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PCB disruption of the hypothalamus-pituitary-interrenal axis involves brain glucocorticoid receptor downregulation in anadromous Arctic charr.

We examined whether brain glucocorticoid receptor (GR) modulation by polychlorinated biphenyls (PCBs) was involved in the abnormal cortisol response to stress seen in anadromous Arctic charr (Salvelinus alpinus). Fish treated with Aroclor 1254 (0, 1, 10, and 100 mg/kg body mass) were maintained for 5 mo without feeding in the winter to mimic their seasonal fasting cycle, whereas a fed group with 0 and 100 mg/kg Aroclor was maintained for comparison. Fasting elevated plasma cortisol levels and brain GR content but depressed heat shock protein 90 (hsp90) and interrenal cortisol production capacity. Exposure of fasted fish to Aroclor 1254 resulted in a dose-dependent increase in brain total PCB content. This accumulation in fish with high PCB dose was threefold higher in fasted fish compared with fed fish. PCBs depressed plasma cortisol levels but did not affect in vitro interrenal cortisol production capacity in fasted charr. At high PCB dose, the brain GR content was significantly lower in the fasted fish and this corresponded with a lower brain hsp70 and hsp90 content. The elevation of plasma cortisol levels and upregulation of brain GR content may be an important adaptation to extended fasting in anadromous Arctic charr, and this response was disrupted by PCBs. Taken together, the hypothalamus-pituitary-interrenal axis is a target for PCB impact during winter emaciation in anadromous Arctic charr.

Adrenocorticotropic Hormone↗

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments.

The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many "side effects" not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by approximately 2 degrees C) and long-lasting (>3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1beta (500 ng/kg iv) was tested. The sham-operated rats developed typical monophasic fevers ( approximately 0.5 degrees C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39-40 degrees C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain.

Animals↗

Regulation of protein breakdown and adrenocortical response to stress in birds during migratory flight.

During long-term fasting at rest, protein utilization is maintained at low levels until it increases at a threshold adiposity. This study examines 1) whether such a shift in energy substrate use also occurs during endurance exercise while fasting, 2) the role of corticosterone, and 3) the adrenocortical response to an acute stressor. Ten species of migrating birds caught after an endurance flight over at least 500 km were examined. Plasma uric acid and corticosterone levels were low in birds with fat stores >5% of body mass and high in birds with smaller fat stores. Corticosterone levels were very high in birds with no visible fat stores and emaciated breast muscles. Corticosterone levels increased with handling time only in birds with large fat stores. These findings suggest that 1) migrating birds with appreciable fat stores are not stressed by endurance flight, 2) a metabolic shift (increased protein breakdown), regulated by an endocrine shift (medium corticosterone levels), occurs at a threshold adiposity, as observed in birds at rest, 3) adrenocortical response to an acute stressor is inhibited after this shift, and 4) an adrenocortical response typical for an emergency situation (high corticosterone levels) is only reached when muscle protein is dangerously low.

Adaptation, Physiological↗

Establishment of a transplantable rat pulmonary carcinoma-derived cell line (IP-B12) as a new model of humoral hypercalcemia of malignancy and bone metastasis.

A cloned cell line (IP-B12) derived from a transplantable rat pulmonary carcinoma (IP), of which neoplastic cells produce parathyroid hormone-related protein (PTHrP), was established. Tumors induced in syngeneic F344 rats by intraperitoneal injection of IP-B12 cells had features of pulmonary adenocarcinomas, consisting of neoplastic cells immunopositive to PTHrP. The IP-B12 tumor-bearing rats developed severe emaciation and hypercalcemia, with a marked elevation of plasma PTHrP level; there was an increase in osteoclastic areas of the femur and calcium depositions in systemic organs, indicating progression to humoral hypercalcemia of malignancy (HHM) in the tumor-bearing rats. In addition, the injection of IP-B12 cells into the left cardiac ventricle of syngeneic rats resulted in osteolytic skeletal metastases in the long bones and vertebrae. In the metastatic lesions, histologically, neoplastic cells showed an immunopositive reaction to PTHrP, and a prominent osteoclastic activity was seen; bone lesions, including osteolysis, fracture, and nerve compression as well as replacement of bone marrow cells by proliferated tumor cells were similar to those reported in human cancer patients with bone metastases. IP-B12 is a new animal model for HHM and osteolytic bone metastases, and will become a useful tool for studies on the pathogenesis and therapeutic strategies for such conditions.

Animals↗

The baromodulatory effect of gamma knife irradiation of the hypothalamus in the obese Zucker rat.

OBJECTIVE: The aim of this study was to evaluate the effect on body weight set point over time of focused, subnecrotic doses of radiation via gamma knife (GK) to the hypothalamus of the genetically obese Zucker rat. METHODS: A total of 36 adolescent animals were used in this experiment and placed in 6 groups of 6. The genetically obese homozygous Zucker rat was used in 4 groups (n = 24) and received GK, subcutaneous cobalt protoporphyrin (CoPP), both treatments combined or sham treatment. The heterozygous lean Zucker rat was used in 2 control groups (n = 12) and received either GK or sham treatment. All animals were weighed at the beginning of the experiment and at weekly intervals for 34 weeks. GK irradiation was accomplished using a specially designed stereotactic frame and a total dose of 40 Gy was given to 2 nearby targets in the medial hypothalamus. The drug subgroups received weekly subcutaneous injections. All animals were housed in the same environment with unlimited access to food. RESULTS: There were no significant differences in weight between the lean GK and sham groups. For the obese cohort, beginning at week 7 and throughout the remainder of the experiment, there were significant and sustained reductions in weight set point for animals that received GK (p < 0.05) and CoPP (p < 0.05) compared to sham-treated animals. Curiously, there was no statistical difference between the combined treatment and sham subgroups, though there was a trend toward weight reduction (p < 0.10). With the exception of one animal in the obese GK cohort in which there was a small area of necrosis lateral to the target area, histopathological analysis failed to reveal any abnormalities. There were no gross behavioral abnormalities noted. CONCLUSION: Our experimental results suggest that a single dose of GK irradiation to the hypothalamus can produce sustained reduction in the weight set point without emaciation in adolescent animals. The effect of this treatment is comparable to a well-studied drug therapy with a metalloporphyrin. We hypothesize that this involves a resetting of the hypothalamic set point for body weight through an as yet uncharacterized neuromodulatory effect.

Animals↗

IGF-I as an early indicator of malnutrition in patients with end-stage renal disease.

The present study was performed to clarify the possibility of IGF-I as an early indicator of malnutrition in patients with end-stage renal disease. Thirty-two patients (19 males, 13 females; mean age 49.6 +/- 10.0 years) undergoing dialysis were enrolled in the study. Body weight, skinfold thickness, and midarm muscle circumferences (MAMCs) were measured for anthropometric nutritional indices. Blood samples were collected to measure the following endocrinological, biochemical and hematological indices: IGF-I, growth hormone, (GH), total protein, prealbumin, albumin, transferrin, hematocrit, and lymphocyte count. Nutritional indices were measured again 1 month later to calculate the percent difference among them. Moreover, 2 patients who showed a decrease in IGF-I and suffered from malnutritional complications, such as hypoproteinemia and emaciation, which could not be successfully treated by conventional therapies were selected in order to confirm the nutritional role of IGF-I mediated by recombinant human GH (r-hGH). The serum IGF-I concentration distribution ranged from 22 to 225 ng/ml. In 15 patients (10 males, 5 females), it fell from 22 to 82 ng/ml below the normal range. Partial correlation coefficient analysis demonstrated that baseline IGF-I and the percent difference of each the body weight, MAMC, prealbumin and albumin were highly significantly correlated (r = 0.431, 0.641, 0.624 and 0.348, respectively; p = 0.014, 0.001, 0.001 and 0.028, respectively). The percent difference of IGF-I did not correlate significantly with that of any other nutritional index during the 1-month observation without administration of r-hGH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Behaviour therapy in the management of patients with anorexia nervosa. A lenient, flexible approach.

Many different treatment approaches have been advocated for anorexia nervosa, and most clinicians now incorporate some aspects of behaviour modification in refeeding an emaciated patient. Traditional operant programmes have required the patient to spend prolonged periods of time confined to a solitary existence in a bedroom devoid of her normal possessions. The present paper evaluated the rate of weight gain in 68 patients with anorexia nervosa (100 consecutive admissions to a specialised eating disorders unit) using a lenient, flexible approach to refeeding. Despite this more humane approach, similar results were achieved when compared to other more rigid behavioural programmes in that they gained 0.16 kg/day. This finding is discussed in the context of the rigid application of behavioural programmes which can be seen as punitive, undermine the patient's co-operation and destroy any therapeutic relationship which may develop.

Adolescent↗

Does so-called streptozocin hypertension exist in rats?

Although the existence of so-called streptozocin hypertension seems well established, some reports have indicated that no rise in blood pressure (BP) occurred after streptozocin treatments. To ascertain the streptozocin-induced BP response, normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with streptozocin, 40 to 45 and 35 mg/kg i.v., respectively, and BP was determined directly and indirectly every week for 3 to 4 weeks. Direct mean BP was determined without anesthesia or restraint through a cannula inserted into the rat's abdominal aorta. Indirect BP was determined at the tail without anesthesia after prewarming the rat in a holder. Compared with control values, indirect BP increased significantly in diabetic WKY 2 weeks after streptozocin treatment. In contrast, direct BP of these rats decreased, compared with control values. Indirect BP of diabetic SHR was as high as that of the controls, whereas direct BP of diabetic SHR decreased significantly 1 week after the treatment and thereafter, compared with control values. These discrepancies between the direct and indirect BP values may be caused by severe emaciation of diabetic rats. Extra pressure in the cuff may be necessary to occlude the bloodstream. These results indicate that under these conditions the value of BP obtained by the direct measurement is more reliable than that by the indirect one; therefore, we concluded that so-called streptozocin hypertension does not exist.

Animals↗

Secondary myelofibrosis in visceral leishmaniasis--case report.

A 39-year-old woman with a history of travel to the Montenegrin coast presented with a 9-month long history of fever and weakness, and on examination was found to be emaciated with hepatosplenomegaly and pancytopenia. Marrow aspiration showed poor cellularity with abundant Leishman Donovan (LD) bodies in the macrophages. Bone marrow trephine biopsy revealed a marked myelofibrosis (Manoharan classification: grade III) with osteosclerosis. The impression smears of a trephine biopsy stained with Güiemsa also showed LD bodies. The patient did not exhibit evidence of any risk factors for visceral leishmaniasis (VL). She was treated with meglumine antimoniate (Glucantime) without any adverse effect. The spleen returned to a normal volume after 4 months and bone marrow trephine biopsy performed 6 months after initiation of the therapy had returned to normal. A diagnosis was difficult to establish as VL is rarely encountered in the continental parts of Yugoslavia, and with the presence of associated myelofibrosis it could easily have been mistaken for chronic idiopathic myelofibrosis. The association of myelofibrosis with visceral leishmaniasis has been reported in the literature only three times; we thus feel that documentation of this case is merited.

Adult↗

Respiratory manifestations of rigid spine syndrome.

Thoracic abnormalities and respiratory muscle function were investigated in nine patients with rigid spine syndrome. A severe restrictive chest wall defect and limited mobility of the spine associated with clinically significant respiratory muscle weakness were present in all patients. Respiratory muscle strength and endurance were less than 60% of control values. Slight to moderate scoliosis was present in five patients and absent in four. Scoliosis appeared to have only a minor additional effect on respiratory muscle function. Six patients were emaciated, and one patient was underweight, but no relationship was seen between body mass index and respiratory muscle strength. Respiratory muscle function was more impaired in patients with hypoventilation than in normocapnic patients. Respiratory muscle involvement appears to be a significant feature of rigid spine syndrome, terminating in hypercapnic ventilatory failure in some patients.

Adolescent↗

Failure of a feeding jejunostomy.

A healthy 16-year-old female pedestrian was hit by a motor vehicle. She sustained multiple injuries including severe head injury. She was admitted to hospital unconscious. There was no recovery of neurological function. After a short period of time, a jejunostomy was performed for feeding purposes. The major clinical problem continued to be a feeding difficulty, with profuse diarrhoea occurring. At no stage was it possible to adequately nourish her. Hyperperistalsis was noted whilst in hospital. She died just over three months after admission. Autopsy revealed an emaciated body weighing only 25kg. An upper jejunostomy was still present containing a No. 20 French catheter. The bulb had threaded down the small bowel so that it was situated 25cm proximal to the ileocaecal valve. The small bowel was empty. The cause of death was given as malnutrition due to failure of function of a feeding jejunostomy due to small bowel hyperperistalsis in an individual with diffuse brain trauma. This complication of feeding jejunostomy causing death from malnutrition has not previously been described in the English literature.

Accidents, Traffic↗

Placement of a duodenal feeding tube via gastrostoma with fiberoptic bronchoscope.

We report a case of esophageal disruption that required a duodenal feeding tube. Because of collapse of the gastric outlet secondary to severe emaciation, several attempts to place a tube into the duodenum via gastrostoma had ended in failure. We finally were able to accomplish it with the aid of a fiberoptic bronchoscope and a Swan-Ganz catheter. The procedure is described and discussed.

Adult↗

Renal toxicity of a nondopaminergic antipsychotic agent, trimethyl imidazopyrazolopyrimidine, in rats.

A nondopaminergic antipsychotic agent, 5-ethyl-1,3,8-trimethyl-1H-imidazo]1,2-c]pyrazolo[3,4-e]pyrimidine (TIPP; PD 112488), has been tested for potential toxicity in rats. As part of a preclinical safety evaluation, 10 Wistar rats per sex were administered TIPP as a dietary admixture, receiving doses of 0, 5, 10, 20, 25, 50, 100, and 200 mg/kg for 2 wk. In addition, 3 groups of 6 male Wistar rats were administered TIPP (PD 114877 and PD 117498, acid hydrolysis products of TIPP) at 100 mg/kg by gavage for 5 days. All animals given 200 mg/kg were euthanatized in moribund condition or found dead after 1 wk of treatment. Clinical evidence of renal toxicity was noted and included emaciation, hematuria, urinary incontinence, and enlarged kidneys at doses of 10 mg/kg and higher. Plasma urea levels were higher than those of controls in all TIPP-treated groups. Significant pathologic changes of the urothelium were evident at all doses and were characterized by necrotizing pyelitis and cystitis. Necrosis and inflammation of the urothelium resulted in secondary hydronephrosis. No renal toxicity was noted with the acid hydrolysis products. The urothelial changes with oral administration of TIPP in rats is species-specific, and the specificity may be related to the metabolism and excretion of the drug.

Administration, Oral↗

A boxer dog with chronic hypertrophic gastritis resembling Menetrier's disease in man.

Chronic hypertrophic gastritis in a 7-year-old Boxer dog is described. This gastritis resembles Menetrier's disease in man. The dog was emaciated, lethargic, vomiting and had a poor appetite over a 4-month period. There was anaemia, and the blood smear was characterized by hypochromasia, strong anisoplania and striking poikilocytosis. There was a protein loss and at a later stage of the disease, a hypoalbuminaemia. On gastroscopic examination the plicae gastricae were numerous and strongly marked; moreover, they were granulated with numerous small haemorrhages. Radiographically, the stomach had a marked folding, primarily at the greater curvature. The passage of contrast medium from the stomach into the duodenum was strongly retarded. The pathological findings included macroscopical folding caused by local gland cell hyperplasia in the body as well as the pylorus, foveolar hyperplasia and, in the fundus and in the corpus near the greater curvature, folding of the muscularis mucosae and the submucosa. A superficial gastritis was found particularly in the fundus and corpus, whereas the pyloric antrum showed a more diffuse inflammation.

Animals↗

The pathogenesis of porcine rectal stricture. I. The naturally occurring disease and its association with salmonellosis.

Rectal stricture occurred in each of 23 pigs submitted for necropsy from eight Indiana farms. Each stricture was an annular cicatrization of the rectal wall, 2.0-5.0 cm anterior to the anorectal junction. Emaciation, colonic dilatation and compression atrophy of abdominal and thoracic viscera were a result of chronic obstipation and inanition. Most pigs with strictures had severe enteric disease 4-8 weeks before the strictures occurred. Salmonella typhimurium was isolated from seven of the eight groups of pigs examined. Ulcerative proctitis, a possible precursor of rectal stricture, was frequently in pigs with enterocolitis caused by S. typhimurium.

Animals↗

A review of exertional rhabdomyolysis in wild and domestic animals and man.

Exertional rhabdomyolysis is a condition arising in several species of newly captured wild animals after some form of physical exertion and stress. It is characterized by muscle necrosis and myoglobinuria. Death may result from secondary renal failure, acute or chronic heart failure and progressive emaciation.

Adrenal Cortex↗

A sarcocystis-like protozoon in a sheep with lymphadenopathy and myocarditis.

A generalized enlargement of the lymph nodes was found in an emaciated adult ewe. Additional autopsy findings included tiny grey-white necrotic foci in the heart muscle, aspiration pneumonia and diffuse pleuritis. Light microscopy showed a generalized lymphadenopathy with perilymphadenitis, depletion of lymphocytes and histiocytosis of the lymph node. In histiocytes and vascular endothelial cells of lymph nodes, septal capillary endothelium of lungs and capillary endothelium of myocardium, early stages of a protozoan parasite were found. In the myocardium, there were many foci of necrosis, some of which contained young cysts in the periphery. These cysts were morphogically similar tho those of Sarcocystis. Electron microscopy of the early protozoan stages yielded evidence of schizogony and formation of merozoites.

Animals↗

Monensin toxicosis in broiler chickens.

Chickens treated at seven weeks of age with 150, 200, or 250 mg of crystalline monensin sodium/kg body weight had signs of toxicosis, including extreme weakness, anorexia, paralysis and death. Gross lesions included emaciation, generalized congestion, myocardial enlargement and pallor, and hydropericardium. Samples of ventricular myocardium, superficial pectoralis (white fibers), anterior latissimus dorsi (intermediate fibers), and sartorius muscles (mixed red, intermediate, and white fibers) were examined by light microscope. Intermyofibrillar vacuolation, histochemically positive for neutral fat, was severe in the myocardium and red muscle fibers and moderate in the intermediate muscle fibers. Myofiber necrosis was limited to the red muscle fibers. Mitochondrial degeneration was apparent in myocardial sections from several chickens. Interstitial infiltration by macrophages and heterophils was common in the myocardium and aerobic skeletal muscle.

Animals↗