Association of Helicobacter pylori with hepatobiliary stone disease, a prospective case control study.

BACKGROUND: Hepatobiliary stone disease is one of the most common surgical conditions worldwide. There are multiple causative agents responsible for the formation of hepatobiliary stones, and bacterial infection is one of them. The presence of Helicobacter DNA species has been investigated in the biliary epithelium of patients with biliary diseases. However, conflicting results have been observed that may have been due to the small number of subjects studied, difficulty in obtaining a healthy control group, absence of controlling for confounding factors, or ethical and regional differences among populations. METHODS: We investigated the presence of Helicobacter pylori species by PCR of 26-kDa surface antigen specific to H. pylori in bile samples from 50 cases with hepatobiliary stones and 25 controls without hepatobiliary stones. The control group comprised of 20 patients of hydatid cyst disease of liver and 5 patients of right colonic growth. RESULT: H. pylori was present in 20 bile samples among cases and was absent in 30 bile samples among cases. Among controls, H. pylori could not be detected. A significant association of the presence of H. pylori with hepatobiliary stone disease was seen (p < 0.001). CONCLUSION: There is an association between bile infection with H. pylori and hepatobiliary stone disease.

Metastases to breast - A 29 year experience in a tertiary care hospital.

Metastatic lesions to the breast are unusual. We present a series of 26 cases of metastatic tumors to breast from extra-mammary sites over a period of 29 years. There were 14 female and 12 male patients, and their ages ranged from 28 to 70 years. The tumor was in the upper outer quadrant in 16 patients. All 26 cases noticed a mass in the breast and more than half of the patients complained of discomfort and pain. The mammary symptoms were present for more than 4 months in all patients. Of the 26 cases, 13 cases had metastatic adenocarcinoma, 12 cases had metastatic squamous cell carcinoma and one case had poorly differentiated carcinoma. On mammography, 16 patients showed high density lesions and on ultrasonography lesions were hypoechoic. Prognosis is poor but appears slightly improved since more refined chemo and immunotherapeutic regimens were available. The clinical, pathologic, and radiographic features of this problem are described.

Management of biliary ascariasis in children living in an endemic area.

BACKGROUND: One quarter of the world's population is known to be infected with ascariasis. It is endemic in various parts of the Indian subcontinent with a high incidence in the Kashmir valley. Although intestinal obstruction is the commonest complication of ascariasis in children, biliary ascariasis remains the second most common complication. We aimed to study the various types of clinical presentations, complications and different diagnostic tools and to assess various options for the management of biliary ascariasis. MATERIALS AND METHODS: Sixty-one cases of ultrasound documented hepatobiliary ascariasis were studied prospectively over a period of 3 years from Jan 2003 to Dec 2005 at the Sheri-Kashmir Institute of Medical Sciences in Srinagar, Kashmir. All patients were children aged between 3 and 14 years. All patients were admitted to hospital and put on intravenous fluids, nothing per os until patients were symptom-free, broadspectrum antibiotics and antispasmodics. All patients received antihelminthics in the form of albendazole 400 mg as soon as patients could accept oral medication. Conservative management was continued until the patients were symptom-free. Endoscopic extraction was deferred until 3 weeks later except in patients with pyogenic cholangitis where urgent endoscopic intervention was carried out. Surgical intervention was carried out if both conservative management and endoscopic extraction failed or ERCP could not be performed for technical reasons or complications developed. RESULTS: The most common presentation was upper abdominal pain in 36 (59%) patients followed by vomiting of worms in 20 (33.3%) cases. Complications included cholangitis in 8 (13.1%), obstructive jaundice in 7 (11.4%), acute pancreatitis in 1 (1.6%) and hepatic abscess in 1 (1.6%) patient. Spontaneous passage of worms from the biliary ducts was observed in 44 (72.1%) patients. ERCP was successful in 8 (13.1%) patients, and 9 (14.7%) patients needed surgical intervention. CONCLUSION: In endemic countries, ascariasis should be suspected in patients with biliary disease. Most patients respond to conservative management although a few may need surgical intervention. Although this disease is prevalent in developing countries, because of increased travel and migration, clinicians elsewhere should be aware of the problems associated with ascariasis.

Identification of genes that confer tumor cell resistance to the aurora B kinase inhibitor, AZD1152.

AZD1152 is a highly selective Aurora B kinase inhibitor currently undergoing Phase I and II clinical evaluation in patients with acute myelogenous leukemia and advanced solid malignancies. We have established two AZD1152-resistant cell lines from SW620 colon and MiaPaCa pancreatic carcinoma lines, which are >100-fold resistant to the active metabolite of AZD1152, AZD1152 HQPA and interestingly, cross-resistant to the pan-Aurora kinase inhibitor, VX-680/MK0457. Using whole-genome microarray analysis and comparative genomic hybridization, we were able to identify MDR1 and BCRP as the causative genes that underlie AZD1152 HQPA-resistance in these models. Furthermore, the upregulation of either of these genes is sufficient to render in vivo tumor growth insensitive to AZD1152. Finally, the upregulation of MDR1 or BCRP is predictive of tumor cell sensitivity to this agent, both in vitro and in vivo. The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy.

Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2.

Small-molecule inhibitors of the Aurora A and B kinases interfere with mitotic centrosome function and disrupt the mitotic spindle assembly checkpoint resulting in polyploidization and apoptosis of proliferating cells. As such, several Aurora kinase inhibitors are at various stages of clinical development as anticancer agents. To identify candidate apoptosis-sensitizing genes that could be exploited in combination with Aurora kinase inhibitors in malignant glioma, we have carried out global gene expression analysis in a D54MG glioma cell derivative treated with three Aurora kinase inhibitors chosen for their distinctive selectivities: MLN8054 (Aurora A-selective), AZD1152 (Aurora B-selective), and VX-680 (Aurora A/B). The modulation of apoptotic gene expression by p53 under these conditions was ascertained, as p53 expression can be toggled on and off in this D54MG derivative by virtue of a stable, inducible, p53-targeting short hairpin RNA (D54MG(shp53)). This analysis identified the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, TRAIL receptor 2 (TRAIL-R2), as an apoptosis-sensitizing gene induced selectively following inhibition of Aurora B. In glioma cell lines where TRAIL-R2 was induced following polyploidization, the sensitivity, kinetics, and magnitude of TRAIL-mediated apoptosis were enhanced. Our data shed light on the apoptotic program induced during polyploidization and suggest that TRAIL-R2 activation is a putative point of therapeutic intervention in combination with inhibitors of Aurora B.

Congenital common bile duct web in association with hepatobiliary pancreatic ductal anomalies.

Congenital webs are extremely rare anomalies of the extrahepatic ductal system. As the vast majority of such cases are asymptomatic, detection is usually incidental during surgery for some other cause. In a young boy presenting with features of cholangitis, a congenital common bile duct web was discovered on T-tube cholangiogram. Further anomalies of the intrahepatic and pancreatic ductal systems were also detected. Since all known causes of acquired web formation were excluded, a congenital origin of the web was assumed and the patient is continuing to do well after a follow-up of 22 months.

Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition.

Rapamycin, a natural product inhibitor of the Raptor-mammalian target of rapamycin complex (mTORC1), is known to induce Protein kinase B (Akt/PKB) Ser-473 phosphorylation in a subset of human cancer cell lines through inactivation of S6K1, stabilization of insulin receptor substrate (IRS)-1, and increased signaling through the insulin/insulin-like growth factor-I/phosphatidylinositol 3-kinase (PI3K) axis. We report that A-443654, a potent small-molecule inhibitor of Akt serine/threonine kinases, induces Akt Ser-473 phosphorylation in all human cancer cell lines tested, including PTEN- and TSC2-deficient lines. This phenomenon is dose-dependent, manifests coincident with Akt inhibition and likely represents an alternative, rapid-feedback pathway that can be functionally dissociated from mTORC1 inhibition. Experiments performed in TSC2-/- cells indicate that TSC2 and IRS-1 cooperate with, but are dispensable for, A-443654-mediated Akt phosphorylation. This feedback event does require PI3K activity, however, as it can be inhibited by LY294002 or wortmannin. Small interfering RNA-mediated knockdown of mTOR or Rictor, components of the rapamycin-insensitive mTORC2 complex, but not the mTORC1 component Raptor, also inhibited Akt Ser-473 phosphorylation induced by A-443654. Our data thus indicate that Akt phosphorylation and activity are coupled in a manner not previously appreciated and provide a novel mode of Akt regulation that is distinct from the previously described rapamycin-induced IRS-1 stabilization mechanism.

Management of Mirizzi syndrome: a new surgical approach.

BACKGROUND: In a prospective study of a patient population of 1,340 with biliary calculus disease, that ran from January 1993 to December 1997, 34 patients (2.53%) were identified as having Mirizzi syndrome. Eight patients were found to have type I (A and B) and 26 patients were found to have type II Mirizzi syndrome. A history of recurrent biliary colic and jaundice was present in the majority of patients. METHODS: Ultrasonography was helpful in five patients and endoscopic retrograde cholangiopancreatography was helpful in 17 patients in the diagnosis of this condition. Because the amount of gall bladder tissue used in choledochoplasty is not yet standardized, a new policy regarding choledochoplasty was adopted. In type IA, retrograde cholecystectomy with simple closure of cystic duct was carried out. In type IB, retrograde cholecystectomy and choledochoplasty with 5 mm cuff of the gall bladder was carried out. In type II lesions the procedure depended on the size of fistula. Patients with fistula sizes of less than one-third of the common bile duct diameter underwent choledochoplasty with 5 mm cuff of the gall bladder, and patients with fistula sizes between one-third and two-thirds of the diameter of the common bile duct underwent choledochoplasty with 10 mm cuff of the gall bladder. Patients with fistula sizes of more than two-thirds of the common bile duct diameter underwent Roux-en-Y hepaticojejunostomy. RESULTS: There was no operative mortality and the complication rate was 17.64%. CONCLUSION: Although, out of 26 choledochoplasties, we encountered only one (3.84%) stump stone in a maximum follow-up period of 59 months, further long-term follow-up studies are required to prove the efficacy of the procedure.

Glucocorticoids oppose translational control by leucine in skeletal muscle.

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.

Postoperative biliary ascariasis: presentation and management--experience.

Subsequent to preoperative and perioperative indications the common bile duct was explored in 705 patients over a 12-year period, from January 1983 to December 1994. Consequent postoperative T-tube cholangiography revealed the presence of worms in 22 patients. Expulsion of the worms followed T-tube irrigation with 0.9% normal saline in 18 patients. Only one patient had to be reexplored to remove the ascaris. In two patients the worm was removed along with the T-tube, and in one patient the worm came out through the T-tube tract.

4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle.

Maintenance of cellular protein stores in skeletal muscle depends on a tightly regulated synthesis-degradation equilibrium that is conditionally modulated under an extensive range of physiological and pathophysiological circumstances. Recent studies have established the initiation phase of mRNA translation as a pivotal site of regulation for global rates of protein synthesis, as well as a site through which the synthesis of specific proteins is controlled. The protein synthetic pathway is exquisitely sensitive to the availability of hormones and nutrients and employs a comprehensive integrative strategy to interpret the information provided by hormonal and nutritional cues. The translational repressor, eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1) have emerged as important components of this strategy, and together they coordinate the behavior of both eukaryotic initiation factors and the ribosome. This review discusses the role of 4E-BP1 and S6K1 in translational control and outlines the mechanisms through which hormones and nutrients effect changes in mRNA translation through the influence of these translational effectors.

Glucocorticoids abate p70(S6k) and eIF4E function in L6 skeletal myoblasts.

The catabolic properties of glucocorticoid hormones are largely attributable to dual regulation of protein degradation and synthesis. With regard to the latter, glucocorticoids modulate the translational machinery, namely that component functional in translation initiation. This investigation revealed that in L6 myoblasts, dexamethasone, a synthetic glucocorticoid, deactivated the ribosomal protein S6 kinase (p70(S6k)) within 4 h, as evidenced by diminished phosphorylation of its physiological substrate, the 40S ribosomal protein S6. This deactivation correlated with dephosphorylation of p70(S6k) at Thr(389), whereas phosphorylation of Ser(411) was unaffected. Furthermore, glucocorticoid administration induced dephosphorylation of the cap-dependent translational repressor, eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), thereby facilitating conjunction of the inhibitor and eIF4E. The mechanism of action is reminiscent of classical transcriptional regulation by steroid hormone receptors in that these effects were preceded by a temporal lag and were sensitive to inhibitors of glucocorticoid receptor function as well as transcriptional and translational inhibition. Okadaic acid and calyculin A corrected the dexamethasone-induced dephosphorylation of p70(S6k) and 4E-BP1, implicating a PP1- and/or PP2A-like protein phosphatase(s) in the observed phenomena. Hence, glucocorticoids attenuate distal constituents of the phosphatidylinositol-3 kinase signaling pathway and thereby encumber the protein synthetic apparatus.

Hydatid cyst of the pancreas.

A rare case of hydatid cyst of the pancreas is reported. Although ultrasonography and computerised tomography scan confirmed the presence of a cystic mass in the body and tail of the pancreas, diagnosis was made only on laparotomy. A distal pancreatectomy was done and the diagnosis of hydatid cyst of the pancreas was confirmed by histopathology. Though very rare, pancreatic hydatidosis should be considered in the differential diagnosis of cystic lesions of the pancreas in the appropriate epidemiological setting.

Among translational effectors, p70S6k is uniquely sensitive to inhibition by glucocorticoids.

Fundamental cellular processes such as cell differentiation and growth, apoptosis and cellular metabolism are regulated differentially by glucocorticoid hormones in a cell-context-related fashion. However, these basic processes are not governed by isolated signals but are influenced by the integration of both synergistic and antagonistic extracellular and intracellular stimuli. Because glucocorticoids and insulin-like growth factor I (IGF-I) reciprocally modulate growth-regulated processes such as translation initiation, especially in skeletal muscle, a study was undertaken to address the nature of this counter-regulation. Quiescent L6 skeletal myoblasts pretreated for 4 h with the synthetic glucocorticoid dexamethasone exhibited a marked attenuation of IGF-I-induced activation of the ribosomal protein S6 kinase (p70(S6k)). The adverse effects of glucocorticoids on the activity of the endogenous enzyme were due to differential dephosphorylation at discrete residues, suggesting that, physiologically, some but not all phosphorylation sites are subject to mitogenic regulation. Furthermore, the translational repressor eIF4E-binding protein 1 (4E-BP1), which in many circumstances is co-ordinately regulated with p70(S6k), was dephosphorylated in response to glucocorticoids; however, hyperphosphorylation of the protein after stimulation with IGF-I was refractory to inhibition by glucocorticoids, as was its dissociation from its binding partner, eIF4E. Although both basal and IGF-I-stimulated rates of protein synthesis were modestly affected by glucocorticoids, the synthesis of EF1A, whose mRNA precursor is a prototype for the terminal oligopyrimidine ('TOP') transcript family and whose expression is controlled by the activity of p70(S6k), was markedly affected. Therefore in this cell system it seems that, despite the mutual control of p70(S6k) and 4E-BP1 that is often observed, p70(S6k) is more sensitive to down-regulation by glucocorticoids under growth-promoting conditions than is 4E-BP1.

Acute attenuation of translation initiation and protein synthesis by glucocorticoids in skeletal muscle.

Glucocorticoids are diabetogenic factors that not only antagonize the action of insulin in target tissues but also render these tissues catabolic. Therefore, in rats, we endeavored to characterize the effects in skeletal muscle of glucocorticoids on translation initiation, a regulated process that, in part, governs overall protein synthesis through the modulated activities of eukaryotic initiation factors (eIFs). Four hours after intraperitoneal administration of dexamethasone (100 microg/100 g body wt), protein synthesis in skeletal muscle was reduced to 59% of the value recorded in untreated control animals. Furthermore, translation initiation factor eIF4E preferred association with its endogenous inhibitor 4E-BP1 rather than eIF4G. Dexamethasone treatment resulted in dephosphorylation of both 4E-BP1 and the 40S ribosomal protein S6 kinase concomitant with enhanced phosphorylation of eIF4E. Moreover, the guanine nucleotide exchange activity of eIF2B was unaffected as was phosphorylation of the alpha-subunit of eIF2. Hence glucocorticoids negatively modulate the activation of a subset of the protein synthetic machinery, thereby contributing to the catabolic properties of this class of hormones in vivo.

Leucine, glutamine, and tyrosine reciprocally modulate the translation initiation factors eIF4F and eIF2B in perfused rat liver.

Leucine, glutamine, and tyrosine, three amino acids playing key modulatory roles in hepatic proteolysis, were evaluated for activation of signaling pathways involved in regulation of liver protein synthesis. Furthermore, because leucine signals to effectors that lie distal to the mammalian target of rapamycin, these downstream factors were selected for study as candidate mediators of amino acid signaling. Using the perfused rat liver as a model system, we observed a 25% stimulation of protein synthesis in response to balanced hyperaminoacidemia, whereas amino acid imbalance due to elevated concentrations of leucine, glutamine, and tyrosine resulted in a protein synthetic depression of roughly 50% compared with normoaminoacidemic controls. The reduction in protein synthesis accompanying amino acid imbalance became manifest at high physiologic concentrations and was dictated by the guanine nucleotide exchange activity of translation initiation factor eIF2B. Paradoxically, this phenomenon occurred concomitantly with assembly of the mRNA cap recognition complex, eIF4F as well as activation of the 70-kDa ribosomal S6 kinase, p70(S6k). Dual and reciprocal modulation of eIF4F and eIF2B was leucine-specific because isoleucine, a structural analog, was ineffective in these regards. Thus, we conclude that amino acid imbalance, heralded by leucine, initiates a liver-specific translational fail-safe mechanism that deters protein synthesis under unfavorable circumstances despite promotion of the eIF4F complex.

Ascaris-induced liver abscess.

The prevalence, symptomatology, and outcome of Ascaris-induced liver abscess was studied prospectively in Kashmir, India, which is an endemic area of ascariasis, from December 1987 to December 1997. Of 510 patients with liver abscess admitted during this period, 74 had biliary ascariasis as the cause (14.51%). Of these 74 patients, 11 had intact ascaridae (live or dead) within the abscess. Six patients had a single abscess, and five had multiple abscesses. Seven patients had associated worms in the bile ducts. Ultrasonography was the main diagnostic procedure used. Ten patients were diagnosed based on clinical and ultrasound findings, and one was diagnosed during laparotomy. Most of the patients were young (age range 3-40 years) with a mean age of 17.20 years. Seven were females, and four were males. Ten patients underwent surgery; nine recovered completely, and one died postoperatively due to septicemia. Another patient died as well: a young child who presented late, was in refractory septic shock following suppurative cholangitis and liver abscess, and could not be taken for surgery. The mortality thus was 9.9%. Liver abscess following invasion of intrahepatic biliary radicles by ascaridae through the ampulla is an unusual complication of an otherwise common disease in Kashmir Valley, affecting children and young adults. The outcome depends on early diagnosis and surgical drainage of the abscess with extraction of worms from the ducts.