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Depressive symptoms are common in South African primary care patients with chronic medical conditions, but are usually unrecognised and untreated. This study evaluated an integrated, task-sharing collaborative approach to management of depression comorbid with chronic diseases in primary health care (PHC) patients in a real-world setting. Existing HIV clinic counsellors provided a manualised depression counselling intervention with stepped-up referral pathways to PHC doctors for initiation of anti-depressant medication and/ or referral to specialist mental health services. Using a comparative group cohort design, adult PHC patients in 10 PHC facilities were screened with the Patient Health Questionnaire-9 with those scoring above the validated cut-off enrolled. PHC nurses independently assessed, diagnosed and referred patients. Referral for treatment was independently associated with substantial improvements in depression symptoms three months later. The study confirms the viability of task-shared stepped-up collaborative care for depression treatment using co-located counselling in underserved real-world PHC settings. [ABSTRACT FROM AUTHOR]

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Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons. [ABSTRACT FROM AUTHOR]

Non-small-cell lung carcinoma (NSCLC) is among the deadliest of human cancers. The CDKN2A locus, which houses the INK4a and ARF tumor suppressor genes, is frequently altered in NSCLC. However, the specific role of ARF in pulmonary tumorigenesis remains unclear. KRAS and other oncogenes induce the expression of ARF, thus stabilizing p53 activity and arresting cell proliferation. To address the role of ARF in Kras-driven NSCLC, we compared the susceptibility of NIH/Ola strain wild-type and Arf-knockout mice to urethane-induced lung carcinogenesis. Lung tumor size, malignancy and associated morbidity were significantly increased in Arf−/− compared with Arf+/+ animals at 25 weeks after induction. Pulmonary tumors from Arf-knockout mice exhibited increased cell proliferation and DNA damage compared with wild-type mice. A subgroup of tumors in Arf−/− animals presented as dedifferentiated and metastatic, with many characteristics of pulmonary sarcomatoid carcinoma, a neoplasm previously undocumented in mouse models. Our finding of a role for ARF in NSCLC is consistent with the observation that benign adenomas from Arf+/+ mice robustly expressed ARF, while ARF expression was markedly reduced in malignant adenocarcinomas. ARF expression also frequently colocalized with the expression of p21CIP1, a transcriptional target of p53, arguing that ARF induces the p53 checkpoint to arrest cell proliferation in vivo. Taken together, these findings demonstrate that induction of ARF is an early response in lung tumorigenesis that mounts a strong barrier against tumor growth and malignant progression. [ABSTRACT FROM AUTHOR]

Reduced expression of the CDK inhibitor p27Kip1 (p27) in human lung cancer correlates with tumor aggressiveness and poor prognosis. However, the regulation of p27 expression and the role of p27 during lung cancer are poorly understood. Urethane-induced lung tumors in mice frequently harbor mutations in the Kras oncogene, and in this study, we use this model to address the regulation of p27 during tumorigenesis. The Ras effector Akt is known to regulate p27 mRNA abundance by phosphorylating and inactivating the FOXO transcription factors. Phosphorylated Akt and FOXO proteins were both increased in lung tumors, correlating with a reduction in p27 mRNA transcript. Akt also directly phosphorylates p27 and regulates its nuclear/cytoplasmic localization. Tumors showed a reduced nuclear/cytoplasmic ratio of p27 protein, together with an increase in phosphorylated Thr197 p27 in the cytoplasmic pool. Treatment of lung tumor-bearing mice with the phosphoinositol-3 kinase inhibitor LY294002 induced a rapid decrease in phosphorylated Akt and phosphorylated p27, concomitant with an increase in nuclear p27. Germline p27 deficiency accelerated both the growth and malignant progression of urethane-induced lung tumors, and did so in a cell autonomous manner, confirming a causal role of p27 in tumor suppression. These results show that p27 is a potent barrier to the growth and malignant progression of Kras-initiated lung tumors. Further, the reduction of nuclear p27 in tumors is mediated by oncogene signaling pathways, which can be reversed by pharmacological agents. [ABSTRACT FROM AUTHOR]

The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics.Oncogene (2008) 27, 3145–3155; doi:10.1038/sj.onc.1210973; published online 3 December 2007 [ABSTRACT FROM AUTHOR]

Aim: Sphygmocardiography via applanation tonometry is a non-invasive, bedside technology which utilises tonometric analysis of the radial artery pulse wave and measurement of peripheral arterial blood pressure (BP) to derive a central arterial pulse wave, central arterial BP and related indices. The present study was designed to determine: (1) the inter-operator variability in measurements obtained using this technique; (2) the relationship between measured peripheral arterial BP and derived central arterial BP. Method: Multiple measurements were made from 25 healthy subjects (15 male), mean age 33 (s.d. 10.3) years, mean arterial BP 90 (s.d. 12) mm Hg by two trained observers at the same time of day on three separate occasions. Results: The mean inter-operator difference was 0.1 (s.d. 1.7) mm Hg for derived systolic aortic BP and 0.1 (s.d. 0.7) mm Hg for derived diastolic aortic BP (Bland and Altman analysis). Pulse wave Augmentation Index (AIx) values, ranged from -222% to +140%, with the inter-operator measurement difference being only 0.4 (s.d. 6.4)%. Buckberg ratio measurements ranged from 119% to 254%, with the inter-operator measurement difference being only 2.7 (s.d. 15.4)%. The relationship between derived central systolic BP and peripheral systolic BP readings in individual patients was not constant and showed significant variance when compared on different days (ANOVA, P = 0.03). This was not explained by any significant variance in heart rate (ANOVA, P = 0.39). Conclusion: Applanation tonometry has excellent inter-observer reproducibility when used by trained observers. Moreover, the inconsistency in the relationship between peripheral and central aortic BP suggests that the former is not a perfect surrogate for the latter. Further prospective studies are required to define whether derived central aortic BP may be a better predictor of cardiovascular morbidity and mortality and the impact of different antihypertensive therapies on the relationship... [ABSTRACT FROM AUTHOR]

The effect of temperature and O saturation on the production of recombinant proteins β-galactosidase and human glucocerebrosidase by Spodoptera frugiperda cells (Sf9) infected with recombinant Autographa californica nuclear polyhedrosis virus was investigated. The rates of cell growth, glucose consumption, O consumption and product expression were measured at temperatures between 22° C and 35° C. The results indicated that possible O limitation may be alleviated without compromising the maximum cell yield by lowering the incubation temperature from 27° C to 25° C. The expression level of the recombinant proteins at 27° C was similar to that obtained at 22° C and 25° C; lower protein yields were obtained at 30° C. An increase in temperature from 22° C to 27° C led to earlier production of the proteins and to an increase in the proportion of the product released outside the cells. [ABSTRACT FROM AUTHOR]

Isolated pancreatic islets were transplanted isogeneically into the subcutaneus tissue, peritoneum and portal vein of diabetic rats. Implantation of islets subcutaneously did not modify the diabetic state. Intraperitoneal islets ameliorated the effects of diabetes but normal urine volumes, blood glucose and urine glucose levels were not achieved. Direct injection of islets into the portal vein resulted in normal urine volumes, normoglycemia and abolition of glycosuria in the rats studied. These effects have been maintained 2 months later. - It is suggested that the portal environment may be the most effective site for transplanted pancreatic islets. [ABSTRACT FROM AUTHOR]

Eudorina elegans does not respond to liquid-holding or to postirradiation medium effects by changes in recovery. A decrease in survival ability is observed if a culture is starved prior to irradiation, or is incubated at 22°C rather than 32°C following UV irradiation. Eudorina loses the ability to photoreactivate UV damage within 10 to 48 h following irradiation, depending upon the pre-and post-UV culture conditions. The results are interpreted as indicating a failure of Eudorina elegans to carry out specific dark repair of UV damage. Some reactivation may occur during cellular DNA synthesis. [ABSTRACT FROM AUTHOR]

3H-Uridine has been used to investigate the sites of RNA synthesis in the post-meiotic G phase of Trillium microspores using electron microscope autoradiography. The dilute, non-condensed component of the nucleus has been found to be the site of synthesis. When the labelled cells were further incubated in non-radioactive medium the label was found to shift towards the condensed chromatin regions within the nucleus. Two hypotheses to explain the observations are considered, one involving migration of the RNA from the relaxed to condensed regions, the other involving a change in state of the nuclear regions involved in the synthesis. The data are interpreted as favoring the latter possibility. [ABSTRACT FROM AUTHOR]

An examination of the correlation between RNA and protein synthesis occurring during meiosis and cytological development was made in Trillium erectum microsporocytes. Various reagents known to act at various steps of protein biosynthesis were administered to cultured buds at different developmental stages with more or less effect depending on the stage rather than the reagent. Syntheses were found to be necessary for continued development of the microsporocytes during early prophase. Synthesis during meiotic prophase was also necessary for the maintainance of the condensed state of the late prophase chromosomes, the initial separation of the paired homologous chromosomes, and the orderly function of the spindle. Cytokinesis was readily disturbed at all treatment times. Pairing of homologous chromosomes was not affected and the prespecification of pairing is believed to occur at or near the time of DNA synthesis. The results indicate that the syntheses occurring during meiosis can be correlated with cytological developmental processes. [ABSTRACT FROM AUTHOR]

At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482. [ABSTRACT FROM AUTHOR]