Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling.

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Successful primary use of VVDL+V ECMO with cephalic drain in neonatal respiratory failure.

OBJECTIVE: To describe the use of double-lumen venovenous (VVDL) extracorporeal membrane oxygenation (ECMO) with cephalic draining cannula (VVDL+V) as a primary approach for all neonatal respiratory diagnoses and to compare our single-center experience with data as collected in the Extracorporeal Life Support Organization (ELSO) database. STUDY DESIGN: We retrospectively reviewed all cases of ECMO for neonatal respiratory failure performed in the neonatal intensive-care unit at a large referral children's hospital, the Children's Healthcare of Atlanta at Egleston (CHOA-E). Comparisons were then made to neonatal respiratory ECMO data retrieved from the ELSO database. RESULTS: At CHOA-E 162 of 189 cases were completed with the VVDL+V approach. Survival in the VVDL+V cohort was 89.1% versus 68.7% from ELSO, P<0.001. For those complications considered, the overall risk of complication favored the CHOA-E VVDL+V group as compared with ELSO (odds ratio (OR) 0.71 (0.52-0.7)) as did the risk of neurologic complications (OR 0.29, (0.15-0.58)), including intracranial hemorrhage (OR 0.39 (0.18-0.97), P=0.011). CONCLUSION: The VVDL+V approach can be used successfully as the primary approach for ECMO for neonatal respiratory failure of various etiologies and in this single-center cohort this approach was associated with improved survival and lower rates of complication as compared with the ELSO database.

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

BACKGROUND: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood. OBJECTIVES: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI. METHODS: In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. RESULTS: A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3). CONCLUSIONS: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.

APOE and ACE polymorphisms and dementia risk in the older population over prolonged follow-up: 10 years of incidence in the MRC CFA Study.

BACKGROUND: dementia risk conferred by apolipoprotein-E (APOE) and angiotensin-1-converting enzyme (ACE) polymorphisms have been reported for the MRC Cognitive Function and Ageing Study (CFAS) at 6-year follow-up. We concentrate on incident dementia risk over 10 years. METHODS: participants come from MRC CFAS, a multi-centre longitudinal population-based study of ageing in England and Wales. Three follow-up waves of data collection were used: 2, 6 and 10 years. Logistic regressions were undertaken to investigate associations between APOE (n = 955) and ACE (n = 856) alleles/genotypes and incident dementia. Two types of control groups were used: non-demented and highly functioning non-demented. Results were back-weighted. RESULTS: compared to APOE epsilon3, epsilon2 conferred protection of odds ratio (OR) = 0.3 (95% confidence interval, CI = 0.1-0.6) and epsilon4 risk of OR = 2.9 (95% CI = 1.7-4.9) for incident dementia. Compared to epsilon3/epsilon3, the epsilon3/epsilon4 and epsilon4/epsilon4 genotypes conferred risks of OR = 3.6 (95% CI = 1.8-7.3) and OR = 7.9 (95% CI = 1.6-39.2), respectively. The epsilon3/epsilon2 genotype protected against dementia (OR = 0.2, 95% CI = 0.1-0.7), and epsilon2/epsilon2 had a similar protective effect but with wide CIs (OR = 0.3, 95% CI = 0.1-1.7). Restricting the control group accentuated these differentials. The effects of ACE alleles/genotypes on incident dementia risk were small. CONCLUSIONS: APOE but not ACE is associated with late-onset incident dementia in the population. Using longer term follow-up with proper adjustment for attrition and incident cases increases estimates of risk.

Mode of reproduction and amplified fragment length polymorphism variation in purple needlegrass (Nassella pulchra): utilization of natural germplasm sources.

A dominant plant of the California grasslands, purple needlegrass [Nassella pulchra (Hitchc.) Barkworth] is an important revegetation species in its native range. The amplified fragment length polymorphism (AFLP) method was used to elucidate mode of reproduction and nucleotide variation among 11 natural populations and three selected natural germplasm releases of N. pulchra. A total of 12 co-dominant AFLPs, informative within eight populations, failed to reveal any heterozygous individuals, indicating very high selfing rates (S(H)=1). Estimates of nucleotide diversity within populations ranged from 0 to 0.00069 (0.00035 average), whereas the total nucleotide divergence among populations ranged from 0.00107 to 0.00382 (0.00247 average). Measures of population differentiation (GS) in terms of Shannon-Weaver diversity values and estimated nucleotide substitutions were 0.90 and 0.86, respectively. Although some of the sample populations contained a mixture of true breeding genotypes, most populations could be distinguished unambiguously. Moreover, geographical distance between the natural source populations was significantly correlated with genetic distance (r = 0.60) among the corresponding sample populations. Results indicate that inbreeding, combined with founder effects and/or selection, has contributed to the differentiation of N. pulchra populations. Foundation seed populations of the selected natural germplasm releases were genetically well defined and most similar to natural seed collected near the corresponding source populations. Thus, these commercial germplasm sources will be made practically available and useful for conservation plantings within the intended areas of utilization.

The clinical assessment of oral dryness is a significant predictor of salivary gland hypofunction.

OBJECTIVES: To compare subjective complaints of xerostomia and salivary gland dysfunction and a clinical assessment of oral dryness with an objective measurement of salivary gland dysfunction, in a group of UK patients attending a Dry Mouth Clinic. The aim of the study was to identify signs and symptoms that may be of predictive value for salivary gland hypofunction (SGH) in clinical practice. METHODS: This prospective study investigated 214 patients who attended a Dry Mouth Clinic, held at Liverpool University Dental Hospital. Patients gave a history of xerostomia for a minimum of 6 months and were asked standardised questions to subjectively assess oral dysfunction. The oral mucosa was then clinically assessed for dryness and sialometry was performed. Unstimulated whole saliva flow rates (UFR) of < 0.2 ml min-1 were considered to be indicative of SGH. RESULTS: One or more symptoms of oral dysfunction were reported in 178 (83%) patients, in addition to xerostomia. The clinician diagnosed oral dryness in 105 patients. Objective evidence of SGH was found in 125 (58%) of patients. The clinicians' subjective assessment of oral dryness was indicative of a reduced UFR (P < 0.0001) and a significant predictor of an UFR < 0.2 ml min-1 using logistic regression analysis (odds ratio 9.6; 95% CI 4.8 and 19.3). The mean UFR of patients who reported symptoms of oral dysfunction was significantly lower than the mean UFR of patients who reported no oral dysfunction. Using logistic and multiple regression analyses, symptoms of oral dysfunction were not found to be significant predictors of either an UFR < 0.2 ml min-1 or a reduced UFR. CONCLUSIONS: The clinical assessment of oral dryness was a significant predictor of SGH, in this selected group of patients. Patients who complain of xerostomia may have additional symptoms of oral dysfunction indicative of a reduced UFR.

Molecular phylogenetic analysis of felid herpesvirus 1.

The position of felid herpesvirus 1 within the alphaherpesvirus subfamily was investigated using molecular phylogenetic techniques applied to multiple sequence alignments of recently reported FHV-1 gene homologs (glycoprotein B, ribonucleotide reductase and DNA polymerase). FHV-1 was most closely related to other carnivore alphaherpesviruses, (phocid herpesvirus 1 and canid herpesvirus 1) and to the equid herpesviruses 1 and 4.

The capsid gene of feline calicivirus contains linear B-cell epitopes in both variable and conserved regions.

In order to map linear B-cell (LBC) epitopes in the major capsid protein of feline calicivirus (FCV), an expression library containing random, short (100- to 200-bp) fragments of the FCV F9 capsid gene was constructed. Analysis of this library showed it to be representative of the region of the capsid gene that encodes the mature capsid protein. The library was screened by using polyclonal antisera from a cat that had been challenged experimentally with F9 to identify immunoreactive clones containing LBC epitopes. Twenty-six clones that reacted positively to feline antisera in immunoblots were identified. FCV-derived sequence from these clones mapped to a region of the capsid that spanned 126 amino acids and included variable regions C and E. An overlapping set of biotinylated peptides corresponding to this region was used to further map LBC epitopes by using F9 antisera. Four principal regions of reactivity were identified. Two fell within the hypervariable region at the 5' end of region E (amino acids [aa] 445 to 451 [antigenic site (ags) 2] and aa 451 to 457 [ags 3]). However, the other two were in conserved regions (aa 415 to 421 [ags 1; region D] and aa 475 to 479 [ags 4; central region E]). The reactivity of the peptide set with antisera from 11 other cats infected with a range of FCV isolates was also determined. Ten of 11 antisera reacted to conserved ags 4, suggesting that this region may be useful for future recombinant vaccine design.

Undifferentiated dementia, Alzheimer's disease and vascular dementia: age- and gender-related incidence in Liverpool. The MRC-ALPHA Study.

BACKGROUND: Does incidence of dementia follow the age pattern of prevalence? Is gender a risk factor? Do patterns of incidence differ between dementias? AIMS: To assess age-specific incidence rates of undifferentiated dementias, Alzheimer's disease and vascular dementia. METHOD: 5222 individuals aged > or = 65 years, were interviewed using the Geriatric Mental State/History and Aetiology Schedule. The AGECAT package was used to identify cases at three interviewing waves at two-year intervals. Diagnoses were made using ICD-10 Research Criteria and validated against neurological and psychological examination, with imaging and neuropathology on unselected subsamples. RESULTS: Incidence rates of the dementias increase with age. Age patterns are similar between Alzheimer's disease and vascular dementia. Gender appears influential in Alzheimer's disease. In England and Wales, 39,437 new cases of Alzheimer's disease (4.9/1000 person-years at risk); 20,513 of vascular dementia (2.6/1000 person-years) and 155,169 of undifferentiated dementia (19/1000 person-years) can be expected each year. CONCLUSIONS: Incidence rates for Alzheimer's disease and vascular dementia appear to behave differently, with an increased risk of Alzheimer's disease for women compared to vascular dementia.

Natural history of pharmacotherapy of older depressed community residents. The MRC-ALPHA Study.

BACKGROUND: Depression in older people is common and has a high mortality, but effective treatments exist. AIMS: To describe drug prescribing in older community residents in relation to depression status. METHOD: The MRC-ALPHA community cohort aged 65 and over were interviewed using the Geriatric Mental State examination drug data collected at index interview and at two and four years. RESULTS: Antidepressants were used by 10.9% of the depressed population. Benzodiazepines were used frequently. Of the antidepressant users, 59.6% took low-dose antidepressants for two years, had a poor outcome and few drug changes. CONCLUSIONS: Trends of increasing antidepressant use have cost implications for primary care groups. Benzodiazepines may be mis-prescribed for treatment of depressive symptoms. Antidepressant users have poor outcome and follow-up.

Community-based case-control study of depression in older people. Cases and sub-cases from the MRC-ALPHA Study.

BACKGROUND: Risk factors of depression in later life, particularly for sub-cases and for psychotic and neurotic types of depression, are unclear. AIMS: To identify such risk factors. METHOD: Over 5200 older people (> or = 65 years), randomly selected from Liverpool, were interviewed using the Geriatric Mental State (GMS) and the Minimum Data Set (MDS). The computer-assisted diagnosis AGECAT identified 483 cases and 575 sub-cases of depression and 2451 with no mental problems. Logistic regression was employed to examine factors relevant to caseness. RESULTS: In multiple logistical regression, odds ratios (ORs) were significantly high for being female (2.04, 95% CI 1.56-2.69), widowed (2.00, 1.18-3.39), having alcohol problems (4.37, 1.40-2.94), physical disablement (2.03, 1.40-2.94), physical illness (1.98, 1.25-3.15), taking medications to calm down (10.04, 6.41-15.71), and dissatisfaction with life (moderate 4.54, 3.50-5.90; more severe 29.00, 16.00-52.59). Good social networks reduced the ORs. If sub-cases were included as controls, the statistical significance was reduced. CONCLUSIONS: Age was not associated with depression in later life whereas gender, physical disablement and dissatisfaction with life were. The sub-cases shared many risk factors with cases, suggesting that prevention may need to be attempted at an early stage.

Socio-economic deprivation and the prevalence and prediction of depression in older community residents. The MRC-ALPHA Study.

BACKGROUND: The Townsend index is a measure of social deprivation. It can be applied to postal districts and has been employed in studies examining the ecological associations of mental illness. AIMS: We examine the utility of the Townsend index in identifying older populations with a high prevalence and risk of developing depression. METHOD: The study was carried out in the context of a cohort study of an age- and gender-stratified sample of 5222 community residents aged 65 years and over. Subjects were interviewed at intervals of two years. The relationships between Townsend score and psychiatric diagnoses (in particular, depression) were examined. RESULTS: High Townsend scores were associated with increased prevalence and incidence of depression and prevalence of organic psychiatric illness. CONCLUSIONS: The Townsend index can be used to prioritize psychiatric and primary care resources so as to cater for older populations likely to suffer from depression and organic psychiatric conditions.

Schizophrenia and delusional disorder in older age: community prevalence, incidence, comorbidity, and outcome.

The opportunity to assess prevalence, incidence, and outcome of schizophrenia and delusional disorder was provided by an age- and sex-stratified random sample of 5,222 persons age 65 years and over. This sample was chosen from general practitioner lists, and interviewed by psychiatric nurses trained to use the Geriatric Mental State (GMS)-AGECAT computerized diagnostic system. GMS-AGECAT ensured the reliability of the selection of cases between the two waves of the study. A subsample was interviewed by a research psychiatrist. The sample was followed up 2 years later using the same method by interviewers blind to the initial findings. The protocols of all nominated cases and subcases of schizophrenia/paranoid disorder diagnosed by AGECAT were reviewed by a clinician and DSM-III-R diagnoses were made. Refusal rate was 13 percent for initial interviews (wave 1) and 15 percent for reinterview 2 years later (wave 2). The prevalence of DSM-III-R schizophrenia was 0.12 percent (95% confidence interval [CI] 0.04-0.25) and delusional disorder 0.04 percent (95% CI 0.00-0.14). The minimum incidence of schizophrenia for new cases was 3.0 (95% CI 0.00 to 110.70); for new and relapsed cases, 45.0 (95% CI 3.54-186.20); and for delusional disorder, 15.6 (95% CI 0.02-135.10) per 100,000 per year. Two of the five cases with schizophrenia were known to have been first diagnosed before age 65. After 2 years, none of the cases of schizophrenia had recovered fully, but none was deluded at followup. Two had developed dementia. The outcome was bad because they remained cases of some type of psychiatric illness but good because of the improvement in their schizophrenia/delusion disorder symptoms.

Do experienced diagnosticians agree about the diagnosis of dementia from survey data? The effects of informants' reports and interviewers' vignettes.

Dementia in community settings is often diagnosed by computerized algorithms. This study examines the extent to which independent diagnosticians agreed among themselves in diagnosing dementia, severity and type when presented with data obtained during a population-based incidence study of cognitive decline and dementia. Secondly, it examines how judgements, based initially on respondents' self-reports and cognitive performance, were affected first by informants' reports and then by short case-vignettes written by trained lay interviewers. Thirdly, it compares diagnosticians' diagnosis of dementia with the algorithmic diagnosis (AGECAT). The items presented were selected from two screening interviews at wave 1 and wave 2 separated by an interval of 2 years and from wave 2 assessment and informant interviews, and included medical, psychiatric and ADL items and interviewers' own observations. The sample (N = 42) was derived from the first year of the wave 2 assessments, potential dementia cases entering consecutively while presumed normals were selected randomly. Informants were available in 30. Agreement on diagnosis and type of dementia improved with increasing information, particularly from informants, but remained poor regarding severity. The number of cases of dementia, defined operationally, increased from 10 to 12 and uncertain cases fell from eight to six, but no respondent initially diagnosed as a dementia case was rediagnosed as a non-case, or vice versa. Dementia type changed from agreement about Alzheimer's disease to agreement about vascular dementia in one case. Operational and algorithmic diagnoses showed good agreement. Causes of disagreement, the role of vignettes and the relevance of the results for population surveys are discussed.

Extent and appropriateness of benzodiazepine use. Results from an elderly urban community.

BACKGROUND: We sought to determine the extent and appropriateness of benzodiazepine use in an elderly community, by measuring prevalence and incidence of benzodiazepines and examining mental health status as a predictor of benzodiazepine use. METHOD: Data were collected from two longitudinal studies of people from the same community, sampled in 1982-1983 and again in 1989-1991. RESULTS: Benzodiazepine prevalence did not decrease during the period under study, but there was a significant reduction in anxiolytic use. Prevalence of benzodiazepines in women in twice that in men, and incidence of hypnotics is slightly higher in women. Prevalence and incidence of hypnotics are strongly associated with increasing age. There were high proportions of long-term users (61 and 70%), and continued use was high (52%) among new users. A large proportion of benzodiazepine use was by those who were concurrently depressed. Similarly, anxiety predicted both current and subsequent use of hypnotics. CONCLUSIONS: Many older people still use benzodiazepines, contrary to official guidelines with regard to their mental health. Our findings add to the weight of opinion that persistent and long-term use should be discouraged.

Prevalence of dementia and depression among elderly people in black and ethnic minorities.

BACKGROUND: This study was designed to identify all elderly people of ethnic minorities living in a defined geographical area in inner-city Liverpool and to identify psychiatric morbidity and barriers to use of services. This paper reports the prevalence of dementia and depression. METHOD: A survey of the community was carried out using the Geriatric Mental State Examination, AGECAT and ethnically matched interviewers. The sampling frame consisted of Family Health Services Authority lists as a basis, with additional information from community lists, 'snow-balling' and a door-to-door survey. RESULTS: 418 people were interviewed, with a high percentage (55%) of young elderly (65-74) men. The prevalence of dementia ranged from 2 to 9% and of depression from 5 to 19%, and there were no significant differences in levels between English-speaking ethnic groups and the indigenous population. Higher levels of dementia were found among non-English-speaking groups. CONCLUSIONS: A complete enumeration of the elderly in ethnic minority groups is best achieved by using several different methods. Diagnosis of dementia may be misleading among those who do not speak the dominant language.

Sequences of the ribonucleotide reductase-encoding genes of felid herpesvirus 1 and molecular phylogenetic analysis.

The felid herpesvirus 1 (FHV-1) genes encoding the two ribonucleotide reductase (RR) subunits (RR1, large subunit and RR2, small subunit) were cloned and their nucleotide (nt) sequence determined. The RR1 open reading frame (ORF) is 2358 nts long and is predicted to encode a protein of 786 amino acids (aa). In common with herpesviruses in the Varicellovirus genus of the alphaherpesvirus subfamily, FHV-1 RR1 lacks the N-terminal serine threonine protein kinase region present in herpes simplex virus (HSV)-1 and -2. FHV-1 RR1 has a predicted aa identity of 47-64% with other alphaherpesvirus RR1 peptides, falling to 26-29% for gammaherpesviruses. The RR2 ORF is 996 nts long, predicted to encode a protein of 332 aa and has aa identities of 64-70% with alphaherpesviruses and 38-39% with gammaherpesviruses. Molecular phylogenetic analysis groups FHV-1 with equid herpesviruses 1 and 4 (EHV 1 and 4), pseudorabies virus (PRV) and bovid herpesvirus 1 (BHV 1) within the genus Varicellovirus.

Cowpox in British voles and mice.

Serosurveys indicate that bank voles, field voles and woodmice are probably reservoir hosts of cowpox virus in western Europe, although virus has not yet been isolated from these species. In this study, bank voles, field voles, woodmice and laboratory mice were shown to be susceptible to combined intradermal and subcutaneous inoculation with 3-20 plaque-forming units (pfu) of cowpox virus. Bank and field voles, but not laboratory mice, were also susceptible to combined oral and nasal inoculation with 50 pfu. Few clinical signs were seen and virus was generally recovered only from inoculation sites. Bank voles were not susceptible to injection of ectromelia virus (5000 pfu) into the skin (as described above). These results provide information on which further pathogenesis and transmission studies can be based, and support the view that the orthopoxvirus antibody detected in British wild voles and woodmice indicates infection with cowpox virus. However, further investigation of the pathogenesis of cowpox in these species is needed to understand better the epidemiology of the disease.

Serological evidence for the reservoir hosts of cowpox virus in British wildlife.

The reservoir host of cowpox virus in Western Europe is not known, but epidemiological evidence from human and feline infections indicates that the virus is probably endemic in small wild rodents. Therefore, serum and tissue samples were collected from a variety of wild British mammals and some birds, and tested for evidence of Orthopoxvirus infection. Antibody reacting with cowpox virus was detected in 9/44 (20%) bank voles (Clethrionomys glareolus), 8/24 (33%) field voles (Microtus agrestis), 17/86 (20%) wood mice (Apodemus sylvaticus) and 1/44 house mice (Mus musculus), but in no other animal species tested. Although virus was not isolated from any animal, this serological survey, together with other evidence, suggests that bank and field voles and wood mice are the main reservoir hosts of cowpox virus in Great Britain.