Blended cognitive behaviour therapy for children and adolescents with mitochondrial disease targeting fatigue (PowerMe): study protocol for a multiple baseline single case experiment.

BACKGROUND: Mitochondrial disease is a rare, hereditary disease with a heterogeneous clinical presentation. However, fatigue is a common and burdensome complaint in children and adolescents with mitochondrial disease. No psychological intervention targeting fatigue exists for paediatric patients with a mitochondrial disease. We designed the PowerMe intervention, a blended cognitive behaviour therapy targeting fatigue in children and adolescents with mitochondrial disease. The aim of the intervention is to reduce perceived fatigue by targeting fatigue-related cognitions and behaviours. METHODS: A multiple baseline single case experiment will be conducted in five children (8-12 years old) and 5 adolescents (12-18 years old) with mitochondrial disease and severe fatigue. Patients will be included in the study for 33 weeks, answering weekly questions about the fatigue. Patients will be randomly assigned a baseline period of 5 to 9 weeks before starting the PowerMe intervention. The intervention consists of face-to-face and online sessions with a therapist and a website with information and assignments. The treatment will be tailored to the individual. Each patient will work on their personalized treatment plan focusing on personally relevant goals. The primary outcome is perceived fatigue. Secondary outcomes are quality of life, school presence and physical functioning. DISCUSSION: The results of the PowerMe study will provide information on the efficacy of a blended cognitive behaviour therapy on reducing perceived fatigue and its impact on daily life in children and adolescents with mitochondrial disease. Strengths and limitations of the study design are discussed. TRIAL REGISTRATION: Dutch Trial Register NTR 7675. Registered on 17 December 2018. Identifier https://www.trialregister.nl/trial/7433.

The safety and efficacy of immune checkpoint inhibitors in patients with advanced cancers and pre-existing chronic viral infections (Hepatitis B/C, HIV): A review of the available evidence.

The treatment paradigm of several cancers has dramatically changed in recent years with the introduction of immunotherapy. Most oncology trials involving immune checkpoint inhibitors (ICIPs) have routinely excluded patients with HIV infection and chronic viral hepatitis B (HBV) and C (HCV) due to concerns about viral reactivation, fears of increased toxicity, and the potential lack of efficacy in these patient subgroups. However, with current antiviral therapies, HIV and HBV infections have become chronic diseases and HCV infections can even be cured. Broadening cancer trial eligibility criteria in order to include cancer patients with chronic viral infections can maximize the ecological validity of study results and the ability to understand the ICPIs' benefit-risk profile in patients with these comorbidities. In this review, we examined the evidence on the efficacy and safety of using ICPIs in cancer patients with concurrent chronic viral infections.

Estimating The Quality of Electroconvulsive Therapy Induced Seizures Using Decision Tree and Fuzzy Inference System Classifiers.

Electroconvulsive therapy (ECT) is an effective and widely used treatment for major depressive disorder, in which a brief electric current is passed through the brain to trigger a brief seizure. This study aims to identify seizure quality rating by utilizing a set of seizure parameters. We used 750 ECT EEG recordings in this experiment. Four seizure related parameters, (time of slowing, regularity, stereotypy and post-ictal suppression) are used as inputs to two classifiers, decision tree and fuzzy inference system (FIS), to predict seizure quality ratings. The two classifiers produced encouraging results with error rate of 0.31 and 0.25 for FIS and decision tree, respectively. The classification results show that the four seizure parameters provide relevant information about the rating of seizure quality. Automatic scoring of seizure quality may be beneficial to clinicians working in this field.

let-7 miRNAs can act through notch to regulate human gliogenesis.

It is clear that neural differentiation from human pluripotent stem cells generates cells that are developmentally immature. Here, we show that the let-7 plays a functional role in the developmental decision making of human neural progenitors, controlling whether these cells make neurons or glia. Through gain- and loss-of-function studies on both tissue and pluripotent derived cells, our data show that let-7 specifically regulates decision making in this context by regulation of a key chromatin-associated protein, HMGA2. Furthermore, we provide evidence that the let-7/HMGA2 circuit acts on HES5, a NOTCH effector and well-established node that regulates fate decisions in the nervous system. These data link the let-7 circuit to NOTCH signaling and suggest that this interaction serves to regulate human developmental progression.

Socio-emotional Problems in Children with CDG.

BACKGROUND: Congenital disorders of glycosylation (CDG) form a group of inherited metabolic diseases. Although the clinical presentation shows extreme variability, the nervous system is frequently affected. Several parents of our patients diagnosed with CDG reported behavioral problems, including mood swings, depressive behavior, and anxiety. This raised the question whether patients with CDG have an increased risk for socio-emotional problems. METHODS: We evaluated 18 children with confirmed CDG. The Child Behavior Checklist (CBCL) was used to screen for socio-emotional problems. To determine the disease progression and severity in CDG, the Nijmegen Paediatric CDG Rating Scale (NPCRS) was used. RESULTS were compared to "norm scores" and to children with mitochondrial disorders and children with other chronic metabolic disorders with multisystem involvement. RESULTS: RESULTS showed a high prevalence of socio-emotional problems in children with CDG. Mean total scores, scores on withdrawn/depressed behavior, social problems, and somatic complaints were significantly increased. More than two thirds of our CDG patients have abnormal scores on CBCL. The mean score on social problems was significantly higher compared to our two control groups of patients with other chronic metabolic disorders. CONCLUSIONS: Patients with CDG have an increased risk of developing socio-emotional problems. A standard screening for psychological problems is recommended for the early detection of psychological problems in CDG patients.

BrachyView: proof-of-principle of a novel in-body gamma camera for low dose-rate prostate brachytherapy.

PURPOSE: The conformity of the achieved dose distribution to the treatment plan strongly correlates with the accuracy of seed implantation in a prostate brachytherapy treatment procedure. Incorrect seed placement leads to both short and long term complications, including urethral and rectal toxicity. The authors present BrachyView, a novel concept of a fast intraoperative treatment planning system, to provide real-time seed placement information based on in-body gamma camera data. BrachyView combines the high spatial resolution of a pixellated silicon detector (Medipix2) with the volumetric information acquired by a transrectal ultrasound (TRUS). The two systems will be embedded in the same probe so as to provide anatomically correct seed positions for intraoperative planning and postimplant dosimetry. Dosimetric calculations are based on the TG-43 method using the real position of the seeds. The purpose of this paper is to demonstrate the feasibility of BrachyView using the Medipix2 pixel detector and a pinhole collimator to reconstruct the real-time 3D position of low dose-rate brachytherapy seeds in a phantom. METHODS: BrachyView incorporates three Medipix2 detectors coupled to a multipinhole collimator. Three-dimensionally triangulated seed positions from multiple planar images are used to determine the seed placement in a PMMA prostate phantom in real time. MATLAB codes were used to test the reconstruction method and to optimize the device geometry. RESULTS: The results presented in this paper show a 3D position reconstruction accuracy of the seed in the range of 0.5-3 mm for a 10-60 mm seed-to-detector distance interval (Z direction), respectively. The BrachyView system also demonstrates a spatial resolution of 0.25 mm in the XY plane for sources at 10 mm distance from Medipix2 detector plane, comparable to the theoretical value calculated for an equivalent gamma camera arrangement. The authors successfully demonstrated the capability of BrachyView for real-time imaging (using a 3 s data acquisition time) of different brachytherapy seed configurations (with an activity of 0.05 U) throughout a 60 × 60 × 60 mm(3) Perspex prostate phantom. CONCLUSIONS: The newly developed miniature gamma camera component of BrachyView, with its high spatial resolution and real time capability, allows accurate 3D localization of seeds in a prostate phantom. Combination of the gamma camera with TRUS in a single probe will complete the BrachyView system.

Frontal brain activation in young children during picture book reading with their mothers.

AIM: This study was to measure changes in frontal brain activation in young children during picture book reading with their mothers. METHODS: The cross-sectional sample consisted of 15 young Japanese children (eight girls and seven boys, mean age 23.1 +/- 3.4). Two experimental tasks were presented as follows: Task 1 (picture book reading with their mothers); Task 2 (viewing of book-on-video). Duration of task stimulus was 180-sec and the 60-sec interval was filled. Brain activation was measured using an optical topography system. RESULTS: Significant increases in oxy-Hb were observed in both right and left frontal areas in response to Task 1 compared with Task 2. There were significant correlations between child's brain activity and mothers' and children's verbal-nonverbal behaviours. CONCLUSION: There was greater frontal lobe activation in children when they were engaged in a picture book reading task with their mothers, as opposed to passive viewing of a videotape in which the story was read to them. Social and verbal engagement of the mother in reading picture books with her young child may mediate frontal brain activity in the child.

Glial reactions and degeneration of myelinated processes in spinal cord gray matter in chronic experimental autoimmune encephalomyelitis.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) result in inflammatory white matter lesions in the CNS. However, information is sparse with regard to the effects of autoimmune demyelinating disease on gray matter regions. Therefore, we studied the late effects of chronic EAE in C57BL/6 mice on the spinal cord gray matter using immunohistochemistry. Here, EAE induced marked astrocytic, microglial, and macrophage activation in the ventral horn gray matter, without any motoneuron loss. Activated caspase-3 was also increased in the ventral horn gray matter. Furthermore, activated poly (ADP-ribose) polymerase (PARP), another apoptotic marker, co-localized with myelin basic protein (MBP) of oligodendrocyte processes, but not with the oligodendroglial cell body marker, adenomatous polyposis coli gene clone CC1 (APC-CC1), or with neurofilament marker (RT-97) or synaptophysin of axonal arbors. However, there was no associated increase in the number of terminal deoxynucleotidyl transferase (TdT) mediated-dUTP nick end labeling positive nuclei in the spinal cord gray matter of EAE mice. In addition, co-localization of MBP and the low-affinity neurotrophin receptor, p75, was demonstrated, further supporting the notion of apoptotic oligodendrocyte process degeneration in the gray matter of EAE mice.

Genetic and environmental factors in complex neurodevelopmental disorders.

Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed.

Ontogenic reduction of Aph-1b mRNA and gamma-secretase activity in rats with a complex neurodevelopmental phenotype.

Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the gamma-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about gamma-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in gamma-secretase cleavage activity towards one of its best-known substrates, the amyloid-beta precursor protein APP. We conclude that the low levels of Aph-1b mRNA and gamma-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

Merosin-deficient congenital muscular dystrophy in two siblings.

Congenital muscular dystrophies are a group of heterogeneous inherited autosomal recessive disorders. The so-called 'pure' or 'occidental' form is further divided into merosin-positive and merosin-negative subgroups. Merosin is also expressed in the nervous system and its deficiency could affect development of the nervous system. The authors report two siblings with merosin-negative congenital muscular dystrophy. The clinical picture, biopsy findings, and abnormalities as detected by the magnetic resonance imaging of the two patients are presented.

Gender-specific proteomic alterations in glycolytic and mitochondrial pathways in aging monkey hearts.

We utilized proteomic techniques in a primate model (Macaca fascicularis) of aging to determine potential mechanisms to explain gender differences in protection of the aging heart. The majority of prior work in this field utilized rodent models, and importantly no prior study utilized a proteomic approach in the aging heart. We studied changes in proteins in seven monkeys in each group (young and old males and females (YMs, OMs, YFs, and OFs, respectively)), and used two-dimensional gel electrophoresis in combination with mass spectrometry in five monkeys in each group. We found decreases (P < 0.05) in the expression of key enzymes in glycolysis (e.g. pyruvate kinase, alpha-enolase, triosephosphate isomerase), glucose oxidation (e.g. pyruvate dehydrogenase E1 beta-subunit), and the tricarboxylic acid (TCA) cycle (2-oxoglutarate dehydrogenase) in left ventricular (LV) samples from OM monkeys; these changes in glycolytic, glucose oxidation, and TCA enzymes were not observed either in YMs, YFs or OFs. We found additional gender differences in the reduced expression and function of proteins that are responsible for electron transport and oxidative phosphorylation in mitochondria only in hearts from OM monkeys, with corresponding decreased oxidation rates with NADH and ascorbate-N,N,N',N' ''-tetramethyl-p-phenylenediamine substrates. The changes in glycolytic and mitochondrial metabolic pathways in OM monkey hearts are similar to changes observed in hearts affected by diabetes or LV dysfunction, and could be involved in the mechanism for the cardiomyopathy of aging. The sparing of these changes in OF hearts could be involved in the mechanism mediating delayed cardiovascular risk in OFs.

Alveolar rhabdomyosarcoma of the cervix.

BACKGROUND: Alveolar rhabdomyosarcoma (RMS) has a high risk for local and distal failure. Multimodal management of a patient with alveolar RMS of the cervix uteri is outlined. CASE: A 39-year-old woman suffered from alveolar RMS of the cervix without involvement of uterus and parametrium. She was treated with total hysterectomy and left salpingo-oophorectomy. Systemic chemotherapy and pelvic irradiation were also offered. She remains in clinical remission 3 years after presentation. CONCLUSION: Postoperative chemotherapy and irradiation could be effective treatments for alveolar rhabdomyosarcoma of the cervix in adult patients.

Cerebral infarction and cerebral salt wasting syndrome in a patient with tuberculous meningoencephalitis.

A 38-year old female with underlying systemic lupus erythematosus was admitted with tuberculous meningoencephalitis. After an initial good response to anti-tuberculous treatment, she developed cerebral infarction and profound hyponatremia. This was due to cerebral salt wasting syndrome, which has only previously been described in 2 cases. The difficulties in diagnosis and management of this case are discussed.

Primary multifocal leptomeningeal gliomatosis.

A 23-year-old female university student was presented with recent onset of non-specific headache and dizziness. She had no neurological deficit on neurological examination and magnetic resonance imaging of the brain revealed diffuse enhancement in the basal cisterns and cerebral sulci. She was treated as tuberculous meningitis but she did not improve and developed respiratory arrest. Autopsy showed primary multifocal leptomeningeal gliomatosis.

Arteriotomy closure by glued patch in the porcine carotid artery.

BACKGROUND: A thoracoscopic approach to coronary bypass grafting warrants renewed search for facilitated vascular anastomosis methods. We reassessed tissue adhesion, sealing properties, and histotoxicity of iso-butyl-cyanoacrylate, in a simplified anastomosis model. METHODS: In 12 Dutch landrace pigs, five arteriotomies were made in each carotid artery. The arteriotomies were closed by conventional microvascular suturing or by pericardial patch (Peri-Strips) and iso-butyl-cyanoacrylate. The animals were sacrificed at 2 hours (n = 2), 2 days (n = 5), and 4 weeks (n = 5). The arteries were examined by flow measurement, angiography, and histologic analysis. RESULTS: The time required to close arteriotomies by conventional suturing was 257 +/- 43 seconds (mean +/- SD) and by glued patch 51 +/- 27 seconds (p < 0.001). In all arteriotomies covered by glued patch, complete hemostasis was obtained. At 2 days and 4 weeks, with both methods the same histologic results were observed. At follow-up, all carotid arteries were patent without stenoses. CONCLUSIONS: Arteriotomy closure by glued patch was simple, fast, reliable, and without signs of histotoxicity. Adhesives deserve to be reconsidered as an alternative to suturing in closed chest beating-heart coronary surgery.

Nodular histiocytic/mesothelial hyperplasia: a lesion potentially mistaken for a neoplasm in transbronchial biopsy.

This report describes two examples of nodular histiocytic/ mesothelial hyperplasia as seen in transbronchial biopsy that initially led to serious consideration of neuroendocrine neoplasm or meningioma. The biopsies showed nodular collections of cohesive polygonal or round cells with ovoid or deeply grooved nuclei and a moderate amount of finely granular cytoplasm. Nuclear pleomorphism was mild. Immunohistochemical studies showed few cells staining for cytokeratin and the mesothelial marker HBME-1, whereas most cells were decorated by the histiocytic marker PG-M1 (CD68). This lesion appears to be identical to nodular mesothelial hyperplasia as described in hernia sacs and mesothelial/monocytic incidental cardiac excrescences, and we propose modifying the designation to "nodular histiocytic/mesothelial hyperplasia" to take into account the marked predominance of histiocytes over mesothelial cells. The clues to recognition of the true nature of the lesion are clinicopathologic correlation and identification of strips of low cuboidal (mesothelial) cells in the vicinity, and the diagnosis can be further confirmed by immunohistochemical staining. Nodular histiocytic/mesothelial hyperplasia probably results from irritation to the mesothelial lining by various causes leading to focal aggregation of histiocytes within retraction pockets or crevices of the serosal cavity.

Accuracy, precision and user-acceptability of self blood glucose monitoring machines.

The performance of six self-monitoring blood glucose (SMBG) machines (Accutrend, Reflolux S, Companion 2, Glucometer GX, Glucometer IV and One Touch II) were examined using venous blood samples from 88 patients. Whole blood glucose (BG) values were measured by four machines from each brand. Machine-generated whole blood glucose (BG) values were corrected before comparison with laboratory plasma glucose values, measured by a glucose oxidase method. Based on error grid analysis, most of the corrected machine-generated BG values were clinically acceptable. Accutrend, Glucometer IV and Companion 2 showed the greatest consistency between machines of the same brand. Over 80% of corrected BG values generated by Glucometer IV fell within +/-10% of the reference values. One Touch II yielded the most reproducible results with a mean CV of 2.7% and was considered the most user friendly machine. More studies are required to examine the performance of these machines in the hands of patients.

Regulation of ciprofloxacin uptake in human promyelocytic leukemia cells and polymorphonuclear leukocytes.

Polymorphonuclear leukocytes (PMNs) actively internalize ciprofloxacin, a capability that can enhance killing of intracellular bacteria and facilitate delivery of the antimicrobial agent to infection sites by migrating PMNs. In this study we investigated mechanisms for up-regulation of this process. Activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP; 100 nM) enhanced PMN ciprofloxacin uptake by 50% (P < 0.05). Phorbol myristate acetate (PMA; > or = 10 nM) enhanced uptake by at least 36-fold, mainly by stimulating an increase in the Vmax of the ciprofloxacin transporter. This effect of PMA was inhibited by antagonists of protein kinase C (H7 and chelerythrine) and the mitogen-activated protein kinase cascade downstream (PD 098059). Under resting and PMA-activated conditions, ciprofloxacin uptake by immature human promyelocytic leukemia (HL-60) cells was much lower than in PMNs. However, when HL-60 cells were induced to mature into PMN-like cells, their ciprofloxacin uptake activity increased markedly. These findings implicate a role for protein kinase C in up-regulation of the ciprofloxacin transporter and suggest that myeloid cells acquire an enhanced ability to take up ciprofloxacin as they mature to end-stage PMNs.