Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma

Gastric cancer is one of the most common gastrointestinal malignancies and is associated with poor prognosis. Exploring alterations in the proteomic landscape of gastric cancer is likely to provide potential biomarkers for early detection and molecules for targeted therapeutic intervention. Using iTRAQ-based quantitative proteomic analysis, we identified 22 proteins that were overexpressed and 17 proteins that were downregulated in gastric tumor tissues as compared to the adjacent normal tissue. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was found to be 7-fold overexpressed in gastric tumor tissues. Immunohistochemical labeling of tumor tissue microarrays for validation of CAMKK2 overexpression revealed that it was indeed overexpressed in 94% (92 of 98) of gastric cancer cases. Silencing of CAMKK2 using siRNA significantly reduced cell proliferation, colony formation and invasion of gastric cancer cells. Our results demonstrate that CAMKK2 signals in gastric cancer through AMPK activation and suggest that CAMKK2 could be a novel therapeutic target in gastric cancer.     

Polymorphonuclear motility: measurement by computer-linked image analysis

Most methods of measuring neutrophil motility provide information mainly about the performance of a small proportion of the fastest moving cells. Application of a computer-linked image analysis technique, using the "Quantimet," provides a convenient, automated method of measuring the motility of the whole cell population. This makes it possible to test whether changes in motility represent a homogeneous alteration affecting all cells or a change in the numbers or performance of a subset of cells. In this study the neutrophils from patients with uncomplicated rheumatoid arthritis were found to perform similarly to normals, while cells from patients with Felty's syndrome were markedly slower. This was an overall, homogeneous slowing of the whole cell population, not due to a loss of fast moving cells.     

The transition of childbirth practices among tribal women in Gujarat,India - a grounded theory approach

Background

Under the National Rural Health Mission, the current emphasis is on achieving universal institutional births through incentive schemes as part of reforms related to childbirth in India. There has been rapid progress in achieving this goal. To understand the choices made as well as practices and perceptions related to childbirth amongst tribal women in Gujarat and how these have been influenced by modernity in general and modernity brought in through maternal health policies.

Method

A model depicting the transition in childbirth practices amongst tribal women was constructed using the grounded theory approach with; 8 focus groups of women, 5 in depth interviews with traditional birth attendants, women, and service providers and field notes on informal discussions and observations.

Results

A transition in childbirth practices across generations was noted, i.e. a shift from home births attended by Traditional Birth Attendants (TBAs) to hospital births. The women and their families both adapted to and shaped this transition through a constant ’trade-off between desirable and essential’- the desirable being a traditional homebirth in secure surroundings and the essential being the survival of mother and baby by going to hospital. This transition was shaped by complex multiple factors: 1) Overall economic growth and access to modern medical care influencing women’s choices, 2) External context in terms of the international maternal health discourses and national policies, especially incentive schemes for promoting institutional deliveries, 3) Socialisation into medical childbirth practices, through exposure to many years of free outreach services for maternal and child health, 4) Loss of self reliance in the community as a consequence of role redefinition and deskilling of the TBAs and 5) Cultural belief that intervention is necessary during childbirth aiding easy acceptance of medical interventions.

Conclusion

In resource poor settings where choices are limited and mortality is high, hospital births are perceived as increasing the choices for women, saving lives of mothers and babies, though there is a need for region specific strategies. Modern obstetric technology is utilised and given meanings based on socio-cultural conceptualisations of birth, which need to be considered while designing policies for maternal health.

     

Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1

Background and purpose:

Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood–brain barriers (BBB) is currently unknown.

Experimental approach:

In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays.

Key results:

All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity.

Conclusions and implications:

Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.     

Complex dislocation of the first metatarsophalangeal joint

Dislocation of the first metatarsophalangeal(MTP) joint is uncommon.1-5 Jahss1has classified these dislocations based on the dislocation of hallux with or without disruption of the sesamoid mass. In this study, we described a case of type Ⅰ complex dislocation of the MTP joint. It was irre-ducible by closed manipulation and required open re-duction achieved through a dorsal approach.     

How Robust are our Methods of Detecting Impaired Glomerular Filtration Rate in the Intensive Care Unit?

Background

Serum creatinine is not a sensitive marker to assess early loss of renal function in acute kidney injury. Timed creatinine clearance and several formula used to predict glomreular filtration rate have not been validated.

Methods

In a prospective observational study in 50 adult patients admitted to the intensive care unit with apparent normal renal function, we assessed the glomerular filtration rate by the formula methods and timed creatinine clearance.

Result

The mean serum creatinine was 0.77mg/dl, SD ± 0.15 (range 0.5-1.14 mg/dl). The mean measured creatinine clearance was 87.15 ml/min/1.73m², SD ± 20.5 (range 56.9-137 ml/min/1.73m²). In 25 (50%) patients, one hour urinary creatinine clearance was <80 ml/min/1.73m² and in two (4%) patients, the creatinine clearance was <60 ml/min/1.73m². Spearman correlation coefficient and regression analysis revealed a statistically significant correlation for the Cockcroft-Gault and predictive equations when compared with measured creatinine clearance. The differences between the predictive equations and creatinine clearance, as illustrated by the ±95% confidence interval in the Bland-Altman graphs was very significant [Cockcroft- Gault = −40.3 to 17.7 ml/min/ 1.73m², Modification of Diet in Renal Disease equation = −46.2 to 30.6 ml/min/1.73m² and the simplified Modification of Diet in Renal Disease equation = −72.8 to 24.8 ml/min/1.73m²].

Conclusion

Formula methods and creatinine clearance are more sensitive than serum creatinine in detecting early phase of acute kidney injury. However, there is no agreement between these methods of glomerular filtration rate estimation.Key Words: Acute kidney failure, Glomerular filtration rate