Modifying Effects of Various Chemicals on Preneoplastic and Neoplastic Lesion Development in a Wide-spectrum Organ Carcinogenesis Model Using F344 Rats

Modifying potentials of various chemicals on tumor development were investigated in a wide-spectrum organ carcinogenesis model using male F344/DuCrj rats. The animals were treated with N-nitroso-diethylamine (100 mg/kg body weight, ip, single injection at the commencement of the study), N-methyl-N-nitrosourea (20 mg/kg body weight, ip, 4 times during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in drinking water, during weeks 3 and 4) for multi-organ initiation and then were given one of 14 test chemicals including 6 hepatocarcinogens, 7 non-hepatocarcinogens and 1 non-carcinogen, or basal diet for 16 weeks. All rats were killed at the end of week 20, and the major organs were carefully examined for preneoplastic and neoplastic lesions. Immunohistochemical demonstration of glutathione S -transferase-positivc foci was also used for quantitative assessment of liver preneoplastic lesion development. Modifying effects were shown for 11 out of 14 test agents in the liver, forestomach, glandular stomach, lung, urinary bladder or thyroid, 7 of them targeting more than two organs. This was the first demonstration to our knowledge that cloflbrate possesses enhancing potential for urinary bladder carcinogenesis and an inhibiting effect on thyroid carcinogenesis. Caprolactam showed no effect in any organ, in agreement with its established inactivity. The results indicated that the system could be reliably applied as a medium-term multiple organ bioassay for assessment of the modification potential of test agents in unknown target sites.     

Aneuploidy of chromosome 20 in invasive breast cancer correlates with poor outcome

Breast carcinoma is a genetically and phenotypically heterogeneous disease and is frequently associated with nonrandom chromosomal alterations. The aim of this study was to investigate the numerical aberrations of chromosome 20 in breast cancer. The observed chromosome-specific numerical abnormalities were evaluated along with the established clinicopathological parameters, the immunohistochemical expression of ER, PR, p53, c-erbB-2, Ki-67 and patients' survival. Nonisotopic in situ hybridization was applied to interphase cell nuclei on paraffin embedded tissue sections. Polysomy of chromosome 20 was the prevalent alteration in 45 of 50 (90%), monosomy in 2 of 50 (4%) and disomy in 3 of 50 (6%) cases. Invasive ductal carcinomas displayed a higher percentage of polysomy than lobular ones. A statistical significant association was demonstrated between Ki-67 immunohistochemical expression and polysomy of chromosome 20. Disomy was inversely correlated with Ki-67, while monosomy was suggestively associated with PR positive expression. Among the patients, those with the highest levels of polysomy showed the worst survival. In conclusion, the gain of chromosome 20 is the prevalent aberration in patients with breast carcinomas and may be useful prognostic marker in breast cancer.     

Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

Tissue inhibitor of metalloproteinase-1 (TIMP-1) has emerged as a multifunctional protein with the contrasting activities of inhibiting tissue-degrading enzymes and promoting cellular growth. In an attempt to elucidate the clinical significance of TIMP-1 in breast cancer, the expression of TIMP-1 mRNA was evaluated in 117 invasive breast carcinomas by mRNA in situ hybridization, in correlation with clinicopathological parameters, immunohistochemical prognostic factors (Ki-67, c-erb-B-2, bcl-2) and clinical outcome. TIMP-1 was detected in stromal cells in areas within the tumours and at the tumour margin. High TIMP-1 mRNA expression in the marginal portion of the tumours was significantly correlated with lymph node metastasis (p<0.05) and c-erbB-2 expression (p<0.05). On the other hand, increased TIMP-1 mRNA expression within the tumours showed a statistically significant correlation with ER detection (p<0.01). Multivariate analysis revealed worse survival for patients with high TIMP-1 mRNA expression in the marginal portion of the tumours; the subgroup of these patients co-expressing high levels of TIMP-1 mRNA within the tumours as well had even worse survival (p=0.042). In conclusion, our data support the multifunctional role of TIMP-1, particularly its growth-promoting activity, on the basis of its significant correlation with lymph node metastasis and adverse prognosis. In addition to the latter property, a probable association of TIMP-1 with tumour cell differentiation is suggested by its topographical correlation with ER detection.     

The development of excitatory transmitter amino acid-containing neurons in the rat visual cortex

The excitatory amino acids l-glutamate and l-aspartate are believed to be utilized as neurotransmitters by the pyramidal neurons in the mammalian cerebral cortex. These cells can be recognized early in development, while glutamate might play an important part in the maturation and plasticity of the cortex. Here, we used light and electron microscopic immunocytochemistry to study the time of appearance and maturation of glutamate and aspartate in neurons of the rat visual cortex. Glutamate- and aspartate-immunoreactive cells were first detected in deep cortical layers at postnatal day 3. During the next 3 weeks, labelled neurons were observed progressively in more superficial layers, but did not demonstrate their adult pattern of distribution until postnatal week 4. Electron microscopic analysis showed that glutamate- and aspartate-labelled neurons gradually develop their cytological and synaptic features during the first 4 postnatal weeks, with this process of differentiation originating in the deep cortical layers and progressively extending to the superficial layers. These findings suggest that cortical pyramidal neurons begin to express detectable levels of transmitter glutamate and/or aspartate after they have completed their migration. Their neurochemical differentiation follows an inside-out pattern similar to the pattern described for the genesis and morphological differentiation of this population of cortical neurons.     

Case report: Role of hepatitis E virus in the etiology of community-acquired non-A,non-B hepatitis in greece

The aim of this study was to determine the frequency of hepatitis E virus (HEV) infection in a population of Greek adults with community-acquired (sporadic) non-A, non-B hepatitis found to be seronegative for antibodies to hepatitis C virus (anti-HCV). All patients admitted to the Liver Unit of Western Attica General Hospital and diagnosed as having acute community-acquired non-A, non-B hepatitis between February, 1986, and May, 1990, were enrolled in follow up studies (n = 66). Nineteen patients with HCV infection and 11 patients with acute non-A, non-B, non-C hepatitis that progressed to chronicity were excluded. Convalescent sera were tested for antibody to HEV (anti-HEV) by a fluorescent antibody blocking assay in 33 of 36 eligible patients. One of the 33 (3%) patients was found to be positive for anti-HEV. Anti-HEV testing of all 20 available serum specimens from this patient showed evidence of anti-HEV seroconversion at the fourth week after the onset of hepatitis. The patient had not travelled abroad or within Greece or had not had apparent contact with people from foreign countries for the previous 3 months. These data show that HEV infection is not a major cause of community-acquired non-A, non-B hepatitis in Greece. However, the reported case of HEV hepatitis suggests that HEV may retain a low endemicity in Greece. More extensive seroprevalence studies are needed for an accurate estimation of the extent of HEV infection in the southeastern European countries. © 1994 Wiiey-Liss, Inc.     

“Aggressive” Feeding of Very Preterm Neonates and Body Mass Index at School Age

Introduction: The effects of “aggressive” neonatal feeding policies of very preterm neonates (VPN) and the risk of metabolic syndrome later in life remain questionable. We aimed to evaluate the effect of our “aggressive” nutrition policies of VPN during hospitalisation on body mass index (BMI) at ages 2 and 8 years. Materials and Methods: Eighty four VPN, who received “aggressive” nutrition during hospitalisation in an effort to minimise postnatal growth restriction (PGR) (group A), and 62 term neonates, as controls (group B), were enrolled in the study. Group A was further divided in four subgroups depending on the type (A1: fortified expressed breast milk and preterm formula; A2: exclusively preterm formula) and quantity of milk received (A3: maximum feeds 180–210 mL/kg/day; A4: maximum feeds 210 and up to 260 mL/kg/day). BMI was calculated at ages 2 and 8 years and plotted on the centile charts. Results: There was no significant difference in BMI between groups A and B at 2 and 8 years, respectively, in both absolute BMI values and their centile chart distribution. There was no significant difference in BMI at 2 and 8 years either between subgroups A1 and A2 or between subgroups A3 and A4. Conclusions: “Aggressive” and individualised feeding policy for VPN did not affect the BMI and obesity rates at ages of 2 and 8 years in our study population. The type and quantity of milk feeds had no impact on their BMI at school age. Further larger studies are needed to confirm our results.     

Correction to: A systematic review of economic evaluations of enzyme replacement therapy in Lysosomal storage diseases

In December 2019, the Digital Health Care Act (“Digitale-Versorgung-Gesetz”) introduced a general entitlement to the provision and reimbursement of digital health applications (DiGA) for insured persons in the German statutory health insurance. As establishing a new digital service area within the solidarity-based insurance system implies several administrative and regulatory challenges, this paper aims to describe the legal framework for DiGA market access and pricing as well as the status quo of the DiGA market. Furthermore, we provide a basic approach to deriving value-based DiGA prices. To become eligible for reimbursement, the Federal Institute for Drugs and Medical Devices evaluates the compliance of a DiGA with general requirements (e.g., safety and data protection) and its positive healthcare effects (i.e., medical benefit or improvements of care structure and processes) in a fast-track process. Manufacturers may provide evidence for the benefits of their DiGA either directly with the application for the fast-track process or generate it during a trial phase that includes temporary reimbursement. After one year of \]reimbursement, the freely-set manufacturer price is replaced by a price negotiated between the National Association of Statutory Health Insurance Funds and the manufacturer. By February 2022, 30 DiGA had successfully completed the fast-track process. 73% make use of the trial phase and have not yet proven their benefit. Given this dynamic growth of the DiGA market and the low minimum evidence standards, fair pricing remains the central point of contention. The regulatory framework makes the patient-relevant benefits of a DiGA a pricing criterion to be considered in particular. Yet, it does not indicate how the benefits of a DiGA should be translated into a reasonable price. Our evidence-based approach to value-based DiGA pricing approximates the SHI’s willingness to pay by the average cost-effectiveness of one or more established therapy in a field of indication and furthermore considers the positive healthcare effects of a DiGA. The proposed approach can be fitted into DiGA pricing processes under the given regulatory framework and can provide objective guidance for price negotiations. However, it is only one piece of the pricing puzzle, and numerous methodological and procedural issues related to DiGA pricing are still open. Thus, it remains to be seen to what extent DiGA prices will follow the premise of value-based pricing.     

Editorial Commentary: Evidence-Based Guidelines for Management of the Hip Capsule During Arthroscopy: Has It Become Personal?

The management of the capsule during hip arthroscopy for femoroacetabular impingement syndrome has been in the spotlight during the last decade. Although there is robust biomechanical evidence that preserving the anatomic integrity of the iliofemoral ligament is important for the stability of the hip joint, the effect of capsular management on patient outcomes is often debated in clinical studies. Mid-term and long-term follow-up studies have shown that capsular closure is associated with decreased risk of hip arthroscopy failure, but no difference in patient outcomes based on capsular management has been found by some case series studies. What is driving the controversy in the literature? It seems to stem from the variation in surgical techniques used to perform hip capsulotomy or capsular repair, worldwide. Given that improvement in patient outcomes must be prioritized, it is time to use the existing knowledge appropriately to establish evidence-based guidelines for the management of hip capsule during hip arthroscopy.