A Multitargeted Receptor Tyrosine Kinase Inhibitor,SU6668, Does Not Affect the Healing of Cutaneous Full-Thickness Incisional Wounds in SKH-1 Mice

Disturbances of angiogenesis have been suggested to result in the impaired healing of skin wounds. Using a murine incisional wound model, we evaluated the effects of SU6668, an inhibitor of the receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), on the healing of skin wounds. Mice were administered vehicle, SU6668 (100 or 400 mg/kg/day, b.i.d.), or dexamethasone (1 mg/kg/day, b.i.d.), and wound healing was monitored histologically and using a tensiometer. SU6668 at a fully efficacious dose of 100 mg/kg/day had no significant effect on the healing process, while at a supratherapeutic dose of 400 mg/kg/day, there were subtle transient histologic changes and slight decreases in tensile strength, suggesting a slight delay in the wound healing process. In conclusion, these data indicate that inhibition of the receptors for VEGF, PDGF, and FGF at levels necessary to inhibit tumor growth in mouse xenograft models does not affect the healing of incisional wounds in mice. Redundant pathways likely compensate for inhibition of VEGF, PDGF, and FGF signaling pathways in the skin healing process.     

SPAK Differentially Mediates Vasopressin Effects on Sodium Cotransporters

Activation of the Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) and the Na⁺-Cl⁻-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor–specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.The furosemide-sensitive Na⁺-K⁺-2Cl⁻-cotransporter (NKCC2) of the thick ascending limb (TAL) and the thiazide-sensitive Na⁺-Cl⁻-cotransporter (NCC) of the distal convoluted tubule (DCT) are key regulators of renal salt handling and therefore participate importantly in BP and extracellular fluid volume homeostasis.¹ Loss-of-function mutants in the SLC12A1/ A3 genes encoding NKCC2 and NCC cause salt-losing hypotension and hypokalemic alkalosis in Bartter’s and Gitelman’s syndromes,^2,3 whereas their overactivity may contribute to essential hypertension.^4,5 Recently, attention has been focused on the two closely related STE20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1), which can phosphorylate NKCC2 and NCC at their N-terminal conserved threonine or serine residues (T96, T101, and T114 of mouse NKCC2 and T53, T58, and S71 of mouse NCC) and thereby activate the transporters.^6–8 Despite the high homology between SPAK and OSR1 and their overlapping renal expression patterns, distinct roles along the nephron have been suggested based on data from SPAK-deficient and kidney-specific OSR1-deficient mice: deletion of SPAK primarily impairs the function of NCC, whereas deletion of OSR1 negatively affects NKCC2.^9–11 The complex functional properties of a WNK-SPAK/OSR1-N(K)CC interaction cascade are currently being defined.¹² Recently, arginine vasopressin (AVP), signaling via the V2 receptor (V2R), has been identified as an efficient activator of both cotransporters, affecting their luminal trafficking and phosphorylation.^13–18 Because plasma AVP levels may vary not only with the sleep-wake cycle or long-term physiologic challenges, but also with pulsatile changes over the short term, distinct, time-dependent responses may occur.¹⁹ SPAK and OSR1 are well placed to regulate distal NaCl reabsorption in response to AVP. Here we tested the role of SPAK in AVP-induced activation of NKCC2 and NCC, acutely and during long-term treatment. The results suggest that SPAK is an essential kinase that modulates distal nephron function in response to AVP stimulation.     

Short-Term Outcomes after Combined Colon and Liver Resection for Synchronous Colon Cancer Liver Metastases: A Population Study

Introduction

The timing of surgical resection for stage IV colon cancer with liver metastasis and the safety of simultaneous colon and liver resection remains controversial. The purpose of our study was to evaluate short-term outcomes after combined colon and liver resection (CCLR) versus colon resection (CR) or liver resection alone (LR) using a population database.

Methods

The National Inpatient Sample was used to select patients who had surgery for colon cancer from 2002 to 2006. We evaluated for in-hospital morbidity, mortality, and prolonged length of stay (PLOS). Our analysis was done using design-weighted unadjusted analysis and logistic regression.

Results

We identified 361,096 patients during our study period (CCLR 3,625; CR 322,286; LR 35,185). CCLR was not associated with an increased risk of complications (odds ratio (OR) 1.12; 95 % confidence interval (CI) 0.94–1.33; P = 0.21) or PLOS (OR 1.19; 95 % CI 0.99–1.4; P = 0.06) compared with CR. In-hospital mortality occurred in 3.5 % of patients who underwent CCLR and was not significantly associated with mortality compared with CR alone (OR 1.17; 95 % CI 0.79–1.74; P = 0.43). Liver lobectomy with CR was associated with a PLOS and a trend toward increased morbidity and mortality. Significant predictors of complications, mortality, and PLOS included: age >70 years, male gender, nonprivate health insurance, and Elixhauser score >1.

Conclusions

CCLR with limited liver resection can be performed with similar morbidity and mortality to colectomy alone. For patients who require hepatic lobectomy, however, strong consideration should be given to a staged approach.     

Body Piercings and Posttraumatic Stress Disorder Symptoms in Young Adults

Body piercing, which is prevalent in young adults, has been suggested to be associated with features usually related to posttraumatic stress disorder (PTSD) such as high‐risk behaviours and psychopathological symptoms and might be motivated by a wish to deal with prior traumatic experiences. However, to date, no research has investigated the relationship between this practice and PTSD symptoms. The present research aims to investigate the possible relationship between body piercing and PTSD symptoms in French‐speaking young adults. According to our results, having two or more body piercings was associated with a twofold increased risk for scoring above the cut‐off score for PTSD on the PTSD checklist. Our findings suggest that two or more body piercings might serve as an identifiable marker for PTSD symptoms and may have important implications for clinical screening. Copyright © 2012 John Wiley & Sons, Ltd.     

Synchronous right hepatectomy and cesarean section in a pregnant lady with hepatocellular carcinoma

INTRODUCTIONCancer in pregnancy is rare and hepatocellular carcinoma (HCC) during pregnancy is even rarer. Due to limited experience, management of these patients remains challenging.PRESENTATION OF CASEA 33-year old pregnant lady presented with HCC at 28 weeks of gestation. She underwent synchronous cesarean section and right hepatectomy at 32 weeks of gestation. The post-operative course was uneventful. She was discharged home on day 10 after surgery. Histolopathology confirmed HCC. The surgical resection margins were clear. At a follow-up of 3 months after surgery, the mother was disease free and the infant was well.DISCUSSIONHCC during pregnancy is extremely rare. The experience in its management and outcomes are lacking. In managing any patient diagnosed with a malignant neoplasm in pregnancy, both the mother and the fetus have to be considered.CONCLUSIONWith adequate preoperative assessment and a good management strategy, good results can be obtained for both the mother and the baby for a pregnant patient with HCC.