Progressive loss of cerebellar volume in childhood-onset schizophrenia

OBJECTIVE: Childhood-onset schizophrenia is a severe and unremitting form of the disorder. Prospective brain magnetic resonance imaging (MRI) studies have found progressive loss of total cerebral volume during adolescence, primarily attributable to accelerated loss of cortical gray matter. Because there is evidence of cerebellar involvement in schizophrenia, the authors examined cerebellar volume and its relation to cortical gray matter development during adolescence in patients with childhood-onset schizophrenia and healthy comparison subjects. METHOD: Total cerebellar volume was algorithmically calculated for 108 anatomical brain MRI scans from 50 patients (20 of whom were female) and 101 scans from 50 age- and gender-matched healthy volunteers (20 of whom were female). The age range of the patients and comparison subjects was 8 to 24. Midsagittal vermal area and posterior-inferior vermal lobe volume were measured by hand. Prospective rescans were obtained at approximately 2-year intervals. Cross-sectional and longitudinal data were combined in mixed model regressions to compare developmental changes for the groups. RESULTS: In contrast to healthy volunteers, patients with schizophrenia showed a progressive loss of cerebellar volume during adolescence. Cerebellar and cerebral volume decreases were significantly correlated in childhood-onset schizophrenia. CONCLUSIONS: Childhood-onset schizophrenia is associated with significant progressive loss of cerebellar volume during adolescence, consistent with previously reported decreases in total cerebral and cortical gray matter. At least in these patients with severe early-onset schizophrenia, the loss appears secondary to a generalized process.     

Vascular risk to late-life depression: evidence from a longitudinal community study

OBJECTIVE: To determine prospectively relationships between minor cerebrovascular episodes and depressive symptoms in a community cohort of older persons. METHOD: In 1988-1989, baseline measurements of vascular risk factors and depressive symptoms were obtained in older community residents (mean age = 67). At 10-year follow-up, three subgroups of subjects still residing in the community were re-assessed: those who had suffered a transient ischaemic attack (TIA) (n = 16) in the intervening period; those with hypertension but no TIAs (n = 38); and, those with neither TIAs nor hypertension (n = 40). RESULTS: Of the 16 persons with depressive symptoms at 10-year follow-up, only three had reported depressive symptoms initially. Subjects who had experienced TIAs during the longitudinal phase had higher rates of depressive symptoms than the subjects from the other two groups (38%vs 13%, p < 0.05). CONCLUSIONS: This study supports the notion that cerebrovascular incidents predispose to late-onset depression in older persons residing in the community. Intrinsically, this provides epidemiological support for the validity of the concept of 'vascular depression'.     

Brain-derived neurotrophic factor-, neurotrophin-3-, and tyrosine kinase receptor-like immunoreactivity in lingual taste bud fields of mature hamster

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), as well as their respective tyrosine kinase (Trk) receptors, TrkB and TrkC, influence peripheral target cell innervation, survival, and proliferation. In the mature taste system the role of neurotrophins and their receptors is not known. The mature hamster is an intriguing model because anterior lingual fungiform, unlike posterior lingual foliate and circumvallate, taste buds survive denervation. In light of this difference, we examined whether the degree of neurotrophin- or neurotrophin receptor-like immunoreactivity (IR) normally differs among lingual gemmal fields. In single- and double-labeled immunofluorescent experiments, 3,209 taste bud sections (profiles) from 13 hamsters were examined for immunopositive gemmal cells or nerve fibers using antibodies to BDNF and NT-3, their respective receptors TrkB and TrkC, and the neural marker ubiquitin c-terminal hydrolase L-1 [protein gene product (PGP) 9.5]. In each gemmal field, more than 75% of taste bud profiles showed immunopositivity to BDNF, NT-3, and TrkB. Across bud fields, BDNF-, TrkB-, and BDNF/TrkB-like IR, as well as PGP 9.5 and PGP 9.5/BDNF-like IR in centrally located, fungiform bud cells was greater (P < 0.0001 to P < 0.002) than in circumvallate or foliate buds. Within bud fields, the number of BDNF-like, labeled bud cells/bud profile was greater than that for NT-3-like IR in fungiform (P < 0.0002) and foliate (P < 0.0001) buds. TrkC was immunonegative in gemmal cells. The average density of TrkB- and TrkC-like fiber IR was more pronounced in fungiform than posterior gemmal-bearing papillae. Thus, fungiform papillae, whose taste buds are least affected by denervation, exhibit specific neurotrophin and receptor enrichment.     

Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.     

Treatment-seeking inpatient cocaine abusers show hypothalamic dysregulation of both basal prolactin and cortisol secretion

Cocaine causes neuroendocrine aberrations in cocaine abusers with pituitary stress hormone secretion providing a window to the stress system in the brain. Substance abusers and control participants were hormonally profiled for 3 weeks. Abusers showed significant basal elevations in prolactin in week 1 with normalization over the 3 weeks. No differences in prolactin secretion were seen with either thyrotropin-releasing hormone stimulation or L-dopa suppression testing. Basal afternoon cortisol secretion was significantly elevated during weeks 1 and 2 comparing abusers to controls. Elevated afternoon cortisol secretion is a sensitive indicator of central stress activation. These results point to the hypothalamus, not the pituitary gland, as being primarily altered in cocaine withdrawal. The data demonstrate that both the dopamine-prolactin and hypothalamic-pituitary-adrenal (HPA) axes are affected during cocaine cessation. As medications are developed to modulate activation of a dysfunctional stress system, future therapeutic studies of substance abuse, withdrawal, craving and relapse should employ more sophisticated tests of hypothalamic pituitary function, especially the HPA axis, as this information may be a guide in the diagnosis and predict clinical responses.     

Information exchange and the robustness of organizational networks

The dynamics of information exchange is an important but understudied aspect of collective communication, coordination, and problem solving in a wide range of distributed systems, both physical (e.g., the Internet) and social (e.g., business firms). In this paper, we introduce a model of organizational networks according to which links are added incrementally to a hierarchical backbone and test the resulting networks under variable conditions of information exchange. Our main result is the identification of a class of multiscale networks that reduce, over a wide range of environments, the likelihood that individual nodes will suffer congestion-related failure and that the network as a whole will disintegrate when failures do occur. We call this dual robustness property of multiscale networks "ultrarobustness." Furthermore, we find that multiscale networks attain most of their robustness with surprisingly few link additions, suggesting that ultrarobust organizational networks can be generated in an efficient and scalable manner. Our results are directly relevant to the relief of congestion in communication networks and also more broadly to activities, like distributed problem solving, that require individuals to exchange information in an unpredictable manner.     

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.     

New technologies and potential cost savings related to morbidity and mortality reduction in Class III/IV heart failure patients in Canada

BACKGROUND: Heart failure affects 1-2% of the Canadian population. The 1-year mortality rates in New York Heart Association Class III/IV heart failure patients range from 11 to 44%. This study evaluates costs associated with current management of Class III/IV heart failure and potential savings if morbidity and mortality are reduced. OBJECTIVES: To construct an economic model to evaluate the components of treating Class III/IV heart failure patients in Canada and the resulting direct medical costs. The model also estimates the potential savings that could result from the introduction of a new technology such as cardiac resynchronization therapy that reduces morbidity and mortality. METHODS: The model evaluates costs of pharmacological therapy, medical care, laboratory and diagnostic tests, and complications, most commonly hospitalization. Estimates are based on a literature review, expert opinion, and standard cost sources using widely accepted health economic methods. RESULTS: The model, under conservative assumptions, estimates that Class III/IV heart failure costs between CAD$1.4 billion and CAD$2.3 billion in Canada overall. Costs are substantial on the provincial level as well and are estimated to be approximately CAD$700 million, CAD$500 million, and CAD$300 million in Ontario, Québec, and British Columbia, respectively. New treatments could bring substantial savings depending on their effectiveness-measured as reduction in morbidity and mortality-and the number of patients who receive that treatment. Potential savings in Canada could reduce the total annual costs for this group of patients by approximately 10% or up to CAD$200 million annually. CONCLUSIONS: The high level of morbidity and mortality in Class III/IV heart failure patients and costs associated with their care are an impetus for the development of new therapies such as cardiac resynchronization therapy, that could deliver long-term benefits including increased exercise tolerance, reduced hospitalizations, and improved quality of life. Successful therapies could provide substantial savings and present a favorable economic profile in the treatment of heart failure. In order to ensure that appropriate technologies are commercialized and marketed, prospective evaluation of new therapies should include critical assessment of direct medical costs in addition to evaluating morbidity, quality of life and survival.