Brain RFamide Neuropeptides in Stress-Related Psychopathologies.

The RFamide peptide family is a group of proteins that share a common C-terminal arginine-phenylalanine-amide motif. To date, the family comprises five groups in mammals: neuropeptide FF, LPXRFamides/RFamide-related peptides, prolactin releasing peptide, QRFP, and kisspeptins. Different RFamide peptides have their own cognate receptors and are produced by different cell populations, although they all can also bind to neuropeptide FF receptors with different affinities. RFamide peptides function in the brain as neuropeptides regulating key aspects of homeostasis such as energy balance, reproduction, and cardiovascular function. Furthermore, they are involved in the organization of the stress response including modulation of pain. Considering the interaction between stress and various parameters of homeostasis, the role of RFamide peptides may be critical in the development of stress-related neuropathologies. This review will therefore focus on the role of RFamide peptides as possible key hubs in stress and stress-related psychopathologies. The neurotransmitter coexpression profile of RFamide-producing cells is also discussed, highlighting its potential functional significance. The development of novel pharmaceutical agents for the treatment of stress-related disorders is an ongoing need. Thus, the importance of RFamide research is underlined by the emergence of peptidergic and G-protein coupled receptor-based therapeutic targets in the pharmaceutical industry.

The Dopaminergic Cells in the Median Raphe Region Regulate Social Behavior in Male Mice.

According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response.

Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications.

The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane's raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels. Surprisingly, depleting cholesterol using cyclodextrin resulted in an unexpected increase in the proportion of raft-associated P-gp within the cell membrane, as determined by UIC2-reactive P-gp. This increase appears to be a compensatory response to cholesterol loss from the plasma membrane, whereby cholesterol-rich raft micro-domains are delivered to the cell surface through an augmented exocytosis process. Furthermore, this exocytotic event is found to be part of a complex trafficking mechanism involving lysosomal exocytosis, which contributes to membrane repair after cholesterol reduction induced by cyclodextrin treatment. Notably, cells overexpressing P-gp demonstrated higher total cellular cholesterol levels, an increased abundance of stable lysosomes, and more effective membrane repair following cholesterol modifications. These modifications encompassed exocytotic events that involved the transport of P-gp-carrying rafts. Importantly, the enhanced membrane repair capability resulted in a durable phenotype for MDR1 expressing cells, as evidenced by significantly improved viabilities of multidrug-resistant Pgp-overexpressing immortal NIH-3T3 MDR1 and MDCK-MDR1 cells compared to their parents when subjected to cholesterol alterations.

Enhancement of Hydrophilicity of Nano-Pitted TiO2 Surface Using Phosphoric Acid Etching.

Our research group developed a novel nano-pitted (NP) TiO2 surface on grade 2 titanium that showed good mechanical, osteogenic, and antibacterial properties; however, it showed weak hydrophilicity. Our objective was to develop a surface treatment method to enhance the hydrophilicity of the NP TiO2 surface without the destruction of the nano-topography. The effects of dilute and concentrated orthophosphoric (H3PO4) and nitric acids were investigated on wettability using contact angle measurement. Optical profilometry and atomic force microscopy were used for surface roughness measurement. The chemical composition of the TiO2 surface and the oxidation state of Ti was investigated using X-ray photoelectron spectroscopy. The ccH3PO4 treatment significantly increased the wettability of the NP TiO2 surfaces (30°) compared to the untreated control (88°). The quantity of the absorbed phosphorus significantly increased following ccH3PO4 treatment compared to the control and caused the oxidation state of titanium to decrease (Ti4+ → Ti3+). Owing to its simplicity and robustness the presented surface treatment method may be utilized in the industrial-scale manufacturing of titanium implants.

Prolactin-Releasing Peptide Contributes to Stress-Related Mood Disorders and Inhibits Sleep/Mood Regulatory Melanin-Concentrating Hormone Neurons in Rats.

Stress disorders impair sleep and quality of life; however, their pathomechanisms are unknown. Prolactin-releasing peptide (PrRP) is a stress mediator; we therefore hypothesized that PrRP may be involved in the development of stress disorders. PrRP is produced by the medullary A1/A2 noradrenaline (NA) cells, which transmit stress signals to forebrain centers, and by non-NA cells in the hypothalamic dorsomedial nucleus. We found in male rats that both PrRP and PrRP-NA cells innervate melanin-concentrating hormone (MCH) producing neurons in the dorsolateral hypothalamus (DLH). These cells serve as a key hub for regulating sleep and affective states. Ex vivo, PrRP hyperpolarized MCH neurons and further increased the hyperpolarization caused by NA. Following sleep deprivation, intracerebroventricular PrRP injection reduced the number of REM sleep-active MCH cells. PrRP expression in the dorsomedial nucleus was upregulated by sleep deprivation, while downregulated by REM sleep rebound. Both in learned helplessness paradigm and after peripheral inflammation, impaired coping with sustained stress was associated with (1) overactivation of PrRP cells, (2) PrRP protein and receptor depletion in the DLH, and (3) dysregulation of MCH expression. Exposure to stress in the PrRP-insensitive period led to increased passive coping with stress. Normal PrRP signaling, therefore, seems to protect animals against stress-related disorders. PrRP signaling in the DLH is an important component of the PrRP's action, which may be mediated by MCH neurons. Moreover, PrRP receptors were downregulated in the DLH of human suicidal victims. As stress-related mental disorders are the leading cause of suicide, our findings may have particular translational relevance.SIGNIFICANCE STATEMENT Treatment resistance to monoaminergic antidepressants is a major problem. Neuropeptides that modulate the central monoaminergic signaling are promising targets for developing alternative therapeutic strategies. We found that stress-responsive prolactin-releasing peptide (PrRP) cells innervated melanin-concentrating hormone (MCH) neurons that are crucial in the regulation of sleep and mood. PrRP inhibited MCH cell activity and enhanced the inhibitory effect evoked by noradrenaline, a classic monoamine, on MCH neurons. We observed that impaired PrRP signaling led to failure in coping with chronic/repeated stress and was associated with altered MCH expression. We found alterations of the PrRP system also in suicidal human subjects. PrRP dysfunction may underlie stress disorders, and fine-tuning MCH activity by PrRP may be an important part of the mechanism.

Hypothalamic Nesfatin-1 Resistance May Underlie the Development of Type 2 Diabetes Mellitus in Maternally Undernourished Non-obese Rats.

Intrauterine growth retardation (IUGR) poses a high risk for developing late-onset, non-obese type 2 diabetes (T2DM). The exact mechanism underlying this phenomenon is unknown, although the contribution of the central nervous system is recognized. The main hypothalamic nuclei involved in the homeostatic regulation express nesfatin-1, an anorexigenic neuropeptide and identified regulator of blood glucose level. Using intrauterine protein restricted rat model (PR) of IUGR, we investigated, whether IUGR alters the function of nesfatin-1. We show that PR rats develop fat preference and impaired glucose homeostasis by adulthood, while the body composition and caloric intake of normal nourished (NN) and PR rats are similar. Plasma nesfatin-1 levels are unaffected by IUGR in both neonates and adults, but pro-nesfatin-1 mRNA expression is upregulated in the hypothalamus of adult PR animals. We find that centrally injected nesfatin-1 inhibits the fasting induced neuronal activation in the hypothalamic arcuate nucleus in adult NN rats. This effect of nesfatin-1 is not seen in PR rats. The anorexigenic effect of centrally injected nesfatin-1 is also reduced in adult PR rats. Moreover, chronic central nesfatin-1 administration improves the glucose tolerance and insulin sensitivity in NN rats but not in PR animals. Birth dating of nesfatin-1 cells by bromodeoxyuridine (BrDU) reveals that formation of nesfatin-1 cells in the hypothalamus of PR rats is disturbed. Our results suggest that adult PR rats acquire hypothalamic nesfatin-1-resistance, probably due to the altered development of the hypothalamic nesfatin-1 cells. Hypothalamic nesfatin-1-resistance, in turn, may contribute to the development of non-obese type T2DM.

Rescue of Vasopressin Synthesis in Magnocellular Neurons of the Supraoptic Nucleus Normalises Acute Stress-Induced Adrenocorticotropin Secretion and Unmasks an Effect on Social Behaviour in Male Vasopressin-Deficient Brattleboro Rats.

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA), but not in the central and basolateral amygdala or lateral hypothalamus. In vitro electrophysiological recordings showed an AVP-induced inhibition of MeA neurons that was prevented by picrotoxin administration, supporting the possible regulatory role of AVP originating in the SON. A memory deficit in the novel object recognition test seen in di/di animals remained unaffected by AVP-AAV treatment. Interestingly, although di/di rats show intact social investigation and aggression, the SON AVP-AAV treatment resulted in an alteration of these social behaviours. AVP released from the magnocellular SON neurons may stimulate adrenocorticotropin secretion in response to defined stressors and might participate in the fine-tuning of social behaviour with a possible contribution from the MeA.

Sleep alterations are related to cognitive symptoms in Parkinson's disease: A 24-hour ambulatory polygraphic EEG study.

BACKGROUND: Sleep disorders are frequent and early non-motor symptoms of Parkinson's disease (PD). As a consequence of histopathological changes, the regulation of rapid eye movement (REM) sleep is affected in PD causing REM sleep behaviour disorder in about half of the patients. Considering the well-known role of sleep in memory formation processes, our aim was to investigate the relationship between sleep alterations and cognitive performance to elucidate the possible association between sleep, and especially REM sleep changes and cognitive dysfunction in PD. METHODS: We investigated 25 PD patients and 20 healthy controls. All participants underwent a 24-hour-long 19-channel polygraphic EEG recording, neurological, neuroimaging and neuropsychological examination. The visually analysed sleep-EEG and neuropsychological data were statistically evaluated. RESULTS: The intergroup analysis showed significant decrease of REM and N3, but increase of N2 sleep ratio, and significantly lower scores in the verbal fluency in PD compared to healthy controls. While we found significant negative correlation between verbal fluency and REM-sleep in the whole sample, we observed a marginal significant correlation between phonemic fluency and REM sleep in the PD group. CONCLUSION: The negative correlation between verbal fluency performance and REM sleep duration suggests the role of decreased REM sleep in cognitive dysfunction in PD. The early involvement of REM sleep regulation with parallel executive dysfunction in PD emphasise the important role of REM sleep deterioration in the neurodegenerative process of PD.

Chemical characterization of pineal neurons in perinatal rats.

Ample evidence indicates that in several mammalian species the pineal body contains neurons. In adult white albino rats neurons are not present in the pineal body; however, in perinatal rats many neurons were described. It was demonstrated that in adult mammalian species the pineal neurons contained some neuropeptides and neurotransmitters such as leu-enkephalin, met-enkephalin, substance-P, somatostatin and γ-aminobutiric acid. Oxytocin, vasopressin mRNAs and peptides were also demonstrated. No data are available on the chemical nature of the neurons in perinatal rats. In the present experiment we used immunohistochemistry to clarify this issue. After paraformaldehyde fixation frozen sections were prepared and stained for immunoreactivities of several neuropeptides and neurotransmitters. Dopamine ß-hydroxylase, neuropeptide-Y, vesicular acetylcholine transporter, vesicular glutamate transporter and calcitonin gene-related peptide antibodies were able to stain fibers. According to previous data these fibers may be sympathetic, parasympathetic or sensory. Vesicular glutamate transporter antibody may stain pinealocytes as well. Some cells were immunoreactive for substance-P, oxytocin, vasopressin, leu-enkefalin and glutamic acid decarboxylase. These immnoreactivities showed colocalization with neuron-specific nuclear protein immunoreactivity indicating that these cells were neurons. Calbindin was observed in oval and elongated cells resembling pinealocytes. Based on the results obtained in adult mammals, the pineal neurons may be analogue to retinal ganglion cells, or they may function as interneurons in the retino-pinealo-retinal neuronal circuit or peptidergic neurons may influence pinealocytes in a paracrine manner.

Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation.

Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor-Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB1R) in these effects. Expression of CB1R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10-9-10-7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10-7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction.

Burnout among Hungarian dentists / Kiégés a magyar fogorvosok körében.

Összefoglaló. Bevezetés: A kiégés jelensége fokozottan érinti az egészségügyi dolgozókat, a nagyfokú stressz, a folyamatos fizikai és emocionális megterhelés miatt. A kiégés mérését fogorvosok körében végeztük, mivel Magyarországon még nem készült csak fogorvosokat méro keresztmetszeti vizsgálat. Célkituzés: Elsodleges célunk a fogorvosi kiégés elofordulásának, súlyosságának mérése, a rizikófaktorok kiszurése volt. Másodlagos célul a kiégés veszélyére való figyelem felkeltését tuztük ki az érintett csoportban. Módszer: Az adatgyujtés a 'Maslach Burnout Inventory - Human Services Survey' 22 tételes magyar, validált változatával történt online formában. Eredmények: Online kérdoívünket 407 fogorvos töltötte ki. A következo eredményeket kaptuk: az emocionális kimerülés esetében a válaszadók 20%-a (81 fo) tartozik a magas kategóriába, a cinizmus dimenziójának esetében a válaszadók 17,5%-át (70 fo) jellemzi a magas pontszám. A teljesítményvesztés magas dimenziója a minta 75%-ában (302 fo) volt igazolható. Szignifikáns (p≤0,05) védofaktornak találtuk a harmonikus kollegiális viszonyt, a hobbi meglétét, a 2-4 óra napi munkát, a támogató otthoni és munkahelyi légkört, az egészségi probléma és a saját vállalkozás hiányát. Szignifikáns negatív eltérést 6-10 éve dolgozó férfiak körében találtunk. Következtetés: Az eredmények felhívják a figyelmet a legfontosabb protektív tényezokre, melyek segítségével csökkentheto a kiégés mértéke. Orv Hetil. 2021; 162(11): 419-424. INTRODUCTION: Burnout has an increased impact on healthcare workers due to severe stress, constant physical and emotional strain. Burnout was measured among dentists, as no such cross-sectional study has been made in Hungary. OBJECTIVE: Our primary goal was to measure the incidence and severity of dental burnout and to screen for the risk factors. Our secondary goal was to raise awareness of the risk of burnout in the affected group. METHOD: Data collection was performed online with the 22-item Hungarian validated version of Maslach Burnout Inventory - Human Services Survey. RESULTS: 407 dentists completed our online questionnaire. The following results were obtained: in the case of emotional exhaustion, 20% of the respondents belong to the high category, in the cynicism dimension, 17.5% of the respondents have high scores. The high dimension of performance loss is typical in 75% of the sample. We found that harmonious collegial relationships, the existence of a hobby, 2-4 hours of daily work, a supportive home and work atmosphere, the lack of health problems and self-employment are significant (p≤0.05) protective factors. Significant negative differences were found among men who had been working for 6-10 years. CONCLUSION: The results draw attention to the most important protective factors that can help reduce the rate of burnout. Orv Hetil. 2021; 162(11): 419-424.

Comparison of Methods for Active Orbital Selection in Multiconfigurational Calculations.

Several methods of constructing the active orbital space for multiconfigurational wave functions are compared on typical moderately strongly or strongly correlated ground-state molecules. The relative merits of these methods and problems inherent in multiconfigurational calculations are discussed. Strong correlation in the ground electronic state is found typically in larger conjugated and in antiaromatic systems, transition states which involve bond breaking or formation, and transition metal complexes. Our examples include polyenes, polyacenes, the reactant, product and transition state of the Bergman cyclization, and two transition metal complexes: Hieber's anion [(CO)3FeNO]- and ferrocene. For the systems investigated, the simplest and oldest selection method, based on the fractional occupancy of unrestricted Hartree-Fock natural orbitals (the UNO criterion), yields the same active space as much more expensive approximate full CI methods. A disadvantage of this method used to be the difficulty of finding broken spin symmetry UHF solutions. However, our analytical method, accurate to fourth order in the orbital rotation angles (Tóth and Pulay J. Chem. Phys. 2016, 145, 164102.), has solved this problem. Two further advantages of the UNO criterion are that, unlike most other methods, it measures not only the energetic proximity to the Fermi level but also the magnitude of the exchange interaction with strongly occupied orbitals and therefore allows the estimation of the correlation strength for orbital selection in Restricted Active Space methods.

Colocalized neurotransmitters in the hindbrain cooperate in adaptation to chronic hypernatremia.

Chronic hypernatremia activates the central osmoregulatory mechanisms and inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline (NE) release into the periventricular anteroventral third ventricle region (AV3V), the supraoptic (SON) and hypothalamic paraventricular nuclei (PVN) from efferents of the caudal ventrolateral (cVLM) and dorsomedial (cDMM) medulla has been shown to be essential for the hypernatremia-evoked responses and for the HPA response to acute restraint. Notably, the medullary NE cell groups highly coexpress prolactin-releasing peptide (PrRP) and nesfatin-1/NUCB2 (nesfatin), therefore, we assumed they contributed to the reactions to chronic hypernatremia. To investigate this, we compared two models: homozygous Brattleboro rats with hereditary diabetes insipidus (DI) and Wistar rats subjected to chronic high salt solution (HS) intake. HS rats had higher plasma osmolality than DI rats. PrRP and nesfatin mRNA levels were higher in both models, in both medullary regions compared to controls. Elevated basal tyrosine hydroxylase (TH) expression and impaired restraint-induced TH, PrRP and nesfatin expression elevations in the cVLM were, however, detected only in HS, but not in DI rats. Simultaneously, only HS rats exhibited classical signs of chronic stress and severely blunted hormonal reactions to acute restraint. Data suggest that HPA axis responsiveness to restraint depends on the type of hypernatremia, and on NE capacity in the cVLM. Additionally, NE and PrRP signalization primarily of medullary origin is increased in the SON, PVN and AV3V in HS rats. This suggests a cooperative action in the adaptation responses and designates the AV3V as a new site for PrRP's action in hypernatremia.

Ionization energies in solution with the QM:QM approach.

We discuss a fragment-based QM:QM scheme as a practical way to access the energetics of vertical electronic processes in the condensed phase. In the QM:QM scheme, we decompose the large molecular system into small fragments, which interact solely electrostatically. The energies of the fragments are calculated in a self-consistent field generated by the other fragments and the total energy of the system is calculated as a sum of the fragment energies. We show on two test cases (cytosine and a sodium cation) that the method allows one to accurately simulate the shift of vertical ionization energies (VIE) while going from the gas phase to the bulk. For both examples, the predicted solvent shifts and peak widths estimated at the DFT level agree well with the experimental observations. We argue that the QM:QM approach is more suitable than either an electrostatic embedding based QM/MM approach, a full quantum description at the DFT level with a generally used functional or a combination of both. We also discuss the potential scope of the applicability for other electronic processes such as Auger decay.

Circadian Variation of Migraine Attack Onset: A Review of Clinical Studies.

Several studies suggested that migraine attack onset shows a circadian variation; however, there has not been an overview and synthesis of these findings. A PubMed search with keywords "migraine" AND "circadian" resulted in ten studies directly investigating this topic. Results of these studies mostly show that migraine attacks follow a monophasic 24-hour cyclic pattern with an early morning or late night peak while other studies reported an afternoon peak and also a biphasic 24-hour cycle of attacks. The identified studies showed methodological variation including sample size, inclusion of medication use, comorbidities, and night or shift workers which could have contributed to the contradictory results. Several theories emerged explaining the diurnal distribution of migraine attacks suggesting roles for different phenomena including a morning rise in cortisol levels, a possible hypothalamic dysfunction, a circadian variation of migraine triggers, sleep stages, and a potentially different setting of the circadian pacemaker among migraineurs. At the moment, most studies show an early morning or late night peak of migraine attack onset, but a significant amount of studies reveals contradictory results. Further studies should investigate the arising hypotheses to improve our understanding of the complex mechanism behind the circadian variation of migraine attacks that can shed light on new targets for migraine therapy.

[Risk assessment of medication-related osteonecrosis of the jaw in general dental practice]. / A gyógyszer által indukált állcsontnecrosis-kockázat mértékének meghatározása az általános fogorvosi gyakorlatban.

Medication-related osteonecrosis of the jaw may appear as adverse effect in antiresorptive therapy. Its successful treatment is challenging. We aimed to gather the systemic and local factors playing a role in etiology, published after its recognition. Risk factors were collected from the PubMed database 1998-2018. The three main groups of risk patients are: patients starting, patients having antiresorptive therapy, osteonecrosis diagnosed patients. The dentist must recognize risk factors, determine appropriate treatment plan and frequency of check-ups. Oncological disease treated intravenously means the greatest risk. Further systemic risk factors are: supportive therapies, concomitant disease, way of life, individual factors. Local risk factors may be: dentoalveolar surgery, periapical and periodontal inflammation, ill-fitting denture, presence of some anatomical structures. The accumulation of risk factors determines the probability of the manifestation of osteonecrosis. The most favorable case is patient starting antiresorptive therapy with a dental status needing no treatment. Orv hetil. 2019; 160(7): 243-251.

Reward-representing D1-type neurons in the medial shell of the accumbens nucleus regulate palatable food intake.

BACKGROUND/OBJECTIVES: Dysfunction in reward-related aspects of feeding, and consequent overeating in humans, is a major contributor to obesity. Intrauterine undernutrition and overnutrition are among the predisposing factors, but the exact mechanism of how overeating develops is still unclear. Consummatory behavior is regulated by the medial shell (mSh) of the accumbens nucleus (Nac) through direct connections with the rostral part of the lateral hypothalamic area (LHA). Our aim was to investigate whether an altered Nac-LHA circuit may underlie hyperphagic behavior. SUBJECTS/METHODS: Intrauterine protein-restricted (PR) male Wistar rats were used as models for hyperphagia. The experiments were performed using young adult control (normally nourished) and PR animals. Sweet condensed milk (SCM) served as a reward to test consumption and subsequent activation (Fos+) of Nac and LHA neurons. Expression levels of type 1 and 2 dopamine receptors (D1R, D2R) in the Nac, as well as tyrosine hydroxylase (TH) levels in the ventral tegmental area, were determined. The D1R agonist SKF82958 was injected into the mSh-Nac of control rats to test the effect of D1R signaling on SCM intake and neuronal cell activation in the LHA. RESULTS: A group of food reward-representing D1R+ neurons was identified in the mSh-Nac. Activation (Fos+) of these neurons was highly proportional to the consumed palatable food. D1R agonist treatment attenuated SCM intake and diminished the number of SCM-activated cells in the LHA. Hyperphagic PR rats showed increased intake of SCM, reduced D1R expression, and an impaired response to SCM-evoked neuronal activation in the mSh-Nac, accompanied by an elevated number of Fos+ neurons in the LHA compared to controls. CONCLUSIONS: Sensitivity of food reward-representing neurons in the mSh-Nac determines the level of satisfaction that governs cessation of consumption, probably through connections with the LHA. D1R signaling is a key element in this function, and is impaired in obesity-prone rats.

[Considerations of elderly patient's dental rehabilitation treated with bisphophonate]. / A fogpótláskészítés szempontjai biszfoszfonáttal kezelt idos páciens esetén.

Recently, drugs targeting the remodelling, vascular circulation and homeostasis of bone are frequently applied with an unquestionable benefit in the therapy of numerous severe medical conditions. Besides bisphosphonates, other antiresorptive and antiangiogenic drugs are also used, however, limited publications are focusing on data of their results. Increasing number of patients arrives the mentioned medication is increasing in the daily dental practice, especially when accurate anamnesis is taken. Our aim is to highlight the preventive considerations that help minimize the occurence of medication-related osteonecrosis of the jaw by presentating a complex dental rehabilitation of a patient at risk. The synchronization of dental surgery, conservative and prosthodontic treatment is essential in the case of an elderly patient having many concomitant disorders. Our aim is also to draw the attention of our colleagues working on different medical fields to the timing of dental procedures. The best and simplest way to prevent jaw necrosis is to achieve good oral health and hygiene before the introduction of antiresorptive therapy. If, however, our patient is already taking this medication, we still have a chance to prevent the appearance of this devastating condition by following the preventive measures. The medication-related necrosis of the jaw is a severe condition leading to a decreased life quality and having a reduced healing expectancy. Orv Hetil. 2018; 159(48): 2031-2036.

Genome sequence of Shigella sonnei 4303.

BACKGROUND: Shigella spp. are Gram-negative intracellular pathogenic bacteria belonging to the family Enterobacteriaceae and can cause bacterial dysentery, a severe diarrheal disease. The pathophysiological impact of the Gram-negative bacteria is highly related to the composition and structural variability of lipopolysaccharides, the major lipoid components of the outer membrane. Out of the 114 genes involved in the lipopolysaccharide biosynthesis pathway, 47 genes are specific to Shigella spp. Changes in the specific genes can lead to loss of the O polysaccharide side chain, resulting in rough (R) type bacteria with increased sensitivity to temperature, or hydrophobic antibiotics. The formation of various different lipopolysaccharides or lipooligosaccharides has been observed previously in a mutant line showing altered biological properties, but the genetic background has not been investigated in detail. RESULTS: The parental strain of the mutant line, Shigella sonnei 4303, was subjected to whole genome sequencing to gain a better insight into the structure and biosynthesis of lipopolysaccharides. The sequencing revealed a 4,546,505 bp long genome including chromosomal and plasmid DNA, and the lipopolysaccharide biosynthesis genes were also identified. A comparison of the genome was performed with the phylogenetically closely related, wild type, well characterized, highly virulent strain, S. sonnei 53G. CONCLUSION: Analysis of the lipopolysaccharide biosynthetic genes helped us to get more insight into the pathogenicity and virulence of the bacteria. The genome revealed high similarities with S. sonnei 53G, which can be used as a standard in characterizing the S. sonnei 4303's R-type isogenic derivatives.