Effect of pentylenetetrazol on carbaryl-induced changes in striatal catecholamines

Administration of pentylenetetrazol (PTZ) (60 mg/kg, s.c.) to normal or carbaryl (200 mg/kg, p.o.) treated adult male albino rats produced characteristic changes in the steady-state levels of striatal dopamine (DA), noradrenaline (NA) and homovanillic acid (HVA) at different time intervals (0.5, 1.0 and 2.0 hr). The elevation of striatal NA level was found to be more pronounced with PTZ than that produced by carbaryl. Treatment of rats with PTZ alone caused a significant elevation of DA levels only at 2.0 hr without any significant change in the level of HVA at any time interval. Carbaryl which did not have any significant effect on striatal DA level produced an elevation of HVA at 0.5 hr and 1.0 hr in striatum. The simultaneous administration of PTZ and carbaryl, under similar conditions, caused a marked reduction in the level of NA at 0.5 hr and DA at 1.0 hr without any significant effect on (i) both the amine levels at 2.0 hr and (ii) HVA level at any of the time intervals. Measurement of (a) alpha-methyl-p-tyrosine (alpha-MpT) (250 mg/kg, i.p.) induced depletion of striatal DA and NA, (b) FLA-63 (25 mg/kg, i.p.) induced disappearance of NA, (c) pargyline (75 mg/kg, i.p.) induced reduction and probenecid (200 mg/kg, i.p.) induced accumulation of striatal HVA in the presence or absence of PTZ and/or carbaryl revealed that: (1) PTZ or carbaryl alone caused a significant increase in the turnover of striatal DA; (2) the turnover of striatal NA was significantly increased after PTZ treatment but not after carbaryl administration; (3) the simultaneous administration of carbaryl and PTZ, on the other hand, attenuated (a) PTZ- or carbaryl-induced increase in metabolic activity of the striatal dopaminergic system, and (b) the enhanced anabolic activity of striatal noradrenergic system caused by PTZ, but failed to affect the enhanced utilization of striatal NA induced by PTZ alone.     

Hepatocellular Carcinoma with Bone Metastases: Incidence,Prognostic Significance,and Management—Single-Center Experience

Background

Hepatocellular carcinoma (HCC) represents one of the most common causes of cancer-related deaths worldwide, with rising incidence in the USA. Bone metastases with HCC, in particular, have an extremely poor prognosis. We present prevalence, treatment, and survival of patients with bone and more specifically spinal metastases from HCC.

Methods

A retrospective analysis was done at a single tertiary care institution of patients with bone metastases from HCC between January 2005 and December 2015.

Results

Among 1017 patients with HCC, 20 were found to have bone metastases of which 11 had spinal metastases. Seventeen (85%) were male, with median age of 58 years at time of HCC diagnosis. Systemic chemotherapy and sorafenib were used in 12 (60%) patients, and 12 (60%) received radiation therapy. Among patients who did not receive therapy, median survival was 76 days. Median survival after diagnosis of metastasis in patients on sorafenib and radiation were 106 and 100 days, respectively.

Conclusion

Bone metastases in HCC are very rare and aggressive. Due to its rarity, optimal treatment strategies are not well defined. Early diagnosis is important for optimal therapy and improved survival.

     

Endoscopic retrograde cholangiopancreatography in the management of pancreaticobiliary disorders in children

BACKGROUND AND AIM: The role of endoscopic retrograde cholangiopancreatography (ERCP) is not yet fully established in children. The purpose of this study was to assess the use of ERCP in the diagnosis and management of various pancreaticobiliary disorders in children. METHODS: Eighty-four ERCPs were performed over 5.5 years in 72 children with suspected pancreaticobiliary tract disorders with an adult-type duodenoscope. In all cases, indications, procedure time, ERCP findings, complications, patients course and therapeutic intervention (if any) were recorded. RESULTS: The mean (+/- SD) age of these children was 8.8 +/- 3.3 years. Successful cannulation was possible in 70 (97%) cases. Of the 44 cases with suspected biliary tract disease, 14 had a choledochal cyst, 13 had portal biliopathy, two each had CBD stones, primary sclerosing cholangitis and a bile leak, one had biliary ascariasis, eight had a normal cholangiogram, and CBD cannulation failed in two. Eight of the 28 children with suspected pancreatic disorders had chronic pancreatitis, five had pancreatic duct disruption, three had pancreas divisum and the rest had a normal pancreatogram (including all eight children with unexplained abdominal pain). Therapeutic ERCP was performed in 22 children, endoscopic nasobiliary or a nasocystic drain was placed in 16, biliary stenting was conducted in two, pancreatic duct stenting was conducted in three, and minor papilla dilation was conducted in one child. Six children had mild procedure-related complications. CONCLUSION: Endoscopic retrograde cholangiopancreatography is very useful in the treatment of cholangitis, bile leak, pseudocyst and pancreatic fistulae in children. However, its role in unexplained abdominal pain is doubtful.     

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.

Pancreatic ductal adenocarcinoma (PDAC) is the major type of pancreatic cancer, with a median overall survival of less than 1 y (1). In addition to an aggressive tumor biology and late stage at diagnosis, the poor prognosis of PDAC is due to its resistance to current therapies. In recent years, studies have profiled its extensively reprogrammed metabolic network and characterized its extreme tumor microenvironment (2–5). These studies have identified PDAC cells’ dependence on glycolysis (2, 6), lipogenesis (2, 7), glutamine metabolism (8, 9), alanine metabolism, and tricarboxylic acid cycle/oxidative phosphorylation (10, 11). Strategies targeting each of these specific metabolic pathways have been attempted but have not been successfully translated into clinical therapeutics. However, all of these rewired metabolic pathways rely on nicotinamide adenine dinucleotide (NAD) or its reduced form, NADH, as cofactors.NAD is central to cellular bioenergetic and metabolic functions. NAD is synthesized via three major pathways: the de novo biosynthesis kynurenine pathway, the Preiss–Handler pathway, and the salvage pathway (12). The kynurenine pathway starts with the catabolism of the amino acid tryptophan that is then converted via two steps to the intermediate kynurenine, which can generate NAD, kynurenic acid, or xanthurenic acid. The Preiss–Handler pathway and the salvage pathway synthesize NAD from pyridine bases. The Preiss–Handler pathway synthesizes NAD from nicotinic acid (NA) in three steps via the intermediate NA adenine dinucleotide. The NAD salvage pathway starts from the recycling of nicotinamide (NAM) to nicotinamide mononucleotide (NMN) by intracellular nicotinamide phosphoribosyltransferase (NAMPT), followed by the conversion of NMN into NAD via the NMN adenylyltransferases (NMNATs) (12). A recent quantitative analysis revealed that liver cells actively synthesize NAD de novo from tryptophan, releasing NAM into the blood, thereby supporting NAD biosynthesis in the rest of the body, whereas both tumor cells and most other tissues use NAM as the main NAD source (13). NAMPT is the rate-limiting step by which tumor cells utilize NAM in the synthesis of NAD. It is also important to note that, while there are many metabolic enzymes that use NAD or NADH as cofactors and affect the NAD/NADH ratio, NAD(H) is consumed and broken down into NAM by the poly(ADP ribose) polymerase (PARP) family proteins, the sirtuin (SIRT) family proteins, and CD38 (14).NAMPT inhibitors (NAMPTis) showed promising potency in a variety of preclinical tumor models, including pancreatic cancer (15–18). Two NAMPTis, FK866 (19) and CHS-828 (20, 21), have been tested in clinical trials, where lack of objective responses and dose-limiting toxicity suggest it is necessary to identify subsets of tumors with high sensitivity to NAMPT inhibition. Multiple studies have examined intracellular factors that affect cancer cell sensitivity to NAMPT inhibition, such as NAMPT levels (22), NA phosphoribosyltransferase levels (23), PPM1D mutations (15), and CD38 levels (24). We hypothesized that, in addition to intracellular factors, the tumor microenvironment also impacts PDAC cell NAD(H) levels and thus the sensitivity to NAMPTis.In this study, we found that type I interferons (IFNs) lower PDAC cell NAD(H) levels through the up-regulation of NAD(H)-consuming enzymes PARP9, PARP10, and PARP14 (PARP9/10/14). Unlike their better studied relatives, PARP1 and PARP2, which catalyze poly-ADP ribosylation, PARP9/10/14 catalyze the transfer of a single unit of ADP ribose to their targets, a process referred to as monoADP ribosylation (25). The roles of PARP9/10/14 in mediating NAD depletion in PDAC cells have not been previously explored to the authors’ knowledge. We further hypothesized that IFN-mediated NAD depletion caused by the up-regulation of PARP9/10/14 sensitizes PDAC cells to NAMPTis, which we confirmed in both in vitro and in vivo PDAC models.     

Cow's milk protein allergy: An entity for recognition in developing countries

Aim:  The aim of this prospective study was to determine cow's milk protein allergy (CMPA) cases in a tertiary care hospital in India and to study its clinical presentations and outcome following treatment.
Methods:  Consecutive children with chronic diarrhea from June 2004 to December 2007 were evaluated with hemogram, anti-endomysial antibody, upper gastrointestinal endoscopy, sigmoidoscopy and intestinal biopsies. Initial diagnosis of CMPA was based on characteristic intestinal biopsy (> 6 eosinophils/HPF) and diagnosis was confirmed by positive milk challenge.
Results:  Forty CMPA cases (25 boys, with a mean age of 17.2 ± 7.8 months and symptom duration of 8.3 ± 6.2 months) presented with diarrhea (bloody in 16, watery in 16, combined in three, recurrent hematemesis in two, rectal bleeding in one and one case each with pain in the abdomen with vomiting and anemia with occult bleeding). Sigmoidoscopy revealed aphthous ulcers in 82% of cases and rectal biopsy was positive in 97% of cases. All children improved on a milk-free diet. Milk challenge was positive in 100% of cases when it was done early (within 6 months). On follow up of 15 ± 9 months, milk was successfully restarted in 25 cases after a median milk-free period of 15 months, 10 were still on a milk-free diet and five were lost to follow up while on a milk-free diet.
Conclusions:  CMPA is not uncommon in a developing country such as India. Presence of aphthous ulcers and abnormal rectal biopsy are clues to initial diagnosis. Milk challenge confirms the diagnosis in all if it is done on time.     

Factors associated with outcome in acute liver failure in an intensive care unit

Aim

To study the factors associated with outcome in acute liver failure (ALF) in an intensive care unit (ICU).

Methods

Consecutive patients with ALF admitted to the ICU from August 2003 to April 2010 were included. Factors associated with the primary outcome, death or survival, were compared.

Results

Of 52 patients of median age 19 years (range 3–65), 35 (67 %) died. The etiology was viral hepatitis in 66 %, drug induced (anti-tubercular therapy) in 15 % and idiopathic in 15 %. Grades III+IV encephalopathy were found in 12 (70.6 %) survivors as against 33 (94.3 %) nonsurvivors (p?=?0.019). The median admission sequential organ failure assessment (SOFA) score was eight in survivors vs. 12 in nonsurvivors (p?<?0.001). Median admission prothrombin time (PT) was 42 s in survivors vs. 51 in nonsurvivors (p?=?0.384); 16/17 (94.1 %) survivors had normal PT on day 4 as compared to 7/35 (20 %) nonsurvivors (p?<?0.001). Median PT on day 4 was 18 s in survivors against 37 in nonsurvivors (p?<?0.001). Serum bilirubin, alanine aminotransferase; and serum creatinine, sodium and phosphorus were similar in survivors and nonsurvivors. Mechanical ventilation, vasopressors and dialysis were used in 65 %, 30 %, and 12 % survivors as against 100 % (p?<?0.001), 51 % and 26 % nonsurvivors. Sixteen patients had upper gastrointestinal (GI) bleed. Blood cultures were positive more often in nonsurvivors (p?=?0.058). On multiple regression analysis, factors independently associated with outcome included admission SOFA score >9.5 and absolute value of PT on day 4.

Conclusions

Grades III and IV encephalopathy, higher SOFA score at admission and a prolonged PT which did not normalize by 4 days were associated with mortality in ALF.     

Pediatric and adult celiac disease: similarities and differences

Differences between children and adults in celiac disease (CD) presentation and epidemiology are reviewed here. Clinical manifestations, histological changes, serology, and response to gluten-free diet are similar. Differences exist in epidemiology, type of clinical presentations, coexisting diseases, complications, and association with obesity. CD is two to five times more common in children than in adults. Classical CD with gastrointestinal symptoms is more common in children whereas nonclassical CD dominates in adults. A gene dose phenomenon (double-dose HLA-DQB1*02 allele) is postulated to be responsible for this difference. Coexisting autoimmune diseases like diabetes mellitus type 1, Sjogren’s syndrome, and dermatitis herpetiformis are more common in adults than in children (42 % vs. 5 %). The association of overweight/obesity and CD is stronger in adults than in children (22.5 % vs. 14 %). Besides poor compliance, pancreatic insufficiency, bacterial overgrowth, lactose intolerance, irritable bowel syndrome, lymphocytic colitis, and microscopic colitis are considered responsible for nonresponsive CD in adults but not in children. Complications like refractory sprue and small intestinal neoplasms are seen exclusively in adults. Existing diagnostic criteria (modified ESPGHAN) are not suitable for diagnosing CD in adults as the majority of cases are either nonclassical or subclinical CD.     

Nutrient drink test: Normative values in Indian children

Background

Nutrient drink test (NDT) is a simple, non-invasive method to assess gastric function including accommodation. However, data on normal satiety drink volume (SDV) in children is scanty with no information about postprandial symptoms (PPS). Our aims were to establish normal values of NDT in healthy children and evaluate its correlation with age, gender, and anthropometry.

Methods

Six- to 18-year-old healthy children underwent the NDT. The nutrient drink (0.94 kcal/mL) was given at a constant rate of 15 mL/min in 6–12-year-old subjects and at 30 mL/min in 13–18-year-old subjects till satiety score of 5 was reached. Postprandial symptoms (30 min) of fullness, nausea, bloating, and pain were scored using a visual analogue scale (0–100 mm) individually and as aggregate score.

Results

Sixty-seven children (40 boys, age 12 [6–18 years]) were enrolled. Median SDV was 360 [180–960 mL], higher in 13–18-year-olds in comparison to 6–12-year-old children (360 [240–1002] vs. 300 [148–960] mL; p=0.005). SDV showed significant correlation with age, weight, and height. SDV was higher in boys than girls (450 [240–1074] vs. 330 [240–480] mL; p=0.02) in the older children (13–18 y), but it was similar in the younger children. Mild fullness (40 [0–80]) was the only PPS seen in 85% children and none had pain. PPS were not different between boys and girls or younger and older children.

Conclusion

The study provides normative data of SDV and PPS by NDT in 6–18-year-old children. SDV correlated with age and was higher in adolescent boys than girls.