Incorporation of Cró thermal water in a dermocosmetic formulation: cytotoxicity effects, characterization and stability studies and efficacy evaluation.

OBJECTIVE: Development of cosmetic formulations to provide a controlled release of hydrophilic active compounds from mineral medicinal waters constitutes an attractive challenge. The objective of this study was the development and the characterization of a dermocosmetic gel formulation with Cró thermal water, from Beira Interior of Portugal, as a major functional ingredient. METHODS: Concentrations of mineral chemical elements of Cró thermal water were previously determined by inductively coupled plasma-optical emission spectrometry or mass spectrometry and cytotoxicity assays using thermal water were carried out on normal human dermal fibroblasts (NHDF) cells. Then, the Cró thermal water was included (more than 90%) in a developed gel formulation that was characterized through rheological and texture analysis and submitted to stability assays during 30 days. The effects on the skin volunteers, namely skin pH, the degree of hydration, transepidermal water loss and skin relief, were evaluated through non-invasive biometric techniques. A gel formulation including purified water was used as a control. RESULTS: Cró thermal water is rich on several chemical elements in particular sodium, silica, potassium and calcium besides some trace elements, with important functions for the skin. NHDF cells adhered and proliferated in the presence of thermal water confirming the biocompatibility of the major component of the gel formulation. The developed gel formulation based on thermal water resulted in an improvement of textural parameters, comparing with the purified water-based one. Significant improvements in the cutaneous biometric parameters (degree of hydration, transepidermal water loss and skin relief) of volunteers were also registered for the gel formulation containing thermal water. CONCLUSION: This study demonstrated for the first time the potential benefits of Cró thermal water in a gel formulation to be used in cosmetic and dermatological applications.

OBJECTIF: Le développement de formulations cosmétiques permettant une libération contrôlée des substances actives hydrophiles à partir d'eaux médicinales minérales constitue un défi attractif. L'objectif de cette étude était le développement et la caractérisation d'une formulation de gel dermocosmétique avec l'eau thermale de Cró, de Beira Interior au Portugal, comme ingrédient fonctionnel majeur. MÉTHODES: Les concentrations en éléments chimiques minéraux de l'eau thermale de Cró ont étés préalablement déterminées par spectrométrie d'émission optique avec plasma couplé par induction ou spectrométrie de masse et des essais de cytotoxicité utilisant de l'eau thermale ont été réalisés sur des cellules de fibroblastes dermiques humains normaux (NHDF). Ensuite, l'eau thermale de Cró a été incluse (plus de 90%) dans une formulation de gel développée qui a été caractérisée par analyse rhéologique et texture et soumise à des tests de stabilité pendant 30 jours. Les effets sur la la peau des volontaires, à savoir le pH de la peau, le degré d'hydratation, la perte d'eau transépidermique et le relief cutané, ont été évalués à l'aide de techniques biométriques non invasives. Une formulation de gel comprenant de l'eau purifiée a été utilisée comme témoin. RÉSULTATS: L'eau thermale de Cró est riche en plusieurs éléments chimiques, en particulier le sodium, la silice, le potassium et le calcium, en plus de certains oligo-éléments, avec des fonctions importantes pour la peau. Les cellules NHDF ont adhéré et ont proliféré en présence d'eau thermale, confirmant la biocompatibilité du composant principal de la formulation du gel. La formulation de gel développée à base d'eau thermale a permis une amélioration des paramètres de texture comparée à celle à base d'eau purifiée. Des améliorations significatives des paramètres biométriques cutanés (degré d'hydratation, perte en eau transépidermique et relief cutané) des volontaires ont également été enregistrées avec la formulation en gel contenant de l'eau thermale. CONCLUSION: Cette étude a démontré pour la première fois les avantages potentiels de l'eau thermale de Cró dans une formulation de gel destinée aux applications cosmétiques et dermatologiques.

A systematic analysis of orphan cyclins reveals CNTD2 as a new oncogenic driver in lung cancer.

As lung cancer has increased to the most common cause of cancer death worldwide, prognostic biomarkers and effective targeted treatments remain lacking despite advances based on patients' stratification. Multiple core cyclins, best known as drivers of cell proliferation, are commonly deregulated in lung cancer where they may serve as oncogenes. The recent expansion of the cyclin family raises the question whether new members might play oncogenic roles as well. Here, we investigated the protein levels of eight atypical cyclins in lung cancer cell lines and formalin-fixed and paraffin-embedded (FFPE) human tumors, as well as their functional role in lung cancer cells. Of the new cyclins evaluated, CNTD2 was significantly overexpressed in lung cancer compared to adjacent normal tissue, and exhibited a predominant nuclear location. CNTD2 overexpression increased lung cancer cell viability, Ki-67 intensity and clonogenicity and promoted lung cancer cell migration. Accordingly, CNTD2 enhanced tumor growth in vivo on A549 xenograft models. Finally, the analysis of gene expression data revealed a high correlation between elevated levels of CNTD2 and decreased overall survival in lung cancer patients. Our results reveal CNTD2 as a new oncogenic driver in lung cancer, suggesting value as a prognostic biomarker and therapeutic target in this disease.

Physicochemical fingerprinting of thermal waters of Beira Interior region of Portugal.

Mineral natural waters and spas have been used for therapeutic purposes for centuries, with Portugal being a very rich country in thermal waters and spas that are mainly distributed by northern and central regions where Beira Interior region is located. The use of thermal waters for therapeutic purposes has always been aroused a continuous interest, being dependent on physicochemical fingerprinting of this type of waters the indication for a treatment in a specific pathological condition. In the present work, besides a literature review about the physicochemical composition of the thermal waters of the Beira Interior region and its therapeutic indications, it was carried out an exhaustive multivariate analysis-principal component analysis and cluster analysis-to assess the correlation between different physicochemical parameters and the therapeutic indications claims described for these spas and thermal waters. These statistical methods used for data analysis enables classification of thermal waters compositions into different groups, regarding to the different variable selected, making possible an interpretation of variables affecting water compositions. Actually, Monfortinho and Longroiva are clearly quite different of the others, and Cró and Fonte Santa de Almeida appear together in all analysis, suggesting a strong resemblance between these waters. Thereafter, the results obtained allow us to demonstrate the role of major components of the studied thermal waters on a particular therapeutic purpose/indication and hence based on compositional and physicochemical properties partially explain their therapeutic qualities and beneficial effects on human health. This classification agreed with the results obtained for the therapeutic indications approved by the Portuguese National Health Authority and proved to be a valuable tool for the regional typology of mineral medicinal waters, constituting an important guide of the therapeutic armamentarium for well and specific-oriented pathological disturbs.

New drug-eluting lenses to be applied as bandages after keratoprosthesis implantation.

Corneal tissue is the most commonly transplanted tissue worldwide. This work aimed to develop a new drug-eluting contact lens that may be used as a bandage after keratoprosthesis. During this work, films were produced using poly(vinyl alcohol) (PVA) and chitosan (CS) crosslinked with glyoxal (GL). Vancomycin chlorhydrate (VA) was impregnated in these systems by soaking. Attenuated total reflectance - Fourier transform infrared spectroscopy was used to confirm crosslinking. The cytotoxic and drug release profile, hydrophilicity, thermal and biodegradation as well as swelling capacity of the samples were assessed through in vitro studies. PVA and PVA/CS films were obtained by crosslinking with GL. The films were transparent, flexible with smooth surfaces, hydrophilic and able to load and release vancomycin for more than 8h. Biodegradation in artificial lachrymal fluid (ALF) with lysozyme at 37°C showed that mass loss was higher for the samples containing CS. Also, the samples prepared with CS showed the formation of pores which were visualized by SEM. All samples revealed a biocompatible character after 24h in contact with cornea endothelial cells. As a general conclusion it was possible to determine that the 70PVA/30CS film showed to combine the necessary features to prepare vancomycin-eluting contact lenses to prevent inflammation after corneal substitution.

Dextran-based hydrogel containing chitosan microparticles loaded with growth factors to be used in wound healing.

Skin injuries are traumatic events, which are seldom accompanied by complete structural and functional restoration of the original tissue. Different strategies have been developed in order to make the wound healing process faster and less painful. In the present study in vitro and in vivo assays were carried out to evaluate the applicability of a dextran hydrogel loaded with chitosan microparticles containing epidermal and vascular endothelial growth factors, for the improvement of the wound healing process. The carriers' morphology was characterized by scanning electron microscopy. Their cytotoxicity profile and degradation by-products were evaluated through in vitro assays. In vivo experiments were also performed to evaluate their applicability for the treatment of skin burns. The wound healing process was monitored through macroscopic and histological analysis. The macroscopic analysis showed that the period for wound healing occurs in animals treated with microparticle loaded hydrogels containing growth factors that were considerably smaller than that of control groups. Moreover, the histological analysis revealed the absence of reactive or granulomatous inflammatory reaction in skin lesions. The results obtained both in vitro and in vivo disclosed that these systems and its degradation by-products are biocompatible, contributed to the re-establishment of skin architecture and can be used in a near future for the controlled delivery of other bioactive agents used in regenerative medicine.

Invasive fungal diseases in haematopoietic cell transplant recipients and in patients with acute myeloid leukaemia or myelodysplasia in Brazil.

Invasive fungal disease (IFD) shows distinct regional incidence patterns and epidemiological features depending on the geographic region. We conducted a prospective survey in eight centres in Brazil from May 2007 to July 2009. All haematopoietic cell transplant (HCT) recipients and patients with acute myeloid leukaemia (AML) or myelodysplasia (MDS) were followed from admission until 1 year (HCT) or end of consolidation therapy (AML/MDS). The 12-month cumulative incidence (CI) of proven or probable IFD was calculated, and curves were compared using the Grey test. Among 237 AML/MDS patients and 700 HCT recipients (378 allogeneic, 322 autologous), the 1-year CI of IFD in AML/MDS, allogeneic HCT and autologous HCT was 18.7%, 11.3% and 1.9% (p <0.001), respectively. Fusariosis (23 episodes), aspergillosis (20 episodes) and candidiasis (11 episodes) were the most frequent IFD. The 1-year CI of aspergillosis and fusariosis in AML/MDS, allogeneic HCT and autologous HCT were 13.4%, 2.3% and 0% (p <0.001), and 5.2%, 3.8% and 0.6% (p 0.01), respectively. The 6-week probability of survival was 53%, and was lower in cases of fusariosis (41%). We observed a high burden of IFD and a high incidence and mortality for fusariosis in this first multicentre epidemiological study of IFD in haematological patients in Brazil.

Hippocampal volume in borderline personality disorder with and without comorbid posttraumatic stress disorder: a meta-analysis.

BACKGROUND: Several studies have found a reduction in hippocampal volume in borderline personality disorder (BPD) patients. METHODS: In order to investigate the degree to which comorbid posttraumatic stress disorder (PTSD) could account for reduction in hippocampal volume in these patients, we conducted a systematic review and meta-analysis of studies that compared hippocampal volume in BPD patients with and without PTSD relative to healthy controls. RESULTS: Seven articles, involving 124 patients and 147 controls, were included. We found a statistically significant reduction for the left and right hippocampus. Data from the four studies that discriminated BPD patients with and without PTSD indicate that hippocampal volumes were reduced bilaterally in BPD patients with PTSD, relative to healthy controls, but that results were mixed for BPD patients without PTSD, relative to healthy controls. CONCLUSIONS: Results from this meta-analysis suggest that hippocampal volumes are reduced in patients with BPD, relative to healthy controls, but particularly in cases in which patients are diagnosed with comorbid PTSD.

Anti-Candida activity of a chitosan hydrogel: mechanism of action and cytotoxicity profile.

Candida spp. are common causative agents of mucocutaneous infections. New therapeutic antifungal drugs are needed to treat chronic disease as these are frequently clinically resistant to azols. Chitosan, among other possible vehicles for active compounds, shows an added value as it appears to have intrinsic antimicrobial properties. The aim of the present study was to evaluate the anti-Candida activity of a medium-molecular-weight chitosan hydrogel (CH), to clarify its possible mechanism of action and to evaluate its cytotoxicity on human fibroblasts. CH antifungal activity was assessed according to CLSI reference M27-A3 protocol; its mechanism of action was investigated by flow cytometry, and its cytotoxicity was studied by MTT assay. CH demonstrated a full inhibition of C. tropicalis, C. krusei, C. guilliermondii and C. parapsilosis growth while impairing C. albicans and C. glabrata viability. Flow cytometry tests showed that CH acts by inducing primary lesion of the cytoplasmic membrane. However, CH showed no cytotoxic effect upon human fibroblasts cells. Resistant strains will require new therapeutic approaches. Chitosan being a good carrier and having itself anti-Candida activity seems to be a promising vehicle to be used for the treatment of mucocutaneous candidosis.

Heart rate, heart rate variability, and blood pressure during perioperative stressor events in abdominal surgery.

STUDY OBJECTIVE: To define the behavior of power spectral heart rate variability (PSHR) during potentially stressful events in the perioperative period, and relate it to changes in blood pressure (BP) and heart rate (HR). DESIGN: Longitudinal clinical study. SETTING: Operating room and recovery suites of a large tertiary care referral center. PATIENTS: 26 ASA physical status I, II, and III patients undergoing elective abdominal surgery. INTERVENTIONS: Anesthesia was induced with thiopental sodium and fentanyl, and maintained with isoflurane/nitrous oxide (N2O)/relaxant or enflurane/N2O/relaxant. The trachea was intubated and intraabdominal surgery was performed. MEASUREMENTS AND MAIN RESULTS: Observations consisted of HR, noninvasive blood pressure, and PSHR. They were made before and after induction of anesthesia, tracheal intubation, and surgical incision, and during maximal surgical stimulation and skin closure. HR and mean arterial pressure (MAP) maxima were also recorded for one hour before and after emergence from anesthesia. PSHR was obtained using a special algorithm and data acquisition system for real time spectral analysis of the instantaneous HRversus time function. The HR power spectrum parameters analyzed were low-frequency (LFA; powerband = 0.04 to 0.10 Hz), respiratory-induced frequency (RFA; powerband = respiratory frequency +/- 0.06 Hz), and the ratio of LFA to RFA. With induction of anesthesia, only RFA power decreased significantly. LFA power reduction became significant only after intubation and continued so until after incision. Immediately after induction, the decline in RFA power (vs. preinduction) was more pronounced when compared with the decline in LFA power (76% vs. 34%; p = 0.01). Hence, the ratio LFA/RFA increased significantly after induction of anesthesia. It was significantly higher than at postintubation, preincision, or skin closure. A significant elevation in LFA, LFA/RFA ratio, and BP occurred with maximal abdominal surgical stimulation. Only preinduction LFA, RFA, and LFA/ RFA ratio were predictive of MAP changes with induction of anesthesia (p = 0.006). In 8 of the 15 patients who had MAP changes of at least 10 mmHg with induction, PSHR indices correctly predicted a change of this magnitude. Late intraoperative HR maxima were positively correlated with the change in HR and incision (r2 = 0.58; p < 0.01). The change in BP with incision was positively correlated with early postoperative HR maxima (r2 = 0.60; p < 0.01). CONCLUSIONS: On anesthetic induction, preoperative, but not intraoperative, spectral indices were predictive of BP changes. Power spectral analysis of HR may provide information about the autonomic state that is not evident from BP or HR. The HR power spectrum, in particular, indicated a striking autonomic imbalance immediately after the induction of anesthesia despite stable HR and BP. LFA and LFA/RFA ratio appeared to track sympathetic autonomic activation during abdominal surgical stimulation, but not during other perioperative stressor events.

Analysis of heart rate variability to assess hemodynamic alterations following induction of anesthesia.

Extensive changes in hemodynamics and cardiac rhythm during induction of anesthesia may be mediated by altered responses of the autonomic nervous system to anesthetic agents. Analysis of the power spectrum of the heart rate (PSHR) variability can supply information about the autonomic nervous system, and may be used in order to assess this phenomenon. In this study, 78 patients undergoing coronary artery bypass graft surgery were evaluated. Anesthesia was induced with sufentanil, and neuromuscular blockade with vecuronium, a combination that may cause a decrease in heart rate. Before and after induction of anesthesia, the heart rate (HR), blood pressure (BP), cardiac output (CO), cardiac index (CI), and PSHR components were recorded. PSHR was obtained by using a special algorithm and data acquisition system for real-time spectral analysis. A low-frequency component (LFa, mainly sympathetic) was analyzed from a band of 0.04 Hz to 0.1 Hz. A high-frequency component (RFa, parasympathetic) was identified by the respiratory frequency spectrum. Alterations of the heart rate after induction of anesthesia were defined in order to separate the patient population into two groups: slow heart rate (slow-HR) and stable heart rate (stable-HR). Slow heart rate was defined as a decrease in HR of more than 20% of the baseline value. The variables were analyzed and compared between the slow-HR (n = 25) and stable-HR (n = 53) groups in order to verify the possibility of identifying patients prone to hemodynamic changes after anesthesia induction. There were no differences in preoperative HR, BP, CO, or CI between groups before anesthesia induction.(ABSTRACT TRUNCATED AT 250 WORDS)

[Circulatory assist device in counterpulsation]. / Dispositivo de assistencia circulatoria em contrapulsacao.

PURPOSE: To test a circulatory assist device (CAD) developed in the University of São Paulo. Heart Institute, Bioengineering Division. It is a valveless chamber working through the counterpulsation principle, aiming at assistance to temporary the left ventricle. PATIENTS AND METHODS: The CAD consists of a rigid polycarbonate shell, which houses in its interior a polyurethane bag with a maximum volume of 110 cm3, driven alternately by pressure and vacuum from an external electropneumatic device synchronized with the ECG. The device worked for 300 hours in a test bench simulating the cardiovascular system in order to verify its resistance to wear and fatigue. The CAD was implanted near the aortic root of five dogs, in whom cardiac failure was induced through the use of propranolol and plasma expanders. The CAD was driven for five periods of 2 minutes separated by pauses of equal duration. The hemodynamic parameters were measured during the mentioned periods. RESULTS: "In vitro" testing resulted in no wear or fatigue. No leakage was observed. In the "in vivo" testing the averages obtained during the on and off periods of the device showed for the on periods; a) lowering of the systolic pressures of both the aorta (17.5%) and the left ventricle (LV) 15.1%), lowering of the final diastolic pressure of the LV (15.4%) and lowering of the diastolic pressure of the aorta (27.4%); b) increase in cardiac output (45.5%); c) increase of the endocardial viability ratio by 37.5%. CONCLUSION: The tested device represents a therapeutic option in cases of acute left ventricle failure, since with it an improved cardiac performance was measured and an increased coronary perfusion can be presumed.

Thermographic study of laser on arteries.

We analyzed the different effects of CO2, Nd-YAG, and argon lasers on aorta by using a Thermovision infrared system that registered the laser interaction with mongrel dog aorta. The images (thermograms) obtained were processed by a computer, which associated each area of the same temperature with a determined color. These thermograms were compared to histological analysis of the respective samples and the following results were obtained: (1) After the application of each laser there is very little propagation of heat in tissue. (2) The CO2 laser makes tissue reach 100 degrees C in less than 0.05 seconds. (3) The heat dissipation time was higher with the Nd-YAG laser due to higher scattering on tissue. Based on this research we conclude that the CO2 laser was best absorbed, the Nd-YAG laser penetrated human tissue with the best results, and the argon laser had the most significant backscattering.

Laser surgery in enclosed spaces: a review.

We describe the results of experiments carried out in the arteries of dogs, rabbits, guinea pigs, and humans, normal or atheromatous, calcified, or not, with the application of the argon and CO2 laser, in vitro or in vivo, directly or indirectly. Similarly, we present the results of laser effects when radiation is delivered through a special catheter with the purpose of producing aortic insufficiency, opening pulmonary valvular stenosis, desobstructing carotid and coronary obstruction induced in dogs as well as atheromatous obstructions in human amputated legs. Arterial wall perforation was present in 50% of all cases. We suggest four options in order to diminish this adverse result: (1) the use of coherent optical bundles which will allow the proper guiding of the laser beam, (2) the construction of a special catheter for proper handling of the laser-carrying fiber, (3) a combination of optical and computer programs which will aid to identify calcified regions, and (4) the use of dyes which will be strongly and selectively absorbed by the atheromas and which will thus allow their destruction at low laser powers.