Effects of localized intracerebral injections of nerve growth factor on the regenerative growth of lesioned central noradrenergic neurones

In the adult rat, the growth of new axonal sprouts from lesioned central catecholamine and indolamine neurones into a denervated iris transplanted to the caudal diencephalon was previously shown to be markedly stimulated by an intraventricular injection of NGF. In the present study a similar stimulatory effect on the regrowth of lesioned central noradrenergic axons has been obtained with 100 times lower doses of the protein, injected locally into the brain tissue close to the cell bodies and axons of the locus coeruleus neurone system. The ingrowth of fibres into the transplant increased similarly when different parts of the noradrenergic neurones (i.e. the cell bodies or the proximal or distal parts of the surviving portions of the lesioned axons) were exposed to NGF, suggesting that the NGF sensitivity is not restricted to any specific part of the neurones. Moreover, experiments with iris transplants incubated in an NGF solution prior to the transplantation suggest a role for the NGF contained in the iris in the process of ‘reinnervation’ of the transplant by central noradrenaline neurones. The possibility of a difference in sensitivity to NGF between different central noradrenaline neurone systems, and between central noradrenaline, dopamine, and indolamine neurone systems is discussed. It was further clarified that the regenerating central neurones — similar to adult peripheral noradrenaline neurones — are most sensitive to the action of NGF during the very early stages of regeneration.     

Paraaortic lymph node irradiation in cervical carcinoma without prior lymphadenectomy

A study of complications associated with paraaortic irradiation was undertaken in patients with uterine cervical cancer who had not undergone prior lymphadenectomy. Between 1975 and 1984, 29 highly selected patients received paraaortic irradiation as part of their definitive treatment for cervical carcinoma. Paraaortic fields were irradiated to a total dose of 4,200-5,000 rad (42-50 Gy), in fractions of 150-180 rad (1.5-1.8 Gy). An anteroposterior-posteroanterior technique was generally used. All fields were treated every day. There were no instances of small-bowel obstruction or other major complications, surgical procedures, or deaths caused by paraaortic irradiation. Eleven patients (38%) have no evidence of recurrent disease 23-120 months after completion of therapy. Paraaortic irradiation was well tolerated in this patient group without prior staging lymphadenectomy. Thus, in selected patients and with appropriate techniques, paraaortic irradiation for cervical carcinoma may be used with relative safety.     

Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys

Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.     

Repair of a large septal perforation with a radial forearm free flap: brief report of a case

We treated a 38-year-old man who had a large septal perforation that had been caused by chronic nasal inhalation of cocaine. We were able to repair the perforation with a left radial forearm free flap. Long-term followup indicates a successful closure of the defect and a natural thinning of the flap. The patient remains symptom-free more than 2 years following surgery.     

Treatment of nicotine addiction

The best available data show smoking to be by far the most important cause of disease and death in our society, contributing to an average of 1000 deaths every day. Although a large majority of current smokers express a desire to quit, the majority of "self-help" attempts to quit are not successful. Further, most smokers indicate never having received advice on cessation from healthcare providers. The combination of pharmacotherapy and behavioral interventions, even on a minimal level, have been shown to be effective in cessation. Such strategies are certainly highly cost-effective, given the enormous costs to society of smoking-related illnesses. Therefore, it is important that all healthcare providers provide at least some form of smoking cessation programs for their patients.     

Development of an intranasal vaccine to prevent urinary tract infection by Proteus mirabilis

Proteus mirabilis commonly infects the complicated urinary tract and is associated with urolithiasis. Stone formation is caused by bacterial urease, which hydrolyzes urea to ammonia, causing local pH to rise, and leads to the subsequent precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate (apatite) crystals. To prevent these infections, we vaccinated CBA mice with formalin-killed bacteria or purified mannose-resistant, Proteus-like (MR/P) fimbriae, a surface antigen expressed by P. mirabilis during experimental urinary tract infection, via four routes of immunization: subcutaneous, intranasal, transurethral, and oral. We assessed the efficacy of vaccination using the CBA mouse model of ascending urinary tract infection. Subcutaneous or intranasal immunization with formalin-killed bacteria and intranasal or transurethral immunization with purified MR/P fimbriae significantly protected CBA mice from ascending urinary tract infection by P. mirabilis (P < 0.05). To investigate the potential of MrpH, the MR/P fimbrial tip adhesin, as a vaccine, the mature MrpH peptide (residues 23 to 275, excluding the signal peptide), and the N-terminal receptor-binding domain of MrpH (residues 23 to 157) were overexpressed as C-terminal fusions to maltose-binding protein (MBP) and purified on amylose resins. Intranasal immunization of CBA mice with MBP-MrpH (residues 23 to 157) conferred effective protection against urinary tract infection by P. mirabilis (P < 0.002).     

The effects of nerve growth factor on the development of septal cholinergic neurons in reaggregate cell cultures

Recent studies suggest that nerve growth factor is present within the central nervous system where it may exert selective trophic effects on cholinergic neurons. We have measured the effects of nerve growth factor on septal cholinergic neurons in three-dimensional reaggregating cell cultures, a system which closely simulates the cellular environment in situ. Septal cells obtained from 15-day-old mouse embryos were dissociated into a single cell suspension and then allowed to reaggregate in culture in a rotary incubator shaker. After 17 days in culture, half of the reaggregates from a flask were sonicated for measurement of choline acetyltransferase activity, and the remaining reaggregates were processed for acetylcholinesterase histochemistry. Addition of nerve growth factor to medium containing septal reaggregates resulted in greater than a three-fold increase in choline acetyltransferase activity and in the number of acetylcholinesterase-positive cells, as well as an enhancement in the staining of acetylcholinesterase-positive fibers. All of these effects of nerve growth factor could be neutralized by antibodies to nerve growth factor. In order to evaluate the possible role of endogenous hippocampal-derived nerve growth factor, antiserum to nerve growth factor was added to the culture media containing septal-hippocampal coaggregates. After 21 days in culture, the presence of nerve growth factor antibodies did not qualitatively affect the pattern or density of cholinergic fibers observed. Synapse formation between cholinergic axons and hippocampal target cells was still in evidence as revealed by electron microscopy. However, there was a modest decrease in choline acetyltransferase activity (20%) and cholinergic cell number (30%) when compared with coaggregates grown in culture medium either without nerve growth factor antiserum or with non-immune serum. The magnitude of these effects was markedly less than the effects observed when exogenous nerve growth factor was added to septal cells grown alone in reaggregate culture. These results suggest that nerve growth factor may play a role during central cholinergic development, but that additional trophic mechanisms are likely to be required.     

Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure

Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure.