Myoepithelial Cells in the Control of Mammary Development and Tumorigenesis: Data From Genetically Modified Mice

Until recently, myoepithelial cells—the second major cell population in the mammary epithelium—were not considered to play an important role in the morphogenetic events during gland development. Mouse mutants with changes in the gene expression pattern characteristic of the basal myoepithelial cell layer have been generated and used to show that these cells influence the proliferation, survival and differentiation of luminal cells, modulate stromal–epithelial interactions and actively participate in mammary morphogenesis. Various cellular and molecular mechanisms may underlie the observed phenotypes. These include an unbalanced expression of matrix degrading metalloproteinases (MMPs) and their inhibitors, leading to changes in the composition and organization of the (extracellular matrix) ECM, the production of soluble growth factors affecting stromal and epithelial cell growth and differentiation and direct signaling through cell–cell contacts between the myoepithelial and luminal cell layers.     

Current therapy for Charcot-Marie-Tooth disease

Opinion statement Charcot-Marie-Tooth (CMT), or heritable peripheral neuropathies, is among the most frequent genetic neuromuscular disorders, with a prevalence of approximately 1:2500. Since 1991, remarkable advances have occurred in determining the precise genetic cause of many forms of CMT and in generating animal models of many of these disorders. However, these advances have not yet resulted in cures for CMT. Recently, potential treatments for the most common form of CMT, CMT-1A, have been shown in rodent models of the disorder. Treatment with onapristone, a progesterone antagonist, has improved the neuropathy of the CMT-1A rat. Treatment with large doses of ascorbic acid (vitamin C) has improved the neuropathy of the CMT-1A mouse. Multicentric trials with ascorbic acid are likely to start in the near future to assess if vitamin C supplementation is effective and what is the dosage required in humans to improve neurologic disability. Because of potential side effects with antiprogesterone therapy, particularly in women of childbearing age, research is actively proceeding with progesterone antagonists to develop safe medications that also can be used in clinical trials of CMT-1A. Although no cures are available for CMT, there are many important treatments available for patients with CMT that can improve their quality of life and help them maintain their independence. Some of these therapies involve physiatry and orthopedic surgery. Others involve pain management. Lastly, there are potential concerns about medications or lifestyle issues that may exacerbate CMT. All of these issues will be discussed.     

BMP binding peptide: a BMP-2 enhancing factor deduced from the sequence of native bovine bone morphogenetic protein/non-collagenous protein.

Forty years ago, Marshall Urist described a partially purified extract of demineralized bone matrix which induced the formation of ectopic bone. This substance, bone morphogenetic protein/non-collagenous protein (BMP/NCP), was never purified to homogeneity but other investigators used similar starting materials to clone a number of recombinant BMPs. Urist recognized that his material probably contained the BMPs which had been cloned by others but always contended that it contained another, more potent, bone inducing material which differed significantly in its physical and chemical properties from the known BMPs. We have used Urist's protocol to isolate a protein that has the chemical and physical properties of Urist's "BMP". It is an 18.5 kD fragment of the bone matrix protein, SPP-24. This fragment contains the cystatin-like domain of SPP-24. We have located a 19 amino acid region which is similar to the TGF-beta/BMP-binding region of fetuin, a member of the cystatin family of protease inhibitors. A cyclic peptide, which we call BMP binding peptide (BBP) was generated using this sequence. The peptide avidly bound rhBMP-2 with a KD of 3 x 10(-5) M. When implanted alone in mouse muscle, the peptide frequently induced dystrophic calcification. When implanted with rhBMP-2, the peptide enhanced the osteogenic activity of the recombinant molecule. We hypothesize that Urist's "BMP" was a fragment of SPP-24 which influenced bone induction by binding to bone morphogenetic proteins. BBP may be clinically useful because of its effects on other bone-inducing substances.     

Lymphocyte 5'-nucleotidase and aminopeptidase N activity in patients on maintenance hemodialysis treated with human recombinant erythropoietin and 1-alpha-D3

BACKGROUND: Patients with end-stage renal disease (ESKD) present an immunodeficiency state paradoxically exacerbated by hemodialysis (HD) and associated with signs of T-cell activation. B cells are also activated in uremia, and this activation could be altered by erythropoietin therapy in HD patients. In this study, the effects of human recombinant erythropoietin (rHu-EPO) and 1-alpha-D3 treatments on lymphocyte immunomodulatory enzymes, aminopeptidase N (APN), and 5'-nucleotidase activity in patients on HD were investigated in hemodialysis patients before and after two-month treatment with s.c. rHu-EPO (15 patients, 2000-3000 U three times weekly) or oral 1-alpha-D3 (14 patients, 2 microg three times weekly). RESULTS: A two-month EPO treatment of 15 HD patients produced a rise in hemoglobin from 6.51 +/- 0.18 to 9.69 +/- 0.14 g/dL. Basal lymphocyte APN activity in HD patients was not significantly different from the level in healthy controls. Treatment of patients with rHu-EPO increased unstimulated lymphocyte APN activity to values significantly higher than those before treatment (p<0.05). A two-month pulse oral 1-alpha-D3 treatment of 14 HD patients increased hematocrit by 21% and raised hemoglobin from 7.11 +/- 0.32 to 8.80 +/- 0.39 g/dL. Unstimulated and Con A-stimulated lymphocyte APN activity after pulse oral 1-alpha-D3 was significantly increased (p<0.01 and p<0.05, respectively) from the pretreatment levels. In HD patients lymphocyte basal, Con A-, and PMA-stimulated 5'-nucleotidase activity was significantly higher (p<0.05) than it was in healthy controls. The two-month treatment with rHu-EPO or pulse oral 1-alpha D3 did not change the level of lymphocyte 5'-nucleotidase in these patients. CONCLUSIONS: This study demonstrated that a two-month treatment of HD patients with rHu-EPO or pulse oral 1-alpha D3 significantly increases activity of lymphocyte APN, important for cleavage of peptides and small proteins, which accumulate in the blood of ESKD patients. In HD patients lymphocyte ecto-5'-nucleotidase activity was significantly higher than that in healthy controls and was not changed after a two-month treatment with rHu-EPO or pulse oral 1-alpha D3. We speculate that oxidative stress activates 5'-nucleotidase and production of adenosine by lymphocytes of HD patients.     

Gleason grading of prostate cancer in needle biopsies or radical prostatectomy specimens: contemporary approach, current clinical significance and sources of pathology discrepancies

The Gleason grading system is a powerful tool to prognosticate and aid in the treatment of men with prostate cancer. The needle biopsy Gleason score correlates with virtually all other pathological variables, including tumour volume and margin status in radical prostatectomy specimens, serum prostate-specific antigen levels and many molecular markers. The Gleason score assigned to the tumour at radical prostatectomy is the most powerful predictor of progression after radical prostatectomy. However, there are significant deficiencies in the practice of this grading system. Not only are there problems among practising pathologists but also a relative lack of interobserver reproducibility among experts.     

Effect of Hypericum perforatum CO2 extract on the motivational properties of ethanol in alcohol-preferring rats

AIMS: Extracts of Hypericum perforatum (HPE) attenuate voluntary ethanol intake in different lines of alcohol-preferring rats. The present study evaluated the effect of the intragastric (IG) administration of a CO(2) Hypericum perforatum extract (HPCO(2)) on operant ethanol self-administration, as well as on voluntary ethanol intake, after a period of ethanol deprivation in genetically selected Marchigian Sardinian alcohol-preferring rats. METHODS: HPCO2 was administered by means of an indwelling IG catheter, 1 h before the tests. For the self-administration experiments, the rats were trained to self-administer 10% (v/v) ethanol in 30-min daily sessions under a fixed ratio 1 schedule of reinforcement. HPCO2 was also tested on 0.2% w/v saccharin self-administration. For the ethanol deprivation experiments, rats that had a previous experience with voluntary ethanol drinking were deprived of ethanol for 9 days, whereas water and food were freely available; HPCO2 was given by IG injection 1 h before the ethanol re-presentation. RESULTS: HPCO2 in doses of 31 or 125 mg/kg but not 7 mg/kg, significantly reduced ethanol self-administration, while it did not modify saccharin self-administration. The same doses of the extract abolished the increased ethanol intake following ethanol deprivation. CONCLUSIONS: These findings provide evidence that HPCO2 markedly reduces the reinforcing properties of ethanol in the self-administration paradigm, as well as the increase of ethanol intake following ethanol deprivation. These findings further support the view that the use of HPE may represent an interesting pharmacological approach in the treatment of alcohol abuse and alcoholism.     

Occupation and thyroid cancer risk in Sweden

OBJECTIVE: The objective of this study was to identify occupations and industries with increased incidence of thyroid cancer in Swedish workers. METHOD: Standardized incidence ratios were computed for each job and industry for the period 1971-1989 through record-linkage with the Swedish National Cancer and Death Registers. Age-, period-, geographically adjusted relative risks were calculated using Poisson models. RESULTS: Increased risks were found for teachers, construction carpenters, policemen, and prison/reformatory officials in men, and medical technicians, shop managers, tailors, and shoecutters among women. Industries with risk excess are manufacture of agricultural machinery, manufacture of computing/accessories, and public administration/police among men; and manufacture of prefabricated wooden buildings, electric installation work, and wholesale of live animals/fertilizers/oilseed/grain among women. CONCLUSIONS: Our results corroborate some previously reported increased risks. Further research is needed to assess the influence of specific chemical agents related with some of the highlighted work environments.     

Income inequality and mortality in Italy

BACKGROUND: The relationship between income inequality and health remains controversial in terms of whether or not it exists and, if so, its extent and the mechanisms involved. This study examines the relationship between income inequality, as indicated by the Gini coefficient, and mortality in Italy. METHODS: Cross-sectional ecological study on the 57,138,489 inhabitants living in the 95 provinces existing in Italy in 1994. Multivariate weighted regression analysis of total and age-specific mortality, income inequality, gender, and interaction between income inequality and median income or geographical area. RESULTS: A positive association between income inequality and total mortality was observed for both genders in provinces with a low per capita income and in Southern and Central Italy. The effect was present for infants and for persons over 24 years of age; it was marked for the elderly, particularly women. A negative association with mortality was observed for males living in the North-west. Interactions between income inequality and median income, and between income inequality and geographical area were found. CONCLUSION: In Italy, the relationship between income inequality and health is mixed and not universal, in so far as a positive association was observed only in provinces with lower absolute income. Elderly persons living in Southern Italy represent the population subgroup most vulnerable to unequal income distribution. Income inequality can, in part, explain the historically higher mortality among women in Southern Italy compared to women in the North. These results indicate that income inequality affects the health of population subgroups differentially.