Alendronate prevents bone loss in patients with acute spinal cord injury: a randomized, double-blind, placebo-controlled study.

CONTEXT: Patients who sustain an acute spinal cord injury (SCI) experience rapid dramatic reductions in bone mineral density (BMD), especially marked in sublesional areas and sometimes leading to hypercalcemia and hypercalciuria, as well as increased fracture risk. OBJECTIVE: In this prospective, double-blind, randomized, placebo-controlled study, we evaluated the hypothesis that oral alendronate administration would preserve BMD when administered soon after acute SCI. PATIENTS AND INTERVENTION: Thirty-one patients with acute SCI were randomly allocated to receive oral alendronate 70 mg/wk or placebo, within 10 d of acute SCI, for 12 months. MAIN OUTCOME MEASUREMENTS: At entry and at 3, 6, 12, and 18 months, total body bone density, lumbar and hip BMD, ultrasound of the calcaneus, 24-h urinary calcium, and serum C-telopeptide (betaCTX) were measured. RESULTS: At study entry, patients in the two groups were well matched for age, gender, severity of neurological deficit, BMD, urinary calcium, and betaCTX. BMD indices declined steadily in the placebo group, and this effect was attenuated significantly by alendronate. After 12 months, there was a 5.3% difference (P<0.001) in total body BMD and a 17.6% difference (P<0.001) in the total hip BMD between the two groups. Alendronate compared with placebo induced significant (P<0.001) reductions in urinary calcium excretion and serum betaCTX. No treatment-related side effects were noted. CONCLUSIONS: We conclude that alendronate therapy, 70 mg/wk, initiated soon after acute SCI, prevents bone loss and is not associated with side effects.

A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

Effects of diary food supplements on bone mineral density in teenage girls.

BACKGROUND: Bone mineral density (BMD) is largely genetically determined and this influence is most powerful in the period of rapid skeletal development in childhood and late adolescence but environmental factors such as exercise and dietary calcium intake may influence up to 20%. AIMS OF THE STUDY: The aims of the study were to examine healthy late adolescent females for the effects and benefits of a high calcium intake from dairy product foods on bone mineral density, body composition, lipids and biochemistry. The secondary aim is determine whether a high intake of dairy product foods in the diet is acceptable for this age group long term. METHODS: Ninety-one teenage girls who participated in a two-year randomised controlled study on the effect of dairy food supplementation on dietary patterns, body composition and bone density in post-pubertal teenage girls were approached one year after the cessation of the study to determine the effects of the cessation of dairy supplements on bone mineral density, dietary habits, biochemical markers, body composition and blood lipids. Bone mineral density and bone mineral content were assessed at the hip, spine and total body. Anthropometric data were collected, and exercise, Tanner, dietary assessment, preference and compliance questionnaires were administered. Lipid profiles, hydroxyproline excretion and urinary calcium and sodium excretion measurements were performed. RESULTS: There were no significant differences between the 2 groups for height, weight, lean and fat mass. The supplemented group had significantly higher calcium, phosphorus and protein intake during the supplementation period (p < 0.001). No differences were seen between the groups 12 months after supplementation finished. There were no significant differences in exercise level, preference or acceptability of dairy products or in the lipids and bone markers between baseline the end of supplementation and 1 year follow-up. There was a significant increase in trochanter (4.6%), lumbar spine (1.5%) and femoral neck (4.8%) BMD (p < 0.05) in the high calcium group at the end of supplementation. There was an increase in bone mineral content at the trochanter (p < 0.05) and lumbar spine; however the latter was not statistically significant, in the high calcium group at the end of supplementation. There was no difference in vertebral height or width at any stage of the study, indicating no influence on bone size. CONCLUSIONS: In this 3 year study (2 years of supplementation, 1 year follow-up), teenage girls, aged 15-18 years, were able to significantly increase their BMD at the trochanter, femoral neck and lumbar spine when supplemented with dairy product foods to a mean calcium intake of 1160 mg/d. There was also an effect seen on the BMC particularly at the trochanter and to a lesser extent at the lumbar spine. The dietary calcium intake achieved did not adversely affect body weight, fat and lean mass or blood lipid profiles. Twelve months after the supplementation finished the girls had returned to their baseline diet, indicating self-selection of a high dairy product diet may be hard to achieve.

Effects of chronic low-frequency stimulation on Ca2+-regulatory membrane proteins in rabbit fast muscle.

Since chronic low-frequency stimulation of fast-twitch muscle fibers has a profound effect on all major functional elements of skeletal muscle, we analyzed the potential changes in the levels of Ca2+-regulatory membrane proteins during fast-to-slow transformation. In this study we show that, in addition to isoform-switching in myosin heavy chains, electrostimulation triggers a decline in fast isoforms and an increase in slow/cardiac isoforms of Ca2+-ATPase and calsequestrin. The levels of excitation-contraction coupling elements, such as the ryanodine receptor, the dihydropyridine receptor, triadin and sarcalumenin, decreased sharply following stimulation. In contrast, levels of Na+/K+-ATPase and calreticulin increased in the microsomal fraction. Crosslinking studies have revealed that in normal and stimulated muscle the Ca2+-ATPase isoforms exist predominantly as oligomeric structures, and that the central elements of excitation-contraction coupling also form large triad complexes. Changes in the levels and pattern of isoform expression of the muscle membrane proteins studied here suggest that these biochemical alterations reflect molecular adaptations to changed demands in ion homeostasis and signal transduction in muscle that exhibits enhanced contractile activity. Overall, these findings support the physiological concept that there are muscle fiber-type specific differences in the fine-tuning of the excitation-contraction-relaxation cycle, as well as the idea that mature skeletal muscle fibers exhibit a high degree of plasticity.

The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy.

PURPOSE: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS). METHODS AND MATERIALS: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia. RESULTS: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor. CONCLUSIONS: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

The kinetics of change in cytokine production by CD4 T cells during conventional allergen immunotherapy.

BACKGROUND: The effect of conventional allergen immunotherapy on allergen-specific T lymphocyte cytokine production is incompletely understood, particularly during the initial phase of treatment. OBJECTIVE: The purpose of this study was to prospectively follow the kinetics of change in CD4(+) T cell cytokine secretion during the course of conventional immunotherapy. METHODS: Six allergic individuals were treated with extracts of Dermatophagoides farinae/Dermatophagoides pteronyssinus or with rye grass pollen (Lolium perenne) allergen, but not both, by using an internally controlled conventional immunotherapy protocol. CD4(+) T cells from peripheral blood were examined in vitro at varying intervals after the initiation of immunotherapy by stimulation with D farinae or L perenne group I antigen. The quantity of IL-4 and IFN-gamma produced and its relationship to clinical improvement was determined. RESULTS: The ratio of allergen-specific IL-4/IFN-gamma production by CD4(+) T cells from 4 of 6 individuals receiving immunotherapy greatly increased during the period when the dose of allergen was increasing. However, after high-dose maintenance therapy was achieved, this ratio decreased in subjects responding clinically to, but not in those failing, immunotherapy. In addition, late-phase skin reactions and allergen-specific IgE levels in responding, but not in nonresponding, subjects diminished over the course of immunotherapy. CONCLUSION: Conventional immunotherapy may initially exacerbate allergic disease by increasing allergen-specific IL-4 and allergen-specific IgE production. Later clinical improvement is associated with a reduction in allergen-specific IL-4 production and in allergen-specific serum IgE.

Thalamic glucose metabolism in temporal lobe epilepsy measured with 18F-FDG positron emission tomography (PET).

Thalamic glucose metabolism has been studied in 24 patients suffering from temporal lobe epilepsy (TLE) using interictal 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). A total of 17 patients had a unilateral TL seizure onset, 11 of these patients had a mesial temporal lobe epilepsy syndrome (MTLE), with mesial gliosis and a mesial TL seizure origin. Three patients had a lateral TL seizure origin, and 3 patients had mesial TL tumors. Bilateral TLE was assumed in 7 patients. Only in the patient group with MTLE (n = 11), the ipsilateral thalamic glucose uptake showed a statistically significant lower value when compared to the thalamus of the contralateral side (Wilcoxon paired sign test, P = 0.012). There was a more pronounced hypometabolism in right TLE compared to left TLE. A 'hypersynchronous seizure onset pattern' in ictal EEG was only seen in 6 (26%) patients (1 patient with bilateral, 5 with unilateral TLE). No correlation existed between the thalamic, temporal glucose metabolism and the 'hypersynchronous seizure onset pattern'.

Chronic treatment with dexmedetomidine desensitizes alpha 2-adrenergic signal transduction.

Tolerance to the hypnotic response was induced in rats by chronically infusing dexmedetomidine, a novel alpha 2-adrenergic agonist. The alpha 2-adrenoceptor affinity for dexmedtomidine and para-iodoclonidine was significantly reduced in tolerant rats, while Bmax was uncharged. The ability of pertussis toxin (PTX) to ribosylate guanine nucleotide regulatory proteins (G proteins) ex vivo was reduced in tolerant rats; the quantity of PTX-sensitive G proteins was unchanged. Forskolin-stimulated adenylyl cyclase was less sensitive to inhibition by dexmedetomidine in the tolerant rats; however, acute intraperitoneal injection of dexmedetomidine still reduced cyclic adenosine monophosphate levels in tolerant rats. Both the decrease in ribosylation and the lower alpha 2-adrenoceptor binding affinity may reflect a decrease in the ability of the G protein to couple to the alpha 2-adrenoceptors in the locus coeruleus of tolerant rats. In this state, the alpha 2 adrenoceptors are less capable of transducing the effector response (inhibition of adenylyl cyclase).

Managing the anxious patient with advancing disease--a flow diagram.

Anxiety can be one aspect of the psychological reaction to cancer and may be present at a clinical level. It can hinder or even prevent the diagnosis and management of other problems and when it develops into an anxiety state it can be disabling. This flow diagram describes the key clinical decisions involved in diagnosing and helping a patient troubled with anxiety.