Iron deficiency transiently suppresses biliary neuronal nitric oxide synthase

BACKGROUND: Iron deficiency results in altered gallbladder and sphincter of Oddi (SO) motility and cholesterol crystal formation. In addition, gallbladder neuronal nitric oxide synthase (nNOS) has been shown to be markedly reduced after 8 weeks on an iron-deficient diet. However, the effects of prolonged iron deficiency on gallbladder and SO nNOS as well as crystal formation have not been determined. Therefore, we tested the hypothesis that iron deficiency would downregulate both gallbladder and SO nNOS expression and that nNOS downregulation and cholesterol crystal formation would progress over time. MATERIALS AND METHODS: Thirty-eight adult female prairie dogs were fed either an ironsupplemented (Fe+) (200 ppm) or an iron-deficient (Fe-) (8 ppm) diet for 8 weeks (Fe+ n = 9, Fe- n = 10) or 16 weeks (Fe+ n = 9, Fe- n = 10). Blood hemoglobin (HbG) was measured; gallbladder cholesterol crystals were counted; and cholesterol saturation indices (CSI) were calculated. Gallbladder and SO nNOS levels were measured by Western blot. RESULTS: The Fe+ prairie dogs had significantly higher HbG than the Fe- animals (16.9 +/- 0.6 g/dl vs 15.2 +/- 0.5 g/dl, respectively, P < 0.05) after 8 weeks. This difference was even greater after 16 weeks (16.1 +/- 0.4 g/dl vs 14.0 +/- 0.5 g/dl, P < 0.01). At 8 weeks, more cholesterol crystals per 10 HPF were observed in the Fe- animals (0.4 +/- 0.3 vs 1.6 +/- 0.4 per 10 HPF, P < 0.05). This difference was even greater after 16 weeks (0.0 +/- 0.0 vs 52.6 +/- 25.3 per 10 HPF, P < 0.01). No difference in the CSI was observed in the four groups. Iron deficiency decreased the nNOS/beta-actin protein levels in the gallbladder and SO at 8 weeks (57.0 +/- 29.6 vs 7.4 +/- 2.6, gallbladder, P < 0.05) (98.4 +/- 39.7 vs 29.9 +/- 11.0, SO, P = 0.09), but these levels returned to baseline at 16 weeks. CONCLUSIONS: We conclude that iron deficiency acutely suppresses gallbladder and SO nNOS, and that compensatory mechanisms return nNOS to baseline levels while cholesterol crystal formation increases over time.     

Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines

Diagnostic and therapeutic strategies for acute biliary inflammation/infection (acute cholangitis and acute cholecystitis), according to severity grade, have not yet been established in the world. Therefore we formulated flowcharts for the management of acute biliary inflammation/infection in accordance with severity grade. For mild (grade I) acute cholangitis, medical treatment may be sufficient/appropriate. For moderate (grade II) acute cholangitis, early biliary drainage should be performed. For severe (grade III) acute cholangitis, appropriate organ support such as ventilatory/circulatory management is required. After hemodynamic stabilization is achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. For patients with acute cholangitis of any grade of severity, treatment for the underlying etiology, including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has improved. For patients with mild (grade I) cholecystitis, early laparoscopic cholecystectomy is the preferred treatment. For patients with moderate (grade II) acute cholecystitis, early laparoscopic or open cholecystectomy is preferred. In patients with extensive local inflammation, elective cholecystectomy is recommended after initial management with percutaneous gallbladder drainage and/or cholecystostomy. For the patient with severe (grade III) acute cholecystitis, multiorgan support is a critical part of management. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy and/or drainage. Delayed elective cholecystectomy may be performed after initial treatment with gallbladder drainage and improvement of the patient's general medical condition.     

A Nomogram for Predicting the Likelihood of Additional Nodal Metastases in Breast Cancer Patients With a Positive Sentinel Node Biopsy

Background:The standard of care for breast cancer patients with sentinel lymph node (SLN) metastases includes complete axillary lymph node dissection (ALND). However, many question the need for complete ALND in every patient with detectable SLN metastases, particularly those perceived to have a low risk of non-SLN metastases. Accurate estimates of the likelihood of additional disease in the axilla could assist greatly in decision-making regarding further treatment.Methods:Pathological features of the primary tumor and SLN metastases of 702 patients who underwent complete ALND were assessed with multivariable logistic regression to predict the presence of additional disease in the non-SLNs of these patients. A nomogram was created using pathological size, tumor type and nuclear grade, lymphovascular invasion, multifocality, and estrogen-receptor status of the primary tumor; method of detection of SLN metastases; number of positive SLNs; and number of negative SLNs. The model was subsequently applied prospectively to 373 patients.Results:The nomogram for the retrospective population was accurate and discriminating, with an area under the receiver operating characteristic (ROC) curve of 0.76. When applied to the prospective group, the model accurately predicted likelihood of non-SLN disease (ROC, 0.77).Conclusions:We have developed a user-friendly nomogram that uses information commonly available to the surgeon to easily and accurately calculate the likelihood of having additional, non-SLN metastases for an individual patient.Drs. Manasseh and Bevilacqua contributed equally to the work.Dr. Bevilacqua is currently affiliated with Hospital Sírio Libanes, Instituto Brasileiro de Controle do Câncer, and Disciplina de Cirurgia Geral, Departamento de Cirurgia, Faculdade de Medicina da Univerdidade de Sao Paulo. São Paulo, Brazil; Dr. Boolbol is currently affiliated with Beth Israel Medical Center, New York, New York.     

Liver Resection with Portal Vein Thrombectomy for Hepatocellular Carcinoma With Vascular Invasion

Introduction  Hepatocellular carcinoma (HCC) tends to invade the intrahepatic vasculature, especially the portal vein.1 The presence of portal vein tumor thrombus (PVTT) in patients with HCC is one of the most significant factors for a poor prognosis.2 ^– 5 The presence of macroscopic PVTT in patients with HCC is also a significant factor for poor prognosis, with a median survival of <3 months without treatment.1 In surgically resected series, in patients with gross PVTT (PVTT in the portal trunk, its first-order branch, or its second-order branch), the 3-year and 5-year survival rates are reportedly 15% to 28% and 0% to 17%, respectively.2 ^– 5 Methods  The patient was a 77-year-old woman with well-compensated hepatitis C virus–related cirrhosis (stage A6 according to Child-Pugh classification) who sought care at our department for vague abdominal discomfort. Triphasic spiral computed tomographic scan confirmed HCC 6 cm in diameter in the left lobe of the liver. In addition, portal vein tumor thrombosis of the left branch that extended to the right portal vein was present. Results  The procedure included left hepatectomy and en-bloc portal vein thrombectomy with clamping of both the common portal vein trunk and the right portal vein. The portal vein was incised at the bifurcation of the right and left portal veins, and the thrombus was extracted from the incision in the portal vein. With this procedure, we were able to examine under direct vision the exact extent of the portal vein thrombus, and we identified whether the tumor thrombus was adherent to the venous wall or was freely floating in the venous lumen. Portal clamping and length of operation were 16 and 330 minutes, respectively. Intraoperative blood loss was 550 mL. The patient was discharged on postoperative day 6, and she was free of disease at 15 months after surgery. Discussion  Liver resection should be considered a valid therapeutic option for HCC with PVTT. Electronic supplementary material  The online version of this article (doi:) contains supplementary video material, which is available to authorized users. Presented to Annual Meeting of the American Hepato-Pancreato-Biliary Association (AHPBA), Miami, Florida, USA, March 9-12, 2006.     

The cholecysto-sphincter of Oddi reflex

Multiple factors including hormonal and neural influences as well as intravascular volume, body temperature, and pharmacologic agents have been shown to influence sphincter of Oddi function. Recent studies have also suggested that mechanical or electrical stimulation of the gallbladder and the degree of gallbladder filling may affect the frequency and amplitude of sphincter of Oddi phasic contractions. However, the effect of gallbladder filling on sphincter of Oddi phasic wave direction has not previously been studied. In acute terminal experiments, eight adult male prairie dogs underwent cannulation of the gallbladder with a pressure-monitored perfusion catheter. The common bile duct was cannulated proximally with a drainage catheter and distally with a triple-lumen, side-hole, closed-tipped catheter. The distal port of this catheter was positioned in the sphincter of Oddi (SO) while the proximal port was in the distal common bile duct (CBD). Distal CBD and SO phasic wave activity was recorded first with the gallbladder perfused with lactated Ringer's solution at 0.1 ml/min (mean intragallbladder pressure 8.1 ± 0.3 mm Hg) and then with the gallbladder (GB) empty. Sphincter of Oddi phasic wave frequency was 6.7 ± 0.9/min with the GB full and 5.4 ± 0.6/min with the GB empty (P < 0.02). Phasic wave amplitude was also greater with the GB full versus empty in both the distal CBD (6.4 ± 0.6 vs 4.3 ± 0.5 mm Hg, P < 0.05) and the SO (9.5 ± 1.5 vs 6.4 ± 0.8, P = 0.075). Baseline pressures and the direction of phasic waves were unaffected by the degree of gallbladder filling. It is concluded that the degree of gallbladder filling reflexly influences sphincter of Oddi phasic wave activity and should be considered in future studies of the choledochoduodenal junction.     

Glucose-Regulated Protein 78 Is a Novel Contributor to Acquisition of Resistance to Sorafenib in Hepatocellular Carcinoma

Background  

Sorafenib is a newly established cancer drug found to be an effective systemic treatment for advanced hepatocellular carcinoma (HCC). However, little is known about any potential effectors that modify tumor cell sensitivity towards sorafenib. Here, we present the first evidence that glucose-regulated protein 78 (GRP78) is intimately associated with acquisition of resistance towards sorafenib.     

A triple-blinded randomized trial comparing the hemostatic effects of large-dose 10% hydroxyethyl starch 264/0.45 versus 5% albumin during major reconstructive surgery

In Canada, hydroxyethyl starch 264/0.45 (HES 264/0.45; molar weight 264 kDa, molar substitution 0.45) has largely replaced albumin as the colloidal fluid of choice for perioperative intravascular volume expansion. The maximum recommended dose of HES 264/0.45 is 28 mL/kg; however, there are no clinical data supporting this limit. In this study we compared the hemostatic effects of HES 264/0.45 versus 5% albumin in doses up to 45 mL/kg over 24 h during major reconstructive head and neck surgery. Fifty patients were randomized to receive HES 264/0.45 or 5% human albumin from the induction of anesthesia until 24 h thereafter. Both albumin and HES 264/0.45 effectively maintained physiologic variables in the perioperative and postoperative periods. The partial thromboplastin time and international normalized ratio were significantly increased in the HES 264/0.45 group compared with the albumin group after infusion of 30 mL/kg and 45 mL/kg (P < 0.05). Factor VIII activity and von Willebrand factor level were significantly reduced in the HES 264/0.45 group compared with the albumin group after infusion of 15 mL/kg, 30 mL/kg, and 45 mL/kg (P < 0.05). Significantly more subjects in the HES 264/0.45 group received allogeneic red blood cell transfusions (P < 0.02). We conclude that HES 264/0.45 infusions >30 mL/kg over 24 h impair coagulation to a greater extent than albumin, possibly leading to more allogeneic transfusions.     

The safety of statins in clinical practice

Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.     

Crystal structure of Pseudomonas aeruginosa bacteriophytochrome: photoconversion and signal transduction

Phytochromes are red-light photoreceptors that regulate light responses in plants, fungi, and bacteria via reversible photoconversion between red (Pr) and far-red (Pfr) light-absorbing states. Here we report the crystal structure at 2.9 Å resolution of a bacteriophytochrome from Pseudomonas aeruginosa with an intact, fully photoactive photosensory core domain in its dark-adapted Pfr state. This structure reveals how unusual interdomain interactions, including a knot and an “arm” structure near the chromophore site, bring together the PAS (Per-ARNT-Sim), GAF (cGMP phosphodiesterase/adenyl cyclase/FhlA), and PHY (phytochrome) domains to achieve Pr/Pfr photoconversion. The PAS, GAF, and PHY domains have topologic elements in common and may have a single evolutionary origin. We identify key interactions that stabilize the chromophore in the Pfr state and provide structural and mutational evidence to support the essential role of the PHY domain in efficient Pr/Pfr photoconversion. We also identify a pair of conserved residues that may undergo concerted conformational changes during photoconversion. Modeling of the full-length bacteriophytochrome structure, including its output histidine kinase domain, suggests how local structural changes originating in the photosensory domain modulate interactions between long, cross-domain signaling helices at the dimer interface and are transmitted to the spatially distant effector domain, thereby regulating its histidine kinase activity.