In rats gestational iron deficiency does not change body fat or hepatic mitochondria in the aged offspring.

Mitochondrial dysfunction and resulting changes in adiposity have been observed in the offspring of animals fed a high fat (HF) diet. As iron is an important component of the mitochondria, we have studied the offspring of female rats fed complete (Con) or iron-deficient (FeD) rations for the duration of gestation to test for similar effects. The FeD offspring were ~12% smaller at weaning and remained so because of a persistent reduction in lean tissue mass. The offspring were fed a complete (stock) diet until 52 weeks of age after which some animals from each litter were fed a HF diet for a further 12 weeks. The HF diet increased body fat when compared with animals fed the stock diet, however, prenatal iron deficiency did not change the ratio of fat:lean in either the stock or HF diet groups. The HF diet caused triglyceride to accumulate in the liver, however, there was no effect of prenatal iron deficiency. The activity of the mitochondrial electron transport complexes was similar in all groups including those challenged with a HF diet. HF feeding increased the number of copies of mitochondrial DNA and the prevalence of the D-loop mutation, however, neither parameter was affected by prenatal iron deficiency. This study shows that the effects of prenatal iron deficiency differ from other models in that there is no persistent effect on hepatic mitochondria in aged animals exposed to an increased metabolic load.

A kinetic analysis of hexose transport in cultured human lymphocytes (IM-9).

3-O-Methyl-D-glucose transport across the plasma membrane of cultured human lymphocytes of the IM-9 line was followed for net entry into sugar-free cells (zero trans entry), net exit into sugar-free medium (zero trans exit) and for equilibration of labelled sugar in cells with the same sugar concentration in the intracellular water as in the medium (equilibrium exchange). The measurements were performed at 37 degrees C (pH 7.4). Equilibrium exchange of 1 mM 3-O-methylglucose (t 1/2 about 7 S) was exponential, suggesting a homogeneous cell suspension. Initial rates of transport showed a Michaelis-Menten dependency on the sugar concentration. The transport system was found to be asymmetric with the following kinetic parameters. Zero trans entry: Km = 2.8 mM, Vmax = 10.7 mM X min-1. Zero trans exit: Km = 9.5 mM, Vmax = 37.9 mM X min-1. Equilibrium exchange: Km = 9.9 mM, Vmax = 44.0 mM X min-1. Finally, the affinity constant for the internal site was measured as approx. 1.2 mM using the infinite cis protocol.

Hydrogen bonding requirements for the insulin-sensitive sugar transport system of rat adipocytes.

(1) The t 1/2 for 1.3 mM D-allose uptake and efflux in insulin-stimulated adipocytes is 1.7 +/- 0.1 min. In the absence of insulin mediated uptake of D-allose is virtually eliminated and the uptake rate (t 1/2 = 75.8 +/- 4.99 min) is near that calculated for nonmediated transport. The kinetic parameters for D-allose zero-trans uptake in insulin-treated cells are Koizt = 271.3 +/- 34.2 mM, Voizt = 1.15 +/- 0.12 mM . s-1. (2) A kinetic analysis of the single-gate transporter (carrier) model interacting with two substrates (or substrate plus inhibitor) is presented. The analysis shows that the heteroexchange rates for two substrates interacting with the transporter are not unique and can be calculated from the kinetic parameters for each sugar acting alone with the transporter. This means that the equations for substrate analogue inhibition of the transport of a low affinity substrate such as D-allose can be simplified. It is shown that for the single gate transporter the Ki for a substrate analogue inhibitor should equal the equilibrium exchange Km for this analogue. (3) Analogues substituted at C-1 show a fused pyranose ring is accepted by the transporter. 1-Deoxy-D-glucose is transported but has low affinity for the transporter. High affinity can be restored by replacing a fluorine in the beta-position at C-1. The Ki for D-glucose = 8.62 mM; the Ki for beta-fluoro-D-glucose = 6.87 mM. Replacing the ring oxygen also results in a marked reduction in affinity. The Ki for 5-thio-D-glucose = 42.1 mM. (4) A hydroxyl in the gluco configuration at C-2 is not required as 2-deoxy-D-galactose (Ki = 20.75 mM) has a slightly higher affinity than D-galactose (Ki = 24.49 mM). A hydroxyl in the manno configuration at C-2 interferes with transport as D-talose (Ki = 35.4 mM) has a lower affinity than D-galactose. (5) D-Allose (Km = 271.3 mM) and 3-deoxy-D-glucose (Ki = 40.31 mM) have low affinity but high affinity is restored by substituting a fluorine in the gluco configuration at C-3. The Ki for 3-fluoro-D-glucose = 7.97 mM. (6) Analogues modified at C-4 and C-6 do not show large losses in affinity. However, 6-deoxy-D-glucose (Ki = 11.08 mM) has lower affinity than D-glucose and 6-deoxy-D-galactose (Ki = 33.97 mM) has lower affinity than D-galactose. Fluorine solution at C-6 of D-galactose restores high affinity. The Ki for 6-fluoro-D-galactose = 6.67 mM. Removal of the C-5 hydroxymethyl group results in a large affinity loss. The Ki for D-xylose = 45.5 mM. The Ki for L-arabinose = 49.69 mM. (7) These results indicate that the important hydrogen bonding positions involved in sugar interaction with the insulin-stimulated adipocytes transporter are the ring oxygen, C-1 and C-3. There may be a weaker hydrogen bond to C-6. Sugar hydroxyls in non-gluco configurations may sterically hinder transport.

Photolabelling of the hexose transporter at external and internal sites: fragmentation patterns and evidence for a conformational change.

The human erythrocyte sugar transporter has been labelled at its internal site with cytochalasin B and at its outside site by the azidosalicoyl derivative of bis(D-mannose) (ASA-BMPA). The cleavage of the transporter by various proteinases has been studied. Chymotrypsin, subtilisin and V8 proteinase give parallel fragmentation patterns for the two labels down to fragments as small as 7 kDa. Thus the binding sites for the two labels can only be separated by a small span of protein. 2-Nitro-5-thiocyanobenzoic acid (NTCB) cleaves at cysteines to give a 15 kDa fragment from the two labels. N-Bromosuccinimide (a reagent which preferentially cleaves at tryptophan residues) has revealed differences in fragmentation of the transporter labelled with either cytochalasin B or with ASA-BMPA. A major cleavage site is proposed to occur at tryptophan 186 which leaves a C-terminal fragment containing both labels. A tryptophan cleavage at residue 388 divides the cytochalasin B site and the ASA-BMPA site. A further tryptophan cleavage gives a cytochalasin B labelled 3 kDa fragment probably from residues 388-412. This gives an assignment of the cytochalasin B site as the inside of the hydrophobic span H 10. Since the ASA-BMPA site is probably only 7 kDa from residue 388 and is on the same 15 kDa NTCB fragment as cytochalasin B we assign this to the outside of hydrophobic span H 9. Thermolysin only cleaves the transporter labelled with cytochalasin B and not with ASA-BMPA. A 18 kDa cytochalasin B labelled fragment is formed. This is indicative of a change in conformation of the transporter when an outside ligand is bound such that the inside of the hydrogen bonding transmembrane segments H 7 and H 8 (and containing the proposed thermolysin cleavage site) are withdrawn from the cytosolic surface. Thus it appears that the core of the transporter (including the external and internal sites plus the transmembrane channel) is located between segments H 7 and H 10.

Identification of a Na+,K+, Cl--cotransport protein of Mr 34 000 from kidney by photolabeling with [3H]bumethanide. The protein is associated with cytoskeleton components.

A polypeptide of Mr 34 000 is photolabeled with [3H]bumethanide after binding of this drug to membranes from the outer renal medulla and irradiation at 345 nm, a wavelength where bumethanide has an absorption maximum. Our data show that the polypeptide of Mr 34 000 is a component of the Na+/K+/Cl--cotransport system. The [3H]bumethanide binding protein is not extracted by concentrations of the nonionic detergent C12E8 that solubilizes 67% of the protein of the membranes including (Na+ + K+)-ATPase. This step increases the capacity for binding of [3H]bumethanide to 681 pmol/mg protein. Extraction of the binding protein requires high ionic strength suggesting that the Na+/K+/Cl--cotransport protein is associated with cytoskeleton components. This association may be important for control of the entry of NaCl into the cytoplasm and for cellular regulation of the rate of active transport of NaCl across the tubule cells in the thick ascending limb of Henles loop.

The fate of labelled glucose molecules in the rat adipocyte. Dependence on glucose concentration.

Isolated rat adipocytes were incubated with 15 nM [3-3H]glucose or 100 nM [U-14C]glucose with or without insulin and in the absence or presence of unlabelled glucose. Following a 2 h incubation with 15 nM [3-3H]glucose, about two thirds of the cell-associated 3H-labelled metabolic products were hydrophilic largely anionic intermediates and about one third was lipids. The equivalent values were 40 and 60%, respectively, when using 100 nM [U-14C]glucose. The only 14C-labelled metabolite escaping to the incubation medium was 14CO2, which accounted for about 15% of the rate of metabolism. Therefore, the rate of incorporation of 100 nM [U-14C]glucose into the cell-associated metabolites was quite a good measure of its net influx rate. The conversion of the two tracers to the sum of the metabolic products in cells treated with a maximally stimulating insulin concentration remained constant with glucose concentrations up to about 100 microM and then decreased progressively. The incorporation of radioactivity into the different metabolites varied markedly over the glucose concentration range 0-100 microM, presumably due to the saturation of different metabolic pools at different glucose concentrations. This variation was much less in cells not stimulated with insulin. Consequently, the maximal effect of insulin on the incorporation of the tracers into a given metabolite (e.g., labelled lipids) varied over the entire glucose concentration range. In addition, the apparent sensitivity (ED50) with respect to the incorporation into a given metabolite was also dependent on the glucose concentration.

The expression of Escherichia coli diaminopimelate decarboxylase in mouse 3T3 cells.

We have subcloned the coding sequence for the Escherichia coli lysA gene coding for diaminopimelic acid decarboxylase (DAP decarboxylase) into a eukaryotic expression vector based on the SV40 early promoter. The activities of a series of constructs with different lengths of non-coding DNA at the 5' and 3' ends of the coding region have been compared by measuring the synthesis of lysine from diaminopimelic acid (DAP) in mouse 3T3 cells. A short non-coding sequence at the 3' end reduced the expression of enzyme activity. Stable lines of 3T3 cells have been produced by co-transfection of the chimeric gene with a plasmid coding for G-418 resistance. Cells were grown in medium containing G-418 and resistant clones were screened for an ability to synthesise lysine from DAP. [3H]Lysine produced from [3H]DAP was incorporated into cell proteins. An enzyme extract from a cell line which had incorporated two copies of the gene synthesised 0.082 nmol of lysine/min per mg protein. In the intact cell the rate of lysine synthesis is limited by the uptake of DAP which is taken up at only 5% of the rate of lysine. lysA has a potential as a reporter gene in studies of gene expression in mammalian cells.

Evidence for negative cooperativity in human erythrocyte sugar transport.

1. When D-glucose exchange influx is measure over a wide range of concentrations then two affinity constants (2.27 and 26.0 mM) are evident. This is consistent with a transport model (the allosteric pore model) in which there is negative cooperativity between subunits of the transport protein. 2. The equations for the allosteric pore model interacting with two substrates (or a substrate and an inhibitor) have been derived and have been used to analyse data from exchange inhibition and for mixed infinite-trans uptake experiments. 3. The exchange inhibition of tracer 3-O-methyl-D-glucose, D-xylose and D-fructose uptake by D-glucose also shows evidence for negative cooperativity and for two inhibition constants which are approximately equal to the D-glucose equilibrium exchange affinity constants. 4. The uptake of D-glucose into infinite-trans D-glucose or 3-O-methyl-D-glucose gives Km values of 2.6 and 2.33 mM, respectively. The uptake of 3-O-methyl-D-glucose into infinite-trans D-glucose or 3-O-methyl-D-glucose gives Km values of 6.0 and 4.6 mM, respectively. V values are slightly higher when the internal sugar is 3-O-methyl-D-glucose. 5. In cells that are treated with fluorodinitrobenzene the apparent Ki value for D-glucose inhibition of tracer D-fructose uptake is lowered. It is proposed that this is due to a partially selective effect of FDNB on the internal subunit interface stability constant (the internal pore gate).

The effect of catecholamines and adenosine deaminase on the glucose transport system in rat adipocytes.

2-Deoxyglucose uptake (3 min) and 3-O-methylglucose transport (2 s) was measured in rat adipocytes preincubated with 5 microM epinephrine plus adenosine deaminase as described by Green (Green, A. (1983) FEBS Lett. 152, 261-264). 2-Deoxyglucose uptake was about 95% depressed in insulin-treated, but not in 'basal', cells preincubated with epinephrine plus adenosine deaminase for 60 min in broad agreement with Green's report. However, this depression was caused by a decrease in sugar phosphorylation rather than transport. In similarly incubated cells, transport of 3-O-methylglucose, a sugar analogue not phosphorylated in the adipocytes, was not affected by catecholamine plus adenosine deaminase. However, a decrease in transport of about 60% was observed both in the absence and the presence of insulin when the albumin concentration was high enough and the cell concentration low enough to prevent accumulation of free fatty acids in the medium. In addition, the insulin sensitivity with regard to hexose transport was markedly reduced. Transport was approximately doubled in cells incubated with 5 microM epinephrine in the absence of adenosine deaminase. Thus, epinephrine at a high concentration stimulates hexose transport in the absence of adenosine deaminase (presence of adenosine) whereas it inhibits both basal and insulin-stimulated transport in the presence of adenosine deaminase (absence of adenosine).

Binding of cytochalasin B to trypsin and thermolysin fragments of the human erythrocyte hexose transporter.

The cleavage of the human erythrocyte hexose transporter by the proteinases trypsin and thermolysin has been studied. When red cell membranes are treated with trypsin, washed and then photolabelled with cytochalasin B, a labelled peak at 18 kDa is obtained. This labelling of the cleaved transporter is D-glucose inhibitable. This probably indicates that the residual 36 kDa portion of the transporter is not required for binding of ligands. Extensive cleavage of the transporter with low concentrations of thermolysin only occurs when transporter is prelabelled with cytochalasin B. This indicates that covalently bound cytochalasin B can cause a conformational change which exposes the thermolysin cleavage site.

Mechanisms of gastroduodenal protection by sucralfate.

Over the past 5-10 years, a number of studies have shown that topical sucralfate enhances a number of gastric and duodenal mechanisms, e.g., the "mucus-bicarbonate barrier," mucosal hydrophobicity, mucosal blood flow, cell viability, and local production of prostaglandins, as well as endogenous mediators of tissue injury and repair. It seems likely that the complex actions of sucralfate are in part related to direct interaction between the drug or its components (aluminum, sucrose, and sulfate) and gastric mucosal tissues, and in part related to effects of the drug on the various mucosal mediators of tissue injury and repair. Local actions may play a role in accelerating healing of ulcer-damaged mucosa, but this does not explain the protective actions of sucralfate on normal mucosa. Thus sucralfate appears to enhance the protective function of the "mucus-bicarbonate" barrier by actions on both components. This may depend in part on an interaction with the unstirred layer overlying gastric epithelium. Sucralfate has also been shown to increase the hydrophobicity of mucus gel. There is little doubt that sucralfate increases local production and release of protective prostaglandins (PGs), but the precise role played by these agents in mediating mucosal protection and in chronic ulcer healing remains uncertain. Currently, the mechanism of action of sucralfate on vascular integrity remains unknown and the role of PGs in this protective function is unclear. There is little evidence that epidermal growth factor plays any role in mediating mucosal protection by sucralfate, but it may be important in its ulcer-healing action. Sucralfate has been shown to be truly "cytoprotective" in that it protects isolated epithelial cells from damage by noxious agents. In animals treated with sucralfate, the surface epithelial cells were disrupted, but necrotic lesions in the deep proliferative zone were virtually absent. It seems likely that investigations of the actions of sucralfate and its components will move ever closer to defining the target cells, the intracellular events, and the mediators that bring about its protective and ulcer-healing activity.

Overview of gastroduodenal mucosal protection.

The ability of the gastric mucosa to resist autodigestion has been recognized for over 200 years. Since these early observations, several components of gastroduodenal defense against injury from damaging luminal contents have been identified. The first line of defense is the thick layer of mucus gel into which bicarbonate is secreted by the underlying epithelial cells. The "mucus-bicarbonate" barrier sustains a pH gradient between the lumen and cell surface such that epithelial cells are maintained at pH 7 to 8, despite the presence of intraluminal acid. The epithelial cells form a second line of defense; since the pH gradient may be overwhelmed by physiologic concentrations of intraluminal acid, this mechanism may be important in maintaining mucosal integrity. The physical properties of the apical cell membrane and intercellular junctions and the presence of surface-active phospholipids on the membrane may be responsible for preventing hydrogen ions (H+) from diffusing into the mucosa by providing a physical barrier to their movement. Furthermore, epithelial cells are capable of rapid turnover and migration and may breach a defect in the epithelium within hours. The aftermath of mucosal damage may generate a further defense mechanism: a thick layer of mucus containing sloughed epithelial cells together with passive movement of bicarbonate-rich fluid from the damaged mucosa. This may prevent exposure of undamaged cell nests to acid and thus aid re-epithelialization. Finally, mucosal blood flow plays a vital role in maintaining epithelial integrity. Studies have shown that increasing or decreasing mucosal blood flow will, respectively, reduce or enhance susceptibility to damage. Although the precise physiologic control mechanisms for mucosal protection have not been defined, there is evidence that local endogenous prostaglandin metabolism may play an important role [4]. The release of neurotransmitters and hormones may also contribute to or modulate the defense mechanisms.

Effect of sucralfate on human gastric bicarbonate secretion and local prostaglandin E2 metabolism.

The protective and ulcer-healing properties of sucralfate on gastroduodenal mucosa are well established. In this study, the possible mode of action of sucralfate in humans has been explored by examining its effect on gastric bicarbonate secretion and luminal prostaglandin E2 (PGE2) output from the intact stomach. The gastric output of bicarbonate and PGE2 has been calculated using a perfusion technique before, during, and after perfusion with sucralfate (8 mg/ml) in eight healthy volunteers. A significant increase in bicarbonate output occurred during the period of sucralfate perfusion returning to basal values during the post-sucralfate period. Pretreatment with indomethacin (25 mg/hour) failed to influence this secretory response. Luminal PGE2 output was significantly increased in the post-sucralfate perfusion period only. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in concentrations of bicarbonate and PGE2. These results suggest that stimulation of gastric bicarbonate secretion and PGE2 output by sucralfate may play a role in its protective actions.

Review article: factors protecting the oesophagus against acid-mediated injury.

Reflux of gastric acid and pepsins into the lower oesophagus causes symptoms such as heartburn and nausea, and tissue injury leading to erosive oesophagitis and stricture formation. This article reviews the mechanisms involved in protecting the oesophagus against acid-mediated injury, including the role of the lower oesophageal sphincter, secondary oesophageal peristalsis and swallowed saliva. The oesophageal mucosa has inherent abilities to resist acid damage, and recent data from three laboratories suggest a secretory function with local production of bicarbonate and mucus responsive to local acidification. The evidence for these putative oesophageal defence mechanisms is discussed.

Gastric mucosal injury and adaptation to oral and rectal administration of naproxen.

INTRODUCTION: Oral nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute gastric mucosal injury but the relative importance of systemic and topical effect of NSAIDs to overall gastric damage remains uncertain. METHODS: Twenty-four healthy volunteers were allocated either oral or rectal naproxen 500 mg b.d. and gastroscoped before and during days 1, 7 and 28 of dosing. Macroscopic gastric damage was assessed using a modified Lanza score, mucosal blood flow recorded using laser Doppler flowmetry and prostaglandin E2 (PGE2) measured in antral mucosal biopsies. RESULTS: Maximal gastric damage occurred during the first 24 h in the oral naproxen group and was associated with a fall in antral mucosal blood flow (mean +/- S.E.M.) from 58.2 +/- 3.3 to 46.6 +/- 4.1 arbitrary units (a.u.) (P < 0.05). With continued administration of oral naproxen, gastric damage resolved and antral mucosal blood flow returned to baseline (54.2 +/- 3.7 a.u.). No macroscopic damage or significant changes in mucosal blood flow were observed during rectal administration. There was no significant difference between mucosal PGE2 concentrations in those receiving oral or rectal naproxen, falling from an initial level of 335 +/- 29 to 155 +/- 49 pg/mg at day 1 (P = 0.06) in those receiving oral naproxen and from 235 +/- 55 to 107 +/- 31 pg/mg at day 1 (P = 0.1) in those receiving rectal naproxen, and remaining suppressed throughout the study in both groups. CONCLUSIONS: These observations suggest that acute mucosal damage and changes in mucosal blood flow are caused by the topical rather than systemic actions of naproxen.

The influence of age, gender, Helicobacter pylori and smoking on gastric mucosal adaptation to non-steroidal anti-inflammatory drugs.

INTRODUCTION: Oral NSAIDs cause acute gastric injury that resolves, despite continued administration, by a process known as adaptation. Little is known about the factors that influence this process. METHODS: Sixty-two healthy volunteers were given a 28-day course of either etodolac 300 mg b.d. (13 subjects), naproxen 500 mg b.d. (23), enteric-coated diclofenac (10) or effervescent diclofenac 50 mg b.d. (16). All subjects were gastroscoped before and on days 1, 7 and 28 during drug administration, to assess gastric mucosal damage using a modified Lanza scale. Subjects were then divided into three categories: those who adapted completely, those who adapted incompletely and those who showed no adaptation. The proportion of subjects in each group was compared with respect to age, gender, smoking, the presence of Helicobacter pylori, and the NSAID prescribed. RESULTS: Fifty-nine subjects (median age 25.0 years, range 18-70) developed initial gastric injury to NSAIDs of whom 42 adapted completely, 13 adapted incompletely and four showed no evidence of adaptation. The mean age of subjects was lower in those who adapted (26.8 +/- 9.8 years) than those who adapted incompletely (32.5 +/- 10.3 years) and those who did not adapt (42.0 +/- 15.7 years, P = 0.01). There was no evidence of gender influencing adaptation. Of 17 H. pylori-positive subjects, a higher proportion had incomplete adaptation, with only nine subjects adapting completely (53% vs. 81%, P = 0.04). Sixteen subjects were smokers, of whom a greater proportion showed no evidence of adaptation (19% vs. 2%, P = 0.03). A smaller proportion of those who took naproxen (48%) adapted completely than those who took enteric-coated diclofenac (89%), effervescent diclofenac (75%) or etodolac (91%, P = 0.03). CONCLUSION: Some adaptation occurred in over 90% of subjects after 4 weeks dosing with an NSAID, but adaptation was less frequent in older subjects and in smokers. Complete adaptation occurred less frequently in H. pylori-positive subjects and in those who were given naproxen.

Gastric mucosal adaptation to etodolac and naproxen.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently cause damage to the gastroduodenal mucosa, principally by suppressing mucosal prostaglandin synthesis. However, such acute mucosal injury usually resolves, despite continued NSAID administration, by a process known as adaptation. Newer NSAIDs, such as etodolac, have been developed to minimize effects on prostaglandin synthesis. AIM: To determine whether etodolac causes less acute damage than naproxen, and whether the damage produced resolves with continued NSAID administration. METHODS: Twenty-four healthy volunteers were given a 28-day course of either etodolac 300 mg b.d. or naproxen 500 mg b.d. Gastroduodenal damage was assessed using a modified Lanza scoring system and mucosal blood flow with laser doppler flowmetry at endoscopy before NSAID administration and during days 1, 7 and 28 of continued intake. RESULTS: Maximum gastric damage (median grade and interquartile range, IQR) occurred during the first 24 h of administration, being greater with naproxen (2.0, IQR 1.0-3.0) than etodolac (1.0, IQR 1.0-1.5; P = 0.03). Such damage was associated with a fall in antral blood flow in the naproxen group (mean +/- S.E.M.) from 54.5 +/- 3.4 to 43.8 +/- 3.4 arbitrary units (P = 0.07) and a slight increase in mucosal blood flow in the etodolac group from 43.5 +/- 2.24 to 49.5 +/- 3.6 arbitrary units. With continued intake this damage resolved in all subjects taking etodolac and in eight of 14 subjects on naproxen. Resolution in the naproxen group was associated with a return to normal of antral blood flow. CONCLUSIONS: These observations suggest that etodolac causes less mucosal damage than naproxen and that adaptation occurs to both.

The use of percutaneous endoscopic gastrostomy (PEG) feeding tubes in patients with neurological disease.

Percutaneous endoscopic gastrostomy (PEG) is being used increasingly in the treatment of patients with neurogenic dysphagia to improve nutrition and prevent choking and aspiration pneumonia. PEG is used in a wide range of general medical conditions, but its role in clinical neurology is sometimes controversial. This paper reviews the place of PEG in the management of 32 patients with a variety of chronic and progressive neurological disorders. All the patients found it to be an effective and acceptable method of feeding that prevented weight loss, reduced chest infections, facilitated nursing care and improved their quality of life. PEG has an important role in neurological rehabilitation.

Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.

Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.

Opioid needs of terminal care patients: variations with age and primary site.

The records of 1383, terminal cancer patients have been reviewed to determine whether opioid requirements vary in a consistent pattern with age and with site of primary cancer. Opioid requirements are shown to decrease with age in a regular pattern and from early adult life. Opioid requirements also differ significantly with site of primary cancer and there appears to be a discernible pattern of opioid need for different cancers. Patients with sexually related cancer have the highest opioid requirements, irrespective of sex. When the sexually determined cancers are excluded, the analgesic needs of men and women are not significantly different (P = 0.191).