Enhancing effect of chitosan on peptide drug delivery across buccal mucosa

The buccal mucosa represents a potentially important topical route for delivery of peptide or protein drugs with some unique advantages such as the avoidance of hepatic first-pass metabolism and the acidity and protease activity encountered in the gastrointestinal tract. However, the bioavailabilities or relative potencies of intraorally administered peptides are usually quite low, unless permeabilizers are employed. Chitosan, a mucopolysaccharide of marine origin, has been claimed to act both as a bioadhesive and permeabilizer, making it a candidate system for mucosal drug delivery. In this study, the enhancement effect of chitosan in gel form for oral mucosa was investigated with a large bioactive peptide, transforming growth factor-beta (TGF-beta). Chitosan gel was prepared at 2% concentration in dilute lactic acid and TGF-beta was incorporated into the gel. The effect of chitosan as a permeabilizer was determined by measuring the flux of TGF-beta across porcine oral mucosa in an in vitro system. The localization of TGF-beta within the oral mucosa was determined by horizontal sectioning and counting. Chitosan was found to exert a marked permeabilizing effect on buccal mucosa for peptide drug.     

The blood vessel supply of the testis in Pekin drakes (Anas platyrhynchos L.). Macroscopic, light microscopic and scanning electron microscopic studies

Testes of Pekin ducks were macerated following injection with plastic at the period of maximal spermatogenesis which occurs during spring. The right and left A. testicularis arise from the A. renalis cranialis. The right testis is additionally supplied by an irregularly occurring A. testicularis accessoria. After penetrating the testicular capsule the arteries run to the centre of the testis and terminate as branching Aa. radiatae centrifugales. The seminiferous tubules are surrounded by intertubular and peritubular capillaries forming a rope-ladder-like system. Venules and veins run peripherally to enter the vein converge into the testicular hilus, and unite to form 2 Vv. testiculares which empty into the V. cava caudalis. Regulation of testicular blood supply is achieved by throttle devices depending on the avian seasonal cycle. The coiled and step-like course of the vessels results in a sufficient contact between blood and seminiferous tubules. Testicular veins surrounding the arteries might be an equivalent of the steroid transfer mechanism in the mammalian spermatic cord.     

Survival prediction of glioblastoma patients—are we there yet? A systematic review of prognostic modeling for glioblastoma and its clinical potential

Glioblastoma is associated with a poor prognosis. Even though survival statistics are well-described at the population level, it remains challenging to predict the prognosis of an individual patient despite the increasing number of prognostic models. The aim of this study is to systematically review the literature on prognostic modeling in glioblastoma patients. A systematic literature search was performed to identify all relevant studies that developed a prognostic model for predicting overall survival in glioblastoma patients following the PRISMA guidelines. Participants, type of input, algorithm type, validation, and testing procedures were reviewed per prognostic model. Among 595 citations, 27 studies were included for qualitative review. The included studies developed and evaluated a total of 59 models, of which only seven were externally validated in a different patient cohort. The predictive performance among these studies varied widely according to the AUC (0.58–0.98), accuracy (0.69–0.98), and C-index (0.66–0.70). Three studies deployed their model as an online prediction tool, all of which were based on a statistical algorithm. The increasing performance of survival prediction models will aid personalized clinical decision-making in glioblastoma patients. The scientific realm is gravitating towards the use of machine learning models developed on high-dimensional data, often with promising results. However, none of these models has been implemented into clinical care. To facilitate the clinical implementation of high-performing survival prediction models, future efforts should focus on harmonizing data acquisition methods, improving model interpretability, and externally validating these models in multicentered, prospective fashion.

     

No evidence for paternal mtDNA transmission to offspring or extra-embryonic tissues after ICSI

There is a risk that ICSI may increase the transmission of mtDNA diseases to children born after this technique. Knowledge of the fate and transmission of paternal mitochondrial DNA is important since mutations in mitochondrial DNA have been described in oligozoospermic males. We have used an adaptation of solid phase mini-sequencing to exclude the presence of levels of paternal mtDNA >0.001% in ICSI families. This method is more sensitive than those used in previous studies and is sufficient to detect the likely paternal contribution (approximately 0.1-0.5% from simple calculations of expected dilution during fertilization). Using this method, we were able to detect concentrations as low as 0.001% paternal mtDNA in a maternal mtDNA background. No paternal mtDNA was detected in the embryonic (blood or buccal swabs) tissue of children born after ICSI nor in extra-embryonic tissue (placenta or umbilical cord). In conclusion, we did not detect paternal mtDNA in blood, buccal swabs, placenta or umbilical cord of children born after ICSI. We have found no evidence that ICSI increases the risk of paternal transmission of mtDNA and hence of mtDNA disorders.     

Response of multicellular tumor spheroids to liposomes containing TNF-α

Summary This publication describes a new model to investigate the influence of tumor necrosis factor- (TNF-) on a three-dimensional glial cell aggregate under defined, standardized, reproducible conditions using the glioma cell line A 172.The cells are initially grown as normal monolayer culture until they reach a cell density of up to 1×10⁶. Subsequently they are grown as spheroids by the liquid overlay technique. Spheroids grown in this way were divided into ten groups of more than 50 cell aggregates. Three groups were coincubated with free TNF- in increasing dosages (100 ng/ml, 200 ng/ml and 1000 ng/ml); three groups were incubated with empty liposomes (0.2 mg/ml, 0.4 mg/ml and 2 mg/ml); three groups received liposomes which had been loaded with TNF-, and one group, which received no treatment, served as control.The diameter of the spheroids ranged from 80 m to 350 m. There was no significant difference in growth between the 3 groups treated with free TNF-. Comparing spheroids treated with TNF- with those which had been coincubated with empty liposomes, there was a significant difference (p<0.001) in growth, which correlated with the amount of liposomes. Similarly, free TNF- had a significantly (P<0.001) stronger growth-inhibiting effect as compared to liposomes loaded with TNF-. Comparing the groups treated with liposomes only to those treated with liposomes loaded with TNF-, the latter exhibited a more marked (although not significantly) growth-inhibiting effect.The preliminary conclusion is that the major growth-inhibiting effect seems to be mediated by the liposomes. This phenomenon is in agreement with results obtained in monolayer cultures.     

Overdrainage and shunt technology

When vertical body position is simulated, conventional differential pressure valves show an absolutely unphysiological flow, which is 2–170 times the normal liquor production rate. Although this is compensated in part by the resistance of the silicon tubes, which may produce up to 94% of the resistance of the complete shunt system, a negative intracranial pressure (ICP) of up to 30–44 cmH₂O is an unavoidable consequence, which can be followed by subdural hematomas, slit ventricles, and other well-known complications. Modern shunt technology offers programmable, hydrostatic, and flow-controlled valves and anti-siphon devices; we have tested 13 different designs from 7 manufacturers (56 specimens), using the Heidelberg Valve Test Inventory with 16 subtests. Programmable valves reduce, but cannot exclude, unphysiological flow rates: even in the highest position and in combination with a standard catheter typical programmable Medos-Hakim valves allow a flow of 93–232 ml/h, Sophy SU-8-valves 86–168 ml/h with 30 cmH₂O. The effect of hydrostatic valves (Hakim-Lumbar, Chhabra) can be inactivated by movements of daily life. The weight of the metal balls in most valves was too low for adequate flow reduction. Antisiphon devices are highly dependent on external, i.e. subcutaneous, pressure which has unpredictable influences on shunt function, and clinically is sometimes followed by shunt insufficiency. Two new Orbis-Sigma valves showed relatively physiological flow rates even when the vertical position (30 cmH₂O) was simulated. One showed an insufficient flow (5.7 ml/h), and one was primarily obstructed. These have by far the smallest outlet of all valves. Additionally, the ruby pin tends to stick. Therefore, a high susceptibility to obliterations and blockade is unavoidable. Encouraging results obtained in pediatric patients contrast with disappointing experiences in some German and Swedish hospitals, which suggests that our laboratory findings are confirmed by clinical results. The concept of strict flow limitation seems to be inadaequate for adult patients, who need a relatively high flow during (nocturnal) ICP crises. The problem of shunt overdrainage remains unsolved.This paper is an updated version of an oral presentation held at the Consensus Conference: Hydrocephalus '92 Assisi, Italy, 26–30 April 1992Deceased     

Effects of female sex steroids on Parkinson's disease in postmenopausal women

There are conflicting reports about estrogen modulating the activity of nigrostriatal dopaminergic neurons. Furthermore, modulation may be influenced by progesterone levels. Therefore, the clinical effects of sex steroids on parkinsonian symptoms in postmenopausal women with Parkinson's disease (PD) were analyzed in the present study. Patients (n = 12) were under the age of 80, able to perform the motor function tests, and showed no contraindications for estrogen suppletion. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and a patient interview on subjective changes. In a placebo-controlled, randomized, double-blind trial lasting 8 weeks, no significant dopaminergic effect of estradiol (E2) could be demonstrated, whereas in an open trial phase lasting 2 weeks, progesterone seemed to have an antidopaminergic effect. Several mechanisms are discussed that can account for the fact that we found no effect of E2 on motor functioning in our patients with PD.     

3-Nitropropionic acid induces a spectrum of Huntington's disease-like neuropathology in rat striatum

Systemic administration of the mitochondrial toxin 3-nitropropionic acid (3-NP) to rats results in selective striatal lesions and serves as an experimental model of Huntington's disease (HD). However, the effects of the 3-NP treatment are unpredictable and result in lesions of variable severity. The present study was aimed at further characterizing the variability of the striatal lesions induced by systemic administration of 3-NP using osmotic pumps. Hematoxylin-eosin (HE) and Nissl stains as well as immunohistochemical labelling of astrocytes and striatal neurones were performed to analyse the neurotoxic effects of 3-NP. In general, chronic systemic administration of 3-NP resulted in obvious bilateral striatal lesions, which ranged from mild to severe, together with a subtle, but detectable behavioural lesion. Severe type lesions showed marked neuronal loss and an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes surrounding the lesion area, whereas in the core of the lesion GFAP-immunoreactivity was absent. The mild type lesion was characterized by a substantial loss of striatal neurones and an increased expression of GFAP-positive astrocytes throughout the lesion. In a number of 3-NP-treated animals, neither type of lesion was observed, although these animals demonstrated behavioural changes in the paw test compared to controls. In the striatum of these tested 3-NP-treated animals, compromised rk' neurones were detected, suggestive of subtle and early 3-NP-induced neuronal injury. Similar dark neurones were also detected in mild and severe lesions and were immunocytochemically characterized as gamma-aminobutyric acid (GABA) and substance P containing spiny neurones, which belong to the neuronal population that is affected in early HD. These results indicate that systemic administration of 3-NP to rats may result in a spectrum of striatal pathology of which the morphology of the mild type lesion resembles the characteristic HD neuropathology most closely.     

Quality of Life following Radical Surgical Treatment of Gastric Carcinoma

Quality of life (QOL) in patients with gastric cancer who underwent total gastrectomy has so far not been studied using the EORTC QLQ-C30 (Quality of Life Core Questionnaire of the European Organization for Research and Treatment of Cancer) as a standardized European QOL instrument. The aim of this study was to evaluate the effect of radical procedures such as extensive lymph node resection and combined resection of adjacent organs on patients' QOL. From 1992 to 1996, 152 patients underwent total gastrectomy. All patients alive on July 1, 1996 were included in the study (77/152). For assessing QOL, the EORTC QOL questionnaire QLQ-C30 version 2.0 and a validated gastric cancer module were sent home to the patients for self-completion. The response rate was 91%. It was possible to evaluate the questionnaires of 62 patients who had undergone resection with curative intent including 13 extended gastrectomies (21%). Of the 62 resections, 50 were combined with D2 lymphadenectomy (80.6%). The global health status was not negatively influenced by D2 lymphadenectomy and extended gastrectomy. Patients with splenectomy were more affected by treatment than patients without splenectomy. Radical gastrectomy combined with D2 lymphadenectomy is the treatment of choice for gastric cancer patients, concerning not just survival but QOL as well.