Assessing the effect of a liquid water layer on the adsorption of hydrate anti-agglomerants using molecular simulations.

We have performed molecular dynamics simulations to study the adsorption of ten hydrate anti-agglomerants onto a mixed methane-propane sII hydrate surface covered by layers of liquid water of various thickness. As a general trend, we found that the more liquid water that is present on the hydrate surface, the less favorable the adsorption becomes even though there are considerable differences between the individual molecules, indicating that the presence and thickness of this liquid water layer are crucial parameters for anti-agglomerant adsorption studies. Additionally, we found that there exists an optimal thickness of the liquid water layer favoring hydrate growth due to the presence of both liquid water and hydrate-forming guest molecules. For all other cases of liquid water layer thickness, hydrate growth is slower due to the limited availability of hydrate-forming guests close to the hydrate formation front. Finally, we investigated the connection between the thickness of the liquid water layer and the degree of subcooling and found a very good agreement between our molecular dynamics simulations and theoretical predictions.

Size dependence of the dissociation process of spherical hydrate particles via microsecond molecular dynamics simulations.

The dissociation process of spherical sII mixed methane-propane hydrate particles in liquid hydrocarbon was investigated via microsecond-long molecular dynamics simulations. A strong dependence of the melting temperature on the particle size was found. Analysis in the context of the Gibbs-Thomson effect provided insights into the fundamental properties of gas hydrates.

FOXO3 determines the accumulation of α-synuclein and controls the fate of dopaminergic neurons in the substantia nigra.

Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of α-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons using viral vectors and explore how this determinant of longevity impacts on neuronal fate in normal and diseased conditions. We find that dopaminergic neurons are particularly vulnerable to changes in FOXO3 activity in the substantia nigra. While constitutive activation has proapoptotic effects leading to neuronal loss, inhibition of FOXO-mediated transcription by a dominant-negative competitor causes oxidative damage and is detrimental at high vector dose. To address the role of FOXO3 in PD, we modulate its activity in dopaminergic neurons overexpressing human α-synuclein. In this pathogenic condition, we find that FOXO inhibition has protective effects, suggesting that this transcription factor ultimately contributes to neuronal cell death. Nevertheless, mild FOXO3 activity also protects nigral neurons against the accumulation of human α-synuclein, albeit to a lesser extent. FOXO3 reduces the amount of α-synuclein present in the soluble protein fraction and promotes the coalescence of dense proteinase K-resistant aggregates, with an accumulation of autophagic vacuoles containing lipofuscin. Consistent with these in vivo observations, we find that FOXO3 controls autophagic flux in neuronal cells. Altogether, these results point to FOXO3 as an important determinant of neuronal survival in the substantia nigra, which may oppose α-synuclein accumulation and proteotoxicity.

Management of acute cholecystitis.

PURPOSE OF REVIEW: Various aspects of the management of acute calculous cholecystitis, including type and timing of surgery, role of antibiotics, and nonoperative management, remain controversial. This review focuses on recently published studies addressing the timing of cholecystectomy, use of cholecystostomy tubes, and role of antibiotics in this condition. RECENT FINDINGS: In most cases, the diagnosis of acute cholecystitis can be initially confirmed with an abdominal ultrasound. Early laparoscopic cholecystectomy (within 24-72 h of symptom onset) is better than delayed surgery (>7 days) for most patients with grade I and II diseases. Percutaneous cholecystostomy and novel endoscopic gallbladder drainage interventions may be used as a temporizing measure or as definitive therapy in those who are too sick to undergo surgery. Studies are conflicting as to whether antibiotics are required for the treatment of uncomplicated cases. SUMMARY: Cholecystectomy remains the only definitive therapy for acute cholecystitis. Current guidelines recommend treatment on the basis of disease severity at presentation. Antibiotics and a variety of minimally invasive nonsurgical interventions, although not definitive, play an adjunctive role in the management of the disease.

Laryngeal tuberculosis in the United States of America: a forgotten disease.

Laryngeal tuberculosis (TB) was a common manifestation of TB in the early twentieth century, but now represents only 1% of all cases. Most modern case series of laryngeal TB originate outside the USA. We report a case of laryngeal TB from our institution and review other US cases published between 1970 and 2012. One hundred twenty-seven cases were identified. The mean patient age was 49 y and 28% were female. The mean duration of symptoms was 19 weeks. Dysphonia and weight loss were the most common manifestations, seen in 96% and 47% of cases, respectively. These symptoms were usually attributed to malignancy initially. Most cases involved the vocal cords. Eighty-six percent of cases had underlying pulmonary involvement. Mortality was 3%. In the USA, laryngeal TB is rarely suspected and often confused with malignancy. This infection should be considered in patients with unexplained dysphonia and weight loss.

Recognizing the roles of fever in host survival and in medical intervention in infectious diseases.

Fever has roles both in host defense against infectious challenges and in guidance of medical intervention. These roles remain insufficiently acknowledged and considered by both health care providers and patients and their families. This review cites reports in support of both roles and provides recommendations regarding the clinician's approach to fever, as well as points relevant for education of patients and their families.

Intra-abdominal fungal infections.

PURPOSE OF REVIEW: The clinical spectrum of intra-abdominal fungal infections has not been systematically analyzed in the literature. RECENT FINDINGS: Even though intra-abdominal fungal infections have been recognized with increasing frequency in the recent years, most clinical experience is limited to case reports or uncontrolled case series. These infections are more common than clinically recognized disease. The clinical presentation varies broadly depending on the organism and host's immune status, but it is frequently severe, difficult to treat, and associated with significant morbimortality. Predisposing factors, clinical characteristics, and advances in the management are discussed. SUMMARY: Intra-abdominal fungal infections are increasingly important in clinical practice. Early recognition and a combined treatment approach, usually consisting of surgical intervention and systemic antifungal therapy, are required for improved outcomes.

Molecular Dynamics Simulations of Asphaltene Aggregation: Machine-Learning Identification of Representative Molecules, Molecular Polydispersity, and Inhibitor Performance.

Molecular dynamics simulations have been employed to investigate the effect of molecular polydispersity on the aggregation of asphaltene. To make the large combinatorial space of possible asphaltene blends accessible to a systematic study via simulation, an upfront unsupervised machine-learning approach (clustering) was employed to identify a reduced set of model molecules representative of the diversity of asphaltene. For these molecules, single asphaltene model simulations have shown a broad range of aggregation behaviors, driven by their structural features: size of the aromatic core, length of the aliphatic chains, and presence of heteroatoms. Then, the combination of these model molecules in a series of mixtures have highlighted the complex and diverse effects of molecular polydispersity on the aggregation process of asphaltene. Simulations yielded both antagonistic and synergistic effects mediated by the trigger or facilitator action of specific asphaltene model molecules. These findings illustrate the necessity of accounting for molecular polydispersity when studying the asphaltene aggregation process and have permitted establishing a robust protocol for the in silico evaluation of the performance of asphaltene inhibitors, as illustrated for the case of a nonylphenol resin.

Five-year outbreak of community- and hospital-acquired Mycobacterium porcinum infections related to public water supplies.

Mycobacterium porcinum is a rarely encountered rapidly growing Mycobacterium (RGM). We identified M. porcinum from 24 patients at a Galveston university hospital (University of Texas Medical Branch) over a 5-year period. M. porcinum was considered a pathogen in 11 (46%) of 24 infected patients, including 4 patients with community-acquired disease. Retrospective patient data were collected, and water samples were cultured. Molecular analysis of water isolates, clustered clinical isolates, and 15 unrelated control strains of M. porcinum was performed. Among samples of hospital ice and tap water, 63% were positive for RGM, 50% of which were M. porcinum. Among samples of water from the city of Galveston, four of five households (80%) were positive for M. porcinum. By pulsed-field gel electrophoresis (PFGE), 8 of 10 environmental M. porcinum were determined to belong to two closely related clones. A total of 26 of 29 clinical isolates subjected to PFGE (including isolates from all positive patients) were clonal with the water patterns, including patients with community-acquired disease. Fifteen control strains of M. porcinum had unique profiles. Sequencing of hsp65, recA, and rpoB revealed the PFGE outbreak clones to have identical sequences, while unrelated strains exhibited multiple sequence variants. M. porcinum from 22 (92%) of 24 patients were clonal, matched hospital- and household water-acquired isolates, and differed from epidemiologically unrelated strains. M. porcinum can be a drinking water contaminant, serve as a long-term reservoir (years) for patient contamination (especially sputum), and be a source of clinical disease. This study expands concern about public health issues regarding nontuberculous mycobacteria. Multilocus gene sequencing helped define clonal populations.

Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

The clinical significance of persistent residual viremia in patients on prolonged highly active antiretroviral therapy (HAART) is not clear. Moreover, it remains to be demonstrated whether residual viremia consists of viruses capable of spreading infection in vivo upon termination of therapy. Using residual viral RNAs (vRNAs) isolated from a HAART-treated patient's plasma, we cloned full-length viral genomes and found that most of them could produce infectious, replication-competent HIVs when transfected into TZM-bl cells, suggesting that residual viruses produced in the absence of therapy can initiate fresh cycles of infection and spread in host cells. The data further indicate that residual viremia may pose a major concern with regard to the emergence of drug-resistant HIVs during periods of low adherence to therapy.

Ranking the Efficiency of Gas Hydrate Anti-agglomerants through Molecular Dynamic Simulations.

Using both computational and experimental methods, the capacity of four different surfactant molecules to inhibit the agglomeration of sII hydrate particles was assessed. The computational simulations were carried out using both steered and non-steered molecular dynamics (MD), simulating the coalescence process of a hydrate slab and a water droplet, both covered with surfactant molecules. The surfactants were ranked according to free energy calculations (steered MD) and the number of agglomeration events (non-steered MD). The experimental work was based on rocking cell measurements, determining the minimum effective dose necessary to inhibit agglomeration. Overall, good agreement was obtained between the performance predicted by the simulations and the experimental measurements. Moreover, the simulations allowed us to gain additional insights that are not directly accessible via experiments, such as an analysis of the mass density profiles, the diffusion coefficients, or the orientations of the long tails.

Treatment Considerations in an HIV Elite Controller.

HIV elite controllers naturally suppress viral loads below limits of detection and evidence lack of evolution of infection for prolonged periods. The role of antiretroviral therapy (ART) in these individuals is controversial. Though recent data suggest that ART may decrease immune activation and prevent complications such as development of accelerated cardiovascular disease (CVD); treatment has not clearly demonstrated a benefit on clinical outcomes (e.g., HIV disease progression, CVD events, mortality). We describe a 49-year-old female HIV elite controller who presented with asymptomatic HIV infection for 26 years and review recent literature on the role of ART in this population.

Persistent Infection Versus Type 2 Immunological Reaction in Lepromatous Leprosy.

The distinction between persistent infection and immunologic reactions in leprosy is often difficult but critically important since their management is different. We present the case of a 51-year-old Vietnamese female who presented in 2015 with areas of erythema and skin infiltration on face and chest, as well as edema on her hands and feet. Skin biopsy was consistent with lepromatous leprosy. She was treated with rifampin, clarithromycin, and levofloxacin for 2 years. Her lower extremity edema was attributed to type 2 immunological reaction for which she was started on prednisone and methotrexate, but she was lost to follow-up for 19 months. She presented with new skin lesions and pain on her extremities. New biopsies revealed an intense neutrophilic infiltrate in the dermis and acid-fast bacilli focally within cutaneous nerve twigs. As compared with the initial biopsy, the inflammatory infiltrates were diminished and the bacilli had a degenerating appearance. These findings were consistent with type 2 immunological reaction. The patient was treated with thalidomide with improvement in the appearance of the skin lesions. A follow-up biopsy showed lack of neutrophilic infiltrates and decreased number of bacilli. This case illustrates the importance of differentiating between persistent infection and immunologic reactions in leprosy. Clinicians should be aware of these complications. A high index of suspicion and accurate interpretation of skin biopsy results are essential for appropriate diagnosis.

Lemierre's Syndrome Due to Methicillin-Resistant Staphylococcus aureus.

Lemierre's syndrome is an uncommon and potentially fatal complication of oropharyngeal and facial infections. It involves an associated septic thrombophlebitis, bacteremia, and septic emboli. Traditionally, compromise of the internal jugular vein has been described in conjunction with an infection caused by anaerobes, especially, Fusobacterium necrophorum. In recent years, however, variant forms have been appearing, including other vessel compromise and other etiologic agents. We present the case of Lemierre's syndrome in a 31-year-old male with facial vein thrombosis, septic emboli to the lungs, and bacteremia caused by methicillin-resistant Staphylococcus aureus. We hope that this case will raise awareness about variant presentations and promote a timely diagnosis and appropriate treatment of this potentially fatal infection.

Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion.

Immune reconstitution inflammatory syndrome (IRIS) affects 30-43% of HIV and tuberculosis (TB) co-infected patients after starting highly active antiretroviral therapy (HAART). Pericarditis and pericardial effusion are rare manifestations of IRIS. We report a case of HIV-TB related IRIS that developed pericardial involvement. This complication resolved after treatment with ibuprofen. Antituberculous treatment and HAART were not interrupted.

Mycobacterium-avium-intracellulare complex immune reconstitution inflammatory syndrome in HIV/AIDS presenting as osteomyelitis.

We report a case of osteomyelitis due to Mycobacterium avium-intracellulare complex (MAC) in an AIDS patient shortly after the initiation of antiretroviral therapy with subsequent immune reconstitution inflammatory syndrome (IRIS). He improved after surgical debridement and treatment with clarithromycin, ethambutol, rifabutin, and low-dose corticosteroids. Antiretroviral therapy was not interrupted. MAC should be suspected in IRIS-related complications such as osteomyelitis.

Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment.

Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the cerebrospinal fluid (CSF) in 75% of patients. One year survival was 75% among patients treated initially with amphotericin B, and was highest with liposomal, or deoxycholate formulations. Mortality was higher in immunocompromised patients, and patients 54 years of age, or older. Six percent of patients relapsed, all of whom had the acquired immunodeficiency syndrome (AIDS), and were poorly adherent with treatment.While CNS histoplasmosis occurred most often in immunocompromised individuals, a significant proportion of patients were previously, healthy. The diagnosis can be established by antigen, and antibody testing of the CSF, and serum, and antigen testing of the urine in most patients. Treatment with liposomal amphotericin B (AMB-L) for at least 1 month; followed by itraconazole for at least 1 year, results in survival among the majority of individuals. Patients should be followed for relapse for at least 1 year, after stopping therapy.

Disseminated Histoplasmosis in Early Human Immunodeficiency Virus Infection.

Early human immunodeficiency virus (HIV) infection leads to transient immunosuppression followed by a quasi-homeostatic state with slow progression towards AIDS. Histoplasmosis has never been reported in early HIV. We present a case of disseminated histoplasmosis with documented recent seroconversion and review the literature regarding other opportunistic infections in early HIV.

Differential expression of Low density lipoprotein Receptor-related Protein 1 (LRP-1) and matrix metalloproteinase-9 (MMP-9) in prostate gland: From normal to malignant lesions.

BACKGROUND: Metalloproteinases (MMPs) are relevant modulators of inflammation, tumor microenvironment, cancer invasion and metastasis. They can be regulated by the Low density lipoprotein Receptor-related Protein 1 (LRP-1), a receptor reported to mediate the clearance of lipoproteins, extracellular matrix (ECM) macromolecules and proteinases. The aim of this study was to evaluate the expression of LRP-1, MMP-2 and MMP-9 across various grades of prostatic diseases as benign prostatic hyperplasia (BPH), BPH plus prostatitis (BPH+P), high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer (PCa). METHODS: LRP-1 was analyzed using immunohistochemistry and MMPs proteolytic activity by zymography in prostate tissues with different prostatic diseases. RESULTS: LRP-1 was detected in epithelial cells in BPH (16/18), BPH+P (21/21) and HGPIN (6/6), with a staining intensity of 1+, 1+/2+ and 3+, respectively. In PCa, LRP-1 was absent in 19/27 samples while a low expression was observed in 8/27 biopsies. MMP-9 activity was higher and statistically significant in PCa than in BPH (p≤0.01). CONCLUSION: Considering that LRP-1, by mediating the clearance of MMPs, is involved in the regulation of ECM remodeling and cell migration, we conclude that a decreased expression of LRP-1 could be involved with the increasing activity of MMPs shown in cancers.

Central nervous system pseudallescheriasis after near-drowning.

BACKGROUND: Clinical characteristics of central nervous system (CNS) pseudallescheriasis after near-drowning have not been systematically analyzed. METHODS: Review of cases reported in the English-language literature. RESULTS: Sixteen patients were identified. The average period between the near-drowning episode and onset of clinical manifestations was 37 days. Common manifestations included fever, altered mental status, headache, seizures, and hemiparesis. All patients developed brain abscesses; however, imaging studies were normal at presentation in 6 patients. Cerebrospinal fluid neutrophilic pleocytosis, elevated protein, and decreased glucose were commonly observed. Most patients were treated with surgical resection and systemic amphotericin B or miconazole. Voriconazole was used in 2 patients. Twelve patients (75%) died. The average time between the near-drowning episode and death was 12 weeks. Four survivors received prompt treatment. CONCLUSIONS: CNS pseudallescheriasis after near-drowning is highly lethal. Early diagnosis and aggressive medical and surgical interventions may improve survival.