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PubMed1966

Episome-mediated Transfer of Drug Resistance in Enterobacteriaceae X. Restriction and Modification of Phages by fi R Factors.

Watanabe, Tsutomu (Keio University, Tokyo, Japan), Toshiya Takano, Toshihiko Arai, Hiroshi Nishida, and Sachiko Sato. Episome-mediated transfer of drug resistance in Enterobacteriaceae. X. Restriction and modification of phages by fi(-) R factors. J. Bacteriol. 92:477-486. 1966.-An fi(-) R factor, which restricts phages lambda, T1, and T7 without modifying them, was found to restrict and not to modify an F(-)-specific phage, W-31, in Escherichia coli K-12, but not to restrict phage P-22 in Salmonella typhimurium LT-2, whereas other fi(-) R factors restricted and modified P-22 but not W-31; fi(+) R factors did not restrict these phages. Transduction and lysogenization with phages lambda and P-22 were reduced by these fi(-) R factors in K-12 and LT-2, respectively, and the transducing phages lambda and P-22 were modified by these fi(-) R factors. Spontaneous as well as ultraviolet-induced production of phage P-22 and zygotic induction of phage lambda were not significantly affected by any R factor. Injection of the nucleic acids of phages T1 and lambda was not affected by R factors, but the injected phage nucleic acids were rapidly broken down in the bacteria carrying fi(-) R factors. The nucleic acids of the modified phages were not broken down in these bacteria. It was assumed from these results that the mechanism of restriction of phages by fi(-) R factors is due to the breakdown of the injected phage nucleic acids by a deoxyribonuclease(s), presumably located near the cell surface in the cells carrying fi(-) R factors. The deoxyribonuclease(s), formed in the cells carrying the nonmodifying fi(-) R factor, is considered to be different from that synthesized in the cells carrying the modifying fi(-) R factors. It was further shown that the average burst sizes of the unmodified as well as modified phages are slightly reduced by the presence of the fi(-) R factors.

Journal Article↗

PubMed1981

Requirement for protein synthesis for survival of unmodified bacteriophage T1 in a restricting host.

At high multiplication of infection, a substantial fraction of restricting cells (P1 lysogens) could be productively infected by unmodified coliphage T1 (T1.0) provided that protein synthesis was uninhibited during the first 5 min of infection. Successful infection under restricting conditions was accompanied by more genetic recombination than was seen under nonrestricting host, the recombination frequency declined for markers on T1.0 genomes; no effect was seen on recombination between markers on modified (T1.P) genomes. This suggested that recombination between unmodified genomes may be essential for their survival under conditions of host restriction. In a restricting host, genetic markers on T1.0 could recombine with T1.P even when the rescuing phage was added 6 min after T1.0 infection. However, even marker rescue recombination was diminished when protein synthesis was inhibited during early infection. Since DNA restriction is an early event, protein synthesis may be required soon after infection of a restricting host by T1.0 in order to preserve restriction-damaged DNA in a form that can participate in recombination. Experiments are also described that rule out some possibilities for the role of such a protein(s).

Chloramphenicol↗

PubMed2004

Binding and susceptibility to postentry restriction factors in monkey cells are specified by distinct regions of the human immunodeficiency virus type 1 capsid.

In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIV(mac) is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIV(mac) capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIV(mac) capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).

Amino Acid Sequence↗

PubMed2001

Potential benefits of restrictions on the transport of teenage passengers by 16 and 17 year old drivers.

OBJECTIVES: The presence of passengers is associated with fatal motor vehicle crashes of teenage drivers. A restriction against newly licensed teenage drivers carrying passengers has been included in some, but not all, graduated licensing systems. The purpose of this study was to predict the net effects on all types of road users, including vehicle occupants and non-occupants, of possible prohibitions against 16-17 year old drivers carrying passengers. METHODS: Two national datasets, a census of fatal crashes and a sample of trips in the United States, were used to compute 1995 road user death rates. Potential effects of restrictions on drivers ages 16-17 carrying passengers younger than 20 were estimated, based on road user death rates and potential choices made by passengers who would have traveled with 16-17 year old drivers if there were no restrictions. RESULTS: There were 1,181 road user deaths in 1995 involving drivers ages 16-17 whose passengers were all younger than age 20. The predicted number of lives in the United States that would be saved annually ranges from 83 to 493 (corresponding to reductions of 7-42% in road user deaths) for drivers ages 16 and 17 combined. Similar percentages of reductions (8-44%) were predicted solely for 16 year old drivers. Assuming passenger restrictions would apply to all 16 year old drivers and at least one third of 17 year old drivers, an estimated 60-344 fewer deaths per year may occur if restrictions are mandated. CONCLUSIONS: Restrictions on carrying passengers younger than 20 should be considered for inclusion in graduated licensing systems. Even if fewer than half the drivers obey the restrictions, a substantial reduction in road user deaths would be expected. Further evaluation based on real world experience is needed to confirm their efficacy.

Accidents, Traffic↗

PubMed1986

Plasma lipids and other factors in the LA/N corpulent rat in the presence of chronic exercise and food restriction.

The effects of regular exercise and food restriction were studied in the LA/N corpulent rat up to age 9 months. This congenic strain of the Lister and Albany rat is normotensive, corpulent, and hyperlipidemic when homozygous for the corpulent (cp) gene derived from the Koletsky strain. Food restriction of corpulent animals to the intake of matched lean rats caused body weight to be significantly lower, although not as low as that of the lean animals. Plasma total cholesterol in freely eating sedentary corpulent animals was significantly higher (210 mg/100 mL) than in food-restricted rats (165 mg/100 mL), in which plasma cholesterol was considerably elevated compared with lean rats (80 mg/100 mL). Exercise caused a modest but significant increase in both total and high density lipoprotein cholesterol in both corpulent and lean rats. The rise was greater in corpulent rats and, in food-restricted exercising corpulent rats, the cholesterol concentrations were equivalent to those of freely eating corpulent animals. Systolic blood pressure in lean rats fell slowly from 146 mmHg at 8 weeks to 132 mmHg at 36 weeks and was not affected by exercise. Sedentary corpulent rats showed a rapid rise in systolic pressure from 107 mmHg at 7 weeks to 128 mmHg at 11 weeks. This rise was reduced by food restriction and completely prevented by the combination of food restriction and exercise. Thus, in this strain of rats exercise was associated with higher plasma cholesterol concentrations, while food restriction had limited effects.

Animals↗

PubMed1992

Diabetic type of cardiomyopathy in food-restricted rats.

We have demonstrated that food restriction that is associated with weight loss can produce a type of cardiac dysfunction similar to that produced by diabetes. As in diabetic atria, the food-restricted atria had a 2-fold increase in contraction force, rate of force development, and rate of force decline compared with controls. Both food-restricted and diabetic atria could tolerate anoxia better than controls. The contractile function of the whole perfused heart from the food-restricted rat was reduced, as in the case of the diabetic heart. As the left ventricular volume was increased, the left ventricular developed pressure and the rate of rise and fall in pressure were significantly reduced in both food-restricted and diabetic hearts, compared with those of age- and weight-matched controls. The positive inotropic responses of atria and whole perfused heart to increasing concentrations of extracellular calcium were similarly altered in food-restricted and diabetic hearts. The possible molecular mechanisms of these findings and some of the differences observed between food-restricted and diabetic hearts are discussed.

Adenosine Triphosphate↗

PubMed1988

Food restriction modulates beta-adrenergic-sensitive adenylate cyclase in rat liver during aging.

Adenylate cyclase activities were studied in rat liver during post-maturational aging of male Fischer 344 rats fed ad libitum or restricted to 60% of the ad libitum intake. Catecholamine (10(-5) M epinephrine, isoproterenol, or norepinephrine)-stimulated adenylate cyclase activity increased by 200-300% between 6 and 24-27 mo of age in ad libitum-fed rats, whereas in food-restricted rats catecholamine response increased by only 58-84% between 6 and 30 mo. In ad libitum-fed rats, glucagon (10(-5) M)-stimulated enzyme activity also increased by 40% between 6 and 12 mo and in restricted rats a similar age-related increase was delayed until 18 mo. beta-Adrenergic receptor density (Bmax, determined from saturation binding of the beta-adrenergic antagonist l-[125I]iodopindolol) increased by 50% between 6 and 24 mo in livers from ad libitum-fed but not food-restricted rats and showed a highly significant correlation with maximal isoproterenol-stimulated adenylate cyclase activity over the post-maturational life span. Age-related increases in unstimulated (basal) adenylate cyclase activity and nonreceptor-mediated enzyme activation (by guanine nucleotides, fluoride, and to a lesser extent forskolin) were retarded by food restriction. The results demonstrate that food restriction diminishes a marked age-related increase in beta-adrenergic-sensitive adenylate cyclase activity of rat liver. Alterations of adrenergic-responsive adenylate cyclase with age and the modulatory effects of food restriction appear to be mediated by changes in both receptor and nonreceptor components of adenylate cyclase.

Adenylyl Cyclases↗

PubMed1994

Regional variations in metabolic responses of white adipose tissue to food restriction.

The effects of food restriction (limited access to food for 2 h/day for 10 days) on lipoprotein lipase (LPL) activities and rates of fatty acid synthesis and glucose utilization in vivo in two superficial (interscapular and subcutaneous) and three deep abdominal white adipose tissue depots (parametrial, perirenal, and mesenteric) of adult female Wistar rats were examined before and at 2 h after a standard laboratory diet meal (5 g). Fasting LPL activities in perirenal (1.6-fold), mesenteric (5.9-fold), and subcutaneous (2.7-fold) adipose tissue, when expressed per unit of delipidated tissue, were increased in response to food restriction. This effect was retained (but not enhanced) after the meal. In contrast, muscle LPL activities were either unchanged or suppressed by food restriction. Stimulation of adipose tissue fatty acid synthesis and glucose utilization evoked by feeding in control rats was greatly enhanced by prior food restriction. There was no relationship between anatomical location and presence or absence of the response of adipose tissue LPL activity to food restriction, but the effect of food restriction to enhance the responses of fatty acid synthesis and glucose utilization to a meal was more marked in perirenal and parametrial adipose tissue than in the more superficial depots. The results thus demonstrate regional specificity in the response of adipose tissue functions to food restriction.

Adipose Tissue↗

PubMed2004

Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats.

In response to reduced oxygen or nutrient supply, the fetus may redistribute cardiac output to conserve brain and heart growth, at the expense of the peripheral tissues; however, it is not known whether alterations in vascular function are maintained after birth or whether reduced fetal oxygen versus nutrient supply produces distinct effects. Using a pressure myograph, we examined isolated carotid and femoral artery responses to phenylephrine and endothelin-1 in neonatal rats, after either reduced maternal oxygen or global nutrient restriction during late gestation. Timed-pregnant Sprague-Dawley rats were randomly assigned to control (n = 10), hypoxia (12% O2, n = 9), or nutrient restriction (NR, 40% of control diet, n = 7) protocol and treated from day 15-21 of pregnancy. Pups were collected 3-12 h after birth. Neonatal weights (P < 0.001) and relative liver weights (P < 0.001) were lower in hypoxia and nutrient restriction treatments compared with control, while relative heart weights were greater in the hypoxia than in the control or nutrient restriction groups (P < 0.01). Constriction to phenylephrine was reduced in carotid arteries from the hypoxia and nutrient restriction groups compared with control (P < 0.001), while the femoral artery response was greater in hypoxia-treated neonates compared with control or nutrient-restricted neonates (P < 0.01). Only the hypoxia reduced carotid responses to endothelin-1, while no differences were observed in the endothelin-1 responses in femoral arteries. Maternal hypoxia and maternal nutrient restriction produced distinct effects on heart growth and neonatal vascular function, suggesting that regional changes in cardiovascular function after poor fetal growth are dependent on the nature of the insult in utero.

Animals↗

PubMed2004

Chronic maternal feed restriction impairs growth but increases adiposity of the fetal guinea pig.

Small size at birth has been associated with an increased risk of central obesity and reduced lean body mass in adult life. This study investigated the time of onset of prenatally induced obesity, which occurs after maternal feed restriction, in the guinea pig, a species that, like the human, develops substantial adipose tissue stores before birth. We examined the effect of maternal feed restriction [70% ad libitum intake from 4 wk before to midpregnancy, then 90% until day 60 gestation (term approximately 69 days)] on fetal growth and body composition in the guinea pig. Maternal feed restriction reduced fetal (-39%) and placental (-30%) weight at 60 days gestation and reduced liver, biceps muscle, spleen, and thymus weights, relative to fetal weight, while relative weights of brain, lungs, and interscapular and retroperitoneal fat pads were increased. In the interscapular depot, maternal feed restriction decreased the volume density of multilocular fat and increased that of unilocular fat, resulting in an increased relative weight of interscapular unilocular fat. Maternal feed restriction did not alter the relative weight of perirenal fat or the volume density of adipocyte populations within the depot but increased unilocular lipid locule size. Maternal feed restriction in the guinea pig is associated with decreased weight of major organs, including liver and skeletal muscle, but increased adiposity of the fetus, with relative sparing of unilocular adipose tissue. If this early-onset obesity persists, it may contribute to the metabolic and cardiovascular dysfunction that these offspring of feed-restricted mothers develop as adults.

Adipose Tissue↗

PubMed1996

Chronic food restriction and acute food deprivation decrease mRNA levels of opioid peptides in arcuate nucleus.

Although opioid administration induces food intake, the relationship between endogenous opioid synthesis and food consumption is unclear. Two studies examined the effects of food restriction and deprivation on opioid mRNA levels in the arcuate nucleus (ARC) of the rat. Body weight significantly decreased following food restriction and deprivation (P < 0.0001). In experiment 1, food restriction of 10,20,30, and 40% (g) of ad libitum intake for 14 days decreased proDynorphin (proDyn), proEnkephalin (proEnk), and proOpiomelanocortin (POMC) mRNA levels in a linear fashion relative to changes in body weight (r = 0.398, P = 0.0011; r = 0.455, P = 0.0028; r = 0.292, P = 0.0642, respectively). In experiment 2, 48 h deprivation significantly decreased mRNA levels of proDyn and POMC by 23.7% (P < 0.05) and 45.6% (P < 0.01), respectively, whereas 24 h food deprivation decreased POMC mRNA by 43.% (P < 0.01). proEnk mRNA was not affected by 24- or 48-h food deprivation. Restricting food intake suppressed mRNA levels of proDyn, proEnk, and POMC by 29.7, 22.3, and 44.4%, respectively, in 20% restricted rats and by 35.5, 26.8, and 45.6%, respectively, in 40%restricted rats (P < 0.01). It appears that ARC mRNA levels of proDyn, proEnk, and POMC are directly related to the amount of food consumed and/or changes in body weight in food-restricted and food-deprived rats.

Animals↗

PubMed2001

Food restriction prevents age-related polyuria by vasopressin-dependent recruitment of aquaporin-2.

The mechanisms underlying the prevention of age-related polyuria by chronic food restriction were investigated in female WAG/Rij rats. The decreased osmolality of renal papilla observed in senescent rats was not corrected by food restriction. A reduced urea content in the inner medulla of senescent rats, fed ad libitum or food-restricted, was suggested by the marked decrease in expression of UT-A1 and UT-B1 urea transporters. Aquaporin-2 (AQP2) downregulation in the inner medulla of senescent rats was partially prevented by food restriction. Both AQP2 and the phosphorylated form of AQP2 (p-AQP2), the presence of which was diffuse within the cytoplasm of collecting duct principal cells in normally fed senescent rats, were preferentially targeted at the apical region of the cells in food-restricted senescent animals. Plasma vasopressin (AVP) was similar in 10- and 30-mo-old rats fed ad libitum, but was doubled in food-restricted 30-mo-old rats. This study indicates that 1) kidney aging is associated with a marked decrease in AQP2, UT-A1, and UT-B1 expression in the inner medulla and a reduced papillary osmolality; and 2) the prevention of age-related polyuria by chronic food restriction occurs through an improved recruitment of AQP2 and p-AQP2 to the apical membrane in inner medulla principal cells, permitted by increased plasma AVP concentration.

Aging↗

PubMed1998

Regional time-dependent changes in vasopressin V2 receptor expression in the rat kidney during water restriction.

Elevations of arginine vasopressin (AVP) binding to renal vasopressin V2 receptors (V2R) enhance water and urea reabsorption in the collecting duct epithelium. This study was designed to quantify the levels of V2R mRNA and protein within the distinct regions of the Sprague-Dawley rat kidney (i.e., the cortex and outer and inner medulla) during 24 and 48 h of water restriction. A competitive reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to quantify changes in the V2R mRNA, in which a deletion mutant RNA transcript was used to control for the efficiency of RT-PCR. Western blot analysis was utilized for the quantification of the V2R protein. The results showed that the steady-state levels of the V2R mRNA decreased in a time-dependent manner in the cortex and outer and inner medulla throughout 48 h of water restriction. Western blot analysis revealed that the V2R protein in the renal cortex decreased after the initial 24 h of water restriction and remained decreased at 48 h. In contrast, outer medullary V2R protein decreased significantly only after 48 h of water restriction, whereas no significant change in the inner medullary V2R protein was observed throughout the 48 h of water restriction. These results suggest that water restriction leads to a regional time-dependent downregulation of the V2R mRNA and protein within the rat kidney. The stability of the plasma membrane V2R protein within the inner medulla may allow for the optimization of urine concentration and minimize water loss during periods of water restriction.

Animals↗

PubMed1995

Effect of voluntary exercise and food restriction in response to lipopolysaccharide in hamsters.

We tested the hypothesis that voluntary running and moderate food restriction alter the acute phase response (APR), one index of nonspecific immune function. Hamsters were kept sedentary or permitted to run and were fed ad libitum or had food restricted for 20 days and were then injected intraperitoneally with saline or lipopolysaccharide (LPS). Fever and circulating interleukin-6, serum amyloid A (SAA), serum iron, and cortisol were measured by biotelemetry, B-9 cell growth assay, indirect enzyme-linked immunosorbent assay, colorimetric analysis, and radioimmunoassay, respectively. The febrile temperature; hypoferremia; and elevation of circulating interleukin-6, SAA, and cortisol after LPS injection were not altered by exercise. Because baseline temperatures were elevated in the exercised hamsters, the change in temperature in response to LPS was less than it was in the sedentary hamsters. Food restriction significantly decreased SAA and elevated cortisol after LPS injection and depressed the absolute temperature to which the core temperature rose in response to LPS in one trial but not in another. Because food restriction depressed baseline temperatures, it also affected the change in temperature after LPS injection. The hypoferremic response to LPS was inhibited in hamsters that were both food restricted and permitted to run. We conclude that exercise does not enhance the APR to a low dose of LPS, whereas food restriction and the combination of exercise and food restriction depress some portions of the APR in hamsters.

Acute-Phase Reaction↗

PubMed2004

Sleep restriction does not affect orthostatic tolerance in the simulated microgravity environment.

Orthostatic intolerance (OI) is a major problem following spaceflight, and, during flight, astronauts also experience sleep restriction. We hypothesized that sleep restriction will compound the risk and severity of OI following simulated microgravity and exaggerate the renal, cardioendocrine, and cardiovascular adaptive responses to it. Nineteen healthy men were equilibrated on a constant diet, after which they underwent a tilt-stand test. They then completed 14-16 days of simulated microgravity [head-down tilt bed rest (HDTB)], followed by repeat tilt-stand test. During HDTB, 11 subjects were assigned to an 8-h sleep protocol (non-sleep restricted), and 8 were assigned to a sleep-restricted protocol with 6 h of sleep per night. During various phases, the following were performed: 24-h urine collections, hormonal measurements, and cardiovascular system identification. Development of presyncope or syncope defined OI. There was a significant decrease in time free of OI (P = 0.02) and an increase in OI occurrence (P = 0.06) after HDTB among all subjects. However, the increase in OI occurrence did not differ significantly between the two groups (P = 0.60). The two groups also experienced similar physiological changes with HDTB (initial increase in sodium excretion; increased excretion of potassium at the end of HDTB; increase in plasma renin activity secretion without a change in serum or urine aldosterone). No significant change in autonomic function or catecholamines was noted. Simulated microgravity leads to increased OI, and sleep restriction does not additively worsen OI in simulated microgravity. Furthermore, conditions of sleep restriction and nonsleep restriction are similar with respect to renal, cardioendocrine, and cardiovascular responses to simulated microgravity.

Adult↗

PubMed1998

Altered alveolar macrophage function in calorie-restricted rats.

Alveolar macrophage functions associated with clearance of bacteria from the lung were assessed in male Fischer 344 rats maintained on a 25% calorie-restricted diet. Calorie-restricted and ad libitum-fed (control) rats were exposed to concentrations of ozone known to compromise phagocytic function of alveolar macrophages. Ozone suppressed alveolar macrophage phagocytosis of latex beads in vitro in ad libitum-fed rats, but not in calorie-restricted rats. In fact, caloric restriction enhanced phagocytic function in both control and ozone-exposed animals. Ad libitum-fed rats exposed to ozone and challenged with Streptococcus zooepidemicus experienced a prolonged infection and influx of polymorphonuclear leukocytes (PMN), whereas calorie-restricted rats exposed to ozone cleared the bacteria in 24 h without an inflammatory response. Bacterial endotoxin-stimulated in vitro production of nitric oxide and tumor necrosis factor (TNF)-alpha as well as expression of TNF-alpha and interleukin-6 messenger RNAs were all lower in alveolar macrophages isolated from calorie-restricted rats. Together, the data suggest that caloric restriction enhances resistance to gram-positive bacteria, while lowering the production of proinflammatory mediators elicited by endotoxin, a component of gram-negative bacteria. Although increased bacterial resistance is considered beneficial, reduction in the lung's ability to induce inflammatory mediators can have both positive and pathophysiologic consequences.

Animals↗

PubMed1982

Measuring restrictiveness of psychiatric care.

"Restrictiveness" is neither a narrow legal concept nor a clinical concept that encompasses all aspects of a patient and his treatment; it refers to several features of treatment that can infringe on individual freedoms. As part of a study to develop a reliable method to measure restrictiveness, 31 mental health professionals were asked to rate the restrictiveness of six dimensions of treatment, such as legal status, and 33 treatment alternatives. Interrater reliability was high for both the importance of dimensions (alpha = .92) and the restrictiveness of alternatives within dimensions (alpha = .99). The treatment dimension judged most important in assessing restrictiveness was "limitations of physical freedom." The scale resulting from these judgments offers a plausible measurement of the restrictiveness of treatment configurations for use in evaluation research. The authors caution that restrictiveness is not in itself a comprehensive index of the quality of psychiatric care.

Commitment of Persons with Psychiatric Disorders↗

PubMed2004

Restricting sales of paracetamol tablets: effect on deaths and emergency admissions for poisoning in Scotland 1991 - 2002.

OBJECTIVE: To identify any effect on deaths and emergency admissions for poisoning resulting from the restriction on paracetamol sales introduced in September 1998. SETTING: Scotland. DATA: Deaths from poisoning were extracted from the General Registrar (Scotland) Office annual reports for 1991 to 2001 and emergency admissions data for 1990/91 to 2001/02 was supplied by the Information and Statistics Division of NHS Scotland. RESULTS: Deaths in the early 1990s, deaths from all poisonings and deaths from paracetamol poisoning were stable. After the restrictions deaths from all poisonings remained stable. Deaths from paracetamol poisoning fell by 45% in 1998 but have risen in each of the three years since to reach pre-restriction levels. RESULTS: Emergency admissions in the early 1990s all poisonings rose steadily. Following the restrictions all admissions fell by 10% and paracetamol poisonings fell by 14%. All admissions remained lower for a further two years but are now rising again. Paracetamol poisonings remained lower for a second year but the last two years have both seen 10% increases to reach record levels. DISCUSSION: The restrictions caused a dramatic 45% fall in deaths from paracetamol poisoning and reversed a relentless upward rise in all admissions for poisoning. The benefits were short-lived lasting about two years. Deaths and admissions are rising again and admissions are at record levels. CONCLUSIONS: Restricting paracetamol sales resulted in significant health gain. Further restrictions and public education on this valuable but dangerous drug are both urgently needed.

Acetaminophen↗