text:
Both authors contributed equally to this study.
Original Article
Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients
Version of Record online: 3 DEC 2012
DOI: 10.1111/j.1365-2249.2012.04675.x
© 2012 British Society for Immunology
Clinical & Experimental Immunology
Volume 171, Issue 1, pages 82–90, January 2013
Additional Information
How to Cite
Gorus, F. K., Balti, E. V., Vermeulen, I., Demeester, S., Van Dalem, A., Costa, O., Dorchy, H., Tenoutasse, S., Mouraux, T., De Block, C., Gillard, P., Decochez, K., Wenzlau, J. M., Hutton, J. C., Pipeleers, D. G., Weets, I. and Belgian Diabetes Registry (2013), Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients. Clinical & Experimental Immunology, 171: 82–90. doi: 10.1111/j.1365-2249.2012.04675.x
Publication History
- Issue online: 3 DEC 2012
- Version of Record online: 3 DEC 2012
- Accepted manuscript online: 26 SEP 2012 02:45AM EST
- Manuscript Accepted: 13 SEP 2012
Funded by
- Juvenile Diabetes Research Foundation. Grant Number: 4–2005-1327
- European Union. Grant Number: 241883
- Belgian Fund for Scientific Research. Grant Numbers: G.0319·01, G.0514·04, G.0311·07, G.0374·08, G.0868·11
- research council of the Brussels Free University. Grant Numbers: OZR1150, 1149, 1615
- Willy Gepts Fund. Grant Numbers: 3–2005, 3/22–2007
- IA-2 antibodies;
- prediction;
- prevention;
- type 1 diabetes;
- zinc transporter 8 antibodies
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
In first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0–39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA+, GADA+, IA-2A+ and/or ZnT8A+ relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0–9, 10–19 and 20–39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A+ and/or ZnT8A+ relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10–39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
Immune intervention trials using anti-T or anti-B lymphocyte antibodies, co-stimulatory blockade or an antigen-specific vaccine have reported efficacy in transiently preserving residual beta cell function in recent-onset type 1 diabetes [1-5]. The best results were obtained in subgroups of participants with a higher functional beta cell mass at diagnosis, short duration of clinically overt diabetes or younger age [1-7], thereby providing a strong argument to plan future interventions at a preclinical stage [8].
Because immune-modulating strategies carry the risk for acute or long-term side effects [1-5], it is important that their testing in non-diabetic subjects is restricted to those with a high risk of developing diabetes in the short term [9]. Also, from a practical standpoint, enrolling individuals with a homogeneously high risk should allow conclusions to be reached more rapidly as to the efficacy of the tested intervention [8]. Considering the number of subjects needed per trial [10-12], screening for islet autoantibodies would need to be performed in thousands of first-degree relatives of type 1 diabetic patients, or in a 10–20 times larger group without family history of diabetes [13-15]. Individuals with a high antibody-inferred diabetes risk could then be stratified further according to risk using standardized tests that assess residual beta cell function [8, 16, 17]. To avoid many high-risk individuals progressing to diabetes before the actual start of an intervention study, potential participants should be identified within a relatively short interval.
At least five different types of molecularly defined diabetes-associated antibodies have been used to stratify diabetes risk [18-21]. However, their frequency – and hence that of multiple antibody positivity – tends to decline with age at diagnosis, except for antibodies against glutamate decarboxylase (GADA) [22-24]. Moreover, the overall progression rate to diabetes decreases with increasing age at first antibody positivity [25, 26]. Because immune intervention trials are expected to be launched first in adults before extending inclusions to adolescents and children [27], antibody screening for secondary prevention trials will be conducted in a first phase in this older age category and antibody-inferred risk should be age-independent. Time constraints and cost-efficiency reasons raise the need to select a limited number of antibody markers.
Antibodies against insulinoma antigen 2 (IA-2A) and zinc transporter 8 (ZnT8A) have been shown to appear later, in general, during the subclinical disease process and to herald more rapid progression to hyperglycaemia than antibodies against insulin (IAA) or GADA [21, 26]. The present paper investigates whether diabetes risk assessment based solely on testing for IA-2A and ZnT8A is equally effective in identifying the majority of rapid progressors to diabetes among children, adolescents and adults with a type 1 diabetic sibling or parent, and could thus represent a cost-effective age-independent strategy for enrolment of participants in secondary prevention trials based on immunointervention.
Materials and methods
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
Between March 1989 and August 2011, the Belgian Diabetes Registry (BDR) recruited consecutively siblings or offspring (under age 40 years at entry) of type 1 diabetic probands according to previously defined criteria [28]. The probands are considered representative of the Belgian population of type 1 diabetic patients [22]. After obtaining written informed consent from each relative or their parents, a short questionnaire with demographic, familial and personal information was completed at each visit and blood samples were taken at entry and yearly thereafter. Only relatives with two or more contacts during follow-up (number of individuals = 6444), the last being at diagnosis in the case of progression to diabetes, were included into this study. This allowed unambiguous ascertainment of the clinical status of relatives at this last time-point. Diabetes was diagnosed according to the American Diabetes Association criteria [29].
The study was conducted in accordance with the guidelines in the Declaration of Helsinki, as revised in 2008 (http://www.wma.net/en/30publications/10policies/b3/index.html, accessed 17 April 2012), and approved by the ethics committees of the BDR and the participating university hospitals. Random blood samples were collected for sera and buffy coats, and aliquots were stored at −80°C until analysed for diabetes-associated autoantibodies and HLA-DQ genotype, respectively, as described previously [21]. Relatives were not prescreened for islet cell cytoplasmic antibodies (ICA), nor were ICA results analysed in the present study. Antibody positivity was defined as persistent if their next sample after baseline was also positive for at least one antibody type. During follow-up, development of diabetes was ascertained through repeated contacts with Belgian endocrinologists and paediatricians, self-reporting through yearly questionnaires and a link with the BDR patient database, where newly diagnosed patients under 40 years of age are registered. Follow-up ended at the time of the last blood sampling or, in the case of progression to diabetes, at clinical onset. Body mass index (BMI) was expressed as a standard deviation score (BMI-SDS) by comparison with an age- and sex-matched cohort [30].
Analytical methods
IAA, GADA, IA-2A and ZnT8A were determined by liquid-phase radiobinding assays [21] and HLA-DQ polymorphisms by allele-specific oligonucleotide genotyping [31], as described previously. Antibody levels were expressed as the percentage binding of added tracer [10 000 counts per minute (cpm)/tube] [21]. cDNAs for the preparation of radio-ligands by in-vitro transcription–translation were kind gifts from Å. Lernmark (when at University of Washington, Seattle, WA, USA) for full-length 65 kDa glutamate decarboxylase, M. Christie (King's College School of Medicine and Dentistry, London, UK) for the intracellular portion of insulinoma-associated protein 2 (IA-2) and J. C. Hutton (Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA) for the dimeric hybrid ZnT8 construct generated by fusion of CR and CW (zinc transporter-8 carboxy-terminal constructs carrying, respectively, Arg325 and Trp325) (CRCW). In the 2009 Diabetes Autoantibody Standardisation Program (DASP) Workshop diagnostic sensitivity and specificity were, respectively, 74 and 97% for GADA, 40 and 98% for IAA, 66 and 99% for IA-2A and 68 and 100% for ZnT8A (CRCW). Cut-off values for positive antibodies were determined as the 99th percentile of antibody levels in 761 non-diabetic controls, and amounted to ≥ 0·6% tracer binding for IAA, ≥ 2·6% for GADA and ≥ 0·44% for IA-2A. As ZnT8A levels tended to decrease slightly with age in control subjects, cut-off values were calculated separately for the age groups 0–14 years (≥ 1·28%) and 15–39 years (≥ 1·02%) for ZnT8A [24]. Between-day coefficients of variation determined for serum pools within the normal range and within the moderately elevated range were, respectively, 35% (0·3% tracer binding) and 12% (6·9% tracer binding) for IAA, 12% (2·1% tracer binding) and 10% (7·1% tracer binding) for GADA, 18% (0·3% tracer binding) and 9% (2·3% tracer binding) for IA-2A and 21% (0·7% tracer binding) and 6% (3·9% tracer binding) for ZnT8A. Proinsulin (PI), C-peptide (CP) and the PI/CP ratio were determined as before [32].
Statistical analysis
Statistical differences between groups were assessed by χ2 test, with Yates' correction or Fisher's exact test for categorical variables and Mann–Whitney U-test for continuous data. Kaplan–Meier analysis was used to estimate diabetes-free survival. The survival curves were compared using the log-rank test. Follow-up started at the time of the first antibody-positive sample and ended at the last contact with the relative or at clinical onset, whichever came first. Two-tailed statistical tests were performed by SPSS for Windows version 20·0 (IBM SPSS Statistics, Chicago, IL, USA). GraphPad Prism version 5·00 for Windows (San Diego, CA, USA) was used for the figures.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
Overall progression to diabetes
We followed 6444 offspring or siblings of a type 1 diabetic patient and identified 394 who were persistently IAA+, GADA+, IA-2A+ and/or ZnT8A+. The degree of overlap between the four antibody types at baseline is shown in Fig. S1. At the time of first antibody positivity the majority (n = 249 or 63%) were IA-2A– and ZnT8A– (positive only for IAA and/or GADA); the others (n = 145 or 37%) presented IA-2A and/or ZnT8A with or without the other two antibodies. After a median (interquartile range; IQR) follow-up time of 63 (31–110) months, 34% of the antibody-positive relatives (n = 132) had developed diabetes [onset after 52 (25–84) months follow-up]. Most (n = 81, 61%) originated from the smaller subgroup with IA-2A+ and/or ZnT8A+, which consequently had a much higher risk of diabetes (81 of 145, 56% progression) than the larger IA-2A– and ZnT8A– subgroup (51 of 249, 21%; P < 0·001). Similar results were obtained when the analysis was conducted on antibody-positive relatives who developed diabetes within a 5-year follow-up period: 55 of the 74 rapid progressors (74%) were IA-2A+ and/or ZnT8A+ and the fraction of IA-2A+ and/or ZnT8A+ relatives who progressed within this short period was again significantly higher (55 of 145, 38%) than that of GADA+ and/or IAA+ relatives at first antibody positivity (19 of 249, 8%; P < 0·001). The general characteristics of IA-2A+ and/or ZnT8A+ relatives compared to those negative for both antibodies are shown in Table 1. Overall, relatives positive for IA-2A and/or ZnT8A had a higher PI/CP ratio (P = 0·001) and a shorter follow-up time (P < 0·001), as expected from their higher fraction of rapid progressors. They carried the HLA-DQ8 risk haplotype (P < 0·001) more often, but not the highest-risk HLA-DQ2/DQ8 genotype P = 0·233). They tended to be less frequently positive for HLA-DQ2 (P = 0·076) and neutral or protective genotypes (P = 0·005). As could be expected, they had a much lower frequency of solitary antibody positivity at baseline (P < 0·001) (Table 1).
|IA-2A+ and/or ZnT8A+
|IA-2A− and ZnT8A−
|(n = 145)
|(n = 249)
|Age, yearsa
|11 (5–17)
|13 (7–19)
|Sex, male/female (ratio)
|83/62 (1·3)
|136/113 (1·2)
|BMI, kg/m2a
|17·9 (16·0–21·4)
|19·2 (16·5–23·5)
|BMI SDSa
|0·05 (-0·75–0·85)
|0·32 (-0·62–1·36)
|PI/CP, ratioa
|2·8 (1·7–2·4)
|2·1 (1·5–3·2)
|Glucose, mmol/la
|4·8 (4·3–5·3)
|4·8 (4·4–5·2)
|Follow-up time, monthsa
|45 (24–81)
|75 (38–125)
|< 0·001
|Relationship with proband
|Sibling, n (%)
|84 (58)
|133 (53)
|Offspring M, n (%)
|20 (14)
|61 (24)
|Offspring F, n (%)
|41 (28)
|55 (22)
|HLA genotype
|DQ2/DQ8, n (%)
|41 (28)
|57 (23)
|Non-DQ2/DQ8, n (%)
|70 (48)
|71 (28)
|< 0·001
|DQ2/non-DQ8, n (%)
|23 (16)
|77 (31)
|Non-DQ2/non-DQ8, n (%)
|11 (8)
|44 (18)
|HLA haplotype
|DQ8, n (%)
|111 (77)
|128 (51)
|< 0·001
|DQ2, n (%)
|64 (44)
|134 (54)
|Antibody positivity
|Solitary antibody+ (1 of 4)
|18 (12)
|201 (81)
|< 0·001
Progression to diabetes according to age and antibody type
In children aged 0–9 years, in adolescents aged 10–19 years and in adults aged 20–39 years progression to diabetes was significantly more rapid in the presence of IA-2A and/or ZnT8A at baseline than in their joint absence (Fig. 1a–c; P < 0·001). The risk conferred by IA-2A+ and by ZnT8A+ was not additive (Fig. 1d; P > 0·05), but screening for ZnT8A in addition to IA-2A increased the number of high-risk individuals identified from 116 to 145 and the number of prediabetic relatives from 64 to 78 (Fig. 1d). When tested for four antibodies, relatives with solitary positivity for IA-2A or ZnT8A were rarely observed and progressed overall less rapidly to diabetes than IA-2A+ or ZnT8A+ individuals presenting with at least one other antibody (Fig. S2; P = 0·044 both for IA-2A+ and for ZnT8A+ relatives). In the latter group, the progression rate was, overall, not affected by the number of additional antibodies present (n = 1, 2 or 3; P = 0·831 for IA-2A+ relatives, P = 0·556 for ZnT8A+ relatives in Fig. S2). Hence, additional determination of other diabetes antibodies (IAA and GADA) is indicated only if IA-2A+ or ZnT8A+ are detected during initial screening for the latter two antibodies. As IA-2A and ZnT8A tend to cluster together [21], this is only a small fraction (18 of 145, 12%) of the relatives positive for either of the two antibodies.
The progression rate to diabetes decreased with increasing age at first antibody positivity only if IAA and/or GADA were present at baseline (Fig. 1e; P = 0·008), or in the case of positivity for more than one of four antibodies (Fig. 1g; P = 0·001), but was age-independent in the case of IA-2A+ and/or ZnT8A+ (Fig. 1f; P > 0·05) or in the case of positivity for more than two to three or two to four antibodies (Fig. 1h,i; P > 0·05). Although IA-2A and ZnT8A titres tended to increase with the number of antibodies present (not shown), progression to diabetes according to tertiles of antibody levels was not significantly different for both antibodies (P > 0·05; Fig. S3). In line with previous findings [33], our data show that relatives carrying the HLA-DQ2/DQ8 high-risk genotype progressed significantly faster than those at lower genetic risk both in the IA-2A+ and/or ZnT8A+ group (P < 0·001) and in antibody positive relatives lacking these two antibodies (P = 0·003, not shown). However, after stratifying the IA-2A+ and/or ZnT8A+ groups according to age at first antibody positivity, significance was reached only after age 10 (P = 0·038 and P = 0·003, respectively, between 10–19 and 20–39 years), despite the lower numbers of individuals in these age groups.
Table 2 confirms that the 5-year progression rate to diabetes and the sensitivity of screening for prediabetes remained age-independent in the case of IA-2A+ and/or ZnT8A+ at baseline, while they tended to decrease with age in the absence of both antibodies. Exclusion of relatives with protective HLA-DQ genotypes [26] or with a diabetic mother decreased the number of high-risk groups to be followed overall by about 20% and increased progression rates by 10–20% at the expense of <10% loss in sensitivity (Table 2). When the diagnostic performance of screening for IA-2A and/or ZnT8A positivity was compared to that of all other possible combinations for two types of antibodies (e.g. IAA and/or ZnT8A, GADA and/or IA-2A, …), the overall 5-year progression rate was highest for IA-2A+ and/or ZnT8A+, however, at the expense of a lower fraction of prediabetic relatives identified (Table S1).
|Age group
|Antibody profile
|All relatives
|Relatives without protective factors*
Progression rate
|Fraction T1D‡ % (n)
Progression rate
Fraction T1D
% (n)
|0–39 years
|≥ 1 antibody+
|22 (17–27)
|100 (74)
|29 (23–35)
|100 (64)
|IA-2A− and ZnT8A−
|9 (5–13)
|26 (19)
|13 (6–19)
|23 (15)
|IA-2A+ and/or ZnT8A+
|44 (35–53)
|74 (55)
|49 (39–59)
|77 (49)
|≥ 2/4 antibodies+
|40 (32–47)
|82 (61)
|44 (35–53)
|86 (55)
|≥ 2/3 antibodies+§
|35 (27–43)
|65 (48)
|42 (32–51)
|72 (46)
|0–9 years
|≥ 1 antibody+
|29 (22–37)
|100 (42)
|36 (26–45)
|100 (35)
|IA-2A− and ZnT8A−
|15 (7–22)
|29 (12)
|19 (8–30)
|26 (9)
|IA-2A+ and/or ZnT8A+
|49 (36–62)
|71 (30)
|51 (37–65)
|74 (26)
|≥ 2/4 antibodies+
|43 (32–54)
|86 (36)
|49 (37–61)
|91 (32)
|≥ 2/3 antibodies+
|38 (27–49)
|67 (28)
|45 (32–58)
|77 (27)
|10–19 years
|≥ 1 antibody+
|18 (11–25)
|100 (21)
|24 (15–34)
|100 (19)
|IA-2A− and ZnT8A−
|8 (2–14)
|29 (6)
|11 (2–20)
|26 (5)
|IA-2A+ and/or ZnT8A+
|39 (23–54)
|71 (15)
|46 (28–64)
|74 (14)
|≥ 2/4 antibodies+
|36 (26–45)
|71 (15)
|41 (24–58)
|74 (14)
|≥ 2/3 antibodies+
|30 (15–45)
|52 (11)
|37 (19–55)
|58 (11)
|20–39 years
|≥ 1 antibody+
|15 (7–23)
|100 (11)
|23 (10–35)
|100 (10)
|IA-2A− and ZnT8A−
|2 (0–7)
|9 (1)
|5 (0–14)
|10 (1)
|IA-2A+ and/or ZnT8A+
|40 (20–59)
|91 (10)
|47 (24–70)
|90 (9)
|≥ 2/4 antibodies+
|34 (16–52)
|91 (10)
|37 (17–57)
|90 (9)
|≥ 2/3 antibodies+
|36 (17–56)
|82 (9)
|40 (18–62)
|80 (8)
The fraction of IA-2A+ and/or ZnT8A+ relatives who progressed to diabetes within 5 years did not decrease with age at first antibody positivity (Table 2). Above age 10 years, screening for IA-2A and ZnT8A was at least as sensitive to detect rapid progressors as screening for positivity for more than two antibodies among IAA, GADA and IA-2A (with or without ZnT8A). Furthermore, the smaller group of IA-2A+ and/or ZnT8A+ adolescents or adults tended to have a 10–20% higher progession rate than the subgroup with more than two positive antibodies. Under age 10 years, screening for four antibodies, with or without exclusion of relatives with protective factors, detected up to 20% more rapid progressors but at the expense of following up to 30% more relatives. In addition, their overall progression rate was slower (Table 2). Of the 36 prediabetic relatives identified on the basis of positivity for more than two of the four antibodies tested, seven were IA-2A– and ZnT8A– at baseline. Of these seven, only three were older than 8 years – the usual lower age limit for inclusion in immunointervention [5] – and two of these three developed IA-2A and/or ZnT8A at a later time-point before diagnosis. One prediabetic child was recognized only by his positivity for IA-2A, and not by positivity for more than two antibodies. Under age 10 years, screening for ZnT8A and IA-2A remained more sensitive in detecting rapid progessors than screening for more than two or three positive antibodies among IAA, GADA and IA-2A.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
Regardless of age, screening for IA-2A and ZnT8A alone identified the majority (74%) of siblings and offspring with a family history of type 1 diabetes who developed diabetes within 5 years, compatible with the knowledge that both antibodies generally occur later during the preclinical disease phase than GADA, and in particular IAA [26, 34]. The screening sensitivity and overall progression rate of IA-2A+ and/or ZnT8A+ relatives compared well with that of various combinations of multiple positive antibodies, at least for the age group older than 10 years at baseline. In relatives aged 0–9 years, additional measurement of IAA and GADA further improved screening sensitivity for rapid progressors, in line with observations from the Diabetes Autoimmunity Study in the Young (DAISY) on the importance of age at seroconversion and IAA levels in the prediction of diabetes in young children [34]. However, to a large extent this age group is – at least at present – not included in immunointervention trials [1-4]. Therefore, screening only for IA-2A and ZnT8A can be generalized as a cost-effective strategy to identify potential participants in secondary immunomodulatory prevention trials with similar antibody-inferred risk in children, adolescents and adults. Omission of relatives with genetic [31] and/or maternal [35] protective factors further improves screening efficiency in all age groups.
The strengths of the present study include the registry-based nature of the group of relatives, its wide age range, including many adults, and the lack of preselection based on ICA positivity. Although ICA have been measured in all samples, they were not taken into account in this study as they are not completely independent of GADA, IA-2A and ZnT8A, which are all believed to contribute to ICA [23]. Moreover, solitary ICA+ is rare and associated with a low risk of diabetes [36]. Our study population was selected among relatives of type 1 diabetic patients who represent only 10–15% of all newly diagnosed diabetic patients [37]. This is a limitation of our study. However, familial and non-familial cases of type 1 diabetes were shown not to differ in genetic, autoimmune and metabolic characteristics [37]; neither were there differences in disease-specific sensitivity of antibody markers between first-degree relatives and the general population [38]. Therefore, it is likely that our results in relatives can be extrapolated to the general population.
Immune interventions before clinical onset of type 1 diabetes require identification of adults and children with a high risk of diabetes in the short term [1-10]. For this type of prevention trial, a high positive predictive value of the marker combinations used – if necessary obtained at the expense of the sensitivity of identifying all prospective diabetic patients – is key to minimize the numbers needed to treat to reach conclusions within a few years [39, 40]. The proposed screening strategy based on IA-2A and ZnT8A testing identifies a group of relatives with an overall 5-year diabetic risk that is higher than what can be achieved by any other screening combination for two autoantibodies. Moreover, the antibody-inferred risk by the proposed strategy is age-independent, but this property is related to the presence of more than two antibodies – which is frequently the case when IA-2A or ZnT8A can be detected – rather than to the type of circulating antibodies. Nevertheless, the screening sensitivity of the proposed approach for rapid progressors is equal or superior to detection of double antibody positivity through screening for three (at any age) or four autoantibodies (in the age group 10–39 years). Our data also indicate that the proposed antibody combination is not a surrogate for HLA-inferred risk or high antibody levels. Rather, these risk factors could complement each other in prediction models [13, 19, 33, 34].
The proposed strategy allows reduction of the numbers of antibody-positive relatives who should undergo standardized beta cell function tests evaluating insulin or C-peptide release after acute or prolonged nutrient stimulation before their final enrolment in secondary prevention trials [2, 6-8, 16, 17]. Indeed, decreased first- and/or second-phase C-peptide release (less than percentile 10 of healthy controls) during hyperglycaemic clamp identified the subgroup of IA-2A+ relatives with rapid progression to diabetes within 2 years [8]. As the second-phase C-peptide release of prediabetic relatives [median (IQR): 58% (44–73) of controls] was still higher than that of recent-onset patients (22% [15-29] of controls) [8, 27], these relatives are likely candidates for participation in immune interventions [2, 27].
Finally, a triple chimeric protein has been produced containing the intracellular domains of IA-2 (amino acids 605–979) and of the two common polymorphysms of ZnT8 (amino acids 268–369 with arginine or tryptophan at position 325) [41]. With this chimeric protein antigen, IA-2–ZnT8WR, a radiobinding assay was shown to detect autoantibodies to IA-2A and both major forms of ZnT8A with the same sensitivity and specificity as assays using the individual proteins as antigen [36]. Using such an assay would halve the cost and amount of serum needed for the screening strategy we propose here.
In conclusion, screening for IA-2A and ZnT8A allows efficient identification of relatives synchronized in the later stages of subclinical islet autoimmunity and to facilitate the identification of individuals with already compromised beta cell function who are likely to benefit most from immune interventions. Their enrolment may minimize the numbers needed to treat to observe significant effects within a reasonable period of 2–3 years, while avoiding the unnecessary exposure of non-progressors to the risk of side effects. If the lower age limit for participation in immune intervention trials is to be lowered in the future, additional determination of IAA and GADA should be considered at under age 10 years. Less aggressive prevention strategies may require other prediction models.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
F. G. designed research, obtained funding, supervised the study, analysed and interpreted data, wrote and edited the manuscript. E. V. B. researched data, provided statistical analysis, analysed and interpreted data, reviewed and edited the manuscript. I. V., S. D., A. V. D., O. C., H. D., S. T., T. M., C. D. B., P. G. and K. D. researched data, reviewed and edited the manuscript. J. M. W., J. C. H. and D. G. P. researched data, contributed essential reagents, contributed to the discussion, reviewed and edited the manuscript. I. W. researched data, provided statistical analysis and advice, contributed to the discussion and reviewed and edited the manuscript. All authors approved the submitted version. The present work was supported by grants from the Juvenile Diabetes Research Foundation (JDRF Center Grant 4–2005-1327), the European Union (FP-7 project 241883), the Belgian Fund for Scientific Research (FWO Vlaanderen projects G.0319·01, G.0514·04, G.0311·07, G.0374·08 and G.0868·11; senior clinical research fellowship for K. D. and I. W.), the research council of the Brussels Free University (projects OZR1150, 1149 and 1615) and the Willy Gepts Fund (projects 3–2005 and 3/22–2007; University Hospital Brussels – UZ Brussel). J. C. H. acknowledges the University of Washington Diabetes Endocrinology Research Center (DERC) [National Institute of Health (NIH) grant P30-DK-57516], NIH grant R01-DK-052068 and JDRF grant 4–2007-1056. The Belgian Diabetes Registry was sponsored by the Belgian National Lottery, the Ministries of Public Health of the Flemish and French Communities of Belgium, Hippo and Friends, Weight Watchers, Ortho-Clinical Diagnostics, Novo Nordisk Pharma, Lifescan, Roche Diagnostics, Bayer and Eli Lilly. The expert technical assistance of co-workers at the central unit of the Belgian Diabetes Registry, Free University Brussels – VUB, Brussels (V. Baeten, G. De Block, T. De Mesmaeker, H. Dewinter, N. Diependaele, S. Exterbille, T. Glorieux, P. Goubert, C. Groven, T. Haulet, A. Ivens, D. Kesler, F. Lebleu, E. Quartier, G. Schoonjans, U. Vandevelde, M. Van Molle, S. Vanderstraeten, K. Verhaeghen and A. Walgrave) is gratefully acknowledged. We would also like to thank the different university teams of co-workers for their excellent assistance in collecting samples and organizing the fieldwork in University Hospital Antwerp – UZA, Antwerp (L. Van Gaal, C. De Block, R. Braspenning, J. Michiels and J. Vertommen), at University Hospital Brussels – UZ Brussel, Brussels (B. Keymeulen, K. Decochez, T. De Mesmaeker, S. Exterbille, P. Goubert, C. Groven, V. Kemels, C. Tettelin, S. Vanderstraeten, U. Van de Velde, A. Walgrave), at University Hospital Ghent – UZ Gent, Ghent (J. M. Kaufman, J. Ruige, A. Hutse, A. Rawoens, N. Steyaert) and in University Leuven – KUL, Leuven (C. Mathieu, P. Gillard, M. Carpentier, M. Robijn, K. Rouffé, A. Schoonis and H. Morobé). We sincerely thank all members of the Belgian Diabetes Registry who contributed to the recruitment of relatives for the present study. The list of members is given in Appendix S1.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
The authors have no conflicts of interest to declare.
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
- 1A single course of anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54:1763–1769., , et al.
- 2Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 2010; 53:614–623., , et al.
- 3Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011; 378:487–497., , et al.
- 4Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 378:412–419., , et al.
- 5Stopping type 1 diabetes: attempts to prevent or cure type 1 diabetes in man. Diabetes 2011; 60:1–8., .
- 6Anti-CD3 antibodies for type 1 diabetes: beyond expectations. Lancet 2011; 378:459–460..
- 7Diabetes: type 1 diabetes mellitus – a door opening to a real therapy? Nat Rev Endocrinol 2011; 7:564–566..
- 8Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients. Diabetologia 2010; 53:36–44., , et al.
- 9Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care 2009; 32:1769–1782., .
- 10Effect of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346:1685–1691., , et al.
- 11European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised intervention before onset of type 1 diabetes. Lancet 2004; 363:925–931., , et al.
- 12Sample size requirements for studies of treatment effects on beta cell function in newly diagnosed type 1 diabetes. PLoS ONE 2011; 6:e26471., , et al.
- 13Can we really predict IDDM? Diabetes 1993; 42:213–220., , .
- 14Prediction of type 1 diabetes in the general population. Diabetes Care 2010; 33:1206–1212., , et al.
- 15Enhancing the understanding of pre-type 1 diabetes in the general population. Diabetes Care 2010; 33:1403–1405., , .
- 16Estimation of beta-cell mass by metabolic tests: necessary, but how sufficient? Diabetes 2007; 56:2420–2424..
- 17Trends of earlier and later responses of C-peptide to oral glucose challenges with progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes Care 2010; 33:620–625., , et al.
- 18Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2009; 32:2269–2274., , et al.
- 19Natural history of type 1 diabetes. Diabetes 2005; 54 (Suppl. 2):S25–S31., , et al.
- 20Prediction of type 1 diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996; 45:926–933., , et al.
- 21Predictive power of screening for antibodies against insulinoma-associated protein 2 beta (IA-2beta) and zinc transporter-8 to select first-degree relatives of type 1 diabetic patients with risk of rapid progression to clinical onset of the disease: implications for prevention trials. Diabetologia 2010; 53:517–524., , et al.
- 22Diabetes registries and early biological markers of insulin-dependent diabetes mellitus. Belgian Diabetes Registry. Diabetes Metab Rev 1997; 13:247–274..
- 23Novel antigens in type 1 diabetes: the importance of ZnT8. Curr Diabetes Rep 2009; 9:105–112., , et al.
- 24Contribution of antibodies against IA-2β and zinc transporter 8 to classification of diabetes diagnosed under 40 years of age. Diabetes Care 2011; 34:1760–1765., , et al.
- 25Predicting adult-onset autoimmune diabetes: clarity from complexity. Diabetes 2010; 59:330–331..
- 26An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age. Diabetologia 2012; 55:413–420., , et al.
- 27Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352:2598–2608., , et al.
- 28Epidemiology, clinical aspects, and biology of IDDM patients under age 40 years. Comparison of data from Antwerp with complete ascertainment with data from Belgium with 40% ascertainment. The Belgian Diabetes Registry. Diabetes Care 1997; 20:1556–1561., , et al.
- 29
- 30Male-to-female excess in diabetes diagnosed in early adulthood is not specific for the immune-mediated form nor is it HLA-DQ restricted: possible relation to increased body mass index. Diabetologia 2001; 44:40–47., , et al.
- 31Relative and absolute HLA-DQA1–DQB1 linked risk for developing type 1 diabetes before 40 years of age in the Belgian population: implications for future prevention studies. Hum Immunol 2002; 63:40–50., , et al.
- 32Proinsulin levels and the proinsulin: C-peptide ratio complement autoantibody measurement for predicting type 1 diabetes. Diabetologia 2005; 48:2322–2329., , et al.
- 33Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes. Diabetologia 2005; 48:687–694., , et al.
- 34Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes. Diabetes Autoimmunity Study in the Young. Diabetes Care 2011; 34:1397–1399., , et al.
- 35Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c). Diabetologia 2008; 51:1245–1252., , et al.
- 36The role of autoantibodies to zinc transporter 8 in prediction of type 1 diabetes in relatives: lessons from the European Nicotinamide Diabetes Intervention Trial (ENDIT) cohort. J Clin Endocrinol Metab 2012; 97:632–637., , et al.
- 37HLA-DQB1-defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. J Clin Invest 1996; 98:2489–2495., , et al.
- 38Prediction of type 1 diabetes among siblings of affected children and in the general population. Diabetologia 2007; 50:2272–2275., , , , , .
- 39The limitations of clinical trials for preventions of IDDM. Diabetes Care 1997; 20:1027–1033., .
- 40Belgian Diabetes Registry. Prospects for predicting and stopping the development of type 1 diabetes. Best Pract Res Clin Endocrinol Metab 2001; 15:371–389., .
- 41Triple chimeric islet autoantigen IA-2-ZnT8WR to facilitate islet autoantibody determination. J Immunol Methods 2010; 353:20–23., , et al.
Supporting Information
- Top of page
- Summary
- Introduction
- Materials and methods
- Results
- Discussion
- Acknowledgements
- Disclosure
- References
- Supporting Information
Fig. S1. Overlap of positivity for the four autoantibody specificities tested at baseline. Prevalence data are expressed as percentage of the total number of relatives (n = 394). Reference: Oliveros, J. C. (2007) VENNY. An interactive tool for comparing lists with Venn diagrams. http://bioinfogp.cnb.csic.es/tools/venny/index.html
Fig. S2. Diabetes-free survival of relatives positive for insulinoma antigen 2A (IA-2A) (a) or zinc transporter 8 autoantibodies (ZnT8A) (b) according to the number of other antibody specificities present (n = 0: purple, n = 1: red, n = 2: blue, n = 3: green). The fraction of relatives progressing to diabetes during follow-up is indicated above each arm in the two panels. *P-value for comparison of IA-2A+ (a) or ZnT8A+ (b) relatives presenting one, two or three additional antibody specificities (log-rank test).**P-value for comparison of solitary IA-2A+ (panel a) or ZnT8+ (panel b) relatives versus relatives positive for at least one additional antibody (n = 1, n = 2 and n = 3) taken together (log-rank test).
Fig. S3. Diabetes-free survival of relatives positive for insulinoma antigen 2A (IA-2A) (a) and those positive for zinc transporter 8 autoantibodies (ZnT8A) (b) according to the titre of IA-2A and ZnT8A, respectively: tertile 1 (green), tertile 2 (blue), tertile 3 (red). P-values by log-rank test. The fraction of relatives progressing to diabetes during follow-up is indicated above each arm in the two panels.
Table S1. Five-year progression to type 1 diabetes according to antibody type in antibody-positive relatives (0–39 years).
Appendix S1. List of the current members of the Belgian Diabetes Registry who participated in the recruitment of relatives and the handling of samples.
Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.


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List all words ending with fetid
Only the word fetid was found, nothing longer.
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Boston's hotel market should see more growth in 2008, with revpar increasing 2.8%, but that's about half of this year's increase, according to PKF Hospitality Research. One factor contributing to the slowdown include fewer major conventions in the city next year as compared to years past, according to one local hotel official.
Full Story:The Boston Globe (tiered subscription model)


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Affiliate Convention is using an interesting approach to their first conference – being held June 17-20th if you include the social activities – at Denver's Convention Center. All affiliates get in free with the companies they act as affiliates for picking up the tab.
The idea of the affiliates who bring the traffic to vendors at their own expense and get paid when a conversion happens is a smart one. The event is a give back for all the branding that the affiliates achieve that in many cases does not convert directly to them.
Affiliate Convention will deliver fun and productive networking opportunities, including the first annual affiliate charity golf tournament where attendees will play while enjoying a day of relaxed networking with other affiliates and affiliate managers. Nighttime brings more community events like the opening party sponsored by Affiliate.com and WebmasterRadio.FM's AffiliateBash.
"We've been working to build a line-up of speakers and sessions that brings ideas, knowledge and information targeted towards affiliate marketers," said agenda organizer Jim Hedger, "We also want to create a dynamic and excited crowd for sponsors and exhibitors to meet and network with. We're coming into the last two weeks before the convention and it looks like we're going to meet and exceed our goals for the first show."
It is an impressive list of web who's who in attendance and I plan on going just for the awesome parties Brandy Babin throws. So see you at the bash.
Related reading
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People like fast websites and so does Google.
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Why your content and SEO strategy need to be joined up
There are some sites creating useful or interesting content, that are being let down by a lack of attention to SEO.
What are the most common on-page SEO issues and how to fix them?
Appearing in the top organic listings of Google is increasingly like pouring a gallon of milk into a shot glass.


text:
|Reviews for Blank Slate
| VisQel Stelar chapter 41 . 11/29/2015
It just HAD to end this way, didn't it? Oh god. Why?!
| Rebel679 chapter 41 . 6/9/2015
OH MY GOSH! THAT GOT SO EMOTIONAL! But it was a great story. I loved it.
| Guest chapter 41 . 12/25/2014
You can't write a story this fucking deep and have THAT as your cover picture
| Guest chapter 41 . 10/4/2014
this really fucked me up. great story and all, but i feel like i need to wander down an empty sidewalk and reevaluate my life and existence itself because one person wrote a fic 3 years ago
| Guest chapter 41 . 4/9/2014
Wow that was one heck of a fic
| Mcat9905 chapter 41 . 11/13/2013
Weird as hell. But I liked it a lot. I also liked where you ended it. Even though endings in general suck, this was placed well. Any further and it would seem like it was running on for too long. Bravo.
| naglisnatalie chapter 41 . 8/26/2013
Wow, man. This, this story. THIS. I can't even begin to describe how amazing this is. It was simple, but I cried so much. Amazing. ;-;
| The Masked Idiot chapter 41 . 7/4/2013
Ehh, I don't know what to say except that this story was good. At first I was like, what's going on? Why's it so slow paced? But then I guess I kinda got hooked on and well, I just think that reading this was very enjoyable. Thank you for writing and posting something like this :D
| ellesra chapter 41 . 6/21/2013
Aaaaaaaaaaaaaaaaah. This story... I just want to see them meet and I want them to be happy. Yet they'll probably never be completely happy with how things went. Either way: this is definitely one of the best fanfictions I've read ever. I like how so little happens, yet you make it so exciting to read.
Also, the way you used time was fantastic. Most people would've just written that a lot of time went by. Not done it in hours, and not as well as you did. So bravo, my dear writer(s).
Now I will go to bed, since this fic has kept me up.
| Obvious Ghost chapter 41 . 6/20/2013
Considering this story wasn't chock-full of action, you made it incredibly powerful. I loved it.
| Ellenthefox chapter 41 . 6/7/2013
I hate you. This story is perfect. Damn you to hell. That bittersweet ending almost killed me. I feel really misrable now...
| Iceagesurvivor123 chapter 41 . 4/9/2013
Oh god I'm going to cry
This story was so amazing
and you handled everything so well
I especially love how when the boys came back it felt off to them
This is all so great omg I love this story so much
That ending though ugh
You're amazing i love you
| AlexandriteCastor chapter 41 . 4/8/2013
Wow this was such a moving story. I kind of get the feeling's that they have... about it not being there world- but at the same time... I don't. Its so sweet that they want to stay in touch and that they stay talking to each other! So awesome! I just love your writing! :)
| emanon chapter 41 . 4/3/2013
Cull me now, that was sooooooo sresfull! I'm glad they can talk again' KK seams much closer to his friends than john. It wwould be interesting to see how they work themselves back into there worlds and how tthere long disrance relationship helps heal there mintle states
And are ther any dangers for them considdering they technicly are from a doomed timeline?
| Jo chapter 13 . 1/27/2013
I can't help but notice that this is chapter... Thirteen.


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RWE, Bankhaus Lampe to Double Size of Renewables Startup Fund
RWE AG, Germany's second-biggest utility, and Bankhaus Lampe KG will add 50 million euros ($67 million) to a fund investing in renewable energy and power storage-technology startups, almost doubling its value.
The utility's renewables unit Innogy and Lampe, a German private bank, will each add 25 million euros to raise the RWE fund to more than 115 million euros with the aim of increasing the number of companies it has invested in to 14 from nine currently, according to a statement e-mailed today.
Lampe will take 22 percent of the fund, RWE said.
Before it's here, it's on the Bloomberg Terminal. LEARN MORE


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ACE Fit Share
Fit Life Articles
Is fasting good for you? Can it help you lose weight? It depends. Fasting can be beneficial for the body when practiced appropriately. But it can also put a great deal of stress on the body. Intermittent fasting, which involves limiting food intake for shorter and more...
When it comes to serving up snacks, you have the power to prepare healthy options in your own home. Here are some great ideas for incorporating whole grains, healthy fats and fresh fruits and vegetables for the perfect between-meal pick-me-ups.
You are the only person in charge of you, and if you want something (better health, a more fulfilling job or a more nourishing relationship), you need to take action. Let go of these five habits in order to be the healthiest version of yourself.


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Primary Care Doctor, Family Practitioner
31 years of experience
31 years of experience
6401 Van Nuys Blvd
Van Nuys, CA 91401 Phone number & directions
Van Nuys, CA 91401 Phone number & directions
License & Identifications
A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. James Ashton:
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Type 2 Diabetes Patient Education Learn about type 2 diabetes symptoms, treatments and medications by reading Vitals' patient education guide.Before Visiting Dr. Ashton Learn More
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Dr. Ashton graduated from Washington University at St. Louis, Saint Louis.
Home > Find a Primary Care Doctor > CA > Van Nuys Primary Care Doctors > Dr. James Ashton, MD
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See Van Nuys Primary Care Doctors.


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New-firm filings lowest in 6 years
Orange County businesses had 3,104 fictitious name filings with the county Clerk Recorder's office in January, the fewest January filings since at least 2004. (Click on image for a larger view.)
[caption id="attachment_30697" align="aligncenter" width="336" caption="Source: O.C. County Clerk Recorder"][/caption]
Fictitious business names, also called DBAs for "doing business as", are an indication of economic activity. They are filed by new businesses and those that sell or move or have another significant change.
The year-over-year monthly filings declined 3.9%. The 12-month running total (which evens out any seasonal highs or lows) was 36,393 filings, down 4.8% from the previous 12 months, according to the county.
However, the January filings were higher than in December, which typically is one of the slowest months of the year because of the Christmas holidays.
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A game for 2 people. Take turns joining two dots, until your opponent is unable to move.
An irregular tetrahedron is composed of four different triangles.
Can such a tetrahedron be constructed where the side lengths are 4,
5, 6, 7, 8 and 9 units of length?
A Hamiltonian circuit is a continuous path in a graph that passes through each of the vertices exactly once and returns to the start.
How many Hamiltonian circuits can you find in these graphs?
A game for 2 players. Can be played online. One player has 1 red
counter, the other has 4 blue. The red counter needs to reach the
other side, and the blue needs to trap the red.
Triangle numbers can be represented by a triangular array of squares. What do you notice about the sum of identical triangle numbers?
Given the nets of 4 cubes with the faces coloured in 4 colours, build a tower so that on each vertical wall no colour is repeated, that is all 4 colours appear.
Use the interactivity to listen to the bells ringing a pattern. Now
it's your turn! Play one of the bells yourself. How do you know
when it is your turn to ring?
If you can copy a network without lifting your pen off the paper and without drawing any line twice, then it is traversable.
Decide which of these diagrams are traversable.
Slide the pieces to move Khun Phaen past all the guards into the position on the right from which he can escape to freedom.
What can you see? What do you notice? What questions can you ask?
This task depends on groups working collaboratively, discussing and
reasoning to agree a final product.
I found these clocks in the Arts Centre at the University of
Warwick intriguing - do they really need four clocks and what times
would be ambiguous with only two or three of them?
Here is a solitaire type environment for you to experiment with. Which targets can you reach?
A and B are two interlocking cogwheels having p teeth and q teeth respectively. One tooth on B is painted red. Find the values of p and q for which the red tooth on B contacts every gap on the. . . .
Lyndon Baker describes how the Mobius strip and Euler's law can
introduce pupils to the idea of topology.
This article for teachers discusses examples of problems in which
there is no obvious method but in which children can be encouraged
to think deeply about the context and extend their ability to. . . .
Can you cross each of the seven bridges that join the north and south of the river to the two islands, once and once only, without retracing your steps?
Take a line segment of length 1. Remove the middle third. Remove
the middle thirds of what you have left. Repeat infinitely many
times, and you have the Cantor Set. Can you picture it?
Use the interactivity to play two of the bells in a pattern. How do
you know when it is your turn to ring, and how do you know which
bell to ring?
Draw a pentagon with all the diagonals. This is called a pentagram.
How many diagonals are there? How many diagonals are there in a
hexagram, heptagram, ... Does any pattern occur when looking at. . . .
The triangle ABC is equilateral. The arc AB has centre C, the arc
BC has centre A and the arc CA has centre B. Explain how and why
this shape can roll along between two parallel tracks.
A circle rolls around the outside edge of a square so that its circumference always touches the edge of the square. Can you describe the locus of the centre of the circle?
The diagram shows a very heavy kitchen cabinet. It cannot be lifted but it can be pivoted around a corner. The task is to move it, without sliding, in a series of turns about the corners so that it. . . .
In a right angled triangular field, three animals are tethered to posts at the midpoint of each side. Each rope is just long enough to allow the animal to reach two adjacent vertices. Only one animal. . . .
ABCD is a regular tetrahedron and the points P, Q, R and S are the midpoints of the edges AB, BD, CD and CA. Prove that PQRS is a square.
Seven small rectangular pictures have one inch wide frames. The
frames are removed and the pictures are fitted together like a
jigsaw to make a rectangle of length 12 inches. Find the dimensions
of. . . .
Four rods, two of length a and two of length b, are linked to form
a kite. The linkage is moveable so that the angles change. What is
the maximum area of the kite?
An extension of noughts and crosses in which the grid is enlarged
and the length of the winning line can to altered to 3, 4 or 5.
Can you fit the tangram pieces into the outlines of the workmen?
Can you fit the tangram pieces into the outlines of the watering can and man in a boat?
Can you fit the tangram pieces into the outlines of Mai Ling and Chi Wing?
Can you fit the tangram pieces into the outlines of the candle and sundial?
Which of these dice are right-handed and which are left-handed?
Euler discussed whether or not it was possible to stroll around Koenigsberg crossing each of its seven bridges exactly once. Experiment with different numbers of islands and bridges.
You can move the 4 pieces of the jigsaw and fit them into both
outlines. Explain what has happened to the missing one unit of
Investigate how the four L-shapes fit together to make an enlarged
L-shape. You could explore this idea with other shapes too.
A game for 2 players. Given a board of dots in a grid pattern, players take turns drawing a line by connecting 2 adjacent dots. Your goal is to complete more squares than your opponent.
Is it possible to rearrange the numbers 1,2......12 around a clock
face in such a way that every two numbers in adjacent positions
differ by any of 3, 4 or 5 hours?
We start with one yellow cube and build around it to make a 3x3x3 cube with red cubes. Then we build around that red cube with blue cubes and so on. How many cubes of each colour have we used?
Can you fit the tangram pieces into the outlines of these clocks?
Can you fit the tangram pieces into the outline of the child walking home from school?
Can you fit the tangram pieces into the outlines of these people?
Can you fit the tangram pieces into the outline of this brazier for roasting chestnuts?
Can you fit the tangram pieces into the outline of this telephone?
Can you fit the tangram pieces into the outline of Little Ming playing the board game?
Can you fit the tangram pieces into the outline of Little Fung at the table?
Can you fit the tangram pieces into the outlines of the lobster, yacht and cyclist?
Show that among the interior angles of a convex polygon there
cannot be more than three acute angles.
Blue Flibbins are so jealous of their red partners that they will
not leave them on their own with any other bue Flibbin. What is the
quickest way of getting the five pairs of Flibbins safely to. . . .
In how many ways can you fit all three pieces together to make
shapes with line symmetry?


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Top Definition
When nerd people that ride the bus and get milk dumped on them because their losers.
I dumped some milk on this geeky kid with glasses the other day becasue he is gay
av TJ 20. mai 2003
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text:
Symptoms of hypertensive crises include:
- headache,
- heart palpitation,
- chest pain,
- increased or decreased heart rate,
- neck stiffness or soreness,
- nausea,
- vomiting,
- sweating, and
- dilated pupils.
Bleeding in the brain also may occur. Patients should be aware of signs and symptoms of hypertensive crisis and should seek immediate medical treatment if these signs or symptoms are present. Hypertensive crisis may be managed with nitroprusside (Nitropress), labetalol (Normodyne, Trandate), or phentolamine.
Orthostatic hypotension (feeling faint upon standing due to decreased blood flow to the brain) also occurs. Patients should rise slowly from a sitting position to reduce the effect of orthostatic hypotension. Orthostatic hypotension may be treated with steroids.
Some patients may experience peripheral edema (swelling of the lower legs and ankles) which can be improved by wearing support stockings.
Weight gain also occurs during MAOI therapy, and tranylcypromine (Parnate) causes more weight gain than other MAOIs. MAOIs also are associated with sexual side effects such as decreased sexual drive, erectile dysfunction, difficulty ejaculating or reaching orgasm. Sexual side effects may diminish with time or a reduction in dose.
What drug interactions may occur with MAOIs?
Quick GuideDepression Hurts: Physical Symptoms of Depression
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Need help identifying pills and medications?
Use the pill identifier tool on RxList.


text:
LG G Pad 8.3: Hands-on pictures with the Nexus 7 challengerPocket-lint
LG's G Pad 8.3 is a smart idea for a tablet. We think this is about the right sort of size for a tablet, not as clunky as a 10-or-more-inch model, but a bit more screen real estate than a 7-inch tablet.
From our, so far, limited time with the G Pad - a review sample will be with us soon - we noticed a lot of similarities to the Nexus 7. The screen resolution is the same, for one, but the larger size means you get a fewer pixels per inch (PPI). In practice, we couldn't really tell this was the case though, and the G Pad screen looks really great.
LG told us there's no LTE or 3G versions yet, although Amazon did accidentally reveal that a model might exist. Even so, that doesn't matter because LG has a really elegant solution to get online when you're out and about. It uses a pairing app, that reminds us in some ways of the BlackBerry Bridge for the Playbook. It's a free app, available on the Google Play store for all handsets, that allows you to share out your internet connection to the tablet.
But there's more too it than that, because it also adds near phone-like abilities to the tablet too. For example, when your phone rings the tablet will show who is calling and you reject the call with a message, if you're too busy. Also, text messages are shown and can be replied too on the G Pad. There are also some sharing options that sync your handwritten notes made on the G Pad back to your phone.
While pairing a tablet with a phone is nothing new, the LG app, called QPair just makes it very simple to do, and gives you some nice features you wouldn't get normally. We're a big fan of the fact that it doesn't require an LG Android phone to work, and it really broadens access for those who don't have a G2 or similar.
Other fun stuff includes much of the same gesture-based stuff found on the G2. You can multitask with a gesture that keeps three apps running at the same time, and allows you to access them more quickly. There's the "tap" to unlock feature that we loved on the G2 too, so we're very pleased about that.
In our time with the tablet, we found that it felt nice and solid, looks nice and wowed us with the screen. The interface was snappy too, and LG has gone with a Snapdragon 600 processor here too, rather than the 800, which helps to keep the cost down a bit lower than packing in all the most high-end toys would allow. That said, the battery is a 4,600 mAh pack, so you should get a really decent amount of use out of each charge, even with that big and high resolution screen.
Perhaps most interesting of all though, the G Pad is currently selling for about £230 at Asda, with a discount code. That puts it very close indeed to the Nexus 7, but gives you some really nice extra functionality and that larger screen.
Best smartphone battery packs: Pokemon power and more
Huawei MateBook review: 5-hours of friendship
Razer has a new iPad Pro mechanical keyboard case for gamers
Here are all the iPhones, iPads, and Macs that won't run Apple's betas
- Huawei MateBook review: 5-hours of friendship
- Razer has a new iPad Pro mechanical keyboard case for gamers
- Kindle's Page Flip lets you skip pages without losing your place
- New Amazon Kindle 2016: Double memory, thinner, lighter and more
- Samsung Galaxy TabPro S review: Taking on the Microsoft Surface Pro
- Life-drawing at the Royal Academy with an iPad Pro
- Win an iPad Pro worth £500 with Travelex Supercard!
- Nvidia might have new Shield gaming tablet on the way, FCC filings reveal
- EE Jay is a fun and budget-friendly 4G tablet for summer travelling
- Next Apple Pencil could have swappable tips and even Touch ID
- Pokemon Go Gym tips: How to battle, train and win
- Pokemon Go: How to raise your XP level, power up and evolve your Pokemon
- Pokemon Go: How to find and catch rare Pokemon like Charizard, Blastoise and Alakazam
- Samsung Galaxy Note 7: Release date, rumours and everything you need to know
- Help! Pokemon Go isn't working: How to fix common Pokemon Go problems
- Apple iPhone 7 vs iPhone 7 Plus vs iPhone 7 Pro: What's the rumoured difference?
- Pokemon Go: How to play and other tips and tricks
- Pokemon Go Plus explained: Release date, price and everything you need to know
- Best smartphones 2016: The best phones available to buy today
- BlackBerry DTEK50 preview: Hands-on with the Alcatel Idol 4 lookalike


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a very sexy, very intelligent vegetarian woman who loves The L Word and other woman.
Whoa that girl so phwaor.
I wish I was as phwaor as she is.
I wish I was as phwaor as she is.
de Misty 15 avril 2005
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KANSAS CITY, Mo. ---- For the third time in as many years, the Auburn University at Montgomery athletic department has received the Champions of Character Five Star Award, the National Association of Intercollegiate Athletics (NAIA) announced recently.
The Warhawks earned 73 points on its 2011-12 Champions of Character Scorecard, a mark which ranked fifth among members of the Southern States Athletic Conference. To qualify for the award, institutions must score 60 points or better for the academic year.
"I am extremely proud of our coaching staff and our student-athletes in the recognition of this award," AUM Athletic Director Steve Crotz said. "The coaches at AUM embrace the teaching of life skills and five core values of the NAIA Champions of Character. This honor rewards the success of our student-athletes in their academic performance, on the field sportsmanship and community outreach involvement. I am proud of the commitment to the development of the total person by our dedicated staff."
Composed of nearly 300 schools across the nation, the NAIA awarded 220 Five Star Awards, with AUM's total finishing in the top 40 percent. In all, 13 members from the SSAC earned the distinction. Joining the Warhawks as Five-Star Institutions from the SSAC were Spring Hill (82), Southern Wesleyan (79), Brewton-Parker (78), Faulkner (76), Mobile (74), Loyola (71), Truett-McConnell (71), Emmanuel (70), Southern Poly (70), William Carey (65) and Belhaven (64). The SSAC was one of 23 conferences to earn the Champions of Character Five-Star Conference award.
More than 80 percent of NAIA member institutions were honored as Five-Star Institutions. Montana Tech tallied the most points, earning a perfect 100. Carroll College (Mont.) finished second with 96 points, while Paul Quinn (Texas), University of Saint Francis (Ind.) and Xavier (La.) finished tied for third with 91 points.
The Scorecard process is based on the NAIA's flagship program Champions of Character, which emphasizes the five core values of integrity, respect, responsibility, sportsmanship and servant leadership. Points are earned based on an institution's character training (52%), conduct in competition (20%), character recognition (14%), academic focus (8%) and character promotion (6%). Institutions earned points based on exceptional student-athlete grade point averages and by obtaining zero ejections during competition throughout the course of the academic year.


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Hello everyone. It has been awhile but the short sleeve shirts are all in and having the heat transfer with the logo done to hopefully be completed this week(12/2-12/6). I will email those that got their order in before the cutoff with the total owed and we can make arrangements to get your shirts to you. If you are happy with how the shirts have turned out we can proceed with the long sleeves. Those that did not get their order in for a short sleeve the first time we can add it to the long sleeve order. This has taken longer to get finalized than I ever thought it would and I appreciate everyone's patience and big thank you to Powell for doing the leg work of ordering shirts and dealing with getting the logo added to the shirts .The price for the short sleeves with the logo is $15.
I have 2 green T-shirts (size =small) for sale if anyone is looking for one. Please contact me via meet up or response to here. Thanks Nancy
0 · January 25, 2014
Yup, I was thinking the same thing Beth. Chuck- where do we meet up to get our shirts!!!!!
0 · January 22, 2014
Hi Chuck! Tom & I are in the same boat as Deborah Plummer. I sent an email with our order directly to you early on after I first sent it in error to Matt. I later posted our order in this conversation b/c I didn't receive a reply. I didn't receive a confirmation or email with regard to the posted order either. I just assume it was overlooked. Unless otherwise notified, I must also assume we'll just have to catch the next batch of shirts & decals. Sorry for the initial confusion, & I do hope we get another opportunity to place an order in the near future. Thanks!
0 · December 19, 2013
We are moving the event date back again this time to mid-January. This is only to keep this event page alive and IN NO WAY CHANGES the delivery date on the shirts it only is changed to keep the page alive. Please read the revised "trip" description for updated information about the shirts and pricing.
0 · December 19, 2013
Hey Chuck, didnt get an email so i assume will you will not have my order? Where is the location for tomorrow? I guess i dont need to be there if i dont have an order ??? I can mail check when my shirts are ready!!!
0 · December 19, 2013
Well, presuming you got my order for the short sleeve, would you please take my name off for the long sleeved one. Thanks.
0 · December 19, 2013
I know this has been a long process of getting these shirts made however I think it is going to be a bit longer still. Remember that the folks who are taking on this HUGE undertaking are doing so for FREE. I would like to thank Chuck and Powell and Matt and anyone else who has worked on this for working this in while they deal with their real lives. My understanding is that all the shirts are in and we are waiting for the printing to be done. Matt, Chuck, Powell, or me will send out an notice on this Meetup site on how to get your shirts and pay for them. Reminder if you ordered it you will be expected to pick it up and PAY FOR what you ordered. Someone (I'm not sure who) has fronted the money to get these shirts ordered (my guess is well over $1,000) and I would be really sad if folks didn't hold up there end of this deal. For those of you who have ordered recently may have to wait until the next order. I'm pushing the date back for this event until mid Dec. so this page stays live.
4 · November 12, 2013
Hey, I got the email, thanks. Give me a ring when you are available. I wound up with 5 shirts (not sure if all green) - hopefully XL - probably one more than I need. If anyone is dying to get one....
0 · December 8, 2013
OK for us who have ordered shirts and stickers but do not live in Bowling Green, how can we get our order without having to travel up there at night and who do we pay and how do we pay them. Can you give me a name and address and amount, and I will send them a check, OK? You can contact me at [masked].
Thanks, JP
0 · November 24, 2013
I sent a email to everyone who responded yes on the RSVP list on Friday. If you did not get it you will find it on the discussion page under time to order shirts. If you have sent me your order in a email you should have got a response from me to let you know I did receive it. Please email your order to me because we need to order quickly(Matt I got your order). If you have changed your mind please change your RSVP to no. Powell has got us a good deal on the shirts and we need to act quickly.
0 · September 29, 2013
Jason & Powell, I sent you both emails and haven't heard back. What do I need to do to get one? I want long sleeve, L royal blue.
0 · November 3, 2013
Why is the long sleeve less expensive than the short sleeve? Both are really reasonable prices.
0 · October 15, 2013
Thanks Chuck for your hard work on the shirts. I sent an email to you with my & Tom's order, but never received a reply. We wanted one long sleeve & one short sleeve for each of us. Tom wants both of his in the color steel & size 4X. I would like mine in steel also, but in size Large. We'd also like 4 decals please. Thanks!
0 · October 17, 2013
Can I get decales later or must be ordered now? , am interested in those also.
0 · October 13, 2013
Hi Chuck please add two long sleeve in gray color...size small
One short sleeve in blue ...small size
0 · October 3, 2013
Hi chuck,
Am interested in one shirt in long sleeve and one short sleeve...in (small size )long sleeve color in navy blue / short in green color, thanks for taking on this project...Debbie Plummer thanks Powell for getting us a great deal !!
1 · October 2, 2013
Chuck, I went by to look at the colors and try on the sizes.
I like royal blue and shockwave green, but will gladly go with the flow. I would like to order 1 men's small long sleeve tee and 1 short sleeve tee. When I tried to respond to your email, I got a return message saying I was trying to send mail to an unmonitored box. Thanks so much for all your work on this! Sally
0 · October 1, 2013
JUst to clarify my order, I want 1 Long Sleeve shirt and one shoert sleeve shirt, both XXL, any color. Still havren't heard what material ? Not Cotton I hope.
3 stickers also.
Who do we pay,and how much?
0 · September 24, 2013
Chuck, a previous post as to how many but I notice I didn't indicate a size. Correct sizing could be an issue depending on men's sizing or women's ~ guess I should be on the safe side and go with XL in 1 long-sleeve and 1 short sleeve ~ 4 stickers at least (1 for each boat and the Vue). I like blue and I also like sage green. Thanks so much ~ you've done a great job! Kudos! Can't wait for the finished products!!! :)
0 · September 23, 2013
Two shirts one olive short sleeve one red long sleeve and two stickers.
0 · September 22, 2013
At least 2 shirts for us. And a decal- guess that will have to go on the car. Inflatables - don't see it sticking. Lol.
0 · September 21, 2013
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Skip to comments.Clinic is caught in the fog of abortion war (Abortion Clinic Closes)
Posted on 10/28/2005 10:39:33 PM PDT by Coleus
When Springfield Healthcare Center mysteriously closed its doors, Rosina San Paolo praised the Lord.
"I danced. I thanked the Blessed Mother. I thanked Jesus," said San Paola, 82, who has spent the past 22 years protesting outside southwest Missouri's only abortion clinic.
But another woman left a starkly different message on the clinic's answering machine after hearing the news that, as of Oct. 19, the facility had been shuttered.
"As a former patient, I just wanted to express my gratitude to everyone who works there," said the woman, who did not leave her name. "You are all godsends for what you do there. . . . I am extremely disgusted by the Springfield community."
Such polarized perspectives on the clinic and the city that harbored it highlight the continued tensions in the region, the state and the nation more than 32 years after the Roe vs. Wade ruling by the Supreme Court in favor of legalized abortion. And that's despite the continued decline in the number of abortions, in Missouri and the country.
As both sides of the abortion issue point out, the dissent goes beyond the surgical procedure. It includes the dispute over differences between RU-486, a pill that causes abortions, and Plan B, the so-called "morning-after" pill that prevents pregnancy.
A companion debate, nationally and in Missouri, focuses on whether pharmacists should be required to stock or dispense Plan B, and if it should be available without a prescription.
There's also a growing argument over the influence of sex education in reproductive choices, and whether groups like Planned Parenthood, which support abortion rights, should be allowed to provide sex information to public schools, even if they ask for it.
The political stakes were underscored this week when Gov. Matt Blunt, who lives near the clinic,
(Excerpt) Read more at stltoday.com ...
More than likely a repeat customer.
Ridiculously euphemistic name for an abortion clinic alert! "Healthcare center" indeed.
40,000,000+ since June 1973 is more than enough. Illegal aliens stream into this county like water, but unborn potential citizens are left in the ashes. It gives the prayer "ashes to ashes, dust to dust" a bad name.
whether groups like Planned Parenthood, which support abortion rights, should be allowed to provide sex information to public schools
Not in my backyard. Never.
"You are all godsends for what you do there..."
Notice the euphemism for "what they do".
God never sends people to kill innocents.
They have decimated the African American Race to the point that they are start lag behind Hispanic and Asian populations in CA.
Good grief.
What god? Moloch?
"protesting hag"???????
What a classy way to honor those who fought the good fight.
I don't know... It was Moloch, though, to whom Canaanites sacrificed infant children, wasn't it?
I think so. I'm going by memory, and my googling offered no help.
You're an ass.
Maybe I am an ass, or maybe I am not: I happen to believe that other people effing is none of mine [or that 82 years old hag's, or yours, for that matter] effing business. Besides, speaking figuratively, why should one thrust oneself between other people's genitalia and play a prophylactics? It is an undignified role to play.
If she is so supportive of the abortion clinic then why doesn't she leave her name? Could it be that her life now is not what would be viewed as "dreamery"? I suspect so.
I think it was "Baal"
When I get to heaven, what will I not hear the soul of an aborted infant (you know, the ones who are sucked out of the womb and fed through the industrial-strength garbage disposal) say?
"You are all godsends for what you do there..."
Of course this "client" is so proud of her patronage that she declines to leave her name.
Huge metal man with bull head, fire between the legs baby placed in red hot arms. You nailed it
What a selfish bitch, excuse my French!
Abortion Clinic Closes
Great news!!!!
You would want the caustic soda at them horns!
Keep praying! It is prayer that shuts these killing places down!
Eugene abortion clinic closes; surprising many (Hooray !!!)
Prayer credited for closing of abortion clinic [Eugene, OR]
Planned Parenthood will shut down 3 clinics [Indiana]
Persevering Students Help Close Abortion Clinic [Santa Paula, CA--Thomas Aquinas College]
Abortion Clinic Managers Quit After Being Outed by Operation Rescue [Wichita, Kansas]
One Man's God Squad: Troy Newman's plan to stop abortions in Wichita, Kansas
Baby Saved From Abortion is Baptized [New Orleans]
Thank You Bishop Rhoades: A Personal Account of An Abortion Protest With A Catholic Bishop -- still praying -- Harrisburg, PA
Judges rule civil suits against Planned Parenthood can proceed [Los Angeles, CA]
CA: Abortion opponents hope to limit access for California girls (Prop 73)
Jill Stanek's Accurate Summary of Cincinnati Abortion Center Closing: 'Debi Does Ohio"
Clinic is caught in the fog of abortion war (Abortion Clinic Closes) [Springfield, Missouri]
"I wanted to make sure that no one had the feeling I had," Collins said.
Let me guess: Guilt???
Thank you for that list.
An estimated 21,000 sliced, diced and hamburgerized innocent babies from 1975 to the closing of this little Auschwitz for babies at Springfield, Missouri. The clinic director was one Michele Collins who, with an Irish name like that, must have had Irish ancestors. Brian Boru would know what to do.
Oh my, GSlob does have his/her/its undies in a bunch, huh?
One reason it is difficult to get accurate followup information on abortions is that a very large percentage of aborters use false names and addresses, and the abortionists don't try to stop them. Being largely a cash on the barrlehead kind of transaction, it isn't necessary to get a "billing" name and address.
No one in this odious business has any vested interest in the truth, from the mother's real name on down to the nature of the procedure itself.
Which means that all followup data provided by PP or other abortion facilities is non-factual, just like this report.
See #14.
There's nothing at all undignified about putting an end to the industrialized slaughter of the unborn.
ProLife Ping!
If anyone wants on or off my ProLife Ping List, please notify me here or by freepmail.
I'm not saying there aren't any satisfied customers patronizing abortion clinics, but something tells me that call was probably from a pro-abort activist. And it wouldn't surprise me a bit if the call was made solely for the benefit of the media.
You're correct, though I've seen it spelled as Molech most of the time.
This is the best thing that could ever happen in any area. I want to be there to celebrate the day the last abortuary in America finally closes its doors for good.
I always thought Baal was the god of fertility, and to honor him they would have huge public ogys...I could be wrong...
Opposition to abortion is not opposition to sex. But I do think this reply explains why support of abortion is so strong because it's seen as necessity for responsibility-free recreational sex, since they've still failed to find a 100% perfect way to keep fertilization from taking place. It's the same motivation for their argument that condoms are the best way to deal with AIDS and so on. It's all about preserving their ability to "eff" without feeling guilty about it or taking responsibility for any of the negative consequences.
I continue to pray ALL abortuaries go the same way!
It was Moloch...It was a large metal image of a cow in which a fire was lit at its belly, the children were sent through an opening in the image's mouth and the child would tumble down the "throat" and be roasted alive in the "belly". This was the God of fertility. It was one of the blasphemies that ancient Israel fell into and was condemned for!
Isn't interesting how, through abortion today, it is usually the firstborn that is still sacrificed to the god of this world (Satan)? The firstborn as well as all the "first-fruits" have always belonged to the true God and Satan tries to steal this as well.
You're welcome. It's good to know that we are winning!
**I wish we could get our murder shop closed here in Mobile.**
Stand outside and pray! Did you see the list above? Prayer shuts them down.
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Award-winning producer Zeke Stern, aka Green Lion, had a hit last year with Mr Williamz' We Run England on his More Spiritual riddim. His latest accomplishment is the Rough Road riddim that draws inspiration from reggae and its sub-genres dubstep, dancehall and dub. A rather bass heavy affair in other words.
It features cuts from the always interesting Jahdan Blakkamoore, Jamaican former rapper Kabaka Pyramid, newcomer Dre Island, the Garnett Silk-sounding Zamunda and unknown talent Cron Syncro.
The Rough Road riddim was put out via iTunes on July 16 and on other retailers since July 30.
Mr Money Man Riddim
By Angus Taylor
New Albums from Etana and Protoje
By Erik Magni
Paint Jamaica
By Erik Magni
Stephen Marley - Revelation Part II: The Fruit Of Life
By Erik Magni
Positive Vibration Festival 2016
By Erik Magni
Ernest Ranglin Retires from Live Performance
By Angus Taylor
Reggae, Dubs and Dabs
By Erik Magni
Tonight by Isha Blender
By Erik Magni
© 2007-2016 United Reggae. All Rights Reserved. Reproduction in whole or in part is prohibited. Read about copyright
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Focal Plane Array with Arbitrary Tunable Spectral Response
Award Information
Small Business Information
6F Gill Street, Woburn, MA, 01801
Principal Investigator:
Qiushui Chen
VP of R&D
(781) 935-2800
VP of R&D
(781) 935-2800
Business Contact:
Y. Zou
(781) 935-2800
(781) 935-2800
Research Institution:
AbstractTarget discrimination capability can be greatly improved by contrasting the spectral energy content of the target against the background radiation. For fast target discrimination, Boston Applied Technologies proposes to develop a composite dynamic optical filtering technology for imaging arbitrary spectral responses. It can perform not only sequential wavelength-by-wavelength tuning, but also reconfigure the combinations of wavebands (even complicated spectral profile over a broad range) at microseconds intervals. Basic concepts of this technology have been experimentally demonstrated in Phase I, which included wavelength-to-wavelength tuning and sophisticated spectral profile reconfiguration. Working range of this device covers from visible to mid-infrared (up to 8.0 micron). In this Phase II proposal, we will capitalize on the Phase I success and develop a mid-IR composite focal plane array with rapid reconfiguration ability with arbitrary spectral response. Several innovative technologies will be implemented, including the synthesis technique for high-performance electro-optical materials, the software and hardware for composing arbitrary transmission curves, as well as the algorisms for fast non-linear regression.
* information listed above is at the time of submission.
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Trash to Treasure: 28 Recycled Crafts
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Mini Bottle Cap Birdcage
By: Linda Peterson
We are adding the craft to your Craft Projects.
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Click here to view your Craft Projects.
Use caps from plastic bottle to create your own miniature bird cage from Linda Peterson! Who knew plastic bottle cap crafts could be so dainty? Hang a Mini Bottle Cap Bird Cage from your rearview mirror to add a little fun to your daily commute.
- Bottlecaps
- 20 gauge annealed steel wire (from hardware store)
- 26 gauge wire black
- Wooden block
- Permanent marker – black
- Needle tool or nail
- Hammer
- Wire cutters
Optional Materials:
- Moss
- Flowers
- Miscellaneous beads and broken jewelry bits
- Bird charm
- Duct tape
- Glitter glue
- Color bottle cap black with permanent marker. Punch eight holes with a hammer and needle tool, evenly spaced into bottle cap. Start with 12 o'clock position, then punch a hole directly opposite at 6, 3 and 9 then 2, 4, 8 and 10. Use a wooden block to protect your work surfaces.
- Cut 4 pieces of annealed wire approximately 2-1/2" to 3" long. Bend into a U shape.
- At the 12 o'clock position insert the end of the wire. Bend end of wire under bottle cap. Place opposite end into the 6 o'clock position and bend wire to secure. Repeat this with remaining wires.
- Cut a piece of 26 gauge black wire to 4". Wrap around top, securing the wires at the top. Add floral moss and flower, beads, charms and additional wire embellishments as desired.
For a step-by-step photo tutorial of this project, check out How to Make a Bottlecap Birdcage Ornament.
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Ask93 7929298
Mar 07, 2016
Very cute project! I will try to make these myself when I locate some bottle caps. Just one thing, the article says it's about plastic bottle caps. However, the instructions are for a metal cap! Oops. I still understand how to proceed, though. Larger sized pictures would be nice too.
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- 18 Projects Every Crafter Wants
- 23 Fabulous Picnic Craft Ideas + Restaurant Copycat Recipes
- 25 Cool Things to Do with Wine Bottles
- 26 Spring Crafts for Kids
- Easter Craft eBook: Blogger Edition
- Garden Crafts
- Hop into Spring: Easter Crafting and Recipe
- Trash to Treasure: 28 Recycled Crafts
Our Newest Projects & Articles
- Roller Skate Booties
- Pom-Pom Booties from 'Vintage Knits'
- Washi Tape Bangle Bracelet
- A-Line Sleeveless Dress for Girls
- DIY Nightstand from an Old Wine Crate
- Easy Square Coaster
- Sun Suit Pattern
- "I Heart You" Crochet Pillow Pattern
- Slip Stitch Hat
- Unforgettable One Skein Knit Scarf