A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R²=0.50–0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.     

Neuropharmacology and Drug Interactions in Clinical Practice

Summary: Absorption, distribution, and clearance are key pharmacokinetic principles. These parameters can be highly variable among patients and among compounds, and are factors that must be considered in the wide variability in response to medications. Current antiepileptic drugs (AEDs) present many challenges in their administration. However, understanding and utilizing pharmacokinetic principles can assist the clinician in the appropriate optimization of AEds.     

Development of the histaminergic neurons and expression of histidine decarboxylase mRNA in the zebrafish brain in the absence of all peripheral histaminergic systems

The histamine-storing neural system in adult and developing zebrafish (Danio rerio) was studied with immunocytochemical and chromatographical methods. Furthermore, the gene for histidine decarboxylase was partially cloned and its expression mapped with in situ hybridization. The histamine-storing neurons were only seen in the caudal hypothalamus, around the posterior recess of the diencephalic ventricle. Almost all parts of the brain, except the cerebellum, contained at least some histamine-immunoreactive fibres. The ascending projections had the rostral part of the dorsal telencephalon as a major target. Descending projections terminated in the torus semicircularis, central grey and inferior olive. A prominent innervation of the optic tectum, which has not been reported in other fish, was seen. The in situ hybridization gave a strong signal in cells with the same anatomical position as the histamine-immunoreactive neurons. The first histamine-immunoreactive neurons appeared in the ventral hypothalamus at about 85 h post-fertilization, and at 90 h, immunoreactive fibres terminated in the dorsal telencephalon. The embryonic histamine production described in mammals was lacking in this species. Both immunocytochemical and chromatographical studies indicated that histamine is absent in all other parts of the zebrafish body, and no specific hybridization was seen in any other part of the fish than the hypothalamus. The zebrafish could therefore be a very useful model for pharmacological in vivo studies of the histaminergic system of the brain, since the powerful peripheral actions of histamine should be lacking in this species.     

Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection?

A vast majority of the transplant recipients are cytomegalovirus (CMV)-seropositive (R+). We sought to assess variables predictive of CMV infection, specifically in R+ liver transplant recipients. Study patients comprised 182 consecutive liver transplant recipients who survived at least 14 days after transplantation. Surveillance testing was used to detect CMV infection. Pre-emptive therapy was employed for the prevention of CMV disease, however, no antiviral prophylaxis was used for CMV infection. CMV infection developed in 32.5% (38 of 117) of R+ patients, 84.6% (33 of 39) of R-/D+, and 3.8% (1 of 26) of R-/D- patients. In R+ patients, Hispanic race (21.6% vs. 7.8%, P = 0.06), donor CMV seropositivity (73.7% vs. 45.6%, P = 0.005), and hepatocellular carcinoma (23.7% vs. 6.3%, P = 0.05) correlated with a higher risk of CMV infection. In a multivariate model, Hispanic race (OR: 3.5, 95% CI: 1.03-11.6, P = 0.045), donor CMV serostatus (OR: 4.0, 95% CI: 1.6-10.2, P = 0.003) and hepatocellular carcinoma (OR: 5.8, 95% CI: 1.6-20.5, P = 0.006) were all significant independent predictors of CMV infection. The aforementioned variables did not portend a higher risk of CMV infection in R-/D+ patients; donor CMV seropositivity overwhelmed all other risk factors in R- patients (P < 0.00001). In conclusion, CMV-seropositive liver transplant recipients at risk for CMV infection can be identified based on readily assessable variables. Preventive strategies may be selectively targeted toward these patients.     

Evaluation of specialized laparoscopic suturing and tying devices.

BACKGROUND: Laparoscopic suturing and tying constitute advanced minimally invasive surgery skills. Developing proficiency in the standard methods with needle drivers is often an arduous process. Recent advances in laparoscopic instrumentations has allowed for easier methods of suturing and tying. This study investigated the hypothesis that the use of a specialized suturing device and a specialized tying device allows inexperienced medical students to suture and tie laparoscopically. METHODS: Preclinical medical students who had not received any training in open or laparoscopic surgery were included in this investigation. Each student was given a 5-minute demonstration of a specialized suturing device and a specialized tying device. The medical students were not allowed to deploy either device before actual use. After the demonstration, each student was given the device to use in a porcine model. Times were recorded and a subjective grade was given for each student. RESULTS: Twenty medical students were involved in this study. All medical students were able to complete the task of suturing and tying. The average time to suture was 104.6 seconds and the average time to tying was 31.2 seconds. The average subjective performance grade was 90 (out of 100). CONCLUSION: Specialized devices are easy to learn and use for laparoscopic suturing and tying with minimal instruction even for inexperienced medical students. Even surgeons who are not well versed in laparoscopic surgery should be able to suture and tie with certain laparoscopic instruments.     

Morphologic and functional changes in nontumorous liver tissue after radiofrequency ablation in an in vivo model: comparison of 18F-FDG PET/CT, MRI, ultrasound, and CT.

Rimlike contrast enhancement on morphologic imaging and increased tracer uptake on (18)F-FDG PET in the periphery of the necrosis can hamper differentiation of residual tumor from regenerative tissue after radiofrequency ablation of liver lesions. This study used MRI, CT, ultrasound, and (18)F-FDG PET/CT to assess the typical appearance of lesions in nontumorous animal liver tissue after radiofrequency ablation. METHODS: Lesions were created by radiofrequency ablation of normal liver parenchyma in 21 minipigs. Follow-up was performed by 3 contrast-enhanced morphologic modalities-MRI, CT, and ultrasound-and by (18)F-FDG PET/CT immediately, 3 and 10 d, and 1, 2, 3, and 6 mo after radiofrequency ablation. Images were evaluated qualitatively for areas of increased enhancement and regions of elevated tracer uptake. Furthermore, all images were assessed quantitatively by determination of ratios comparing enhancement/tracer uptake in the periphery of the necrosis with enhancement/tracer uptake in normal liver parenchyma. Imaging findings were compared with histopathology findings. RESULTS: Immediately after radiofrequency ablation, no increase in (18)F-FDG uptake was visible, whereas elevated enhancement was noticed in the periphery of the necrosis on all morphologic imaging procedures. At further follow-up, an area of rimlike increase in (18)F-FDG uptake surrounding the necrosis was detected on PET/CT. The rimlike pattern of increased enhancement in the arterial phase was present for all liver lesions on CT, MRI, and ultrasound, especially between day 3 and month 1 after the radiofrequency ablation. Both elevated glucose metabolism and enhancement persisted for 6 mo postinterventionally. Histologic examination showed a hemorrhagic border converting into a regeneration capsule. CONCLUSION: If performed immediately after radiofrequency ablation, (18)F-FDG PET/CT probably has benefits over those of morphologic imaging procedures when assessing liver tissue for residual tumor. Later follow-up may be hampered by visualization of peripheral hyperperfusion and tissue regeneration. Further studies on a patient population are essential.     

Clinical risk factors for fractures in multi-ethnic women: the Women's Health Initiative.

To identify risk factors for fractures in multi-ethnic women, we studied 159,579 women enrolled in the Women's Health Initiative. In general, risk factors for fractures were similar across ethnic groups. However, irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures. INTRODUCTION: Fracture rates tend to be lower in minority women, but consequences may be greater. In addition, the number of fractures is expected to increase in minority women because of current demographic trends. There are limited prospective data on risk factors for fractures in minority women. MATERIALS AND METHODS: We studied 159,579 women 50-79 yr of age enrolled in the Women's Health Initiative. Information on risk factors was obtained by questionnaire or examination. Nonspine fractures that occurred after study entry were identified over an average follow-up of 8 +/- 2.6 (SD) yr. RESULTS: Annualized rates (%) of fracture in whites, blacks, Hispanics, Asians, and American Indians were 2.0, 0.9, 1.3, 1.2, and 2.0, respectively. Significant predictors [HR (95% CI)] of fractures by ethnic group were as follows: blacks: at least a high school education, 1.22 (1.0, 1.5); (+) fracture history, 1.7 (1.4, 2.2); and more than two falls, 1.7 (1.9, 2.0); Hispanics: height (>162 cm), 1.6 (1.1, 2.2); (+) fracture history, 1.9 (1.4, 2.5); more than two falls, 1.8 (1.4, 2.3); arthritis, 1.3 (1.1, 1.6); corticosteroid use, 3.9 (1.9, 8.0); and parental history of fracture, 1.3 (1.0, 1.6); Asians: age (per 5 yr), 1.2 (1.0, 1.3); (+) fracture history, 1.5 (1.1, 2.0); current hormone therapy (HT), 0.7 (0.5, 0.8); parity (at least five), 1.8 (1.1, 3.0); more than two falls, 1.4 (1.1, 1.9); American Indian: (+) fracture history, 2. 9 (1.5, 5.7); current HT, 0.5 (0.3, 0.9). Women with eight or more risk factors had more than a 2-fold higher rate of fracture compared with women with four or fewer risk factors. Two ethnicity x risk factor interactions were identified: age and fall history. CONCLUSIONS: Irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures.     

The effects of illicit drug use and HIV infection on sex hormone levels in women.

Drug use and HIV infection may affect sex hormone levels in women. One hundred and ninety-six women with and without a history of illicit drug use (50 HIV-negative and 148 HIV-infected), with regular menses, who never used antiretrovirals, were evaluated. Luteinizing hormone levels were significantly higher in women with a CD4 cell count <200/microl (p < 0.002). Current methadone use was associated with lower levels of total testosterone (p = 0.03) and higher levels of prolactin (p = 0.002); mean estradiol levels were 43% lower in women who used intravenous drugs (p < 0.001). Alcohol and crack cocaine use was not associated with sex hormone levels. Age, race, body mass index and degree of HIV immunosuppression were also associated with differences in sex hormone levels.     

Comparison of dynamic and step-and-shoot intensity-modulated radiation therapy planning and delivery.

Intensity-modulated radiation therapy (IMRT) is commonly delivered using the dynamic or segmental mode of multileaf collimators (DMLC or SMLC). Both methods are designed to deliver intensity-modulated beams as determined by inverse planning software. In this study, we have used the Helios IMRT planning system to generate ideal treatment plans for 10 cases of 2 common treatment sites (prostate and head and neck) and have investigated the actual treatment fluence distributions generated for each of the MLC leaf motion choices. The 2 dose delivery techniques were dosimetrically compared to each other and to the treatment plans. For each technique, point doses were measured in a water phantom using ionization chambers. Also for each technique, 2-dimensional dose distributions at a selected depth in a plastic phantom were obtained, using extended range film. The total delivery time and the number of monitor units (MU) delivered by each method were also compared. Our results indicate that the 2 delivery methods produce comparable results dosimetrically. For the cases reviewed, the delivery time was an average of 15% longer for SMLC deliveries, while the number of MUs (beam-on time) required by SMLC was an average of 15% fewer, than that for the DMLC. In the interest of simplicity, lower beam-on time, and potentially fewer mechanically-related problems, we think that the SMLC delivery technique may be the better choice when Helios is used for planning and Varian linear accelerators are used for delivery.     

Significance of Anticardiolipin Antibodies on Short and Long Term Allograft Survival and Function following Kidney Transplantation

The significance of anticardiolipin antibodies (ACAs) prior to renal transplantation is unclear. We studied a cohort of 337 patients who underwent renal transplantation from 1996 to 2001. Follow-up continued until allograft loss, patient death or 31 December 2002. The primary outcome was a composite endpoint of death-censored allograft loss or a 25% reduction in estimated glomerular filtration rate (GFR) from 1-month post-transplant. Secondary outcomes were allograft loss, a 25% reduction in GFR, acute rejection and creatinine at 1 year. IgG and IgM ACA titers were positive (> or =15) in 18.1% of recipients. There were no significant differences at baseline between recipients, except coumadin therapy in those with positive ACA titers (20% vs. 7.4%). Post-transplant, there was no increase in the primary outcome in ACA-positive patients, even after adjustment for anticoagulation with coumadin (HR = 1.42 [0.68, 2.96]). There was no difference in secondary outcomes between those with or without positive titers. Two of five patients with very high titers (>50) who were not anticoagulated had early graft loss. A positive ACA titer prior to kidney transplantation was not associated with inferior renal outcomes after transplantation, although more research is required to address the prognostic significance of very high ACA titers.