Islet amyloid polypeptide in patients with pancreatic cancer and diabetes

Population-based psychiatric admission rates vary across geographic areas, but reasons for this variation are unknown. Insofar as Community Mental Health Centers (CMHCs) provide outpatient services that may deter the need for hospitalization, the presence and structural characteristics of CMHCs may have an impact on a population's psychiatric admission rates. This study uses small area analysis to examine how general hospital psychiatric admission rates are associated with CMHC characteristics. Based on a survey of all CMHCs in Iowa and corresponding small area variation data, it was found that population admission rates were higher in areas closer to the CMHC and lower in outlying catchment areas, adjusting for age, sex, and urban/rural differences in populations. There was little evidence that differences in staffing and service variables influenced admission rates, although greater CMHC staff coverage by social workers and psychiatric residents was associated with lower admission rates. The results suggest that CMHCs do not lower an area's hospitalization rate, and in fact, the presence of CMHCs may promote a "supplier-induced demand" phenomenon of higher admissions.     

The membrane affinities of the aliphatic amino acid side chains in an alpha-helical context are independent of membrane immersion depth

Understanding, predicting, and designing the binding of peptides and proteins to bilayers require quantifying the intrinsic propensities of individual amino acid residues to bind membranes as a function of structural context and bilayer depth. A host-guest study was performed using the peptide host named helix5 in order to determine the membrane affinities of the aliphatic side chains both in an alpha-helical context and as a function of bilayer depth. Use of the alpha-helical host with a constrained geometry allowed the placement of guest sites at three different depths in bilayers and minimized secondary structural changes due to guest substitutions. Circular dichroism and electron paramagnetic resonance (EPR) were used to characterize the aqueous and bilayer-bound structures of the peptide variants. EPR was also used to measure the bilayer-water partition constants of the peptide variants, and the Delta DeltaGtr values (relative to Gly) of the aliphatic amino acid side chains were subsequently calculated. Surprisingly, the DeltaDeltaGtr values did not significantly vary as a function of the guest site depth in bilayers. In addition, the Delta DeltaGtr values determined in an alpha-helical context are reduced to approximately two-thirds of Delta DeltaGtr values determined in other studies for the bilayer-water and octanol-water partitioning of amino acid side chains in extended and unstructured hosts. Both the relative reduction in Delta DeltaGtr values in the context of an alpha-helical host and the invariance of Delta DeltaGtr values with respect to bilayer depth are consistent with the membrane affinities of the aliphatic residues being largely determined by the classical hydrophobic effect.     

Fetal islet xenotransplantation in rodents and primates

(E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide-diphosphate reductase, has been shown to have anti-tumor activity against solid tumors and sensitize tumor cells to ionizing radiation. Pentoxifylline (PTX) can potentiate the cell killing induced by DNA-damaging agents through abrogation of DNA-damage-dependent G2 checkpoint. We investigated the cytotoxic, radiosensitizing and cell-cycle effects of FMdC and PTX in a human colon-cancer cell line WiDr. PTX at 0.25-1.0 mM enhanced the cytotoxicity of FMdC and lowered the IC50 of FMdC from 79 +/- 0.1 to 31.2 +/- 2.1 nM, as determined by MTT assay. Using clonogenic assay, pre-irradiation exposure of exponentially growing WiDr cells to 30 nM FMdC for 48 hr or post-irradiation to 0.5 to 1.0 mM PTX alone resulted in an increase in radiation-induced cytotoxicity. Moreover, there was a significant change of the radiosensitization if both drugs were combined as compared with the effect of either drug alone. Cell-cycle analysis showed that treatment with nanomolar FMdC resulted in S-phase accumulation and that such an S-phase arrest can be abrogated by PTX. Treatment with FMdC prior to radiation increased post-irradiation-induced G2 arrest, and such G2 accumulation was also abrogated by PTX. These results suggest that pharmacological abrogation of S and G2 checkpoints by PTX may provide an effective strategy for enhancing the cytotoxic and radiosensitizing effects of FMdC.     

Brain abscess in solid organ transplant recipients receiving cyclosporine-based immunosuppression

There is currently a stark therapeutic void in the treatment of evolving stroke. Although P-selectin is rapidly expressed by hypoxic endothelial cells in vitro, the functional significance of P-selectin expression in stroke remains unexplored. In order to identify the pathophysiological consequences of P-selectin expression and to identify P-selectin blockade as a potential new approach for the treatment of stroke, experiments were performed using a murine model of focal cerebral ischemia and reperfusion. Early P-selectin expression in the postischemic cerebral cortex was demonstrated by the specific accumulation of radiolabeled anti-murine P-selectin IgG, with the increased P-selectin expression localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the functional significance of increased P-selectin expression in stroke, neutrophil accumulation in the ischemic cortex of mice expressing the P-selectin gene (PS +/+) was demonstrated to be significantly greater than that in homozygous P-selectin-null mice (PS -/-). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measured by laser Doppler) in the PS -/- mice. In addition, PS -/- mice demonstrated smaller infarct volumes (5-fold reduction, P<.05) and improved survival compared with PS +/+ mice (88% versus 44%, P<.05). Functional blockade of P-selectin in PS +/+ mice using a monoclonal antibody directed against murine P-selectin also improved early reflow and stroke outcome compared with control mice, with reduced cerebral infarction volumes noted even when the blocking antibody was administered after occlusion of the middle cerebral artery. These data are the first to demonstrate a pathophysiological role for P-selectin in stroke and suggest that P-selectin blockade may represent a new therapeutic target in the treatment of stroke.     

Time-dependent effects of repeated amphetamine treatment on norepinephrine in the hypothalamus and hippocampus assessed with in vivo microdialysis

The effects of repeated amphetamine (AMPH) pretreatment on norepinephrine (NE) neurotransmission in the hypothalamus and hippocampus were assessed using in vivo microdialysis. Rats were pretreated with either saline or an escalating-dose AMPH regimen (1-->10 mg/kg) over 10 consecutive days, and then were withdrawn from AMPH for either 1 day or 30 days, at which time the animals underwent two consecutive days of testing. As expected, repeated treatment with AMPH resulted in time-dependent changes in both spontaneous locomotor activity and in the psychomotor response to a subsequent challenge injection of AMPH. In addition, repeated exposure to AMPH resulted in time-dependent and regionally-specific changes in the basal concentrations of NE in dialysate, and in the NE response to an AMPH challenge. For example, AMPH pretreatment produced a persistent (at least one month) increase in the basal concentration of NE in the hippocampus, but not the hypothalamus, although the response to an AMPH challenge was altered in both structures. It is suggested that AMPH treatment produces adaptations in NE systems that far outlast the acute effects of the drug, and that these may contribute to both transient and more persistent behavioral sequelae associated with the discontinuation of chronic AMPH use.     

Hepatic hemangioma. Analysis of 103 cases. Clinical considerations and imaging methods

Hemangiomas are the most common benign vascular tumor found in the liver. In this study, 103 cases of hepatic hemangiomas were analysed in a retrospective manner. Image aspects such as those seen in ultrassonography, computed tomography, nuclear magnetic resonance and arteriography are discussed. The incidence was higher amongst the female sex, between individuals from 40 to 60 years old, which presented predominantly without symptoms (66%) and localized mainly in the right hepatic lobe (74%). The meaning of those aspects, when adopted, permits the clinicians to differentiate benign from malignant nodular lesions in the liver.     

Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group

A prospective study was performed to establish criteria for the microbiological diagnosis of prosthetic joint infection at elective revision arthroplasty. Patients were treated in a multidisciplinary unit dedicated to the management and study of musculoskeletal infection. Standard multiple samples of periprosthetic tissue were obtained at surgery, Gram stained, and cultured by direct and enrichment methods. With reference to histology as the criterion standard, sensitivities, specificities, and likelihood ratios (LRs) were calculated by using different cutoffs for the diagnosis of infection. We performed revisions on 334 patients over a 17-month period, of whom 297 were evaluable. The remaining 37 were excluded because histology results were unavailable or could not be interpreted due to underlying inflammatory joint disease. There were 41 infections, with only 65% of all samples sent from infected patients being culture positive, suggesting low numbers of bacteria in the samples taken. The isolation of an indistinguishable microorganism from three or more independent specimens was highly predictive of infection (sensitivity, 65%; specificity, 99.6%; LR, 168.6), while Gram staining was less useful (sensitivity, 12%; specificity, 98%; LR, 10). A simple mathematical model was developed to predict the performance of the diagnostic test. We recommend that five or six specimens be sent, that the cutoff for a definite diagnosis of infection be three or more operative specimens that yield an indistinguishable organism, and that because of its low level of sensitivity, Gram staining should be abandoned as a diagnostic tool at elective revision arthroplasty.