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Ketone body mediated histone β-hydroxybutyrylation is reno-protective.

Starvation, intermittent fasting and exercise, all of which are recommended lifestyle modifiers share a common metabolic signature, ketogenesis to generate the ketone bodies, predominantly β-hydroxybutyrate. β-hydroxybutyrate exerts beneficial effects across various contexts, preventing or mitigating disease. We hypothesized that these dynamic health benefits of β-hydroxybutyrate might stem from its ability to regulate genome architecture through chromatin remodeling via histone β-hydroxybutyrylation, thereby influencing the transcriptome. Focusing on the kidney, which is an end organ protected by β-hydroxybutyrate, we examined histone β-hydroxybutyrylation-mediated chromatin remodeling. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. Significant β-hydroxybutyrylation was observed in the kidneys and the most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures were enriched with genes related to immune function such as protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which exhibited reduced transcription and translation. These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly to protect kidneys and lower hypertension.

Blood pressure

Nutrition and longevity - diet in centenarians.

BACKGROUND: Nutrition plays a central role in the biological mechanisms that shape aging, health span, and longevity. Micronutrients—including vitamins, trace elements, and polyphenols—support genomic stability, mitochondrial integrity, and antioxidant defense, while dietary patterns rich in plant-based foods modulate inflammation, metabolic regulation, and epigenetic processes. Centenarian populations consuming Mediterranean, Okinawan, Nordic, and Nicoyan diets offer a natural model for understanding how nutrient-rich, minimally processed foods, moderate caloric intake, and balanced lifestyles interact with molecular pathways to extend functional life. MAIN BODY: This review synthesizes current evidence on how micronutrients influence DNA repair, oxidative stress reduction, and mitochondrial protection, particularly through the actions of vitamins C and E, niacin-dependent PARP activity, folate-mediated methylation, and metal cofactors involved in antioxidant enzymes. Plant-based diets rich in fiber and polyphenols enhance microbial diversity and promote beneficial taxa such as Akkermansia and Bifidobacterium, supporting gut barrier integrity and immune balance. Caloric restriction and intermittent fasting activate nutrient-sensing pathways, including AMPK and sirtuins, reduce mTOR activity, and stimulate autophagy, collectively improving cellular resilience. Findings from centenarian regions highlight the convergence of lifestyle, nutrition, and cultural practices that reduce systemic inflammation, maintain metabolic flexibility, and support healthy aging trajectories. CONCLUSIONS: Diet emerges as a decisive modifiable determinant of lifespan and health span. The convergence of molecular nutrition, microbiome composition, and traditional dietary habits underlies the exceptional longevity observed in centenarian populations. Future research should integrate nutrigenomics, metabolomics, and microbiome profiling to clarify causal mechanisms and guide precision nutrition strategies for aging societies.

Humans

Time dependent effects on contractile properties, fibre population, myosin light chains and enzymes of energy metabolism in intermittently and continuously stimulated fast twitch muscles of the rabbit.

Fast-twitch tibialis anterior and extensor digitorum longus rabbit muscles were subjected to long-term intermittent (8 h daily) or continuous (24 h daily) indirect stimulation with a frequency pattern resembling that of a slow motoneuron. Increases in time to peak of isometric twitch contraction were observed without parallel changes in the pattern of myosin light chains or alterations in the distribution of slow and fast fibres as discernible by the histochemical ATPase reaction. However, changes in the fibre population and in the myosin light chain pattern were observed after intermittent stimulation periods exceeding 40 days or continuous stimulation periods longer than 20 days. Under these conditions even higher increases were found in contraction time. In one animal a complete change in fbire population was observed. In this case myosin light chains of the slow (LCS1, LCS2) and of the fast type (LCf1) were obviously synthetized simultaneously within the same fibre. Early changes in the enzyme activity pattern of energy metabolism indicated a conversion of the fibres including their mitochondrial population. These changes and the earlier reported changes in the sarcoplasmic reticulum are probably responsible for the early changes in contractile properties which occur before the transformation of the myosin.

Adenosine Triphosphatases

A Qualitative Analysis of Cancer Survivors' Experience in a Time-Restricted Eating vs Control Clinical Trial to Address Cancer-Related Fatigue.

PURPOSE: To describe cancer survivors' lived experiences in a clinical trial that tested an individualized nutrition counseling with or without time-restricted eating to address cancer-related fatigue. METHODS: The Fatigue REDuction After cancer study was a two-arm, randomized controlled trial. Participants were adult cancer survivors who were 2 months to 2 years post-treatment. All participants received individualized nutrition counseling; those in the time-restricted eating group self-selected a consistent 10-hour eating window for 12 weeks. After the study, semi-structured exit interviews were conducted to gauge participants' experiences in the trial. Interviews were transcribed and two independent coders thematically analyzed the interviews using inductive and deductive coding. NVivo software was used for data organization and analysis. RESULTS: Participants (n = 24; TRE = 11; Control = 13) were 55 ± 13 years old, 75% were female, and they had a variety of cancer types. The majority of participants found that being in the study helped them to set and achieve lifestyle goals and would therefore recommend the study to others. Participants in the time-restricted eating group noted that time-restricted eating helped them set a better routine, providing a positive sense of control. However, some noted difficulty switching to a 14-hour fasting schedule, as it can interfere with their regular routine or employment schedules. Many participants noted they were happy that cancer-related fatigue was gaining more attention, hoping to find solutions for persistent cancer-related fatigue. CONCLUSION: The majority of participants found the study useful and, regardless of their group assignment or the intervention's impact on their fatigue, found the study helped them to gain better control of their dietary habits.

Humans

Changes in weight and metabolic health during and after cessation of a time-restricted feeding plus aerobic training in Swiss mice fed a high-fat diet.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with a high-fat diet (HFD) during an 8-wk intervention of TRF (8-h food access in the active phase) or TRF combined with EXE (60-min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest body weight and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations. These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.NEW & NOTEWORTHY This study demonstrates that combining time-restricted feeding with aerobic training improves weight and metabolic health in Swiss mice fed a high-fat diet. Importantly, we show that most metabolic benefits are lost after intervention cessation. However, insulin sensitivity and aspects of hepatic lipid metabolism are partially maintained after cessation of the intervention. These findings provide new insight into the durability of metabolic improvements induced by lifestyle interventions and highlight the potential of combined dietary and exercise strategies to counteract diet-induced obesity and metabolic dysfunction.

Animals

Effects of time-restricted eating on markers of glucose metabolism and regulation in individuals with prediabetes or type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials.

AIMS/HYPOTHESIS: This systematic review and meta-analysis aimed to investigate the effects of time-restricted eating (TRE) on glucose metabolism and regulation in individuals with prediabetes (fasting blood glucose of 5.6-6.9 mmol/l or HbA1c of 39-47 mmol/mol [5.7-6.4%]) or type 2 diabetes (fasting blood glucose &#x2265;7 mmol/l or HbA1c &#x2265;48 mmol/mol [6.5%]). METHODS: A literature search was performed in MEDLINE, Embase and CENTRAL from inception to 5 August 2025. Moreover, forward and backward citation searches were performed. Eligible studies were RCTs in adults with prediabetes or type 2 diabetes, lasting &#x2265;2 weeks, reporting markers of glucose metabolism and regulation, comparing TRE (&#x2264;12 h eating window) with a non-time-restricted control diet. Studies involving pregnancy, other fasting regimens, or non-peer-reviewed publications were excluded. Data were pooled as weighted mean differences with 95% CIs using random-effects generic inverse variance models in Cochrane Review Manager Web, and results are presented as forest plots. The certainty of evidence was defined using Grading of Recommendations, Assessment, Development and Evaluations methodology, and risk of bias was estimated by using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). RESULTS: Out of 2043 records identified through the database search, as well as 1249 from forward and backward citation searches, ten RCTs including 599 participants were included. The mean length of the studies was 4 months, and the eating windows ranged from 4 to 10 h per day. The pooled meta-analysis showed no overall effect of TRE on HbA1c (-3.33 mmol/mol; 95% CI -6.87, 0.20 (-0.30% points; -0.63, 0.02); p=0.06, moderate certainty). Nevertheless, following stratification by subgroups, TRE resulted in a reduction in HbA1c of 0.93 mmol/mol (-1.70, -0.17 [-0.09% points; -0.16, -0.02]; p=0.02) in individuals with prediabetes but not in individuals with type 2 diabetes (-4.68 mmol/mol; -10.08, 0.72 (-0.43% points; -0.92, 0.07); p=0.09). TRE reduced fasting blood glucose in the pooled analysis (-0.30 mmol/l; -0.53, -0.07; p<0.01, moderate certainty) as well as in the subgroup analyses in individuals with prediabetes (-0.14 mmol/l; -0.27, -0.01; p=0.03) and with type 2 diabetes (-0.48 mmol/l; -0.78, -0.17; p<0.01). Moreover, TRE lowered body weight by 1.6 kg (-2.2, -1.0; p<0.001) in the pooled analysis. The evidence was limited by imprecision arising from wide confidence intervals in some of the included studies, which may be due to small sample sizes. Lastly, the effects of TRE on markers of insulin sensitivity, beta cell function and continuous glucose monitoring measurements were inconclusive. CONCLUSIONS/INTERPRETATION: Moderate-certainty evidence indicates that TRE reduces fasting blood glucose but not HbA1c. The subgroup analyses revealed that TRE improved HbA1c and fasting glucose in individuals with prediabetes and improved fasting glucose in individuals with type 2 diabetes. Future large-scale studies should investigate long-term effects of TRE in prevention and treatment of type 2 diabetes. TRIAL REGISTRATION: PROSPERO CRD42024523591 FUNDING: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Three authors (JS, A-DT, THA) are employed at Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, partly funded by a grant from the Novo Nordisk Foundation.

Humans

Effects of intensive lifestyle interventions with calorie-carbohydrate-restricted diet versus time-restricted eating on appetite and binge eating in type 2 diabetes: A randomized controlled trial.

The impact of intensive lifestyle interventions on appetite regulation and binge eating in individuals with type 2 diabetes (T2D) remains unclear. This study evaluated the effects of combined lifestyle interventions on appetite responses and binge eating in overweight or obese adults with T2D. In a randomized trial, 120 participants with T2D were allocated to three groups (n&#xa0;=&#xa0;40 each): (1) Calorie-carbohydrate restriction (CCR), (2) Time-restricted eating with CCR (TRE&#xa0;+&#xa0;CCR), or (3) Control. Intervention groups received structured exercise and behavioral education based on the Information-Motivation-Behavioral Skills model. Appetite perceptions (hunger, satiety, desire to eat, and prospective food consumption) and binge eating (Binge Eating Scale; BES and objective binge episodes) were evaluated at baseline, week 12, and week 24 using linear mixed models. Both CCR and TRE&#xa0;+&#xa0;CCR significantly improved subjective appetite compared with the control group at 12 and 24 weeks (all p&#xa0;<&#xa0;0.01). At 24 weeks, hunger decreased by -24.1&#x202f;mm (95% CI: -35.8, -12.5) in the CCR group and -32.7&#x202f;mm (95% CI: -44.2, -21.3) in the TRE&#xa0;+&#xa0;CCR group. Satiety also increased by 21.7&#x202f;mm (95% CI: 9.46, 33.9) and 29.4&#x202f;mm (95% CI: 17.4, 41.4), respectively. Significant reductions were observed for desire to eat and prospective food consumption. In contrast, changes in BES and objective binge episodes were not significantly different between groups at any time point. No significant differences were detected between the CCR and the TRE&#xa0;+&#xa0;CCR groups. Intensive lifestyle interventions incorporating CCR or TRE&#xa0;+&#xa0;CCR effectively reduced appetite in adults with T2D but did not significantly affect binge eating. Future research should target individuals with higher baseline BES scores to clarify potential benefits for binge eating behavior.

Humans

Secretion pattern of secretin in man: regulation by gastric acid.

Median concentration of plasma secretin in the fasting state in 11 achlorhydria patients, 17 normal subjects, eight duodenal ulcer patients, and 11 Zollinger-Ellison patients was 0.3, 1.2, 2.5, and 5.9 pmol x 1(-1), respectively. Aspiration of gastric acid normal subjects and duodenal ulcer patients was followed by a significant lowering of the plasma secretin concentration. In normal subjects insulin-induced hypoglycaemia resulted in increased secretin levels when gastric acid was allowed to enter the duodenum, whereas no changes were observed when gastric acid was aspirated. Simultaneous measurements of intraduodenal pH and plasma secretin concentration in the fasting state and in response to a meal showed that rapid falls in intraduodenal pH were followed by short-lived increments in plasma secretin concentration. These changes in pH and in secretin levels were diminished after cimetidine. It is concluded that gastric acid in man does trigger release of secretin and that secretin is secreted intermittently both in the fasting state and in response to a meal when boluses of acid enter the duodenum.

Adult

Influence of intermittent long-term stimulation on contractile, histochemical and metabolic properties of fibre populations in fast and slow rabbit muscles.

Slow (m.soleus) and fast (m.tibialis anterior) muscles of the rabbit were subjected to indirect long-term intermittent stimulation (3 weeks, 8 hrs daily) with a frequency pattern of 10 imp/sec. Whereas no changes were observed in case of the slow muscle, stimulation induced profound changes in the fast tibialis anterior muscle. These consisted in a rearrangement of the enzyme activity pattern of energy-supplying metabolism, e.g. decrease in glycogenolytic and glycolytic enzyme activities and severalfold increase in key enzymes of aerobic endoxidation of substrates in beta-oxidation and the citric acid cycle. Concomitant with the increase in aerobic oxidative capacity, there was an increased resistance to fatigue. Histochemical studies revealed a strong increase in mitochondria of all fibres. The bimodal distribution of fibre cross-sectional area in the normal tibialis anterior muscle was changed by stimulation into a more homogeneous population of fibres with a smaller cross-sectional area. Despite a 50% increase in time to peak of isometric twitch contraction no changes were observed in the fibre population with regard to myofibrillar ATPase reaction in quantitative evaluation of whole cross-sections of the muscles. The percentage of fibres histochemically classified as slow amounted to 2.8% and 3.1% in control and stimulated tibialis anterior muscle. Nevertheless the data suggest a transformation of the fibre population under the influence of long-term intermittent stimulation.

Adenosine Triphosphatases

Transmission and contraction fatigue of rat motor units in relation to succinate dehydrogenase activity of motor unit fibres.

1. The fatigue in rat anterior tibial (a.t.) motor units was studied and related to microphotometric determinations of succinate dehydrogenase (SDH) activity of the motor unit muscle fibres. 2. Anterior tibial contains fast-twitch type II fibre units with an average contraction time of 11 msec and about 5% slow-twitch type I fibre units with an average contraction time of 20 msec. 3. In type II fibres stained for SDH, absorbance varied continuously from 0.046 to 0.569 and inversely to fibre size, except for the largest fibres. 4. Resistance to fatigue of fast motor units to 100 Hz intermittent stimulation varied continuously within a wide range in near linear relations to absorbance for SDH of unit fibres and inversely to tetanic tension, except for motor units with the largest fibres and the largest tetanic tension. 5. Neither resistance to fatigue nor SDH activity lent itself to any categorization of motor units or fibres into well demarcated functional or histochemical types, since both parameters varied continuously in the unit and fibre population of the muscle. 6. The direct relation between resistance to fatigue of fast-twitch motor units and SDH activity of unit fibres appeared valid for fatigue resistance of: (a) neuromuscular transmission, tested with 100 Hz intermittent stimulation which gave concomitant failure of electrical and mechanical response, (b) excitation--contraction coupling, demonstrated by post-stimulatory depression of twitch tension with preserved maximum tetanus tension and action potential, and (c) contractile mechanism; excitation--contraction coupling?, tested with low frequency stimulation which gave decline of twitch and maximum tetanus tension with preserved action potential. 7. It is suggested that the endurance of each link in the chain of events leading to contraction, including neuromuscular junction and the excitation--contraction coupling system, is under aerobic conditions matched to the contractile capacity of the fibre expressed by its oxidative enzyme activity.

Action Potentials

[Electromyographic study of the canine stomach after transection and mucosal bridge anastomosis (author's transl)].

In order to clarify the propagation mechanism of canine gastric electrical activity, the stomach was transected and reanastomosed at the middle antrum in 3 dogs and at the distal corpus in 3 dogs. Two bipolar electrodes were implanted in the pre- and postanastomosis stomach. Electromyographic recordings were performed intermittently for 8 to 13 weeks in fasting and after feeding. In one of the 6 dogs, 11 weeks after the initial surgery, one half of the anterior muscle wall of the greater curvature side was reapproximated. In fasting, the BER interval in the preanastomosis remained unchanged, but that in the postanastomosis became prolonged. After feeding, the BER interval in the postanastomosis was shortened and showed an advancement to close to that in the preanastomosis. 3 weeks after reapproximation of partial muscle wall, the BER interval in the postanastomosis recovered to the same BER interval as in the preanastomosis in fasting and after feeding stages. Dysrhythmia in the postanastomosis was of temporal occurrance. These results suggest that an inherent automatism in the gastric wall plays a role in the recovery of the BER interval and close muscle approximation is essential for propagation of gastric electrical activities.

Animals

Delayed fluorescence from bacteriochlorophyll in Chromatium vinosum chromatophores.

Delayed fluorescence from bacteriochlorophyll in Chromatium vinosum chromatophores was studied at room temperature and under intermittent illuminations. The decay of delayed fluorescence was constituted of two components; a fast component decayed with a half time of about 8 ms, a slow one decayed in parallel with the reduction of photooxidized bacteriochlorophyll (P+) with a half time of 100-200 ms. The biphasic decay of delayed fluorescence indicated that a rapid equilibrium was established between the primary electron acceptor and the secondary acceptor. In the presence of o-phenanthroline, the time course of the decay of delayed fluorescence was identical with that of the reduction of P+ in reaction center-rich subchromatophore particles, although they did not necessarily coincide with each other in "intact" chromatophores. The intensity of the slow component was increased and the decay was accelerated at basic pH values. Reagents that dissipate the proton gradient across the chromatophore membranes such as carbonylcyanide m-chlorophenylhydrazone (CCCP) and nigericin accelerated the decay of the slow component. These effects are probably resulting from changes in internal pH of chromatophore vesicles. Reagents that dissipate the membrane potential such as CCCP and valinomycin decreased the intensity.

Bacterial Chromatophores

Cerebral cortical isolation in infantile neuroaxonal dystrophy.

Three patients with infantile neuroaxonal dystrophy (INAD, Seitelberger's disease) studied between ages 2 and 5 years, with the characteristic electroencephalographic pattern of high-voltage, fast (16-24 c/sec) rhythms and absence of reactivity on eye-opening or closure (Radermecker and Dumon-Radermecker 1972), also showed no changes in response to intermittent photic stimulation and absence of evoked potentials to flashes, clicks or median nerve stimuli. Although some theta rhythms and delta activity appeared during drowsiness and sleep, the fast rhythms persisted as the dominant feature. There were no central transients or K-complexes. When the patients cried, with hyperventilation, and also during breath-holding spells, slow rhythms appeared and the fast rhythm was reduced. These findings are interpreted as evidence of cerebral cortex isolation, the fast rhythm representing the spontaneous ("idling") activity of the cortex largely disconnected from subcortical or remote cortical influences by the slowly progressive, selective degeneration of axons, characteristic of the pathology of INAD, but the cortex remains responsive to chemical influences. These electrophysiological features become established furing the third year of age, prior EEGs being normal and later ones showing paroxysmal and other abnormal features in addition to the fast rhythm.

Acoustic Stimulation

Effects of continuous and intermittent feeding on biliary lipid outputs in man: application for measurements of intestinal absorption of cholesterol and bile acids.

Hepatic outputs of biliary lipids can be measured by intestinal perfusion techniques, either during constant infusion of liquid formula into the duodenum or through-out a 24-hour period during which time three meals are given along with an overnight fast. The purpose of this study was to compare these two methods for estimating secretion of biliary lipids. In 21 subjects, mean hourly outputs measured during continuous feeding were highly comparable to those during intermittent feeding, showing that the constant infusion technique gave valid estimations of overall daily secretion rates of biliary lipids. On the other hand, the intermittent mode of feeding showed phasic changes of outputs and composition of biliary lipids in response to feeding and fasting apart from total outputs over 24 hours. However, it takes longer to complete and requires the use of a meal marker. By combining the intestinal perfusion technique with measurements of fecal excretion of neutral steroids and bile acids, this method may be used to estimate absorption of cholesterol and bile acids from the intestine. Thus, these measurements allow quantification of a number of parameters of the enterohepatic circulation.

Adult

[Diabetes mellitus in childhood and adolescence. Clinical types].

It is today's general medical opinion that children's diabetes mellitus was uncommon in the past. It was generally admitted at that time the initail stages were so sudden as to make difficut its early diagnosis. It's increased incidence is at present an alarming truth; however, a parallel increase of diabetic coma or of mulminant types has rather dropped. Diabetes may be diagnosed by just considering the main symptoms at the onset which are polydipsia, polyuria and weight loss. If an early diagnosis is not made, acidosis (abdominal pain, nausea, vomiting) may appear within a few days or weeks followed by coma (Kussamul's acidotic respiration and dehydration). Coma may be avoided by an early diagnosis and a life may be saved. It must be stressed that an important percentage of children and adolescents show a slow and gradual evolution (week or months) of their diabetes: gradual weight loss, sometimes with noticeable polyphagia, occasional enuresis, but without other associated symptoms. Asymptomatic, intermittent glucosurias are also frequent; they vary in magnitude an almost always they appear without ketonuria and with fasting normal glycemia. According to our experience they may precede in weeks or months the clinical manifestations of the disease. Postprandial glycemia is a sure diagnostic resource; it is of greater trustworthines than fasting glycemia; therefore we advise it as a routine diagnostic procedure which we recommend widely. In uncertain situations, the oral glucose tolerance test is advisable.

Adolescent

Sleep patterns of the laboratory cat.

The effects of feeding schedule and external stimuli on sleep patterns were investigated in cats fed to maintain their mean body weight. The ECoG, EOG and EMG wer recorded from 3 male cats fed once daily and under a 12:12 light--dark schedule. The results for 15 working days were compared with those obtained at week-ends and under continuous lighting, fasting, reduced food intake or overfeeding. Feeding was also divided into 3 meals per day. Despite some differences in their responsiveness. All cats exhibited the usual values for the critical variables of SWS: diurnal placement, intermittency and total amount. A low percentage of PS per 24 h was recorded. This was related both to the restricted amount of food eaten and to the feeding schedule. Reduced external stimuli at week-ends resulted in concentration of sleep during daytime, whereas sleep was reduced during continuous lighting in conjunction with an increased percentage of drowsinessess. The most marked effect of fasting (pig fat) was fragmentation of sleep episodes. Divided meals and an increased food intake both increased the total sleep duration. It is suggested that the restricted amount of food and relatively enriched environment used, accompanied by a reduced sleep duration, may be comparable to that seen in free animals. Sleep patterns in the cat are very responsive to light--dark schedule, reduced external stimuli and fasting.

Animals

Alterations in amounts and rates of serotonin transported in an axon of the giant cerebral neurone of Aplysia californica.

1. The giant cerebral neurone of the sea hare, Aplysia californica, is a unipolar serotonergic cell. Its axon bifurcates, one branch travelling in the cerebrobuccal connective, the other in the posterior lip nerve. 2. I13H]serotonin was injected under pressure into the cell body of the giant cerebral neurone. We studied fast axonal transport of the radioactive transmitter substance along the lip nerve when the cerebrobuccal connective was cut close to the bifurcation. 3. When the connective was cut, more than twice as much [3H]serotonin was transported along the lip nerve compared to uncut control nervous systems. 4. The increased [3H]serotonin appearing in the nerve probably was originally destined to enter the connective, but was diverted from the cut stump which was occluded with backed-up material. 5. The incremental [3H]serotonin in the lip nerve was not the result of increased export from the soma in response to injury. 6. Not only was more [3H]serotonin transported along the lip nerve, but also a far greater fraction of the transmitter moved at very fast transport rates, approaching 120 mm/day. In uncut control nerves only a small fraction of total [3H]serotin moved faster than 70 mm/day. 7. These results are interpreted with a model for fast axonal transport. We suggest that serotonergic vesicles move at a fixed, maximal speed when attached to essentially immobile tracks, but that the vesicles are only intermittently associated with the tracks. We presume that the rate-limiting step in movement of vesicles is the concentration-dependent and reversible binding to the tracks. Transport along axons may be considered analogous to those enzymatic reactions in which formation of the enzyme-substrate complex limits the appearance of product. Translocation is here analogous to formation of product. The process may therefore be approached theoretically by modification of the Michaelis-Menten formulation.

Animals

Comparison of the convulsant effects of cocaine and pseudococaine in the rhesus monkey.

The convulsant effects of cocaine and its C2-epimer, pseudococaine on EEG, respiration, heart rate and behavior were studied in the rhesus monkeys with electrodes implanted in the brain. Intravenous injections of cocaine (3.0 to 8.0 mg/kg) and pseudococaine (3.0 to 7.0 mg/kg) in the animals produced a similar pattern of clonic convulsions accompanied by marked increases in the heart and respiratory rates with mydriasis and excessive salivation. However, both isomers showed different effects on the EEG and animal's behavior following convulsions; e.g., the cocaine-induced convulsions were followed by low-voltage fast waves in the EEGs associated with behavioral hyperexcitation, while pseudococaine-induced convulsions were followed by high-voltage slow waves associated with behavioral depression and drowsiness with intermittent sleep. Pseudococaine was more potent than cocaine in producing convulsions in the same monkeys. The durations of convulsions produced by these drugs were dose-dependent.

Animals