A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder of motile cilia. With few exceptions, PCD is an autosomal recessive condition, and there are over 40 genes associated with the condition. We present a case of a newborn female with clinical features of PCD, specifically the Kartagener syndrome phenotype, due to variants in TTC25. This gene has been previously associated with PCD in three families. Two multi-gene panels performed as a neonate and at two years of age were uninformative. Exome sequencing was performed by the Care4Rare Canada Consortium on a research basis, and an apparent homozygous intronic variant (TTC25:c.1145+1G > A) was identified that was predicted to abolish the canonical splice donor activity of exon 8. The child's mother was a heterozygous carrier of the variant. The paternal sample did not show the splice variant, and homozygosity was observed across the paternal locus. Microarray analysis showed a 50 kb heterozygous deletion spanning the genes TTC25 and CNP. This is the first example of a pathogenic gross deletion in trans with a splice variant, resulting in TTC25-related PCD.

Dietary fatty acids and risk of Alzheimer's disease and related dementias: Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP).

INTRODUCTION: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. METHODS: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05). DISCUSSION: Higher intake of DHA and EPA are protective for AD.

Oral lichen sclerosus: an overview and report of three cases.

Lichen sclerosus is an unusual, chronically relapsing mucocutaneous disease that usually afflicts the anogenital region. Oral lesions of lichen sclerosus are rare, with only 36 histologically verified cases reported to date. The classic histopathologic findings of oral lichen sclerosus include: an area of subepithelial hyalinization, loss of elastic fibres, and band-like mononuclear inflammatory infiltrate. Despite its rarity, oral lichen sclerosus should be included in the differential diagnosis of porcelain- or ivory-white macules. Here we present three new cases of oral lichen sclerosus. A review of these cases and the previously reported cases revealed that oral lichen sclerosus is slightly more common in women and can affect individuals of any age. Oral lesions of lichen sclerosus usually do not require treatment, except when there are significant symptoms or aesthetic complaint. Almost 50% of the patients with oral lichen sclerosus present with extraoral manifestations. Thus, referral to a dermatologist and a gynaecologist is advised. Although no cases of malignant transformation of oral lichen sclerosus have been reported, regular, long-term follow-up of patients with oral lichen sclerosus is indicated.

Asthma and lung function in adulthood after a viral wheezing episode in early childhood.

BACKGROUND: Viral aetiology of infection has a significant role in the long-term outcome of early-childhood wheezing. OBJECTIVE: This study examines asthma and lung function in adulthood after early-childhood wheezing induced by respiratory syncytial virus (RSV) and rhinovirus (RV). METHODS: A total of 100 children were hospitalized for a wheezing episode at less than 24 months of age from 1992 to 1993 in Kuopio University Hospital (Finland). Adenovirus, influenza A and B virus, parainfluenza (1-3) virus, and RSV were tested on admission using antigen detection and antibody assays, and RSV and RV were tested by polymerase chain reaction (PCR). In 2010, 49 cases and 60 population controls attended a follow-up study, which included spirometry with bronchodilation test and fractionally exhaled nitric oxide (FENO ) measurements. RESULTS: Current asthma was present in 64% of the cases with RV-induced wheezing (OR 17.0 [95%CI 3.9-75.3] vs controls), in 43% of the cases with RSV-induced wheezing episode (6.1 [1.5-24.9] vs controls), and in 12% of the controls. The RV group showed significantly higher mean FENO values than the RSV group and controls. RV-positive cases had lower MEF50 before bronchodilation and higher MEF50, FEV1, and FEV1/FVC bronchodilation responses than controls. RSV-positive cases had lower FVC than controls before bronchodilation. CONCLUSION: Cases with RV- and RSV-induced early-childhood wheezing had increased risk for asthma in adulthood, and RV-positive cases had significantly higher FENO values than RSV-positive cases and controls. Compared to controls, RV-positive cases showed more bronchial reactivity, and RSV-positive cases showed lower FVC before bronchodilation in lung function testing. CLINICAL RELEVANCE: Children with RV- or RSV-induced wheezing in early childhood have an increased risk for asthma and lung function abnormalities in adulthood.

Adiposity indicators and dementia over 32 years in Sweden.

BACKGROUND: High midlife and late-life adiposity may increase risk for dementia. Late-life decrease in body mass index (BMI) or body weight within several years of a dementia diagnosis has also been reported. Differences in study designs and analyses may provide different pictures of this relationship. METHODS: Thirty-two years of longitudinal body weight, BMI, waist circumference, and waist-to-hip ratio (WHR) data, from the Prospective Population Study of Women in Sweden, were related to dementia. A representative sample of 1,462 nondemented women was followed from 1968 at ages 38-60 years, and subsequently in 1974, 1980, 1992, and 2000, using neuropsychiatric, anthropometric, clinical, and other measurements. Cox proportional hazards regression models estimated incident dementia risk by baseline factors. Logistic regression models including measures at each examination were related to dementia among surviving participants 32 years later. RESULTS: While Cox models showed no association between baseline anthropometric factors and dementia risk, logistic models showed that a midlife WHR greater than 0.80 increased risk for dementia approximately twofold (odds ratio 2.22, 95% confidence interval 1.00-4.94, p = 0.049) among surviving participants. Evidence for reverse causality was observed for body weight, BMI, and waist circumference in years preceding dementia diagnosis. CONCLUSIONS: Among survivors to age 70, high midlife waist-to-hip ratio may increase odds of dementia. Traditional Cox models do not evidence this relationship. Changing anthropometric parameters in years preceding dementia onset indicate the dynamic nature of this seemingly simple relationship. There are midlife and late-life implications for dementia prevention, and analytical considerations related to identifying risk factors for dementia.

Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study).

OBJECTIVE: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and INTERVENTIONS: 176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. MAIN OUTCOME MEASURES: Lung function, the number of exacerbations and growth. RESULTS: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth. CONCLUSIONS: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.

Microbial-associated oral lichenoid reactions.

OBJECTIVE: The objective of the present study was to compare a new type of symptomatic lichenoid reaction, specifically located on the mucosal side of the lips, and associated with microorganisms, with a matched group presenting with reticular oral lichen planus (OLP) of the buccal mucosa. PATIENTS AND METHODS: The mean age for both groups was 66 years with a predominance of women (62%). The lichenoid reaction group (n = 25) presented with a reticular reaction pattern embracing various degrees of erythema. Patients presenting with OLP had similar lesions confined to the buccal mucosa but not on the mucosal side of the lips. RESULTS: In both groups, 80% were on any type of medication. However, 56% of the patients with lichenoid reactions medicated with more than three drugs compared with 29% (P < 0.05) in the OLP group. The former group more often used medicaments prescribed for cardiovascular diseases (48%vs 25%). Twenty-two of the patients with lichenoid reactions were treated with chlorhexidine. In 80% of these patients (n = 18), the lesions improved or completely healed, indicating a microbial association. CONCLUSION: Lichenoid reactions present on the mucosal side of the lips may be initiated by microbial plaque precipitated on the buccal surfaces of the anterior teeth.

Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial.

BACKGROUND: Probiotic bacteria are suggested to reduce symptoms of the atopic eczema/dermatitis syndrome (AEDS) in food-allergic infants. We aimed to investigate whether probiotic bacteria have any beneficial effect on AEDS. METHODS: Follow-up of severity of AEDS by the Severity Scoring of Atopic Dermatitis (SCORAD) index in 230 infants with suspected cow's milk allergy (CMA) receiving, in a randomized double-blinded manner, concomitant with elimination diet and skin treatment, Lactobacillus GG (LGG), a mixture of four probiotic strains, or placebo for 4 weeks. Four weeks after the treatment, CMA was diagnosed with a double-blind placebo-controlled (DBPC) milk challenge in 120 infants. RESULTS: In the whole group, mean SCORAD (at baseline 32.5) decreased by 65%, but with no differences between treatment groups immediately or 4 weeks after the treatment. No treatment differences were observed in infants with CMA either. In IgE-sensitized infants, however, the LGG group showed a greater reduction in SCORAD than did the placebo group, -26.1 vs-19.8 (P=0.036), from baseline to 4 weeks after the treatment. Exclusion of infants who had received antibiotics during the study reinforced the findings in the IgE-sensitized subgroup. CONCLUSION: Treatment with LGG may alleviate AEDS symptoms in IgE-sensitized infants but not in non-IgE-sensitized infants.

Factors associated with the self-care of home-dwelling elderly.

The purpose of this study was to examine how functional capacity, activities of daily living (ADL), instrumental activities of daily living (IADL), life satisfaction and self-esteem are related to the self-care behaviour styles of home-dwelling elderly persons. Data were collected by qualitative interviews (self-care) and structured interviews (functional capacity, life satisfaction and self-esteem) from home-dwelling elderly persons (n=40) aged 75 or more. The persons were living in a medium-sized city in northern Finland. The qualitative data were analysed using deductive content analysis. The classification frame consisted of a theoretical classification developed in an earlier study. The categories were quantified and the relationship between the variables analysed by cross-tabulation. The persons whose self-care behaviour style was responsible, formally guided or independent carried out their daily activities without assistance from others, while those who showed abandoned self-care did not manage their daily activities without help. Life satisfaction was the highest among the formally guided persons and self-esteem among the responsible ones. Poor life satisfaction and self-esteem correlated with abandoned self-care behaviour.

Mechanical ventilation in children with severe asthma.

Hospital admissions for childhood asthma have increased during the past few decades. The aim of this study was to describe the need for mechanical ventilation for severe asthma exacerbation in children in Finland from 1976 to 1995. We reviewed medical records and collected data retrospectively from all 5 university hospitals in Finland, thus covering the entire population of about 5 million. The endpoints selected were the number of admissions and readmissions leading to mechanical ventilation, duration of stay in the hospital, and mortality. Moreover, asthma medications prescribed prior to admission and administered in the intensive care unit (ICU), as well as the etiology of the exacerbation associated with mechanical ventilation were examined. Mechanical ventilation was required in 66 ICU admissions (59 patients). This constituted approximately 10% of all 632 admissions for acute asthma to an ICU. The number of admissions decreased from 1976 to 1995: 41 admissions between 1976 and 1985 vs. 25 admissions during the next 10-year period. The mean age at admission to the ICU was 3.6 years, and 46% of the patients were boys. Prior to the index admission, 70% of the patients had used asthma medication such as oral bronchodilator (50%), inhaled bronchodilator (20%), theophylline (38%), inhaled glucocorticoid (18%), oral glucocorticoid (5%), and cromoglycate (7%). Respiratory infection was by far the most common cause of all the exacerbations (61%), followed by food allergy (8%) and gastroesophageal reflux (3%). In 28% of cases the cause of the severe asthma exacerbation could not be identified. In the mechanically ventilated patients readmissions occurred 38 times between 1976 and 1985 vs. 5 times between 1986 and 1995. Five of the patients who received mechanical ventilation died, and in 3 of these patients asthma was the event causing death. In conclusion, there has been decrease in the number of first and repeat ICU admission for asthma requiring mechanical ventilation between 1970 and 1995. This trend occurred despite a simultaneous 5% yearly increase in hospital admissions for childhood asthma during these 2 decades.

Acute childhood asthma in Finland: a retrospective review of hospital admissions from 1976 to 1995.

The prevalence of childhood asthma has increased markedly in many Western societies during recent decades. We wanted to study whether the incidence and severity of childhood asthma in Finland had changed during the time-period 1976-95. Hospital admission rates from 1976 to 1995 were obtained from the National Hospital Discharge Register and the individual intensive care unit (ICU) registers of the five university hospitals in Finland. The number and length of treatment periods for childhood asthma in all Finnish hospitals and at the ICUs of the five university hospitals were analyzed. The number of children receiving special reimbursement for asthma medication costs was obtained from the central register of the Social Insurance Institution. The data showed that during the time-period investigated, hospital admissions as a result of asthma had increased by 2.8-fold, but the mean length of hospital stay had more than halved (from 7.3 to 2.6 days). The increase in hospital admissions showed greatest significance in the 0-4-year age-group among both sexes (p <0.001). In contrast, a significant reduction in hospital admissions was found among the 10-14-year age-group (p <0.001). No discernible change in admission to ICUs was seen. During the same time-period, the number of children receiving special reimbursement for asthma medication costs increased 7.5-fold. Hence, a major increase has occurred in the number of children diagnosed with asthma that has not been paralleled by a proportionate increase in the number of hospital admissions. While the prevalence of mild and moderate asthma has increased, the occurrence of severe asthma has remained essentially unchanged.

Diagnosis of food allergy in Finland: survey of pediatric practices.

Food-related symptoms are common in the first years of life, and food allergy should be diagnosed using an elimination challenge test. We surveyed Finnish hospital-based pediatricians using a self-completion questionnaire to ascertain the current clinical practice: 24 of the 25 pediatricians (representing 24 of 25 hospitals) so approached gave evaluable responses. Food allergies were diagnosed using a clinical elimination challenge test in patients with suspected allergy to cow's milk or cereals (wheat, rye, barley, oats). Of the 24 departments, four reported that they performed challenge in all patients before diagnosis was confirmed, and 14 performed challenge in most patients before diagnosis was confirmed. The duration of the challenge varied from 0.5 to 7 days (median 4 days). A 1-week challenge was used in eight hospitals. The double-blind placebo-controlled challenge was used in seven of the hospitals, and in none routinely. Altogether, 16 of the respondents agreed that there is a need to establish clinical guidelines for the diagnosis of food allergy. In conclusion, despite a long tradition of medical education on the subject of food allergy, practices vary for its diagnosis. There is therefore a requirement for appropriate clinical guidelines.

Breast-feeding and the development of cows' milk protein allergy.

Early feeding with cows' milk (CM) may cause cows' milk allergy (CMA). Breast milk contains many immune factors which compensate for the undeveloped defence mechanisms of the gut of the newborn infant. We studied the effect of supplementary CM feeding at the maternity hospital on the subsequent incidence of CMA, the effects of formula and breast feeding on the subsequent immunologic types of CMA, and the importance of immune factors present in colostrum in the immune responses of infants with CMA. In a cohort of 6209 infants, 824 were exclusively breast-fed and 87% required supplementary milk while in the maternity hospital: 1789 received CM formula, 1859 pasteurized human milk, and 1737 whey hydrolysate formula. The cumulative incidence of CMA, verified by a CM elimination-challenge test, was 2.4% in the CM, 1.7% in the pasteurized human milk and 1.5% in the whey hydrolysate group. Among these infants, exposure to CM at hospital and a positive atopic heredity increased the risk of CMA. Of the exclusively breast-fed infants, 2.1% had CMA. Risk factors for the development of IgE-mediated CMA were: exposure to CM at hospital, breast-feeding during the first 8 weeks at home either exclusively or combined with infrequent exposure to small amounts of CM and long breast-feeding. The content of transforming growth factor-beta1 (TGF-beta1) in colostrum from mothers of infants with IgE-mediated CMA was lower than from mothers of infants with non-IgE-mediated CMA. In infants with CMA, TGF-beta1 in colostrum negatively correlated with the result of skin prick test and the stimulation of peripheral blood mononuclear cells to CM, but positively with infants' IgA and IgG antibodies to CM proteins. Feeding of CM formula at maternity hospital increases the risk of CMA, but exclusive breast-feeding does not eliminate the risk. Prolonged breast-feeding exclusively or combined with infrequent exposure to small amounts of CM during the first 8 weeks induces the development of IgE-mediated CMA. Colostral TGF-beta1 may inhibit IgE- and cell mediated reactions and promote IgG-IgA antibody production to CM in infants prone to developing CMA.

Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma.

Respiratory syncytial virus (RSV) bronchiolitis in infancy can lead to bronchial hyper-reactivity or recurrent obstructive bronchitis. The aim of the present study was to determine whether the type of treatment has an influence on respiratory status after RSV bronchiolitis. The study involved 117 infants (mean age 2.6 months), who needed hospital treatment because of RSV bronchiolitis. The patients were divided randomly into three groups. All received the same symptomatic treatment. Group I children received symptomatic treatment only, group II children were treated for 7 days with inhaled budesonide, 500 microg three times per day, administered via a nebulizer. Group III children received nebulized budesonide, 500 microg twice per day for two months. Follow-up consisted of out-patient check-ups 2 and 6 months after the infection, and telephone contact two years after the infection. Statistically significant differences were seen between the groups. In group I 37% of the children had asthma, in group II 18%, and in group III 12%. According to the present study it seems that inhaled corticosteroid treatment during and after the acute phase of infant RSV bronchiolitis may have a beneficial effect on subsequent bronchial wheezing tendency.

Model for the self-care of home-dwelling elderly.

The aim of this study was to develop a model to clarify the existing knowledge concerning the self-care of home-dwelling elderly people. The data were collected in Oulu, a medium-sized city in northern Finland, by interviewing 40 home-dwelling elderly persons aged 75 or more. Data were analysed using the constant comparative method of the grounded theory approach. The model consists of four modes of self-care with different conditions for action and different meanings: responsible self-care consists of responsible activity by the elderly person based on a positive orientation towards the future and a positive experience of ageing. The meaning of responsible self-care is a desire to continue living as an active agent. Formally guided self-care consists of uncritical observance of instructions and routine performance of daily tasks. This approach is based on life experiences of taking care of others and realistic awareness of the effects of old age. The meaning of formally guided self-care is a tendency to accept life as it comes. Independent self-care is based on the person's desire to listen to his/her own internal voice. These persons aim to manage in life independently and deny the prospect of growing old. The meaning of independent self-care is an attempt to maintain the constancy of life. Abandoned self-care is characterized by helplessness and lack of responsibility. It involves bitterness and a negative attitude towards ageing. The meaning of abandonment is a desire to 'give up'. According to this study, self-care is not a separate part of old men's or women's lives, it is associated closely with their past life and with the future. As an activity, self-care is not just a rational way to maintain health. It also reflects the person's overall attitude towards health care, illnesses and manner of living.

Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants.

BACKGROUND: Early feeding with cow's milk (CM) may increase the risk of cow's milk allergy (CMA). OBJECTIVE: We sought to examine prospectively whether supplementary feeding of CM at the maternity hospital would increase the risk when compared with feeding with pasteurized human milk or hydrolyzed formula. METHODS: We studied 6209 unselected healthy, full-term infants, of whom 5385 (87%) required supplementary milk while in the hospital. The infants were randomly assigned to receive CM formula (1789 infants), pasteurized human milk (1859 infants), or whey hydrolysate formula (1737 infants). The comparison group (824 infants) was composed of infants who were exclusively breast-fed. The infants were followed for 18 to 34 months for symptoms suggestive of CMA. The primary endpoint was a challenge-proven adverse reaction to CM after a successful CM elimination diet. RESULTS: The cumulative incidence of CMA in the infants fed CM was 2.4% compared with 1.7% in the pasteurized human milk group (odds ratio [OR], 0.70; 95% confidence interval [CI], 0. 44-1.12) and 1.5% in the whey hydrolysate group (OR, 0.61; 95% CI, 0. 38-1.00). In the comparison group, CMA developed in 2.1% of the infants. Among the infants who required supplementary feeding at hospital, both exposure to CM while in the hospital (OR, 1.54; 95% CI, 1.04-2.30; P =.03) and obvious parental atopy (OR, 2.32; 95% CI, 1.53-3.52; P <.001) increased the risk of CMA. CONCLUSIONS: Our data indicate that feeding of CM at maternity hospitals increases the risk of CMA when compared with feeding of other supplements, but exclusive breast-feeding does not eliminate the risk.

Relation between weak HLA-DR expression on human breast milk macrophages and cow milk allergy (CMA) in suckling infants.

The precise role of breast milk leukocytes is unknown. We therefore studied the cellular composition of breast milk and the activation of breast milk macrophages in mothers with a cow milk-allergic infant and in those with a healthy infant. Further, we sought to determine the influence of the cellular composition of mother's milk on the infant's risk of developing cow milk allergy. Thirty-six asymptomatic mothers (26 with atopic constitution) whose babies had challenge-proven cow milk allergy and 24 asymptomatic mothers (17 with atopic constitution) with healthy infants were recruited. Geometric mean ages of the infants were 3.2 mo (95% confidence interval [CI], 2.3 to 4.4) and 2.4 mo (95% CI, 1.6 to 3.7), respectively. After separation of the fat layer, breast milk cells were incubated with fluorescein-labeled MAb to CD antigens (CD14, 45, 3, 4, 8, 19, 23, and HLA-DR) and analyzed by flow cytometry. Breast milk samples, collected with a breast pump, were processed immediately. Cytospin preparations of milk samples, made after separation of the fat layer, were stained with May-Grunwald-Giemsa and examined with a light microscope. HLA-DR expression on breast milk macrophages was significantly lower in the mothers whose infant was allergic to cow milk, 58.3% (95% CI, 44.9 to 75.6), than in the mothers of a healthy infant, 86.9% (95% CI, 78.7 to 96.1), p=0.012 (ANOVA). There was also a significant difference in the total number of breast milk leukocytes between the mothers with an allergic child, 0.17 x 10(6)/mL (95% CI, 0.12 to 0.25), and those with a healthy child, 0.08 x 10(6)/mL (95% CI, 0.05 to 0.14), p=0.019 (Mann-Whitney U test). These results suggest impaired function of breast milk macrophages in mothers whose infants had cow milk allergy. They may also reflect decreased antigen presentation to the inexperienced T cells in the gut or on other mucosal surfaces of the suckling infant, leading to subsequent development of food or respiratory allergies, e.g. asthma.