Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy.

Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN-/-) mouse model. Our results demonstrate that expression of GFP-hASYN in primary neurons derived from a transgenic mouse impaired axonal trafficking and processing of APP. In addition, axonal transport of BACE1, Rab5, Rab7, lysosomes and mitochondria were also reduced in these neurons. Interestingly, axonal transport of these organelles was also affected in ASYN-/- neurons, suggesting that ASYN plays an important role in maintaining normal axonal transport function. Therefore, selective impairment of trafficking and processing of APP by ASYN may act as a potential mechanism to induce pathological features of Alzheimer's disease (AD) in PD patients.

Lipopolysaccharide from Porphyromonas gingivalis, but Not from Porphyromonas endodontalis, Induces Macrophage M1 Profile.

Apical Lesions of Endodontic Origin (ALEO) are initiated by polymicrobial endodontic canal infection. Porphyromonas gingivalis (Pg) and Porphyromonas endodontalis (Pe) lipopolysaccharides (LPS) can induce a pro-inflammatory macrophage response through their recognition by TLR2 and TLR4. However, polarization responses induced by Pg and/or Pe LPS in macrophages are not fully understood. We aimed to characterize the polarization profiles of macrophages differentiated from THP-1 cells following Pg and/or Pe LPS stimulation from reference strain and clinical isolates. A modified LPS purification protocol was implemented and the electrophoretic LPS profiles were characterized. THP-1 human monocytes differentiated to macrophages were stimulated with Pg and Pe LPS. Polarization profiles were characterized through cell surface markers and secreted cytokines levels after 24 h of stimulation. TLR2 and TLR4 cell surfaces and transcriptional levels were determined after 24 or 2 h of LPS stimulation, respectively. LPS from Pg induced a predominant M1 profile in macrophages evidenced by changes in the expression of the surface marker CD64 and pro-inflammatory cytokine profiles, TNF-α, IL-1ß, IL-6, and IL-12. Pe LPS was unable to induce a significant response. TLR2 and TLR4 expressions were neither modified by Pg or Pe LPS. Pg LPS, but not Pe LPS, induced a macrophage M1 Profile.

Biological models in multiple sclerosis.

Considering the etiology of multiple sclerosis (MS) is still unknown, experimental models resembling specific aspects of this immune-mediated demyelinating human disease have been developed to increase the understanding of processes related to pathogenesis, disease evolution, evaluation of therapeutic interventions, and demyelination and remyelination mechanisms. Based on the nature of the investigation, biological models may include in vitro, in vivo, and ex vivo assessments. Even though these approaches have disclosed valuable information, every disease animal model has limitations and can only replicate specific features of MS. In vitro and ex vivo models generally do not reflect what occurs in the organism, and in vivo animal models are more likely used; nevertheless, they are able to reproduce only certain stages of the disease. In vivo MS disease animal models in mammals include: experimental autoimmune encephalomyelitis, viral encephalomyelitis, and induced demyelination. This review examines and describes the most common biological disease animal models for the study of MS, their specific characteristics and limitations.

Oxidative stress involvement in the molecular pathogenesis and progression of multiple sclerosis: a literature review.

Multiple sclerosis (MS) is an autoimmune debilitating disease of the central nervous system caused by a mosaic of interactions between genetic predisposition and environmental factors. The pathological hallmarks of MS are chronic inflammation, demyelination, and neurodegeneration. Oxidative stress, a state of imbalance between the production of reactive species and antioxidant defense mechanisms, is considered one of the key contributors in the pathophysiology of MS. This review is a comprehensive overview of the cellular and molecular mechanisms by which oxidant species contribute to the initiation and progression of MS including mitochondrial dysfunction, disruption of various signaling pathways, and autoimmune response activation. The detrimental effects of oxidative stress on neurons, oligodendrocytes, and astrocytes, as well as the role of oxidants in promoting and perpetuating inflammation, demyelination, and axonal damage, are discussed. Finally, this review also points out the therapeutic potential of various synthetic antioxidants that must be evaluated in clinical trials in patients with MS.

Visual outcomes in tuberculum sellae meningiomas comparing transcranial and endoscopic endonasal approaches.

Background: Tuberculum sellae meningiomas (TSM) account for 3-10% of intracranial meningiomas. Visual loss is the presenting symptom in up to 80% of cases. Surgical management poses a great challenge due to tumor proximity to neurovascular structures such as the optic nerve and the internal carotid artery (ICA); hence, there is controversy regarding the optimal approach. The aim of this study is to determine differences in visual outcomes between transcranial (TCA) and endoscopic endonasal (EEA) approaches. Methods: A retrospective study including 29 patients with TSM surgically treated by TCA or EEA between 2011 and 2023 in a single referral center was conducted. Pre-and post-operative neuro-ophthalmologic evaluations, focusing on visual acuity and campimetry, were evaluated. Results: Sixteen (55.16%) patients were intervened through a TCA and the remaining 13 (44.84%) via an EEA. The lesions in each group were similar in terms of pre- operative volume (15.12 vs 12.9 cm3, p = 0.497) and neurovascular invasion (optic canal invasion 48.26 vs 41.37%, p = 0.664; ICA 44.81 vs 31.03%, p = 0.797). There were no significant differences in visual outcomes between both approaches; TCA presented an improvement of 5.18 points in visual fields (p = 0.140), whereas EEA had an improvement of 17.39 points in visual acuity (p = 0.114). Conclusion: EEA seems to offer greater improvement in visual acuity than TCA. However, the ideal approach should be individualized; taking into account the tumor's volume and invasiveness, as well as the patient's visual complaints.

Multiple sclerosis in Central America and Caribbean countries: frequency and clinical characterization of an emergent disease.

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3-3.5 × 100,000 inhabitants, and the lowest, 0.07-0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.

The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway.

1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. IPI-926 is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926 is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, IPI-926 has desirable pre-clinical absorption, distribution, metabolism and excretion properties.

Impact of Ketamine on Quality of Recovery after Laparoscopic Surgery: A Single-Centre Single-Blinded Trial Using the QoR-15 Questionnaire.

Background: The quality of recovery is a cluster of patient-related outcomes that emphasise not only pain but different physical and emotional dimensions. Traditionally, ketamine is used to improve postoperative analgesia and avoid opioid consumption and opioid-related side effects. Objective: The present study sought to evaluate if intraoperative ketamine administration (as a part of multimodal analgesia) influences the quality of recovery after laparoscopic surgery. Design: A prospective two-armed, single-blinded trial. Settings. Tertiary single-centre trial between July 2021 and January 2022. Patients. From the 146 patients initially admitted to the study, 127 patients were enrolled, 60 in the ketamine group (group K) and 67 in the control group (group NK). Intervention. Both groups received a rigid intraoperative anaesthesia protocol; furthermore, in group K, 0.5 mg/kg of the ideal body weight of ketamine was administered. Main Outcome Measures. The primary outcome was to evaluate the effect of ketamine administration on the postoperative quality of recovery using the Portuguese version of the Quality of Recovery-15 (QoR-15) Questionnaire 24 h after surgery. The total score and minimal clinically significant difference (MCID) of the QoR-15 were compared. Other variables were also assessed such as the presence of emergence delirium (ED), the Numeric Rating Scale (NRS) for pain, and the presence of postoperative nausea and vomiting (PONV). Results: A total of 127 patients were allocated to the study groups, 60 in group K and 67 in group NK. Regarding the primary outcome, no differences were found in individual categories (15 items) and in the total score of QoR-15 (p=0.214). Concerning improvement (MCID ≥ 8) or worsening (MCID ≤ 8) in quality of recovery, no difference was found between the groups (24 vs. 32 and 6 vs. 6; p=0.776). Finally, no difference was found in secondary postoperative outcomes including ED (p=0.55), NRS (p=0.401), and PONV (p=0.55). Conclusion: In this study, the administration of ketamine in laparoscopic surgery had no impact on the quality of recovery 24 h after surgery. This trial is registered with NCT03724019.

Capsaicin 8% for Peripheral Neuropathic Pain Treatment: A Retrospective Cohort Study.

BACKGROUND: Chronic neuropathic pain is a disabling condition that affects quality of life. Despite recommendations and guidelines, treatment remains suboptimal as it often does not result in significant symptom relief. Capsaicin 8% patch has been used for the treatment of several peripheral neuropathic pain etiologies with encouraging results. OBJECTIVES: To assess the results of capsaicin 8% patch on neuropathic pain by evaluating pain intensity and the painful treatment area. STUDY DESIGN: Observational retrospective cohort study. SETTING: All patients submitted to capsaicin treatment at the Chronic Pain Unit of the Hospital Centre of Tondela Viseu, from 2011 through 2019. METHODS: Records of capsaicin treatments were reviewed, and the data collected. The primary outcome was pain intensity and painful treatment area reduction between the first and last treatment. Also, the number of treatments performed, neuropathic pain duration, anatomic location, pain etiology, and concomitant oral pain medication at baseline and upon treatment conclusion was also listed. RESULTS: Postsurgical neuropathic pain was the most common etiology (49%), followed by postherpetic (28%). The median (interquartile range [IQR]) baseline pain intensity assessed by the Numeric Rating Scale (NRS-11) was 6 (5-8) and the median (IQR) final NRS-11 was 3 (1-5), with a median (IQR) relative difference of -0.5 (-0.85-0.17) with statistically significant differences (P < 0.001) between baseline and last pain intensity, regarding all groups. Also, there was a reduction in the painful treatment area between baseline and the last evaluation, with a median (IQR) relative difference of -0.4 (-0.625-0.167). LIMITATIONS: A relatively small sample and occasional different timing for pain intensity and pain treatment area assessment due to logistical difficulties. CONCLUSIONS: Capsaicin 8% patch is a valuable option for the treatment of peripheral neuropathic pain, providing a significant reduction in pain intensity and painful area. It is well tolerated and has a high treatment compliance.Ethics Committee Reference Number: 16/16//04/2021.

Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression.

Aryl hydrocarbon receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding to numerous endogenous and exogenous ligands. For example, AHR is activated by the metabolite kynurenine, which is secreted into the tumor microenvironment by cancer cells leading to broad immunosuppression. Therefore, AHR inhibition provides a novel and ideal approach to stimulate immune-mediated recognition and subsequent eradication of tumor cells. We report here the discovery and characterization of IK-175, a novel, potent and selective AHR antagonist with favorable ADME and pharmacokinetic profiles in preclinical species. IK-175 inhibits AHR activity in experimental systems derived from multiple species including mouse, rat, monkey, and humans. In human primary immune cells, IK-175 decreased AHR target gene expression and anti-inflammatory cytokine release and increased proinflammatory cytokine release. Moreover, IK-175 led to a decrease in suppressive IL17A-, IL-22+ expressing T cells in a Th17 differentiation assay. IK-175 dose dependently blocks ligand-stimulated AHR activation of Cyp1a1 transcription in mouse liver and spleen, demonstrating on-target in vivo activity. IK-175 increases proinflammatory phenotype of the tumor microenvironment in mouse syngeneic tumors and in adjacent tumor-draining lymph nodes. As a monotherapy and combined with an anti-PD-1 antibody, IK-175 demonstrates antitumor activity in syngeneic mouse models of colorectal cancer and melanoma. IK-175 also demonstrates antitumor activity combined with liposomal doxorubicin in syngeneic mouse tumors. These studies provide rationale for targeting AHR in patients with cancer. IK-175 is being evaluated in a phase I clinical trial in patients with advanced solid tumors.

Difference in mortality rates in hospitalized COVID-19 patients identified by cytokine profile clustering using a machine learning approach: An outcome prediction alternative.

COVID-19 is a disease caused by the novel Coronavirus SARS-CoV-2 causing an acute respiratory disease that can eventually lead to severe acute respiratory syndrome (SARS). An exacerbated inflammatory response is characteristic of SARS-CoV-2 infection, which leads to a cytokine release syndrome also known as cytokine storm associated with the severity of the disease. Considering the importance of this event in the immunopathology of COVID-19, this study analyses cytokine levels of hospitalized patients to identify cytokine profiles associated with severity and mortality. Using a machine learning approach, 3 clusters of COVID-19 hospitalized patients were created based on their cytokine profile. Significant differences in the mortality rate were found among the clusters, associated to different CXCL10/IL-38 ratio. The balance of a CXCL10 induced inflammation with an appropriate immune regulation mediated by the anti-inflammatory cytokine IL-38 appears to generate the adequate immune context to overrule SARS-CoV-2 infection without creating a harmful inflammatory reaction. This study supports the concept that analyzing a single cytokine is insufficient to determine the outcome of a complex disease such as COVID-19, and different strategies incorporating bioinformatic analyses considering a broader immune profile represent a more robust alternative to predict the outcome of hospitalized patients with SARS-CoV-2 infection.

Neuromyelitis Optica Spectrum Disorder in Central America and the Caribbean: A Multinational Clinical Characterization Study.

Here, a study of NMOSD in Central America and the Caribbean with a multinational collaborative, multicentric and descriptive approach involving 25 institutions from 9 countries is presented. Demographics, clinical manifestations, expanded disability scale status (EDSS), brain and spinal cord MRI, serological anti-AQP4-IgG and anti-MOG-IgG antibodies, and cerebrospinal fluid (CSF) oligoclonal bands were included. A central serological repository utilized the cell-based assay. The specimens outside of this network employed diverse methodologies. Data were collected at the Gorgas Commemorative Institute of Health Studies (ICGES), Panama, and included 186 subjects, of which 84% were females (sex ratio of 5.6:1). Mestizos constituted 72% of the study group. The median age was 42.5 years (IQR: 32.0-52.0). Associated autoimmune diseases (8.1%) were myasthenia gravis, Sjögren's syndrome and systemic lupus erythematosus. The most common manifestation was optic neuritis-transverse myelitis (42.5%). A relapsing course was described in 72.3% of cases. EDSS scores of 0-3.5 were reported in 57.2% of cases and higher than 7.0 in 14.5%. Positive anti-AQP4-IgG antibody occurred in 59.8% and anti-MOG-IgG antibody in 11.5% of individuals. Antibody testing was lacking for 13.4% of patients. The estimated crude prevalence of NMOSD from Panama and the Dominican Republic was 1.62/100,000 (incidence of 0.08-0.41) and 0.73/100,000 (incidence 0.02-0.14), respectively. This multinational study contributes additional insights and data on the understanding of NMOSD in this Latin American region.

High thoracic kyphosis: impact on total thoracic kyphosis and cervical alignment in patients with adolescent idiopathic scoliosis.

PURPOSE: To evaluate the impact of proximal thoracic segment (T1-T5) on global thoracic kyphosis, as well as its influence on cervical alignment (lordotic, kyphotic or straight) in patients with adolescent idiopathic scoliosis (AIS). METHODS: We conducted a retrospective study of 80 patients with AIS. The inclusion criteria were patients between 10 and 18 years of age with a posteroanterior (PA) and lateral full-length radiographs, excluding those subjected to surgery, orthotic treatment, with other spinal disease or with poor X-ray quality. The parameters evaluated were age, sex, pelvic incidence (PI), sacral slop (SS), pelvic tilt (PT), global sagittal balance (GSB), scoliotic curvatures (differentiated according to primary curve, lumbar modifier and sagittal modifier), cervical spine alignment, thoracic sagittal Cobb angle between T1 and T5, T5 and T12 and between T1 and T12. RESULTS: In patients with AIS, the proximal sagittal thoracic Cobb segment, contrary to the distal, demonstrated a significant positive correlation with cervical spine alignment (p < 0.05). As there is an increase in proximal thoracic angle, there is an increase in cervical lordosis. We also demonstrated that the correlation between an increase in scoliotic curvature and a decrease in kyphosis only occurred in the distal thoracic segment (T5-T12). Relative to the spinopelvic parameters, the PI was not related with the dorsal kyphosis or shape of the cervical spine. CONCLUSIONS: In AIS, proximal (T1-T5) and distal (T5-T12) thoracic kyphosis have different contributions on the global thoracic sagittal curvature and in the phenomenon of hypokyphosis. On the other hand, only the proximal segment is significantly related to the shape of the cervical spine. LEVEL OF EVIDENCE: IV.

Contact dermatitis: Clinical practice findings from a single tertiary referral hospital, a 4-Year retrospective study.

BACKGROUND: It is estimated that 20% of the general population is sensitized to some kind of contact allergen. Contact dermatitis is one of the major occupational diseases worldwide. This disease has a higher prevalence in the female gender and is more frequently observed in the third or fourth decade of life. The main objective of this study was to describe the main sociodemographic and clinical characteristics of patients with contact dermatitis treated in the Allergy Unit of the San Juan De Dios Hospital - Caja Costarricense de Seguro Social. METHODS: Clinical records of contact dermatitis outpatients from a single hospital were analyzed, in a 4-year retrospective observational study. RESULTS: At the time of the patch testing, patients showed a mean age of 42.2 years. Disease frequency was higher in the female population (female/male ratio of 4.2:1) and in patients mostly dedicated to household workchores. Most patients presented several years of disease history, and the hands were the highest affected body part. Patch testing revealed that nickel sulfate, Cl+Me-Isothiazolinone (Kathon CG), and thimerosal were allergens regularly associated with contact dermatitis in the analyzed population. CONCLUSIONS: To a great extent, sociodemographic and clinical characteristics identified in these patients resemble what is reported in other regions, including the Americas and worldwide. It is worth highlighting a high female proportion rate probably related to cultural aspects, a smaller percentage of irritant contact dermatitis that may be associated to institutional patient management, and a slight difference in the most common allergens when compared to other published studies.

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.

Structure-activity relationships of a peptide inhibitor of the human FcRn:human IgG interaction.

A family of five peptides was previously discovered by phage display techniques that binds to the human neonatal Fc receptor (FcRn) and inhibits the human IgG:human FcRn protein-protein interaction [Proc. Nat. Acad. Sci. U.S.A.2008, 105, 2337-2342]. The consensus peptide motif consists of the sequence GHFGGXY where X is preferably a hydrophobic amino acid, and also includes a disulfide bridge enclosing 11-amino acids in varying positions about the consensus sequence. We describe herein the structure-activity relationships of one of the five peptides in binding to FcRn using surface plasmon resonance and IgG:FcRn competition ELISA assays. Modifications of the peptide length, cyclization, and the incorporation of amino acid substitutions and dipeptide mimetics were studied. The most potent analogs exhibited a 50- to 100-fold improvement of in vitro activity over that of the phage-identified peptide sequence.

Use of US in the evaluation of patients with symptoms of deep venous thrombosis of the lower extremities.

Deep venous thrombosis (DVT) is a major health problem and is estimated to have an incidence of 600,000 cases per year. Clinical signs and symptoms of DVT are unreliable. If clinical signs alone were used to diagnose DVT, 42% of patients would receive unnecessary anticoagulation therapy. Most patients evaluated with ultrasonography (US) do not have DVT. The key to making a precise diagnosis is recognizing the characteristics of various diseases on US images. The anatomic approach is the most useful strategy for characterizing the spectrum of pathologic conditions seen in patients with symptoms that simulate DVT. The inferior extremity can be divided into four regions-inguinal, thigh, popliteal, and lower leg-with the rough limits defined for each as they are examined at US. The differential diagnoses affecting the lower extremities include infectious, neoplastic, traumatic, inflammatory, vascular, and miscellaneous entities. Some pathologic conditions seen in the inguinal region are adenopathies, lymphangitis, soft-tissue tumors, hematomas, adductor tendonitis, and hernias. In the thigh, cellulitis, myositis, abscess, benign and malignant tumors, and sports-related lesions are seen. In the popliteal region, cellulitis, arthritis, benign and malignant masses, muscle contusions, ruptured popliteal cysts, and thrombophlebitis are seen. And in the lower leg, cellulitis, lipomas, tennis leg, superficial thrombophlebitis, tendonitis, and soft-tissue hydrostatic edema secondary to cardiac and renal failure can simulate DVT.

[In vitro growth kinetics of two Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) clones in myocardial cells from rodents of different susceptibility]. / Cinética de crecimiento in vitro de dos cepas de Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) en células miocárdicas de roedores con diferente susceptibilidad.

In vitro growth kinetics of two Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae) clones in myocardial cells from rodents of different susceptibility. Two Trypanosoma cruzi isolates, TCR-4 from Costa Rica and UES-1 from El Salvador, were studied in vitro to compare their infectivity or resistance and intracellular replication in myocardial cells in three strains of mice and rats: NGP white mice, C3 H mice and Sprague Dowley rats. Myocardial cells were cultured on coverslips at 37 degrees C in a humid 10% CO2 atmosphere and then infected at a ratio of one tripomastigote per cell. Samples were studied after 24, 72, 96 and 120 h of infection to determine parasite infection capacity and intracellular multiplication. Both parasites had the highest infection capacity in C3 H mice, followed by NGP mice cells with a very low infection rate. Lastly, almost no Trypanosoma cruzi multiplication was observed in Sprague Dowley rats, suggesting a strong natural resistance in this animal to both strains of the parasite. The UES-1 isolate presented higher multiplication and greater invasion than the TCR-4 strain, showing greater virulence of UES-1 in heart cells, at least in vitro.

Molecular Pathogenesis of Alzheimer's Disease: An Update.

Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered a consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness is usually unaffected. Alzheimer's disease (AD) is the most common form of dementia; symptoms include memory loss, difficulty solving problems, disorientation in time and space, among others. The disease was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer. One hundred and ten years since its first documentation, many aspects of the pathophysiology of AD have been discovered and understood, however gaps of knowledge continue to exist. This literature review summarizes the main underlying neurobiological mechanisms in AD, including the theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, the role of tau protein, and the involvement of oxidative stress and calcium.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.