Synthesis of a Cu-infiltrated Zr-doped SBA-15 catalyst for CO2 hydrogenation into methanol and dimethyl ether.

A catalytically active nanoassembly comprising Cu-nanoparticles grown on integrated and active supports (large pore Zr-doped mesoporous SBA-15 silica) has been synthesized and used to promote CO2 hydrogenation. The doped mesoporous material was synthesized using a sol-gel method, in which the pore size was tuned between 11 and 15 nm while maintaining a specific surface area of about 700 m2 g-1. The subsequent Cu nanoparticle growth was achieved by an infiltration process involving attachment of different functional groups on the external and internal surfaces of the mesoporous structure such that 7-10 nm sized Cu nanoparticles grew preferentially inside the pores. Chemisorption showed improved absorption of both CO2 and H2 for the assembly compared to pure SBA-15 and 15% of the total CO2 was converted to methanol and dimethyl ether at 250 °C and 33 bar.

Shape engineering boosts antibacterial activity of chitosan coated mesoporous silica nanoparticle doped with silver: a mechanistic investigation.

In this study, mesoporous silica nanoparticles (MSPs) of different size and shape were developed, and their surface coatings were utilized to study their differential effects in enhancing antibacterial activity. In brief, MSPs with three different aspect ratios (1, 2 and 4) were prepared, doped with silver ions and finally coated with the polymer chitosan. Both Gram-positive and Gram-negative bacteria were treated with the MSPs. Results indicate that silver ion doped and chitosan coated MSPs with the aspect ratio of 4 (Cht/MSP4:Ag+) have the highest antimicrobial activity among the prepared series. Further studies revealed that Cht/MSP4:Ag+ was most effective against Escherichia coli (E.coli) and least effective against Vibrio cholerae (V. cholerae). To investigate the detailed inhibition mechanism of the MSPs, the interaction of the nanoparticles with E.coli membranes and its intracellular DNA was assessed using various spectroscopic and imaging-based techniques. Furthermore, to increase the efficiency of the MSPs, a combinatorial antibacterial strategy was also explored, where nanoparticles, in combination with kanamycin (antibiotic), were used against Vibrio Cholerae (V. cholerae). Toxicity screening of these on MSPs was conducted on Caco-2 cells, and the results show that the dose used for antibacterial screening is below the limit of the toxicity threshold. Our findings show that both shape and surface engineering contribute positively towards killing bacteria, and the newly developed silver ion-doped and chitosan-coated MSPs have good potential as antimicrobial nanomaterials.

Proinsulin/C-peptide ratio, glucagon and remission in new-onset Type 1 diabetes mellitus in young adults.

AIMS: After initiation of treatment in Type 1 diabetes, a period with lower insulin requirement often follows, reflecting increased insulin sensitivity and improved insulin secretion. We explored if efficiency of proinsulin processing is associated with the remission phenomenon. METHODS: Seventy-eight patients with new-onset Type 1 diabetes were followed prospectively for 3 years. Daily insulin dosage, HbA(1c) , plasma glucose, proinsulin, C-peptide, glucagon concentrations and islet antibodies were determined at diagnosis and after 3, 6, 9, 12, 18, 24, 30 and 36 months. We studied remission, defined as an insulin dose ≤ 0.3 U kg(-1) 24 h(-1) and HbA(1c) within the normal range, in relation to the above-mentioned variables. RESULTS: A rise and subsequent decline in plasma proinsulin and C-peptide concentrations was observed. Forty-five per cent of the patients experienced remission at one or more times, characterized by higher proinsulin and C-peptide levels, and lower proinsulin/C-peptide ratios, indicating more efficient proinsulin processing, compared with those not in remission. Non-remission also tended to be associated with higher glucagon values. Patients entering remission were more often men, had higher BMI at diagnosis, but did not differ at baseline with respect to islet antibody titres compared with patients with no remission. CONCLUSIONS: Remissions after diagnosis of Type 1 diabetes were associated with lower proinsulin/C-peptide ratios, suggesting more efficient proinsulin processing, and tended to have lower glucagon release than non-remissions. This indicates that, in remission, the residual islets maintain a secretion of insulin and glucagon of benefit for control of hepatic glucose production.

Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment.

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was approximately 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

Role of cage material, working style and hearing sensitivity in perception of animal care noise.

During daily care, laboratory animals are exposed to a variety of sounds which may have effects on welfare and also cause physiological and behavioural changes. So far, almost no attention has been paid to individual sounds or the sound level caused by animal care or the sound level inside the animal cage. In this study, sounds from selected rat care procedures were recorded: pulling cage out of the rack, placing it onto a table and replacing the cage back into the rack; with measurements made inside the rat cage and in the adjacent cage. Diet was poured into the food hopper and sounds were recorded inside the cage and also the adjacent cage. The work was repeated in a calm and also in a hurried style, using stainless steel and polycarbonate cages. Finally, the sounds produced by running tap water were recorded. Differences between rat and human hearing were compared using novel species-specific sound level weightings: R-weighting for rats dB(R) and H-weighting for human dB(H). Hurried work with steel caused sound exposure levels exceeding 90 dB(R) when the cages were placed into the rack and about 80 dB(R) when pulling them out of the rack or placing onto a table. With polycarbonate, the levels were 10-15 dB(R) lower. Unhurried calm working produced lower sound exposure levels than hurried working in many procedures. When the procedures were repeated with measurements in the adjacent cage, the sound exposure levels were lower, but the results were similar. Pouring food pellets into a hopper above the rat's head caused 15 dB(R) higher sound exposure levels than pouring food to an adjacent cage. In general, humans hear these sounds about 10-15 dB louder than rats. In conclusion, cage material, working style and hearing sensitivity all have an impact on the sound exposure level in the rodent cage. With correct working methods, high sound levels can be efficiently avoided in most cases.

Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non-autoimmune (type 2) diabetes.

OBJECTIVE: To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults. MATERIAL AND METHODS: Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. RESULTS: Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001). CONCLUSIONS: Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.

Blood glucose in acute stroke, different therapeutic targets for diabetic and non-diabetic patients?

OBJECTIVES: To study the impact of blood glucose concentrations on early stroke mortality in diabetic and non-diabetic stroke patients, and to identify the optimal blood glucose concentration for each patient category. MATERIAL AND METHODS: A representative sample of 81 diabetic and 366 non-diabetic stroke patients was studied. Logistic regression analyses were performed in order to estimate the impact of blood glucose concentrations on admission and during hospital stay and other clinical parameters on 30-day case-fatality. Receiver operating characteristic curves were used to predict case-fatality by blood glucose. RESULTS: Blood glucose, body temperature and level of consciousness were independently related to early stroke mortality in diabetic and non-diabetic patients. The mean blood glucose concentration had a greater impact on 30-day case-fatality than the admission blood glucose, particularly in diabetic patients. A mean blood glucose concentration above 10.3 mmol/l predicted 30-day case-fatality in diabetic patients. The corresponding value was 6.3 mmol/l in non-diabetic patients. CONCLUSION: Improved blood glucose control has a potential to reduce early stroke mortality. The optimal glucose concentration seems to be higher in diabetic than in non-diabetic patients.

Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in Type 1 diabetes.

AIM: To identify clinical, immunological and biochemical factors that predict remission, and its duration in a large cohort of young adults with Type 1 diabetes mellitus (DM). METHODS: In Sweden, 362 patients (15-34 years), classified as Type 1 DM were included in a prospective, nation-wide population-based study. All patients were followed at local hospitals for examination of HbA(1c) and insulin dosage over a median period after diagnosis of 5 years. Duration of remission, defined as an insulin maintenance dose 12 months. Among patients with antibodies (ab(+)), bivariate analysis suggested that adult age, absence of low BMI, high plasma C-peptide concentrations, lack of ketonuria or ketoacidosis at diagnosis and low insulin dose at discharge from hospital were associated with a high possibility of achieving remission. Multiple regression showed that normal weight (BMI of 20-24.9 kg/m(2)) was the only factor that remained significant for the possibility of entering remission. In survival analysis among ab(+) remitters, a low number of islet antibodies, one or two instead of three or four, were associated with a long duration of remissions. CONCLUSION: In islet antibody-positive Type 1 DM, normal body weight was the strongest factor for entering remission, whilst a low number of islet antibodies was of importance for the duration.

Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden.

OBJECTIVES: To establish the prevalence of remaining beta-cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later. DESIGN: Population-based cohort study. SETTING: Nationwide from all Departments of Medicine and Endocrinology in Sweden. SUBJECTS: A total of 312 young (15-34 years old) adults diagnosed with diabetes during 1987-88. MAIN OUTCOME MEASURE: Plasma connecting peptide (C-peptide) 8 years after diagnosis. Preserved beta-cell function was defined as measurable C-peptide levels. Three islet antibodies - cytoplasmic islet cell antibodies (ICA), glutamic acid decarboxylase antibodies and tyrosine phosphatase antibodies - were measured. RESULTS: Amongst 269 islet antibody positives (ab+) at diagnosis, preserved beta-cell function was found in 16% (42/269) 8 years later and these patients had a higher body mass index (median 22.7 and 20.5 kg m-2, respectively; P = 0.0003), an increased frequency of one islet antibody (50 and 24%, respectively; P = 0.001), and a lower prevalence of ICA (55 and 6%, respectively; P = 0.007) at diagnosis compared with ab+ without remaining beta-cell function. Amongst the 241 patients without detectable beta-cell function at follow-up, 14 lacked islet antibodies, both at diagnosis and at follow-up. CONCLUSIONS: Sixteen per cent of patients with autoimmune type 1 diabetes had remaining beta-cell function 8 years after diagnosis whereas 5.8% with beta-cell failure lacked islet autoimmunity, both at diagnosis and at follow-up.

Increasing body mass index at diagnosis of diabetes in young adult people during 1983-1999 in the Diabetes Incidence Study in Sweden (DISS).

OBJECTIVE: To study trends in body mass index (BMI) at diagnosis of diabetes in all young Swedish adults in the age range of 15-34 years registered in a nation-based registry. DESIGN: The BMI was assessed at diagnosis in diabetic patients 15-34 years of age at diagnosis, for a period of 17 years (1983-1999). Islet cell antibodies (ICA) were measured during three periods (1987-1988, 1992-1993 and 1998-1999). SETTING: A nationwide study (Diabetes Incidence Study in Sweden). SUBJECTS: A total of 4727 type 1 and 1083 type 2 diabetic patients. MAIN OUTCOME MEASURES: Incidence-year specific BMI adjusted for age, gender and time of diagnosis (month). RESULTS: Body mass index at diagnosis increased significantly both in type 1 (21.4 +/- 3.6 to 22.5 +/- 4.0; P < 0.0001) and in type 2 (27.4 +/- 6.8 to 32.0 +/- 6.0; P < 0.0001) diabetic patients, also when adjusted for age, gender and month of diagnosis. A similar significant increase in BMI was found in type 1 diabetic patients and in type 2 diabetic patients in the periods 1987-1988, 1992-1993 and 1998-1999; years when ICA were assessed and considered in the classification of diabetes. Despite this increase in BMI, there was no increase in the incidence of diabetes in young-adult people in Sweden. CONCLUSION: Body mass index at diagnosis of diabetes in subjects 15-34 years of age has substantially increased during 1983-1999 in Sweden when adjusted for age, gender and month of diagnosis.

Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yrs) in the Diabetes Incidence Study in Sweden (DISS).

AIMS/HYPOTHESIS: We aimed to evaluate how an aetiology-based classification, as recommended in the ADA and WHO guidelines for classification of diabetes mellitus, matches clinical judgement in the Diabetes Incidence Study in Sweden (DISS), a study covering incident cases of diabetic patients aged 15 to 34 years. METHODS: During a 1-year period (1998), blood samples were taken at diagnosis and 4 months (median) thereafter. Patients were classified according to clinical judgement by the reporting physicians and assessments of islet antibodies (ICA, GADA, and IA-2A) and plasma C-peptide. RESULTS: In 1998, 422 patients were registered in DISS. Among the 313 patients participating in the follow-up, most with clinical Type 1 diabetes (185/218, 85%, 95% CI 79-89%) were islet antibody positive (ab+) at diagnosis. In addition, 14 out of 58 (24%, 14-37%) with clinical Type 2 diabetes and 21 out of 37 (57%, 40-73%) with unclassifiable diabetes were antibody positive at diagnosis. Further to this, 4 out of 33 (12%, 3-28%) were antibody negative with clinical Type 1 diabetes and 4 out of 44 (9%, 3-22%) with Type 2 had converted to antibody positive at follow-up. Among those who were constantly antibody negative, 10 out of 29 (34%, 18-54%) with clinical Type 1 and 1 out of 16 (6%, 0-30%) with unclassifiable diabetes had fasting plasma C-peptide concentrations below the normal range (<0.25 nmol/l) at follow-up. CONCLUSION/INTERPRETATION: Most young adults with clinical Type 1 diabetes (199/218, 91%) had objective Type 1 (ab+ at diagnosis/follow-up and/or low fasting plasma C-peptide concentrations at follow-up), as did one third (18/58, 31%) with clinical Type 2 diabetes and more than half (22/37, 59%) with unclassifiable diabetes. About 10% of those who were antibody negative converted to antibody positive. Our study underlines that a classification considering aetiology is superior to clinical judgement.

Visualization of in vivo olfactory uptake and transfer using fluorescein dextran.

Nasal administration of a 3 kDa fluorescein dextran (FD3) solution to rats resulted in transcellular absorption across the olfactory epithelium and transfer to the olfactory bulb within 15 min. After entering the lamina propria, FD3 was transferred in the connective tissue surrounding the olfactory nerve bundles to the olfactory bulb of the brain. More FD3 was absorbed across the olfactory epithelium than across the respiratory epithelium and to the nasal associated lymphoid tissue. Further, the amount of FD3 crossing the olfactory epithelium was region-dependent, with higher amounts absorbed in the turbinates than in the nasal septum. Plastic embedding and sectioning followed by fluorescence microscopy, enabled simultaneous visualization of FD3 in the mucosa and olfactory bulb, as well as the opportunity to store the tissue blocks for a prolonged period of time.

The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983-1998.

AIMS/HYPOTHESIS: To analyse the incidence of Type I (insulin-dependent) diabetes mellitus in the 0-34 years age group in Sweden 1983-1998. METHODS: Incidence and cumulative incidence per 100 000 and Poisson regression analysis of age-period effects was carried out using 11 751 cases from two nation-wide prospective registers. RESULTS: Incidence (95%-CI) was 21.4 (20.8-21.9) in men and 17.1 (16.6-17.5) in women between 0 and 34 years of age. In boys aged 0-14 and girls aged 0-12 years the incidence increased over time, but it tended to decrease at older age groups, especially in men. Average cumulative incidence at 35 years was 748 in men and 598 in women. Cumulative incidence in men was rather stable during four 4-year periods (736, 732, 762, 756), while in women it varied more (592, 542, 617, 631). In males aged 0-34 years, the incidence did not vary between the 4-year periods ( p=0.63), but time changes among the 3-year age groups differed ( p<0.001). In females the incidence between the periods varied ( p<0.001), being lower in 1987-1990 compared to 1983-1986, but time changes in the age groups did not differ ( p=0.08). For both sexes median age at diagnosis was higher in 1983-1986 than in 1995-1998 ( p<0.001) (15.0 and 12.5 years in males; 11.9 and 10.4 in females, respectively). CONCLUSION/INTERPRETATION: During a 16-year period the incidence of Type I diabetes did not increase in the 0-34 years age group in Sweden, while median age at diagnosis decreased. A shift to younger age at diagnosis seems to explain the increasing incidence of childhood Type I diabetes.

Levels of dopamine in blood and brain following nasal administration to rats.

The aim of this study was to investigate the levels of [(3)H]dopamine in blood, the cerebrospinal fluid (CSF) and brain tissue samples in rats and to find out whether the drug is transferred along the olfactory pathway to the central nervous system following nasal administration. [(3)H]Dopamine (50 microCi) was given to male Sprague-Dawley rats either intravenously or nasally to the right nostril. For the absorption study, blood samples were withdrawn from the carotid artery. The CSF samples were taken by cisternal puncture and then brain tissue samples were excised. The presence of unchanged dopamine in the samples was ascertained using thin layer chromatography (TLC). The radioactivity in the samples was measured using liquid scintillation. The greatest amount of the total radioactivity absorbed from the nasal mucosa into the systemic circulation was observed at the first sampling point 15 min after administration. The bioavailability of the total radioactivity was 68+/-30%. The uptake of [(3)H]dopamine in the brain was significantly higher 30 min after nasal administration than after intravenous administration (P<0.01). TLC data showed that approximately 59%, 14% and 68% of the radioactivity in the olfactory bulb, CSF and olfactory mucosa, respectively, coeluted with dopamine. In conclusion, these results show that unchanged dopamine is transferred into the olfactory bulb via the olfactory pathway in rats.

Family characteristics and life events before the onset of autoimmune type 1 diabetes in young adults: a nationwide study.

OBJECTIVE: To elucidate whether family characteristics and stressful life events were associated with onset of autoimmune type 1 diabetes in young adults. RESEARCH DESIGN AND METHODS: This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of newly diagnosed patients aged 15-34 years. Patients clinically classified as type 1 diabetic with antibodies to islet cells and/or to GAD65 were compared with age- and sex-matched control subjects via questionnaire. The questionnaire covered diabetes heredity, social environment, educational level, and life events experienced during the 12 months before diagnosis. RESULTS: The rate of response was 82% for the diabetic patients and 65% for the control subjects. Questionnaires from 349 diabetic patients and 979 control subjects were considered. Diabetes in relatives was more frequent in the patients (odds ratio [OR]2.6) who were born in Sweden and whose mothers were of Swedish origin. No major stress factors were detected in the diabetic patients; however, in comparison with the control subjects, the diabetic patients had experienced fewer conflicts with their parents and had less often broken contacts with friends. CONCLUSIONS: Young adults with recent-onset type 1 diabetes were more exposed to heredity for diabetes, but no major prediabetic stress factors were detected. Our study does not directly support the concept that psychosocial stressful life events are involved in the development of autoimmune type 1 diabetes in young adults.

Combinations of beta cell specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage.

To explore the natural course of beta cell function in recent onset diabetes, a subgroup (n=157) of all incident cases (n=879) 15-34 years old, 1992-1993 in Sweden, and with positivity for at least one autoantibody of islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A) were followed prospectively for the first four years with annual analysis of C-peptide. The aim was to relate the course of beta cell function, measured as C-peptide, in early diabetes with the presence of different islet autoantibodies at diagnosis. We found that patients positive for ICA alone (n=11) had significantly higher C-peptide levels both at diagnosis and during the first three years compared with the other patients (n=146; p=0.022, p<0.001, p=0.004 and p=0.0022). Patients positive for GADA alone or in combination with other antibodies (n=125) had significantly lower C-peptide during the first three years after diagnosis compared with the other patients (n=32, p<0.001, p=0.0011 and p=0.0136). Patients with two or three autoantibodies had C-peptide levels similar to levels found in patients positive only for GADA. However, after four years, there were no significant differences between any of the groups of different autoantibody combinations. At diagnosis, 55% (86/157) of the patients had C-peptide levels above the lower normal range of 0.25 nmol/l, but the frequency of patients with beta cell function above this level decreased after two years to 41% (65/157; p=0.035) and after four years to 22% (35/157; p=0.0041). It is concluded that young adult diabetic patients positive only for ICA at diagnosis have a better preserved beta cell function with higher levels of C-peptide during the first three years compared with patients positive for GADA alone or in combinations with other autoantibodies.

Nasal administration of a physostigmine analogue (NXX-066) for Alzheimer's disease to rats.

The nasal route has been receiving attention for the administration of systemically active drugs because delivery is convenient, reliable and rapid. The aims of this study were to investigate the systemic absorption of nasally administered (3aS)-cis-1, 2, 3, 3a, 8, 8a-hexahydro-1, 3a, 8-trimethyl-pyrrolo-[2,3b]-indol-5-yl 3, 4 dihydro-2-isoquinolincarboxylate (NXX-066), a physostigmine analogue, in rats and to compare the uptake of the drug into the cerebrospinal fluid (CSF) after nasal and intravenous administration. NXX-066 (3 micromol/kg) was administered to both nostrils or into the vena jugularis of male Sprague-Dawley rats. Blood and CSF samples were obtained at regular intervals from the arteria carotis and by cisternal puncture, respectively. The concentrations of NXX-066 in the blood and CSF samples were measured using HPLC with fluorescence detection. NXX-066 was absorbed rapidly after nasal administration with the peak concentration occurring within 1.5 min. The nasal bioavailability of NXX-066 was 100+/-30% and the elimination from plasma was as rapid as that following intravenous administration. Low concentrations of NXX-066 were detected in the CSF after both intravenous and nasal administration. In conclusion, NXX-066 was rapidly and totally absorbed into the systemic circulation and uptake into the CSF was not enhanced by nasal administration in rats.

Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds.

BACKGROUND: Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. METHODS: In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. RESULTS: Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was significant for insulin treatment within 3 years (OR=18.8; 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. CONCLUSIONS: A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis.

Beta-cell activity and destruction in type 1 diabetes.

Type 1 diabetes is the result of a chronic inflammatory process that causes elimination of insulin-producing beta-cells, resulting in insulin deficiency and hyperglycemia. The destruction is thought to be mediated by an autoimmune process involving cytotoxic T cells recognizing beta-cell autoantigens in the context of MHC class I-peptide complexes. Autoantibodies against insulin, glutamic acid decarboxylase (GAD) and and ICA 512 protein tyrosine phosphatase are frequently found. At the clinical onset of diabetes, some beta-cells remain and after initiation of insulin treatment, most patients enter a period of remission, a phenomenon that may reflect diminished autoimmune activity in the islets. There is evidence to suggest that a further loss of beta-cells can be curtailed, and that patients, who maintain endogenous insulin production, have better glycemic control and less risk of complications. This is the basis for our current research. We are characterizing the remission phenomenon in epidemiological studies in order to identify determinants of beta-cell survival. In randomized, prospective multicenter trials, we are evaluating the benefit of beta-cell secretory rest for rescue of insulin production in patients at onset of clinical disease. In experimental studies, we are investigating expression and regulation of the key molecules of an autoimmune process in the islets. Further, selective beta-cell damage is induced in rat islets and measures to enhance beta-cell resistance and repair are being examined. We have recently identified a remarkable, beta-cell protective effect of K(ATP)-channel opening.

Retrieval-induced forgetting: evidence for a recall-specific mechanism.

Previous work has shown that recalling information from long-term memory can impair the long-term retention of related representations--a phenomenon known as retrieval-induced forgetting (Anderson, Bjork, & Bjork, 1994). We report an experiment in which the question of whether retrieval is necessary to induce this form of impairment was examined. All the subjects studied six members from each of eight taxonomic categories (e.g., fruit orange). In the competitive practice condition, the subjects practiced recalling three of the six members, using category-stem cues (e.g., fruit or__). In the noncompetitive practice condition, the subjects were reexposed to these same members for the same number of repetitions but were asked to recall the category name by using the exemplar and a stem as cues (e.g., fr__orange). Despite significant and comparable facilitation of practiced items in both conditions, only the competitive practice subjects were impaired in their ability to recall the nonpracticed members on a delayed cued-recall test. These findings argue that retrieval-induced forgetting is not caused by increased competition arising from the strengthening of practiced items, but by inhibitory processes specific to the situation of recall.