Activin controls skin morphogenesis and wound repair predominantly via stromal cells and in a concentration-dependent manner via keratinocytes

The transforming growth factor-beta family member activin is a potent regulator of skin morphogenesis and repair. Transgenic mice overexpressing activin in keratinocytes display epidermal hyper-thickening and dermal fibrosis in normal skin and enhanced granulation tissue formation after wounding. Mice overexpressing the secreted activin antagonist follistatin, however, have the opposite wound-healing phenotype. To determine whether activin affects skin morphogenesis and repair via activation of keratinocytes and/or stromal cells, we generated transgenic mice expressing a dominant-negative activin receptor IB mutant (dnActRIB) in keratinocytes. The architecture of adult skin was unaltered in these mice, but delays were observed in postnatal pelage hair follicle morphogenesis and in the first catagen-telogen transformation of hair follicles. Although dnActRIB-transgenic mice showed slightly delayed wound re-epithelialization after skin injury, the strong inhibition of granulation tissue formation seen in follistatin-transgenic mice was not observed. Therefore, although endogenous activin appeared to affect skin morphogenesis and repair predominantly via stromal cells, overexpressed activin strongly affected the epidermis. The epidermal phenotype of activin-overexpressing mice was partially rescued by breeding these animals with dnActRIB-transgenic mice. These results demonstrate that activin affects both stromal cells and keratinocytes in normal and wounded skin and that the effect on keratinocytes is dose-dependent in vivo.     

Histomorphometry and autoradiography of cultured fetal rat long bones

The behavior of fetal rat long bones cultured in vitro according to Raisz's technique (1969) was studied by histomorphometry and autoradiography for a period of four days. The changes were recorded daily both on the trabecular and cortical bone by measuring the bone volume, the number of osteoclasts, and the number of nuclei per osteoclast. Radioactive calcium release was measured and compared to the changes in bone volume and in the number of osteoclasts. An autoradiographic study, using ³H-proline and ³H-thymidine in flash labeling in the medium and ³H-thymidine in follow-up labeling after one injection in vivo was performed to evaluate the bone formation, the cellular proliferation rate and cell differentiation. After four days in culture, an increase in total calcified bone volume was observed which correlatd with changes in the trabecular bone. No significant changes were recorded in the cortical bone. The results showed a good maintenance of the resorption and formation phenomena through an active process of cellular multiplication and differentiation. Undifferentiated cells were labeled in flash label and osteoblast, osteocyte and some osteoclast nuclei were labeled in follow-up studies.     

Comparative regional analysis of 2-fluorodeoxyglucose and methylglucose uptake in brain of four stroke patients. With special reference to the regional estimation of the lumped constant

The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the "lumped constant," be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g-1 min-1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution of labeled methylglucose in the normal regions was 0.46 ml g-1 and was the same in both gray and white matter structures. The average brain glucose content corresponding to this value was 1.3 mumol g-1, assuming a Michaelis constant (Kt) of 3.7 mM for glucose transport across the blood-brain barrier. The lumped constant varied insignificantly between 0.4 and 0.5 in most regions, with an overall average of 0.44. It did not vary significantly between the patients and was the same in gray and white matter structures, but was inversely related to the calculated metabolic rate. This observation indicates that metabolic rates calculated with a fixed lumped constant (e.g., 0.40) would be slightly underestimated at high metabolic rates and slightly overestimated at low metabolic rates. The average glucose metabolic rates of the 365 normal regions, in which gray matter regions prevailed by 20:1, was 32 mumol 100 g-1 min-1. The average glucose phosphorylation rate in white matter was 20 mumol 100 g-1 min-1 with a lumped constant of 0.45. In the recently infarcted areas, the lumped constants varied from 0.37 to 2.83, corresponding to glucose metabolic rates varying from 2 to 18 mumol 100 g-1 min-1. Two infarct types were identified. In one type, the phosphorylation-limited type, glucose content and the lumped constant were close to normal (1 mumol g-1 and 0.40, respectively). In the other, the transport/flow-limited type, the glucose content was low (0.2 mumol g-1), and the lumped constant in excess of unity. The evidence from the present study upholds the model of Sokoloff et al. in every detail.     

Towards compatibility of EUnetHTA JCA methodology and German HTA: a systematic comparison and recommendations from an industry perspective

The European Journal of Health Economics - The transferability of the EU joint clinical assessment (JCA) reports for pharmaceuticals for the German benefit assessment was evaluated by...     

Impairment of neocortical metabolism predicts progression in Alzheimer's disease

Progression rates of Alzheimer's disease (AD) vary considerably, and they are particularly difficult to predict in patients with mild cognitive impairment. We performed a prospective multicenter cohort study in 186 patients with possible or probable AD, mostly with presenile onset. In a cross-sectional analysis at entry, impairment of glucose metabolism in temporoparietal or frontal association areas measured with positron emission tomography was significantly associated with dementia severity, clinical classification as possible versus probable AD, presence of multiple cognitive deficits and history of progression. A prospective longitudinal analysis showed a significant association between initial metabolic impairment and subsequent clinical deterioration. In patients with mild cognitive deficits at entry, the risk of deterioration was up to 4.7 times higher if the metabolism was severely impaired than with mild or absent metabolic impairment. Copyrightz1999S.KargerAG, Basel     

Quality of life—a measure of the quality of nursing care?

Quality of life is a very complex phenomenon in the life of cancer patients. Individual perceptions might change with the state of disease and with necessary interventions. Some definitions seem to be more useful in cancer care than others. There has been considerable controversy in the quantity versus quality debate. Some confusion in the measurement of quality of life concerns objectivity and subjectivity, referring either to the content of information or to persons other than the patient eliciting it. The relation between quality of life and quality of care has to be further explored: some dimensions of care might be of little or of potential relevance to the patient's quality of life. The dimensions of proven relevance concern psychological well-being through, for example, promotion of self-care or an enhanced perception of self-worth. These findings emphasise the importance of the concept of care, which is the essence of nursing. Contemporary professional and political difficulties require critical analysis.     

Morphological changes in anaplastic gliomas treated with radiation and chemotherapy

Summary The effects of antineoplastic treatment on gliomas are related to tumour cell cycle and proliferation kinetics, glioma tissue architecture, and the surrounding environment. Morphological changes induced by radiation and chemotherapy are characterized by cell necrosis and severe alterations in cell and nuclear morphology caused by changes in the cell kinetic parameters which, however, may also occur spontaneously in untreated anaplastic gliomas.Comparative studies of cytological imprints and routine histological preparations of biopsy and autopsy specimens were performed in four groups of anaplastic astrocytomas and glioblastomas (78 cases) with postsurgical irradiation, combination chemotherapy, and CCNU treatment, and without specific postsurgical treatment (control group). Following radiation and chemotherapy, in addition to increased necrosis and vascular response, a variety of characteristic but nonspecific changes were observed in cell and nuclear morphology with prominent formation of multinucleated giant and monstrous cells, irregular and hyperchromatic nuclei, and severe cytoplasmic degeneration indicating both inhibition of cell division and cell damage. Statistically significant findings were a posttreatment increase in the number of multinucleated giant and monstrous cells and a decrease in the number of mitoses. These changes were more pronounced after chemotherapy than after radiation, while no significant dissimilarities were found between combination chemotherapy and CCNU. The implications of these changes on the mechanisms of antitumour treatment in anaplastic gliomas are discussed.

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Morphologische Veränderungen in anaplastischen Gliomen nach Strahlen- und Chemotherapie

Zusammenfassung Die Wirkung anuneoplastisdier Behandlung auf Gliome ist abhängig von der Tumorzeil- und Proliferationskinetik, der Gliomarchitektur und dem umgebenden Hirngewebe. Durch Strahlen- und Chemotherapie induzierte morphologische Veränderungen sind gekennzeichnet durch Zellnekrosen sowie schwere Zell- und Kernschäden durch Eingriffe in die Zellkinetik, doch können diese auch spontan in unbehandelten anaplastischen Gliomen auftreten.Vergleichsuntersuchungen von zytologischen Abstrichen und histologischen Routinepräparaten an Biopsie- und Autopsiematerial von 4 Gruppen anaplastischer Astrozytome und Glioblastome (78 Fälle) wurden nach postoperativer Strahlenbehandlung, Polychemotherapie und CCNU-Behandlung sowie ohne spezifische postoperative Therapie (Kontrollgruppe) vorgenommen. Nach Strahlen- und Chemotherapie fanden sich neben gesteigerter Nekrose und Gefäßreaktion verschiedene charakteristische, aber unspezifische Zell- und Kernveränderungen mit gesteigerter Neigung zur Bildung vielkerniger Riesen- und Monsterzellen, Kernhyperchromasie sowie schwerer Zytoplasmadegeneration als Hinweise auf Mitosestörungen und Zellschädigung. Nach antineoplastischer Therapie fand sich eine statistisch signifikante Zunahme von Riesen- und vielkernigen Monsterzellen sowie Abnahme der Mitosen, wobei diese Veränderungen nach Chemotherapie stärker ausgeprägt waren als nach Bestrahlung. Zwischen Polychemo- und CCNU-Behandlung ergaben sich keine wesentlichen Abweichungen. Die Bedeutung dieser zytologischen Spätbefunde auf die Effekte antineoplastischer Behandlung anaplastischer Gliome wird diskutiert.

     

The National Alliance for the Mentally Ill: A decade later

The National Alliance for the Mentally Ill (NAMI) was conceived a decade ago in the tradition of self-organized parents' groups for handicapped and chronically ill children. The character of the organization and its rapid growth are thought to be due to its clear identity as a mental illness group, its control and direction by parents and relatives of people suffering from mental illness, and its relationships with staff and professionals. The author believes that the NAMI movement is at an important juncture in its development and identifies factors that could influence its character in the next decade.