Gabriel Dinari

ImmuKnow: A new parameter in immune monitoring of pediatric liver transplantation recipients†

Lifelong immunosuppression is mandatory for optimal graft and patient survival following liver transplantation. Nevertheless, graft rejection or numerous adverse events associated with overimmunosuppression or underimmunosuppression cannot be completely avoided. The ImmuKnow assay measures cell‐mediated immunity and is able to discern between conditions of overimmunosuppression and underimmunosuppression. The aim of this study was to evaluate the ImmuKnow assay in the evaluation of the immune function in pediatric liver transplant recipients and to assess its correlation with the patients clinical and biochemical status. Eighty‐nine whole blood samples were collected from 23 liver transplant recipients that were 1 to 18 years old. The net state of immune function was determined by the quantitative measurement of the intracellular adenosine 5‐triphosphate level in CD4+ lymphocytes after phytohemagglutinin stimulation. Comprehensive clinical data were correlated with the ImmuKnow assay results. In 23 of the 28 samples collected during clinical quiescence, ImmuKnow results were correlated with the clinical status, expressing the patients moderate immune function. However, a correlation between measured therapeutic drug levels and clinical quiescence was found in only 18 of the 28 samples. In 6 patients who suffered from clinical complications, ImmuKnow measurements showed a wide range of deviations, expressing the unstable immunological status of these patients. In conclusion, the ImmuKnow assay correlates with the clinical status of liver‐transplanted children. It serves as a reliable and unique parameter of the cellular immune function. We conclude that the ImmuKnow assay, together with existing clinical tools, may allow for the immune monitoring of pediatric liver recipients. Liver Transpl 14:893–898, 2008.

Naloxone is protective against indomethacin-induced intestinal ulceration in the rat

Naloxone, an opiate antagonist, was reported to protect against stress ulcers in dogs and rats. We studied its possible protective effect against indomethacin-induced intestinal ulceration in the rat. Naloxone was indeed found to possess a marked protective effect on the intestinal mucosa (ulcer index 73.3 +/- 13.6 vs. 273.8 +/- 21.8, p less than 0.001). Naloxone was found to elevate basal intestinal mucosal prostaglandin E2 (p less than 0.001) and cyclic adenosine monophosphate levels (p less than 0.005) but was unable to overcome the inhibition of prostaglandin E2 caused by indomethacin. An increase of cyclic adenosine monophosphate levels was seen, however, even in the presence of indomethacin, suggesting that cyclic adenosine monophosphate, but not prostaglandins, may play a role in the protective effect of naloxone.

Tooth exfoliation and osteonecrosis of the maxilla after trigeminal herpes zoster

1. Asano Y, Albrecht P, Viekers JH: hnmunogenicity of wild and attenuated varicella-zoster virus strains in pygmy marmosets. Proc Soc Exp Biol Med 173:501, 1983. 2. Asano Y, Takahashi M: Studies on neutralization of varicella-zoster virus and serological follow-up of cases of varicella and zoster. Biken J 21:15, 1978. 3. Ozaki T, Ichikawa T, Matsui Y, Nagai T, Asano Y, Yamanishi K, Takahashi M: Viremic phase in nonimmunocompromised children with varicella. J PEDIATR 104:85, 1984. 4. Okuno T, Yamanishi K, Shiraki K, Takahashi M: Synthesis and processing of glycoproteins of varicella-zoster virus (VZV) as studied with monoclonal antibodies to VZV antigens. Virology 129:357, 1983. 5. Grose C: Variation on a thema by Fenner: The pathogenesis of chickenpox. Pediatrics 68:735, 1981. 6. Feldman S, Epp E: Detection of viremia during incubation of varicella. J PEDIATR 94:746, 1979. 7. Einstein P, Schneeberger EE, Colton HR: Synthesis of the second component of complement by long-term primary cultures of human monocyte. J Exp Med 143:114, 1976. 8. Daniels CA, Kleinerman ES, Synderman R: Abortive and .productive infections of human mononuclear phagocytes by type I herpes simplex virus. Am J Pathol 91:119, 1978. 9. Rinehart J J, Orser M, Kaplan ME: Human monocytes and macrophage modulation of lymphocyte proliferation. Cell Immunol 44:131, 1979. 10. Albeit RD, Zaia JA, Valerio MA, Levin M J: Infection of human peripheral blood mononuelear cells by varicella-zoster virus. Intervirology 18:56, 1982.

Short Stature as the Major Manifestation of Celiac Disease in Older Children

Celiac disease was diagnosed by jejunal biopsy and response to gluten elimination in 11 of 23 children with short stature referred after negative endocrine evaluation. The mean age of the group was 11 years, with a range of 5-16. All had been followed for a mean of 2.5 years at a large pediatric endocrine clinic for the evaluation of growth retardation. Bone age retardation of more than 25 percent of the chronologic age was found in all children. Microcytic anemia and past history of gastrointestinal problems were typical of the celiac group but were not documented in the nonceliac patients. Stool fat excretion was a specific but insensitive test, while the 1-hour blood xylose test was of no value in differentiating between the two groups. Close cooperation between pediatric endocrinology and gastroenterology clinics may be fruitful in the identification of celiac patients, especially in a group of older children with short stature, bone age retardation, and microcytic anemia.

Differential Leukocyte Count in Acute Gastroenteritis An Aid to Early Diagnosis

The total and differential leukocyte counts of 238 infants with acute gastroenteritis were evaluated as an aid in differentiating between nonbacterial and bacterial infection. In contrast to the total leukocyte count, which was noncontributory, the absolute band count and the ratio between band and total neutrophil count (B/N ratio) were helpful, with the highest values seen in patients with Shigellosis. A B/N ratio greater than 0.10 can help differentiate Shigella, Salmonella, and Campylobacter infections from E. coli and nonbacterial gastroenteritis with a sensitivity of 84.3 per cent and a specificity of 74.5 per cent.

Sucralfate Is Protective against Indomethacin-induced Intestinal Ulceration in the Rat

The therapeutic effects of sucralfate on ulcerated gastric and duodenal mucosa is well known. There is, however, very little information about its effect on the mucosa of the small intestine. We studied the possible protective effect of sucralfate against indomethacin-induced intestinal ulceration in the rat. Sucralfate was found to possess a marked protective effect on the intestinal mucosa (ulcer index 23.16 +/- 6.58 vs. 225 +/- 36.37; p less than 0.001). Sucralfate elevated basal mucosal prostaglandin E2 generation (p less than 0.001), and partially overcame the inhibition of prostaglandin E2 synthesis caused by indomethacin (p less than 0.03), but had no effect on mucosal cAMP level. The effect of sucralfate on prostaglandin E2 content might partially explain its protective effect on the intestinal mucosa.

Susceptibility-Guided vs. Empiric Retreatment of Helicobacter pylori Infection After Treatment Failure

Successful eradication of Helicobacter pylori after failure of standard triple therapy is difficult because of the higher resistance to metronidazole and clarithromycin. We evaluated the efficacy of susceptibility-guided vs. empiric retreatment for H. pylori after at least one treatment failure and determined the prevalence of posttreatment antibiotic resistance. Forty-nine patients in whom at least one treatment regimen for H. pylori eradication had failed underwent gastric biopsy and culture and were retreated according to the in vitro susceptibility results. Findings were compared with those for 49 control patients referred to our center for a 13C-urea breath test. H. pylori eradication was assessed by urea breath test at least 6 weeks after retreatment in both groups. Susceptibility-guided retreatment was associated with better eradication rates than empiric treatment. The difference remained significant in stratified and multivariate analysis. Susceptibility-guided retreatment appears to be significantly more effective than empiric retreatment in eradicating H. pylori after at least one previous treatment failure.

The effect of opiates on the intestinal immune response to cholera toxin in mice

We studied the effect of opiates on the intestinal immunoglobulin A response in mice. C57BL mice were orally immunized by two doses of 10 micrograms of cholera toxin, 2 weeks apart. Experimental groups received subcutaneous injections of morphine, either 10 or 20 mg/kg/day, in two divided doses. Morphine was given for 4 days, starting 1 day prior to each cholera toxin dose. Intestinal secretions were collected by lavage 1 week after the last cholera toxin dose, and assayed for specific anticholera toxin antibody and total immunoglobulin A. Results were expressed as units of anticholera toxin per nanogram immunoglobulin A. It was found that morphine, 20 mg/kg/day, reduced the response from 30.9 +/- 3.11 to 9.78 +2- 1.42 units/ng (M +/- SEM; p less than 0.0001). 10 mg/kg/day of morphine slightly reduced the immune response to 21.38 +/- 3.51 units/ng (M +/- SEM), but failed to achieve statistical significance. Naloxone administration prior to morphine injections abolished the inhibitory effects of morphine. Morphine administration had no effect on the response to a booster dose of cholera toxin 3 months after the initial cholera toxin immunization and morphine administration. It is concluded that morphine has a significant inhibitory effect on the intestinal immune response, but does not effect long-term mucosal immunological memory. The effect is probably mediated by a specific opiate receptor, as it is blocked by naloxone. This effect may have clinical implications.

L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: Possible role of an α-2-adrenergic mechanism

Dopaminergic agents ameliorate experimentally induced gastroduodenal mucosal injury, but there is no information about their effect on small intestinal mucosa. We studied the effect of L-dopa and related substances on indomethacin-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after refeeding fasted rats. Total ulcer area was measured 24 hrs after indomethacin administration. L-dopa, 5 mg/kg given in two divided doses 5 h apart, starting 30 minutes before administration of indomethacin, was found to protect the small bowel mucosa against indomethacin- induced damage (ulcer area 122 +/- 5.5 vs 224.2 +/- 5.4 mm2, mean +/- SEM, p less than 0.006). Administration of 5 mg/kg haloperidol, a dopa antagonist, did not abolish the protective effect of L-dopa. On the other hand, yohimbine, an alpha-2-adrenoreceptor antagonist, almost completely abolished the protective effect (180.4 +/- 5.3 vs 122 +/- 5.5, p less than 0.004). Clonidine 20 micrograms/kg, an alpha-2-adrenoreceptor agonist, closely mimicked the protective effect of L-dopa (141.5 +/- 10.9 vs 224.2 +/- 5.4, p less than 0.006). All drugs were give i.p. in two divided doses, at the same schedule as described for L-dopa. The results demonstrate that L-dopa has a protective effect on indomethacin-induced small bowel injury in the rat. The protective effect is probably mediated through stimulation of alpha-2-adrenoreceptors.

Pentagastrin Protects the Proximal Small Intestine against Indomethacin-induced Ulcers in the Rat

The possible protective effects of pentagastrin on indomethacin-induced small intestinal ulceration were investigated in rats. Ulcers were induced by subcutaneous injection of 30 mg/kg indomethacin, 30 min after refeeding rats fasted for 24 h. Administration of pentagastrin at a dose of 250 or 400 micrograms/kg i.p., 3 h prior to refeeding, reduced total ulcer area from 27.6 +/- 6.5 to 7.2 +/- 1.97 mm2 (mean +/- SEM; p less than 0.02) in the proximal small intestine only. Cyclic adenosine monophasphate, but not prostaglandin E2 levels were significantly raised by 250 micrograms/kg pentagastrin (0.15 +/- 0.05 vs. 0.38 +/- 0.07 pmol/mg protein; mean +/- SEM; p less than 0.02) in the same intestinal segment.