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1.
MMW Fortschr Med ; 166(Suppl 2): 32-34, 2024 07.
Article in German | MEDLINE | ID: mdl-38980615

ABSTRACT

Since the development of an effective antiretroviral therapy (ART) in 1996, substantial progress has been made in terms of efficacy, safety and ease of use. While at the beginning of the ART era the foremost goal necessarily was patient survival, over time it has become increasingly possible to shift the focus towards aspects of patient's quality of life. The latest developments are the long-acting injection therapies (LAI), foregoing for the first time the necessity to take pills. The only available injection therapy so far comprises 2 intramuscular injections every 2 months, with 3 ml of Cabotegravir 600 mg and 3 ml of Rilpivirine 900 mg being injected, respectively. Through this, patient's needs that were hitherto precluded from consideration could be addressed. These needs are inextricably linked to the stigmata people living with HIV (PLWH) are still confronted with on a daily basis. LAI have the potential to relieve PLWH of some of the heavy psychological burdens associated with the continued stigmatization. However, as a new therapy, new challenges need to be considered the use of LAI.


Subject(s)
Anti-HIV Agents , Delayed-Action Preparations , HIV Infections , Humans , HIV Infections/drug therapy , Injections, Intramuscular , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/adverse effects , Rilpivirine/administration & dosage , Rilpivirine/therapeutic use , Pyridones/administration & dosage , Pyridones/therapeutic use , Pyridones/adverse effects , Quality of Life , Diketopiperazines
2.
Infect Dis Rep ; 15(5): 470-477, 2023 Aug 25.
Article in English | MEDLINE | ID: mdl-37736994

ABSTRACT

Sexually transmitted infections (STIs) are increasing among men who have sex with men (MSM). Screening can improve the detection and outcome of asymptomatic STIs in high-risk populations. Self-sampling may be a resource-optimized strategy; however, its diagnostic reliability compared to testing by healthcare professionals (HCPs) requires further investigation. In this prospective, multicenter cohort study in a high-income country, asymptomatic MSM with a sexual risk profile for STIs were included. Sequential swabs for STI nucleic acid-based diagnosis of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) were performed after randomization, either through self-sampling or HCP-performed sampling. Baseline demographic information, sexual risk behavior, and acceptance and feedback on self-sampling were recorded using an electronic questionnaire. Out of 236 asymptomatic MSM, 47 individuals (19.9%) tested positive for CT and/or NG through self- or HCP-performed sampling. For CT, the sensitivity was 93.3% for both sampling methods, while for NG, it was 90.0% for self-sampling and 95.0% for HCP-performed sampling. Our study demonstrates that self-sampling for asymptomatic STIs has a comparable diagnostic outcome to HCP-performed sampling, with high acceptance in high-risk MSM.

3.
Int J STD AIDS ; 34(13): 956-961, 2023 11.
Article in English | MEDLINE | ID: mdl-37461288

ABSTRACT

BACKGROUND: At the beginning of the COVID-19 pandemic, when mortality was high, social distance was the only option to prevent transmission of SARS-CoV-2 and prohibit uncontrolled spreading. As the impact of social distancing on sexual behavior was unclear, we aimed to assess the influence of sexual risk behavior on SARS-CoV-2 seroconversion in HIV pre-exposition prophylaxis (PrEP) users after declaration of the pandemic. METHODS: Prospective study on SARS-CoV-2 IgG-antibody seroconversion rate over time in men having sex with men (MSM) using PrEP at a single tertiary university hospital in Munich, Germany, during quarterly (Q) routine HIV-PrEP visits over 1 year per participant (May 2020 - September 2021). Seroconversion was defined as at least one positive anti-nucleocapsid (anti-N) SARS-CoV-2 IgG antibody test as surrogate for past infection. In addition, sexually transmitted infections (STIs), personal estimated risk behavior and sexual contacts were assessed. RESULTS: Seroconversion rate during the full observation period was 7.3% (9/124 subjects) by September 2021. Percentage of subjects with symptomatic STIs (T. pallidum, N. gonorrhoeae, C. trachomatis and M. genitalium) was 18.7% in Q3-20, 8.1% in Q4-20, 11.1% in Q1-21, 11.6% in Q2-21 and 9.5% in Q3-21. Perception of subjective threat of SARS-CoV-2 infection and adequacy of preventive measures decreased during the observation period. However, self-reported sex behavior remained stable during the observation period. CONCLUSIONS: Our cohort showed low proportion of PrEP-users with anti-N IgG by September 2021, comparable to the local incidence. Sexual behavior in this cohort did not change, despite local recommendations for social distancing.


Subject(s)
COVID-19 , HIV Infections , Pre-Exposure Prophylaxis , Sexual and Gender Minorities , Sexually Transmitted Diseases , Male , Humans , COVID-19/epidemiology , SARS-CoV-2 , Homosexuality, Male , HIV Infections/drug therapy , Pandemics/prevention & control , Prospective Studies , Seroconversion , Sexually Transmitted Diseases/epidemiology , Sexual Behavior , Antibodies, Viral , Immunoglobulin G
5.
BMC Vet Res ; 18(1): 242, 2022 Jun 24.
Article in English | MEDLINE | ID: mdl-35751056

ABSTRACT

BACKGROUND: Canine tonsillectomy is performed due to acute or chronic tonsillitis, neoplasia, trauma or occasionally brachycephalic obstructive airway syndrome. Several tonsillectomy techniques are used but information about surgical complications is scarce. This retrospective study of patient records at the University Animal Hospital aimed to investigate complications related to canine tonsillectomy performed by 20-min clamping combined with monopolar electrosurgery. Inclusion criteria were bilateral tonsillectomy performed with "20-min clamping technique combined with monopolar electrosurgery without suture or ligation". Exclusion criteria were unilateral tonsillectomy, tonsillar neoplasia, additional surgical procedures other than tonsillectomy, cases where sutures were used initially, and cases where unspecified or other methods of tonsillectomy were used. The search of the patient records of the University Animal Hospital included a 10-year period. Complications that required additional anaesthesia were defined as major complications. Minor complications were handled during surgery or after surgery without surgical intervention. RESULTS: Of 39 dogs that fulfilled the inclusion criteria, 11 dogs had complications and out of those 1 dog had two complications. Altogether, of the 12 complications, 2 were classified as major complications and 10 as minor. The most frequent complication was bleeding from the surgical site, in total 11 incidences; 10 dogs had an incidence of bleeding and out of those, 1 dog bled twice, both during and after surgery. Of these 10 dogs that bled, seven incidences of bleeding occurred during surgery and four incidences occurred after surgery. The two dogs with major complications were re-anaesthetized due to bleeding after surgery. No lethal complications occurred and all dogs survived to discharge. CONCLUSIONS: Bleeding during and after surgery was a common complication in dogs after bilateral tonsillectomy using "20-min clamping technique combined with monopolar electrocautery". Revision intervention was often needed, sometimes urgently. Although no comparison was made with another technique, the studied technique should be used with caution.


Subject(s)
Dog Diseases , Tonsillectomy , Tonsillitis , Animals , Constriction , Dog Diseases/surgery , Dogs , Electrosurgery/adverse effects , Electrosurgery/veterinary , Humans , Retrospective Studies , Tonsillectomy/adverse effects , Tonsillectomy/methods , Tonsillectomy/veterinary , Tonsillitis/surgery , Tonsillitis/veterinary
6.
AIDS Res Ther ; 18(1): 78, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34702284

ABSTRACT

BACKGROUND: Symptoms of primary HIV infection, including fever, rash, and headache, are nonspecific and are often described as flu-like. COVID-19 vaccination side effects, such as fever, which occur in up to 10% of people following COVID-19 vaccination, can make the diagnosis of acute HIV infection even more challenging. CASE PRESENTATION: A 26-year-old man presented with fever and headache following COVID-19 vaccination. The symptoms were initially thought to be vaccine side effects. A diagnostic workup was conducted due to persisting fever and headache > 72 h following vaccination, and he was diagnosed with Fiebig stage II acute HIV infection, 3 weeks after having unprotected anal intercourse with another man. CONCLUSION: Thorough anamnesis is key to estimating the individual risk of primary HIV infection, in patients presenting with flu-like symptoms. Early diagnosis and initiation of antiretroviral therapy is associated with better prognosis and limits transmission of the disease.


Subject(s)
COVID-19 , HIV Infections , Adult , COVID-19 Vaccines , HIV Infections/diagnosis , HIV Infections/drug therapy , Humans , Male , SARS-CoV-2 , Vaccination/adverse effects
7.
Sex Transm Dis ; 48(6): 436-442, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33156290

ABSTRACT

BACKGROUND: Data on ocular syphilis (OS) and its clinical presentation are currently insufficient. This study aimed to investigate the characteristics of a cohort with a high OS incidence at a university hospital in Germany, focusing on the clinical presentation of OS. METHODS: This single-center cohort study retrospectively analyzed data on 90 patients with 109 episodes of syphilis between 2008 and 2018. Cases of OS were identified and additionally reevaluated through a study-specific secondary assessment by an ophthalmologist specializing in uveitis. RESULTS: Twenty-three patients (26%) were diagnosed with OS, 16 (70%) of whom were with binocular involvement. Uveitis, especially that of the posterior segment, showed a high prevalence. Lumbar puncture was performed in 20 OS patients (87%), of whom 17 (85% of those with lumbar puncture/74% in total) met the 2018 Centers for Disease Control and Prevention criteria for likely neurosyphilis. Five (22%) of 23 patients had HIV infection, of whom 2 did not receive antiretroviral therapy. The preferred syphilis treatment regimens were benzylpenicillin and ceftriaxone, which yielded favorable serological, clinical, and ophthalmological outcomes. CONCLUSIONS: A high incidence of OS was identified, and physicians should be aware of uveitis as a manifestation of syphilis. Most patients presented with uveitis and syphilis in an early or late latent stage and showed central nervous system involvement.


Subject(s)
HIV Infections , Neurosyphilis , Syphilis , Cohort Studies , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , Neurosyphilis/diagnosis , Neurosyphilis/drug therapy , Neurosyphilis/epidemiology , Retrospective Studies , Syphilis/diagnosis , Syphilis/drug therapy , Syphilis/epidemiology , Syphilis Serodiagnosis , Tertiary Care Centers
8.
Front Vet Sci ; 7: 572691, 2020.
Article in English | MEDLINE | ID: mdl-33240952

ABSTRACT

Objective: The objective of this study was to increase knowledge regarding long-term prognosis of mild to moderate elbow dysplasia (ED) using a canine orthopedic index. Study Design: Cross-sectional observational study. Sample Population: Sixty dogs randomly selected from each of five different breeds and three ED groups: ED0 (control), ED1, and ED2, based on the Kennel Club's screening results. The total number of selected dogs was 900 (60*5*3). Methods: Questionnaires were administered to owners by telephone interview. Bayesian network modeling was used to assess the relation between ED grade, treatment options, dog demographics, and quality-of-life indicators. Results: Seven hundred sixty-five questionnaires were collected (85% response rate), of which 61 concerned dogs euthanized due to osteoarthritis. There was no direct association between ED grade and owner's perceived quality of life, but ED1 and ED2 dogs were more likely to receive veterinary care and subsequent NSAID treatment compared to ED0 dogs. A significant association was found between the occurrence of euthanasia due to orthopedic disease and ED scores 1 and 2 in the sample (p < 0.001). Conclusion: The degree of osteoarthritis was not directly associated with the canine orthopedic index, except for ED2 and lameness score. It can be speculated that owners who paid closer attention to orthopedic symptoms and perceived them as impairing their dogs' lives were also more likely to seek veterinary care and get treatment, irrespective of the ED grading. Impact: ED1-graded dogs had a lower risk than might be expected to develop visible clinical symptoms and showed a similar quality of life as dogs with ED0. ED2-graded dogs were more likely than ED0-graded dogs to have their lives impaired by lameness, according to the owners' perception.

9.
Am J Pathol ; 186(11): 2934-2944, 2016 11.
Article in English | MEDLINE | ID: mdl-27639167

ABSTRACT

Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a+/Cre; Hes1fl/fl). Using this model, we studied the role of Hes1 in both acinar cell plasticity and pancreatic regeneration after caerulein-induced pancreatitis and in KrasG12D-driven PDAC development. We show that, although pancreatic development is not perturbed on the deletion of Hes1, terminal acinar differentiation in the adult pancreas is compromised. Moreover, the loss of Hes1 leads to the impaired regeneration of the exocrine compartment, accelerated fatty metaplasia, and persistent ADM after acute caerulein-induced pancreatitis. In KrasG12D-driven carcinogenesis, Hes1 ablation resulted in increased ADM, decreased formation of high-grade pancreatic intraepithelial neoplasias, and accelerated development of PDAC with shortened survival time. In conclusion, Hes1 plays a key role in acinar cell integrity and plasticity on cellular insults. Furthermore, Hes1 is an essential component of the pancreatic intraepithelial neoplasias-to-PDAC route in KrasG12D-driven mouse pancreatic carcinogenesis.


Subject(s)
Carcinoma, Pancreatic Ductal/etiology , Pancreatic Neoplasms/etiology , Signal Transduction , Transcription Factor HES-1/metabolism , Acinar Cells/pathology , Acinar Cells/physiology , Animals , Carcinogenesis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Differentiation , Cell Plasticity , Ceruletide/adverse effects , Disease Models, Animal , Female , Humans , Male , Metaplasia , Mice , Pancreas/pathology , Pancreas/physiology , Pancreas, Exocrine/pathology , Pancreas, Exocrine/physiology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatitis/chemically induced , Pancreatitis/pathology , Regeneration , Stem Cells/pathology , Stem Cells/physiology , Transcription Factor HES-1/genetics
10.
AIDS Res Ther ; 12: 18, 2015.
Article in English | MEDLINE | ID: mdl-26045712

ABSTRACT

A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay®) and tenofovir disaproxil fumarate/emtricitabine (Truvada®) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments.

11.
J Thromb Thrombolysis ; 40(1): 54-60, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25115839

ABSTRACT

Liver cirrhosis, myeloproliferative disorders (MPDs) and prothrombotic mutations are aetiologic factors for portal vein thrombosis (PVT). The role and frequency of thrombophilic genetic risk factors in cirrhotic patients is not well established. In this case-control study, we investigated the frequency of Janus kinase 2 (JAK2) (JAK2 V617F), Factor V Leiden (FVL G1691A), and Prothrombin (G20210A) mutations in cirrhotic patients with PVT (LCi+/PVT+ group, n = 21) in comparison with two control collectives (cirrhotic patients without PVT, LCi+/PVT- group, n = 43; PVT patients without liver cirrhosis, LCi-/PVT+ group, n = 29). In the LCi+/PVT+ group, JAK2 V617F was present in 2/21 patients (10 %; p = 0.104 compared to LCi+/PVT-; p = 0.092 compared to LCi-/PVT+), whereas 0/43 LCi+/PVT- patients (0 %; p < 0.001 compared to LCi-/PVT+) and 9/29 LCi-/PVT+ patients (31 %) harboured this mutation. The FVL G1691A mutation was identified in 1/21 patients (5 %) in the LCi+/PVT+ group, in 5/43 patients (12 %) in the LCi+/PVT- group, and in 2/29 patients (7 %) in the LCi-/PVT+ group. The Prothrombin G20210A mutation was present in 0/21 LCi+/PVT+ patients (0 %), in 1/43 LCi+/PVT- patients (2 %), and in 4/29 patients (14 %) in the LCi-/PVT+ group. This study provides evidence that a relevant proportion of cirrhotic patients with PVT harbours a JAK2 V617F mutation.


Subject(s)
Janus Kinase 2/genetics , Liver Cirrhosis/genetics , Portal Vein , Venous Thrombosis/genetics , Adult , Aged , Case-Control Studies , Factor V/genetics , Factor V/metabolism , Female , Genetic Markers/genetics , Humans , Janus Kinase 2/blood , Liver Cirrhosis/blood , Liver Cirrhosis/diagnosis , Male , Middle Aged , Mutation/genetics , Portal Vein/pathology , Prothrombin/genetics , Prothrombin/metabolism , Venous Thrombosis/blood , Venous Thrombosis/diagnosis
13.
Mycopathologia ; 177(3-4): 193-7, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24710759

ABSTRACT

BACKGROUND: Severe alcoholic hepatitis (AH) has a poor short-term prognosis often caused by infections. However, the incidence of invasive mycosis in patients with AH treated with corticosteroids and its impact still remains unknown. METHODS: Retrospective analyses of twelve medical ICU patients (out of 120 patients with liver cirrhosis) with histological proven AH. RESULTS: Twelve patients were diagnosed with histological proven AH during there stay at the ICU. All patients were treated with corticosteroids; three patients were treated with corticosteroids and pentoxifylline. Five patients had invasive aspergillosis (IA); three patients had candidemia; and two had fungal colonization with candida species. Only two patients had no evidence for fungals. IA was associated with death in all cases. Death occured in most cases shortly after diagnosis despite antifungal medication. Two patients with candidemia died; one patient died in the group with fungal colonization. Overall, the mortality rate was 100% in patients with IA and 70% in the group with candidemia. CONCLUSIONS: Patients with severe AH have an increased susceptibility to invasive mycosis associated with high mortality. A high level of suspicion of invasive mycosis in AH patients and prophylactic strategies are needed in those patients.


Subject(s)
Hepatitis, Alcoholic/complications , Mycoses/epidemiology , Adrenal Cortex Hormones/adverse effects , Adrenal Cortex Hormones/therapeutic use , Adult , Female , Hepatitis, Alcoholic/drug therapy , Humans , Intensive Care Units , Male , Middle Aged , Mycoses/etiology , Mycoses/mortality , Retrospective Studies
14.
Hepatology ; 57(6): 2469-79, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23315998

ABSTRACT

UNLABELLED: Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown. By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell-specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification of embryonic hepatoblasts, but also-when expressed in up to 6-month-old adult livers-rapidly reprograms adult hepatocytes to biliary cells with formation of tubular-cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable of inducing a ductular reaction. Furthermore, we characterized the significance of key effectors of canonical Notch signaling during normal development and in N2IC-expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC-induced specification and morphogenesis of embryonic hepatoblasts and biliary conversion of adult hepatocytes all critically rely on canonical Notch signaling via recombination signal binding protein (RBP)-Jκ but do not require Hes1. CONCLUSION: Notch2 appears to be the main determinant not only of biliary commitment of embryonic hepatoblasts during development but also of biliary reprogramming of adult hepatocytes. Notch2-dictated cell fates and morphogenesis in both embryonic hepatoblasts and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active. (HEPATOLOGY 2013).


Subject(s)
Liver/embryology , Liver/metabolism , Receptor, Notch2/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Hepatocytes/physiology , Homeodomain Proteins/metabolism , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Mice , Mice, Transgenic , Morphogenesis , Rabbits , Rats , Receptor, Notch2/genetics , Signal Transduction , Transcription Factor HES-1
15.
Proc Natl Acad Sci U S A ; 107(30): 13438-43, 2010 Jul 27.
Article in English | MEDLINE | ID: mdl-20624967

ABSTRACT

Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.


Subject(s)
Adenocarcinoma/pathology , Carcinoma in Situ/pathology , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Receptor, Notch2/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Animals , Blotting, Western , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/metabolism , Cell Line, Tumor , Disease Progression , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Mice , Mice, Knockout , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Receptor, Notch2/genetics , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction
16.
Hepatology ; 48(2): 607-16, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18666240

ABSTRACT

UNLABELLED: The Notch pathway is an evolutionary conserved, intercellular signaling pathway that plays an important role in cell fate specification and the embryonic development of many organs, including the liver. In humans, mutations in the Notch receptor ligand Jagged1 gene result in defective intrahepatic bile duct (IHBD) development in Alagille syndrome. Developmental abnormalities of IHBD in mice doubly heterozygous for Jagged1 and Notch2 mutations propose that interactions of Jagged1 and its receptor Notch2 are crucial for normal IHBD development. Because different cell types in the liver are involved in IHBD development and morphogenesis, the cell-specific role of Notch signaling is not entirely understood. We investigated the effect of combined or single targeted disruption of Notch1 and Notch2 specifically in hepatoblasts and hepatoblast-derived lineage cells on liver development using AlbCre transgenic mice. Hepatocyte differentiation and homeostasis were not impaired in mice after combined deletion of Notch1 and Notch2 (N1N2(F/F)AlbCre). However, we detected irregular ductal plate structures in N1N2(F/F)AlbCre newborns, and further postnatal development of IHBD was severely impaired characterized by disorganized ductular structures accompanied by portal inflammation, portal fibrosis, and foci of hepatocyte feathery degeneration in adulthood. Further characterization of mutant mice with single deletion of Notch1 (N1(F/F)AlbCre) or Notch2 (N2(F/F)AlbCre) showed that Notch2 but not Notch1 is indispensable for normal perinatal and postnatal IHBD development. Further reduction of Notch2 gene dosage in Notch2 conditional/mutant (N2(F/LacZ)AlbCre) animals further enhanced IHBD abnormalities and concomitant liver pathology. CONCLUSION: Notch2 is required for proper IHBD development and morphogenesis.


Subject(s)
Bile Ducts, Intrahepatic/growth & development , Bile Ducts, Intrahepatic/metabolism , Receptor, Notch1/metabolism , Receptor, Notch2/metabolism , Animals , Animals, Newborn , Bile Ducts, Intrahepatic/abnormalities , Bile Ducts, Intrahepatic/pathology , Fibrosis , Gene Dosage , Hepatocytes/pathology , Liver/growth & development , Liver/metabolism , Liver/pathology , Mice , Mice, Knockout , Mice, Transgenic , Receptor, Notch1/genetics , Receptor, Notch2/genetics , Severity of Illness Index
17.
Gastroenterology ; 134(2): 544-55, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18242220

ABSTRACT

BACKGROUND & AIMS: The mechanisms for tissue regeneration and renewal after acute pancreatitis are not well understood but may involve activation of Notch signaling. To study the effect of Notch signaling ablation during acute experimental pancreatitis, we used a chemical and genetic approach to ablate Notch signaling in cerulein-induced pancreatitis in mice. METHODS: Acute pancreatitis was induced by cerulein treatment in mice treated with the gamma-secretase inhibitor dibenzazepine or in conditional Notch1 knockout mice. Mice were characterized using immunohistologic, biochemical, and molecular methods. To investigate Notch and beta-catenin interaction, acinar 266-6 cells were analyzed using transfection and biochemical assays. RESULTS: Loss of Notch signaling results in impaired regeneration after acute pancreatitis with fewer mature acinar cells in dibenzazepine-treated and Notch1-deficient mice in the regenerative phase 3 days after induction. beta-catenin expression was increased and prolonged during exocrine regeneration. Crosstalk between Notch and beta-catenin-mediated signaling was identified, with Notch1-IC inhibiting beta-catenin-mediated transcriptional activity. This inhibition was dependent on a functional RAM domain. CONCLUSIONS: Inhibition of Notch signaling in vivo leads to impaired regeneration of the exocrine pancreas after acute pancreatitis. Our results suggest an interaction of Notch and Wnt signaling in pancreatic acinar cells, providing evidence for a role of these pathways in the regulation of the maturation process of acinar cells.


Subject(s)
Pancreas, Exocrine/physiology , Pancreatitis/metabolism , Receptor, Notch1/metabolism , Regeneration/physiology , beta Catenin/metabolism , Acute Disease , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Cell Line, Tumor , Ceruletide , Dibenzazepines/pharmacology , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Knockout , Pancreas, Exocrine/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/physiopathology , Pancreatitis/chemically induced , Pancreatitis/pathology , Receptor, Notch1/genetics , Signal Transduction/physiology , Wnt Proteins/physiology
18.
Vet Immunol Immunopathol ; 117(3-4): 296-301, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17451811

ABSTRACT

Serum amyloid A (SAA) is a major acute phase protein in dogs. However, knowledge of qualitative properties of canine SAA and extent of its synthesis in extrahepatic tissues is limited. The aim of the study was to investigate expression of different SAA isoforms in serum and synovial fluid in samples obtained from dogs (n=16) suffering from different inflammatory or non-inflammatory conditions, which were either related or unrelated to joints. Expression of SAA isoforms was visualized by denaturing isoelectric focusing and Western blotting. Serum amyloid A was present in serum from all dogs with systemic inflammatory activity, and up to four major isoforms with apparent isoelectric points between 6.1 and 7.9 were identified. In synovial fluid from inflamed joints one or more highly alkaline SAA isoforms (with apparent isoelectric points above 9.3) were identified, with data suggesting local production of these isoforms in the canine inflamed joint.


Subject(s)
Dog Diseases/metabolism , Joint Diseases/veterinary , Serum Amyloid A Protein/analysis , Acute Disease , Animals , Blotting, Western , Dog Diseases/blood , Dogs , Female , Isoelectric Focusing , Joint Diseases/blood , Joint Diseases/metabolism , Male , Protein Isoforms/analysis , Protein Isoforms/blood
19.
Am J Vet Res ; 67(6): 978-84, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16740090

ABSTRACT

OBJECTIVE: To compare and correlate B-mode and color Doppler ultrasonographic characteristics with histopathologic findings of benign and malignant superficial lymph nodes in dogs. STUDY POPULATION: 50 superficial lymph nodes that were normal, abnormally large on physical examination, or represented regional lymph nodes draining an area of suspected primary malignancy in 30 dogs. PROCEDURES: Before excision, lymph nodes were evaluated via B-mode and color Doppler ultrasonography to assess size, echogenicity, presence of a hilus, acoustic transmission, and vascular flow. Formalin-fixed, paraffin-embedded tissue sections of excised lymph nodes were stained with H&E and examined for the presence and extent of necrosis, fibrosis, fat, metastases, and tissue heterogeneity. To assess vascularity, the number and distribution of vessels stained by the Verhoeff van Gieson technique were recorded. RESULTS: In superficial lymph nodes, a varied echogenicity corresponded to tissue heterogeneity. The ultrasonographic detection of a hilus was associated with the presence of fibrous tissue, fat, or both in the hilar region. Acoustic enhancement corresponded to presence of areas of intranodal necrosis. There was significant correlation between both the distribution and the number of vessels detected via ultrasonography and that detected by histopathology. The amount of flow estimated via ultrasonography was typically higher than that estimated via histologic examination. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that histopathologic changes in canine lymph nodes have associated ultrasonographic changes and suggest that lymph node ultrasonography has an important role in the evaluation of lymph nodes in dogs in general and in dogs with neoplastic disease in particular.


Subject(s)
Dog Diseases/diagnostic imaging , Lymph Nodes/diagnostic imaging , Lymphoma/veterinary , Ultrasonography, Doppler/veterinary , Animals , Dog Diseases/diagnosis , Dog Diseases/pathology , Dogs , Lymph Nodes/pathology , Lymphoma/diagnosis , Ultrasonography, Doppler/methods
20.
Am J Vet Res ; 67(6): 985-91, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16740091

ABSTRACT

OBJECTIVE: To compare and correlate B-mode and color Doppler ultrasonographic characteristics with the histologic findings of benign and malignant mammary tumors in dogs. STUDY POPULATION: 49 mammary tumors in 26 dogs. PROCEDURES: Before excision, tumors were evaluated via B-mode and color Doppler ultrasonography to assess size, echogenicity, echopattern, acoustic transmission, invasiveness, and vascularity. Paraffin-embedded microsections of the tumors were stained with H&E and examined for presence of necrosis, cysts, cartilage, bone, mineralization, invasion of surrounding tissue, and tissue heterogeneity. To assess vascularity, the number and distribution of vessels that were stained by the Verhoeff van Gieson technique were recorded. RESULTS: Tumor echogenicity and echopattern on ultrasonographic images correlated with tissue heterogeneity detected histologically. Acoustic enhancement was correlated with the presence of necrotic or cystic areas. Tumor invasion into surrounding tissues as determined ultrasonographically did not correlate with the histologic findings. There was a significant correlation between the number of detected vessels and distribution of flow within the tumors determined via ultrasonographic and histologic examinations. CONCLUSIONS AND CLINICAL RELEVANCE: In canine mammary tumors, ultrasonographic characteristics appear to be correlated with histopathologic changes. Data suggest that ultrasonography may have an important role in the evaluation of mammary tumors in dogs, particularly in the evaluation of tissue composition and tumor vascularity.


Subject(s)
Dog Diseases/diagnostic imaging , Mammary Neoplasms, Animal/diagnostic imaging , Adenoma/diagnosis , Adenoma/diagnostic imaging , Adenoma/veterinary , Animals , Carcinoma/diagnosis , Carcinoma/diagnostic imaging , Carcinoma/veterinary , Dog Diseases/diagnosis , Dog Diseases/pathology , Dogs , Female , Hyperplasia/diagnosis , Hyperplasia/diagnostic imaging , Hyperplasia/veterinary , Mammary Neoplasms, Animal/diagnosis , Mammary Neoplasms, Animal/pathology , Ultrasonography
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