Thereza Quirico-Santos

Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas

BACKGROUND Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. Perillyl alcohol has shown to have both chemopreventive and chemotherapeutic activities in preclinical studies. The underlying action mechanism(s) of POH has yet to be delineated but may involve effects on the TGF-beta and/or the Ras signaling pathways. The intranasal delivery allows drugs that do not cross the BBB to enter the CNS; moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. METHODS We are conducting a phase I/II study to evaluate the antitumoral activity of POH intranasal delivery in a 4x daily schedule in patients with recurrent MG. The objective was to determine PFS at 6 months and the safety for POH in adult patients who failed conventional treatment. Assessments were performed every 27 days. Thirty-seven patients with progressive disease after prior surgery, radiotherapy, and at least temozolomide-based chemotherapy were enrolled, 29 of whom had GBM, 5 who had anaplastic astrocytoma, and 3 had AO. RESULTS One patient (3.4%) with GBM and 1 patient (33.3%) with AO achieved partial response; 13 patients (44.8%) with GBM, 3 patients (60%) with AA, and 1 (33.3%) with AO achieved stable disease; 15 (51.7%) patients with GBM, 2 (40%) patients with AA, and 1 (33.3%) with AO showed progressive disease. Progression-free survival (partial response and stable disease) was 48.2% for patients with GBM, 60% for patients with AA, and 66.6% for patients with AO. CONCLUSIONS There were no toxicity events. Perillyl alcohol is well tolerated and regression of tumor size in some patients is suggestive of antitumor activity. This work discusses POH intranasal delivery as a potential adjuvant therapeutic strategy for patients with malignant gliomas.

Clinic and radiological improvement of lipoid pneumonia with multiple bronchoalveolar lavages

To assess the potential role of multiple bronchoalveolar lavages (BALs) in the treatment of children with lipoid pneumonia (LP).

Pattern of metalloprotease activity and myofiber regeneration in skeletal muscles of mdx mice

Matrix metalloproteases (MMPs) are key regulatory molecules in the formation, remodeling, and degradation of extracellular matrix components in both physiological and pathological processes. Skeletal muscles of mdx dystrophic mice show distinct patterns of inflammation and regeneration, suggesting that factors within the microenvironment influence the adaptive responses of muscles with predominantly slow‐twitch or fast‐twitch fibers. This study aimed to verify the pattern of MMP activity in gastrocnemius, soleus, and diaphragm muscles and correlate it with the regenerative capability at distinct stages of the mdx myopathy. Marked inflammation and myonecrosis was associated with increased MMP‐9 activity and TNF‐α (tumor necrosis factor‐alpha) production, whereas muscle regeneration, evidenced by NCAM (neural cell adhesion molecule) expression and MMP‐2 activity, varied at different stages of the disease. Soleus muscles showed a high percentage of NCAM‐positive myofibers in the early stages (2 weeks) of the disease, but they appeared in the gastrocnemius muscles at 12 weeks and in the diaphragm at 24 weeks. Increased MMP‐2 activity in the diaphragm throughout all stages of the disease suggests important tissue remodeling, which is probably associated with persistent inflammation. The results indicate that the microenvironment of distinct skeletal muscle may influence a particular kinetic pattern of MMP activity, which ultimately favors persistent inflammation and myofiber regeneration at different stages of the myopathy in mdx mice. Muscle Nerve, 2008

Intake of butter naturally enriched with cis9,trans11 conjugated linoleic acid reduces systemic inflammatory mediators in healthy young adults

A conjugated linoleic acid (CLA) depletion-repletion study was carried out to investigate the effects of dietary c9,t11 CLA on C-reactive protein, transcription factor NFκB, metalloproteinases 2 and 9, inflammatory mediators (adiponectin, TNFα, IL-2, IL-4, IL-8, IL-10), body composition, and erythrocyte membrane composition in healthy normal-weight human adults. CLA depletion was achieved through an 8-week period of restricted dairy fat intake (depletion phase; CLA intake was 5.2±5.8 mg/day), followed by an 8-week period in which individuals consumed 20 g/day of butter naturally enriched with c9,t11 CLA (repletion phase; CLA intake of 1020±167 mg/day). The participants were 29 healthy adult volunteers (19 women and 10 men, aged 22 to 36 years), with body mass index between 18.0 and 29.9 kg m(-2). Blood samples were collected at baseline and at the end of both depletion and repletion phases. The content of CLA in erythrocytes decreased during CLA-depletion and increased during CLA-repletion. Intake of CLA-enriched butter increased the serum levels of anti-inflammatory IL-10 but reduced transcription factor NFκB in blood and serum levels of TNFα, IL-2, IL-8 and inactive metalloproteinase-9. Moreover, reduced activity of metalloproteinases 2 and 9 in serum was observed during the CLA-repletion period. In contrast, intake of CLA-enriched butter had no effects on body composition (DXA analysis) as well as on serum levels of adiponectin, C-reactive protein, and IL-4. Taken together, our results indicate that the intake of a c9,t11 CLA-enriched butter by normal-weight subjects induces beneficial changes in immune modulators associated with sub-clinical inflammation in overweight individuals.

Evolução da pneumonia lipoide exógena em crianças: aspectos clínicos e radiológicos e o papel da lavagem broncoalveolar

OBJECTIVE To present aspects of the evolution of lipoid pneumonia in children, based on clinical, radiological and bronchoalveolar lavage fluid findings, emphasizing the importance of bronchoalveolar lavage for the diagnosis and treatment. METHODS We included 28 children, with a mean age of 20 months (range, 1-108 months), diagnosed with chronic pneumonia refractory to antimicrobial therapy, with TB or with a combination of the two. Most of the children had at least one risk factor for aspiration, and all of them had a history of mineral oil ingestion for intestinal constipation (23/28) or complicated ascaridiasis (5/28). Clinical evaluations, tomographic evaluations and analyses of bronchoalveolar lavage fluid were carried out at the beginning of treatment and throughout a follow-up period of 24 months. RESULTS Tachypnea and cough were the most common symptoms. The most common radiological alterations were areas of consolidation (23/28), perihilar infiltrates (13/28) and hyperinflation (11/28). Chest CT scans showed areas of consolidation with air bronchogram (24/28), decreased attenuation in the areas of consolidation (16/28), ground-glass opacities (3/28) and crazy-paving pattern (1/28). In the analysis of the bronchoalveolar lavage fluid, Sudan staining revealed foamy macrophages, confirming the diagnosis of lipoid pneumonia. After treatment with multiple bronchoalveolar lavages (mean = 9.6), 20 children became asymptomatic, 18 of those presenting normal tomographic images. CONCLUSIONS A diagnosis of lipoid pneumonia should be considered in patients with chronic refractory pneumonia or TB, especially if there is a history of mineral oil ingestion. Bronchoscopy with multiple bronchoalveolar lavages was an efficient treatment for the clearance of mineral oil from the lung parenchyma and the prevention of fibrosis. This strategy contributed to reducing the morbidity of lipoid pneumonia, which remains a rare diagnosis.

Long-term Outcome in Patients with Recurrent Malignant Glioma Treated with Perillyl Alcohol Inhalation

As you begin the journey to understand the Emotional Core Therapy process please keep in mind the scientific method. The scientific method is a process for creating models of the natural world that can be verified experimentally. The scientific method requires making observations, recording data, and analyzing data in a form that can be duplicated by other scientists. The subject of a scientific experiment has to be observable and reproducible. Observations may be made with the unaided eye or any other apparatus suitable for detecting the desired phenomenon. The apparatus for making a scientific observation has to be comprised of well-known scientific principles. The scientific method requires that theories be testable. If a theory cannot be tested, it cannot be a scientific theory. The scientific method requires and relies on direct evidence. This means evidence that can be directly observed and tested. Scientific experiments are designed to be repeated by other scientists and to demonstrate unequivocally the point they are trying to prove by controlling all the factors that could influence the results. Source (Scientificpsychic.com/Scientific Method) Here are the four steps to the scientific method and the Emotional Core Therapy process. 1). Observation made both visually and with scientific equipment Stress affects both the mind and body. There exists a cause and effect relationship with stress. Oftentimes this stress can be uncomfortable for humans. 2) Formulation of a hypothesis to explain the phenomenon in the form of a causal mechanism/method/approach. Many psychology methods (REBT, CBT, ACT, DBT, etc.), religious approaches (Buddhism, 12 steps, etc.), and educational programs (Smart Recovery) have attempted to fully and completely explain via a model, how this cause and effect relationship with stress occurs. Up until this point in time, we have not had a model in the world that can successfully depict how this stress occurs each and every time. To their credit, many of these methods partially work and have contributed greatly to humanity. See Wiki.com for information on all the psychology methods and techniques mentioned in this book. With the invention/discovery of Emotional Core Therapy (ECT) we now have a psychology method that accurately can depict this causal relationship between stress and humans through my Eight Step Emotional Core Therapy Flowchart. With ECT, we now have a psychology approach that identifies and treats the root cause of psychological stress. The root cause is the temporary arousal of one of the four true emotions (joy, grief, fear, and relief). ECT also shares and borrows many psychological techniques from the aforementionedMethods: Adult male Wistar rats (225-275 g) were selected randomly and divided into 10 groups. All groups underwent stereotaxic surgery and in order to induce dependency, morphine was administered subcutaneously) Sc) at an interval of 12 hours for nine continuous days. On the ninth day of the experiment, animals received vehicle or CBX (100, 400, 600 μg/10μl/ rat, ICV) or MFQ (50, 100 and 200 μg/10μl/rat, ICV) after the last saline or morphine (Sc) injection. Morphine withdrawal symptoms were precipitated by naloxone hydrochloride 10 min after the treatments. The withdrawal signs including: jumping, rearing, genital grooming, abdomen writhing, wet dog shake and stool weight, were recorded for 60 minutes.D to the effect of thoracotomy on respiratory and circulatory systems, the anesthetic technique, one lung ventilation (OLV) is applied. With the consistent improvement and widespread application of double lumen endobronchial tube and novel endobronchial blockers, OLV is more popular for surgical performance. However, there are some issues of OLV, such as the dismatching of ventilation perfusion ratio, hypoxemia, SpO2 and increase of Pmax, which limited the use of OLV. Recently, many studies have been done in the advancement of safety of OLV and on the prevention and treatment of hypoxemia. This review briefly introduces the progress of OLV and discusses the function of OLV in anesthesia.BACKGROUND Treatment of patients with chronic conditions requiring hospitalization requires patient acceptance and cooperation and adoption of coping strategies. Inappropriate coping strategies such as substance abuse are concerning in the course of treatment. This study sought to explore the association of coping strategies with suicidal behavior in substance abusers and non substance abuser patients with chronic pulmonary diseases namely asthma and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS This comparative study was performed on 100 patients with asthma and COPD selected via convenience sampling. Subjects with and without substance abuse were separated into two groups of 50 patients each. Ways of Coping Questionnaire of Lazarus (WOCQ) and Suicide Behavior Questionnaire-Revised (SBQ-R) were completed by them. Five Persian speaking patients rated this questionnaire to be easily understandable in the pre-test stage. Cronbachs alpha was calculated to measure the internal consistency. RESULTS The mean (±standard deviation) age of participants was 40 (±14) years; 58% of individuals were men; 62% had chosen problem-focused coping. The most abused substances were cigarettes (78%) and opium (42%); 6% of substance abusers had thought about suicide five times or more in the past year; 5% of substance abusers had seriously attempted suicide. Tendency to commit suicide was greater in men, substance abusers and participants who had chosen emotion-focused coping strategies, based on a regression model. Average score of suicide tendency was significantly higher in substance abusers (B=2.196, P =0.007). CONCLUSION Chronic disease is a crisis and patients need to acquire appropriate coping strategies to deal with it, especially in substance abusers and suicidal patients. Precise recognition of coping strategies in chronic pulmonary patients with substance abuse is necessary via a team cooperation among psychiatrics, psychologists and an internal physician in hospitals because medical treatment alone is not sufficient in such cases.N oxide is a colorless and virtually odorless gas with a faint, sweet smell. It is a safe and effective tool used in dental clinics to reduce anxiety, produce analgesia, and cause the depression of the central nervous system (CNS), leading to the sensation of euphoria with little effect on the respiratory system. It also enhances effective communication between the patient and their healthcare provider. The decision to use nitrous oxide/oxygen must take into consideration the alternative behavioral guidance modalities, the patient’s dental needs, the effect on the quality of dental care, the patient’s emotional development, and the patient’s physical considerations.AIM This retrospective study aimed to evaluate the long-term response and toxicity of recurrent malignant glioma patients to inhalation chemotherapy with perillyl alcohol (POH). PATIENTS AND METHODS The cohort included 117 men and 81 women with primary glioblastoma multiforme (GBM; n=154), grade III astrocytoma (AA; n=26) and anaplastic oligodendroglioma (AO; n=5). POH inhalation schedule 4-times daily started with 66.7 mg/dose; 266 mg/day and escalated up to 133.4 mg/dose; 533.6 mg/day. Clinical toxicity and overall survival following treatment were compared with tumor size, topography, extent of peritumoral edema and histological classification. RESULTS Adhesion to the protocol was high (>95%), POH (533.6 mg/daily) occasionally caused nose soreness but rarely nosebleed. Tumor size, peritumoral edema and the oligodendroglial component influenced response to treatment. CONCLUSION After 4 years under exclusive POH treatment, 19% of patients still remain in clinical remission. Long-term POH inhalation chemotherapy is a safe and non-invasive strategy efficient for recurrent malignant glioma.

Resolution of skeletal muscle inflammation in mdx dystrophic mouse is accompanied by increased immunoglobulin and interferon-γ production

Mdx mouse, the animal model of Duchenne muscular dystrophy, develops an X‐linked recessive inflammatory myopathy with an apparent sustained capacity for muscle regeneration. We analysed whether changes in the skeletal muscle during myonecrosis and regeneration would correlate with functional alterations in peripheral lymphoid tissues. Here we show that during the height of myonecrosis, mdx mice display marked atrophy of peripheral lymph nodes and extensive muscle inflammation. In contrast, enlargement of draining lymph nodes with accumulation of CD4+ CD44+, CD4+ CD25+, CD8+ CD44+ T lymphocytes and type‐2 B cells was consistently observed during amelioration of the muscle lesion. In addition, regeneration of the muscular tissue was accompanied by concomitant increase of immunoglobulin‐secreting cells in regional lymph nodes and bone marrow. Double immunolabelling analysis revealed intense B cell proliferation and formation of germinal centre in the follicles of dystrophic regional lymph nodes. Furthermore, lymph node cells produced large amounts of IFN‐γ but not IL‐4, IL‐6 or IL‐10 after in vitro mitogen stimulation with Concanavalin A. As these alterations occurred mainly during the recovery period, we suggested that local activation of the immune system could be an influence which mitigates the myonecrosis of muscular tissue in the mdx dystrophic mouse.

The anticancer drug perillyl alcohol is a Na/K-ATPase inhibitor

The monoterpene perillyl alcohol (POH) is a drug used in the treatment of several malignant tumors, including gliomas. The present study defines a POH inhibitory effect on Na/K-ATPase activity from kidney and brain guinea pig extracts and from a human glioblastoma cell line. This inhibition showed a high degree of selectivity toward the kidney enzyme expressing, as do glioblastoma cells, the α1 subunit. Kinetic studies with purified enzymes showed a noncompetitive POH inhibition profile to Na+ and K+ and an uncompetitive inhibition towards ATP. Furthermore, potassium activated p-nitrophenylphosfatase activity of these purified preparations was not inhibited by POH, suggesting that this drug, differently from the classical inhibitor ouabain, acted in the initial phase of the enzyme’s catalytic cycle. We suggest that POH antitumor action could be linked to its Na/K-ATPase binding properties.

Nicotinic acetylcholine receptor activation reduces skeletal muscle inflammation of mdx mice.

Mdx mice develop an inflammatory myopathy characterized at different ages by myonecrosis with scattered inflammatory infiltrates followed by muscular regeneration and later persistent fibrosis. This work aimed to verify the putative anti-inflammatory role of nicotinic acetylcholine receptor (nAChR) in the mdx muscular lesion. Mitigation of myonecrosis and decreased TNFα production were accompanied by increased numbers of F4/80 macrophages expressing nAChRα7. In vivo treatment with nicotine attenuated muscular inflammation characterized by reduced metalloprotease MMP-9 activity, TNFα and NFkB content and increased muscular regeneration. Our data indicate that nAChR activation influences local inflammatory responses in the muscular lesion of mdx mice.

Resection of the epileptogenic lesion abolishes seizures and reduces inflammatory cytokines of patients with temporal lobe epilepsy

Persistent neuroinflammation is implicated in the pathogenesis of seizures and neuronal degeneration of temporal lobe epilepsy (TLE). Circulating level of inflammatory cytokines was determined during inter-ictal period of 25 non-operated and 10 patients (OP) submitted to anterior temporal lobectomy. OP patients showed marked reduction of IL-1β, TNFα, MIP-1α, but not IL-6 and TGF-β1. Paired analysis done before and after lobectomy showed reduction of inflammatory cytokines but increased TGF-β1 levels, and lack of seizures for more than 6 months. Maintenance of high TGF-β1 and IL-6 cytokines in both groups suggests a role in down-regulation of neuroinflammation and promotion of brain tissue remodeling for neuronal reorganization.