No abstract

.-Pathological rates of gallbladder salt and water transport may promote the formation of cholesterol gallstones. Because prairie dogs are widely used as a model of this event, we characterized gallbladder ion transport in animals fed control chow by using electrophysiology, ion substitution, pharmacology, isotopic fluxes, impedance analysis, and molecular biology. In contrast to the electroneutral properties of rabbit and Necturus gallbladders, prairie dog gallbladders generated significant short-circuit current (I sc; 171 Ϯ 21 A/cm 2 ) and lumen-negative potential difference (Ϫ10.1 Ϯ 1.2 mV) under basal conditions. Unidirectional radioisotopic fluxes demonstrated electroneutral NaCl absorption, whereas the residual net ion flux corresponded to I sc. In response to 2 M forskolin, Isc exceeded 270 A/cm 2 , and impedance estimates of the apical membrane resistance decreased from 200 ⍀ ⅐ cm 2 to 13 ⍀ ⅐ cm 2 . The forskolin-induced Isc was dependent on extracellular HCO 3 Ϫ and was blocked by serosal 4,4Ј-dinitrostilben-2,2Ј-disulfonic acid (DNDS) and acetazolamide, whereas serosal bumetanide and Cl Ϫ ion substitution had little effect. Serosal trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chroman and Ba 2ϩ reduced Isc, consistent with the inhibition of cAMP-dependent K ϩ channels. Immunoprecipitation and confocal microscopy localized cystic fibrosis transmembrane conductance regulator protein (CFTR) to the apical membrane and subapical vesicles. Consistent with serosal DNDS sensitivity, pancreatic sodium-bicarbonate cotransporter protein pNBC1 expression was localized to the basolateral membrane. We conclude that prairie dog gallbladders secrete bicarbonate through cAMP-dependent apical CFTR anion channels. Basolateral HCO 3 Ϫ entry is mediated by DNDS-sensitive pNBC1, and the driving force for apical anion secretion is provided by K ϩ channel activation.disease; ion transport; cystic fibrosis conductance membrane regulator; sodium-bicarbonate symporters ALTHOUGH GALLBLADDER DISEASE is the most frequent indication for abdominal surgery in the United States (19), the factors that confer susceptibility to gallstones remain poorly understood. Prairie dogs have been widely studied as an experimental model of human cholelithiasis due to their unique propensity for developing gallstones on high-cholesterol chow (7). Prior studies in cholesterol-fed prairie dogs (4) have demonstrated that gallbladder salt and water transport are altered before gallstones form, a phenomenon that may cause cholesterol to precipitate in the gallbladder lumen. The potential for targeting gallbladder ion transport as a strategy for preventing cholelithiasis is underscored by data showing that amiloride inhibits the formation of gallstones in cholesterol-fed prairie dogs (56).To use the prairie dog as a model to investigate this event, we performed a detailed characterization of gallbladder ion transport in animals fed control chow. Classic studies in Necturus and rabbit gallbladders established the paradigm for electr...

Relative total dose intensity of chemotherapy higher than 60 % among patients with inoperable locally advanced carcinoma gall bladder conferred no significant improvement in clinical benefit and subsequent rates of extended cholecystectomy. Higher RTDI however led to significantly increased toxicity among these patients.

Inequitable radiotherapy availability in India leads to non-compliance in many cases, as patients need to travel long distances for treatment; this has long-term implications for achieving the United Nations sustainable development goals. Notably, the number of functional radiotherapy units in India is below the limit recommended by the World Health Organization, and most centers in this vast country are located in urban centers. This creates a serious barrier to accessibility for the socioeconomically disadvantaged sections of the rural population. Recent reports suggest that despite the availability of free treatments for a wide variety of cancers, many patients are non-compliant owing to the high costs incurred on travel to distant centers. In view of the current distribution of radiotherapy units, and the low ratio of radiotherapy units serving the vast population, distances traveled for radiotherapy are likely to have considerable impact on realization of the United Nations sustainable development goals. It is also likely to have considerable impact on the existing weak infrastructure of healthcare facilities, as poor cancer control will increase the need for palliative care and support, thereby further reducing resource allocation to cancer control. Policies directed towards reducing travel times for radiotherapy are currently lacking in India. However, this issue needs urgent consideration to ensure optimal utilization of available resources. Until measures to reduce travel time can be implemented, reducing travel-related patient distress may improve compliance in the short term; urgent measures in this regard will help achieve the targets of the United Nations sustainable development goals.