Porta hepatis in relation to portal vein among Indians.

The porta hepatis / hilum of liver is a transverse fissure located in the inferior surface, where the major vessels and ducts enter or leave the organ. The major structures traversing the porta hepatis are the portal vein, the hepatic artery and the hepatic duct. Porta hepatis is an area of surgical and radiological significance. The knowledge of variations in structures traversing the porta hepatitis will reduce the risk of surgeries involving this area. Study was conducted in the department of anatomy dissection lab after obtaining ethical clearance. 30 liver specimens were used for these studies which were removed from the cadaver during under graduate teaching. Anatomical knowledge of variations in relations of structures present in porta hepatis is of immense help to surgeons and radiologists when they engage patients for clinical procedures like liver transplant, cholecystectomy and diagnostic procedures. Hence this study was aimed to observe the relations of portal vein in porta hepatis.

Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions.

The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-ß and α-synuclein pathology were rated on a scale of 0 (absent)-3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman's rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = - 0.27 to r = - 0.46), and (2) tau with BA35 (r = - 0.31) and SRLM thickness (r = - 0.33). In amyloid-ß and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = - 0.40), BA35 (r = - 0.55), subiculum (r = - 0.42) and CA1 thickness (r = - 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-ß suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Complex abdominal wall hernia repair with biologic mesh in elderly: a propensity matched analysis.

BACKGROUND: Complex abdominal wall reconstruction (CAWR) has become a common surgical procedure both in non-elderly and elderly patients. OBJECTIVE: The aim of this study is to analyze the outcomes of the elderly compared to nonelderly undergoing CAWR using propensity score matching. METHODS: All patients who underwent CAWR using porcine-derived, non-crosslinked acellular dermal matrix (ADM) (Strattice™) between January 2014 and July 2017 were studied retrospectively. Propensity matched analysis was performed for risk adjustment in multivariable analysis and for one-to-one matching. The outcomes were analyzed for differences in postoperative complications, reoperations, mortality, hospital length of stay and adverse discharge disposition. RESULTS: One hundred-thirty-six patients were identified during the study period. Non-elderly (aged 18-64 years) constituted 70% (n = 95) and elderly (aged ≥ 65 years) comprised 30% of the overall patient population (n = 41). Seventy-three (56.7%) were females. After adjustment through the propensity score, which included 35 pairs, the surgical site infection (p = 1.000), wound necrosis (p = 1.000), the need for mechanical ventilation (p = 0.259), mortality (p = 0.083), reoperation rate (p = 0.141), hospital length of stay (p = 0.206), and discharge disposition (p = 0.795) were similar. CONCLUSION: Elderly patients undergoing CAWR with biological mesh have comparable outcomes with non-elderly patients when using propensity matching score.

A novel tool to evaluate bias in literature on use of biologic mesh in abdominal wall hernia repair.

PURPOSE: Biologic meshes are being increasingly used for abdominal hernia repair in high-risk patients or patients with a previous history of wound infection, due to their infection-resistant properties. Several studies have been carried out to assess whether biologic mesh is superior to synthetic mesh, as well as to establish guidelines for their use. Unfortunately, most of these studies were not rigorously designed and were vulnerable to different types of bias. The systematic reviews that have been published so far on this topic contain the same biases and limitations of the primary articles that are analyzed. The lack of a literature review on the bias on the use of biological mesh prompted us to conduct the literature search, assessment and plan this article. METHODS: We performed a literature search in PubMed, Embase and Cochrane databases of systematic reviews on biologic mesh for ventral hernia repair. The literature review was conducted using the Population, Intervention, Comparisons, Outcomes and Design approach. We identified 40 studies that matched the stringent criteria we had set. We then created a 13-point instrument to assess for bias and applied it on the primary studies that we intended to analyze. RESULTS: Most primary studies are case series or case reports of patients undergoing abdominal hernia repair with biologic mesh, without any comparison group, and the inclusion of cases was only specified to be consecutive in 6 out of 40 cases. In terms of assessing outcomes, in none of the 40 articles were the outcome assessors blinded to the intervention or exposure status of participants. CONCLUSION: The instrument that we created could allow to assess the risk of bias in different kind of studies. Our assessment of the studies based on the criteria that we had set up in the instrument clearly identified that further research needs to be done due to the lack of unbiased studies regarding the use of biologic meshes for abdominal hernia repair.

Glutamate imaging (GluCEST) reveals lower brain GluCEST contrast in patients on the psychosis spectrum.

Psychosis commonly develops in adolescence or early adulthood. Youths at clinical high risk (CHR) for psychosis exhibit similar, subtle symptoms to those with schizophrenia (SZ). Malfunctioning neurotransmitter systems, such as glutamate, are implicated in the disease progression of psychosis. Yet, in vivo imaging techniques for measuring glutamate across the cortex are limited. Here, we use a novel 7 Tesla MRI glutamate imaging technique (GluCEST) to estimate changes in glutamate levels across cortical and subcortical regions in young healthy individuals and ones on the psychosis spectrum. Individuals on the psychosis spectrum (PS; n=19) and healthy young individuals (HC; n=17) underwent MRI imaging at 3 and 7 T. At 7 T, a single slice GluCEST technique was used to estimate in vivo glutamate. GluCEST contrast was compared within and across the subcortex, frontal, parietal and occipital lobes. Subcortical (χ2 (1)=4.65, P=0.031) and lobular (χ2 (1)=5.17, P=0.023) GluCEST contrast levels were lower in PS compared with HC. Abnormal GluCEST contrast levels were evident in both CHR (n=14) and SZ (n=5) subjects, and correlated differentially, across regions, with clinical symptoms. Our findings describe a pattern of abnormal brain neurochemistry early in the course of psychosis. Specifically, CHR and young SZ exhibit diffuse abnormalities in GluCEST contrast attributable to a major contribution from glutamate. We suggest that neurochemical profiles of GluCEST contrast across cortex and subcortex may be considered markers of early psychosis. GluCEST methodology thus shows promise to further elucidate the progression of the psychosis disease state.

The impact of measurement of respiratory quotient by indirect calorimetry on the achievement of nitrogen balance in patients with severe traumatic brain injury.

BACKGROUND: This study evaluated the impact of IC on the optimization of nutritional support and the achievement of +NB in patients with TBI. MATERIALS AND METHODS: 27 patients (GCS ≤ 8), treated with a 5-day multimodality monitoring and goal-directed therapy protocol, received enteral nutrition on day 1 followed by IC on days 3 and 5 and assessment of NB on day 7. In the first cohort (n = 11), no adjustment in kcal was made. In the second cohort (n = 16), nutrition was targeted to an RQ of 0.83 by day 3. The first cohort was analyzed with respect to NB status; the second cohort was compared to patients with (-) and +NB of the first cohort. Data (mean ± SD) were analyzed with unpaired t test, and Chi square and Fisher exact tests. RESULTS: 4/11(36 %) patients in the first cohort had +NB. The predicted mortality by TRISS, substrate utilization, and RQ was significantly lower compared to the second cohort. The mortality predicted by the CrasH model did not differ between the two cohorts. A RQ of 0.74 was associated with the preferential use of fat and protein and -NB, whereas a RQ of 0.84 favored utilization of carbohydrates and +NB. All patients whose kcal intake was adjusted based on the RQ on day 3 reached a +NB by day 7. CONCLUSION: An increase in kcal ≥25 % in patients with a RQ < 0.83 on day 3 improves substrate utilization, decreases protein utilization and optimizes the achievement of +NB by day 7.

Isolated transverse process fractures: insignificant injury or marker of complex injury pattern?

INTRODUCTION: This study investigates the incidence of isolated transverse process fractures (ITPFx) amongst vertebral fractures in trauma patients, and specific-associated injury patterns present in patients with ITPFx. MATERIALS AND METHODS: A retrospective, 4-year review of our Level 1 Trauma Center registry was performed. Patients with blunt spinal column fractures were identified. Data collected included patient demographics, Injury Severity Score (ISS), type of imaging obtained, and concomitant injuries, including rib and pelvic fractures, liver, spleen, and kidney injury (SOI). RESULTS: Of the 10,186 patients admitted during the study period, 881 (8.6%) suffered blunt thoraco-abdominal trauma resulting in vertebral fractures; 214/881 (24%) had ITPFx. All patients (10,186) underwent dedicated spinal multi-detector CT (MDCT) imaging; 26/214 (12.1%) patients had MRI. In all 26 patients, the MRI confirmed the CT findings. 202/214 (94.4%) had associated injuries: rib and pelvic fractures, 45.5 and 20.2%, respectively, and splenic, liver and kidney injury with an incidence of 13.8, 10.9, and 9.4%, respectively. A higher incidence of rib fractures was associated with ITPFx at the T1-4 levels, whereas ITPFx at the level of L5 were associated with pelvic fractures and SOI. Multiple logistic regression analysis identified T1-4 and L5 fractures as predictors of rib fractures and pelvic fractures independent of ISS, with OR: 2.55 (95% CI: 1.12-5.82) and 6.81 (95% CI: 3.14-14.78), respectively. CONCLUSIONS: Based on the results of this study, we conclude that: (1) the use of MDCT imaging has increased the rate of identification of ITPFx; (2) dedicated spinal MDCT reconstruction and MRI may not be necessary to diagnose isolated thoracic and lumbar ITPFx; and (3) ITPFx of the thoracic spine and lower lumbar spine are markers of associated rib fractures and pelvic ring fractures, respectively, as well as of solid organ injuries.

Two consecutive partial liver transplants in a patient with Classic Maple Syrup Urine Disease.

Maple syrup urine disease is caused by a deficiency in the branched chain ketoacid dehydrogenase (BCKAD) complex. This results in the accumulation of branched chain amino acids (BCAA) and branched chain ketoacids in the body. Even when aggressively treated with dietary restriction of BCAA, patients experience long term cognitive, neurological and psychosocial problems. Liver transplantation from deceased donors has been shown to be an effective modality in introducing adequate BCKAD activity, attaining a metabolic cure for patients. Here, we report the clinical course of the first known patient with classic MSUD who received two consecutive partial liver grafts from two different living non-carrier donors and his five year outcome posttransplant. We also show that despite the failure of the first liver graft, and initial acute cellular rejection of the second liver graft in our patient, his metabolic control remained good without metabolic decompensation.

Incidental findings in youths volunteering for brain MRI research.

BACKGROUND AND PURPOSE: MRIs are obtained in research in healthy and clinical populations, and incidental findings have been reported. Most studies have examined adults with variability in parameters of image acquisition and clinical measures available. We conducted a prospective study of youths and documented the frequency and concomitants of incidental findings. MATERIALS AND METHODS: Youths (n = 1400) with an age range from 8-23 years were imaged on the same 3T scanner, with a standard acquisition protocol providing 1.0 mm(3) isotropic resolution of anatomic scans. All scans were reviewed by an experienced board-certified neuroradiologist and were categorized into 3 groups: 1) normal: no incidental findings; 2) coincidental: incidental finding(s) were noted, further reviewed with an experienced pediatric neuroradiologist, but were of no clinical significance; 3) incidental findings that on further review were considered to have potential clinical significance and participants were referred for appropriate clinical follow-up. RESULTS: Overall, 148 incidental findings (10.6% of sample) were noted, and of these, 12 required clinical follow-up. Incidental findings were not related to age. However, whites had a higher incidence of pineal cysts, and males had a higher incidence of cavum septum pellucidum, which was associated with psychosis-related symptoms. CONCLUSIONS: Incidental findings, moderated by race and sex, occur in approximately one-tenth of participants volunteering for pediatric research, with few requiring follow-up. The incidence supports a 2-tiered approach of neuroradiologic reading and clinical input to determine the potential significance of incidental findings detected on research MR imaging scans.

Vascular complications in pediatric liver transplantation; single-center experience from Singapore.

AIM: Vascular complications (VC) are a major cause of significant morbidity and mortality in pediatric liver transplantation (LT). We reviewed our series to study the evolution of vascular reconstructions and its effect on the incidence of VC after LT, particularly with regard to the portal vein (PV). METHODS: The medical records of 81 pediatric LT performed in 76 children (38 boys) from 1991 to 2010 in the National University Hospital, Singapore, were reviewed to identify VC pertaining to PV, hepatic artery (HA), and hepatic veins (HV) and to analyse the data for the entire series and in 2 consecutive cohorts: initial 40 LT (group 1) and subsequent 41 LT (group 2). Specific interventions in group 2 were characterized by surgical innovations for reconstruction of the difficult PV and routine use of Doppler ultrasound intraoperatively and postoperatively. RESULTS: The overall incidence of VC was 19.7% (n = 16) and individually HA thrombosis 4.9% (n = 4), HA stenosis 1.2% (n = 1), PV thrombosis 12.3% (n = 9), PV stenosis 1.2% (n = 1), and HV thrombosis 1.2% (n = 1). The overall 1- and 5-year survival rates in our series were 89% and 85%, respectively. The 1- and 5-year survival rates in patients with and without VC were 81.25% and 68.75% and 90.8% and 89.2%, respectively. The incidence of VC decreased from 27.5% in group 1 to 12.1% in group 2 (p = .08). The major contribution to this appears to be a decrease in PV complications from 17.5% in group 1 to 7.3% in group 2 (P = .1). The incidence of HA (3 vs 2) and HV (1 vs 0) complications was similar between the 2 groups. CONCLUSIONS: Vascular reconstructions in small recipients are technically challenging and associated with a learning curve. Application of meticulous techniques in general, surgical innovations to the difficult PV in particular and attention to postoperative monitoring contribute toward a major reduction in VC.

Unusual shunt for symptomatic portal vein thrombosis after liver transplantation - Clatworthy revisited.

PV thrombosis is not an uncommon occurrence following pediatric LT. Symptomatic PHT following PV thrombosis is treated medically, surgical portosystemic shunting (mesorex, splenorenal, and mesocaval) being reserved for refractory cases. A 10-yr-old boy suffered recurrent malena and hemorrhagic shock because of chronic PV thrombosis following LT nine yr ago (1999). Extensive work-up failed to localize the bleeding source. The liver function remained normal. Initial attempts at surgical shunts failed owing to thrombosis (mesocaval 2001, splenorenal, inferior mesenteric-left renal vein, splenic-left external iliac vein 2008). In this situation, we performed a Clatworthy shunt by anastomosing the divided lower end of the LCIV to the side of SMV. There was a single, large caliber anastomosis. Post-operatively, the malena stopped completely, and clinically, there was no lower limb edema or encephalopathy. Doppler USG revealed persistence of hepatopetal flow within the portal collaterals. Follow-up at two yr reveals stable hepatic function with a patent shunt. To the best of our knowledge, we are not aware of a Clatworthy shunt being performed in a transplant setting. We reviewed the literature pertaining to this shunt in non-transplant patients with PHT.

Expanding the donor pool for liver transplantation in the setting of an "opt-out" scheme: 3 years after new legislation.

INTRODUCTION: The revised Human Organ Transplant Act (HOTA) was implemented in Singapore in July 2004. We aim to evaluate expanding the potential donor pool for liver transplant in Singapore with the inclusion of marginal donors. MATERIALS AND METHODS: All donor referrals between July 2004 and June 2007 were studied. All potential deceased liver donors were heart-beating. After being reviewed by the transplant coordinator, potential donors were assessed by a transplant hepatologist and a transplant surgeon for suitability of organ donation strictly based on the programme's donor assessment protocol. Reasons for rejection as potential donors were documented. The clinical characteristics of all donor referrals were retrospectively reviewed, and an independent decision was made as to whether liver retrieval in each rejected case might have been possible. RESULTS: Among the 128 potential donor referrals, 20 donors (15.6%) underwent liver retrieval. Of the 20 livers retrieved, 16 were implanted and 4 were not implanted (3 unfit recipients, and 1 donor liver with 40% steatosis). Another 10 donor livers were assessed intraoperatively and were rejected because of varying levels of steatosis. Of these livers assessed, 5 donor livers had steatosis <40% and 5 had steatosis >40%. Of the remaining potential donors, 45 were deemed not possible because of prolonged hypotension (9), on-going or unresolved sepsis (13), high-risk behaviour (4), non-actualisation (8), or pre-existing medical conditions (11). Another 53 donors may potentially have been suitable donors but were rejected because of possible sepsis (13), no suitable recipients (12), transient hypotension (10), transient abnormal liver function test (6), history of alcohol ingestion (5), non-actualisation because of consent (4) and other reasons (3). Overall, it was deemed that 61 donors (47.7%) might potentially have been suitable liver donors. CONCLUSIONS: Despite new legislation (HOTA) in Singapore, the utilisation of cadaveric donor livers showed no increase in the last 3 years. By expanding our donor criteria to include marginal donors, we could potentially increase the availability of deceased donor livers to meet our waiting list demands.

Molecular mechanism of manganese exposure-induced dopaminergic toxicity.

Manganese (Mn) is an essential mineral that is found in varying amounts in aerosols or dust. Exposure to atmospheric Mn at high concentration is a risk factor in humans that can manifest as neuronal degeneration resembling Parkinson's disease (PD). Since the underlying mechanism of Mn and dopamine (DA) interaction-induced cell death remains unclear, here, we showed that Mn exposure alone to mesencephalic cells for 24h induced minimal apoptotic cell death. However, cells pre-exposed to DA for 2h accelerated Mn-induced apoptosis. The vulnerability of Mn-induced apoptotic cell death to DA was determined by measuring lactate dehydrogenase (LDH) and Apoptag TUNEL staining (terminaldeoxynucleotidyl transferase DNA labeling). This was further confirmed by the cell viability assay to support our hypothesis that DA at the cellular level interacts with Mn and causes cells to be more susceptible. Pretreatment with nitric oxide blocker (7-nitroindazole, 7-NI), vitamin E or NF-kappaB inhibitor (SN50) significantly protected the cells from Mn and DA interaction-induced reactive oxygen species (ROS) and apoptosis. Western blot analysis showed that Mn in the presence of DA markedly induced induction of NOS (iNOS) expression. Pretreatment with 7-NI, SN50 or vitamin E significantly attenuated increased iNOS expression indicating that iNOS expression is regulated by ROS and the transcription factor NF-kappaB. Further, the generation of ROS as an early event in Mn and DA interaction is not controlled by NF-kappaB as SN50 pretreatment did not prevent ROS. These findings suggest that NF-kappaB induction and the activation of nitric oxide synthase through ROS represent a proximate mechanism for Mn-induced neurotoxicity.

1Alpha,25-dihydroxyvitamin D3 attenuates cyanide-induced neurotoxicity by inhibiting uncoupling protein-2 up-regulation.

1Alpha,25-dihydroxyvitamin D(3) (VD(3)) is a neuroprotectant that can reduce cytotoxicity produced by a variety of toxicants. The mechanism of the neuroprotection was studied in rat primary cortical cells in which Wy14,643, an agonist of peroxisome proliferator activated receptor-alpha (PPARalpha), enhances cyanide (KCN) neurotoxicity. In this cell model, Wy14,643 pretreatment enhanced cyanide-induced cell death, and the increased cell death was linked to up-regulation of uncoupling protein-2 (UCP-2). VD(3) reversed cyanide-induced mitochondrial dysfunction in cells pretreated with Wy14,643, as reflected by restoration of cellular ATP and mitochondrial membrane potential (DeltaPsi(m)). Analysis of cellular state 4 oxygen consumption showed increased mitochondrial uncoupling accompanied by up-regulation of UPC-2. The uncoupling was attenuated by prior treatment with VD(3). The interaction of VD(3) with UCP-2 was attributed to increased expression of IkappaB, an inhibitor of NF-kappaB (transcription factor that regulates UCP-2 expression). The increased IkappaB levels lead to reduced nuclear translocation and DNA binding of nuclear factor-kappaB. The role of oxidative stress in the response was then evaluated. Cotreatment with Wy14,643 and cyanide markedly increased reactive oxygen species generation and decreased reduced glutathione levels. The oxidative stress was blocked by VD(3) pretreatment. It was concluded that VD(3) blocks Wy14,643 enhancement of cyanide neurotoxicity by suppressing the redox-mediated transcriptional up-regulation of UCP-2, resulting in reduced mitochondrial proton leak and stabilization of mitochondrial function.

Effects of Low Dose Vasopressin in Catecholamine Resistant Septic Shock.

BACKGROUND: Septic shock commonly leads to death in critically ill patients. Severe hypotension resistant to conventional catecholamine leads to multiorgan failure. We studied the effectiveness of low dose vasopressin in resistant septic shock. METHODS: Thirty critically ill patients with catecholamine resistant hypotension were included in the study. After adequate fluid resuscitation, infusion of norepinephrine and dobutamine was started. If the patient remained hypotensive, vasopressin was infused at a fixed rate of 0.04 unit/minute for 24 hours. Haemodynamic parameters and mortality rates were recorded. RESULT: There was a significant improvement in systolic and mean arterial pressure within four hours of starting vasopressin. This improvement continued throughout the 24-hour period. In addition, it was possible to withdraw dopamine in all the patients and significantly reduce infusion rates of dobutamine and norepinephrine. No significant complication was noted. CONCLUSION: Low dose vasopressin at the rate of 0.04 unit/minute is an effective vasopressor in adult patients with catecholamine resistant septic shock.

Awake Craniotomy for Tumour Excision.

BACKGROUND: Craniotomy and excision of tumours can produce neurological deficits if the tumour is located close to eloquent areas of the brain. One technique of overcoming this problem is to keep the patient 'awake' during surgery. METHODS: Eight patients with intra cranial space occupying lesions (ICSOL) were operated 'awake', using a combination of skull block with sedation and analgesia. A mixture of 0.125% bupivacaine and 0.5% lignocaine was used for various nerve and field blocks. Midazolam, fentanyl and propofol in titrated doses were used to achieve conscious sedation. RESULT: The procedure was successful in all the patients. They tolerated the procedure well and were able to follow the commands intraoperatively as desired. There were no significant complications. CONCLUSION: Awake craniotomy with skull blocks with sedation and analgesia is a well established procedure. It requires a good rapport between surgeon, anaesthesiologist and the patient.

Upregulation of BNIP3 and translocation to mitochondria mediates cyanide-induced apoptosis in cortical cells.

Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), a Bcl-2 homology domain 3 (BH3) domain only protein, has been identified as a mitochondrial mediator of hypoxia-induced cell death. Since cyanide produces histotoxic anoxia (chemical hypoxia), the present study was undertaken in primary rat cortical cells to determine involvement of the BNIP3 signaling pathway in cyanide-induced death. Over a 20 h exposure KCN increased BNIP3 expression, followed by a concentration-related apoptotic death. To determine if BNIP3 plays a role in the cell death, expression was either increased with BNIP3 cDNA (BNIP3+) or knocked down with small interfering RNA (RNAi). In BNIP3+ cells, cyanide-induced apoptotic death was markedly enhanced and preceded by reduction of mitochondrial membrane potential (delta psim), release of cytochrome c from mitochondria and elevated caspase 3 and 7 activity. Pretreatment with the pan-caspase inhibitor N-benzyloxycarbonyl-Ala-Asp-fluoromethyl ketone (zVAD-fmk) suppressed BNIP3+-mediated cell death, thus confirming a caspase-dependent apoptosis. On the other hand, BNIP3 knockdown by RNAi or antagonism of BNIP3 by a transmembrane-deleted dominant-negative mutant (BNIP3 delta TM) markedly reduced cell death. Immunohistochemical imaging showed that cyanide stimulated translocation of BNIP3 from cytosol to mitochondria and displacement studies with BNIP3 delta TM showed that integration of BNIP3 into the mitochondrial outer membrane was necessary for the cell death. In BNIP3+ cells, cyclosporin-A, an inhibitor of mitochondrial pore transition, blocked the cyanide-induced reduction of delta psim and decreased the apoptotic death. These results demonstrate in cortical cells that cyanide induces a rapid upregulation of BNIP3 expression, followed by translocation to the mitochondrial outer membrane to reduce delta psim. This was followed by mitochondrial release of cytochrome c to execute a caspase-dependent cell death.

Cystic lymphangioma of the mesentery causing intestinal obstruction.

Mesenteric cystic lymphangioma is a rare lesion that is not often described in the literature. A four-year-old boy, who presented with abdominal distension and pain, is reported. At surgery, a huge mesenteric cyst was found to be the cause of the intestinal obstruction and was completely excised. Histology was consistent with a cystic lymphangioma. Abdominal lymphangioma is a rare cause of bowel obstruction. Clinical presentation varies and may be misleading due to a lack of awareness of the clinical condition. Occasionally, the diagnosis is made during surgery. General awareness of this entity with a high index of suspicion is needed to avoid complications.

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress.

Uncoupling protein 2 (UCP-2) is an inner mitochondrial membrane proton carrier that modulates mitochondrial membrane potential (DeltaPsi(m)) and uncouples oxidative phosphorylation. We have shown that up-regulation of UCP-2 by Wy14,643, a selective peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, enhances cyanide cytotoxicity. The pathway by which Wy14,643 up-regulates UCP-2 was determined in a dopaminergic cell line (N27 cells). Since dopaminergic mesencephalic cells are a primary brain target of cyanide, the N27 immortalized mesencephalic cell was used in this study. Wy14,643 produced a concentration- and time-dependent up-regulation of UCP-2 that was linked to enhanced cyanide-induced cell death. MK886 (PPARalpha antagonist) or PPARalpha knock-down by RNA interference (RNAi) inhibited PPARalpha activity as shown by the peroxisome proliferator response element-luciferase reporter assay, but only partially decreased up-regulation of UCP-2. The role of oxidative stress as an alternative pathway to UCP-2 up-regulation was determined. Wy14,643 induced a rapid surge of ROS generation and loading cells with glutathione ethyl ester (GSH-EE) or pre-treatment with vitamin E attenuated up-regulation of UCP-2. On the other hand, RNAi knockdown of PPARalpha did not alter ROS generation, suggesting a PPARalpha-independent component to the response. Co-treatment with PPARalpha-RNAi and GSH-EE blocked both the up-regulation of UCP-2 by Wy14,643 and the cyanide-induced cell death. It was concluded that a PPARalpha-mediated pathway and an oxidative stress pathway independent of PPARalpha mediate the up-regulation of UCP-2 and subsequent increased vulnerability to cyanide-induced cytotoxicity.