Progressive Histopathological Changes Research Articles

Liver Dysfunction in Sternness Burn Injury in Association to Age Estimate: A Conceivable Role of Antioxidant Biomarker and Tumor Necrosis Factor Alpha

Background: Burn injuries represent one of the greatest public health problems that induce significant patient morbidity and mortality. Scalds are the most common cause of burn injuries which is known to have long term grave consequences on general health. Aim: The current study was performed to identify the age of scald burn from histopathological changes and TNF-α immunoexpression. As well, study the probable relation between the scald age and the hepatic function impairment. Materials and Methods: A total number of 40 adult male albino rats were used in the study. Eight kept as control group I. Thirty-two rats were exposed to scald injury involving 20% of total body surface area (TBSA). Histopathological examination for the scald area, liver, and skin TNF-α immunohistochemistry was performed. Liver function tests and liver tissue malondialdehyde (MDA) were also determined. The study was carried out after 2, 7 days, 1 and 3 months of scald incidence. Results: Progressive histopathological changes and elevated liver enzymes were observed in the early scald ages while manifestations of healing and improvement in liver parameters, started to occur after 1 and 3 months of scald infliction in comparison with the other periods. There was a highly significant (P < 0.001) increase in malondialdehyde level and TNF-α expression in scald injured groups after 2 and 7 days compared with control group I. Conclusion: Overall, the results showed the ability to identify the age of scald injury using routine histopathological examination. Also, scald injury involving 20% of TBSA may cause long term impairment of hepatic function. Moreover, the proinflammatory results revealed that TNF-α may consider as mediators in the post-burn pathophysiological process. Furthermore, our results declare a significant correlation between MDA levels and the degree of burn complications, including shock and remote organ damage.

The immunomodulatory effects of mesenchymal stem cells on long term pulmonary complications in an animal model exposed to a sulfur mustard analog

IntroductionSulfur Mustard (SM) is one of the most lethal chemicals with major complications manifested in the lungs. Although the pathogenesis behind SM-induced lung injury still remains poorly understood, prolonged activation and the imbalance of two major macrophage populations (M1 and M2) have been suggested to be involved. Here, we tried to investigate the effectiveness of adipose-derived mesenchymal stem cells (AD-MSC) on long-term lesions induced by CEES, an SM analog. The modulation of pulmonary immune cells and alveolar macrophage phenotype alteration was studied in the animal model used. MethodsHistopathological changes were investigated in the lungs and analysis of surface markers of alveolar macrophages as well as their cytokine expression in the BAL fluid was carried out by flow cytometry and ELISA, respectively. ResultsTreatment of mice with AD-MSC after intraperitoneal administration of CEES (10 mg/kg) reduces progressive histopathologic changes in the lung. Flow cytometric analysis of isolated alveolar macrophages in the bronchoalveolar lavage showed that the accumulation of both M1 and M2 macrophages in response to CEES was reduced by MSC administration. AD-MSCs caused a marked reduction in the CD86- and CD206-expressing macrophages compared to the untreated groups. The modulating effect of AD-MSCs in the M1-subset was much more significant compared to M2.These findings suggest that AD-MSCs understand their environment and restore the balance in disorders associated with Th1 or Th2 imbalance. Our results indicate that MSCs may represent an effective approach to repair lung injury induced by mustards.

Age estimation for Scald Injury and its Probable Relation to Testicular Function Impairment

BBackground and Rationale: From the medicolegal point of view, long term systemic consequences of scald injury should be identified for proper compensation and legal action, especially for scald injury involving skin full-thickness in 20% of total body surface area (TBSA) which is known to have long term grave consequences on general health. Aim of the Study: The current experimental study was carried out to: 1-identify the histopathological changes and TNF-α Immunoexpression of different ages of a full thickness scald injury occupying 20% of the total body TBSA; 2- study the probable relation between the scald age and the testicular function impairment. Materials and Methods: A total number of 40 adult male albino rats were used in the study. Histopathological examination for the scald area and testis were performed with hematoxyline & eosin stain and TNF-α Immunoexpression. Epididymal semen analysis and serum testosterone were also performed. These procedures were carried out after 2 days, 7 days, 1 month and 3 months of scald infliction. Results: Progressive histopathological changes were observed in the early scald ages while healing manifestations and improvement in testosterone serum levels, when compared to the other periods, started to appear after 1 and 3 months of scald infliction. Conclusion: It can be concluded that scald injury involving 20% of TBSA can cause long term impairment of testicular function.

Progressive histopathological changes in experimental skin carcinogenesis in rats

Progressive histopathological changes in experimental skin carcinogenesis in rats

Biochemical and morphological biomarkers of the liver damage in the Neotropical fish, Piaractus mesopotamicus, injected with crude extract of cyanobacterium Radiocystis fernandoi.

Cyanobacterial proliferation in river and lakes is the result of eutrophication. The cyanobacterium Radiocystis fernandoi strain R28 produces mostly two MC variants MC-RR and MC-YR and small amounts of other oligopeptides, but does not produce MC-LR. The present study investigated the hepatotoxic potential of the crude extract of the R. fernandoi strain R28 on the Neotropical fish, Piaractus mesopotamicus, at 3, 6, and 24h after intraperitoneal injection (100μg MC-LR equivalent per kg-1 body mass) using biochemical and morphological biomarkers of liver damage. Although the protein phosphatases PP1 and PP2A were not inhibited during the 24-h treatment, liver parenchyma and hepatocyte structure were disrupted. Alkaline phosphatase increased at 3h post-injection and decreased after 24h; alanine aminotransferase and aspartate aminotransferase increased in a time-dependent manner up to 24h indicating impaired liver function. Progressive histopathological changes were consistent with biochemical results demonstrating alterations in liver structure and function. In conclusion, the crude extract of R. fernandoi strain R28 has high hepatotoxic potential and can severely compromise fish health.

Progressive light microscopic changes in chronic recurrent outbreaks of hepatic coccidiosis in domestic rabbits

Hepatic coccidiosis is an important economic disease of rabbits. The progressive histopathological changes in liver of rabbits infected with Eimeria stiedae in chronic recurrent outbreaks of coccidiosis in organized rabbitries are discussed. One hundred and fifty morbid specimens of rabbit liversamples from known cases of hepatic coccidiosis preserved in 10% formalin were studied. The hepatic parenchyma revealed multifocal areas of coagulative to liquefactive necrosis, congestion, haemorrhages and vacuolar degenerative changes in hepatocytes along with periportal infiltration of numerous lymphocytes and a few neutrophils. Biliary ducts were hyperplastic with pappilomatous ingrowths of epithelium into lumen. In chronic infections, multifocal areas of severe periportal cirrhosis with islands of hepatic parenchyma were seen along with extensive infiltration of lymphocytes, plasma cells and macrophages and prominent calcification of bile ducts. Gall bladder epithelium also showed early lesions of hyperplasia of epithelial cells in mucosa with necrosis and severe inflammation and extensive fibrosis. The intensive growing conditions and contributory factors like high humidity, moisture, feeding and manure disposal system may lead to recurrent outbreaks of hepatic coccidiosis in rabbits.

Histopathological study on the effect of antioxidants (vitamin E and selenium) in hepatotoxicity induced by lead acetate in rats

The study was carried out to evaluate histopathological changes inrats liver induced by different doses and durations of lead acetate toxicity and to investigate the therapeutic effects of vitamin E and Selenium together against lead poisoning.Thirty two adult male rats (Rattus rattus), randomized into four groups (n=8) were used for this study. In group I rats received only drinking water as control while in group II , III and IV rats were given o.5%,1%,1.5% lead acetate respectively in drinking water for ten weeks. Two animals from each group were sacrificed and and dissected after five weeks and ten weeks of treatment with lead acetate.One week later animal groups were treated orally with vitamin E and selenium as a daily dose for two weeks(100mg Vit.E and 0.25mg Se/kg B.W) for first week and (200mg Vit.E and 0.5mg Se/kg B.W) for second week respectively. Also two animals from each group were sacrificed at the end of each period.The obtained results showed that lead acetate caused progressive histopathological changes depending upon the duration of exposure and concentration of lead acetate in drinking water but the treatment with antioxidants (vitamin E and Selenium together) decrease the damage to liver cells . It can be concluded that those antioxidants seem to have abenefit effects to recovery the liver tissue lead burden and had a therapeutic effects against hepatoxicity.

Forensic Image Analyses of Skin and Underlying Muscles as a Tool for Postmortem Interval Delimitation: Histopathologic Examination.

One of the biggest challenges for forensic pathologists is to diagnose the postmortem interval (PMI) delimitation; therefore, the aim of this study was to use a routine histopathologic examination and quantitative analysis to obtain an accurate diagnosis of PMI. The current study was done by using 24 adult male albino rats divided into 8 groups based on the scarification schedule (0, 8, 16, 24, 32, 40, 48, and 72 hours PMI). Skin specimens were collected and subjected to a routine histopathologic processing. Examination of hematoxylin-eosin-stained sections from the skin, its appendages and underlying muscles were carried out. Morphometric analysis of epidermal nuclear chromatin intensities and area percentages, reticular dermis integrated density, and sebaceous gland nuclei areas and chromatin condensation was done. Progressive histopathologic changes could be detected in epidermis, dermis, hypodermis, underlying muscles including nerve endings, and red blood cells in relation to hours PMI. Significant difference was found in epidermal nuclear chromatin intensities at different-hours PMI (at P < 0.001). The highest intensity was detected 40 hours PMI. Quantitative analysis of measurements of dermal collagen area percentages revealed a high significant difference between 0 hours PMI and 24 to 72 hours PMI (P < 0.001). As the PMI increases, sebaceous gland nuclei and nuclear chromatin condensation showed a dramatic decrease. Significant differences of sebaceous gland nuclei areas between 0 hours and different-hours PMI (P < 0.001) were obtained. A combination between routine histopathologic examination and quantitative and morphometric analysis of the skin could be used to evaluate the time of death in different-hours PMI.

Folate receptor-targeted aminopterin therapy is highly effective and specific in experimental models of autoimmune uveitis and autoimmune encephalomyelitis

EC0746 is a rationally designed anti-inflammatory drug conjugate consisting of a modified folic acid-based ligand linked to a γ-hydrazide analog of aminopterin. In this report, EC0746's effectiveness was evaluated against experimental retinal S-antigen (PDSAg) induced autoimmune uveitis (EAU) and myelin-basic-protein induced autoimmune encephalomyelitis (EAE). In both models, functional FR-β was detected on activated macrophages in local (retinal or central-nervous-system, respectively) and systemic (peritoneal cavity) sites of inflammation. In myelin-rich regions of EAE rats, an increased uptake of (99m)Tc-EC20 (etarfolatide; a FR-specific radioimaging agent) was also observed. EC0746 treatment at disease onset suppressed the clinical severity of both EAU and EAE, and it strongly attenuated progressive histopathological changes in the affected organs. In all parameters assessed, EC0746 activity was completely blocked by a benign folate competitor, suggesting that these therapeutic outcomes were specifically FR-β mediated. EC0746 may emerge as a useful macrophage-modulating agent for treating inflammatory episodes of organ-specific autoimmunity.

Molecular and Functional Alterations in a Mouse Cardiac Model of Friedreich Ataxia: Activation of the Integrated Stress Response, eIF2α Phosphorylation, and the Induction of Downstream Targets

Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2α phosphorylation, which precedes activation of autophagy and apoptosis.

PPARδ induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation.

The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In this study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathologic changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to 5 months. Histopathologic changes occurred concurrently with an increase in an inflammatory, invasive, metabolic, and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning 1 week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTOR signaling that were attenuated by treatment with the mTOR inhibitor everolimus. Our findings are the first to show a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease.

Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24h to 168h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury.

Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1d–28d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS+ and cyclooxygenase-2+) and alternatively activated profibrotic (YM-1+ and galectin-3+) macrophages appeared in the lung following NM administration; this was evident within 1d, and persisted for 28d. AG administration (50mg/kg, 2×/day, 1d–3d) abrogated NM-induced injury, oxidative stress and inflammation at 1d and 3d post exposure, with no effects at 7d or 28d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis.

Role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase in vesicant-induced lung injury and inflammation

Nitrogen mustard (NM) is a toxic vesicant known to damage the respiratory tract by alkylating proteins, lipids and nucleic acids and causing oxidative stress. Acute injury is associated with increased expression of inducible nitric oxide synthase (iNOS) in lung macrophages and epithelial cells. In these studies we analyzed the effects of inhibiting iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Male Wistar rats were treated IT with NM (0.125 mg/kg) or control. Animals were sacrificed 1–28 days later and lungs analyzed for markers of injury, oxidative stress and inflammation. Exposure of rats to NM resulted in progressive histopathological changes including perivascular and peribronchial edema, inflammatory cell infiltration, luminal and alveolar accumulation of debris and fibrin, bronchiolization of the alveolar septal wall, fibroplasia and fibrosis. This was correlated with increased bronchoalveolar lavage protein and inflammatory cell content. NM intoxication also resulted in increased expression of iNOS and COX-2, as well as HO-1 and Mn-SOD at all the post exposure times. Evidence of Type II cell proliferation, as well as YM1 and galectin-3 positive pro-fibrotic macrophages were also noted in the lung 3–28 days post NM exposure. Treatment of rats with AG (50 mg/kg, 2x/day for 3 days) abrogated acute injury, inflammation and oxidative stress induced by NM 1–3 days post exposure; with no effects at 7–28 days. These findings indicate that RNS generated via iNOS contribute to early events in NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis.

Progressive histopathological changes and β-cell loss in the pancreas of a new spontaneous rat model of type 2 diabetes

The eSMT rat is a new spontaneous model of type 2 diabetes that develops a progressive diabetic syndrome with a stronger incidence in males than in females. We decide to investigate the progression of the pancreatic histopathological changes during the lifespan of the eSMT rat, especially those associated with islet cell populations. Besides that, some plasmatic parameters were evaluated in order to correlate them with the morphological findings. Male eSMT and Sprague-Dawley control rats were used.The results showed a dramatic decrease of the volume density (VD) of endocrine tissue in the eSMT rats without evidence of insulitis. Islets became fragmented structures with strong presence of interstitial fibrosis. Consequently, plasma insulin levels showed a significant decrease, while plasma glucose, cholesterol and triglyceride levels were increased. Normal rats showed no significant changes in the VD of endocrine tissue, except for the older animals, where the VD of β-cell population was increased.Early derangements observed in islets, together with the progressive decrease of endocrine tissue and the metabolic disorders described, would be responsible for an irreversible pathologic condition which avoids the animal survival beyond about 18 months of age.However, there is still a need to investigate the causes of endocrine tissue decrease and its possible association with an inflammatory process that it could be associated with the development and progression of fibrosis.

Prognostic Value of the Resistance Index in the Undescended Testis Relative to Patient's Age and Time-Point of Surgery

Purpose The undescended testis is one of the most common disease in paediatric urology. The aim of the present study was to analyse the testicular parenchymal blood flow as measured by the resistance index (RI) in relation to the patient's age and potential changes in RI following surgery. Material and Methods From 04/07 – 03/09 we prospectively studied 100 boys with uni- or bilateral undescended testes aged 1 to 14 using a high resolution linear ultrasound scanner. The RI was determined with simultaneous detection of B-mode and colour-flow Doppler before and 6 weeks after surgery. The obtained indices were compared with those of the descended contralateral testis. Results A total of 143 undescended testes (43 bilateral, 57 unilateral) and 57 descended contralateral testes were examined. In both groups the mean RI was 0,55 irrespecitve of the patient's age. Similarly, we did not observe any significant changes in RI following surgical correction of the undescended testis. Conclusions In contrast to progressive histo-pathological changes in untreated undescended testis over time, the time-point of surgery appears to have no relevant impact on the testicular parenchymal blood perfusion as measured by the RI. Therefore, the RI failed to show a predictive value with regard to both diagnosis and therapy of the undescended testis.

Nonalcoholic Steatohepatitis and the Cardiometabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the United States and involves a spectrum of progressive histopathologic changes. Common risk factors associated with NAFLD include obesity, diabetes, and hyperlipidemia. Although most patients with NAFLD have simple hepatic steatosis, a significant number develop nonalcoholic steatohepatitis, which may progress to fibrosis, cirrhosis, or end-stage liver disease. There is increasing evidence that NAFLD is a common feature in patients with the cardiometabolic syndrome, a onstellation of metabolic, cardiovascular, renal, and inflammatory abnormalities in which insulin resistance is thought to play a key role in end-organ pathogenesis. NAFLD is usually diagnosed after abnormal liver chemistry results are found during routine laboratory testing. No therapy has been proven effective for treating NAFLD/nonalcoholic steatohepatitis. Expert opinion emphasizes the importance of exercise, weight loss in obese and overweight individuals, treatment of hyperlipidemia, and glucose control.

Longitudinal serological surveys of Atlantic salmon, Salmo salar L., using a rapid immunoperoxidase‐based neutralization assay for salmonid alphavirus

Longitudinal serological surveys for salmon pancreas disease virus (SPDV), the causal agent of pancreas disease (PD), were conducted on multiple caged populations of Atlantic salmon, Salmo salar L., on two farms over a 77-week period (farm 1, freshwater and marine stages) and a 36-week period (farm 2, marine stage only), using a microtitre-based virus neutralization (VN) assay. Collected sera were also screened for viraemia with SPDV, and pancreas, heart and muscle tissues were examined for lesions consistent with PD. Outbreaks of PD occurred during the marine phase on both farms, as demonstrated by seroconversion, the isolation of virus and progressive histopathological changes consistent with a PD outbreak. All populations monitored showed a progressive increase in seroprevalence of 90-100%, typically accompanied by rises in geometric mean antibody titres. With the exception of one caged population, which showed a marked biphasic seroprevalence pattern, the seroprevalence figures in the remaining four monitored populations remained high (> or =70%) until the end of the study period. Peak VN titres of > or =1/1280 were detected on both farms. The results provide essential baseline information for the interpretation of SPDV VN serology results, and indicate that this methodology is suited to both the diagnosis and seroepidemiology of SPDV infections.

Phlorizin treatment prevents the decrease in plasma insulin levels but not the progressive histopathological changes in the pancreatic islets during aging of Zucker diabetic fatty rats.

A hallmark of Type 2 diabetes mellitus (T2DM) is chronic hyperglycemia, which is thought to play a role in pancreatic beta-cell failure. Here we investigated whether treatment of Zucker diabetic fatty (ZDF) rats, an animal model for T2DM, with the renal glucose transport inhibitor phlorizin could prevent alterations in the pancreatic islets. ZDF rats were treated with phlorizin or vehicle for 13 weeks starting with 6-week-old rats and before the onset of hyperglycemia. During the treatment, blood glucose levels in sham-treated ZDF rats increased rapidly from 7.7 +/- 0.3 to 24.8 +/- 0.6 mmol/l, whereas those in phlorizin-treated ZDF rats increased only slightly, but significantly, from 7.0 +/- 0.2 to 8.9 +/- 0.6 mmol/l. Phlorizin prevented the decrease in plasma insulin levels and caused a higher increase in body weight of the ZDF rats. Compared to 6-week-old untreated ZDF rats, in 19-week-old sham- and phlorizin-treated ZDF rats similar changes were found in islet architecture (more irregular boundaries and a disrupted mantle of peripheral islet cells) and in the mitochondria at the ultrastructural level (swelling of the matrix and disruption of the cristae). Using reverse transcriptase-polymerase chain reaction, no differences in mRNA expression levels were found for insulin, islet amyloid polypeptide (IAPP), and the prohormone convertase (PC) 1 and PC2 between 6-week-old untreated ZDF rats and 19-week-old sham- and phlorizin-treated ZDF rats. However, immunohistochemistry revealed similar decreases in insulin and IAPP protein expression in 19-week-old sham- and phlorizin-treated ZDF rats compared to those in 6-week-old untreated ZDF rats. These observations indicate that during aging of ZDF rats phlorizin treatment does not prevent the decreases in insulin and IAPP protein expression and the progressive histopathological changes in the pancreatic islets. Therefore, it is highly unlikely that these changes are caused by chronic hyperglycemia.

Molecular pathogenesis of precursor lesions of pancreatic ductal adenocarcinoma

<h2>Summary</h2> Precursor lesions are assuming greater importance in the study of pancreatic ductal adenocarcinoma. As pancreatic cancer is almost universally fatal due to late clinical presentation and biological aggressiveness, characterisation of its precursor lesions may create scope for early diagnosis and improved outcome with conventional therapies as well as the development of novel therapeutic and preventative strategies. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous tumours (IPMTs) are thought to be precursor lesions of ductal adenocarcinoma of the pancreas. Recent work has focused on the molecular aberrations associated with these lesions leading to the formulation of a progression model for pancreatic cancer. Progressive histopathological changes along the progression model are associated with aberrations of cell cycle regulatory and growth factor signalling molecules that occur in pancreatic cancer at high frequency and are common to many cancers. Characterisation of these molecular aberrations provides scope for the development of novel diagnostic and treatment strategies that will ultimately impact on the outcome for people who develop pancreatic cancer.