A multicentre, randomized, double-blind trial of the safety and efficacy of mannose-6-phosphate in patients having Zone II flexor tendon repairs.

The safety, tolerability and preliminary efficacy of mannose 6-phosphate in enhancing the outcome in Zone II flexor tendon repair was studied in a multicentre parallel double-blinded randomized controlled trial. Eight UK teaching hospitals were involved in treating repaired flexor tendons with a single intraoperative intrathecal dose of 600 mM mannose 6-phosphate, with follow-up over 26 weeks. A total of 39 patients (mannose 6-phosphate, n = 20; standard care, n = 19) were randomized. Seven were excluded from the safety and tolerability analysis because of intraoperative findings and eight were excluded due to early dropout (n = 4) or tendon rupture (n = 4), leaving 24 (mannose 6-phosphate, n = 13; standard care, n = 11) for assessment of total active motion. The safety, tolerability and other side effects were comparable between the groups. There was no significant difference between the two groups in the total active motion at Week 26. We concluded that mannose 6-phosphate, although safe and tolerable, had no beneficial effect on finger range of motion after Zone II tendon division.Level of evidence 1b.

New estimates of the costs of universal screening for gestational diabetes mellitus in Ireland.

The new International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria have been predicted to increase the prevalence of gestational diabetes mellitus 2-to-3 fold and will have important resource implications for healthcare systems. A bottom-up, prevalence-based analysis was undertaken to estimate the costs of universal screening for gestational diabetes mellitus in Ireland using the new criteria. Healthcare activity was identified from the Atlantic Diabetes in Pregnancy database and grouped into five categories: (i) screening and testing, (ii) GDM treatment, (iii) prenatal care, (iv) delivery care, and (v) neonatal care. When individual resource components were valued using unit cost data and aggregated, the total healthcare cost was estimated at Euro 46,311,301 (95% CI: Euro 36,381,038, Euro 68,007,432). The average cost per case detected was Euro 351 (95% CI: (Euro 126, Euro 558) and the average total cost per case detected and treated was Euro 9,325 (95% CI: Euro 5,982, Euro 13,996). Further research is required to determine the cost effectiveness of screening in the region with a view to improving resource allocation in this area in the future.

The impact of travel distance on the decision to attend for screening for gestational diabetes mellitus.

This paper estimates the impact of travel distance on the decision to attend for screening for gestational diabetes mellitus (GDM), controlling for a range of personal, clinical and lifestyle characteristics. The results suggest that women who live further away from a screening site are less likely to attend for screening. In particular, the probability of attending for screening is reduced by 1.8% [95% CI: 1.2% to 2.4%] for every additional 10 kms of travel. This is consistent wth previous research that shows geographic inequalities in access to GDM screening in Ireland. We also find that older women, those with a family history of diabetes, and those who are obese are more likely to accept the screening offer, suggesting that certain higher-risk groups may be either self-selecting into the screening programme or are being targeted by health care professionals through specific initiatives.

Is there a socioeconomic gradient in the prevalence of gestational diabetes mellitus?

Previous studies have shown an association between Type 2 diabetes and lower socioeconomic status. This link is less clear in those with gestational diabetes mellitus (GDM). We test for a socioeconomic gradient in the prevalence of GDM by analysing data on 9,842 pregnant women who were offered testing for GDM in the Atlantic Diabetes in Pregnancy universal screening programme. A bivariate probit model relating GDM prevalence to socioeconomic status was estimated, controlling for variation in screening uptake rates across socioeconomic groups. The estimated increased prevalence of GDM is 8.6% [95% CI 2.7%-12.0%] for women in the lowest socioeconomic group when compared to the highest, suggesting a strong socioeconomic gradient in the prevalence of GDM. This gradient is found to be driven by differences in personal, clinical and lifestyle factors across socioeconomic groups.

Where do young adults want opportunistic chlamydia screening services to be located?

BACKGROUND: This study measured the acceptability of urine-based chlamydia screening to young adults, where young adults wanted opportunistic chlamydia screening services to be located, and by whom they wanted to be offered screening. METHODS: A cross-sectional survey of 5685 university students and 400 young adult healthcares setting attendees (age: 18-29 years). RESULTS: Ninety-six percent of males and 93% of females said that they would find it acceptable to be offered chlamydia screening. Seventy-six percent of males and 77% of females wanted to be offered screening by a doctor or nurse. Young women would prefer female staff. Most respondents preferred that screening be located in traditional healthcare settings such as General Practices, and offered by either doctors or nurses. More than 90% of respondents did not want screening services to be located in pharmacies and almost all rejected public non-health care screening settings. CONCLUSIONS: Opportunistic chlamydia screening services should be located in traditional healthcare/medical settings, and screening should be offered by doctors and nurses.

The cost of universal screening for gestational diabetes mellitus in Ireland.

AIMS: To estimate the costs associated with universal screening for gestational diabetes mellitus in Ireland. METHODS: Bottom-up, prevalence-based cost analysis. Healthcare activity identified using the Atlantic Diabetes in Pregnancy (ATLANTIC DIP) database was grouped into five categories: screening and testing, gestational diabetes treatment, prenatal care, delivery care and neonatal care. A vector of unit cost data (euros in 2008 prices) was applied to specified resource use and the total healthcare cost calculated. A series of one-way and probabilistic sensitivity analyses were undertaken to explore the uncertainty in the analysis. RESULTS: When individual resource components were valued and aggregated, the total healthcare cost of gestational diabetes in Ireland was estimated at €12 433 320 (95% CI €9 298 228-16 778 193). The average cost per case detected was €1621 (95% CI €524-2603) and the average total cost per case detected and treated was €11 903 (95% CI €7645-16 121). CONCLUSIONS: This research provides the first estimates of the healthcare costs associated with gestational diabetes mellitus in Ireland. Further research is required to determine the cost-effectiveness of gestational diabetes screening in the region with a view to improving resource allocation in this area in the future.

The tension band principle and angular testing of extensor tendon repairs.

Extensor tendons in the finger are flat and not amenable to repair by core and epitendinous sutures. Mattress sutures and Kessler repairs without epitendinous stitching are often used for extensor tendon divisions in the fingers. Except when in full extension, the finger presents a series of curved surfaces (at each joint) to the tendon. It was hypothesized that extensor tendons are subject to the 'tension band' principle and that they might be amenable to repair by dorsal-only epitendinous sutures. A Silfverskiöld dorsal-only repair was compared with mattress and Kessler repairs in vitro on a curvilinear testing apparatus. The epitendinous technique was found to be significantly more resistant to gapping and rupture, as well as more resistant to deformation (i.e. stiffer) than the conventional techniques.

Argon plasma coagulation in the management of symptomatic gastrointestinal vascular lesions: experience in 100 consecutive patients with long-term follow-up.

BACKGROUND: The long-term efficacy of argon plasma coagulation (APC) in the management of gastrointestinal vascular lesions has not been evaluated in a large and well-defined series. The impact of APC on transfusion requirements and hemoglobin, and technical parameters including complications and number of treatment sessions, is assessed in this series. METHODS: Patients who underwent APC for bleeding gastrointestinal vascular lesions were identified via interrogation of an established endoscopic database, excluding patients with radiation proctitis, tumors, residual polypectomy tissue and acute ulcer bleeding. Follow-up data were collected via interview with patients and referring doctors, review of medical records, and follow-up blood tests. RESULTS: One hundred patients were enrolled, males = 46, median age = 74 yr (range: 19-99 yr). Median follow-up time was 16 months (range: 4-47 months). Lesions treated were arteriovenous malformations (n = 74) and gastric antral vascular ectasia (n = 26). Fifty-three patients required transfusion. In this group, median hemoglobin improved from 66 g/L (range: 35-114) to 111 g/L (range: 55-155, p < 0.001). Median transfusion velocity fell from 2 units/month (range: 0.1-6) to 0 units/month (range: 0-4, p < 0.001). Transfusion requirement was abolished in 77%. In non-transfusion-requiring patients, median hemoglobin improved from 105 g/L (range: 58-143) to 123 g/L (range: 79-158, p < 0.001). No complications occurred. CONCLUSIONS: APC is effective and safe in the management of gastrointestinal vascular lesions.

Fatal multifocal metastasis of Clostridium septicum: a case report.

Clostridium septicum infection produces rapidly spreading tissue necrosis, often, but not exclusively, associated with trauma or large bowel malignancy. We present a unique case of atraumatic infection leading to multifocal metastatic spread in a neutropenic patient, emphasising the devastating potential of this disease.

A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful?

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor with a key role in many physiological and pathological processes. Investigation into the implications of circulating levels of this cytokine is progressing at an exponential rate. However, there are important inconsistencies between reports ranging from method of sample collection, processing, software manipulation and data interpretation and controversy as to whether plasma, serum or whole blood will provide the best prognostic information. Different techniques of centrifugation and temperature on sample handling and the impact of in vitro collection of blood on subsequent VEGF results have not been fully appreciated. We provide a critical review of the literature, report the results of our further investigations, suggest a uniform protocol for handling blood samples and highlight previously unsuspected problems in data interpretation.

Deficiency of reproductive tract alpha(1,2)fucosylated glycans and normal fertility in mice with targeted deletions of the FUT1 or FUT2 alpha(1,2)fucosyltransferase locus.

The fucose alpha(1-->2) galactose beta structure is expressed by uterine epithelial cells in the mouse and has been implicated in blastocyst adhesion events thought to be required for murine implantation. Fucalpha(1-->2)Galbeta moieties and cognate fucosyltransferases are also expressed by epithelial cells of the male reproductive tract and have been implicated in sperm maturation events that may contribute to fertilization. To determine directly if Fucalpha(1-->2)Galbeta moieties are required for fertility, we have generated strains of mice that are deficient in genes encoding FUT1 and FUT2, a pair of GDP-L-fucose:beta(1-->4)-D-galactosyl-R 2-alpha-L-fucosyltransferase enzymes (EC 2.4.1.69) responsible for Fucalpha(1-->2)Galbeta synthesis and expression. FUT1 null mice and FUT2 null mice develop normally and exhibit no gross phenotypic abnormalities. The Fucalpha(1-->2)Galbeta epitope is absent from the uterine epithelia of FUT2 null mice and from the epithelia of the epididymis of FUT1 null mice. Fully normal fertility is observed in FUT1 null intercrosses and in FUT2 null intercrosses. These observations indicate that Fucalpha(1-->2)Galbeta moieties are not essential to blastocyst-uterine epithelial cell interactions required for implantation and are not required for sperm maturation events that permit fertilization and that neither the FUT loci nor their cognate fucosylated glycans are essential to normal development.

Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles.

Mechanoelectrical transduction channels of hair cells allow for the entry of appreciable amounts of Ca(2+), which regulates adaptation and triggers the mechanical activity of hair bundles. Most Ca(2+) that enters transduction channels is extruded by the plasma membrane Ca(2+)-ATPase (PMCA), a Ca(2+) pump that is highly concentrated in hair bundles and may be essential for normal hair cell function. Because PMCA isozymes and splice forms are regulated differentially and have distinct biochemical properties, we determined the identity of hair bundle PMCA in frog and rat hair cells. By screening a bullfrog saccular cDNA library, we identified abundant PMCA1b and PMCA2a clones as well as rare PMCA2b and PMCA2c clones. Using immunocytochemistry and immunoprecipitation experiments, we showed in bullfrog sacculus that PMCA1b is the major isozyme of hair cell and supporting cell basolateral membranes and that PMCA2a is the only PMCA present in hair bundles. This complete segregation of PMCA1 and PMCA2 isozymes holds for rat auditory and vestibular hair cells; PMCA2a is the only PMCA isoform in hair bundles of outer hair cells and vestibular hair cells and is the predominant PMCA of hair bundles of inner hair cells. Our data suggest that hair cells control plasma membrane Ca(2+)-pumping activity by targeting specific PMCA isozymes to distinct subcellular locations. Because PMCA2a is the only Ca(2+) pump present at appreciable levels in hair bundles, the biochemical properties of this pump must account fully for the physiological features of transmembrane Ca(2+) pumping in bundles.

Total intravenous versus inhalational anaesthesia for colonoscopy: a prospective study of clinical recovery and psychomotor function.

A randomized, prospective study was conducted on 69 patients comparing recovery after two different anaesthetic techniques for ambulatory colonoscopy. Thirty-five patients received an intravenous fentanyl (1 microg/kg), midazolam (0.05 to 0. 075 mg/kg) and propofol (10 to 20 mg boluses as required) combination. 34 patients received sevoflurane in 67% nitrous oxide. Drug administration was titrated to clinical signs. At baseline and 30, 60, 90 and 120 minutes after the procedure patient performance on a comprehensive battery of psychomotor tests was recorded. Emergence times were noted. Depth of sedation was assessed at 5 minute intervals for 30 minutes after the end of the procedure. Emergence times were faster in the fentanyl/midazolam/propofol group by 2.2 minutes. A lower sedation score was detected at 20 minutes in the sevoflurane/nitrous oxide group. Psychomotor impairment was of a greater magnitude and more prolonged by 30 to 90 minutes in the fentanyl/midazolam/propofol group. It is concluded that a sevoflurane/nitrous oxide anaesthetic has a suitable recovery profile for ambulatory colonoscopy and results in faster recovery of cognitive function compared with a fentanyl, midazolam and propofol combination.

Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate.

Glomerular epithelial protein 1 (GLEPP1) is a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte. The GLEPP1 gene (PTPRO:) was disrupted at an exon coding for the NH(2)-terminal region by gene targeting in embryonic stem cells. Heterozygote mating produced the expected genotypic ratio of 1:2:1, indicating that the Ptpro(-/-) genotype does not lead to embryonic or neonatal lethality. Kidney and glomerular structure was normal at the gross and light microscopic levels. Scanning and transmission electron microscopy showed that Ptpro(-/-) mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podocyte and that there were blunting and widening of the minor (foot) processes in association with altered distribution of the podocyte intermediate cytoskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular nephrin content and reduced glomerular filtration rate in Ptpro(-/-) mice. There was no detectable increase in the urine albumin excretion of Ptpro(-/-) mice. After removal of one or more kidneys, Ptpro(-/-) mice had higher blood pressure than did their wild-type littermates. These data support the conclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.

Engineering of the myosin-ibeta nucleotide-binding pocket to create selective sensitivity to N(6)-modified ADP analogs.

Distinguishing the cellular functions carried out by enzymes of highly similar structure would be simplified by the availability of isozyme-selective inhibitors. To determine roles played by individual members of the large myosin superfamily, we designed a mutation in myosin's nucleotide-binding pocket that permits binding of adenine nucleotides modified with bulky N(6) substituents. Introduction of this mutation, Y61G in rat myosin-Ibeta, did not alter the enzyme's affinity for ATP or actin and actually increased its ATPase activity and actin-translocation rate. We also synthesized several N(6)-modified ADP analogs that should bind to and inhibit mutant, but not wild-type, myosin molecules. Several of these N(6)-modified ADP analogs were more than 40-fold more potent at inhibiting ATP hydrolysis by Y61G than wild-type myosin-Ibeta; in doing so, these analogs locked Y61G myosin-Ibeta tightly to actin. N(6)-(2-methylbutyl) ADP abolished actin filament motility mediated by Y61G, but not wild-type, myosin-Ibeta. Furthermore, a small fraction of inhibited Y61G molecules was sufficient to block filament motility mediated by mixtures of wild-type and Y61G myosin-Ibeta. Introduction of Y61G myosin-Ibeta molecules into a cell should permit selective inhibition by N(6)-modified ADP analogs of cellular processes dependent on myosin-Ibeta.