Protective Role of Curcumin against N-Nitrosodiethylamine (NDEA)-Induced Toxicity in Rats

The present investigation was aimed at studying the possible role of curcumin against N-nitrosodiethylamine (NDEA)-induced toxicity in albino rats. Administration of NDEA to rats at a concentration of 0.1 mg/ml in drinking water ad libitum for 21 days produced toxicity in them, which was evident from histopathological changes in the rat livers, and increased levels of blood serum enzyme markers, i.e. aspartate transaminase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase. In addition, the levels of oxidative stress markers like lipid peroxidation (LPO), protein carbonyl (PCC), and glutathione-S-transferase (GST) activity were elevated and the total glutathione (GSH) content was reduced in the livers. The administration of curcumin to rats at concentrations of 10, 20, and 40 mg/ml in drinking water along with 0.1 mg/ml of NDEA for 21 days effectively suppressed NDEA-induced toxicity and also resulted in a dose-dependent reduction in the levels of blood serum enzyme markers (AST, ALT, ALP, and LDH). Moreover, LPO, PCC, and GST activity were reduced and the GSH level was increased upon the administration of curcumin along with NDEA. The results obtained for the comet assay in rat hepatocytes and blood lymphocytes showed a significant dose-dependent decrease in the mean tail length. The micronucleus assay performed on rat hepatocytes also showed a dose-dependent reduction in the frequency of micronucleated cells along with curcumin administration. These results suggest that curcumin has a protective role against NDEA-induced toxicity in albino rats.     

Schizophrenia following new-onset refractory status epilepticus secondary to antiphospholipid syndrome

New-onset refractory status epilepticus (NORSE) is a drug-resistant status epilepticus that often has a catastrophic outcome. Our patient was diagnosed with NORSE and had an EEG reading that showed status epilepticus persisting for 8 months in general anesthesia. After autoimmune workup showed positive antiphospholipid antibodies, his seizure was controlled, and he was discharged with good condition apart from moderate cognitive impairment. However, he later developed schizophrenia. Although psychiatric disorders have been associated with antiphospholipid syndrome, to the best of our knowledge, it has not been reported to be associated with status epilepticus. We recommend vigilance of psychological complications of refractory status epilepticus’ patients for early psychiatric referral, diagnosis, and treatment.

New-onset refractory status epilepticus (NORSE) is a syndrome of new-onset drug-resistant status epilepticus that often has a catastrophic outcome. Epilepsy is usually associated with psychiatric disorders of different manifestations of which psychosis is an example.1 However, not much is found in the literature review regarding psychiatric disorders following NORSE although a recent study concluded 32% of NORSE patients ended up with altered behavioral states like aggression.2 Schizophrenia following NORSE like in the rare presentation of this case has not been reported in the literature review before, although an association between schizophrenia and autoimmune disorders like APS has been reported.3     

Development of a Simple Model of Extrinsic Denervation of the Small Bowel in Mouse

Small bowel transplantation (SBT) is associated with poorly understood enteric dysfunction. The study of SBT in mice is hindered by the technical difficulty of orthotopic SBT in the mouse. Our aim was to develop an easy preparation of extrinsic denervation of the entire jejunoileum in mice as a model of orthotopic SBT. All neurolymphatic tissues accompanying the superior mesenteric artery (SMA) and vein (SMV) were ligated just distal to the middle colic vessels. The SMA and SMV were then stripped of investing adventitia, and the mesentery to jejunum and colon were transected radially. Jejunum and colon were not transected and reanastomosed. To confirm extrinsic denervation 1, 3, and 6 months later, segments of small bowel were stained for protein gene product 9.5 (PGP9.5) and tyrosine hydroxylase (TH). Tyrosine hydroxylase immunoreactive intensity was then quantified using a semiquantitative analysis. Immunohistochemical fluorescence showed persistence of PGP9.5 immunoreactivity confirming enteric nerves in jejunoileum; however, there was no TH immunoreactivity in jejunoileum in denervated mice despite the expected preservation of TH immunoreactivity in the still-innervated duodenum at 1 month. At 3 months, sparse immunoreactivity for TH was present, and by 6 months, reinnervation of TH-containing nerves appeared similar to controls. Quantification of intensity at each time-point further confirmed this trend. This technique in the mouse accomplishes a complete extrinsic denervation of jejunoileum early postoperatively (1 and 3 months); reinnervation occurs by 6 months. This is an easily learned murine model of orthotopic SBT. Presented at the American Gastroenterological Association during Digestive Disease Week in Los Angeles, CA, as a poster presentation on May 23 2006. Abstract published in GastroenterologyE 2006; 130:A604.     

Nonfluent aphasia in a patient with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is an uncommon low-grade lymphoma. Cognitive impairment due to central nervous system infiltration by lymphoplasmocytoid cells (Bing-Neel syndrome) has been rarely reported. We describe a 54-year-old man who was referred to a memory disorder clinic with a 9-month history of clinically obvious nonfluent aphasia and WM. He underwent extensive neuropsychological testing, clinical examination and structural and functional brain imaging. The diagnosis of the diffuse form of the Bing-Neel syndrome was supported by abnormal lymphoid cells found in the cerebrospinal fluid. Structural and functional brain imaging revealed impairment of brain areas due to white matter changes and subsequent functional deficits mimicking the neuropsychological syndrome encountered in progressive nonfluent aphasia. The diffuse form of Bing-Neel syndrome and neurological deficits are assumed to be the result of leptomeningeal infiltration by malignant cells and/or neoplastic vascular obstruction.     

Hepatic UDP-glucose 13C isotopomers from [U-13C]glucose: a simple analysis by 13C NMR of urinary menthol glucuronide.

Menthol glucuronide was isolated from the urine of a healthy 70-kg female subject following ingestion of 400 mg of peppermint oil and 6 g of 99% [U-(13)C]glucose. Glucuronide (13)C-excess enrichment levels were 4-6% and thus provided high signal-to-noise ratios (SNRs) for confident assignment of (13)C-(13)C spin-coupled multiplet components within each (13)C resonance by (13)C NMR. The [U-(13)C]glucuronide isotopomer derived via direct pathway conversion of [U-(13)C]glucose to [U-(13)C]UDP-glucose was resolved from [1,2,3-(13)C(3)]- and [1,2-(13)C(2)]glucuronide isotopomers derived via Cori cycle or indirect pathway metabolism of [U-(13)C]glucose. In a second study, a group of four overnight-fasted patients (63 +/- 10 kg) with severe heart failure were given peppermint oil and infused with [U-(13)C]glucose for 4 hr (14 mg/kg prime, 0.12 mg/kg/min constant infusion) resulting in a steady-state plasma [U-(13)C]glucose enrichment of 4.6% +/- 0.6%. Menthol glucuronide was harvested and glucuronide (13)C-isotopomers were analyzed by (13)C NMR. [U-(13)C]glucuronide enrichment was 0.6% +/- 0.1%, and the sum of [1,2,3-(13)C(3)] and [1,2-(13)C(2)]glucuronide enrichments was 0.9% +/- 0.2%. From these data, flux of plasma glucose to hepatic UDPG was estimated to be 15% +/- 4% that of endogenous glucose production (EGP), and the Cori cycle accounted for at least 32% +/- 10% of GP.     

Monoclonal Antibody Specific for TIRC7 Induces Donor-specific Anergy and Prevents Rejection of Cardiac Allografts in Mice

T cell immune response c-DNA (TIRC7) is up-regulated during the early stages of T-cell activation in response to alloantigens. In this study, we analyzed the effects of newly developed monoclonal antibodies (mAb) against TIRC7 in acute cardiac allograft rejection. Fully vascularized heterotopic allogeneic heart transplantation was performed in mice across a full-mismatch barrier (C57Bl/10 into CBA). Recipients received seven injections (day 0-7) of a novel anti-TIRC7 mAb or remained untreated. Graft survival, histology and ex vivo lymphocyte functions were tested. Targeting of TIRC7 with an anti-TIRC7 mAb diminishes lymphocyte infiltration into grafts resulting in delay of morphological graft damage and prolongation of allograft survival. The lymphocytes from anti-TIRC7 mAb-treated animals exhibit hypo-responsiveness without evidence of lymphocyte depletion against the donor allo-antigens. Proliferation and expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were down-regulated while interleukin-4 (IL-4) and IL-10 expression were spared. Moreover, anti-TIRC7 mAb enhanced up-regulation of CTLA-4 expression but suppressed up-regulation of CD25 on stimulated lymphocytes in vitro and in vivo. Ligation of TIRC7 has important effects on the regulation of co-stimulatory signaling pathways associated with suppressing of T-cell activation. Targeting of TIRC7 may therefore provide a novel therapeutic approach for modulating T cell immune responses during organ transplantation.     

Prophylactic use of chlorpromazine to improve survival of random skin flaps in pigs

On the basis of earlier success in rat studies, chlorpromazine was evaluated as a probable agent for improving survival of random skin flaps in pigs. The aim was to exclude the possibility that the effect of the chlorpromazine is species specific and to find out if it is dose dependent. One hundred and five dorsally-based 12×4 cm flaps were raised unilaterally on the backs of 15 pigs. The animals were divided into three groups using 15 mg/kg chlorpromazine, 7.5 mg/kg chlorpromazine, and a saline-treated control group. Flaps in the control group averaged 40.57±3.17% necrosis, while flaps in the 15 mg/kg and 7.5 mg/kg chlorpromazine-treated groups averaged 31.53±4.77% and 11.47±2.22% necrosis respectively. These results demonstrate dose dependent beneficial affects of chlorpromazine and the survival of random skin flaps in the pig. Although ideal dose levels are still to be determined, flap survival improved with the prophylactic use of chlorpromazine at the lower 7.5 mg/kg dosage.