Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and ß-arrestin (ßarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR1a conformations toward Gαq activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR1a-related brain disorders involving the pathological dysregulation of dopamine.

Transradial and transulnar access for iliac artery interventions using sheathless guiding systems: A feasibility study.

PURPOSE: Our aim was to evaluate the acute success and complication rates of the transradial and transulnar access for iliac artery stenting using sheathless guiding systems. METHODS: Clinical and angiographic data from 156 consecutive patients with symptomatic iliac artery stenosis who were treated with transradial or transulnar access were evaluated. All patients underwent Duplex ultrasound before and after the intervention. The primary endpoints were the procedural success rate, major adverse events, and access site complication rates. The secondary endpoints were the angiographic result of the iliac artery intervention, fluoroscopy time, X-ray dose, procedure length, crossover rate to another puncture site and hospitalization duration. The impact of the learning curve was also investigated, along with right or left radial access. RESULTS: The indication for the intervention was intermittent claudication in 109 patients (69.9%), critical limb ischemia in 44 (28.2%) subjects and acute limb ischemia in three individuals (1.9%). Technical success was achieved in 155 patients (99.4%), with a crossover rate of 3.8%. Radial and ulnar artery access was used in 151 (96.8%) and 7 (4.5%) patients, respectively. The Ankle-brachial index increased from 0.69 [0.65-0.72] to 0.91 [0.88-0.95] as a result of the procedures (P < 0.001). The cumulative incidence of major adverse events was 3.8% at the 2-month follow-up (0% in patients with intermittent claudication and 13.8% in patients with critical limb ischemia). Radial artery access site complications were encountered in eight patients (5.1%). We documented decreased X-ray doses (1742.0 [783.9-2701] vs. 1435 [991.1-1879] vs. 692.8 [275.3-1110] Gy cm-2 P < 0.05) over time; however, the fluoroscopy time, procedure time, and contrast consumption were not significantly different. Left hand access was not associated with significantly better results than right radial artery access. CONCLUSIONS: Iliac artery stenting can be safely and effectively performed using radial or ulnar artery access and sheathless guiding catheters, with acceptable complication rates and high levels of technical success. The physician learning curve plays an important role in decreasing the X-ray dose. © 2016 The Authors. Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc.

Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models.

BACKGROUND: Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models. METHODS: Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.v. injection and irinotecan by i.v. weekly × 4 schedules. For the combination, MSC was administered daily via the oral route for 7 days in mice and daily for 14 days in rats before and concurrent with drug administration. RESULTS: Se-methylselenocysteine significantly protected against organ-specific toxicity induced by lethal doses of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan. These include diarrhoea, stomatitis, alopecia, bladder, kidney, and bone marrow toxicities. Protection from lethal toxicity by MSC was associated with enhanced antitumour activity in rats bearing advanced Ward colorectal carcinoma and in nude mice bearing human squamous cell carcinoma of the head and neck, FaDu, and A253 xenografts. CONCLUSIONS: Se-methylselenocysteine offers selective protection against organ-specific toxicity induced by clinically active agents and enhances further antitumour activity, resulting in improved therapeutic index. These data provided the rationale for the need to clinically evaluate MSC as selective modulator of the antitumour activity and selectivity of anticancer drugs.

[Disclosure of a mental disorder in the workplace and work accommodations: two factors associated with job tenure of people with severe mental disorders]. / La divulgation du trouble mental et les mesures d'accommodements de travail : deux facteurs du maintien en emploi des personnes aux prises avec un trouble mental grave.

Job tenure for people with severe mental disorders (e.g., schizophrenia) remains a stumbling-block to their work integration. However, the length of job tenure can vary according to the workplace (e.g., provided resources) and the work context (e.g., regular market, social firms). This gap can be explained in part by diverse organisational components, particularly the implementation of work accommodations, which is related to the disclosure of the mental disorder in the workplace. Indeed, in the scientific literature, the principal reason associated with disclosure is in regards to requesting work accommodations. The main objective of this paper is to increase our understanding of the relationships between these three concepts - disclosure of a mental disorder, work accommodations and natural supports, and job tenure - by reviewing the specialized literature and presenting the work of the authors of this paper. To do so, the authors will address the following questions: How do we define 'disclosure' of a mental disorder in the workplace and what are the strategies to consider before disclosing? What is the decision-making process related to disclosure in the workplace? How are the three concepts - disclosure of the mental disorder in the workplace, work accommodations and job tenure - intertwined? Finally, how can employment specialists facilitate the work integration of people with severe mental disorders by considering the three concepts mentioned above? Results from a review of the literature show that disclosure of a mental disorder is a dialectical process that goes beyond the question: to tell or not to tell? In fact, it is not a single binary decision. Several components are associated with the disclosure concept, and can be summarized by the questions: What, how, when and to whom to disclose his/her mental condition? Reasons for disclosing his/her mental disorder in the workplace are numerous, characterized by personal, interpersonal and work environmental factors, on one hand. On the other hand, disclosure has potential consequences, both positive (e.g., to obtain work accommodations) and negative (e.g., stigma). A decision-making process takes place when people with a severe mental disorder think about the possibility of disclosing their mental condition in the workplace - a complex decisional process involving the need to evaluate different aspects (i.e. individual, interpersonal and work environmental factors). Also, the literature supports the fact that requiring work accommodations is often related to the disclosure of the mental disorder, when natural supports in the workplace are not available. The literature is scarce regarding the correlations between the concepts of disclosure, implementation of work accommodations and job tenure; however, a more recent study demonstrated this significant relationship, in which the supervisor and co-worker supports are crucial. Employment specialists or counselors recognise the importance of planned disclosure as a means to obtain access to work adjustments in the workplace and to prevent stigma. The employment specialist working in supported employment programs for instance, could adopt with his/her clients a plan for managing the pros and cons of disclosure of the mental disorder in the workplace; this plan is entitled: Managing personal information. It consists of several steps - for example, to collect details of any sensitive information such as diagnosis, to identify work restrictions with the client, to have a common agreement (employment specialists and clients together) on terms to describe work restrictions - to help clients feel empowered and more confident as productive and valued workers. This plan allows employment specialists to work through the disclosure concept, often negatively connoted, and to adopt a more normalising strategy. Furthermore, additional tools for supporting the management of personal information plan could be used such as the Decision-Making About Disclosure Scale, the Barriers to Employment and Coping Efficacy Scale, and the Work Accommodation and Natural Support Scale, to name a few. To conclude, job tenure for people with severe mental disorders is not a pious vow, several pragmatic ingredients for intervening on this issue are now available.

[Disclosure of conflicts of interest in hospital pharmacy posters in France: we still have a long way to go]. / Les conflits d'intérêt dans les communications de pharmacie hospitalière en France : la route est encore longue.

INTRODUCTION: Since 1995, disclosure of conflicts of interest in international scientific publications became systematic, but, in France, there is yet no obligation to mention them in oral communications or posters of pharmacy. OBJECTIVE: To assess the rate of posters in hospital pharmacy meetings which mention potential conflicts of interest. METHODS: A prospective study. All abstracts presented in printed poster format were evaluated during three hospital pharmacy meetings organized in France between November 2011 and March 2012 for the presence of the conflicts of interest disclosure, even if there were no conflicts of interest. The main outcome was the rate of posters with mentions of potential conflicts of interest. A subgroup analysis was conducted about geographic origin of authors. RESULTS: On 294 announced posters, 263 were displayed, 252 did not mention any conflict of interest, 11 mentioned the possibility or not of conflict of interest (4.2%): the rate ranged from 1.1 to 25% according to the meeting. Posters from France disclosed less often conflicts of interest (<2%) than foreign ones (>40%). DISCUSSION-CONCLUSION: The rate of spontaneous disclosure of conflicts of interest is very low within French pharmacists. The instructions given by French meeting organizers should be more directive on the matter.

A novel isoform of the orphan receptor RORγt suppresses IL-17 production in human T cells.

T helper (Th)17 cells constitute a distinct subset of CD4(+) helper T cells that is mainly characterized by abundant interleukin (IL)-17 production and is involved in the host defence against bacteria and fungi as well as in the pathogenesis of autoimmune diseases. The retinoic orphan receptor (ROR)γt directs the transcriptional activation of the IL17 gene. Here, we report the presence of a novel RORγt isoform, RORγt-Δ(5-8), which lacks the hinge-encoding exons 5-8 and represses potently IL17 and IL21 gene transcription. It thereby reduces the expression of multiple Th17-assigned cytokines. We propose that RORγt-Δ(5-8) acts as a dominant-negative regulator of RORγt-mediated gene regulation and the balance between the full-length RORγt and the novel repressor isoform may arbitrate IL-17 production in human T cells.

T cell receptor (TCR) signal strength controls arthritis severity in proteoglycan-specific TCR transgenic mice.

T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and back-crossed into arthritis-prone BALB/c background. Although more than 90% of CD4(+) T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4(+) T cells expressed approximately twice more TCR-Vß4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4(+) T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: 'optimal' TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas 'supra-optimal' TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease.

Protein disorder prevails under crowded conditions.

Crowding caused by the high concentrations of macromolecules in the living cell changes chemical equilibria, thus promoting aggregation and folding reactions of proteins. The possible magnitude of this effect is particularly important with respect to the physiological structure of intrinsically disordered proteins (IDPs), which are devoid of well-defined three-dimensional structures in vitro. To probe this effect, we have studied the structural state of three IDPs, α-casein, MAP2c, and p21(Cip1), in the presence of the crowding agents Dextran and Ficoll 70 at concentrations up to 40%, and also the small-molecule osmolyte, trimethylamine N-oxide (TMAO), at concentrations up to 3.6 M. The structures of IDPs under highly diluted and crowded conditions were compared by a variety of techniques, fluorescence spectroscopy, acrylamide quenching, 1-anilino-8-naphthalenesulfonic acid (ANS) binding, fluorescence correlation spectroscopy (FCS), and far-UV and near-UV circular dichroism (CD) spectroscopy, which allow us to visualize various levels of structural organization within these proteins. We observed that crowding causes limited structural changes, which seem to reflect the functional requirements of these IDPs. α-Casein, a protein of nutrient function in milk, changes least under crowded conditions. On the other hand, MAP2c and, to a lesser degree, p21(Cip1), which carry out their functions by partner binding and accompanying partially induced folding, show signs of local structuring and also some global compaction upon crowded conditions, in particular in the presence of TMAO. The observations are compatible with the possible preformation of binding-competent conformations in these proteins. The magnitude of these changes, however, is far from that of the cooperative folding transitions elicited by crowding in denatured globular proteins; i.e., these IDPs do remain in a state of rapidly interconverting structural ensemble. Altogether, our results underline that structural disorder is the physiological state of these proteins.

A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease diagnosed on the presence of a constellation of clinical and laboratory findings. At the pathogenetic level, multiple factors using diverse biochemical and molecular pathways have been recognized. Succinct recognition and classification of clinical disease subsets, as well as the availability of disease biomarkers, remains largely unsolved. Based on information produced by the present authors' and other laboratories, a lupus gene expression array consisting of 30 genes, previously claimed to contribute to aberrant function of T cells, was developed. An additional eight genes were included as controls. Peripheral blood was obtained from 10 patients (19 samples) with SLE and six patients with rheumatoid arthritis (RA) as well as 19 healthy controls. T cell mRNA was subjected to reverse transcription and PCR, and the gene expression levels were measured. Conventional statistical analysis was performed along with principal component analysis (PCA) to capture the contribution of all genes to disease diagnosis and clinical parameters. The lupus gene expression array faithfully informed on the expression levels of genes. The recorded changes in expression reflect those reported in the literature by using a relatively small (5 ml) amount of peripheral blood. PCA of gene expression levels placed SLE samples apart from normal and RA samples regardless of disease activity. Individual principal components tended to define specific disease manifestations such as arthritis and proteinuria. Thus, a lupus gene expression array based on genes previously claimed to contribute to immune pathogenesis of SLE may define the disease, and principal components of the expression of 30 genes may define patients with specific disease manifestations.

Percutaneous decompression for the treatment of Mueller-Weiss syndrome.

This report describes the case of a young athlete, who presented with a painful foot and was eventually diagnosed with early-stage Mueller-Weiss syndrome (spontaneous osteonecrosis of the navicular) by MRI. As non-operative management was unsuccessful, a percutaneous decompression of the navicular was performed. The patient made a full recovery and was able to return to her previous level of sporting activity. Subsequent imaging showed complete remodelling of the bony architecture of the affected navicular.

Mitochondrial protective effects of PARP-inhibition in hypertension-induced myocardial remodeling and in stressed cardiomyocytes.

AIMS: During oxidative stress mitochondria become the main source of endogenous reactive oxygen species (ROS) production. In the present study, we aimed to clarify the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes. MAIN METHODS: L-2286, a quinazoline-derivative PARP inhibitor, protects against cardiovascular remodeling and heart failure by favorable modulation of signaling routes. We examined the effects of PARP-1 inhibition on mitochondrial quality control processes and function in vivo and in vitro. Spontaneously hypertensive rats (SHRs) were treated with L-2286 or placebo. In the in vitro model, 150 µM H2O2 stress was applied on neonatal rat cardiomyocytes (NRCM). KEY FINDINGS: PARP-inhibition prevented the development of left ventricular hypertrophy in SHRs. The interfibrillar mitochondrial network were less fragmented, the average mitochondrial size was bigger and showed higher cristae density compared to untreated SHRs. Dynamin related protein 1 (Drp1) translocation and therefore the fission of mitochondria was inhibited by L-2286 treatment. Moreover, L-2286 treatment increased the amount of fusion proteins (Opa1, Mfn2), thus preserving structural stability. PARP-inhibition also preserved the mitochondrial genome integrity. In addition, the mitochondrial biogenesis was also enhanced due to L-2286 treatment, leading to an overall increase in the ATP production and improvement in survival of stressed cells. SIGNIFICANCE: Our results suggest that the modulation of mitochondrial dynamics and biogenesis can be a promising therapeutical target in hypertension-induced myocardial remodeling and heart failure.

Decreased levels of Cx43 gap junctions result in ameloblast dysregulation and enamel hypoplasia in Gja1Jrt/+ mice.

Coordinated differentiation of the ameloblast cell layer is essential to enamel matrix protein deposition and subsequent mineralization. It has been hypothesized that this process is governed by Cx43-based gap junctional intercellular communication as oculodentodigital dysplasia (ODDD) patients harboring autosomal-dominant mutations in Cx43 exhibit enamel defects typically resulting in early adulthood tooth loss. To assess the role of Cx43 in tooth development we employ a mouse model of ODDD that harbors a G60S Cx43 mutant, Gja1(Jrt)/+, and appears to exhibit tooth abnormalities that mimic the human disease. We found that total Cx43 plaques at all stages of ameloblast differentiation, as well as within the supporting cell layers, were greatly reduced in Gja1(Jrt)/+ incisors compared to wild-type littermate controls. To characterize the Gja1(Jrt)/+ mouse tooth phenotype, mice were sacrificed prior to tooth eruption (postnatal day 7), weaning (postnatal day 21), and adulthood (2 months postnatal). A severely disorganized Gja1(Jrt)/+ mouse ameloblast layer and abnormal accumulation of amelogenin were observed at stages when the cells were active in secretion and mineralization. Differences in enamel thickness became more apparent after tooth eruption and incisor exposure to the oral cavity suggesting that enamel integrity is compromised, leading to rapid erosion. Additional analysis of incisors from mutant mice revealed that they were longer with a thicker dentin layer than their wild-type littermates, which may reflect a mechanical stress response to the depleted enamel layer. Together, these data show that reduced levels of Cx43 gap junctions result in ameloblast dysregulation, enamel hypoplasia, and secondary tissue responses.

Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor.

BACKGROUND AND AIMS: Treatment of colorectal adenomas with selective cyclooxygenase-2 inhibitors can contribute to the chemoprevention of colorectal cancer (CRC), but the molecular background of their effect is not fully understood. We analysed the gene expression modulatory effect of N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS398) on HT29 cells to be correlated with expression data gained from biopsy samples. METHODS: HT29 colon adenocarcinoma cells were treated with NS398, and global mRNA expression was analysed on HGU133Plus2.0 microarrays. Discriminatory transcripts between normal and adenoma and between adenoma and CRC biopsy samples were identified using HGU133Plus2.0 microarrays. The results were validated using RT-PCR and immunohistochemistry. RESULTS: Between normal and adenoma samples, 20 classifiers were identified, including overexpressed cadherin 3, KIAA1199, and downregulated peptide YY, glucagon, claudin 8. Seventeen of them changed in a reverse manner in HT29 cells under NS398 treatment, 14 (including upregulated claudin 8, peptide YY, and downregulated cadherin 3, KIAA1199) at a significance of P<0.05. Normal and CRC could be distinguished using 38 genes, the expression of 12 of them was changed in a reverse manner under NS398 treatment. CONCLUSION: NS398 has a reversal effect on the expression of several genes that altered in colorectal adenoma-carcinoma sequence. NS398 more efficiently inverted the expression changes seen in the normal-adenoma than in the normal-carcinoma transition.

Inventory management.

A critical aspect of blood transfusion is the timely provision of high quality blood products. This task remains a significant challenge for many blood services and blood systems reflecting the difficulty of balancing the recruitment of sufficient donors, the optimal utilization of the donor's gift, the increasing safety related restrictions on blood donation, a growing menu of specialized blood products and an ever-growing imperative to increase the efficiency of blood product provision from a cost perspective. As our industry now faces questions about our standard practices including whether or not the age of blood has a negative impact on recipients, it is timely to take a look at our collective inventory management practices. This International Forum represents an effort to get a snap shot of inventory management practices around the world, and to understand the range of different products provided for patients. In addition to sharing current inventory management practices, this Forum is intended to foster an exchange of ideas around where we see our field moving with respect to various issues including specialty products, new technologies, and reducing recipient risk from blood transfusion products.

Retrograde stem removal in revision hip surgery: removing a loose or broken femoral component with a retrograde nail.

INTRODUCTION: Removal of a cemented femoral stem during revision total hip arthroplasty is a technically demanding procedure that requires a multitude of surgical techniques and tools. To gain full access to the cement and the stem, distal fenestration or a transfemoral approach is often required. This paper presents a technique of retrograde removal of femoral stems and cement from the distal femur. MATERIALS AND METHODS: The authors present five clinical cases. In two cases the femoral component and the surrounding cement was removed using this technique. In the other three cases, due to femoral component fracture, the distal fragment of the femoral component with its cement mantle was removed using the same technique. In an experimental study, we simulated the above technique and compared it with a windowing technique on six, paired cadaveric femora (12 femurs in all). RESULTS: In all of the clinical cases the stem and the cement were removed completely without any complications. The cadaveric experiments clearly showed that the biomechanical resistance of the femur against compression and torsion forces is greatly decreased by using a window to access the proximal femur, compared with the retrograde technique, which shows no significant change. CONCLUSION: Retrograde component removal provides a simple, rapid, and less invasive technique for stem and cement extraction in elective revision hip arthroplasty.

Electrophysiological and behavioral properties of 4-aminopyridine-induced epileptic activity in mice.

4-aminopyridine (4-AP) is a widely used drug that induces seizure activity in rodents, especially in rats, although there is no consensus in the literature on the dose to be used in mice. The aim of the present study was to investigate the effect of the intraperitoneal administration of 4-AP in two doses (4 and 10 mg/kg) in vivo. EEG, movement, and video recordings were made simultaneously in male B6 mice to specify the details of the seizures and to determine whether there is a suitable non-lethal dose for seizure induction and for further molecular studies. Seizure behavior in mice differs from that seen in rats, with no characteristic stages of epileptic seizures, but with spiking and seizure activity. Seizure activity, although produced at both doses without being lethal, induced different changes of the EEG pattern. Smaller dose induced a lower amplitude seizure activity, decreased spiking activity and later onset of seizures, while higher dose induced a much more intense brain seizure activity and severe trembling. It is concluded that the intraperitoneal administration of 4-AP at a dose of 10 mg/kg induces explicit seizure activity in mice which is repeatable and can be suitable for further molecular research.

Target-specific expression of presynaptic mossy fiber plasticity.

Mossy fiber synaptic transmission at hippocampal CA3 pyramidal cells and interneurons was compared in rat brain slices to determine whether mossy terminals are functionally equivalent. Tetanic stimulation of mossy fibers induced long-term potentiation in pyramidal neurons but was either without effect or it induced depression at synapses onto interneurons. Unlike transmission onto pyramidal neurons, transmission onto interneurons was not potentiated after adenosine 3',5'-monophosphate (cAMP) activation. Furthermore, metabotropic glutamate receptor depression of transmission onto interneurons did not involve cAMP-dependent pathways. Thus, synaptic terminals arising from a common afferent pathway do not function as a single compartment but are specialized, depending on their postsynaptic target.

Lung Transplantation in Hungary From Cardiac Surgeons' Perspective.

Thoracic organ transplantation made a fresh start in Hungary with the first double lung transplant in December 2015. This major leap in Hungarian transplantation was preceded by almost 10 years of preparation, new infrastructure development, and structural changes not only at the organizational level but in human resources as well. In the following years, until recently, altogether 47 lung transplants were performed on 24 men and 23 women. The underlying pathologies were as follows: chronic obstructive pulmonary disease, 25; cystic fibrosis, 11; idiopathic pulmonary fibrosis, 7; as well as other diseases, including bronchiectasis, eosinophilic granuloma, lymphangioleiomyomatosis, and primary pulmonary hypertension in 4 cases. The youngest recipient was 13 and the oldest was 65 years old. Overall survival rates at 30 days and at 1 year were 96% and 82%, respectively. No patients were lost in the cystic fibrosis and other diseases group, whereas the 1-year survival rates of the chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis groups were 73% and 71%, respectively. The results show the robustness and viability of the program, although there is still opportunity for further improvement. In this short paper, we summarize the fields of possible further cooperation of thoracic and cardiac teams as well as future challenges facing the new Hungarian lung transplant program.

Antibody-Mediated Rejection in a Multiple Lung Transplant Patient: A Case Report.

Lung transplant is an effective way to treat many end-stage lung diseases. However, one of the main barriers of allograft organ transplant is still the immunologic rejection of transplanted tissue, which is a response of the HLA molecules. Rejection is a complex process involving both T-cell-mediated delayed-type hypersensitivity reactions and antibody-mediated hypersensitivity reactions to histocompatibility molecules on foreign grafts. We report the case of a 25-year-old female patient with cystic fibrosis who underwent 2 lung transplants because of her initial diagnosis and appearance of bronchiolitis obliterans syndrome after the first transplant. Only 13 months after the second transplant, despite the therapies applied, a new rejection occurred associated with high mean fluorescent intensity donor-specific antibody levels, which resulted later in the death of the patient. The present case draws attention to the importance of matching HLA molecules between donor and recipient in addition to immunosuppressive therapy.