Inhibition of mediator release in systemic mastocytosis is associated with reversal of bone changes

A 59-year-old male presented with systemic mastocytosis with extensive skeletal involvement resulting in vertebral compression fractures and bone pain. Histomorphometric analysis of bone revealed increased mast cells, elevated static parameters of bone resorption, and low bone formation. Serum calcium, phosphorus, and alkaline phosphatase were normal; however, serum 1,25-dihydroxyvitamin D3 and osteocalcin levels were low. Histamine levels in plasma and urine were elevated. Following therapy with ketotifen, the patient had resolution of bone pain along with decreased flushing and pruritus. Elevated plasma and urine histamine levels normalized, as did 1,25-dihydroxyvitamin D3 and osteocalcin levels. Indices of low bone formation improved on therapy. Eroded surfaces improved but remained elevated. This case is the first demonstration that bone symptoms and histomorphometric change in systemic mastocytosis are reversed with inhibition of mast cell degranulation. The role of mast cells and their products in bone metabolism is poorly understood, but the therapy of bone disease in systemic mastocytosis should include inhibition of the release of mast cell products along with the use of histamine antagonist.     

Separation of internal derangements of the temporomandibular joint using sound analysis

This clinical-arthrographic investigation compares power spectral analysis of temporomandibular joint sounds with different arthrographic characteristics of intracapsular dysfunction. The quantitative comparison of specific parameters of the sound power-spectrum waveform may provide a sensitive and accurate noninvasive tool for diagnosis and treatment.     

Influence of diabetes mellitus on the results of coronary bypass surgery. Follow-up of 212 diabetic patients ten to 15 years after surgery

To determine the long-term influence of the severity of preoperative diabetes mellitus on the results of coronary bypass, a review was made of 212 diabetics operated on between 1968 and 1973, of whom 87 patients (41%) were receiving no drugs, 108 patients (50.9%) were receiving oral hypoglycemic agents, and 17 patients (8%) were receiving insulin. They were compared with 1,222 nondiabetic patients operated on over the same period. Perioperative mortality was similar in the diabetics and nondiabetics: 7.1% vs 4.5%. Improvement in anginal symptoms was similar in all patient groups: 85.9% to 92.7%. Overall 15-year survival probability was .53 for the nondiabetic group, .43 for the diabetics not receiving drugs, .33 for those receiving oral agents, and .19 for the insulin-treated patients. Late graft patency ranged from 78% to 90% and was comparable in all groups. The preoperative blood glucose level was an important predictor of late mortality in all diabetic patients. Thus, coronary bypass surgery was effective in all groups of diabetic patients in long-term relief of anginal symptoms. Intermediate-term survival rates were good in all groups, but the initial severity of the diabetes was an important determinant of long-term survival rates.     

Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo.

The objective of this study was to determine the effects of flavonoids on the in vitro monocarboxylate transporter 1 (MCT1)-mediated transport and in vivo disposition of the drug of abuse, gamma-hydroxybutyrate (GHB). The uptake of GHB in rat MCT1 gene-transfected MDA-MB231 cells was significantly decreased in the presence of the flavonoids apigenin, biochanin A, chrysin, diosemin, fisetin, genistein, hesperitin, kaempferol, luteolin, morin, narigenin, phloretin, and quercetin, but was not affected by the flavonoid glycosides phloridzin and rutin. The IC(50) values for luteolin, morin, and phloretin were 0.41 +/- 0.14, 6.41 +/- 2.01, and 2.57 +/- 0.48 microM, with the inhibition mechanism for luteolin being competitive. [(3)H]Kaempferol and [(3)H]biochanin A did not exhibit MCT1-mediated uptake, suggesting that these flavonoids are not substrates for MCT1. The combination of luteolin and phloretin inhibited the uptake of GHB in a synergistic manner; however, the combination of luteolin and morin was antagonistic. GHB 1000 mg/kg was administered to rats by i.v. bolus, with or without the concomitant administration of luteolin 10 mg/kg i.v. After luteolin treatment, the renal and total clearances of GHB were significantly increased, probably because of inhibition of the MCT1-mediated renal reabsorption of GHB, and the sleep time significantly decreased (121 +/- 5 min versus 165 +/- 10 min) compared with control rats. Overall, the results of this study indicate that flavonoids from food or herbal products may significantly alter the pharmacokinetics and pharmacodynamics of MCT substrates.     

Autologous graft-versus-host disease: a novel approach for antitumor immunotherapy.

Autologous bone marrow transplantation (BMT) is a therapeutic option for the treatment of lymphohematopoietic malignancies and solid tumors. Despite the intensive cytoreductive therapy, however, the rates of tumor recurrence after autologous BMT remain unacceptably high. Current studies suggest that the administration of cyclosporine (CsA) disrupts the reconstitution of self-tolerance following autologous BMT leading to the induction of an autoimmune graft-versus-host disease (GVHD). Studies in a rat tumor model and preliminary clinical trials suggest that this autoimmune or autologous GVHD provides a significant antitumor effect. Moreover, the antitumor effect of autologous GVHD can be enhanced by administration of gamma-interferon, which upregulates the antigen recognized by the autoreactive effector cells of autologous GVHD. These studies indicate that the induction of an autoimmune GVHD after autologous BMT may be a promising immunotherapeutic approach for treatment of certain neoplastic diseases.     

Disseminating tumor cells and their interactions with leukocytes visualized in the brain.

Brain tumors are increasingly prevalent. Recent advances focus attention on individual, disseminated tumor cells that cannot be imaged or eliminated. Cells of the immune system may be ideally suited to attack individual tumor cells, but more basic understanding is needed. We describe a rat model, using the lacZ reporter gene, that allows identification of individual tumor cells, and tumor-leukocyte interactions in vivo. The model demonstrates how widely tumor can disseminate, without secondary tumorigenesis or recruitment of nonneoplastic cells. It demonstrates that leukocytes have access to disseminating tumor. Among its many applications, this work lays a foundation for developing cell-mediated immunotherapy against individual brain tumor cells.     

An investigation of the suitability of bra fit in women referred for reduction mammaplasty.

Reduction mammaplasty is rationed in NHS plastic surgery provision, despite abundant evidence that most women who undergo this operation obtain significant improvement in their physical health and quality of life. We suspected that women seeking reduction mammaplasty often wear ill-fitting bras, which may exacerbate some of their symptoms. Therefore, we studied 103 women who attended a nurse-run pre-assessment clinic, asking them what size bra they currently wore and then measuring them to see whether their bra size was correct. We also questioned bra manufacturers, designers and shop bra fitters about bra manufacture, sizing and fitting techniques, and we reviewed these findings. Of the 102 women suitable for inclusion in the study, all wore the wrong size bra. Their mean 'claimed' back measurement was 36 inches (range: 30-42 in.) and their mean cup size was F (range: C-J). We found that all but one underestimated their back measurement (by a mean of 4 in.; range: -2-10 in.) and overestimated their cup size (by a mean of three sizes; range: one size smaller to seven sizes larger) when compared with manufacturers' fitting guidelines. Multiple regression analysis used to assess the relationships of various factors to incorrect bra sizing showed a strong link (Pearson correlation=0.54; P<0.001) between obesity and inaccurate back measurement. The reasons why women with breast hypertrophy wear incorrectly fitting bras are discussed. We conclude that obesity, breast hypertrophy, fashion and bra-fitting practices combine to make those women who most need supportive bras the least likely to get accurately fitted bras, so exacerbating the symptoms for which they seek surgery.     

Association of angiotensin II type 1 receptor gene polymorphism with essential hypertension

The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A→C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT₁R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/ Bfr I restriction fragment length polymorphism analysis. Frequency of the C¹¹⁶⁶allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (χ²= 13, P = 0.0015) and allele (χ²= 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA+AC = 7.3 [95% CI, 1.9–31.9). The present results implicate the AT₁R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.