Inhibition of metastases by a serum factor associated to concomitant resistance induced by unrelated murine tumors.

Murine lung metatases growing undisturbed by the primary tumor were significantly inhibited by the concomitant resistance induced by a secondary subcutaneous implant of two unrelated tumors. Such inhibition was T-independent since it was also observed in nude mice; its full expression was dependent on the presence of the secondary tumor implant and it was exerted on both macroscopic and microscopic established metastases and not on the process of tumor cell dissemination from the primary tumor. Direct and indirect mechanisms seemed to be involved, the former affecting the metastatic cells per se by causing a decrease in proliferation and an increase in apoptosis while the latter affected neo-vascularization. These antitumor and antiangiogenic effects could be attributed to a serum factor induced by the unrelated tumors generating concomitant resistance. This factor proved to be heat, acid and alkaline resistant and dialysable; it was recovered in an HPLC column with maximum absorption at 215 and 266 nm; it was anionic at neutral pH, exhibiting free carboxil groups and one or more molecules of tyrosine, with a molecular weight between 870 and 1300 Dalton. Intravenous administration of this factor significantly inhibited lung metastases, decreasing mitosis and increasing apoptosis similar to that observed in the presence of the unrelated tumors.     

Childhood non-Hodgkin malignant lymphomas: A clinicopathologic retrospective study

Between 1968 and 1975, 44 evaluable children under 16 years of age with the histologic diagnosis of non-Hodgkin malignant lymphoma (ML) were treated at the Istituto Nazionale Tumori of Milan. Histologic diagnoses were reclassified as follows: 13 lymphoblastic (others) ML, 15 convoluted cell type lymphoblastic ML, 9 Burkitt type ML, and 7 immunoblastic ML. Only 36% of the patients had stage I and II disease. At diagnosis 25% showed malignant cells in the bone marrow smears. Bone marrow infiltration was particularly frequent in the convoluted cell type lymphoblastic ML and in the lymphoblastic (others) ML subgroups. Burkitt type ML frequently was associated with abdominal lesions and subsequently a high incidence of central nervous system involvement. Patients with stage I and II ML were encountered mostly in the immunoblastic ML subgroup. After 1973 more intensive chemotherapy plus radiotherapy seems to have slightly improved the survival of the patients, except in the Burkitt type ML subgroup.     

Long term results of Roux-en-Y hepaticojejunostomy

One hundred and twenty-three patients with benign diseases involving the bile ducts, curable by biliary bypass, underwent a Roux-en-Y hepaticojejunostomy, and the long term results of this operation were evaluated to ascertain if hepaticojejunostomy is a safe and durable procedure. There were no operative deaths. A peptic ulcer developed postoperatively in two patients. Only one instance of anastomotic stenosis was observed at follow-up study, averaging 5.5 years. Six of the 11 patients with postoperative biliary symptoms had intrahepatic lithiasis, a possible indication that the symptoms were due to temporary obstruction of the anastomosis by residual stones. A refined operative technique has improved the results which over-all are highly satisfactory.     

Sensory neuronopathy and small cell lung cancer: antineuronal antibody reacting with neuroblastoma cells

The anti-Hu antibody is associated with a paraneoplastic subacute sensory neuronopathy (SSN) described in cases of small cell lung cancer (SCLC). The Hu antigen is a pan-neuronal nuclear antigen with a molecular weight of 35–40 kDa. In this study we demonstrated the presence of the paraneoplastic Hu antigen in different neuroblastoma cell lines. We showed that by indirect immunocytochemistry the serum of patients with SSN and SCLC reacts with the nuclei of neuroblastoma cell lines SKN-SH and LAN-1. Western blot analysis of nuclear extracts from neuroblastoma cell lines SKN-SH, IMR-32 and LAN-1 confirmed the presence of the Hu antigen in these neuroblastoma cell lines. By comparing the immunocytochemical method and the Western blot analysis we were able to determine that the Western blot analysis was a more sensitive test. Screening of the sera of a large population (a total of 122 patients with SCLC, 17 with paraneoplastic disorders as well as 121 controls with other neurological disorders) was performed and showed all 5 of the patients with SSN and SCLC to be positive for the anti-Hu antibody, whereas only 11 of the 122 SCLC patients and none of the controls were positive, thereby suggesting that this test has a very high degree of sensitivity.     

A Novel Model of Urinary Tract Differentiation,Tissue Regeneration,and Disease: Reprogramming Human Prostate and Bladder Cells into Induced Pluripotent Stem Cells

Background

Primary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation.

Objective

To generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation.

Design, setting, and participants

Prostate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs.

Outcome measurements and statistical analysis

The potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used.

Results and limitations

Successful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies.

Conclusions

IPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.     

Subjectivity in the Perception and Measurement of Quality of Life: Conceptualization and Development of the Seville Questionnaire

Quality of life (QoL) is a significant parameter in estimating the social and interpersonal impact of psychopathology, clinical course, and response to treatment in many mental illnesses, particularly schizophrenia. The clinician's assessment and patient's subjective report are essential ingredients of this process. We describe the development and structure of a QoL questionnaire based on the patient's subjective understanding of the problems. Ninety areas identified by four groups of experts resulted in a 126-item questionnaire administered to 279 patients with a DSM-IV diagnosis of schizophrenia. A factorial approach led to 59 total items and two final scales (favorable and unfavorable), with three factors each. The Seville QoL Questionnaire (SQLQ) results can be presented as individual scores for each scale, or a total for both. Its psychometric properties have proven quite acceptable in reliability and validity, comparing favorably with other scales. SQLQ may prove to be a useful addition to QoL-measuring instruments.     

Plasmids in Salmonella typhi in Lima, Peru, 1987-1988: epidemiology and lack of association with severity of illness or clinical complications.

A prospective study was conducted to better characterize the epidemiology of plasmid-bearing strains of Salmonella typhi in an endemic area of Lima, Peru, and to determine if plasmids were associated with specific manifestations of typhoid fever. Of 228 S. typhi isolated from patients at Cayetano Heredia University Hospital in Lima during 1987-1988, 76 (33%) contained plasmids. Ten different plasmid profiles were identified, with ten distinct plasmids present within these profiles. There was significant temporal clustering of isolates having common plasmid profiles. Two plasmids (both from the same isolate) carried antibiotic resistance genes. Two cryptic plasmids with approximate sizes of 55 and 65 kilobases (kb) appeared to be closely related, based on restriction endonuclease digestions and Southern blot analysis. An ampicillin resistance plasmid from a 1989 patient isolate differed by only a single restriction fragment from the cryptic 65-kb plasmid. No association was found between any plasmid or plasmid profile and severity or clinical manifestations of disease.     

Engaged urokinase receptors enhance tumor breast cell migration and invasion by upregulating alpha(v)beta5 vitronectin receptor cell surface expression

We have previously shown that urokinase receptor physically and functionally interacts with alpha(v)beta5 vitronectin receptor, leading to tumor breast cell migration and invasion. Here, the link between these 2 receptors was further investigated by analyzing the expression levels of urokinase receptor and alpha(v)beta5 integrin in 35 human breast carcinomas and 5 benign breast lesions. The occurrence of a positive correlation between urokinase receptor and alpha(v)beta5 protein levels in benign and malignant tumor specimens prompted us to investigate whether engaged urokinase receptors might modulate alpha(v)beta5 expression. Here, we report the receptor-dependent ability of catalytically inactive urokinase to upregulate the alpha(v) and beta5 chains in MDA-MB-231 and MCF-7 breast carcinoma cell lines in a time- and concentration-dependent manner. This effect is dependent on protein kinase C activity and requires new protein synthesis. Accordingly, the availability of assembled alpha(v)beta5 receptors on the cell surface increases upon urokinase treatment, as shown by immunoprecipitation and immunocytochemical analyses. Exposure to urokinase leads to enhanced tumor cell migration and invasion, which is prevented by the "phosphorylation-like" urokinase receptor antagonist His-uPA(138E/303E), the DNA-binding drug mithramycin, the protein kinase C inhibitor calphostin C and anti-alpha(v)beta5 antibodies. Finally, urokinase enables benign breast MCF-10A cells to cross Matrigel in a alpha(v)beta5- and urokinase receptor-dependent manner, indicating that urokinase controls a regulatory circuitry crucial to breast tumor progression.     

Left ventricular structural and functional characteristics in Cushing's syndrome

OBJECTIVES: This study was designed to evaluate left ventricular (LV) anatomy and function in patients with Cushing's syndrome. BACKGROUND: A high prevalence of LV hypertrophy and concentric remodeling has been reported in Cushing's syndrome, although no data have been reported on LV systolic and diastolic function. METHODS: Forty-two consecutive patients with Cushing's syndrome and 42 control subjects, matched for age, gender, and blood pressure, were studied. Left ventricular mass index (LVMI) and relative wall thickness (RWT) were measured by echocardiography, endocardial and midwall fractional shortening (FS) were assessed, and diastolic filling was measured by Doppler transmitral flow. RESULTS: The RWT was significantly greater in Cushing patients than in controls. Left ventricular hypertrophy and concentric remodeling were observed in 10 and 26 patients with Cushing's syndrome, respectively. In Cushing patients, midwall FS was significantly reduced compared with controls (16.2 +/- 3% vs. 21 +/- 4.5%, p = 0.01). The ratio of transmitral E and A flow velocities was reduced and E deceleration time was prolonged in Cushing patients compared with controls (p = 0.03 and p < 0.001, respectively). CONCLUSIONS: In patients with Cushing's syndrome, cardiac structural changes are associated with reduced midwall systolic performance and with diastolic dysfunction that may contribute to the high risk of cardiovascular events observed in these patients.     

Physical activity types and health-related quality of life among middle-aged and elderly adults: The Rotterdam Study

Objectives

Physical activity (PA) is associated with health-related quality of life (HRQL). The specific PA types that provide beneficial effects in an older population remain unclear. We assessed the association of total PA, walking, cycling, domestic work, sports and gardening with HRQL in middle-aged and elderly adults.

Design

Cross-sectional study.

Setting

Rotterdam, the Netherlands.

Participants

5,554 participants, with a mean age of 69 years.

Measurements

Total PA was categorized in five groups to evaluate the dose-response effect of PA and specific PA types were categorized in tertiles. HRQL was measured with the EuroQoL 5-dimension. The outcome of every HRQL domain (i.e. mobility, self-care, daily activities, pain and mood) was expressed as having any problems versus not having problems. Logistic and linear regression analyses were used, adjusting for confounders, to examine associations of total PA and PA types with HRQL domains.

Results

In both middle-aged (<65 years) and elderly adults (>65 years), we found a dose-response association between total PA and better HRQL (i.e. lower odds of having problems in HRQL domains). In the middle-aged, sports was the only PA type associated with lower odds of having problems with all HRQL domains. In the elderly, all PA types were associated with less problems with HRQL domains, but cycling contributed most to the beneficial effect.

Conclusions

Total PA was associated with better HRQL. Sports and cycling were the activity types that contributed most to this association in the middle-aged and elderly, respectively. Since PA levels tend to decline with aging, cycling and sports should be promoted with the aim to improve HRQL.