Persistent or recurrent acromegaly. Long-term endocrinologic efficacy and neurologic safety of postsurgical radiation therapy.

As in other clinics, pituitary surgery was definitive treatment in less than 50% of cases of acromegaly treated at one institution over several decades. From 1965 to 1989, 24 acromegalic patients who had noncurative pituitary surgery received radiation therapy at the National Institutes of Health, with a basal human growth hormone level of greater than 5 ng/ml as the criterion for active disease. Using megavoltage irradiation, more than 60% of these patients stabilized at a normal hormonal range, and the overwhelming majority had decreasing growth hormone levels with time. No major side effects of irradiation were encountered except panhypopituitarism of varying degrees. The authors evolved a policy of surgery as the first option, followed by irradiation for patients with postoperative growth hormone levels more than 5 ng/ml.     

Cerebral radioprotection by pentobarbital: dose-response characteristics and association with GABA agonist activity

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose (60 mg/kg intraperitoneally). Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time. Ketamine and hypothermia were without protective effect. Protection from acute radiation-induced mortality by pentobarbital in the rat model is a reproducible phenomenon and is associated with the GABA agonistic activity of the compound. This property of GABA agonists offers the potential for a novel approach to enhancement of the efficacy of radiation therapy in the treatment of brain tumors.     

Lymphocytic adenohypophysitis presenting as infertility. Case report

The authors report a nulliparous patient presenting with infertility and hyperprolactinemia. She underwent transsphenoidal surgery after radiological investigation disclosed an enlarged pituitary gland which did not respond to bromocriptine therapy. The removed tissue had histological features consistent with adenohypophysitis including a diffuse lymphocytic infiltrate. The lymphocyte subsets present in the infiltrate were characterized by immunohistochemical methods to establish the contribution of different elements of the cellular immune response. Lymphocytes bearing CD4 antigen (helper-inducer cells) were most prominent and appeared to bear the majority of the interleukin-2 receptor (expressed during lymphocytic activation) present in the pituitary gland. A few B lymphocytes were also observed. The location of the major histocompatibility antigen (classes I and II) and interleukin-2 receptor correlated with the lymphocytes and macrophages rather than with the stromal or parenchymal elements of the pituitary. Lymphocytic adenohypophysitis is an unusual cause of pituitary enlargement which can mimic a pituitary tumor, and is sometimes associated with hyperprolactinemia. In women of child-bearing age, it almost always occurs during pregnancy or the postpartum stage. The autoimmune disorder reported here has not previously been associated with infertility nor has the lymphocytic infiltrate of the pituitary previously been analyzed in detail by modern immunological methods.     

Convection-enhanced delivery of macromolecules in the brain.

For many compounds (neurotrophic factors, antibodies, growth factors, genetic vectors, enzymes) slow diffusion in the brain severely limits drug distribution and effect after direct drug administration into brain parenchyma. We investigated convection as a means to enhance the distribution of the large and small molecules 111In-labeled transferrin (111In-Tf; M(r), 80,000) and [14C]sucrose (M(r), 359) over centimeter distances by maintaining a pressure gradient during interstitial infusion into white matter to generate bulk flow through the brain interstitium. The volume of distribution (Vd) containing > or = 1% concentration of infusion solution increased linearly with the infusion volume (Vi) for 111In-Tf(Vd/Vi, 6:1) and [14C]sucrose (Vd/Vi, 13:1). Twenty-four hours after infusion, the distribution of 111In-Tf was increased and more homogeneous, and penetration into gray matter had occurred. By using convection to supplement simple diffusion, enhanced distribution of large and small molecules can be obtained in the brain while achieving drug concentrations orders of magnitude greater than systemic levels.     

Structural and functional evidence supporting a role for leptin in central neural pathways influencing blood pressure in rats

Leptin, a peptide hormone normally associated with body weight homeostasis, is implicated in the generation of obesity-induced hypertension. Administration of leptin increases sympathetic nerve activity and blood pressure; however, the neural circuity involved in this pressor effect is not clearly defined. In this review we describe experiments in which pseudorabies virus was injected into the heart, kidney and the vasculature within skeletal muscle to reveal the distribution of neurones in the hypothalamus that project to these cardiovascular tissues. This distribution is compared to the well-documented distribution of leptin receptors. Finally we discuss microinjection studies designed to examine the effect of leptin, in these regions, on sympathetic nerve discharge and arterial blood pressure. Leptin injected directly into the ventromedial hypothalamus, arcuate nucleus and lateral hypothalamic area (particularly the perifornical area) increased lumbar sympathetic nerve activity. In addition, microinjection into the ventromedial hypothalamus and parvocellular paraventricular nucleus increased blood pressure. Our results demonstrate a discrete set of hypothalamic pathways that may underlie the involvement of leptin in obesity-induced hypertension.     

Fos immunoreactivity in the lamina terminalis of adrenalectomized rats and effects of angiotension II type 1 receptor blockade or deoxycorticosterone

Neural activity, as measured immunohistochemically by the presence of Fos protein, was determined in the lamina terminalis, a thin strip of tissue forming the anterior wall of the third brain ventricle, after adrenalectomy. Several weeks after surgery, the adrenalectomized rats were maintained with access to water and a low sodium diet for five days. In addition, hypertonic (0.5M) NaCl solution was available for the entire five-day period (sodium available) or only during the first four days (sodium unavailable). The number of neurons expressing Fos, determined at the end of the fifth day, was increased in the adrenalectomized rats with or without NaCl solution to drink. Fos activity in the median preoptic nucleus was increased only in adrenalectomized rats without access to NaCl solution. Treatment of adrenalectomized rats with the sodium-retaining mineralocorticoid hormone, deoxycorticosterone, at the end of the fourth day, decreased Fos expression in the subfornical organ and the organum vasculosum of the lamina terminalis when NaCl solution was available but not when the NaCl solution was unavailable. In the adrenalectomized rats with NaCl solution available, mineralocorticoid treatment decreased both urinary sodium excretion and daily sodium intake. Brain nuclei in the lamina terminalis also became activated in intact rats made sodium deplete by treatment with the diuretic, furosemide. Relative to sodium-deplete intact rats, however, sodium-deplete adrenalectomized rats had a greater number of neurons expressing Fos in the organum vasculosum. Treatment of sodium-deplete rats, adrenalectomized or intact, with the angiotensin II-type 1 receptor antagonist, ZD7155, decreased sodium intake and Fos expression in the subfornical organ but not in the organum vasculosum of the lamina terminalis or median preoptic nucleus.In conclusion, the results demonstrated that activation of the brain nuclei located in the lamina terminalis of adrenalectomized rats was primarily related to sodium deficit and not to the absence of the mineralocorticoid hormones, although the adrenal hormones may have a role in limiting the activation of organum vasculosum of the lamina terminalis during sodium depletion. Furthermore, the results obtained with the administration of the angiotensin receptor antagonist are consistent with the proposal that sodium appetite of the sodium-deplete rat, adrenalectomized or intact, is mediated by circulating angiotensin II acting in the subfornical organ.     

Social Determinants and COVID-19 in a Community Health Center Cohort

Associations between social determinants of health (SDOH), demographic factors including preferred language, and SARS-CoV-2 detection are not clear. We conducted a retrospective cohort study among those seeking testing for SARS-CoV-2 at a multi-site, urban community health center. Logistic regression and exact matching methods were used to identify independent predictors of SARS-CoV-2 detection among demographic, SDOH, and neighborhood-level variables. Of 1,361 included individuals, SARS-CoV-2 was detected among 266 (19.5%). Logistic regression demonstrated that SARS-CoV-2 detection was less likely in White participants relative to Hispanic participants (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI] 0.05–0.46). and more likely in patients who prefer Spanish relative to those that prefer English (aOR 2.04, 95% CI 1.43–2.96). No observed SDOH predicted SARS-CoV-2 detection in adjusted models. A robustness analysis using a matched subset of the study sample produced findings similar to those in the main analysis. Preferring to receive care in Spanish is an independent predictor of SARS-CoV-2 detection in a community health center cohort.

     

Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection

To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the other two groups (p less than 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure. Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise "unsafe" doses of radiation in patients with CNS neoplasms.