Disturbances of cerebral purine and pyrimidine metabolism in young children with chronic renal failure

Chronic renal failure during childhood may be associated with delayed cognitive development. From 10 children with chronic renal failure, aged 2-59 months, plasma and cerebrospinal fluid (CSF) purines and pyrimidines have been determined. A marked increase of pseudouridine and cytidine was demonstrated in CSF of 10 and 8 children, respectively. The plasma concentration of pseudouridine was increased in a varying degree to a maximal value of more than 10 times the upper limit of normal. The plasma concentration of cytidine showed only moderately elevated values. In 3 children the study of CSF and plasma was repeated 6 weeks after the start of continuous ambulatory peritoneal dialysis. The abnormal concentrations of pseudouridine and cytidine were still present in CSF and plasma. Further studies are necessary to elucidate the cause of this unknown biochemical aberration of the central nervous system.     

Neurofeedback improves executive functioning in children with autism spectrum disorders

Seven autistic children diagnosed with autism spectrum disorders (ASD) received a neurofeedback treatment that aimed to improve their level of executive control. Neurofeedback successfully reduced children's heightened theta/beta ratio by inhibiting theta activation and enhancing beta activation over sessions. Following treatment, children's executive capacities were found to have improved greatly relative to pre-treatment assessment on a range of executive function tasks. Additional improvements were found in children's social, communicative and typical behavior, relative to a waiting list control group. These findings suggest a basic executive function impairment in ASD that can be alleviated through specific neurofeedback treatment. Possible neural mechanisms that may underlie neurofeedback mediated improvement in executive functioning in autistic children are discussed.     

The projection of the nucleus reticularis tegmenti pontis and adjacent regions of the pontine nuclei to the central cerebellar nuclei in the cat

The projection of the nucleus reticularis tegmenti pontis (NRTP) and the pontine nuclei (NP) to the central cerebellar nuclei (CCN) was investigated by means of anterograde transport of tritiated leucine. Although termination was found in all the CCN, it was most pronounced in the lateral nucleus and the lateral aspect of the posterior interposed nucleus. The extreme lateral aspect of the anterior interposed nucleus and the caudal part of the fastigial nucleus received a projection of modest intensity. Termination in the infracerebellar nucleus and group Y is likely to be present but could not be confirmed with certainty from the light microscopical material. The contribution from the NP was small and originated from the dorsolateral and dorsal paramedian subdivisions of the NP. Within the NRTP the total area giving rise to projections to the CCN was extensive, and the origin of the projections to the individual CCN overlapped considerably. The projection of the NRTP to the ventrocaudal part of the lateral nucleus was found in conjunction with a projection to the ventrolateral part of the posterior interposed nucleus. Both projections seemed to branch off the fiber bundle terminating in the ventral paraflocculus. Similar correlations could be established in the projection of the NRTP to the dorsal paraflocculus and crus II of the ansiform lobule with other parts of the lateral and posterior interposed nuclei. It was concluded that the transverse, lobular organization of mossy fibers, which differs fundamentally from the longitudinal, modular organization of climbing fibers, is maintained in the collateral projection to the CCN. The results are further discussed in relation to the corticonuclear projection and the engagement of the NRTP and different parts of the CCN in pontocerebellar circuits.     

Combination of Amphotericin B and Flucytosine against Neurotropic Species of Melanized Fungi Causing Primary Cerebral Phaeohyphomycosis

Primary central nervous system phaeohyphomycosis is a fatal fungal infection due mainly to the neurotropic melanized fungi Cladophialophora bantiana, Rhinocladiella mackenziei, and Exophiala dermatitidis. Despite the combination of surgery with antifungal treatment, the prognosis continues to be poor, with mortality rates ranging from 50 to 70%. Therefore, a search for a more-appropriate therapeutic approach is urgently needed. Our in vitro studies showed that with the combination of amphotericin B and flucytosine against these species, the median fractional inhibitory concentration (FIC) indices for strains ranged from 0.25 to 0.38, indicating synergy. By use of Bliss independence analysis, a significant degree of synergy was confirmed for all strains, with the sum ΔE ranging from 90.2 to 698.61%. No antagonism was observed. These results indicate that amphotericin B, in combination with flucytosine, may have a role in the treatment of primary cerebral infections caused by melanized fungi belonging to the order Chaetothyriales. Further in vivo studies and clinical investigations to elucidate and confirm these observations are warranted.     

肠上皮细胞DNA含量变化与炎症性肠病癌变相关性的研究

目的 探讨肠黏膜上皮细胞DNA含量和p53蛋白表达状态与炎症性肠病（IBD）癌变的关系.方法 选择83例炎症性肠病患者库存活检样本,其病理诊断分别为低度异常增生、高度异常增生的癌前病变（pre-CRC组）和结直肠腺癌（CRC组）,配对选取144例仅有炎症而无异常增生或癌变的样本（no-CRC组）作为对照,分别用流式细胞技术和免疫组化技术检测样本中的DNA倍体状态和肠上皮细胞p53蛋白的表达.DNA指数＞1.35为异倍体,p53阳性细胞＞15%为阳性.结果 DNA异倍体在pre-CRC的克罗恩病和溃疡性结肠炎组分别为52.6%和57.8%,肿瘤组为80%和100%,显著高于no-CRC的3.2%和7.3%（P＜0.001）;p53突变型在pre-CRC的克罗恩病和溃疡性结肠炎组分别为36.7%和42.1%,肿瘤组为80%和100%,明显高于no-CRC的8.1%和9.7%（P＜0.01）.结论 DNA异倍体和突变型p53的表达不仅在炎症性肠病相关的结直肠癌肠黏膜上皮细胞中,而且在炎症性肠病的癌前病变的异常增生阶段即有明显增加,提示此两个生物标志物与炎症性肠病癌变密切相关,有可能用于辅助内镜监测,预测癌症风险.     

Reverse line blot hybridisation screening of Pseudallescheria/Scedosporium species in patients with cystic fibrosis

The PCR-RLB (reverse line blot hybridisation) was applied as a molecular technique for the detection of members of Pseudallescheria and Scedosporium from sputum of patients with cystic fibrosis (CF). Fifty-nine sputum samples were collected from 52 CF patients, which were analysed by culture and PCR-RLB. Conventional and semi-selective culture yielded five positive samples, but the PCR-RLB hybridisation assay permitted the detection of members of Pseudallescheria/Scedosporium in 32 out of 52 patients (61.5%). In total, PCR-RLB yielded 47 positives. Pseudallescheria apiosperma was detected in 20 samples, while Pseudallescheria boydii and Pseudallescheria aurantiacum were detected in 17 and eight samples, respectively. Six samples gave a positive reaction with two distinct species-specific probes and one sample with three probes. In conclusion, the PCR-RLB assay described in this study allows the detection of Scedosporium spp. in CF sputum samples and the identification of Pseudallescheria apiosperma, P. boydii, S. aurantiacum, Scedosporium prolificans and Pseudallescheria minutispora.     

An asthma-related quality of life instrument is unable to identify asthmatic children with major psychosocial problems

Evidence shows that psychosocial problems among children and adolescents with asthma interfere with adherence to treatment and therefore need attention in asthma care. It is unknown whether the already frequently implemented asthma-related quality of life (QoL) instruments reflect psychosocial problems in children with asthma. The aim of this study was to assess the relationship between asthma-related QoL and psychosocial problems and to determine whether an asthma-related QoL instrument is able to identify those children and adolescents with asthma with major psychosocial problems. In a multicenter study psychosocial problems (Strengths and Difficulties Questionnaire) and asthma-related QoL (Pediatric Asthma (Caregivers) Quality of Life Questionnaire) were obtained in children and adolescents with asthma aged 6–16 years and their caregivers. A total of 339 children and adolescents (response rate 95%) from four pediatric outpatient clinics in the Netherlands with doctor-diagnosed asthma participated. Of the caregivers, 43% reported major or minor psychosocial problems of their child or adolescent which is two times more than in the reference group, whereas the percentage of adolescents reporting psychosocial problems was comparable to a reference population. Adolescents and caregivers reported few impairments in asthma-related QoL (median score between 6.2 and 7.0). However, an optimal asthma-related QoL did not rule out major psychosocial problems: 10% of the adolescents with an optimal asthma-related QoL score reported major psychosocial problems. And in one out of seven children with an optimal caregiver’s asthma-related QoL score, major psychosocial problems were reported. The prevalence of psychosocial problems in children and adolescents with asthma is considerable. Assessment of asthma-related QoL alone is insufficient to identify those children with major psychosocial problems. We recommend the implementation of psychosocial screening, besides assessment of asthma-related QoL, in routine pediatric asthma care, to improve asthma management.     

Painful neuropathies: the emerging role of sodium channelopathies

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage‐gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na_V1.7, Na_V1.8, and Na_V1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain‐of‐function SCN9A mutations. Recent studies have expanded this spectrum with gain‐of‐function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch‐clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell‐type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length‐dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain‐of‐function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.     

A Multiplex Bead Array Analysis to Monitor Donor-Specific Cytokine Responses After Withdrawal of Immunosuppression in HLA-Identical living Related Kidney Transplant Patients

Immune reactivity after HLA-identical living related (LR) kidney transplantation can be caused by minor histocompatibility antigen and non-HLA antigen mismatches between donor and recipient. In our center, HLA-identical LR kidney transplant recipients receive azathioprine (AZA) or mycophenolate mofetil (MMF) in combination with corticosteroids for 1 year after transplantation. Thereafter, AZA or MMF was withdrawn, and the patients were treated with steroid monotherapy as maintenance therapy. We questioned whether withdrawal of AZA or MMF affected the donor-specific lymphocyte proliferation and cytokine production. Donor and third-party T-cell reactivities were determined by mixed lymphocyte reactions and by cytokine production using multiplex bead array technique. The donor and third-party proliferative capacities were not affected after withdrawal of AZA or MMF. Thirteen of 17 cytokines were detected by the multiplex bead array technique. No differences were observed after third-party induced cytokine production after withdrawal of AZA or MMF. However, production of donor-specific interferon-γ and macrophage inflammatory protein-1β increased after discontinuation of AZA or MMF, but no clinically relevant acute rejection was observed. In conclusion, after HLA-identical LR kidney transplantation, donor-specific cytokine responses can be found when AZA or MMF therapy is discontinued. The clinical relevance of this phenomenon is still not evident.     

The rostral dorsal cap and ventrolateral outgrowth of the rabbit inferior olive receive a GABAergic input from dorsal group Y and the ventral dentate nucleus

The dorsal cap and ventrolateral outgrowth of the inferior olive are involved in the control of eye movements. The caudal dorsal cap is predominantly involved in the horizontal optokinetic reflex; it receives most of its GABAergic input from the nucleus prepositus hypoglossi. In the present study, we determined the source of a major inhibitory input to the rostral dorsal cap and the ventrolateral outgrowth, which are the olivary subnuclei mainly involved in the “vertical” optokinetic reflexes. We studied these subnuclei in the rabbit with the use of retrograde tracing of horseradish peroxidase and anterograde tracing of wheat germ agglutinin-coupled horseradish peroxidase combined with postembedding immunocytochemistry. The ventral dentate nucleus of the cerebellum and dorsal group y project contralaterally to the rostral dorsal cap and ventrolateral outgrowth; this projection is entirely GABAergic. The terminals of this input form predominantly symmetric synapses with extraglomerular and intraglomerular dendrites; the remaining terminals are axosomatic. In addition, the dorsal cap and ventrolateral outgrowth contain significantly more crest synapses than any other olivary subnucleus. The terminals that form these crest synapses are derived from dorsal group y and/or the ventral dentate nucleus. None of the terminals in the dorsal cap or ventrolateral outgrowth was glycinergic.