International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (M. fascicularis).

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Mass spectrometry imaging reveals lipid upregulation and bile acid changes indicating amitriptyline induced steatosis in a rat model.

As a consequence of the detoxification process, drugs and drug related metabolites can accumulate in the liver, resulting in drug induced liver injury (DILI), which is the major cause for dose limitation. Amitriptyline, a commonly used tricyclic anti-depressant, is known to cause DILI. The mechanism of Amitriptyline induced liver injury is not yet completely understood. However, as it undergoes extensive hepatic metabolism, unraveling the molecular changes in the liver upon Amitriptyline treatment can help understand Amitriptyline's mode of toxicity. In this study, Amitriptyline treated male rat liver tissue was analyzed using Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) to investigate the spatial abundances of Amitriptyline, lipids, and bile acids. The metabolism of Amitriptyline in liver tissue was successfully demonstrated, as the spatial distribution of Amitriptyline and its metabolites localize throughout treatment group liver samples. Several lipids appear upregulated, from which nine were identified as distinct phosphatidylcholine (PC) species. The detected bile acids were found to be lower in Amitriptyline treatment group. The combined results from histological findings, Oil Red O staining, and lipid zonation by MSI revealed lipid upregulation in the periportal area indicating drug induced macrovesicular steatosis (DIS).

Quantitative targeted bile acid profiling as new markers for DILI in a model of methapyrilene-induced liver injury in rats.

Recently, bile acids (BAs) were reported as promising markers for drug-induced liver injury (DILI). BAs have been suggested to correlate with hepatocellular and hepatobiliary damage; however a clear connection of BA patterns with different types of DILI remains to be established. To investigate if BAs can improve the assessment of liver injury, 20 specific BAs were quantitatively profiled via LC-MS/MS in plasma and liver tissue in a model of methapyrilene-induced liver injury in rats. Methapyrilene, a known hepatotoxin was dosed daily over 14-days at doses of 30 and 80mg/kg, followed by a recovery phase of 10days. Conventional preclinical safety endpoints were related to BA perturbations and to hepatic gene expression profiling for a mechanistic interpretation of effects. Histopathological signs of hepatocellular and hepatobiliary damage with significant changes of clinical chemistry markers were accompanied by significantly increased levels of indivdual BAs in plasma and liver tissue. BA perturbations were already evident at the earliest time point after 30mg/kg treatment, and thereby indicating better sensitivity than clinical chemistry parameters. Furthermore, the latter markers suggested recovery of liver injury, whereas BA levels in plasma and liver remained significantly elevated during the recovery phase, in line with persistent histopathological findings of bile duct hyperplasia (BDH) and bile pigment deposition. Gene expression profiling revealed downregulation of genes involved in BA synthesis (AMACR, BAAT, ACOX2) and hepatocellular uptake (NTCP, OATs), and upregulation for efflux transporters (MRP2, MRP4), suggesting an adaptive hepatocellular protection mechanism against cytotoxic bile acid accumulation. In summary, our data suggests that specific BAs with high reliability such as cholic acid (CA) and chenodeoxycholic acid (CDCA) followed by glycocholic acid (GCA), taurocholic acid (TCA) and deoxycholic acid (DCA) can serve as additional biomarkers for hepatocellular/hepatobiliary damage in the liver in rat toxicity studies.

Use of locally delivered dequalinium chloride in the treatment of vaginal infections: a review.

BACKGROUND: Vaginal infections are responsible for a large proportion of gynaecological outpatient visits. Those are bacterial vaginosis (BV), vulvovaginal candidosis (VVC), aerobic vaginitis (AV) associated with aerobic bacteria, and mixed infections. Usual treatments show similar acceptable short-term efficacy, but frequent recurrences and increasing microbial resistance are unsolved issues. Furthermore, vaginal infections are associated with a variety of serious adverse outcomes in pregnancy and generally have a major impact on quality of life. Identifying the correct therapy can be challenging for the clinician, particularly in mixed infections. FINDINGS: Dequalinium chloride (DQC) is an anti-microbial antiseptic agent with a broad bactericidal and fungicidal activity. Systemic absorption after vaginal application of DQC is very low and systemic effects negligible. Vaginal DQC (Fluomizin vaginal tablets) has been shown to have equal clinical efficacy as clindamycin in the treatment of BV. Its broad antimicrobial activity makes it appropriate for the treatment of mixed vaginal infections and in case of uncertain diagnosis. Moreover, resistance of pathogens is unlikely due to its multiple mode of action, and vaginal DQC provides also a reduced risk for post-treatment vaginal infections. CONCLUSIONS: Vaginal DQC (10 mg) as 6-day therapy offers a safe and effective option for empiric therapy of different vaginal infections in daily practice. This review summarizes the available and relevant pharmacological and clinical data for the therapy of vaginal infections with vaginal DQC and provides the rationale for its use in daily gynaecologic practice.

HPV vaccination: acceptance and influencing factors among young men in Germany.

AIMS: This study aims to determine the factors that influence the acceptance of the HPV vaccination among German males. PATIENT & METHODS: In 2014, we conducted a population-based cross-sectional study in men aged 15-25 years. A questionnaire was mailed to male trainees of the Bayerische Motorenwerke AG (BMW) insured at the BMW health insurance company. RESULTS: The response rate was 10.8%. Of the 378 included men, 74.1% would agree to receive HPV vaccination. Most men primarily consult their physician for health-related topics, but 92.9% had never been informed about HPV infection, risk factors and prevention methods by their doctor. CONCLUSION: Our results demonstrate a high acceptance of male HPV vaccination. Education about HPV infection is low and should be intensified by medical professionals.

The osmolality of nonionic, iodinated contrast agents as an important factor for renal safety.

OBJECTIVE: Nonionic iodinated contrast agents (CAs) can be divided into monomeric, low-osmolar, and dimeric, iso-osmolar classes. In clinical practice, renal tolerance of CAs is a concern, especially in patients with impaired renal function. With regard to renal safety, we wanted to evaluate the role of osmolality and viscosity in renal tolerance. MATERIAL AND METHODS: We generated a formulation (iodixanol/mannitol) consisting of the dimeric iodixanol with an osmolality of the monomeric iopromide. Male Han-Wistar rats were intravenously injected with low-osmolar iopromide 300, iso-osmolar iodixanol 320, and iodixanol/mannitol. Saline and diatrizoate were used as controls. A total number of 227 rats were used in the following experiments. We compared the impact of osmolality on renal iodine retention using computed tomography 2 and 24 hours postinjection (p.i.). The animals were killed 2, 24, and 72 hours after injection, and the kidneys were excised for further investigations. Changes in renal cell proliferation were analyzed by 5-bromo-2'-deoxyuridine incorporation 48 hours p.i. as a degree of tissue regeneration after induced injury. To specify potential renal injury, we quantified the expression of acute kidney injury (AKI) markers (kidney injury marker-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and plasminogen activator inhibitor-1 [PAI-1]) by quantitative real-time polymerase chain reaction. Furthermore, the kidneys were analyzed histologically, including immunofluorescence analysis. RESULTS: After intravenous application of the CAs into Han-Wistar rats, renal iodine concentration was increased (3-fold) for iodixanol 2 hours p.i. and iodine retention was detected to be prolonged 24 hours p.i. compared with iopromide injection (iodixanol, 520 ± 50 Hounsfield Units [HU] vs iopromide, 42 ± 5 HU). The higher iodine concentration 2 hours p.i. upon iodixanol injection was reduced almost to the level of iopromide when injecting iodixanol/mannitol (iopromide: 289 ± 68 HU vs iodixanol/mannitol: 343 ± 68 HU). In addition, iodixanol application induced increased renal cell proliferation (2.7-fold vs saline), indicating renal injury, which was significantly lower in iopromide-treated animals (1.6-fold vs saline). More detailed analysis of markers for AKI revealed that iodixanol significantly induced the expression of PAI-1 (7.7-fold at 2 hours) as well as KIM-1 (2.1-fold) and NGAL (3.2-fold) at 2 and 24 hours when compared with saline treatment. In contrast, the expression of markers for AKI was low after iopromide (1.4-fold NGAL, 1.7-fold PAI-1, KIM-1 not significant) and iodixanol/mannitol (1.6-fold NGAL, 2.6-fold PAI-1, KIM-1 not significant) injection. CONCLUSION: The present results clearly show that prolonged iodine retention and the enhanced expression of kidney injury markers are caused mainly by the explicitly higher urine viscosity induced by iodixanol. We conclude that the osmolality of low-osmolar CAs such as iopromide induces a positive diuretic effect that is responsible for rapid iodine clearance and prevents increased expression of acute injury markers in the kidney.

A comparison of dequalinium chloride vaginal tablets (Fluomizin®) and clindamycin vaginal cream in the treatment of bacterial vaginosis: a single-blind, randomized clinical trial of efficacy and safety.

AIMS: To investigate if vaginal application of dequalinium chloride (DQC, Fluomizin®) is as effective as vaginal clindamycin (CLM) in the treatment of bacterial vaginosis (BV). METHODS: This was a multinational, multicenter, single-blind, randomized trial in 15 centers, including 321 women. They were randomized to either vaginal DQC tablets or vaginal CLM cream. Follow-up visits were 1 week and 1 month after treatment. Clinical cure based on Amsel's criteria was the primary outcome. Secondary outcomes were rate of treatment failures and recurrences, incidence of post-treatment vulvovaginal candidosis (VVC), lactobacillary grade (LBG), total symptom score (TSC), and safety. RESULTS: Cure rates with DQC (C1: 81.5%, C2: 79.5%) were as high as with CLM (C1: 78.4%, C2: 77.6%). Thus, the treatment with DQC had equal efficacy as CLM cream. A trend to less common post-treatment VVC in the DQC-treated women was observed (DQC: 2.5%, CLM: 7.7%; p = 0.06). Both treatments were well tolerated with no serious adverse events occurring. CONCLUSION: Vaginal DQC has been shown to be equally effective as CLM cream, to be well tolerated with no systemic safety concerns, and is therefore a valid alternative therapy for women with BV [ClinicalTrials.gov, Med380104, NCT01125410].

A review of preclinical safety data for magnevist (gadopentetate dimeglumine) in the context of nephrogenic systemic fibrosis.

OBJECTIVES: Magnevist (gadopentetate dimeglumine, Bayer Healthcare, Bayer) is a gadolinium-based contrast agent (GBCA) for magnetic resonance imaging approved for clinical use in various indications since 1988. A possible association between the administration of GBCAs to patients with severe kidney impairment, and a condition first identified in 2000 and later described as "nephrogenic systemic fibrosis" (NSF), was published in early 2006. In the light of this reported association and the published histologic findings of certain NSF patients, Bayer, with support of external experts, reassessed the preclinical safety data from in vivo studies in healthy rats and dogs that were conducted with Magnevist during the drug development process in the mid-80s. These studies, which were performed according to standard regulatory requirements as defined in pertinent guidelines and which were conducted before the reported association between GBCAs and NSF, were not specifically designed to detect NSF-like lesions. Instead, the intention of this reassessment was to analyze whether the acquired knowledge on NSF would lead to a revised interpretation of the original preclinical data. MATERIALS AND METHODS: Studies on repeat-dose toxicity of Magnevist performed in the mid-80s with healthy rats and dogs were re-evaluated, with special emphasis on the retrospective analysis of morphologic findings which have come to be considered potentially suggestive of NSF. In particular, histologic slides of the skin of repeat-dose toxicity studies were re-examined by Bayer pathologists, with a special focus on the occurrence of morphologic lesions that have subsequently been identified as consistent with NSF. In addition, slides from selected studies were also subjected to a blinded external peer review by an independent international Pathology Working Group. RESULTS: A review of the preclinical data from the repeated-dose toxicity studies provided no evidence for toxicological effects after administration of Magnevist, which could be construed as suggestive of or consistent with NSF. More specifically, histopathology peer reviews of skin samples from repeated-dose toxicity studies with rats and dogs revealed no signs of skin lesions even after repeated high-dose administration to rats of 5.0 mmol Gd/kg of Magnevist (50 times the standard diagnostic dose). CONCLUSIONS: No findings were observed in any of the preclinical studies with Magnevist in healthy rats and dogs which could be characterized as similar to the types of morphologic lesions that have subsequently been identified as consistent with NSF. This preclinical assessment is in contrast to the reported clinical evidence of rare NSF cases in patients with severe kidney impairment after Magnevist administration. The differences between the preclinical models and their predictive limitations with regard to the clinical situation of renally impaired patients are discussed.

Thyroid Dysplasia in Wistar Hannover GALAS Rats.

Thyroid dysplasia was recognized in WistarHan GALAS rats and confirmed as a heritable congenital disorder. The gene or genes involved were not identified, but homozygous animals with thyroid dysplasia also exhibited stunted growth, had reduced pituitary gland growth hormone (GH) and were hypothyroid. Heterozygous animals exhibited thyroid dysplasia with normal thyroid hormonal homeostasis and no difference in the incidence of preneoplastic or neoplastic lesions in oncogenicity studies.

Symptom-oriented follow-up of early breast cancer is not inferior to conventional control. Results of a prospective multicentre study.

BACKGROUND: The homogeneity of the schemes for follow-up care after curative surgical treatment of early breast cancer is still a matter of debate in Germany. We investigated whether symptom-oriented follow-up is equivalent in terms of survival rates to conventional surveillance based on scheduled tests. PATIENTS AND METHODS: In a prospective, non-randomised, multicentre cohort study carried out between 1995 and 2000, 244 patients underwent a conventional follow-up (scheduled laboratory tests including CEA and CA 15-3, chest X-rays and liver ultrasound). 426 patients were monitored in a symptom-oriented manner (additional tests only in the case of symptoms indicating possible recurrence). Mammography, structured histories and physical examinations were done regularly in both branches. 1,108 patients did not participate in the project. They represent 'real world patients', unaffected by the implications of a study. RESULTS: The symptom-oriented follow- up group produced results not inferior to those of the intensive one (p < 0.05) in terms of overall and relapse-free survival. Furthermore, no difference was indicated in terms of overall survival between study participants and the 'real world patients' (p = 0.316). CONCLUSION: The results confirm that regular imaging and laboratory tests have no relevant effect on overall survival of patients after curative primary therapy of early breast cancer and support the implementation of a symptom-oriented routine follow-up.

Comparison of the skeletal effects of the progestogens desogestrel and levonorgestrel in oral contraceptive preparations in young women: controlled, open, partly randomized investigation over 13 cycles.

AIM: This 12-month study was conducted to evaluate the skeletal effects of two monophasic oral contraceptives containing 20 mug of ethinylestradiol and 100 mug of levonorgestrel (LEVO) or 150 mug of desogestrel (DESO). METHODS: Fifty-two women (18-24 years) were randomized into the DESO group or the LEVO group; 36 women served as controls. The areal bone mineral density (aBMD) of the femoral neck and the lumbar spine was evaluated by DXA, and parameters of bone geometry and volumetric bone mineral density (vBMD) were assessed by peripheral quantitative computed tomography at the distal radius and the tibia. RESULTS: The LEVO group did not lose vertebral aBMD, whereas women in the DESO group lost 1.5%. At the distal radius and the tibia (shank level, 14%), LEVO induced an increase in total cross-sectional area, indicating increased periosteal bone formation. Radial trabecular vBMD declined by 1.4+/-1.8% in the DESO group, while it remained unchanged in the LEVO group. CONCLUSION: Our study suggests that the skeletal effects of OC preparations may be influenced by progestogenic components in young women.

[Knee arthrodesis with external ring fixator after infected knee arthroplasty]. / Knaeartrodese med ekstern ringfiksator efter inficeret knaealloplastik.

INTRODUCTION: Infection following knee arthroplasty is a severe complication which may lead to arthrodesis or even amputation. We wanted to examine the results after arthrodesis of the knee using the Ilizarov ring fixator in eight patients. MATERIALS AND METHODS: Eight patients (seven females, one male) who underwent knee arthrodesis with the Ilizarov external fixator were studied retrospectively. Their median age was 63 (51-84) years. The mean follow-up period after removal of the fixator was 10 months. RESULTS: Six arthrodeses healed without further operation. One patient died before the end of follow-up. One patient had an above-knee amputation because of chronic infection. Associated complications were the complications/problems which are already well known. DISCUSSION: The Ilizarov ring fixator is a reliable method for performing arthrodesis after removal of an infected total knee arthroplasty.

Ablation of Ca(v)2.3 / E-type voltage-gated calcium channel results in cardiac arrhythmia and altered autonomic control within the murine cardiovascular system.

Voltage-gated calcium channels are key components in cardiac electrophysiology. We demonstrate that Ca(v)2.3 is expressed in mouse and human heart and that mice lacking the Ca(v)2.3 voltage-gated calcium channel exhibit severe alterations in cardiac function. Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the expression of three different Ca(v)2.3 splice variants. The ablation of Ca(v)2.3 was found to be accompanied by a compensatory upregulation of the Ca(v)3.1 T-type calcium channel, while other voltage-gated calcium channels remained unaffected. Telemetric ECG recordings from Ca(v)2.3 deficient mice displayed subsidiary escape rhythm, altered atrial activation patterns, atrioventricular conduction disturbances and alteration in QRS-morphology. Furthermore, time domain analysis of heart rate variability (HRV) in Ca(v)2.3(-/-) mice exhibited a significant increase in heart rate as well as in the coefficient of variance (CV) compared to control mice. Administration of atropin/propranolol revealed that increased heart rate was due to enhanced sympathetic tonus and that partial decrease of CV in Ca(v)2.3(-/-) mice after autonomic block was in accordance with a complete abolishment of 2(nd) degree atrioventricular block. However, escape rhythms, atrial activation disturbances and QRS-dysmorphology remained unaffected, indicating that these are intrinsic cardiac features in Ca(v)2.3(-/-) mice. We conclude that the expression of Ca(v)2.3 is essential for normal impulse generation and conduction in murine heart.

Age at first oral contraceptive use as a major determinant of vertebral bone mass in female endurance athletes.

It was the aim of this retrospective analysis to examine the influence of low-dose monophasic oral contraceptives (OCs) on bone mineral density (BMD) of the femoral neck and of the spine in young female endurance athletes. Data on training intensity, dietary intake, menarche, menstrual cycle disorders, years of OC use, and age at first OC use were determined by a self-report questionnaire. Only athletes performing regular endurance exercise for more than 3 years with more than 3 h of exercise per week were included in this study and underwent a clinical assessment including measurement of weight, height, spine, and hip BMD by dual-energy X-ray absorptiometry, and collection of a blood sample. The data from 75 regularly exercising endurance athletes aged 18-35 years (26.5 +/- 4.8 years) were initially included in this analysis. Six athletes were later excluded due to oligo-/amenorrhea. Subjects were allocated into the OC group when they reported OC use for more than 3 years in women younger than 22 years of age, or when they reported OC use for more than 50% of the time after menarche in women aged 22-35 years. There were no differences in age, weight, height, body mass index (BMI), body fat, menarche, training intensity, age at start of training, or any serum parameters between OC users (n = 31) and control subjects (n = 38). However, OC users had 7.9% lower spine BMD and 8.8% lower proximal femur BMD (P < 0.01 for both sites). When the relationship between BMD of the spine and OC use was further analyzed by a stepwise model of multiple regression analysis using OC years, age at OC initiation, BMI, and menarche as independent variables, age at first OC use was found to be the best predictor of vertebral BMD, while the only significant predictor of femoral neck BMD was BMI. We conclude that OC use is associated with decreased BMD of the spine and the femoral neck in female endurance athletes, and that early age at initiation of OC use may be an important risk factor for low peak bone mass in young women.