Variation in the CBP gene involved in epigenetic control associates with cognitive function

Research into the pathologic mechanisms of neurodegenerative diseases has revealed that CREB binding protein (CBP) plays an important role in cognitive dysfunction. Loss of one copy of this gene leads to a syndrome with severe cognitive dysfunction. We investigated the association between four common variants in the CBP gene and cognitive function in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Baseline associations between genetic variation and cognitive function were assessed with linear regression. Longitudinal associations were assessed with linear mixed models. All analyses were adjusted for sex, age, education, country, version of test, and pravastatin use. The intron 4CT and intron 3AC polymorphisms in the CBP gene were associated with better cognitive performance at baseline and during follow-up. Furthermore, the haplotype with the variant alleles of these two polymorphisms also showed a protective effect on cognitive function in all cognitive domains (all p < 0.03). Genetic variation in the CBP gene is associated with better cognitive performance in an elderly population. Future research is necessary to investigate the effect of these polymorphisms on the expression of CBP levels and how these polymorphisms affect the gene expression mediated by CBP.     

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study

Background  

To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients.     

Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma

OBJECTIVE: To assess the accuracy of ultrasonography (US)-guided fine-needle aspiration cytology (FNAC) for detecting occult lymph node metastases in patients with squamous cell carcinoma of the penis. PATIENTS AND METHODS: Forty-three patients with 83 clinically node-negative inguinal regions were assessed with US and FNAC. The results were compared with histology from subsequent dynamic sentinel-node biopsy (DSNB) or inguinal lymph node dissection. RESULTS: Thirty-four groins in 27 patients were considered to be suspicious by US and the lymph nodes were aspirated. Nine nodes contained tumour cells and this was confirmed by subsequent lymph node dissection. The sensitivity and specificity of US-guided FNAC were 39% (nine of 23) and 100% (60 of 60), respectively. The number of groins requiring DSNB was reduced by 11% (nine of 83). CONCLUSION: US-guided FNAC can be used as the initial investigation in clinically node-negative groins. If tumour is confirmed then therapeutic inguinal lymph node dissection can be earlier and fewer DSNBs are required.     

Histopathologic validation of the sentinel node concept in oral and oropharyngeal squamous cell carcinoma

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), the presence of lymph node metastases is the most important prognosticator. Sentinel node (SN) biopsy has been shown to be an accurate staging technique for patients with breast cancer and melanoma and might also be suited for patients with HNSCC. This study was undertaken to determine whether the SN concept holds true for HNSCC and could be exploited for SN biopsy. METHODS: In 22 patients with T2 to T4 N0 oral or oropharyngeal squamous cell carcinoma (SCC) who were scheduled to undergo combined primary tumor excision and elective unilateral (n = 17) or bilateral (n = 5) neck dissection, SN identification was performed the day before surgery by use of lymphoscintigraphy after peritumoral injections of 99mTc-labeled colloidal albumin. After the neck dissection specimens were removed, all SNs, all other radioactive lymph nodes, and all nonradioactive lymph nodes were retrieved for histopathologic analysis, including serial sectioning at 250-microm intervals and immunohistochemical analysis (IHC). RESULTS: Overall, in 21 (78%) of 27 neck sides, an SN was identified by scintigraphy. Of the six neck sides in which SNs were not identified by scintigraphy, four were from three patients who underwent bilateral neck dissection. In another patient treated by bilateral neck dissection, the SN identified by scintigraphy could not be found in the specimen. In the remaining 20 neck dissection specimens, 23 SNs and 30 additional radioactive lymph nodes could be found. At histologic examination of the 20 neck specimens in which the SN was found, at least one SN was tumor positive in eight cases. In one neck specimen, a metastasis was detected in a nonradioactive lymph node, whereas the SN was tumor free, also at serial sectioning and IHC. In the remaining 11 neck sides in which the SN was tumor negative, none of the other radioactive (n = 13) and none of the nonradioactive (n = 279) lymph nodes contained tumor at histopathologic analysis, including serial sectioning and IHC. The sensitivity of the SN procedure for predicting lymph node metastases, therefore, was 89% (eight of nine neck specimens) when an SN was identified by scintigraphy and found in the specimen. The overall accuracy of the SN procedure for predicting the presence or absence of lymph node metastases in the neck was 95% (19 of 20 neck specimens). CONCLUSIONS: Our study seems to validate the SN hypothesis for oral and oropharyngeal cancer. The role of SN biopsy in the management of the N0 neck in such patients has yet to be established through prospective trials. SN identification (and thus biopsy) does not seem to be reliable in patients with tumors located in or close to the midline.     

The value of the Rehabilitation Activities Profile (RAP) as a quality sub-system in rehabilitation medicine

Purpose: To determine whether interdisciplinary team care, using the Rehabilitation Activities Profile (RAP) as a team tool, results in a better rehabilitation outcome.

Method: A multilevel prospective cohort study, with a controlled before and after design. Eighteen rehabilitation teams in eight rehabilitation centres in the Netherlands and Belgium participated. Based on the level of implementation of the RAP, we compared three study groups. Consecutive adult patients (n = 933) with stroke, amputation of the lower limb, spinal cord injury, multiple sclerosis, or other neuromuscular disorders, were followed during inpatient or outpatient rehabilitation. Main outcome measures were Barthel Index, RAP-CPM (sum score of the domains communication, personal care and mobility), Nottingham Health Profile (NHP), length of rehabilitation (LOR) and discharge destination (home vs elsewhere).

Results: Overall results show that scores on the Barthel Index, the RAP-CPM and the NHP improved, on average, by 18.4%, 12.7%, and 6.7%, respectively. However, treatment from a rehabilitation team that uses the RAP was associated with a significantly lower Barthel score, and small, non-significant effects on the RAP-CPM and the NHP. Partial use of the RAP resulted in non-significant, lower scores on these measures. With respect to discharge destination and LOR, there were also no significant differences between the three study groups, with the exception of a shorter outpatient rehabilitation period for the group in which partial use was made of the RAP.

Conclusion: The RAP, at the current level of implementation, does not improve rehabilitation outcome.     

Role of peg formation in clamp cell fusion of homobasidiomycete fungi

In most filamentous basidiomycetes, clamp cells are found at the septa of dikaryotic mycelia. Clamp cell formation starts at hyphal tip cells with the development of a lateral bulge at a position slightly apical to the future septum. Relative to the growth direction of the hypha, the protrusion expands backwards into a hook-like structure. Next, the two genetically different haploid nuclei within the hyphal tip cell divide. A septum appears between clamp cell and hyphal tip cell, thereby trapping one nucleus within the clamp cell. Another septum is laid within the hypha, separating a nucleus of the other type in the newly generated subapical hyphal cell from the two different nuclei kept together in the new apical hyphal cell. Through fusion of clamp and subapical cell, the two solitary nuclei become united within the subapical hyphal compartment. In 1933, Buller described subapical formation of a peg to which the clamp cell fuses as an additional, subsequently neglected step in this series of events. In this study, we represent evidence for subapical peg formation and its role in clamp cell fusion. Our observations potentially indicate a B mating type regulated extracellular communication between clamp and subapical hyphal cell.     

Understanding the pattern of functional recovery after stroke: facts and theories

Longitudinal studies show that almost all stroke patients experience at least some predictable degree of functional recovery in the first six months post stroke. However, the non-linear pattern as a function of time is not well understood. Several mechanisms are presumed to be involved, such as recovery of penumbral tissues, neural plasticity, resolution of diaschisis and behavioural compensation strategies. Rehabilitation is believed to modulate this logistic pattern of recovery, probably by interacting with these underlying processes. However, prediction models that are adjusted for the effects of time after stroke onset suggest that outcome is largely defined within the first weeks post stroke, although functional improvement has been found to extend beyond six months post stroke. In addition, kinematic studies show that functional improvement is more than recovery from impairments alone, suggesting that patients are able to improve in terms of gait or dexterity deficits using behavioural compensation strategies. Therefore, understanding the impact of task-dependent cortical activation patterns in non-invasive methods requires not only information derived from longitudinal studies pertaining to functional outcomes, but also a better understanding of what is kinematically learned during the acquisition of new skills.     

Analysis of B cell receptor production and rearrangement. Part I. Light chain rearrangement

A probabilistic model of allelic exclusion fails to explain the status of receptor genes and the receptor phenotype of most B cells. A large proportion of B cells have incompletely rearranged H and/or L chain genes (e.g. kappa0/kappa+) and most B cells express only one receptor. These properties seem to require deterministic features of B cell development such as special mechanisms that stop rearrangement. However, receptor editing has revealed that rearrangement-stop is not stable and that multi-receptor lymphocytes make up a significant fraction of certain B and T cell populations. Consequently we have revived the purely probabilistic approach in a model that now includes receptor editing and allows for some multi-receptor B cells. We find that this model can explain the observed properties of B cells when the frequency of self-reactive B cells is high. Indeed, as we illustrate for anti-DNA, this is the case. Hence the probabilistic model has life and assiduous use of the model suggests unexpected but not unrealistic features of lymphocyte development.     

Characterization of the human Ly-6 antigens,the newly annotated member Ly-6K included,as molecular markers for head-and-neck squamous cell carcinoma

The E48 antigen is a successfully explored molecular marker for the diagnosis and therapy of HNSCC. The applicability of E48 as an HNSCC-associated antigen, however, is restricted due to its heterogeneous expression in 30% of tumors; and identification of additional target antigens is therefore desired. E48 belongs to the Ly-6 antigen family, comprising a group of highly homologous, low m.w., GPI-anchored surface proteins, of which some show tissue-restricted expression patterns. To identify novel human HNSCC-associated Ly-6 members with squamous cell-associated expression patterns, we performed comprehensive gene-screening consisting of BLAST searches within GenBank databases, followed by expression analysis. Using this approach, the Ly-6K gene could be annotated as a novel member of the human Ly-6 family. Expression of the human Ly-6 genes E48, Ly-6K, PSCA, GML, RIG-E, G6C and Ly-6H was prescreened by qualitative RT-PCR and subsequently analyzed by quantitative RT-PCR in normal keratinocytes, HNSCC cell lines, normal mucosa, HNSCC tumors as well as normal peripheral blood and bone marrow cells. PSCA was highly expressed in normal mucosa, but 100-fold decreased expression was seen in HNSCC. For Ly-6H, GML and G6C, no or very low expression was observed in keratinocytes and HNSCC. Expression of RIG-E was high in normal and malignant squamous cells and in peripheral blood and bone marrow cells, thus limiting its applicability as an HNSCC-associated marker. In contrast, besides the E48 gene, the Ly-6K gene also appeared to be selectively expressed in HNSCC and normal squamous cells. Moreover, expression of Ly-6K was shown in HNSCC cell lines, in which no E48 expression could be detected. These data justify further evaluation of Ly-6K as potential target antigen for the diagnosis and therapy of HNSCC.     

Higher risk behaviour and rates of sexually transmitted diseases in Mwanza compared to Uganda may help explain HIV prevention trial outcomes

OBJECTIVE: To determine to what extent the higher impact of treatment for sexually transmitted diseases (STD) on HIV incidence in Mwanza, Tanzania than in Rakai and Masaka, Uganda might be explained by baseline differences between the trial populations. DESIGN: A re-analysis of baseline data from the three trial populations comparing demography, sexual risk behaviour and HIV/STD epidemiology. METHODS: Data were compared after age-standardization and adjustments for sample selection where necessary. STD rates were also adjusted for the sensitivities and specificities of the diagnostic techniques used. RESULTS: Demographic patterns were similar across populations, apart from effects of AIDS on fertility and mortality (including widowhood) in Uganda. Higher sexual risk behaviours, including younger age of sexual debut, higher numbers of recent partners and lower frequency of condom use, were apparent in Mwanza compared to Masaka and Rakai. High-titre serological syphilis, gonorrhoea, chlamydia infection and trichomoniasis were all more prevalent in Mwanza, except for chlamydia infection in males. There was little difference between sites in the seroprevalence of Herpes simplex virus type-2. Age patterns in the prevalence of short-duration STD and current risk behaviours were similar across sites but all-titre serological syphilis was more prevalent among older participants in Rakai and Masaka than Mwanza. CONCLUSIONS: Differences between trial populations included higher reported risk behaviour and higher rates of curable STD in Mwanza compared to Rakai and Masaka. These differences probably relate to previous reductions in risk behaviour in Uganda and may explain, at least in part, the contrasting results of these trials.