Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: influence of substituents at the phthaloyl moiety on the activity and stereoselectivity

The synthesis and tumor necrosis factor (TNF)-alpha production enhancing activity of substituted 3'-methylthalidomides on human leukemia cell line HL-60 stimulated with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) are described. Though the introduction of an electron-donating amino group at the phthaloyl moiety of alpha-methylthalidomides enhanced the activity, substituted alpha-methylthalidomides showed decreased stereoselectivity as compared to that of non-substituted alpha-methylthalidomide. The data indicates that the TNF-alpha production enhancing activity of thalidomide derivatives depends on both the electronic-state of substituents at the fused benzene ring and the stereochemistry of the glutarimide moiety.     

Treatment with the oral growth hormone secretagogue MK-677 increases markers of bone formation and bone resorption in obese young males

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19-49 years of age, with body mass index > 30 kg/m2 were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK-677; serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively, MK-677 increased serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43-44% after 2-8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP-4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin-6 was not significantly changed by active treatment. In conclusion, short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF-1 and IGFBP-5 and a transient increase in serum IGFBP-4 were found. Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.     

RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs

RasGRP, a guanyl nucleotide-releasing protein for the small guanosine triphosphatase Ras, was characterized. Besides the catalytic domain, RasGRP has an atypical pair of "EF hands" that bind calcium and a diacylglycerol (DAG)-binding domain. RasGRP activated Ras and caused transformation in fibroblasts. A DAG analog caused sustained activation of Ras-Erk signaling and changes in cell morphology. Signaling was associated with partitioning of RasGRP protein into the membrane fraction. Sustained ligand-induced signaling and membrane partitioning were absent when the DAG-binding domain was deleted. RasGRP is expressed in the nervous system, where it may couple changes in DAG and possibly calcium concentrations to Ras activation.     

Home visiting the newborn baby as a basis for developmental surveillance at child welfare centres

Home visiting is a part of the Swedish child health surveillance programme. In the present study, part of a longitudinal prospective project, the predictive power of observations at home visits to 338 newborn babies was evaluated. The regular home visit was made by the nurse at a Child Welfare Centre also using a check-list developed for this project. Her check-list assessments seemed valid in identifying families with stressful psychosocial conditions. When the general home situation was judged as "poor" or "dubious", the boys showed signs of a delayed mental development at 4-5 years of age. Assessments of "feeding problems" among boys were associated with behavioural problems at 4-5 years of age. The results underline the importance of an early home visit as a base for the developmental surveillance at Child Welfare Centres. However, the results of the home visit observations were not followed by any extra interventions at CWC. It seems the nurse should feel confident in her check-list judgement and initiate interventions where appropriate.     

Histopathologic spectrum of vaginal adenosis and related changes in stilbestrol-exposed females

A total of 98 colposcopically directed biopsies were obtained from the vagina, cervix, and cervicovaginal ridge (hood) of 80 young women believed to have had intrauterine exposure to stilbestrol (DES). Specific investigation of the patient's medical records corroborated the history of maternal stilbestrol administration in 36 patients (45%), while in the remainder the drug history was regarded as presumptive since medical records were unavailable for review. The findings did not differ significantly in those biopsies taken from patients with confirmed or presumptive drug histories. Histologic evidence of vaginal adenosis was detected in vaginal biopsies from 43 patients. In 30 cases (70%) benign Müllerian-type glandular epithelium was in the superficial vaginal wall, residing on the mucosal surface and/or in the lamina propria. The glandular epithelium predominantly was of endocervical type, but in six instances it resembled endometrial or fallopian tubal epithelium. The glands were accompanied by varying degrees of squamous metaplasia in 22 cases. When extensive the metaplasia produced transformation zones similar to those seen in the normal cervix. Vaginal biopsies of adenosis from the other 13 patients (30%) revealed squamous metaplasia without demonstrable glands due to complete transformation of all antecedent glandular epithelium by squamous metaplasia. Our studies indicate that squamous metaplasia is a component of major importance in the natural history of adenosis and that the concept of adenosis should be broadened to include those examples comprised exclusively of metaplastic epithelium. In such examples metaplasia is identified by the immaturity and poor glycogenation of the squamous cells and their accompanying squamous pegs which often contain residual gland openings or squamous "eddies." Similar findings were present in biopsies of seven cervicovaginal ridges and in cervical biopsies from 37 patients, except for the absence of endometrial or tubal type glands in the latter site. Although no adenocarcinomas were detected, six patients had squamous dysplasia of the vagina and/or cervix. In no case were premalignant or dysplastic changes of glandular cells found. Our findings support the thesis that stilbestrol-associated adenosis represents anomalous embryologic localization of the original squamocolumnar junction in the vagina rather than in the cervix. It is closely related to so-called cervical "erosions." The development of squamous metaplasia accounts for modifications in the clinical and histologic appearances by producing transformation zones which then may be subject to the same oncogenic stimuli for squamous neoplasia as are their counterparts in the cervix.     

LIPID AND CHOLESTEROL OXIDATION,COLOR CHANGES,AND VOLATILE PRODUCTION IN IRRADIATED RAW PORK BATTERS WITH DIFFERENT FAT CONTENT1

An emulsion-type product was prepared to determine the effect of irradiation on lipid and cholesterol oxidation, color change, and volatile production in raw pork with different fat contents. Lipid oxidation increased with an increase in fat content or irradiation dose. Irradiated batters had higher cholesterol oxides than nonirradiated, and the major cholesterol oxides formed in irradiated pork batters were 7α- and 7β-hydroxycholesterol. Hunter color a- and b-values of raw pork batters were decreased by irradiation regardless of fat content. Irradiation increased the amount ofvolatiles significantly. Although lipid oxidation of high fat products (10 and 15% fat) was higher than that of low fat products (4%), high fat products did not always produce greater amount of volatiles. In summary, irradiation increased lipid and cholesterol oxidation, volatiles production and had detrimental effects on the color of raw pork batters under aerobic condition.     

Summary of the Closing Session

Plausible costs of photovoltaic power plants of concentration are presented. Costs are based as much as possible on the recent experience of solar thermal plants. Efficiencies, on the existing world experience of PV power plants. The result is that the costs of concentrating photovoltaic plants should be of 0.08 ECUs/ kWh, about 1/3 of that of flat module plants, and of the same order of magnitude, even lower, than those attributed to solar thermal plants of present technology.

For the future, high concentration systems based on Si or tandem cells seem to be the most promising, also in the range of costs of the advanced solar thermal plants.     

A prospective randomized comparison of epidural infusion of fentanyl and intravenous administration of morphine by patient-controlled analgesia after radical retropubic prostatectomy

In a prospective, randomized study, continuous infusion of epidural fentanyl citrate (group E) was compared with patient-controlled intravenously administered morphine sulfate (group P) for analgesia in 66 men after radical retropubic prostatectomy. Although both methods provided satisfactory analgesia, the mean comfort level scores were lower (that is, greater comfort) in group E than in group P at all observation times. The difference in mean resting comfort level scores between groups E and P was statistically significant (P < or = 0.05) at 9 of the 11 observation times. In addition, significant differences in comfort level scores were noted at 8 of the 11 observation times during deep breathing, 5 of 11 during coughing, and 3 of 9 during ambulation. Maximal and minimal comfort level scores recorded by each patient during the course of the study were significantly lower (that is, less pain) in group E than in group P for all four categories of activity. The percentage of patients who reported no pain was significantly higher in group E than in group P at 9 of 11 observation times during resting and 5 of 11 observation times during deep breathing. No significant differences were noted in side effect profiles or duration of hospital stay. In summary, when two effective methods of analgesia used after radical retropubic prostatectomy were compared prospectively, patients who received epidural infusion of fentanyl were more comfortable than those with patient-controlled intravenous administration of morphine, as evidenced by lower mean, maximal, and minimal comfort level scores and a greater proportion of patients with complete relief of pain.