Comparison of the metabolism of 10 chemicals in human and pig skin explants.

Skin metabolism is important to consider when assessing local toxicity and/or penetration of chemicals and their metabolites. If human skin supply is limited, pig skin can be used as an alternative. To identify any species differences, we have investigated the metabolism of 10 chemicals in a pig and human skin explant model. Phase I metabolic pathways in skin from both species included those known to occur via cytochrome P450s, esterases, alcohol dehydrogenases and aldehyde dehydrogenases. Common Phase II pathways were glucuronidation and sulfation but other conjugation pathways were also identified. Chemicals not metabolized by pig skin (caffeine, IQ and 4-chloroaniline) were also not metabolized by human skin. Six chemicals metabolized by pig skin were metabolized to a similar extent (percentage parent remaining) by human skin. Human skin metabolites were also detected in pig skin incubations, except for one unidentified minor vanillin metabolite. Three cinnamyl alcohol metabolites were unique to pig skin but represented minor metabolites. There were notable species differences in the relative amounts of common metabolites. The difference in the abundance of the sulfate conjugates of resorcinol and 4-amino-3-nitrophenol was in accordance with the known lack of aryl sulfotransferase activity in pigs. In conclusion, while qualitative comparisons of metabolic profiles were consistent between pig and human skin, there were some quantitative differences in the percentage of metabolites formed. This preliminary assessment suggests that pig skin is metabolically competent and could be a useful tool for evaluating potential first-pass metabolism before testing in human-derived tissues.

Comparison of protocols measuring diffusion and partition coefficients in the stratum corneum.

Partition (K) and diffusion (D) coefficients are important to measure for the modelling of skin penetration of chemicals through the stratum corneum (SC). We compared the feasibility of three protocols for the testing of 50 chemicals in our main studies, using three cosmetics-relevant model chemicals with a wide range of logP values. Protocol 1: SC concentration-depth profile using tape-stripping (measures KSC/v and DSC /HSC2 , where HSC is the SC thickness); Protocol 2A: incubation of isolated SC with chemical (direct measurement of KSC/v only) and Protocol 2B: diffusion through isolated SC mounted on a Franz cell (measures KSC/v and DSC /HSC2 , and is based on Fick's laws). KSC/v values for caffeine and resorcinol using Protocol 1 and 2B were within 30% of each other, values using Protocol 2A were ~two-fold higher, and all values were within 10-fold of each other. Only indirect determination of KSC/v by Protocol 2B was different from the direct measurement of KSC/v by Protocol 2A and Protocol 1 for 7-EC. The variability of KSC/v for all three chemicals using Protocol 2B was higher compared to Protocol 1 and 2A. DSC /HSC2 values for the three chemicals were of the same order of magnitude using all three protocols. Additionally, using Protocol 1, there was very little difference between parameters measured in pig and human SC. In conclusion, KSC/v, and DSC values were comparable using different methods. Pig skin might be a good surrogate for human skin for the three chemicals tested. Copyright © 2017 The Authors Journal of Applied Toxicology published by John Wiley & Sons Ltd.

Correlation between VITOM(®) videocolposcopy and histopathology for pathognomonic grading criteria.

OBJECTIVE: "Every colposcopic criterion must be mirrored by histopathology". We investigated the histomorphologic equivalent of four colposcopic criteria, which are associated with CIN 2 and/or CIN 3 and therefore called pathognomonic. PATIENTS AND METHODS: We diagnosed inner border sign, ridge sign, rag sign and/or cuffed gland openings using VITOM(®) videocolposcopy in 255 patients which are consistent with major change. Histopathologic examination included immunohistochemical staining for p16, Ki 67 and stathmin-1 and micro-photographic documentation. RESULTS: The histopathologic pattern specific for each of the four pathognomonic colposcopic criteria was reproducibly identified: inner border sign showed a sharp demarcation between low- and high-grade CIN, in ridge sign high-grade CIN adjoined directly the squamocolumnar junction, in rag sign, high-grade CIN was detached from stroma, and in cuffed gland openings, the entrance to a gland was rimmed by CIN, respectively. In 255 patients, the leading pathognomonic sign was inner border in 12.1 %, ridge in 34.1 %, rag in 18 %, and cuffed glands in 35.7 %, respectively. Inner border sign, ridge sign, rag sign and/or cuffed gland openings were associated with CIN 2 or 3 in 97, 98, 98 and 98 %, respectively. In 153 out of 255 patients, we found a combination of pathognomonic signs with ridge sign being the most frequent combined criterion (in 21 % of patients as second pathognomonic sign). CONCLUSION: The morphology of the four pathognomonic colposcopic criteria, inner border sign, ridge sign, rag sign and cuffed crypt openings, is reproduced in histopathology. These criteria are highly associated with CIN 2 or CIN 3.

[Epithelioid angiomyolipoma of the kidney after successfully treated malignant melanoma]. / Epitheloides Angiomyolipom der Niere nach stattgehabtem malignem Melanom.

BACKGROUND: Therapy of epitheloid angiomyolipomas (eAML) may be challenging, since unlike classical angiomyolipomas this rare subclass of benign mesenchymal angiomyolipomas may present with lymph node metastases, local recurrent disease, and/or systemic metastatic disease in up to 30% of cases. OBJECTIVES: We report here for the first time in Germany a case of eAML after successful treatment of malignant melanoma. MATERIALS AND METHODS: Clinical and histological findings as well as results of the genetic analysis of the angiomyolipoma are presented. RESULTS: A somatic, truncating mutation of the TSC2 gene was found in the angiomyolipoma. CONCLUSION: The relationship to histologically similar tumor entities are presented and therapeutic options based on the genetic classification are discussed.

Elicitation of the immune response to p-phenylenediamine in allergic patients: the role of dose and exposure time.

BACKGROUND: Usage of hair dye products containing p-phenylenediamine (PPD) is a concern for PPD-allergic individuals. OBJECTIVES: The present study investigates the role of dose and exposure time on elicitation of allergic contact dermatitis under conditions of permanent hair dyeing. METHODS: Elicitation responses after application of a typical hair dye product containing 2% PPD for 30 min followed by rinsing were analysed in 38 PPD-allergic individuals with a documented history of hair dye-related allergy. Skin binding experiments in vitro were performed to distinguish the dose available for elicitation from the dose applied. RESULTS: A positive reaction was elicited in 20 of 20 patients with grades ++ to +++ and 12 of 18 with grade + according to the classification of the International Contact Dermatitis Research Group. Under conditions of diagnostic patch testing (48 h exposure), the dose available for elicitation is more than 10-fold higher compared with the dose available for hair dyeing (30-min exposure, rinsing of product). CONCLUSIONS: This investigation demonstrates that under simulated hair dye use conditions the actual exposure to PPD is more than an order of magnitude lower than under diagnostic patch testing, although sufficient to elicit a clearly noticeable reaction in 84% of PPD patch test-positive individuals.

[Extramural Gastral GIST Manifested by Spontaneous Perforation with Acute Intraabdominal Bleeding and Haemoperitoneum]. / Extramuraler GIST des Magens mit Manifestation durch Spontanruptur und akuter intraabdomineller Blutung mit Hämatoperitoneum.

We report on the case of a 38-year-old male patient with a huge extramural gastrointestinal stromal tumour (GIST) of the stomach, located in the left upper and middle abdominal cavity that was diagnosed on the basis of a spontaneous -rupture and consecutive haemoperitoneum. The lesion was resected completely in an emergency operation. The tumour was classified as a high-risk lesion for aggressive biological behaviour and with regard to tumour rupture with perforation of the serosa, an adjuvant systemic therapy was indicated.

Principles for the safety evaluation of cosmetic powders.

Consumer exposure to cosmetic (personal care) products is mostly by dermal contact, however additional considerations with regards to potential inhalation exposure from some cosmetics, such as sprays and powders, may be needed for a robust and reliable safety assessment. To get a deeper understanding of the exposure to airborne particles and droplets during product application, a team of international experts was founded under the umbrella of the European Association of the Cosmetic Industry "Cosmetics Europe" (CE) in Brussels. This expert team has worked out a pragmatic strategy how small and medium sized enterprises (SMEs), but also relevant authorities, could handle the safety evaluation of cosmetic powder products. Sufficient information on the aerodynamic diameter of sprayed droplets and here specifically of airborne particles is essential in addition to knowing the exposure after typical product application. The current article is focused on the determination of inhalation exposure to solids, and the derivation of safe exposure levels for cosmetic powder products found in the market. The principles described herein are very similar to spray products as published earlier and should be applied in a similar way (Steiling et al., 2014). Prediction models for the best estimate of inhalation exposure, developed with data from computer simulation programs, individual real-time measurements or finally by experience from the market were introduced and applied. Safety assessment approaches for exposure from powder spray products were developed and have been already considered in regulatory guidelines like the EC Cosmetics Regulation.

Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2.

Recently, interferon-gamma-inducing-factor (IGIF) has been described as a novel monokine that is a more potent interferon-gamma (IFN-gamma) inducer than IL-12. By cloning IGIF from affected tissue and studying IGIF gene expression, we describe for the first time a close association of this cytokine with an autoimmune disease. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide. IGIF mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IGIF mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-gamma mRNA, and subsequently diabetes. Interestingly, these kinetics mimick that of IL-12p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IGIF cDNA from pancreas RNA followed by sequencing revealed identity with the IGIF sequence cloned from Kupffer cells and in vivo preactivated macrophages. When extending our study to macrophages of the spleen we observed that NOD mouse macrophages responded to cyclophosphamide with IGIF gene expression while macrophages from Balb/c mice treated in parallel did not. The IGIF gene position is located within the Idd2 interval on mouse chromosome 9 and therefore it is a candidate for the Idd2 susceptible gene. We conclude that IGIF expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development.

Comparison of protocols for measuring cosmetic ingredient distribution in human and pig skin.

The Cosmetics Europe Skin Bioavailability and Metabolism Task Force aims to improve the measurement and prediction of the bioavailability of topically-exposed compounds for risk assessment. Key parameters of the experimental design of the skin penetration studies were compared. Penetration studies with frozen human and pig skin were conducted in two laboratories, according to the SCCS and OECD 428 guidelines. The disposition in skin was measured 24h after finite topical doses of caffeine, resorcinol and 7-ethoxycoumarin. The bioavailability distribution in skin layers of cold and radiolabelled chemicals were comparable. Furthermore, the distribution of each chemical was comparable in human and pig skin. The protocol was reproducible across the two laboratories. There were small differences in the amount of chemical detected in the skin layers, which were attributed to differences in washing procedures and anatomical sites of the skin used. In conclusion, these studies support the use of pig skin as an alternative source of skin should the availability of human skin become a limiting factor. If radiolabelled chemicals are not available, cold chemicals can be used, provided that the influence of chemical stability, reactivity or metabolism on the experimental design and the relevance of the data obtained is considered.

[Lymph node metastases in ypT1/2 rectal cancer after neoadjuvant chemoradiotherapy : The Achilles heel of organ-preserving operative procedures?]. / Lymphknotenmetastasen beim ypT1/2-Rektumkarzinom nach neoadjuvanter Radiochemotherapie : Die Achillesferse organerhaltender Operationsverfahren?

BACKGROUND: For patients with rectal cancer and complete remission (ypT0) or with good response and residual tumor restricted only to the bowel wall (ypT1-2) after neoadjuvant chemoradiotherapy (CRT), local excision has been suggested as an alternative to avoid the significant morbidity and functional deficits associated with total mesorectal excision (TME). The aim of this investigation was to investigate the incidence, distribution and tumor-related localization of mesorectal lymph node (LN) metastases in TME specimens with complete remission (ypT0), intramural (ypT1-2) and extramural (ypT3-4) residual tumor tissue. PATIENTS AND METHODS: Specimens of TME from 81 patients with locally advanced rectal cancer (UICC II-III) undergoing neoadjuvant CRT within the phase III German rectal cancer trial CAO/ARO/AIO-04 were prospectively evaluated. The entire mesorectal compartment was microscopically screened after complete paraffin embedding. The number and localization of all detectable LN metastases were documented in relation to the primary tumor. RESULTS: Whereas 50 patients (62 %) had ypT3-4 rectal cancer after neoadjuvant CRT, 20 patients (25 %) presented with residual tumor within the bowel wall (ypT1-2), 11 patients (14 %) had pathological complete remission (ypT0), an average of 28 ± 13.7 LN were detected per specimen and 25 patients (31 %) had residual LN metastases after CRT. Although the incidence of LN metastases was higher in the ypT3-4 group (40 %), 25 % of patients in the ypT1-2 group with intramural residual tumor had a mean number of 2.2 residual LN metastases of which 55 % were located far from the primary lesion in the proximal mesorectum. None of the patients with ypT0 status (complete response) had residual LN metastases. CONCLUSION: Even in patients with good response and post-CRT tumor tissue restricted only to the bowel wall (ypT1-2), there is still a considerable risk for residual LN metastases. Local excision of residual rectal cancer was accompanied by a higher rate of local failure and radical surgery with TME should remain the standard treatment in these patients. To date, valid selection criteria for patients eligible for organ-sparing surgery are still lacking.

Strategies of protection from nitric oxide toxicity in islet inflammation.

Nitric oxide is thought to contribute to beta cell destruction during islet inflammation in animal models of type I diabetes. In vitro, inhibition of inducible nitric oxide synthase protects islet cells from the damaging effects of inflammatory cells or cytokines. However, the administration of several inducible nitric oxide synthase inhibitors to prediabetic animals had variable effects on disease progression. An alternative approach is to prevent the lethal consequences of nitric oxide action at the level of islet cells. We observed that the suppression of poly-(ADP-ribose)-polymerase ensures survival of islet cells exposed to nitric oxide. Cells could also be rendered resistant by the induction of endogenous stress proteins in particular of heat shock protein 70. Nitric oxide is not only a strong cytotoxic agent, but is also able to modulate immune reactions by interfering with Th1/Th2 reactivities. This may occur via induction of the interleukin-12 antagonist IL-12(p40)2. Development of type 1 diabetes is known to be correlated with a shift from a Th2 status during benign insulitis to a Th1 status during destructive insulitis. This shift was found dependent on local interleukin-12 gene expression. Indeed, administration of a natural interleukin-12 antagonist suppressed the progression of islet inflammation and concomitant upregulation of the inducible nitric oxide synthase.

Disease resistant, NOD-related strains reveal checkpoints of immunoregulation in the pancreas.

The autoimmune diabetic NOD mouse serves as a model for human type 1 diabetes. Disease development is due to islet beta cell destruction in the context of immune cell infiltration of islets and inflammatory changes throughout the pancreas. In the present study we tried to identify immune reactivity patterns in the pancreas associated with diabetes resistance in NOD-related mouse strains. The pancreata of diabetes-prone female NOD/LtJ, NOD/Bom and of genetically related but diabetes-resistant strains; NOR, NON, NON.NOD-H2g7, NOD.NON-H-2nbl were obtained at the age of 70 days for semiquantitative analysis of insulitis and of mRNA expression by reverse transcriptase PCR. In addition, the response to a single dose of cyclophosphamide for synchronizing and accelerating the progression of insulitis was determined. The progression of insulitis and immune gene expression in response to cyclophosphamide revealed characteristic differences between the six strains. NOD/LtJ and NOD/Bom mice were found significantly to upregulate pancreatic IL-12p40 and IL-18 expression after cyclophosphamide treatment, followed by an increase in IFN-gamma mRNA levels. In contrast, the two MHC-haplotype H-2nbl expressing strains either up-regulated neither IL-12/IL-18 nor IFN-gamma gene expression. The two strains sharing MHC haplotype H-2g7 expression with NOD did respond to cyclophosphamide with IL-12p40/IL-18 gene expression. However, NON.NOD-H-2g7 mice failed to progress to IFN-gamma gene expression. NOR mice progressed to IFN-gamma expression but exhibited sustained IL-4 gene expression. Only severe intra-insulitis was associated with the expression of inducible NO synthase. The comparison of diabetes-prone and diabetes-resistant strains revealed three checkpoints of immune regulation in the pancreas. The earliest checkpoint is the induction of an IL-12p40/IL-18 response in innate immune or antigen-presenting cells. The next level of control is at the induction of IFN-gamma gene expression, and a third checkpoint is the maintenance or loss of antagonistic Th2 type reactions.

Effect of feeding ractopamine hydrochloride on growth performance and responses to handling and transport in heavy-weight pigs.

The impact of feeding ractopamine hydrochloride (RAC) on growth performance and responses to handling and transport in heavy BW pigs was evaluated in a study performed as a split-plot design with a 3 × 3 factorial arrangement of treatments: 1) RAC level (0 vs. 5 vs. 7.5 mg/kg of feed) and 2) handling intensity (HI; gentle vs. moderate vs. aggressive); RAC level was the main plot and HI was the subplot. A total of 288 pigs housed in groups of 8 were used to evaluate growth performance over a 28-d RAC feeding period (98.5 ± 4.58 to 131.5 ± 7.45 kg BW). On d 29 of the study, the HI treatment was applied to 216 pigs (6/pen; 2/pen on each HI). This was followed by transportation for 1 h on a livestock trailer at the end of which pigs were subjected to a final handling procedure. Blood samples (to measure acid-base, cortisol, and catecholamine levels) were collected and rectal temperature was measured 2 h before the HI treatment (baseline) and after the final handling procedure (final). Feeding RAC (5 and 7.5 mg/kg) improved ( < 0.01) ADG (9.9 and 9.0% for 5 and 7.5 mg/kg RAC, respectively) and G:F (8.8 and 11.8%, respectively) compared to controls, with no differences ( > 0.05) between the 2 RAC levels. Increasing the intensity of handling decreased ( < 0.001) final blood pH, bicarbonate, and base excess and increased ( < 0.001) final blood lactate and plasma cortisol and norepinephrine levels. Aggressive compared to gentle handling increased ( < 0.05) the incidence of pigs exhibiting open-mouth breathing and skin discoloration after the final handling procedure but had no effect ( > 0.05) on the incidence on nonambulatory, noninjured pigs. There was no effect ( > 0.05) of feeding RAC on final rectal temperature or blood acid-base measurements. Feeding 7.5, but not 5, compared to 0 mg/kg RAC increased ( < 0.05) final plasma epinephrine levels and the incidence of nonambulatory, noninjured pigs. This study confirms the improved growth performance of pigs fed RAC and the negative effects of aggressive handling on physical, metabolic, and physiological responses of pigs. It also suggests that pigs fed 5 compared to 0 mg/kg RAC showed similar responses to transport and handling. However, pigs fed 7.5 mg/kg of RAC had a greater incidence of nonambulatory, noninjured pigs when subjected to the handling/transport model and this warrants further investigation.

Cervical Strip Biopsy for High-Grade Cervical Intraepithelial Lesions: a Valid Alternative to Conventional Punch Technique.

Introduction: To evaluate, if targeted strip biopsies decrease trauma/pain perception while maintaining diagnostic accuracy in patients with the diagnosis of high-grade squamous intraepithelial lesions of the uterine cervix. Patients and Methods: Between July 1st and December 31st 2014 we performed colposcopically directed strip biopsies in 102 patients with colposcopic suspicion of high-grade squamous intraepithelial lesions of the uterine cervix. We used a 3 mm curette for harvesting tissue samples under VITOM® videocolposcopy. So far, 60 patients underwent additional loop excision. Histologic examination of strip biopsies and loop specimens included routine hematoxylin and eosin staining as well as immunohistochemical staining for p16, Ki 67 and stathmin-1. Results: 55 patients (53 %), were histologically diagnosed with cervical intraepithelial neoplasia grade 3 on strip biopsies. Adenocarcinoma in situ was diagnosed in 2 patients (2 %), cervical intraepithelial neoplasia grade 2 in 35 patients (34 %), and cervical intraepithelial neoplasia grade 1 in 10 patients (10 %). The agreement between histologic results of strip biopsy and loop specimen was highly significant: In all 60 strip biopsies diagnosed with high-grade squamous intraepithelial lesions this diagnosis was confirmed histologically during follow-up loop specimen excision (high-grade squamous intraepithelial lesions in 58 patients, invasive disease in 2 patients). The pain level experienced during strip biopsy was rated on average 0.25 on a scale from 0 to 10. No clinically significant bleeding was reported. Conclusion: Targeted strip biopsies with a 3 mm curette are a reliable procedure to diagnose high-grade squamous intraepithelial lesions of the uterine cervix and yield high patient satisfaction (Video 1).

Transcription and translation of inducible nitric oxide synthase in the pancreas of prediabetic BB rats.

The inducible NO synthase (iNOS) was found to be expressed in pancreatic lesions of adult diabetes-prone BB rats. Pancreatic iNOS mRNA was detected by reverse transcriptase PCR in pancreatic RNA of adult diabetes-prone BB rats but not in normal Wistar rats, young diabetes-prone BB rats without insulitis or in diabetes-resistant BB rats. Immunohistochemistry of pancreatic sections using an iNOS-specific antiserum labeled the pancreas of adult diabetes-prone BB rats but not Wistar rats. Parallel staining for ED1-positive macrophages showed restriction of iNOS expression to areas of islet infiltration by macrophages. In conclusion, the data provide direct evidence for enhanced expression of inducible NO synthase in tissue lesions during the development of autoimmune diabetes.

Pre- and postnatal development of the primary visual cortex of the common marmoset. I. A changing space for synaptogenesis.

The primary visual cortex of Callithrix jacchus occupies a large portion of the occipital neocortex and can be safely delineated from fetal stages onwards. In 20 animals ranging in age from fetal to adult age the morphological development of area 17 was evaluated and compared with the growth of whole brain, skull, and head size. Cortical thickness, surface area, and volume of the area were determined in addition to predominant growth directions. The volume of area 17 approximately doubles between birth (241 mm3) and three months of age (506 mm3). This maximum value marks an overshoot in growth (volume: 180%, surface area: 150%, thickness: 122%), which is followed by a considerable reduction before adult values (100%) are reached. Although these values seem to indicate that the overall reduction in size is fairly isometric, growth and regression are locally anisometric. For example, layers II-IVc contribute disproportionately to the overshoot; thickening is less pronounced than tangential growth and follows a slightly different time course. These data suggest that the developing visual cortex represents a highly dynamic distribution space for the developing synaptic junctions which should be taken into account in studies on synaptogenesis. By comparison it is suggested that this growth dynamic is not restricted to area 17 but also occurs in some other parts of the cerebral cortex. In contrast, most subcortical brain regions apparently do not undergo overshoot growth. Structural changes of the skull compensate the overshoot in cortex growth, so that head size increases steadily.

Primary nonfunction of islet grafts in autoimmune diabetic nonobese diabetic mice is prevented by treatment with interleukin-4 and interleukin-10.

In isologous islet transplantation in spontaneously diabetic nonobese (NOD) mice, destruction of the islet graft is caused by recurrence of T helper (Th)1-driven insulitis[fnc,1. We established a model of transplantation in which female NOD recipients were rendered diabetic by a single injection of cyclophosphamide (250 mg/kg). Under these conditions, 500 freshly isolated islets from young NOD mice transplanted under the kidney capsule did not lead to normoglycemia within 3 day after transplantation, but underwent immediate impairment of function. This primary nonfunction was seen in > 80% of the recipients. Treatment of the recipients with the Th2-associated cytokine interleukin (IL)-4 alone did not prevent primary nonfunction, whereas treatment of the recipients with a combination of IL-4 and IL-10 restored immediate function of the grafts. Cytokine treatment did not prevent later rejection of grafts. Histological analysis of the grafts revealed less severely infiltrated islets, with well preserved islet architecture, in only normoglycemic animals treated with IL-4 or with IL-4 and IL-10. Staining for lymphocytes, macrophages, and tumor necrosis factor (TNF)-alpha did not show differences between the groups, but IFN-gamma was markedly less expressed in IL-4- and IL-10-treated grafts. Concomitantly, analysis of animals treated for 8 days after injection of cyclophosphamide, with IL-4 and IL-10, revealed a reduction of IL-12 mRNA in the pancreas. We conclude from these data that primary nonfunction of islet grafts is prevented by treatment of the recipients with a combination of IL-4 and IL-10, via downregulation of Th1 cytokines.

The APC1 concept of type I diabetes.

Type I diabetes appears to be a T cell dependent disease. T cell reactivity is regulated by antigen presenting cells (APCs). In animal models of type I diabetes, abnormal reactivity of APCs, in particular of macrophages, probably is responsible for the progression of islet inflammation from T helper type 2 dependent benign periinsulitis to T helper type I dependent destructive intrainsulitis. The functional state of APCs during preferential stimulation of Th1 reactivities (APC1 state) is characterized by the release of TNFalpha, IL-12 and/or IL-18. The bias towards APC1 reactivity has been found due to defective inhibition via IL-10 and PGE2.

Oxygen radical production is increased in macrophages from diabetes prone BB rats.

Macrophages from autoimmune diabetes prone BB rats were found to produce radical oxygen intermediates (ROI) at an enhanced rate when compared to diabetes resistant BB or normal Wistar rats. The release of ROI was determined by chemiluminescence using in parallel luminol and lucigenin as detector molecules. In diabetes prone BB rats the spontaneous release of ROI was upregulated in macrophages from different compartments, i.e. peritoneum and spleen. Also, maximal output of ROI after activation of macrophages either in vivo by injection of Corynebacterium parvum or in vitro by LPS and IFN was highest for cells from diabetes prone BB rats. This macrophage abnormality was seen in animals prior to recognizable islet inflammation and also was present at the level of macrophages grown in vitro from precursor cells of diabetes prone BB rats. Hypersecretion of oxygen radicals may contribute to Beta cell loss and diabetes development in BB rats.