Myocardial aging

This review questions the old paradigm that describes the heart as a post-mitotic organ and introduces the notion of the heart as a self-renewing organ regulated by a compartment of multipotent cardiac stem cells (CSCs) capable of regenerating myocytes and coronary vessels throughout life. Because of this dramatic change in cardiac biology, the objective is to provide an alternative perspective of the aging process of the heart and stimulate research in an area that pertains to all of us without exception. The recent explosion of the field of stem cell biology, with the recognition that the possibility exists for extrinsic and intrinsic regeneration of myocytes and coronary vessels, necessitates reevaluation of cardiac homeostasis and myocardial aging. From birth to senescence, the mammalian heart is composed of non-dividing and dividing cells. Loss of telomeric DNA is minimal in fetal and neonatal myocardium but rather significant in the senescent heart. Aging affects the growth and differentiation potential of CSCs interfering not only with their ability to sustain physiological cell turnover but also with their capacity to adapt to increases in pressure and volume loads. The recognition of factors enhancing the activation of the CSC pool, their mobilization, and translocation, however, suggests that the detrimental effects of aging on the heart might be prevented or reversed by local stimulation of CSCs or the intramyocardial delivery of CSCs following their expansion and rejuvenation in vitro. CSC therapy may become, perhaps, a novel strategy for the devastating problem of heart failure in the old population.     

Sex hormone profile and endometrial cancer risk in primary biliary cirrhosis: a case-control study

OBJECTIVE: To investigate the sex hormone profile and endometrial histology in primary biliary cirrhosis (PBC). STUDY DESIGN: A prospective case-control study. Twenty-two females with PBC and 22 sex- and age-matched healthy controls underwent complete gynaecological examination including endometrial biopsy and a sex hormone serological profile including: oestrone, 17-beta oestradiol, testosterone, progesterone, dehydroepiandrosterone sulphate (DHEA-S) and sex hormone binding protein (SHBG). The sex hormone profile was evaluated with respect to the body mass index (BMI), anthropometric measurements and endometrial histological/cytological patterns in each case. Statistical analysis was done with the chi-squared method, Student's t-test for unpaired data, linear regression analysis, Spearman's rank correlation test and stepwise multiple regression analysis. RESULTS: The BMI was comparable in the two groups, while PBC cases had significantly smaller subscapular, waist, bicipital, tricipital and calf fold measurements than controls. Testosterone serum levels were significantly lower in PBC cases than in controls (0.9+/-0.6 versus 1.4+/-0.7 mmol/l, P<0.03), whereas SHBG was significantly higher than in controls (88.6+/-72.1 versus 63.6+/-27.6, P<0.005). No significant differences between the two groups were found for oestrone, 17-beta oestradiol, DHEA-S, and progesterone levels. No difference patterns were observed in endometrial histological/cytological patterns. Multiple regression analysis identified SHBG as an independent variable associated with PBC. CONCLUSIONS: Changes in sex hormone profile are secondary to hepatic dysfunction in PBC. Females with PBC do not appear to carry a higher risk of endometrial cancer.     

Intra-hepatic cholestasis of pregnancy in hepatitis C virus infection

BACKGROUND: Aims of this study were to investigate whether hepatitis C virus infection influences the incidence and natural history of intrahepatic cholestasis of pregnancy (ICP) and whether ICP has different characteristics in hepatitis C virus (HCV) positive women from ICP in HCV negative women. METHODS: A prospective study for the prevalence of the HCV infection and for the incidence of ICP was carried out in the 5840 patients admitted to the Prenatal Department of Padua University, Italy, between January 1996 and January 1999. Testing was done for HCV by the enzyme linked immunosorbent assay (ELISA 3), recombinant immuno blot assay (RIBA 3) and polymerase chain reaction (PCR). The diagnosis of ICP was made on clinical grounds based on the occurence of pruritus with onset during pregnancy, persisting up to the time of delivery and disappearing after delivery, supported by demonstrating an elevation of both serum ALT and total serum bile acids. The Student's t-test, one way anova and chi-square tests were used for statistical analysis. RESULTS: During the study period, 56 of 5840 patients developed ICP (0.96%). Of these, 12 were also HCV-RNA positive. The rate of ICP was observed more commonly in HCV-RNA positive women than in HCV-RNA negative women (20.33% or 12/59 versus 0.78% or 44/5767, P = 0.001 CONCLUSIONS: Occurrence of ICP during the third trimester should be an indication to investigate the HCV status of the patient. Although the diagnosis of ICP is not confirmed by specific tests, we confirmed a higher risk of HCV infection in this condition. Therefore, occurence of ICP during the third trimester should be an indication to investigate the HCV status of the patient. Broader studies are necessary to assess the impact of infection on the perinatal outcome of ICP.     

Comparison of hysteroscopic and hysterectomy findings for assessing the diagnostic accuracy of office hysteroscopy

OBJECTIVE: To assess the diagnostic accuracy of office hysteroscopy by comparing the hysteroscopic findings with the histologic findings on the hysterectomy specimens.DESIGN: Retrospective clinical study.SETTING: University-affiliated hospital.PATIENT(S): Review of the hospital records of 443 patients who underwent office hysteroscopy and, within 2 months, hysterectomy.INTERVENTION(S): We compared the hysteroscopic findings (including targeted biopsies) with the histologic findings that were obtained after hysterectomy. The results of this study were then compared with those of a previous study in which we examined the diagnostic accuracy of dilatation and curettage (D&C).MAIN OUTCOME MEASURE(S): We evaluated the diagnostic accuracy of office hysteroscopy.RESULT(S): When compared with the histologic diagnosis of the uterus, the hysteroscopic findings showed a diagnostic sensitivity of 98%, a specificity of 95%, a positive predictive value (PPV) of 96%, and a negative predictive value (NPV) of 98%. Hysteroscopy was found to have a greater diagnostic accuracy than D&C: the sensitivity and the NPV of the two diagnostic procedures were statistically different.CONCLUSION(S): Office hysteroscopy is confirmed as a powerful diagnostic tool, but targeted biopsies, performed with a small diameter operative hysteroscope, must be performed in cases of suspect endometrium to confirm the image-based diagnosis.     

Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency

Common variable immunodeficiency (CVID) and X-linked lymphoproliferative (XLP) disease are two immunodeficiencies that may share a similar immunological phenotype making differential diagnosis difficult. We report two patients initially diagnosed as affected with CVID who, using molecular analysis, have been subsequently found to be affected with XLP disease. Distinguishing between these two diseases is essential since they have different prognosis, treatment and genetic counselling. CONCLUSION: current techniques, such as genetic analysis of the SH2D1A gene and expression of signalling lymphocyte activation molecule-associated protein, allow a definite diagnosis of X-linked lymphoproliferative disease.     

Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A

Endometrial cancer (EC) is a hormone-dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in its etiology and progression has been reported. The possibility that even gonadotropins (GT) could play a role in the genesis and establishment of EC is supported by the fact that specific receptors for the GT luteinizing hormone/human chorionic GT (LH/hCG) have been detected in a high percentage of ECs, and their expression is apparently related to the cancer grading. However, the precise mechanisms by which GTs might exert their effect on EC is still obscure. The aim of this study was to determine the effects of LH/hCG on the invasion potential of EC cell lines and primary human EC cells. Human recombinant (hr) LH (and hCG) induced a significant increase in cell invasiveness through Matrigel-coated porous membranes in an EC human cell line Hec1A, which expresses the LH/hCG receptor. This effect turned out to depend on hrLH binding to its specific receptors and to the subsequent activation of protein kinase A (PKA). Moreover the hrLH-induced increase in Hec1A invasiveness relied upon a PKA-dependent functional activation of beta(1) integrin receptors, as well as the subsequent induction of matrix metalloproteinase-2 secretion in its active form. The same mechanisms were also found to be operative in primary EC cells. In fact, a significant percentage of primary ECs expressed the LH/hCG receptor, and hrLH addition to primary EC cells, which expressed the specific receptors produced an increase in cell invasiveness only in those tumor cells possessing the specific receptors. This effect was also dependent on PKA activity. We conclude that LH/hCG can regulate EC cells invasiveness, and this result provides a rationale for the use of inhibitors of LH secretion such as GnRH analogues in the treatment of EC.     

Recovery of stromal stem cells in bone sarcoma patients after chemotherapy: implication for cell-based therapy in bone defect reconstruction

Bone sarcomas, such as osteosarcoma (OS) or Ewing sarcoma (ES), frequently arise in the intramedullary region of long bones. Patients affected by bone sarcomas are treated with preoperative aggressive chemotherapy immediately after diagnosis. After chemotherapy, patients undergo surgery that frequently entails the excision of wide bone segments. If a large segment of the bone is lost (defined as a critical defect) the patient undergoes bone reconstruction. Because bone marrow derived stromal stem cells (SSC) offer great promise for cell-based regenerative medicine in bone reconstruction, we investigated whether SSC could be isolated from chemotherapy-treated bone sarcoma patients. We also investigated whether chemotherapy modified SSC differentiation capability. We studied 9 SSC derived from OS and ES patients that had undergone chemotherapy and 5 SSC derived from bone sarcoma patients that had not undergone chemotherapy. SSC could be obtained from all the patients analyzed regardless of whether the patients received chemotherapy or not. Our results also showed that post-chemotherapy SSC can be cultured and expanded ex vivo, these cells retained the ability to differentiate toward the osteogenic lineage in vitro. In conclusion, our results support that SSC cells can be obtained from bone sarcoma patients that undergo chemotherapy and suggest that SSC can be used for cell-based bone reconstruction techniques in bone sarcoma patients treated with preoperative chemotherapy.     

Occupational risk of blood-borne viruses in healthcare workers: a 5-year surveillance program.

OBJECTIVE: This study presents the results of a 5-year surveillance program involving the prospective follow-up of healthcare workers (HCWs) in the Veneto region of Italy exposed to blood-borne viruses. DESIGN: All HCWs who reported an occupational exposure to blood-borne infection joined the surveillance program. Both HCWs and patients were tested for viral markers (hepatitis B surface antigen [HBsAg], antibody to hepatitis B surface antigen [anti-HBs], antibody to hepatitis B core antigen [anti-HBc], antibody to hepatitis C virus [anti-HCV], HCV RNA, and antibody to human immunodeficiency virus [HIV]) and had these markers plus transaminases assayed at 3, 6, and 12 months and then yearly thereafter. Moreover, a program of hepatitis B virus (HBV) prophylaxis was offered to those whose anti-HBs levels were less than 10 IU/mL. PARTICIPANTS: Two hundred forty-five HCWs (156 women and 89 men) with a mean age of 37 (+/- 10) years who reported occupational exposure during the 5-year period. RESULTS: At the time of exposure, 1 HCW was positive for HBsAg (0.4%) and 2 were positive for HCV RNA (0.8%). Among the patients involved, 28 (11.4%) were positive for HBsAg, 68 (27.8%) were positive for HCV RNA, 6 (2.4%) were positive for HIV, and 147 (60.0%) were negative for all viral markers (4 patients were positive for both HCV and HIV). During the follow-up period after exposure (mean, 2.7 [+/- 1.6] years), there was no increase in transaminases or seroconversions to any of the viral markers. CONCLUSION: Our accurate postexposure follow-up revealed a lack of transmission of HBV, HCV, and HIV.