Efficacy of milnacipran in patients with fibromyalgia

OBJECTIVE: Fibromyalgia (FM) is a common musculoskeletal condition characterized by widespread pain, tenderness, and a variety of other somatic symptoms. Current treatments are modestly effective. Arguably, the best studied and most effective compounds are tricyclic antidepressants (TCA). Milnacipran, a nontricyclic compound that inhibits the reuptake of both serotonin and norepinephrine, may provide many of the beneficial effects of TCA with a superior side effect profile. METHODS: One hundred twenty-five patients with FM were randomly assigned in a 3:3:2 ratio to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months in a double-blind dose-escalation trial; 92% of twice-daily and 81% of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg. RESULTS: The primary endpoint was reduction of pain. Both the once- and twice-daily groups showed statistically significant improvements in pain, as well as improvements in global well being, fatigue, and other domains. Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression, but placebo response rates were considerably higher in depressed patients, leading to significantly greater overall efficacy in the nondepressed group. CONCLUSION: In this Phase II study, milnacipran led to statistically significant improvements in pain and other symptoms of FM. The effect sizes were equal to those previously found with TCA, and the drug was generally well tolerated.     

Regulation of renal Na+-K+-ATPase in the rat by adrenal steroids

The effects of single and multiple injections of aldosterone and dexamethasone on renal Na+-K+-ATPase, in vitro renal gluconeogenesis, and urinary electrolyte excretion were examined in adrenalectomized rats in a dose-dependent manner. Single maximal and supramaximal doses of aldosterone (defined by the effect of electrolyte excretion) had no effect on Na+-K+-ATPase or gluconeogenesis. By contrast, a single administration of dexamethasone (in a dose range that increased fasting blood sugar, stimulated renal gluconeogenesis, and had no mineralocorticoid effects) yielded clear-cut activation of Na+-K+-ATPase. Multiple submaximal doses of dexamethasone produced quantitatively similar stimulation of Na+-K+-ATPase and gluconeogenesis. Multiple supramaximal doses of aldosterone stimulated Na+-K+-ATPase and gluconeogenesis, but maximal and submaximal doses of the hormone were without effect. Aldosterone had no effect on hepatic Na+-K+-ATPase or gluconeogenesis. These results suggest that activation of renal Na+-K+-ATPase can be considered a putative glucocorticoid (not mineralocorticoid) effect. Renal Na+-K+-ATPase activation by chronic aldosterone treatment may be mediated by glucocorticoid receptor sites and, hence, may not represent a genuine mineralocorticoid effect.     

Clinical manifestations and diagnosis of distant metastases of differentiated thyroid carcinoma after initial therapy

We studied 58 patients with distant metastases of differentiated thyroid carcinoma diagnosed after initial therapy. Lymph node metastases were observed in 65% of the patients on initial presentation. All lymph node metastases, ninety percent of the lung metastases and only 25% of the bone metastases were asymptomatic. Radiography revealed lytic metastases in cases of bone involvement, was normal in 39.6% of the patients, and showed micrometastases in 34.5% and macrometastases in 25.8% of the patients with lung disease. Thyroglobulin (Tg) under thyroxine use was detectable in all patients without antibodies at a cut-off > 1 ng/ml, in 90% at > 5 ng/ml and in 80% at > 10 ng/ml, and after thyroxine withdrawal in 100% at a cut-off > 5 ng/ml and in 94% at > 10 ng/ml. In the case of patients with antibodies (13.8%), Tg was undetectable in half of them. Diagnostic scanning was positive in 83 and 77.6% of the patients with bone and lung metastases, respectively. After ablative therapy, the sensitivity was 100 and 93%, respectively. Eighty-five percent of patients with a negative diagnostic scan had lung metastases visible on radiographs. The determination of serum Tg is the best method in the follow-up of patients with differentiated thyroid cancer. Elevated Tg levels suggest the presence of metastases, indicating the need for ablative therapy with posttreatment scanning, which might reveal non-apparent metastases.     

Effect of diet, age and sex on the renal response to immune injury in the rat

We investigated the effect of three factors, namely dietary protein intake, age and sex, on the susceptibility of the renal glomerulus to the binding of antiglomerular basement membrane antibody (anti-GBM) in the early (heterologous) phase of anti-GBM nephritis, and the consequent reduction in glomerular filtration rate (GFR) as measured by inulin clearance (CIn). The effect of diet was examined in approximately equal to 8 week-old female Munich-Wistar rats fed a 40% high (HP) or a 6% low (LP) protein diet, and that of sex and age in male and female rats, 6 week or 10 month old. Following an intravenous dose (3 to 20 micrograms/g body wt) of radiolabeled nephritogenic anti-GBM, assessment of glomerular function was followed by quantitation of anti-GBM binding (values corrected for GBM surface area) in isolated glomeruli. At a given plasma level of antibody, the degree of binding of anti-GBM was slightly but significantly higher in HP than LP-fed rats; the decrease in GFR was significantly more pronounced in HP than LP-fed animals. The amount of anti-GBM binding was significantly greater in adult than young animals; however, the consequent decrease in GFR was more pronounced in the young than adult animals. Sex dependency was not discernible in anti-GBM binding or reduction in GFR. In all of the above experimental groups, the degree of anti-GBM binding was closely correlated with the plasma level of anti-GBM, but not with effective renal plasma flow rate, measured by PAH clearance. Separate groups of rats were subjected to experimental manipulation of single nephron GFR, glomerular capillary hydraulic pressure and glomerular plasma flow rate, by partial aortic constriction and saralasin administration. This set of experiments, using a tracer amount of non-nephritogenic anti-GBM, revealed that glomerular anti-GBM binding is independent of any of the above parameters. The studies indicate that dietary protein intake and age, but not sex, are among the factors determining the susceptibility of the glomerulus to acute immune injury. Since the binding of anti-GBM is determined by the affinity property of the glomerulus per se, and not by the prevailing hemodynamic pattern, the observed dependence of susceptibility to functional impairment on age and protein intake appears to also reflect a property of the glomerulus, which is influenced by age and the degree of dietary protein intake.     

Abnormal skeletal response to parathyroid hormone in dogs with chronic uremia

Summary The release of cyclic AMP from bone in response to stimulation with PTH 1–34 was examined in 20 dogs with long-term chronic renal failure (CRF) produced by unilateral nephrectomy and contralateral partial renal artery ligation. After 9 to 15 months of uremia, the tibiae were removed and perfused in vitro. Seven dogs with CRF served as controls, 7 dogs with CRF were treated with 24,25(OH)₂D₃ — 2.5 μg per day, and 6 CRF dogs underwent thyroparathyroidectomy (TPTX) 42 h before they were sacrificed. The release of cyclic AMP from bone in response to PTH 1–34 in the CRF dogs was severely reduced compared to the response observed in 7 dogs with normal renal function (net accumulation of cyclic AMP release 86±8.5 versus 426±59.0 pmol/30 min). Long-term treatment of uremic dogs with 24,25(OH)₂D₃ had no effect on the release of cyclic AMP by bone. However, the release of cyclic AMP was restored to normal levels in the CRF dogs that underwent thyroparathyroidectomy. All CRF dogs had secondary hyperparathyroidism and the fact that TPTX returned the cyclic AMP response to normal values suggests that desensitization to PTH of the adenylate cyclase system of bone exists in chronic uremia.     

Effect of dietary lipids on renal function in rats with subtotal nephrectomy

Female rats with 1-3/4 nephrectomy were divided in two groups and pair fed for five weeks diets differing in their linoleic acid content. Five weeks after subtotal nephrectomy, values for glomerular filtration rate and renal plasma flow were significantly higher and the values of blood pressure significantly lower in rats fed a diet rich in linoleic acid. Systolic blood pressure averaged 156 +/- 5.6 mm Hg in high and 215 +/- 8.1 mm Hg in low linoleic acid-fed rats. Differences in the values of blood pressure between the two groups were observed three weeks after subtotal renal ablation and persisted throughout the period of observation. Inulin clearance averaged 0.89 +/- 0.07 ml/min in the high and 0.44 +/- 0.05 ml/min in the low linoleic acid group. Protein excretion in the urine was significantly less in rats fed the high linoleic acid diet (36.9 +/- 4.4 mg/24 hr) than in those fed the low linoleic acid diet (90.1 +/- 12.5 mg/24 hr). The weight of the remnant kidney five weeks after subtotal renal ablation was greater in rats fed a low linoleic acid diet as compared to those fed a high linoleic acid diet (P less than 0.05). Glomerular lesions were more severe in rats fed a low linoleic acid diet than in those fed a high linoleic acid diet. Feeding high linoleic acid diets to normal and subtotally nephrectomized rats increased the content of linoleic and arachidonic acid in renal cortex and medulla.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of Cone-beam Computed Tomographic Artifacts from Different Intracanal Materials on Birooted Teeth

Introduction

This study quantitatively evaluated the type and amount of image artifacts generated by different intracanal materials in birooted teeth scanned at different exposure parameters.