DMPP-evoked increases in postganglionic sympathetic nerve activity and blood pressure occurs by two mechanisms in the rat

1 Intravenous administration of the ganglionic nicotinic receptor agonist DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) into urethane-anaesthetized rats evoked dose-dependent increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). 2 The ganglionic nicotinic receptor antagonists pentolinium and hexamethonium either alone or combined did not inhibit the increase in RSNA and MAP evoked by 50 to 200 μg kg^?1 doses of DMPP. The increase in renal sympathetic nerve activity evoked by DMPP occurred as a brief burst in firing. 3 The increase in MAP, but not RSNA, evoked by DMPP in the presence of pentolinium was inhibited by the selective α₁-adrenergic receptor antagonist prazosin. 4 The non-selective α-adrenoceptor and NPY receptor antagonist benextramine also inhibited the increase in MAP without inhibiting the increase in RSNA. Surprisingly, the combination of benextramine and pentolinium, or benextramine and hexamethonium, completely blocked the DMPP-evoked increase in RSNA and thus the increase in MAP. 5 The uptake₁ antagonist desipramine combined with pentolinium did not affect the DMPP-evoked increases in MAP or RSNA when compared to the responses evoked in the presence of pentolinium alone. 6 Adding the selective M₁ muscarinic receptor antagonist telenzepine to pentolinium and prazosin did not inhibit the increase in RSNA evoked by a 100 μg kg^?1 dose of DMPP. 7 While the DMPP-evoked increase in MAP in the presence of ganglionic nicotinic receptor antagonists is primarily dependent upon activation of α₁-adrenoceptors, the increase in RSNA occurs via activation of ganglionic nicotinic receptors and activation of a mechanism susceptible to blockade by benextramine.     

Specification of the Dose to Organs at Risk in External Beam Radiotherapy

Reporting of the clinical relevant dose to organs at risk (OR) and other normal tissues is crucial in trials and protocols where the aim is to assess late complications and to increase the therapeutic ratio for external beam radiotherapy. The dose distribution in normal tissues and ORs are, however, most often heterogeneous, at least when more than two opposing beams are applied. To decide the most clinical relevant dose with respect to late occurring complications is therefore not a straight forward problem. In this work we discuss what parameters characterise the dose-volume-histogram (DVH) best by calculating normal tissue complication probabilities (NTCPs) by using the Lyman model and various sets of statistical parameters drawn out from the DVHs. These NTCPs are compared to NTCPs calculated from the full DVHs, when the sets of parameters are evaluated. Our calculations indicate that the NTCP based on the Lyman model is best correlated to the D_max value, for serially organised tissues such as the spinal cord. For organs, described largely as tissues organised in parallel, the D_median or D_mean of the DVH may be applied. Our calculations reveal that D_mean is the parameter of choice when D_meclian is quite small, but when the two parameters approach each other, D_mediarl will be a better choice, using a unity volume fraction. For ORs characterised by a mixed serial and parallel functional structure, as the heart, neither D_max, D_median, nor D_mi,_an may predict the actual NTCP.     

Regulation of fibroblast-induced collagen gel contraction by interleukin-1β

Fibroblasts incorporated within collagen gels induce a cell-mediated contraction of the gel to form a three-dimensional, tissue-like structure by a mechanism thought to mimic wound contraction in vivo . In this study a gel contraction model was used to investigate the ability of fibroblasts derived from adult gingiva, adult skin and fetal skin to organise a collagen matrix. In addition the effects of interleukin-1β (IL-1β) on the contraction process was also investigated. Over the concentration range 5-50 U/ml, IL-1β induced a statistically significant inhibition of gel contraction in all fibroblast cell types ( P <0.05), although fetal fibroblasts appeared least responsive and gingival fibroblasts most responsive to the inhibitory effects of this cytokine. Comparison of gel contraction by the different fibroblast strains indicated that fetal and gingival fibroblasts shared similar contraction kinetics. For the adult skin fibroblasts, three of five strains studied showed significantly diminished levels of gel contraction compared to fetal and gingival cells. This apparent difference in fibroblast phenotype may, at least in part, explain the fetal-like wound healing pattern seen in the oral mucosa.     

Encouraging Underscreened Women to Have Cervical Cancer Screening: The Effectiveness of a Computer Strategy

Background.Computers that collect data from patients and provide both patients and practitioners with printed feedback on a range of health risks are a tool for assisting general practitioners with preventive care. This study assessed the impact of computer-generated printed feedback on cervical screening among women who were underscreened for cervical cancer.Method.Female attenders at two Australian general practices were randomly allocated to Experimental or Control groups. Women in both groups completed a health risk survey on a touch screen computer prior to their consultation. Those in the Experimental group received printed pages summarizing their results, including their eligibility for cervical screening and last Pap test, for themselves and their doctor. The number and proportion of underscreened women who had a Pap test in the 6 months after completing the computer survey, as determined by pathology records, were examined.Results.Of the 679 participants, 139 were classified as underscreened on the basis of self-report (74 Experimental, 65 Control) and 272 on the basis of their pathology records (148 Experimental, 124 Control). Overall about one-third of women had a test in the 6-month period, and the differences between the groups were not significant for women overall (18–70 years) or for women 18–49 years. Among women 50–70 who were underscreened based on self-report, those receiving the printout were more likely to have a Pap test in the next 6 months (P< 0.05). This pattern was also evident, but did not reach statistical significance, for older women who were underscreened based on pathology records.Conclusions.We are unable to draw conclusions regarding the effectiveness of the computer system due to the modest proportions of women screened, the small numbers, and the fact that the computer survey may have created an intervention effect in the Control group. As the study suggests the computer system is acceptable to women and may be effective for encouraging screening among older women, further exploration of the system is desirable.     

Individual differences and surrogate medical decisions: Differing preferences for life-sustaining treatments

This study examines the relationships between patient characteristics and surrogate decision maker characteristics on surrogates' preferences for life-sustaining treatments. Caucasian and African-American caregivers and noncaregivers (n=110) responded to a vignette involving a medical crisis in a hospitalized older man who suffered cardiac arrest, one of the most common causes of death among older Americans. This man was described as either a cognitively intact or moderately demented family member. Participants made decisions regarding cardiopulmonary resuscitation (CPR), CPR and ventilation, and CPR and tube feeding. Analyses followed a 2 (cognitive status) 2 (caregiving status) 2 (racial background) analysis of covariance design, with education and income used as covariates. In general, participants were less likely to initiate life-sustaining treatments in demented patients. Caucasian caregivers were less likely to initiate CPR and ventilation and CPR and tube feeding. Results indicate that characteristics of the patient and the interplay between cultural issues and experience with caregiving affect surrogate judgements regarding life-sustaining treatments.     

Neuropeptides in idiopathic chronic constipation (slow transit constipation)

Tissue specimens from the large bowel of 18 patients with long-standing slow transit constipation were investigated to determine the distribution and density of several neuropeptides and amines in the enteric nerve system, and also of endocrine cells in comparison to normal individuals. CGRP (calcitonin gene-related peptide), galanin, glucagon, GRP (gastrin-releasing peptide), metenkephalin, motilin, neuropeptide Y (NPY), PACAP, peptide YY (PYY), serotonin, somatostatin, substance P and VIP were studied by immunohistochemistry. Tissue concentrations of VIP, substance P and galanin were also measured by radioimmunoassay. Significantly increased VIP, SP and galanin contents were found in specimens from the ascending colon. Levels of VIP and galanin were also increased in the transverse colon. Immunohistochemistry revealed only marginal changes with an increased density of PACAP nerve fibres in the smooth muscle and of VIP and PACAP nerves in the myenteric plexus of the transverse colon. In the descending colon substance P and NPY immunoreactivity were also increased in the myenteric plexus while the density of VIP nerve fibres was reduced in the mucosa/submucosa. The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients.     

Cortical and subcortical T2 shortening in multiple sclerosis.

Low signal intensity on long-repetition-time MR sequences has been observed in deep gray matter structures in patients with multiple sclerosis. This T2 shortening most likely represents a nonspecific degenerative process. We recently observed T2 shortening in the pericentral cortical gray matter and subcortical white matter in a patient with severe multiple sclerosis and we postulate that this represents an additional manifestation of neural degeneration.     

Pressor response to posterior hypothalamic administration of carbachol is mediated by muscarinic M3 receptor.

Unilateral microinjection of the acetylcholine receptor agonist carbachol into the posterior hypothalamic nucleus evokes a pressor response in the conscious, freely moving rat. To further localize this response 3.3 or 5.5 nmol of carbachol was microinjected in a volume of 50 nl directly into and outside the region of the posterior hypothalamic nucleus. Administration of carbachol outside the posterior hypothalamic nucleus failed to evoke a change in blood pressure indicating that the carbachol-induced pressor response is mediated from the posterior hypothalamic nucleus. Since posterior hypothalamic administration of atropine completely blocks the carbachol-induced increase in blood pressure and atropine blocks the three pharmacologically identified muscarinic receptor subtypes, methylatropine and progressively more selective muscarinic antagonists were administered into the posterior hypothalamic nucleus prior to 5.5 nmol of carbachol. Microinjection of the M1/M2/M3 muscarinic antagonist methylatropine (0.19-12.5 nmol), the M1/M3 antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine; 0.9-3.6 nmol), the M1 antagonist pirenzepine (9.5-38 nmol), the M2 antagonist methoctramine (5.5-44 nmol), or the M3 antagonist p-F-HHSiD (para-fluoro-hexahydro-sila-difenidol; 2.1-8.3 nmol) inhibited the peak increase in mean arterial pressure and the area under the curve of the change in mean arterial pressure versus time plot in a dose-dependent manner. Log ID50s calculated for the antagonists from the dose-response curves were found to correlate significantly with the log Kis of the antagonists for the muscarinic M3 receptor subtype. These results demonstrate that the increase in mean arterial pressure evoked by microinjection of carbachol into the posterior hypothalamic nucleus is mediated by the muscarinic M3 receptor.