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Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.

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Vaginal pessaries still have a role in the management of uterine prolapse, particularly in elderly patients. However, they are known to cause serious complications if proper care is not taken. We present a case of a rectovaginal fistula, developing secondary to a forgotten vaginal pessary. The shelf pessary was found to have eroded through into the rectum. A review of the relevant literature was undertaken and complications associated with vaginal pessaries are discussed.

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In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability of the HepG2 cells they were cultured in 4-32 microM copper(II) sulphate (CuSO4)). These levels were comparable to the circulatory and tissue concentrations of copper recorded for these two diseases. Specific uptake comparable to levels of copper recorded in the livers of patients with Wilson's disease and ICC was measured in the HepG2 cells. After 48 h acid vesicle function increased from 4 to 32 microM Cu2+ but significantly declined at 64 microM compared to the controls. Lysosomal acid phosphatase showed a concentration dependent decline in activity at 72 h. Cellls exposed to 64 microM Cu2+ had a potential doubling time (Tpot) 21 h longer than the control cells due to a prolonged DNA synthesis phase. At 64 microM Cu2+, increases of necrosis up to 18% were seen whereas comparable levels of apoptotic and necrotic cells (<5%) were seen below this concentration. Chronic exposure over 8 weeks impaired colony-forming efficiency at concentrations of 16 microM Cu2+ and above. This study suggests that when liver cells sequester large amounts of copper, the toxic effects include delayed cell-cycle progression, a gradual loss of replicative capacity, and an increased incidence of cell death.

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Four patients with pseudocyst of the spleen gave histories of abdominal trauma. In one patient the pseudocyst had ruptured, necessitating emergency splenectomy 34 years after the original injury. In a second patient the pseudocyst was discovered incidentally, and was managed by spleen-preserving excision; and the third and fourth presented with abdominal pain and had splenectomy and spleen-preserving surgery, respectively. All patients with conservatively treated splenic injury are at risk of developing a pseudocyst of the spleen, and the lesion can be detected by computed tomography or ultrasound. When there are no symptoms the natural history is unknown; but if surgery is necessary, splenectomy can sometimes be avoided.

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In Indian childhood cirrhosis (ICC) and related disorders of infancy, hepatic copper overload is associated with cirrhosis. Since copper administration alone has not been shown to induce cirrhosis in animals, synergy between copper and a second hepatotoxin has been suggested. This study investigates the ability of long-term exposure to copper and a pyrrolizidine alkaloid, retrorsine, to produce a model of copper-associated cirrhosis in rats. Groups of rat pups suckled on mothers fed 25 mg/kg diet retrorsine were weaned onto a diet containing 0.5 g/kg diet copper and retrorsine in varying dosage for 13 weeks. Histological similarities between the human disease and rats given copper with retrorsine 5 mg/kg diet included parenchymal destruction, fibrosis, nodular regeneration, and copper accumulation. There were significant histological differences from the human disorder, possibly attributable to inter-species variability or the critical timing or duration of exposure to hepatotoxins in the neonatal period. The hypothesis that ICC results from copper and a second hepatotoxin has not been disproved.

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Throughout the world tuberculosis is associated with poverty, deprivation, and human immunodeficiency virus infection. Abdominal tuberculosis is usually of insidious onset with diverse symptoms and signs. A few present with acute complications of perforation, obstruction, or bleeding. The diagnosis is difficult, especially in areas where the disease is less common, as many patients do not have evidence of pulmonary tuberculosis or a positive skin test. The main differential diagnosis ranges from Crohn's disease in the young and advanced malignancy in the elderly. Delayed diagnosis is common, resulting in high mortality. Many investigations provide findings suggestive but not diagnostic of tuberculosis. With peritoneal tuberculosis, assay of ascitic fluid adenosine deaminase activity is a valuable, simple method of diagnosis that may reduce the need for laparoscopic biopsy. If the clinical suspicion of abdominal tuberculosis is high, a trial of medical treatment is appropriate. Surgery should be reserved for the complications of the disease. All patients require treatment with three antituberculous drugs over a 6-month course.

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AIMS: To explore the hypothesis that a second xenobiotic agent is required with excess copper to produce Indian Childhood Cirrhosis, this study investigated the effect of the pyrrolizidine alkaloid retrorsine fed to the mother during the suckling period upon the serial changes in neonatal copper status. METHODS: Female Wistar rats with new-born litters were fed either a control or a retrorsine (50 mg/kg) diet. At 0, 4, 8, 11, 15, 18 and 21 days, pups from each litter were weighed, sacrificed and their livers removed for copper, DNA and metallothionein analysis. Serum samples were assayed for caeruloplasmin oxidase activity and albumin. RESULTS: 1) Higher than adult level of hepatic copper in normal rats which rose post-natally before declining from day 11 after birth, 2) raised hepatic copper concentrations and total copper in the retrorsine group from day 15; levels were higher than adult at birth, 3) reduced serum caeruloplasmin oxidase activity and albumin levels in retrorsine group, but both groups lower than adult, 4) lower hepatic metallothionein levels in retrorsine group, but both groups higher than adult, and 5) reduced liver DNA in the retrorsine group when expressed as total DNA and per gram of tissue. These changes were not secondary to under-nutrition as a small study on under-nourished rat neonates showed that copper handling is not significantly altered when compared to well-nourished rats. CONCLUSIONS: Retrorsine passing to rat neonates via breast milk causes: 1) the accumulation of hepatic copper, 2) impairment of the rise in serum caeruloplasmin, which could indicate a decline in synthesis or failure of copper incorporation into the apo-protein, 3) a decrease in hepatic metallothionein and serum albumin levels, again suggesting diminished protein synthesis, and 4) reduced hepatic DNA indicative of decreased cell number but increased cell size. Accumulation of liver copper but reduction of copper-binding proteins could result in free copper and explain the synergistic hepatotoxicity of copper and retrorsine.

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1. The alpha 1-adrenoceptor-mediated responses of the rat urethra to phenylephrine have been examined in vitro. Phenylephrine caused concentration-dependent contractions of the isolated urethra which were antagonized by WB4101 (3-30 nM) and prazosin (10-100 nM) but not idazoxan (1.5 microM). Schild plot analysis of the antagonism by prazosin and WB4101 yielded straight lines with slopes not significantly different from unity. The pA2 value of 9.0 for WB4101 was significantly greater than the value previously obtained at the alpha 1B-adrenoceptor of the rat spleen. 2. 5-Methylurapidil (30 nM) and abanoquil (1 nM) caused dextral shifts of concentration-response curves yielding pKB values of 8.3 and 9.4 respectively. Maximal responses to phenylephrine were also reduced by this concentration of abanoquil. 3. Preincubation with chloroethylclonidine (25 microM for 40 min) failed to alter responses, but removing extracellular calcium or the presence of nifedipine (1 microM) almost abolished contractions to phenylephrine. 4. These results indicate that the responses of the rat urethra to phenylephrine are mediated via the alpha 1A-adrenoceptor subtype and are dependent on the influx of extracellular calcium.

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Sixty-seven consecutive aortograms in non-diabetic patients were studied to establish the distribution of atherosclerosis in the arteries of 134 lower limbs. Prolonged filming and multiple exposures of the feet showed ankle vessels in 131 of the limbs (98%) and a pedal arch or collaterals in 126 (93%). In 51% of the limbs at least one of the calf arteries was occluded and only 24% had two patent arteries at ankle level. The pedal arch was complete in only 16%. The patency rate of the pedal arch was similar in all three symptom groups (p greater than 0.05). Two separate analyses were performed. The first was based on symptoms. Critical ischaemia was present in 18 limbs (13%), claudication in 69 limbs (52%) and 47 limbs were symptomless (35%). The second analysis was based on the sites of major occlusion. Occlusions were already present in 81% of the symptomless limbs, predominantly in the distal vessels. In limbs with claudication or critical ischaemia there were more occlusions above the knee (77 and 89%, respectively) than in limbs without symptoms (36%) (chi 2 = 27.60, p less than 0.001). Occlusion of the popliteal artery was significantly more frequent in the patients with symptoms of critical ischaemia (50%) than in either of the other two groups (chi 2 = 15.61, p less than 0.001). Atherosclerosis appears to develop in the small vessels of the calf and foot at an early stage. The extent of this involvement may influence the progression of symptoms and the outcome of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hemorrhage from a peptic ulcer during pregnancy is a rare complication that occurs most frequently near term or in the puerperium. A case of massive hematemesis from a duodenal ulcer on the third puerperal day is described. Emergency surgery with vagotomy and pyloroplasty was performed. The mother had no symptoms of peptic ulceration until the onset of mild abdominal pain 4 days before delivery.

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One hundred consecutive aortograms were studied to establish the efficacy of conventional arteriography in demonstrating distal vessels and the pedal arch. The standard technique was modified by using a long injection time, a large volume of contrast material (iopamidol 370), prolonged filming and multiple exposures of the feet. On the basis of these examinations each limb was classified as having aorto-iliac disease (18 limbs), superficial femoral disease (103 limbs), combined segment disease (28 limbs) or generalised disease (51 limbs). Calf and ankle arteries were seen in 196 of the 200 limbs (98%). Patency of the pedal arch was established in 184 (92%). Fourteen percent of the group of patients with combined segment disease did not have their pedal arch visualised and this group contained most of the examination failures. This modified method of aortography can demonstrate the entire arterial tree from the aorta to the foot in 92% of limbs with symptomatic chronic atherosclerotic disease. This allows the majority of peripheral vascular reconstructions to be planned and performed without the need for intra-operative arteriography.

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Over a four-year period, 28 patients with abdominal tuberculosis were seen, of whom 24 were immigrants and 22 under 45 years. Emergency surgery was carried out in 10 patients; another 14 had elective laparotomy. The diagnosis was suspected pre-operatively in 75 per cent of those having elective surgery and 10 per cent of those having emergency laparotomy. Perforated ileal strictures were found in 30 per cent of those with acute symptoms. Half of those with chronic disease had hyperplastic ileocaecal disease and half tuberculous peritonitis. Positive histology was obtained in 23 patients, but culture was positive in only four. The only death was of an elderly white man with a perforated ileal stricture. The four patients treated without surgery showed a rapid symptomatic response to antituberculous drugs.

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Nine postoperative colonic and rectal strictures were treated using dilatation balloons passed over a guide-wire introduced endoscopically. Six strictures resolved after a single dilatation. The method is simple, safe, effective and avoids further surgery.

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Small bowel perforation occurs in up to 2 percent of patients with abdominal tuberculous. Patients present with an acute abdomen. Resection of the diseased segment and 18 months treatment with anti-tuberculosis drugs is recommended.

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