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BACKGROUND: We have recently reported that oral treatment of adult male C57BL/6J mice with a non-absorbable antibiotic cocktail resulted in an increase in ethanol intake and in significant reductions in butyrate-producing gut microbiota populations. This work led us to hypothesize that reduction in butyrate levels within the gut is linked to antibiotic-induced increases in voluntary ethanol consumption. OBJECTIVE: This study tested whether ad libitum sodium butyrate supplementation can prevent antibiotic-induced ethanol consumption in mice. METHODS: Sodium butyrate was provided to adult male C57BL/6J mice in drinking water alone or in combination with antibiotic cocktail. Effects on ethanol (20%) intake were measured using drinking in the dark and modified 2-bottle choice paradigms. Body parameters, food and liquid intake, cecum and adipose tissues were measured during and/or at the conclusion of the drinking in the dark study. Cecal 16s rRNA was analyzed for microbiota diversity and changes in specific bacterial phyla/species. RESULTS: In drinking in the dark, sodium butyrate supplementation prevented antibiotic-induced increases in ethanol intake without altering basal ethanol consumption. Furthermore, sodium butyrate supplementation lowered ethanol preference in the 2-bottle choice study. Ethanol intake was correlated to specific bacterial phyla/species. Sodium butyrate did not affect the changes in microbiota diversity and composition induced by antibiotic cocktail. CONCLUSIONS: The findings support a role of gut microbiota-derived butyrate in regulating alcohol-induced behaviors. Additionally, the work contributes to efforts in development of novel microbiome-based strategies as novel preventative and intervention-based therapeutics to address alcohol use disorder.

Efficient detection methods are vital for the control of viruses and phytoplasmas in fruit and other perennial crops. This paper reviews the diagnostic tests currently available for detecting such pathogens. Biological tests are generally slow and results may be difficult to interpret. Serological assays are reliable and easy to conduct and some are very rapid. An abundance of molecular techniques offers higher sensitivity and facilitates the introduction of laboratory tests for diseases that currently have to be assayed biologically.

This paper describes the development and testing of the Acid Deposition and Oxidant Model (ADOM), a nine-year project funded by a consortium consisting of Environment Ontario, Environment Canada, the German Umweltbundesamt, and the Electric Power Research Institute. The project consisted of three major phases: a design phase, an implementation phase, and an evaluation phase. In the design phase, the system being modeled was divided into its components—transport, gas phase chemistry, aqueous phase chemistry, dry deposition and cloud processes. The formulation of the modules for each of these processes was guided by the requirement that the modules reflect the state of the art, and at the same time be consistent with the available numerical resources. In the implementation phase, submodels were constructed, and then subjected to several tests, which included mathematical consistency checks, sensitivity studies, and evaluation against field and laboratory data. The modules were then assembled and interfaced with the input data sets. The codes for the modules as well as the overall model were vectorized to take advantage of the capabilities of supercomputers such as the CRAY. The North American and West German versions of the model are being tested against data collected in North America and in Europe. This paper describes the evaluation of ADOM with data associated with a regional ozone episode in Ontario in June 1983, and measurements made during an experiment to study the scavenging characteristics of spring storms in the central and northeastern United States in April 1981.

The current study investigated the effects of propofol on P2X4 receptors expressed in Xenopus oocytes using two-electrode voltage clamp. We also tested the effects of 100 mM ethanol on the same oocytes used to test propofol. Propofol potentiated ATP-gated currents in a concentration dependent manner in P2X4 receptors. In agreement with our previous findings, ethanol inhibited P2X4 receptors. The opposite effects of propofol and ethanol on P2X4 receptor function suggest that these anesthetics act via different sites/mechanisms in P2X receptors as has been suggested for GABA(A) and glycine receptors.

The gas chromatographic (GC) determination of the herbicide paraquat, the 1,1'-dimethyl-4,4'-dipyridyl cation in human plasma is described. In poisoning cases, plasma concentrations provide a necessary index of the severity of intoxication and a means of monitoring subsequent therapy. The methods may be extended to the specific trace analysis of paraquat in body fluids of post-mortem tissue. Reduction of fully ionised paraquat salts with sodium borohydride yields a hexahydro derivative, a diene, amenable to solvent extraction and GC. Employing 1,1'-diethyl-4,4'-dipyridyl dichloride as the internal standard, plasma concentrations of 0.1 microgram/ml (+/- 6% S.D.) may be determined with flame ionisation detection and 0.025 microgram/ml with nitrogen-selective flame ionisation. Further enhancement of specificity is achieved using selected ion monitoring mass spectrometry and the value of this technique in forensic analysis is illustrated.

Previous in vitro evidence suggests that adrenaline causes K influx in skeletal muscle by stimulating a ouabain sensitive Na/K ATPase membrane pump. However in rabbits, adrenaline induced hypokalaemia was not significantly altered by pretreatment with digoxin (50 micrograms/kg). Rats were infused with adrenaline or saline after being given a tracer dose of 42KCl. Adrenaline caused a highly significant uptake of 42K in skeletal muscle and a decrease in 42K uptake in ventricle. Rats were also studied after receiving a high dose of digoxin (1.4 mg/kg) which by itself produced a significant increase in plasma K, a decrease in plasma Na and a decreased uptake of 42K in ventricle and lung. These results suggest that adequate widespread Na/K ATPase inhibition had been achieved by this dose of digoxin but despite this, adrenaline still caused hypokalaemia and also still caused significant 42K tissue uptake by skeletal muscle. These results suggest that adrenaline causes K influx by skeletal muscle and K efflux by cardiac tissue. Furthermore, the former mechanism was not inhibited by pretreatment with digoxin.

Simultaneous measurements of the plasma concentrations of renin, renin-substrate, angiotensin II and aldosterone were made in seven patients with the nephritic syndrome and in five normal subjects studied under the same controlled conditions. Plasma renin-substrate concentration was found to be reduced in some patients. Although plasma renin concentration was frequently elevated, plasma angiotensin II and aldosterone concentrations were generally within the normal range.

1. 1. Evidence bearing on the importance of the renin/angiotensin system in the regulation of aldosterone secretion in man is reviewed. 2. 2. Elevation of plasma angiotensin II concentration in simple dietary sodium deprivation has been confirmed. 3. 3. In primary renin deficiency, both angiotensin II and aldosterone are deficient. In these circumstances plasma aldosterone can remain unresponsive to very large rises in plasma potassium, but increase promptly on infusion of angiotensin II. 4. 4. Sodium depletion in normal man increases the adrenocortical sensitivity to angiotensin II, while diminishing the presser effect. 5. 5. The Na E /renin and Na E /angiotensin II interrelations are normal in primary hyper-aldosteronism both before and after treatment, and also in untreated essential hypertension with normal renin levels. 6. 6. These relationships are depressed in low-renin essential hypertension. 7. 7. In renal and malignant hypertension the relationships are enhanced. 8. 8. In renal and malignant hypertension the angiotensin II-pressor relationship is enhanced, and the angiotensin II-aldosterone relationship steepened as compared with normal subjects acutely infused with angiotensin. 9. 9. A hypothetical mechanism for the suppression of renin in essential hypertension is outlined.

The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum. creatinine and urea increased. Enalapril alone caused a longterm reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.

Plasma electrolytes, renin, and aldosterone concentrations were measured in 50 patients with primary hyperaldosteronism. Although plasma-potassium concentration varied over a considerable range in most cases, the levels were consistently lower than 3·7 meq. per litre in 27 patients, and intermittently so in all but 1 of the remainder. It is particularly important to avoid forearm exercise immediately before venepuncture if falsely high potassium values are to be avoided. Plasma-renin concentration was subnormal at least once in 42 patients, and consistently so in 24 of these. The remaining results were normal, most of them falling near the lower limit observed in normal subjects. In several cases sodium restriction caused distinct increases in plasma-renin concentration, and in 1 patient the final level was within the range found in sodium-deprived normal subjects. Plasma-aldosterone concentration was abnormally high on at least one occasion in 38 of the 39 patients in whom it was measured.

Hypertensive patients with chronic renal failure show evidence of an abnormal relationship between sodium and the reninangiotensin system in that circulating levels of renin and angiotensin II are abnormally high in relation to exchangeable sodium. The abnormality may well contribute to the hypertension in this syndrome. In a minority of cases blood pressure cannot be controlled by dialysis. In these, renin levels are particularly high and rise even further in response to therapeutic sodium depletion. It is suggested that this may perpetuate the hypertension. In most patients, however, blood pressure can be controlled by dialysis and, in these, renin and angiotensin II levels are lower, but, again, their relation to exchangeable sodium is abnormal. It is suggested that the rise in arterial pressure in this group results from a failure of renin to suppress normally with sodium retention. This would also explain the fall in blood pressure with sodium depletion at hemodialysis. The inflexibility of the renin-angiotensin system in its relation to sodium may be the cause of hypertension as well as the basis for its cure.

A study of the frequency distribution of plasma-renin concentration in 81 patients with essential hypertension produced no evidence of a distinct sub-population with low renin levels. An arbitrary dividing line was used, therefore, to define low-renin hypertension (36% of patients). Patients in this group were older than those with normal renin levels, and there was a significant negative correlation between renin and age among all patients. Low-renin hypertension was not characterised by increased exchangeable sodium, but exchangeable potassium was significantly lower than in patients with normal plasma-renin. This difference became insignificant when five patients in the low-renin group with persistent hypokalaemia were excluded. It is concluded that low-renin hypertension does not represent a separate diagnostic entity but that plasma-renin falls with age in essential hypertension.

1. Evidence bearing on the importance of the renin/angiotensin system in the regulation of aldosterone secretion in man is reviewed. 2. Elevation of plasma angiotensin II concentration in simple dietary sodium deprivation has been confirmed. 3. In primary renin deficiency, both angiotensin II and aldosterone are deficient. In these circumstances plasma aldosterone can remain unresponsive to very large rises in plasma potassium, but increase promptly on infusion of angiotensin II. 4. Sodium depletion in normal man increases the adrenocortical sensitivity to angiotensin II, while diminishing the pressor effect. 5. The NaE/renin and NaE/angiotensin II interrelations are normal in primary hyper-aldosteronism both before and after treatment, and also in untreated essential hypertension with normal renin levels. 6. These relationships are depressed in low-renin essential hypertension. 7. In renal and malignant hypertension the relationships are enhanced. 8. In renal and malignant hypertension the angiotensin II-pressor relationship is enhanced, and the angiotensin II–aldosterone relationship steepened as compared with normal subjects acutely infused with angiotensin. 9. A hypothetical mechanism for the suppression of renin in essential hypertension is outlined.

In a prospective controlled study mean systolic blood pressure had risen by 10.2 mmHg and mean diastolic pressure by 6.0 mmHg after 2yr in 186 women taking oestrogen-progestogen oral contraceptives. After 5 yr, 15 of these women showed mean increases of 12.3 mmHg systolic and 8.8 mmHg diastolic. The greatest rise in systolic pressure was 41 mmHg and the highest systolic level reached was 168 mmHg. In two cases diastolic pressure increased by 34 and 24 mmHg to 94 and 98 mmHg respectively. In a second study no significant correlation was found between blood pressure and concurrent plasma concentrations of renin, renin-substrate, angiotensin II, aldosterone, cortisol or DOC in women taking oestrogen-progestogen steroid contraceptives. Total exchangeable sodium and potassium were not affected by oral contraceptive administration and there was no correlation between total exchangeable sodium and blood pressure.

The clinical and biochemical findings in 136 patients with low-renin ("primary") hyperaldosteronism are described. A pathological diagnosis was made in 82 cases and a unilateral adrenocortical adenoma was found in 62. However, a tumor was not identified in 17, the adrenal glands then usually showing hyperplasia of the zona glomerulosa, often with nodular changes. The adrenal lesion in a further three cases proved fifficult to classify. Patients with an adrenocortical adenoma were significantly younger than those in whom a tumor was not found. The female/male ratio was greater than 2:1 in the adenoma group, but no sex difference was observed in the group without tumor. Vascular complications of hypertension occurred in 23 per cent and there was histologic evidence of malignant-phase hypertension in four. It is concluded that this condition is not a benign form of hypertension. Biochemical abnormalities were more marked among patients with an adrenocortical adenoma, compared with those in whom a tumor was not found. Mean plasma concentrations of aldosterone, sodium and tCO 2 , and mean exchangeable sodium were significantly higher, while plasma potassium and renin concentrations and mean exchangeable potassium were significantly lower. Although plasma aldosterone was above normal at least once in all, levels were often only intermittently raised. Hypokalemia occurred in all patients with a proved adenoma and was usually persistent. Among patients in whom a tumor was not found, hypokalemia was less severe and usually intermittent, while plasma potassium was persistently normal in three of 17 patients in this group. In addition to the aldosterone excess, plasma deoxycorticosterone was raised in 13 of 26 patients, plasma corticosterone was marginally raised in two and plasma 18-OH-DOC in four of 15. There was a significant inverse correlation between plasma renin concentration and age in the non-adenoma group but not among patients with an aldosterone-producing adenoma. Weak positive correlations were observed in the adenoma group between total exchangeable sodium and both systolic and diastolic blood pressure and between exchangeable sodium and plasma aldosterone concentrations. Such correlations were not seen in the non-tumor group. The hypertension may have a different basis in these two groups.