inositol phosphates caused by thrombin. On the other hand, thrombin-induced fibrin formation was not affected by YD-3, indicating YD-3 does not inhibit the proteolytic activity of thrombin. 3. In washed human platelets, however, YD-3 had only mild inhibitory effect on the low concentration (0.05 u ml(-1)) of thrombin-induced human platelet aggregation, and did not affect that induced by higher concentrations (> or =0.1 u ml(-1)) of thrombin or SFLLRN, the protease-activated receptor 1 (PAR1) agonist peptide. By contrast, YD-3 inhibited both human and rabbit platelet aggregation elicited by trypsin with IC(50) values of 38.1 microM and 5.7 microM, respectively. 4. YD-3, at 100 microM, had no effect on ristocetin-induced glycoprotein Ib (GPIb)-dependent aggregation of human platelets. In addition, platelets treated with chymotrypsin, which cleaves GPIb, enhanced rather than attenuated the inhibition of YD-3 on thrombin-induced human platelet aggregation. These data indicate that GPIb plays no role in the antiplatelet effect of YD-3. 5. In SFLLRN-desensitized human platelets, high concentration of thrombin (1 u ml(-1)) could still elicit intracellular Ca(2+) mobilization, and the rise of [Ca(2+)](i) was prevented by either leupeptin or YD-3. 6. Our results suggest that YD-3 inhibits a non-PAR1 thrombin receptor which mediates the major effect of thrombin in rabbit platelets, but in human platelets, this receptor function becomes significant only when the function of PAR1 has been blocked or attenuated.

Animals↗

PubMed2003

The Hospital Infection Standardised Surveillance (HISS) programme: analysis of a two-year pilot.

In 1998 the New South Wales (NSW) Health Department funded the development and implementation of the State's first standardized methodology for the surveillance of healthcare-associated infection for public hospitals. Fifteen pilot hospitals targeted inpatient groups considered to represent their core patient groups to act as sentinel measurements of patient safety. The aggregated rates of surgical site infection for coronary artery bypass graft (CABG) (chest & leg) surgery was 1.7% (95%CI: 1.1-2.5), CABG (chest only) 2.1% (95%CI: 1.0-3.7), vascular 7.1% (95%CI: 4.6-10.3), hip prosthesis 1.3% (95%CI: 0.5-2.7), knee prosthesis 6.1% (95%CI: 2.8-11.2) and colorectal 12.5% (95%CI: 9.5-16.1). The development of a bloodstream infection (BSI) associated with a central venous catheter (CVC) was not significantly (P=0.6) different when examined by duration of exposure with 3.7 BSI per 1000 line-days for CVC in situ six or more days compared with 4.0 BSI per 1000 line-days for CVC in situ for five or less days. A significantly (P<0.0001) greater proportion of patients whose CVC was in situ six or more days (6.8 per 100 patients, 95%CI: 4.2-10.2) developed a BSI compared with the proportion of patients whose CVC was in situ for five or fewer days (0.6 per 100 patients, 95%CI: 0.3-1.3). Significantly (P<0.0001) different rates of patients acquiring a new methicillin-resistant Staphylococcus aureus infection were found when hospital type was examined with rates ranging from 0.2 to 5.0 per 10000 occupied acute-care bed-days. The pilot highlighted that the collection of data for aggregation of some procedures and intravascular catheters may take many years before a reliable benchmark can be identified and many hospitals may not achieve reliable local rates annually. For surveillance to provide timely measures of patient safety we should consider surveillance methods for many small to medium sized hospitals that includes active surveillance only for infections with concurrent passive surveillance of the relevant denominators.

Catheterization↗

PubMed2006

Guidelines for improving the reproducibility of quantitative multiparameter immunofluorescence measurements by laser scanning cytometry on fixed cell suspensions from human solid tumors.

BACKGROUND: Laser scanning Cytometry (LSC) is a versatile technology that makes it possible to perform multiple measurements on individual cells and correlate them cell by cell with other cellular features. It would be highly desirable to be able to perform reproducible, quantitative, correlated cell-based immunofluorescence studies on individual cells from human solid tumors. However, such studies can be challenging because of the presence of large numbers of cell aggregates and other confounding factors. Techniques have been developed to deal with cell aggregates in data sets collected by LSC. Experience has also been gained in addressing other key technical and methodological issues that can affect the reproducibility of such cell-based immunofluorescence measurements. METHODS AND RESULTS: We describe practical aspects of cell sample collection, cell fixation and staining, protocols for performing multiparameter immunofluorescence measurements by LSC, use of controls and reference samples, and approaches to data analysis that we have found useful in improving the accuracy and reproducibility of LSC data obtained in human tumor samples. We provide examples of the potential advantages of LSC in examining quantitative aspects of cell-based analysis. Improvements in the quality of cell-based multiparameter immunofluorescence measurements make it possible to extract useful information from relatively small numbers of cells. This, in turn, permits the performance of multiple multicolor panels on each tumor sample. With links among the different panels that are provided by overlapping measurements, it is possible to develop increasingly more extensive profiles of intracellular expression of multiple proteins in clinical samples of human solid tumors. Examples of such linked panels of measurements are provided. CONCLUSIONS: Advances in methodology can improve cell-based multiparameter immunofluorescence measurements on cell suspensions from human solid tumors by LSC for use in prognostic and predictive clinical applications.

Cell Aggregation↗

PubMed2005

Epidemiological and health economical evaluation of intraoperative antibiosis as a protective agent against endophthalmitis after cataract surgery.

OBJECTIVE: To evaluate risk factors for endophthalmitis after cataract surgery and to retest recent findings on the protective effect of intraoperative antibiosis and the promoting effect of the clear corneal as compared to sclerocorneal incision. In addition, the economics of intraocular intraoperative antibiosis as a prophylaxis in cataract surgery are asketched. DESIGN: Survey study. PARTICIPANTS: Five hundred thirty-eight ophthalmosurgical centres in Germany. MAIN OUTCOME MEASURE: epidemiological evaluation: responder specific endophthalmitis incidence in year 2000; economical evaluation: direct cost analysis based on incidence data and local cost estimates (health service's perspective). RESULTS: A total of 310 (58%) questionnaires were computed resulting in an overall count of 404,356 cataract surgeries and 291 self-reported endophthalmitis cases (crude rate 0.072%). The risk of postoperative endophthalmitis for sclerocorneal versus clear corneal incisions was not significantly reduced (relative risk 0.97, 99% confidence interval 0.69-1.38). The hypothesis of a protective effect of intraocular antibiosis could be confirmed by a significantly decreased risk ratio of 0.69 (99% confidence interval 0.48-0.99) indicating a significant benefit from intraoperative intraocular antibiosis. A similar tendency was observed for an intraoperative periocular antibiosis with a significantly reduced risk ratio of 0.68 (99% confidence interval 0.49-0.96). These risk estimates had been adjusted for the size of the surgical centre: a significantly reduced risk ratio of 0.70 (99% confidence interval 0.49-0.98) for postoperative endophthalmitis was observed for local centres. Cost evaluation for the prophylactic use of intraocular intraoperative antibiosis in cataract surgery revealed an economically relevant decrease in direct endophthalmitis associated costs. CONCLUSIONS: Whereas this 2000 appraisal of a recent survey in 1996 could not reproduce the benefit of sclerocorneal incision, the protective effect of intraoperative intraocular antibiotic prophylaxis could be confirmed. However, the results of this survey have to be interpreted with care, since it is not based on individual case information, but rather on aggregate questionnaire data.

Antibiosis↗

PubMed2006

Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: correlation between VEGF expression and the FAB category.

Recent data suggest that vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and plays a key role as an autocrine regulator and mediator of angiogenesis. We examined the expression of VEGF in paraffin-embedded bone marrow sections obtained from normal donors (n = 5) and 46 patients with myelodysplastic syndromes [MDS, French-American-British (FAB)-type refractory anemia (RA), n = 10; refractory anemia with ringed sideroblasts (RARS), n = 10; refractory anemia with excess blasts (RAEB), n = 10; RAEB in transformation (RAEB-T), n = 8; chronic myelomonocytic leukemia (CMML), n = 8] by immunohistochemistry using an anti-VEGF antibody. In normal bone marrow, the anti-VEGF antibody was found to react with myeloid progenitor cells, immature monocytic cells, plasma cells and megakaryocytes, but not with erythroid cells or mature granulocytic cells. Higher levels of VEGF were found in patients with MDS, subtypes RAEB, RAEB-T and CMML, compared to patients with RA or RARS, or the normal bone marrow. These differences were found to result from expression of VEGF in immature myeloid cells in RAEB, RAEB-T and CMML. The microvessel density was also higher in patients with RAEB-T and CMML compared to RA and RARS or the normal bone marrow. Expression of VEGF mRNA was demonstrable in isolated neoplastic cells by reverse transcriptase-polymerase chain reaction in all patients examined. In aggregate, these data show that VEGF is expressed in bone marrow cells in patients with MDS. The amount of expressed VEGF is related to the percentage of immature myeloid cells (blasts and monocytic progenitors) and correlates with the FAB category.

Adult↗

PubMed2005

Eptifibatide: a review of its use in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention.

Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein (GP) IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischaemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI (STEMI).

Angioplasty, Balloon, Coronary↗

PubMed2006

Spotlight on eptifibatide in patients with acute coronary syndromes and/or undergoing percutaneous coronary intervention.

Eptifibatide (Integrilin) is a highly specific, reversible, intravenously administered glycoprotein IIb/IIIa receptor antagonist that acts at the final common step of the platelet aggregation pathway. Data from large clinical trials indicate that intravenous eptifibatide as adjunctive therapy to standard care is effective in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). In the ESPRIT (Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy) trial in patients undergoing PCI with stenting, eptifibatide, compared with placebo, achieved significant reductions in death and ischemic complications and was better than a strategy of reserving treatment for the bailout situation. In the large PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial in patients with NSTE ACS, eptifibatide was associated with a significant reduction in the incidence of death or myocardial infarction (MI) compared with placebo. Eptifibatide is well tolerated in these trials. Ongoing trials are currently investigating the efficacy and tolerability of regimens that include this agent in other indications, including ST-segment elevation MI.

Angioplasty, Balloon, Coronary↗

PubMed1996

The effect of castration on steady state levels of luteinizing hormone-releasing hormone (LHRH) mRNA and proLHRH processing: time course study utilizing semi-quantitative reverse transcription/polymerase chain reaction.

Many studies have consistently shown that castration induces a prompt increase in serum levels and pituitary content of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as a concomitant rise in steady state levels of the messenger RNAs directing their synthesis. The reports of effects of castration on the overall physiology of hypothalamic luteinizing hormone-releasing hormone (LHRH)--steady state levels of LHRH mRNA, post-translational processing and secretion--have, however, not been consistent. The goal of the studies reported here was to provide the first analysis of the effect of castration, at multiple postoperative time points, on steady state levels of LHRH mRNA and on the levels of hypothalamic proLHRH. All these data are correlated with hypothalamic levels of the mature LHRH decapeptide and with serum and pituitary levels of immunoreactive LH and FSH. Adult male rats were either castrated or sham-castrated (controls) and then sacrificed at 1, 3, 5, 7, 14, 21 or 28 days postoperatively. As expected, there was a prompt and sustained rise in serum immunoreactive LH and FSH in castrates compared with sham-operated animals. Intra-pituitary LH levels rose above levels in the sham-operated animals by 14 days post castration. Intra-pituitary FSH showed a biphasic response, first falling significantly below control levels, then rising above control levels at 21 days. Steady state levels of LHRH mRNA in castrates, measured by reverse transcription/polymerase chain reaction, were increased about 2-fold above control levels by 1 day postoperatively, but were virtually identical to control levels at each of the other time points despite marked changes in the gonadotropins. ProLHRH content in castrates was 1.8-times that seen in controls at 1 day post castration (P<0.05), concomitant with the rise in steady state levels of LHRH mRNA at that time point. However, proLHRH content in castrates was no different from that seen in controls at each of the later time points examined. LHRH content was unchanged through 7 days after castration, but then fell significantly to 57% of control levels in hypothalami from animals gonadectomized 14 to 21 days previously (P<0.001 vs control), and to 54% of sham-operated levels at 28 days postoperatively (P<0.001). We conclude that: (1) changes in steady state levels of LHRH mRNA after castration are small and transient and (2) increased proLHRH coupled with unchanged LHRH levels at 1 day post castration, and castrate animal proLHRH at control levels coupled with falling LHRH at later post-castration time points indicate that the effect of gonadectomy on post-translational processing of proLHRH to LHRH is, likewise, small and transient. In aggregate our data suggest that most of the increase in serum LH and FSH seen in male rats after castration is not mediated at the hypothalamic level.

Analysis of Variance↗

PubMed2002

Evaluation of agreements between managed care organizations and providers of community-based mental illness and addiction disorder treatments.

OBJECTIVE: To analyze the scope, content, and nature of contracts between managed care organizations (MCOs) and community-based mental illness and addiction disorder treatment and prevention service providers, focusing on implications for managed care policy. STUDY DESIGN: Qualitative and quantitative document content analysis. METHODS: We reviewed and coded 107 provider contracts from 17 states. Data were aggregated on MCO and provider demographics, scope of services, contractual obligations, and financial reimbursement mechanisms. Results were compared with those from a similar study conducted in 1996 with a sample of 50 contracts to identify changes over time. RESULTS: The MCOs purchased relatively few services from providers, omitting many services integral to the proper management of mental illness and addiction disorders. Service duties were often ambiguously described, leading to potentially significant and unanticipated financial risk for providers. The MCOs exert strong control over treatment decision making. Capitation and other risk-based payment arrangements are increasingly common, although most continue to use fee-for-service reimbursement methods. Contracts are structured to remove provider bargaining power; they allow MCOs to unilaterally amend all provisions on notice and without negotiation and permit termination "at will." CONCLUSIONS: Managed care contracts favor the needs of the managed care industry and are constructed to (1) shift significant amounts of financial risk onto providers and (2) manage and restrain providers' choices over the use of benefits through close oversight, financial controls, and incentives. Because a signed contract is a precondition to access to patients and insurance revenues, health professionals must sign them and indicate a general inability to negotiate their terms.

Community Mental Health Services↗

PubMed1999

The genetics of hereditary melanoma and nevi. 1998 update.

Although the first English-language report of melanoma in 1820 contained a description of a melanoma-prone family, it was 1983 before formal genetic analysis suggested an autosomal dominant mode of inheritance for both melanoma and the then newly described melanoma precursor, dysplastic nevi (DN). Subsequent genetic studies have assumed this model to be correct, although when viewed in aggregate, the data are inconsistent. The first proposed melanoma gene (CMM1) was mapped to chromosome 1p36. This gene assignment has not been confirmed. A second melanoma gene, designated CMM2, has been mapped to chromosome 9p21. This gene assignment has been confirmed, and the cell cycle regulator CDKN2A has been proposed as the candidate gene. Germline mutations in this gene have been identified in about 20% of melanoma-prone families that have been studied to date. Pancreatic cancer occurs excessively in melanoma families with germline mutations in CDKN2A. Germline mutations in the cyclin-dependent kinase gene CDK4 (chromosome 12q14) have been described in three melanoma families. This finding represents a third melanoma gene but one that accounts for only a tiny fraction of all hereditary melanoma. Recently, a familial melanoma-astrocytoma syndrome has been reported. Large germline deletions of 9p21 occur in these families, with the p19 gene implicated in its pathogenesis. At present, clinical predictive genetic testing for mutations in the CDKN2A gene is available commercially, but its use has been limited by uncertainty as to how test results would affect the management of melanoma-prone family members. Currently, management recommendations include monthly skin self-examination, clinical skin examination once or twice yearly, a low threshold for simple excision of changing pigmented lesions, moderation of sun exposure, and appropriate use of sunscreens. A heritable determinant for total nevus number has been suggested by twin studies. Other data suggest the presence of a major gene responsible for "total nevus density" in melanoma-prone families. Approximately 55% of the mole phenotype in multiplex melanoma families was explained by this proposed gene. An autosomal dominant mode of inheritance has been proposed for DN, and data exist to suggest that DN may be a pleiotropic manifestation of the 1p36 familial melanoma gene. However, there clearly are melanoma-prone families that do not express the dysplastic nevus trait, and some of the families linked to CDKN2A also present with dysplastic nevi. Several studies have shown a surprisingly high prevalence of DN on the skin of family members of probands with DN. In light of the extensive evidence documenting that persons with DN (both sporadic and familial) have an increased prospective risk of melanoma, these family studies suggest that relatives of persons with DN should be examined for both DN and melanoma. Genetic determinants play a major role in the pathogenesis of normal nevi, DN, and melanoma. Identifying the molecular basis of these genetic events promises to enhance melanoma risk-reduction strategies and, ultimately, reduce melanoma-associated mortality.

Adult↗

PubMed1999

Reconsidering "between-group psychotherapy outcome research and basic science:" applications to child and adolescent psychotherapy outcome research.

Borkovec and Miranda (1996) proposed that the purpose of controlled outcome studies is to increase our understanding of the change mechanisms associated with psychotherapy, and they suggested several ways that between-group outcome research establishes cause-and-effect relationships. Child psychotherapy outcome research presents special challenges for the issues raised by Borkovec and Miranda and four of these are discussed herein: (a) the multitude of influences on children and adolescents that affect their functioning and therapy outcomes, (b) accurately defining the referral problem, (c) identifying appropriate outcome measures and reliable informants of change in child and adolescent treatment, and (d) considering developmental processes that influence therapeutic effectiveness. It is suggested that transporting clinical trials methods to natural settings is of limited value in identifying cause-and-effect relationships, and an alternative methodology is proposed for advancing child therapy outcome research. This approach advocates developing a profile of the underlying causes that predict psychopathology and therapy outcome for individual children in real clinical settings and then aggregating the data for youth with similar profiles and outcomes. These data can then be used to generate hypotheses about what interventions work for specific children, and investigators can employ prospective studies of therapy outcome for youth with similar profiles.

Adolescent↗

PubMed2000

Temporal analysis of growth factor mRNA expression in myelinating rat brain aggregate cultures: increments in CNTF, FGF-2, IGF-I, and PDGF-AA mRNA are induced by antibody-mediated demyelination.

Myelinogenesis in rat brain aggregate cultures is associated with a pattern of growth factor mRNA expression comparable to that of the developing brain. The rate of increase in platelet-derived growth factor-AA (PDGF-AA) expression was greatest just before the detection of myelin basic protein (MBP) mRNA in the cultures and remained high thereafter, consistent with in vivo observations. Levels of fibroblast growth factor-2 (FGF-2) and of ciliary neurotrophic factor (CNTF) mRNA increased continuously over the period of MBP accumulation. High rates of transforming growth factor beta1 (TGF-beta1), insulin-like growth factor-I (IGF-I), and neurotrophin-3 (NT-3) expression at early time points during the culture gradually decreased over time, indicative of a key regulatory role during oligodendrocyte development. The addition of demyelinative anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibody resulted in a significant increase in MBP peptide fragments with a C-terminus at phenylalanine 89 indicating proteolytic breakdown of MBP after myelin phagocytosis. Immediately after antibody treatment the expression of CNTF mRNA was significantly increased, compared with controls, while that of FGF-2 and IGF-I, and of PDGF-AA peaked during the early and later stages of recovery respectively. Thus, specific growth factors combine to regulate myelination and remyelination in the aggregates; these data have implications for demyelinating disease in which protective growth factor secretion may be central to regeneration.

Animals↗

PubMed1997

The selection of internal migration models for European regions.

"A full multiregional projection model requires migration data that are simultaneously classified by age and gender and region of origin and region of destination. Except for a very small number of regions, these data requirements are so high that aggregation of the data (which is equivalent to simplification of the model) is called for. This paper investigates the extent to which the full internal migration matrix can be simplified without seriously affecting the performance of the resulting multiregional model. Using IPF (iterative proportional fitting) methods, a log-linear analysis of alternative model specifications is made, using data for Italy, the Netherlands and the UK....A reasonable balance between goodness-of-fit and parsimony is found for the model in which time interacts with the main effects only (i.e. with age/sex, with origin and with destination)."

Age Factors↗