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.

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.

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.

Use of phage immunity in molecular cloning experiments.

Immunity to phage superinfection is a useful selective marker in molecular cloning experiments. Plasmids which have unique sites for several different restriction endonucleases and which specify immunity to bacteriophage are described.

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.

Gamma-interferon inhibits Fc receptor II-mediated phagocytosis of tumor cells by human macrophages.

In vitro, monocyte-derived macrophages (MDM) are capable of efficient antibody-mediated phagocytosis of human nucleated tumor cells. These MDM express on their cell surface all three classes of Fc receptors for IgG (Fc gamma R). Fc gamma R specificity for murine antibody isotype allowed us to examine the phagocytic role of Fc gamma RII on control and gamma-interferon (IFN-gamma)-primed MDM. Monoclonal antibody 520C9 (IgG1) mediates phagocytosis through Fc gamma RII. This monoclonal antibody is directed against the HER-2/neu protooncogene product overexpressed on a variety of adenocarcinomas including the breast carcinoma cell line SK-BR-3. Our results showed that IFN-gamma treatment of differentiated MDM (days 8-12 in culture) inhibited Fc gamma RII-mediated phagocytosis in a dose-dependent manner with negative effects noted at doses as low as 0.1 units/ml. The percentage reduction in antibody-mediated phagocytosis observed following IFN-gamma priming (40 units/ml for 18 h) ranged from 23-89% of control. The inhibitory effect was evident when exposure to IFN-gamma was transient. Fc gamma RII expression was not altered by IFN-gamma treatment. In our model, IFN-gamma did not up-regulate or down-regulate HER-2/neu protein expression on our targets or affect the level of CD14 antigen expression on our MDM. Although IFN-gamma is a potent activator of monocytes/macrophages and can enhance certain tumoricidal mechanisms, our data show that antibody-dependent phagocytosis through the type II Fc receptor is inhibited by IFN-gamma priming. Nonspecific phagocytosis was not affected.

Inactivation of a volume-sensitive basolateral potassium conductance in turtle colon: effect of metabolic inhibitors.

Previous work has shown that the basolateral membrane of turtle colon epithelium contains a quinidine-sensitive potassium conductance which can be activated by osmotic cell swelling. In this work and in the present study, potassium flow across the basolateral membrane was measured as a short-circuit current across intact pieces of epithelial tissue in which amphotericin B was used to permeabilize the apical membrane. Quinidine-sensitive currents were generated when the mucosal bath contained chloride, a permeant anion. Replacement of chloride by sulfate or addition of sucrose to the bathing solutions abolished 75-90% of the current and caused the quinidine-inhibitable fraction of the current to go from over 90% to around 6%--suggesting that decreases in cell volume had brought about inactivation of the quinidine-sensitive conductance. When metabolic inhibitors were present, inactivation of the conductance by these maneuvers was prevented. Activation of the conductance by replacement of mucosal SO4 by Cl, however, was not affected.

A cautionary note on the use of certain restriction endonucleases with methylated substrates.

Methylation of adenine and cytosine residues in DNA isolated from common strains of Escherichia coli K-12 can render that DNA resistant to cleavage by certain restriction endonucleases at those sites at which the recognition sequence for such an endonuclease overlaps (but does not include) a sequence recognized by methylases specified by the dam or dcm gene.

Controllable alteration of cell genotype in bacterial cultures using an excision vector.

We have used recombinant DNA techniques to construct a derivative of phage lambda, called an excision vector, which retains only those functions necessary for conditional maintenance of lysogeny and integration/excision. The tyrA+ gene was cloned on this excision vector, integrated into the Escherichia coli chromosome, and stably maintained and expressed under permissive conditions. Upon shift to non-permissive conditions, the excision vector and its passenger gene were very efficiently excised from the chromosome and lost, leaving a culture of Tyr- bacteria. This illustrates a new class of conditional mutations in which the genotype changes in response to external stimuli.

Tetracycline resistance determined by pBR322 is mediated by one polypeptide.

Only one polypeptide specified by plasmid pBR322 is necessary to determine tetracycline resistance. Small deletions in pBR322 constructed in vitro which result in the lack of ability to confer tetracycline resistance in vivo also result in the absence or alteration of this polypeptide in vivo. Other deletions define the extent of material necessary to encode this polypeptide. A correction to the DNA sequence of the tetracycline resistance cistron has been determined which confirms these observations.

A gene cassette for adapting Escherichia coli strains as hosts for att-Int-mediated rearrangement and pL expression vectors.

A cassette of genes from bacteriophage lambda, when carried on a derivative of bacteriophage Mu, renders strains of Escherichia coli (and in principle other Mu-sensitive bacteria) capable of supporting lambda-based expression vectors, such as rearrangement vectors and pL vectors. The gene cassette contains a temperature-sensitive allele of the repressor gene, cIts857, and a shortened leftward operon comprising, oLpL, N, xis and int. Transfection and lysogenization of this cassette into various host bacteria is mediated by phage Mu functions. Examples of regulated expression of the gene encoding T4 DNA ligase are presented.

A plasmid cloning vehicle allowing a positive selection for inserted fragments.

We describe a plasmid cloning vehicle, pTR262, which allows a strong positive selection (resistance to tetracycline) for transformants bearing plasmids which have DNA insertions. pTR262 is derived from plasmid pBR322 and contains the cI gene and adjacent regulator region oRpR or the bacteriophage lambda. The expression of the tetracycline resistance (tet-r) gene(s) in pTR262 requires transcription from pR and is repressed by the cI gene product, lambda repressor. Insertion of a DNA fragment into the HindIII or Bc/I sites in pTR262 inactivates the cI gene and allows expression of the tet-r gene(s) in the host bacterium. A 100-fold increase in the number of tetracycline-resistant transformants is obtained when HindIII- or Bc/I-generated fragments are added to a ligation mixture containing HindIII- or Bc/I-digested pTR 262 DNA.

Airways obstruction in patients with long-term asthma consistent with 'irreversible asthma'.

OBJECTIVE: To describe a series of eight patients with long-term asthma and pulmonary function consistent with "end-stage," irreversible obstruction. DESIGN: Retrospective descriptive analysis of patients with severe asthma. SETTING: A university-based allergy-immunology service with a large population of corticosteroid-dependent patients with asthma. PATIENTS: Eight patients with long-standing asthma and apparently irreversible airways obstruction despite long-term oral and inhaled corticosteroid therapy. MEASUREMENTS: Pulmonary function data, radiographic studies including chest radiograph and high-resolution CT of the chest, and serologic analysis to rule out allergic bronchopulmonary aspergillosis and alpha1-antitrypsin deficiency had been performed as indicated, and these results were obtained through chart review. RESULTS: The age of the patients ranged from 41 to 58 years, with a mean duration of asthma of 39 years (SD = 12.4 years). No patient had evidence of any other pulmonary disease process. The mean duration of daily or alternate-day oral corticosteroid treatment was 15.8 years (SD=11.8 years). Despite intensive pharmacotherapy, all patients had an FEV1 57% (42+/-12%) with marked small airways disease as reflected in the forced expiratory flow between 25% and 75% of the FVC. Three of the eight patients demonstrated an accelerated decline in FEV1 despite continuous systemic corticosteroids. CONCLUSIONS: We have described a series of eight patients with long-standing asthma who demonstrate irreversible airways obstruction despite long-term systemic and inhaled corticosteroids. The term "end-stage asthma" or irreversible asthma might be applied to these patients in whom fixed obstruction has occurred in the absence of other pulmonary diseases.

Mixed erythrocyte chimerism: implications for tolerance of the donor immune system to recipient non-ABO system red cell antigens.

We report a case of a minor degree of ABO incompatibility in a BMT recipient, demonstrating mixed RBC chimerism, who, late in the post-transplant period, developed a warm autoimmune hemolytic anemia and subsequently developed antibodies with donor-anti-recipient specificities for non-ABO system RBC antigens. While this implies a lack of tolerance of the donor immune system for recipient non-ABO system RBC antigens, other factors may be operating and should be evaluated before such a conclusion is reached. Underscored is the importance of obtaining pretransplant RBC antigen phenotypes on both the recipient and donor.

Bronchial asthma and hyperreactivity after early childhood bronchiolitis or pneumonia. An 8-year follow-up study.

OBJECTIVE: To determine the infantile risk factors and long-term outcome up to 8 to 10 years of age for bronchial asthma and hyperreactivity in children with early-childhood bronchiolitis or pneumonia. DESIGN: Prospective follow-up of three groups of children. SETTING: University hospital providing primary hospital care and outpatient consultations for all pediatric patients in a defined area. INTERVENTIONS: None. PATIENTS: The study groups consisted of 62 children with early-childhood bronchiolitis, 29 children with early-childhood pneumonia with no wheezing, and 52 control children. METHODS: Infantile risk factors were prospectively registered until 2 years of age. Clinical examination, performed 7 to 8 years later, included recording of atopic and asthmatic symptoms from the preceding 12 months. The methacholine inhalation challenge test was used to assess bronchial hyperreactivity, and mean midexpiratory flow results were used to assess bronchial obstruction. MAIN RESULTS: Bronchial asthma was present in nine (15%) of the 62 children from the bronchiolitis group, compared with 7% in the pneumonia group and 2% in the control group. Bronchial hyperreactivity indicated by methacholine inhalation challenge was far more common; it was present in 62% of the bronchiolitis group and in 45% of the pneumonia group. Both groups differed significantly from the control group. Decreased mean midexpiratory flow values were observed in 29% and 21% of the bronchiolitis and pneumonia groups, respectively. All 10 asthmatic patients had bronchial hyperreactivity, but only 20% of hyperreactive children had asthma. An analysis of infantile risk factors disclosed only one, an early onset of wheezing, with a significant effect on bronchial hyperreactivity at school age. Elevated IgE values measured during infancy were associated with the development of clinical asthma. CONCLUSIONS: The risk of bronchial asthma was increased after infantile bronchiolitis. Moreover, bronchial hyperreactivity was increased after both infantile bronchiolitis and pneumonia. Methacholine inhalation challenge was a sensitive but nonspecific test for diagnosing bronchial asthma. Both bronchiolitis and pneumonia resulting in hospitalization in early childhood distinguish a group of children with an increased risk for long-term lung function abnormalities and pulmonary illnesses.

Diet in infancy and bronchial hyperreactivity later in childhood.

Sixty-seven atopy-prone children (atopic family group, AFG) and 52 children with no family history of atopy (NAFG) were followed for 10 years. During infancy, the mothers of the newborn AFG children were advised to adjust their infants' diet, with a view toward minimizing the risk of atopy, and not to keep pets. Pulmonary function tests, methacholine inhalation challenge (MIC), and skin prick tests (SPT) were done in order to evaluate the bronchial reactivity and skin reactivity in the two groups. A pathological result in MIC was found in 20 (30%) of the AFG children and in 10 (19%) of the NAFG children. Such results of MIC were more common in the children with positive SPT results than in those without (67% vs. 24%). In regard to the diet consumed in infancy, MIC was pathological in 23% of children with and in 36% without prophylactic diet in infancy. For MIC, using the new, Spira electro 2 dosimeter equipment, the sensitivity was 75% and specificity 97%, but the predictive value for diagnosing bronchial asthma was only 25%. The important advantage of our method is that the degree of bronchial reactivity can be estimated by responses to increasing provocative doses. Our observations confirm that the new method is suitable for detecting bronchial asthma in clinical practice but it seems not to be optimal for epidemiological studies. We concluded that later bronchial hyperreactivity can not be diminished by avoiding home pets or providing a hypoallergenic diet during infancy.

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.

Demographics, Prevalence, and Clinical Features of the Schizo-obsessive Subtype of Schizophrenia.

The schizo-obsessive subtype of schizophrenia has been proposed to describe the condition of patients with chronic psychotic disorders and prominent obsessive-compulsive (OC) symptoms. These patients differ from others with schizophrenia not only in their psychopathology, but perhaps also in their prognosis and pharmacotherapeutic response. Potent serotonin reuptake blockers, such as clomipramine, fluvoxamine, and fluoxetine, in conjunction with antipsychotics, can prove helpful in improving these patients' OC symptoms. The current study to access the demographics, prevalence, and clinical features of the schizo-obsessive subtype included established outpatients with a principal diagnosis of schizophrenia or schizoaffective disorder treated at a large urban public hospital. More than 50% of the hospital's psychiatric population is Hispanic. The Modified Maudsley Obsessive Compulsive Inventory (MMOCI) was used to identify prominent compulsive symptoms. Of the 52 patients who fulfilled the specific screening criteria, 17 (33%) also had prominent OC symptoms. Surprisingly, there was a statistical trend (P=0.06) for Hispanic patients to meet our threshold for the schizo-obsessive subtype. The MMOCI proved to be an adequate and efficient self-rated screening tool. The prevalence of the schizo-obsessive subtype, especially among Hispanic patients, highlights the importance for mental health professionals working with this population to identify and appropriately treat this group of patients.

Total serum IgE in trimellitic anhydride-induced asthma.

The objective of this study was to determine whether total serum IgE levels are elevated in workers with trimellitic anhydride-induced asthma as compared with anhydride-exposed workers without an occupational immunologic syndrome. Sera from 12 highly exposed workers with trimellitic anhydride-induced asthma, and from 31 similarly exposed workers without occupational immunologic disease, were assayed for total immunoglobulin E (IgE) levels by Total IgE II FAST analysis. The mean total IgE levels were 176.74 ng/mL and 34.55 ng/mL respectively. The difference between the two groups was statistically significant, but considerable overlap of IgE levels between groups was seen. In conclusion, although mean total IgE levels are significantly different between TMA-exposed workers with or without occupational asthma, the significant amount of overlap and poor sensitivity of the test preclude the use of this assay in the individual evaluation of these workers.