The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64.

The aim of the current research project was to explore the possibilities of combining pressurized carbon dioxide with hot stage extrusion during manufacturing of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64) and to evaluate the ability of the pressurized gas to act as a temporary plasticizer as well as to produce a foamed extrudate. Pressurized carbon dioxide was injected into a Leistritz Micro 18 intermeshing co-rotating twin-screw melt extruder using an ISCO 260D syringe pump. The physicochemical characteristics of the extrudates with and without injection of carbon dioxide were evaluated with reference to the morphology of the solid dispersion and dissolution behaviour and particle properties. Carbon dioxide acted as plasticizer for itraconazole/PVP-VA 64, reducing the processing temperature during the hot stage extrusion process. Amorphous dispersions were obtained and the solid dispersion was not influenced by the carbon dioxide. Release of itraconazole from the solid dispersion could be controlled as a function of processing temperature and pressure. The macroscopic morphology changed to a foam-like structure due to expansion of the carbon dioxide at the extrusion die. This resulted in increased specific surface area, porosity, hygroscopicity and improved milling efficiency.     

Treatment of intervention sites of malignant pleural mesothelioma with radiotherapy: a Dutch-Belgian survey.

A survey was performed on the radiotherapy practice of malignant pleural mesothelioma in The Netherlands and Belgium in 2002. Thirty-eight out of 47 centres (81%) responded. Prophylactic radiotherapy to intervention sites is given by 32/38 (84%) centres, with all centres offering palliative radiation. For both prophylactic and palliative indications, all centres use hypo-fractionated schedules. The present study shows that in the radiotherapy community in The Netherlands and in Belgium, a de facto consensus exists that both prophylactic and symptomatic radiotherapy to intervention sites of malignant pleural mesothelioma are effective and that hypo-fractionated schedules should be used.     

The influence of stigma on the sexual risk behavior of rural men who have sex with men.

Research investigating predictors of risky sexual behavior of rural MSM is sparse, even though the prevalence of HIV in rural areas has increased. This study explored two sets of predictors of 93 rural MSM's levels of risky sexual behavior: mental health variables and stigma emanating from men's family members, health care professionals, and people in the rural communities in which they live. Over 47% of the men were found to be at modified high to high risk. Logistic regression using a continuation logit model was used to test the relationship of the predictor variables and the four levels of risk. Findings indicate that self-esteem was predictive of the highest sexual risk behavior but not lower levels of risk. Stigma was predictive of modified high sexual risk when compared to low and no risk categories. No variables differentiated men at low risk from men at no risk.     

Perioperative complications following sagittal split osteotomy of the mandible.

INTRODUCTION: The aim of this study was to review complications in a series of 1264 consecutive patients who were operated in a single centre during a 20-year-period. MATERIAL AND METHODS: Complications were documented, their incidences calculated and compared with data from the literature. RESULTS: In 35 patients (2.8%) infection developed requiring extraoral incision and drainage; in 27 patients (2.1%) the inferior alveolar nerve was inadvertently cut; 18 patients (1.4%) had to undergo re-operation due to bending or fracture of osteosynthesis material; 15 patients (1.2%) suffered from bleeding complications; in 12 patients (0.9%) an unfavourable split occurred. In 8 patients (0.6%) foreign bodies were left in situ; in 7 patients a partial weakness of the facial nerve occurred, which was permanent in 1 patient. Six patients (0.5%) with a significantly higher age than average (mean: 33.6 years in comparison with 23.1 years) developed non-union at the site of osteotomy, and the mandible had to be bone grafted. Two patients (0.2%) developed osteomyelitis, and in one patient airway problems led to a need for tracheostomy (0.1%). CONCLUSION: Although some of these complications of bilateral sagittal split with osteotomy carry severe limitations in health related quality of life, it remains an overall safe procedure, demanding, however, comprehensive informed consent. Good knowledge of technical reasons for these complications should help to reduce their incidence.     

Highly resolved in vivo 1H NMR spectroscopy of the mouse brain at 9.4 T.

An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models.     

Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness

OBJECTIVE Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN Critically ill adults (n=40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n=10), GHRH and GHRP-2 (n=10), GHRP-2 and GHRH+GHRP-2 (n=10), GHRH+GHRP-2 and GHRH+GHRP-2+TRH (n=10). The GHRH and GHRP-2 doses were 1μg/kg and the TRH dose was 200μg. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection. MEASUREMENTS Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA. RESULTS Critically ill patients presented a striking GH response to GHRP-2 (mean±SEM peak GH 51±9 μg/l in older patients and 102±2μg/l in younger patients; P=0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P=0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P=0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P=0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response < ninefold (P=0.005), elicited a 60% rise in serum T3 (P=0.01) and an 18% increase in T4 (P=0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P=0.007). GHRP-2 increased basal serum cortisol levels (531±29nmol/l) by 35% (P=0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P=0.05). CONCLUSIONS The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.     

Dynamic contrast-enhanced MR imaging assessment of vascularized free fibular grafts

Magnetic resonance (MR) imaging may be a noninvasive method for assessing perfusion of vascularized bone grafts placed for treatment of avascular necrosis. One proximal femur of seven beagles was devascularized, with insertion of a vascularized fibular graft. MR imaging at 1 week (seven dogs) and 6 weeks (five dogs) after surgery included pre- and postcontrast spin-echo sequences, unenhanced twodimensional time-of-flight (TOF) vascular imaging, and dynamic gradient-echo imaging during infusion of gadolinium. Relative signal intensity values of selected regions obtained from the dynamic gradientecho images were plotted as percent enhancement versus time. In the operated hip, MR imaging did not show enhancement in six of seven femoral heads and greater trochanters at 1 week after surgery, with similar results after 6 weeks. MR imaging of fibular grafts 6 weeks after surgery showed an initial rapid increase in enhancement and a subsequent slower increase in five of five dogs, although no enhancement was seen in six of seven dogs at 1 week. These findings contrasted with a rapid initial increase in enhancement followed by slow decline in non-operated hips. Two-dimensional TOP imaging did not show the vascular pedicle of the graft in any dog. Findings of radionuclide bone scanning performed 1 week after surgery were consistent with devascularization of the operated femur and fibular graft. However, tetracycline distribution and histologic findings confirmed the viability of five of five grafts within the devascularized femurs 6 weeks after surgery. Thus, dynamic contrast-enhanced MR imaging at 6 weeks after surgery is valuable for assessing vascular bone graft perfusion, while similar imaging at 1 week may suggest otherwise.