Reduced hematopoietic function and enhanced radiosensitivity of transforming growth factor-beta1 transgenic mice

The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in some tissue responses to radiation. Previous studies have demonstrated that exogenous TGF-beta1 increased the lethality of radiation in mice, but the effects of endogenous TGF-beta1 have not been investigated. To this end, we examined mice that are transgenic for active TGF-beta1 (Alb/TGF-beta1), over-expressed via an albumin promoter in the liver with resultant elevation of circulating levels of this cytokine. Alb/TGF-beta1 mice subjected to 8 Gy of total body irradiation at 3 or 5 weeks of age experienced significantly higher mortality than wild type age- and sex-matched controls by 1 to 2 weeks after irradiation. Alb/TGF-beta1 3 weeks of age also succumbed to 2 and 4 Gy of whole-body irradiation, while no mortality was observed in wild type mice. Four-week-old Alb/TGF-beta1 mice exhibited mild anemia and mild uremia. At one week after whole body irradiation with 2 Gy, 4-week-old Alb/TGF-beta1 mice had significantly reduced white blood cell counts, hematocrit, and platelet counts. Histopathologically, irradiated Alb/TGF-beta1 mice exhibited decreased bone marrow cellularity and decreased splenic extramedullary hematopoiesis. These results suggest that chronic over-expression of active TGF-beta1 is associated with increased radiosensitivity and that this effect may be mediated by increased sensitivity of bone marrow to the suppressive effects of radiation. Since TGF-beta1 levels can be greatly elevated in patients with certain tumors, these findings may be significant for radiotherapy. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 13-21 (2000). Published 2000 Wiley-Liss, Inc.     

Changes in energy during treatment of depression: an analysis of fluoxetine in double-blind, placebo-controlled trials

More than two thirds of patients with depression present with symptoms of fatigue, low energy, and listlessness. Because daytime sedation may be a concern in such patients, a "nonsedating" antidepressant should be considered. The authors examined the effects of fluoxetine on depression-related disturbances in energy. Data from seven double-blind, placebo-controlled clinical trials in 2,075 patients with major depression were retrospectively analyzed. The Hamilton Rating Scale for Depression (HAM-D) Retardation factor score (total of items 1, 7, 8, and 14) was used as the primary measure of energy improvement, whereas the HAM-D-17 total score was used to assess changes in overall depression. Elderly patients (aged 60 years and older) were included in the overall group and were also analyzed separately. In addition, a subgroup analysis was performed using the HAM-D Retardation factor score to categorize patients as having low (score < 8) or high (score > or = 8) levels of retardation at baseline. Beginning at week 3, fluoxetine-treated patients experienced statistically significant reductions in their HAM-D Retardation factor score compared with placebo-treated patients. The reductions for the elderly subgroup were less than those for the overall population, but they were still statistically significant beginning at week 4. Patients in both the low and high baseline retardation groups improved significantly. HAM-D-17 total scores for fluoxetine-treated patients in all groups (total, elderly, high retardation, and low retardation) improved significantly compared with placebo-treated patients. These findings demonstrate that fluoxetine-treated patients experience an improvement in energy symptoms as their overall depression improves.     

Polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose in combination with interleukin 2 in patients with cancer: clinical and immunological effects.

We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.     

Blood choline and response to clonazepam and haloperidol in Tourette's syndrome

This paper reports the results of a single blind clinical study of drug treatment response of 20 patients with Tourette's syndrome to haloperidol and clonazepam. Because patients with Tourette's syndrome have been reported to have increased red blood cell choline levels, choline levels were examined in relation to treatment response. Differential drug treatment response was found among patients with high versus low red blood cell-to-plasma choline ratios. Patients with high red blood cell-to-plasma choline ratios responded better to clonazepam than to haloperidol. This suggests that there may be two distinct subtypes of patients with Tourette's syndrome.     

Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7).

The definitive mammalian kidney forms as the result of reciprocal interactions between the ureteric bud epithelium and metanephric mesenchyme. As osteogenic protein 1 (OP-1/bone morphogenetic protein 7), a member of the TGF-beta superfamily of proteins, is expressed predominantly in the kidney, we examined its involvement during metanephric induction and kidney differentiation. We found that OP-1 mRNA is expressed in the ureteric bud epithelium before mesenchymal condensation and is subsequently seen in the condensing mesenchyme and during glomerulogenesis. Mouse kidney metanephric rudiments cultured without ureteric bud epithelium failed to undergo mesenchymal condensation and further epithelialization, while exogenously added recombinant OP-1 was able to substitute for ureteric bud epithelium in restoring the induction of metanephric mesenchyme. This OP-1-induced nephrogenic mesenchyme differentiation follows a developmental pattern similar to that observed in the presence of the spinal cord, a metanephric inducer. Blocking OP-1 activity using either neutralizing antibodies or antisense oligonucleotides in mouse embryonic day 11.5 mesenchyme, cultured in the presence of metanephric inducers or in intact embryonic day 11.5 kidney rudiment, greatly reduced metanephric differentiation. These results demonstrate that OP-1 is required for metanephric mesenchyme differentiation and plays a functional role during kidney development.     

The conflict between anticoagulation and hemostasis during hemodialysis

Anticoagulation with comparatively small amounts of heparin has been carried out in more than 3,000 acute and chronic hemodialysis procedures without problems. In a selected high risk group of postoperative and polytrauma patients no patient hemorrhages have occurred, nor have there been any clotting problems in the dialyser circuit. Studies to elucidate the underlying mechanisms of coagulation and anticoagulation in the extracorporeal environment have been performed. Minimal intermittent heparin administration based on plastic anticoagulation monitoring with the APTT method, has proven to be particularly safe.     

A neurologic comparison of pre-term and full-term infants at term conceptional age.

There are currently no neurologic examinations designed for pre-term infants with sufficient data to determine neurologic deviance at various gestational or conceptional ages (gestational age plus age from birth). In this study a neurologic examination standardized for full-term newborn infants was administered to 97 full-term newborn infants was administered to 97 full-term newborn infants and 97 pre-term infants at their expected date of birth, 40 weeks' conceptional age. The pre-term infants had more weak responses than did the full-term infants despite being at a higher level of activity state throughout the examination. The pre-term infants also had more asymmetric responses. There was no correlation between gestational age and the incidence of weak responses in the pre-term infants, but the pre-term infants of lowest birth weight at all gestational ages had the greatest number of weak responses. The latter may be because pregnancy and neonatal problems contribute more to the neurologic findings than does the length of gestation.     

Low socioeconomic status of the opposite sex is a risk factor for middle aged mortality

OBJECTIVES: To examine the relations between subjective social status, and objective socioeconomic status (as measured by income and education) in relation to male/female middle aged mortality rates across 150 sub-regions in Hungary. DESIGN: Cross sectional, ecological analyses. SETTING: 150 sub-regions of Hungary. PARTICIPANTS AND METHODS: 12,643 people were interviewed in the Hungaro-study 2002 survey, representing the Hungarian population according to sex, age, and sub-regions. Independent variables were subjective social status, personal income, and education. MAIN OUTCOME MEASURE: For ecological analyses, sex specific mortality rates were calculated for the middle aged population (45-64 years) in the 150 sub-regions of Hungary. RESULTS: In ecological analyses, education and subjective social status of women were more significantly associated with middle aged male mortality, than were male education, male subjective social status, and income. Among the socioeconomic factors female education was the most important protective factor of male mid-aged mortality. Subjective social status of the opposite sex was significantly associated with mid-aged mortality, more among men than among women. CONCLUSION: Pronounced sex interactions were found in the relations of education, subjective social status, and middle aged mortality rates. Men seem to be more vulnerable to the socioeconomic status of women than women to the effects of socioeconomic status of men. Subjective social status of women was an important predictor of mortality among middle aged men as was female education. The results suggest that improved socioeconomic status of women is protective for male health as well as for female health.     

Treatment of second degree facial burns with allografts--preliminary results

Facial burns are very common and have significant clinical impact. However, the treatment regimen for superficial to deep facial burns is not well defined. The purpose of this study was to investigate the effects of cadaver skin grafting in deep partial thickness facial burns in comparison to standard care. In a prospective open study design severely injured patients with superficial and deep partial thickness burns were randomized into the group receiving open treatment with silversulfadiazine (standard n=5) or into the group receiving early superficial debridement followed by coverage with glycerolized cadaver skin (n=5). The outcome measures were time and quality of wound healing, and incidence of hypertrophic scarring at 3 and 6 months post burn. There were no significant differences in demographics between groups. In the group treated with the allogenic material time to reepithelialization was 10.5 days, while it was 12.4 days in the silversulfadiazine group (p<0.05). Scar quality was found to be significantly improved in the allogenic treatment group. Three and 6 months postburn there were no patients with significant hypertrophic scarring in the allogenic group while there were two patients who developed hypertrophic scars in the silversulfadiazine group (p<0.05). In this study, we demonstrated that glyzerolized cadaver allograft skin represents a superior biological dressing for shallow and deep partial thickness facial burns. This is in concordance with other reports on scalds. It would be worthwhile to perform more clinical studies with a larger number of patients to further evaluate the effect and function of allogenic skin for facial burns.