Articular chondrocytes isolated from the knee and ankle joints of human tissue donors demonstrate similar redox-regulated MAP kinase and Akt signaling.

OBJECTIVE: To compare key intracellular redox-regulated signaling pathways in chondrocytes derived from knee joint femoral cartilage and ankle joint talar cartilage in order to determine if differences exist that might contribute to the lower prevalence of ankle osteoarthritis (OA). METHODS: Femoral and talar chondrocytes were treated with H2O2 generators (menadione or 2-3-dimethoxy-1,4-napthoquinone (DMNQ), fragments of fibronectin (FN-f)) to stimulate MAP kinase signaling (MAPK), or with IGF-1 to stimulate the Akt signaling pathway. Hyperoxidation of the peroxiredoxins, used as a measure of redox status, and phosphorylation of proteins pertinent to MAPK (p38, ERK, JNK, c-Jun) and Akt (Akt, PRAS40) signaling cascades were detected by immunoblotting. RESULTS: Treatment of femoral and talar chondrocytes with menadione, DMNQ or FN-f led to a time dependent increase in extracellular-regulated kinase (ERK) and p38 phosphorylation. DMNQ and FN-f stimulation enhanced phosphorylation of JNK and its downstream substrate, c-Jun. Menadione treatment did not stimulate JNK activity but hyperoxidized the peroxiredoxins and inhibited IGF-1-induced Akt activation. In all experiments, chondrocytes derived from the femur and talar joints displayed comparable MAP kinase responses after treatment with various catabolic stimuli, as well as similar Akt signaling responses after IGF-1 treatment. CONCLUSIONS: MAP kinase and Akt signaling in response to factors that modulate the intracellular redox status were similar in chondrocytes from knee and ankle joints suggesting that redox signaling differences do not explain differences in OA prevalence. Talar chondrocytes, when isolated from their native matrix, can be used to examine redox-regulated cell signaling events relevant to OA in either joint.

A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease.

Post-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.

Characterization of proximal femoral anatomy in the skeletally-immature patient.

PURPOSE: The morphology of the proximal femur has been extensively studied in the adult population. However, no literature providing a comprehensive evaluation of the anatomy in paediatric patients exists. The current study aims to characterize such anatomy in skeletally-immature patients, examine potential differences between genders, and analyze how these anatomical parameters change with age. METHODS: Cadaveric femurs from the Hamann-Todd Osteological Collection were examined. Specimens with open physes and no skeletal disease or deformity were included for analysis. Age and gender were recorded for each specimen. Each femur was photographed in standardized modified axial and anteroposterior views. In all, 14 proximal femoral anatomical parameters were measured from these photographs. Comparisons between genders and age were calculated. RESULTS: A total of 43 femurs from ages four to 17 years met inclusion criteria. The majority were female (56%); no difference existed in age between genders (p = 0.62). The specimens had a neutral mean neck-shaft angle (130.7º) and anteversion (12.8º), and the sphericity of the ossified femoral heads was symmetrical. Male specimens had significantly higher alpha angles (p = 0.01), posterior offset (p = 0.02), neck width (p = 0.04) and head-neck length ratio (p = 0.02) values than female specimens. Strong positive correlations exist between length/size parameters and age, while negligible correlations were noted for angular measurements. CONCLUSIONS: This study establishes reference values for a comprehensive list of anatomical parameters for the skeletally-immature ossified proximal femur. It highlights gender differences in morphology and demonstrates that angular characteristics remain relatively stable while length parameters generally increase with age. LEVEL OF EVIDENCE: Level III Diagnostic.

U. S. consumer perceptions of U. S. and Canadian beef quality grades.

A U.S. consumer (n = 642) study (Baltimore, MD; Phoenix, AZ; and Lubbock, TX) was conducted to compare consumer sensory scores of U.S. beef (83 USDA Choice [Choice] and 96 USDA Select [Select]) and Canadian beef (77 AAA and 82 AA) strip loins. Strip loins (n = 338) were obtained from beef processors in Canada and the United States and were wet aged until 21 d postmortem at 2°C. Marbling scores were assigned at 21 d and loins were paired according to quality grades and marbling score. Strip loins were fabricated into 2.54-cm thick steaks; steaks were vacuum packaged and frozen until further evaluations. Proximate analysis was performed to compare fat, moisture, and protein. Choice and Canadian AAA had similar marbling scores and intramuscular fat. Both Choice and Canadian AAA had greater (P < 0.05) marbling scores and intramuscular fat than Canadian AA, but Select strip loins had intermediate values that were not different from any of the other grades (P > 0.05). Consumers' opinions did not differ when comparing equivalent grades (Choice with Canadian AAA and Select with Canadian AA), but they rated Choice and Canadian AAA more palatable than Select and Canadian AA for all sensory attributes (P < 0.05). Regarding percentage of acceptability and likelihood to buy score, consumers indicated a preference and greater probability to buy (P = 0.001 and P = 0.004, respectively) strip loin steaks from higher quality grade carcasses (Choice and Canadian AAA) than lower quality grade carcasses (Select and Canada AA). Additionally, consumers gave their opinion of Canadian beef, where its quality and safety were rated as "good" to "excellent" for both attributes (76.72% and 88.36%, respectively; P < 0.05), feeling confident in beef that is imported from Canada. In the same way, consumers indicated that country-of-origin labeling was a minimal factor influencing their beef steak purchasing decisions. Results from this consumer study indicated U.S. consumers could not differentiate between U.S. and Canadian beef within comparable quality grades; however, strip loin steaks from higher quality grades were more palatable than lower quality grades according to consumer scores for eating quality traits.

Symptomatic response to imatinib mesylate in cutaneous mastocytosis associated with chronic myelomonocytic leukemia.

Mastocytosis is an uncommon disorder defined by increased and abnormal mast cells in one or more tissues. Cutaneous mastocytosis (cm) is limited to the skin, with varying degrees of rash, pruritus, and disfigurement. Systemic mastocytosis (sm) typically involves the bone marrow, sometimes in association with other bone marrow disorders, including chronic myelomonocytic leukemia (cmml). Mastocytosis has been associated with somatic mutations in the gene encoding the tyrosine kinase Kit, leading to identification of Kit as a therapeutic target. The Kit inhibitor imatinib mesylate is approved for aggressive sm. We present an unusual patient with disabling pruritus from telangiectasia macularis eruptiva perstans, a subtype of cm, and cmml, but with no evidence of systemic mast cell disease. She was treated with imatinib and experienced marked improvement in her pruritus. Concomitant cm and cmml have not previously been reported, and the present report is the first of successful imatinib therapy in an adult patient with cm.

Oxygen and pH-sensitivity of human osteoarthritic chondrocytes in 3-D alginate bead culture system.

OBJECTIVE: To identify the effect of alterations in physical parameters such as oxygen and pH on processes associated with cellular redox balance in osteoarthritic chondrocytes. METHOD: Human osteoarthritic chondrocytes (HOAC) were isolated from total knee arthroplasty samples and cultured in 3-D alginate beads in four different oxygen tensions (<1%, 2%, 5% and 21% O2), at pH 7.2 and 6.2 and in the presence or absence of 10 ng/ml, interleukin-1ß (IL-1ß). Cell viability, media glycosaminoglycan (GAG) levels, media nitrate/nitrate levels, active matrix metalloproteinase (MMP)-13 and intracellular adenosine triphosphate (ATPi) were measured over a 96-h time course. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential, intracellular pH and reduced/oxidised glutathione (GSH/GSSG) were additionally measured after 48-h incubation under these experimental conditions. RESULTS: Hypoxia (2% O2) and anoxia (<1% O2), acidosis (pH 6.2) and 10 ng/ml IL-1ß reduced HOAC cell viability and increased GAG media levels. Acidosis and IL-1ß increased nitrite/nitrate release, but increases were moderate at 2% O2 and significantly reduced at <1% O2. ATPi was significantly reduced following hypoxia and anoxia and acidosis. At 48 h cellular ROS levels were increased by acidosis and IL-1ß but reduced in hypoxia and anoxia. Mitochondrial membrane potential was reduced in low oxygen, acidosis and IL-1ß. Anoxia also resulted in intracellular acidosis. GSH/GSSG ratio was reduced in low oxygen conditions, acidosis and IL-1ß. CONCLUSIONS: This study shows that oxygen and pH affect elements of the redox system in HOAC including cellular anti-oxidants, mitochondrial membrane potential and ROS levels.

Use of qualitative methods to identify solutions to selected equine welfare problems in Ireland.

This paper explores the views of those in the Irish equine industry, organisations and government regarding necessary improvements to equine welfare in Ireland at unregulated gatherings and during the disposal process. Three qualitative research methods were employed, namely semistructured interviews, focus groups and a structured, facilitated workshop. Representatives from industry, welfare societies, socially disadvantaged groupings and government engaged with this process and shared their views regarding horse welfare and implementable solutions with merit to address welfare problems. A consensus was achieved that equine welfare in Ireland could be improved by the development of a comprehensive identification system, a Code of Practice for horse gatherings, a horse licensing scheme, ring-fenced funding to promote responsible, humane horse disposal and better means of raising awareness of the value of safeguarding horse welfare for the benefit of all parties.

Are patient characteristics associated with the accuracy of hysterosalpingography in diagnosing tubal pathology? An individual patient data meta-analysis.

BACKGROUND: Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics. METHODS: We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model. RESULTS: We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age [factor 0.93 per year (P = 0.05)]. The specificity of HSG was very stable across all subgroups. CONCLUSIONS: The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples.

Evaluation of current equine welfare issues in Ireland: causes, desirability, feasibility and means of raising standards.

REASONS FOR PERFORMING STUDY: Significant potential threats to the health and welfare of horses exist in Ireland when supply exceeds demand and the identification system for horses is not yet robust. OBJECTIVES: To secure engagement with stakeholder groups and determine their perception of equine welfare in Ireland and encourage the development of inclusive, rather than imposed, policy solutions. METHODS: A 3 round, web-based Policy Delphi incorporating novel vignette methodology was conducted from November 2007-March 2008 to canvass opinion (in both quantitative and qualitative forms) on the perceived most significant equine welfare issues. Vignettes (narratives depicting potential compromise to equine welfare) were employed. Quantitative data were collected in the form of scoring on a 9 point Likert scale with labelled end-points, qualitative information as text subsequently analysed for themes. RESULTS: All 44 respondents completed all rounds. Major equine welfare issues were identified as welfare of horses during the disposal process and at unregulated gatherings. Assessed quantitatively on a 9 point Likert scale (0 = minimal; 8 = maximal), respondents scored the desirability and feasibility of improving standards, median 8 and 6, respectively, for both issues identified. Basic themes identified in respondents' quotes as reasons to raise equine welfare standards were ideological, protection of animal welfare, safe-guarding the reputation of the equine industry and safety (of people, horses and environment). Themes for reasons for low standards were societal norms, fiscal pressures, indolence, indifference and ignorance. Themes underpinning potential means for achieving meaningful change (solutions) were legislation, enforcement, education/training, fiscal remedies, increasing awareness and a combination of these. CONCLUSIONS: Mechanisms aimed at raising standards must be based on an understanding of motivational drivers for currently low standards. POTENTIAL RELEVANCE: The challenge is to translate the findings and this heightened awareness into meaningful change to the benefit of horses and those who care for them.

Moisture enhancement and blade tenderization effects on the shear force and palatability of strip loin steaks from beef cattle fed zilpaterol hydrochloride.

Two trials investigated zilpaterol hydrochloride (ZH) feeding duration, enhancement, blade tenderization, and postmortem aging effect on Warner-Bratzler shear force (WBSF; trial 1) and consumer sensory ratings (trial 2). For trial 1, USDA Select beef strip loins were obtained from carcasses of beef steers fed ZH (6.8 g/t on 90% DM) the last 0, 20, 30, or 40 d of the feeding period. One-half of each strip loin was enhanced (110%) with a brine solution, whereas the remaining portion was not enhanced. Both pieces were portioned into steaks, which were aged 7, 14, or 21 d for WBSF analysis. For trial 2, paired USDA Select beef strip loins were obtained from carcasses of beef steers fed ZH the last 0 or 20 d of feeding. Paired strip loins were fabricated into 4 pieces and assigned to control, moisture enhanced, blade tenderized, and blade tenderized + moisture enhanced treatments. Strip loin pieces were then portioned into steaks that were aged 14 or 21 d postmortem. Consumers panelists (n = 458) indicated their like or dislike of tenderness, juiciness, flavor, and overall like of each sample using 8-point, verbally anchored scales, as well as tenderness and overall acceptability. With exception of 20 d ZH-treated steaks, results from trial 1 indicate WBSF values decreased (P < 0.05) with enhancement. Among enhanced steaks, steaks from cattle fed ZH for 20, 30, and 40 d had greater (P < 0.05) WBSF values than controls. Among nonenhanced steaks, 20 d ZH-treated steaks had WBSF values similar to 0, 30, and 40 d ZH-treated steaks, whereas 30 and 40 d ZH-treated steaks had greater (P < 0.05) WBSF values than controls. Postmortem aging for 21 d improved (P < 0.05) WBSF values for all ZH durations when compared with 7-d aging treatments. Results from trial 2 indicate ZH feeding for 20 d had no effect on flavor scores, decreased tenderness scores (P < 0.05), and tended (P < 0.10) to decrease juiciness and overall like scores when compared with controls for steaks aged 14 d. After 21 d aging, steaks from 20 d ZH-fed cattle had reduced (P < 0.05) tenderness, juiciness, and overall like scores and tended (P < 0.10) to have decreased flavor scores when compared with controls. These results indicate enhancement improved WBSF, but was not sufficient to overcome the detrimental effect of ZH feeding duration on WBSF until steaks were aged for 21 d postmortem. Consumer scores indicate 20 d ZH feeding had no effect on overall acceptability, but decreased tenderness and tenderness acceptability scores when compared with controls.

Unstable familial transmissions of Huntington disease alleles with 27-35 CAG repeats (intermediate alleles).

There are inconsistent reports regarding the likelihood of repeat instability for alleles with 27-35 CAG repeats in the Huntington disease (HD) gene. We have examined the intergenerational stability of such intermediate alleles in 51 families from the University of British Columbia's DNA and Tissue Bank for Huntington Disease Research (UBC-HD Databank). A total of 181 transmissions were identified, with 30% (n = 54/181) of the alleles being unstable upon transmission. The unstable transmissions included both expansions (n = 37) and contractions (n = 17) of CAG size. Of the expanded alleles, 68% (n = 25/37) expanded into the HD range (>36 CAG). Therefore, 14% (n = 25/181) of the 27-35 CAG allele transmissions examined expanded into the disease-associated range resulting in a new mutation for HD. Significantly, of these new mutations, 40% (n = 10/25) originated from an allele with 35 CAG repeats with CAG repeat expansions ranging from +1 CAG to +23 CAG. The proportion of new mutations in the UBC-HD Databank is consistent with the most recent new mutation rate for HD, estimated to be at least 10%. The observed difference in the stability of HD intermediate allele transmissions in this data set and in other studies may be a reflection of a small sample size. Alternately, these inconsistencies may indicate an underlying difference in genetic factors which influence repeat instability between the different populations examined. Additional studies determining the frequency and magnitude of repeat instability in this CAG repeat range and factors that influence instability are urgently needed. Until we understand the clinical implications of HD alleles with 27-35 CAG repeats and establish reliable risks of instability, we should exercise caution when translating these results to the clinic.

Harvestman (Opiliones) fauna associated with Maine lowbush blueberry fields in the major production areas of Washington and Hancock counties.

Over a period of 19 yr, the harvestman (Opiliones) community associated with the lowbush blueberry agro-ecosystem in Maine was studied. Eight species representing five genera, four subfamilies, and two families of harvestmen belonging to the suborder Eupnoi were collected. The harvestman community was dominated by two introduced, synanthropic species: Phalangium opilio in all but 1 yr (that year dominated by Rilaena triangularis). Rilaena was recorded for the first time from eastern North America. Relative abundance of harvestman adults increases throughout the season and the temporal pattern of trap capture does not refute speculated life cycles of the harvestmen being univoltine with overwintering eggs. Some blueberry management practices were found to affect trap capture. We did find that on average (with opposite results 1 yr) trap captures are greater in pruned fields than in fruit-bearing fields. Organic fields were found to have higher relative abundance of harvestmen than conventionally managed fields. Conventionally managed fields with reduced-risk insecticides showed no difference in harvestmen relative abundance compared with those conventionally managed fields using the older more persistent organophosphate insecticides. Insecticide trials with common insecticides used in blueberry insect pest management showed that the organophosphate insecticide, phosmet, and the pyrethroid insecticide, esfenvalerate, were detrimental to P. opilio adults when exposed to leaf residues, whereas the reduced-risk insecticide, spinosad, showed no negative effects compared with nonsprayed foliage.

What is the most valid comparison treatment in trials of intrauterine insemination, timed or uninfluenced intercourse? A systematic review and meta-analysis of indirect evidence.

BACKGROUND: Timed intercourse (TI), which is the usual control treatment in trials of intrauterine insemination (IUI), is not a typical coital activity and could impair fertility. This review summarizes the trials of IUI of male partner's prepared semen among subfertile couples according to whether the control group had TI or expectant management. METHODS: A search of relevant databases and bibliographies until February 2008 yielded 150 citations of which 31 were potentially relevant and 11 met all criteria. The total estimates of the differences in pregnancy rates per couple were calculated with weights equal to the inverse variance. The primary analysis was a categorical meta-analysis by the type of control treatment (TI or expectant management). RESULTS: In 11 trials with 13 comparisons of IUI and intercourse among 1329 couples with subfertility, the average difference in pregnancy rate between IUI and controls was 6.1% in trials with TI and 3.9% in trials with expectant management, as the control. The adjusted indirect estimate of the difference between the types of control groups was 2.8% (95% CI -6.3, 10.7). The difference by type of control treatment was not significant, neither in the 11 most relevant trials (P = 0.82), nor in a broader group of 19 trials and 2512 patients (P = 0.20). CONCLUSIONS: The additional benefit accruing to IUI, where TI is the control, is not significant, but it is consistent with the possibility that pregnancy may be less likely in TI controls than in expectant management controls.

Segmentation of whole cells and cell nuclei from 3-D optical microscope images using dynamic programming.

Communications between cells in large part drive tissue development and function, as well as disease-related processes such as tumorigenesis. Understanding the mechanistic bases of these processes necessitates quantifying specific molecules in adjacent cells or cell nuclei of intact tissue. However, a major restriction on such analyses is the lack of an efficient method that correctly segments each object (cell or nucleus) from 3-D images of an intact tissue specimen. We report a highly reliable and accurate semi-automatic algorithmic method for segmenting fluorescence-labeled cells or nuclei from 3-D tissue images. Segmentation begins with semi-automatic, 2-D object delineation in a user-selected plane, using dynamic programming (DP) to locate the border with an accumulated intensity per unit length greater that any other possible border around the same object. Then the two surfaces of the object in planes above and below the selected plane are found using an algorithm that combines DP and combinatorial searching. Following segmentation, any perceived errors can be interactively corrected. Segmentation accuracy is not significantly affected by intermittent labeling of object surfaces, diffuse surfaces, or spurious signals away from surfaces. The unique strength of the segmentation method was demonstrated on a variety of biological tissue samples where all cells, including irregularly shaped cells, were accurately segmented based on visual inspection.

Karyotypic analysis of adult pluripotent stem cells.

Three categories of precursor cells have been identified in postnatal mammals: tissue-committed progenitor cells, germ layer lineage-committed stem cells and lineage-uncommitted pluripotent stem cells. Progenitor cells are the immediate precursors of differentiated tissues. Germ layer lineage stem cells can be induced to form multiple cell types belonging to their respective ectodermal, mesodermal, and endodermal embryological lineages. Pluripotent stem cells will form somatic cell types from all three primary germ layer lineages. Progenitor cells demonstrate a finite life span before replicative senescence and cell death occur. Both germ layer lineage stem cells and pluripotent stem cells are telomerase positive and display extensive capabilities for self-renewal. Stem cells which undergo such extensive replication have the potential for undergoing mutations that may subsequently alter cellular functions. Gross mutations in the genome may be visualized as chromosomal aneuploidy and/or chromosomes that appear aberrant. This study was designed to determine whether any gross genomic mutations occurred within the adult pluripotent stem cells. Karyotypic analysis was performed using pluripotent stem cells purified from adult male rats using established procedures. Giemsa Banding was used in conjunction with light microscopy to visualize metaphase chromosome spreads. To date over 800 metaphase spreads have been analyzed. We found that the metaphase spreads averaged 42 chromosomes and concluded that these pluripotent stem cells isolated from adult rats have a normal karyotype.

Surgery or embolisation for varicocele in subfertile men.

BACKGROUND: A varicocele is a meshwork of distended blood vessels in the scrotum, usually left-sided, due to dilatation of the spermatic vein. Although the concept that varicocele causes, and varicocelectomy cures, male subfertility has been around for almost fifty years, the mechanisms by which varicocele would affect fertility have not yet been satisfactorily explained, and neither have the mechanisms by which varicocelectomy would restore fertility. Furthermore, it has been questioned whether a causal relation exists at all between the distension of the pampiniform plexus and impairment of fertility. OBJECTIVES: To evaluate the effect of varicocele treatment on pregnancy rate in subfertile couples. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched 12 Sept 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE (January 1966 to May 2004), EMBASE (January 1985 to May 2004) and reference lists of articles. In addition, we hand searched 22 specialist journals in the field from their first issue until 2004. We also checked cross references, references from review articles, and contacted researchers in the field. SELECTION CRITERIA: RCTs were included if they were relevant to the clinical question posed, if they reported pregnancy rates as an outcome measure, and if they reported data in treated (surgical ligation or radiological embolization of the internal spermatic vein) and untreated groups. DATA COLLECTION AND ANALYSIS: Nine studies met the inclusion criteria for this review. One was an extension of a previously published study (Nieschlag 1995/1998), which left eight studies for analysis (Nilsson 1979; Breznik 1993; Madgar 1995; Yamamoto 1996; Nieschlag 1995/1998; Grasso 2000; Unal 2001; Krause 2002). All eight only included men from couples with subfertility problems, one (Madgar 1995) excluded men with sperm counts <5 mill/mL, one (Krause 2002) men with sperm counts <2 mill/mL and/or progressive motility <10%, two trials involving clinical varicoceles included some men with normal semen analysis (Nilsson 1979; Breznik 1993). Three studies (Yamamoto 1996; Grasso 2000; Unal 2001) specifically addressed only men with subclinical varicoceles. Two authors independently screened potentially relevant trials. Any differences of opinion were resolved by consensus (none occurred for this review). Studies were excluded from meta-analysis if they made comparisons other than those specified above. MAIN RESULTS: The combined Peto odds ratio (OR) of the eight studies is 1.10 (95%CI 0.73 to 1.68), indicating no benefit of varicocele treatment over expectant management in subfertility couples in whom varicocele in the man is the only abnormal finding. REVIEWERS' CONCLUSIONS: There is no evidence that treatment of varicocele in men from couples with otherwise unexplained subfertility improves the couple's chance of conception.

Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models.

BACKGROUND: Several models have been published for the prediction of spontaneous pregnancy among subfertile patients. The aim of this study was to broaden the empirical basis for these predictions by making a synthesis of three previously published models. METHODS: We used the original data from the studies of Eimers et al. (1994), Collins et al. (1995) and Snick et al. (1997) on couples consulting for various forms of subfertility. We developed a so-called three-sample synthesis model for predicting spontaneous conception leading to live birth within 1 year after intake based on the three data sets. The predictors used are duration of subfertility, women's age, primary or secondary infertility, percentage of motile sperm, and whether the couple was referred by a general practitioner or by a gynaecologist (referral status). The performance of this model was assessed according to a 'jack-knife' analysis. Because the post-coital test (PCT) was not assessed in one of the samples, a synthesis model including the PCT was based on two samples only. RESULTS: The ability of the synthesis models to distinguish between women who became pregnant and those who did not was comparable to the ability of the one-sample models when applied in the other samples. The reliability of the predictions by the three-sample synthesis model was somewhat better. Predictions improved considerably by including the PCT. CONCLUSIONS: The synthesis models performed better and had a broader empirical basis than the original models. They are therefore better suitable for application in other centres.

Current perspectives on oral contraceptive use.

Oral contraceptives are one of the most highly effective forms of contraception and provide many short- and long-term noncontraceptive health benefits. They control menstrual cycle irregularities, such as breakthrough bleeding and amenorrhea, and are effective in treating dysfunctional uterine bleeding. In addition, for decades after oral contraceptive use is discontinued they are associated with substantial decreases in the risk of ovarian cancer (up to 80%) and of endometrial cancer (40%-50%), and nearly eliminate benign functional ovarian cysts. Long-term oral contraceptive use confers protection against benign breast disease and colorectal cancer, may help prevent rheumatoid arthritis, decreases ectopic pregnancy and hospitalizations for pelvic inflammatory disease, and helps preserve bone mineral density to reduce risk of fractures. Large bodies of evidence from extensive research have clarified the perceived association of oral contraceptive use with cardiovascular disease and with breast cancer. Findings indicate that there is no increased risk of myocardial infarction or stroke associated with oral contraceptive use in healthy, nonsmoking, normotensive women. Although there is a 3- to 4-fold increased risk of venous thromboembolism with current oral contraceptive use, the absolute risk is very small and is half that associated with pregnancy. Women of all reproductive ages, including perimenopausal women, can realize many health benefits through oral contraceptive use, including improved health status later in life.

Current perspectives on benefits and risks of hormone replacement therapy.

Hormone replacement therapy with estrogen alone or with added progestin relieves menopausal symptoms and physical changes associated with depleted endogenous estrogen levels. Estrogen replacement has also demonstrated a clear benefit in the prevention of osteoporosis. Hormone replacement therapy with added progestin maintains spinal bone density, protects against postmenopausal hip fractures, and provides these benefits even when therapy is started after age 60. More recently, additional benefits have emerged. Current estrogen and hormone replacement therapy users have a 34% reduction in the risk of colorectal cancer and a 20% to 60% reduction in the risk of Alzheimer's disease. Until recently, the body of evidence indicated that hormone replacement therapy with estrogen only reduced cardiovascular disease risk by 40% to 50% in healthy patients; whether the findings of 3 ongoing trials will change this conclusion is pending availability of the final results. The many benefits of estrogen and hormone replacement therapy must be weighed against a slight increase in the risk of breast cancer diagnosis with use for 5 or more years, but which disappears following cessation of therapy. Overall, estrogen and hormone replacement therapy improves the quality of life and increases life expectancy for most menopausal women.