ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.     

Overexpression of Akt/PKB modulates N‐myristoyltransferase activity in cancer cells

N‐myristoyltransferase (NMT) catalyses the myristoylation reaction. Since NMT activity is elevated in various cancers and activated Akt/PKB leads to cell survival, we were interested in studying if activation of Akt/PKB has any effect on NMT. Overexpression of constitutively active Akt/PKB in HepG2 cells (HepG2‐CA‐Akt/PKB) led to an approximately 50% reduction of NMT compared with parental HepG2 cells. Reduced NMT activity in HepG2‐CA‐Akt/PKB was found to be due to the NMT1 phosphorylation. We determined NMT activity in various human breast cancer cell lines with differing metastatic potentials and pseudo‐normal breast cells (HBL‐100). Tumourigenic or metastatic breast cancer cell lines such as MDA‐MB‐231, MDA‐MB‐435, and Hs 578T displayed reduced NMT activity. Western blot analysis revealed that NMT1 is phosphorylated in these breast cancer cells. Furthermore, patients' breast cancer tissue array revealed strong positivity and high intensity for NMT in malignant breast tissues compared with normal breast cells. A gradation in the NMT staining was observed for grade I, II, and III infiltrating ductal carcinoma breast tissues. These studies demonstrate that overexpression of Akt/PKB results in NMT1 phosphorylation and that NMT1 is phosphorylated in breast cancer cells. Immunohistochemical analysis suggests that NMT may prove to be an added diagnostic biomarker for breast cancer. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Stage Ie malignant lymphoma of paranasal sinus —A report of 5 cases and review of literature

Primary lymphoma is the most common nonepithelial malignant tumour arising from the paranasal sinus region. It occurs mostly in middle aged and elderly patients with a nonspecific clinical profile resembling that of commoner epithelial sinonasal malignancies. Modified Rappaport’s and the Working Formulation are the frequently used histopathological classification systems. Radiation therapy is the mainstay of treatment with excellent local control of the disease. Most of the failures occur at distant sites outside the treatment area or in the form of disseminateed disease. Chemotherapy, though used in limited number of patients in some series, seems to have a better role to play in the management of these tumours in future as most of the sinonasal lymphomas are of poorly differentiated variety or of unfavourable histology.     

Surgical Strategy for Cystic Diseases of the Liver in a Western Hepatobiliary Center

The aim of this study was to define the indications and evaluate the results of various management options in patients with cystic liver disease. Between 1992 and 1999 we managed 60 consecutive patients with cystic liver disease. Diagnoses included a simple cyst (solitary 12, multiple 10), adult polycystic liver disease (APLD 17), Caroli’s disease (8), hydatid cysts (4), and neoplastic cysts (9). Half of the patients with simple cysts had mild or no symptoms and required no treatment. Percutaneous drainage in eight patients (simple cyst 4, APLD 4) was followed by symptomatic recurrence in three. Laparoscopic deroofing in three patients (multiple simple cysts 2, APLD 1) was followed by symptomatic enlargement of the remaining cysts that required further intervention (laparoscopic deroofing 2, transplantation 1). Laparoscopic hepatectomy was successful in three patients with solitary simple cysts. Of 18 patients who underwent open hepatic resection (neoplastic 8, Caroli’s 4, simple cysts 3, hydatid cysts 2, APLD 1), 2 patients with Caroli’s disease required liver transplantation for disease progression. Nine patients (Caroli’s 5, APLD 4) underwent liver transplantation, and three had a concomitant renal transplant. Seven patients developed complications, and three died (5%). Cholangiocarcinoma developed in three patients with bilateral Caroli’s disease, and all died. Radiologic treatment has a limited role in the management of patients with simple cysts or APLD. Laparoscopic deroofing of simple cysts may have to be repeated, whereas resection minimizes cyst recurrence. Unilobar Caroli’s disease may be resected, whereas bilateral disease requires early liver transplantation owing to the high risk of malignancy. Transplantation is a reserved option in patients with extensive APLD.     

HLA associations with HBV carriage and proteinuria

Human leucocyte antigen (HLA) associations have been reported in children with hepatitis B virus (HBV) associated membranous nephropathy (MN). In a previous study, we found an association with HLA DQB1*0603 in black children with HBVMN. To determine whether HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria, we studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603. HBV was determined using third generation ELISA, slot-blot hybridisation, and nested polymerase chain reaction. HLA class I antigens were determined using a two-staged lymphocytotoxic test whereas class II antigen typing was done using sequence-specific primers. Abnormal proteinuria was defined by a protein/creatinine ratio > or =0.2. Associations of HLA DQB1*0603 with HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative versus those with DQB1*0603 who were HBV positive was not significant (anti-log sum =2.0559 and average 0.23). When a similar calculation was made for abnormal proteinuria, there were no significant findings (anti-log sum =3.8587 and average 0.43). This lack of association of HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 that distinguishes family members from HBVMN is the degree of proteinuria, which is a reflection of the severity of glomerular basement membrane damage in the latter.     

Treatment of hepatitis B virus-associated nephropathy in black children

The efficacy of interferon (IFN) in the treatment of hepatitis B virus (HBV)-associated nephropathy in black children has not been established. Twenty-four black children with biopsy-proven HBV-associated nephropathy were recruited into the study during the period April 1997 to June 1999. Five defaulted treatment and were excluded from the primary analysis. IFNalpha 2b was administered for 16 weeks. Response to treatment was defined as loss of HBeAg, decrease in proteinuria, and prevention of deterioration in renal and liver function. A control group of 20 patients was followed up for the same period. Ten (52.6%) of the treated children responded with clearance of HBeAg by 40 weeks. None cleared HBsAg. All responders showed remission of proteinuria, 90% maintained normal renal function and 1 (10%) showed improvement of renal function. HBV DNA levels decreased in this group. Nine patients did not clear HBeAg; none showed remission of proteinuria, and two showed deterioration of renal function. Liver enzymes rose during treatment but subsequently declined irrespective of response to therapy. No serious side effects were encountered. Only 5% of controls showed spontaneous clearance of HBeAg, and none had remission of proteinuria. Black children with HBV-associated nephropathy show accelerated clearance of HBeAg with remission of proteinuria following treatment with IFNalpha 2b. IFNalpha 2b was well tolerated.     

Human,Rat, and Mouse Metabolism of Resveratrol

Purpose. Resveratrol, a phenolic phytoalexin occurring in grapes, wine, peanuts, and cranberries, has been reported to have anticarcinogenic, antioxidative, phytoestrogenic, and cardioprotective activities. Because little is known about the metabolism of this potentially important compound, the in vitro and in vivo metabolism of trans-resveratrol were investigated. Methods. The in vitro experiments included incubation with human liver microsomes, human hepatocytes, and rat hepatocytes and the in vivo studies included oral or intraperitoneal administration of resveratrol to rats and mice. Methanol extracts of rat urine, mouse serum, human hepatocytes, rat hepatocytes, and human liver microsomes were analyzed for resveratrol metabolites using reversed-phase high-performance liquid chromatography with on-line ultraviolet-photodiode array detection and mass spectrometric detection (LC-DAD-MS and LC-UV-MS-MS). UV-photodiode array analysis facilitated the identification of cis- and trans-isomers of resveratrol and its metabolites. Negative ion electrospray mass spectrometric analysis provided molecular weight confirmation of resveratrol metabolites and tandem mass spectrometry allowed structural information to be obtained. Results. No resveratrol metabolites were detected in the microsomal incubations, and no phase I metabolites, such as oxidations, reductions, or hydrolyzes, were observed in any samples. However, abundant trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate were identified in rat urine, mouse serum, and incubations with rat and human hepatocytes. Incubation with -glucuronidase and sulfatase to release free resveratrol was used to confirm the structures of these conjugates. Only trace amounts of cis-resveratrol were detected, indicating that isomerization was not an important factor in the metabolism and elimination of resveratrol. Conclusion. Our results indicate that trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate are the most abundant metabolites of resveratrol. Virtually no unconjugated resveratrol was detected in urine or serum samples, which might have implications regarding the significance of in vitro studies that used only unconjugated resveratrol.