Phenotypic spectrum of Salla disease, a free sialic acid storage disorder

Salla disease (MIM 269920) represents the mildest phenotype among recessively inherited lysosomal-free sialic acid storage disorders. Although the vast majority of Salla disease patients in Finland share the same founder mutation, R39C in the SLC17A5 gene, there still is a wide clinical variation among mentally retarded, ataxic patients. We evaluated neurologic and neurocognitive findings of Salla disease in a cross-sectional study of 41 Finnish patients who were 11 months to 63 years of age (median = 19.5 years). The phenotype of Salla disease could be classified into two main categories. The majority of patients (90%) had so-called conventional phenotype, including a subgroup of seven patients with relatively mild symptoms. All but two patients with conventional phenotype were homozygous for the Finnish founder mutation. Four severely disabled, profoundly mentally retarded patients, 15-28 years of age, clearly could be clinically delineated as a separate group, likely reflecting the underlying compound heterozygous genotype. A typical developmental pattern could be outlined in the conventional type of the disease, emphasizing a strong motor handicap in Salla disease. The cognitive profile consisted of better verbal ability, especially speech comprehension, compared with nonverbal functioning in all patients. Our results indicate a partial genotype-phenotype correlation, although factors other than the molecular background are also involved in the phenotypic manifestation of Salla disease.     

Responses of songbirds to aerial spraying of the microbial insecticide Bacillus thuringiensis var. kurstaki (FORAY 48B) on Vancouver Island,British Columbia,Canada

Use of bacterial insecticides containing Bacillus thuringiensis var. kurstaki (Btk) is gaining popularity as an environmentally safe control measure against lepidopteran pests, but indirect effects on nontarget organisms through reduced prey base have received little attention. Aerial spraying of Btk (Foray 48B) over a 12,803-ha area on southeastern Vancouver Island (BC, Canada) in May to June 1999 as part of a gypsy moth (Lymantria dispar) control program provided us with an opportunity to examine the responses of songbirds to spray application. To obtain an estimate of species richness and relative abundance, we conducted standard songbird point-count surveys in Garry oak (Quercus garryana)-dominated habitats in Btk-sprayed and unsprayed areas in April to June 1999 and, one year after spraying, in 2000. These surveys revealed no patterns consistent with adverse effects of spraying on the relative abundance of adult birds or singing males for any of the species, whether examined individually or when combined into foraging guilds. An exception was the spotted towhee (Pipilo maculatus), which in 1999, but not in 2000, occurred at significantly lower numbers in sprayed plots after Btk treatment. Intensive searches of plots in sprayed and unsprayed areas revealed no differences in the numbers of songbird broods between the two areas for any of the species examined.     

Overnight urinary isoflavone excretion in a population of women living in the United States, and its relationship to isoflavone intake.

Dietary isoflavones are biologically active in humans, but few observational data exist on the relationship between isoflavone intake and excretion in Western populations. We examined associations between self-reported soy intakes and overnight urinary isoflavone excretion in a population-based sample of western Washington State women, and we investigated the usefulness of one versus two overnight urine samples, collected 48 h apart, as a biomarker of intake. Isoflavones (genistein, daidzein, O-desmethylangolensin, and equol) were measured in two overnight urine collections from 363 women recruited from a health maintenance organization. Soy food intakes were assessed using two 1-day diet records completed on each day prior to the urine collections and a food frequency questionnaire (FFQ) that had been completed by 312 of the women with regard to their dietary habits 3.5 years (range, 2-5 years) before the urine collections. Twenty-one percent of the women consumed soy on either day of the diet recall, and 13% and 34% of the women consumed soy at least once a week or at least once a month, respectively, according to the FFQ. Women who consumed soy at either of the two diet recalls or at the FFQ (at least once a week or at least once a month) had a significantly higher urinary excretion of isoflavones than women who did not consume soy (P < 0.01). Among women who consumed soy at either of the two diet recalls or at the FFQ (soy consumed at least once a month), isoflavone intake and excretion correlated significantly (P < 0.01). Excretion of the individual isoflavones correlated significantly between the two urine samples collected 48 h apart (genistein, r = 0.41 and P < 0.001; daidzein, r = 0.30 and P < 0.001; O-desmethylangolensin, r = 0.46 and P < 0.001; equol, r = 0.60 and P < 0.001). Differences between soy consumers and nonconsumers and associations between intakes and excretion remained significant whether one or both urine collections were considered. Measuring isoflavone excretion in one overnight urine collection serves as a biomarker of recent or past isoflavone intake, even in populations whose intake of soy foods is relatively low.     

High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart

Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.     

Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic condition that may affect women during the third trimester of pregnancy. Symptoms experienced by these women generally resolve spontaneously following delivery, but prior to delivery the fetus is at increased risk of intrauterine distress and sudden intrauterine death. The genetic etiology of most cases of ICP is unknown, although heterozygous carriers of mutations causing progressive familial intrahepatic cholestasis (PFIC) diseases may experience ICP. When examining linkage to known cholestasis genes, affected members of four Finnish ICP families shared haplotypes around ATP8B1, the gene responsible for PFIC1. This gene was subsequently screened in 176 familial and sporadic ICP patients. A total of 17 sequence changes were detected, five exonic and 12 intronic. No intronic change was associated with ICP in sporadic cases. Four intronic changes segregated with ICP in three families, a different change in each of two families and three changes in another family, although the significance of this is currently unknown. Three exonic changes were nonsynonymous, one (in exon 23) is probably a polymorphism while two predict novel amino-acid replacements (N45T and K203R). These changes, in exons 2 and 7, were detected in one individual each, and may have predisposed these individuals to ICP. In conclusion, although the exon 2 and 7 changes may have functioned as risk alleles, ATP8B1 is probably not a major gene contributing to the occurrence of ICP.     

Distinct properties of functional KCC2 expression in immature mouse hippocampal neurons in culture and in acute slices

A hallmark in the development of GABAergic neurotransmission is the switch in GABA(A)-mediated responses from depolarizing to hyperpolarizing. This occurs due to a gradual decrease in the intracellular concentration of chloride caused by the functional expression of the neuron-specific K-Cl cotransporter KCC2. Whether a mere increase in the amount of KCC2 protein is the rate-limiting step in vivo, or a further activation of the otherwise nonfunctional cotransporter is required, is not clear. Imposing a fixed Cl(-) load via patch pipette we measured the resultant somato-dendritic gradients in reversal potential of GABAergic currents to determine the time course of functional maturation of KCC2-mediated Cl(-) extrusion in two preparations: cultured mouse hippocampal neurons plated at embryonic day 17 and CA1 pyramidal cells in acute slices. We found that in immature neurons in both preparations the gradient is initially small or not detectable. It undergoes an abrupt increase at around days 13-14 in culture, while a more gradual increase occurs between postnatal days 5-14 in slices. Consistent with the presence of a nonfunctional form of KCC2 in immature hippocampal neurons grown in culture, application of the broad-spectrum kinase inhibitor staurosporine produces a rapid and potent up-regulation of KCC2 function in these cultured neurons, but not in neonatal slices. Taken together with our previously published data, these results indicate that the functional activity of KCC2 in vivo parallels the developmental expression of the protein, whereas cultured neurons require an additional activation step (mimicked by staurosporine) for KCC2 to become functional.     

Occupational allergic contact dermatitis from lichens in present-day Finland

Lichens are abundant in forests, living on trees, soil, stones and rocks. They contain usnic acid and other lichen acids that are contact allergens. Lichens and liverworts cause woodcutter's dermatitis, eczema that appears in the forest on the bare skin areas, especially in cold and wet weather. Occupational allergic contact dermatitis from lichens occurs in forestry and horticultural workers and in lichen pickers. Lichens can cause immediate allergy, contact urticaria, rhinitis and asthma and probably also photoallergic contact dermatitis. Lichens are used for the manufacture of oak moss absolute, a fragrance constituent. Oak moss absolute contains lichen acids and is one of the commonest contact allergens. Lichen acid allergy develops either from contact with lichens or from fragrances. We describe 4 cases of occupational allergic contact dermatitis from lichens during the past decade: 2 were farmers and 2 gardeners. 3 of them had allergic reactions to fragrance mix and oak moss absolute. Lichen contact allergy is an old, partly forgotten, syndrome that should be remembered for symptoms in contact with barked wood or wood dust.     

Cutaneous, but not airway, latex exposure induces allergic lung inflammation and airway hyperreactivity in mice

As respiratory symptoms are common in addition to skin reactions in natural rubber latex allergy, we investigated the significance of different allergen exposure routes in the development of lung inflammation and airway hyperreactivity (AHR). Both intracutaneous (IC) and intraperitoneal (IP) exposure followed by airway challenge with latex proteins induced an influx of mononuclear cells and eosinophils to the lungs. AHR and lung mucus production increased significantly after IC and IP but not after intranasal (IN) exposure. Infiltration of inflammatory cells was associated with the induction of T-helper type 2 (Th2) cytokines and several CC chemokines. Only a marginal induction of these mediators was found after IN exposure. On the contrary, increased levels of transforming growth factor-beta1 and forkhead box 3 mRNA, markers of regulatory activities, were found in the lungs after IN but not after IC exposure. Finally, IC and IP, but not IN, latex exposure induced a striking increase in specific immunoglobulin E (IgE) levels. Cutaneous latex exposure in the absence of adjuvant followed by airway challenge induces a local Th2-dominated lung inflammation and a systemic IgE response. Cutaneous exposure to proteins eluting from latex products may therefore profoundly contribute to the development of asthma in latex allergy.     

Laparoscopy in chronic abdominal pain: a prospective nonrandomized long-term follow-up study

GOAL: Our aim was to assess the long-term efficacy of diagnostic laparoscopy and adhesiolysis on the treatment of intractable chronic abdominal pain. STUDY: This was a prospective nonrandomized study of 72 patients (60 women and 12 men). One surgeon performed a total of 79 diagnostic laparoscopies including 61 adhesiolysis. The patients' demographic data, operative findings, and long-term postoperative course were carefully recorded. A quality-of-life questionnaire was mailed after the mean follow-up of 3.7 years to find out the late course of any chronic abdominal symptoms after the surgery. RESULTS: Intra-abdominal adhesions were found in 61 patients (85%) in the laparoscopy, gynecologic disorders in 4, chronic appendicitis in 1, and no abnormality in 6 patients. The abdominal wall pain was a likely reason for pain in 12 patients (17%). The complication rate was minimal, including only four bleedings (one major), one perforation of urinary bladder, and three wound infections. At 1-month control, 38% of the patients were completely free of pain. In the long-term follow-up, chronic abdominal pain was totally healed in 33%, diminished in 46%, and unchanged in 21% of the patients. A total of 65 patients (90%) reported that the surgery had been beneficial for their intractable pain. CONCLUSIONS: By careful selection, for patients with chronic abdominal pain, laparoscopy alleviates the symptoms in more than 70% of the patients, and it should be considered if other diagnostics tests are negative. A placebo-controlled study is needed, in which the patients are randomized into laparoscopy and conservatively treated groups with a quality-of-life measurement.     

Neurocognitive profiles in Salla disease

Salla disease, a free sialic acid storage disorder, is one of the 36 currently known disorders in Finland that form the Finnish disease heritage. Salla disease leads to learning disability* with a wide clinical variation. Two main categories of the disease have been classified: a conventional subtype and a severe subtype with more severe defects. We present detailed neurocognitive profiles of 41 Finnish patients with Salla disease (19 females, 22 males; age range 11mo to 63y, median 19y). The neurocognitive development of patients with Salla disease was assessed by psychological and neuropsychological testing. All patients were also examined by a paediatric neurologist and a speech therapist. The characteristic cognitive profile consisted of a lower non-verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual-constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand-eye coordination, maintenance of visual attention, and those requiring short-term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients' interactive and non-verbal communication skills were quite strong. Another typical pattern with Salla disease was severe motor disability. After the second decade of life, the decline in these skills was more pronounced than patients' cognitive deterioration. Our results indicate that even though there is a considerable variation in the clinical findings of patients with Salla disease, the characteristic neurocognitive profile of the disease can be outlined.