Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases.

Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.

Hereditary angioedema: a prospective study of a Brazilian single-center cohort.

BACKGROUND: Hereditary angioedema (HAE) is rare and still underdiagnosed in some countries. We aimed to describe HAE diagnosis and sociodemographic and clinical features in patients with HAE due to C1 inhibitor deficiency (HAE-C1-INH) followed up at a tertiary-level center in Rio de Janeiro, Brazil. METHODS: A descriptive, cross-sectional study with prospective data collection of 138 Brazilian patients with HAE was performed. From the total, 107 patients with HAE-C1-INH were selected. Data were assessed based on a specific questionnaire. RESULTS: One hundred and five patients had HAE type I (76.1%), and two had HAE type II (1.4%). Seventy-two were female (67.3%), and 35 were male  (32.7%). Mean age was 38.0 ± 15.0 years (range: 12-73 years). A long delay (17.7 ± 12.6 years) until diagnosis was observed. About 86.9% had a familial history. Cutaneous edema (95.8%), abdominal pain (88.5%), and laryngeal edema (65.6%) were the most frequent symptoms. Triggering factors (95.8%) and prodromal symptoms (47.9%) were referred. Attacks were severe in 55.1% and moderate in 24.3%. Eleven (10.3%) were asymptomatic. HAE attacks were more frequent and severe (P = 0.021) in females. CONCLUSIONS: We observed a considerable delay in diagnosis, even with familial history. The severity of HAE attacks, especially in females, highlights the need for an awareness of disease by gynecologists and obstetricians. Screening of familial members, including asymptomatic individuals, is critical for earlier diagnosis. Regional evaluation of patient profiles can be helpful to draw more attention about HAE and to improve quality of life.

Comparison between direct contact and extract exposure methods for PFO cytotoxicity evaluation.

A series of recent acute blindness cases following non-complicated retinal detachment surgery caused the release of several health alerts in Spain. The blindness was attributed to certain lots of perfluoro-octane (PFO; a volatile and transient medical device). Similar cases have been reported in other countries. This has raised questions regarding the validity of cytotoxicity test methods currently used to certify the safety of PFO lots. The tests were performed according to the International Organization for Standardization (ISO) norms, using the extract dilution method or the indirect contact method as applied to L929 cells, a line derived from mouse fibroblasts. The limitations of those methods have been resolved in this study by proposing a new cytotoxicity test method for volatile substances. The new method requires direct contact of the tested substance with cells that are similar to those exposed to the substance in the clinical setting. This approach includes a few new technical steps that are crucial for detecting cytotoxicity. Our new method detected toxic PFO lots that corresponded to the lots producing clinical blindness, which previous methods failed to detect. The study suggests applying this new method to avoid occurrence of such cases of blindness.

ACUTE RETINAL DAMAGE AFTER USING A TOXIC PERFLUORO-OCTANE FOR VITREO-RETINAL SURGERY.

PURPOSE: To describe a series of retinal acute toxicity cases with severe visual loss after intraocular use of a toxic perfluoro-octane (PFO). The clinical presentation is described, and the likely causes are analyzed. New biological methods for testing safety of intraocular medical devices are proposed. METHODS: Information regarding a series of eyes suffering acute severe events after intraocular use of a toxic PFO was analyzed. Four types of spectroscopy, nuclear magnetic resonance, and chromatography were used to identify the potential PFO contaminants. Cultures of human retinal pigment epithelial cells (ARPE-19) and porcine neuroretina were used to quantify the toxicity of the suspect PFO lots. RESULTS: Of 117 cases of intraocular toxicity, 96 were considered clearly related to the use of PFO. Fifty-three cases had no light perception, and 97 had no measurable visual acuity. Retinal necrosis (n = 38) and vascular occlusion (n = 33) were the most characteristic findings. Two hydroxyl compounds, perfluorooctanoic acid and dodecafluoro-1-heptanol, and benzene derivatives were identified as the suspected toxic agents. While existing toxicity testing failed, we proposed new tests that demonstrated clear toxicity. CONCLUSION: Protocols to determine cytotoxicity of intraocular medical devices should be revised to assure safety. Acute toxic events should be reported to health authorities and scientific media.

Current focus of stem cell application in retinal repair.

The relevance of retinal diseases, both in society's economy and in the quality of people's life who suffer with them, has made stem cell therapy an interesting topic for research. Embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adipose derived mesenchymal stem cells (ADMSCs) are the focus in current endeavors as a source of different retinal cells, such as photoreceptors and retinal pigment epithelial cells. The aim is to apply them for cell replacement as an option for treating retinal diseases which so far are untreatable in their advanced stage. ESCs, despite the great potential for differentiation, have the dangerous risk of teratoma formation as well as ethical issues, which must be resolved before starting a clinical trial. iPSCs, like ESCs, are able to differentiate in to several types of retinal cells. However, the process to get them for personalized cell therapy has a high cost in terms of time and money. Researchers are working to resolve this since iPSCs seem to be a realistic option for treating retinal diseases. ADMSCs have the advantage that the procedures to obtain them are easier. Despite advancements in stem cell application, there are still several challenges that need to be overcome before transferring the research results to clinical application. This paper reviews recent research achievements of the applications of these three types of stem cells as well as clinical trials currently based on them.

Efficacy of Different Treatment Alternatives for Obesity Hypoventilation Syndrome. Pickwick Study.

RATIONALE: The incidence of obesity hypoventilation syndrome (OHS) may be increasing in parallel with the present obesity epidemic. Despite extensive noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) use in patients with OHS, information regarding efficacy is limited. OBJECTIVES: We performed a large, multicenter randomized controlled study to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) using daytime PaCO2 as the main outcome measure. METHODS: Sequentially screened patients with OHS with severe sleep apnea were randomized into the above-mentioned groups for a 2-month follow up. Arterial blood gas parameters, clinical symptoms, health-related quality-of-life assessments, polysomnography, spirometry, 6-minute-walk distance, dropouts, compliance, and side effects were evaluated. Statistical analysis was performed using intention-to-treat analysis, although adjustments for CPAP and NIV compliance were also analyzed. MEASUREMENTS AND MAIN RESULTS: In total, 351 patients were selected, and 221 were randomized. NIV yielded the greatest improvement in PaCO2 and bicarbonate, with significant differences relative to the control group but not relative to the CPAP group. In the CPAP group, PaCO2 improvement was significantly different than in the control group only after CPAP compliance adjustment. Additionally, clinical symptoms and polysomnographic parameters improved similarly with NIV and CPAP relative to the control. However, some health-related quality-of-life assessments, the spirometry, and 6-minute-walk distance results improved more with NIV than with CPAP. Dropouts were similar between groups, and compliance and secondary effects were similar between NIV and CPAP. CONCLUSIONS: NIV and CPAP were more effective than lifestyle modification in improving clinical symptoms and polysomnographic parameters, although NIV yielded better respiratory functional improvements than did CPAP. Long-term studies must demonstrate whether this functional improvement has relevant implications. Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

Statistical and nonlinear analysis of oximetry from respiratory polygraphy to assist in the diagnosis of Sleep Apnea in children.

Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a sleep related breathing disorder that has important consequences in the health and development of infants and young children. To enhance the early detection of OSAHS, we propose a methodology based on automated analysis of nocturnal blood oxygen saturation (SpO(2)) from respiratory polygraphy (RP) at home. A database composed of 50 SpO(2) recordings was analyzed. Three signal processing stages were carried out: (i) feature extraction, where statistical features and nonlinear measures were computed and combined with conventional oximetric indexes, (ii) feature selection using genetic algorithms (GAs), and (iii) feature classification through logistic regression (LR). Leave-one-out cross-validation (loo-cv) was applied to assess diagnostic performance. The proposed method reached 80.8% sensitivity, 79.2% specificity, 80.0% accuracy and 0.93 area under the ROC curve (AROC), which improved the performance of single conventional indexes. Our results suggest that automated analysis of SpO(2) recordings from at-home RP provides essential and complementary information to assist in OSAHS diagnosis in children.

A controlled trial of noninvasive ventilation for chronic obstructive pulmonary disease exacerbations.

PURPOSE: This prospective, multicenter, double-blind, placebo-controlled study tested the hypothesis that noninvasive positive pressure ventilation reduces the need for endotracheal intubation in patients hospitalized in a pulmonary ward because of acute exacerbation of chronic obstructive pulmonary disease. MATERIALS AND METHODS: Seventy-five consecutive patients with exacerbation (pH, 7.31 +/- 0.02; Pao(2), 45 +/- 9 mm Hg; Paco(2), 69 +/- 13 mm Hg) were randomly assigned to receive noninvasive ventilation or sham noninvasive ventilation during the first 3 days of hospitalization on top of standard medical treatment. RESULTS: The need for intubation (according to predefined criteria) was lower in the noninvasive ventilation group (13.5% vs 34%, P < .01); in 31 patients with pH not exceeding 7.30, these percentages were 22% and 77%, respectively (P < .001). Arterial pH and Paco(2) improved in both groups, but changes were enhanced by noninvasive ventilation. Length of stay was lower in the noninvasive ventilation group (10 +/- 5 vs 12 +/- 6 days, P = .06). In-hospital mortality was similar in both groups. CONCLUSIONS: These results demonstrate that noninvasive positive pressure ventilation, in a pulmonary ward, reduces the need for endotracheal intubation, particularly in the more severe patients, and leads to a faster recovery in patients with acute exacerbation of chronic obstructive pulmonary disease.