Outcomes and complications associated with malar onlays: literature review and case series of 119 implants.

Alloplastic malar onlays have been used by surgeons to correct or enhance the midfacial skeleton for over 40 years. Case series have shown respectable results using different alloplastic materials in various maxillofacial subsites. However, these articles include small numbers of patients with limited follow up. We present a literature review specifically concentrating on porous polyethylene (Medpor, Stryker) and polyethyl ether ketone (PEEK) malar onlays. We illustrate the technique used by a single oral and maxillofacial surgeon for placement of 119 implants in 61 patients over a 14-year period, and show the results of this work with long-term follow up. A complication rate of 2.5% in this cohort was reported, with follow up of three years, demonstrating that this technique for midfacial correction is successful in both the short and the long term.

Label-free electrochemical impedance biosensor to detect human interleukin-8 in serum with sub-pg/ml sensitivity.

Biosensors with high sensitivity and short time-to-result that are capable of detecting biomarkers in body fluids such as serum are an important prerequisite for early diagnostics in modern healthcare provision. Here, we report the development of an electrochemical impedance-based sensor for the detection in serum of human interleukin-8 (IL-8), a pro-angiogenic chemokine implicated in a wide range of inflammatory diseases. The sensor employs a small and robust synthetic non-antibody capture protein based on a cystatin scaffold that displays high affinity for human IL-8 with a KD of 35 ± 10 nM and excellent ligand specificity. The change in the phase of the electrochemical impedance from the serum baseline, ∆θ(ƒ), measured at 0.1 Hz, was used as the measure for quantifying IL-8 concentration in the fluid. Optimal sensor signal was observed after 15 min incubation, and the sensor exhibited a linear response versus logarithm of IL-8 concentration from 900 fg/ml to 900 ng/ml. A detection limit of around 90 fg/ml, which is significantly lower than the basal clinical levels of 5-10 pg/ml, was observed. Our results are significant for the development of point-of-care and early diagnostics where high sensitivity and short time-to-results are essential.

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial.

UNLABELLED: The cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration. INTRODUCTION: Bone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration. METHODS: This was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study. RESULTS: Both regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern. CONCLUSION: Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome.

PURPOSE: We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome. MATERIALS AND METHODS: This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg). RESULTS: At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p <0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea. CONCLUSIONS: The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome.

What are the occlusal outcomes for unilateral cleft lip and palate patients? A national project in the UK.

AIM: This national project assessed the orthodontic outcome for unilateral cleft lip and palate (UCLP) patients in the UK. METHOD: Six consecutively treated fixed appliance cases where orthognathic surgery was not undertaken were assessed using the peer assessment rating (PAR) index on orthodontic study models. These cases were submitted by NHS consultant orthodontists undertaking treatment on patients with cleft lip and/or palate. SETTING: UK NHS consultant-led hospital service. RESULTS: The mean reduction in PAR score was 69% + or - 22. The mean start PAR score was 41 + or - 11. The mean end of treatment PAR was 12 + or - 9. The proportion of cases where the score was worse or no different was 7.5%. CONCLUSION: The mean percentage PAR reduction compares well with other national projects looking at outcome from patients treated in the hospital service. The mean PAR reduction could be used as a benchmark for outcome in UCLP orthodontic treatments in future audit projects and the annual consultant appraisal process.

Spontaneous condensation in DNA-polystyrene- b-poly(l-lysine) polyelectrolyte block copolymer mixtures.

We investigated the condensation of calf thymus DNA by amphiphilic polystyrene(m)-b-poly(l-lysine)(n) block copolymers ( PS(m)-b- PLys(n), m, n = degree of polymerization), using small-angle X-ray scattering, polarized optical microscopy and laser scanning confocal microscopy. Microscopy studies showed that the DNA condenses in the form of fibrillar precipitates, with an irregular structure, due to electrostatic interactions between PLys and DNA. This is not modified by the presence of hydrophobic PS block. Scattering experiments show that the structure of the polyplexes corresponds to a local order of DNA rods which becomes more compact upon increasing n. It can be concluded that for DNA/ PS(m)-b- PLys(n) polyplexes, the balance between the PLys block length and the excess charge in the system plays an essential role in the formation of a liquid crystalline phase.

Adenine nucleotide loss in the skeletal muscles during exercise in chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle adenine nucleotide loss has been associated with fatigue during high intensity exercise in healthy subjects but has not been studied in patients with chronic obstructive pulmonary disease (COPD). Changes in adenine nucleotides and other metabolites in the skeletal muscles were measured in patients with COPD and age matched healthy volunteers by obtaining biopsy samples from the quadriceps muscle at rest and following a standardised exercise challenge. METHODS: Eighteen patients with COPD (mean (SD) forced expiratory volume in 1 second 38.1 (16.8)%) and eight age matched healthy controls were studied. Biopsy samples were taken from the vastus lateralis muscle at rest and immediately after a 5 minute constant workload cycle test performed at 80% peak work achieved during a maximal incremental cycle test performed previously. RESULTS: The absolute workload at which exercise was performed was substantially lower in the COPD group than in the controls (56.7 (15.9) W v 143.2 (26.3) W, p<0.01). Despite this, there was a significant loss of adenosine triphosphate (mean change 4.3 (95% CI -7.0 to -1.6), p<0.01) and accumulation of inosine monophosphate (2.03 (95% CI 0.64 to 3.42), p<0.01) during exercise in the COPD group that was similar to the control group (-4.8 (95% CI -9.7 to 0.08), p = 0.053 and 1.6 (95% CI 0.42 to 2.79), p<0.01, respectively). CONCLUSIONS: These findings indicate that the ATP demands of exercise were not met by resynthesis from oxidative and non-oxidative sources. This suggests that significant metabolic stress occurs in the skeletal muscles of COPD patients during whole body exercise at low absolute workloads similar to those required for activities of daily living.

Actin-dependent motility of melanosomes from fish retinal pigment epithelial (RPE) cells investigated using in vitro motility assays.

Melanosomes (pigment granules) within retinal pigment epithelial (RPE) cells of fish and amphibians undergo massive migrations in response to light conditions to control light flux to the retina. Previous research has shown that melanosome motility within apical projections of dissociated fish RPE cells requires an intact actin cytoskeleton, but the mechanisms and motors involved in melanosome transport in RPE have not been identified. Two in vitro motility assays, the Nitella assay and the sliding filament assay, were used to characterize actin-dependent motor activity of RPE melanosomes. Melanosomes applied to dissected filets of the Characean alga, Nitella, moved along actin cables at a mean rate of 2 microm/min, similar to the rate of melanosome motility in dissociated, cultured RPE cells. Path lengths of motile melanosomes ranged from 9 to 37 microm. Melanosome motility in the sliding filament assay was much more variable, ranging from 0.4-33 microm/min; 70% of velocities ranged from 1-15 microm/min. Latex beads coated with skeletal muscle myosin II and added to Nitella filets moved in the same direction as RPE melanosomes, indicating that the motility is barbed-end directed. Immunoblotting using antibodies against myosin VIIa and rab27a revealed that both proteins are enriched on melanosome membranes, suggesting that they could play a role in melanosome transport within apical projections of fish RPE.

Clinical and bacteriologic efficacy of amoxycillin b.d. (45 mg/kg/day) versus amoxycillin t.d.s (40 mg/kg/day) in children with group A beta-hemolytic streptococcal tonsillopharyngitis.

This randomized, observer-blind, multicenter, parallel-group study compared the clinical and bacteriologic efficacy and safety of amoxycillin, 45 mg/kg/day b.d. and amoxycillin, 40 mg/kg/day t.d.s. after 7 days of treatment in 517 children with acute bacterial tonsillopharyngitis. At the end of treatment, a successful clinical response was recorded in more than 96% of patients in each of the treatment groups. A similar result was obtained at follow-up. Among those patients who were bacteriologically evaluable at the end of treatment, a successful bacteriologic response was achieved in more than 94% in each treatment group. Both treatments were well tolerated. Drug-related adverse events were recorded in just 12 patients (4.6%) in the b.d. group and six (2.4%) in the t.d.s. group. The study demonstrated that a twice-daily regimen of amoxycillin, 45 mg/kg/day, was as effective and as well tolerated as the standard three-times-daily regimen of amoxycillin, 40 mg/kg/day, in the treatment of acute bacterial tonsillopharyngitis in children.

Altered postprandial hormone and metabolic responses in a simulated shift work environment.

The circadian rhythms of most night shift workers do not adapt fully to the imposed behavioural schedule, and this factor is considered to be responsible for many of the reported health problems. One way in which such disturbances might be mediated is through inappropriate hormonal and metabolic responses to meals, on the night shift. Twelve healthy subjects (four males and eight females) were studied on three occasions at the same clock time (1330 h), but at different body clock times, after consuming test meals, first in their normal environment, secondly after a forced 9 h phase advance (body clock time approximately 2230 h) and then again 2 days later in the normal environment. They were given a low-fat pre-meal at 0800 h, then a test meal at 1330 h with blood sampling for the following 9 h. Parameters measured included plasma glucose, non-esterified fatty acids (NEFAs), triacylglycerol (TAG), insulin, C-peptide, proinsulin and glucose-dependent insulinotropic polypeptide, and urinary 6-sulphatoxymelatonin. In contrast with a previous study with a high-fat pre-meal, postprandial glucose and insulin responses were not affected by the phase shift. However, basal plasma NEFAs were lower immediately after the phase shift (P < 0.05). Incremental (difference from basal) TAG responses were significantly higher (P < 0.05) immediately after the phase shift compared with before. Two-day post-phase shift responses showed partial reversion to baseline values. This study suggests that it takes at least 2 days to adapt to eating meals on a simulated night shift, and that the nutritional content of the pre-meals consumed can have a marked effect on postprandial responses during a simulated phase shift. Such findings may provide a partial explanation for the increased occurrence of cardiovascular disease reported in shift workers.

Respiratory symptoms and ventilatory performance in workers exposed to grain and grain based food dusts.

A health surveillance study of male grain food manufacturing workers used a respiratory health questionnaire and spirometry to assess the prevalence of work-related respiratory symptoms and impaired ventilatory performance. The prevalence of cough, breathlessness, wheeze and chest tightness was between 8-13% but was 20% for rhinitis. Rhinitis was the most common symptom with 37% of those reporting rhinitis describing this as work-related. A case-control analysis of workers reporting rhinitis did not identify any specific occupational activities associated with increased risk of rhinitis. Smoking habit and all respiratory symptoms apart from rhinitis had a significant effect upon ventilatory performance. Occupational exposure to raw grains, flour, ingredients and finished food was categorized as high, medium or low in either continuous or intermediate patterns. Multiple regression analysis confirmed the effects of height, age and smoking upon ventilatory performance. However, occupational exposure to grain, flour, food ingredients and cooked food dusts had no effect upon ventilatory performance. It is concluded that smoking habit is the major determinant of respiratory symptoms and impaired ventilatory function. The excess complaints of rhinitis warrant further study but it would appear that the current occupational exposure limits for grain, flour, food ingredients and cooked food dusts are adequate to protect workers against impairment of ventilatory performance.

Adaptation of the 6-sulphatoxymelatonin rhythm in shiftworkers on offshore oil installations during a 2-week 12-h night shift.

The circadian rhythms of most shiftworkers do not adapt to night shift. We have studied oil workers on a rotating system involving 2 weeks day shift (0600-1800 h) and 2 weeks night shift (1800-0600 h) throughout a day and night shift sequence. Urine samples were collected 3-hourly whilst awake, with an over-sleep collection, for the measurement of 6-sulphatoxymelatonin by radioimmunoassay. In three separate groups results showed adaptation by delay of the 6-sulphatoxymelatonin rhythm in the first week of night shift. The rates of phase shift (mean +/- SEM) were 1.51 +/- 0.16 h/day (n = 5), 1.32 +/- 0.41 h/day (n = 5) and 1.77 +/- 0.31 h/day (n = 17). Specific environmental and social factors together with the shift schedule on oil rigs may facilitate adaptation to a 12 h night shift within a week.

Treatment of circadian rhythm disorders--melatonin.

Melatonin has clear acute and delayed effects on sleep and circadian rhythms. Decrements in core temperature and alertness have been found at different times of day following low pharmacological and physiological doses of melatonin. When correctly timed, melatonin induces both phase advances and phase delays of the circadian system in humans. When timed to advance, the decrement in temperature and alertness and the degree of shift are closely related to dose. In both simulation and field studies, correctly timed melatonin can alleviate some of the problems of shiftwork and jet lag, notably enhancing sleep and alertness and hastening adaptation of rhythms to the imposed schedule. Performance effects and changes in sleep architecture need to be fully evaluated. The optimization of dose and formulation is also an area that requires further work. Whether or not recently developed melatonin analogs (72) will prove more or less useful than melatonin in adapting to phase shift remains to be seen. If incorrectly timed, melatonin has the potential to induce deleterious effects. While short-term studies indicate that it has very low toxicity, there are no long-term safety data. All of the studies reported here concern healthy adult volunteers and the use of a preparation licensed for human experimental use and available on a named patient basis on prescription. There are no data on uncontrolled preparations available over the counter in some countries. Its effects in pregnancy, interaction with other medications, and many other considerations remain to be addressed. Thus, while melatonin is useful in well-controlled conditions, the indiscriminate use of unlicensed preparations is not advisable.

Postprandial hormone and metabolic responses in simulated shift work.

This study was designed to investigate postprandial responses to a mixed meal in simulated shift work conditions. Nine normal healthy subjects (six males and three females) were studied on two occasions at the same clock time (1330 h) after consuming test meals, first in their normal environment and secondly after a 9 h phase advance (body clock time 2230 h). Plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), triacylglycerol (TAG) and non-esterified fatty acids (NEFAs) were determined at intervals for 6 h after each test meal. Postprandial plasma glucose, insulin, GIP and GLP-1 profiles were evaluated by calculating areas under the curve (AUC) for the first 2 h and the last 4 h of the sampling together with total AUC. Significantly higher postprandial glucose responses (total AUC) were observed after the phase shift than before (AUC 0-360 min, 2.01 (1.51-2.19) vs 1.79 (1.56-2.04) mmol/l.min; P < 0.02; mean (range)). No significant difference was observed when the first 2 h of each response was compared, but significantly higher glucose levels were observed in the last 4 h of the study after the phase shift than before (AUC 120-360 min, 1.32 (1.08-1.42) vs 1.16 (1.00-1.28) mmol/l.min; P < 0.05). Similar results were obtained for insulin (AUC 0-360 min, 81.72 (30.75-124.97) vs 58.98 (28.03-92.57) pmol/l.min; P < 0.01; AUC 120-360 min, 40.73 (16.20-65.25) vs 25.71 (14.25-37.33) pmol/l.min; P < 0.02). No differences were observed in postprandial plasma GIP and GLP-1 responses before and after the phase shift. Postprandial circulating lipid levels were affected by phase shifting. Peak plasma TAG levels occurred 5 h postprandially before the phase shift. Postprandial rises in plasma TAG were significantly delayed after the phase shift and TAG levels continued to rise throughout the study. Plasma postprandial NEFA levels fell during the first 3 h both before and after the phase shift. Their rate of return to basal levels was significantly delayed after the phase shift compared with before. This study demonstrates that a simulated phase shift can significantly alter pancreatic B-cell responses and postprandial glucose and lipid metabolism.

Analysis of MHC class I expression in equine trophoblast cells using in situ hybridization.

Down-regulation of major histocompatibility complex (MHC) genes by trophoblast cells is considered to be a primary mechanism preventing maternal immune rejection of the fetal-placental unit in mammalian pregnancy by rendering these cells, which form the primary barrier between mother and fetus, relatively non-antigenic. In situ hybridization with probes encoding human and horse MHC class I genes was used to characterize the pattern of MHC class I mRNA expression in the various forms of horse trophoblast. Strong hybridization signals were observed in the invasive trophoblast cells of chorionic girdle tissue. In contrast, no hybridization signal specific for MHC class I mRNA transcripts was observed in the descendent endometrial cup trophoblast cells. In the non-invasive trophoblast cells of the allantochorion, no hybridization signals specific for horse MHC class I mRNA transcripts were consistently detected. In parallel to the in vivo results, strong hybridization signals were observed in the small, mononuclear cells present in chorionic girdle cell explant cultures, but not in the population of large binucleate cells corresponding to endometrial cup cells. The results obtained using in situ hybridization are consistent with the hypothesis that expression of MHC class I genes may be controlled at the transcriptional level in horse invasive and non-invasive trophoblast cells, and suggest that down-regulation of MHC class I antigen expression in endometrial cup cells may be accomplished by the same mechanisms in vivo and in vitro.

Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns.

The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP-1(7-36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7-36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7-36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7-36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism.

Screening for coronary risk factors in occupational health practice.

Screening for coronary risk factors (blood cholesterol greater than 5.2 mmol/l; body mass index greater than 25; blood pressure greater than 140/90 and positive smoking history) using nurse administered voluntary health assessments was studied in occupational health practice. A high employee participation rate (80.9 per cent) was achieved with few employees declining to attend, confirming the advantages of workplace based screening. Hypercholesterolaemia, overweight and smoking were the most prevalent risk factors. Men had higher rates than women as judged by independent or concomitant risk factor rates; 56.5 per cent of men were over ideal body weight, 40 per cent of men smoked, 35.7 per cent of men had two risk factors and 2 per cent of men had four risk factors. Blood cholesterol and blood pressure were shown to increase with increasing body weight. It is suggested that body weight reduction and smoking cessation are the preferred intervention strategies in occupational health practice.