Metabolism and requirements for calcium and phosphorus in the fast-growing chicken as affected by age

Three series of experiments were conducted with fast-growing chickens in order: to evaluate the effects of dietary Ca and P on cholecalciferol metabolism and expression; to determine dietary Ca requirements; to determine dietary P requirements. The results of the first series confirmed previous results on the effects of dietary Ca and P on some variables of vitamin D metabolism and expression, Ca homeostasis and P metabolism in the young chicken (1- to 21-d-old), and extended them to older birds (22- to 43-d-old). The bone formation rate and the duodenal calbindin content were maintained at high levels until the age of 43 d. Dietary Ca or P restriction increased duodenal calbindin and decreased bone ash in both 22- and 43-d-old chickens, but the effect on bone ash was less pronounced in the 43-d-old birds than in the younger ones. These results suggest that: (a) the capabilities for adaptation to dietary Ca and P restriction remain high during the whole growing period; (b) the growing broilers express a high adaptive capability even when the diet contains the recommended Ca and P contents. The results of the second and third series of experiments suggest that: (c) unlike the Ca requirements of the 1- to 22-d-old chick, P requirements for growth and bone ash are similar, and are as high in the older chicks as in the younger ones (7.4-8.3 g P/kg or 4.8-5.7 g non-phytate P/kg diet); (d) although growth and bone ash in the 29- to 43-d-old chickens appear to be less sensitive to dietary Ca content, within a range close to the calculated P requirement, 10 g Ca/kg diet appears to be required for best tibia mineralization, and to a lesser extent for better growth at this age.     

Immigrant and native-born female heroin addicts in Israel

There are an estimated 25,000 heroin addicts in Israel and nearly one out of every five is a woman. Also, about one fourth of the addict population immigrated to Israel from the former Soviet Union (mostly from Russia and the Ukraine) since 1989. In this study, native born and immigrant female addicts were interviewed to develop an understanding of their background characteristics, patterns of drug use, and attitudes based on group status. Results show that the two groups of women are similar in many respects; however, differences do exist. Russian-speaking women tend to be better educated and have a greater concern about their personal health and maintaining custody of their children. Additionally, immigrant women are more inclined to use heroin and other substances while receiving treatment and are more likely to have a father who abuses alcohol. Discussion is given to the study findings as well as issues relevant to the formation of policy regarding services to female addicts in the country.     

Additive interaction between peripheral and central mechanisms involved in the antinociceptive effect of diclofenac in the formalin test in rats

It has been proposed that the antinociception of systemic diclofenac is the outcome of peripheral and central actions. Hence, our purpose was to examine if systemic diclofenac is able to achieve effective concentrations at local and spinal sites and to characterize the interaction between its local and spinal actions. Pain was produced in the rat using the formalin test. Oral diclofenac (1-10 mg/kg) reduced formalin-induced pain. The antinociceptive effect of oral diclofenac (10 mg/kg) was abolished by local or spinal administration of either L-NAME (1-100 microg and 1-50 microg) or glibenclamide (12.5-100 microg and 25-75 microg). These results suggest that oral diclofenac achieves effective concentrations producing an antinociceptive effect involving participation of the NO-potassium channel pathway at both, the local and spinal levels. In an additional experimental series, diclofenac was administered either locally (25-200 mug) or spinally (12.5-100 mug), yielding an antinociceptive effect by both routes. Then, diclofenac was given simultaneously by these two routes in a fixed-ratio, and antinociception was assayed. Isobolographic analysis revealed an additive interaction between the local and spinal effects of diclofenac. Hence, our results provide evidence that the overall antinociceptive effect induced by systemic diclofenac is the outcome of central and peripheral mechanisms.     

Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study

Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case‐control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR‐10a, ‐10b, ‐21‐3p, ‐21‐5p, ‐30c, ‐106b, ‐155 and ‐212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT‐PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR‐10b, ‐21‐5p, ‐30c and ‐106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p‐values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR‐10a, ‐10b, ‐21‐5p, ‐30c, ‐155 and ‐212) overall, and for four miRs (‐10a, ‐10b, ‐21‐5p and ‐30c) at shorter follow‐up time between blood collection and diagnosis (≤5 yr, ≤2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose‐response trend with risk (p‐value = 0.0006). For shorter follow‐up (≤5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR‐212) to 0.79 (miR‐21‐5p).     

Neoadjuvant therapy of rectal carcinoma with UFT-leucovorin plus radiotherapy.

BACKGROUND: The object of this phase II study was to assess the impact of preoperative external radiation therapy combined with UFT and leucovorin on tumor response, sphincter preservation and tumor control in patients with rectal carcinoma. PATIENTS AND METHODS: Forty-one patients with resectable extraperitoneal rectal adenocarcinoma received radiation therapy and two courses of chemotherapy. Chemotherapy consisted of a 2-h infusion of 6S-steroisomer of leucovorin (6SLV) 250 mg/m2 on day 1, oral 6SLV 7.5 mg every 12 h on days 2-14, and UFT either 350 or 300 mg/m2 on days 1 to 14 every 28 days. Six additional courses of chemotherapy were given after surgery. RESULTS: Seven of 16 patients (43%) who received 350 mg/m2/day of UFT had grade 3-4 diarrhea and two other patients (12%) had grade 3-4 dermatitis. The next 25 patients received 300 mg/m2/day of UFT and only 14% of them had grade 3-4 diarrhea. Surgery consisted of low-anterior resection in 26 patients (63%) and abdominal-perineal amputation in 15 (37%). There were six histological complete responses (15%). Downstaging occurred in 25 patients (63%). The overall survival at 3 years was 90% and the pelvic disease-free survival 92%. CONCLUSIONS: Preoperative therapy with radiotherapy and UFT-6SLV downstaged 63% of tumors and allowed a sphincter-preserving procedure in some patients. Toxicity was moderate. This scheme is convenient because of the oral administration of chemotherapy.     

Etoposide,doxorubicin and cisplatin alternating with 5-fluorouracil,doxorubicin and high-dose methotrexate in patients with advanced adenocarcinoma of the stomach or the gastroesophageal junction

Both the etoposide, doxorubicin, cisplatin (EAP) and 5-fluorouracil, doxorubicin, high-dose methotrexate (FAMTX) schedules have been reported to be active in advanced gastric cancer. Since these regimens include non-cross resistant agents, a regimen that consists of EAP alternating with FAMTX may have an advantage over each regimen alone. We undertook a phase II trial to evaluate EAP/FAMTX in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. Of the 56 patients treated, an objective response was observed in 34%, including complete response in 7%. Median response duration was 8 months and median survival for the entire group was 9 months. The main toxicity was myelosuppression. Hospitalization for granulocytopenic fever was required in 32% of patients and 34% required red blood cells (RBC) transfusion. Non-hematological toxicity was moderate. There were three drug-related deaths associated with granulocytopenic fever. We conclude that the alternating EAP/FAMTX regimen is associated with occasional lethal events and has no obvious advantage over either regimen alone.     

Relations between immunologically different p53 forms,p21(WAF1) and PCNA expression in ovarian carcinomas

The role of tumor suppressor p21WAF1 expression in epithelial ovarian cancer has not been definitely explained and the clarification of mutual p53 and p21WAF1 relations considering proliferative activity seems to be very important for understanding of a functional link between p53 and cell-cycle control. Therefore the expression of p53 and p21WAF1 was assessed immunohistochemically in a series of 50 ovarian carcinomas considering clinicopathological variables. The reactivity of three anti-p53 monoclonal antibodies (DO-7, PAb240, PAb1620) recognizing immunologically distinct forms of p53 were analysed in relation to p21WAF1 level in individual patients. p21WAF1 was expressed in 24 (48%) of all cases. The detection of p53 protein was related to the antibody applied and DO-7 antibody appears to be better than both PAb240 and PAb1620. However, independently of antibody used significant inter- and intratumoral heterogeneity in p53 and p21WAF1 expression was revealed. The identification of different p53/p21WAF1 phenotypes reflect the complex and multiple relations between these two cell-cycle regulators indicating that in ovarian carcinomas p21WAF1 activation may be both p53-dependent and p53-independent. High cell proliferation was usually accompanied by undetectable or weak p21WAF1 staining. There was no significant correlation between p53 and p21WAF1 expression and histology, stage and grade of ovarian carcinomas (p>0.05).     

Temperature-sensitive Ovarian Carcinoma Cell Line (OvBH-1)

OvBH-1 cells from a patient with ovarian clear cell carcinoma were established and their biochemical status was analyzed. Cells grown at 37°C exhibited normal cell cycle distribution, whereas the cells shifted to 31°C were arrested in the G₂/M phase of the cell cycle. Immunochemical analysis using anti-p53 antibodies (DO-1, PAb240, PAb421, and PAbl620) revealed that only the DO-1 antibody reacted with p53 with a high and similar percentage at both temperatures. PAb240 reacted with a low percentage of cells at 37°C and no reaction was observed at 31°C. PAb421 antibody stained a significantly lower percentage of cells at 37°C than at 31°C. Cells were not stained with PAbl620 antibody and were negative for antibodies against p21^WAF1 and MDM2 proteins independently of the temperature. Sequencing of all coding exons of the p53 gene demonstrated only a neutral genetic polymorphism, i.e. a G-to-A substitution (GAG to GAA) at nucleotide position 13 432. Thus, the observed temperature sensitivity of OvBH-1 cells cannot be ascribed to a p53 primary structure mutation. Based upon immunochemical analyses, we consider, however, that p53 in nuclei of OvBH-1 cells is in a highly unstable conformation. Furthermore, the N-terminal portion of the p53 protein at Ser20 has not been modified, and Lys373 and/or Ser378 of the C-terminus is acetylated and/or phosphorylated. The nuclear location signal of p53 is preserved. Induction of MDM2 protein is uncoupled from the cell regulatory machinery and the induction of p21^WAF1 by p53 is unpaired in OvBH-1 cells.     

The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.     

Cancer and non-cancer controls in studies on the effect of tobacco and alcohol consumption.

A comparison of risk estimates using controls with other cancers versus controls with acute diseases unrelated to tobacco and alcohol consumption in the study of the effect of these two factors has been performed using data on tumours of the oral cavity and pharynx from an ongoing case-control surveillance programme in Northeastern Italy. Similar results were obtained using either type of controls: as compared to never smokers, moderate smokers (less than or equal to 14 cigarettes/day) showed age- and sex-adjusted odds ratio (OR) = 5.2 (95% confidence interval (CI): 2.9-9.2) when using cancer controls and 5.8 (95% CI: 3.3-10.1) when using non-cancer controls. Similarly, those who had smoked for 40 years or longer showed ORs of 7.4 (95% CI: 4.0-13.6) and 8.8 (95% CI: 4.9-15.6), respectively, using cancer and non-cancer controls. For moderate drinkers of alcoholic beverages (21-34 drinks/week) and heavy drinkers (greater than or equal to 84 drinks/week) the ORs, as compared to individuals who drank less than 21 drinks/week, were 1.9 (95% CI: 1.0-3.6) and 2.2 (95% CI: 1.2-4.0) and 10.6 (95% CI: 5.5-20.6) and 11.4 (95% CI: 6.0-21.4) using cancer and non-cancer controls, respectively. The same comparability of ORs for tobacco- and alcohol-related variables using either type of controls was observed when separate analyses of the two sexes were performed. The close similarity between cancer and non-cancer controls in studies on tobacco- and alcohol-related risks may be exploited when the choice of other types of controls would increase the costs and the feasibility of the study, and thus hamper its statistical power.(ABSTRACT TRUNCATED AT 250 WORDS)