IgE sensitization to food allergens and airborne allergens in relation to biomarkers of type 2 inflammation in asthma.

BACKGROUND: We have recently reported that sensitization to food allergens and sensitization to airborne allergens had independent associations with increased fraction of exhaled nitric oxide (FeNO) and blood eosinophils in middle-aged adults and in young subjects with asthma. OBJECTIVE: To investigate the relation between IgE sensitization and several type 2 inflammation biomarkers in adult asthmatics. METHODS: FeNO, urinary eosinophil-derived neurotoxin (U-EDN), serum eosinophil cationic protein (S-ECP) and periostin were measured in 396 asthmatics, aged 17-76 years, from the Swedish GA2LEN study. Sensitization to airborne allergens was examined with skin prick tests (≥3 mm wheal) and sensitization to food allergens with measurement of specific IgE (≥0.35 kU/L). RESULTS: Asthmatics sensitized to food allergens had higher FeNO, 22.3 ppb (18.6, 26.7) vs 16.1 ppb (14.2, 18.2) (P = .005), S-ECP, 17.7 mg/L (14.8, 21.1) vs 12.8 mg/L (10.9, 14.9) (P = .01), and periostin, 73.7 (67.5, 80.3) ng/mL vs 59.9 (55.8, 64.2) ng/mL (P = .003), than non-sensitized subjects. Periostin levels in this group were also significantly higher than in the group sensitized only to airborne allergens (P = .01). Sensitization to food allergens related independently to FeNO (P = .02), S-ECP (P = .006) and periostin (P = .004), whereas sensitization only to airborne allergens related only to FeNO (P = .02) after adjustments for age, sex, height, weight and smoking history. FeNO correlated weakly with S-ECP (r = .17, P < .001), periostin (r = .19, P < .001) and U-EDN (0.16, P < .001). S-ECP also correlated weakly with U-EDN (r = .12, P = .02). None of the correlations between the remaining pairs of markers of type 2 inflammation were significant. CONCLUSIONS & CLINICAL RELEVANCE: Sensitization to food allergens related to several local and systemic type 2 inflammation markers, such as FeNO, S-ECP and periostin. Assessing the profile of allergic sensitization, including to food allergens, might improve the understanding and interpretation of inflammatory markers and potentially improve asthma management.

Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN.

BACKGROUND: Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear. AIM: To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics. METHODS: Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life. RESULTS: Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma. CONCLUSION: We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Cytologic features of focal papillary thyroid carcinoma arising within follicular adenoma: a masked cytomorphologic analysis of 17 cases.

BACKGROUND/OBJECTIVE: Focal papillary thyroid carcinoma (PTC) arising within a follicular adenoma (PTCFA) represents a clinically significant, but rare, histopathologic subset of papillary carcinomas whose cytologic features have not been well described. This uncommon presentation of PTC may contribute to a subset of thyroid aspirates interpreted as 'atypia of undetermined significance/follicular lesion of undetermined significance' (AUS/FLUS). STUDY DESIGN: Seventeen fine-needle aspiration biopsy (FNAB) cases diagnosed as 'PTCFA' on corresponding surgical excision were identified from the archival records of 2 large academic medical centers. A control group of 40 FNAB comprised of 20 follicular adenomas (FA) and 20 PTC was identified (based on the corresponding surgical pathology diagnosis) for comparison. All 57 FNAB were reviewed in a masked fashion and scored for a series of 31 cytomorphologic features. The intraclass correlation between diagnostic categories and overall agreement between cytopathologists was statistically evaluated. RESULTS: Aspirates of PTCFA were originally diagnosed as 'negative' (n = 3), 'AUS/FLUS' (n = 7), 'suspicious for a follicular neoplasm' (n = 3), 'suspicious for malignancy' (n = 3), and 'malignant' (n = 1). On masked review, the most common cytomorphologic features of PTCFA were a nonmacrofollicular cytoarchitectural pattern (71%), medium-large cell size (74%), and micronucleoli (79%). Intranuclear pseudoinclusions and a papillary architecture were absent in 85 and 88% of the cases, respectively. Relative to the 2 control groups, the PTCFA cases demonstrated overlapping features between FA and PTC for the majority of the 31 examined cytomorphologic features. CONCLUSION: PTCFA represent a rare subset of PTC that is difficult to recognize as PTC by FNAB. Most cases exhibit overlapping features between a benign thyroid nodule and conventional PTC, and they are often interpreted as 'AUS/FLUS'.

Gamma knife surgery for brain metastases: indications for and limitations of a local treatment protocol.

OBJECTIVE: The purpose of this retrospective study was to evaluate results of a local treatment protocol using gamma knife surgery (GKS) for brain metastases without upfront whole brain radiation therapy (WBRT). METHODS: Results for 521 consecutive patients satisfying the following 3 criteria were analysed: 1) a maximum of 3 tumours with a diameter of 25 mm or more; 2) no prior WBRT; 3) no surgically in accessible large (>30 mm) tumours. Large tumours were surgically removed and all smaller lesions were treated by GKS without up front WBRT. New lesions, detected with follow-up MRI, were appropriately treated with repeat GKS. Overall survival (OS), neurological survival (NS), qualitative survival (QS) and new lesion-free survival (NLFS) curves were calculated and the prognostic values of covariates were obtained. OS and NS were compared according to tumour number. RESULTS: In total, 1023 separate sessions were required to treat 4562 lesions. The primary organs were lung in 369 patients, gastro-intestinal tract in 70, breast in 33, urinary tract in 24, and others/unknown in 25. The median OS period was 9.0 months. On multivariate analysis, the significant prognostic factors for OS were found to be extracranial disease (risk factor: active), Karnofsky performance status (KPS) score (<70) and gender (male). NS and QS at one year were 85.6% and 73.0%, respectively. The only significantly poor prognostic factor for NS was carcinomatous meningitis. NLFS at 6 months was 68.9%. For both OS and NS, the differences between a few (10) tumours had a significantly poorer prognosis than those with

Hyodeoxycholic acid efficiently suppresses atherosclerosis formation and plasma cholesterol levels in mice.

We examined the effect of hyodeoxycholic acid (HDCA) on plasma cholesterol levels and atherosclerosis in mice. In wild-type C57BL/6 mice, feeding increasing amounts of HDCA resulted in i) progressive decrease in dietary cholesterol absorption, ii) increased concentrations of HDCA in the gallbladder bile, iii) decreased liver cholesterol content, iv) increased liver cholesterol synthesis, and v) increased plasma concentrations of HDCA. In C57BL/6 LDL-receptor knockouts (LDLR-KO) the addition of HDCA to chow and a 0.5% cholesterol diet decreased their total plasma cholesterol levels by 21% and 62%, respectively, because of a decrease in VLDL and LDL cholesterol. Turnover studies showed that HDCA has no effect on VLDL removal from plasma. Furthermore, the addition of HDCA to chow- and 0.5% cholesterol-fed LDLR-KO mice decreased the aortic root atherosclerosis lesion area by 50% and 80%, respectively. Finally, we tested the effect of HDCA on intestinal tumor formation. Feeding C57BL/6 ApcMin mice with HDCA did not affect the number of tumors but decreased the tumor volume in these animals. These results suggest that HDCA might have beneficial effects in the treatment of increased plasma cholesterol levels and atherosclerosis.

Influences of venous involvement on postoperative brain damage following the anterior interhemispheric approach.

BACKGROUND: The anterior interhemispheric approach offers us an excellent surgical view for suprasellar lesions. Following this approach, we occasionally encounter postoperative brain damage in the frontal lobes. To assess the determinants of such a complication, we undertook a clinical study. METHOD: Potential causes for such brain damage were evaluated in 28 consecutive patients with suprasellar tumours extirpated using this approach. We focused particularly on the influences of venous involvement during surgery. The draining territory index (DTI) was originally devised for estimating the extent of the draining area of the sacrificed bridging veins. FINDINGS: CT evident brain damage was observed in five of 28 patients (17.8%), but only one patient (3.6%) showed clinically significant postoperative deficits. The patient's age, tumour pathology, tumour character, tumour size, duration of surgery, and radicality of the surgery did not affect the incidence of the brain damage. Of the twelve patients whose bridging veins were sacrificed during surgery, four (33.3%) showed brain damage in the frontal lobes. In contrast, such damage was observed in only one patient out of 16 (6.3%) whose bridging veins were preserved. Among the brain-damaged group, the average DTI of the sacrificed veins was significantly higher than that among the non-brain-damaged group. INTERPRETATION: Venous involvement during surgery significantly aggravated postoperative brain damage following the anterior interhemispheric approach. The DTI was useful in predicting the risk of brain damage, and a large bridging vein with a DTI over 50% should not be sacrificed during surgery.

Prevalence of risk factors for aneurysmal subarachnoid haemorrhage: results of a Japanese multicentre case control study for stroke.

The pathogenesis of subarachnoid haemorrhage (SAH) is still unclear. To evaluate the risk factors for aneurysmal SAH, we conducted a multicentre case control study. All aneurysms were detected by cerebral angiography and the patients with SAH other than ruptured aneurysms were excluded. Information on past medical histories and other possible risk factors for SAH were assessed by a structured questionnaire. Data on the total 127 pairs (59 male and 68 female) were analysed. In a univariate analysis, family history of SAH [odds ratio (OR) 9.45], systemic hypertension (OR 2.65), cigarette smoking (OR 2.54) and regular alcohol consumption (OR 1.92) were significant risk factors for aneurysmal SAH. Heavy alcohol consumption (>350 g ethanol/week) was significant (OR 3.22), whereas light consumption (=<350 g/week) did not to increase the risks (OR 0.95). Both light (<20 cigarettes/day, OR 2.44) and heavy smoking (>=20 cigarettes/day, OR 2.72) were associated with an increased risk of SAH. In a multivariate analysis, after adjustment for other risk factors, family history of SAH, cigarette smoking and hypertension remained significant.

Treatment of asymptomatic unruptured intracranial aneurysms. A clinical decision analysis.

SUMMARY: The indication of preventive surgery for patients who harbor asymptomatic un ruptured intracranial aneurysms remains controversial. To evaluate the benefit of this treatment, we investigated the management outcome in 128 patients with 157 unruptured aneurysms. Surgery was planned in patients 70 years old or younger without serious systemic complications. A total of 77 patients underwent surgery including four endovascular interventions, and conservative management was chosen in 51 patients. There was no mortality and 6.5% morbidity as postoperative results, and no complication was found after endovascular treatment. Among the patients in conservative management, four patients suffered from subsequent rupture during the total follow-up period of 148 person-years. The annual rupture rate was estimated at 2.7%. According to the clinical decision analysis based on our data, preventive surgery is beneficial for a Japanese 70 years old or younger. However, the expected utility decreases if the rupture rate is set at 0.5% or 0.05%, posing a doubt about the benefit of the surgery. Decision analysis provides an aid for logical and objective choice in the management of unruptured aneurysms. The actual risk of rupture has a major impact on decision making in therapeutic strategy.

Prevention of cerebrospinal fluid leakage and delayed loss of preserved hearing after vestibular schwannoma removal: reconstruction of the internal auditory canal in the suboccipital transmeatal approach--technical note.

The suboccipital transmeatal approach uses packing of a muscle or fat graft into the internal auditory canal (IAC) to prevent postoperative cerebrospinal fluid (CSF) leakage. However, preserved hearing after removal of vestibular schwannomas may decline over time because of the progressive constriction of cochlear vascular supply due to scarring of the IAC. We propose a surgical technique for IAC reconstruction, which separates the preserved cochlear nerve and vasculature from the graft, and regains the CSF space in the IAC. Prior to the drilling of the posterior wall of the IAC, the dura mater of the petrous bone forming the posterior wall of the IAC is harvested for IAC reconstruction. After completion of tumor removal, a "roof" of the IAC is reconstructed using the dura mater, and a muscle or fat graft soaked with fibrin glue is placed on the "roof" of the IAC. The IAC was reconstructed using this technique in 26 consecutive patients with vestibular schwannomas who underwent tumor removal via the suboccipital transmeatal approach. Postoperative magnetic resonance imaging confirmed the regained CSF space in the IAC. No delayed hearing loss occurred in four patients with preserved hearing. No CSF leakage occurred after surgery. This new technique of IAC reconstruction may prevent delayed hearing loss as well as postoperative CSF leakage after removal of vestibular schwannomas via the suboccipital transmeatal approach.

Genetic alteration of the DCX gene in Japanese patients with subcortical laminar heterotopia or isolated lissencephaly sequence.

We examined mutations of the doublecortin (DCX) gene, which is responsible for X-linked subcortical laminar heterotopia (SCLH) and lissencephaly, in eight unrelated Japanese patients, four with SCLH and four with isolated lissencephaly sequence (ILS). Polymerase chain reaction (PCR) disclosed a deletion of part of the DCX gene in one male ILS patient. Single-strand conformational polymorphism analysis and subsequent sequence analysis were carried out in the remaining seven patients. One male ILS patient had a nonsense mutation in exon V, which would result in premature termination of the gene product. One female SCLH patient had a missense mutation in exon IV. Our results indicate that in the Japanese, as has been seen elsewhere, abnormality of the DCX gene is the common cause of SCLH and ILS.

Gamma knife treatment for multiple metastatic brain tumors compared with whole-brain radiation therapy.

OBJECT: The purpose of this retrospective study was to compare the effectiveness of gamma knife radiosurgery (GKS) for multiple cerebral metastases with that of whole-brain radiation therapy (WBRT). METHODS: Ninety-six consecutive patients with cerebral metastases from nonsmall cell lung cancer were treated between 1990 and 1999. The entry criteria were the presence of between one and 10 multiple brain lesions at initial diagnosis, no surgically inaccessible tumors with more than a 30-mm diameter, no carcinomatous meningitis, and more than 2 months of life expectancy. The patients were divided into two groups: the GKS group (62 patients) and the WBRT group (34 patients). In the GKS group, large lesions (> 30 mm) were removed surgically and all other small lesions (< or = 30 mm) were treated by GKS. New distant lesions were treated by repeated GKS without prophylactic WBRT. In the WBRT group, the patients were treated by the traditional combined therapy of WBRT and surgery. In both groups, chemotherapy was administered according to the primary physician's protocol. The two groups did not differ in terms of age, sex, initial Karnofsky Performance Scale (KPS) score, type, lesion number, and size of lesion, systemic control, and chemotherapy. Neurological survival and qualitative survival of the GKS group were longer than those of the WBRT group. In multivariate analysis, significant poor prognostic factors were systemically uncontrolled patients, WBRT group, and poor initial KPS score. CONCLUSIONS: Gamma knife radiosurgery without prophylactic WBRT could be a primary choice of treatment for patients with as many as 10 cerebral metastases from nonsmall cell cancer.

Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations.

Twenty-seven Japanese patients with the tuberous sclerosis complex (TSC), consisting of 23 sporadic and 4 familial cases, were tested for mutations in the TSC1 and TSC2 genes, using single-strand conformational polymorphism analysis and direct sequencing. Four possible pathogenic mutations were found in the TSC1 gene, including three frame shifts and a nonsense mutation in a familial case. All mutations were expected to result in a truncated hamartin gene product. The TSC2 gene analysis identified six possible pathogenic mutations only in the sporadic cases, including two frame shifts, one in-frame deletion, and three missense mutations. Two of the TSC2 mutations were expected to result in a truncated tuberin gene product. These results of the Japanese TSC patients were compatible with the reports from Europe and the United States, i.e., (1) TSC1 mutations are rarer in sporadic cases than in familial cases, (2) substantial numbers of sporadic cases arise from mutations in the TSC2 gene, and (3) mutations of the TSC1 gene may cause premature truncation of hamartin.

Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a patient with HIV infection.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from lytic infection of oligodendrocytes by the papovavirus JC (JCV). PML has also been recognized as an AIDS-defining illness. The incidence of PML has increased since 1987 and it occurs in up to 4% of patients with AIDS. To date, there is no treatment available for PML and it usually results in death within 3-6 months of diagnosis. However, there are some reports of remission of PML after antiretroviral therapy. We report a 12-year-old child with hemophilia B and developing AIDS with the onset of PML. With highly active antiretroviral therapy, PML subsided with an increase of CD4 count from 10 to 300/microl in spite of about 1.0 X 10(4) human immunodeficiency virus (HIV)-1-RNA copies. He has survived more than 1 year without specific therapy against JCV. Highly active antiretroviral therapy appears to have improved his prognosis in HIV-associated PML.

[Connatal type of Pelizaeus-Merzbacher disease: a case report].

Pelizaeus-Merzbacher disease (PMD) is a hereditary disorder with myelin dysplasia in the central nervous system. The connatal type is a more severe form compared to the classical type and shows developmental arrest or deterioration, nystagmus, spasticity, and/or convulsions in the neonatal period. A 1 1/4-year-old Japanese boy diagnosed as connatal type PMD is reported here. Soon after his birth, he demonstrated horizontal and rotatory nystagmus and opisthotonic posture. At the age of 10 months, he had difficulty in feeding. At the age of 1 year, he presented more severe opisthotonic posture and frequent vomiting. He showed deterioration in gross motor development. His chromosome analysis showed a normal male karyotype. Electroencephalogram did not show a sleep spindle. Auditory evoked brainstem responses (ABR) showed only wave I on both sides. Visual evoked potentials (VEP) showed prolongation of latencies. These results were compatible with PMD. Nuclear magnetic resonance imaging (MRI) demonstrated in the white matter of cerebrum and brainstem no high intensities on T1-weighted images and diffuse high intensities on T2-weighted images. Such absence of myelination including the brainstem was characteristic to the connatal type PMD. The diffuse disturbance of myelination appeared to correlate with the severity of clinical symptoms.

Recovery of hearing after removal of a large jugular foramen schwannoma: report of two cases.

BACKGROUND: Although hearing loss is a common presenting symptom of jugular foramen schwannoma (JFS), recovery of hearing after tumor removal has rarely been reported. We report two cases of a large JFS presenting with severe hearing loss and recovering normal hearing after tumor removal. METHODS AND RESULTS: Two patients complaining of progressive hearing loss each proved to have a large JFS involving the posterior fossa. The hearing losses, which exceeded 90 dB, were not associated with dysfunction of the 9th, 10th, or 11th cranial nerves. Schwannomas were removed by a suboccipital retrosigmoid approach, preserving labyrinthine structures. The vestibulocochlear nerve, stretched and displaced rostrally by the tumor, was preserved with surrounding arachnoidal tissue. Soon after surgery, recovery of hearing began; normal hearing was restored within 3 months. CONCLUSIONS: In a case of JFS with severe hearing loss, normal hearing may be attainable by tumor removal using a retrosigmoid approach that preserves labyrinthine structures. The arachnoidal tissue separating the vestibulocochlear nerve from the schwannoma is important to hearing preservation.

[Leiomyoma of the lung: a case report].

An asymptomatic 43-year-old female was admitted to the Hospital because of an abnormal nodule in the left lung field on screening chest X-ray. Chest CT showed a tumor shadow mass (4 x 3 cm) in the left lower lobe. Bronchofiberscopy revealed an endobronchial polypoid mass obstructing the lower lobe bronchus at the orifice of left B10. Lt lower lobectomy was performed. Histopathological examination of the specimen showed the tumor (4.5 x 3.6 x 3.6 cm) developing not only within the tracheal lumen, but also in the lung tissue. Because immunohistochemical staining for desmin and alpha-smooth muscle actin was positive, we diagnosed leiomyoma. As MRI revealed multiple uterine masses after operation, we discussed the diagnostic problems in the relation to metastasizing leiomyoma of the uterus.

Effects of troglitazone on the growth and differentiation of hematopoietic cell lines.

Troglitazone (Tro), one of the thiazolidinediones, is a novel antidiabetic agent for patients with type 2 diabetes mellitus. Tro is a specific ligand of PPARgamma, the nuclear receptor that regulates the growth and differentiation of cells at the transcriptional level. We attempted to investigate the effect of Tro on HL-60 and other hematopoietic cell lines and thus found HL-60 cells to be arrested at the G1 phase and to differentiate into monocytes. In addition, apoptosis was also induced by Tro at higher concentrations. The G1 arrest was induced in all the hematopoietic cell lines examined while differentiation into the monocytic lineage was observed not only in the myelogenous and promonocytic cell lines but also in an erythroleukemia cell line.