Changes in lateral standing posture following orthognathic surgery: a cohort study.

Altering neuromuscular and musculoskeletal relationships also affects standing body posture, particularly in the head and neck areas. This prospective cohort study assessed the effects of orthognathic surgery on head posture in the lateral standing view. Thirty-one patients who underwent single-jaw orthognathic mandibular surgery were included. The patients underwent cephalometric and photographic evaluations of their habitual posture before and 6 months after surgery. The craniovertebral angle and Frankfort angle were determined and measured using MB-Ruler software. Mandibular positional changes were also measured by superimposing lateral cephalograms and recording changes in the menton point. All data were analysed by paired t-test. The craniovertebral angle increased significantly in patients with Class II malocclusion (P = 0.001) and decreased significantly in Class III patients (P = 0.004). Furthermore, the Frankfort angle was significantly increased in both Class II (P = 0.005) and Class III (P = 0.012) patients. The tendency towards forward head posture decreased in Class II patients, and the neck posture improved. Conversely, a slight but significant tendency towards a forward head posture was observed in Class III patients after surgery. Furthermore, the natural head position changed in both study groups, leading to a more upright head posture.

Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay.

Oxytocin (OT) is a potential treatment for multiple neuropsychiatric disorders. As OT is a peptide, delivery by the intranasal (IN) route is the preferred method in clinical studies. Although studies have shown increased cerebrospinal fluid (CSF) OT levels following IN administration, this does not unequivocably demonstrate that the peripherally administered OT is entering the CSF. For example, it has been suggested that peripheral delivery of OT could lead to central release of endogenous OT. It is also unknown whether the IN route provides for more efficient entry of the peptide into the CSF compared to the intravenous (IV) route, which requires blood-brain barrier penetration. To address these questions, we developed a sensitive and specific quantitative mass spectrometry assay that distinguishes labeled (d5-deuterated) from endogenous (d0) OT. We administered d5 OT (80 IU) to six nonhuman primates via IN and IV routes as well as IN saline as a control condition. We measured plasma and CSF concentrations of administered and endogenous OT before (t=0) and after (t=10, 20, 30, 45 and 60 min) d5 OT dosing. We demonstrate CSF penetrance of d5, exogenous OT delivered by IN and IV administration. Peripheral administration of d5 OT did not lead to increased d0, endogenous OT in the CSF. This suggests that peripheral administration of OT does not lead to central release of endogenous OT. We also did not find that IN administration offered an advantage compared to IV administration with respect to achieving greater CSF concentrations of OT.

Do antiplatelet drugs increase the risk of bleeding after tooth extraction? A case-crossover study.

The aim of this study was to assess the risk of bleeding after tooth extraction in patients taking aspirin or clopidogrel. This case-crossover study evaluated patients taking aspirin (80mg/day) or clopidogrel (75mg/day) and undergoing tooth extraction. In the first session, extraction was performed without discontinuing aspirin (group 1) or clopidogrel (group 2). In the second session, patients ceased using antiplatelet drugs 5days prior to tooth extraction. Bleeding was evaluated using a visual analogue scale (VAS) for 72h after tooth extraction. The platelet function assay (PFA) was performed for group 1 and flow cytometry assessment of vasodilator-stimulated phosphoprotein (VASP) was performed for group 2, in both sessions. Thirty-eight patients were studied: 20 in group 1 and 18 in group 2. Analysis of the data did not demonstrate any difference in bleeding severity between sessions 1 and 2 in either group (P>0.05). There was a significant difference between sessions 1 and 2 in group 1 for the mean collagen/epinephrine membrane closure time (PFA) (P=0.001). A significant difference in platelet reactivity index (flow cytometry for VASP) was noted between sessions 1 and 2 in group 2 (P=0.001). According to this case-crossover study, dental extraction can be performed safely without withdrawal of aspirin or clopidogrel.

The Prevalence of Human T-Cell lymphotropic Virus Type 1 in Pregnant Women and Their Newborns.

The prevalence of HTLV1 virus antibodies was determined in pregnant women and their neonates in Mashhad, northeast of Iran, as shown in this prospective cross-sectional study. 407 women who were hospitalized for delivery participated in this study. Venous blood sampling of pregnant women and umbilical cord of their neonates was done. The first samples of all women were tested for HTLV1 seropositivity by ELISA test and confirmed by PCR method. Then, the presence of HTLV1 in samples of umbilical cords blood in neonates who were delivered to an HTLV1-positive mother was determined by PCR method. All HTLV1-positive infants were called again at the age of 9-12 months, and PCR test was done using HTLV1-specific primers for them. Of all the participating women, 6 persons were HTLV1 seropositive by ELIZA test which was confirmed by PCR test. HTLV1 antibodies were found in cord blood samples by PCR test in 6 newborns who were born to HTLV1-seropositive women. All the six infants at the age of 9-12 months showed positive PCR results by HTLV1 LTR-specific primers; however, only one of them was PCR positive using HTLV1 TAX-specific primers. The prevalence of HTLV1 antibodies in pregnant women was 1.5%, and the vertical transmission rate to their neonates was 16.6%.

Quantification of unbound prednisolone, prednisone, cortisol and cortisone in human plasma by ultrafiltration and direct injection into liquid chromatrography tandem mass spectrometry.

BACKGROUND: The existing methods for quantitative analysis of free corticosteroids require high volume of plasma and laborious extraction processes. Development of ultrafiltration followed by the liquid chromatrography tandem mass spectrometry (LC-MS/MS) method that requires 300 microL of plasma, does not entail any offline extraction and achieves good sensitivity was described. METHODS: Unbound corticosteroids were separated by the ultrafiltration of plasma using Microcon centrifugal filter devices (10,000 Dal nominal molecular weight limit). A 30 microL aliquot of the ultrafiltrate was directly injected into a two-dimensional high-performance liquid chromatography clean-up and separation system coupled with API-4000 mass spectrometer. The clean-up was performed on a Strata-X on-line extraction cartridge. A Zorbax-SB Phenyl, Rapid Resolution HT (2.1 x 100 mm) column was employed to chromatographically resolve cortisol and prednisolone from each other, from cortisone and prednisone as well as from interferences found in plasma from stable kidney transplant recipients. RESULTS: Intra- and inter-run imprecision and inaccuracy within +/-15% were achieved during a three-batch validation for quality control samples at six concentrations in ultrafiltrate from charcoal-stripped plasma and three concentrations from normal plasma, over a 2000-fold dynamic range. The lower limit of quantification was 0.100 ng/mL for all four corticosteroids. CONCLUSIONS: A highly selective, sensitive, simple and robust LC-MS/MS method was developed for the simultaneous quantification of free cortisol, cortisone, prednisolone and prednisone. The performance of the Strata-X on-line extraction cartridge was maintained for over 700 injections. The assay was successfully applied for the analysis of the analytes in over 500 plasma samples from stable kidney transplant recipients.

Simultaneous determination of plasma prednisolone, prednisone, and cortisol levels by high-performance liquid chromatography.

Recipients of organ transplants remain particularly dependent on prednisolone as part of their maintenance immunosuppression. Despite this, the pharmacokinetics of prednisolone have never been fully characterized in these patients, and consequently dosing remains empirical. Accurate monitoring of prednisolone, its primary metabolite prednisone, and endogenous cortisol suppression in such patients may provide a means of improving the clinical outcome by adjusting for variability in prednisolone pharmacokinetics and pharmacodynamics. Measurement of endogenous cortisol may provide an independent marker of prednisolone pharmacodynamics. A simple isocratic reverse-phase high-performance liquid chromatography procedure, using betamethasone as an internal standard, was developed to quantify plasma prednisolone, prednisone, and cortisol simultaneously. The steroids were extracted from 0.5 mL plasma with 3 mL (1:1 v/v) ethyl acetate/tert-methyl butyl ether and 0.1 mL phosphoric acid, washed in 0.1 mol/L NaOH before a final drying step and reconstitution in mobile phase for injection. Separation was achieved using a Supelcosil LC-18-DB, 150 x 4.6-mm, 5-microm particle size, reverse-phase column attached to a Newguard 15 x 3-mm, RP8 guard column maintained at 25 degreesC, with ultraviolet detector set at 254 nm. The mobile phase consisted of 16% isopropanol in water containing 0.1% trifluoroacetic acid, set at a flow rate of 1.2 mL/min. The assay was linear up to 1,002 microg/L for prednisolone, 982 microg/L for prednisone, and 545 microg/L for cortisol. Mean intra-assay and interassay imprecision levels were 6.0% and 7.2%, respectively, for prednisolone, 5.8% and 7.2% for prednisone, and 5.6% and 7.9% for cortisol. Intra-assay inaccuracy was <7% of nominal values for prednisolone, prednisone, and cortisol. The lower limit of quantification was 7 microg/L for prednisolone and prednisone and 10 microg/L for cortisol. Corticosteroid recoveries were 73%, 74%, and 90% for prednisolone, prednisone, and cortisol, respectively. The authors describe a robust, inexpensive, and simple method suitable for therapeutic drug monitoring or pharmacokinetic studies of prednisolone; it may also be used to measure the suppression of endogenous cortisol production.

Pharmacokinetics of cyclosporine in heart transplant recipients receiving metabolic inhibitors.

BACKGROUND: Inhibitors of cyclosporine metabolism are commonly co-administered with cyclosporine in transplant recipients. The aim of this study was to compare cyclosporine pharmacokinetics using the conventional formulation (Sandimmune) and after switching to the microemulsion (Neoral) formulation, in stable heart transplant recipients receiving various cyclosporine metabolic inhibitors. METHODS: Steady-state blood concentration-time profiles of Sandimmune were studied in 47 transplant recipients receiving either cyclosporine alone (Group A, n = 11) or in combination with diltiazem (120 mg/day, Group B, n = 11), ketoconazole (200 mg/day, Group C, n = 13), or both ketoconazole and diltiazem (200 and 120 mg/day, respectively, Group D, n = 12), and restudied 1 week after switching to Neoral. RESULTS: Neoral resulted in more rapid cyclosporine absorption as judged by the shorter absorption half-lives in all groups (p < 0.05). The mean percentage increase in the values of area-under-the-concentration-time curve was 42% and 37.5% higher for Neoral compared with Sandimmune for Groups A and B, respectively, but only 5.4% higher for Group C and 9.5% higher for Group D. The mean morning trough concentration of cyclosporine was not significantly different after administration of Neoral compared with Sandimmune in any of the groups studied (179 vs. 167 microg/liter for Group A; 171 vs. 147 microg/liter for Group B; 189 vs. 194 microg/liter for Group C; and 181 vs 201 microg/liter for Group D). Neoral did not alter serum concentrations of sodium, potassium, creatinine, and urea in any of the study groups. CONCLUSIONS: The faster absorption and improved bioavailability of cyclosporine (around 40%) with Neoral compared with Sandimmune was not seen in patients receiving ketoconazole, where in fact cyclosporine bioavailability was already maximal. Mean morning trough levels of cyclosporine did not reflect the improvement in bioavailability seen in patients switching from Sandimmune to Neoral. Cyclosporine dose adjustment may be needed when switching from Sandimmune to Neoral for patients not receiving sparing agents or who receive diltiazem, but trough levels cannot necessarily be relied upon to determine the degree of adjustment needed. For patientson ketoconazole, the absorption profile is already optimized and no dosage alteration seems necessary.

Randomized trial of blood eosinophil count monitoring as a guide to corticosteroid dosage adjustment after heart transplantation.

BACKGROUND: Increases in blood eosinophil counts (EOS) beyond 0.06 x 10(9)/liter precede treated heart allograft rejection. An oral prednisolone dose of 0.35 mg/kg/day usually suppresses EOS below this threshold. METHODS: We designed a randomized trial to compare our empirical protocol for steroid dose adjustment with a novel protocol guided by EOS monitoring during the first 3 months after heart transplantation. Eighty patients were randomized to either have their EOS reported and used for steroid dose adjustment (RG; n=40), or not reported (NG; n=40). RG patients had their steroid dosage increased if EOS exceeded 0.06 x 10(9)/liter. RESULTS: RG patients had an 83% lower risk of treated rejection (P=0.035) and lower median intravenous dose of methyl-prednisolone (P=0.017) than NG during the first 6 postoperative weeks. The proportion of diagnostic increases in EOS that were followed within 2 weeks by treated rejection was 42% greater in NG than RG (P=0.0001), compatible with a direct impact of EOS-guided prednisolone dose adjustment on the risk of subsequent rejection. Overall, RG had less than half the risk of rejection of any grade (P<0.001) and significantly more rejection-free biopsies than NG (P=0.001). The mean oral prednisolone dosage was significantly greater in RG than NG during the first (P=0.014) and second (P=0.001) 6 weeks of follow-up. This did not increase the incidence of serious steroid-related side effects. CONCLUSIONS: EOS monitoring is a simple, cheap, and effective means of optimizing steroid immunosuppression. Restriction of the EOS-guided steroid dosing protocol to periods of prolonged hospitalisation during the first 3 postoperative months should limit the requirement for higher prednisolone dosage without affecting immunosuppressive efficacy.

Cyclosporine plasma unbound fraction in heart and lung transplantation recipients.

To investigate the variability in the unbound fraction (fu) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fu was determined ex vivo in plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (x100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53%+/-0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fu were significantly lower (p < 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade la rejections. The value of fu did not vary with organ transplanted (p = 0.35) or etiology of organ failure (p = 0.32). Cyclosporine fu was negatively correlated with the age of the patient (r = -0.18, p < 0.05). Correlations were not observed between fu and blood biochemical and cytologic indices. However, fu was significantly lower (p < 0.01) in hypercholesterolemic transplant recipients (1.37+/-0.52%) than in normocholesterolemic patients (1.60+/-0.63%). Administration of simvastatin resulted in a significant increase in the mean fu from 1.40+/-0.09%) to 1.82+/-0.13% (paired t test, n = 13; p < 0.01). In patients who received ketoconazole, fu was not different from controls. These findings suggest that the level of cyclosporine fu may be an important determinant of immunosuppressive activity of cyclosporine. Moreover, the variation in fu could be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.

Unbound cyclosporine and allograft rejection after heart transplantation.

BACKGROUND: To determine the impact of cyclosporine plasma protein binding on organ rejection after cardiac transplantation, the incidence of cardiac rejection episodes was compared among patients who had differing levels of cyclosporine plasma fraction unbound (fU). METHODS: Forty-six consecutive cardiac transplant recipients were sampled at 1, 3, 6, and 12 months after transplantation, and cyclosporine plasma fU was determined, using a specially developed equilibrium dialysis method. At the completion of the study, incidences of cardiac rejection episodes were compared among patients having mean cyclosporine fU (Csfu) that were low (LCsfu; mean+/-SD, 1.33+/-0.10%, n=15), intermediate (ICsfu; 1.60+/-0.07%, n= 16), and high (HCsfu; 1.99+/-0.30%, n=15). RESULTS: Percentage of endomyocardial biopsies (grade 3a, 3b, and 4) with respect to the total number of biopsies performed in the first 3 months after transplant was significantly higher in the LCsfu group than the other groups (40.9% in LCsfu vs. 28.5% for ICsfu and 32.1% for HCsfu groups, P=0.02). The linearized rate of rejection (episodes of rejection/100 patient-days) in the first month after transplant was 6.5+/-1.7 for LCsfu, 3.5+/-0.8 for ICsfu and 4.3+/-0.9 for the HCsfu group (P<0.05, low vs. intermediate-high). The mean (95% confidence interval) of time interval between the first and second episodes of rejections was 10.7 (5.6-16.0) days for LCsfu, 18.0 (8.6-29.0) days for the ICsfu, and 26.0 (15.1-36.9) days for the HCsfu group (P<0.01). The total number of rejections requiring treatment per patient in the first 3 months after transplant was higher in the LCsfu group compared with the others (4.0+/-1.7 episodes for LCsfu vs. 2.9+/-1.1 for ICsfu and 3.2+/-1.2 episodes for HCsfu; P<0.05). Four patients in the low group, one patient in the intermediate group, and no patients in the high group required treatment with total lymphoid irradiation (P<0.02). CONCLUSIONS: This finding suggests that patients with lower levels of cyclosporine fU are more prone to cardiac rejection and that the level of cyclosporine fraction unbound may be clinically important for determination of response to cyclosporine therapy.

Indirect estimation of the unbound fraction of cyclosporine in plasma.

The unbound fraction (fU) of cyclosporine in plasma is approximately 0.02. The measurement of cyclosporine fU requires a laborious equilibrium dialysis procedure, which is not practical in a clinical setting. A mathematical model was developed to estimate cyclosporine fU from concentrations of serum lipoproteins, the major binding proteins for cyclosporine. Values of fU were determined ex vivo in 126 plasma samples obtained from 58 recipients of heart and lung transplants, using equilibrium dialysis. Concentrations of serum lipids, measured using standard enzymatic techniques, were used as concentration markers for serum lipoproteins. Patients were randomly assigned to either of two equal-sized groups. One group (subgroup 1) was used to evaluate the parameters of the model, and the other group (subgroup 2) was used to examine its predictive performance. The parameters were estimated using least squares non-linear regression. A model incorporating concentrations of serum HDL- and LDL-cholesterol, serum albumin, and time after transplantation gave the best fit. For subgroup 2, mean prediction error (ME), a measure of bias, and root mean squared error (RMSE) and median absolute error (MAE), measures of precision, and their 95% confidence intervals were estimated. For the best fit model, ME was 0.07 x 10(-2) (-0.065 x 10(-2) - 0.1 x 10(-2)), indicating that the model provided an unbiased estimate of the value of cyclosporine fU. Root mean squared error and MAE were 0.536 x 10(-2) (0.398 x 10(-2) - 0.645 x 10(-2)) and 0.27 x 10(-2) (0.226 x 10(-2) - 0.409 x 10(-2)), respectively. Prediction error was normally distributed; approximately 30% of the prediction errors were <10% and <5% of prediction errors were >50%. This model has shown a reasonable predictive performance in the patients with cardiac transplants studied; however, its predictive performance will need to be validated in a larger number of recipients of transplants of various types.

Management of maxillofacial injuries in the Iran-Iraq War.

PURPOSE: This study discusses types of maxillofacial injury, their treatment, and complications encountered in the Iran-Iraq war. PATIENTS AND METHODS: During 1981 to 1986, 210 casualties were treated with 250 operations in Mostafa-Khomeini hospital in Tehran. Their records were analyzed retrospectively. The operations were mostly reconstructive and consisted of methods adopted because of available instruments of that time. RESULTS: Mandibular defects were the most prominent kind of injury (43.2%), and approximately two thirds of them needed tracheostomy. Ophthalmic injuries represented 20% of midfacial injuries. Osteomyelitis was a common complication of primary phases of treatment. CONCLUSION: The inability to evacuate and promptly treat patients with gunshot wounds can result in complications, especially infections, that make the later phases of treatment difficult.

Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients.

AIMS: To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients. METHODS: Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate-concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P-PHARM software) the ratio of dose rate to trough concentration at steady state (DR/C[SS trough]), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/C(SS trough) was calculated for each patient before and after simvastatin administration. RESULTS: The mean fu increased by 29%, from 1.40 +/- 0.1% (mean +/- s.d.) to 1.82 +/- 0.22% after simvastatin administration (P < 0.01). Mean trough concentrations of cyclosporine in whole blood were 349 microg l-1 before and 242 microg l-1 after simvastatin administration (P < 0.0001). The mean cyclosporine daily dosage was 2.87 mg kg-1 and 2.33 mg kg-1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/C(SS trough) was significantly increased from 24.5 l h-1 before to 28.9 l h-1 after simvastatin administration (P < 0.05). Furthermore the median increase in cyclosporine DR/C(SS trough) was 18 l h-1 (-3.1 to 42.1 l h-1, interquartile range). CONCLUSIONS: Cyclosporine fraction unbound and clearance are increased following co-administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.

In-shoe biaxial shear force measurement: the Kent shear system.

The Kent shear system is introduced and preliminary clinical results are presented. A technique utilising copolymer piezoelectric film has allowed the manufacture of biaxial in-shoe transducers capable of simultaneously measuring two orthogonal shear forces. Bipedal measurements are carried out inside everyday footwear over multiple footsteps.