Role of VEGFs in metabolic disorders.

Obesity and metabolic disorders are important public health problems. In this review, the role of vasculature network and VEGF in the adipose tissue maintenance and supplementation is discussed. Angiogenesis is a key process implicated in regulation of tissues homeostasis. Dysregulation of new blood vessels formation may be crucial and contribute to the onset of several pathological conditions, including metabolic syndrome-associated disorders. Adipose tissue homeostasis is fine regulated by vascular network. Vessels support adipose structure. Vasculature modulates the balance between positive and negative regulator factors. In white adipose tissue, vascular endothelial growth factor (VEGF) controls the metabolic activities of adipocytes promoting the trans-differentiation from white to beige phenotype. Trans-differentiation results in an increase of energy consumption. VEGF exerts an opposite effect on brown adipose tissue, where VEGF increases oxygen supply and improves energy expenditure inducing the whitening of adipocytes.

Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment.

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing.

Microglia, the innate immune cells of the central nervous system (CNS), react to endotoxins like bacterial lipopolysaccharides (LPS) with a pronounced inflammatory response. To avoid excess damage to the CNS, the microglia inflammatory response needs to be tightly regulated. Here we report that a single LPS challenge results in a prolonged blunted pro-inflammatory response to a subsequent LPS stimulation, both in primary microglia cultures (100 ng/ml) and in vivo after intraperitoneal (0.25 and 1mg/kg) or intracerebroventricular (5 µg) LPS administration. Chromatin immunoprecipitation (ChIP) experiments with primary microglia and microglia acutely isolated from mice showed that LPS preconditioning was accompanied by a reduction in active histone modifications AcH3 and H3K4me3 in the promoters of the IL-1ß and TNF-α genes. Furthermore, LPS preconditioning resulted in an increase in the amount of repressive histone modification H3K9me2 in the IL-1ß promoter. ChIP and knock-down experiments showed that NF-κB subunit RelB was bound to the IL-1ß promoter in preconditioned microglia and that RelB is required for the attenuated LPS response. In addition to a suppressed pro-inflammatory response, preconditioned primary microglia displayed enhanced phagocytic activity, increased outward potassium currents and nitric oxide production in response to a second LPS challenge. In vivo, a single i.p. LPS injection resulted in reduced performance in a spatial learning task 4 weeks later, indicating that a single inflammatory episode affected memory formation in these mice. Summarizing, we show that LPS-preconditioned microglia acquire an epigenetically regulated, immune-suppressed phenotype, possibly to prevent excessive damage to the central nervous system in case of recurrent (peripheral) inflammation.

Which cytological criteria are the most discriminative to distinguish carcinoma, lymphoma, and soft-tissue sarcoma? A probabilistic approach.

The reliability of fine-needle aspiration cytology (FNA) for distinguishing between carcinoma, lymphoma, and sarcoma was established in a previous study (Thunnissen et al., Cytopathology 1993; 4:107-114). The purpose of this study was to investigate which criteria were useful for a probabilistic diagnosis. A total of 78 randomly chosen FNA smears (31 carcinomas, 24 lymphomas, and 23 sarcomas) was sent around and read "blindly" by six cytopathologists. Each pathologist completed a list of 16 criteria for every case. Histology was used as a reference standard. A statistical analysis led to the selection of three criteria: "lymphoglandular bodies," "well-defined clusters," and "spindle-cell nuclei," associated with lymphoma, carcinoma, and soft-tissue sarcoma, respectively. Given the scores on these criteria, the probabilities to be assigned to the three diagnostic categories can be read from a table. It turns out, as one might expect, that the classification of the most probable disease is pretty reliable if one cytologic criterion scores much higher than the other two criteria. On other cases, fuzziness appears and misclassifications are far from improbable. This study offers a general cytologic approach. The cytologic criteria "lymphoglandular bodies," "well-defined clusters," and "spindle-cell nuclei" can be used both in daily practice and in education to assign posterior probabilities to carcinoma, lymphoma, and soft-tissue sarcoma.

Further evaluation of quantitative nuclear image features for classification of lung carcinomas.

The usefulness of quantitative nuclear image features (QNI) for the histological classification of lung carcinomas was investigated. As no clear distinction could be established between the distributions of these features for the nuclei of squamous cell, adenocarcinoma, and large cell carcinoma, the attention was restricted to the discrimination between small cell lung carcinoma (SCLC) and non-small cell carcinoma (NSCLC). This discrimination is the crucial one in discussions about the choice of treatment. The differences between SCLC and NSCLC are statistically highly significant for various QNI features. The use of more than one QNI feature hardly raised the discriminatory performance with respect to the distinction between SCLC and NSCLC. Inferences were made about the probability and confidence interval of SCLC for a given QNI feature. It is concluded that in cases of uncertainty or disagreement, nuclear characteristics are useful for the discrimination between SCLC and NSCLC.

[The effect of thymectomy in patients with myasthenia gravis without thymoma; a statistical analysis]. / Het effect van thymectomie bij patiënten met myasthenia gravis zonder thymoom; een statistische analyse.

In order to determine the effect of thymectomy on the prognosis of patients with myasthenia gravis, an analytical-descriptive study was carried out in the Neurological Clinic of the Groningen University Hospital and the Mathematical Institute of Groningen University. In 183 patients with generalized myasthenia gravis without thymoma, with onset between 9 and 46 years of age, the severity of the disease was scored by one neurologist at fixed times (0.5, 1, 2, 3, etcetera up to 15 years) after onset. Thymectomy was performed in 144 patients at different times (0.5, 1, 2, 3, etcetera up to 7 years) after onset. Logistic regression analysis was carried out with, as the criterion for marked improvement, a decrease of the disease score by 50%. Using this criterion, age, sex, duration of the disease and severity of the disease prior to operation played no distinct parts as prognostic factors. At different periods after the onset of the disease, groups of patients operated or not (yet) operated were compared. Patients subjected to thymectomy within 5 years after onset of myasthenia gravis had a better probability of halving of the severity score than patients not subjected to operation. These data render it possible in the individual patient to make an adequate estimate of the probability of marked improvement if thymectomy is performed or postponed.

Reference values of anthropometric measurements in Dutch children. The Oosterwolde Study.

In the period 1979-1980 the following anthropometric measurements were recorded in 2351 healthy Dutch children from 0-17 years of age: height, weight, sitting height, arm span, lengths of upper-arm, lower-arm and hand, tibial length, foot length, biacromial diameter, biiliacal diameter, and head circumference. Corresponding percentile values were constructed on the basis of normality assumptions, the mean and standard deviation at age t being determined by a cubic spline approximation. The results are compared with other studies and given in the form of growth charts.

Determining nucleolar multiplicity and cell number from sectional data.

The occurrence of more than one nucleolus within the cellular nucleus (polynucleolarity) is a well-known phenomenon during the proliferative cell cycle, both under normal and pathological conditions (e.g. neoplasia). It can also be observed in neuronal nuclei at early stages of their maturation. Polynucleolarity merits investigation for cytological reasons. In an histological section, the observed number of nucleoli in a nucleus may be smaller than the actual number. In order to estimate the true distribution of the number of nucleoli per nucleus from the observed distribution, the mathematical relation between these distributions is derived on the basis of rather restrictive stereological assumptions. It is indicated how these distributions can be estimated from the data available and how the statistical uncertainties involved can be expressed. This paper arose from making cell counts. Two methods may be applied: all visible nuclear profiles are counted, nuclear profiles are only included if at least one nucleolus is visible in the section. We recommended a combination of these two methods. An advantage of our theory for determining cell number is that one can often manage without the rather restrictive stereological assumptions needed hitherto. The advantage of expressing statistical uncertainties in estimated nucleolar multiplicity probabilities and cell numbers is indicated.

Toward individual prognosis of IgA nephropathy.

The individual prognosis of adult IgA nephropathy patients was studied using the proportional hazards model for the time from biopsy until endstage renal disease. After selection of the most relevant prognostic factors, the 75 patients were stratified with respect to hypertension and its treatment. In these strata, individual prognosis was based on the initial age-adjusted glomerular filtration rate, the initial proteinuria, the presence/absence of gross hematuria, and the presence/absence of microscopic hematuria. Using the scores of a patient on these variables, the probability of surviving any given period of time can be estimated either graphically or by calculation. Prediction is feasible up to about 10 years. Attention has been given to supply all relevant estimates with confidence limits. For each patient the estimated 5-year survival probability as predicted by the model was compared with the actual outcome.

Smoothing techniques for obtaining reference values for measurements of children.

Constructing reference values for measurements of children, e.g. the mean height as function of age, one needs a smoothing technique. Various techniques will be discussed and applied to a particular study of anthropometric growth. The overall conclusion is that reliable curves can be obtained by using computer programs based on approximations by cubic splines, and by using the eye for choosing from the corresponding outputs.