Motor and non-motor sequence learning in children and adolescents with cerebellar damage.

Cerebellar involvement in motor and non-motor sequence learning was examined with serial reaction time tasks (SRT). Our sample consisted of 8 children and adolescents who had undergone surgical removal of a benign posterior fossa tumor (PFT) during childhood. None of them had undergone chemotherapy or cranial radiation therapy (CRT). Ages ranged from 1-11 years at surgery and 9-17 years at testing. The children were tested not earlier than 2.5 years after surgery (M = 5.9 years), enabling brain plasticity and recovery of functions. Their performance was compared with a matched control sample. The PFT group was not impaired in the implicit learning of sequences, as reflected in their performance in blocks with a repeated sequence, both before and after a random block. However, in the perceptual task, their performance deteriorated more than that of the control group when a random block was introduced, suggesting that it was more difficult for the patients to respond flexibly or change their response set when encountering changing task demands. These results are in line with another study by our group on task switching with the same patients.     

Lymphedema as a presenting sign of toxocariasis

Summary Toxocariasis in children is usually an asymptomatic infection and those with clinical illness have non-specific systemic or local manifestations. We present a 24-month-old boy with bilateral lymphedema of the feet as the main clinical manifestation of toxocariasis. The child presented with limping and nonpitting edema of both feet. Laboratory investigation revealed leucocytosis of <20,000/mm³ with a differential count of <50% eosinophils. No other cause of edema was found. The ELISA for toxocariasis revealed a high titer of 1:4,096. The limping and the lymphedema disappeared during the third week of his illness. We suggest that toxocariasis should be considered as a possible cause of lymphedema and eosinophilia in young children.Zusammenfassung Die Toxocariasis nimmt bei Kindern in der Regel einen asymptomatischen Verlauf. Wenn Krankheitszeichen auftreten, handelt es sich um unspezifische Allgemeinsymptome oder lokale Symptome. Wir berichten über einen 24 Monate alten Jungen, bei dem ein bilaterales Lymphödem der Füße die Hauptmanifestation der Toxocariasis war. Das Kind hinkte und hatte an beiden Füßen ein nicht dellenbildendes Ödem. Dabei bestand eine Leukozytose von >20 000/mm³ mit >50% Eosinophilen im Differentialblutbild. Andere Ursachen für das Ödem waren nicht zu finden. Der ELISA für Toxocariasis ergab einen hohen Titer von >1:4 096. Hinken und Lymphödem verschwanden im Verlauf von drei Wochen. Wir verweisen auf die Möglichkeit einer Toxocariasis als mögliche Ursache für Lymphödem und Eosinophilie bei kleinen Kindern.

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Lymphödem als Primärsymptom einer Toxocariasis

     

Repetitive milrinone therapy in ambulatory advanced heart failure patients

BackgroundAdvanced heart failure (HF) patients usually poorly tolerate guideline‐directed HF medical therapy (GDMT) and suffer high rates of morbidity and mortality. The use of continuous inotropes in the outpatient settings is hampered by previous data showing excess morbidity. We aimed to assess the safety and efficacy of repetitive, intermittent, short‐term intravenous milrinone therapy in advanced HF patients with an intention to introduce and up‐titrate GDMT and improve functional class.HypothesisRepetitive, intermittent milrinone therapy may assist with the stabilization of advanced HF patients.MethodsAdvanced HF patients treated with beta‐blockers and implanted with defibrillators were initiated with repetitive, intermittent short‐term intravenous milrinone therapy at our HF outpatient unit. Patients were prospectively followed with defibrillator interrogation, functional class assessment, B‐natriuretic peptide (BNP) levels, and echocardiography parameters.ResultsThe cohort included 24 patients with a mean 330 ± 240 days of milrinone therapy exposure. Mean age was 73 ± 6 years with male predominance (96%). Following milrinone therapy, median BNP levels decreased significantly (882 [286−3768] to 631 [278−1378] pg/ml, p = .017) with a significant reduction in the number of patients with New York Heart Association (NYHA) Class III and IV (p = .012, 0.013) and an increase in number of patients on GDMT. Importantly, the number of total sustained ventricular tachycardia events and HF hospitalizations did not change.ConclusionsIn this small cohort of advanced HF, repetitive, intermittent, short‐term milrinone therapy was found to be safe and potentially efficacious.     

Changing Methods of Imaging the Common Bile Duct in the Laparoscopic Cholecystectomy Era in Western Australia: Implications for Surgical Practice

OBJECTIVE: To assess changes in the use of endoscopic retrograde cholangiopancreatography (ERCP), intraoperative cholangiography (IOC), and surgical exploration of the common bile duct (CBD) associated with the introduction of laparoscopic cholecystectomy (LC). SUMMARY BACKGROUND DATA: The optimal strategy for dealing with potential stones of the CBD during LC remains controversial. METHODS: The authors conducted a population-based study of all cases of cholecystectomy (20,084) in Western Australia in the periods before, during, and after the introduction of LC (1988-1994). Index admissions were linked to previous or subsequent admissions for ERCP. Factors associated with ERCP were analyzed by multivariate regression models. RESULTS: Between 1988 and 1994, admissions for ERCP almost doubled, whereas the use of IOC decreased from 71% to 51%. Different trends were found for open and laparoscopic procedures. Exploration of the CBD declined because of the infrequent use of this procedure in LC. Preoperative ERCP was significantly more common in older patients and men; the reverse was found for IOC. There was an adjusted 3.5-fold increase in preoperative ERCP both during and after the introduction of LC. The adjusted odds ratios for IOC were 0.48 and 0.52 for these periods. CONCLUSIONS: The introduction of LC was associated with increasing reliance on ERCP to image the CBD and a decrease in the use of IOC. These changes were observed in both LC and open cholecystectomy. They suggest that the use of ERCP before cholecystectomy has partly replaced IOC for visualization of the CBD for suspected stones. Although more than 40% of patients undergoing LC had IOC, surgeons appear to be reluctant to perform surgical exploration of the CBD when stones are present. Savings in terms of both complications and cost can be expected if preoperative ERCPs performed for suspicion of uncomplicated CBD stones are replaced by IOC.     

CD81 costimulation skews CAR transduction toward naive T cells

Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells.

Genetic manipulation of T cells has enabled adoptive T cell therapy to be translated to the clinic (1–10). Chimeric antigen receptor (CAR) therapy has evoked recent enthusiasm upon mediating curative outcomes in aggressive, refractory B cell malignancies (1–7, 11–15), leading to Food and Drug Administration approval (16–18). The process of ex vivo transduction and expansion of T cells to express CARs influences the phenotype, function, and ultimate fate of the final CAR T cell product (19–23). Preclinical data in animal models indicate that selecting specific T cell subsets for CAR transduction improves efficacy (21, 22, 24–26). Naive-derived T cells have been shown to exhibit greater replicative capacity, persistence, and antitumor function, compared with both effector- and memory-derived T cells (19, 20, 27). Naive CD4⁺ T cells, specifically, have a critical role in enhancing the cytotoxic effect of the CD8⁺ cooperating central memory cell subset (21). Furthermore, the translational CAR experience demonstrates that the presence of cells consistent with the naive and early memory phenotype in premanufactured T cell products correlates with successful clinical responses in both pediatric and adult B cell leukemia (28–30). Here, we explore if selective activation of naive T cells can result in skewing of transduction toward this specific T cell subset without the need for physical subset sorting.CAR constructs rely on intrinsic costimulatory signals, such as the intracellular domains of CD28 or 41BB, for efficacy (1–9). Here we focus on exogenous costimulatory signals necessary to induce proliferation and permit viral-mediated gene transfer. Prior to CAR transduction and antigen encounter, the majority of T cells are in a state of rest. Resting T cells mandate primary and costimulatory signals for activation (31, 32). CD28 is best known for its ability to costimulate T cells (33–38) and along with CD3 activation renders T cells susceptible to viral transduction (1, 39). CD81 is a member of the tetraspanin family that physically associates with CD4 and CD8 on the surface of T cells. CD81 was shown to have independent costimulatory properties and, when used with anti-CD3 and -CD28 antibodies, preferentially activates naive T cells as compared with effector and memory T cells, despite conserved surface CD81 expression across T cell subsets (40). Tetraspanins have no known cell-surface ligands, and therefore antibodies are used to engage and stimulate them. CD81 is the only tetraspanin whose complete three-dimensional structure has been solved (41). Moreover, the crystal structure of 5A6, the anti-CD81 antibody used in our study, in complex with CD81 has also been most recently solved (42). These authors demonstrate that engagement by this antibody changes the conformation of the large extracellular loop of the CD81 molecule. This conformational change may affect the interaction of CD81 with its associated CD4 and CD8 molecules.Here, we costimulate purified T cells with CD81 as a proof of principle to illustrate that the in vitro activation window prior to CAR transduction can be leveraged to favor transduction of a specific T cell subset.     

Pseudotumor cerebri manifesting as stiff neck and torticollis

Stiff neck and torticollis are significant signs of neurologic disease. Nuchal rigidity is often associated with meningitis, subarachnoid hemorrhage, and posterior fossa tumor. Torticollis may be encountered in inflammatory disorders, such as cervical lymphadenitis, or it can be a sign of spinal cord syrinx or of central nervous system neoplasm. We report on three prepubertal children in whom stiff neck and torticollis were the presenting signs of pseudotumor cerebri. In all, the removal of 6-7 mL of cerebrospinal fluid led to prompt relief of symptoms and signs. We suggest that in the presence of unexplained stiff neck or torticollis in children, the optic discs should be examined to exclude pseudotumor cerebri.     

Oligomycin,inhibitor of the F0 part of H+-ATP-synthase,suppresses the TNF-induced apoptosis

The release of cytochrome c from the intermembrane space of mitochondria into the cytosol is one of the critical events in apoptotic cell death. In the present study, it is shown that release of cytochrome c and apoptosis induced by tumor necrosis factor alpha (TNF) in HeLa cells can be inhibited by (i) overexpression of an oncoprotein Bcl-2, (ii) Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (PTP) or (iii) oligomycin, an inhibitor of H+- ATP-synthase. Staurosporine-induced apoptosis is sensitive to Bcl-2 but insensitive to Cyclosporin A and oligomycin. The effect of oligomycin is not due to changes in mitochondrial membrane potential or to inhibition of ATP synthesis/hydrolysis since (a) uncouplers (CCCP, DNP) which discharge the membrane potential fail to abolish the protective action of oligomycin and (b) aurovertin B (another inhibitor of H+-ATP-synthase, affecting its F1 component) do not affect apoptosis. A role of oligomycin-sensitive F0 component of H+-ATP-synthase in the TNF-induced PTP opening and apoptosis is suggested.