One third of cases of new-onset diabetic ketosis in adults are associated with ketosis-prone type 2 diabetes-A systematic review and meta-analysis.

AIMS: Ketosis-prone type 2 diabetes was defined by the World Health Organization in 2019. According to the literature, the diagnosis is based on the presence of ketosis, islet autoantibody negativity and preserved insulin secretion. Our meta-analysis assessed the prevalence and clinical characteristics of ketosis-prone type 2 diabetes among patients hospitalised with diabetic ketoacidosis (DKA) or ketosis. METHODS: The systematic search was performed in five main databases as of 15 October 2021 without restrictions. We calculated the pooled prevalence of ketosis-prone type 2 diabetes (exposed group) within the diabetic population under examination, patients with ketoacidosis or ketosis, to identify the clinical characteristics, and we compared it to type 1 diabetes (the comparator group). The random effects model provided pooled estimates as prevalence, odds ratio and mean difference (MD) with 95% confidence intervals. RESULTS: Eleven articles were eligible for meta-analysis, thus incorporating 2010 patients of various ethnic backgrounds. Among patients presenting with DKA or ketosis at the onset of diabetes, 35% (95% CI: 24%-49%) had ketosis-prone type 2 diabetes. These patients were older (MD = 11.55 years; 95% CI: 5.5-17.6) and had a significantly higher body mass index (BMI) (MD = 5.48 kg/m2 ; 95% CI: 3.25-7.72) than those with type 1 diabetes. CONCLUSIONS: Ketosis-prone type 2 diabetes accounts for one third of DKA or ketosis at the onset of diabetes in adults. These patients are characterised by islet autoantibody negativity and preserved insulin secretion. They are older and have a higher BMI compared with type 1 diabetes. C-peptide and diabetes-related autoantibody measurement is essential to identify this subgroup among patients with ketosis at the onset of diabetes.

Astrocyte- and NMDA receptor-dependent slow inward currents differently contribute to synaptic plasticity in an age-dependent manner in mouse and human neocortex.

Slow inward currents (SICs) are known as excitatory events of neurons elicited by astrocytic glutamate via activation of extrasynaptic NMDA receptors. By using slice electrophysiology, we tried to provide evidence that SICs can elicit synaptic plasticity. Age dependence of SICs and their impact on synaptic plasticity was also investigated in both on murine and human cortical slices. It was found that SICs can induce a moderate synaptic plasticity, with features similar to spike timing-dependent plasticity. Overall SIC activity showed a clear decline with aging in humans and completely disappeared above a cutoff age. In conclusion, while SICs contribute to a form of astrocyte-dependent synaptic plasticity both in mice and humans, this plasticity is differentially affected by aging. Thus, SICs are likely to play an important role in age-dependent physiological and pathological alterations of synaptic plasticity.

Risk factors for diabetes mellitus after acute pancreatitis: a systematic review and meta-analysis.

Introduction: Within 5 years of having acute pancreatitis (AP), approximately 20% of patients develop diabetes mellitus (DM), which later increases to approximately 40%. Some studies suggest that the prevalence of prediabetes (PD) and/or DM can grow as high as 59% over time. However, information on risk factors is limited. We aimed to identify risk factors for developing PD or DM following AP. Methods: We systematically searched three databases up to 4 September 2023 extracting direct, within-study comparisons of risk factors on the rate of new-onset PD and DM in AP patients. When PD and DM event rates could not be separated, we reported results for this composite outcome as PD/DM. Meta-analysis was performed using the random-effects model to calculate pooled odds ratios (OR) with 95% confidence intervals (CI). Results: Of the 61 studies identified, 50 were included in the meta-analysis, covering 76,797 participants. The studies reported on 79 risk factors, and meta-analysis was feasible for 34 risk factor and outcome pairs. The odds of developing PD/DM was significantly higher after severe and moderately severe AP (OR: 4.32; CI: 1.76-10.60) than mild AP. Hypertriglyceridemic AP etiology (OR: 3.27; CI: 0.17-63.91) and pancreatic necrosis (OR: 5.53; CI: 1.59-19.21) were associated with a higher risk of developing PD/DM. Alcoholic AP etiology (OR: 1.82; CI: 1.09-3.04), organ failure (OR: 3.19; CI: 0.55-18.64), recurrent AP (OR: 1.89; CI: 0.95-3.77), obesity (OR: 1.85; CI: 1.43-2.38), chronic kidney disease (OR: 2.10; CI: 1.85-2.38), liver cirrhosis (OR: 2.48; CI: 0.18-34.25), and dyslipidemia (OR: 1.82; CI: 0.68-4.84) were associated with a higher risk of developing DM. Discussion: Severe and moderately severe AP, alcoholic and hypertriglyceridemic etiologies, pancreatic necrosis, organ failure, recurrent acute pancreatitis and comorbidities of obesity, chronic kidney disease liver disease, and dyslipidemia are associated with a higher risk of developing PD or DM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021281983.

Modulation of motor behavior by the mesencephalic locomotor region.

The mesencephalic locomotor region (MLR) serves as an interface between higher-order motor systems and lower motor neurons. The excitatory module of the MLR is composed of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), and their activation has been proposed to elicit different modalities of movement. However, how the differences in connectivity and physiological properties explain their contributions to motor activity is not well known. Here we report that CnF glutamatergic neurons are more electrophysiologically homogeneous than PPN neurons and have mostly short-range connectivity, whereas PPN glutamatergic neurons are heterogeneous and maintain long-range connections, most notably with the basal ganglia. Optogenetic activation of CnF neurons produces short-lasting muscle activation, driving involuntary motor activity. In contrast, PPN neuron activation produces long-lasting increases in muscle tone that reduce motor activity and disrupt gait. Our results highlight biophysical and functional attributes among MLR neurons that support their differential contribution to motor behavior.

Topographical Organization of M-Current on Dorsal and Median Raphe Serotonergic Neurons.

Dorsal and median raphe nuclei (DR and MR, respectively) are members of the reticular activating system and play important role in the regulation of the sleep-wakefulness cycle, movement, and affective states. M-current is a voltage-gated potassium current under the control of neuromodulatory mechanisms setting neuronal excitability. Our goal was to determine the proportion of DR and MR serotonergic neurons possessing M-current and whether they are organized topographically. Electrophysiological parameters of raphe serotonergic neurons influenced by this current were also investigated. We performed slice electrophysiology on genetically identified serotonergic neurons. Neurons with M-current are located rostrally in the DR and dorsally in the MR. M-current determines firing rate, afterhyperpolarization amplitude, and adaptation index (AI) of these neurons, but does not affect input resistance, action potential width, and high threshold oscillations.These findings indicate that M-current has a strong impact on firing properties of certain serotonergic neuronal subpopulations and it might serve as an effective contributor to cholinergic and local serotonergic neuromodulatory actions.

Orexinergic actions modify occurrence of slow inward currents on neurons in the pedunculopontine nucleus.

Orexins are neuromodulatory peptides of the lateral hypothalamus which regulate homeostatic mechanisms including sleep-wakefulness cycles. Orexinergic actions stabilize wakefulness by acting on the nuclei of the reticular activating system, including the pedunculopontine nucleus. Orexin application to pedunculopontine neurons produces a noisy tonic inward current and an increase in the frequency and amplitudes of excitatory postsynaptic currents. In the present project, we investigated orexinergic neuromodulatory actions on astrocyte-mediated neuronal slow inward currents of pedunculopontine neurons and their relationships with tonic currents by using slice electrophysiology on preparations from mice. We demonstrated that, in contrast to several other neuromodulatory actions and in line with literature data, orexin predominantly elicited a tonic inward current. A subpopulation of the pedunculopontine neurons possessed slow inward currents. Independently from the tonic currents, actions on slow inward currents were also detected, which resembled other neuromodulatory actions: if slow inward currents were almost absent on the neuron, orexin induced an increase of the charge movements by slow inward currents, whereas if slow inward current activity was abundant on the neurons, orexin exerted inhibitory action on it. Our data support the previous findings that orexin elicits only inward currents in contrast with cannabinoid, cholinergic or serotonergic actions. Similar to the aforementioned neuromodulatory actions, orexin influences slow inward currents in a way depending on control slow inward current activity. Furthermore, we found that orexinergic actions on slow inward currents are similarly independent from its actions on tonic currents, as it was previously found with other neuromodulatory agonists.

Astrocyte-Dependent Slow Inward Currents (SICs) Participate in Neuromodulatory Mechanisms in the Pedunculopontine Nucleus (PPN).

Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep. Using slice electrophysiology, optogenetics and morphological reconstruction, we revealed that SICs are present in a population of PPN neurons. The frequency of SICs recorded on PPN neurons was higher when the soma of the given neuron was close to an astrocytic soma. SICs do not appear simultaneously on neighboring neurons, thus it is unlikely that they synchronize neuronal activity in this structure. Occurrence of SICs is regulated by cannabinoid, muscarinic and serotonergic neuromodulatory mechanisms. In most cases, SICs occurred independently from tonic neuronal currents. SICs were affected by different neuromodulatory agents in a rather uniform way: if control SIC activity was low, the applied drugs increased it, but if SIC activity was increased in control, the same drugs lowered it. SICs of PPN neurons possibly represent a mechanism which elicits network-independent spikes on certain PPN neurons; forming an alternative, astrocyte-dependent pathway of neuromodulatory mechanisms.

Cannabinoid signalling inhibits sarcoplasmic Ca2+ release and regulates excitation-contraction coupling in mammalian skeletal muscle.

KEY POINTS: Marijuana was found to cause muscle weakness, although the exact regulatory role of its receptors (CB1 cannabinoid receptor; CB1R) in the excitation-contraction coupling (ECC) of mammalian skeletal muscle remains unknown. We found that CB1R activation or its knockout did not affect muscle force directly, whereas its activation decreased the Ca2+ -sensitivity of the contractile apparatus and made the muscle fibres more prone to fatigue. We demonstrate that CB1Rs are not connected to the inositol 1,4,5-trisphosphate pathway either in myotubes or in adult muscle fibres. By contrast, CB1Rs constitutively inhibit sarcoplasmic Ca2+ release and sarcoplasmic reticulum Ca2+ ATPase during ECC in a Gi/o protein-mediated way in adult skeletal muscle fibres but not in myotubes. These results help with our understanding of the physiological effects and pathological consequences of CB1R activation in skeletal muscle and may be useful in the development of new cannabinoid drugs. ABSTRACT: Marijuana was found to cause muscle weakness, although it is unknown whether it affects the muscles directly or modulates only the motor control of the central nervous system. Although the presence of CB1 cannabinoid receptors (CB1R), which are responsible for the psychoactive effects of the drug in the brain, have recently been demonstrated in skeletal muscle, it is unclear how CB1R-mediated signalling affects the contraction and Ca²âº homeostasis of mammalian skeletal muscle. In the present study, we demonstrate that in vitro CB1R activation increased muscle fatigability and decreased the Ca2+ -sensitivity of the contractile apparatus, whereas it did not alter the amplitude of single twitch contractions. In myotubes, CB1R agonists neither evoked, nor influenced inositol 1,4,5-trisphosphate (IP3 )-mediated Ca2+ transients, nor did they alter excitation-contraction coupling. By contrast, in isolated muscle fibres of wild-type mice, although CB1R agonists did not evoke IP3 -mediated Ca2+ transients too, they significantly reduced the amplitude of the depolarization-evoked transients in a pertussis-toxin sensitive manner, indicating a Gi/o protein-dependent mechanism. Concurrently, on skeletal muscle fibres isolated from CB1R-knockout animals, depolarization-evoked Ca2+ transients, as well qas Ca2+ release flux via ryanodine receptors (RyRs), and the total amount of released Ca2+ was significantly greater than that from wild-type mice. Our results show that CB1R-mediated signalling exerts both a constitutive and an agonist-mediated inhibition on the Ca2+ transients via RyR, regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase and enhances muscle fatigability, which might decrease exercise performance, thus playing a role in myopathies, and therefore should be considered during the development of new cannabinoid drugs.

The M-current contributes to high threshold membrane potential oscillations in a cell type-specific way in the pedunculopontine nucleus of mice.

The pedunculopontine nucleus is known as a cholinergic nucleus of the reticular activating system, participating in regulation of sleep and wakefulness. Besides cholinergic neurons, it consists of GABAergic and glutamatergic neurons as well. According to classical and recent studies, more subgroups of neurons were defined. Groups based on the neurotransmitter released by a neuron are not homogenous, but can be further subdivided. The PPN neurons do not only provide cholinergic and non-cholinergic inputs to several subcortical brain areas but they are also targets of cholinergic and other different neuromodulatory actions. Although cholinergic neuromodulation has been already investigated in the nucleus, one of its characteristic targets, the M-type potassium current has not been described yet. Using slice electrophysiology, we provide evidence in the present work that cholinergic neurons possess M-current, whereas GABAergic neurons lack it. The M-current contributes to certain functional differences of cholinergic and GABAergic neurons, as spike frequency adaptation, action potential firing frequency or the amplitude difference of medium afterhyperpolarizations (AHPs). Furthermore, we showed that high threshold membrane potential oscillation with high power, around 20 Hz frequency is a functional property of almost all cholinergic cells, whereas GABAergic neurons have only low amplitude oscillations. Blockade of the M-current abolished the oscillatory activity at 20 Hz, and largely diminished it at other frequencies. Taken together, the M-current seems to be characteristic for PPN cholinergic neurons. It provides a possibility for modulating gamma band activity of these cells, thus contributing to neuromodulatory regulation of the reticular activating system.

Cholinergic and endocannabinoid neuromodulatory effects overlap on neurons of the pedunculopontine nucleus of mice.

The pedunculopontine nucleus (PPN) is a part of the reticular activating system and one of the main sources of the cholinergic fibers in the midbrain, while it is also subject to cholinergic modulation. This nucleus is known to be a structure that controls sleep-wake cycles, arousal, and locomotion. Neurons of the PPN are targets of several neuromodulatory mechanisms, which elicit heterogeneous pharmacological responses including hyperpolarization and depolarization, whereas lack of response can also be observed. In agreement with previous findings, we found that PPN neurons respond to the muscarinic agonist carbachol in a heterogeneous manner: they were depolarized and showed increased firing rate, decreased firing frequency, and were hyperpolarized, or showed no response. The heterogeneity of the muscarinic activation was similar to our previous observations with type 1 cannabinoid (CB1) receptor agonists; therefore, we investigated whether muscarinic and endocannabinoid modulatory mechanisms elicit the same action on a certain neuron. To achieve this, whole-cell patch clamp experiments were conducted on midbrain slices containing the PPN. Carbachol was applied first and, after recording the changes in the membrane potential and the firing frequency and achieving washout, the CB1 receptor agonist arachidonyl-2'-chloroethylamide (ACEA) was applied. A marked but not full overlap was observed: all neurons depolarized by carbachol were depolarized by the CB1 receptor agonist ACEA, and all neurons lacking response to carbachol lacked response to ACEA as well. However, neurons hyperpolarized by carbachol were depolarized, hyperpolarized, or not affected by the ACEA. These results indicate that endocannabinoid and muscarinic modulatory effects involve similar mechanisms of action.

Endocannabinoid signaling modulates neurons of the pedunculopontine nucleus (PPN) via astrocytes.

The pedunculopontine nucleus (PPN) is known as the cholinergic part of the reticular activating system (RAS) and it plays an important role in transitions of slow-wave sleep to REM sleep and wakefulness. Although both exogenous and endocannabinoids affect sleep, the mechanism of endocannabinoid neuromodulation has not been characterized at cellular level in the PPN. In this paper, we demonstrate that both neurons and glial cells from the PPN respond to cannabinoid type 1 (CB1) receptor agonists. The neuronal response can be depolarization or hyperpolarization, while astrocytes exhibit more frequent calcium waves. All these effects are absent in CB1 gene-deficient mice. Blockade of the fast synaptic neurotransmission or neuronal action potential firing does not change the effect on the neuronal membrane potential significantly, while inhibition of astrocytic calcium waves by thapsigargin diminishes the response. Inhibition of group I metabotropic glutamate receptors (mGluRs) abolishes hyperpolarization, whereas blockade of group II mGluRs prevents depolarization. Initially active neurons and glial cells display weaker responses partially due to the increased endocannabinoid tone in their environment. Taken together, we propose that cannabinoid receptor stimulation modulates PPN neuronal activity in the following manner: active neurons may elicit calcium waves in astrocytes via endogenous CB1 receptor agonists. Astrocytes in turn release glutamate that activates different metabotropic glutamate receptors of neurons and modulate PPN neuronal activity.

[Health care of the students at the Elisabeth University in Pécs between 1924 and 1950]. / Az Erzsébet Tudományegyetem hallgatóinak egészségvédelme 1924-1950.

In this study, we present the arrangements of the Erzsébet University, seated in Pécs since 1923, on student health protection via analyzing the archive resources. Due to the scattered resources, we cannot give an account on the preceding Pozsony (1914-20) or Budapest (1920-23) era. In this period, the resources mention only the boarding-students' medical attendance by an internist teaching assistant. After the University moved to Pécs, Dr. János Angyán was the one, who considered the (health protection) issue significant. In his proposition, he suggested the University should set up a hospital association and the pre-examination of the boarding-students. The actual examination of the students was introduced along with the compulsory physical education. While it was compulsory for male students, female students could participate voluntarily since the fall of 1927. From 1923, the cost of medical arrangements of the students of the fourth faculty, of the Evangelical Theological Faculty, was covered by a separate fund financed by university students. In the early 1930s, it was Dr. János Angyán again who made a proposition that the examinations should be institutionalized, which in the new settings took place in the school year of 1936-37. In three consecutive years all the students were subject to examinations. The participation rate differed among the faculties. It was high among the freshmen of the Medical Faculty and of the Humanities, however, it was 22 percent of the Faculty of Law at the beginning and even later, in the fall of 1948 it was only 48 percent. Besides the management of the University, other universities and non-governmental organizations of the country stood up to fight against contagions of the era, such as the Tuberculosis and venereal diseases. These initiatives were carefully considered by the management of the university, which took proper action in each and every case. In the 1940s the examinations continued, which were suspended during the war. The management planned to restart the examinations in 1947, however, no data survived from this period.