Experience-Dependent Plasticity and Modulation of Growth Regulatory Molecules at Central Synapses

Structural remodeling or repair of neural circuits depends on the balance between intrinsic neuronal properties and regulatory cues present in the surrounding microenvironment. These processes are also influenced by experience, but it is still unclear how external stimuli modulate growth-regulatory mechanisms in the central nervous system. We asked whether environmental stimulation promotes neuronal plasticity by modifying the expression of growth-inhibitory molecules, specifically those of the extracellular matrix. We examined the effects of an enriched environment on neuritic remodeling and modulation of perineuronal nets in the deep cerebellar nuclei of adult mice. Perineuronal nets are meshworks of extracellular matrix that enwrap the neuronal perikaryon and restrict plasticity in the adult CNS. We found that exposure to an enriched environment induces significant morphological changes of Purkinje and precerebellar axon terminals in the cerebellar nuclei, accompanied by a conspicuous reduction of perineuronal nets. In the animals reared in an enriched environment, cerebellar nuclear neurons show decreased expression of mRNAs coding for key matrix components (as shown by real time PCR experiments), and enhanced activity of matrix degrading enzymes (matrix metalloproteinases 2 and 9), which was assessed by in situ zymography. Accordingly, we found that in mutant mice lacking a crucial perineuronal net component, cartilage link protein 1, perineuronal nets around cerebellar neurons are disrupted and plasticity of Purkinje cell terminal is enhanced. Moreover, all the effects of environmental stimulation are amplified if the afferent Purkinje axons are endowed with enhanced intrinsic growth capabilities, induced by overexpression of GAP-43. Our observations show that the maintenance and growth-inhibitory function of perineuronal nets are regulated by a dynamic interplay between pre- and postsynaptic neurons. External stimuli act on this interaction and shift the balance between synthesis and removal of matrix components in order to facilitate neuritic growth by locally dampening the activity of inhibitory cues

The Influence of Decontamination Procedures on the Surface of Two Polymeric Liners Used in Prosthodontics

Polymeric liners are materials commonly used in prosthodontics to reshape denture surfaces contacting the soft tissues of the oral cavity. The aim of the study was to determine the impact of different cleaning methods on two polymeric materials used in prosthodontics as non-adhesive permanent liners. The material for the research consisted of samples made from Mollosil Plus (Detax, Ettlingen, Germany)—direct polysiloxan liner; and Plastitanium (Pressing Dental, San Marino, Republic of San Marino)—an injection-molded liner. A total of 198 samples were made, 99 of each assessed material. They were exposed to different cleaning methods—a toothbrush, a toothbrush and soap, a toothbrush and toothpaste (BlendaMed, Procter&Gamble, Cincinnati, OH, USA), a toothpaste and denture cleaning paste (Protefix Hygiene Denture Paste, Queisser Pharma, Germany), denture cleansing tablets (Protefix Hygiene Cleaning Tablets, Queisse Pharma, Germany), and a disinfecting spray (Aftermat, Port Jefferson Station, New York City, NY, USA)—for 1 min, 5 min, 10 min, and 15 min. The image acquisition was performed with scanning electron microscopy and samples were analyzed for the homogeneity of their surfaces—the presence of holes, grooves, precipitate, and small and large separating pieces of the material marking departures from this homogeneity. For each type of damage, one point was given. Continuous data from two groups were compared with Mann–Whitney U testing. Due to a small sample size and distribution of variables other than normal, to compare more than two groups, Kruskal–Wallis testing with post hoc analysis (Dunn test with Bonferroni correction) was used. Categorical data were compared with the chi-square test and the Fisher’s exact test. The Mollosil Plus material should be decontaminated with the use of a toothbrush or toothbrush with soap, while Plastitanium material should be disinfected. Plastitanium samples are more susceptible to damage during the decontamination procedures than Mollosil Plus

Noradrenaline Modulates the Membrane Potential and Holding Current of Medial Prefrontal Cortex Pyramidal Neurons via β1-Adrenergic Receptors and HCN Channels

The medial prefrontal cortex (mPFC) receives dense noradrenergic projections from the locus coeruleus. Adrenergic innervation of mPFC pyramidal neurons plays an essential role in both physiology (control of memory formation, attention, working memory, and cognitive behavior) and pathophysiology (attention deficit hyperactivity disorder, posttraumatic stress disorder, cognitive deterioration after traumatic brain injury, behavioral changes related to addiction, Alzheimer’s disease and depression). The aim of this study was to elucidate the mechanism responsible for adrenergic receptor-mediated control of the resting membrane potential in layer V mPFC pyramidal neurons. The membrane potential or holding current of synaptically isolated layer V mPFC pyramidal neurons was recorded in perforated-patch and classical whole-cell configurations in slices from young rats. Application of noradrenaline (NA), a neurotransmitter with affinity for all types of adrenergic receptors, evoked depolarization or inward current in the tested neurons irrespective of whether the recordings were performed in the perforated-patch or classical whole-cell configuration. The effect of noradrenaline depended on β1- and not α1- or α2-adrenergic receptor stimulation. Activation of β1-adrenergic receptors led to an increase in inward Na+ current through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which carry a mixed Na+/K+ current. The protein kinase A- and C-, glycogen synthase kinase-3β- and tyrosine kinase-linked signaling pathways were not involved in the signal transduction between β1-adrenergic receptors and HCN channels. The transduction system operated in a membrane-delimited fashion and involved the βγ subunit of G-protein. Thus, noradrenaline controls the resting membrane potential and holding current in mPFC pyramidal neurons through β1-adrenergic receptors, which in turn activate HCN channels via a signaling pathway involving the βγ subunit

Cutaneous and bony metastases after treatment of endometrial cancer – case report and review of the literature

In terms of incidence, endometrial cancer is the sixth most common malignancy in women. Endometrial cancer disseminates mainly by the lymphatics to regional lymph nodes. Hematogenous spread usually concerns lungs, liver and bones. Distant metastases are infrequent, usually develop in the lungs and occur in not more than 4.6% of the cases. Cutaneous metastases of endometrial cancer are extremely rare and are associated with a poor prognosis. We present a case of a 47-year-old patient, operated on for endometrial cancer. Histological study of surgical specimens revealed adenocarcinoma of uterine corpus at moderate grade of histological malignancy and at FIGO stage IIB. Four years after surgery, the patient developed metastases to bones and skin, including scalp. The case is a great rarity not only because of aggressive clinical course concomitant with a prognostically favorable histological diagnosis, but also in view of an highly unusual location of metastases. The paper outlines basic processes governing organ-specific location of metastases. Molecular mechanisms of development of metastases of endometrial cancer, particularly distant ones, is still relatively poorly understood. The paper presents evidence supporting the role of products of genes RUNX1/AML1 and ETV5/ERM in increasing the invasiveness of this tumor and development of metastases. Studies performed to date indicate that assessment of level of expression of these genes might help to identify patients at higher risk for a more aggressive clinical course, thereby contributing to the development of more effective treatment protocols.Pod względem zapadalności kobiet na wszystkie nowotwory rak trzonu macicy znajduje się na szóstym miejscu. Rak endometrium przerzutuje głównie drogą naczyń chłonnych do regionalnych węzłów chłonnych. Szerzące się drogą krwionośną przerzuty odległe najczęściej umiejscawiają się w płucach, wątrobie i kościach. Przerzuty odległe występują niezbyt często, w przeważającej mierze do płuc, dotyczą nie więcej niż 4,6% przypadków. Przerzuty raka trzonu macicy do skóry występują niezmiernie rzadko i wiążą się z bardzo niekorzystnym rokowaniem. W pracy przedstawiono przypadek 47-letniej pacjentki operowanej z powodu raka trzonu macicy. W badaniu histopatologicznym materiału pooperacyjnego stwierdzono obecność gruczolakoraka trzonu macicy o średnim stopniu dojrzałości histologicznej, w stopniu zaawansowania klinicznego FIGO IIB. Po czterech latach od operacji u chorej wystąpiły mnogie przerzuty do kości oraz skóry, w tym skalpu. Opisany przypadek stanowi niezwykłą rzadkość nie tylko ze względu na agresywny przebieg choroby przy zwykle dobrze rokującym rozpoznaniu histopatologicznym, lecz także z uwagi na wyjątkowo spotykane umiejscowienie przerzutów. W niniejszej pracy nakreślono podstawowe procesy warunkujące narządowo swoistą lokalizację przerzutów. Mechanizm tworzenia przerzutów raka endometrium, a szczególnie przerzutów odległych, pod względem molekularnym jest wciąż stosunkowo słabo poznany. W artykule przedstawiono dowody świadczące o wpływie produktów genów RUNX1/AML1 i ETV5/ERM na wzrost inwazyjności tego nowotworu oraz formowanie przerzutów. Dotychczasowe badania pozwalają żywić nadzieję, że w przyszłości ocena poziomu ekspresji tych genów będzie pomocna przy rozpoznaniu pacjentek z wyższym ryzykiem agresywnego przebiegu choroby nowotworowej, a co za tym idzie – w stworzeniu bardziej skutecznych schematów leczenia

Renal denervation decreases blood pressure and renal tyrosine hydroxylase but does not augment the effect of hypotensive drugs

The effect of renal denervation on the efficacy of antihypertensive drugs has not yet been elucidated. Twenty-week-old spontaneously hypertensive rats were treated with metoprolol, losartan, indapamide, or saline (controls) and assigned to renal denervation or a sham procedure. Acute hemodynamic measurements were performed ten days later. Series showing a significant interaction between renal denervation and the drugs were repeated with chronic telemetry measurements. In the saline series, denervated rats showed a significantly lower mean arterial blood pressure (blood pressure) than the sham-operated rats. In contrast, in the metoprolol series denervated rats showed a significantly higher blood pressure than sham rats. There were no differences in blood pressure between denervated and sham rats in the losartan and indapamide series. In chronic studies, a 4-week treatment with metoprolol caused a decrease in blood pressure. Renal denervation and sham denervation performed 10 days after the onset of metoprolol treatment did not affect blood pressure. Denervated rats showed markedly reduced renal nerve tyrosine hydroxylase levels. In conclusion, renal denervation decreases blood pressure in hypertensive rats. The hypotensive action of metoprolol, indapamide, and losartan is not augmented by renal denervation, suggesting the absence of synergy between renal denervation and the drugs investigated in this study

Distribution of polyethylenimine in zebrafish embryos

Background. Polyethylenimine (PEI) plays important roles in the pharmaceutical design of non-viral gene delivery systems. Due to a set of unique physicochemical properties this cationic polymer has a great potential in modern gene therapies. Objective. The aim of the present study was to determine the distribution of branched PEI (0.8 kDa) in zebrafish embryos (Danio rerio). Material and methods. Zebrafish embryos at 3 hours post-fertilization (hpf) were incubated with PEI (10 μg/ml) for 24 and 48 hours and studied using the confocal laser microscopy. Results. The obtained results show that PEI effectively distributed into the layers of the chorion and yolk sac in developing embryos due to first 24 hours of exposure. In contrast, PEI was found in the yolk, head, trunk and tail of the embryos due to prolonged treatments (48 hours). Conclusion. The study evidences a high distribution of the branched PEI (0.8 kDa) polymer in the zebrafish embryo tissues

Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite.

An increased blood trimethylamine N-oxide (TMAO) has emerged as a marker of cardiovascular mortality, however, the mechanisms of the increase are not clear. We evaluated if hypertension was associated with changes in the colon permeability to trimethylamine (TMA), a TMAO precursor. We did experiments on male, 24-26-week-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and SHR treated with enalapril, an antihypertensive drug (SHR-E). To check the colon permeability and liver TMA clearance, blood was collected from the portal vein and hepatic veins confluence, at baseline and after the intracolonic administration of TMA. Arterial blood pressure (BP) and intestinal blood flow (IBF) recordings and histological assessment of the colon were performed. SHR showed an increased gut-blood barrier permeability to TMA. Namely, at baseline SHR had a higher BP and portal blood TMA, but a lower IBF than WKY. After the intracolonic administration of TMA, SHR had a significantly higher portal blood TMA and higher TMA liver clearance than WKY. In SHR the arteriolar walls of the colon mucosa were significantly thicker than in WKY. Furthermore, SHR showed a significant decrease in the height of the mucosa. In contrast, SHR-E had lower portal blood TMA, lower BP and smaller thickness of arteriolar walls, but higher IBF than SHR, which indicates improved function of the gut-blood barrier in SHR-E. All groups had similar immunostaining of occludin and zonula occludens-1, markers of tight junctions. In conclusion, hypertensive rats show an increased permeability of the colon to TMA, which is accompanied by morphological and hemodynamic alterations in the colon. Therefore, cardiovascular diseases may be characterized by an increased permeability of the gut-blood barrier to bacterial metabolites such as TMA