Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.

Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.

Reduced fractional anisotropy in the uncinate fasciculus in patients with major depression carrying the met-allele of the Val66Met brain-derived neurotrophic factor genotype.

Experimental studies support a neurotrophic hypothesis of major depressive disorder (MDD). The aim of this study was to determine the effect of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism on the white matter fiber tracts connecting hippocampus and amygdala with the prefrontal lobe in a sample of patients with MDD and healthy controls. Thirty-seven patients with MDD and 42 healthy volunteers were recruited. Diffusion tensor imaging (DTI) data with 61 diffusion directions were obtained with MRI 3 Tesla scanner. Deterministic tractography was applied with ExploreDTI and Val66Met BDNF SNP (rs6265) was genotyped. Fiber tracts connecting the hippocampus and amygdala with the prefrontal lobe, namely uncinate fasciculus (UF), fornix, and cingulum were analyzed. A significant interaction was found in the UF between BDNF alleles and diagnosis. Patients carrying the BDNF met-allele had smaller fractional anisotropy (FA) in the UF compared to those patients homozygous for val-allele and compared to healthy subjects carrying the met-allele. A significant three-way interaction was detected between region of the cingulum (dorsal, rostral, and parahippocampal regions), brain hemisphere and BDNF genotype. Larger FA was detectable in the left rostral cingulum for met-allele carriers when compared to val/val alelle carriers. We provide evidence for the importance of the neurotrophic involvement in limbic and prefrontal connections. The met-allele of the BDNF polymorphism seems to render subjects more vulnerable for dysfunctions associated with the UF, a tract known to be related to negative emotional-cognitive processing bias, declarative memory problems, and autonoetic self awareness.

Effects of donepezil on cognitive functioning in Down syndrome.

Our goal in this study was to determine whether donepezil, an acetylcholinesterase inhibitor, would improve cognitive functioning in 19 subjects with Down syndrome and no dementia. They were assigned to either a donepezil or placebo group. Cognitive functioning and caregiver ratings were measured at baseline, 4 weeks, and 12 weeks. With the exception of one area (language), no improvement was noted in any of the cognitive subtests, behavioral scores, or caregiver ratings. Subjects in the donepezil group showed an improvement in language scores compared to subjects in the placebo group. The results suggest that donepezil may improve language performance in subjects with Down syndrome and no dementia, but further studies need to be done on a larger group to confirm this result.

Value of immunocytochemistry in the study of malignant effusions.

Recognition of malignant effusion relies heavily on cytologic examination despite the difficulty of distinguishing atypical mesothelial hyperplasia from metastatic carcinoma. The combination of CEA, EMA, vimentin, keratin, high-molecular-weight cytokeratin (HMWK), low-molecular-weight cytokeratin (LMWK), and Alcian blue was tested in 51 cytologic specimens of pleural, peritoneal, and pericardial effusions. These showed metastatic carcinoma in 38 cases (ovary, 14; lung, 8; breast, 7; GI, 4; endometrium, 4; bladder, 1) and mesothelial processes in 13 (hyperplasia, 9; mesothelioma, 4). Strong positivity for EMA (92%), CEA (90%), and Alcian blue (71%) was noted in metastatic carcinoma but not in the mesothelial processes. Keratin was positive in all cases of mesothelioma but occurred also in mesothelial hyperplasias (44%) and metastatic carcinomas (47%). In mesothelial cells, HMWK was consistently stronger than LMWK, whereas in adenocarcinoma the reverse was true. There was no difference in the degree or distribution of positivity of any of the markers among the various primary sites of the neoplasms. Our findings are consistent with the view that immunocytochemistry with a battery of antibodies is useful in the recognition of malignant effusions but cannot, as yet, determine the site of origin of metastatic neoplasms.

Experience with a new human skin equivalent for healing venous leg ulcers.

Leg ulcers affect about 650,000 adults each year and in every setting--rural, urban, and both economically developed and impoverished areas. Both the physical and the psychologic aspects of treatment present challenges to the caregiver. The nurse must be aware of new techniques for treatment and be able to educate patients about potential modalities for healing. A human skin equivalent, Apligraf, will soon be available for treatment of these wounds. The results of controlled, multicenter studies indicate that human skin equivalent interacts with the patient's own cells, responds to individual wound characteristics, and promotes healing. The nursing professional can readily master the application technique and will find that this tissue-engineered skin product offers a new approach to wound management.

Challenges of long-term care call for new policies.

Americans are living longer today because of changes in life-style and improvements in technology. As a result, the number of persons with debilitating conditions is increasing, leading to a greater need for care. How will we meet this need, and who will pay? Both social and public policy must meet the challenge of caring for disabled persons. We must identify the social good we wish to achieve and the issues that affect the realization of that good. The issues to be considered in forming policies on long-term care include: Age as the primary criterion; Basis for benefits; Informal support; Medical/social mix; Home care; Mental/physical health mix; Reimbursement techniques; Quality control; Competition; For-profit/not-for-profit mix; Freedom of choice; Burden of payment.

A new role for the Church. Dioceses should do more in providing care for dependent and dying persons.

In 1988, with the publication of Catholic Health Ministry: A New Vision for a New Century, the Commission on Catholic Health Care Ministry called on the Church to redefine its healing mission in society. Unfortunately, despite various efforts, the Church has not yet fully articulated a shared vision of Catholic healthcare, healing, and support. Healing human brokenness has always been the Church's work in the world, whether the brokenness be physical, emotional, intellectual, moral, or spiritual. The Church, having a broader definition of brokenness than that of the larger healthcare system, must sometimes act as a countercultural critic of that system. Two of the great challenges facing healthcare today are providing care for dependent persons (people with chronic illnesses and older people) and for dying persons. In both cases, much more coordination of the various actors is needed. The Church could ensure that this coordination is carried out. In each diocese, the bishop should organize a pastoral health and social service planning group to assess community needs and apply Church resources to them. Local Catholic healthcare providers and social service agencies should develop a corporate culture of healing and support. Parishes should accept the idea that healing and supporting frail people are integral parts of parish life.

Effects of ZNF804A on auditory P300 response in schizophrenia.

The common variant rs1344706 within the zinc-finger protein gene ZNF804A has been strongly implicated in schizophrenia (SZ) susceptibility by a series of recent genetic association studies. Although associated with a pattern of altered neural connectivity, evidence that increased risk is mediated by an effect on cognitive deficits associated with the disorder has been equivocal. This study investigated whether the same ZNF804A risk allele was associated with variation in the P300 auditory-evoked response, a cognitively relevant putative endophenotype for SZ. We compared P300 responses in carriers and noncarriers of the ZNF804A risk allele genotype groups in Irish patients and controls (n=97). P300 response was observed to vary according to genotype in this sample, such that risk allele carriers showed relatively higher P300 response compared with noncarriers. This finding accords with behavioural data reported by our group and others. It is also consistent with the idea that ZNF804A may have an impact on cortical efficiency, reflected in the higher levels of activations required to achieve comparable behavioural accuracy on the task used.

Mood congruent psychotic symptoms and specific cognitive deficits in carriers of the novel schizophrenia risk variant at MIR-137.

OBJECTIVE: The Schizophrenia Psychiatric Genome-wide Association (GWAS) Consortium recently reported on five novel schizophrenia susceptibility loci. The most significant finding mapped to a micro-RNA, MIR-137, which may be involved in regulating the function of other schizophrenia and bipolar disorder susceptibility genes. METHOD: We genotyped 821 patients with confirmed DSM-IV diagnoses of schizophrenia, bipolar affective disorder I and schizoaffective disorder for the risk SNP (rs1625579) and investigated the clinical profiles of risk allele carriers using a within-case design. We also assessed neurocognitive performance in a subset of cases (n=399) and controls (n=171). RESULTS: Carriers of the risk allele had lower scores for an OPCRIT-derived positive symptom factor (p=0.04) and lower scores on a lifetime measure of psychosis incongruity (p=0.017). Risk allele carriers also had more cognitive deficits involving episodic memory and attentional control. CONCLUSION: This is the first evidence that the MIR-137 risk variant may be associated with a specific subgroup of psychosis patients. Although the effect of this single SNP was not clinically relevant, investigation of the impact of carrying multiple risk SNPs in the MIR-137 regulatory network on diagnosis and illness profile may be warranted.

Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

Corporate ethical decision making in health care institutions.

The health care environment in which ethical decisions are made is changing rapidly. Ultimately, these changes may produce a more effective health care system. However, they also create new ethical dilemmas and greater complexity in ethical decision making. To clarify the problems of ethical decision making in health care institutions, and to define some guidelines for making these decisions, Ross Laboratories convened a roundtable of ethicists, attorneys, and health care practitioners, including physicians, nurses, and dietitians. The roundtable was chaired by Monsignor Charles Fahey of Fordham University's Third Age Center, who reflected on the discussions and, in this issue of Hospital Administration Currents, shares his thoughts on the issues of ethical decision making by corporate health care entities.

A novel treatment for venous leg ulcers.

Venous ulceration, a relatively common manifestation of venous hypertension, is often difficult to treat. This article reports the authors' experience with a new wound-healing technology using a bilayered, culture-derived human skin equivalent (HSE, Apligraf) for treatment of venous ulcers. In the patients studied, HSE appeared to promote wound healing in three ways: 1) apparent graft "take"; 2) temporary wound closure (persistence of HSE with subsequent wound re-epithelialization from wound margins); and 3) stimulation of host healing without temporary persistence by acting as a biologic dressing. The demonstrated efficacy of HSE suggests that it will prove useful for promoting the healing of venous ulcers.