Effectiveness and safety of Omalizumab in the treatment of chronic spontaneous urticaria: Systematic review and meta-analysis

Introduction: Chronic spontaneous urticaria (CSU) affects approximately 1% of the population, affecting both children and adults. Omalizumab (Oma) is a therapeutic option for patients with refractory forms of CSU. Objectives: To determine the effectiveness and safety of Oma in the treatment of CSU. Methods: Systematic review (Cochrane Collaboration methodology) of randomized clinical trials comparing Oma to placebo in refractory CSU treatment. The search is based on MEDLINE; EMBASE, Central Cochrane Library, and LILACS. The outcomes evaluated were: control of the illness, adverse events, and quality of life. Results: Of the 848 identified studies 13 were selected for further review and six were included in the meta-analysis. For all outcomes, high-quality evidence has confirmed that Oma is effective in the treatment of CSU. The dosage of 300mg/month achieved better results; namely a significant reduction in pruritus, papules, and urticaria activity, as well as an increase in the number of patients with a controlled condition, improvement in the quality of life and no differences in adverse events compared to the placebo. Conclusions: High-quality evidence demonstrates that Oma is effective and safe in the treatment of CSU refractory to therapy with H1 antihistamines

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Effectiveness and safety of Omalizumab in the treatment of chronic spontaneous urticaria: Systematic review and meta-analysis.

INTRODUCTION: Chronic spontaneous urticaria (CSU) affects approximately 1% of the population, affecting both children and adults. Omalizumab (Oma) is a therapeutic option for patients with refractory forms of CSU. OBJECTIVES: To determine the effectiveness and safety of Oma in the treatment of CSU. METHODS: Systematic review (Cochrane Collaboration methodology) of randomized clinical trials comparing Oma to placebo in refractory CSU treatment. The search is based on MEDLINE; EMBASE, Central Cochrane Library, and LILACS. The outcomes evaluated were: control of the illness, adverse events, and quality of life. RESULTS: Of the 848 identified studies 13 were selected for further review and six were included in the meta-analysis. For all outcomes, high-quality evidence has confirmed that Oma is effective in the treatment of CSU. The dosage of 300mg/month achieved better results; namely a significant reduction in pruritus, papules, and urticaria activity, as well as an increase in the number of patients with a controlled condition, improvement in the quality of life and no differences in adverse events compared to the placebo. CONCLUSIONS: High-quality evidence demonstrates that Oma is effective and safe in the treatment of CSU refractory to therapy with H1 antihistamines.

Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study.

The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42-75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1-6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1-98.3%), with a CR rate of 86.5% (95% CI 71.2-95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3-83.3%) and 88.9% (95% CI 73.1-95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.

Doctors’ awareness concerning primary immunodeficiencies in Brazil

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs

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Doctors' awareness concerning primary immunodeficiencies in Brazil.

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.

Superovulatory response in Japanese Black cows receiving a single subcutaneous porcine follicle-stimulating hormone treatment or six intramuscular treatments over three days.

To reduce labor for superovulation treatment by twice-daily intramuscular (im) administration of FSH for more than 3 to 4 days, we investigated the superovulatory responses of Japanese Black cows to porcine FSH (pFSH) used as a single subcutaneous (sc) administration at two different doses in two different volumes of saline. In experiment 1, 20 Armour units (AU) of pFSH dissolved in either 10 mL (treatment A; n = 14) or 50 mL (treatment B; n = 14) of saline was administered subcutaneously in the neck region. In experiment 2, 30 AU of pFSH dissolved in either 10 mL (treatment C; n = 15) or 50 mL (treatment D; n = 15) of saline was administered subcutaneously in the neck region. The control animals in experiment 1 (n = 14) and experiment 2 (n = 15) received 20 AU of pFSH administered intramuscularly twice daily in decreasing doses for more than 3 days. In experiment 1, mean (±SEM) numbers of CL (15.4 ± 2.5, 18.1 ± 3.4, and 17.2 ± 2.6), total number of ova and embryos (12.9 ± 1.4, 15.9 ± 3.5, and 16.2 ± 2.8), and transferable embryos (7.5 ± 2.0, 10.4 ± 2.8, and 8.0 ± 2.1) did not differ among treatments A, B, and control. In experiment 2, mean (±SEM) numbers of CL (20.5 ± 4.3, 20.4 ± 2.7, and 20.1 ± 3.4), total number of ova and embryos (21.7 ± 4.2, 17.3 ± 3.4, and 16.5 ± 3.2), and transferable embryos (8.1 ± 1.6, 9.3 ± 2.2, and 9.5 ± 1.9) did not differ among treatments C, D, and control. Although there were no differences in serum pFSH concentrations among the three treatments at each of the time points in experiment 1, in experiment 2, the serum pFSH concentration at 6 and 8 hours after pFSH administration in treatment C (3.1 ± 0.8, 2.7 ± 0.5 ng/mL, mean ± SEM) was significantly greater (P < 0.05) than in the control (0.7 ± 0.1, 1.1 ± 0.2 ng/mL). At 10 hours after administration, the pFSH concentration had decreased and there were no differences among the three treatments at subsequent time points. These results suggest that increasing the volume of saline or the dose of pFSH does not affect the absorption pattern of pFSH administered as a single sc administration. In conclusions, single sc administration of pFSH at a dose of 20 or 30 AU dissolved in 10 or 50 mL of saline is able to induce a superovulatory response comparable with that obtained by twice-daily im administration in Japanese Black cows.

First measurement of time evolution of electron temperature profiles with Nd:YAG Thomson scattering system on Heliotron J.

A Nd:YAG Thomson scattering system has been developed for Heliotron J. The system consists of two 550 mJ 50 Hz lasers, large collection optics, and 25 radial channel (∼1 cm spatial resolution) interference polychromators. This measurement system achieves a S/N ratio of ∼50 for low-density plasma (ne ∼ 0.5 × 10(19) m(-3)). A time evolution of electron temperature profiles was measured with this system for a high-intensity gas-puff (HIGP) fueling neutral-beam-injection plasma. The peripheral temperature of the higher-density phase after HIGP recovers to the low-density pre-HIGP level, suggesting that improving particle transport in the HIGP plasma may be possible.

Highly time-resolved evaluation technique of instantaneous amplitude and phase difference using analytic signals for multi-channel diagnostics.

A fluctuation analysis technique using analytic signals is proposed. Analytic signals are suitable to characterize a single mode with time-dependent amplitude and frequency, such as an MHD mode observed in fusion plasmas since the technique can evaluate amplitude and frequency at a specific moment without limitations of temporal and frequency resolutions, which is problematic in Fourier-based analyses. Moreover, a concept of instantaneous phase difference is newly introduced, and error of the evaluated phase difference and its error reduction techniques using conditional/ensemble averaging are discussed. These techniques are applied to experimental data of the beam emission spectroscopic measurement in the Heliotron J device, which demonstrates that the technique can describe nonlinear evolution of MHD instabilities. This technique is widely applicable to other diagnostics having necessity to evaluate phase difference.

A novel electron density reconstruction method for asymmetrical toroidal plasmas.

A novel reconstruction method is developed for acquiring the electron density profile from multi-channel interferometric measurements of strongly asymmetrical toroidal plasmas. It is based on a regularization technique, and a generalized cross-validation function is used to optimize the regularization parameter with the aid of singular value decomposition. The feasibility of method could be testified by simulated measurements based on a magnetic configuration of the flexible helical-axis heliotron device, Heliotron J, which has an asymmetrical poloidal cross section. And the successful reconstruction makes possible to construct a multi-channel Far-infrared laser interferometry on this device. The advantages of this method are demonstrated by comparison with a conventional method. The factors which may affect the accuracy of the results are investigated, and an error analysis is carried out. Based on the obtained results, the proposed method is highly promising for accurately reconstructing the electron density in the asymmetrical toroidal plasma.

Reticulon1-C modulates protein disulphide isomerase function.

Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status. By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S-nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function.

Density fluctuation measurements using beam emission spectroscopy on Heliotron J.

This paper describes the measurement of the density fluctuation using beam emission spectroscopy in Heliotron J, having the non-symmetrical helical-magnetic-axis configuration. In order to optimize the sightlines, the numerical calculations are carried out to estimate the spatial resolution and the observation location. When a tangential neutral beam is used as diagnostic one, suitable sightlines from the newly installed diagnostic port are selected whose spatial resolution Δρ is less than ± 0.07 over the entire plasma region. Modification of the interference filter and the detection systems enables us to measure the radial profile of the density fluctuation. Each of the three coherent modes due to the fast-ion-driven magnetohydrodynamic instabilities has different radial structure of the density fluctuation.

Ictal SPECT of thalamocortical coupling in a patient with frontal absence.

Petit mal absence has been reported with 3-Hz generalized spike-and-wave discharges induced by secondary bilateral synchrony. Absence seizure may be present in patients with frontal lobe epilepsy. The thalamic rhythmogenic mechanisms responsible for spike-and-wave discharges have been investigated, providing a better understanding of the underlying anatomico-physiological mechanisms. We report the thalamocortical coupling in a patient with frontal absence by performing synchronous ictal single photon emission computed tomography (SPECT) analysis. Ictal SPECT revealed thalamic hyperperfusion combined with ipsilateral frontal cortical hyperperfusion in the patient. Moreover, lateral indexes of cerebral blood flow in the frontal region and thalamus were higher than those from non-epileptic control subjects. Thalamocortical coupling was thus revealed by ictal SPECT. Frontal absences should be considered as a secondarily generalized epilepsy syndrome originating from the frontal regions. The thalamus may play a crucial role as a pacemaker of rhythmic electroencephalographic activities such as secondary bilateral synchronous discharges in patients with frontal absences.

Application of beam emission spectroscopy to NBI plasmas of Heliotron J.

This paper describes the application of the beam emission spectroscopy (BES) to Heliotron J, having the nonsymmetrical helical-magnetic-axis configuration. The spectral and spatial profile of the beam emission has been estimated by the numerical calculation taking the collisional excitation processes between plasmas (electrons/ions) and beam atoms. Two sets of the sightlines with good spatial resolution are presented. One is the optimized viewing chords which have 20 sightlines and observe the whole plasma region with the spatial resolution Δρ less than ±0.055 using the newly designed viewing port. The other is 15 sightlines from the present viewing port of Heliotron J for the preliminary measurement to discuss the feasibility of the density fluctuation measurement by BES. The beam emission has been measured by a monochromator with a CCD camera. A good consistency has been obtained between the spectral profiles of the beam emission measured by the monochromator and the beam emission spectrum deduced by the model calculation. An avalanche photodiode with an interference filter system was also used to evaluate the signal-to-noise (S/N) ratio of the beam emission in the present experimental setup. The modification of the optical system is being planned to improve the S/N ratio, which will enable us to estimate the density fluctuation in Heliotron J.

Multichannel Langmuir probe for turbulence study in Heliotron J.

New multichannel Langmuir probe system was developed and installed to Heliotron J. The objective of the new probe is to characterize basic turbulence property and the resulting transport in advanced helical configuration. The probe developed here consists of four sets of triple probe and one pin for floating potential measurement. Initial experiments in neutral beam heating plasma were conducted and fluctuation profile of radial and poloidal electric fields and Reynolds stress were estimated. For precise evaluation of the electric fields and Reynolds stress, a technique to compensate radial change of tilt angle between probe array and magnetic surface was proposed and applied to the initial results obtained in edge region of Heliotron J where the complicated magnetic structure exists.

Acetylation of RTN-1C regulates the induction of ER stress by the inhibition of HDAC activity in neuroectodermal tumors.

Reticulons are a family of highly conserved proteins, localized in the endoplasmic reticulum (ER) and involved in different cellular functions, such as intracellular membrane trafficking, apoptosis and nuclear envelope formation. The reticulon protein family consists of four members, but their specific functions are presently poorly understood. RTN-1C overexpression triggers apoptosis, regulating ER stress versus DNA damage-induced cell death in a mutually exclusive way. The different RTN isoforms share a C-terminal reticulon homology domain containing two hydrophobic segments and a 66-amino acid hydrophilic loop. In the C-terminal region of RTN-1C, a unique consensus sequence (GAKRH) has recently been identified, showing 100% identity with the DNA-binding domain of histone H4. In this study, we show that this sequence is essential for RTN-1C-mediated apoptosis. It is noteworthy that the lysine 204 present in this region is post-translationally modified by acetylation and that this event is associated with a significant decrease in histone deacetylase activity and contributes to RTN-1C binding to DNA. These data demonstrate a molecular mechanism by which RTN-1C controls apoptosis and indicate this protein to be a novel potential target for cancer therapy.

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin.

Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclin-treated tumor cells. Here, we investigated the role of cellular Ca(2+) homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca(2+) concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca(2+) depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca(2+), targeted expression of the ligand-binding domain of the IP(3) receptor and inhibition of the sarco-endoplasmic reticulum Ca(2+)-ATPase pump reduced endoplasmic reticulum Ca(2+) load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca(2+) levels control the exposure of CRT.

Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma.

The Birt-Hogg-Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP-sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline-mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real-time quantitative PCR (RQ-PCR) was very low. Renal tumour subtype/nephron segment-specific gene expression detected by RQ-PCR demonstrated that the tumour expressed relatively high amounts of alpha-methylacyl-CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11-beta-hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub-classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron-associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD-mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification.

Immunohistochemical characterization of hepatoblastomas in B6C3F1 mice treated with diethylnitrosamine and sodium phenobarbital.

Hepatoblastomas (HBs) were induced in B6C3F1 male mice by diethylnitrosamine (DEN) and sodium phenobarbital (PB). Six-week-old mice received a single intraperitoneal dose of DEN followed by a continuous treatment with PB in diet at a concentration of 0 (group 1) or 500 (group 2) ppm for 50 weeks. HBs were observed in 13 of 21 (62%) group 2 mice, with typical histologic features as reported previously, while no such tumors were observed in group 1. Seven of 13 (54%) HBs were found in and/or adjacent to hepatocellular adenomas (HCAs) or hepatocellular carcinomas (HCCs). Immunohistochemically, all HBs were positive for S-100 protein but negative for keratin, alpha-fetoprotein (AFP), albumin (ALB) and vimentin, while HCC cells occasionally reacted positively for AFP with a mosaic pattern. HCC and HCA cells were occasionally positive for ALB. Non-neoplastic hepatocytes and normal bile ducts were positively stained for ALB and keratin/S-100 protein, respectively. S-100 protein is known to be expressed in many mesenchymal tissues and neoplasms including neuroectodermal elements but negative in cells of the hepatic lineage. Thus, the present immunohistochemical results suggested that mesenchymal differentiation occurs in mouse HB cells as observed in human HBs, one of the most frequent infant liver tumors in humans. Although the susceptibility of mouse HBs to PB-promotion suggests a hepatocytic histogenesis, the present immunohistochemical results support the hypothesis that the mouse HB is derived from pluripotent endodermal stem-like cells.

Greater expression of transforming growth factor alpha and proliferating cell nuclear antigen staining in mouse hepatoblastomas than hepatocellular carcinomas induced by a diethylnitrosamine-sodium phenobarbital regimen.

Transforming growth factor alpha (TGF-alpha) is a potent stimulator of normal hepatocyte proliferation, considered to have relationship to the liver regeneration or carcinogenesis. In this study, we investigated immunohistochemically the association between expression of TGF-alpha and cell proliferation activity in mouse hepatoblastomas (HBs) and hepatocellular carcinomas (HCCs) induced in B6C3F1 mice by diethylnitrosamine and sodium phenobarbital. The TGF-alpha-positive rate in HBs (29.2%) was significantly higher than that in HCCs (12.7%). Likewise, the proliferating cell nuclear antigen-positive rate (22.2%) was higher than the HCC value (14.5%). On the individual data for both TGF-alpha and PCNA, most of the HBs showed higher positive rates than HCCs. In HBs, TGF-alpha was localized only in the nuclei, whereas some HCC cells stained positive both in their nuclei and cytoplasm (0.6%). These results suggest expression of TGF-alpha and its localization might be linked to cell proliferation and play a role in malignant progression of mouse HBs.