Preface to the ‘UKCCCR guidelines for the Welfare of animals in experimental neoplasia’

Preface to the UKCCCR guidelines for the Welfare of animals in experimental neoplasia     

How pediatricians can respond to the psychosocial implications of disasters. American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health, 1998-1999

Natural and human-caused disasters, violence with weapons, and terrorist acts have touched directly the lives of thousands of families with children in the United States.1 Media coverage of disasters has brought images of floods, hurricanes, and airplane crashes into the living rooms of most American families, with limited censorship for vulnerable young children. Therefore, children may be exposed to disastrous events in ways that previous generations never or rarely experienced. Pediatricians should serve as important resources to the community in preparing for disasters, as well as acting in its behalf during and after such events.     

Mechanisms of in utero overgrowth

D'Ercole AJ. Mechanisms of in utero overgrowth. Acta Pædiatr 1999; Suppl 428: 31–6. Stockholm. ISSN 0803–5326
Determination of the mechanisms that lead to in utero overgrowth has proved elusive. Recently, however, our knowledge has significantly expanded as a result of the generation of experimental mouse models, engineered to disrupt the expression of one or more genes (knockout mice), and by detailed molecular and genetic analyses of infants and children with overgrowth syndromes. Studies of knockout mice have largely defined the essential roles of the insulin-like growth factors (IGF-I and IGF-II), insulin and their receptors in embryonic and fetal growth, and have provided compelling evidence that increased IGF-II gene expression and/or abundance can stimulate excessive fetal somatic growth. The IGF-II gene is usually expressed only by the paternally derived allele; however, when this imprinting is erased and IGF-II expression is biallelic, fetal overgrowth ensues. Such increased IGF-II expression would appear to explain the overgrowth in Beckwith-Wiedemann syndrome. Using the information gathered from knockout mice as a guide to human studies, detailed genetic investigations are likely to unravel the mechanisms behind other human overgrowth syndromes. □ Beckwith-Wiedemann syndrome, gene expression, imprinting, insulin, insulin-like growth factors, insulin-like growth factor receptors, insulin receptor, overgrowth syndromes     

Embolic vascular seeding of endometrial adenocarcinoma, a complication of hysteroscopic endometrial biopsy

OBJECTIVE: A case of embolic vascular seeding of endometrial adenocarcinoma following hysteroscopy is reported. METHODS: This phenomenon was recognized in the uterus specimen from a hysterectomy performed 1 week after hysteroscopic endometrial biopsy. Tissue processing artifact was excluded. RESULTS: Since the patient was otherwise low risk, treatment was limited to hysterectomy. The patient was not given adjuvant therapy. Two years later she remains alive and well with no evidence of disease. The surgical, morphologic, and clinical features of this case are presented and illustrated. CONCLUSION: Previous reports of peritoneal tumor seeding associated with hysteroscopy are reviewed. Tumor embolization during hysteroscopic endometrial biopsy was not followed by tumor recurrence in this case.     

CB 1954 revisited

Summary Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 g/ml in mice, while 25 mg/kg gave peak palsma concentrations of 27 g/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t_1/2 values were 1.4–2 h in mice and 2.5–4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%–90%, while brain: plasma ratios were lower, at 37%–50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%–29%, of which 16%–25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t_1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new mixed-function sensitizers.     

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39-73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2-5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.     

Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases

Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110alpha (2 nmol/L), p110beta (3 nmol/L), p110delta (3 nmol/L), and p110gamma (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 micromol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic.     

Canine units: the softer side of security

Try a different breed of security officer to improve safety and boost morale in your facility.     

Delirium Tremens

The varied clinical manifestations and management of 14 male patients with delirium tremens (DT) have been studied. Eight patients were initially hospitalised for diseases unrelated to ethanol abuse i.e. 2 each for gun shot wound, myocardial infarction and stroke, and one each for pneumonia and gastroenteritis. One patient was going through withdrawal because of prodrome of viral hepatitis before he was hospitalised for uncontrolled agitation and delirium. Two known cases of mild essential hypertension on dietary therapy reported for agitation, abnormal behaviour, a single episode of tonic clonic seizure and hypertensive encephalopathy as they could not/did not get alcohol for 3 days. Three patients presented denovo with DT without concomitant illness. The other features besides delirium and hallucinations were tremulousness in 10, tachycardia in 12, fever in 3, diaphoresis in 2 and tonic clonic seizures in 4 patients. The symptoms fluctuated markedly at short intervals and 2 patients did not have any features of sympathetic overactivity. Altered hepatic biochemical parameters and ketonuria with normal blood sugar were noted in 4 and one patients respectively. Other biochemical parameters including serum electrolytes were normal. CT scan brain done for 5 patients revealed subdural haematoma in one. Cerebro spinal fluid (CSF) and EEG findings were noncontributory. All made good recovery with heavy doses of intravenous vitamin B complex, glucose and oral benzodiazepine. Short course of haloperidol was used in 2 patients. Two patients developed pancreatitis during follow up. All patients made complete recovery, and 8 patients have been followed for 8 to 12 months without relapse. The reason for hospitalisation in such cases is often unrelated to alcohol abuse; hence a detailed history of alcoholism is mandatory to identify those at risk as well as for prompt treatment and decreasing the mortality.Key Words: Alcohol withdrawal, Concomitant illnesses, Delirium, Precipitating events