Bile-duct diameter at the porta hepatis and liver biopsies in Indian children with biliary atresia

Fibrous remnants from the porta hepatis and wedge biopsies of the liver were studied in 60 patients with biliary atresia. The patients were divided into three groups on the basis of bile duct diameter — I: no ducts; II: <50 m; III: >50 m. The liver damage was classified into three grades on the basis of ductular and parenchymal histopathologic changes and extent of inflammatory pathology. There was no correlation between severity of hepatic damage and duct diameter, although the levels of serum bilirubin and alkaline phosphatase varied in direct proportion to the degree of hepatic damage. There was an inverse relationship between age and duct diameter, but neither correlated with bile flow at surgery or in the postoperative period. The data suggest that Indian children with biliary atresia follow a different clinical course compared to those from Japan and Western countries. Correspondence to: V. Bhatnagar     

Gunshot wounds to the hand: management and economic impact

Low-velocity firearms represent the majority of civilian gunshot wounds to the hand, yet much of the literature is based on high-velocity injuries. The authors reviewed their treatment regimen for civilian gunshot wounds to the hand and offer a treatment algorithm that emphasizes early debridement and fracture stabilization. They also address the economic impact on society. The authors reviewed 121 fractures in 90 patients with gunshot wounds to the hand treated at an urban trauma center during the last 5 years. All patients were managed with irrigation and debridement, elevation, intravenous antibiotics, and early fracture stabilization. Sixty fractures were managed with rigid internal or external fixation: Kirshner wires (26%), miniplates (16%), and external fixation (8%). Fifty-six fractures were managed with closed reduction. Five fractures required amputation. There was one subsequent infection and two late amputations. The cost of hospitalization and operative care was more than $1.7 million. For gunshot wounds to the hand the authors advocate immediate irrigation and debridement, intravenous antibiotics, early fracture stabilization, and a low threshold for internal fixation. This regimen is supported by their low infection and complication rates.     

Timing of surgery for common pediatric surgical conditions

Depending upon various factors the surgical procedures in childhood are divided into three groups—immediate, intermediate and elective. The timing of surgery is probably the most important factor governing the outcome of surgical correction in pediatric surgery. With continuing research and clinical experience our understanding of the various conditions have improved and with that has come a change in the optimum timing of many surgical procedures. This paper highlights the best timing of surgery for some of the commoner pediatric surgical procedures and the reasons behind these so that the children may be referred to pediatric surgeons in time.     

Gastric perforation secondary to recurrent trichobezoar

A rare case of 10-year-old female child with recurrent trichobezoar stomach is reported, which presented with features of gastric outlet obstruction with perforation.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Enhanced Delivery of 5-Iodo-2′-Deoxyuridine to the Brain Parenchyma

5-Ester derivatives of 5-iodo-2-deoxyuridine (IDU) with varying degrees of lipophilicity were examined to evaluate the effectiveness of lipophilic ester prodrugs for enhanced and sustained delivery of IDU to the brain parenchyma. Approximately 1.0% (1.0 ± 0.19; n = 4) of the total radioactivity was found in the brain at 30 min following intravenous administration of the lipophilic benzoyl-5-ester of ¹²⁵I-labeled IDU, whereas IDU per se yielded only 0.01% (0.01 ± 0.06; n = 4). Since the IDU 5-esters generated significantly higher levels of IDU in the brain, an HPLC analysis of IDU in the presence of 5-esters and the metabolite 5-iodouracil was developed to characterize IDU uptake in the brain. The drug was detected at levels of 6.6 and 9.5 µg/g of brain tissue at 3 hr following intravenous administration of valeryl and benzoyl IDU, respectively, at a dose level of 40 mg/kg IDU equivalent each. IDU, on the other hand, when injected at a similar dose level, produced concentration levels below 0.01 µg/g of brain tissue, which was too low to be detected accurately by the HPLC assay. These results suggest that the 5-ester derivatives cross the blood-brain barrier effectively and generate significantly higher brain levels of the parent drug in the brain parenchyma. The regenerated hydrophilic drug because of its polarity is locked in the brain and is subsequently metabolized by pyrimidine phosphorylase to 5-iodouracil. A higher concentration of IDU was generated following administration of the benzoyl ester probably because the ester itself is slowly hydrolyzed by the brain cholinesterases, thereby competitively inhibiting the metabolism of IDU to 5-iodouracil by brain pyrimidine phosphorylase. 5-Benzoyl IDU appears to be a promising bioreversible analogue which can provide enhanced and sustained delivery of IDU to the brain parenchyma.     

Effects of L-ascorbic acid supplementation on dieldrin toxicity in rats

Chronic dieldrin administration to rats (5 mg/kg/day) produced pathological changes in liver and kidney tissues. Dieldrin treated rats showed high levels of liver ascorbic acid and increased activities of inorganic pyrophosphatase in brain and glucose-6-phosphatase in liver. The activities of Mg²⁺-ATPase in liver and acetylcholinesterase in brain were decreased under toxic doses of dieldrin. L-Ascorbic acid supplements in treated animals could partially prevent the pathological alterations, as observed histologically in liver and kidney tissues. Administration of this vitamin could also prevent alterations in some enzyme activities produced by toxic dieldrin doses.     

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.