Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2

Prostaglandin D₂ (PGD₂) is an extensively studied sleep-promoting substance, but the neuroanatomical basis of PGD₂-induced sleep is only partially understood. To determine potential regions involved in this response, we used Fos immunohistochemistry to identify neurons activated by infusion of PGD₂ into the subarachnoid space below the rostral basal forebrain. PGD₂ increased nonrapid eye movement sleep and induced striking expression of Fos in the ventrolateral preoptic area (VLPO), a cluster of neurons that may promote sleep by inhibiting the tuberomammillary nucleus, the source of the ascending histaminergic arousal system. Fos expression in the VLPO was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus. PGD₂ also increased Fos immunoreactivity in the basal leptomeninges and several regions implicated in autonomic regulation. These observations suggest that PGD₂ may induce sleep via leptomeningeal PGD₂ receptors with subsequent activation of the VLPO.     

A longitudinal immunologic evaluation of hemophiliac patients

Over an average span of one year, we performed a prospective clinical and immunologic evaluation of 30 patients with hemophilia. No patient developed life-threatening opportunistic infection or malignancy; however, the immunologic abnormalities and lymphadenopathy initially present in nine patients (lymphadenopathy group) persisted. In addition, five patients, representing 24% of the initial group without lymphadenopathy, developed generalized lymphadenopathy (converter group). One episode of idiopathic thrombocytopenia (ITP) and one episode of staphylococcal sepsis occurred in this "converter" group; one episode of ITP also occurred in the lymphadenopathy group. Sixteen patients remained asymptomatic. At the time of the follow-up evaluation, those differences in mononuclear cell (MNC) percentages and numbers noted initially among the three hemophiliac groups were no longer present. Natural killer cell function alone or in the presence of biologic response modifiers was not different among hemophiliac and control groups. Before developing lymphadenopathy, the converter group of patients had significantly better lymphocyte mitogenic function than did the other two groups of patients with hemophilia. However, lymphocyte mitogenic responses of all groups of patients with hemophilia significantly deteriorated over the course of the study. The abnormal mitogenic responses noted in these patients was explained in part by higher levels of spontaneous suppressor cell activity in mononuclear cell preparations from patients with hemophilia. We conclude that long-term immunologic studies of this patient population requires both quantitative and qualitative evaluations. Our data show that patients with hemophilia have progressive dysfunction of cell- mediated immunity.     

In vitro characterization of the human recombinant soluble granulocyte- macrophage colony-stimulating factor receptor

We have cloned, expressed, and partially purified a naturally occurring, truncated, soluble form of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit to investigate its biochemical and biologic properties. The soluble receptor species lacks the transmembrane and cytoplasmic domains that are presumably removed from the intact receptor cDNA by a mechanism of alternative splicing. The resulting soluble 55- to 60-kD glycosylated receptor species binds GM-CSF with a dissociation constant (kd) of 3.8 nmol/L. The soluble GM-CSF receptor successfully competes for GM-CSF binding not only with the transmembrane-anchored GM-CSF receptor alpha subunit but also with the native oligomeric high-affinity receptor complex. In addition, in human bone marrow colony-forming assays, the soluble GM-CSF receptor species can antagonize the activity of GM-CSF. Our data suggest that the soluble GM-CSF receptor may be capable of acting in vivo as a modulator of the biologic activity of GM-CSF.     

Hypothalamic pathology in Alzheimer's disease

The hypothalamus was examined in 3 cases of Alzheimer's disease and 3 control brains, using combined acetylcholinesterase (AChE) and thioflavin-S staining. Neurons undergoing neurofibrillary degeneration were restricted to 3 AChE-positive cell populations (lateral tuberal, lateral posterior and tuberomammillary) that have been found in the rat and monkey to project to the cerebral cortex. Our results suggest that the neurofibrillary degeneration in the hypothalamus involves primarily neurons that innervate cortical areas involved by Alzheimer's disease. This finding is consistent with the hypothesis that Alzheimer's disease is transmitted from neuron to neuron via normal neuronal connections.     

Otago Glaucoma Surgery Outcome Study: long‐term results of 841 trabeculectomies

Background: To describe the long‐term outcomes of trabeculectomies performed at Dunedin Hospital and followed in the Otago Glaucoma Surgery Outcome Study. Methods: Prospective non‐comparative case series of 841 eyes of 607 patients who had first trabeculectomies for primary open‐ or closed‐angle glaucoma at Dunedin Hospital between 1976 and 2005 and followed for a mean of 7.5 years (standard deviation 6.0). Results: The probability of a trabeculectomy controlling the intraocular pressure at 21 mmHg or less at 1, 10 and 20 years was 0.96 (95% confidence interval [CI] 0.95, 0.97), 0.86 (95% CI 0.83, 0.89) and 0.79 (95% CI 0.74, 0.83), respectively. Visual acuity was maintained or improved between preoperative assessment and final follow up in 68% of cases. The probability of not being blind following trabeculectomy at 1, 10 and 20 years was 0.98 (95% CI 0.96, 0.98), 0.83 (95% CI 0.80, 0.87) and 0.70 (95% CI 0.64, 0.76), respectively. The proportion of those with glaucomatous field loss increased during follow up from 16% (44/283) at 0–5 years to 50% (10/20) for those with 21 or more years of follow up. A repeat drainage procedure was required in 65 eyes (8%) (56 Molteno implant insertions and 9 repeat trabeculectomies). Conclusions: Intraocular pressure was well controlled by trabeculectomy; however, a steady decline in intraocular pressure control, visual acuity and visual field occurred during follow up.     

Differential expression of orexin receptors 1 and 2 in the rat brain

Orexins (hypocretins) are neuropeptides synthesized in the central nervous system exclusively by neurons of the lateral hypothalamus. Orexin-containing neurons have widespread projections and have been implicated in complex physiological functions including feeding behavior, sleep states, neuroendocrine function, and autonomic control. Two orexin receptors (OX(1)R and OX(2)R) have been identified, with distinct expression patterns throughout the brain, but a systematic examination of orexin receptor expression in the brain has not appeared. We used in situ hybridization histochemistry to examine the patterns of expression of mRNA for both orexin receptors throughout the brain. OX(1)R mRNA was observed in many brain regions including the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, ventromedial hypothalamic nucleus, dorsal raphe nucleus, and locus coeruleus. OX(2)R mRNA was prominent in a complementary distribution including the cerebral cortex, septal nuclei, hippocampus, medial thalamic groups, raphe nuclei, and many hypothalamic nuclei including the tuberomammillary nucleus, dorsomedial nucleus, paraventricular nucleus, and ventral premammillary nucleus. The differential distribution of orexin receptors is consistent with the proposed multifaceted roles of orexin in regulating homeostasis and may explain the unique role of the OX(2)R receptor in regulating sleep state stability.     

Geriatric headache. How to make the diagnosis and manage the pain

Approximately 10% of women and 5% of men at age 70 experience severe recurrent or constant headaches. Severe headache presenting for the first time in a patient over age 50 is unusual and requires a thorough medical and neurologic examination. Primary headache etiologies in older patients include migraine, tension-type, cluster, and the rare hypnic headache. For all of these, effective pain control includes pharmacologic and nonpharmacologic interventions. Secondary etiologies include temporal arteritis, medication-induced headache, cerebrovascular or cardiac ischemia, and intracranial hemorrhage or tumors. Head pain may also be cervicogenic or related to glaucoma or sleep apnea. In secondary cases, pain management is specific to treatment of the underlying structural or systemic disease.     

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping

Five of the six families with the Berardinelli Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.