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Background: Children require anesthesia for MRI to maintain immobility and reduce discomfort; clear indications about the best anesthesiologic management are lacking and each center developed its own protocol. Moreover, children with neuropsychiatric disorders more likely require sedation and are described in literature as more prone to general and respiratory complications. Aim of this study was to analyze the applicability of a sevoflurane-based approach, to describe general and respiratory complications and to identify risk factors in a pediatric neuropsychiatric population., Methods: Retrospective cohort study, university Hospital (January 2007-December 2016). All the 1469 anesthesiologic records of children addressed from Neuropsychiatric Unit to undergo MRI under general anesthesia were analyzed; 12 patients equal or older than 18-year-old were excluded. We identified post-hoc nine macro-categories: static encephalopathies, metabolic/evolutive encephalopathies, epileptic encephalopathies, neuromuscular diseases, autistic spectrum disorders, migraine, psychiatric disorders, intellectual disabilities, others. A logistic regression model for events with low frequency (Firth's penalized likelihood approach) was carried out to identify the mutually adjusted effect among endpoints (complications) and the independent variables chosen on the basis of statistical significance (univariate analysis, p ≤ 0.05) and clinical judgment., Results: Of 1457 anesthesiologic records (age 4.0 (IQR 2.0 to 7.0) year-old, males 891 (61.2%), weight 17.0 (IQR 12.0 to 24.9) kg), 18 were cancelled for high anesthesiologic risk, 50 were cooperative, 1389 were anesthetized. A sevoflurane-based anesthesia was feasible in 92.3%; these patients required significantly less mechanical ventilation (8.6 vs. 16.2%; p = 0.012). Complications' rate was low (6.2%; 3.1% respiratory). The risk for general complications increases with ASA score > 1 (OR 2.22, 95 CI% 1.30 to 3.77, p = 0.003), male sex (OR 1.73, 95% CI 1.07 to 2.81, p = 0.025), multi-drug anesthesia (OR 2.98, 95 CI% 1.26 to 7.06, p = 0.013). For respiratory complications, it increases with ASA score > 1 (OR 2.34, 95 CI% 1.19 to 4.73, p = 0.017), autumn-winter (OR 2.01, 95 CI% 1.06 to 3.78, p = 0.030), neuromuscular disorders (OR 3.18, 95 CI% 1.20 to 8.41, p = 0.020). We had no major complications compromising patients' outcome or requiring admission to ICU., Conclusions: Sevoflurane anesthesia is feasible and safe for children affected by neuropsychiatric disorders undergoing MRI. Specific risk factors for general and respiratory complications should be considered.

Cyclin-dependent kinase like-5 (CDKL5) disorder is a rare neurodevelopmental disease caused by mutations in the CDKL5 gene. The consequent misexpression of the CDKL5 protein in the nervous system leads to a severe phenotype characterized by intellectual disability, motor impairment, visual deficits and early-onset epilepsy. No therapy is available for CDKL5 disorder. It has been reported that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to a given protein. We demonstrate that TAT-CDKL5 fusion protein is efficiently internalized by target cells and retains CDKL5 activity. Intracerebroventricular infusion of TAT-CDKL5 restored hippocampal development, hippocampus-dependent memory and breathing pattern in Cdkl5-null mice. Notably, systemically administered TAT-CDKL5 protein passed the blood-brain-barrier, reached the CNS, and rescued various neuroanatomical and behavioral defects, including breathing pattern and visual responses. Our results suggest that CDKL5 protein therapy may be an effective clinical tool for the treatment of CDKL5 disorder.

A recently discovered neurodevelopmental disorder caused by the mutation of the cyclin-dependent kinase-like 5 gene (CDKL5) entails complex autistic-like behaviours similar to Rett syndrome, but its impact upon physiological functions remains largely unexplored. Sleep-disordered breathing is common and potentially life-threatening in patients with Rett syndrome; however, evidence is limited in children with CDKL5 disorder, and is lacking altogether in adults. The aim of this study was to test whether the breathing pattern during sleep differs between adult Cdkl5 knockout (Cdkl5-KO) and wild-type (WT) mice. Using whole-body plethysmography, sleep and breathing were recorded non-invasively for 8 h during the light period. Sleep apneas occurred more frequently in Cdkl5-KO than in WT mice. A receiver operating characteristic (ROC) analysis discriminated Cdkl5-KO significantly from WT mice based on sleep apnea occurrence. These data demonstrate that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice, and suggest that sleep-disordered breathing should be evaluated routinely in CDKL5 patients., (© 2017 European Sleep Research Society.)

Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase predominantly expressed in the brain. Mutations of the CDKL5 gene lead to CDKL5 disorder, a neurodevelopmental pathology that shares several features with Rett Syndrome and is characterized by severe intellectual disability. The phosphorylation targets of CDKL5 are largely unknown, which hampers the discovery of therapeutic strategies for improving the neurological phenotype due to CDKL5 mutations. Here, we show that the histone deacetylase 4 (HDAC4) is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention. Nuclear HDAC4 binds to chromatin as well as to MEF2A transcription factor, leading to histone deacetylation and altered neuronal gene expression. By using a Cdkl5 knockout (Cdkl5 -/Y) mouse model, we found that hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, thereby reducing histone 3 acetylation. This effect was reverted by re-expression of CDKL5 or by inhibition of HDAC4 activity through the HDAC4 inhibitor LMK235. In Cdkl5 -/Y mice treated with LMK235, defective survival and maturation of neuronal precursor cells and hippocampus-dependent memory were fully normalized. These results demonstrate a critical role of HDAC4 in the neurodevelopmental alterations due to CDKL5 mutations and suggest the possibility of HDAC4-targeted pharmacological interventions., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a rare neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability and Rett syndrome-like features. CDKL5 is highly expressed in the brain during early postnatal stages, suggesting its importance for brain maturation. Using a newly-generated Cdkl5 knockout (Cdkl5 -/Y) mouse, we recently found that loss of Cdkl5 impairs postnatal hippocampal development with a reduction in neuronal precursor survival and maturation. These defects were accompanied by increased activity of the glycogen synthase kinase 3β (GSK3β) a crucial inhibitory regulator of many neurodevelopmental processes. The goal of the current study was to establish whether inhibition of GSK3β corrects hippocampal developmental defects due to Cdkl5 loss. We found that treatment with the GSK3β inhibitor SB216763 restored neuronal precursor survival, dendritic maturation, connectivity and hippocampus-dependent learning and memory in the Cdkl5 -/Y mouse. Importantly, these effects were retained one month after treatment cessation. At present, there are no therapeutic strategies to improve the neurological defects of subjects with CDKL5 disorder. Current results point at GSK3β inhibitors as potential therapeutic tools for the improvement of abnormal brain development in CDKL5 disorder., (Copyright © 2015. Published by Elsevier Inc.)

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene., (Copyright © 2014. Published by Elsevier Inc.)

In pianos, the transfer of energy from strings to soundboard and the radiation of sound are highly dependent on the dynamical properties of the soundboard. In this paper, a numerical study is conducted for various rib configurations, showing that even slight irregularities in rib spacing can induce a strong localization of the soundboard velocity pattern. The effective vibrating area can be further reduced due to the spatial filtering effect of the bridge. Numerical predictions of modal shapes and operating deflection shapes are confirmed by series of measurements made on upright piano soundboards. Simulations of radiated pressure based on measured and calculated soundboard velocity fields show that localization tends to broaden the cone of directivity and to reduce the number of lobes.

The brown spider, genus Loxosceles, is becoming of great medical importance, with envenomation (Loxoscelism) occurring throughout the world. The biological activities of the brown spider venom usually include dermonecrotic lesions at the bite site accompanied by hemolytic and haemorrhagic effects and also by renal failure. The objective of the present study was to describe the histology of the venom gland of L. intermedia using glands from adult spiders which were investigated by light microscopy, using immunohistochemical and staining methods, by transmission electron microscopy, and by scanning electron microscopy. The organization of the venom gland of Loxosceles intermedia follows the general architecture of spiders' venom glands. Using light microscopy and transmission electron microscopy we observed that the venom glands of L. intermedia present two layers of striated muscle fibers, an external layer and an internal layer in touch with an extracellular matrix which is a basement membrane structure and a fibrillar collagen matrix separating the muscular region from epithelial cells of the venom gland. Muscle cells are multinucleated, with nuclei peripherally placed and their cytoplasm rich in sarcoplasmic reticulum, myofibrills and continuous Z lines. By using scanning electron microscopy we can detect muscular cells from external layer as branching cells. Epithelial cells have their cytosol extremely rich in rough endoplasmic reticulum, mitochondria collection, Golgi apparatus, interdigitating membranes and secretory vesicles that ultimately accumulate the venom, a complex protein mixture.

Purpose: To test the following hypothesis: The greater the increase in the mean computed tomographic (CT) number of a radiologically indeterminate lung nodule from the CT number on a 140-kVp CT image to that on an 80-kVp CT image, the more likely the nodule is benign (ie, contains calcium)., Materials and Methods: Two hundred forty indeterminate lung nodules were prospectively studied at four institutions: Mayo Clinic Scottsdale, Ariz (n = 160); Mayo Clinic Rochester, Minn (n = 50); Shiga Health Insurance Hospital, Otsu, Japan (n = 25); and Duke University Medical Center, Durham, NC (n = 5). Of the 240 nodules, 157 met the entrance criteria for this study and had a diagnosis. All nodules included were solid, 5-40-mm diameter, relatively spherical, homogeneous, and without visible evidence of calcification or fat. Each nodule was evaluated by using 3-mm-collimation, nonenhanced CT scans with both 140- and 80-kVp x-ray beams., Results: There were 86 (55%) benign and 71 (45%) malignant nodules. The median increase in the nodule mean CT number from the CT number on 140-kVp images to that on 80-kVp images was 2 HU for benign nodules and 3 HU for malignant nodules. This difference was not statistically significant. The area under the receiver operating characteristic curve was 0.505., Conclusion: Dual-kilovolt peak analysis with current CT technology does not appear to be helpful in the identification of benign lung nodules.

Purpose: To test the hypothesis that absence of statistically significant lung nodule enhancement (< or =15 HU) at computed tomography (CT) is strongly predictive of benignity., Materials and Methods: Five hundred fifty lung nodules were studied. Of these, 356 met all entrance criteria and had a diagnosis. On nonenhanced, thin-section CT scans, the nodules were solid, 5-40 mm in diameter, relatively spherical, homogeneous, and without calcification or fat. All patients were examined with 3-mm-collimation CT before and after intravenous injection of contrast material. CT scans through the nodule were obtained at 1, 2, 3, and 4 minutes after the onset of injection. Peak net nodule enhancement and time-attenuation curves were analyzed. Seven centers participated., Results: The prevalence of malignancy was 48% (171 of 356 nodules). Malignant neoplasms enhanced (median, 38.1 HU; range, 14.0-165.3 HU) significantly more than granulomas and benign neoplasms (median, 10.0 HU; range, -20.0 to 96.0 HU; P < .001). With 15 HU as the threshold, the sensitivity was 98% (167 of 171 malignant nodules), the specificity was 58% (107 of 185 benign nodules), and the accuracy was 77% (274 of 356 nodules)., Conclusion: Absence of significant lung nodule enhancement (< or = 15 HU) at CT is strongly predictive of benignity.

We describe our initial experience with the admission of 129 patients for 132 episodes of ventilator-dependence to a self-contained ventilator-dependent unit (VDU) in a general hospital and present a survival comparison between VDU patients and a historic control population from the same institution. Forty-three patients were screened and denied admission to the VDU because long-term ventilator dependence was not felt to be a probable outcome (56%); they were medically unstable, often requiring electrocardiographic monitoring (19%), they had poor rehabilitation potential because of markedly depressed mental status (13%), or they preferred to be treated closer to their homes (12%). Thirteen (9.8%) of the VDU patients died in the hospital compared to 44 (42%) in the historic control group. After exclusion of patients with multiorgan failure (who made up 26% of the control group) and using a proportional hazard model to adjust for group differences in age and disease class, the difference in hospital mortality remained highly significant (p < or = 0.01). Ninety-one of the 119 VDU patients (77%) were ultimately able to return home; 16 (13%) continued to use a ventilator intermittently at night; 26 patients (22%) were permanently placed in nursing homes, all off of the ventilator. Overall, 88% of the 119 patients discharged had been liberated from mechanical ventilation. Ninety-seven (82%) and 86 (72%) remain alive 1 and 2 years after discharge, respectively. Some of the survival benefits may be directly attributed to the VDU. Others reflect a change in treatment philosophy, which was nevertheless reinforced by our VDU experience.

A case is reported of prosthetic mitral valve obstruction in a patient who had had three hospital admissions with massive hemoptysis. A diagnosis was finally made after two-dimensional echocardiography with Doppler and cardiac catheterization were performed. The patient was successfully treated with re-replacement of the valve. Any new pulmonary or cardiac symptom in a patient with a prosthetic valve requires prompt evaluation and treatment.

The evaluation and management of a patient with an SPN is guided by principles that were derived from earlier surgical studies. Stability or no growth for at least 2 years, the presence of calcium in characteristic patterns, and age less than 35 years without any associated risk factors are reliable indicators of a benign process. Fluoroscopy and localized tomography are helpful in evaluation of an SPN. If the nodule is still considered indeterminate, CT scanning, with the use of thin section cuts through the nodule, is now widely employed. If calcium is present in a characteristic pattern, the nodule is considered benign. If the nodule is very dense or more dense than a phantom reference nodule, the nodule has a high likelihood of being benign. Nodules that are less dense than the phantom nodule are indeterminate, and approximately 25% of these nodules will be benign. Computed tomography scan of the chest and upper abdomen is indicated in patients with a previous history of malignancy or when there is a high suspicion that the nodule is malignant. The further evaluation and management of SPNs that are indeterminate after CT examination are controversial. Some recommend tissue biopsy via transbronchoscopic or transthoracic approach, whereas others recommend immediate thoracotomy. Observation is indicated in certain situations when the chance of malignancy is quite low, the patient is not an operable candidate, or when the patient refuses further invasive evaluation. The physician's role in the management of a patient with an SPN is to educate and advise. The physician must be aware of the patient's anxieties, fears, and attitude and provide an opportunity for active participation by the patient in the decision-making process. Multiple pulmonary nodules are most commonly encountered in patients with metastatic disease to the lungs. Other less commonly encountered diseases that present as multiple pulmonary nodules include infections, arteriovenous malformations, Wegener's granulomatosis, and lymphoma. The evaluation and management of the patient with multiple pulmonary nodules are usually guided by the history, physical examination, and laboratory findings.

The outcomes in 61 patients admitted to a chronic ventilator-dependent unit (CVDU) at Saint Marys Hospital in Rochester, Minnesota, during an 18-month period are summarized. This unit was designed for patients who could not be weaned from mechanical ventilators after repeated attempts. Most patients had been ventilator dependent for more than 21 days, but some patients were admitted to the CVDU after briefer periods if special circumstances suggested that weaning from mechanical ventilation would be difficult. The unit was organized to provide a multidisciplinary approach to the general medical and respiratory management of these patients, including a physiologic evaluation of the respiratory system to determine the actual cause of ventilator dependence and complete medical, nursing, and psychosocial assessments to help adopt a plan of care and weaning from the ventilator. Of the numerous causes for ventilator dependence in this study group, chronic obstructive pulmonary disease was the most frequent underlying diagnosis. Of the 61 patients admitted to the CVDU, 58 survived, and 53 were liberated from the mechanical ventilator. Ultimately, 35 patients were dismissed directly home from the CVDU. Five of these patients required nocturnal mechanical ventilation. An additional eight patients were dismissed home after rehabilitation. After being weaned from mechanical ventilation, 11 patients were eventually transferred to nursing homes, and 3 additional patients were transferred to a local hospital or physical medicine unit. One patient remains in the CVDU. Thus, the CVDU has successfully liberated patients from ventilator dependence. In addition, because of a decreased need for nursing care, the unit has been cost-effective.

Impairment of exercise tolerance is a common problem in patients with severe chronic obstructive pulmonary disease. The cause of exercise intolerance in patients with severe chronic obstructive pulmonary disease is multifactorial and includes impaired lung mechanics, fatigue of inspiratory muscles, impaired gas exchange, right ventricular dysfunction, malnutrition, occult cardiac disease, deconditioning, and psychologic problems; however, impaired lung mechanics and gas exchange abnormalities seem to be the major limiting factors. Recently, the approach to management of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease has changed because improvement in exercise tolerance has been demonstrated after pulmonary rehabilitation. Other adjunctive measures that have been shown to contribute to the observed improvement in exercise tolerance include administration of oxygen, nutritional support, cessation of smoking, and psychosocial support. The roles of ventilatory muscle endurance training, respiratory muscle rest therapy, nasally administered continuous positive airway pressure, and training of the muscles of the upper extremities are less clearly defined.

We reviewed the Mayo Clinic experience with nocturnal nasal ventilation (NNV) and retrospectively assessed the clinical benefits, patient compliance, and complications. NNV had been instituted in 26 patients with daytime hypercapnia and nocturnal hypoventilation due to neuromuscular diseases or chronic obstructive pulmonary disease. After initiation of NNV, 21 of 26 patients continued to use this treatment regularly (81% compliance rate) and considered their life-style improved. In this subset of patients, the arterial partial pressure of carbon dioxide during unassisted breathing decreased from 64 +/- 13 to 51 +/- 7 mm Hg, and the arterial partial pressure of oxygen increased from 58 +/- 12 to 68 +/- 8 mm Hg. No significant change was noted in the forced vital capacity or maximal respiratory pressures. Four of the five patients in whom NNV had been discontinued cited discomfort related to the mask or severity and poor prognosis of the underlying illness as reasons for cessation of treatment. We conclude that NNV is well tolerated by most patients and may improve alveolar ventilation and arterial oxygenation in patients with chronic respiratory failure.

Open lung biopsies from 14 patients and autopsy tissue from one patient with polymyositis/dermatomyositis were reviewed in an attempt to correlate histologic features with clinical, radiographic, and prognostic variables. Three major groups based on histologic patterns were identified: bronchiolitis obliterans organizing pneumonia (BOOP), usual interstitial pneumonia (UIP), and diffuse alveolar damage (DAD). Patients with BOOP had a more favorable prognosis than did patients with UIP. Patients with DAD had a uniformly poor prognosis. One patient had a cellular interstitial pneumonia and did well. Histologic subclassification of the interstitial lung disease proved to be a better predictor of survival than did the radiographic appearance or the clinical presentation. These findings suggest that there is a broader range of histologic findings in polymyositis-dermatomyositis than is suggested in the literature and subclassification may be useful for prognosis.

In this article, we describe an integrated approach for detection and evaluation of solitary pulmonary nodules. Initial evaluation of the solitary pulmonary nodule includes tomography, fluoroscopy, and comparison with previously obtained roentgenograms. Subsequently, thin-section computed tomography and phantom densitometry can be used for analysis, if indicated. The rationale for the use of computed tomography in the radiologic staging of bronchogenic carcinoma is to expedite and assist in the identification of the subset of patients with resectable tumors. For nonsurgical tissue diagnosis, fiberoptic bronchoscopy is generally the initial procedure for lesions 2.0 cm or larger in diameter, and transthoracic needle biopsy is used for those smaller than 2.0 cm.

Recently, interest in the use of mechanical ventilation outside the hospital setting has been increasing. Patients with various types of chronic respiratory failure may benefit from this approach. Evaluation for long-term mechanical ventilation necessitates assessment of the underlying disease process, the goals of the medical team, and the needs of the patient and family. Externally applied negative-pressure devices can provide adequate ventilation for many patients, particularly those with neuromuscular diseases. Positive-pressure ventilation by means of a tracheostomy provides greater control of the airway, allows adjustment of tidal volume and minute ventilation, and may be delivered by portable equipment. Ongoing care and support services in the home must be provided. A variety of mechanical devices and new techniques of ventilator support have made home mechanical ventilation a realistic option for long-term care.