Night-time sedating H1 -antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial.

BACKGROUND: Many physicians believe that the most effective way to treat chronic urticaria is to take a nonsedating second-generation H1 -antihistamine in the morning and a sedating first-generation H1 -antihistamine, usually hydroxyzine, at night to enhance sleep. But is this belief well founded? OBJECTIVES: To test this belief by comparing the effectiveness and prevalence of unwanted sedative effects when treating patients with chronic spontaneous urticaria (CSU) with levocetirizine 15 mg daily plus hydroxyzine 50 mg at night (levocetirizine plus hydroxyzine) vs. levocetirizine 20 mg daily (levocetirizine monotherapy). METHODS: In this randomized, double-blind, cross-over study, 24 patients with difficult-to-treat CSU took levocetirizine plus hydroxyzine or levocetirizine monotherapy for periods of 5 days each. At the end of each treatment period, assessments were made of quality of life (Chronic Urticaria Quality of Life Questionnaire, CU-Q2 oL), severity of urticaria symptoms (Urticaria Activity Score, UAS), sleep disturbance during the night and daytime somnolence. RESULTS: Both treatments significantly decreased UAS, night-time sleep disturbances and CU-Q2 oL scores (P < 0·001) without significant differences between the two. Compared with baseline, daytime somnolence was significantly reduced by levocetirizine monotherapy (P = 0·006) but not by levocetirizine plus hydroxyzine (P = 0·218). Direct comparison of the two treatment modalities in terms of daytime somnolence favoured levocetirizine monotherapy (P = 0·026). CONCLUSIONS: The widespread belief that sleep is aided by the addition of a sedating first-generation H1 -antihistamine, usually hydroxyzine, at night is not supported. These results are in line with the urticaria guidelines, which state that first-line treatment for urticaria should be new-generation, nonsedating H1 -antihistamines only.

Real life clinical study design supporting the effectiveness of extra-fine inhaled beclomethasone/formoterol at the level of small airways of asthmatics.

BACKGROUND: In an attempt to establish how treatment with inhaled extra-fine beclomethasone/formoterol (I-EF-BDP/F) formulation differs from other combinations of inhaled corticosteroid (ICS) and long acting beta-agonist (LABA), we studied lung function and markers of airway inflammation upon switching to the extra-fine formulation and after 8 weeks of treatment with it. METHODS: We carried out a real-life clinical observation of undercontrolled asthmatic patients switched over from dry powder inhalers of fluticasone/salmeterol and budesonide/formoterol to I-EF-BDP/F (Foster(®), Chiesi Farmaceutici S.p.A., Italy). The effects of 8-weeks of treatment were documented by means of visual analog scale (VAS), quality of life by Asthma Quality of Life Questionnaire (AQLQ), spirometry and markers of airway or systemic inflammation: exhaled breath temperature (EBT), blood eosinophils (Eos), and high sensitivity C-reactive protein (CRP). Before/after treatment differences between forced vital capacity percent of predicted (%FVC), a simple indicator of small airways involvement, were calculated and subjects were ranked accordingly to reflect the magnitude of the therapeutic response. Subjects above the 75th percentile (n = 15), "top responders", were then compared with those below the 25th percentile (n = 15) "poor responders". RESULTS: On average, the 59 patients completing the study (mean age ± SD 51 ± 12 years, 38 women) had significant improvement in VAS and QLQ scores at the end of the treatment period (49.1 ± 2.4 vs. 73.1 ± 2.05 and 146.1 ± 2.7 vs. 176.7.1 ± 3.4 respectively, P < 0.001), but not in the inflammatory indicators (EBT, CRP and Eos). However, when comparing the "top responders" with the "poor responders", significant improvement in these inflammatory indicators was observed: EBT significantly decreased from 34.04/mean/± 0.30/s.e.m./[°C] to 33.57 ± 0.33, P = 0.003, Eos in blood fell from 381.7 ± 91.2 [cells/µL] to 244.2 ± 43.2, P = 0.02. Before/after treatment differences in hsCRP decreased significantly in the top responders compared with the poor responders (Mann-Whitney test, P = 0.04). CONCLUSION: Asthmatic subjects who had the most improvement in FVC after transition to I-EF-BDP/F from other combined ICS/LABA preparations also demonstrated a significant decrease in some indicators of airway/systemic inflammation. These results support the notion that I-EF-BDP/F exerts an effect also at the level of the small airways through a reduction of the level of air trapping. Patients in whom inflammation of the small airways plays an important clinical role are the ones to derive most benefit from this small airways tailored treatment. However, improved compliance due to the "promise of a new drug" effect should also be considered as contributing to the treatment results.

The spectral changes in EMG during a second bout eccentric contraction could be due to adaptation in muscle fibres themselves: a simulation study.

The mechanism of marked reduction in damage symptoms after repeated bout of similar eccentric contractions is still unknown. The neuronal adaptation leading to reduction of muscle fibre propagation velocity (MFPV) due to increased activation of slow-twitch motor units (MUs), decrease in activation of fast-twitch MUs, and/or increase in MU synchronization was suggested as a cause for lower EMG frequency characteristics. However, the repeated bout effect could occur also after electrically stimulated exercise. Prolonged elevation of cytoplasmic Ca(2+) due to the increased membrane permeability after eccentric contractions was reported. Elevated Ca(2+) induced peripheral changes that included alteration of intracellular action potential and MFPV reduction. We simulated and compared changes in EMG frequency characteristics related to effects of central nervous system (CNS) or to peripheral changes. The simulations were performed for different electrode arrangements and positions. The results showed that the peripheral effects could be similar or even stronger than the effects related to CNS. We hypothesised that the repeated bout effect was a consequence of the adaptation in muscle fibres necessary for avoiding Ca(2+)-induced protein and lipid degradation due to Ca(2+) overload resulting from the increased membrane permeability after eccentric contraction. The possibilities for noninvasive testing of this hypothesis were discussed.

Analyzing the forces binding a restriction endonuclease to DNA using a synthetic nanopore.

Restriction endonucleases are used prevalently in recombinant DNA technology because they bind so stably to a specific target sequence and, in the presence of cofactors, cleave double-helical DNA specifically at a target sequence at a high rate. Using synthetic nanopores along with molecular dynamics (MD), we have analyzed with atomic resolution how a prototypical restriction endonuclease, EcoRI, binds to the DNA target sequence--GAATTC--in the absence of a Mg(2+) ion cofactor. We have previously shown that there is a voltage threshold for permeation of DNA bound to restriction enzymes through a nanopore that is associated with a nanonewton force required to rupture the complex. By introducing mutations in the DNA, we now show that this threshold depends on the recognition sequence and scales linearly with the dissociation energy, independent of the pore geometry. To predict the effect of mutation in a base pair on the free energy of dissociation, MD is used to qualitatively rank the stability of bonds in the EcoRI-DNA complex. We find that the second base in the target sequence exhibits the strongest binding to the protein, followed by the third and first bases, with even the flanking sequence affecting the binding, corroborating our experiments.

Nanopores in solid-state membranes engineered for single molecule detection.

A nanopore is an analytical tool with single molecule sensitivity. For detection, a nanopore relies on the electrical signal that develops when a molecule translocates through it. However, the detection sensitivity can be adversely affected by noise and the frequency response. Here, we report measurements of the frequency and noise performance of nanopores

Stretching and unzipping nucleic acid hairpins using a synthetic nanopore.

We have explored the electromechanical properties of DNA by using an electric field to force single hairpin molecules to translocate through a synthetic pore in a silicon nitride membrane. We observe a threshold voltage for translocation of the hairpin through the pore that depends sensitively on the diameter and the secondary structure of the DNA. The threshold for a diameter 1.5 < d < 2.3 nm is V > 1.5 V, which corresponds to the force required to stretch the stem of the hairpin, according to molecular dynamics simulations. On the other hand, for 1.0 < d < 1.5 nm, the threshold voltage collapses to V < 0.5 V because the stem unzips with a lower force than required for stretching. The data indicate that a synthetic nanopore can be used like a molecular gate to discriminate between the secondary structures in DNA.

Nanoelectromechanics of methylated DNA in a synthetic nanopore.

Methylation of cytosine is a covalent modification of DNA that can be used to silence genes, orchestrating a myriad of biological processes including cancer. We have discovered that a synthetic nanopore in a membrane comparable in thickness to a protein binding site can be used to detect methylation. We observe a voltage threshold for permeation of methylated DNA through a <2 nm diameter pore, which we attribute to the stretching transition; this can differ by >1 V/20 nm depending on the methylation level, but not the DNA sequence.

Comparison of the efficacy and safety of bilastine 20 mg vs desloratadine 5 mg in seasonal allergic rhinitis patients.

BACKGROUND: Bilastine is a novel, nonsedating H(1)-antihistamine developed for symptomatic treatment of Allergic Rhinitis and Chronic Idiopathic Urticaria. The objective of this study was to compare the efficacy and safety of bilastine 20 mg vs placebo and desloratadine 5 mg in subjects with seasonal allergic rhinitis (SAR). METHODS: This randomized, double blind, placebo-controlled, parallel-group multicentre study evaluated the effect of 2 weeks' treatment with bilastine 20 mg, desloratadine 5 mg or matched placebo once daily, in 12-70 years old symptomatic SAR patients. All subjects assessed the severity of nasal (obstruction, rhinorrhoea, itching, and sneezing) and nonnasal (ocular itching, tearing, ocular redness, itching of ears and/or palate) symptoms on a predetermined scale to provide a total symptom score (TSS), composed of nasal and nonnasal symptom scores (NSS and NNSS, respectively). The primary efficacy measure was the area under the curve (AUC) for the TSS over the entire treatment period. RESULTS: Bilastine 20 mg significantly reduced the AUC of TSS to a greater degree from baseline compared to placebo (98.4 with bilastine vs 118.4 with placebo; P < 0.001), but not compared to desloratadine 5 mg (100.5). Bilastine 20 mg was not different from desloratadine 5 mg but significantly more effective than placebo in improving the NSS, NNSS, and rhinitis-associated discomfort scores (P < 0.05), and rhinoconjunctivitis quality of life questionnaire total (P < 0.005) and four out of seven individual domain (P < 0.05) scores. The incidence of treatment emergent adverse events was similar for bilastine (20.6%), desloratadine (19.8%), and placebo (18.8%). CONCLUSION: Bilastine 20 mg once daily was efficacious, safe and not different from desloratadine 5 mg once daily in the treatment of SAR symptoms.

Small-Signal Performance and Modeling of sub-50nm nMOSFETs with f above 460-GHz.

We have fabricated and tested the performance of sub-50nm gate nMOSFETs to assess their suitability for mixed signal applications in the super high frequency (SHF) band, i.e. 3-30GHz. For a 30nm×40 µm×2 device, we found f(T) =465GHz at V(ds)=2V, V(g)=0.67V, which is the highest cut-off frequency reported for a MOSFET produced on bulk silicon substrate so far. However, our measurements of f(max) and noise figure indicate that parasitics impose limitations on SHF operation. We also present a high-frequency ac model appropriate to sub-50nm gate length nanotransistors, which incorporates the effects of the parasitics. The model accurately accounts for measurements of the S and Y parameters in the frequency range from 1 to 50GHz.

Centre-specific multichannel electrogastrographic testing utilizing wavelet-based decomposition.

Although the principles of electrogastrography (EGG) have been known for years, the clinical utility of EGG has not been clearly demonstrated, and EGG recording and analysis techniques have not been fully standardized. The aim of this study was to develop a multichannel EGG technique for detecting abnormal gastric motility using an EGG database specifically designed for a particular testing centre, maximizing the sensitivity and the specificity of the test. Eight healthy volunteers formed a reference group to which 4 study groups (17 gastro-oesophageal reflux disease (GORD) patients, 7 functional dyspepsia patients, 8 post-fundoplication patients and 12 healthy volunteers) were compared. Eight-channel EGG was recorded in the postprandial and fasting states for 30 min each. The recorded signals were wavelet compressed and the resulting error (per cent root mean square difference (PRD)) after the compression was utilized to compare the study groups to the reference group. A threshold in the number of channels with significantly different PRD values was introduced. Sensitivity (SE), specificity (SP) and correct classification rate (CC) of the test in recognizing each clinical condition in the study groups for several channel thresholds and compressions were calculated, and were maximized. Increasing the compression and channel threshold levels improved the specificity, but decreased the sensitivity of the multichannel EGG test. An optimal combination region was identified based on a centre-specific adjustment of the channel threshold and the wavelet compression. The achieved maximum sensitivity, specificity and correct classification for this region in our test centre were as follows: GORD--SE 82.4%, SP 83.3%, CC 82.8%; functional dyspepsia--SE 100%, SP 75%, CC 84.2%; post-fundoplication--SE 75.0%, SP 83.3%, CC 80.0%. The utilization of a wavelet-based decomposition technique to process multichannel EGG signals can be a very effective method for enhancing the clinical utility of EGG, provided it is specifically developed for a given testing centre.

In vivo transfection and/or cross-priming of dendritic cells following DNA and adenoviral immunizations for immunotherapy of cancer--changes in peripheral mononuclear subsets and intracellular IL-4 and IFN-gamma lymphokine profile.

In order to provoke an immune response, a tumor vaccine should not only maximize antigen-specific signals, but should also provide the necessary "co-stimulatory" environment. One approach is to genetically manipulate tumor cells to either secrete lymphokines (GM-CSF, IL-12, IL-15) or express membrane bound molecules (CD80, CD86). Furthermore, patient dendritic cells can be loaded with tumor-associated antigens or peptides derived from them and used for immunotherapy. Genetic modification of dendritic cells can also lead to presentation of tumor-associated antigens. Transfection of dendritic cells with DNA encoding for such antigens can be done in vitro, but transfection efficiency has been uniformly low. Alternatively, dendritic cells can also be modulated directly in vivo either by "naked" DNA immunization or by injecting replication-deficient viral vectors that carry the tumor specific DNA. Naked DNA immunization offers several potential advantages over viral mediated transduction. Among these are the inexpensive production and the inherent safety of plasmid vectors, as well as the lack of immune responses against the carrier. The use of viral vectors enhances the immunogenicity of the vaccine due to the adjuvant properties of some of the viral products. Recent studies have suggested that the best strategy for achieving an intense immune response may be priming with naked DNA followed by boosting with a viral vector. We have successfully completed a phase I and phase II clinical trials on immunotherapy of prostate cancer using naked DNA and adenoviral immunizations against the prostate-specific membrane antigen (PSMA) and phase I clinical trial on colorectal cancer using naked DNA immunization against the carcinoembryonic antigen (CEA). The vaccination was tolerated well and no side effects have been observed so far. The therapy has proven to be effective in a number of patients treated solely by immunizations. The success of the treatment clearly depends on the stage of the disease proving to be most efficient in patients with minimal disease or no metastases. A panel of changes in the phenotype of peripheral blood lymphocytes and the expression of intra-T-cell lymphokines seems to correlate with clinical improvement.

Argentophilic structures of the miracidium of Echinostoma trivolvis (Cort, 1914) (Trematoda: Echinostomatidae).

Argentophilic structures of the miracidium of Echinostoma trivolvis were described from 80 specimens reared from material originally collected in eastern Pennsylvania, U.S.A. Miracidia were impregnated with 0.5% aqueous silver nitrate solution. The miracidium has 18 epidermal plates arranged in 4 rows of 6 + 6 + 4 + 2 = 18. Up to 20 papillalike structures on the terebratorium were arranged along 3 axes and in 5 groups. A single papilla was located at the base of each of the 6 epidermal plates of the first row. The eyespots were located posterior to the first row of plates and 2 excretory pores were located anterior to the last row of plates.

Argentophilic structures of the miracidia and cercariae of Philophthalmus distomatosa n. comb. from Israel.

The morphology and patterns of distribution of the argentophilic structures of miracidia and cercariae of Philophthalmus distomatosa n. comb. are described. The epidermal plate arrangement of the vast majority (94.2%) of miracidia studied conformed to the formula 6:8:4:2 = 20. The rest (5.8%) displayed the following patterns of arrangement of epidermal plates: 6:7:4:2 = 19; 6:6:4:2 = 18; and 6:4:4:2 = 16. Twenty papillalike structures were observed on the terebratorium. They were arranged along 1 axis, in 3 groups. Most commonly, 16 papillae were present on the body, located between epidermal plates of the first and second rows. The eye spots were located dorsally, near interepidermal space S1. The numbers, arrangements, and locations of the excretory pores varied. Patterns of distribution of the tegumentary papillae of P. distomatosa n. comb. cercariae are given, including those of the cephalic regions, periacetabular region, and tail. Argentophilic structures of the mentioned larval stages and of other parameters clearly distinguishing between the presently described species and those of P. lucipetus from Israel are summarized. On the basis of comparison of the presently described larval stages and those of other Melanoides tuberculata-associated larval stages of Philophthalmus in Israel and Jordan, the possibility exists that a third species occurs in Israel.

Argentophilic structures of miracidia and cercariae of Philophthalmus lucipetus (Philophthalmidae: Trematoda) from Israel.

Argentophilic structures of Philophthalmus lucipetus miracidia and cercariae from Israel are described. Eighty-four of 87 miracidia examined displayed an epidermal plate arrangement of 6:8:4:2 = 20, similar to other Philophthalmus species. Twenty papilla-like structures are arranged on the terebratorium in 3 groups, along 1 axis. Sixteen body papillae are located at the bases of epidermal plates of row 1. Eyespots are mediodorsal, between rows 1 and 2. Excretory pores are lateral, between rows 2 and 3. Features common to Israeli and Bulgarian isolates, differentiating them from other species, include the presence of 16 body papillae as opposed to 10 in other species, and a maximum of 20 papillae on the terebratorium as opposed to 19 in the others. About 3% of the miracidia displayed different plate arrangements. Among the argentophilic structures of P. lucipetus cercariae, the Israeli and Bulgarian P. lucipetus show a common pattern of 2-4 excretory pores in the tail, but arrangement of cephalic CI3 and CI5 papillae in the 2 isolates is insufficiently unequivocal for species determination. The data presented show that miracidial characteristics, rather than those of cercariae, aid in determining the species of philophthalmids. They also support former evidence attesting to the identity of the Bulgarian and Israeli species.

Wavelet analysis in a canine model of gastric electrical uncoupling.

Abnormal gastric motility function could be related to gastric electrical uncoupling, the lack of electrical, and respectively mechanical, synchronization in different regions of the stomach. Therefore, non-invasive detection of the onset of gastric electrical uncoupling can be important for diagnosing associated gastric motility disorders. The aim of this study is to provide a wavelet-based analysis of electrogastrograms (EGG, the cutaneous recordings of gastric electric activity), to detect gastric electric uncoupling. Eight-channel EGG recordings were acquired from 16 dogs in basal state and after each of two circular gastric myotomies. These myotomies simulated mild and severe gastric electrical uncoupling, while keeping the separated gastric sections electrophysiologically active by preserving their blood supply. After visual inspection, manually selected 10 min EGG segments were submitted to wavelet analysis. Quantitative methodology to choose an optimal wavelet was derived. This 'matching' wavelet was determined using the Pollen parametrization for 6-tap wavelet filters and error minimization criteria. After a wavelet-based compression, the distortion of the approximated EGG signals was computed. Statistical analysis on the distortion values allowed us to significantly (p < 0.05) distinguish basal state from mild and severe gastric electrical uncoupling groups in particular EGG channels.

Chaetotaxy of cercariae of Opisthioglyphe ranae (Frölich, 1791) (Trematoda: Plagiorchidae).

A detailed observation of the sensory apparatus of Opisthioglyphe ranae (Frölich, 1791) cercariae was carried out. The species was determined on the basis of an experimental study of the life cycle and morphology of sporocysts, cercariae, metacercariae, and adults. In contrast to other species of the family Plagiorchidae, no papillae were present in the positions CId1, CId2, CII0, CII3 and CII4. Papillae with markedly ventral situation on the postacetabular zone were found very rarely. Some of the cercariae possessed ventral papillae variously distributed in the preacetabular zone. A comparative analysis of the chaetotaxy revealed that the cercaria studied by us was very similar to Cercaria 4 of Richard, 1971, with the exception of the number of acetabular papillae and some groups of ventral papillae. Compared to the cercaria of O. ranae studied by Dobrovolskiy (1965). AID papillae and a part of ventral papillae were distributed differently. The chaetotaxy was identical with that of experimentally obtained cercariae of O. ranae from L. stagnalis and of cercariae of the same species obtained from Bulgaria.

An adequate kinetic model of photochemical aerosol formation in Titan's atmosphere.

The photochemistry of hydrocarbons in Titan's atmosphere is modeled by a comprehensive kinetic scheme, containing 732 elementary reactions and 147 species up to C60. Four groups of the hydrocarbons are considered: Polyacetylenes (PA), Polyvinyles (PV), Vinylacetylenes (VA) and Allenes (Polyenes).

Argentophilic structures of the miracidium of Echinochasmus perfoliatus (Trematoda: Echinostomatidae).

Argentophilic structures of the miracidium of Echinochasmus perfoliatus were described from material collected in the vicinity of Vladivostok, Far East of Russia. Impregnated with 0.5% solution of AgNO3 miracidium showed 21 epidermal plates arranged in four rows: 6 + 9 + 4 + 2. Up to 23 papilla-like structures on the terebratorium were arranged along three axes and in four groups. A single papilla was located at the base of each of ventral and dorsal epidermal plates of the first row. Two papillae were located at the base of each of lateral epidermal plates of the first row. The eyespots were located posterior to the first row of plates. Two excretory pores were located anterior to the last row of plates. The results obtained were compared with the argentophilic structures of closely related species of the genus Echinochasmus.

Is there an alternative approach to abdominoperineal resection for the treatment of very low lying rectal cancer? Five-year results.

PURPOSE: To investigate whether sphincter-saving surgery combined with preoperative radiotherapy and postoperative adjuvant chemotherapy can compare successfully with abdominoperineal resection in the treatment of very low lying rectal cancer. PATIENTS AND METHODS: Two groups of patients were studied. Group I included 65 patients (T2-3 N0-2 M0) with very low lying rectal cancer treated since 1995 by a sphincter- saving surgical procedure. All of them received preoperatively external radiotherapy and postoperatively adjuvant chemotherapy with 5-fluorouracil (5-FU) and folinic acid. This group was prospectively evaluated. Group II included 122 patients with the same tumor stage and location as Group I, who were treated by abdominoperineal resection and were retrospectively evaluated. The rate of local recurrence was compared between the two groups. RESULTS: In Group I patients the local recurrence rate was 13.84% (9 patients) for a period ranging from 6 months to the end of the second year after the operation. This group of patients were followed up to 60 months after the initial treatment. The local recurrence rate in Group II patients was 17.21% (21 patients; p >0.05). CONCLUSION: We consider that sphincter-preserving surgery combined with preoperative radiotherapy and postoperative adjuvant chemotherapy represents a successful alternative to abdominoperineal resection of very low lying rectal adenocarcinoma.

A case of exocrine-endocrine neoplasm of the pancreas in a patient with ulcerative colitis with literature review.

Until now only Japanese authors have reported 4 cases of pancreatic neoplasm associated with ulcerative colitis (UC). We report on a case of a 44-year-old woman who was operated on for complicated UC and an exocrine-endocrine neoplasm of the pancreas, where the endocrine component was presented by pancreatic polypeptide (PP)-producing cells. By means of molecular genetics methods we found microsatellite instability (MSI) in the markers D18S35, FGA and p53 in the colonic lining, and loss of heterozygosity (LOH) in the p53 marker in the pancreatic tumor. A literature review concerning the coexistence of these two conditions showed that PP is involved in the pathogenesis of the UC and that UC increases the risk of development of extracolonic neoplasms.