Doxycycline compared with prednisolone therapy for patients with bullous pemphigoid: cost-effectiveness analysis of the BLISTER trial.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering skin disorder associated with significant morbidity and mortality. Doxycycline and prednisolone to treat bullous pemphigoid were compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of doxycycline-initiated and prednisolone-initiated treatment for patients with BP. METHODS: Quality-of-life (EuroQoL-5D-3L) and resource data were collected as part of the BLISTER trial: a multicentre, parallel-group, investigator-blinded RCT. Within-trial analysis was performed using bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case, there was no robust difference in costs or QALYs per patient at 1 year comparing doxycycline- with prednisolone-initiated therapy [net cost £959, 95% confidence interval (CI) -£24 to £1941; net QALYs -0·024, 95% CI -0·088 to 0·041]. However, the findings varied by baseline blister severity. For patients with mild or moderate blistering (≤ 30 blisters) net costs and outcomes were similar. For patients with severe blistering (> 30 blisters) net costs were higher (£2558, 95% CI -£82 to £5198) and quality of life poorer (-0·090 QALYs, 95% CI -0·22 to 0·042) for patients starting on doxycycline. The probability that doxycycline would be cost-effective for those with severe pemphigoid was 1·5% at a willingness to pay of £20 000 per QALY. CONCLUSIONS: Consistently with the clinical findings of the BLISTER trial, patients with mild or moderate blistering should receive treatment guided by the safety and effectiveness of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, prednisolone-initiated treatment may be more cost-effective for patients with severe blistering.

Evidence based treatment for unstable slipped upper femoral epiphysis: Systematic review and exploratory patient level analysis.

The management of slipped upper femoral epiphysis is controversial and evolving as insight into the condition develops. Loder introduced the concept of slip stability and demonstrated a strong association between poor outcome and instability. Almost half of patients with unstable slip developed femoral head osteonecrosis. This has been influential in surgeons' choice of treatments. Some surgeons have adopted a minimal intervention approach such as pinning in situ or gentle reduction and pinning whereas others advocated an urgent open reduction and stabilisation of slip using various surgical techniques. In this review we analysed the influence of various interventions, timing of surgery and severity of the slip on the outcome of unstable slip.

Ciclosporin compared with prednisolone therapy for patients with pyoderma gangrenosum: cost-effectiveness analysis of the STOP GAP trial.

BACKGROUND: Pyoderma gangrenosum (PG) is a painful, ulcerating skin disease with poor evidence for management. Prednisolone and ciclosporin are the most commonly used treatments, although not previously compared within a randomized controlled trial (RCT). OBJECTIVES: To compare the cost-effectiveness of ciclosporin and prednisolone-initiated treatment for patients with PG. METHODS: Quality of life (QoL, EuroQoL five dimensions three level questionnaire, EQ-5D-3L) and resource data were collected as part of the STOP GAP trial: a multicentre, parallel-group, observer-blind RCT. Within-trial analysis used bivariate regression of costs and quality-adjusted life years (QALYs), with multiple imputation of missing data, informing a probabilistic assessment of incremental treatment cost-effectiveness from a health service perspective. RESULTS: In the base case analysis, when compared with prednisolone, ciclosporin was cost-effective due to a reduction in costs [net cost: -£1160; 95% confidence interval (CI) -2991 to 672] and improvement in QoL (net QALYs: 0·055; 95% CI 0·018-0·093). However, this finding appears driven by a minority of patients with large lesions (≥ 20 cm2 ) (net cost: -£5310; 95% CI -9729 to -891; net QALYs: 0·077; 95% CI 0·004-0·151). The incremental cost-effectiveness of ciclosporin for the majority of patients with smaller lesions was £23 374/QALY, although the estimate is imprecise: the probability of being cost-effective at a willingness-to-pay of £20 000/QALY was 43%. CONCLUSIONS: Consistent with the clinical findings of the STOP GAP trial, patients with small lesions should receive treatment guided by the side-effect profiles of the drugs and patient preference - neither strategy is clearly a preferred use of National Health Service resources. However, ciclosporin-initiated treatment may be more cost-effective for patients with large lesions.

Antibiotic use in acute pancreatitis: An audit of current practice in a tertiary centre.

INTRODUCTION: Intravenous antibiotic prophylaxis is not recommended in acute pancreatitis. According to current international guidelines antibiotics together with further intervention should be considered in the setting of infected necrosis. Appropriate antibiotic therapy particularly avoiding over-prescription is important. This study examines antibiotic use in acute pancreatitis in a tertiary centre using the current IAP/APA guidelines for reference. METHODS: Data were collected on a consecutive series of patients admitted with acute pancreatitis over a 12 month period. Data were dichotomized by patients admitted directly to the centre and tertiary transfers. Information was collected on clinical course with specific reference to antibiotic use, episode severity, intervention and outcome. RESULTS: 111 consecutive episodes of acute pancreatitis constitute the reported population. 31 (28%) were tertiary transfers. Overall 65 (58.5%) patients received antibiotics. Significantly more tertiary transfer patients received antibiotics. Mean person-days of antibiotic use was 23.9 (sd 29.7) days in the overall study group but there was significantly more use in the tertiary transfer group as compared to patients having their index admission to the centre (40.9 sd 37.1 vs 10.2 sd 8.9; P < 0.005). Thirty four (44%) of patients with clinically mild acute pancreatitis received antibiotics. CONCLUSIONS: There is substantial use of antibiotics in acute pancreatitis, in particular in patients with severe disease. Over-use is seen in mild acute pancreatitis. Better consideration must be given to identification of prophylaxis or therapy as indication. In relation to repeated courses of antibiotics in severe disease there must be clear indications for use.

Cardiopulmonary exercise testing for preoperative risk assessment before pancreaticoduodenectomy for cancer.

OBJECTIVE: Pancreaticoduodenectomy is the standard of care for tumors confined to the head of pancreas and can be undertaken with low operative mortality. The procedure has a high morbidity, particularly in older patient populations with preexisting comorbidities. This study evaluated the role of cardiopulmonary exercise testing to predict postoperative morbidity and outcome in high-risk patients undergoing pancreaticoduodenectomy. METHODS: In a prospective cohort of consecutive patients undergoing pancreaticoduodenectomy, those aged over 65 years (or younger with comorbidity) were categorized as high risk and underwent preoperative assessment by cardiopulmonary exercise testing (CPET) according to a predefined protocol. Data were collected on functional status, postoperative complications, and survival. RESULTS: A total of 143 patients underwent preoperative assessment, 50 of whom were deemed to be at low risk for surgery per study protocol. Of 93 high-risk patients, 64 proceeded to surgery after preoperative CPET. Neither anaerobic threshold (AT) nor maximal oxygen consumption ([Formula: see text] O 2 MAX) predicted patient mortality or morbidity. However, ventilatory equivalent of carbon dioxide ([Formula: see text] E/[Formula: see text] CO 2) at AT was a predictive marker of postoperative mortality, with an area under the curve (AUC) of 0.84 (95 % confidence interval [CI] 0.63-1.00, p = 0.020); a threshold of 41 was 75 % sensitive and 95 % specific (positive predictive value 50 %, negative predictive value 98 %). Above this threshold, raised [Formula: see text] E/[Formula: see text] CO 2 predicted poor long-term survival (hazard ratio 2.05, 95 % CI 1.09-3.86, p = 0.026). CONCLUSIONS: CPET is a useful adjunctive test for predicting postoperative outcome in patients being assessed for pancreaticoduodenectomy. Raised CPET-derived [Formula: see text] E/[Formula: see text] CO 2 predicts early postoperative death and poor long-term survival.

A prospective trial of temporary sacral nerve stimulation for constipation associated with neurological disease.

AIM: This study assessed the effectiveness of temporary sacral nerve stimulation (SNS) in patients with constipation associated with neurological disease using an off-on-off design, and evaluated the long-term response in patients undergoing permanent SNS. METHOD: Patients with chronic constipation associated with neurological disease receiving specialist clinic care at the University Hospital North Durham over a 2-year period were recruited to a trial of SNS. Recordings of bowel function were made for 6 weeks (baseline) and a temporary electrode was then inserted and recordings were made for the next 3 weeks (stimulation). The electrodes were then removed and assessment was continued for a further 3 weeks (posttreatment). Patient-completed questionnaires were used to determine the severity of constipation (Global Assessment of Symptoms, Constipation, GA Constipation), symptoms (Patient Assessment of Constipation Symptoms score, PAC-SYM) and quality-of-life (Patient Assessment of Constipation-Quality Of Life score, PAC-QOL; European Quality of Life-Five-Domain score; European Quality of Life-Visual Analogue Score). Information was obtained on bowel function and medication. Physiological data were also available for transit and laser Doppler flow cytometry to measure mucosal blood flow. RESULTS: Twenty-two patients were recruited, of whom 18 completed the trial. GA Constipation reduced significantly during temporary SNS: -1.09 (95% CI -1.59 to -0.59; P = 0.0003). PAC-SYM and PAC-QOL scores showed similar improvements. There was also a significant fall in the time spent in the toilet (P = 0.04) and a decrease in laxative use (P = 0.03). Twelve (67%) patients responded to temporary SNS and received a permanent implant with long-term success in 50%. CONCLUSION: Sacral nerve stimulation can be effective in treating some patients with refractory severe neuroconstipation. A response to temporary SNS may predict long-term benefit in only half the patients undergoing permanent SNS.

Topical treatments for chronic plaque psoriasis of the scalp: a systematic review.

BACKGROUND: Chronic plaque psoriasis is the most common type of psoriasis and is characterized by redness, thickness and scaling. First-line management is with topical treatments. OBJECTIVES: Our objective was to establish the effectiveness, tolerability and safety of topical treatments for people with chronic plaque psoriasis of the scalp, assessing placebo-controlled trials of all treatments and head-to-head trials that assessed vitamin D analogues. METHODS: As part of a Cochrane review of topical treatments for psoriasis, we systematically searched electronic databases for randomized controlled trials. The review included 26 randomized controlled trials of treatments for psoriasis of the scalp with 8020 participants. Trials used several measures to assess changes in psoriasis severity: these were combined using the standardized mean difference metric and interpreted by reporting as a six-point global improvement score. RESULTS: On effectiveness grounds, very potent or potent steroid treatments should be preferred to vitamin D3 analogue with approximately an average 10% additional improvement on a six-point scale. Vitamin D3 analogue combined with potent steroid appears slightly more effective than potent steroid monotherapy (3% additional improvement on a six-point scale). Rates of withdrawal from treatment and adverse events in trials were generally low and similar to those for placebo. There remains uncertainty about the atrophic potential of corticosteroid treatments for scalp psoriasis. CONCLUSIONS: Corticosteroids are more effective than vitamin D analogues and similarly tolerated. However, further research is needed to inform long-term maintenance treatment and provide appropriate safety data.

Cardiopulmonary exercise testing for preoperative risk assessment before hepatic resection.

BACKGROUND: Contemporary liver surgery practice must accurately assess operative risk in increasingly elderly populations with greater co-morbidity. This study evaluated preoperative cardiopulmonary exercise testing (CPET) in high-risk patients undergoing hepatic resection. METHODS: In a prospective cohort referred for liver resection, patients aged over 65 years (or younger with co-morbidity) were evaluated by preoperative CPET. Data were collected prospectively on functional status, postoperative complications and survival. RESULTS: Two hundred and four patients were assessed for hepatic resection, of whom 108 had preoperative CPET. An anaerobic threshold (AT) of 9·9 ml O(2) per kg per min predicted in-hospital death and subsequent survival. Below this value, AT was 100 per cent sensitive and 76 per cent specific for in-hospital mortality, with a positive predictive value (PPV) of 19 per cent and a negative predictive value (NPV) of 100 per cent: no deaths occurred above the threshold. Age and respiratory efficiency in the elimination of carbon dioxide (VE/VCO(2)) at AT were statistically significant predictors of postoperative complications. Receiver operating characteristic (ROC) curve analysis showed that a threshold of 34·5 for VE/VCO(2) at AT provided a specificity of 84 per cent and a sensitivity of 47 per cent, with a PPV of 76 (95 per cent confidence interval (c.i.) 58 to 88) per cent and a NPV of 60 (48 to 72) per cent for postoperative complications. Long-term survival of those with an AT of less than 9·9 ml O(2) per kg per min was significantly worse than that of patients with a higher AT (hazard ratio for mortality 1·81, 95 per cent c.i. 1·04 to 3·17; P = 0·036). CONCLUSION: CPET provides a useful prognostic adjunct in the preoperative assessment of patients undergoing hepatic resection.

Incentivizing preventive services in primary care: perspectives on Local Enhanced Services.

BACKGROUND: General practitioners in the UK play a key role in prevention but provision of preventive services is variable. The 2004 General Medical Services contract allows Primary Care Trusts (PCTs) to address health needs through providing locally agreed payments for Local Enhanced Services (LESs). This study identifies how this contractual flexibility is used for preventive services and explores its perceived effectiveness. METHODS: Semi-structured interviews were carried out (2008-09) in 10 purposively selected case study sites in England. Details of LESs for these sites were collected (2009) through Freedom of Information requests or local contacts. A national on-line survey of PCTs (2009) provided a national context for case study findings. RESULTS: LESs were considered to be effective in incentivizing preventive activity. However, specifications and performance management were often weak, awareness of how to optimize incentives was low and, as optional services, LESs were perceived to be at risk in a financial downturn. CONCLUSIONS: Using LESs for preventive services highlights gaps in 'core' primary care responsibilities and in the national pay-for-performance framework. Current incentive arrangements are complex, could increase inequalities and provide only a partial, short-term solution to developing a proactive approach to prevention in primary care.

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability.

It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.

Evidence for low temperatures and biologic diversity in cretaceous high latitudes of australia.

A diverse terrestial biota inhabited polar latitudes during the Cretacous, 105 to 130 Ma (million years ago), along what is now the southeast coast of Australia This biota, from rocks in the Otway and Strzelecki groups, cnsisted of more than 150 taxa of vertebrates, invertebrates, and plants. Oxygen isotope ratios in diagenetic calcite suggest that mean annual temperatures were most likely less than 5 degrees C, and rings present in the fossil araucarian-podocarp-ginko woods indicate saonality. Southeastern Austalia, thus, seems to have had a cool, seasonal, nontropical climate. Dinosaurs that have been recovered are up to five species and three genera of hypsilophodontids, all of which were endemic, and three species of theropods. The occurrence of Allosaurus sp. and labyrinthodont amphibians, which had become extinct elsewhere in the Jurassic, indicate that isolation may have allowed extended surival of these taxa in Australia. In that dinosaurs coped with high latitude for at least 65 million years [Valaginian to Albian time in Australia and Campanian to Maastrictian time (80 to 65 Ma) in Alaska] suggests that cold and darkness may not have been prime factors bringing about the extinction of dinosaurs and some other groups at the Cretaceous-Tertiary boundary, unless they were prolonged.

Regulation of telomere length in Drosophila.

Telomeres in all organisms must perform the same vital functions to ensure cell viability: to act as a protective chromosome cap that distinguishes natural chromosome ends from DNA double strand breaks, and to balance the loss of DNA from the chromosome end due to incomplete DNA replication. Most eukaryotes rely on a specialized reverse transcriptase, telomerase, to generate short repeats at the chromosome end to maintain chromosome length. Drosophila, however, uses retrotransposons that target telomeres. Transposition of these elements may be controlled by small RNAs and spreading of silent chromatin from the telomere associated sequence, both of which limit the retrotransposon expression level. Proteins binding to the retrotransposon array, such as HP1 and PROD, may also modulate transcription. It is not clear however, that simply increasing transcript levels of the telomeric retrotransposons is sufficient to increase transposition. The chromosome cap may control the ability of the telomere-specific elements to attach to chromosome ends. As in other organisms, chromosomes can be elongated by gene conversion. Although the mechanism is not known, HP1, a component of the cap, and the Ku proteins are key components in this pathway.

The unusual telomeres of Drosophila.

The telomeres of most eukaryotes contain short, simple repeats that are highly conserved. Drosophila, on the other hand, does not have such sequences, but carries at the ends of its chromosomes one or more LINE-like retrotransposable elements. Instead of elongation by telomerase, incomplete DNA replication at the termini of Drosophila chromosomes is counterbalanced by transposition of these elements at high frequency specifically to the termini. These transposable elements are not responsible for distinguishing telomeric ends in Drosophila from broken chromosome ends; the structure performing this function is not yet known. Proximal to the terminal array of transposable elements are regions of tandem repeats that are structurally, and probably functionally, analogous to the subterminal regions in other eukaryotes.

WITHDRAWN: Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs).

BACKGROUND: Selective serotonin reuptake inhibitors are thought to have better discontinuation rates (i.e. less people dropping out) than tricyclic and heterocyclic antidepressant drugs. It is important to quantify the drop-out rates of different antidepressant drugs in order to have a better understanding of the relative tolerability of these drugs. OBJECTIVES: To assess the comparative tolerability of selective serotonin reuptake inhibitors and tricyclic/heterocyclic antidepressant drugs. SEARCH STRATEGY: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (1997 to 1999), MEDLINE (1966 to 1999), EMBASE (1974 to 1999) We also searched specialist journals, the reference lists of relevant papers and previous systematic reviews, conference abstracts and government documents. Representatives of the pharmaceutical industry were contacted. SELECTION CRITERIA: Parallel group randomised controlled trials comparing selective serotonin reuptake inhibitors with tricyclic or heterocyclic antidepressants in people with depression. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and a third reviewer checked any cases of disagreement. MAIN RESULTS: We included 136 trials. The selective serotonin reuptake inhibitors showed less participants dropping out compared to the tricyclic/heterocyclic group (odds ratio 1.21, 95% confidence interval 1.12 to 1.30). A statistically significant difference was found in total drop-outs between the selective serotonin reuptake inhibitors and the old tricyclics as well as the newer tricyclics. When the selective serotonin reuptake inhibitors were compared to the heterocyclic antidepressants, there was a non significant difference favouring the selective serotonin reuptake inhibitors. The poor tolerability profile of the old tricyclics was explained by differences in drop-outs for side-effects, but not for inefficacy. AUTHORS' CONCLUSIONS: Whilst selective serotonin reuptake inhibitors do appear to show an advantage over tricyclic drugs in terms of total drop-outs, this advantage is relatively modest. This has implications for pharmaco-economic models, some of which may have overestimated the difference of drop-out rates between selective serotonin reuptake inhibitors and tricyclic antidepressants. These results are based on short-term randomised controlled trials, and may not generalise into clinical practice.

Inhibition of the spindle assembly checkpoint kinase Mps-1 as a novel therapeutic strategy in malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity. We found that CFI-402257 suppresses MM growth. We found that Mps-1 is overexpressed in MM and that its expression correlates with poor patients' outcome. In vitro, CFI-402257-mediated inhibition of Mps-1 resulted in abrogation of the mitotic checkpoint, premature progression through mitosis, marked aneuploidy and mitotic catastrophe. In vivo, CFI-402257 reduced MM growth in an orthotopic, syngeneic model, when used as a single agent, and more so when used in combination with cisplatin+pemetrexed, the current standard of care. Our preclinical findings indicate that CFI-402257 is a promising novel therapeutic agent to improve the efficacy of the current chemotherapeutic regimens for MM patients.

Colorectal cancer with synchronous hepatic metastases: Systematic review of reports comparing synchronous surgery with sequential bowel-first or liver-first approaches.

BACKGROUND: The management of colorectal cancer with synchronous liver-limited metastases currently lacks randomised trial evidence to inform case selection for any of the bowel-first, liver-first or synchronous surgery routes. We examine the literature to report outcome data from reports utilising all three approaches. METHODS: A systematic review was conducted using OvidSP (including Embase, EBM Reviews and MEDLINE databases) to find articles reporting discrete peri-operative and long-term outcomes for patients undergoing sequential bowel-first, liver-first surgery or synchronous liver and bowel surgery. RESULTS: Of 223 unique citations, 3 cohort studies were identified comprising a pooled population of 1203 patients who completed treatment protocols between 1982 and 2011. Patients were allocated to bowel-first surgery (748 patients, 62.2%), liver-first surgery (75, 6.2%) or synchronous liver/bowel surgery (380, 31.6%). Minor complications were similar between procedures. Major complications were consistent with a pooled fixed estimate of 9.1% (95%CI: 7.6%-10.8%, I(2) = 48%). Post-operative death was rare and consistent with a pooled fixed effect estimate of 3.1% (95%CI: 2.2%-4.3%, I(2) = 0%). Median follow-up ranged from 25.1 to 40.0 months, with a pooled underlying 5-year survival fixed effect estimate of 44% (I(2) = 39%). CONCLUSION: This review assesses outcomes of patients with colorectal cancer with synchronous liver metastases managed by either synchronous, sequential liver-first or bowel-first surgery. Overall treatment-related mortality is low and survival is similar among the three groups. These findings provide support for the continued use of all three pathways until better evidence to guide selection of an individual treatment option is available.

The SSTARS (STeroids and Stents Against Re-Stenosis) Trial: Different stent alloys and the use of peri-procedural oral corticosteroids to prevent in-segment restenosis after percutaneous coronary intervention.

BACKGROUND: Stent design and technological modifications to allow for anti-proliferative drug elution influence restenosis rates following percutaneous coronary intervention (PCI). We aimed to investigate whether peri-procedural administration of corticosteroids or the use of thinner strut cobalt alloy stents would reduce rates of binary angiographic restenosis (BAR) after PCI. METHODS: This was a two centre, mixed single and double blinded, randomised controlled trial using a factorial design. We compared (a) the use of prednisolone to placebo, starting at least six hours pre-PCI and continued for 28days post-PCI, and (b) cobalt chromium (CoCr) to stainless steel (SS) alloy stents, in patients admitted for PCI. The primary end-point was BAR at six months. RESULTS: 315 patients (359 lesions) were randomly assigned to either placebo (n=145) or prednisolone (n=170) and SS (n=160) or CoCr (n=160). The majority (58%) presented with an ACS, 11% had diabetes and 287 (91%) completed angiographic follow up. BAR occurred in 26 cases in the placebo group (19.7%) versus 31 cases in the prednisolone group (20.0%) respectively, p=1.00. For the comparison between SS and CoCr stents, BAR occurred in 32 patients (21.6%) versus 25 patients (18.0%) respectively, p=0.46. CONCLUSION: Our study showed that treating patients with a moderately high dose of prednisolone for 28days following PCI with BMS did not reduce the incidence of BAR. In addition, we showed no significant reduction in 6month restenosis rates with stents composed of CoCr alloy compared to SS (http://www.isrctn.com/ISRCTN05886349).

Orientation disruptor (ord): a recombination-defective and disjunction-defective meiotic mutant in Drosophila melanogaster.

The effects of a semidominant autosomal meiotic mutant, orientation disruptor (symbol: ord), located at 2-103.5 on the genetic map and in region 59B-D of the salivary map, have been examined genetically and cytologically. The results are as follows. (1) Crossing over in homozygous females is reduced to about seven percent of controls on all chromosomes, with the reduction greatest in distal regions. (2) Crossing over on different chromosomes is independent. (3) Reductional nondisjunction of any given chromosome is increased to about thirty percent of gametes from homozygous females. The probability of such nondisjunction is the same among exchange and nonexchange tetrads with the exception that a very proximal exchange tends to regularize segregation. (4) Equational nondisjunction of each chromosome is increased to about ten percent of gametes in homozygous females; this nondisjunction is independent of exchange. (5) The distributive pairing system is operative in homozygous females. (6) In homozygous males, reductional nondisjunction of each chromosome is increased to about ten percent, and equational nondisjunction to about twenty percent, of all gametes. (7) Cytologically, two distinct meiotic divisions occur in spermatocytes of homozygous males. The first division looks normal although occasional univalents are present at prophase I and a few lagging chromosomes are seen at anaphase I. However, sister chromatids of most chromosomes have precociously separated by metaphase II. Possible functions of the ord(+) gene are considered.