Expression of inhibin/activin proteins and receptors in the human hypothalamus and basal forebrain.

The inhibin/activin family of proteins is known to have a broad distribution of synthesis and expression in many species, as well as a variety of functions in reproductive and other physiological systems. Yet, our knowledge regarding the production and function of inhibin and activin in the central nervous system is relatively limited, especially in humans. The present study aimed to explore the distribution of inhibin/activin protein subunits and receptors in the adult human brain. The human hypothalamus and surrounding basal forebrain was examined using post-mortem tissues from 29 adults. Immunocytochemical studies were conducted with antibodies directed against the inhibin/activin α, ßA, and ßB subunits, betaglycan and the activin type IIA and IIB receptors. An immunoassay was also utilised to measure dimeric inhibin A and B levels in tissue homogenates of the infundibulum of the hypothalamus. Robust ßA subunit immunoreactivity was present in the paraventricular, supraoptic, lateral hypothalamic, infundibular, dorsomedial and suprachiasmatic nuclei of the hypothalamus, in the basal ganglia, and in the nucleus basalis of Meynert. A similar staining distribution was noted for the ßB subunit, betaglycan and the type II receptor antibodies, whereas α subunit staining was not detected in any of the major anatomical regions of the human brain. Inhibin B immunoreactivity was present in all tissues, whereas inhibin A levels were below detectable limits. These studies show for the first time that the inhibin/activin protein subunits and receptors can be co-localised in the human brain, implicating potential, diverse neural functions.

Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation.

Evidence continues to build for the role of atrial natriuretic peptide (ANP) in reducing cerebrospinal fluid (CSF) formation rate, and thus, intracranial pressure. ANP binds to choroid plexus (CP) epithelial cells. This generates cGMP, which leads to altered ion transport and the slowing of CSF production. Binding sites for ANP in CP are plentiful and demonstrate plasticity in fluid imbalance disorders; however, specific ANP receptors in epithelial cells need confirmation. Using antibodies directed against NPR-A and NPR-B, we now demonstrate immunostaining not only in the choroidal epithelium (including cytoplasm), but also in the ependyma and some endothelial cells of cerebral microvessels in adult rats (Sprague-Dawley). The choroidal and ependymal cells stained almost universally, thus substantiating the initial autoradiographic binding studies with 125I-ANP. Because ANP titers in human CSF have previously been shown to increase proportionally to increments in ICP, we propose a compensatory ANP modulation of CP function to down-regulate ICP in hydrocephalus. Further evidence for this notion comes from the current finding of increased frequency of "dark" epithelial cells in CP of hydrocephalic (HTx) rats, which fits our earlier observation that the "dark" choroidal cells, associated with states of reduced CSF formation, are increased by elevated ANP in CSF. Altogether, ANP neuroendocrine-like regulation at CSF transport interfaces and blood-brain barrier impacts brain fluid homeostasis.

Autopsy-proven Creutzfeldt-Jakob disease in a patient with a negative 14-3-3 assay and nonspecific EEG and MRI.

Detection of 14-3-3 protein in cerebrospinal fluid (CSF), in combination with findings on electroencephalography (EEG) and magnetic resonance imaging (MRI), is a highly sensitive and specific diagnostic test for sporadic Creutzfeldt-Jakob disease (CJD) in patients premortem. We present a case of classic, sporadic CJD, confirmed on autopsy and by Western blot. However, all routine premorbid testing was negative, the CSF was negative for the 14-3-3 protein, EEG did not show periodic sharp wave complexes (PSWC), and MRI failed to show hyperintense signal in the basal ganglia. Thus, laboratory support for the diagnosis of CJD was not obtained premortem. The chances of all three diagnostic testing modalities to be negative in a single case of sporadic CJD are extremely remote. Autopsy with neuropathologic confirmation remains the only definitive way to make a diagnosis of CJD.

Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain.

The distribution of estrogen receptor protein-alpha (ER-alpha)-containing cells in the human hypothalamus and adjacent regions was studied using a monoclonal antibody (H222) raised against ER-alpha derived from MCF-7 human breast cancer cells. Reaction product was found in restricted populations of neurons and astrocyte-like cells. Neurons immunoreactive for ER-alpha were diffusely distributed within the basal forebrain and preoptic area, infundibular region, central hypothalamus, basal ganglia and amygdala. Immunoreactive astrocyte-like cells were noted within specific brain regions, including the lamina terminalis and subependymal peri-third-ventricular region. These data are consistent with the location of estrogen receptors in the basal forebrain of other species and the known effects of estrogens on the cellular functions of both neurons and supporting elements within the human hypothalamus and basal forebrain.

Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma.

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with beta-amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to beta-amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

Intracerebral hemorrhage in two patients with Down's syndrome and cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is an important cause of spontaneous intracerebral hemorrhages in the elderly and is often seen in the brains of patients with Alzheimer's disease, Down's syndrome (DS), and hereditary cerebral hemorrhage with amyloidosis of the Dutch type. We report two patients with DS and extensive CAA who died of intracerebral hemorrhage; only two other such case reports exist in the literature. We believe the incidence of such cases is higher than is reported and that the likelihood of hemorrhage in the setting of CAA is independent of the patient's underlying disease.

Forearm velocity in carpal tunnel syndrome: when is slow too slow? .

OBJECTIVE: To correlate the frequency of superimposed processes (SPs) such as radiculopathies, polyneuropathies, and plexopathies with median motor forearm conduction velocity (MMFCV) in patients with carpal tunnel syndrome (CTS). DESIGN: All cases of diagnosed CTS were retrospectively analyzed for evidence of SPs. SETTING: Electrophysiology laboratory of a tertiary care center. PARTICIPANTS: One hundred fifty-five patients (44 men, 111 women), ages 19 to 94, who were referred for and met electrophysiologic criteria for CTS, both with and without MMFCV slowing. MAIN OUTCOME MEASURE: The frequency of SPs in patients with no, mild, moderate, and severe MMFCV slowing. RESULTS: A total of 192 arms from 155 patients were studied. Of 14 arms with mild slowing (MMFCV of 47.0 to 49.9 m/sec), 2 (14%) had an SP. Of 15 arms with moderate slowing (MMFCV of 43.0 to 46.9 m/sec), 7 [corrected] (46%) had an SP. Of 9 arms with severe slowing (MMFCV of < 43.0 m/sec), 4 (44%) had an SP. The frequency of SPs for both the moderate and severe groups was significantly higher than that in patients with a normal MMFCV (p < .01); of 154 arms with a normal MMFCV, only 9 (6%) had an SP. CONCLUSION: In cases of CTS, the finding of moderate to severe slowing of MMFCV (< 47.0 m/sec) should prompt a careful electrophysiologic investigation to exclude an SP.

White-light schlieren optics using bacteriorhodopsin as an adaptive image grid.

A schlieren apparatus using a bacteriorhodopsin film as an adaptive image grid with white-light illumination is demonstrated for the first time to our knowledge. Relevant spectral properties of the film are characterized. Potential applications include a single-ended schlieren system for gas-leak detection.

Disulfiram for alcohol use disorders in adolescents.

Alcohol abuse and dependence in adolescents is a serious health concern with significant morbidity and mortality. Disulfiram has been used to treat alcoholism in adults since 1948, but there are no known reports of disulfiram treatment in minors. Case reports are presented on the use of disulfiram in two adolescent males with alcohol dependence and strong family histories of alcoholism. Prolonged abstinence from alcohol occurred in the first case, whereas poor pharmacological compliance resulted in an early relapse in the second case. The judicious use of disulfiram in adolescents is recommended for consideration in those with alcohol use disorders. A protocol is proposed that recommends a thorough medical and psychiatric evaluation, documentation of a serious alcohol use disorder, careful assessment for comorbid diagnoses, family involvement when possible, and obtainment of informed consent that encompasses education about the nature and effects of disulfiram along with its potential interactions with other medications.