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Along with the most common mutation, JAK2V617F, several other acquired JAK2 mutations have now been shown to contribute to the pathogenesis of myeloproliferative neoplasms (MPNs). However, here we describe for the first time a germline mutation that leads to familial thrombocytosis that involves a residue other than Val617. The novel mutation JAK2R564Q, identified in a family with autosomal dominant essential thrombocythemia, increased cell growth resulting from suppression of apoptosis in Ba/F3-MPL cells. Although JAK2R564Q and JAK2V617F have similar levels of increased kinase activity, the growth-promoting effects of JAK2R564Q are much milder than those of JAK2V617F because of at least 2 counterregulatory mechanisms. Whereas JAK2V617F can escape regulation by the suppressor of cytokine signaling 3 and p27/Kip1, JAK2R564Q-expressing cells cannot. Moreover, JAK2R564Q-expressing cells are much more sensitive to the JAK inhibitor, ruxolitinib, than JAK2V617F-expressers, suggesting that lower doses of this drug may be effective in treating patients with MPNs associated with alternative JAK2 mutations, allowing many undesirable adverse effects to be avoided. This work provides a greater understanding of the cellular effects of a non-JAK2V617F, MPN-associated JAK2 mutation; provides insights into new treatment strategies for such patients; and describes the first case of familial thrombosis caused by a JAK2 residue other than Val617.

The effect of different intakes of salt for 12 mo on bone calcium content and urinary excretion of calcium and hydroxyproline were examined in sham operated and oophorectomized (OX) rats to determine the long term effects of high sodium intake and its interaction with estrogen deficiency. Sham operated (n = 24) and OX (n = 24) rats were divided into groups of six rats in a 2 x 4 design. One group of sham and one of OX rats were given 0, 2, 6 or 18 g/L sodium chloride to drink. Urine samples were collected at 0, 2, 4, 6, 10 and 12 mo for the measurement of sodium, calcium, creatinine and hydroxyproline. At the end of 12 mo, blood was taken for measurement of calcium, albumin, alkaline phosphatase and creatinine and the left femur was removed and analyzed for calcium and phosphate. Body weights of the OX rats were higher than the sham operated controls. At the start of the experiment (10 d after OX) urinary excretions of calcium and hydroxyproline were significantly higher in OX rats. However, after 4-6 mo, they were significantly lower in OX rats. Calcium excretion and hydroxyproline excretion were increased by high salt intake, and there was a significant correlation between sodium and calcium excretion (r = 0.962). Bone calcium content of OX rats was lower than their corresponding sham-operated controls. Sodium intake also had a significant effect on bone calcium content. Multiple regression analysis showed that OX and sodium intake explained 7.6% and 1.5% of the variation in bone calcium content. We conclude that high sodium intake causes increased loss of calcium and reduces bone calcium content in sham-operated as well as OX rats.

The effect of feeding high protein (40%) and high salt intake (18 gm/L of sodium chloride in drinking water) for 4 months on the urinary excretion of calcium and hydroxyproline (OHP) in sham operated and oophorectomized (OX) rats was studied. OX rats had higher body weight and increased excretion of calcium and OHP. Feeding a high-salt diet caused an increase in the excretion of calcium, phosphate, and OHP. The high-protein diet had a similar effect. There was a significant interaction between the effects of salt and protein on calcium excretion. OX did not influence the effect of high salt or high protein intakes. It is concluded that high protein and/or high salt intake increases the excretion of calcium and OHP. The effect is seen even after 4 months of the diet. Oophorectomy did not cause any additional effect.

Inferior vena caval obstruction is an unusual but important clinical problem for which adequate treatment previously has not been available. Recently, a polytetrafluoroethylene (PTFE) graft with external rigid spiral supports was developed that appeared particularly applicable to the venous system. In 18 dogs a 15 cm length of Impraflex was placed from the proximal right common iliac vein to the inferior vena cava (IVC) at the level of the renal veins after IVC and right iliac vein interruption. End-to-end and end-to-side iliac vein anastomoses were alternated, with and without distal femoral arteriovenous (AV) fistulas (AVFs). At 2 months, with a distal AV fistula, 11 of 12 (92%) grafts were patent, angiograms demonstrated no evidence of intraluminal clot, and there was no hind limb edema. Following AVF ligation 2 months after graft insertion, 10 grafts remained patent, but five developed some intraluminal thrombus and one of them progressed to complete occlusion. Four months after fistula ligation (6 months after graft insertion) 9 of 12 grafts (75%) remained patent. All six grafts without distal AVF were occluded within 1 week. This procedure was performed on one severely symptomatic patient who had IVC occlusion, and currently the patient shows marked improvement. Thus IVC bypass is possible when an externally supported PTFE prosthesis is complemented by a temporary AVF.