Neuropathology of bovine herpesvirus type 5 (BHV-5) meningo-encephalitis in a rabbit seizure model

CI-994 (acetyldinaline) is an orally active anticancer drug currently in Phase 1 clinical trials. To assess its preclinical toxicity, CI-994 was administered orally as suspensions to Wistar rats (10/sex/dose) and in capsules to beagle dogs (3/sex/dose) once daily for two weeks. Doses were 1.5, 5, and 15 mg/kg for rats (9, 30, and 90 mg/m2, respectively), and 0.5, 2, and 5 mg/kg for dogs (10, 40, and 100 mg/m2, respectively). Systemic exposure was dose-proportional based on toxicokinetic analysis in dogs. Severe clinical signs and mortality occurred at the highest dose in both species beginning on Day 10. Neutropenia, lymphocytopenia, thrombocytopenia, lymphoid depletion, bone marrow hypocellularity, and testicular degeneration were observed in both species, primarily at the mid- and high-doses. Despite continued treatment, neutrophil counts in dogs returned to control levels in Week 2. Other microscopic findings in rats included splenic hematopoietic depletion at all doses and epithelial cell necrosis in various tissues at 15 mg/kg. Additional bone marrow changes in dogs involved myeloid and megakaryocyte hyperplasia at 2 mg/kg and abnormal myeloid and megakaryocyte maturation at 2 and 5 mg/kg. Except for the testicular effects in both species, all changes were reversible within a 4-week (rat) or 9-week (dog) recovery period. The results of these studies show that target organ effects of CI-994 principally involve tissues with rapidly dividing cell populations and that bone marrow suppression is the dose-limiting toxicity. CI-994 also seems to interfere with the release and/or maturation of cells in the bone marrow.     

Expression of fibronectin splicing variants in organ transplantation: a differential pattern between rat cardiac allografts and isografts

Allograft rejection is associated with infiltration of inflammatory cells and deposition of extracellular matrix proteins. The extent to which diversity in the extracellular matrix regulates inflammatory cell function in transplants remains unclear. One group of extracellular matrix proteins, termed fibronectins (FNs), exhibits inherent diversity as a consequence of alternative splicing in three segments: EIIIA, EIIIB, or V. Although the EIIIA segment has documented functions in mesenchymal cell differentiation, neither this segment nor the EIIIB segment have been tested for effects specific to leukocyte functions. By contrast, the V region can include the CS-1 segment to which leukocytes may adhere through alpha 4 beta 1 integrins. In this study, we demonstrate that EIIIA+, EIIIB+, and V+ FN variants are synthesized, primarily by macrophages in distinct temporal and spatial patterns in two rat cardiac transplant models: either with antigenic challenge, allografts, or without challenge, isografts. The ratio of EIIIA inclusion into FN increases by day 1 in allografts and isografts and remains high until allografts are rejected (approximately 7 days) but falls to normal levels in tolerated isografts (day 6). EIIIB+ FN ratios in allografts peak later than do EIIIA+ FNs (day 4). EIIIB+ FN ratios remain relatively low in isografts. Interestingly, EIIIA+ and EIIIB+ FNs are deposited prominently in the myocardium of rejecting allografts in close association with infiltrating leukocytes, and FN expression and deposition are prominent at sites of infarction. By contrast, these FNs are largely restricted to the epicardium and to a lesser degree in the immediately adjacent myocardium in isografts. CS-1+ FNs increase in allografts and isografts at 3 hours after transplantation but are particularly prominent in allografts 1 to 3 days before rejection. Our data suggest that FN splicing variants have a differential role in the effector functions of leukocytes in allografts and isografts and provide a foundation for testing their function on leukocytes and a rationale for FN-based therapeutics to modulate allograft rejection in transplant recipients.     

The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy

BACKGROUND: The effect of topical corticosteroids after excimer laser photorefractive keratectomy (PRK) remains a matter of some controversy. Refractive effects may be different according to the amount of myopia and timing of instillation. METHODS: Two groups of patients were studied: Study A consisted of 215 eyes (128 patients) with PRK (mean baseline myopia, -6.53 +/- 2.22 D) that received no corticosteroids (No Corticosteroid Group) unless significant regression or corneal haze appeared (Delayed Corticosteroid Group), and in Study B, we randomly assigned eyes to the Initial Corticosteroid Group (mean baseline myopia, -6.39 +/- 1.84 D) or the No/delayed Corticosteroid Group (mean baseline myopia -5.78 +/- 2.02 D). Clinical results after PRK for low-to-moderate and high myopia were compared. RESULTS: In the first group, 70.9% (73 eyes) of moderately myopic eyes (mean, -4.56 +/- 1.10 D) belonged to the No Corticosteroid Group that had a mean refraction of -5.39 +/- 1.77 D. Delayed Corticosteroid Group eyes were more myopic (mean, -7.52 +/- 2.10 D), and showed more severe haze than those in the No Corticosteroid Group. In study B, only in high myopes with more than -6.00 D (mean, -7.76 +/- 1.15 D) did refraction and corneal haze outcomes show significant difference between the Initial Corticosteroid Group and the No/delayed Corticosteroid Group. CONCLUSIONS: The effects of topical corticosteroids after PRK were less in moderate myopes compared to high myopes. Delayed instillation of corticosteroids did not reverse the regression or haze whereas initial instillation showed a beneficial effect on high myopes but not on moderate myopes.     

Hemodynamic response to in situ latissimus dorsi muscle stimulation: implications in dynamic cardiomyoplasty

Dynamic cardiomyoplasty (DCM) involves the electrical stimulation of a pedicled latissimus dorsi muscle flap wrapped around the falling ventricle as a means of cardiac assist. To further elucidate a potential neurohumoral mechanism for improvement of cardiac output after myoplasty, we evaluated the hemodynamic effects of in situ stimulation of the latissimus dorsi muscle (in the absence of cardiomyoplasty). In seven mongrel dogs, a nerve cuff electrode (Medtronic 6901) was placed around the left thoracodorsal nerve (TDN). This was attached to a pulse generator (Medtronic, Itrel 7420), delivering a 4.0 volt, 0.19 second on, 0.81 second off, 33 Hz, 210 microsecond pulse width, cyclic bursts similar to that used in DCM. Stroke volume index (SVI) and other hemodynamic parameters as well as plasma norepinephrine (NE) levels were measured at five stages: baseline, stimulator on at 0, 2, and 5 minutes, and stimulator off at 30 minutes after. The animals were then subjected to 4 weeks of rapid pacing at 240 beats/min (Medtronic 8329) to induce heart failure, and as the rapid pacing was discontinued, measurements were repeated as above. After rapid pacing, cardiac function was significantly depressed, and NE was elevated (133 +/- 69 versus 500 +/- 353 pg/mL, p < 0.05). In the normal hearts, TDN stimulation increased SVI, heart rate, systemic pressure, and NE levels. In heart failure, however, no significant changes in cardiac function and NE levels were noted. In conclusion, our data indicate that in the normal hearts, afferent impulses from TDN stimulation alone may augment cardiac function by means of a neurohumoral effect that is not seen in severe heart failure. The implications of these findings in DCM are discussed.     

Regulation of depth and composition of airway surface liquid

The depth and composition of human airway surface liquid (ASL) may depend on secretion from airway glands, ion transport across the surface epithelium, goblet cell discharge, transepithelial gradients in hydrostatic pressure, and surface tension. Published values for the frequency of airway glands and for the secretory rates of individual glands suggest that total gland secretion in human trachea can amount to approximately 60 microL x cm(-2) x h(-1). Volume absorption directly measured across cultures of surface epithelium from human trachea is approximately 5 microL x cm(-2) x h(-1). These flows should alter the depth of ASL at +10 and -1 microm x min(-1). We have looked for changes in ASL depth of this magnitude using low-temperature scanning electron microscopy (LT-SEM) of rapidly frozen specimens of bovine trachea. Stimulation of gland secretion with methacholine led to an initial increase in depth of approximately 25 microm x min(-1) followed by a decline at approximately 1.5 microm x min(-1). Whereas the initial increase in depth was probably due to transient gland secretion, the later decline reflected active absorption of liquid across the surface epithelium. Finally, we present preliminary data showing that LT-SEM can be combined with X-ray microanalysis to determine the elemental composition of ASL.     

Family practice physicians' firearm safety counseling beliefs and behaviors

The purpose of this study was to identify family physicians' firearm safety counseling beliefs and behaviors. A survey was mailed to a random sample of 600 members of the American Academy of Family Physicians. A three wave mailing technique was used to maximize the response rate and yielded 271 usable surveys (55% response rate). Outcome measures included training experience in firearm safety counseling, the prevalence of firearm safety counseling by family physicians, and their perceptions regarding such counseling. The majority (78%) of family physicians lacked formal training on how to counsel patients about firearm safety and 49% believed more time should be spent in residency programs on firearm safety counseling. The majority (84%) of respondents never or rarely counseled patients on firearm safety and 50% believed firearm safety counseling should be a low priority in their delivery of primary care. The majority of respondents did not regularly counsel patients about firearm safety, did not believe firearm safety counseling should be a priority, and did not believe firearm safety counseling would be effective in reducing firearm-related trauma.     

Paediatric upper gastrointestinal endoscopy: a 2-year review

OBJECTIVE: To review the paediatric upper gastrointestinal endoscopy service in a paediatric department in Hong Kong. METHODS: Records of all endoscopies undertaken in this department from May 1995 to January 1996 were retrieved and analysed. RESULTS: The commonest indication for upper endoscopy was dyspepsia with 88% positive histological findings. Helicobacter pylori (H. pylori) was found in 25% of this group of children. CONCLUSION: Paediatric upper gastrointestinal endoscopy service is invaluable in a paediatric department by providing useful diagnostic information which would otherwise be missed.     

Exclusion of BMP6 as a candidate gene for cleidocranial dysplasia

Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia in humans that has been mapped to the short arm of chromosome 6. We report linkage of a CCD mutation to 6p21 in a large family and exclude the bone morphogenetic protein 6 gene (BMP6) as a candidate for the disease by cytogenetic localization and genetic recombination. CCD was linked with a maximal two-point LOD score of 7.22 with marker D6S452 at theta = 0. One relative with a recombination between D6S451 and D6S459 and another individual with a recombination between D6S465 and CCD places the mutation within a 7 cM region between D6S451 and D6S465 at 6p21. A phage P1 genomic clone spanning most of the BMP6 gene hybridized to chromosome 6 in band region p23-p24 using FISH analysis, placing this gene cytogenetically more distal than the region of linkage for CCD. We derived a new polymorphic marker from this same P1 clone and found recombinations between the marker and CCD in this family. The results confirm the map position of CCD on 6p21, further refine the CCD genetic interval by identifying a recombination between D6S451 and D6S459, and exclude BMP6 as a candidate gene.     

Efficacy of a smoking cessation program for hospital patients

BACKGROUND: Hospitalization may be an opportune time to change smoking behavior because it requires smokers to abstain from tobacco at the same time that illness can motivate them to quit. A hospital-based intervention may promote smoking cessation after discharge. METHODS: We tested the efficacy of a brief bedside smoking counseling program in a randomized controlled trial at Massachusetts General Hospital, Boston. The 650 adult smokers admitted to the medical and surgical services were randomly assigned to receive usual care or a hospital-based smoking intervention consisting of (1) a 15-minute bedside counseling session, (2) written self-help material, (3) a chart prompt reminding physicians to advise smoking cessation, and (4) up to 3 weekly counseling telephone calls after discharge. Smoking status was assessed 1 and 6 months after hospital discharge by self-report and validated at 6 months by measurement of saliva cotinine levels. RESULTS: One month after discharge, more intervention than control patients were not smoking (28.9% vs 18.9%; P=.003). The effect persisted after multiple logistic regression analyses adjusted for baseline group differences, length of stay, postdischarge smoking treatment, and hospital readmission (adjusted odds ratio, 2.19; 95% confidence interval, 1.34-3.57). At 6 months, the intervention and control groups did not differ in smoking cessation rate by self-report (17.3% vs 14.0%; P=.26) or biochemical validation (8.1% vs 8.7%; P=.72), although the program appeared to be effective among the 167 patients who had not previously tried to quit smoking (15.3% vs 3.7%; P=.01). CONCLUSIONS: A low-intensity, hospital-based smoking cessation program increased smoking cessation rates for 1 month after discharge but did not lead to long-term tobacco abstinence. A longer period of telephone contact after discharge might build on this initial success to produce permanent smoking cessation among hospitalized smokers.