[Rheumatoid arthritis : These dermatoses lead you to the diagnosis]. / Rheumatoide Arthritis : Bei welchen Hautveränderungen sollte man daran denken?

BACKGROUND: Rheumatoid arthritis is one of the most common autoimmune disorders. In addition to chronic arthritis, rheumatoid arthritis may present a variety of extra-articular manifestations, most commonly of the skin. OBJECTIVES: Cutaneous manifestations associated with rheumatoid arthritis can be diverse, both specific and nonspecific. Which dermatoses should lead you to the diagnosis of an underlying rheumatoid arthritis? METHODS: Evaluation of exemplary overviews, case presentations and relevant textbook articles. RESULTS: Rheumatoid arthritis presents various specific and nonspecific skin manifestations. Besides visual diagnosis like classic rheumatoid nodules a histopathologic correlation or an interdisciplinary approach is often needed, such as for diagnosis of pyoderma gangrenosum. CONCLUSIONS: The early detection and correct classification of cutaneous manifestations associated with rheumatoid arthritis can be groundbreaking for a successful therapy and a consequently better prognosis for patients with rheumatoid arthritis. Therefore dermatologists bear responsibility in the patient-centered care.

Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation.

BACKGROUND: The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). METHODS: 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference. RESULTS: Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI. CONCLUSION: Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.

[Chronic low back pain and psychological comorbidity : A review]. / Chronische untere Rückenschmerzen und psychische Komorbidität : Eine Übersicht.

BACKGROUND: Back pain is a common, disabling problem in Germany. Previous research has evaluated associations between low back pain (LBP), depression, and fear. OBJECTIVES: The results should provide ideas of how to optimize preventive measures, give guidelines for rehabilitation of patients with LBP, and to develop new therapies. MATERIALS AND METHODS: A systematic review of the literature including primary publications and meta-analyses using set search criteria in PubMed was performed. A meta-analysis was then done. RESULTS: In all, 34 studies met the inclusion and quality criteria, whereby 14 studies were included in the meta-analysis. In the literature, significantly different depression scores were reported for people with LBP compared to a healthy control group. The pain perception in persons with LBP is associated with depression and fear. The correlation between depression and pain perception was highly significant in 5 studies (p < 0.01) and significant in 8 studies (p < 0.05). Fear and pain perception were highly significant in 4 studies (highly significant, p < 0.01) and significant in 3 studies (p < 0.05); 5 studies had no significant results. The studies were very heterogeneous. CONCLUSIONS: The results can improve the understanding of the complexity of LBP perception and its therapy. The generalization of the results is limited. To cover the correlation of psychosocial and lifestyle factors and pain perception of LBP, further research is required. To obtain a clearer picture of pain perception in persons with LBP, standardized pain assessment would be beneficial. In addition, we recommend that future studies follow standardized procedures to allow greater comparability.

Patient-individual local SAR determination: in vivo measurements and numerical validation.

Tissue heating during magnetic resonance measurements is a potential hazard at high-field MRI, and particularly, in the framework of parallel radiofrequency transmission. The heating is directly related to the radiofrequency energy absorbed during an magnetic resonance examination, that is, the specific absorption rate (SAR). SAR is a pivotal parameter in MRI safety regulations, requiring reliable estimation methods. Currently used methods are usually based on models which are neither patient-specific nor taken into account patient position and posture, which typically leads to the need for large safety margins. In this work, a novel approach is presented, which measures local SAR in a patient-specific manner. Using a specific formulation of Maxwell's equations, the local SAR is estimated via postprocessing of the complex transmit sensitivity of the radiofrequency antenna involved. The approximations involved in the proposed method are investigated. The presented approach yields a sufficiently accurate and patient-specific local SAR measurement of the brain within a scan time of less than 5 min.

Regulation of early spontaneous network activity and GABAergic neurons development by thyroid hormone.

Early in development spontaneous activity modulates survival and connectivity of neurons and thus plays a crucial role in the formation of neural networks. The emergence of synchronous activity in cultured neocortical networks initially is driven by large GABAergic interneurons. Here we studied the impact of thyroid hormone on early network development and especially on the development of large GABAergic neurons. Triiodothyronine enhances the frequency of early spontaneous synchronous network activity and an overall increase in network connectivity is indicated by the increased density of glutamatergic and GABAergic synapses. The hormone-induced increase of activity parallels cell type-specific changes in neuronal soma size and cell density, with strong effects on somatic and axonal growth of large GABAergic interneurons. Interestingly, large GABAergic neuron growth is both activity- and hormone-regulated. Blocking neuronal activity by tetrodotoxin or the glutamate receptor blockers D-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione disodium reveals a direct contribution of triiodothyronine to somatic growth, which also precedes the formation of synchronous network activity. The hormone-mediated effects on spontaneous activity and on large GABAergic neurons growth can be blocked by the nuclear thyroid hormone receptors antagonist 1-850. Thus, our data suggest that triiodothyronine actions result in functional maturation of early cortical networks and cell type-specific structural alterations. The increase in spontaneous activity might initially follow the growth of the large GABAergic neurons, which show an exquisite sensitivity to the presence of thyroid hormones. For the most part, however, the hormone-mediated growth of the GABAergic neurons relies strongly on the maturation of glutamatergic synaptic activity.

First Report of Pithomyces chartarum Causing a Leaf Blight of Miscanthus × giganteus in Kentucky.

Miscanthus × giganteus is a warm-season perennial grass, native to eastern Asia. Brought into the United States as a landscape plant, it is currently being considered as a potential biomass fuel crop. In August 2009, a newly established and a 2-year-old M. × giganteus field research trial near Lexington, KY were found to have 100% incidence of severe leaf blight. Brown, mosaic-like, coalesced necrotic lesions covered leaf blades and sheaths on every stand, ultimately killing some leaves and tillers. The disease was more destructive in the newly established trial where 4- to 5-month-old M. × giganteus tillers were killed. No fruiting bodies were found immediately on diseased leaves. However, surface-disinfested diseased leaf tissue produced a sooty black mass of conidia after 1 week following incubation in a petri dish moisture chamber at 25°C in the dark. Single conidia isolations were made on half-strength potato dextrose agar (HSPDA) amended with 25 mg/liter of rifamycin and incubated at 25°C. Morphological characteristics of the fungus fit those originally described for Pithomyces chartarum (Berk. & Curt.) M.B. Ellis (2). Colonies were fast growing on HSPDA, at first hyaline, then shortly punctiform, grayish black, up to 1-mm diameter, and then became confluent, producing several dark brown multicellular conidia on small peg-like denticles on branched conidiophores. Every detached conidium had a small piece of the denticle attached to its base. The conidia were echinulate, broadly ellipsoidal, pyriform, 18 to 29 × 11 to 18 µm, with three transverse septa, and a longitudinal septum constricted at the transverse septa. The identity of the fungus was confirmed by sequence analysis of the internal transcribed spacers (ITS) region of the nuclear ribosomal DNA. The 615-bp cloned and sequenced amplicon (Accession No. GU195649) was 99% identical to sequences from multiple isolates of Leptosphaerulina chartarum (anamorph Pithomyces chartarum) in the GenBank. Five potted M. × giganteus plants (45 days old) were spray inoculated with an aqueous conidial suspension (2 × 106 conidia/ml) and incubated in one tier of a two-tiered-growth chamber at 86 to 90% relative humidity. Initial incubation was in the dark at 26°C for 48 h, and thereafter at alternating 15 h of light (320 µmol) at 25°C and 9 h of darkness at 23°C. Control plants were sprayed with sterile water and incubated in the second tier of the same growth chamber. A week after inoculation, leaf blight developed on all inoculated plants, but not the controls. P. chartarum was reisolated from infected leaves 2 weeks after inoculation. To our knowledge, this is the first report of P. chartarum causing a disease on Miscanthus (3). The fungus is cosmopolitan, usually saprophytic, but can cause diseases on a wide range of plants as well as produce mycotoxins (3). It has been reported to cause a leaf spot of smooth bromegrass (Bromus inermis) in Nebraska (1) and a leaf blight of wheat (Triticum aestivum) in Hungary (4). The observed disease severity suggests P. chartarum could potentially limit M. × giganteus production as an ethanol feedstock. References: (1) C. Eken et al. Plant Dis. 90:108, 2006. (2) M. B. Ellis. Dematiaceous Hyphomycetes. Commonwealth Mycological Institute, Kew, Surrey, England, 1971. (3) D. F. Farr et al. Fungal Databases, Systematic Mycology and Microbiology Laboratory. Online publication. ARS, USDA, 2010. (4) B. Tóth et al. J. Plant Pathol. 89:405, 2007.

Accessory muscle in the hypothenar region: a functional approach.

An accessory muscle was found in the hypothenar region on both hands during routine cadaver dissection. This muscle originated from the tendon of the flexor carpi radialis, crossed the palma manus region superficially and inserted together with the abductor digiti minimi muscle into the ulnar aspect of the basis of the fifth proximal phalanx. The muscle was supplied by one branch arising from the main trunk of the ulnar nerve. Abnormalities of the hypothenar muscles have been described by many authors with a focus on their structural aspects, but there is not enough data about the possible functions they could induce. In our study, we try to elucidate the functions of this accessory muscle. We did not name the variant muscle as it has various functions, each similar to that of individual hypothenar muscles.

Synchronous oscillatory activity in immature cortical network is driven by GABAergic preplate neurons.

Neurons dissociated from embryonic cerebral rat cortex form a differentiated network of synaptic connections and develop synchronous oscillatory network activity with the beginning of the second week in culture. During an initial phase lasting 3-4 d, synchronous calcium transients can be blocked completely by either CNQX or bicuculline, showing that both glutamatergic and GABAergic neurons are required for the generation of this form of activity. By manipulating dissociation and growth conditions, cultures containing different populations of GABAergic neurons were obtained. These cultures revealed that a distinct population of large GABAergic neurons is a key element in the generation of synchronous oscillatory network activity. A minimal number of two large GABAergic neurons per square millimeter are required for the occurrence of synchronous activity. Changes in the density of all other types of GABAergic or non-GABAergic neurons has no influence on the synchronous activity. Electron microscopic analysis shows that the large GABAergic neurons form an interconnected network. Exceptionally high somatodendritic innervation and extended axonal arborization enable these neurons to collect electric network activity and to distribute it effectively throughout the neuronal network. Additional experiments indicated that most neurons developing in culture to large GABAergic neurons are derived from the primordial plexiform layer and reside in the subplate at the time of birth. We suggest that they function as an integrating element that synchronizes neuronal activity during early cortical development by collecting incoming extrinsic and intrinsic signals and distributing them effectively throughout the developing cortical plate.

On the connection between the T-system and the subsynaptic folds in the motor end plate of amphibians.

Using lanthanum as an extracellular marker, the transition between the subsynaptic folds of the motor end plate and the T-system of frog muscle fibres is portrayed for the first time. On the lower segment of the subsynaptic folds of frogs, there are numerous caveolae which can connect with one another to form meandering, branching tubes. The T-system is in contact with these tubes (which run through the sarcoplasm) beneath the motor end plate. In those segments of the end plate with massed sarcoplasm and a cell nucleus, these tubes form networks in close proximity to the cellular organelles. The morphological findings obtained here are compared with findings from mammals. The physiological significance of the transition between the subsynaptic fold and the T-system is discussed.

The T-tubular network and its triads in the sole plate sarcoplasm of the motor end-plate of mammals.

The transition between the subsynaptic folds and the T-tubules demonstrated in a former paper was further investigated in the sole plate area by using the extracellular marker Lanthanum. A tubular network of the T-system of the sole plate area which is connected to the subsynaptic folds and to the t-tubular elements between the myofibrils is described for the first time. T-tubules of this network criss-cross through the sarcoplasm of the sole plate and lie in close proximity to sole plate nuclei and mitochondria. Cisterns of sarcoplasmic reticulum of the sole plate area make contact with these t-tubules forming triads. The possible physiological role of this sole plate network and its triads will be discussed with regard to a transport of substances in tubules with the dimension of nanotubes and Ca2+ activated processes in the sole plate area.

Astroglia inhibit the proliferation of neocortical cells and prevent the generation of small GABAergic neurons in vitro.

We quantitatively studied the dynamics of rat neocortical precursor proliferation in vitro, and additionally examined the effects of neuron-glia interactions on the proliferation and differentiation of neurons, and particularly of gamma-aminobutyric acid (GABA)-containing cells. In cultures grown on glia-free substrate, cellular proliferation was detected at least until the end of the second week in vitro, but most neurons which expressed detectable amounts of microtubule-associated protein at 12 days in vitro were generated early during the first week. Further double-labelling experiments, combining 5'-bromo-2'-deoxyuridine with GABA or beta-tubulin III immunohistochemistry, provided direct evidence that neuronal proliferation continued through the second week in vitro, and that a population of small GABAergic neurons was generated between 3 and 12 days in vitro. Culturing cells on a glial substrate significantly reduced the generation of small GABAergic cells and strongly inhibited the total cell proliferation. Inhibition also occurred if astrocytes were added to the culture after 6 days in vitro, but was significantly decreased if cells were grown on a fixed glial substrate, suggesting that the effect might be at least partially mediated by active interactions between neurons and glia. In conclusion, our results show that the sustained proliferation of precursor cells in neocortical cultures is necessary for the differentiation of small GABAergic neurons, and that mature astroglia effectively inhibit the proliferation of neocortical precursors thereby affecting the appearance of a population of GABAergic cells.

[Quality of life and well-being in a housing project in Berlin--experiences gained in cooperation between a community health promotion office and a university-based public health project]. / Lebensqualität und Wohlbefinden in einer Berliner Grosssiedlung--Erfahrungen aus der Kooperation zwischen einer kommunalen Gesundheitsförderungsbehörde und einem Public Health-Projekt.

The realization of a community-based health promotion within the framework of a cooperation between a public health office and a university-based PH project is described and discussed. First of all, the project, the cooperating partners and the common aims are described. We will then deal with telephone survey as the method used, and present the results. In a third step the methods and results of the "future workshops" are discussed. Finally there is a critical reflection on the course of the project, the limiting factors of the actions and consideration of further developments. The project dealt with was a cooperation of a community public health agency (Plan- und Leitstelle) in the district of Berlin-Wilmersdorf and the research project A8 "Cooperative project development for communal health promotion" of the Berlin Centre for Public Health at the Technical University Berlin. Starting point was the agreement for those politically responsible of the district that the living quarter "Schlangenbader Strasse" was a focus of social problems. The quarter had been built in 1980 above a highway with 1800 apartments for 4000 people. Health promotion was defined as a concern of a wide range of sectors within the community. Mutual rights and responsibilities of the cooperating partners were laid down in a contract. The Plan- und Leitstelle tried to gain experience with the definition of health promotion the university partners stood for. This introduces a notion of health beyond bio-medical understanding and deals with the connection of quality of life, well-being and the environment in the residential area. Thus health- or sickness-related variables were not specifically asked for. One result is that actors within the given framework are reluctant to permit operationalisation of this concept. The telephone survey reached 324 household within 10 working days. 68p.c. of the interviewed were pleased with the comfort of the apartments, 37p.c. enjoyed the peace and quiet and 35p.c. the green around the housing project. Unpleasant were for 51p.c. the dirt, 33p.c. complained about vandalism, 30p.c. about the high rent, especially the extras. Safety improvements were asked for by 17p.c. Some 12p.c. were willing to become involved in bringing about those improvements. This willingness was confirmed by the good response to two future workshops with those living in the quarter.

Intravenous itasetron: establishing the effective dose range for the prophylactic control of acute emesis in cancer patients undergoing high-dose cisplatin chemotherapy.

Nausea and vomiting induced by chemotherapy are a major cause of distress to patients and reduce compliance with potentially beneficial treatment. Itasetron hydrochloride is a new 5-hydroxytryptamine3 (5-HT3) antagonist with potent antiemetic properties. It is more potent than ondansetron in animal models and in early clinical studies it demonstrates a long half-life and does not undergo hepatic biotransformation before elimination. The aim of this open, uncontrolled study was to establish the effective dose range of itasetron hydrochloride given intravenously (i.v.) to patients due to receive high-dose cisplatin chemotherapy (50-120 mg/m2) for the first time. Thirty-nine patients were enrolled in the trial and received a single i.v. infusion of itasetron hydrochloride at a dose of 17-280 microg/kg body weight before commencing the cisplatin infusion (median dose 90-110 mg/m2). Antiemetic protection was demonstrated by doses in the range of 35-280 microg/kg. The 17 microg/kg dose was not effective. Treatment failure (>5 emetic episodes/24 hours) was reported in only six (16%) of the 38 evaluable patients over all treatment groups. Adverse events were generally mild or moderate and of a similar type and incidence to those of current 5-HT3 antagonists. Physicians' and patients' assessments of efficacy and tolerability of itasetron hydrochloride were similar, the majority rating the treatment as 'good' or 'very good'. In conclusion, itasetron hydrochloride is effective in the dose range 35-280 microg/kg in preventing cisplatin-induced emesis. Taken together with results from a larger dose-finding study, a dose corresponding to 35 microg/kg (equivalent to 2.5 mg itasetron, calculated as free base) has been pursued in Phase III studies with the i.v. formulation.

Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study.

We performed a phase I trial to evaluate the safety and tolerability of repeated skin injections of IL-2-transfected autologous melanoma cells into patients with advanced disease. Cell suspensions, propagated from excised metastases, were IL-2 gene transfected by adenovirus-enhanced transferrinfection and X-irradiated prior to injection. Vaccine production was successful in 54% of the patients. Fifteen patients (37%) received two to eight skin vaccinations of either 3 x 10(6) (intradermal) or 1 x 10(7) (half intradermal, half subcutaneous) transfected melanoma cells per vaccination (secreting 140-17,060 biological response modifier program units of IL-2/10(6) cells/24 hr). Analyses of safety and efficacy were carried out in 15 and 14 patients, respectively. Overall, the vaccine was well tolerated. All patients displayed modest local reactions (erythema, induration, and pruritus) and some experienced flu-like symptoms. Apart from newly appearing (4 of 14) and increasing (5 of 14) anti-adenovirus and newly detectable anti-nuclear antibody titers (1 of 15), recipients developed de novo or exhibited increased melanoma cell-specific delayed-type hypersensitivity (DTH) reactions (8 of 15) and vitiligo (3 of 15) and showed signs of tumor regression (3 of 15). This supports the idea of a vaccine-induced or -amplified anti-cancer immune response. None of the patients exhibited complete or partial regressions, but five of them experienced periods of disease stabilization. Three of these individuals received more than the four planned vaccinations and their mean survival time was 15.7 +/- 3.5 months as compared to 7.8 +/- 4.6 months for the entire patient cohort. These data indicate that IL-2-producing, autologous cancer cells can be safely administered to stage IV melanoma patients and could conceivably be of benefit to patients with less advanced disease.

Junctions between subsynaptic folds and rough sarcoplasmic reticulum of muscle fibres.

Serial sections through motor end plate regions of mouse muscle fibres demonstrated junctions between the subsynaptic folds and the rough sarcoplasmic reticulum of the sole plate nuclei. The shape of these structures resembles that of the well-known peripheral couplings, diads and triads of muscle fibres. However, the location of the new junctions between the surface membrane and the sole plate nuclei at a large distance from myofibrils, indicates a different function. The connection with the rough sarcoplasmic reticulum possibly influence the regulation of fibre protein metabolism, for example, gene expression of acetylcholine receptor synthesis.

Air pollution in the Latrobe Valley and its impact upon respiratory morbidity.

OBJECTIVE: To assess the relationship between air pollution and respiratory morbidity. DESIGN: An ecological study of the daily hospital admissions abstracted for the 1988 calendar year. Air quality data, including nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates, were obtained from the relevant authorities. SETTING: Latrobe Valley, Victoria. SUBJECTS: Hospital admissions for asthma and Chronic Obstructive Airways Disease. (COAD). RESULTS: There were significant associations (r = 0.11 to 0.17) between airborne particles, nitrogen dioxide and respiratory morbidity. There was no significant relationship between any of the pollutants and asthma admissions. However, multi-variate analysis confirmed that NO2 and particulates were associated with admissions for COAD. CONCLUSION: Respiratory morbidity appears to be affected even by the low air pollution levels in the Latrobe Valley.

Identification of two distinct populations of gamma-aminobutyric acidergic neurons in cultures of the rat cerebral cortex.

Two types of neurons containing gamma-aminobutyric acid (GABA) were identified in cultures of embryonic rat neocortex. Large GABAergic neurons were already present 4 hours after plating, whereas small ones appeared later. Both types were shown to be neurons by double labeling with GABA and microtubule-associated protein 2 (MAP2) immunocytochemistry. The large GABAergic neurons represented less than 5% of the adherent cells, developed neurites rapidly, and progressed synchronously through the polarization and differentiation steps characteristic of the whole neuronal population. During the second week in culture, these GABA-immunoreactive cells developed into large, stellate neurons with fairly homogeneous morphology and poorly ramified, straight dendrites. At the same time, the GABAergic neuropil increased greatly, and neurites of GABAergic neurons showed advancing maturity and smoothness. The axon of each cell covered extensive areas of the culture, frequently encircling the somata of unlabeled neurons in a basket-like fashion. Significant numbers of small GABAergic cells developed only in the absence of the mitotic inhibition routinely used to control glial proliferation. These late-born GABAergic neurons went through neuritogenesis when most of the other neurons were already forming synapses on their somatodendritic surfaces. In mature cultures, they had a multipolar or fusiform morphology with spine-bearing dendrites. They had small somata and were often present inside clusters of neurons. Their short axons showed no obvious basket-like pattern of arborization. Thus, the two types of GABAergic neurons identified in cortical cultures differed in their morphology, distribution, and developmental history. We propose that intercellular interactions during early synaptogenesis may play a role in the development of different morphological types of GABAergic neurons in vitro.

Neuritic differentiation and synaptogenesis in serum-free neuronal cultures of the rat cerebral cortex.

To better understand the dynamics of the cellular processes involved in early neocortical development, we studied the neuritic differentiation and synaptogenesis of dispersed neurons grown in serum-free cultures under a wide variety of culture conditions. Microtubule-associated protein (MAP2), phosphorylated neurofilament (SMI 31) and synaptophysin immunocytochemistry was complemented with time-lapse studies. During the first week in vitro dissociated cortical neurons developed from roundish cells without processes to neurons with axons and differentiated dendrites, going through five distinct phases. The sequence of these phases was unaltered in a wide range of culturing methods, but the timing of the steps varied among cultures started with different cell densities. Synaptic terminals were first observed after 3-4 days in vitro, coincident with the beginning of dendritic differentiation. Synaptogenesis progressed at least until the end of the third week in vitro, despite a decline in cell density during the second week in vitro. The process of cellular differentiation of cerebral cortical neurons in vitro resembled the development of these cells in the intact tissue, suggesting that organized cell migration is not a prerequisite for the differentiation of single cortical neurons.

Comparison of oral itasetron with oral ondansetron: results of a double-blind, active-controlled phase II study in chemotherapy-naive patients receiving moderately emetogenic chemotherapy.

Itasetron hydrochloride is a new 5-hydroxytryptamine3 (5-HT3) antagonist. Experimental investigations show that orally it is rapidly absorbed (about 90 min), is highly bioavailable (greater than 90%), has a long half-life (about 12 h) and is more potent (about 10 times) in animal models than ondansetron, currently standard therapy for the prophylactic control of chemotherapy induced nausea and vomiting. This paper describes the results of a study designed to assess the efficacy and tolerability of five (0.5, 1, 2, 4 and 8 mg) twice-daily doses of itasetron hydrochloride, in comparison with 8 mg b.i.d. ondansetron. Assessments were made in patients (n = 104) with histologically confirmed cancer (excluding head and neck tumors) and about to receive their first course of moderately emetogenic chemotherapy. Itasetron hydrochloride demonstrated comparable efficacy to ondansetron; no statistically significant between-group differences were observed in the primary (complete response rate) or secondary (nausea and delayed emesis) efficacy criteria. Adverse events were similar in type and incidence across all treatment groups, and were those expected for this therapeutic class. The tolerability of itasetron hydrochloride was assessed as 'very good' or 'rather good' by 81% of patients and 89% of physicians. In conclusion, itasetron hydrochloride is effective and well tolerated in patients receiving moderately emetogenic chemotherapy. Oral doses of 1 mg b.i.d. or above will be used in further clinical studies.

Synchronization of neuronal activity promotes survival of individual rat neocortical neurons in early development.

Neural activity is thought to play a significant role during the development of the cerebral cortex. In this study, we examined the effects of global activity block or enhancement and the effects of patterned firing on the ability of cultured rat neocortical neurons to survive during the second week in vitro, beyond the beginning of synaptogenesis. Blockade of neuronal activity by adding tetrodotoxin (TTX) and increasing magnesium concentration in the medium strongly reduced the survival of cortical cells. Increasing neuronal activity by raising the external potassium concentration significantly improved the survival of cortical neurons. We postulated that in a developing neuronal network the survival of nerve cells is regulated by synaptically mediated events that involve changes in the intracellular calcium concentration. To examine this question further, we monitored the activity of the developing network by optically recording the intracellular calcium signals of many neurons simultaneously. These recordings show that in low magnesium neocortical neurons express synchronized oscillation of their intracellular calcium concentration. The ability of a network to synchronize the changes in intracellular calcium of multiple cells appeared gradually during the second week in culture, paralleled by both an increase in the synaptic density and a decline in the number of surviving neurons. By examining the fate of identified cells several days after a recording session, we found that those nerve cells that were co-activated with other neurons had a significantly higher chance to survive than cells that did not participate in synchronized events. These experiments demonstrate that during early cortical network development cortical neurons show synchronized firing activity and that the survival of neurons is at least partially dependent on this pattern of neuronal activity.