Visceral leishmaniasis (VL) is a serious parasitic disease for which control measures are limited and drug resistance is increasing. First and second generation vaccine candidates have not been successful. The goal of the present study was to select possibly immunogenic L. donovani donovani GP63 peptides using immunoinformatics tools and to test their immunogenicity in vitro. The amino acid sequence of L. donovani donovani GP63 [GenBank accession: ACT31401] was screened using the EpiMatrix algorithm for putative T cell epitopes that would bind to the most common HLA class II alleles (DRB1*1101 and DRB1*0804) among at–risk populations. Four T cell epitopes were selected from nine potential candidates. Stimulation of whole blood from healthy volunteers using the peptides separately produced mean IFN-γ and IL-4 levels that were not significantly different from negative controls, while the pooled peptides produced a moderate IFN-γ increase in some volunteers. However, mean IL-10 levels were significantly reduced for all individuals compared with controls. The immunogenicity of these epitopes may be harnessed most effectively in a vaccine delivered in combination with immune-modulating adjuvants.
visceral leishmaniasis; vaccine; T cell epitopes; EpiMatrix
In the title compound, C23H20BrNO4, the pyran ring has a flattened boat conformation with the O and methine C atoms lying to one side of the plane [0.160 (5) and 0.256 (6) Å, respectively] defined by the remaining atoms. Nevertheless, the 4H-benzo[h]chromene ring system approximates a plane (r.m.s. deviation = 0.116 Å) with the bromobenzene ring almost perpendicular [dihedral angle = 83.27 (16)°] and the ester group coplanar [C—C—C—O = 3.4 (5)°]; the methoxy substituent is also coplanar [C—O—C—C = 174.5 (3)°]. In addition to an intramolecular N—H⋯O(ester carbonyl) hydrogen bond, the ester carbonyl O atom also forms an intermolecular N—H⋯O hydrogen bond with the second amine H atom, generating a zigzag supramolecular chain along the c axis in the crystal packing. The chains are linked into layers in the bc plane by N—H⋯Br hydrogen bonds, and these layers are consolidated into a three-dimensional architecture by C—H⋯π interactions.
Water hyacinth, Eichhornia crassipes (Mart) Solms, originating in the amazonian basin, is a warm water aquatic plant. Water hyacinth is considered one of the most productive plants on earth and, accordingly, is considered one of the top ten world's worst weeds. Water hyacinth spread to other tropical and subtropical regions by humans. It invaded about 62 countries in Africa, Asia and North America, and propagated extremely serious ecological, economical and social problems in the region between 40 degrees north and 45 degrees south. The dense weed of water hyacinth forms dense monocultures that can threaten local native species diversity and change the physical and chemical aquatic environment, thus altering ecosystem structure and function by disrupting food chains and nutrient cycling. We have separated and identified nine active fractions from water hyacinth and showed their promising therapeutic activities. Several compounds (alkaloid, phthalate derivatives, propanoid and phenyl derivatives) were identified in the extract of water hyacinth.
water hyacinth; antimicrobial; anticancer; active compounds
Post kala-azar dermal leishmanaisis (PKDL) in Sudan is associated with elevated interferon-γ. To study interferon-γ pathways in PKDL, we genotyped 80 trios from the Masalit ethnic group for polymorphisms at −470 ins/delTT, -270T/C, -56T/C and +95T/C in IFNGR1, and at −179G/A and +874T/A in IFNG. No associations occurred at IFNG. Global association with haplotypes comprising all 4 markers at IFNGR1 (χ210df = 21.97, P=0.015) was observed, associated with a significant (χ21df=4.54, P=0.033) bias in transmission of the haplotype insTT T T T, and less (χ21df=5.59, P=0.018) than expected transmission of insTT C C C. When compared with data on malaria associations from The Gambia, the results suggest a complex pattern of haplotypic variation at the IFNGR1 promoter locus associated with different infectious disease in African populations that reflect the complex roles of IFN-γ in parasite killing versus inflammation and pathogenesis.
PKDL; leishmaniasis; association; IFNGR1
Ultrasound-induced thermal strain imaging (US-TSI) for carotid artery plaque detection requires both high imaging resolution (<100 μm) and sufficient US induced heating to elevate the tissue temperature (~1-3°C within 1-3 cardiac cycles) in order to produce a noticeable change in sound speed in the targeted tissues. Since the optimization of both imaging and heating in a monolithic array design is particularly expensive and inflexible, a new integrated approach is presented that utilizes independent ultrasound arrays to meet the requirements for this particular application. This work demonstrates a new approach in dual-array construction. A 3D printed manifold was built to support both a high resolution 20 MHz commercial imaging array and 6 custom heating elements operating in the 3.5-4 MHz range. For the application of US-TSI on carotid plaque characterization, the tissue target site is 20 to 30 mm deep, with a typical target volume of 2 mm (elevation) × 8 mm (azimuthal) × 5 mm (depth). The custom heating array performance was fully characterized for two design variants (flat and spherical apertures), and can easily deliver 30 W of total acoustic power to produce intensities greater than 15 W/cm2 in tissue target region.
Severe burns cause profound hormonal and metabolic disturbances resulting in hypermetabolism, reflected in extreme elevation of resting energy expenditure (REE) and extensive skeletal muscle catabolism. Aerobic and resistive exercise programs during rehabilitation have shown substantial benefits, although whether such training potentially exacerbates basal metabolism is unknown. We therefore examined the effects of exercise training upon REE during the rehabilitation of severely burned pediatric patients.
Children with 40% total body surface area (TBSA) burns and greater were enrolled on admission to our burn intensive-care unit to participate in a twelve-week, hospital-based exercise program (EX), or a home-based standard of care program (SOC), commencing six months post-injury.
Twenty-one patients (7–17 years) were enrolled and randomized to SOC (n=10) or EX (n=11). Age, gender, and TBSA burned were similar. Mean change (± sd) in REE, normalized to individual lean body mass (LBM), was almost negligible between SOC and EX group patients (0.03 ± 17.40%, SOC vs. 0.01 ± 26.38%, EX). A significant increase in LBM was found for EX patients (2.06 ± 3.17%, SOC vs. 8.75 ± 5.65%, EX; p=0.004), which persisted when normalized to height (0.70 ± 2.39%, SOC vs. 6.14 ± 6.46%, EX; p=0.02). Peak torque also improved significantly more in EX patients (12.29 ± 16.49%, SOC vs. 54.31 ± 44.25%, EX; p=0.02), reflecting improved strength.
Exercise training significantly enhanced lean mass and strength, without observed exacerbation of post-burn hypermetabolism. We therefore advocate use of exercise conditioning as a safe and effective component of pediatric burn rehabilitation.
muscle strength; peak torque; hypermetabolism; indirect calorimetry; metabolic rate
Procainamide and its major metabolite, N-acetyl procainamide (NAPA), prolong the QTc interval and can promote potentially fatal ventricular arrhythmias. Excretion of procainamide and NAPA is reduced in patients with chronic kidney disease (CKD) resulting in drug accumulation and toxicity. The elimination of procainamide or NAPA in patients undergoing continuous renal replacement therapy (CRRT) has not been evaluated increasing the risk for subtherapeutic or toxic dosing regimens. This case report describes a patient undergoing CRRT who was administered procainamide for recurring ventricular tachycardia (VT) over approximately a 36 hour period. The patient required increased vasopressor therapy and developed QTc prolongation during procainamide administration. The VT resided following pacemaker adjustments, procainamide administration, and multiple direct current cardioversion attempts. Procainamide and NAPA concentrations were determined over a 120 hour period as part of routine clinical care and a pharmacokinetic (PK) model was developed using NONMEM. The developed PK model was used to simulate several procainamide dosing regimens to optimize therapy during CRRT. Based on the model-based simulations, a 50% reduction in the procainamide maintenance dose (2 mg/min) in CKD patients on CRRT can achieve therapeutic plasma procainamide and combined procainamide/NAPA concentrations.
Visceral leishmaniasis (VL) is a neglected parasitic disease that is fatal if left untreated and is endemic in eastern Sudan. We estimated the direct and indirect costs of treatment of VL from the perspective of the provider and the household at three public hospitals in Gedaref State. The median total cost for one VL episode was estimated to be US$450. Despite the free provision of VL drugs at public hospitals, households bore 53% of the total cost of VL with one episode of VL representing 40% of the annual household income. More than 75% of households incurred catastrophic out-of-pocket expenditures. The length of treatment of 30 days led to important costs for both health providers and households. Alternative treatment regimens that reduce the duration of treatment are urgently needed.
Microsurgical vascularized bone flaps are a versatile technique for reconstructing large bone defects. However, assessment of perfusion is challenging, as clinical examination is difficult intra-operatively and often not possible post-operatively. Therefore, it is important to develop techniques to assess perfusion of vascularized bone flaps, and potentially improve surgical outcomes. Near-infrared (NIR) fluorescence imaging has been previously shown to provide real-time, intra-operative evaluation of vascular perfusion. This pilot study investigates the ability of NIR imaging to assess perfusion of vascularized bone flaps.
Materials and Methods
Vascularized bone flaps were created on female Yorkshire pigs using well-established models for porcine forelimb osteomyocutaneous flap allotransplantation (N = 8) and hindlimb fibula flaps (N = 8). Imaging of the bone flaps was performed during harvest using the FLARE™ intraoperative fluorescence imaging system following systemic injection of indocyanine green (ICG). Perfusion was also assessed using standard of care by clinical observation and Doppler. NIR fluorescence perfusion assessment was confirmed by intermittent clamping of the vascular pedicle.
NIR fluorescence imaging can identify bone perfusion at the cut end of the osteotomy site. When the vascular pedicle is clamped or ligated, NIR imaging demonstrates no fluorescence when injected with ICG. With clamp removal, the osteotomy site emits fluorescence indicating bone perfusion. Results using fluorescence imaging show 100% agreement with clinical observation and Doppler.
Vascularized bone transfers have become an important tool in reconstructive surgery; however, no established techniques adequately assess perfusion. Our pilot study indicates that NIR imaging can provide real-time, intra-operative assessment of bone perfusion.
Near-infrared imaging; vascularized bone flaps; bone perfusion; microsurgery; free flap; composite tissue allotransplantation
Ameloblastomas are rare, slowly growing and locally invasive tumours with high recurrence rate, if not treated they can grow to enormous size; we report five such cases in our article and discuss their surgical management. We report five cases of giant ameloblastoma presented in our institute between 2007 and 2010, we treated them surgically with wide margin of resection. It is widely reported that recurrence of ameloblastoma in many cases reflects the inadequacy or failure of the primary surgical procedure. We treated all our cases with radical excision with free flap reconstruction with no recurrence in any of our patients in 2 years follow-up. Radical excision of these benign but locally invasive lesions, which grows to giant size with reconstruction using micro vascular free flaps forms the best modality of treatment.
Ameloblastoma; Surgical management; Radical excision
Retinal neuropathy is an early event in the development of diabetic retinopathy. One of the potential enzymes that are activated by oxidative stress in the diabetic retina is poly (ADP-ribose) polymerase (PARP). We investigated the effect of the PARP inhibitor 1,5-isoquinolinediol on the expression of the neurodegeneration mediators and markers in the retinas of diabetic rats. After two weeks of streptozotocin-induced diabetes, rats were treated with 1,5-isoquinolinediol (3 mg/kg/day). After 4 weeks of diabetes, the retinas were harvested and the levels of reactive oxygen species (ROS) were determined fluorometrically and the expressions of PARP, phosporylated-ERK1/2, BDNF, synaptophysin, glutamine synthetase (GS), and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, PARP-1/2, phosphorylated ERK1/2, and cleaved caspase-3 were significantly increased, whereas the expressions of BDNF synaptophysin and GS were significantly decreased in the retinas of diabetic rats, compared to nondiabetic rats. Administration of 1,5-isoquinolinediol did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of PARP, ROS, ERK1/2 phosphorylation, and cleaved caspase-3 and downregulation of BDNF, synaptophysin, and GS. These findings suggest a beneficial effect of the PARP inhibitor in increasing neurotrophic support and ameliorating early retinal neuropathy induced by diabetes.
Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model.
Isoflurane, ketamine-xylazine (KX), or pentobarbital, with or without buprenorphine, were administered prior to scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 hours, and compared to unburned shams. In a second experiment, 120 rats underwent the same scald-burn injury using KX, and 24 hours later were euthanized under anesthesia or carbon dioxide (CO2). Additionally, we compared euthanasia by exsanguination versus decapitation. Serum cytokine levels were determined by ELISA.
In the first experiment, isoflurane was associated with elevation of cytokine-induced neutrophil chemoattractant (CINC)-2, and monocyte chemotactic protein-1 (MCP-1), and KX and pentobarbital with elevation of CINC-1 and 2, interleukin (IL)-6 and MCP-1. Pentobarbital also decreased IL-1β. Interleukin-6 increased significantly when isoflurane or pentobarbital were combined with buprenorphine. In the second experiment, euthanasia performed by exsanguination under isoflurane was associated with reduced levels of IL-1β, CINC-1 and 2, and MCP-1, while KX reduced CINC-2 and increased IL-6 levels. Meanwhile, pentobarbital reduced levels of IL-1β and MCP-1, and CO2 reduced CINC-2 and MCP-1. Additionally, decapitation following KX, pentobarbital or CO2 decreased IL-1β and MCP-1, whilst we found no significant difference between isoflurane and controls. Euthanasia by exsanguination compared to decapitation using the same agent also led to modulation of several cytokines.
Differential expression of inflammatory markers with the use of anesthetics and analgesics should be considered when designing animal studies and interpreting results, as these appear to have significant modulating impact. Our findings indicate a brief anesthesia with isoflurane immediately prior to euthanasia by decapitation exerted the least dampening effect on the cytokines measured. Conversely, KX with buprenorphine may offer a better balance during longer procedures to avoid significant modulation. Standardization across all experiments that are compared and awareness of these findings is essential for those investigating the pathophysiology of inflammation in animal models.
Isoflurane; ketamine; xylazine; pentobarbital; buprenorphine; animal model; sacrifice techniques; IL-1β; IL-6; TNF-α; CINC-1; CINC-2; MCP-1
sepsis; adrenoceptor; burns; trauma; perioperative care
The release of prothoracicotropic hormone, PTTH, or its blockade is the major endocrine switch regulating the developmental channel either to metamorphosis or to pupal diapause in the Chinese silk moth, Antheraea pernyi. We have cloned cDNAs encoding two types of serotonin receptors (5HTRA and B). 5HTRA-, and 5HTRB-like immunohistochemical reactivities (-ir) were colocalized with PTTH-ir in two pairs of neurosecretory cells at the dorsolateral region of the protocerebrum (DL). Therefore, the causal involvement of these receptors was suspected in PTTH release/synthesis. The level of mRNA5HTRB responded to 10 cycles of long-day activation, falling to 40% of the original level before activation, while that of 5HTRA was not affected by long-day activation. Under LD 16:8 and 12:12, the injection of dsRNA5HTRB resulted in early diapause termination, whereas that of dsRNA5HTRA did not affect the rate of diapause termination. The injection of dsRNA5HTRB induced PTTH accumulation, indicating that 5HTRB binding suppresses PTTH synthesis also. This conclusion was supported pharmacologically; the injection of luzindole, a melatonin receptor antagonist, plus 5th inhibited photoperiodic activation under LD 16:8, while that of 5,7-DHT, induced emergence in a dose dependent fashion under LD 12:12. The results suggest that 5HTRB may lock the PTTH release/synthesis, maintaining diapause. This could also work as diapause induction mechanism.
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF−/−, or p53−/−), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value.
The association of human leukocyte antigen B27 (HLA-B27) with anterior uveitis is well known. The prevalence of HLA-B27 and its relation to anterior uveitis is related to race and geographic location. The association is strongest in Western countries and weakest in Eastern countries. Data regarding this association from Middle Eastern countries are limited. Thus, we undertook the study reported here to evaluate the association of HLA-B27 with anterior uveitis in patients in a tertiary center in the western region of the Saudi Arabia.
The study involved a retrospective analysis of the records of patients with anterior uveitis, referred to the uveitis clinic in Magrabi Eye and Ear Hospital, Jeddah, Saudi Arabia, from 1999 to 2010. The cost-effectiveness of HLA-B27 testing was analyzed.
Among the 587 cases of uveitis, 335 (57.1%; mean age 37.56±12.82 years; 203 male and 132 female) cases were of anterior uveitis. All patients with anterior uveitis were investigated for HLA-B27 positivity. Idiopathic anterior uveitis was the most common (80%), followed by Fuchs heterochromic cyclitis (7.45%) and ankylosing spondylitis (3.8%). Only two patients were HLA-B27 positive. The cost-effectiveness of HLA-B27 testing was found to be 165,000 Saudi riyals (44,594 US dollars) per positive case.
HLA-B27-related uveitis appears to be very rare in our part of the world. Idiopathic uveitis is the most common type of anterior uveitis. The cost-effectiveness of HLA-B27 testing is low for patients with anterior uveitis in the western region of Saudi Arabia.
HLA-B27; Saudi population; cost-effectiveness; idiopathic anterior uveitis; Fuchs heterochromic cyclitis; ankylosing spondylitis
How the direction of axon guidance is determined is not understood. In Caenorhabditis elegans the UNC-40 (DCC) receptor mediates a response to the UNC-6 (netrin) guidance cue that directs HSN axon development. UNC-40 becomes asymmetrically localized within the HSN neuron to the site of axon outgrowth. Here we provide experimental evidence that the direction of guidance can be explained by the stochastic fluctuations of UNC-40 asymmetric outgrowth activity. We find that the UNC-5 (UNC5) receptor and the cytoskeletal binding protein UNC-53 (NAV2) regulate the induction of UNC-40 localization by UNC-6. If UNC-40 localization is induced without UNC-6 by using an unc-53 mutation, the direction of UNC-40 localization undergoes random fluctuations. Random walk models describe the path made by a succession of randomly directed movement. This model was experimentally tested using mutations that affect Wnt/PCP signaling. These mutations inhibit UNC-40 localization in the anterior and posterior directions. As the axon forms in Wnt/PCP mutants, the direction of UNC-40 localization randomly fluctuates; it can localize in either the anterior, posterior, or ventral direction. Consistent with a biased random walk, over time the axon will develop ventrally in response to UNC-6, even though at a discrete time UNC-40 localization and outgrowth can be observed anterior or posterior. Also, axon formation is slower in the mutants than in wild-type animals. This is also consistent with a random walk since this model predicts that the mean square displacement (msd) will increase only linearly with time, whereas the msd increases quadratically with time for straight-line motion.
Caenorhabditis elegans; DCC receptor; Netrin; Stochastic Process; UNC-6; Axon guidance; Wnt signaling; Neurons
Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.
Composite tissue allografts (CTAs) including partial face transplantation have been achieved clinically. However, risks of complications including tissue ischemia, rejection, and transplant failure are significant. Safe and effective techniques to assess perfusion are needed to decrease complications in composite tissue flaps. Near-infrared (NIR) fluorescence imaging has been previously shown to provide a real-time, intraoperative evaluation of perfusion. This study investigates the use of NIR imaging in partial face CTA harvest.
Materials and Methods
Hemifacial CTAs (N = 8) were created using an established porcine model. This included ear cartilage, nerve, lymphoid tissue, muscle, and skin with perfusion by the carotid artery and external jugular vein. Animals were injected systemically with indocyanine green (ICG), and NIR fluorescence images were obtained simultaneously with color video. In addition, the elevated hemifacial flaps were assessed using standard of care, i.e. clinical examination and Doppler.
Flap design was facilitated by NIR imaging with localization of perforators to the hemifacial CTA flap. In particular, an arterial and venous phase could be clearly identified. Perfusion of the flap was assessed by NIR fluorescence intensity following injection of ICG. Sequential clamping of the artery and vein confirmed correlation of perfusion deficits with NIR imaging as well as with clinical examination and Doppler.
Evaluation and assessment of perfusion is important in facial transplantation. The results from our pilot study indicate that NIR imaging has the capability to assess perfusion of partial facial CTAs. This emergent technology shows promise in assessing tissue perfusion in a composite flap.
Near-infrared imaging; face transplantation; composite tissue allotransplantation; microsurgery; free flap
To verify the association between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) and evaluate the influence of sildenafil and doxazosin either as single agents or combined on both symptoms.
Material and Methods:
A prospective randomized study including 150 patients presented with LUTS caused by BPH in association with clinically diagnosed ED, with age equal or more than 45 years from April 2010 to April 20011. They were categorized into three comparative groups each one containing 50 patients. These groups were comparable regarding pretreatment international prostate symptoms score (IPSS) and international index of erectile function (IIEF). The patients of the first group were given sildenafil 50 mg as monotherapy, those of the second group were given doxazosin 2 mg and those of the third group were given combination of both drugs for 4 months for each group. The main post-treatment parameters for assessment and comparison include assessment of patient's symptoms by repeated IPS Sand IIEF, uroflowmetry and assessment of PVR. The statistics was done by use of the Qui--square test.
Pre-treatment parameters were assessed and compared between the three groups. After 4 months of treatment, the comparative parameters were applied to all groups and the differences were measured post-treatment regarding IPSS, erectile function score, uroflowmetry, and post-void residual (PVR) urine. Sildenafil alone caused mild improvement in IPSS, more improvement in IIEF score, and little effect on flow rate and PVR urine. Doxazosin alone caused more improvement in IPSS, flow rate and PVR urine and less improvement in IIEF score. A combination of both sildenafil and doxazosin caused more improvement in all of the comparative parameters than when each drug was given alone.
There is a strong relationship between LUTS and ED. Doxazosin or sidenafil as a single drug could be used in treating mild or mild to moderate symptoms but more severe symptoms may usually need a combination of both drugs.
Doxazosin; erectile dysfunction; lower urinary tract symptoms; sildenafil
Diabetic retinopathy (DR), the most common long-term complication of diabetes mellitus, remains one of the leading causes of blindness worldwide. Tight glycemic and blood pressure control has been shown to significantly decrease the risk of development as well as the progression of retinopathy and represents the cornerstone of medical management of DR. The two most threatening complications of DR are diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). Focal/grid photocoagulation and panretinal photocoagulation are standard treatments for both DME and PDR, respectively. Focal/grid photocoagulation is a better treatment than intravitreal triamcinolone acetonide in eyes with DME. Currently, most experts consider combination focal/grid laser therapy and pharmacotherapy with intravitreal antivascular endothelial growth factor agents in patients with center-involving DME. Combination therapy reduces the frequency of injections needed to control edema. Vitrectomy with removal of the posterior hyaloid seems to be effective in eyes with persistent diffuse DME, particularly in eyes with associated vitreomacular traction. Emerging therapies include fenofibrate, ruboxistaurin, renin-angiotensin system blockers, peroxisome proliferator-activated receptor gamma agonists, pharmacologic vitreolysis, and islet cell transplantation.
Diabetic Retinopathy; Review; Treatment
Non-calcified coronary artery plaque (NCAP) may be an important predictor of cardiovascular events, however, few studies have directly measured NCAP in HIV-infected individuals.
We completed a prospective cross-sectional evaluation of NCAP and coronary calcium scores using CT angiography in HIV-infected subjects (n=26) without known coronary artery disease (CAD), but who had one or more CAD risk factor and compared them to controls matched on age, race, sex, body mass index and Framingham risk score (n=26).
There was no difference in coronary calcium scores (114 ± 218 vs. 124 ± 298 p=0.89) or NCAP volume (65 ± 86 mm3 vs. 63 ± 82 mm3, p=0.38) between HIV-infected subjects and controls, respectively. Among HIV-infected subjects, lower CD4 count was associated with increased NCAP volume (r=-0.52, p=0.006). CD4 count remained a significant predictor of NCAP in a multivariate analysis that adjusted for age and duration of antiretroviral therapy.
Plaque burden is similar between HIV-infected and uninfected individuals when matched on traditional CAD risk factors, however immune function may mediate the development of atherosclerosis in HIV infection.
non-calcified coronary plaque (NCAP) volume; HIV; cardiovascular disease
Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, the TH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the “superstar” at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights into TH17's contributions to autoimmunity.
Women with X-chromosome monosomy, or Turner syndrome (TS), are at increased risk for aortic dilation and dissection. To better understand the pathology and develop tools to monitor the risk of aortic disease, we investigated N-terminal pro brain natriuretic peptide (NT-proBNP) levels in women with TS and healthy female controls.
We evaluated NT-proBNP levels in women with karyotype-proven TS and healthy female volunteers in relation to ascending aortic diameter (AAD) and descending aortic diameter (DAD) measured by cardiovascular MRI.
NT-proBNP levels were strongly and positively correlated with AAD and DAD in both cohorts. The TS group (n = 114, age = 37.4 ± 12 yr) had greater BSA-indexed aortic diameters and higher NT-proBNP levels than the control group (n = 27, age = 46.4 ± 11 yr): 88.3 ± 62.7 vs. 53.5 ± 35 pg/mL; P = 0.0003. Within the TS group, NT-proBNP levels were higher in those with dilated ascending aorta (n = 42; 112.4 ± 75.7 pg/mL) compared to those with normal aortic dimensions (n = 72; 74.2 ± 49 pg/mL, P = 0.0014). Abnormally high BNP levels were seen in 3 of 4 TS women that presented with previously undetected aortic aneurysm and/or dissection.
NT-proBNP levels are positively associated with aortic diameters in women with and without TS, suggesting a role for BNP in arterial wall homeostasis. Further study is necessary to determine whether NT-proBNP measurement may be used to monitor aortic diameter and/or detect aortic pathology in individuals at risk for aortic disease.