Probing IgG1 FC-Multimodal Nanoparticle Interactions: A Combined Nuclear Magnetic Resonance and Molecular Dynamics Simulations Approach.

In this study, NMR and molecular dynamics simulations were employed to study IgG1 FC binding to multimodal surfaces. Gold nanoparticles functionalized with two multimodal cation-exchange ligands (Capto and Nuvia) were synthesized and employed to carry out solution-phase NMR experiments with the FC. Experiments with perdeuterated 15N-labeled FC and the multimodal surfaces revealed micromolar residue-level binding affinities as compared to millimolar binding affinities with these ligands in free solution, likely due to cooperativity and avidity effects. The binding of FC with the Capto ligand nanoparticles was concentrated near an aliphatic cluster in the CH2/CH3 interface, which corresponded to a focused hydrophobic region. In contrast, binding with the Nuvia ligand nanoparticles was more diffuse and corresponded to a large contiguous positive electrostatic potential region on the side face of the FC. Results with lower-ligand-density nanoparticles indicated a decrease in binding affinity for both systems. For the Capto ligand system, several aliphatic residues on the FC that were important for binding to the higher-density surface did not interact with the lower-density nanoparticles. In contrast, no significant difference was observed in the interacting residues on the FC to the high- and low-ligand density Nuvia surfaces. The binding affinities of FC to both multimodal-functionalized nanoparticles decreased in the presence of salt due to the screening of multiple weak interactions of polar and positively charged residues. For the Capto ligand nanoparticle system, this resulted in an even more focused hydrophobic binding region in the interface of the CH2 and CH3 domains. Interestingly, for the Nuvia ligand nanoparticles, the presence of salt resulted in a large transition from a diffuse binding region to the same focused binding region determined for Capto nanoparticles at 150 mM salt. Molecular dynamics simulations corroborated the NMR results and provided important insights into the molecular basis of FC binding to these different multimodal systems containing clustered (observed at high-ligand densities) and nonclustered ligand surfaces. This combined biophysical and simulation approach provided significant insights into the interactions of FC with multimodal surfaces and sets the stage for future analyses with even more complex biotherapeutics.

Continuous positive airway pressure therapy suppresses inflammatory cytokines and improves glucocorticoid responsiveness in patients with obstructive sleep apnea and asthma: A case-control study.

CONTEXT: Asthma and obstructive sleep apnea (OSA) are prevalent respiratory disorders that frequently coexist. Continuous positive airway pressure (CPAP) therapy is the standard treatment for OSA. However, its effects on systemic inflammation and glucocorticoid responsiveness in OSA patients with asthma are largely unknown. AIMS: To examine the potential role of CPAP therapy in reducing systemic inflammation and improving glucocorticoid responsiveness in asthmatic patients with OSA. SETTINGS AND DESIGN: A case-control study was conducted at the respiratory and sleep clinics involving patients with OSA and patients with asthma and OSA. METHODS: The levels of inflammatory asthma biomarkers (interleukin [IL]-4, IL-17A, IL-8, IL-2, and interferon-γ [IFN-γ]), and glucocorticoid receptors (GR)-α and GR-ß, were determined to compare systemic inflammation and glucocorticoid responsiveness between pre- and post-1-month CPAP treatment in both groups. STATISTICAL ANALYSIS: The Wilcoxon signed-rank test was used to compare inflammatory biomarkers before and after CPAP therapy. P < 0.05 considered statistically significant. The analysis was performed using SPSS. RESULTS: Recruited patients (n = 47), 51% (n = 24) had OSA and 49% (n = 23), had OSA with asthma. Interestingly, the blood levels of IL-17 and IL-8 were significantly decreased post-CPAP therapy in OSA patients, whereas IL-4, IL-17, and IFN-γ were significantly reduced post-CPAP treatment in OSA patients with asthma. Remarkably, CPAP therapy improved glucocorticoid responsiveness in asthmatic patients with OSA, but not in the OSA group and an increase in the GR-α/GR-ß ratio was noted post-CPAP therapy. CONCLUSIONS: Continuous positive airway pressure therapy improved responsiveness to glucocorticoid treatment and demonstrated a suppressive effect on proinflammatory cytokines in asthmatics with OSA.

Respiratory disorders in the Middle East: a review.

The spectrum of pulmonary pathology in the Middle East is as versatile as its civilizations and cultures. In this review, we outline the key challenges confronting pulmonologists in the Middle East. We shed light on the diverse conditions commonly encountered in the region, from the centuries-old illnesses of tuberculosis, to contemporary problems such as lung complications from chemical warfare. We specifically highlighted unique aspects related to respiratory illnesses in the Middle East, for example, climate factors in the desert region, cultural habits, for example, water-pipe smoking and disorders unique to the region, such as Behçet's disease. Pulmonologists are also faced with the consequences of modernization, including large immigrant population and associated social and health issues, rising incidence of obesity and sleep apnoea, and drug-resistant tuberculosis. Tackling these health issues will require an integrated approach involving public health, primary care as well as specialist pulmonology input, taking into consideration the unique cultural and environmental factors to ensure effective management and compliance to medical care.

Bridging Gaussian Density Fluctuations from Microscopic to Macroscopic Volumes: Applications to Non-Polar Solute Hydration Thermodynamics.

The hydration of hydrophobic solutes is intimately related to the spontaneous formation of cavities in water through ambient density fluctuations. Information theory-based modeling and simulations have shown that water density fluctuations in small volumes are approximately Gaussian. For limiting cases of microscopic and macroscopic volumes, water density fluctuations are known exactly and are rigorously related to the density and isothermal compressibility of water. Here, we develop a theory-interpolated gaussian fluctuation theory (IGFT)-that builds an analytical bridge to describe water density fluctuations from microscopic to molecular scales. This theory requires no detailed information about the water structure beyond the effective size of a water molecule and quantities that are readily obtained from water's equation-of-state-namely, the density and compressibility. Using simulations, we show that IGFT provides a good description of density fluctuations near the mean, that is, it characterizes the variance of occupancy fluctuations over all solute sizes. Moreover, when combined with the information theory, IGFT reproduces the well-known signatures of hydrophobic hydration, such as entropy convergence and solubility minima, for atomic-scale solutes smaller than the crossover length scale beyond which the Gaussian assumption breaks down. We further show that near hydrophobic and hydrophilic self-assembled monolayer surfaces in contact with water, the normalized solvent density fluctuations within observation volumes depend similarly on size as observed in the bulk, suggesting the feasibility of a modified version of IGFT for interfacial systems. Our work highlights the utility of a density fluctuation-based approach toward understanding and quantifying the solvation of non-polar solutes in water and the forces that drive them toward surfaces with different hydrophobicities.

Evaluation of guanidine-based multimodal anion exchangers for protein selectivity and orthogonality.

In this paper, we examined the chromatographic behavior of a new class of guanidine-based multimodal anion exchange resins. The selectivities and protein recoveries on these resins were first evaluated using linear gradient chromatography with a model acidic protein library at pH 5, 6 and 7. While a single-guanidine based resin exhibited significant recovery issues at high ligand density, a bis-guanidine based resin showed high recoveries of all but two of the proteins evaluated in the study. In addition, the bis-guanidine resin showed a more pH dependent selectivity pattern as compared to the low density single-guanidine resin. The salt elution range for the low density single-guanidine and bis-guanidine resins was also observed to vary from 0.250 to 0.621 M and 0.162 to 0.828 M NaCl, respectively. A QSAR model was then developed to predict the elution behavior of these proteins on the guanidine prototypes at multiple pH with overall training and test scores of 0.88 and 0.85, respectively. In addition, molecular dynamics simulations were performed with these ligands immobilized on a self-assembled monolayer (SAM) to characterize their conformational preferences and to gain insight into the molecular basis of their chromatographic behavior. Finally, a recently developed framework was employed to evaluate the separability of the bis-guanidine resin as well as its orthogonality to the multimodal cation exchanger, Nuvia cPrime. This evaluation was carried out using a second model protein library which included both acidic and basic proteins. The results of this analysis indicated that the bis-guanidine prototype exhibited both higher pair separability (0.73) and pair enhancement (0.42) as compared to the less hydrophobic commercial Nuvia aPrime 4A with pair separability and enhancement factors of 0.57 and 0.22, respectively. The enhanced selectivity and orthogonality of this new multimodal anion exchange ligand may offer potential opportunities for bioprocessing applications.

Incidence and management of diaphragmatic palsy in patients after cardiac surgery.

BACKGROUND: Diaphragm is the most important part of the respiratory system. Diaphragmatic palsy following cardiac surgery is not uncommon and can cause deterioration of pulmonary functions and attendant pulmonary complications. OBJECTIVES: Aim of this study was to observe the incidence of diaphragmatic palsy after off pump coronary artery bypass grafting (OPCAB) as compared to conventional CABG and to assess the efficacy of chest physiotherapy on diaphragmatic palsy in post cardiac surgical patients. DESIGN AND SETTING: An observational prospective interventional study done at a tertiary care cardiac centre. PATIENTS: 2280 consecutive adult patients who underwent cardiac surgery from February 2005 to august 2005. RESULTS: 30 patients out of 2280 (1.31%) developed diaphragmatic palsy. Patients were divided based on the presence or absence of symptoms viz. breathlessness at rest or exertion or with the change of posture along with hypoxemia and / or hypercapnia. Group I included 14 patients who were symptomatic (CABG n=13, post valve surgery n=1), While Group II included 16 asymptomatic patients (CABG n=12, post valve surgery n=4), 9 patients (64%) from Group I (n=14) and 4 patients (25%) from group II showed complete recovery from diaphragmatic palsy as demonstrated ultrasonographically. CONCLUSION: The incidence of diaphragmatic palsy was remarkably less in our adult cardiac surgical patients because most of the cardiac surgeries were performed off pump and intensive chest physiotherapy beginning shortly after extubation helped in complete or near complete recovery of diaphragmatic palsy. Chest Physiotherapy led to marked improvement in functional outcome following post cardiac surgery diaphragmatic palsy. We also conclude that ultrasonography is a simple valuable bed-side tool for rapid diagnosis of diaphragmatic palsy.

Analytical Determination of Nicotine and Tar Levels in Various Dokha and Shisha Tobacco Products.

In the Middle East, there is no precise data and literature on tobacco-based products, such as dokha and shisha. The proposed study aims to quantify the levels of nicotine and tar in different kinds of dokha and shisha products that are sold in the local marketplace. The amount of nicotine in dokha and shisha products can be quantitatively determined using a combination of the "kissling" and "silicotungstic acid" method proposed by Robert M. Chapin. The tar residue from the smoke sample was collected on a glass wool placed before the stopcock (tap) of a separatory funnel as the smoke passes through the inlet of an electronically controlled vacuum pump. The nicotine levels in dokha and shisha samples ranged from 23.83 to 52.80 mg/g and 0.80 to 20.52 mg/g, respectively. The nicotine level varies between different tobacco products. It varies from 0.5 to 19.5 mg/g in cigarettes, from 10.3 to 23.1 mg/g in snuff tobacco, from 11 to 18 mg/g in electronic cigarettes and from 2.9 to 16.6 mg/g in chewing tobacco. The tar levels in the dokha and shisha samples ranged from 21.6 to 45.02 mg/g and 1.68 to 11.87 mg/g, respectively. Smokers are at a high risk of getting lung cancer, chronic obstructive pulmonary disease, emphysema and coronary artery disease owing to the high levels of nicotine and tar present in dokha and shisha tobacco products. These findings contradict the widespread belief among teenagers that dokha and shisha tobacco products are safer alternatives to cigarettes.

An observational study to know the association of leukocytosis and fever with infection in post cardiac surgery patients.

BACKGROUND: Leukocytosis and fever in the absence of infection are common phenomena in post surgical period. The systemic inflammatory response syndrome induced by surgical trauma is a well-known entity, with resultant release of variety of inflammatory cytokines leading to fever and/or leukocytosis in spite of the absence of infection. AIMS AND OBJECTIVE: To know the association of leukocytosis and fever with infection in immediate post cardiac surgical period. METHODS: It was a retrospective, observational study including 569 patients, who underwent cardiac surgeries in our institute. All demographic data, comorbidities and other factors associated with fever and/or leukocytosis were analyzed. The sensitivity and specificity of fever and/or leukocytosis were analyzed for the diagnosis of infection. RESULTS: Out of 569 patients; 49 patients (9%) had evidence of infection on microbiological culture. Mean total leukocyte counts (TLC) on zero and 1st postoperative days were associated with infection with a sensitivity (75.5% and 63.3%) and specificity (15.8% and 24.0%) respectively. Mean maximum temperature (Tmax) on zero and 1st postoperative days were associated with infection with a sensitivity (20.4% and 24.5%) and specificity of (82.5% and 83.3%) respectively. The combined sensitivity and specificity of leukocytosis and fever for the diagnosis of infection on 2nd postoperative day was 14.3% and 91.5% respectively. CONCLUSION: Fever and leukocytosis are poor predictors of diagnosing infection on the first two postoperative days. However, fever and leukocytosis combined together have low sensitivity (14.3%) with high specificity (91.5%) for the diagnosis of infection on the 2nd and subsequent postoperative days.

Joint statement for the diagnosis, management, and prevention of chronic obstructive pulmonary disease for Gulf Cooperation Council countries and Middle East-North Africa region, 2017.

Smoking and subsequent development of COPD is an ever-increasing epidemic in Arabian Gulf and Middle East countries, with no signs of decline. The important fact to be highlighted is that this COPD epidemic of increasing incidence and prevalence is mostly unrecognized by patients, due to the common attribution of symptoms to "smoker's cough", and the underdiagnosis and undertreatment by physicians because the common signs and symptoms masquerade as asthma. Consequently, there are long-term adverse effects of missing the diagnosis. The purpose of this review article is to focus upon the status of COPD in Arabian Gulf and Middle East countries, stressing the increasing burden of smoking and COPD, to emphasize the specific factors leading to rise in prevalence of COPD, to bring to light the underdiagnosis and undermanagement of COPD, and to treat COPD in conformity with standard guidelines with local and regional modifications. This review ends with suggestions and recommendations to the health department to formulate policies and to generate awareness among the general public about the side effects of smoking and consequences of COPD.

Cardiac herniation following atrial septal defect closure using port access surgery.

Cardiac herniation, a rare entity, is seen most commonly after traumatic rupture of the pericardium or following pneu-monectomy with partial pericardiactomy. It is rarely seen to occur following closure of a sinus venosus atrial septal defect through the port access technique. A review of the literature in English did not reveal any such case report.

Obesity and Sleep-Related Breathing Disorders in Middle East and UAE.

A pandemic of obesity is sweeping all across the globe and the Middle East region also does not remain untouched by this prevailing pandemic. In fact, as per WHO report, Kuwait has the second highest obesity prevalence followed closely by other Middle East (ME) countries, namely, Qatar, Saudi Arabia, and United Arab Emirates (UAE). Apart from direct medical, psychological, and quality of life related adverse effects of obesity, many indirect medical comorbidities, namely, obstructive sleep apnea (OSA), obesity hypoventilation syndrome (OHS), diabetes mellitus (DM), hypertension (HTN), and metabolic syndrome, imposes a significant health burden on the individual and community with consequent morbidity and mortality. The purpose of this review is to shed light on the very high prevalence of obesity, undiagnosed sleep apnea, and other obesity related disorders with discussion of the contributing factors specific to the region including the fair insight into the current status of sleep medicine services in Middle East and UAE despite huge number of patients having undiagnosed sleep disorders. We will also suggest to control this epidemic of obesity and OSA so that the corrective measure could be taken at health ministry level to help people of this region to fight against obesity and related disorders, primarily OSA.

Prevalence of symptoms and risk of sleep apnea in Dubai, UAE.

PURPOSE: The United Arab Emirates (UAE) ranks 18th on the 2007 Forbes list of fattest countries with 68.3% of its citizens with an unhealthy weight and it is well known that weight gain and obesity are important determinants in the progression of obstructive sleep apnea syndrome (OSAS). The purpose of this study is to estimate the prevalence of symptoms and risk of OSAS in the primary health care setting in Dubai, and the relationship between obesity and sleep apnea. METHODS: In this prospective survey, a trained medical nurse administered the Berlin Questionnaire to a consecutive random sample of patients in the age group older than 14 years, who attended the primary health care center in Dubai Health Authority, Dubai, UAE, from September 2011 to March 2012. Based on the questionnaire answers, individuals were classified into high risk and low risk groups for OSAS. RESULTS: Based on the responses and measurement of the Berlin Questionnaire of 1214 subjects studied, 58% (n = 704) of the respondents were female, while 42% (n = 510) were male. Two-hundred-fifty-four respondents met the criteria for the high risk scoring. This gives a prevalence rate of 20.9% (out of which 22.9% of the male respondents were high risk for OSAS, while 19.5% of the females were high risk for OSAS), while the remainder of the participants were classified as low risk. The overall mean age of the high risk for OSAS female respondents was 39.95 years (standard deviation [SD] 11.73 years) and was 41.18 years (SD 14.95 years) for male respondents The highest prevalence was observed between age 51 to 60 in both genders. Seventy percent of the high risk group had a body mass index (BMI) ≥ 30 kg/m(2) and nearly 75% of the low risk group had a BMI < 30 kg/m(2), and the mean BMI was 32.06 kg/m(2) (SD 5.67 kg/m(2)) for males and 33.59 kg/m(2) (SD 6.44 kg/m(2)) for females. CONCLUSION: In the primary health care setting, the prevalence of symptoms of OSAS among adult UAE citizens is very high, and UAE patients are at risk for OSAS and may benefit from proper evaluation for OSAS.

Thoracic epidural analgesia in obese patients with body mass index of more than 30 kg/m2 for off pump coronary artery bypass surgery.

Perioperative Thoracic epidural analgesia (TEA) is an important part of a multimodal approach to improve analgesia and patient outcome after cardiac and thoracic surgery. This is particularly important for obese patients undergoing off pump coronary artery bypass surgery (OPCAB). We conducted a randomized clinical trial at tertiary care cardiac institute to compare the effect of TEA and conventional opioid based analgesia on perioperative lung functions and pain scores in obese patients undergoing OPCAB. Sixty obese patients with body mass index >30 kg/m2 for elective OPCAB were randomized into two groups (n=30 each). Patients in both the groups received general anesthesia but in group 1, TEA was also administered. We performed spirometry as preoperative assessment and at six hours, 24 hours, second, third, fourth and fifth day after extubation, along with arterial blood gases analysis. Visual analogue scale at rest and on coughing was recorded to assess the degree of analgesia. The other parameters observed were: time to endotracheal extubation, oxygen withdrawal time and intensive care unit length of stay. On statistical analysis there was a significant difference in Vital Capacity at six hours, 24 hours, second and third day postextubation. Forced vital capacity and forced expiratory volume in one second followed the same pattern for first four postoperative days and peak expiratory flow rate remained statistically high till second postoperative day. ABG values and PaO2/FiO2 ratio were statistically higher in the study group up to five days. Visual analogue scale at rest and on coughing was significantly lower till fourth and third postoperative day respectively. Tracheal extubation time, oxygen withdrawal time and ICU stay were significantly less in group 1. The use of TEA resulted in better analgesia, early tracheal extubation and shorter ICU stay and should be considered for obese patients undergoing OPCAB.

Thoracic epidural analgesia for off-pump coronary artery bypass surgery in patients with chronic obstructive pulmonary disease.

The benefits of thoracic epidural analgesia in patients undergoing coronary artery bypass grafting are well documented. However, the literature available on the role of high thoracic epidural analgesia (HTEA) in patients with chronic obstructive pulmonary disease undergoing off-pump coronary artery bypass graft (OPCAB) surgery is scarce. We conducted a randomized clinical trial to establish whether HTEA is beneficial in patients with chronic obstructive pulmonary disease undergoing elective OPCAB surgery. After institutional ethics board approval and informed consent, 62 chronic obstructive pulmonary disease patients undergoing elective OPCAB were randomly grouped into two (n = 31 each). Both groups received general anesthesia (GA), but in the HTEA group patients, TEA was also administered. Standardized surgical and anesthetic techniques were used for both the groups. Pulmonary function tests were performed pre-operatively, 6 h and 24 h post-extubation and on days 2, 3, 4 and 5 along with arterial blood gas analysis (ABG) analysis. Time for extubation (h) and time for oxygen withdrawal (h) were recorded. Pain score was assessed by the 10-cm visual analogue scale. All hemodynamic/oxygenation parameters were noted. Any complications related to the TEA were also recorded. Patients in the HTEA group were extubated earlier (10.8 h vs. 13.5 h, P < 0.01) and their oxygen withdrawal time was also significantly lower (26.26 h vs. 29.87 h, P < 0.01). The VAS score, both at rest and on coughing, was significantly lower in the HTEA group at all times, post-operatively (P < 0.01). The forced vital capacity improved significantly at 6 h post-operatively in the HTEA group (P = 0.026) and remained significantly higher thereafter. A similar trend was observed in forced expiratory volume in the first second on day 2 in the HTEA group (P = 0.024). We did not observe any significant side-effects/mortality in either group. In chronic obstructive pulmonary disease patients undergoing elective OPCAB surgery, HTEA is a good adjunct to GA for early extubation, faster recovery of pulmonary function and better analgesia.

Anesthetic management of right atrial mass removal and pulmonary artery thrombectomy in a patient with primary antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome (APLAS) characterises a clinical condition of arterial and venous thrombosis associated with phospholipids directed antibodies. APLAS occurs in 2% of the general population. However, one study demonstrated that 7.1% of hospitalised patients were tested positive for at least one of the three anticardiolipin antibody idiotype. Antiphospholipid antibodies often inhibit phospholipids dependent coagulation in vitro and interfere with laboratory testing of hemostasis. Therefore, the management of anticoagulation during cardiopulmonary bypass can be quite challenging in these patients. Here, we present a case of right atrial mass removal and pulmonary thrombectomy in a patient of APLAS.