SLE pachymeningitis and multiple cranial nerve palsies: a case report and review of the literature.

Hypertrophic pachymeningitis (HP) is a relatively uncommon disease associated with focal or diffuse thickening of the dura mater secondary to underlying chronic inflammation. The link between systemic lupus erythematosus (SLE) and hypertrophic pachymeningitis (HP) is extremely rare, with only six other cases reported in the literature. We, however, report the first case of SLE pachymeningitis presenting with multiple cranial nerve palsies. The patient showed good response to steroids and cyclophosphamide therapy. One should maintain a high index of suspicion to make the diagnosis in patients with SLE presenting with neurological dysfunction. Prompt therapy prevents long-term neurological sequelae.

Novel role of cardiovascular MRI to contextualise tuberculous pericardial inflammation and oedema as predictors of constrictive pericarditis.

Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome have reached epidemic proportions, particularly affecting vulnerable populations in low- and middle-income countries of sub-Saharan Africa. TB pericarditis is the commonest cardiac manifestation of TB and is the leading cause of constrictive pericarditis, a reversible (by surgical pericardiectomy) cause of diastolic heart failure in endemic areas. Unpacking the complex mechanisms underpinning constrictive haemodynamics in TB pericarditis has proven challenging, leaving various basic and clinical research questions unanswered. Subsequently, risk stratification strategies for constrictive outcomes have remained unsatisfactory. Unique pericardial tissue characteristics, as identified on cardiovascular magnetic resonance imaging, enable us to stage and quantify pericardial inflammation and may assist in identifying patients at higher risk of tissue remodelling and pericardial constriction, as well as predict the degree of disease reversibility, tailor medical therapy, and determine the ideal timing for surgical pericardiectomy.

Issues in Medicine.

Rasmussen aneurysms are abnormalities of the pulmonary arterial system caused by tuberculosis (TB). They are associated with a highmortality rate when they cause life-threatening haemoptysis. High TB-prevalence regions have a large burden of TB-related haemoptysisbut often limited resources. This series of 25 patients who presented with life-threatening haemoptysis from current and/or previous TBwere found to have abnormal pulmonary arteries on computed tomography pulmonary angiogram (CTPA), which were judged to belikely contributors to their bleeding, either in isolation or with concomitant abnormal bronchial or systemic vasculature. These patientsunderwent transcatheter placement of Amplatzer vascular plugs in the feeder pulmonary artery. Bronchial and systemic lesions wereaddressed separately as needed. Immediate technical success was achieved in all patients, but four of them experienced intraoperativehaemoptysis related to dislodgement of the occluding platelet plug by the high-pressure automatic injector and wire. At 48 hours after theprocedure, 18 (72%) remained haemoptysis-free. Six of these experienced recurrence within 1 year of their procedure. Pulmonary arteryplacement of an Amplatzer vascular plug is a feasible option for treating bleeding Rasmussen aneurysms, but should be part of a combinedapproach to addressing suspected culprit vascular lesions in all intrathoracic vascular systems.

The importance of bacterial membrane composition in the structure and function of aurein 2.2 and selected variants.

For cationic antimicrobial peptides to become useful therapeutic agents, it is important to understand their mechanism of action. To obtain high resolution data, this involves studying the structure and membrane interaction of these peptides in tractable model bacterial membranes rather than directly utilizing more complex bacterial surfaces. A number of lipid mixtures have been used as bacterial mimetics, including a range of lipid headgroups, and different ratios of neutral to negatively charged headgroups. Here we examine how the structure and membrane interaction of aurein 2.2 and some of its variants depend on the choice of lipids, and how these models correlate with activity data in intact bacteria (MICs, membrane depolarization). Specifically, we investigated the structure and membrane interaction of aurein 2.2 and aurein 2.3 in 1:1 cardiolipin/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (CL/POPG) (mol/mol), as an alternative to 1:1 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(POPC)/POPG and a potential model for Gram positive bacteria such as S. aureus. The structure and membrane interaction of aurein 2.2, aurein 2.3, and five variants of aurein 2.2 were also investigated in 1:1 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE)/POPG (mol/mol) lipids as a possible model for other Gram positive bacteria, such as Bacillus cereus. Solution circular dichroism (CD) results demonstrated that the aurein peptides adopted α-helical structure in all lipid membranes examined, but demonstrated a greater helical content in the presence of POPE/POPG membranes. Oriented CD and ³¹P NMR results showed that the aurein peptides had similar membrane insertion profiles and headgroup disordering effects on POPC/POPG and CL/POPG bilayers, but demonstrated reduced membrane insertion and decreased headgroup disordering on mixing with POPE/POPG bilayers at low peptide concentrations. Since the aurein peptides behaved very differently in POPE/POPG membrane, minimal inhibitory concentrations (MICs) of the aurein peptides in B. cereus strain C737 were determined. The MIC results indicated that all aurein peptides are significantly less active against B. cereus than against S. aureus and S. epidermidis. Overall, the data suggest that it is important to use a relevant model for bacterial membranes to gain insight into the mode of action of a given antimicrobial peptide in specific bacteria.

The utility of endobronchial ultrasound-guided transbronchial needle aspiration in a community with a high HIV and tuberculosis burden.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become the gold standard in diagnosing and performing nodal staging in patients with suspected lung cancer and diagnosing other malignant and benign diseases. Studies from countries with low tuberculosis (TB) incidence suggest that it has a sensitivity of 90 - 95% and a specificity of 100%. Objectives: To investigate the utility of EBUS-TBNA in a community with a high HIV and TB burden. Methods: We retrospectively reviewed all patients who underwent EBUS-TBNA to confirm a tissue diagnosis during a 2-year period from January 2017 - December 2018. Only patients with complete medical, pathology and radiology records and follow-up were included. Results: During the 2 years, a total of 201 patients underwent EBUS-TBNA. Some patients (n=19) had incomplete notes or follow-up and 104 cases were ultimately diagnosed with benign nodal disease. In the 182 patients who were ultimately included in the present study, EBUS-TBNA had a sensitivity of 95.1% (95% confidence interval (CI) 88.6 - 98.2), specificity of 100% (95% CI 94.20 - 100), positive predictive value (PPV) of 100.00% (95% CI 95.3 - 100) and negative predictive value (NPV) of 94.1% (95% CI 86.0 - 97.8) for all diagnoses. The overall diagnostic accuracy was 97.3% (95% CI 93.9 - 99.2). Out of the 64 patients who had lung cancer, EBUS-TBNA had a sensitivity of 95.2% (95% CI 86.7 - 99.0), specificity of 100% (95% CI 5.5 - 100), PPV of 100.0% and NPV of 58.3% (95% CI 31.7 - 80.9). The overall diagnostic accuracy for lung cancer was 95.5% (95% CI 87.2 - 99.1%). Conclusion: EBUS-TBNA has high diagnostic accuracy, even in a population with a high HIV and TB burden.

Rapid Assembly of Infection-Resistant Coatings: Screening and Identification of Antimicrobial Peptides Works in Cooperation with an Antifouling Background.

Bacterial adhesion and the succeeding biofilm formation onto surfaces are responsible for implant- and device-associated infections. Bifunctional coatings integrating both nonfouling components and antimicrobial peptides (AMPs) are a promising approach to develop potent antibiofilm coatings. However, the current approaches and chemistry for such coatings are time-consuming and dependent on substrates and involve a multistep process. Also, the information is limited on the influence of the coating structure or its components on the antibiofilm activity of such AMP-based coatings. Here, we report a new strategy to rapidly assemble a stable, potent, and substrate-independent AMP-based antibiofilm coating in a nonfouling background. The coating structure allowed for the screening of AMPs in a relevant nonfouling background to identify optimal peptide combinations that work in cooperation to generate potent antibiofilm activity. The structure of the coating was changed by altering the organization of the hydrophilic polymer chains within the coatings. The coatings were thoroughly characterized using various surface analytical techniques and correlated with the efficiency to prevent biofilm formation against diverse bacteria. The coating method that allowed the conjugation of AMPs without altering the steric protection ability of hydrophilic polymer structure results in a bifunctional surface coating with excellent antibiofilm activity. In contrast, the conjugation of AMPs directly to the hydrophilic polymer chains resulted in a surface with poor antibiofilm activity and increased adhesion of bacteria. Using this coating approach, we further established a new screening method and identified a set of potent surface-tethered AMPs with high activity. The success of this new peptide screening and coating method is demonstrated using a clinically relevant mouse infection model to prevent catheter-associated urinary tract infection (CAUTI).

Self-Limiting Mussel Inspired Thin Antifouling Coating with Broad-Spectrum Resistance to Biofilm Formation to Prevent Catheter-Associated Infection in Mouse and Porcine Models.

Catheter-associated urinary tract infections (CAUTIs) are one of the most commonly occurring hospital-acquired infections. Current coating strategies to prevent catheter-associated biofilm formation are limited by their poor long-term efficiency and limited applicability to diverse materials. Here, the authors report a highly effective non-fouling coating with long-term biofilm prevention activity and is applicable to diverse catheters. The thin coating is lubricous, stable, highly uniform, and shows broad spectrum prevention of biofilm formation of nine different bacterial strains and prevents the migration of bacteria on catheter surface. The coating method is adapted to human-sized catheters (both intraluminal and extraluminal) and demonstrates long-term biofilm prevention activity over 30 days in challenging conditions. The coated catheters are tested in a mouse CAUTI model and demonstrate high efficiency in preventing bacterial colonization of both Gram-positive and Gram-negative bacteria. Furthermore, the coated human-sized Foley catheters are evaluated in a porcine CAUTI model and show consistent efficiency in reducing biofilm formation by Escherichia coli (E. coli) over 95%. The simplicity of the coating method, the ability to apply this coating on diverse materials, and the high efficiency in preventing bacterial adhesion increase the potential of this method for the development of next generation infection resistant medical devices.

Importance of residue 13 and the C-terminus for the structure and activity of the antimicrobial peptide aurein 2.2.

Previous studies on aurein 2.2 and 2.3 in DMPC/DMPG and POPC/POPG membranes have shown that bilayer thickness and phosphatidylglycerol content have a significant impact on the interaction of these peptides with membrane bilayers. Further examination with the DiSC(3)5 assay has indicated that aurein 2.2 induces greater membrane leakage than aurein 2.3 in Staphylococcus aureus C622. The only difference between these peptides is a Leu to Ile mutation at residue 13. To better understand the importance of this residue, the structure and activity of the L13A, L13F, and L13V mutants were investigated. In addition, we investigated a number of peptides with truncations at the C-terminus to determine whether the C-terminus, which contains residue 13, is crucial for antimicrobial activity. Solution circular dichroism results demonstrated that the L13F mutation and the truncation of the C-terminus by six residues resulted in decreased helical content, whereas the L13A or L13V mutation and the truncation of the C-terminus by three residues showed little to no effect on the structure. Oriented circular dichroism results demonstrated that only an extensive C-terminal truncation reduced the ability of the peptide to insert into lipid bilayers. (31)P NMR spectroscopy showed that all peptides disorder the headgroups. The implications of these results in terms of antimicrobial activity and the ability of these peptides to induce leakage in S. aureus are discussed. The results suggest that the presence of the 13th residue in aurein 2.2 is important for structure and activity, but the exact nature of residue 13 is less important as long as it is a hydrophobic residue.

The aetiology of severe community-acquired pneumonia requiring intensive care unit admission in the Western Cape Province, South Africa.

BACKGROUND: Community-acquired pneumonia (CAP) is a common condition, with mortality increasing in patients who require intensive care unit (ICU) admission. A better understanding of the current aetiology of severe CAP will aid clinicians in requesting appropriate diagnostic tests and initiating appropriate empiric antimicrobials. OBJECTIVES: To assess the comorbidities, aetiology and mortality associated with severe CAP in a tertiary ICU in Cape Town, South Africa. METHODS: We retrospectively analysed a prospective registry of all adults admitted to the medical intensive care unit at Tygerberg Hospital with severe CAP over a 1-year period. RESULTS: We identified 74 patients (mean (SD) age 40.0 (15.5) years; 44 females). The patients had a mean (SD) APACHE II score of 21.4 (7.9), and the mean ICU stay was 6.6 days. Of the 74 patients, 16 (21.6%) died in ICU. Non-survivors had a higher mean (SD) APACHE II score than survivors (28.3 (6.8) v. 19.4 (7.1); p<0.001). Mycobacterium tuberculosis (n=16; 21.6%) was the single most common agent identified, followed by Pseudomonas aeruginosa (n=9; 12.2%). All P. aeruginosa isolates were sensitive to first-line treatment. No organism was identified in 32 patients (43.2%). CONCLUSION: M. tuberculosis was the single most common agent identified in patients presenting with CAP. The mortality of CAP requiring invasive ventilation was relatively low, with a strong association between mortality and a higher APACHE II score.

Insights into the mechanism of action of two analogues of aurein 2.2.

The naturally occurring host defense peptide (HDP), aurein 2.2, secreted by the amphibian Litoria aurea, acts as a moderate antibacterial, affecting Gram positive bacteria such as Staphylococcus aureus by forming selective ion pores. In a quest to find more active analogues of aurein 2.2, peptides 73 and 77 were discovered. These peptides were rich in arginine and tryptophan and found to have MICs of 4 µg/mL. Here we examined what impact the increased charge from +2 to +3 and a slight increase in hydrophobic moment relative to aurein 2.2 had on the mechanism of action of these two analogues. Using a time-kill assay, both peptides 73 and 77 were found to kill bacteria more effectively than the parent peptide. Using solution CD and NMR, the peptides were found to not adopt a continuous α-helical structure, i.e. the analogues were not helical from residue 1-13 like the parent peptide. Results obtained from oriented CD (OCD), DiSC35 and pyranine assays and a gel retardation experiment showed that the peptides did not function by membrane perturbation and further showed that peptide 73 and 77 did not interact with DNA. Overall, the data were consistent with these peptides acting as cell penetrating peptides with intracellular targets, which did not appear to be DNA.

Effect of membrane composition on antimicrobial peptides aurein 2.2 and 2.3 from Australian southern bell frogs.

The effects of hydrophobic thickness and the molar phosphatidylglycerol (PG) content of lipid bilayers on the structure and membrane interaction of three cationic antimicrobial peptides were examined: aurein 2.2, aurein 2.3 (almost identical to aurein 2.2, except for a point mutation at residue 13), and a carboxy C-terminal analog of aurein 2.3. Circular dichroism results indicated that all three peptides adopt an alpha-helical structure in the presence of a 3:1 molar mixture of 1,2-dimyristoyl-sn-glycero-3-phosphocholine/1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPC/DMPG), and 1:1 and 3:1 molar mixtures of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPC/POPG). Oriented circular dichroism data for three different lipid compositions showed that all three peptides were surface-adsorbed at low peptide concentrations, but were inserted into the membrane at higher peptide concentrations. The (31)P solid-state NMR data of the three peptides in the DMPC/DMPG and POPC/POPG bilayers showed that all three peptides significantly perturbed lipid headgroups, in a peptide or lipid composition-dependent manner. Differential scanning calorimetry results demonstrated that both amidated aurein peptides perturbed the overall phase structure of DMPC/DMPG bilayers, but perturbed the POPC/POPG chains less. The nature of the perturbation of DMPC/DMPG bilayers was most likely micellization, and for the POPC/POPG bilayers, distorted toroidal pores or localized membrane aggregate formation. Calcein release assay results showed that aurein peptide-induced membrane leakage was more severe in DMPC/DMPG liposomes than in POPC/POPG liposomes, and that aurein 2.2 induced higher calcein release than aurein 2.3 and aurein 2.3-COOH from 1:1 and 3:1 POPC/POPG liposomes. Finally, DiSC(3)5 assay data further delineated aurein 2.2 from the others by showing that it perturbed the lipid membranes of intact S. aureus C622 most efficiently, whereas aurein 2.3 had the same efficiency as gramicidin S, and aurein 2.3-COOH was the least efficient. Taken together, these data show that the membrane interactions of aurein peptides are affected by the hydrophobic thickness of the lipid bilayers and the PG content.

Clinical & pathological features of acute toxicity due to Cassia occidentalis in vertebrates.

Cassia occidentalis is an annual shrub found in many countries including India. Although bovines and ovines do not eat it, parts of the plant are used in some traditional herbal medicines. Several animal studies have documented that fresh or dried beans are toxic. Ingestion of large amounts by grazing animals has caused serious illness and death. The toxic effects in large animals, rodents and chicken are on skeletal muscles, liver, kidney and heart. The predominant systems involved depend upon the animal species and the dose of the beans consumed. Brain functions are often affected. Gross lesions at necropsy consist of necrosis of skeletal muscle fibres and hepatic centrilobular necrosis; renal tubular necrosis is less frequent. Muscle and liver cell necrosis is reflected in biochemical abnormalities. The median lethal dose (LD(50)) is 1 g/kg for mice and rats. Toxicity is attributed to various anthraquinones and their derivatives and alkaloids, but the specific toxins have not been identified. Data on human toxicity are extremely scarce. This review summarizes information available on Cassia toxicity in animals and compares it with toxic features reported in children. The clinical spectrum and histopathology of C. occidentalis poisoning in children resemble those of animal toxicity, affecting mainly hepatic, skeletal muscle and brain tissues. The case-fatality rate in acute severe poisoning is 75-80 per cent in children.

Aurein-Derived Antimicrobial Peptides Formulated with Pegylated Phospholipid Micelles to Target Methicillin-Resistant Staphylococcus aureus Skin Infections.

Antimicrobial peptides have been the focus of considerable research; however, issues associated with toxicity and aggregation have the potential to limit clinical applications. Here, a derivative of a truncated version of aurein 2.2 (aurein 2.2Δ3), namely peptide 73, was investigated, along with its d-amino acid counterpart (D-73) and a retro-inverso version (RI-73). A version that incorporated a cysteine residue to the C-terminus (73c) was also generated, as this form is required to covalently attach antimicrobial peptides to polymers (e.g., polyethylene glycol (PEG) or hyperbranched polyglycerol (HPG)). The antimicrobial activity of the 73-derived peptides was enhanced 2- to 8-fold, and all the derivatives eradicated preformed Staphylococcus aureus biofilms. Formulation of the peptides with compatible polyethylene glycol (PEG)-modified phospholipid micelles alleviated toxicity toward human cells and reduced aggregation. When evaluated in vivo, the unformulated d-enantiomers aggregated when injected under the skin of mice, but micelle encapsulated peptides were well absorbed. Pegylated micelle formulated peptides were investigated for their potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. Formulated peptide 73 reduced abscess size by 36% and bacterial loads by 2.2-fold compared to the parent peptide aurein 2.2Δ3. Micelle encapsulated peptides 73c and D-73 exhibited superior activity, further reducing abscess sizes by 85% and 63% and lowering bacterial loads by 510- and 9-fold compared to peptide 73.

Atrialized right ventricular myxoma in a patient with Ebstein's anomaly.

Ebstein's anomaly is a rare entity affecting around 1 in 200,000 live births and accounts for less than 1% of congenital heart diseases. Ebstein's anomaly with an associated right-sided myxoma is extremely rare, with only one other case report found in the literature. Previous reports have also noted cases of Ebstein's anomaly associated with left-sided myxomas. We describe a female patient with, to our knowledge, the first case of a histopathologically confirmed right ventricular myxoma in the setting of Ebstein's anomaly.

Technical aspects of the Naval Dosimetry Center quality assurance programme.

The purpose of this paper is to describe the technical aspects of the Naval Dosimetry Center (NDC) quality programme. The Navy has been formally monitoring personnel for occupational exposure to ionising radiation since at least 1946. The current system, the DT-702/PD, is the Harshaw 8840 holder and 8841 card. New card and holder checks are performed to verify that the correct LiF elements and holder filters are in the correct location and are of the correct composition. Element correction coefficient (ECC) magnitude and repeatability are also verified. Several quality assurance parameters are checked by a specially designed shipping machine. Calibration cards are used to calibrate each reader and quality control cards are inserted throughout a group of field cards to verify reader operation during the read process. The success of the programme is measured by annual proficiency tests administered by the National Voluntary Laboratory Accreditation Programme and Pacific Northwest National Laboratories.

The application of LiF:Mg,Cu,P to large scale personnel dosimetry: current status and future directions.

LiF:Mg,Cu,P is starting to replace LiF:Mg,Ti in a variety of personnel dosimetry applications. LiF:Mg,Cu,P has superior characteristics as compared to LiF:Mg,Ti including, higher sensitivity, improved energy response for photons, lack of supralinearity and insignificant fading. The use of LiF:Mg,Cu,P in large scale dosimetry programs is of particular interest due to the extreme sensitivity of this material to the maximum readout temperature, and the variety of different dosimetry aspects and details that must be considered for a successful implementation in routine dosimetry. Here we discuss and explain the various aspects of large scale LiF:Mg,Cu,P based dosimetry programs including the properties of the TL material, new generation of TLD readers, calibration methodologies, a new generation of dose calculation algorithms based on the use of artificial neural networks and the overall uncertainty of the dose measurement. The United States Navy (USN) will be the first US dosimetry processor who will use this new material for routine applications. Until June 2002, the Navy used two types of thermoluminescent materials for personnel dosimetry, CaF2:Mn and LiF:Mg,Ti. A program to upgrade the system and to implement LiF:Mg,Cu,P, started in the mid 1990s and was recently concluded. In 2002, the new system replaced the LiF:Mg,Ti and is scheduled to start replacing the CaF2:Mn system in 2006. A pilot study to determine the dosimetric performance of the new LiF:Mg,Cu,P based dosimetry system was recently completed, and the results show the new system to be as good or better than the current system in all areas tested. As a result, LiF:Mg,Cu,P is scheduled to become the primary personnel dosimeter for the entire US Navy in 2006.

The emerging epidemic of HIV infection and AIDS in Asia and the Pacific.

PIP: The countries of Asia in 1988 did not seem to be at great risk of sharing in the virtually global HIV/AIDS epidemic. HIV transmission was not occurring on a large scale in those countries and no dominant pattern of transmission had been established. That situation has, however, dramatically changed such that Asia and the Pacific are now fully part and parcel of the global pandemic. Indeed, Australia and New Zealand were among the first developed countries to record high rates of AIDS incidence during the early 1980s, while Thailand had documented alarming increases in HIV seroprevalence by 1988. In New Zealand and Australia, sex between men was quickly established as the dominant route of transmission, with IV drug use remaining a rare mode. IV drug use appears to have been the major transmission route in southern China, northern Malaysia, and northern Myanmar, while heterosexual transmission dominates in the majority of Asian and Pacific countries. Tuberculosis is the major opportunistic infection in the countries of Asia and a fungal pathogen of increasing importance in the region, Penicillium marneffei, had not been associated with HIV infection until the virus reached Asia. Some governments have been slow to respond, yet others including Australia and Thailand have implemented comprehensive national strategies. Many community level prevention activities are ongoing. Despite these activities and some important successes, HIV infection and its related social, economic, and political consequences continue to threaten Asia and the Pacific.^ieng