The relationships between autonomic function and heart rate in essential hypertension

The circadian variation of blood pressure (BP) may be mediated at least in part by circadian variation of autonomic nervous system activity. In the present study power spectral analysis of hourly R-R intervals for 24 hours was done to obtain the low frequency variability (LF: 0.04 to 0.15Hz) and high frequency variability(HF: 0.15 to 0.40Hz) in 93 patients with untreated essential hypertension. LF/HF ratio and HF were considered to be an index of sympathetic nervous activity and parasympathetic nervous activity, respectively. The relationship between heart rate (HR) and systolic blood pressure (SBP), diastolic blood pressure (DBP), HF, and LF/HF was examined. Both SBP and DBP were correlated positively with HR(r = 0.28, p < 0.05 and r = 0.27, p < 0.05, respectively) in the daytime. HF was correlated negatively and significantly with HR in both daytime and nighttime (r = -0.40, p < 0.05, and r = -0.38, p < 0.05 respectively). After averaging for SBP of 24 hours, HR in the patients whose SBP was 135mmHg or more was significantly higher than that in the patients whose SBP was less than 135mmHg. These results suggest that the decreased parasympathetic nervous activity seems to be responsible for the rise in BP.     

Conservation of genes encoding HLA-B5 and B35 cross-reactive group antigens in various races

HLA-B5 and B35 CREG antigens include HLA-B35, B51, B52, B53, and B78. Recent studies suggest that the genes encoding the HLA-B5, B35 CREG, and HLA-B58 antigens share a common ancestor. We sequenced the exons of the genes encoding HLA-B51, B53, and B58 from American black individuals and the gene HLA-B52 encoding from an Arabic individual, and compared them with previously reported sequences of HLA-B51 (B^*5101) and HLA-B52 (B^*5201) from Japanese, HLA-B53 (B^*5301) from an Algerian, and HLA-B58 (B^*5801) from a Sardinian. The sequences of the genes from the American black and Arabic individuals were identical to those from the other races. These findings support the hypothesis that these antigens have evolved prior to divergence of the major ethnic groups.     

The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role

PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-gamma. The T-cell proliferative responses and IFN-gamma production that were induced by IFN-gamma-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin.     

Interaction of cyclosporin derivatives with the ATPase activity of human P-glycoprotein

1. P-glycoprotein, a 170–180 kDa membrane glycoprotein that mediates multidrug resistance, hydrolyses ATP to efflux a broad spectrum of hydrophobic agents. In this study, we analysed the effects of three MDR reversing agents, verapamil, cyclosporin A and [3′-keto-Bmt]-[Val^*]-cyclosporin (PSC 833), on the adenosine triphosphatase (ATPase) activity of human P-glycoprotein.
2. P-glycoprotein was immunoprecipitated with a monoclonal antibody (MRK-16) and the P-glycoprotein-MRK-16-Protein A-Sepharose complexes obtained were subjected to a coupled enzyme ATPase assay.
3. While verapamil activated the ATPase, the cyclosporin derivatives inhibited both the substrate-stimulated and the basal P-glycoprotein ATPase. No significant difference was observed between PSC 833 and cyclosporin A on the inhibition of basal P-glycoprotein ATPase activity. PSC 833 was more potent than cyclosporin A for the substrate-stimulated activity.
4. Kinetic analysis indicated a competitive inhibition of verapamil-stimulated ATPase by PSC 833.
5. The binding of 8-azido-[α-³²P]-ATP to P-glycoprotein was not altered by the cyclosporin derivatives, verapamil, vinblastine and doxorubicin, suggesting that the modulation by these agents of P-glycoprotein ATPase cannot be attributed to an effect on ATP binding to P-glycoprotein.
6. The interaction of the cyclosporin derivatives with ATPase of P-glycoprotein might present an alternative and/or additional mechanism of action for the modulation of P-glycoprotein function.

     

Age-related changes of the myelinated fibers in the human corticospinal tract: a quantitative analysis

A quantitative analysis was made of the myelinated fibers in the lateral corticospinal tract (LCST) at the levels of the 6th cervical, 7th thoracic and 4th lumbar spinal segments in 20 patients between 19 and 90 years old, and who died of non-neurological diseases. The diameter frequency histograms of myelinated fibers of LCST showed a bimodal pattern with a sharp peak of the small myelinated fibers and broad slope of the large myelinated fibers. The ratio of small fiber to large fiber densities was significantly higher in the 6th cervical (P<0.05) and 4th lumbar segments (P<0.01) than in the 7th thoracic segments. The density of small myelinated fibers was significantly lowered with advancing age (P<0.050.001), while that of large myelinated fibers was not significantly decreased in the aged patients, although it showed a slight age-dependent declining tendency. Age-dependent decline of small fiber density was more prominent in the cervical and lumbar segments. Retraction of the axon-collaterals from large-diameter myelinated fibers, which are abundant in the cervical and lumbar segments, may contribute to the age-related diminution of the small myelinated fibers in the LCST.Part of this work was supported by grants from the Ministry of Welfare and Health of Japan, and a grant from Uehara Memorial Research Foundation     

Phyllodes tumor of the breast with a grossly malignant appearance: A case report

A huge phyllodes tumor of the breast that appeared grossly malignant in a 43-year-old woman is described. The patient suffered from a large breast tumor that suddenly increased in size over 5 months to occupy the entire breast. The tumor was hard, ulcerated and 20 cm in greatest diameter. Diagnostic imaging (US, CT and MRI) demonstrated a circumscribed mass with a large cystic cavity. She underwent total mastectomy under a diagnosis of malignant breast tumor. Grossly, the cut surface of the tumor showed a large cystic cavity surrounding a fleshy, hemorrhagic and necrotic mass with a lobulared or trabeculared appearance. Unexpectedly, benign phyllodes tumor (PT) without any stromal overgrowth was diagnosed histologically. She has been doing well since total mastectomy. In our case and in many other reported cases, PT does not show any distinctive correlation between pathologic findings and tumor behavior. Thus wide local excision is the preferred initial treatment for PT.     

Functioning and nonfunctioning adrenal medullary tumors

Recent development of imaging tools such as computed tomography, ultrasonography, and magnetic resonance imaging have incidentally discovered hormonally functioning or nonfunctioning adrenal tumors. Most adrenal medullary tumors are pheochromocytomas and neuroblastoma group tumors. They are representative of neuroendocrine tumors and can be diagnosed using neuroendocrine markers such as chromogranin A, synaptophysin, and neurofilament proteins. Catecholamine-synthesizing enzymes are also useful markers for these catecholamine-producing tumors. Both pheochromocytoma and neuroblastoma group tumors have cells that are immunohistochemicaJly positive for many peptide hormones including m-enkephalin, neuropeptide Y, somatostatin, vasoactive intestinal peptide, corticotropinreleasing hormone, adrenocorticotropic hormone, calcitonin, and calcitonin gene-related peptide, among others. The evidence for production of these hormones is confirmed by mRNA analysis using in situ hybridization or Northern blot hybridization and by measuring protein levels with radioimmunoassay. Only a limited number of patients, however, complain of clinical symptoms associated with excessive peptide hormone production such as watery diarrhea, hypokalemia, and achlorhydria syndrome or Cushing’s syndrome. The monoclonal human neuroblastoma cell line (NB-1) is a good model by which to understand the mechanism of excessive hormone production. NB-1 cells are usually nonfunctioning, but when they are stimulated by cyclic adenosine monophosphate and phorbol ester, they become capable of production and release of many peptide hormones and undergo morphological changes in their endocrine features. Thus, microenvironmental change seems to be one of the factors regulating gene expression and hormone production. Some molecular studies of oncogenes and growth factors are reviewed to gain an understanding of cell differentiation and proliferation. Finally, several chromosomal abnormalities reported in multiple endocrine neoplasia are introduced as potential tumorigenic factors.     

The expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase associates with angiogenesis in epithelial ovarian cancer

Background The object of this study is to clarify the association of an angiogenic factor, PD-ECGF (platelet-derived endothelial cell growth factor/thymidine phosphorylase), with clinicopathologic factors, in this case tumor angiogenesis, in epithelial ovarian cancers. Methods Tumor specimens were obtained at the time of surgery from the primary lesion in 60 patients with epithelial ovarian cancer. Histologic cell types were assigned to tumors according to the World Health Organization classification: 26 were classified as serous adenocarcinoma, 15 as endometrioid adenocarcinoma, 9 as mucinous adenocarcinoma, 9 as clear cell carcinoma, and 1 as undifferentiated carcinoma. Surgical staging was based on the international Federation of Gynecology and Obstetrics (FIGO) staging system: 16 were stage I, 6 were stage II, 34 were stage III, and 4 were stage IV. Expression of PD-ECGF was evaluated by immunohistochemical staining. Microvessel density was assessed by immunostaining for factor VIII-related antigen in the most neovascularized area. Results Stroma cells stained more strongly than cancer cells (80% vs. 33%). The immunopositivity of PD-ECGF in stroma cells was higher in cases of advanced cancer. Expression of PD-ECGF in mucinous adenocarcinomas was significantly higher than that in serous adenocarcinomas, while PD-ECGF expression in clear cell carcinomas was significantly lower. The microvessel density in the cases with marked PD-ECGF-positive stroma cells was significantly higher than that in the cases with absent/minimal PD-ECGF-positive stroma cells (P<0.05). Conclusion The expression of PD-ECGF may play a crucial role in the promotion of angiogenesis in epithelial ovarian cancers.