Underreporting of Lyme and Other Tick-Borne Diseases in Residents of a High-Incidence County, Minnesota, 2009.

Lyme disease (LD), anaplasmosis, babesiosis and other tick-borne diseases (TBDs) attributed to Ixodes ticks are thought to be widely underreported in the United States. To identify TBD cases diagnosed in 2009, but not reported to the Minnesota Department of Health (MDH), diagnostic and procedural billing codes suggestive of tick-borne diseases were used to select medical charts for retrospective review in medical facilities serving residents of a highly endemic county in Minnesota. Of 444 illness events, 352 (79%) were not reported. Of these, 102 (29%) met confirmed or probable surveillance case criteria, including 91 (26%) confirmed LD cases with physician-diagnosed erythema migrans (EM). For each confirmed and probable LD, probable anaplasmosis and confirmed babesiosis case reported to MDH in 2009, 2.8, 1.3, 1.2 and 1.0 cases were likely diagnosed, respectively. These revised estimates provide a more accurate assessment and better understanding of the burden of these diseases in a highly endemic county.

Biphasic insulin aspart 70/30 vs. insulin glargine in insulin naïve type 2 diabetes patients: modelling the long-term health economic implications in a Swedish setting.

OBJECTIVES: To evaluate the long-term clinical and economic outcomes of biphasic insulin aspart 70/30 (BIAsp 70/30) treatment vs. insulin glargine in insulin naïve, type 2 diabetes patients failing oral antidiabetic drugs in a Swedish setting. METHODS: A published and validated computer simulation model (the CORE Diabetes Model) was used to project life expectancy, quality-adjusted life expectancy (QALE) and costs over patient lifetimes. Cohort characteristics [54.5% male, mean age 52.4 years, 9 years mean diabetes duration, mean glycosylated haemoglobin (HbA1c) 9.77%] and treatment effects were based on results from the Initiate Insulin by Aggressive Titration and Education (INITIATE) clinical trial. Direct medical costs were accounted in 2006 Swedish Kronor (SEK) and economic and clinical benefits were discounted at 3% per annum. RESULTS: Biphasic insulin aspart 70/30 treatment when compared with insulin glargine treatment was associated with improvements in discounted life expectancy of 0.21 years (13.10 vs. 12.89 years) and QALE of 0.21 quality-adjusted life years (QALYs) (9.16 vs. 8.96 QALYs). Reductions in the incidence of diabetes-related complications in the BIAsp 70/30 treatment arm led to reduced total costs of SEK 10,367 when compared with insulin glargine (SEK 396,475 vs. SEK 406,842) over patient lifetimes. BIAsp 70/30 treatment was projected to be dominant (cost and lifesaving) when compared with insulin glargine in the base case analysis. CONCLUSIONS: Biphasic insulin aspart 70/30 treatment was associated with improved clinical outcomes and reduced costs compared with insulin glargine treatment over patient lifetimes. These results were driven by improved HbA1c levels associated with BIAsp 70/30 compared with insulin glargine and the accompanying reduction in diabetes-related complications despite increases in body mass index.

Irbesartan treatment of patients with type 2 diabetes, hypertension and renal disease: a UK health economics analysis.

The objective of the study was to determine the impact of irbesartan treatment on life expectancy (LE), costs and progression to end-stage renal disease (ESRD) in hypertensive type 2 diabetes patients. A peer-reviewed and published Markov model was used to simulate progression from microalbuminuria to overt nephropathy, doubling of serum creatinine, ESRD and all-cause mortality in hypertensive patients with type 2 diabetes. Three treatment strategies were evaluated: (i) 'control' regimen of conventional antihypertensive therapy (excluding angiotensin-converting enzyme inhibitors, angiotensin-2-receptor antagonists and dihydropyridine calcium-channel blockers), (ii) 'early irbesartan' 300 mg daily and (iii) 'late irbesartan' 300 mg daily (started when overt nephropathy developed). Transition probabilities determining nephropathy progression were taken from the Irbesartan in Reduction of Microalbuminuria-2 study, Irbesartan in Diabetic Nephropathy Trial and other published sources. Outcomes were projected over 25 years. The mean +/- SD cumulative incidence of ESRD was reduced by 8.8% +/- 0.6 and 12.4% +/- 0.7 in patients treated with early irbesartan compared with late irbesartan and control respectively. Early irbesartan treatment improved undiscounted LE by 1.38 +/- 0.08 years (discounted: 0.81 +/- 0.04 years) compared with late irbesartan and 1.41 +/- 0.08 years (discounted: 0.83 +/- 0.04 years) compared with control. Early irbesartan treatment was projected to save (mean +/- SD) pounds 2310 +/- 327 and pounds 3801 +/- 327 over patient lifetimes compared with late irbesartan and control respectively. Irbesartan treatment is predicted to improve survival and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria compared with 'control'. Early irbesartan treatment is more effective than late irbesartan. Irbesartan is a valuable treatment option in this patient group in a UK setting.

Therapy conversion to insulin detemir among patients with type 2 diabetes treated with oral agents: a modeling study of cost-effectiveness in the United States.

The aim of this study was to gain a preliminary indication of the long-term clinical and economic implications of converting treatment for patients with type 2 diabetes to insulin detemir+/-oral hypoglycemic agents (OHAs) in a routine clinical practice setting in the United States. With the use of outcome data and patient characteristics reported from an ongoing prospective observational trial, a validated computer simulation model of diabetes was used to project the clinical and cost outcomes associated with therapy conversion to insulin detemir over a 35-y period from (1) OHA only, (2) neutral protamine Hagedorn insulin (NPH)+/-OHA, and (3) insulin glargine+/-OHA. Cost-effectiveness was assessed from a third-party healthcare payer perspective for the year 2005. Costs and clinical outcomes were discounted at a rate of 3%. Treatment with insulin detemir+/-OHA was associated with increases in quality-adjusted life expectancy of 0.309, 0.350, and 0.333 quality-adjusted life-years (QALYs) versus treatment with OHA alone, NPH+/-OHA, and insulin glargine+/-OHA, respectively. Increases in pharmacy costs were partially offset by reduced complications, rticularly renal complications and neuropathy. Projected incremental cost-effectiveness ratios were well within the range considered to represent good value in the United States, at $7412, $6269, and $3951 per QALY gained for treatment with Idet+/-OHA versus OHA alone, NPH+/-OHA, and Iglarg+/-OHA, respectively. On the basis of preliminary evidence of short-term improvements in glycemic control and reduced hypoglycemia, therapy conversion to insulin detemir+/-OHA from OHA alone, NPH+/-OHA, or insulin glargine+/-OHA was projected to increase quality-adjusted life expectancy and to represent a cost-effective treatment option in the United States.

Insulin therapy in type 2 diabetes patients failing oral agents: cost-effectiveness of biphasic insulin aspart 70/30 vs. insulin glargine in the US.

OBJECTIVES: To project the long-term clinical and economic outcomes of treatment with biphasic insulin aspart 30 (BIAsp 70/30, 30% soluble and 70% protaminated insulin aspart) vs. insulin glargine in insulin-naïve type 2 diabetes patients failing to achieve glycemic control with oral antidiabetic agents alone (OADs). METHODS: Baseline patient characteristics and treatment effect data from the recent 'INITIATE' clinical trial served as input to a peer-reviewed, validated Markov/Monte-Carlo simulation model. INITIATE demonstrated improvements in HbA1c favouring BIAsp 70/30 vs. glargine (-0.43%; p < 0.005) and greater efficacy in reaching glycaemic targets among patients poorly controlled on OAD therapy. Effects on life expectancy (LE), quality-adjusted life expectancy (QALE), cumulative incidence of diabetes-related complications and direct medical costs (2004 USD) were projected over 35 years. Clinical outcomes and costs were discounted at a rate of 3.0% per annum. Sensitivity analyses were performed. RESULTS: Improvements in glycaemic control were projected to lead to gains in LE (0.19 +/- 0.24 years) and QALE (0.19 +/- 0.17 years) favouring BIAsp 70/30 vs. glargine. Treatment with BIAsp 70/30 was also associated with reductions in the cumulative incidences of diabetes-related complications, notably in renal and retinal conditions. The incremental cost-effectiveness ratio was $46 533 per quality-adjusted life year gained with BIAsp 70/30 vs. glargine (for patients with baseline HbA1c >/= 8.5%, it was $34 916). Total lifetime costs were compared to efficacy rates in both arms as a ratio, which revealed that the lifetime cost per patient treated successfully to target HbA1c levels of <7.0% and

Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration.

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.

Synthesis and biological activity of a novel series of indole-derived PPARgamma agonists.

The synthesis and structure-activity relationships of a novel series of indole 5-carboxylic acids that bind and activate peroxisome proliferator-activated receptor gamma (PPARgamma) are reported. These new analogs are selective for PPARgamma vs the other PPAR subtypes, and the most potent compounds in this series are comparable to in vitro potencies at PPARgamma reported for the thiazolidinedione-based antidiabetic drugs currently in clinical use.

Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates.

[formula: see text] The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps involved the enantioselective transfer hydrogenation of imine 8 employing Noyori's catalyst, the stereoselective crystallization and methanolysis of trans-bataines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14. The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.

Herbicide resistance caused by spontaneous mutation of the cytoskeletal protein tubulin.

The dinitroaniline herbicides (such as trifluralin and oryzalin) have been developed for the selective control of weeds in arable crops. However, prolonged use of these chemicals has resulted in the selection of resistant biotypes of goosegrass, a major weed. These herbicides bind to the plant tubulin protein but not to mammalian tubulin. Here we show that the major alpha-tubulin gene of the resistant biotype has three base changes within the coding sequence. These base changes swap cytosine and thymine, most likely as the result of the spontaneous deamination of methylated cytosine. One of these base changes causes an amino-acid change in the protein: normal threonine at position 239 is changed to isoleucine. This position is close to the site of interaction between tubulin dimers in the microtubule protofilament. We show that the mutated gene is the cause of the herbicide resistance by using it to transform maize and confer resistance to dinitroaniline herbicides. Our results provide a molecular explanation for the resistance of goosegrass to dinitroanaline herbicides, a phenomenon that has arisen, and been selected for, as a result of repeated exposure to this class of herbicide.

A novel family of small cysteine-rich antimicrobial peptides from seed of Impatiens balsamina is derived from a single precursor protein.

Four closely related peptides were isolated from seed of Impatiens balsamina and were shown to be inhibitory to the growth of a range of fungi and bacteria, while not being cytotoxic to cultured human cells. The peptides, designated Ib-AMP1, Ib-AMP2, Ib-AMP3, and Ib-AMP4, are 20 amino acids long and are the smallest plant-derived antimicrobial peptides isolated to date. The Ib-AMPs (I. balsamina antimicrobial peptides) are highly basic and contain four cysteine residues which form two intramolecular disulfide bonds. Searches of protein data bases have failed to identify any proteins with significant homology to the peptides described here. Characterization of isolated cDNAs reveals that all four peptides are encoded within a single transcript. The predicted Ib-AMP precursor protein consists of a prepeptide followed by 6 mature peptide domains, each flanked by propeptide domains ranging from 16 to 35 amino acids in length. Such a primary structure with repeated alternating basic mature peptide domains and acidic propeptide domains has, to date, not been reported in plants.

Predictors of waist circumference change in healthy young adults.

OBJECTIVE: To identify predictors of a change in waist circumference in a group of healthy young adults. SUBJECTS: Caucasian, 121 women and 109 men, participating in a longitudinal investigation of cardiovascular risk factors in parents and their young children. MEASUREMENTS: Evaluations of body weight, waist and hip circumferences, dietary intake, physical activity, cigarette smoking, and alcohol intake were performed annually. Age was recorded and family history of disease was assessed. RESULTS: For women, covariates and modifiable predictors accounted for 67% of the variance in waist circumference change from Year 1 to Year 3. Women with lower baseline waist girths, lower baseline hip girths, higher baseline body weight, and a greater change in body weight had larger increases in waist girth. For men, covariates and modifiable predictors accounted for 72% of the variance in waist circumference change. Men with lower baseline waist girth, a greater change in hip girth, higher baseline body weight, greater increases in body weight, and less percent of fat in the diet at baseline had larger increases in waist girth. Other non-modifiable variables did not predict change in either gender. CONCLUSION: Reducing excess body weight and decreasing weight gain appear to be the most important factors in preventing the accumulation of upper body fat.

Substrate specificity in short-chain phospholipid analogs at the active site of human synovial phospholipase A2.

The substrate specificity at the active site of recombinant human synovial fluid phospholipase A2 (hs-PLA2) was investigated by the preparation of a series of short-chain phospholipid analogs and measurement of their enzymatic hydrolysis at concentrations well below the critical micelle concentration. Substrates used in the study included 1,2-dihexanoylglycerophospholipids, 1,2-bis(alkanoylthio)glycerophospholipids, and 1-O-alkyl-2-(alkanoylthio)phospholipids. Turnover was observed for only a few of the 1,2-dihexanoylglycerophospholipids, and the rate of hydrolysis was very low, near the limit of detection of the assay. In contrast, selected 2-(alkanoylthio)-glycerophospholipids were hydrolyzed by hs-PLA2 at much higher rates at concentrations well below their critical micelle concentration (cmc). Thus, the 1,2-bis(hexanoylthio)glycerophosphatidylmethanol exhibits a k(cat)/K(M) = 1800 L mol-1 s-1. Over the calculated log P (cLogP) range of 3-9, cLogP and log(k(cat)/K(M) were linearly related for compounds with straight-chain sn-1 and sn-2 substituents. At comparable cLogP's, the sn-1 ethers and thioesters were hydrolyzed at comparable rates. A negative charge in the phosphate head group was required for enzyme activity. Unsaturation, aromaticity, and branching in the sn-2 substituent reduce turnover dramatically. The same structural modifications in the sn-1 substituent have less effect on turnover. Certain of these substrates, e.g., 1,2-bis(hexanoylthio)glycerophosphatidylmethanol, may be useful in assaying for active site inhibitors of PLA2. The structure--activity relationships established here for substrates should serve as a reference for the structure--activity relationships of substrate-based inhibitors.

6-Azasteroids: structure-activity relationships for inhibition of type 1 and 2 human 5 alpha-reductase and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase.

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) to explore the structure-activity relationship of this novel series in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Compounds with picomolar IC50's versus human type 2 5AR and low nanomolar Ki's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor-induced prostate involution and dog pharmacokinetic measurements identified a series of 17 beta-[N-(diphenylmethyl)carbamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the minimum, low nanomolar potency toward both human 5AR's and selectivity versus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone, such as benign prostatic hyperplasia.

Germin, a protein marker of early plant development, is an oxalate oxidase.

Germin is a homopentameric glycoprotein, the synthesis of which coincides with the onset of growth in germinating wheat embryos. There have been detailed studies of germin structure, biosynthesis, homology with other proteins, and of its value as a marker of wheat development. Germin isoforms associated with the apoplast have been speculated to have a role in embryo hydration during maturation and germination. Antigenically related isoforms of germin are present during germination in all of the economically important cereals studied, and the amounts of germin-like proteins and coding elements have been found to undergo conspicuous change when salt-tolerant higher plants are subjected to salt stress. In this report, we describe how circumstantial evidence arising from unrelated studies of barley oxalate oxidase and its coding elements have led to definitive evidence that the germin isoform made during wheat germination is an oxalate oxidase. Establishment of links between oxalate degradation, cereal germination, and salt tolerance has significant implications for a broad range of studies related to development and adaptation in higher plants. Roles for germin in cell wall biochemistry and tissue remodeling are discussed, with special emphasis on the generation of hydrogen peroxide during germin-induced oxidation of oxalate.

Primary small cell carcinoma of the vagina arising in a background of atypical adenosis.

BACKGROUND: Primary small cell carcinoma of the vagina is rare, with only nine cases published to date. The authors report what they believe to be the first case of primary small cell carcinoma of the vagina arising in a setting of atypical adenosis. METHODS: The tumor was studied by light and electron microscopy and immunohistochemistry. RESULTS: Intracytoplasmic electron-dense neurosecretory type granules were seen, and immunohistochemical demonstration of chromogranin A was documented. CONCLUSIONS: These features were found to be similar to small cell carcinomas arising elsewhere in the female genital tract (i.e., cervix, endometrium, ovary, and vulva).

Female adnexal tumor of wolffian origin.

We describe a female adnexal tumor of probable wolffian origin with stage 2B disease. The presence of peritoneal implants suggests a more aggressive clinical course than is usually expected. We present the findings of light microscopic and ultrastructural evaluation as well as those of immunohistochemical and DNA ploidy analysis, which, to our knowledge, have not been previously described for this type of tumor.