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A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.

Moderately potent, selective S1P1 receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P1 agonists represented by 7. Many of the new compounds are potent S1P1 agonists that select against the S1P2, S1P3, and S1P4 (although not S1P5) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.

The pharmacokinetics and hepatic metabolism of [3H] ivermectin (IVM) and [3H]cyclosporin A (CSA) were investigated in a subpopulation of the CF-1 mouse stock naturally deficient in mdr1a p-glycoprotein (PGP). A survey of key drug-metabolizing activities in liver fractions from PGP-deficient (-/-) or wild-type (+/+) animals indicated the two subpopulations are not different in hepatic metabolic activity and capacity. Intravenous pharmacokinetics of CSA were identical between the two groups, and results from microsomal incubations indicated similar biotransformation of IVM and CSA in liver. Intestinal excretion of [3H]IVM and [3H]CSA was enhanced in PGP (+/+) animals. Absence of PGP resulted in higher blood concentrations of IVM after oral dosing, suggesting enhanced absorption of IVM in (-/-) mice. Concentrations of [3H]IVM and [3H]CSA were always greater in the brains of (-/-) mice compared with (+/+) mice after either i.v. or oral administration. In contrast, liver concentrations of either compound were not different between (+/+) and (-/-) animals after an i.v. dose. These results show the PGP (-/-) and (+/+) subpopulations of CF-1 mice are useful for studying the role of mdr1a PGP in systemic exposure and tissue disposition of PGP substrates in the absence of metabolism differences.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

A case is reported of the rare association between progressive multifocal leucoencephalopathy and carcinoma. A 66-year-old man underwent a laryngectomy for carcinoma. Four years later he developed a local recurrence. Simultaneously there were behavioural disturbances and a left motor neglect followed by dense hemiplegia and coma. The patient died a further 5 months later. Anergy was demonstrated by skin tests. CT scan showed asymmetrical non-enhancing low-density areas in the hemispheric white matter, brain-stem and cerebellum and neuropathological examination confirmed extensive myelin loss with typical papovavirus inclusions in oligodendrocytes identified by electron microscopy.

Two cases of neurological dysfunction are presented. Neurological deficits after recovery from anaesthesia are unusual in young women perioperatively. In the first case, a 39-yr-old woman presented at 36-wk gestation with antepartum haemorrhage and in labour. Pregnancy had been complicated by pre-eclampsia and she underwent emergency Caesarean section under general anaesthesia without complication. The trachea was extubated when she was awake but almost immediately she became hypertensive, obtunded and reintubation was required. Her pupils became fixed and dilated but the Computerised Axial Tomogram (CT) was normal. A coagulopathy was evident. She made a full neurological recovery within 24 hr. On the same day, a previously healthy 4l-yr-old woman who had undergone uneventful surgery for uterine prolapse 24 hr previously developed headache, nausea and over the next four hours signs of progressive brainstem ischaemia. The CT scan showed oedema of the mid- and hindbrain. Brainstem death was confirmed 12 hr later and the post-mortem revealed acute dissection of the vertebral artery secondary to cystic medial necrosis. Such dramatic neurological sequelae are rare but the importance of identifying “at risk” groups is underlined as is early recognition of neurological injury postoperatively.

A 22-year-old man developed a severe sensorimotor neuropathy following ingestion of podophyllin, which had been prescribed for genital condylomata. The initial toxic symptoms were vomiting and diarrhoea, followed by peripheral neuropathy. The neuropathy was still present 18 months later. Nerve conduction studies and sural nerve biopsy confirmed the presence of axonal degeneration.

The Prune Belly Syndrome is a congenital disorder in which a major urinary tract malformation, usually obstructive, is associated with abdominal wall muscle deficiency. Males are more often affected and it has been suggested that urethral obstruction is the primary disorder, the other features being secondary (Pagon et al, 1979).

Congenital cystic adenomatoid malformation of the lung (CCAM) is an uncommon developmental abnormality presenting most often in the neonatal period. We report the clinical, radiological and pathological findings in a 9-year-old boy who presented with acute chest pain.

Hypersecretion of TSH by a pituitary adenoma is thought to be a rare form of hyperthyroidism. We describe three such patients, each of whom presented with clinical hyperthyroidism and a diffuse goitre, without eye signs or dermatopathy. Two were receiving long-term phenothiazine, one of these was also acromegalic. Plasma thyroxine, free T4 and tri-iodothyronine were repeatedly raised in each; plasma TSH was grossly elevated in one and inappropriately normal in the other two. Plasma TSH did not rise in response to thyrotrophin-releasing hormone or metoclopramide and was not suppressed by L-dopa in any patient. Anti-thyrotrophin receptor antibodies were undetectable. Skull ra0diographs showed erosion and expansion of the pituitary fossa and CT scans confirmed a pituitary mass in each patient. A pituitary adenoma was removed by trans-sphenoidal surgery in two patients and a TSH-secreting adenoma was confirmed by immunocytochemical staining and electron microscopy. Both patients were clinically euthyroid post-operatively but still had evidence of TSH excess. Pituitary surgery was technically unsuccessful in the third patient. Although two patients had hyperthyroidism of long duration, all three were diagnosed within one year of the introduction of a sensitive TSH assay to our laboratory. A TSH-secreting pituitary adenoma may be a more common cause of hyperthyroidism than has been believed.