Evaluate the effect of nicotine on anti-VEGF therapy in the treatment of neovascular age-related macular degeneration (AMD).
One group of mice received nicotine in drinking water and the other group received water only. Choroidal neovascularization (CNV) was induced with a laser. Nicotinic acetylcholine receptor (nAChR) α7 expression was evaluated by immunohistochemistry (IHC). Bevacizumab or adiponectin peptide II (APNpII) was injected intravitreally on day 7 post-laser and the effects were evaluated on days 14 and 21. α-bungerotoxin was injected intraperitoneally on days 2–5 and its effect evaluated on day 14.
Expression of nAChR α7 was 2–7 times higher between days 3 and 7 post-laser compared to naïve mice. In water fed mice, APNpII, bevacizumab, and α-bungarotoxin significantly reduced CNV size. In nicotine fed mice, treatment with APNpII or bevacizumab did not significantly reduce CNV size, whereas α-bungerotoxin did have an effect. Comparing water and nicotine mice, CNV size was 61–86% smaller in water mice except for the α-bungarotoxin group where there was no difference. PDGF and VEGF expression was 1.5–2.5 fold higher at day 14 in nicotine treated mice.
Nicotine significantly blocks the effect of anti-VEGF therapy in the treatment of laser induced neovascular AMD. nAChR α7 is significantly up-regulated during the formation of CNV and treatment with a nAChR α7 antagonist decreases CNV size irrespective of nicotine administration-
Adiponectin; age-related macular degeneration; Bevacizumab; choroidal neovascularization; mouse model; nicotine acetylcholine receptor; platelet derived growth factor; smoking; vascular endothelial growth factor; α-bungerotoxin
The aim of this study was to determine a genetic basis for IgA concentration in milk of Bos taurus. We used a Holstein-Friesian x Jersey F2 crossbred pedigree to undertake a genome-wide search for QTL influencing IgA concentration and yield in colostrum and milk. We identified a single genome-wide significant QTL on chromosome 16, maximising at 4.8 Mbp. The polymeric immunoglobulin receptor gene (PIGR) was within the confidence interval of the QTL. In addition, mRNA expression analysis revealed a liver PIGR expression QTL mapping to the same locus as the IgA quantitative trait locus. Sequencing and subsequent genotyping of the PIGR gene revealed three divergent haplotypes that explained the variance of both the IgA QTL and the PIGR expression QTL. Genetic selection based on these markers will facilitate the production of bovine herds producing milk with higher concentrations of IgA.
Understanding the pathology resulting from Staphylococcus aureus and Pseudomonas aeruginosa polymicrobial wound infections is of great importance due to their ubiquitous nature, increasing prevalence, growing resistance to antimicrobial agents, and ability to delay healing. Methicillin-resistant S. aureus USA300 is the leading cause of community-associated bacterial infections resulting in increased morbidity and mortality. We utilized a well-established porcine partial thickness wound healing model to study the synergistic effects of USA300 and P. aeruginosa on wound healing. Wound re-epithelialization was significantly delayed by mixed-species biofilms through suppression of keratinocyte growth factor 1. Pseudomonas showed an inhibitory effect on USA300 growth in vitro while both species co-existed in cutaneous wounds in vivo. Polymicrobial wound infection in the presence of P. aeruginosa resulted in induced expression of USA300 virulence factors Panton-Valentine leukocidin and α-hemolysin. These results provide evidence for the interaction of bacterial species within mixed-species biofilms in vivo and for the first time, the contribution of virulence factors to the severity of polymicrobial wound infections.
Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion–diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion–diffusion mismatch (Tmax>6 seconds, ratio>1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion–diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.
brain ischemia; cerebrovascular disease; diffusion-weighted MRI; MRI; thrombolysis
To examine the effects of crossing over from optimized multiple daily injection (MDI) therapy to sensor-augmented pump (SAP) therapy for 6 months, and the effects of 18 months’ sustained use of SAP.
RESEARCH DESIGN AND METHODS
The 6-month, single-crossover continuation phase of Sensor-Augmented Pump Therapy for A1C Reduction (STAR 3) provided SAP therapy to 420 subjects who completed the 1-year randomized study. The primary outcome was change in A1C in the crossover group.
A1C values were initially lower in the continuing-SAP group than in the crossover group (7.4 vs. 8.0%, P < 0.001). A1C values remained reduced in the SAP group. After 3 months on the SAP system, A1C decreased to 7.6% in the crossover group (P < 0.001); this was a significant and sustained decrease among both adults and children (P < 0.05).
Switching from optimized MDI to SAP therapy allowed for rapid and safe A1C reductions. Glycemic benefits of SAP therapy persist for at least 18 months.
Predicting the dynamics of zoonoses in wildlife is important not only for prevention of transmission to humans, but also for improving the general understanding of epidemiological processes. A large dataset on sylvatic plague in the Pre-Balkhash area of Kazakhstan (collected for surveillance purposes) provides a rare opportunity for detailed statistical modelling of an infectious disease. Previous work using these data has revealed a host abundance threshold for epizootics, and climatic influences on plague prevalence. Here, we present a model describing the local space–time dynamics of the disease at a spatial scale of 20 × 20 km2 and a biannual temporal scale, distinguishing between invasion and persistence events. We used a Bayesian imputation method to account for uncertainties resulting from poor data in explanatory variables and response variables. Spatial autocorrelation in the data was accounted for in imputations and analyses through random effects. The results show (i) a clear effect of spatial transmission, (ii) a high probability of persistence compared with invasion, and (iii) a stronger influence of rodent abundance on invasion than on persistence. In particular, there was a substantial probability of persistence also at low host abundance.
Yersinia pestis; great gerbil; space–time dynamics; Bayesian imputation; spatial correlation
Recanalization of arterial obstruction is associated with improved clinical outcomes. There are no controlled data demonstrating whether arterial obstruction status predicts the treatment effect of intravenous (IV) tissue plasminogen activator (tPA). We aimed to determine if the presence of arterial obstruction improves the treatment effect of IV tPA over placebo in attenuating infarct growth.
We analyzed 175 ischemic stroke patients treated in the 3-6 hour time window from the EPITHET trial (randomized to IV tPA or placebo) and DEFUSE study (all treated with IV tPA). Infarct growth was calculated as the difference between baseline DWI and final T2 lesion volumes. Baseline arterial obstruction of large intracranial arteries was graded on magnetic resonance angiography (MRA).
Among the 116 patients with adequate baseline MRA and final lesion assessment, 72 had arterial obstruction (48 tPA, 24 placebo) and 44 no arterial obstruction (33 tPA, 11 placebo). Infarct growth was lower in the tPA than placebo group (median difference 26mL, 95% CI 1 to 50) in patients with arterial obstruction, but was similar in patients with no arterial obstruction (median difference 5mL, 95%CI -3 to 9). Infarct growth attenuation with tPA over placebo treatment was greater among patients with arterial obstruction than those without arterial obstruction by a median of 32 mL (95%CI 21to 43, p<0.001).
The treatment effect of IV tPA over placebo was greater with baseline arterial obstruction, supporting arterial obstruction status as a consideration in selecting patients more likely to benefit from IV thrombolysis.
Fluid-attenuated inversion recovery (FLAIR) hyperintensity within an acute cerebral infarct may reflect delayed onset time and increased risk of hemorrhage after thrombolysis. Given the important implications for clinical practice, we examined the prevalence of FLAIR hyperintensity in patients 3–6 h from stroke onset and its relationship to parenchymal hematoma (PH).
Baseline DWI and FLAIR imaging with subsequent hemorrhage detection (ECASS criteria) were prospectively obtained in patients 3–6 h after stroke onset from the pooled EPITHET and DEFUSE trials. FLAIR hyperintensity within the region of the acute DWI lesion was rated qualitatively (dichotomized as visually obvious or subtle (i.e. only visible after careful windowing)) and quantitatively (using relative signal intensity (RSI)). The association of FLAIR hyperintensity with hemorrhage was then tested alongside established predictors (very low cerebral blood volume (VLCBV) and diffusion (DWI) lesion volume) in logistic regression analysis.
There were 49 patients with pre-treatment FLAIR imaging (38 received tissue plasminogen activator (tPA), 5 developed PH). FLAIR hyperintensity within the region of acute DWI lesion occurred in 48/49 (98%) patients, was obvious in 18/49 (37%) and subtle in 30/49 (61%). Inter-rater agreement was 92% (κ = 0.82). The prevalence of obvious FLAIR hyperintensity did not differ between studies obtained in the 3–4.5 h and 4.5–6 h time periods (40% vs. 33%, p = 0.77). PH was poorly predicted by obvious FLAIR hyperintensity (sensitivity 40%, specificity 64%, positive predictive value 11%). In univariate logistic regression, VLCBV (p = 0.02) and DWI lesion volume (p = 0.03) predicted PH but FLAIR lesion volume (p = 0.87) and RSI (p = 0.11) did not. In ordinal logistic regression for hemorrhage grade adjusted for age and baseline stroke severity (NIHSS), increased VLCBV (p = 0.002) and DWI lesion volume (p = 0.003) were associated with hemorrhage but FLAIR lesion volume (p = 0.66) and RSI (p = 0.35) were not.
Visible FLAIR hyperintensity is almost universal 3–6 h after stroke onset and did not predict subsequent hemorrhage in this dataset. Our findings question the value of excluding patients with FLAIR hyperintensity from reperfusion therapies. Larger studies are required to clarify what implications FLAIR-positive lesions have for patient selection.
Stroke; Tissue plasminogen activator; MRI; Fluid-attenuated inversion recovery
Anomalous diffusion can be characterized by a mean-squared displacement 〈x2(t)〉 that is proportional to tα where α≠1. A class of one-dimensional moving boundary problems is investigated that involves one or more regions governed by anomalous diffusion, specifically subdiffusion (α<1). A novel numerical method is developed to handle the moving interface as well as the singular history kernel of subdiffusion. Two moving boundary problems are solved: the first involves a subdiffusion region to the one side of an interface and a classical diffusion region to the other. The interface will display non-monotone behaviour. The subdiffusion region will always initially advance until a given time, after which it will always recede. The second problem involves subdiffusion regions to both sides of an interface. The interface here also reverses direction after a given time, with the more subdiffusive region initially advancing and then receding.
moving boundary; anomalous diffusion; subdiffusion; fractional diffusion equation
The aim of this study was to determine if automated MRI Analysis Software (RAPID) can be used to identify stroke patients in whom reperfusion is associated with an increased chance of good outcome.
Baseline diffusion (DWI) and perfusion-weighted MRI scans (PWI) from DEFUSE (n=74) and EPITHET (n=100) were reprocessed with RAPID. Based on RAPID-generated DWI and PWI lesion volumes, patients were categorized according to three pre-specified MRI profiles that were hypothesized to predict benefit (Target Mismatch), harm (Malignant), and no effect (No Mismatch) from reperfusion. Favorable clinical response was defined as a NIHSS score of 0–1 or a ≥8 point improvement on the NIHSS score at day 90.
In Target Mismatch patients reperfusion was strongly associated with a favorable clinical response (odds ratio 5.6; 95% CI 2.1–15.3) and attenuation of infarct growth (10±23 mL with reperfusion vs 40±44 mL without reperfusion p<0.001). In Malignant profile patients reperfusion was not associated with favorable clinical response (odds ratio 0.74; 95% CI 0.1–5.8) or attenuation of infarct growth (85±74mL with reperfusion vs 95±79 mL without reperfusion p=0.7). Reperfusion was also not associated with favorable clinical response (odds ratio 1.05; 95% CI 0.1–9.4) or attenuation of lesion growth (10±15 mL with reperfusion vs 17±30 mL without reperfusion p=0.9) in No Mismatch patients.
MRI profiles that are associated with a differential response to reperfusion can be identified with RAPID. This supports the use of automated image analysis software such as RAPID for patient selection in acute stroke trials.
Stroke; tissue plasminogen activator; MRI
A total of 41 Clostridium botulinum serotype E strains from different geographic regions, including Canada, Denmark, Finland, France, Greenland, Japan, and the United States, were compared by multilocus sequence typing (MLST), amplified fragment length polymorphism (AFLP) analysis, variable-number tandem-repeat (VNTR) analysis, and botulinum neurotoxin (bont) E gene sequencing. The strains, representing environmental, food-borne, and infant botulism samples collected from 1932 to 2007, were analyzed to compare serotype E strains from different geographic regions and types of botulism and to determine whether each of the strains contained the transposon-associated recombinase rarA, involved with bont/E insertion. MLST examination using 15 genes clustered the strains into several clades, with most members within a cluster sharing the same BoNT/E subtype (BoNT/E1, E2, E3, or E6). Sequencing of the bont/E gene identified two new variants (E7, E8) that showed regions of recombination with other E subtypes. The AFLP dendrogram clustered the 41 strains similarly to the MLST dendrogram. Strains that could not be differentiated by AFLP, MLST, or bont gene sequencing were further examined using three VNTR regions. Both intact and split rarA genes were amplified by PCR in each of the strains, and their identities were confirmed in 11 strains by amplicon sequencing. The findings suggest that (i) the C. botulinum serotype E strains result from the targeted insertion of the bont/E gene into genetically conserved bacteria and (ii) recombination events (not random mutations) within bont/E result in toxin variants or subtypes within strains.
To refine the definition of the Malignant MRI profile in acute stroke patients using baseline DWI and PWI findings from the pooled DEFUSE/EPITHET database.
Patients presenting with acute stroke within 3-6 hours from symptom onset were treated with tPA or placebo. Baseline and follow-up DWI and PWI images from both studies were reprocessed using the same software program. An ROC curve analysis was used to identify Tmax and DWI volumes that optimally predicted poor outcomes (mRS 5-6) at 90 days in patients who achieved reperfusion.
Sixty-five patients achieved reperfusion and 46 did not reperfuse. ROC analysis identified a PWI (Tmax>8s) volume of >85 mL as the optimal definition of the Malignant profile. Eighty-nine percent of the Malignant profile patients had poor outcome with reperfusion versus 39% without reperfusion (p=0.02). Parenchymal hematomas occurred more frequently in Malignant profile patients who experienced reperfusion vs. no reperfusion (67% vs. 11%, p<0.01). DWI analysis identified a volume of 80 mL as the best DWI threshold, but this definition was less sensitive than PWI-based definitions.
Stroke patients likely to suffer parenchymal hemorrhages and poor outcomes following reperfusion can be identified from baseline MRI findings. The current analysis demonstrates that a PWI threshold (Tmax>8s) of approximately 100 mL is appropriate for identifying these patients. Exclusion of Malignant profile patients from reperfusion therapies may substantially improve the efficacy and safety of reperfusion therapies.
Clinical Trial Registration Information
EPITHET study is registered on www.clinicaltrials.gov, unique identifier NCT00238537.
Acute Stroke; DWI; PWI; MRI; Thrombolysis; tPA; Reperfusion
Riley’s Stuttering Severity Instrument (SSI) is widely-used. The manuals allows SSI assessments to be made in different ways (e.g. from digital recordings or whilst listening to speech live). Digital recordings allow segments to be selected and listened to while the entire recording has to be judged when listened to live. Comparison was made between expert judges when they used these digital and live procedures to establish whether one method was more sensitive and reliable than the other.
Five expert judges assessed eight speakers four times each in two judgment conditions (digital versus live). The eight speakers were chosen so that they spanned a wide range of stuttering severity. SSI version 3 (SSI-3) estimates were obtained on all occasions.
An ANOVA showed a three-way interaction between sessions, speakers and condition that indicated that digital and live judgments varied across speakers and across sessions.
The predictions that were upheld were: 1) SSI-3 scores made from digital segements are more sensitive than SSI-3 scores made on the entire live signal; 2) Digital and live judgments vary with respect to speaker’s stuttering severity and across test sessions.
Developmental stuttering; severity estimates; stuttering severity instrument; persistent stuttering; recovered stuttering
African sleeping sickness is a parasitic disease transmitted through the bites of tsetse flies of the genus Glossina. We constructed mechanistic models for the basic reproduction number, R0, of Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, respectively the causative agents of West and East African human sleeping sickness. We present global sensitivity analyses of these models that rank the importance of the biological parameters that may explain variation in R0, using parameter ranges based on literature, field data and expertize out of Uganda. For West African sleeping sickness, our results indicate that the proportion of bloodmeals taken from humans by Glossina fuscipes fuscipes is the most important factor, suggesting that differences in the exposure of humans to tsetse are fundamental to the distribution of T. b. gambiense. The second ranked parameter for T. b. gambiense and the highest ranked for T. b. rhodesiense was the proportion of Glossina refractory to infection. This finding underlines the possible implications of recent work showing that nutritionally stressed tsetse are more susceptible to trypanosome infection, and provides broad support for control strategies in development that are aimed at increasing refractoriness in tsetse flies. We note though that for T. b. rhodesiense the population parameters for tsetse – species composition, survival and abundance – were ranked almost as highly as the proportion refractory, and that the model assumed regular treatment of livestock with trypanocides as an established practice in the areas of Uganda experiencing East African sleeping sickness.
trypanosomiasis; next-generation matrix; mathematical model; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense
Antiplatelet resistance is emerging as a significant factor in effective secondary stroke prevention. Prevalence of aspirin and clopidogrel resistance is dependent upon laboratory test and remains contentious. Large studies in cardiovascular disease populations have demonstrated worse ischemic outcomes in patients with antiplatelet resistance, particularly in patients with coronary stents. Thromboembolism is a complication of neurointerventional procedures that leads to stroke. Stroke rates related to aneurysm coiling range from 2 to 10% and may be higher when considering silent ischemia. Stroke associated with carotid stenting is a major cause of morbidity. Antiplatelet use in the periprocedure setting varies among different centers. No guidelines exist for use of antiplatelet regimens in neurointerventional procedures. Incidence of stroke in patients post procedure may be partly explained by resistance to antiplatelet agents. Further research is required to establish the incidence of stroke in patients with antiplatelet resistance undergoing neurointerventional procedures.
antiplatelet resistance; thromboembolism; endovascular; neurointervention; aspirin; clopidogrel
The use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators.
RESEARCH DESIGN AND METHODS
We selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS–adjusted CMH P value and odds ratio (OR).
Rankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P < 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P < 0.0001; OR 1.4 [95% CI 1.3–1.6]) and diabetic (P = 0.1; 1.3 [1.05–1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P < 0.0001; 1.4 [1.2–1.6 ]) and those who have (P = 0.02; 1.3 [1.04–1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS.
Outcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified.
Current recommendations are that people with Type 1 and Type 2 diabetes mellitus exercise regularly. However, in cases in which insulin or insulin secretagogues are used to manage diabetes, patients have an increased risk of developing hypoglycemia, which is amplified during and after exercise. Repeated episodes of hypoglycemia blunt autonomic nervous system, neuroendocrine and metabolic defenses (counter-regulatory responses) against subsequent episodes of falling blood glucose levels during exercise. Likewise, antecedent exercise blunts counter-regulatory responses to subsequent hypoglycemia. This can lead to a vicious cycle, by which each episode of either exercise or hypoglycemia further blunts counter-regulatory responses. Although contemporary insulin therapies cannot fully mimic physiologic changes in insulin secretion, people with diabetes have several management options to avoid hypoglycemia during and after exercise, including regularly monitoring blood glucose, reducing basal and/or bolus insulin, and consuming supplemental carbohydrates.
exercise; hypoglycemia; hypoglycemia-associated autonomic failure; insulin; insulin secretagogues; physical activity; Type 1 diabetes mellitus; Type 2 diabetes mellitus
The genetic relatedness of Clostridium botulinum type E isolates associated with an outbreak of wildlife botulism was studied using random amplification of polymorphic DNA (RAPD). Specimens were collected from November 2000 to December 2008 during a large outbreak of botulism affecting birds and fish living in and around Lake Erie and Lake Ontario. In our present study, a total of 355 wildlife samples were tested for the presence of botulinum toxin and/or organisms. Type E botulinum toxin was detected in 110 samples from birds, 12 samples from fish, and 2 samples from mammals. Sediment samples from Lake Erie were also examined for the presence of C. botulinum. Fifteen of 17 sediment samples were positive for the presence of C. botulinum type E. Eighty-one C. botulinum isolates were obtained from plants, animals, and sediments; of these isolates, 44 C. botulinum isolates produced type E toxin, as determined by mouse bioassay, while the remaining 37 isolates were not toxic for mice. All toxin-producing isolates were typed by RAPD; that analysis showed 12 different RAPD types and multiple subtypes. Our study thus demonstrates that multiple genetically distinct strains of C. botulinum were involved in the present outbreak of wildlife botulism. We found that C. botulinum type E is present in the sediments of Lake Erie and that a large range of bird and fish species is affected.
Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals.
RESEARCH DESIGN AND METHODS
Thirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m2, A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m2, A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg−1 · min−1) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study.
Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes.
In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.
To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.
Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.
A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.
We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions <18 mL (77% versus 18% placebo, OR=15.0, P<0.001). Benefit from tPA was also seen with DWI lesions up to 25 mL (69% versus 29% placebo, OR=5.5, P=0.03), but not for DWI lesions >25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.
ischemic stroke; diffusion MRI; perfusion MRI; thrombolysis
Little information is available to guide the selection, preparation, and support of a traveling team physician.
To determine the types of injuries and medical problems, as well as general team health and performance issues, encountered by physicians traveling internationally with youth national soccer teams.
Physicians assigned to travel abroad with the under-17 men’s and women’s US national soccer teams during a 2-year period documented all encounters with team and staff members. Physicians also documented consultations related to team health and performance issues.
The 108 cases (5.71 per 10 days) were evenly divided between injuries (n = 54) and noninjuries (n = 54). Players sought care at a higher rate than did staff (2.28 vs 1.09 per 100 person days). Mean severity for all player cases was 5.19 days missed (injuries, 10.48; noninjuries, 0.23). Nearly 69% of injuries involved the lower extremities: strains, sprains, and contusions accounted for 74.1% of injuries. Gastrointestinal, dermatologic, and otolaryngologic complaints accounted for 77.8% of noninjuries. Medications were administered in 71% of cases, with analgesics, cough and cold remedies, antibiotics, and gastrointestinal agents accounting for the majority. The leading team health and performance concerns were nutrition/hydration, conditioning, prevention, and doping control.
Physicians traveling internationally with youth soccer teams manage an equal proportion of musculoskeletal and medical problems using simple medications.
travel; sports; soccer
To date, there are no data investigating the effects of GABAA activation on counterregulatory responses during repeated hypoglycemia in humans. The aim of this study was to determine the effects of prior GABAA activation using the benzodiazepine alprazolam on the neuroendocrine and autonomic nervous system (ANS) and metabolic counterregulatory responses during next-day hypoglycemia in healthy humans.
RESEARCH DESIGN AND METHODS
Twenty-eight healthy individuals (14 male and 14 female, age 27 ± 6 years, BMI 24 ± 3 kg/m2, and A1C 5.2 ± 0.1%) participated in four randomized, double-blind, 2-day studies. Day 1 consisted of either morning and afternoon 2-h hyperinsulinemic euglycemia or 2-h hyperinsulinemic hypoglycemia (2.9 mmol/l) with either 1 mg alprazolam or placebo administered 30 min before the start of each clamp. Day 2 consisted of a single-step hyperinsulinemic-hypoglycemic clamp of 2.9 mmol/l.
Despite similar hypoglycemia (2.9 ± 1 mmol/l) and insulinemia (672 ± 108 pmol/l) during day 2 studies, GABAA activation with alprazolam during day 1 euglycemia resulted in significant blunting (P < 0.05) of ANS (epinephrine, norepinephrine, muscle sympathetic nerve activity, and pancreatic polypeptide), neuroendocrine (glucagon and growth hormone), and metabolic (glucose kinetics, lipolysis, and glycogenolysis) counterregulatory responses. GABAA activation with alprazolam during prior hypoglycemia caused further significant (P < 0.05) decrements in subsequent glucagon, growth hormone, pancreatic polypeptide, and muscle sympathetic nerve activity counterregulatory responses.
Alprazolam activation of GABAA pathways during day 1 hypoglycemia can play an important role in regulating a spectrum of key physiologic responses during subsequent (day 2) hypoglycemia in healthy man.
During February and March 2010, the New York State Department of Health investigated secondary and tertiary vaccinia contact transmission from a military vaccinee to 4 close contacts. Identification of these cases underscores the need for strict adherence to postvaccination infection control guidance to avoid transmission of the live virus.
Military vaccination; secondary transmission; tertiary transmission; vaccinia; smallpox vaccination; wrestling; viruses; contact transmission; dispatch