Dreaming during REM sleep: autobiographically meaningful or a simple reflection of a Hebbian-based memory consolidation process?

REM sleep is a state of desynchronized electrophysiological activity of the brain. It is usually accompanied by mental activity characterized by a succession of complex visual experiences commonly referred to as dreaming. Although REM sleep and dreaming are not implicitly conjoined, when they co-occur, they have a very distinct phenomenology, as, typically, the dream plot is bizarre and incohesive which is mirrored in heightened brain activation coupled with strongly attenuated coherence levels. At the same time, owing to increased limbic system activity, REM sleep dreams are highly emotional. Moreover, concrete emotions are often unrelated to dream events. Nevertheless, REM sleep dreams are often subjectively perceived as story-like and autobiographically meaningful. Indeed, elements of salient life events, attachment figures, and personally relevant emotions, especially trauma, seem to have a higher probability of re-appearing in dreams, albeit the dream plot itself remains highly distorted. This has prompted several theories on the interpretability of dreams, some authors leaning towards dreams reflecting waking mentation, others suggesting complete dissociation between waking and dreaming, both sides not fully accounting for empirical findings. In this review, we provide an overview of recent findings on the factors mediating REM sleep neurophysiology and dream content. As a first step towards integration of conflicting research results, we introduce a testable model (Trace-Spur-model) based on Hebbian theory of neural networks, proposing that dream bizarreness is a function of state-related modulations in synaptic strength allowing for hyper-associative mental activity, possibly enabling either a restructuring and integrative consolidation or extinction of learning experiences acquired in waking. In this model, dreams are viewed as phenomenological expressions of this neurophysiologic activity where dream recall allows a fragmentary witnessing of such processes, similar to peeking into an enduring and complex networking system. However, the content of the recollected dream is probably strongly deterred by autobiographical memory bias, favoring those images we can form some sort of association with.

Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model.

AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.

Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection.

Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10%. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 h after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.

Sleep quality in a family with hereditary parkinsonism (PARK6).

OBJECTIVES: The autosomal recessive disorder PARK6 manifests as early-onset Parkinson's disease (PD) with a particularly mild progression. PARK6 is of particular scientific interest, since it is caused by loss-of-function mutations in the mitochondrial protein kinase PINK1 and may thus serve as a model for oxidative damage in PD and in other basal ganglia disorders. Sleep disturbances are very common in PD but have not yet been reported for PARK6 patients. The present study reports on sleep of a Spanish family with PARK6. Of the 5 siblings, 3 were homozygous and severely affected, and 2 were heterozygous and clinically asymptomatic. Research questions concerned possible differences in sleep recordings between homozygote and heterozygote siblings and similarities between PARK6 and sporadic PD sleep profiles. METHOD: The data from detailed clinical interviews of the patients and their bedpartners are reported and compared with polysomnographic data from second-night recordings. CONCLUSIONS: All siblings had good subjective and objective sleep quality. Restless legs syndrome and rapid eye movement (REM) sleep behaviour disorder (RBD) were not observed, suggesting that sleep disturbances are not commonly found in PARK6 patients. Good sleep quality and the absence of RBD might be a useful diagnostic guide in the differential diagnosis of sporadic PD versus PARK6.

DNA probes in human disease.

Nucleic acid probes are able to detect the presence of particular sequences in a sample down to the level of a few hundred molecules. They can discriminate between similar sequences to a resolution of better than one part in 10(9). They are capable of detecting inherited defects in tissues where the phenotype is not being expressed, and in cases where the biochemical aberration is not understood. They can characterize acquired diseases in somatic cells (both tumours and infectious agents). Additionally, they can be used to characterize multifactorial (either polygenic or requiring an environmental stimulus to interact with a genetic predisposition) diseases. Nucleic acid 'fingerprints' provide an unequivocal identification of the origin of cells which may be applied in criminal law, civil law, and in the follow up to bone marrow transplants. In spite of this tremendous potential, there is still a large gap between their use in research laboratories and their widespread application in pathology laboratories. There are two basic reasons for this. The first is the number of labour-intensive steps involved in the various 'blotting' techniques which greatly reduces the rate at which assays may be performed. The second is the need to use probes labelled with isotopes which are short-lived and may require stringent safety measures to be employed. Recent work both in this laboratory and elsewhere is designed to circumvent both these problems.

Stages of sleep pathology in spinocerebellar ataxia type 2 (SCA2).

BACKGROUND: Autosomal dominant spinocerebellar ataxia type 2 (SCA2) bears clinical and neuropathologic similarities to sporadic multisystem atrophy (MSA) or Parkinson disease, in which sleep pathology is well documented. However, those clinical entities have a marked variability of the reported sleep disturbances, and their etiology is heterogeneous. In contrast, the study of SCA2 provides an opportunity to examine a molecularly homogeneous patient group, in which disease stages can be defined not only based on disease duration and ataxia scores, but also with regard to modulatory effects of mutation size. OBJECTIVE: To examine the presence and progression of sleep pathology in SCA2. METHODS: We analyzed eight patients with disease durations of 3 to 31 years, all with medium size SCA2 expansions (CAG 38 to 49), using clinical scores, sleep interviews, and video-polysomnography (VPSG) recordings. RESULTS: Almost all patients reported good subjective sleep quality and negated incidents of REM behavior disorder (RBD). At early disease stages, however, REM without atonia in four patients' VPSG suggested subclinical RBD. This was accompanied by a consistent reduction of REM density. In three patients at later SCA2 stages, REM sleep was undetectable, whereas slow wave sleep (SWS) was markedly increased at the cost of light sleep. Periodic leg movements, apnea, or hypopnea were not prominent. CONCLUSIONS: Progressive loss of dream recall in spinocerebellar ataxia type 2 was found and correlated with stages of REM more than non-REM pathology in video-polysomnography. These stages correspond to the progressive atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.

Information processing and coping style during the wake/sleep transition.

Information processing of meaningful events (subject's own name, neutral name and tones) was studied during the transition from wakefulness to sleep in two groups of subjects with opposing information processing styles, Monitors and Blunters. In two experimental sets, subjects were instructed to execute a fingerlift response to a predetermined stimulus type. Subject's own name produced the greatest number of K-complexes and arousals relative to other name and tones. A task relevance effect was found for arousals but not for K-complexes. The overall P3 amplitude was larger for Monitors than for Blunters, whereas Blunters showed a larger N350 to target stimuli than Monitors. The findings suggest that higher level processing continues during light sleep and that N350 may reflect a process related to sleep maintenance.

Effect of potassium on isolated bovine facial and human saphenous veins.

A moderate elevation of external (K0+) (5--10 mM) induces relaxation in bovine facial and human saphenous veins. A further increase of (K0+) leads to biphasic reactions (relaxation followed by contraction). Concentrations of (K0+) higher than about 15 mM cause contractions only. The potassium-induced relaxation may be explained by the stimulation of an electrogenic sodium pump.

Effects of AR-L 115 BS on arterial and venous muscle tone in vitro.

The effects of the cardiotonic drug 2-[(2-methoxy-4-methyl-sulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) on strips from isolated human veins and on strips from bovine veins and arteries were studied. The effects depended on the type and on the site of origin of the vessel. Pre-stretched human saphenous vein strips always relaxed in presence of AR-L 115 BS (greater than 10(-4) mol/l) while jugular vein strips seemed rather unaffected. Pre-stretched bovine facial vein strips always relaxed in presence of AR-L 115 BS, proximal branches being significantly more sensitive to the drug than distal branches. In bovine facial arteries AR-L 115 BS (greater than 10(-4) mol/l) produced either no change or a small increase in tension. When the arteries were pre-contracted by application of 50 mmol/l K+, low concentrations (less than 10(-5) mol/l) increased the tension while high concentrations (greater than 10(-5) mol/l) induced relaxation. The relaxing power of AR-L 115 BS on pre-contracted vein strips seemed better than that of nifedipine and less than that of Na nitroprusside.

[Clinical and endoscopic radiologic results after transduodenal papilloplasty (author's transl)]. / Klinische und endoskopisch-radiologische Spätergebnisse nach transduodenaler Papillenplastik.

The study comprises 56 patients, who underwent transduodenal papilloplasty. More than 15% were symptom-free at least 4 years following surgery. All the symptoms the patients suffered from were nonspecific and the pathological findings of the blood samples were not correlated with the width of the orificium of the papilla of Vater or the diameter of the common bile duct. In 49 patients the ERCP was performed. In 48 cases the retrograde cholangiography was successful, in 1 case only the retrograde pancreatography was possible. In all patients we found normal efflux of contrastmedium out of the papilla. Bile stones, one localized in the common bile duct and the other in the cyst remnant were the most important findings. The diameters of the common bile ducts varied considerably and were not dependent on the velocity of the efflux of the contrast medium. Contrary to the observations of other authors, in only 15% of our patients free air bubbles were found in the bile tree. Peripapillary diverticula of the duodenum were detected in 15% of our patients, but did not lead to compression or obstruction of the common bile duct. Even without histologic examination of the liver, we believe that a broad papilloplasty of the papilla prevents an ascending cholangitis or other related complications.

ERP and behavioral changes during the wake/sleep transition.

Event-related potentials (ERPs) following infrequent and frequent stimuli were studied as subjects moved from wakefulness to sleep. Subjects were instructed to respond to the infrequent "target" stimuli (attend condition) or to ignore the stimuli (ignore condition). Parietal P300, prominent following target ERPs in wakefulness under the attend condition, disappeared in association with reduced behavioral responsiveness and emergence of a central negativity (N350). The N350 and preceding and following positivities (P220 and P450) became the dominant feature of both target and nontarget ERPs under both attend and ignore conditions. The P220-N350-P450 complex was larger and peak latencies were shorter under the attend condition. Peak amplitudes tended to be larger following targets, especially under the attend condition. The findings suggest that, although the processes underlying P300 are less likely to be engaged, processing of stimulus deviance and task relevance continues in sleepiness and sleep, and is reflected by variance in N350 and related activity.

Effect of neonatal sympathectomy by 6-hydroxydopamine on volume and resistance regulation in stroke-prone spontaneously hypertensive rats.

1. Neonatal sympathectomy with 6 hydroxy-dopamine (6-OHDA) was used as a tool to assess the significance of an increased sympathetic vascular tone for the development of high blood pressure in stroke-prone spontaneously hypertensive rats. After administration of 6-OHDA the rise in blood pressure was blunted for the following 9 weeks until innervation was re-established. 6-OHDA-treated rats retained more sodium and had larger plasma and blood volumes than sham-treated rats. 2. Catecholamines in plasma were increased 2-10-fold immediately after sympathectomy, but their concentrations were subnormal on day 7. Eight weeks after sympathectomy plasma noradrenaline and dopamine were not elevated, but plasma adrenaline has increased twofold. 3. The reactivity of resistance vessels to noradrenaline was markedly enhanced and the neuronal uptake and metabolism of noradrenaline were still reduced 8 weeks after neonatal sympathectomy. 4. These results confirm the significance of an intact sympathetic nervous system for the development in these rats. Sodium retention and increased plasma and blood volume may be considered as a compensatory mechanism for the vasodilatation resulting from decreased vasomotor tone.

Effects of neonatal sympathectomy by 6-hydroxydopamine on blood pressure and intravascular volume in young stroke-prone spontaneously hypertensive rats.

1. Stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) were 'chemically sympathectomized' immediately after birth with 6-hydroxydopamine (6-OHDA, 100 mg/kg s.c. daily) for the first 10 days of life. 2. Body weight gain was diminished in both groups as compared with sham-treated controls. Blood pressure was reduced in 'sympathectomized' SHRSP, and also WKY rats had a slightly lower blood pressure than control rats. 3. Plasma concentration of angiotensin II and renin content of the kidney were not influenced by 6-OHDA. 4. 'Sympathectomized' SHRSP retained similar amounts of sodium than sham-treated SHRSP when sodium retention is expressed per body weight gained. Plasma and blood volumes were increased in both SHRSP and WKY rats, whereas packed cell volume was significantly decreased. 5. These results demonstrate the significance of an intact sympathetic nervous system for the development of hypertension in SHRSP. The expanded plasma and blood volume in 'sympathectomized' rats indicate an important role of the sympathetic nervous system and/or the arterial blood pressure for the regulation of intravascular volume.