No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia

Mutations of the chromatin modifying protein 2B gene (CHMP2B) were identified, in a Danish pedigree, to cause familial frontotemporal dementia (FTD). To explore the possible genetic contribution of common CHMP2B variants in sporadic FTD, we analyzed 14 single nucleotide polymorphisms covering the entire genomic region of CHMP2B. After adjustment for multiple testing single marker and haplotype analysis revealed no significant association with sporadic FTD. Thus, we conclude that CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of FTD.     

Sex hormones, sleep, and core body temperature in older postmenopausal women

STUDY OBJECTIVES: Assessment of relationships between polysomnographic sleep, sex hormones, and core body temperature in postmenopausal women. DESIGN AND PARTICIPANTS: Ten women aged 57 to 71 years, at least 5 years past menopause. SETTING: Laboratory of Human Chronobiology at Weill Cornell Medical College. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Lower estradiol (E2) and higher luteinizing hormone (LH) levels were significantly correlated with indices of poor sleep quality. Relationships between LH and polysomnographic variables were more robust than those for E2. Significant increases from basal LH levels (i.e., LH pulses) occurred more frequently after sleep onset than prior to sleep onset, and 30 of 32 of these LH pulses occurred prior to long awakenings from sleep. In addition, higher body core temperature prior to and during sleep was significantly correlated with poorer sleep efficiency and higher LH levels. CONCLUSIONS: Most investigations of relationships between sleep, sex hormones, and body temperature have focused on perimenopausal women, menopausal phenomena such as hot flashes, the role of declining estrogen, and treatment with exogenous estrogen. The current results suggest that altered levels of both sex steroids and gonadotropins may contribute to sleep disturbance in older women and confirm the results of previous studies indicating that higher body core temperature is associated with poorer sleep quality, even in women without vasomotor symptoms. The findings also raise the possibility of alternate treatment avenues for menopause- and age-related sleep disturbance that focus on altering LH levels.     

Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder

BACKGROUND: We sought to determine the prevalence of, and association between, reproductive cycle-associated mood symptoms in women with affective disorders. We hypothesized that symptoms would correlate with each other across a woman's reproductive life span in both major depression (MDD) and bipolar I disorder (BP). METHODS: 2412 women with, MDD or BP were asked standardized questions about mood symptoms prior to menstruation, within a month of childbirth and during perimenopause. Lifetime rates for each of these symptom types were determined and an odds ratio was calculated correlating each of the types with the others. RESULTS: Of 2524 women with mood disorders, 67.7% reported premenstrual symptoms. Of those at risk, 20.9% reported postpartum symptoms and 26.4% reported perimenopausal symptoms. The rates did not differ between women with MDD and BP but were significantly different from women who were never ill. The symptoms were significantly correlated in women with MDD with odds ratios from 1.66 to 1.82, but were not in women with BP. LIMITATIONS: This is a secondary analysis of a sample that was collected for other purposes and is based upon retrospective reporting. CONCLUSIONS: Reproductive cycle-associated mood symptoms were commonly reported in women with mood disorders and did not differ based on diagnosis. In MDD, but not BP, the occurrence of these symptoms was trait-like as the presence of one predicted the occurrence of the others. Further prospective study is required to clarify the determinants of this trait.     

Characterization of a Trypanosoma cruzi acetyltransferase: cellular location, activity and structure

Trypanosomatids are widespread parasites that cause three major tropical diseases. In trypanosomatids, as in most other organisms, acetylation is a common protein modification that is important in multiple, diverse processes. This paper describes a new member of the Trypanosoma cruzi acetyltransferase family. The gene is single copy and orthologs are also present in the other two sequenced trypanosomatids, Trypanosoma brucei and Leishmania major. This protein (TcAT-1) has the essential motifs present in members of the GCN5-related acetyltransferase (GNAT) family, as well as an additional motif also found in some enzymes from plant and animal species. The protein is evolutionarily more closely related to this group of enzymes than to histone acetyltransferases. The native protein has a cytosolic cellular location and is present in all three life-cycle stages of the parasite. The recombinant protein was shown to have autoacetylation enzymatic activity.     

Proteome analysis of Leishmania (Viannia) braziliensis by two-dimensional gel electrophoresis and mass spectrometry

Leishmania (Viannia) braziliensis, a protozoan parasite widespread in the New World, is responsible for the infection of different mammal orders, including humans. This species is considered to be a major etiological agent of American cutaneous leishmaniasis. A proteomic study was carried out to identify proteins expressed by L. (V.) braziliensis. One hundred and one spots representing 75 protein entries were identified by MALDI-TOF-TOF. Isoelectric point values estimated by gel electrophoresis matched closely with predicted values, although some discrepancies existed suggesting that post-translational protein modifications may be common in L. braziliensis. Moreover, 20 hypothetical proteins were experimentally identified. Identified proteins were classified into 15 groups according to biological process. Among the proteins identified, approximately 40% have not been previously reported in a proteomic map of Leishmania. In addition, a number of potential virulence factors and drug targets were identified in this protein map, including some proteins associated with the metastatic phenotype. This study describes the first compilation of a proteomic reference map for L. braziliensis (pI 4-7, M(r) 10-130 kDa) and provides a very useful tool for comparative studies of strains isolated from patients presenting different clinical manifestations of leishmaniasis as well as a potential tool to identify markers for clinical diagnosis, therapeutics, and prognosis.     

RANBP2 and CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors

Inflammatory myofibroblastic tumors (IMTs) are rare soft tissue tumors occurring primarily in children and young adults. ALK gene rearrangements have been identified in this neoplasm, with fusion of the ALK gene at 2p23 to a number of different partner genes. Metaphase cytogenetic analyses of these tumors have been relatively few, however, and may help to identify additional variant partners. We report on an IMT from a 2-year-old boy with a karyotype of 45,XY,der(2)inv(2)(p23q12)del(2)(p11.1p11.2),-22. FISH showed ALK-RANBP2 fusion in this tumor. The breakpoint was cloned and the fusion was confirmed, making this the third reported case of IMT with ALK-RANBP2 fusion. In addition, we identified the ALK fusion partner in a previously reported IMT with t(2;17)(p23;q23) as CLTC, a gene reported to be involved in four other IMTs, and showed that the breakpoint involved a novel ALK-CLTC fusion. FISH evaluation of nine other IMTs identified CLTC as the fusion partner in one additional case, but RANBP2 was not involved in the remaining eight IMTs, suggesting that the variant partners involved in ALK rearrangements in IMTs are diverse.     

Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and "fine tuning" modulation

This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential.     

Perceptions and attitudes toward the menopause among middle aged women from Guayaquil, Ecuador

BACKGROUND: Studies reporting the perspective of Latin American women, Ecuador, included, regarding the menopausal phenomena are scarce or lacking. OBJECTIVES: Obtain information regarding the perception and attitudes toward the menopause among middle aged women of Guayaquil, Ecuador. METHODS: Women aged 40 or more, nursing staff members of two major associated teaching hospitals of the Universidad Católica de Santiago de Guayaquil, Ecuador, were surveyed with a structured questionnaire containing items intended to assess women's perception and attitudes toward the menopause. Secondarily level of information related to the menopause was explored. RESULTS: During the study period, 349 women were surveyed of which mean age was 48+/-6.8 years. A 41.3% were postmenopausal, 55% premenopausal and 3.7% had a history of hysterectomy with conserved ovaries. Women more frequently perceived the menopause as a positive event as they agreed that it is a normal (93.7%) and important event (73.6%), that it gives more confidence and maturity (78.8%), that they may fully enjoy sexual relations (74.8%), that there is a relief as the risk of becoming pregnant is null (65.3%) and that life becomes easier and calmer (60.7%). A relatively high rate demonstrated a preoccupying attitude toward the menopause as 79.4% responded to be concerned about it indicating that seeking medical attention was important, moreover, 77.9% responded that health during this phase be taken care of and life styles changed. Less than 50% of surveyed women considered having enough information regarding the menopause whereas a high rate indicated wanting to receive educational sessions related to the menopause. Married and lower educated women were not concerned about the menopause in a higher rate than their counterparts. CONCLUSIONS: Despite the fact that women perceived the menopause as a positive event, displaying a concerned attitude toward it, their related knowledge was low.     

Expression of activation markers on basophils in a controlled model of anaphylaxis

BACKGROUND: Anaphylaxis has variable clinical presentations and lacks reliable biomarkers. Expression of activation markers on basophils has been useful in assessing sensitization in IgE-mediated diseases but has not been examined in vivo in anaphylaxis. OBJECTIVE: The study's goals were to assess the baseline expression of activation markers on basophils in individuals with a sting reaction history, the degree of change in expression of these markers after intentional sting challenge, and the relationship between in vitro and in vivo activation marker expression. METHODS: Patients allergic to insect venom were enrolled and grouped by clinical category defined by a history of a systemic or large local reaction and use of venom immunotherapy. Blood was collected before and after sting challenge. Enriched basophils were analyzed for activation marker expression. In select subjects, basophils were examined after in vitro stimulation with insect venom for activation marker expression and histamine release. RESULTS: Of 35 sting-challenge participants, 21 provided adequate samples for analysis. Pre-sting basophil CD63 expression was significantly higher in systemic reactors on immunotherapy. Following sting challenge, the rise in basophil CD69 expression and CD203c was significantly higher in systemic reactors on immunotherapy. Levels of activation markers on basophils were greater after in vitro venom stimulation than after in vivo challenge. CONCLUSION: Broader shifts in expression of basophil activation markers after in vivo challenge occurred among subjects with a history of in vivo systemic anaphylaxis despite venom immunotherapy. CLINICAL IMPLICATIONS: Basophil activation markers may be potential biomarkers for anaphylaxis.     

HLA-DRB1 alleles control allergic bronchopulmonary aspergillosis-like pulmonary responses in humanized transgenic mice

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a lung hypersensitivity disease mediated in part by CD4(+) T(H)2 cells. There is a significant association between ABPA and the HLA-DR2 genotypes DRB1(*)1501 and DRB1(*)1503, whereas resistance might be associated with HLA-DRB1(*)1502. OBJECTIVE: We sought to elucidate the role of HLA-DR alleles in allergic inflammation in lungs. METHODS: HLA-DR humanized transgenic mice expressing either the susceptible or resistant alleles were analyzed for the nature and extent of pulmonary inflammation after exposure to Aspergillus species antigens. RESULTS: Exposed DRB1(*)1501 and DRB1(*)1503 transgenic mice displayed infiltrates made up prominently of eosinophils, which is consistent with the inflammation found in ABPA. The resistant DRB1(*)1502 mice, on the other hand, displayed minimal to moderate inflammation, consisting mainly of T-cell infiltrates. Significantly more mucin was produced in the DRB1(*)1503 and DRB1(*)1501 mice, and their ability to limit the number of Aspergillus species conidia within the lung parenchyma was impaired. Despite their differences, both the DRB1(*)1503 and DRB1(*)1502 strains mounted comparable T cell-proliferative responses to Aspergillus species antigens. CONCLUSION: The HLA-DR2 alleles DRB1(*)1501 and DRB1(*)1503 play a major role in the development of allergic pulmonary inflammation. In contrast, the HLA-DR2 allele DRB1(*)1502 mediates a nonallergic T(H)1-like response to the organism, possibly explaining an ABPA resistance factor. These results are in support of our published human studies in patients with cystic fibrosis and asthma. CLINICAL IMPLICATIONS: HLA-DR typing in patients with cystic fibrosis and asthma will aid in the identification of individuals at risk for ABPA.