Painless stress fractures in diabetic neuropathic feet.

We describe two patients with diabetes mellitus and associated neuropathy, who presented with painless foot swelling and no history of trauma. X-Rays revealed recent underlying fractures-in one of a metatarsus, and the other of a proximal phalanx. These were assumed to be ''stress'' fractures unassociated with pain because of the severe sensory neuropathy. Though spontaneous fractures in neuropathic feet have been previously described, they almost always occur in association with Charcot joints, and are usually painful. The differential diagnosis of acute swelling in the foot of a diabetic patient with sensory neuropathy should include stress fracture.     

Relationship between baroreflex sensitivity, renin suppression and natriuresis in salt-sensitive rabbits.

This study determined the influence of baroreflex sensitivity (BRS) on the rate of urinary sodium excretion and plasma renin activity (PRA) in response to a saline infusion in conscious male rabbits specifically bred for high (Group I; n = 7) and low (Group II; n = 10) BRS and in seven control animals. Only Group II showed significant increases in blood pressure on a chronic high-salt intake. After ensuring that each animal was in sodium balance, a (0.7-0.9%) saline infusion of 3-4 ml/kg per h for 90 min (25% daily sodium intake for each rabbit) was given and urine collected at 15-min intervals via a bladder catheter. No differences were found in control urine volumes, urinary sodium or PRA. Group I excreted over 50% of the sodium load and Group II less than 20% within 90 min. PRA fell by more than 30% within 30 min in six Group I rabbits but decreased by less than 30% or increased in Group II. In the control animals, sodium excretion rates and PRA suppression were also much greater in those with high BRS. A highly significant correlation (r = 0.808, P less than 0.01) was found between the per cent of the sodium load excreted and BRS. It is suggested that the delayed sodium excretion and blood pressure elevation in salt-sensitive subjects may be due to a genetic impairment in baroreflex control of renal sympathetic nerve activity.     

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%.     

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.     

The control of sodium excretion by reflexes from the low pressure system independent of adrenal activity

An experimental increase in left atrial pressure (eLAP↗) leads to an increase in sodium excretion (UNa \(\dot V\) ). This ‘atrial natriuresis’ is probably involved in the adjustment of sodium balance, but the mechanism is not well understood. The present studies were undertaken to examine

1. the influence of eLAP↗ on plasma renin activity (PRA) and UNa \(\dot V\) in conscious dogs, and
2. the influence of eLAP↗ on UNa \(\dot V\) with and without the presence of adrenal glands.

Twenty-three female beagle dogs were kept under controlled environmental conditions. They had chronically implanted instruments (purse string around the mitral annulus, catheter in the left atrium, carotid loop; 5 dogs were adrenalectomized). PRA waselevated by a chronic low sodium intake (LSI). When eLAP↗ was performed (+1.0 kPa), PRA decreased by about 50% within at least 60 min. PRA was chronicallylowered by a high sodium intake (HSI). Even under HSI conditions a decrease of PRA could be demonstrated if eLAP↗ was performed (by about 50%). However both HSI and LSI dogs showed a marked increase in UNa \(\dot V\) if eLAP↗ was performed. After the removal of the adrenals a decrease in glomerular filtration rate was observed (40% of the control values), but eLAP↗ led to a similar increase in UNa \(\dot V\) to that found in intact dogs (Δ mean 110%). These results indicate that stretching of the left atrium leads to a reduction of tubular sodium reabsorption in a twofold manner: 1st by reduction of PRA, possibly followed by a reduction in aldosterone secretion and 2nd by activating an adrenal independent mechanism of unknown origin. This could be a direct influence of angiotensin II on the tubular reabsorption of sodium. These results are compatible with the hypothesis that reflexes out of the low pressure system are important for the adjustment of sodium balance independent of changes in mineralocorticoid activity.     

Silver-Staining Nucleolar Organizer Region Quantification in Pituitary Adenomas

Nucleolar organizer regions (NORs) are segments of DNA, encoding for ribosomal RNA. They are associated with argyrophilic proteins and, thus, they can be localized through silver staining. A correlation has been shown between the number, the size, or the intranuclear localization of AgNORs, and the proliferative activity of cells. The aim of this study was to examine numerous features of AgNORs in pituitary adenomas and to relate them to immunohistochemical typing of tumor. Histologic slides from 32 pituitary tumors and one normal pituitary were silver-stained and analyzed with a computerized system for microscopic image analysis, supported by an AgNORmeter95 program. All the tumors were also immunocyto chemically characterized. We have found that gonadotropinomas, when compared with plurihormonal adenomas, revealed a lower proportion of nuclei with a single AgNOR and a higher percentage of marginal dots. Recurrent adenomas, when compared with primary adenomas, showed a higher proportion of nuclei with three AgNOR dots, a larger total area of dots in the nuclei, and a higher standard deviation of the AgNOR dot area in the nucleus. Adenomas immunopositive for prolactin, when compared with immunonegative ones, showed a larger mean area of the AgNOR dot, a larger area of the biggest dot in the nucleus, and a higher proportion of nuclei within a single dot. These results suggest that the estimated parameters of AgNOR dots differ according to tumor aggressiveness and to the hormone immunopositivity of pituitary adenomas.     

Atrial natriuresis under the condition of a constant renal perfusion pressure

An experimental elevation of left atrial pressure (eLAP ) by means of a reversible mitral stenosis is accompanied with an increase in sodium excretion (UNa—) and arterial blood pressure (by about 20 mm Hg, 2.7 kPa), and by a decrease in plasma renin activity.It is well established that an increase in renal perfusion pressure (Pren) can augment UNa—. Therefore the present study was undertaken to examine whether the eLAP -induced natriuresis was caused by the increased Pren. — Four female beagle dogs were kept under controlled environmental conditions. They received asodium rich diet (14.5 mmol/Na/kg/d). The dogs were chronically instrumented: purse string around the mitral annulus, catheter in the left atrium, carotid loop, pneumatic cuff above the renal arteries, pressure transducer below the renal arteries. Pren was kept constant by means of a digital servofeedback control circuit. The dogs served as their own controls (13 experiments without and 15 experiments with a controlled renal perfusion pressure were performed).After eLAP(+1.0 kPa), UNa— rose from 4.1±2.6 to 10.3±3.9 mol Na/min/kg. If Pren was kept constant, the corresponding values were 4.2±2.8 and 9.3±2.9 mol/min/kg. These data clearly indicate that the atrial natriuresis is not mediated by an augmentation of renal perfusion pressure. Therefore these results support the hypothesis that atrial natriuresis probably is due to an eLAP-induced suppression of the renin-angiotensin-system or other natriuretic mechanisms.Abbreviations ADP 3×20 min After distension period - AN Atrial natriuresis - bw kg Body weight - CP 3×20 min Control period - DP 3×20 min Distension period - eLAP kPa Experimental increase of left atrial pressure (during all DP's about +1.0 kPa) - HR l/min Heart rate - LAP kPa Left atrial pressure - n ₁ Number of dogs used - n ₂ Number of experiments (1 expt/day) - n ₃ Number of collection periods (urine) or number of samples (HR) - Part kPa Mean systemic arterial blood pressure (carotid artery) - Pren kPa Mean renal perfusion pressure (aorta, below the renal arteries) - UCI— mol/min/kg Chloride excretion - UK— mol/min/kg Potassium excretion - UNa— mol/min/kg Sodium excretion - Uosm— osm/min/kg Osmolar excretion - — l/min/kg Urine volume Preliminary parts of this work have been presented in Kiel (Spring meeting of the Deutsche Physiologische Gesellschaft, March 1979) and in Stockholm, Sweden (III. European Colloquium on Renal Physiology, June 1979).     

Effect of agomelatine in the chronic mild stress model of depression in the rat.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT(2C) antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT(1)/MT(2) antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT(2C) antagonist properties.