Clinical laboratory values during diabetic pregnancies.

BACKGROUND: Physiological pregnancy can affect routine laboratory tests, e.g., the erythrocyte sedimentation rate increases above the reference range for healthy non-pregnant adults and little is known about whether diabetes and pregnancy together can cause additional changes that require monitoring of blood-tests. OBJECTIVE: The purpose of this study was to investigate changes in clinical chemistry and haematological laboratory test results during pregnancies of type 1 diabetics and to compare the results with changes during normal pregnancies. METHODS: We studied 25 type 1 diabetic women with standard clinical chemistry and haematological blood-tests during pregnancy. RESULTS: Haemoglobin, haematocrit, and erythrocyte number decreased until the 3rd trimester and leucocytes and platelets did not change significantly. The erythrocyte sedimentation rate increased by over 200%. Protein and albumin decreased until the 3rd trimester to below the reference range. Urea did not change, creatinine decreased and uric acid increased within the reference range. AST and ALT remained within the reference range. Alkaline phosphatase and leucine aminopeptidase increased until above the reference range. Cholesterol and triglycerides increased until the third trimester above results from normal pregnancies. CONCLUSION: A wide range of biochemistry and haematology laboratory values changed during diabetic pregnancy comparable to physiological pregnancies. No additional routine laboratory-testing during diabetic pregnancies compared with physiological pregnancies is required.

Time-dependent hierarchical regulation analysis: deciphering cellular adaptation.

Cells adapt to changes in their environment by the concerted action of many different regulatory mechanisms. Examples of such mechanisms are feedback inhibition by intermediates of metabolism, covalent modification of enzymes and changes in the abundance of mRNAs and proteins. These mechanisms act in parallel at different levels in the cellular hierarchy while regulating a single process. Existing hierarchical regulation analysis determines the relative importance of these mechanisms when the cell regulates a transition from one steady-state to another. Here, the analysis is extended to the regulation of time-dependent phenomena, for which two methods are introduced and illustrated with a kinetic model incorporating transcription and translation of metabolic enzymes.

On the vicissitudes of early primary surrogate mothering II: loss of the surrogate mother and arrest of mourning.

Among the catastrophic events experienced by infants and young children, one of the most frequent is the loss of an early primary surrogate mother (EPSM). Usually permanent, the loss is often followed by the advent of a new, "replacement" caregiver. One aspect of the emotional environment is unique to this kind of caregiving situation: that parents are often unable to validate the true nature of their child's relationship with the EPSM or, ultimately, the trauma experienced by the child when the EPSM leaves. The marked discrepancy between the parent's and the infant or child's experience of the surrogate mothering leads to an arrest of the child's mourning process, with the potential for serious developmental consequences. Issues related to EPSM loss and its aftermath are examined in the light of two examples. Further exploration of the environment of this kind of caregiving directs attention to the critical need to nurture and protect the attachments of both the infant or child and the parent to the ESPM.

Pain intensity and blood pressure reactions during a cold pressor test in IDDM patients.

OBJECTIVE: To determine the contribution of altered pain perception to the impaired blood pressure reactions during a cold pressor test in diabetic patients. Reduced blood pressure increases have been observed in diabetic patients during a cold pressor test and have been attributed to an impaired efferent sympathetic function. RESEARCH DESIGN AND METHODS: We investigated pain intensities and blood pressure reactions simultaneously during a cold pressor test in 30 IDDM patients (diabetes duration 12 +/- 6 years, HbA1c 7.5 +/- 1.4%) and in 30 normal control subjects with comparable sex distribution, age, height, BMI, physical fitness, and smoking habits. RESULTS: Initial pain intensities and respective time courses did not differ between the two groups. The initial blood pressure response was significantly smaller in diabetic patients (P < 0.002). Correlations of diastolic blood pressure increases in diabetic patients with initial pain intensity, standard cardiovascular reflex tests, age, clock time, smoking habits, disease duration, and actual blood glucose concentrations did not reach statistical significance. Pain intensity and diastolic blood pressure increases, however, were correlated to HbA1c concentrations in diabetic patients. CONCLUSIONS: Impaired pain perception is not the cause of the impaired reactions of blood pressure in diabetic patients during the cold pressor test, leaving very early deterioration of either cerebral processing of pain stimuli, cardiac function, efferent sympathetic nerves, or decreased vascular reactivity as possible explanations.

Modifications of glial metabolism of glutamate after serotonergic neuron degeneration in the hippocampus of the rat.

We have investigated the role of serotonergic neurons on the astrocytes catabolism of glutamate by analyzing glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression in the hippocampus after the degeneration of serotonergic neurons by a specific neurotoxin (5,7-DHT). 5,7-DHT caused reactive gliosis with hypertrophy (increase in glial fibrillary acidic protein (GFAP) expression) but not proliferation of astrocytes. Glutamate metabolism appeared preferentially regulated by a control of GDH expression rather than GS since the expression of GDH was specifically and significantly induced in the hippocampus whereas the level of GS remained unchanged. The inhibition of serotonin synthesis (by para-chlorophenylalanine (p-CPA) administration) produced no significant increase of GDH level. This suggests that serotonin is not the principal factor involved in this control of GDH expression.

Long-term astroglial reaction to serotonergic fiber degeneration.

Glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) expression were analysed by Western and Northern blotting in the hippocampus, the frontal and occipital cortex, and the cerebellum of the adult rat, as a manifestation of the astroglial reaction, 2 and 3 months after 5,7-dihydroxytryptamine injection into the lateral ventricule. 5HT injury stimulated GFAP and GS expression in a temporally and regionally specific fashion. At 2 months postlesion, the GFAP-mRNA and GFAP levels appeared enhanced but returned to control levels at 3 months. The GFAP-mRNA and GS-mRNA levels increased in the frontal cortex at 3 months. Such a delayed astroglial reactivity might implicate astrocytes in neurodegenerative disorders.

Differentiation of a medulloblastoma cell line towards an astrocytic lineage using the human T lymphotropic retrovirus-1.

Constituent cells of medulloblastoma, the most common brain tumor occurring in childhood, resemble the primitive neuroepithelial cells normally found in the developing nervous system. However, mutational events prevent their further differentiation. We used the human T cell lymphotrophic virus type 1 to activate these deregulated immature cells by means of its transactivating protein Tax. Concomitant with viral infection was a decrease in cell proliferation characterized by inhibition of [3H]thymidine incorporation and in the number of cells in the G2/M phase of the cell cycle. Morphological changes suggested that medulloblastoma cells differentiated along the astrocytic lineage. The glial phenotype was confirmed by the induction of the glial fibrillary acidic protein and the glial enzyme glutamine synthetase. A direct viral effect and/or secondary effects to viral infection via paracrine/autocrine pathways could counterbalance the maturational defect in these medulloblastoma cells.

Somatotopic organization of tyrosine hydroxylase expression in the rat locus coeruleus: long term effect of RU24722.

Tyrosine hydroxylase (TH) tissue concentration was determined by immunostaining of tissue sections directly transferred onto nitrocellulose membranes in the restricted region of the noradrenergic perikarya of the locus coeruleus (LC) along its postero-anterior axis. TH containing cells were systematically counted on adjacent post fixed sections stained by immunohistochemistry. The absolute quantity of TH was estimated in each section and was found to be linearly related to the number of TH immuno-positive cells found in the adjacent section. The ratio between these two parameters was thus used as an index of the cellular concentration of TH in noradrenergic cells. In the LC of control rats, the TH cellular concentration was lower (-39%) in the anterior than in the posterior half of the structure. Three days after an injection of 20 mg/kg of RU24722, an eburnamine derivative known to increase the quantity of TH in the LC, increases in quantities of TH were found in both portions of the LC. Moreover in the posterior LC the increase in the amount of TH resulted from a significant increase in the number of TH-immunopositive cells. In the anterior part, however, it was primarily the result of a significant increase in TH cellular concentration. Throughout the LC there was an increase in the cellular concentration of TH which was inversely proportional to the concentrations found in control animals. TH mRNA content was measured by a quantitative in situ hybridization in sections of both the posterior and anterior LC one day after a single injection of RU24722 at the same dose. The quantity of TH mRNA was significantly increased in both parts. The number of TH mRNA-expressing neurons also increased, especially in the anterior LC. Thus the effects at the level of TH protein and TH mRNA were strikingly parallel though increase in TH protein occurred later than the increase in the TH mRNA. These results suggest that in the rat LC: (1) there is a significant population of 'sleeping cells' in which TH expression is either inactivated or, at a low level of activation; (2) TH cellular concentration could exert a retrocontrol on its own expression in cells of the LC that contained TH and (3) TH expression appears to be regulated by different selective mechanisms in these two different subpopulations of noradrenergic cells within the LC.

Developmental neuron-glia interactions: role of serotonin innervation upon the differentiation of the ependymocytes of the rat subcommissural organ.

The rat subcommissural organ (SCO), which forms the roof of the third ventricle is an adequate model to study certain mechanisms of neuron-glia interactions in vivo. The ependymocytes, the main component of the SCO, have a glial origin. They possess particular phenotypic characteristics: they accumulate [3H]GABA by a specific uptake mechanism, contain transitory GFAP during ontogenesis and do not express PS100; on the other hand they receive a 5HT input which forms typical synaptic contacts. This innervation is of particular interest to approach neuron-glia interactions during the differentiation. Studies of GABA uptake carriers during ontogenesis in SCO ependymocytes show a correlation between the onset of the 5HT innervation and the advent of the GABA uptake. Moreover, destruction of the 5HT innervation by a neurotoxin (5-7-dihydroxytryptamine), before its arrival at the SCO in newborn rat, inhibits the formation of the GABA uptake system and causes the expression of PS100 in adult SCO cells. On the other hand, the SCO of newborn rats transplanted to the fourth ventricle of an adult host rat had no capacity to take up GABA and expressed PS100 3 months after its transplantation. Finally, the SCO ependymocytes of species devoid of 5HT innervation (rabbit, mice) were unable to take up GABA and contain PS100. These data suggest that neuron-glia interactions are necessary for the advent of GABA uptake carriers and can control the expression of glial markers during ontogenesis in SCO ependymocytes.

Developmental expression of glial markers in ependymocytes of the rat subcommissural organ: role of the environment.

The rat subcommissural organ (SCO), principally composed of modified ependymocytes (a type of glial cell), is a suitable model for the in vivo study of glial differentiation. An immunohistochemical study of the ontogenesis of rat SCO-ependymocytes from embryonic day 13 to postnatal day 10 shows that these cells express transitory glial fibrillary acidic protein (GFAP) from embryonic day 19 until postnatal day 3. However, S100 protein (S100) is never expressed in the SCO-cells, contrasting with the ventricle-lining cells of the third ventricle, which contain S100 as early as embryonic day 17. Environmental factors could be responsible for the repression of GFAP and S100 in adult rats, because GFAP and S100 are observed in ependymocytes of SCO 3 months after being grafted from newborn rat into the fourth ventricle of an adult rat. Neuronal factors might be involved in the control of the expression of S100, since after the destruction of serotonin innervation by neurotoxin at birth, S100 can be observed in some SCO-ependymocytes of adult rats. On the other hand, GFAP expression is apparently not affected by serotonin denervation, suggesting the existence of several factors involved in the differentiation of SCO-cells.

Developmental neuron-glia interaction: role of the serotonin innervation upon the onset of GABA uptake into the ependymocytes of the rat subcommissural organ.

The subcommissural organ (SCO) of the rat allows the analysis of neuron-glia interactions, in vivo, during the maturation of the brain. The SCO contains a single glial cell type which receives a homogeneous serotonin (5-HT) innervation. The onset of gamma-aminobutyric acid (GABA) uptake transport into the SCO ependymocytes is dependent on the 5-HT innervation since destruction of this innervation, at birth, or transplantation of newborn rat SCO ependymocytes to the fourth ventricle of adult host rats prevented the appearance of [3H]GABA uptake as visualized by autoradiography.

[Neuron-glia interactions]. / Interactions neurone-glie.

The progress of research in the Central Nervous System (CNS) had led to the consideration of neurons and glia as indissociable functional complexes. Neuron-glia interactions are essential for the maturation of the CNS. Glial cells release trophic factors for neurons (NGF) and neurons release trophic factors for glia (GGF). Furthermore, the latter provide a substrate for the migration of neurons and guidance of axons by mean of adhesion molecules. In adults, the interactions between neurons and glial cells serve to maintain homeostasis. Thus, the glial cells perform the restoration of the metabolic equilibrium overthrown by the transmission of the nerve impulse and provide the glucose required for neuronal activity. The nerve impulse provokes increases in the cellular space of CO2, K+, NH3 and neurotransmitters which must be taken up to allow neuronal activity to continue (in normal conditions). Astrocytes perform the uptake of the extracellular K+ by means of passive ionic channels, ionic voltage-dependent channels and a sodium-potassium-ATPase-dependent pump. The oligodendrocytes are involved in the metabolism of CO2 by converting CO2 into carbonic acid by means of carbonic anhydrase. Oligodendrocytes and astrocytes play a role in terminating neural transmission by the uptake of the amino acid neurotransmitters, such as GABA, glutamate and aspartate. The catabolism of glutamate to glutamine by means of glutamine synthetase allows both the conversion of an excitatory amino acid into a neutral amino acid (which can diffuse in the extracellular space without causing neural transmission) and the reduction of cerebral NH3 content.(ABSTRACT TRUNCATED AT 250 WORDS)

[Demonstration of viral proteins and RNA in hypothalamus of mice infected by canine distemper virus]. / Mise en évidence de protéines et d'ARN viraux dans l'hypothalamus de souris infectées par le virus de la maladie de Carré.

There are a number of reports suggesting that neurological disorders may be due to infectious agents, such as viruses. In order to study the role of viruses on cellular plasticity in the central nervous system, we established a model of virus infection in the mouse. Inoculation of mouse with canine distemper virus (CDV) led to an acute encephalitis, late neurological disorders and an obesity syndrome. To analyse the role of viral replication on the development of this syndrome we studied the cerebral distribution of viral products during the course of infection. Viral proteins and RNA accumulated in mouse brain from the 9th day to the 6th week post-inoculation, particularly in hypothalamus, a cerebral structure implicated in obesity. Such selective viral tropism may explain some of the unexpected features of viral-induced disorders.

Neuron-glia interactions: effect of serotonin on the astroglial expression of GFAP and of its encoding message.

The trophic effect of serotonin on the glial fibrillary acidic protein (GFAP) expression was investigated in rat brainstem astrocytes in primary culture. GFAP immunolabelling decreased and gliofilaments appeared localized in the cytoplasm periphery. GFAP protein level decreased in parallel with a decrease in its encoding message. Serotonin may act as an inhibitor of GFAP expression either on the transcription or on the stability of the GFAP-mRNA.

Antipseudomonal effects of selected dithiocarbamates alone and in combination with gentamicin or aztreonam.

The antipseudomonal effects conferred by combinations of substituted dithiocarbamates, gentamicin or aztreonam (Azactam) were measured and compared to those produced by single agents alone in female BALB/C mice bearing overwhelming Pseudomonas aeruginosa infections. Dimethyldithiocarbamate (DMDTC), diethyldithiocarbamate (DEDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMGDTC) were chosen as representative substituted dithiocarbamates. All three dithiocarbamates rescued some cisplatin-immunosuppressed mice from pseudomonal infections but DMDTC and NMGDTC produced better results than DEDTC. Single daily injections of DMDTC at doses of 5 mg/kg/day or higher for a total of 7 days rescued 14 of 18 mice given 10(6) viable Pseudomonas aeruginosa by tail vein inoculation. Similar dose regimens of 10 mg/kg/day or higher NMGDTC for a total of 7 days rescued 15 of 18 mice. DEDTC at doses of 5 mg/kg/day or higher for 7 days rescued 7 of 18 mice. Combinations of DMDTC or NMGDTC with gentamicin failed to produce better results than each agent alone in mice immunosuppressed with methyl-prednisolone (Solumedrol) at the dose range evaluated in mice inoculated with 10(6) viable organisms via tail veins. Combinations of DMDTC and aztreonam were effective in mice immunosuppressed with methylprednisolone and given overwhelming numbers of viable Pseudomonas aeruginosa (10(7) or more, ip). Combinations of 6 mg/kg/day or higher of each agent with multiple daily injections rescued 11 of 18 mice. The results yielded by either agent alone were not impressive. Similar results were obtained when mice immunosuppressed with cisplatin were given ip injections of 10(8) or more viable bacteria. No mice were rescued by the use of DMDTC, NMGDTC, aztreonam or gentamicin only. Combinations of DMDTC (6 mg/kg) and aztreonam (6 mg/kg) with multiple daily injections for seven days rescued 11 of 20 infected mice while combinations of NMGDTC with aztreonam were less effective (3 of 20 rescued). The concurrent administration of DMDTC and aztreonam offers considerable promise in the treatment of overwhelming pseudomonal infections in mice and may prove to be of value in human patients as well.

On the vicissitudes of Freud's early mothering. III: Freiberg, screen memories, and loss.

Utilizing clinical examples, I attempt to show that the memories Freud recalled on his return to his childhood home in adolescence screened the traumata he had suffered when he lost his Kinderfrau, then his playmates and the Freiberg countryside during his early childhood.

On the vicissitudes of Freud's early mothering. II: Alienation from his biological mother.

Continuing an exploration of the vicissitudes of Freud's early mothering experience, this paper utilizes three clinical examples to focus on alienation between Freud and his biological mother. This state of affairs is demonstrated in his reticence about her, his concern about dying before her, and, finally, in his perception of daughter Anna's being his surrogate mourner at the time of his mother's death.

On the vicissitudes of Freud's early mothering. I: Early environment and loss.

Utilizing case examples and published accounts of Freud's infancy, I attempt to demonstrate that an upheaval in Freud's life, with a desperate turning to his mother and to oedipal issues, was the result of the loss of his nurse.

Effects of diethyldithiocarbamate and structural analogs in mice with systemic candidal infections.

Three different substituted dithiocarbamates: sodium diethyldithiocarbamate (DDTC), sodium dimethyldithiocarbamate (DmDTC), and sodium N-methyl-D-glucamine dithiocarbamate (NMG-DTC) were evaluated for their ability to combat the growth and development of three human pathogenic strains of Candida albicans, in vitro and in vivo, in mice. DDTC and DmDTC produced marked growth inhibition on agar plates, in vitro, of three different strains of Candida albicans, while NMG-DTC displayed little inhibitory effect. Low, nontoxic doses of each compound administered to immunosuppressed mice exhibited impressive therapeutic effects in treating candidiasis. NMG-DTC showed the best consistent therapeutic antifungal effect against Candida albicans in mice immunosuppressed with Solu-Medrol. Combinations of low doses of DDTC and Amphotericin-B appeared to be effective in treating systemic candidal infections, and the results suggested that these combinations may offer therapeutic advantages over those produced by the use of either agent alone.