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PubMed2005

T1 G1 urinary bladder carcinoma: fact or fiction?

OBJECTIVES: To record the occurrence of well-differentiated bladder carcinoma reported as T1 G1 to the Swedish Urinary Bladder Cancer Registry, to review the staging and grading of the carcinomas and to scrutinize the validity of the data on T1 G1 tumours reported to the registry during the period 1997-2000. MATERIAL AND METHODS: The primary histopathological diagnoses of 98 cases of well-differentiated bladder carcinoma reported to the Registry were compared with the data delivered by the local urologists. Also, the histopathology slides were obtained from the local laboratories and re-examined. RESULTS: Fifty-five cases had been erroneously reported to the Registry as T1 tumours by the urologists, even though they were clearly described as non-infiltrating G1 tumours by the pathologists. The results of the re-examination of the pathology slides were concordant with the judgements of the local pathologists in only 50% of cases (20 stage T and 29 grade G tumours). Most importantly, the re-evaluation did not reveal a single invasive G1 tumour. Simply by providing the urologists with information about this problem, it was possible to reduce the number of errors in the reports from 27 in 1997 to only five in 2000. CONCLUSIONS: Well-differentiated urothelial carcinoma (G1) has no propensity to infiltrate the bladder mucosa. For investigating specific problems the data collected in the Swedish Urinary Bladder Cancer Registry have to be validated.

Cell Division↗

PubMed1996

Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel.

BACKGROUND: Microtubules are cellular organelles with functions that include control of cell division by mitosis, cell morphology, and transport of material within the cell. The anticancer drug paclitaxel (Taxol) promotes accelerated assembly of excessively stable microtubules. Consequently, treated cells tend to become arrested in mitosis. The drug also induces apoptotic cell death in vitro and in vivo. Prior to this study, the relative contributions of mitotic arrest and apoptosis to the in vivo antitumor effect and the relationship between the two factors had not been established; moreover, it is not known whether paclitaxel-induced mitotic arrest inevitably results in cell death. PURPOSE: Our aim was to quantify the mitotic arrest and apoptosis induced by paclitaxel in 16 murine tumors in vivo and to correlate these two factors with the drug's antitumor effect. METHODS: Inbred C3Hf/Kam mice were implanted with one of the following 16 syngeneic tumors: seven adenocarcinomas (MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VII), six sarcomas (FSa, FSa-II, Sa-IIa, Sa-NH, NFSa, and Sa-4020), and one lymphoma (Ly-TH). The tumor growth delay induced by paclitaxel (40 mg/kg body weight given intravenously) was measured in 163 control and 163 treated mice, and its significance was assessed by Student's t test. In a separate group of 439 mice, the percentage of cells in mitosis or apoptosis was scored micromorphometrically at various times after paclitaxel administration. The significance of correlations between paclitaxel-induced tumor growth delay and paclitaxel-induced levels of mitosis or apoptosis was determined by simple correlation and Spearman's rank correlation. P values reported represent two-sided tests of statistical significance. RESULTS: Statistically significant tumor growth delays were found in response to paclitaxel treatment of mice for three of four murine mammary carcinomas (all P < or = .010), an ovarian carcinoma (P = .00003), a salivary gland adenocarcinoma (P = .0002), a lymphoma (P = .0002), and two of six sarcomas (both P < or = .034), but not for either of two squamous cell carcinomas or for the hepatocellular carcinoma. Paclitaxel-induced mitotic arrest was apparent in all tumor types, but to various degrees, and was not significantly correlated with growth delay (R2 = .16; P = .124). In contrast, apoptotic cell death in response to paclitaxel was not ubiquitous, but it was strongly correlated with growth delay (R2 = .59; P = .001). The pretreatment level of apoptosis was correlated with both paclitaxel-induced apoptosis (R2 = .71; P = .00004) and tumor growth delay (R2 = .55; P = .001). CONCLUSION: The antitumor effect of paclitaxel was correlated with paclitaxel-induced apoptosis and base-line apoptosis, but not with mitotic arrest. IMPLICATIONS: Apoptosis is an important mechanism of cell death in response to paclitaxel treatment of in vivo murine tumors. An underlying tumor type-specific propensity for apoptosis is implied by the correlation between pretreatment and paclitaxel-induced apoptosis. Both the extent of pretreatment apoptosis and the paclitaxel-induced percentage of apoptosis may be useful predictors of response to the drug.

Adenocarcinoma↗

PubMed2005

Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer.

OBJECTIVE: To appraise the economics of a recurrence score (RS), based on an assay that predicts distant recurrence-free survival in lymph-node-negative (LN-), estrogen-receptor-positive (ER+) patients with early-stage breast cancer receiving tamoxifen. STUDY DESIGN: Cost-utility analyses using a decision analytic model. METHODS: Using a Markov model, we forecast overall survival, costs, and cost effectiveness of using the RS in patients classified as having low or high risk of distant recurrence based on National Comprehensive Cancer Network (NCCN) clinical guidelines. Data from a large multicenter clinical trial (NSABP B-14) were analyzed to derive risk classification based on guideline criteria and RS assignments. Efficacy of adjuvant chemotherapy (CT) on distant recurrence-free survival (DRFS) was based on published meta-analyses of CT trials. The analysis took a societal perspective, considering survival, quality of life, and relevant costs. RESULTS: Fifty-three patients (8%) were classified as having low risk of distant recurrence by NCCN guidelines and the RS reclassified 15 of these patients (28%) to an intermediate/high-risk group. The remaining 615 patients (92%) were classified at high risk of distant recurrence by NCCN guidelines and the RS reclassified 300 of these patients (49%) to a low-risk group. Among a hypothetical cohort of 100 patients, RS is predicted on average to increase quality-adjusted survival by 8.6 years and reduce overall costs by $202 828. RS was cost saving in more than two-thirds of probabilistic simulations, with cost effectiveness most influenced by the propensity to administer CT based on RS results, and by the proportion of patients at low risk as defined by NCCN guidelines. CONCLUSIONS: The RS predicts more accurately than current guidelines recurrence risk in LN-, ER+ patients with early-stage breast cancer. If applied appropriately, the assay is predicted to increase quality-adjusted survival and save costs.

Breast Neoplasms↗

PubMed2005

Correlation of HER2 gene amplification with expression of the apoptosis-suppressing genes bcl-2 and bcl-x-L in ductal carcinoma in situ of the breast.

The protein product of the HER2 oncogene is overexpressed in an estimated 25 to 30% of breast carcinomas and is considered an indicator of poor clinical outcome. The bcl-2 and the bcl-x-L genes are the 2 main genes of the bcl-2 gene family that suppress tumor cell death/apoptosis. HER2 gene amplification is also described in a percentage of cases of ductal carcinoma in situ (DCIS) of the breast. However, the relationship of such overexpression with the apoptosis-suppressing genes is currently unknown. A total of 37 consecutive cases of DCIS were immunostained for HER2 overexpression (clone CB11, Ventana), and expression of bcl-2 and bcl-x-L. DCIS cases were graded using the criteria of Holland et al. HER2 overexpression was scored 0 to 3+; 0 and 1+ were considered negative staining and 2+ and 3+ were considered positive staining. HER2 gene amplification was also confirmed with fluorescent in situ hybridization (FISH). HER2 was positive in 22 of the 37 DCIS cases (60%) in accordance with previous reports. Immunohistochemical overexpression of HER2 was also highly correlated with HER2 amplification by FISH. HER2 overexpression (confirmed by FISH) was mostly seen in grade II (9 of 17) and grade III (9 of 12) DCIS lesions. Only 1 of the HER2-amplified cases was a grade I lesion. Furthermore, HER2 overexpression correlated with the presence of necrosis (P=0.003). Similarly, of the cases overexpressing HER2 at the highest level (3+), 90% were grade II or grade III lesions. A total of 73% of these cases also exhibited necrosis. Overexpression of HER2 3+ was also highly correlated with the presence of the apoptosis-suppressing gene bcl-x-L (coexpression in 87% of cases, P=0.01) but not with the prototype apoptosis-suppressing gene bcl-2 (coexpression in 50% of cases, P value not significant). First, in DCIS overexpression of HER2 the majority of grade II and grade III lesions is seen, and this correlates with the presence of necrosis. Second, HER2 overexpression is also highly correlated with the expression of the apoptosis-suppressing gene bcl-x-L, but not with the prototype apoptosis-suppressing gene bcl-2. These differences may prove useful in defining groups of DCIS lesions with enhanced tumor cell growth and propensity for progression to invasion.

Apoptosis↗

PubMed1993

Synergistic effects of haemodynamic stabilisation and beta blockade on ventricular fibrillation threshold in coronary artery ligated pigs.

OBJECTIVE: The aim was (1) to test the hypothesis that the prevention of haemodynamic deterioration decreases arrhythmia formation in the infarcting heart and augments the antiarrhythmic effects of beta blockade; and (2) to assess the ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold as an index of innate arrhythmogenic propensity. METHODS: Changes in ventricular fibrillation threshold were determined for 50 min after anterior descending coronary artery occlusion in open chest pigs (group 1, n = 5). In group 2 (n = 9), ventricular fibrillation threshold was studied in the same way but cardiac output was maintained at 100 ml.min-1.kg-1 body weight and mean aortic pressure at 60(SEM 3) mm Hg by means of right heart and arterio-arterial bypass. In both groups intravenous propranolol 1.2 mg.kg-1 was injected 35-40 min after coronary artery occlusion. In group 3 (n = 6) spontaneous arrhythmias following coronary artery occlusion were recorded to test how well the ventricular fibrillation threshold reflected the incidence and time course of these arrhythmias. RESULTS: In group 1, there was a deep trough in ventricular fibrillation threshold--from 11.3(0.3) mA to 6.0(0.3) mA--within 10 min of coronary artery occlusion (47% decrease, p < 0.001). There was a shallower trough between 10 and 30 min. In group 2, preocclusion ventricular fibrillation threshold increased from 13.9(1.2) mA to 32.1(5.6) mA (p < 0.05) because of stabilised haemodynamics. After coronary occlusion, fibrillation threshold remained high throughout, being 22.7(1.3) mA and 20.4(1.1) mA at the times of the expected troughs (p < 0.005 v group 1 for both values). Propranolol increased ventricular fibrillation threshold by 24(7)% in group 1 (p < 0.05) and by 53(8)% in group 2 (p < 0.0005). In group 3 spontaneous arrhythmias followed a biphasic pattern, similar to group 1. There was a positive correlation between ventricular fibrillation threshold and arrhythmia score (r = 0.84). CONCLUSIONS: (1) Haemodynamic stabilisation increased ventricular fibrillation threshold during ischaemia and enhanced the antiarrhythmic effects of beta blockade. (2) The ventricular fibrillation threshold accurately reflects the incidence and time course of spontaneous arrhythmias in this model.

Adrenergic beta-Antagonists↗

PubMed2000

Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America.

Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.

Adult↗

PubMed1997

Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug.

The present experiment examined the contribution of locomotor response to novelty and prior exposure to amphetamine to rats' predisposition to self-administer a low dose of the drug. Rats were screened for their locomotor response to a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor scores were above or below the median activity level of the subject sample. Animals were then pre-exposed to nine daily injections of either saline (1 ml/kg, i.p.) or amphetamine (1.5 mg/kg, i.p.). Starting 1 week after pre-exposure, animals in the four different groups (HR pre-exposed to saline or amphetamine; LR pre-exposed to saline or amphetamine) were given the opportunity, in each of ten daily sessions, to lever press for a low dose of amphetamine (10 micrograms/kg per infusion) in a two lever (active versus inactive) continuous reinforcement operant task. Initial lever press performance revealed no difference in active versus inactive lever pressing between amphetamine and saline pre-exposed animals. However, in agreement with previous reports, with successive test sessions amphetamine pre-exposed rats maintained higher levels of active versus inactive lever pressing for drug while saline pre-exposed rats showed a progressive decrease in the pressing of either lever. Interestingly, this enhanced active lever pressing was observed in HR but not LR rats pre-exposed to amphetamine. In addition, HR saline pre-exposed animals showed initial active versus inactive lever pressing equivalent to that of HR amphetamine pretreated rats but this enhanced responding for drug diminished over days and by the last day of self-administration was indistinguishable from that of LR animals having been pre-exposed either to amphetamine or saline. These findings confirm that prior exposure to amphetamine promotes the subsequent self-administration of the drug and suggest that response to novelty may be a predictor more closely linked to an animal's propensity to become sensitized to the facilitatory effects of the drug rather than to an animal's current sensitization state and predisposition to self-administer the drug.

Amphetamine↗

PubMed2002

Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice.

The forced swim test (FST) and tail suspension test (TST) are widely used and well established screening paradigms for antidepressants. A variety of antidepressive agents are known to reduce immobility time in both FST and TST. To identify genetic determinants of immobility duration in both tests, we analyzed 560 F2 mice from an intercross between C57BL/6 (B6) and C3H/He (C3) strains. Composite interval mapping revealed five major loci (suggestive and significant linkage) affecting immobility in the FST, and four loci for the TST. The quantitative trait loci (QTL) on chromosomes 8 and 11 overlap between the two behavioral measures. Genome-wide interaction analysis, which was developed to identify locus pairs that may contribute epistatically to a phenotype, detected two pairs of chromosomal loci for the TST. The QTL on chromosome 11 and its associated epistatic TST-QTL on chromosome X encode gamma-aminobutyric acid type A (GABA(A)) receptor subunits as candidates. Sequence and expression analyses of these genes from the two parental strains revealed a significantly lower expression of the alpha1 subunit gene in the frontal cortex of B6 mice compared to C3 mice. The present quantitative trait study should open up avenues for identifying novel molecular targets for antidepressants and unraveling the complex genetic mechanisms of depressive and anxiety disorders.

Animals↗

PubMed1998

Important variables that influence base-line micronucleus frequency in cytokinesis-blocked lymphocytes-a biomarker for DNA damage in human populations.

The cytokinesis-block micronucleus (CBMN) assay has been adopted by numerous laboratories as a means for rapidly assessing base-line chromosome damage (breakage and loss) in human populations. However, the appropriate implementation of this assay requires a thorough understanding of both experimental variables and biological factors that can have impact on micronucleus (MN) frequency. The paper describes, with the help of experimental data the from the author's laboratory as well as other data, the impact of these variables. With regards to experimental variables, the scoring of micronuclei on slides by different technicians has been identified as an important factor; however, the use of different culture media, namely RPMI 1640 and McCoy's medium, did not have a significant effect on base-line frequencies. The paper also describes results showing that the MN index in cytokinesis-blocked cells, measured once every three months over a 12-month period for 53 healthy subjects, remains constant and the data measured on these occasions were significantly and positively correlated (R=0.477 to 0.684, P<0. 0001) with each other thus indicating the reliability and intra-individual variability of the assay over time. Inter-individual variation for males and female subjects has been estimated for each decade of age between 20 and 80 years; the difference between the 25th and 75th percentile of MN frequency varied between 1.4 fold and 2.3 fold and the minimum and maximum values for MN frequency varied by a factor of 4.7 and 12.5 depending on the age group. Age and gender are the most important demographic variables impacting on the MN index with MN frequencies in females being greater than those in males by a factor of 1.2 to 1.6 depending on the age group. For both sexes, MN frequency was significantly and positively correlated with age (R=0.62 in males and R=0.65 in females) and the slope of the regression line in males was 0.314 (P<0.0001) and in females it was 0.517 (P<0.0001). The main dietary factors influencing the MN index in subjects who are not folate deficient are plasma B12 (R=-0.315, P=0.0127) and plasma homocysteine (R=0.415, P=0.0086). In addition, it was proposed that the MN index is likely to be influenced by the propensity of an individual's cells to undergo apoptosis when damaged so that one might expect the MN frequency to be negatively correlated with apoptotic rate although this has yet to be tested. The above indicates the importance of maintaining an international network of scientists working with the CBMN assay to ensure appropriate quality control and for the development of standard experimental and documentation protocols. The human micronucleus (HUMN) project launched in 1997 is briefly described and proposed as the vehicle for these activities.

Adult↗

PubMed1994

A comprehensive analysis of craniofacial trauma.

A review of the literature identified a need for a prospective study of the complete range of craniofacial trauma. The aims of this study were to determine the incidence, etiology, and mechanisms of craniofacial and associated injuries, enabling a greater understanding of their range and magnitude. Nine hundred fifty consecutive patients seen at an urban university hospital with any degree of craniofacial trauma were prospectively investigated. Craniofacial trauma was found to be very common at all ages. The causes were directly related to age, sex, and alcohol consumption, and determine the type and severity of injury. The commonest cause of soft-tissue injury was falls, whereas that of fractures was interpersonal violence. Falls accounted for most of the injuries in children and the elderly, whereas interpersonal violence was mainly responsible for those occurring in patients aged 15 to 50 years. Interpersonal violence mostly involved young male adults: fights occurring mainly between strangers who had consumed excessive amounts of alcohol. Women were usually assaulted by assailants known to them, their partners. Pedestrians showed a propensity to sustain cranial fractures, whereas motor vehicle occupants tended to sustain midfacial fractures and bicyclists mandibular fractures. Pedestrians incurred the severest injuries of all road users, and a significant proportion of road user collisions involved bicyclists. Sports were responsible for a significant proportion of craniofacial injuries in youths and young adults. Craniofacial soft-tissue injuries overall occurred most frequently on the forehead, nose, lips, and chin, and a method for their classification is proposed. The commonest craniofacial fracture was that of the nasal bones (45%), followed by cranial bones (24%), mandible (13%), zygoma (13%), orbital blow-out (3%), and maxilla (2%). The incidence of craniofacial trauma can be greatly reduced by improvements in interior home design, school education in alcohol abuse and handling potentially hostile situations (especially for men), improvement in automotive safety devices and compliance by motor vehicle occupants, and utilization of full-face helmets by bicyclists and motorcyclists.

Accidental Falls↗

PubMed2005

Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

OBJECTIVES: To determine the relative efficacy and cost-effectiveness of five of the most commonly used antimicrobial preparations for treating mild to moderate facial acne in the community; the propensity of each regimen to give rise to local and systemic adverse events; whether pre-existing bacterial resistance to the prescribed antibiotic resulted in reduced efficacy; and whether some antimicrobial regimens were less likely to give rise to resistant propionibacterial strains. DESIGN: This was a parallel group randomised assessor-blind controlled clinical trial. It was a pragmatic design with intention-to-treat analysis. All treatments were given for 18 weeks, after a 4-week treatment free period. Outcomes were measured at 0, 6, 12 and 18 weeks. SETTING: Primary care practices and colleges in and around Nottingham and Leeds, and one practice in Stockton-on-Tees, England. PARTICIPANTS: Participants were 649 people aged 12--39 years, all with mild to moderate inflammatory acne of the face. INTERVENTIONS: Study participants were randomised into one of five groups: 500 mg oral oxytetracycline (non-proprietary) twice daily (b.d.) + topical vehicle control b.d.; 100 mg oral Minocin MR (minocycline) once daily (o.d.) + topical vehicle control b.d.; topical Benzamycin (3% erythromycin + 5% benzoyl peroxide) b.d. + oral placebo o.d.; topical Stiemycin (2% erythromycin) o.d. + topical Panoxyl Aquagel (5% benzoyl peroxide) o.d. + oral placebo o.d., and topical Panoxyl Aquagel (5% benzoyl peroxide) b.d. + oral placebo o.d. (the active comparator group). MAIN OUTCOME MEASURES: The two primary outcome measures were: (1) the proportion of patients with at least moderate self-assessed improvement as recorded on a six-point Likert scale, and (2) change in inflamed lesion count (red spots). RESULTS: The best response rates were seen with two of the topical regimens (erythromycin plus benzoyl peroxide administered separately o.d. or in a combined proprietary formulation b.d.), compared with benzoyl peroxide alone, oxytetracycline (500 mg b.d.) and minocycline (100 mg o.d.), although differences were small. The percentage of participants with at least moderate improvement was 53.8% for minocycline (the least effective) and 66.1% for the combined erythromycin/benzoyl peroxide formulation (the most effective); the adjusted odds ratio for these two treatments was 1.74 [95% confidence interval (CI) 1.04 to 2.90]. Similar efficacy rankings were obtained using lesion counts, acne severity scores and global rating by assessor. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective regimen (ratio of means 12.3; difference in means -0.051 units/GBP, 95% CI -0.063 to -0.039). The efficacy of oxytetracycline was similar to that of minocycline, but at approximately one-seventh of the cost. For all regimens, the largest reductions in acne severity were recorded in the first 6 weeks. Reductions in disability scores using the Dermatology Quality of Life Scales were largest for both topical erythromycin-containing regimens and minocycline. The two topical erythromycin-containing regimens produced the largest reductions in the prevalence and population density of cutaneous propionibacteria, including antibiotic-resistant variants, and these were equally effective in participants with and without erythromycin-resistant propionibacteria. The clinical efficacy of both tetracyclines was compromised in participants colonised by tetracycline-resistant propionibacteria. None of the regimens promoted an overall increase in the prevalence of antibiotic-resistant strains. Systemic adverse events were more common with the two oral antibiotics. Local irritation was more common with the topical treatments, particularly benzoyl peroxide. Residual acne was present in most participants (95%) at the end of the study. CONCLUSIONS: The response of mild to moderate inflammatory acne to antimicrobial treatment in the community is not optimal. Only around half to two-thirds of trial participants reported at least a moderate improvement over an 18-week study period; extending treatment beyond 12 weeks increased overall benefit slightly. Around one-quarter dropped out when using such treatments, and 55% sought further treatment after 18 weeks. Topical antimicrobial therapies performed at least as well as oral antibiotics in terms of clinical efficacy. Benzoyl peroxide was the most cost-effective and minocycline the least cost-effective therapy for facial acne. The efficacy of all three topical regimens was not compromised by pre-existing propionibacterial resistance. Benzoyl peroxide was associated with a greater frequency and severity of local irritant reactions. It is suggested that the use of a combination of topical benzoyl peroxide and erythromycin gives less irritation and better quality of life. There was little difference between erythromycin plus benzoyl peroxide administered separately and the combined proprietary formulation in terms of efficacy or local irritation, except that the former was nearly three times more cost-effective. The data on cost-effectiveness, and outcomes in patients with resistant propionibacterial floras, did not support the first line use of minocycline for mild to moderate inflammatory acne of the face. Three priority areas for clinical research in acne are: defining end-points in acne trials (i.e. what is a satisfactory outcome?); developing and validating better patient-based measures for assessing treatment effects on facial and truncal acne; and exploring patient characteristics that may modify treatment effects (efficacy and tolerability).

Acne Vulgaris↗

PubMed2001

Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians.

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians.

Aging↗

PubMedDate not supplied

[Preliminary validation of the French translation of anxiety sensibility index-revised (ASI-R)].

Anxiety sensitivity represents a stimulus-outcome expectancy that reflects individual differences in the propensity to experience fear in response to one's arousal-related bodily sensations. It refers to the fear of anxiety-related symptoms that are based on beliefs that such sensations have negative somatic, social or psychological consequences. Anxiety sensitivity occupies an important place in theory and research on panic and related interoceptive fear disorders. Findings from this body of research indicate that this construct may act as a specific vulnerability variable in the development of panic attacks and anxiety symptoms. However, anxiety sensitivity theory also has been applied to understanding mood disorders and chronic pain disorders. Thus, as a psychological construct, anxiety sensitivity holds specific relevance to understanding panic disorders and general relevance for expanding knowledge about negative emotional functioning in other pathologies. All the research on anxiety sensitivity has been completed with the 16-item Anxiety Sensitivity Index (ASI). The review of the literature using this instrument suggested that anxiety sensitivity has three lower-order factors that all load on a single higher-order factor. The lower-order factors represent Physical-Concerns, Mental Incapacitation Concerns, and Social Concerns, and the higher-order factor represents the global anxiety sensitivity construct (21). Taylor and Cox (22) suggested that this questionnaire was not designed on an a priori basis to measure the identified lower-order factors. The low number of items for the Social and Mental Incapacitation dimensions of the 16-item ASI often leads to relatively lower levels of reliability compared to the third dimension. To address this issue, Taylor and Cox (22) developed an expanded measure of the anxiety sensitivity construct. The 36-item Revised Anxiety Sensitivity Index (ASI-R) maintains the same format as the 16-item ASI, but expands the number of content domains assessed. The ASI-R was designed to assess 6 lower-order domains identified in previous factor analytic research using the 16-item ASI (21), including fear of cardiovascular symptoms, fear of respiratory symptoms, fear of gastrointestinal symptoms, fear of publicity observable reactions, fear of dissociative and neurological symptoms, and fear of cognitive dyscontrol. The principal components factor analysis using the ASI-R among psychiatric outpatients indicated that there were 4 lower-order factors tapping the constructs of (1) fear of respiratory symptoms, (2) fear of publicly observable anxiety reactions, (3) fear of cardiovascular symptoms, and (4) fear of cognitive dyscontrol (22). A recent study (27) provided an initial psychometric evaluation of the ASI-R in a large, diverse sample of people (n = 2,786) from 6 different countries: Canada, United States, Mexico, Spain, The Netherlands and France. The data suggested that the two-factor solution is most replicable than other solutions (2 to 6 factors). The underlying structure of the anxiety sensitivity construct was generally similar across countries, tapping fear about the negative consequences of anxiety-related physical and social-cognitive sensations. Lower-order factors were moderately to strongly correlated with one another and showed good internal consistency. This manuscript presents the French translation of the ASI-R and a preliminary validation study. This research was realized conjointly with the transcultural study previously mentioned (27). Seven hundred and one French university students (non-clinical participants) completed the questionnaire at the beginning of a class. Subjects were undergraduate students from 2 universities (psychology and classics). Table I provides age, sex and marital status. There were no differences between the two groups on sex. The two groups were not comparable on age and marital status. The psychology group was older than the other was. The psychology students were also more married. The total group (n = 701) comprises 79 men and 622 women, with a mean age of 21.29 (4.85). Table II provides the normative means and standard deviations for both groups of students. There was no difference between the two groups on the total of the questionnaire (no significant interaction between group and age). In regard to the physical concerns subscale and the social-cognitive concerns subscale, there was also no significant interaction between group and age. Assessment of the internal consistency of the ASI-R yielded an overall Cronbach alpha of 0.91 for the entire questionnaire, with an alpha of 0.88 for the fear of anxiety-related physical sensations subscale and 0.83 for the fear of anxiety-related social-cognitive sensations subscale. A series of ANOVAs between male and female groups revealed significant gender differences. As shown in table IV, women had significantly higher total score than did men. They also had significantly higher physical factor and social-cognitive factor scores than did men. This finding is consistent with research that indicates that women generally report more intense fears and men less intense fears, and that they differ in levels of overall anxiety sensitivity specifically (29). This preliminary report was the first attempt to examine the construct of anxiety sensitivity using the ASI-R in a French university students. It can serve as a reference point for future research.

Adult↗

PubMed2006

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

Black or African American↗

PubMed2005

HLA-DQA1, -DQB1 polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy in Hans of northern China.

Autoimmune mechanisms are likely to participate in the pathogenesis of at least a subgroup of idiopathic dilated cardiomyopathy (IDC), and components of the major histocompatibility complex (MHC) may serve as markers for the propensity to develop immune-mediated myocardial damage. Human leukocyte antigen (HLA) class II genes, especially HLA-DQ genes, which are highly polymorphic, play an important role in the activation of immune responses and thus control the predisposition to, or protection from, IDC. This study was conducted to investigate the association of HLA-DQA1, -DQB1 allele polymorphisms with an autoantibody against the myocardial mitochondria ADP/ATP carrier, and to explore susceptibility to idiopathic dilated cardiomyopathy (IDC) among the Han ethnic group in northern China and the immunological mechanisms and hereditary susceptibility to IDC. Polymerase chain reaction sequence-specific primer (PCR-SSP) techniques were used to analyze polymorphisms of the second exon of HLA-DQA1 and -DQB1 alleles among 68 unrelated IDC patients, 4 probands of IDC pedigrees, and 100 healthy controls, all of Han nationality and having lived in northern China for a long time. Following echocardiography examination the IDC subjects were stratified according to ejection fraction (EF) values. Those with EF values higher than 50% were placed in subgroup 1, subgroup 2 included the patients with an EF value of 15-35%, and subgroup 3 consisted of those whose EF values were less than 15%. An autoantibody against the myocardial mitochondria ADP/ATP carrier was examined using immunoblot analysis. The frequencies of HLA-DQA1*0501 and HLA-DQB1*0303 were 0.3889 and 0.1806 in the IDC group, significantly higher than those of the healthy controls (0.0900 and 0.0364 respectively, both P < 0.05). The OR was 5.20 (95% CI: 3.60-8.50) and 4.85 (95% CI: 2.56-9.39) respectively. Further analysis of the three subgroups showed a higher frequency of HLA-DQA1*0501 among patients whose EF was less than 15% than those whose EF values were > or =15%. Conversely, the frequencies of HLA-DQA1*0201 and -DQB1*0502, *0504 were significantly lower in the IDC group (0.0139, 0.0139 and 0.0417 respectively) than in the control group (0.2000, 0.0727 and 0.1091 respectively) (P < 0.05). The frequency of the HLA-DQA1*0501 allele was significantly higher in IDC patients whose autoantibody is positive in contrast with those whose autoantibody is negative (18.57% vs. 5.86%, P < 0.05); the relative risk (RR) was 4.32. The other frequencies of HLA-DQA1 and -DQB1 alleles showed no significant difference in the antibody positive and negative groups of IDC patients. The alleles of HLA-DQA1*0501 and HLA-DQB1*0303 were closely associated with poor EF values in the IDC group, and may be involved in susceptibility to the disease. The DQA1*0201 and DQB1*0502, *0504 alleles may confer protection to IDC among individuals of northern Chinese Han nationality. The SER(57) residue in the second exon of DQB1*0502 and *0504 may confer resistance to IDC, and defects or substitution of this amino acid residue at position 57 of the DQbeta chain may be associated with IDC susceptibility. HLA-DQ allele polymorphisms may serve as genetic markers for IDC and be involved in the regulation of the immune specific response to auto or exterior anti-myocardium antibodies.

Adult↗