Branch retinal vein occlusion. A clinicopathologic case report

The eyes of a 72-year-old woman with a history of two branch retinal vein occlusions involving the left eye, were obtained postmortem and studied histopathologically. Prior to her death, she had been enrolled in the multicentered, prospective, randomized clinical trial on branch vein occlusion and treated with peripheral argon laser photocoagulation for disc neovascularization. Routine fluorescein angiograms and fundus photographs were available for clinical correlation. Despite photocoagulation, the patient had frequent recurrent episodes of vitreous hemorrhage. On histologic examination, both venous occlusions were found at arteriovenous crossings and associated with moderately sclerotic retinal arterioles. One occlusion was recanalized. Retinal inner ischemic atrophy was observed distal to the site of both venous occlusions and corresponded to areas of nonperfusion. Cystoid macular edema was not present. Three areas of neovascularization were found; one at the optic nerve head, one at the peripapillary retina, and one at the fovea. It is likely the patient's repeated vitreous hemorrhages were from one or all three areas of neovascularization demonstrated histopathologically.     

Intravenous 6-thioguanine or cisplatin, fluorouracil and leucovorin for advanced non-small cell lung cancer: a randomized phase II study of the cancer and leukemia group B.

This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols with topical antiinflammatory activity.

The synthesis, biological evaluation, and structure-activity relationships of a series of 1-(pyridylphenyl)-1-phenyl-2-imidazolylethanols are described. These compounds show potent dose-dependent topical antiinflammatory activity in murine models of skin inflammation. This effect is likely due to inhibition of cytochrome P450 and consequent reduction in levels of 12R-HETE in the skin. These compounds were examined for their ability to inhibit the oxidative metabolism of arachidonic acid; they specifically inhibit the formation of prostacyclins in mouse macrophages. To study the effects of structure on the in vivo activity, three general features of the molecules were varied: the position of attachment of the pyridine nucleus (A), the second aromatic residue (B), and the nitrogen base on the ethanol chain (C). 1-[4-(4-Pyridyl)phenyl]-1-(4-fluorophenyl)-2- imidazolylethanol (2a, DuP 983) shows a very attractive profile of antiinflammatory activity and has been selected for clinical evaluation as a topical antiinflammatory agent.     

Maximum relaxation rate of the diaphragm during weaning from mechanical ventilation.

BACKGROUND--The maximum relaxation rate (MRR; percentage fall in pressure/10 ms) of oesophageal (POES) and transdiaphragmatic (PDI) pressure slows under conditions of loaded breathing, and has been measured previously in normal subjects. MRR has not been measured in intubated patients weaning from mechanical ventilation. METHODS--Five postoperative patients who were expected to wean and nine patients who had previously failed were studied. POES and PDI MRR, peak oesophageal pressure during spontaneous breathing, maximum oesophageal pressure, and the inspiratory duty cycle were measured at rest during mechanical ventilation, in the first two minutes of spontaneous breathing, and after reventilation in those patients who failed, or before extubation in those patients who succeeded. RESULTS--At rest POES MRR in intubated patients had a range of 5.6-11 and PDI MRR 6.9-10.0, with a coefficient of variation of 9.9% and 7.3% respectively. POES and PDI MRR were similar before and after extubation in five postoperative patients, and POES MRR was reflected by endotracheal MRR measured at the airway. In five patients who failed to wean POES and PDI MRR slowed by 47% and 44%, and fully recovered after 10 minutes reventilation. In four patients who were successfully weaned MRR was unchanged during spontaneous breathing. At the time when MRR decreased, the respiratory muscles were heavily loaded in relation to their strength. CONCLUSIONS--Weaning failure occurs when the applied load exceeds the capacity of the respiratory muscles, and this is associated with a slowing of respiratory muscle MRR.     

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

Cross sectional investigation of the effects of inhaled corticosteroids on bone density and bone metabolism in patients with asthma

BACKGROUND: Bone mineral density has been reduced in patients with asthma taking inhaled corticosteroids in some cross sectional studies and this could be important if treatment is continued for several decades. The possibility of confounding by age, menopausal status, physical activity and, especially, past oral steroid use has not been excluded in most studies. The present study was designed to assess the magnitude of any reduction in bone mineral density in relation to inhaled steroid use after adjusting for these factors. METHODS: Bone mineral density (BMD), vertebral fractures, and markers of bone metabolism (serum osteocalcin, procollagen peptide I, bone-specific alkaline phosphatase, and urinary deoxypyridinoline cross links) were measured in 81 patients with asthma age 20-40 years; 34 patients (19 men) who had never had inhaled or systemic steroids and 47 (19 men) who had taken inhaled steroids for at least five years with limited exposure to systemic steroids in the past. Data relating to past medication use, physical activity, smoking, and other confounding factors were collected by questionnaire. The relation between inhaled steroid dose and duration and BMD was assessed by linear regression analysis, accounting for potential confounders including weight, exercise, and oral steroid use. RESULTS: The 47 patients taking an inhaled steroid had a mean current dose of 620 micrograms/day (range 100-3000 micrograms), a mean duration of use of 7.8 years, and had had a mean of 0.85 courses of prednisolone in the past. There was no significant difference in mean BMD values between those who were and those who were not on inhaled steroids in men or women. However, on multivariate analysis, cumulative inhaled steroid dose was associated with a reduction in posterior-anterior (P-A) and lateral lumbar spine bone mineral density in women, equivalent to a 0.11 standard deviation reduction in bone density per 1000 micrograms/day inhaled steroid per year after adjustment for potential confounding factors (95% CI for P-A spine 0.01 to 0.22; for lateral spine 0.02 to 0.21). Previous oral steroid use was not an important confounding factor in these patients. Inhaled steroid use was not related to BMD at the wrist or hip in women or at any skeletal site in men. Women taking an inhaled steroid had lower levels of serum osteocalcin than those not taking them, although this was not dose related. Inhaled steroid use was not associated with differences in other markers of bone metabolism in men or women or with the presence of vertebral fractures. CONCLUSIONS: Although an effect of confounding factors cannot be excluded entirely in a cross sectional study, our findings are in keeping with an effect of inhaled steroid therapy in reducing bone density in the spine in women and provide an estimate of the magnitude of this effect.


     

Mucolytic agents and otitis media with effusion

Middle ear effusion was obtained from children with otitis media with effusion and separated into thick (mucoid) and thin (serous) pools. Both effusion types contained similar amounts of non-dialysable solids. However, the thick effusions contained more mucus glycoprotein than the thin effusions, 25% and 8.2% respectively. Amino acid and carbohydrate analysis of the CsCl purified mucus glycoproteins demonstrated that the glycoprotein from the thick and thin effusions differed in their protein core, those from the thick effusions possessing a higher percentage of serine and threonine, the amino acids to which the sugar side-chains attach. They are also more glycosylated. N-acetyl cysteine and mercaptoethanol caused a fall in the viscosity of solutions of purified middle ear glycoprotein and effusion homogenate. However, longer term incubation caused a rise above the starting viscosity. This effect was concentration-dependent, and was mediated by low molecular weight components in the effusion and not the mucus glycoprotein. S-carboxymethyl cysteine had no effect on the viscosity of either the purified mucus glycoprotein or the effusion homogenate. Therefore, to produce a decrease in effusion viscosity in vivo, the concentration of mucolytic reaching the middle ear and the time it remains there are critical factors.