A trans-synaptic nanocolumn aligns neurotransmitter release to receptors.

Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency.

[Adrenal cavernous hemangioma: A case report and literature review].

A 57-year-old male patient was referred to our department with complaints of his right adrenal gland occupancy and hypertension about 6 months. When admitted to the hospital, the blood pressure was about 160/100 mmHg, and the heart rate was 110 beats/min. He was no obvious obesity, acne, abnormal mood, without weakness of limbs, acral numbness, palpitation and headache. He presented with type 2 diabetes for more than 3 years, with oral administration of metformin enteric coated tablets and subcutaneous injection of insulin glargine to control blood glucose, and satisfied with blood glucose control. Enhanced CT showed that: the right adrenal gland showed a kind of oval isodense, slightly hypodense shadow, the edge was clear, lobular change, the size was about 5.8 cm×5.4 cm, uneven density, there were nodular and strip calcification, round lipid containing area and strip low density area, and the CT value of solid part was about 34 HU. Enhanced scan showed heterogeneous nodular enhancement in the solid part of the right adrenal gland, nodular enhancement could be seen inside. The CT values of solid part in arterial phase, venous phase and delayed phase were 45 HU, 50 HU and 81 HU, respectively. Considering from the right adrenal gland, cortical cancer was more likely. No obvious abnormality was found in his endocrine examination. After adequate preoperative preparation, retroperitoneal laparoscopic adrenalectomy was performed under general anesthesia. During the operation, the 6 cm adrenal tumor was closely related to the inferior vena cava and liver, and after careful separation, the tumor was completely removed and normal adrenal tissue was preserved. The operation lasted 180 min and the blood loss was 100 mL, and the blood pressure was stable during and after the operation. There was no obvious complication. The results of pathological examinations were as follows: the size of the tumor was 7.5 cm×6.0 cm×3.5 cm, soft, with intact capsule and grayish-red cystic in section. Pathological diagnosis: (right adrenal gland) cavernous hemangioma, secondary intravascular thrombosis, old hemorrhagic infarction with calcification and ossification. After 6 months of observation, no obvious complications and tumor recurrence were found. In summary, cavernous hemangioma of adrenal gland is a rare histopathological change. Its essence is a malformed vascular mass. Blood retention is the cause of thrombosis and calcification in malformed vessels. The imaging findings were inhomogeneous enhancement of soft tissue masses, and the adrenal function examination showed no obvious abnormalities. Retroperitoneal laparoscopic surgery is feasible after adequate preoperative preparation. It is difficult to diagnose the disease preoperatively and needs to be confirmed by postoperative pathology.

A machine learning based deep potential for seeking the low-lying candidates of Al clusters.

A Machine-Learning based Deep Potential (DP) model for Al clusters is developed through training with an extended database including ab initio data of both bulk and several clusters in only 6 CPU/h. This DP model has good performance in accurately predicting the low-lying candidates of Al clusters in a broad size range. Based on our developed DP model, the low-lying structures of 101 different sized Al clusters are extensively searched, among which the lowest-energy candidates of 69 sized clusters are updated. Our calculations demonstrate that machine-learning is indeed powerful in generating potentials to describe the interaction of atoms in complex materials.

Flatband in a three-dimensional tungsten nitride compound.

Herein, the flatband of a W1N2 crystal is theoretically investigated. It is revealed that the flatband can be well-described by a tight-binding model of the N12 skeleton, where the dispersion of the flatband is governed by both the ppσ bonding strength (Vppσ) and the ppπ bonding strength (Vppπ) between the nearest-neighbor N atoms. It is also found that the proper strength of the ppπ bonding between neighboring N atoms plays a prime role in the formation of the flatband. In addition, when the compound is doped with holes, the electrons at the flatband are fully polarized, showing a ferromagnetic character. This behavior has a weak correlation with the on-site Coulomb interaction U. Moreover, several three-dimensional compounds possessing flatbands in the whole k space are predicted.

First-principles study of intrinsic point defects in MgSiAs2.

MgSiAs2 is a potential infrared-nonlinear optical (IR-NLO) material, due to its fine second harmonic generation (SHG) performance and high laser damage threshold (LDT). In this study we systematically investigate its native point defects including vacancies, interstitials, and antisites using first-principles calculations with the Heyd-Scuseria-Ernzerhof hybrid functional. The defect formation energies and transition levels at the dilute limit are evaluated. Of the thirteen different point defects studied, nine kinds of defects show deep transition levels, which might contribute to the limiting of the transparency spectrum of MgSiAs2 compounds. The defects with the highest concentration at equilibrium are found to be cation antisites, MgSi and SiMg, serving as acceptors and donors respectively. Because of their significantly low formation energies, they lead to Fermi level pinning in the band gap and constrain the carrier concentration doping. Our calculations show that a change in growth conditions affects modestly the formation energy of defects or the concentration of charge carriers.

Protein Crowding within the Postsynaptic Density Can Impede the Escape of Membrane Proteins.

Mechanisms regulating lateral diffusion and positioning of glutamate receptors within the postsynaptic density (PSD) determine excitatory synaptic strength. Scaffold proteins in the PSD are abundant receptor binding partners, yet electron microscopy suggests that the PSD is highly crowded, potentially restricting the diffusion of receptors regardless of binding. However, the contribution of macromolecular crowding to receptor retention remains poorly understood. We combined experimental and computational approaches to test the effect of synaptic crowding on receptor movement and positioning in Sprague Dawley rat hippocampal neurons. We modeled AMPA receptor diffusion in synapses where the distribution of scaffold proteins was determined from photoactivated localization microscopy experiments, and receptor-scaffold association and dissociation rates were adjusted to fit single-molecule tracking and fluorescence recovery measurements. Simulations predicted that variation of receptor size strongly influences the fractional synaptic area the receptor may traverse, and the proportion that may exchange in and out of the synapse. To test the model experimentally, we designed a set of novel transmembrane (TM) probes. A single-pass TM protein with one PDZ binding motif concentrated in the synapse as do AMPARs yet was more mobile there than the much larger AMPAR. Furthermore, either the single binding motif or an increase in cytoplasmic bulk through addition of a single GFP slowed synaptic movement of a small TM protein. These results suggest that both crowding and binding limit escape of AMPARs from the synapse. Moreover, tight protein packing within the PSD may modulate the synaptic dwell time of many TM proteins important for synaptic function. SIGNIFICANCE STATEMENT: Small alterations to the distribution within synapses of key transmembrane proteins, such as receptors, can dramatically change synaptic strength. Indeed, many diseases are thought to unbalance neural circuit function in this manner. Processes that regulate this in healthy synapses are unclear, however. By combining computer simulations with imaging methods that examined protein dynamics at multiple scales in space and time, we showed that both steric effects and protein-protein binding each regulate the mobility of receptors in the synapse. Our findings extend our knowledge of the synapse as a crowded environment that counteracts molecular diffusion, and support the idea that both molecular collisions and biochemical binding can be involved in the regulation of neural circuit performance.

Inguinal hernia in neonates and ex-preterm: complications, timing and need for routine contralateral exploration.

BACKGROUND/PURPOSE: Aim of this study was to present a series of neonates and ex-preterm babies who underwent inguinal hernia repair focusing on complications and possible indication to perform routine contralateral groin exploration. METHODS: This is a retrospective study of a series of consecutive patients weighing less than 5 kg who underwent inguinal hernia repair between January 2007 and December 2012. Only the affected side was treated. Patients have been routinely followed up postoperatively. We resorted to available outpatients' charts and admission notes to record demographic data, surgical details, complications and the occurrence of metachronous hernias. A questionnaire was administered to all patients' relatives to confirm the long-term outcome. RESULTS: One hundred fifty-four patients were operated for a total of 184 herniotomies (88 right sided, 36 left sided and 30 bilateral). Median length of follow-up was 42 months (range 6 months-7.5 years). Thirteen patients (13/124 = 10.5 %) developed metachronous hernia that proved to be significantly more frequent in patients weighing less than 1,500 g at birth (p < 0.05). We observed 10 % of complications, including 2.7 % testicular atrophy and 4.5 % recurrence. Atrophy proved to occur more frequently in patients who experienced preoperative incarceration (p < 0.05). No other risk factors were identified. CONCLUSIONS: The results of our series demonstrated that, though technically demanding, herniotomy in the neonate and ex-preterm is associated with a relatively low incidence of complications. Based on our results and in accordance with literature data, we do not advocate routine contralateral exploration in case of unilateral hernia but surgery to be performed only on the symptomatic side, as soon as possible after initial diagnosis. Very low birth weight patients should be followed with care in the early postoperative period due to the higher likelihood of developing a metachronous hernia.

Cost Analysis of Treating Pediatric Supracondylar Humerus Fractures in Community Hospitals Compared With a Tertiary Care Hospital.

OBJECTIVE: In the current healthcare environment, providing cost-efficient care is of paramount importance. One emerging strategy is to use community hospitals (CHs) rather than tertiary care hospitals (TCHs) for some procedures. This study assesses the costs of performing closed reduction percutaneous pinning (CRPP) of pediatric supracondylar humerus fractures (SCHFs) at a CH compared with a TCH. METHODS: A retrospective review of 133 consecutive SCHFs treated with CRPP at a CH versus a TCH over a 6-year period was performed. Total encounter and subcategorized costs were compared between the procedures done at a CH versus those done at a TCH. RESULTS: Performing CRPP for a SCHF at a CH compared with a TCH saved 44% in costs (P < 0.001). Cost reduction of 51% was attributable to operating room costs, 19% to anesthesia-related costs, 16% to imaging-related costs, and 7% to supplies. DISCUSSION: Performing CRPP for a SCHF at a CH compared with a TCH results in a 44% decrease in direct cost, driven largely by surgical, anesthesia, and radiology-related savings.

Control of Transmembrane Protein Diffusion within the Postsynaptic Density Assessed by Simultaneous Single-Molecule Tracking and Localization Microscopy.

Postsynaptic transmembrane proteins are critical elements of synapses, mediating trans-cellular contact, sensitivity to neurotransmitters and other signaling molecules, and flux of Ca and other ions. Positioning and mobility of each member of this large class of proteins is critical to their individual function at the synapse. One critical example is that the position of glutamate receptors within the postsynaptic density (PSD) strongly modulates their function by aligning or misaligning them with sites of presynaptic vesicle fusion. In addition, the regulated ability of receptors to move in or out of the synapse is critical for activity-dependent plasticity. However, factors that control receptor mobility within the boundaries of the synapse are not well understood. Notably, PSD scaffold molecules accumulate in domains much smaller than the synapse. Within these nanodomains, the density of proteins is considerably higher than that of the synapse as a whole, so high that steric hindrance is expected to reduce receptor mobility substantially. However, while numerical modeling has demonstrated several features of how the varying protein density across the face of a single PSD may modulate receptor motion, there is little experimental information about the extent of this influence. To address this critical aspect of synaptic organizational dynamics, we performed single-molecule tracking of transmembrane proteins using universal point accumulation-for-imaging-in-nanoscale-topography (uPAINT) over PSDs whose internal structure was simultaneously resolved using photoactivated localization microscopy (PALM). The results provide important experimental confirmation that PSD scaffold protein density strongly influences the mobility of transmembrane proteins. A protein with a cytosolic domain that does not bind PSD-95 was still slowed in regions of high PSD-95 density, suggesting that crowding by scaffold molecules and perhaps other proteins is sufficient to stabilize receptors even in the absence of binding. Because numerous proteins thought to be involved in establishing PSD structure are linked to disorders including autism and depression, this motivates further exploration of how PSD nanostructure is created. The combined application PALM and uPAINT should be invaluable for distinguishing the interactions of mobile proteins with their nano-environment both in synapses and other cellular compartments.

European multicenter survey on the laparoscopic treatment of gastroesophageal reflux in patients aged less than 12 months with supraesophageal symptoms.

BACKGROUND: This multicenter survey includes neonates and infants who underwent surgery for primary gastroesophageal reflux (GER) who presented with supraesophageal symptoms of unknown origin with a minimum of 12 months postoperative follow-up. METHODS: A total of 726 patients underwent GER surgery in 10 European Centers in the period 1998-2002. Respiratory symptoms were present in 204 patients (28%); 135 patients (17%) had surgery under 1 year of age, and 46 of them (6.3%) because of respiratory symptoms. Surgery was performed without any previous medical treatment in 10 cases (21%). The type of procedure included 37 complete 360 degrees wraps (80%) (Nissen, 12, and Rossetti, 25) and nine partial wraps (20%) (Thal five, Lortat Jacob one, Toupet one, others two). Gastrostomy was associated in 17 cases (37%) (6 PEG and 11 modified Stamm). No gastric emptying procedures were recorded. RESULTS: No major intraoperative complications were reported. Six patients developed complications (13%) and a redo operation was performed in three (6.5%). Respiratory outcome after antireflux surgery was good in 35 patients (76%) and fair with significantly improved respiratory symptoms in 11 (24%). CONCLUSIONS: This multicenter survey underlines that GER has to be suspected and aggressively treated in infants with difficult-to-treat supraesophageal symptoms, and also in high-risk cases, in order to prevent major complications.

[Neonatal characteristics in the physiopathology of shock]. / Peculiarità neonatali nella fisiopatologia dello shock.

In this work we tried to analyse the different factors which cooperate to produce and maintain a shock condition; we considered in particular pathophysiology and haemodynamic features of the different types of shock and the pathophysiology of MOSF (multiple systems organ failure). Furthermore, we remembered peculiarities and effects of the "reperfusion syndrome" which can occur after cardiopulmonary resuscitation of the patient due to superoxides. Finally we outlined the substantial and significant differences between newborn and not newborn concerning the haemodynamic responses and the cardiocirculatory management in the newborn during shock treatment.

[Apple peel small bowel: surgical correction and post-operative treatment]. / Apple peel small bowel: correzione chirurgica e trattamento post-operatorio.

The authors describe 6 cases of Apple Peel Small Bowel observed in the last ten year experience in Institute G. Gaslini of Genoa, Italy. They make a precision on early diagnosis and on surgical treatment, which is original, and also on post-operatory medical treatment. The importance of making an optimal nutritional support with total and partial parenteral nutrition for long time is of great significance to have a better outcome and psycho-physical development in such patients.

[Nosocomial infection caused by multiresistant Staphylococci in a neonatal and pediatric intensive care unit]. / Infezioni nosocomiali da stafilococchi multiresistenti in Terapia Intensiva neonatale e pediatrica.

We selected a paediatric population with a high risk of nosocomial infection formed by 116 newborns (42.8%) and 155 not newborns (57.2%) admitted into the ICU of the Giannina Gaslini Institute during the period 1-1-1992-30-9-1992; we compared it with a reference paediatric population studied in the same department during the period 1-1-1987-30-6-1988 formed by 310 newborns (44.3%) and 391 not newborns (55.7%). The purpose of this study is to evaluate the possible change in the incidence of colonizations and ICU specific nosocomial infections, the possible increase of nosocomial infections by multiresistant Staphylococci and the appearance of new multiresistant germs. The two populations obviously present similar factors of high risk of nosocomial infection (naso-tracheal intubation, mechanical ventilation, total parenteral nutrition, surgical procedures, thoracic and/or abdominal prothesis, etc.). The obtained data have been examined with the Chi-square method. The incidence of colonizations remained unchanged while we noted a significant increase (10.3% compared to 4.9%-p > 0.0014) of the "ICU" specific nosocomial infections; the increase regarded mainly the neonatal population (18.9% compared to 7%-p > 0.00001). Significant increase of the nosocomial infections by multiresistant Staphylococcus (Staphylococcus haemolyticus) with in vitro and in vivo resistance to teicoplanin. Furthermore, presence in the performed study of multiresistant gram negative germs.

[The clinical assessment and intensive treatment of meningoencephalitis in newborns and children of subsequent ages]. / Valutazione clinica e trattamento intensivo delle meningo-encefaliti in età neonatale e successive età pediatriche.

We focused on the best timing and management when admitting into intensive care unit a pediatric patient with central nervous system infection. The modified scales for pediatric patients did not prove satisfactory and reliable for making such decision. In fact the final score is obtained by adding the partial scores regarding the different clinical aspects. That bears a loss of informations. For this reason we think that the cardiorespiratory and metabolic parameters, assessed in a period of time, may indicate the moment when it is necessary to start an intensive care in these patients, regardless of consciousness. We therefore discussed the monitoring precociously required in these patients after assessing the initial clinical status. We also discussed the intensive care procedure employed in severely ill patients with cardio-circulatory and metabolic problems due to septic shock caused by bacterial meningoencephalitis (infants) and meningitis (other pediatric ages). In patients affected by infectious or post-infective encephalitis with respiratory failure and/or brain edema, it is essential to apply the organ protection procedures and particularly neuroprotection.

[Teicoplanin therapy in neonatal and pediatric intensive therapy]. / La terapia con teicoplanina in terapia intensiva neonatale e pediatrica.

We administered teicoplanin as specific antibiotic therapy for nosocomial "ICU specific" infections with methicillin-resistant Staphylococcus aureus and epidermidis (MRSA-MRSE). The above mentioned drug has been given to 20 patients (15 newborns and 5 not-newborns) admitted into intensive care unit during the years 1988, 1989, 1990 with MRSA-MRSE localized and/or systemic infection, affected by severe disease (RDS, pulmonary edema, congenital cardiac disease, cystic fibrosis) undergoing invasive procedures which presented high nosocomial infective risk (tracheal intubation, mechanical ventilation, venous and arterial cannulation, total parenteral nutrition, etc.). Complete recovery from systemic or localized infection (sepsis, low respiratory tract infection, high respiratory tract infection) occurred in 19 out of 20 patients, with a rate of success of 95%. Teicoplanin treatment lasted from a minimum of nine days to a maximum of thirty days. The dose was 5-6 mg/kg/die in one administration for the first three days, then 4 mg/kg/die. The tolerability of teicoplanin has proven satisfactory, since we had no major side effects during treatment and follow up.

[Role of extracorporeal circulation in reversible acute cardiorespiratory insufficiency in neonatal and pediatric intensive care]. / Ruolo della circolazione extracorporea nell'insufficienza cardiorespiratoria acuta reversibile in terapia intensiva neonatale e pediatrica.

In the present study we try to analyze indications, contra-indication, side effects and limits of the use of extracorporeal circulation in neonatal and pediatric patients affected by reversible acute cardiorespiratory failure. The greatest experience on this technique has been achieved in the neonatal age (about 6000 newborns have been treated until now), while the employment in the pediatric age appears more recent (about 500 patients). Moreover, we focused on the drop-in criteria for neonatal and pediatric patients and on the clinical aspects and laboratory findings which can anticipate the surviving rate; the latter appears in any case much greater in the neonatal patient compared to the other pediatric ages.

Wilbrand knee.

Wilbrand and Saenger(1) studied optic chiasms after unilateral enucleation, noting inferonasal crossing fibers curved anteriorly into the contralateral optic nerve (Wilbrand knee; figure, A). This explains contralateral superotemporal visual field defects (junctional scotomas) with optic nerve lesions at the chiasmal junction. However, Wilbrand knee may be an enucleation artifact.(2) The anisotropic light-reflecting properties of myelinated axons permitted imaging of normal human chiasms. Thin sections (25 µm) were illuminated and digitally imaged from 3 incident angles. Each of the images was pseudocolored (red, green, or blue) and merged, revealing an anomalously oriented fiber tract (appearing white) that reversed direction at the optic nerve-chiasm junction, found in inferior (figure, C) but not in superior sections (figure, B), consistent with Wilbrand and Saenger's original description.

Congenital diaphragmatic hernia repair during whole body hypothermia for neonatal hypoxic ischemic encephalopathy.

Major malformations, surgery and persistent pulmonary hypertension (PHT) have been considered contraindications to therapeutic hypothermia (TH) in newborns with hypoxic-ischemic encephalopathy (HIE). We report two patients with undiagnosed congenital diaphragmatic hernia (CDH) who developed HIE after birth. Diagnosis of moderate HIE was formulated based on clinical, laboratory and electroencephalographic criteria. The patients were treated with whole body hypothermia (33.5 °C) for 72 h. During hypothermia the patients underwent surgical repair with regular perioperative course. Ventilatory support with high-frequency oscillatory ventilation, oxygen requirements and inotropic support remained stable during hypothermia. Serial echocardiographic evaluations did not demonstrate any change in pulmonary pressure values. In our experience TH did not increase the risk of hemodynamic instability, PHT or bleeding. Hypothermia may be considered in patients with HIE and CDH or other surgical conditions with favorable prognosis.

Parental role in the Intensive Care Unit for children affected by Werdnig Hoffmann disease.

AIM: The aim of this study was to determine the role of parents after extubation of their children affected by Spinal Muscular Atrophy Type 1 (SMA1) in the Pediatric Intensive Care Unit. Currently, children affected by SMA1 are often treated with non-invasive mechanical ventilation and mechanical support of cough. During the first two or three years of life they frequently present severe respiratory failure requiring intubation. Extubation may be at severe risk of failure even because of inadequate care. METHODS: Parents of SMA1 children were offered an early education on the most critical aspects and a training in non-invasive respiratory support after diagnosis. They were asked and allowed to stay as longer as possible with their child after extubation. Quality and quantity of care given by parents during the first 24 hours after extubation were recorded. RESULTS: All parents participated to the success of the weaning procedure: they gave continuous care and all children could be extubated. CONCLUSION: The presence of parents after extubation of SMA1 patients is important for the success of the procedure; otherwise, the presence of a skilled nurse is needed, with a nurse-patient ratio of 1:1.