Prehospital care of orthopedic injuries

Orthopedic injuries are predominant among combat casualties, and carry the potential for significant morbidity. An expert consensus process (Prehospital care of military orthopedic trauma: A consensus meeting, Israel Defense Forces Medical Corps, May 2003) was used to create guidelines for the treatment of these injuries by military prehospital providers. The consensus treatment guidelines developed by experienced orthopedic trauma personnel from leading trauma centers in Israel are presented in this paper. For victims with open fractures, the first priority is hemorrhage control. Splinting, irrigation, and wound care should be performed while waiting for transport, or, in any scenario, in the case of an isolated limb injury. The use of traction splints was advocated for both the rapid transport scenario (up to one hour from the time of injury to arrival at the hospital) and the delayed transport scenario. In the urban setting, traction splints may not be necessary. Any victim experiencing pelvic pain following a high-energy mechanism of injury should be presumed to have an unstable pelvic fracture, and a sheet should be tied around the pelvis. The panel agreed that field-reduction of dislocations should be avoided by the medical officer unless it is anticipated that the patient will need to go through a long evacuation chain and the medical officer is familiar with specific reduction techniques.     

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

The combination of hyperoxaluria and hypocitraturia can trigger Ca²⁺-oxalate stone formation, even in the absence of hypercalciuria, but the molecular mechanisms that control urinary oxalate and citrate levels are not understood completely. Here, we examined the relationship between the oxalate transporter SLC26A6 and the citrate transporter NaDC-1 in citrate and oxalate homeostasis. Compared with wild-type mice, Slc26a6-null mice exhibited increased renal and intestinal sodium-dependent succinate uptake, as well as urinary hyperoxaluria and hypocitraturia, but no change in urinary pH, indicating enhanced transport activity of NaDC-1. When co-expressed in Xenopus oocytes, NaDC-1 enhanced Slc26a6 transport activity. In contrast, Slc26a6 inhibited NaDC-1 transport activity in an activity dependent manner to restricted tubular citrate absorption. Biochemical and physiologic analysis revealed that the STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediated both the physical and functional interactions of these transporters. These findings reveal a molecular pathway that senses and tightly regulates oxalate and citrate levels and may control Ca²⁺-oxalate stone formation.Formation of calcareous stones is a major health problem, mainly afflicting the kidney¹ and salivary glands.² Most stones are Ca²⁺-oxalate, with the minority being Ca²⁺-phosphate.¹ Ca²⁺-oxalate stone formation can result from hyperoxaluria, hypercalciuria, or reduction in the major urinary Ca²⁺ buffer citrate.³ Ca²⁺-oxalate stones can form in the absence of hypercalciuria when hyperoxaluria is coupled with hypocitraturia. The anion transporter slc26a6 (National Center for Biotechnology Information [NCBI] accession no. {"type":"entrez-nucleotide","attrs":{"text":"NM_134420","term_id":"158341685","term_text":"NM_134420"}}NM_134420) has a major role in controlling systemic oxalate metabolism.⁴ Slc26a6 is expressed at high levels in most epithelia, including the proximal intestine, renal proximal tubule, salivary glands, and pancreas.⁵ Slc26a6 functions as a 1Cl⁻/2HCO₃ ⁶ or 1Cl⁻/1oxalate and 1Cl⁻/1formate exchanger.⁷ Its pivotal role in oxalate homeostasis was demonstrated in slc26a6^−/− mice, where the most prominent phenotype is increased serum and urine oxalate that lead to Ca²⁺-oxalate kidney stones.⁸Dietary oxalate is an important source of exogenous oxalate and is absorbed by the intestinal epithelium via the paracellular pathway.⁹ The liver is the main source of endogenous oxalate; however, under physiologic conditions, a small fraction of the bodily oxalate is derived from hepatic production.¹⁰ Studies using slc26a6^−/− mice showed that increased serum oxalate is the result of impaired intestinal excretion that, in turn, leads to increased filtered renal oxalate load and formation of Ca²⁺-oxalate stones.⁸ However, under normal physiologic conditions, two major factors prevent Ca²⁺-oxalate stones formation. Slc26a6 mediates oxalate clearance via the intestine,⁹ and urinary citrate chelates the Ca²⁺ to reduce the free Ca²⁺ available for binding to oxalate.¹¹ Citrate binds Ca²⁺ at a higher affinity than does oxalate;¹² thus, in the presence of a high citrate concentration, Ca²⁺-oxalate does not reach the super-saturation needed for stone formation. In addition, once crystals are formed, citrate adsorbs to the crystal surfaces and suppresses their growth and attachment to epithelia.¹³ By attaching to crystal surfaces, citrate also amplifies the protective effect of other stone inhibitors, such as the Tamm-Horsfall protein¹⁴ and osteopontin.¹⁵At a pH of 7.4, citrate is mostly in the form of a tricarboxylic acid, but it can be reabsorbed only by the proximal tubule epithelium in its divalent form.¹⁶ The luminal pH at the proximal tubule drops from 7.4 to 6.5,¹⁷ which favors the divalent form of citrate and thereby allows citrate transport. In mammals, the major luminal citrate transporter in both the intestine and proximal tubule is the Na⁺-dependent dicarboxylate co-transporter, NaDC-1 (NCBI accession no. {"type":"entrez-nucleotide","attrs":{"text":"AY186579","term_id":"28195240","term_text":"AY186579"}}AY186579).¹⁸ NaDC-1 (Slc13a2), the second member of the SLC13 family, has 11 transmembrane domains, with cytoplasmic N- and extracellular C-termini.¹⁸ In light of the importance of the citrate/oxalate balance in regulating free Ca²⁺ in bodily fluids, we hypothesized that citrate/oxalate balance may be regulated by a molecular mechanism that fine-tunes citrate and oxalate concentrations. Such a mechanism should involve the two major transporters, slc26a6 and NaDC-1.In the present work, we report on a new pathway that involves interplay between slc26a6 and NaDC-1 that determines citrate/oxalate homeostasis. The pathway involves the mutual but reciprocal regulation of slc26a6 (activation) and NaDC-1 (inhibition). The interaction between the oxalate and citrate transporters is mediated by the slc26a6 STAS domain and the NaDC-1 first intracellular loop (ICL1), which recapitulate the function of the full-length transporters. These findings reveal a molecular pathway that tightly regulates oxalate and citrate to guard against Ca²⁺-oxalate stone formation.     

IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway

Fluid and HCO(3)(-) secretion are fundamental functions of epithelia and determine bodily fluid volume and ionic composition, among other things. Secretion of ductal fluid and HCO(3)(-) in secretory glands is fueled by Na(+)/HCO(3)(-) cotransport mediated by basolateral solute carrier family 4 member 4 (NBCe1-B) and by Cl(-)/HCO(3)(-) exchange mediated by luminal solute carrier family 26, member 6 (Slc26a6) and CFTR. However, the mechanisms governing ductal secretion are not known. Here, we have shown that pancreatic ductal secretion in mice is suppressed by silencing of the NBCe1-B/CFTR activator inositol-1,4,5-trisphosphate (IP(3)) receptor-binding protein released with IP(3) (IRBIT) and by inhibition of protein phosphatase 1 (PP1). In contrast, silencing the with-no-lysine (WNK) kinases and Ste20-related proline/alanine-rich kinase (SPAK) increased secretion. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. Silencing of SPAK and IRBIT in the same ducts rescued ductal secretion due to silencing of IRBIT alone. These findings stress the pivotal role of IRBIT in epithelial fluid and HCO(3)(-) secretion and provide a molecular mechanism by which IRBIT coordinates these processes. They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis.