Preferential liver gene expression with polypropylenimine dendrimers.

Previously, the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (<1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations. In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration.     

Adjuvant radiotherapy in carcinomas of the uterine cervix: the prognostic value of hemoglobin levels

Anemia has been associated with a poorer treatment response and reduced survival in women undergoing primary radiotherapy (RT) or radiochemotherapy for advanced cervical carcinoma. This study aimed to determine the influence of anemia on outcome in patients with cervical carcinoma undergoing adjuvant RT. Medical records were reviewed for 183 cervical cancer patients who had received adjuvant RT because of risk factors after radical surgery (n= 109) or inadequate primary surgery (simple hysterectomy; n= 74). Kaplan-Meier and Cox regression analyses were used to study hemoglobin levels before and during adjuvant RT in relation to recurrence-free and overall survival. Hemoglobin values > or =11 g/dL were considered normal, while those <11 g/dL indicated anemia. Hemoglobin levels before RT influenced significantly overall survival and recurrence-free survival across the whole group (overall survival--log rank(all patients)= 7.5; df = 1; P= 0.006). However, subgroup analysis showed that the observed difference was mainly due to the group of women who had undergone inadequate primary surgery (overall survival--log rank(inadequate surgery)= 10.8; df = 1; P= 0.001). Multifactorial regression analyses comparing hemoglobin before RT with grading and tumor stage confirmed the prognostic value of hemoglobin values. Maintaining normal hemoglobin values before and during adjuvant RT seems to be important, especially in patients who have had inappropriate simple hysterectomy, which may resemble a therapeutic situation.     

Effect of estrogens on bone marrow adipogenesis and Sirt1 in aging C57BL/6J mice

Age-related bone loss has been associated with high levels of marrow adipogenesis. Estrogens (E₂) are known to regulate the differentiation of marrow precursors into osteoblasts, however, their role in bone marrow adipogenesis remain unknown. E₂ regulate adipocyte differentiation in subcutaneous and visceral fat through interaction with other nuclear receptors. This interaction has not been assessed in bone marrow adipocytes in vivo. In this study, we compared two groups of animals, young and old, after either oophorectomy (OVX) or oophorectomy plus E₂ (OVX + E₂) replacement. We found that absence of E₂ was associated with higher levels of PPARγ and lower levels of Sirt1 most significantly in the old group. In addition, old mice responded better to E₂ replacement in terms of reducing adipogenesis and PPARγ expression as well as increasing levels of Sirt1 expression. Our findings represent a new understanding of the role of E₂ in age-related bone loss, which could be mediated through the regulation of Sirt1 expression within the bone marrow. In addition, this evidence suggests that old individuals may show a better response to E₂ administration in terms of reverting the high levels of marrow fat seen in age-related bone loss.     

Steroid conversion and prostaglandin production by chorionic and decidual cells in relation to term and preterm labour

The production of progesterone from pregnenolone, of cortisol from cortisone and of prostaglandin E (PGE) under basal and arachidonic acid-stimulated conditions was measured in cells dispersed from chorion and decidua. The cells were obtained after delivery from four groups of women: following spontaneous labour at term (38-42 weeks gestation), at elective caesarean section at term before the onset of labour, after induced labour at term, and after uncomplicated preterm (27-36 weeks) labour. Chorionic cells had a high progesterone output with relatively low cortisol and PGE production, whereas decidual cells had a high cortisol and PGE production rate. Free arachidonic acid stimulated PGE production in both decidual and chorionic cells. There were no significant differences in either steroid or PGE production among the four groups studied. These data suggest that steroid dehydrogenase activity in choriodecidual cells is not related to the mode of onset of labour and that the increased prostaglandin production in intrauterine tissues associated with parturition is due to enhanced availability of arachidonic acid.     

A survey of hospitals in New York State treating psychiatric patients with chemical abuse disorders.

Eighty-eight of 143 hospitals in New York State providing psychiatric inpatient treatment responded to a mailed questionnaire designed to determine the size of three subgroups of chemical abusers--alcohol abusers, drug abusers, and polychemical abusers--among inpatients with psychiatric diagnoses, as well as the availability of services for these patients. Data for New York City and its metropolitan area were analyzed separately. In 1987 almost one-third of psychiatric admissions both in and outside the metropolitan area had comorbid chemical abuse disorders. Seventy-five percent of patients in the metropolitan area with comorbid chemical abuse had a drug abuse disorder; in rural areas 88 percent of patients with chemical abuse disorders abused alcohol. Both hospital- and community-based aftercare services, especially in the metropolitan area, were less available to psychiatric patients with chemical abuse than to patients without these disorders.     

Results of long-term leukocyte interferon (alpha IFN) therapy using an individually determined dose schedule in recurrent laryngeal papillomatosis

Out of 24 patients with laryngeal papillomatosis 6 (5 female, 1 male) suffered from repeated relapses and underwent long-term treatment with alpha-IFN-therapy. Age at onset of the disease: 1 5/12-16 2/12 years. Duration of illness: 1-7 years, with several relapses were treated surgically and with laser-coagulation. Three out of 6 patients had a tracheal cannula and were cauterized by podophylline at 2-4 week intervals. IFN was given in dosages of 5-20 X 10(4) U/kg 2 or 3 times a week. IFN-dosage for each patient was determined using the induction kinetics of (2'-5')-oligo(A)synthetase (OAS) in the mononuclear cells of the circulating blood of patients with laryngeal papillomatosis. A continuous effect could be achieved by the dose of IFN determined in the described way always before OAS activity decreased to its initial level. All 6 patients responded favorably to the alpha-IFN-therapy. Two patients treated only with IFN showed remission without relapses. In 2 cases IFN was successfully used to prevent relapses after surgical treatment and laser-coagulation. In 2 patients with papillomatosis extending into the main bronchi the disease could only be brought to a standstill, i.e. it was not necessary to remove the papillomas. Two out of 3 patients with laryngeal papillomatosis could be decannulated. Long-term therapy following the above described principles is efficient and without significant side-effects. Three patients are in treatment for more than 3 10/12 years.