A patient with persistent consolidation and a pulmonary mass.

Community-acquired pneumonia is a common condition and 6-24% of patients will fail to improve as expected. We present a patient who was initially treated for community-acquired pneumonia but did not make the anticipated recovery. We explore potential differentials, and the investigation and management of the rare condition we subsequently diagnosed.

Randomised controlled trial evaluating the role of tirofiban in high-risk non-ST elevation acute coronary syndromes: an East Indian perspective.

INTRODUCTION: Glycoprotein IIb/IIIa inhibitors such as tirofiban inhibit platelet aggregation. We evaluated the immediate and early outcomes in patients with high-risk non-ST elevation acute coronary syndrome (NSTE ACS) who received tirofiban with conventional therapy compared to patients who received only conventional therapy (a combination of aspirin, clopidogrel, low-molecular-weight heparin with or without beta-blockers and angiotensin-converting enzyme inhibitors). METHODS: A total of 165 patients received conventional therapy with a placebo, and 136 patients received conventional therapy with tirofiban after randomisation. The outcomes were measured on Day 7, Day 14, one month and three months after the administration of therapy. RESULTS: A significant reduction was noted in the occurrence of primary endpoints in patients receiving tirofiban, compared to those who received a placebo at seven days (14 versus 32; p-value is 0.036), 14 days (14 versus 28; p-value is 0.043), one month (19 versus 34; p-value is 0.01) and three months (30 versus 44; p-value is less than 0.001) after administration. There was a significant reduction in the occurrence of fatal myocardial infarction (MI) (1 versus 8; p-value is 0.044) and non-fatal MI at Day 7 (1 versus 8; p-value is 0.044), and refractory ischaemia at the end of one month (14 versus 24; p-value is 0.04) and three months (25 versus 36; p-value is less than 0.01) in patients receiving tirofiban as compared to those receiving a placebo. CONCLUSION: It may be concluded that tirofiban has a definite role in improving the outcome of patients with high-risk NSTE ACS.

Parathyroid hormone-related protein in pancreatic exocrine cancer associated with hypercalcaemia.

Hypercalcaemia is a common complication of malignancy seen in about 10% of cases of advanced cancer. Although hypercalcaemia is not uncommon with endocrine tumour of the pancreas, hypercalcaemia with cancer of the exocrine pancreas unrelated to bone metastasis has been rarely reported. We report a case of undifferentiated pancreatic cancer with severe hypercalcaemia due to parathyroid hormone-related protein produced by the tumour cells that did not respond to medical management.

Bone metabolism during antler growth in female reindeer.

Two female reindeer (Rangifer tarandus) were investigated for alterations in skeletal metabolism during the annual antler growth cycle. During July and January, rib samples were obtained by biopsy after double tetracycline labeling for gravimetric, chemical, and histomorphometric analyses. Though antler length increased from 8 to 55 cm between April and September, body weight increased from only 56 to 77 kg. Rib bone density (g/cm3) increased from 1.39 +/- 0.01 (mean +/- SEM) in July to 1.53 +/- 0.01 in January, and Ca content (mg/cm3) increased from 213 +/- 8 to 300 +/- 14, respectively. Histomorphometric data indicated that rib bones were more porous and active in July and had a higher turnover rate than did January samples. Plasma 1,25(OH)2D, parathyroid hormone (PTH), and osteocalcin levels were significantly lower and estradiol levels were significantly higher in the January as opposed to the July samples. The data indicate that during antler growth, female reindeer undergo bone loss that corresponds to the changes in plasma calcemic hormones and estradiol levels. This bone loss is eventually repaired when antler growth stops.

Blood pressure and hypothalamic norepinephrine and dopamine in calcium-deficient rats.

The influence of dietary calcium (Ca) on systolic blood pressure (BP) and hypothalamic norepinephrine (NE), dopamine (DA) and DA metabolites dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations was investigated in male Sprague-Dawley rats raised on diets containing 0.005, 0.17, 1.4, and 2.8% Ca for eight weeks starting at four weeks of age. Blood pressure was significantly higher in the 0.005% Ca and lower in the 2.8% Ca group respectively, compared with the control (1.4% Ca) group. Hypothalamic NE and DA were lower only in the 0.005% Ca group. DOPAC concentration was higher in both Ca-deficient and -excess groups. No change in HVA was observed in any group. Plasma Ca was reduced and parathyroid hormone (PTH) was increased in Ca-deficient groups, but plasma Ca and PTH were increased and decreased, respectively, (nondetectable) in the Ca-excess group. These results suggest that changes in BP due to altered dietary Ca metabolism may be due in part to altered adrenergic system, as well as to dietary-induced changes in calcium metabolism.

Low-calcium diet increases blood pressure and alters peripheral but not central angiotensin II binding sites in rats.

The mechanism by which low-calcium (Ca) diet causes hypertension is unknown. We investigated angiotensin II (Ang II) receptor binding in brain, adrenals and urinary bladders in male Sprague-Dawley rats pair-fed a low-Ca (0.005% Ca; 0.5% P) and normal-Ca (1.4% Ca) diet for 8 weeks beginning at 4 weeks of age. The Ang II receptor sites in hypothalamus-thalamus-septum (HTS), adrenal glands and urinary bladder smooth muscle were measured by saturation isotherm binding using 125I-sarcosine1isoleucine8 Ang II (125I-SI Ang II). Systolic blood pressure was determined at 2-week intervals by tail-cuff method. Serum total Ca, Na+, K+ aldosterone and Ang II and bone density and mineral content were determined at the time of sacrifice. Chronic Ca deficiency in rats raised blood pressure and decreased Ang II receptor density in bladder smooth muscles and tended to increase adrenal Ang II receptors. Serum Ca. bone density and mineral content were significantly lower in the Ca-deficient rats, while serum Na+ was elevated in this group. Serum Ang II and aldosterone were unaltered after the 8-week dietary regimen. Possible mechanisms for the hypertensive actions of reduced dietary Ca intake involving the renin-angiotensin-aldosterone system are discussed.

Histomorphometry and vitamin D metabolism of valgus-varus deformity in broiler chickens.

Vitamin D metabolite levels and tibiotarsal histomorphometric characteristics were determined in 49-day-old male broilers. Valgus-varus bone deformity was present in 5.2% and tibial dyschondroplasia (TD) in 3% of these broilers, which were raised on floor litter under seemingly normal nutritional, space, and lighting conditions. No significant weight differences were observed between normal and lame broilers. The plasma levels of 25-OH-D were the same in lame and normal broilers. However, 1,25-(OH)2D plasma levels were reduced 28% in broilers with valgus-varus deformities but normal in broilers with TD. Anatomically, there were three different patterns of bone development in the undecalcified mid-diaphyseal sections. The pattern with the least periosteal growth, lowest tetracycline labeling, and smallest marrow cavity was most often seen in valgus-varus deformities. Patterns with greatest periosteal growth, high tetracycline labeling, and larger marrow cavities were more representative of normal broilers. It was hypothesized that defective prostaglandin metabolism reduced 1,25-(OH)2D levels, contributing to the overall reduction in bone formation and bone resorption observed in broilers with valgus-varus bone deformity.

Hypotensive action of parathyroid hormone in hypoparathyroid and hyperparathyroid rats.

Experimental and clinical data suggest an association between chronic hyperparathyroidism and hypertension, but acute infusion of parathyroid hormone causes vasodilation and hypotension. These observations imply that chronic and acute parathyroid states affect blood pressure through different mechanism(s), either by modification of vascular receptors or by an ionophoretic effect of parathyroid hormone. The effect of parathyroid status induced by dietary calcium manipulations or by surgical ablation of the parathyroid gland on the hypotensive response of parathyroid hormone infusion was studied in rats. At 4 weeks of age 24 male rats were divided into four equal groups. Three groups were sham-operated, and one group was thyroparathyroidectomized. Only the thyroparathyroidectomized group was treated with thyroxine, 10 micrograms/kg/day. The control and thyroparathyroidectomized groups were raised on a 1.4% calcium diet; the other two groups were raised on 0.005% and 2.8% calcium diets. After 8 weeks on the diets, parathyroid hormone was infused through a venous cannula at 5 and 10 micrograms/kg doses and blood pressure was measured through arterial cannulas. The results indicate that hyperparathyroidism and hypocalcemia induced by the low calcium diet attenuated the hypotensive response to parathyroid hormone compared with responses in rats raised on a 1.4% calcium diet. In hypoparathyroid rats (2.8% Ca diet) with hypercalcemia, the hypotensive response was also reduced. However, in hypoparathyroid (thyroparathyroidectomized) rats with hypocalcemia, the hypotensive response was enhanced. The data suggest that chronic parathyroid status, as well as hypercalcemia, alters the hypotensive response to parathyroid hormone infusion, presumably by altering the vascular parathyroid hormone receptors or by some other mechanism.

Plasma calcemic hormones in mature female reindeer, Rangifer tarandus.

The plasma calcemic hormones in mature female reindeer were measured during the major portion of the antler growth cycle, between the months of March and November. Blood samples were collected every 2 months, a total of five samples each from eight reindeer. Plasma levels of 25-hydroxyvitamin D, PTH, and osteocalcin were found to increase progressively from May through July and decline thereafter except 1,25-dihydroxyvitamin D level which peaked in September. No change in plasma total Ca was observed at any time of the year. Plasma estradiol level was elevated in March only. All animals grew and shed antlers between April and February. This suggests that during the antler growth period when the deer undergoes cyclic bone loss, corresponding changes in plasma calcemic hormones occur, which may account for the reported skeletal bone changes seen during the growth of the antler.

Altered pressor response to norepinephrine in calcium- and vitamin D-deficient rats.

Norepinephrine (NE: 100-1000 ng/kg) pressor response studies in calcium- (0.005, 0.17, 1.4, and 2.8% in diet) and vitamin D-supplemented (0, 95, 190, and 950 U vitamin D3/day) normotensive conscious male rats were performed prior to and after administration of propranolol (100 ng/kg). Eight weeks of the above dietary treatments (beginning at 4 weeks of age) increased blood pressure (B.P.) in the 0.005% Ca group but reduced it in the 2.8% Ca group compared with the 1.4% Ca (control) group, whereas infusion of NE produced increased and decreased pressor responses, respectively. In the vitamin D groups, B.P. was increased only in the 0 U group, but NE pressor response was decreased in all groups compared with the 190 U (control) group. Plasma and bone calcemic parameters reflected disturbed Ca metabolism due to Ca and vitamin D deficiencies and excesses. These data suggest that Ca and vitamin D-induced changes in B.P. regulation in rats may in part be due to an altered adrenergic system.

Induction of metal binding proteins in striped bass, Morone saxatilis, following cadmium treatment.

1. The time course of induction of cytosolic metal binding proteins (MBP) was observed follow up to three daily intramuscular injections of cadmium chloride (0.2 mg cadmium/injection). 2. Low molecular weight binding proteins were resolved by gel permeation chromatography on Sephadex G-75. Based on total metal binding capacity, the concentration of crude MBP increased 2.6 fold. This level of induction of MBP was confirmed by polarographic analysis. 3. Initial binding of cadmium to MBP resulted in displacement of zinc, while at later times, zinc associated with MBP increased above control levels. 4. Using 35S-cysteine incorporation, it was shown that the rate of hepatic MBP synthesis was significantly greater than controls and sham injected fish 18 hr after the third cadmium injection. 5. Due to interfering proteins of molecular weights similar to the metal binding proteins one dimensional PAGE was not capable of verifying induction. However, the metal binding proteins were resolved using two dimensional gel electrophoresis.

Cholangioma in white perch (Morone americana) from the Chesapeake Bay.

Cholangiomas found in two of 21 wild-caught white perch (Morone americana) from the Chesapeake Bay are described. The two fish were part of a study investigating a condition of abnormal hepatic copper storage in this species. The tumors were superficial, solitary masses consisting of cuboidal to columnar cells in tubuloglandular arrangement. Mild to marked peribiliary inflammation and fibrosis was seen also. Environmental pollution, the condition of abnormal copper storage, peribiliary fibrosis, and/or parasites may have contributed to the development of these tumors.

Abnormal hepatic copper storage in a teleost fish (Morone americana).

Excessive copper storage in livers of feral white perch (Morone americana) from the Chesapeake Bay is described. Age-related, progressive accumulation of hepatic copper in levels often exceeding 1,000 micrograms/g wet weight was associated with peribiliary fibrosis and inflammation, bile duct hyperplasia, prominent, enlarged melanomacrophage centers, and disruption of hepatic architecture in older fish. Levels of zinc were mildly elevated compared to striped bass (Morone saxitilis) and adult rats. Cholangiomas were found in two perch. Rubeanic acid-stained liver had abundant copper-positive cytoplasmic granules in hepatocytes and cells of melanomacrophage centers. Subcellular fractionation showed that 90% of hepatocellular copper was in nuclei/cell debris fractions (which also contain tertiary lysosomes). Using electron probe microanalysis, high copper levels were localized in hepatocellular cytoplasmic bodies. Resolution of hepatic cytosol by gel permeation chromatography indicated that approximately 50% of the cytosolic copper in the white perch was bound to non-specific high molecular weight proteins, with the remaining 50% eluting at a peak where rat metallothionein is located. Ultrastructural examination revealed abundant lysosomes, increased size and number of peroxisomes, and increased density and numbers of mitochondrial matrix granules. This study indicates that white perch may be a model for studying effects of excessive copper accumulation and cellular mechanisms which control copper kinetics.

Adrenal catecholamine concentration after chronic treatment with bromocriptine and haloperidol.

Adrenal catecholamine concentration was measured by HPLC with electrochemical detection in male rats after ten days of bromocriptine and haloperidol (0.05, 0.5 and 5.0 mg kg-1) and vehicle (1.0 ml kg-1) treatments subcutaneously. There were four rats in each group. The results indicate that bromocriptine treatment significantly increased dopamine (DA), noradrenaline (NA) and adrenaline (A) content in a dose-dependent manner. The NA/DA ratio was unchanged, but the A/NA ratio was significantly increased after treatments with two higher doses of the drug. Haloperidol treatment, on the other hand, had no significant effect on dopamine and a biphasic effect on adrenaline content. Noradrenaline concentration increased only after the lowest dose of the drug. There was no significant change in NA/DA or A/NA ratios in any group. The dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), was not detected in any adrenal gland.

Effect of in vivo antiestrogen pretreatment on rabbit atrial chronotropic response to histamine.

The chronotropic response (delta rate) to histamine (1.4 to 18 X 10(-6) M) of isolated atria from antiestrogen (tamoxifen)-pretreated immature female rabbit was investigated. Tamoxifen treatment (1.0 and 10.0 mg/kg/day for 14 days) had no significant effect on the delta rate. The Rmax and D1/2max were not significantly different in the two tamoxifen-treated groups compared to the oil-treated (1.0 ml/kg/day for 14 days) control group. Cimetidine (2.8 X 10(-7) M) inhibited the delta rate to histamine in all groups: control, 27%; tamoxifen (1.0 mg/kg), 38%; and tamoxifen (10.0 mg/kg), 28%. Only the low dose of tamoxifen was found to be estrogenic (uterotropic). We conclude that tamoxifen pretreatment, both at estrogen-agonist and estrogen-antagonist doses, is without effect on atrial chronotropic response to histamine.

Alteration of dopamine metabolism in different brain regions of the rabbit by estradiol and tamoxifen.

Tamoxifen citrate, a mixed estrogen agonist-antagonist, and estradiol 17-beta administered separately for 14 days significantly reduced dopamine and dihydroxyphenylacetic acid in the cortex and hypothalamus regions of the brain in immature female rabbits. In addition to these areas, estradiol also reduced dopamine and dihydroxyphenylacetic acid in the striatum but tamoxifen treatment significantly reduced only dihydroxyphenylacetic acid concentration in the striatum. When estradiol and tamoxifen were injected together, dopamine and dihydroxyphenylacetic acid concentrations were reduced only in the cortex. Specific binding of [3H]spiperone to dopamine receptors was significantly increased by both estradiol and tamoxifen in the hypothalamus but only tamoxifen increased dopamine binding in the striatum. A low dose of tamoxifen, either alone or in combination with estradiol, increased uterine weight, but a higher dose of tamoxifen was neither an estrogen agonist nor antagonist. These studies indicate that estradiol and tamoxifen alter dopamine metabolism in the various regions of brain differentially. The estrogen agonist activity of tamoxifen does not correspond to antidopaminergic action of estradiol in the striatum.