Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic condition characterized by glucose fluctuations. Laboratory studies suggest that cognition is reduced when glucose is very low (hypoglycemia) and very high (hyperglycemia). Until recently, technological limitations prevented researchers from understanding how naturally-occurring glucose fluctuations impact cognitive fluctuations. This study leveraged advances in continuous glucose monitoring (CGM) and cognitive ecological momentary assessment (EMA) to characterize dynamic, within-person associations between glucose and cognition in naturalistic environments. Using CGM and EMA, we obtained intensive longitudinal measurements of glucose and cognition (processing speed, sustained attention) in 200 adults with T1D. First, we used hierarchical Bayesian modeling to estimate dynamic, within-person associations between glucose and cognition. Consistent with laboratory studies, we hypothesized that cognitive performance would be reduced at low and high glucose, reflecting cognitive vulnerability to glucose fluctuations. Second, we used data-driven lasso regression to identify clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations. Large glucose fluctuations were associated with slower and less accurate processing speed, although slight glucose elevations (relative to person-level means) were associated with faster processing speed. Glucose fluctuations were not related to sustained attention. Seven clinical characteristics predicted individual differences in cognitive vulnerability to glucose fluctuations: age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and neck circumference. Results establish the impact of glucose on processing speed in naturalistic environments, suggest that minimizing glucose fluctuations is important for optimizing processing speed, and identify several clinical characteristics that may exacerbate cognitive vulnerability to glucose fluctuations.

Single-Cell Analysis of the Periodontal Immune Niche in Type 2 Diabetes.

Periodontitis (PD) is a common source of uncontrolled inflammation in obesity-associated type 2 diabetes (T2D). PD apparently fuels the inflammation of T2D and associates with poor glycemic control and increased T2D morbidity. New therapeutics are critically needed to counter the sources of periodontal infection and inflammation that are accelerated in people with T2D. The precise mechanisms underlying the relationship between PD and T2D remain poorly understood. Every major immune cell subset has been implicated in the unresolved inflammation of PD, regardless of host metabolic health. However, analyses of inflammatory cells in PD with human periodontal tissue have generally focused on mRNA quantification and immunohistochemical analyses, both of which provide limited information on immune cell function. We used a combination of flow cytometry for cell surface markers and enzyme-linked immunospot methods to assess the subset distribution and function of immune cells isolated from gingiva of people who had PD and were systemically healthy, had PD and T2D (PD/T2D), or, for flow cytometry, were systemically and orally healthy. T-cell subsets dominated the cellular immune compartment in gingiva from all groups, and B cells were relatively rare. Although immune cell frequencies were similar among groups, a higher proportion of CD11b+ or CD4+ cells secreted IFNγ/IL-10 or IL-8, respectively, in cells from PD/T2D samples as compared with PD-alone samples. Our data indicate that fundamental differences in gingival immune cell function between PD and T2D-potentiated PD may account for the increased risk and severity of PD in subjects with T2D. Such differences may suggest unexpected therapeutic targets for alleviating periodontal inflammation in people with T2D.

Practical implementation of cost-effective genomic selection in commercial pig breeding using imputation.

Genomic selection can be implemented in pig breeding at a reduced cost using genotype imputation. Accuracy of imputation and the impact on resulting genomic breeding values (gEBV) was investigated. High-density genotype data was available for 4,763 animals from a single pig line. Three low-density genotype panels were constructed with SNP densities of 450 (L450), 3,071 (L3k) and 5,963 (L6k). Accuracy of imputation was determined using 184 test individuals with no genotyped descendants in the data but with parents and grandparents genotyped using the Illumina PorcineSNP60 Beadchip. Alternative genotyping scenarios were created in which parents, grandparents, and individuals that were not direct ancestors of test animals (Other) were genotyped at high density (S1), grandparents were not genotyped (S2), dams and granddams were not genotyped (S3), and dams and granddams were genotyped at low density (S4). Four additional scenarios were created by excluding Other animal genotypes. Test individuals were always genotyped at low density. Imputation was performed with AlphaImpute. Genomic breeding values were calculated using the single-step genomic evaluation. Test animals were evaluated for the information retained in the gEBV, calculated as the correlation between gEBV using imputed genotypes and gEBV using true genotypes. Accuracy of imputation was high for all scenarios but decreased with fewer SNP on the low-density panel (0.995 to 0.965 for S1) and with reduced genotyping of ancestors, where the largest changes were for L450 (0.965 in S1 to 0.914 in S3). Exclusion of genotypes for Other animals resulted in only small accuracy decreases. Imputation accuracy was not consistent across the genome. Information retained in the gEBV was related to genotyping scenario and thus to imputation accuracy. Reducing the number of SNP on the low-density panel reduced the information retained in the gEBV, with the largest decrease observed from L3k to L450. Excluding Other animal genotypes had little impact on imputation accuracy but caused large decreases in the information retained in the gEBV. These results indicate that accuracy of gEBV from imputed genotypes depends on the level of genotyping in close relatives and the size of the genotyped dataset. Fewer high-density genotyped individuals are needed to obtain accurate imputation than are needed to obtain accurate gEBV. Strategies to optimize development of low-density panels can improve both imputation and gEBV accuracy.

Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects.

BACKGROUND: The pharmacokinetics of polyethylene glycol 3350 (PEG-3350) have not been fully described because of lack of a sufficiently sensitive analytical method. AIM: To describe the pharmacokinetics of PEG-3350 in humans. METHODS: A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. RESULTS: Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. CONCLUSIONS: For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG-3350 in humans. These studies confirmed that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

Clinical trial: an efficacy evaluation of reduced bisacodyl given as part of a polyethylene glycol electrolyte solution preparation prior to colonoscopy.

BACKGROUND: In an attempt to further improve patient preparation experience with reduced volume gut lavage solutions using 2-L sulphate-free electrolyte lavage solution plus 20-mg bisacodyl (HalfLytely with Bisacodyl Tablets Bowel Prep Kit, Braintree Laboratories, Inc., Braintree, MA, USA), a low bisacodyl dose preparation was developed using 10 mg bisacodyl. AIM: To compare preparation methods using the 10- or 20-mg bisacodyl with 2-L sulphate-free electrolyte lavage method. METHODS: At 10 US centres, 455 patients undergoing colonoscopy for routine clinical indications were equally randomized to receive 10- or 20-mg bisacodyl with 2-L sulphate-free electrolyte lavage method. Colonoscopists rated the efficacy of colon cleansing, blinded to the preparation assignment. RESULTS: Physician assessment of colon cleansing showed no difference between those randomized to receive the 10- or 20-mg bisacodyl preparations (P = 0.52). The 10-mg preparation had lower symptom scores for cramping (P < 0.001) and overall discomfort (P = 0.001). Other reported adverse experiences were few, mild and not different between groups. CONCLUSION: Two-litre sulphate-free electrolyte lavage method solution with 10-mg bisacodyl is as effective as the 20-mg bisacodyl preparation for cleansing the colon prior to colonoscopy. The 10-mg bisacodyl regimen has an improved safety profile, with significantly reduced cramping, nausea and overall discomfort.

An open-label study of chronic polyethylene glycol laxative use in chronic constipation.

BACKGROUND: Polyethylene glycol 3350 (MiraLAX, Braintree Laboratories Inc., Braintree, MA, USA) is approved for the short-term treatment of occasional constipation. AIM: To extend the safety data of polyethylene glycol used for chronic treatment of chronic constipation. METHODS: Study subjects who met defined criteria for chronic constipation were enrolled in this open-labelled, single-treatment multi-centre study to receive polyethylene glycol laxative as a single daily dose of 17 g for 12 months. Subjects returned to their study centres after 2, 4, 6, 9 and 12 months of treatment where blood and urine samples were collected and adverse events were reviewed. At each visit, subjects were queried for ROME constipation criteria and they rated their overall improvement using a global efficacy scale. RESULTS: 311 patients including 117, age 65 and older, were enrolled and received treatment at one of 50 centres. One hundred and eighty-four completed all 12 months of treatment. With respect to the 'Global Efficacy Assessment', depending on the month of observation, 80-88% of enrolled patients, and 84-94% of the elderly, were treated successfully. Similar results were obtained from secondary efficacy measures that assessed individual ROME constipation criteria at each visit. The response to treatment was durable over time. Over the 1-year course of study representing 218 patient-years at the labelled dose, medication-associated adverse effects were gastrointestinal complaints of diarrhoea, loose stool, flatulence and nausea. These effects were generally mild or moderate in severity. There were no clinically significant changes in haematology or blood chemistry, particularly electrolytes, for the study population as a whole or the elderly group. CONCLUSIONS: Polyethylene glycol laxative is safe and effective for treating constipation in adult and elderly patients for periods up to 12 months, with no evidence of tachyphylaxis.

Changes in inbreeding of U.S. Herefords during the twentieth century.

Genetic diversity in the U.S. Hereford population was characterized by examining the level and rate of inbreeding and effective population size. Pedigree records for 20,624,418 animals were obtained from the American Hereford Association, of which 96.1% had both parents identified. Inbreeding coefficients were computed and mean inbreeding (Fx) calculated by year from 1900 to 2001. Inbreeding increased rapidly between 1900 and 1945. From 1946, inbreeding increased linearly to a maximum of 11.5% in 1966. Throughout the 1970s and 1980s, mean inbreeding decreased to mid-century levels. Several alternatives were investigated to explain this decline. The average relationship between prominent sires fell from 20 to 12% during the time that the level of inbreeding decreased, which reflects an increase in the popularity of certain less fashionable sire lines that would have temporarily decreased inbreeding. Pedigrees were constructed for animals born after 1990. This subsample of animals with no missing ancestors in at least 12 generations did not exhibit a decrease in inbreeding. Missing ancestral information therefore contributed to the apparent decline. One cause of missing ancestry results from outcrossing to imported animals. The effect of missing ancestry was investigated by simulating the missing ancestors. In 2001, Fx was 9.8%, and approximately 95% of individuals were inbred. The maximal inbreeding coefficient was 76%. The annual change in mean inbreeding (DeltaFx) was estimated for Herefords born during five time periods from 1946 to 2001, where inbreeding was changing at different linear rates. The DeltaFx for the most recent generation (1990 to 2001) was 0.12%/yr. Assuming a generation interval of 4.88 yr, the estimated effective population size was 85. This study provides a benchmark of current genetic diversity in the Hereford population. Results indicate that inbreeding is accumulating linearly and below critical levels. Increases in the adoption of reproductive technologies could decrease genetic diversity, and in the future, we may need to consider strategies to minimize inbreeding.

New polyethylene glycol laxative for treatment of constipation in adults: a randomized, double-blind, placebo-controlled study.

BACKGROUND: This study evaluated the safety and effectiveness of a new polyethylene glycol (PEG) laxative (MiraLax, Braintree Laboratories Inc, Braintree, Mass) in 23 patients reporting a history of constipation. METHODS: After a 7-day placebo control period, patients were randomized into a double crossover trial of placebo versus 17 g of PEG daily for 4 days. Patient maintained a stool diary. RESULTS: Daily ingestion of a 17 g dose of PEG increased mean daily bowel movement frequency to once per day by the last 7 days of the 14-day treatment period. This was a statistically significant improvement over placebo, which provided about 1 bowel movement every 2 days during the last week of therapy. Patient diary ratings of related subjective symptoms were improved with PEG treatment over placebo. Both investigator and patients rated PEG therapy superior to placebo. No clinically significant changes in blood chemistry, complete blood count (CBC), or urinalysis were observed. CONCLUSIONS: Daily therapy with 17 g of PEG laxative for 14 days resulted in a significant improvement in bowel movement frequency in constipated patients relative to placebo by the second week of treatment.

Cutaneous infection due to Mycobacterium kansasii.

A patient presented with chronic leg ulcers after a mowing accident. He received several courses of antibiotics for presumed cellulitis, underwent surgical debridement, and was treated empirically with cyclosporin for presumed pyoderma gangrenosum, all without improvement. Cultures from prior debridement revealed Mycobacterium kansasii, and he was successfully treated with triple antituberculous regimen. Cutaneous infections due to this slow growing Mycobacterium are rare and may resemble cellulitis or sporotrichosis. Mycobacterium kansasii should be included in the differential diagnosis of skin infections with an indolent course and lack of response to antibiotics.

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.

Identification of the familial cylindromatosis tumour-suppressor gene.

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

Cutaneous fibrosis induced by docetaxel: a case report.

BACKGROUND: Docetaxel is a taxoid antineoplastic agent approved for use in the treatment of metastatic breast carcinoma. The current study reports an unusual case of generalized cutaneous fibrosis in a 39-year-old white female after treatment with 18 cycles of docetaxel for metastatic breast carcinoma. METHODS: Cutaneous fibrosis represents a rare and unique reaction associated with the cyclic use of docetaxel. The reaction is manifested by a distinct sequence of events involving pronounced edema followed by the rapid development of cutaneous fibrosis in dependent areas. RESULTS: Cessation of therapy results in dramatic reversal of the fibrotic process. CONCLUSIONS: This case report further substantiates the belief that docetaxel represents one of a very limited number of agents that appear capable of giving rise to scleroderma-like features.

A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative.

OBJECTIVE: This study was designed to determine the efficacy and safety of a new laxative, Braintree polyethylene glycol (PEG) laxative (Miralax, Braintree Laboratories, Braintree, MA). METHODS: This investigation was designed as a placebo-controlled, blinded, randomized, multicenter parallel trial. Study subjects were constipated but otherwise healthy outpatients who had < or =2 stools during a 7-day qualification period. Braintree PEG laxative 17 g or dextrose placebo p.o. in 8 oz of water for a 14-day treatment period. A diary recorded each bowel movement and subjective symptoms of stool consistency, ease of passage, cramps, and flatus. CBC, blood chemistries and urinalysis were performed before and after the treatment period. RESULTS: There were 151 randomized subjects, 131 female and 20 male. An increase in bowel movement frequency was observed with the PEG laxative as compared to placebo (p<0.001), with the greatest difference in efficacy in wk 2 of treatment (p<0.001). By wk 2 of treatment, on average, placebo subjects had 2.7 bowel movements/wk and PEG-treated study subjects had 4.5 movements/wk (p<0.01), or more than one bowel movement every 2 days. Investigator (p<0.005) and patient (p<0.001) subjective assessment of perception of treatment effectiveness, and patient evaluations of stool consistency and passage showed significant improvement in the active treatment group (p<0.001). There were no significant differences in laboratory changes or adverse experiences recorded between groups. CONCLUSION: Braintree PEG laxative is safe and effective in the short term for the treatment of constipation.

Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies.

Although in vitro studies support a pathophysiologic role for lipoprotein(a) [Lp(a)] in the development of atherosclerosis, and retrospective studies consistently report that there is a relationship between Lp(a) and ischemic heart disease (IHD), the conclusions drawn from prospective studies about this relationship have been inconsistent. To address this issue, we have performed a metaanalysis of data available from prospective studies. Lp(a) concentrations expressed as mass units vary markedly between studies, reflecting the need for assay standardization. In 12 of 14 prospective studies, Lp(a) concentrations are higher in subjects who later develop IHD (cases) than in those who do not (controls), although there is variation in the size of the effect. Sample storage temperature may contribute to this variability. When the studies are analyzed collectively, Lp(a) concentrations are significantly higher in cases than in controls, and the extent of the effect is similar in men and women. These findings provide evidence in support of a causal role for Lp(a) in the development of atherosclerosis. Measurement of Lp(a) may be useful to guide management of individuals with a family history of IHD or with existing disease. The separation in values between cases and controls is not, however, sufficient to allow the use of Lp(a) as a screening test in the general population.

Clinicopathologic correlations of soluble amyloid beta-protein precursor in cerebrospinal fluid in patients with Alzheimer disease and controls.

The authors compared concentrations of soluble beta-amyloid protein precursor (s beta PP) in cerebrospinal fluid (CSF) in 45 patients diagnosed with probable Alzheimer disease (AD) and 26 normal older control volunteers. Soluble beta-amyloid protein precursor concentrations were measured in 125 CSF samples using an enzyme-linked immunosorbent assay. All subjects had Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDRS) scores and assessment of disease duration. The s beta PP concentrations in CSF in the probable AD group (mean +/- SD = 493 +/- 268 micrograms/L) were decreased significantly compared with the age-matched control group (mean = 831 +/- 302 micrograms/L; p < 0.0001). In the probable AD group, MMSE scores correlated positively with s beta PP concentrations (correlation coefficient r = 0.53, p < 0.0001), and CDRS ratings and disease duration correlated inversely with s beta PP concentrations (r = -0.59, p < 0.0001 and r = -0.479, p = 0.0006, respectively). Although the decrease in CSF s beta PP from levels found in healthy elderly controls was significant in AD subjects, there was substantial overlap. In AD, CSF s beta PP was most reduced in patients in later stages of the disease. The s beta PP concentrations reflect disease severity, but utility in differential diagnosis has not been determined.

The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.

BACKGROUND: Transdermal nicotine therapy is widely used to aid smoking cessation, but there is uncertainty about its safety in patients with cardiac disease. METHODS: In a randomized, double-blind, placebo-controlled trial at 10 Veterans Affairs medical centers, we randomly assigned 584 outpatients (of whom 576 were men) with at least one diagnosis of cardiovascular disease to a 10-week course of transdermal nicotine or placebo as an aid to smoking cessation. The subjects were monitored for a total of 14 weeks for the primary end points of the study (death, myocardial infarction, cardiac arrest, and admission to the hospital due to increased severity of angina, arrhythmia, or congestive heart failure); the secondary end points (admission to the hospital for other reasons and outpatient visits necessitated by increased severity of heart disease); any side effects of therapy; and abstinence from smoking. RESULTS: There were 48 primary and 78 secondary end points noted in a total of 95 subjects. At least one of the primary end points was reached by 5.4 percent of the subjects in the nicotine group and 7.9 percent of the subjects in the placebo group (difference, 2.5 percent; 95 percent confidence interval, -1.6 to 6.5 percent; P=0.23). In the nicotine group, 11.9 percent of the subjects had at least one of the secondary end points, as compared with 9.7 percent in the placebo group (difference, 2.2 percent; 95 percent confidence interval, -2.2 to 7.4 percent; P= 0.37). After 14 weeks the rate of abstinence from smoking was 21 percent in the nicotine group, as compared with 9 percent in the placebo group (P=0.001), but after 24 weeks the abstinence rates were not significantly different (14 percent vs. 11 percent, P= 0.67). CONCLUSIONS: Transdermal nicotine does not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. However, the efficacy of transdermal nicotine as an aid to smoking cessation in such patients is limited and may not be sustained over time.

Lipoteichoic acid preparations of gram-positive bacteria induce interleukin-12 through a CD14-dependent pathway.

Interleukin 12 (IL-12) strongly augments gamma interferon production by natural killer (NK) and T cells. IL-12 also promotes effective cell-mediated immune responses, which are particularly important against intracellular bacteria such as Listeria monocytogenes. While the lipopolysaccharide (LPS) of gram-negative bacteria induces monocyte production of IL-12, the relevant gram-positive components which induce IL-12 production are uncharacterized. We used the human monocytic cell line THP-1 to study IL-12 induction by gram-positive bacteria. Muramyl dipeptides as well as the major muramyl tetrapeptide component of Streptococcus pneumoniae were inactive for inducing IL-12. In contrast, lipoteichoic acid (LTA), a predominant surface glycolipid of gram-positive bacteria, potently induced IL-12 p40 gene expression. A competitive LPS antagonist, Rhodobacter sphaeroides LPS, inhibited LTA-induced IL-12 production, suggesting a common pathway for LPS and LTA in IL-12 activation. Pretreatment of cells with anti-CD14 monoclonal antibody blocked both LPS and LTA induction of IL-12 p40 expression. LTA also induced Thl development in naive CD4 T cells by an IL-12-dependent mechanism, indicating direct induction of physiologic levels of IL-12. Together, these results show that LTA is a potent surface structure of gram-positive bacteria which induces IL-12 in monocytes through a CD14-mediated pathway.

Regulation of interleukin 12 p40 expression through an NF-kappa B half-site.

Interleukin 12 (IL-12) is an inducible cytokine composed of 35- and 40-kDa subunits that is critical for promoting T helper type 1 development and cell-mediated immunity against pathogens. The 40-kDa subunit, expressed by activated macrophages and B cells, is induced by several pathogens in vivo and in vitro and is augmented or inhibited by gamma interferon (IFN-gamma) or IL-10, respectively. Control of IL-12 p40 expression is therefore important for understanding resistance and susceptibility to a variety of pathogens, including Leishmania major and perhaps human immunodeficiency virus. In this report, we provide the first characterization of IL-12 p40 gene regulation in macrophages. We localize inducible activity of the promoter to the sequence -122GGGGAATTTTA-132 not previously recognized to bind Rel family transcription factors. We demonstrate binding of this sequence to NF-kappa B (p50/p65 and p50/c-Rel) complexes in macrophages activated by several p40-inducing pathogens and provide functional data to support a role for NF-kappa B family members in IL-12 p40 activation. Finally, we find that IFN-gamma treatment of cells enhances this binding interaction, thus potentially providing a mechanism for IFN-gamma augmentation of IL-12 production by macrophages.