Depression and anxiety symptoms: onset, developmental course and risk factors during early childhood

Background:  Depressive and anxiety disorders are among the top ten leading causes of disabilities. We know little, however, about the onset, developmental course and early risk factors for depressive and anxiety symptoms (DAS).
Objective:  Model the developmental trajectories of DAS during early childhood and to identify risk factors for atypically high DAS.
Method:  Group-based developmental trajectories of DAS conditional on risk factors were estimated from annual maternal ratings (1½ to 5 years) in a large population sample ( n  =   1759).
Results:  DAS increased substantially in two of the three distinct trajectory groups identified: High-Rising (14.7%); Moderate-Rising (55.4%); and Low (29.9%). Two factors distinguished the High-Rising group from the other two: Difficult temperament at 5 months (High-Rising vs Moderate-Rising: OR = 1.32; 95% CI = 1.13–1.55; High-Rising vs Low: OR = 1.31, CI = 1.12–1.54) and maternal lifetime major depression (High-Rising vs Moderate-Rising: OR = 1.10; CI = 1.01–1.20; High-Rising vs Low: OR = 1.19; CI = 1.08–1.31). Two factors distinguished the High-Rising group from the Low group: High family dysfunction (OR = 1.24; CI = 1.03–1.5) and Low parental self-efficacy (OR = .71; CI = .54–.94).
Conclusions:  DAS tend to increase in frequency over the first 5 years of life. Atypically high level can be predicted from mother and child characteristics present before 6 months of age. Preventive interventions should be experimented with at risk infants and parents.     

Smoking prevention counseling practices of Montreal general practitioners

BACKGROUND: Primary care physicians are potentially important sources of interventions aimed at preventing youth smoking. Yet recent surveys suggest that physician smoking prevention practices are less than optimal. OBJECTIVES: To document prevention counseling practices and to identify correlates of these activities in a random sample of general practitioners in Montreal, Quebec. METHODS: A cross-sectional mail survey. RESULTS: Of 440 eligible general practitioners (GPs), 337 (77%) completed the questionnaire. General practitioners were more likely to ascertain the smoking status of adolescents (70.9%) than preadolescents (35.7%). Although about half of the GPs offered advice to prevent smoking onset in young adults (48.6%) and adolescents (48.3%), fewer did so for preadolescents (34.4%); only 12.1% advised parents to discuss smoking onset with their children. Correlates of ascertaining smoking status included female sex (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.07-3.41), lower proportion of walk-in patients (OR, 2.73; 95% CI, 1.31-5.80), awareness of the "stage of behavior change" model (OR, 2.17; 95% CI, 1.18-4.04), and higher self-efficacy (OR, 4.12, 95% CI, 2.00-8.69). Correlates of provision of prevention advice included more hours spent in direct patient care (OR, 1.93; 95% CI, 1.13-3.34), favorable beliefs and attitudes (OR, 1.73; 95% CI, 1.06-2.83), and higher self-efficacy (OR, 4.32; 95% CI, 2.25-8.44). CONCLUSIONS: Our results point to the need for renewed efforts to enhance preventive efforts in primary care settings. Intervention programs for GPs should emphasize overcoming unfavorable beliefs and attitudes and low self-efficacy. Future research should evaluate the effect of brief prevention counseling adapted to increasingly busy practices.     

High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain.

The mitochondrial theory of aging proposes that mitochondrial DNA (mtDNA) accumulates mutations with age, and that these mutations contribute to physiological decline in aging and degenerative diseases. Although a great deal of indirect evidence supports this hypothesis, the aggregate burden of mtDNA mutations, particularly point mutations, has not been systematically quantified in aging or neurodegenerative disorders. Therefore, we directly assessed the aggregate burden of brain mtDNA point mutations in 17 subjects with Alzheimer's disease (AD), 10 elderly control subjects and 14 younger control subjects, using a PCR-cloning-sequencing strategy. We found that brain mtDNA from elderly subjects had a higher aggregate burden of mutations than brain mtDNA from younger subjects. The average aggregate mutational burden in elderly subjects was 2 x 10(-4) mutations/bp. The bulk of these mutations were individually rare point mutations, 60% of which changed an amino acid. Control experiments ensure that these results were not due to artifacts arising from PCR error, mistaken identification of nuclear pseudogenes or ex vivo oxidation. Cytochrome oxidase activity correlated negatively with increasing mutational burden. These findings significantly bolster the mitochondrial theory of aging.     

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice

Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors.     

Tandem pore domain K+‐channel TASK‐3 (KCNK9) and idiopathic absence epilepsies

Recently, the gene coding for the tandem pore domain K⁺‐channel TASK‐3 (KCNK9) has been localized to the chromosomal region 8q24. Because mutations in ion channel genes have been recognized as an important factor in the etiology of abnormal neuronal excitability, TASK‐3 is an interesting candidate gene for epilepsies linked to 8q24. We therefore performed a mutation analysis of the TASK‐3 gene in 65 patients with childhood and juvenile absence epilepsy. Only one silent nucleotide exchange (636C/T) was detected in exon 2 of the TASK‐3 coding region. No evidence for an allelic association was found between the exon 2 polymorphism and absence epilepsy. Accordingly, genetic variation of the TASK‐3 coding region does not play a major role in the etiology of idiopathic absence epilepsies. © 2002 Wiley‐Liss, Inc.     

Psychosocial impact of predictive testing for myotonic dystrophy type 1

In the Saguenay-Lac-Saint-Jean region (Quebec, Canada), a predictive DNA-testing program for myotonic dystrophy type 1 (DM1) has been available as a clinical service since 1988. From 1 to 12 years (median, 5 years) after receiving predictive testing, a total of 308 participants (44 carriers and 264 non-carriers) answered a questionnaire to determine the psychosocial impact of this genetic testing. The main reasons for wanting to be tested were to learn if children are at risk for DM1 or for reproductive decision making (75%) and to relieve the uncertainty for themselves (17%). The majority of participants (96.1%) remembered correctly their test result. At the time of the survey, the perception of the general well-being, the psychological distress (Psychiatric Symptom Index), and the self-esteem (Rosenberg Self-Esteem Scale) were similar in carriers, in non-carriers, and in the reference (Quebec) population. When participants indicated a change in different aspects of their lives following predictive testing, it was perceived as a change for the better by non-carriers and as a change for the worse by carriers. Nevertheless, for a majority of carriers and of non-carriers, the test result did not bring changes in their lives. All respondents believed that predictive testing should be available for the at-risk population and the vast majority of carrier and of non-carriers would recommend the use of predictive testing to their family members. Predictive testing for individuals at-risk of DM1 can be offered safely within a well-organized clinical and genetic counseling program that includes careful pre-test counseling, pre-test clinical assessment, post-test psychological support, and follow-up for those identified as carriers.     

Cerebro-osseous-digital syndrome: four new cases of a lethal skeletal dysplasia--distinct from Neu-Laxova Syndrome

Neu-Laxova Syndrome (NLS) is a severe disorder with intrauterine growth retardation, edema, and characteristic face (including microcephaly with receding forehead, protuberant eyes, a flattened nose, deformed ears, cleft palate, and micrognathia). Ichthyosis is often present. Limb anomalies include hypoplastic fingers and syndactyly of fingers and toes. Patients are usually stillborn or die shortly after birth. We report five unrelated patients--four with atypical NLS and one with typical NLS. All five patients were stillbirths. Clinically, the atypical NLS patients showed a large skull; rhizo-, meso-, and acromelia; and hypoplasia of the metacarpals and phalanges. The feet were similarly affected. Radiographically, the atypical patients showed interpediculate narrowing and hypoplastic vertebral bodies. The long bones were stick-like, showing diaphyseal widening that spared the metaphyses and was more pronounced in the lower extremities. The ilia had a half-moon configuration with widening of the sacrosciatic notches. The ischia were vertical and the pubic bone was absent. The typical NLS patient showed microcephaly, normal vertebral body, and long bone ossification, but a pelvic configuration similar to that of the atypical NLS patients. The common and distinguishing clinical and radiographic features are reviewed. Scott et al. [1981: Am J Med Genet 9:165-175] described two patients with NLS with radiographic and clinical findings similar to patients 1-4 reported here. Patients 1-4 of this report lack the typical findings of NLS and likely represent a distinct lethal skeletal dysplasia.     

Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina

Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impairments consistent with a retinal neurotransmission defect. To understand the subcellular basis of this retinal disorder, we generated a mouse with a loss-of-function mutation by inserting a self-excising Cre-lox-neo cassette into exon 7 of the murine orthologue, Cacna1f. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wild-type mouse and absence of the post-receptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging in Fluo-4 loaded retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wild-type mice. The absence of post-receptoral ERG responses and the diminished photoreceptor calcium signals are consistent with a loss of Ca((2+)) channel function in photoreceptors. Immunocytochemistry showed no detectable Ca(v)1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Together, these findings in the Cacna1f-mutant mouse reveal that the Ca(v)1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses. Moreover, the outcome of this study provides critical clues to the pathophysiology of the human retinal channelopathy of X-linked incomplete CSNB.     

Risk of hepatitis-related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: a 20-year prospective study

BACKGROUND: Progression of liver-related disease is accelerated in individuals coinfected with HIV and hepatitis C virus (HCV). Because the life expectancy of HIV-infected drug users (DUs) improved after the widespread use of highly active antiretroviral therapy (HAART), HCV-related death is likely to become more important. To disentangle the effects of HCV and HIV, we compared the overall and cause-specific mortality between HCV/HIV-infected DUs and HCV-infected DUs and DUs without HCV or HIV, followed up between 1985 and 2006. METHODS: A total of 1295 participants in the Amsterdam Cohort Study were included. Cause-specific hazard ratios (CHRs) were estimated for the eras before (<1997) and since HAART (> or =1997) within and among serologic groups. RESULTS: The risk of dying decreased for most causes of death > or =1997; this decrease was not the same for the different serologic groups. Among HCV/HIV-coinfected DUs, the risk of hepatitis/liver-related death did not substantially change over time (CHR = 0.87, 95% confidence interval [CI]: 0.21 to 3.58), whereas the risk of AIDS-related mortality decreased. Compared with DUs solely infected with HCV, HCV/HIV-coinfected DUs were at increased risk of dying from hepatitis/liver-related disease (CHR = 7.15, 95% CI: 1.98 to 25.8), other natural causes (CHR = 3.09, 95% CI: 1.41 to 6.79), and nonnatural causes (CHR = 2.30, 95% CI: 1.07 to 4.95) in the HAART era. CONCLUSIONS: HCV/HIV-coinfected DUs remain at increased risk of dying from hepatitis/liver-related death in the HAART era compared with HCV-monoinfected DUs. This risk did not change in HCV/HIV-coinfected DUs after HAART was introduced, suggesting that in the HAART era, HIV continues to accelerate HCV disease progression. Efforts should be made to establish effective treatment for HCV infection in HCV/HIV-coinfected individuals.