Health Related Quality of Life and Emotional Health in Children with Chronic Granulomatous Disease: A Comparison of Those Managed Conservatively with Those That Have Undergone Haematopoietic Stem Cell Transplant

Purpose

Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency that predisposes to life-threatening infections and inflammation. Haematopoietic stem cell transplant (HSCT) can cure CGD. Chronic illness reduces quality of life. Children with haematological malignancies report improved quality of life post-HSCT. There are no data for children with CGD. This study evaluated quality of life and emotional well-being in CGD children treated conventionally or transplanted.

Methods

Parents and children completed the Pediatric Quality of Life Inventory v4.0 (PedsQL) and Strengths and Difficulties Questionnaires (SDQ). Mean scores were compared with published UK norms. Comparisons were made for those that had or had not undergone HSCT.

Results

Forty-seven parents completed PedsQL (children aged 3–15). Twenty-one were post-HSCT. Forty-two completed SDQ (children aged 3–15). Nineteen post-HSCT. Median age for non-HSCT group 9 years. Median age for post-HSCT group 10 years. The HSCT group were median 3 years post-HSCT (range 1–9 years). HSCT survival was 90 %—two died without completing questionnaires Parent and self-reported quality of life for non-transplanted children was significantly lower than healthy children. Parents reported increased emotional difficulties compared to published norms. PedsQL and SDQ scores for transplanted children were not significantly different from healthy norms.

Conclusions

This study demonstrates the quality of life is reduced in CGD. Transplanted patients have quality of life comparable to levels reported in healthy children. This data will help inform families and clinicians when deciding about treatment and may have relevance for other immunodeficiencies treated with transplant.     

Working memory performance of older adults with insomnia

Older individuals suffering insomnia typically report declines in their cognitive performance beyond what they consider to be normal changes due to the aging process. Recent neuro‐imaging studies have demonstrated frontal lobe hypo‐activation among insomniac populations when compared with healthy, good sleepers. However, research is yet to confirm whether frontal lobe hypo‐activation translates into objective declines when performing tasks hypothesized to draw upon this brain region. This study aimed to investigate whether older insomnia sufferers demonstrate significantly impaired performance on a challenging working memory task when compared with age‐matched good sleepers. Forty‐nine older individuals (mean age = 69.43 years, SD = 4.83) suffering from sleep maintenance insomnia were compared with 49 age‐matched good sleepers. Cognitive performance was assessed using the Double Span Memory Task, a computer‐based working memory task that requires participants to indicate the names and/or spatial locations of increasingly longer sequences of visually presented objects. After controlling for general intelligence, the individuals suffering from insomnia did not perform differently when compared with the good sleepers on either the simpler or more cognitively demanding components of the task. Older individuals with insomnia did not display an observable impairment of working memory in this study relative to good sleepers. Despite the mixed results from previous research, this study adds weight to the absence of objective impairment in insomniacs, at least while performing short‐term demanding cognitive tasks.     

Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

     

Non-diphtheriae Corynebacterium species: an emerging respiratory pathogen

The purpose of the study was to describe the microbiological and clinical features of ten cases of lower respiratory tract infection due to Corynebacterium striatum, Corynebacterium propinquum and Corynebacterium pseudodiphtheriticum. Respiratory samples were recovered from hospitalised patients who were diagnosed of pneumonia and exacerbations of chronic respiratory infections. The samples were Gram-stained and seeded on conventional bacterial growing media. Bacteria were identified by matrix-assisted linear desorption/ionisation–time-of-flight mass spectrometry (MALDI-TOF MS). Antibiotic susceptibility was tested by the disk diffusion method. All patients presented an acute respiratory onset, most of them in the context of an underlying disease and/or immunosuppression. In all patients, the microscopical examination of Gram-stained respiratory samples showed numerous polymorphonuclear cells and Gram-positive bacilli, suggestive of the Corynebacterium morphotype. A pure culture growth of Corynebacterium was obtained in the majority (72 %) of samples. The conclusions are that non-diphtheriae Corynebacterium species are an emerging cause of respiratory infection among patients with chronic respiratory disease and/or immunosuppression, and cannot always be considered as mere colonisers. The microorganism’s predominance in Gram-stained purulent respiratory samples together with abundant growth in the culture is the key for the microbiological diagnosis.     

Prevalence and severity of atherosclerosis in different arterial territories and its relation with obesity

BackgroundThere is uneven association between obesity, traditional risk factors, and cardiovascular events. We aimed to analyze the relation between cardiovascular risk factors, including obesity, with the severity of atherosclerosis in different arterial territories.MethodsArteries from five territories (circle of Willis, carotids, coronaries, aorta, and renal) were taken from 185 persons, newborn to 90 years undergoing autopsy in the Forensic Medical Service in Mexico City, to determine atherosclerotic lesions by histopathological study. Lesions were classified according to the American Heart Association grading system as early (types I–III) and advanced (types IV–VI). The degree of atherosclerosis was correlated with arterial territories and risk factors.ResultsFrequencies of advanced lesions according to arterial territories were as follows: circle of Willis, 28%; right carotid, 36%; left carotid, 25%; right coronary, 71%; left coronary, 85%; right renal, 26%; left renal, 29%; and aorta, 52%; P=.0001, for all analyses. There was a higher risk for advanced lesions with increasing body mass index (BMI) (P=.004). However, after adjusting for age, gender, smoking status, hypertension, and diabetes mellitus, BMI was not independently associated with advanced lesions.ConclusionsCoronary arteries are significantly more affected than other arterial territories regardless of risk factors, showing the effect of local and systemic factors in the severity of atherosclerosis. We did not find an independent association between advanced atherosclerotic lesions and obesity.     

Antioxidative effects of cysteamine,hyaluronan and fetuin on post‐thaw semen quality,DNA integrity and oxidative stress parameters in the Brown Swiss bull

The aim of this study was to compare the effectiveness of antioxidants including cysteamine (2.5, 7.5 mm ), hyaluronan (0.25, 1 mg ml^?1) and fetuin (5, 10 mg ml^?1) in the freezing of Brown Swiss bull semen. The best percentages of CASA motilities were achieved with 10 mg ml^?1 of fetuin and 2.5 mm of cysteamine. For sperm morphology, 10 mg ml^?1 of fetuin and 2.5 mm of cysteamine had better protective effects (P < 0.001). The results of hypo‐osmotic swelling test showed that the percentage values of membrane integrity in all the groups, excluding that supplemented with 5 mg ml^?1 of fetuin, were higher than those of the control group (P < 0.001). Results obtained for the DNA damage of sperm cells demonstrated that 0.25 mg ml^?1 of hyaluronan, and 2.5 and 7.5 mm of cysteamine led to lower rates of spermatozoa with damaged DNA, compared with the control group (P < 0.001). The maintenance of superoxide dismutase and glutathione peroxidase antioxidant activities following freeze‐thawing with 2.5 and 7.5 mm of cysteamine and 10 mg ml^?1 of fetuin was demonstrated to be at a higher level in comparison with the control group (P < 0.001). Malondialdehyde formation was found to be lower in the groups supplemented with 0.25 mg ml^?1 of hyaluronan and 7.5 mm of cysteamine after the freeze‐thawing process (P < 0.001).     

Is moral beauty different from facial beauty? Evidence from an fMRI study

Is moral beauty different from facial beauty? Two functional magnetic resonance imaging experiments were performed to answer this question. Experiment 1 investigated the network of moral aesthetic judgments and facial aesthetic judgments. Participants performed aesthetic judgments and gender judgments on both faces and scenes containing moral acts. The conjunction analysis of the contrasts ‘facial aesthetic judgment > facial gender judgment’ and ‘scene moral aesthetic judgment > scene gender judgment’ identified the common involvement of the orbitofrontal cortex (OFC), inferior temporal gyrus and medial superior frontal gyrus, suggesting that both types of aesthetic judgments are based on the orchestration of perceptual, emotional and cognitive components. Experiment 2 examined the network of facial beauty and moral beauty during implicit perception. Participants performed a non-aesthetic judgment task on both faces (beautiful vs common) and scenes (containing morally beautiful vs neutral information). We observed that facial beauty (beautiful faces > common faces) involved both the cortical reward region OFC and the subcortical reward region putamen, whereas moral beauty (moral beauty scenes > moral neutral scenes) only involved the OFC. Moreover, compared with facial beauty, moral beauty spanned a larger-scale cortical network, indicating more advanced and complex cerebral representations characterizing moral beauty.     

Regulation of erythropoietin production in a human hepatoblastoma cell line

Production of immuno and biologically active erythropoietin was documented to occur in the human hepatoblastoma cell line HepG-2. The expression of the erythropoietin gene was further verified by Northern blot analysis using a single stranded RNA probe. In vitro studies showed that erythropoietin production by these cells was not stimulated by hypoxia or cobalt chloride, but was related to the proliferative activity of the cells in culture. In addition it was found that the secretion of erythropoietin was almost completely abrogated by tunicamycin, an inhibitor of N-linked glycosylation. This effect of tunicamycin was also observed in a permanently transfected cell line that secretes erythropoietin in large quantities.     

An alternative extrinsic pathway of human blood coagulation

To study the interrelationships of the major human coagulation pathways, factor X activation in normal and various deficient human plasmas was evaluated when clotting was triggered by dilute rabbit or human thromboplastin. Various dilutions of thromboplastin were added to plasma samples containing 3H-labeled factor X, and the time course of factor X activation was determined. At a 1/250 dilution of rabbit brain thromboplastin the rate of factor X activation in factor VIII or factor IX deficient plasma was only 10% of the activation rate seen for normal or factor XI deficient plasma. Reconstitution of the deficient plasmas with factors VIII or IX, respectively, restored normal factor X activation. Similar results were obtained when various dilutions of human thromboplastin replaced the rabbit thromboplastin. From these experiments, it is inferred that normal activation of factor X in plasma due to dilute thromboplastin requires factors VII, IX and VIII. An alternative extrinsic pathway that involves factors VII, IX, and VIII may be a major physiologic extrinsic pathway, and this pathway may help to explain the clinical observations of bleeding diatheses in patients deficient in factors IX or VIII.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.