The effect of lithium on growth factor production in long-term bone marrow cultures

We have previously reported that lithium chloride (LiCl) stimulates the production of granulocyte-macrophage colony-forming cells (GM-CFC), pluripotent stem cells (CFU-S), and differentiated granulocytes, macrophages and megakaryocytes in murine Dexter marrow cultures and that this effect appears to be mediated indirectly by a radioresistant adherent marrow cell. In this study we have established that exposure of murine Dexter cultures to LiCl (4 mEq/L) causes an increase of colony-forming cell megakaryocytes (CFU-meg) over 1 to 6 weeks of culture in both supernatant (188% to 611%) and stromal phases (123% to 246%). Moreover, we have shown that lithium treatment of either irradiated (1,100 rad) or unirradiated stromal cells increased production of activities stimulating formation of megakaryocyte, granulocyte, macrophage, and mixed lineage colonies and proliferation of the factor-dependent cell line, FDC-P1. This FDC-P1 stimulatory activity was completely blocked by an antibody to purified recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF). The baseline or lithium-induced--stromal-derived bone marrow colony stimulating activity was partially blocked by the antibody to rGM-CSF and by an antibody to purified colony stimulating factor I (CSF-1); the two antibodies combined resulted in greater than 90% inhibition of the lithium-induced marrow stimulatory activity. In addition, radioimmunoassay (RIA) showed that although CSF-1 was detectable in supernatants of these cultures, exposure to lithium did not increase CSF-1 levels. These data indicate that Dexter stromal cells produce CSF- 1 and GM-CSF and that lithium appears to exert its stimulatory effects on in vitro myelopoiesis by inducing production of GM-CSF.     

Assessment of aldehyde dehydrogenase in viable cells

Cytosolic aldehyde dehydrogenase (ALDH), an enzyme responsible for oxidizing intracellular aldehydes, has an important role in ethanol, vitamin A, and cyclophosphamide metabolism. High expression of this enzyme in primitive stem cells from multiple tissues, including bone marrow and intestine, appears to be an important mechanism by which these cells are resistant to cyclophosphamide. However, although hematopoietic stem cells (HSC) express high levels of cytosolic ALDH, isolating viable HSC by their ALDH expression has not been possible because ALDH is an intracellular protein. We found that a fluorescent aldehyde, dansyl aminoacetaldehyde (DAAA), could be used in flow cytometry experiments to isolate viable mouse and human cells based on their ALDH content. The level of dansyl fluorescence exhibited by cells after incubation with DAAA paralleled cytosolic ALDH levels determined by Western blotting and the sensitivity of the cells to cyclophosphamide. Moreover, DAAA appeared to be a more sensitive means of assessing cytosolic ALDH levels than Western blotting. Bone marrow progenitors treated with DAAA proliferated normally. Furthermore, marrow cells expressing high levels of dansyl fluorescence after incubation with DAAA were enriched for hematopoietic progenitors. The ability to isolate viable cells that express high levels of cytosolic ALDH could be an important component of methodology for identifying and purifying HSC and for studying cyclophosphamide-resistant tumor cell populations.     

Dual Diagnosis in Older Adults: A Review

Dual diagnosis is associated with frequent relapse, poor treatment engagement and overall unsatisfactory treatment outcomes. A comprehensive review of the contemporary literature examining this issue was conducted, finding a paucity of literature concerning dual diagnosis in older adults. Of the literature appraised for this review, a number of studies examined US Veteran's Affairs populations, which were largely male. Studies concerning older mental health populations were scarce. During the literature search, a number of background studies that influenced contemporary research regarding dual diagnosis in older adults were found; these studies were examined regarding their contribution to contemporary paradigms concerning older adults with co-occurring mental illness and substance use disorders. This review presents the results of the contemporary literature concerning dual diagnosis in older adults. Several recurring themes emerge from the literature, including the notion of a statistically small population that, in absolute terms, represents a sizeable number of individuals coming to the attention of aged mental health services in the future. Additionally, the potential for under-diagnosis in this cohort is highlighted, potentially creating a hidden population of older adults with dual diagnosis.     

Anal intraepithelial neoplasia and squamous cell carcinoma in HIV‐infected adults

Anal cancer is one of the most common non‐AIDS‐defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV‐infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV‐related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV‐infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV‐infected adults.     

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.The set of conditions diagnosed as autism spectrum disorders (ASDs) vary enormously in their presentation (1). The most severely impaired individuals—often those with intellectual disabilities, limited speech, and severe behavioral problems—can require lifelong care. At the other end of the functional spectrum, people diagnosed with ASDs can be verbally fluent and academically gifted and can achieve independence in adulthood (2, 3). The broad range of cognitive and behavioral profiles seen in diagnosed ASDs has been long viewed as a challenge by the research community (4). Although it is well established that (i) the cognitive/behavioral profile of people diagnosed with ASDs varies widely and (ii) the set of genetic factors related to ASDs varies widely (5, 6), the degree to which phenotype can be used to predict patterns in disease architecture remains unclear.Recent insights into the genetic influences on ASDs offer an opportunity to investigate this question through the lens of de novo vs. familial effects. On average, ASDs run in families. The siblings of children with ASDs are 10–20 times more likely to receive a diagnosis of ASD themselves (7, 8); the parents of children with ASDs are more likely to manifest autistic features, as well as a variety of other neuropsychiatric conditions, such as schizophrenia and bipolar disorder (9, 10). These epidemiologic observations are consistent with analyses suggesting that ASDs are influenced by thousands of common genetic variants transmitted between generations. It has been estimated that common, genotyped SNPs account for 20–60% of variation in ASD risk, although the effect of any individual SNP is likely very small (11–13). Many of these influences are shared with other psychiatric disorders (12, 14), which at least in part explains the familial clustering of different types of behavior problems.However, statistics about ASD heritability reflect an average. For example, there are likely many affected families for whom sibling recurrence risk is less than 10–20%. The strongest evidence toward this claim comes from studies of rare, severely deleterious genetic events that are associated with ASDs (15–20). Events of this type, for example copy number variants and loss of function (LOF) mutations, are often de novo (not seen in an affected individual’s parents). Although cases of ASDs involving a de novo mutation could reflect a concert of spontaneous and inherited genetic events, de novo events of large effect may reduce the likelihood of seeing psychiatric problems in an affected individual’s family members.     

Parental Depression Confers Greater Prospective Depression Risk to Females than Males in Emerging Adulthood

Females are at greater risk of depression than males, a pattern arising in adolescence and continuing in adulthood. One hypothesis is that major risk factors operate more robustly for females. We tested whether parental depression history imposes greater prospective depression risk for female emerging adults in a large community sample (ages 18–19, N = 637). Utilizing linear mixed regressions to model symptom changes over 2 years, we found the predictive utility of parental depression varied by gender. Females had higher depression symptoms overall, and those with parental depression remained at high levels throughout the adulthood transition, compared to at-risk males whose elevated symptoms decreased. This effect was specific to offspring depression (versus anxiety) and was found only for parental depression (versus other disorders). Female emerging adults with a parental depression history are at increased risk for future depression symptom elevations, which may partially explain their increased risk for depressive disorders in adulthood.     

Self‐perceived preparedness for dental practice amongst graduates of The University of Hong Kong’s integrated PBL dental curriculum

Objectives: To determine how prepared for dental practice graduates from the integrated problem‐based learning (PBL) dental undergraduate curriculum at The University of Hong Kong (HKU) perceive themselves to be and to identify factors associated with self‐perceived preparedness. Materials and methods: A postal questionnaire was sent to five cohorts of dentists who had graduated from HKU’s integrated PBL curriculum between 2004 and 2008. Using a 4‐point Likert scale, the questionnaire assessed the self‐perceived level of preparedness in 59 competencies grouped in nine domains. Responses were dichotomised into ‘poorly prepared’ and ‘well prepared’. Results: The response rate was 66% (159/241). The mean proportion (± standard deviation) of respondents indicating well‐preparedness was 72.0 ± 15.1% overall, and for each domain was as follows: general patient management, 93.1 ± 12.1%; practice management, 81.0 ± 22.2%; periodontology and dental public health, 73.5 ± 19.3%; conservative dentistry, 92.5 ± 13.1%; oral rehabilitation, 62.8 ± 24.0%; orthodontics, 23.0 ± 32.9%; managing children and special‐needs patients, 64.8 ± 28.9%; oral and maxillofacial surgery, 52.2 ± 25.2%; and drug and emergency management, 84.7 ± 22.6%. The odds of self‐perceived well‐preparedness were increased for cohorts graduating in 2004 and 2005 and graduates working in a non‐solo dental practice. Conclusions: Dental graduates of HKU’s integrated PBL curriculum felt well prepared for the most fundamental aspects of dental practice. However, apparent deficiencies of training in orthodontics and oral and maxillofacial surgery will need to be addressed by continuing education, postgraduate training and planning for the new 6‐year undergraduate curriculum in 2012.