O-GlcNAcylation of key nuclear and cytoskeletal proteins: reciprocity with O-phosphorylation and putative roles in protein multimerization

BACKGROUND: Registered mortality from cryptogenic fibrosing alveolitis (CFA) in England and Wales has increased substantially since the specific International Classification of Diseases code for CFA was introduced in 1979. However, since a significant proportion of deaths from CFA are misclassified as post inflammatory fibrosis (PIF), it is possible that the observed rise in CFA mortality is due to diagnostic transfer from this code. To investigate this, and to assess mortality trends in other countries, annual CFA and PIF mortality data from England and Wales, USA, Australia, Scotland, Canada, New Zealand, and Germany were analysed. METHODS: Crude annual mortality rates were calculated and rates standardised by Poisson regression to allow assessment of changes over time and comparison between countries, sexes, and age groups. The relative trends in mortality from CFA and PIF were assessed by calculating the annual ratio of CFA to PIF deaths. RESULTS: Men were more likely than women to die from both CFA and PIF in all countries. The highest standardised CFA mortality rate occurred in England and Wales, and the lowest in Germany. Since 1979 mortality from CFA has increased in England and Wales, Australia, Scotland and Canada, but there was no trend in CFA mortality in New Zealand or Germany. In the USA mortality from CFA was low and has fallen. Mortality from PIF increased in all countries except New Zealand and Germany, and the highest PIF mortality, together with the greatest increase over time, was seen in the USA. Changes over time in the annual ratio of CFA to PIF deaths in all countries were small, implying that diagnostic transfer is not a major cause of the increasing CFA mortality. CONCLUSIONS: Mortality from CFA continues to increase in England and Wales and in many other countries. Diagnostic transfer from PIF does not appear to be a major cause of this.     

Enriching the egg yolk in n − 3 fatty acids by feeding hens with diets containing horse fat produced in Uruguay

The present study was conducted to evaluate the ability of horse fat produced in Uruguay, compared with other lipid sources supplemented in the diet of laying hens, to modify the lipid composition and the n − 6/n − 3 fatty acid ratio of the produced eggs. For this purpose, 60 laying hens (Gallus domesticus) were fed for 30 days with five experimental diets (12 hens/diet) containing 3% sunflower oil (SO), rice oil (RO), beef tallow (BT), pressed-fat (PF), obtained by pressing fat from bovine viscera, and horse fat (HF) obtained from horse bone medulla. Throughout the trial, feeding rate, shell index, weight and total lipid contents of eggs, were not affected by the different diets. Feeding on the SO and RO diets significantly increased the amount of linoleic acid of the egg, although it was lower in the RO than in the SO eggs. Diet BT did not affect the saturated fatty acid content of the yolks. The diets with animal fats containing 18:3n − 3 (diets PF and HF), resulted in a significant increase in the n − 3 fatty acid contents of the eggs, through an increase of linolenic (18:3n − 3) and docosahexaenoic acid (DHA, 22:6n − 3) contents. Eggs from hens fed the HF diet showed increased linolenic acid (46 mg/yolk) and DHA (71 mg/yolk, 1.7% of total fatty acids) contents. These levels were obtained after two weeks of feeding. Moreover, the fatty acid profiles of eggs from treatment HF were not significantly affected by thermal treatment of the yolks. In conclusion, the fat from horse bone medulla, as produced in Uruguay, can be considered as a suitable lipid source for diets of laying hens, to modify the nutritional composition of the eggs in n − 3 PUFA content, especially DHA, and consequently, the n − 6/n − 3 fatty acid ratio.     

Leptin concentration in women is influenced by regional distribution of adipose tissue

Leptin concentrations in humans are increased with obesity, and women have higher leptin concentrations than men. This sex difference reflects the greater fat mass of women. However, there is evidence that factors other than the size of the adipose tissue mass contribute to serum leptin concentrations. This study was undertaken to determine whether anthropometric factors influenced leptin concentrations in our population. Leptin concentrations were measured in 375 persons from a population study of hypertension and diabetes for whom body-composition data (bio-electrical impedance analysis and anthropometry) were available. Serum leptin concentrations were more than four times higher in women than in men (18.5 +/- 13.9 compared with 3.8 +/- 3.6 ng/L, P < 0.0001). In individuals with comparable body mass indexes, these differences persisted after adjustment for either percentage fat (P < 0.05) or fat mass (P < 0.0001) by multivariate-regression analysis. After fat mass was adjusted for, the serum leptin concentration in both men and women was independent of waist circumference but in women was associated with hip circumference. Hip circumference is a proxy measure of peripheral fat and these results suggest that the larger hips of women may contribute to the sex difference in serum leptin concentration.     

Picrotoxin-sensitive receptors mediate gamma-aminobutyric acid-induced modulation of synaptic plasticity in rat superior cervical ganglion

Activity-dependent changes of synaptic efficacy in the superior cervical ganglion (SCG) can be prevented by gamma-aminobutyric acid (GABA). We have studied the effects of picrotoxin (PTX) on GABA-mediated inhibition of long-term potentiation (LTP) of synaptic transmission in the rat SCG. Compound action potentials were recorded extracellularly in the postganglionic internal carotid nerve in response to preganglionic nerve stimulation. PTX (100 microM) antagonized the inhibition by exogenous GABA (250 microM) of LTP induced by strong tetanic stimulation (20 Hz, 20s, supramaximal stimulation, partial blockade of transmission by hexamethonium). Additionally, PTX alone (50 microM) facilitated the induction of LTP by a weak tetanus (20 Hz, 5 s, submaximal stimulation). These results further support previous data indicating that activation of GABAA-like receptors can prevent the occurrence of synaptic plasticity at this peripheral synapse.     

cis-Amminedichloro(2-methylpyridine) platinum(II) (AMD473), a novel sterically hindered platinum complex: in vivo activity, toxicology, and pharmacokinetics in mice

A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance due to reduced drug transport (41M/41McisR) or enhanced DNA repair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In this study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked in vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) and human ovarian carcinoma xenograft models, including several possessing acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i. p. administration. In a head-to-head comparison using CH1cisR xenografts and equitoxic doses (q7dx4 schedule), comparative growth delays were as follows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days against this model). In this model, oral activity was also noted with a growth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts that had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cisplatin). Across the whole panel of cisplatin-sensitive to cisplatin-resistant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 mg/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c- mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay was observed in the plasma with a rapid distribution t1/2alpha of 24 min followed by a slow elimination t1/2beta of 44 h. Platinum accumulated in various organs with platinum tissue to plasma area under the curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for heart, 5.2 for lung, and 5 for tumor. The plasma and tissue concentration time curve following i.p. administration was similar to that observed following i.v. administration, with a bioavailability of 89%. When AMD473 was given p.o., the platinum absorption was rapid (K01 of 30 min) and the bioavailability was 40%. A less than proportional increase in area under the curve and Cmax was noted in tissue, plasma, and plasma ultrafiltrate following increasing oral doses of AMD473. In vitro, with AMD473, the rate of binding to different plasma proteins was approximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recovery represented 13% of the administered dose after 3 days. Similar results were observed following oral and i.v. administration of 20 mg/kg, but significantly more was excreted in the feces (over 50% of the administered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration. The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity of AMD473, together with its lack of nephrotoxicity and favorable pharmacokinetic profile, suggests that AMD473 is a good candidate for clinical development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.     

Functioning of the hypophyseal-adrenocortical system in rats selected for the sensitivity threshold to the electric current

Although behavioral and neuropsychological data regarding the existence of images for odors are inconclusive, reconsideration of earlier EEG work provides reasonably clear evidence for an inner nose. However, further EEG studies and neuroimaging data seem essential for conclusive demonstration of an inner nose.     

Mediastinal bronchogenic cyst: diagnosis and follow-up

A 5-year-old girl with an asymptomatic posterior mediastinal cyst from birth was followed with repeated echocardiograms. The cyst developed communication with the bronchus spontaneously around 8 months of age without clinical symptoms. This was detected from the sudden disappearance of the mass on echocardiogram, and an unusual air-pocket on chest roentgenogram. Computed tomography (CT) of the chest confirmed the diagnosis of communicating bronchogenic cyst (BC). She was treated successfully with complete surgical excision of the cyst and closure of the defect in the bronchus. We emphasize that surgery is indicated in all mediastinal BCs because of potential complications.     

Intellectual performance in multi-infarct dementia and Alzheimer''s disease a replication study

A comparative study was conducted to evaluate the efficacy of a metal or flexible plastic 8 mm cannula for artificial abortion by vacuum aspiration for patients at six to 10 weeks' gestation. Complication rates, amounts of retained tissue (obtained with a curette check), frequencies of cannula obstructions and procedure times were used as criteria for determining the efficacy of the two types of cannulae. Two physicians participated in the study: one was responsible for the preliminary examination and performance of the abortion, and the other physician, who was kept unaware of the type of cannula used, was responsible for patient care after completions of the abortion to the time of the follow-up visit. Paracervical block anesthesia was used in all cases. Differences in complication rates (controlled for gestational age) between groups of subjects aborted with either the metal or flexible plastic cannula were not significantly different (p less than .05). For both patient groups shock was the most frequently reported immediate complication (2.7% in the metal cannula group, 4,7% in the flexible plastic cannula group), and leukorrhea was the most frequently reported complication at the time of follow-up (3.3% metal, 5.3% flexible plastic). Amounts of retained tissue and frequency of cannulae obstruction were similar for both groups. Procedure times were also similar for both groups (means of 5.7 minutes and 5.5 minutes, respectively, for procedures performed with the metal and flexible plastic cannulae).     

Differentiation of HL-60 promyelocytic leukemia cells is accompanied by a modification of magnesium homeostasis

The concentrations of ammonia in the plasma of the mudskipper Boleophthalmus boddaerti exposed to cyanide for 1-6 days were significantly greater than the respective values of the controls. This was due to an increase in the production of NH3 in the muscle and an increase in the retention of NH3 and/or NH4+ in the blood of the cyanide-exposed fish when compared to controls. Cyanide exposure significantly increased the specific activity of muscle AMP deaminase. Since adenylosuccinate synthetase and lyase were also present in the muscle, exposure to cyanide might increase the production of NH3 from the catabolism of purine nucleotides. B. boddaerti exposed to cyanide excreted significantly less ammonia than the control fish. Results indicate changes in the permeability of the epithelial surfaces of the cyanide-exposed fish to NH3 and/or NH4+. Since the tissues and organs needed time to activate the inducible cyanide detoxification mechanisms, the increase in the production of NH3 might be an important defensive mechanism for B. boddaerti during the early phase of cyanide exposure.     

Platelet coagulant activities and serum lipids in transient cerebral ischemia

To determine whether platelets play a part in the pathogenesis of transient cerebrovascular ischemia, we studied 22 patients with transient ischemia, 18 control patients and 38 normal subjects. Platelet aggregation and [14C]-serotonin release by ADP, epinephrine and collagen were normal in all patients, as were plasma coagulation assays, except for shortened partial thromboplastin times in the patients with transient ischemia. Platelet coagulant activities concerned with initiation and early stages of intrinsic coagulation were increased two to three times in 12 patients with transient ischemic attacks with normal serum lipids and normal in the 10 others with Type IV hyperlipoproteinemia. These results indicate an association between platelet coagulant hyperactivity and transient ischemic attacks in a group of patients with normal serum lipids.