The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Neuroendocrine factors regulating blood glucose, plasma FFA and insulin in the development of obesity

A number of neurotransmitters and neuropeptides in the hypothalamus play a role in the control of food intake, metabolism, and body weight. Particularly, noradrenergic mechanisms in several areas of the hypothalamus are involved. Control of peripheral metabolism by the hypothalamus is achieved via autonomic modulation of the function of hepatocytes, adipocytes, and the endocrine cells in the islets of Langerhans. The autonomic control mechanisms ultimately lead to an appropriate shaping of blood glucose, plasma FFA, and insulin profiles to guarantee an adequate flow of nutrients under different physiological situations. Peripheral insulin and glucose can penetrate into the brain where they might affect the function of those brain structures involved in control of food intake, metabolism, and body weight.     

Ethanol:water mutually enhanced transdermal therapeutic system. I: Nitroglycerin solution properties and membrane transport

The solution properties of aqueous ethanol donor solutions were characterized for the particular case of an increased flux nitroglycerin transdermal system. Permeation through porous and nonporous polymer membranes was investigated and modelled. While the permeation of ethanol through the porous membranes is adequately described by theory, clogging of pores occurs in the presence of lactose. Permeation through ethylene vinyl acetate membranes reflects interactions of the solute and solvent with the polymer.     

Renin-producing renal cell carcinomas—clinical and experimental investigations on a special form of renal hypertension

Summary The pathogenetic relationship between tumour and hypertension was investigated in 129 patients with renal cell carcinoma, of whom 41 (31.8%) were hypertensive. Of these 41 patients with renal tumours and hypertension, 6 (14.6%) were found to have primary reninism. In these patients the plasma renin activity in blood from the renal veins showed a tumour kidney to contralateral kidney ratio of between 4 and 7, and 2 patients also had secondary hyperaldosteronism. In the same 6 cases the renin content in the renal tumour tissue was significantly higher than that in tissue from the adjacent tumour-free renal cortex of the ipsilateral kidney. Immunohistochemical demonstration of renin in the tumour was only possible in these 6 cases. In 5 of these patients blood pressure returned to normal following nephrectomy; in the 6th case there was a drop in blood pressure after nephrectomy. In 3 renin-positive tumours examined, autonomous renin production was demonstrated in cell culture. Renin-producing renal cell carcinomas are an uncommon cause of renal hypertension. The differential diagnosis of hypertension should therefore also include renal tumour.     

Fluorescence in situ hybridization BCR/ABL fusion signal rate in interphase nuclei of healthy volunteer donors: a test study for establishing false positive rate

Fluorescence in situ hybridization (FISH) using chromosome-specific DNA probes is rapidly becoming a part of clinical laboratory practice. However, as a relatively new clinical test, it is not yet standardized and for practical reasons each laboratory must establish its own criteria. For this purpose we have evaluated the specificity of a dual-color BCR/ABL translocation probe by establishing the range of BCR/ABL fusion-positive scores in a healthy donor group. The false positive rate (FPR), determined by the percent of FISH BCR/ABL fusion-positive cells found in the specimens of healthy donors, was estimated at 2.3% (mean = 1%-4%). Thus the cut-off value for false positive nuclei was set at 5%.     

Modification of collagen matrices for enhancing angiogenesis

The vascularization of engineered tissues in many cases does not keep up with the ingrowth of cells. Nutrient and oxygen supply are not sufficient, which ultimately leads to the death of the invading cells. The enhancement of the angiogenic capabilities of engineered tissues therefore represents a major challenge in the field of tissue engineering. The immobilization of angiogenic growth factors may be useful for enhancing angiogenesis. The most potent angiogenic growth factor specific to endothelial cells, vascular endothelial growth factor (VEGF), occurs in several splice variants. The variant with 165 amino acids both has a high angiogenic activity and a high affinity for heparin. We therefore incorporated heparin molecules into collagen matrices by covalently cross-linking them to amino functions on the collagen. Physical binding of VEGF to the heparin may then prevent a rapid clearance from the implant, while the release rate may become coupled to the degradation of the collagen matrix. The modified matrices were characterized by determination of the extent of the heparin immobilization, the in vitro degradation rate by collagenase. For testing the angiogenic properties, non-modified and heparinized collagen specimens were--either loaded with VEGF or non-loaded--subcutaneously implanted on the back of rats. Specimens were explanted after varying periods of implantation, the dry weights and the hemoglobin contents, as well as immunostained histological sections were evaluated: heparinized collagen matrices loaded with VEGF are vascularized to a substantially higher extent as compared to non-modified matrices.     

Thyroid-stimulating hormone and thyroid-stimulating hormone receptor structure-function relationships

This review focuses on recent advances in the structure-function relationships of thyroid-stimulating hormone (TSH) and its receptor. TSH is a member of the glycoprotein hormone family constituting a subset of the cystine-knot growth factor superfamily. TSH is produced by the pituitary thyrotrophs and released to the circulation in a pulsatile manner. It stimulates thyroid functions using specific membrane TSH receptor (TSHR) that belongs to the superfamily of G protein-coupled receptors (GPCRs). New insights into the structure-function relationships of TSH permitted better understanding of the role of specific protein and carbohydrate domains in the synthesis, bioactivity, and clearance of this hormone. Recent progress in studies on TSHR as well as studies on the other GPCRs provided new clues regarding the molecular mechanisms of receptor activation. Such advances are a result of extensive site-directed mutagenesis, peptide and antibody approaches, detailed sequence analyses, and molecular modeling as well as studies on naturally occurring gain- and loss-of-function mutations. This review integrates expanding information on TSH and TSHR structure-function relationships and summarizes current concepts on ligand-dependent and -independent TSHR activation. Special emphasis has been placed on TSH domains involved in receptor recognition, constitutive activity of TSHR, new insights into the evolution of TSH bioactivity, and the development of high-affinity TSH analogs. Such structural, physiological, pathophysiological, evolutionary, and therapeutic implications of TSH-TSHR structure-function studies are frequently discussed in relation to concomitant progress made in studies on gonadotropins and their receptors.     

Only minor spinal motor reflex effects from feline group IV muscle nociceptors

The contribution of group III and IV muscle nociceptors activated by injection of KCl or bradykinin into the muscle artery (i.a.) of the gastrocnemius-soleus muscle to spinal motor reflex pathways was investigated in high spinal cats. Group I-III fibres were completely blocked by TTX, leaving group IV-fibre conduction intact. Thus, effects from i.a. KCl or bradykinin injection persisting after TTX were attributed to TTX resistant group IV fibres while the contribution of group III fibres was approximately defined by the difference between those effects and the control effects before TTX. Confirming former findings the chemical activation of group III and IV muscle afferents induced distinct reflex facilitation of the flexor posterior biceps semitendinosus and inhibition of the extensor quadriceps. After the block of all myelinated fibres by TTX the same stimuli induced only minor reflex effects mediated by the persistently conducting TTX resistant group IV afferents. It is concluded that the main functional meaning of group IV muscle afferents, which respond preferentially with a higher threshold to mechanical stimuli, is probably less related to reflex motor control than that of group III afferents.