Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.

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Glial and neuronal control of brain blood flow.

Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD(+)CD25(+) T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4(+) population of regulatory T cells in the circulation of humans expressing high levels of CD25 that exhibit in vitro characteristics identical with those of the CD4(+)CD25(+) regulatory cells isolated in mice. With TCR cross-linking, CD4(+)CD25(high) cells did not proliferate but instead totally inhibited proliferation and cytokine secretion by activated CD4(+)CD25(-) responder T cells in a contact-dependent manner. The CD4(+)CD25(high) regulatory T cells expressed high levels of CD45RO but not CD45RA, akin to the expression of CD45RB(low) on murine CD4(+)CD25(+) regulatory cells. Increasing the strength of signal by providing either costimulation with CD28 cross-linking or the addition of IL-2 to a maximal anti-CD3 stimulus resulted in a modest induction of proliferation and the loss of observable suppression in cocultures of CD4(+)CD25(high) regulatory cells and CD4(+)CD25(-) responder cells. Whereas higher ratios of CD4(+)CD25(high) T cells are required to suppress proliferation if the PD-L1 receptor is blocked, regulatory cell function is shown to persist in the absence of the PD-1/PD-L1 or CTLA-4/B7 pathway. Thus, regulatory CD4 T cells expressing high levels of the IL-2 receptor are present in humans, providing the opportunity to determine whether alterations of these populations of T cells are involved in the induction of human autoimmune disorders.

CD4+CD25high Regulatory Cells in Human Peripheral Blood

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing “consumptive hypothyroidism” as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium. (Endocrine Reviews 23: 38–89, 2002)

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.

/pdf/neuron-to-astrocyte-signaling-is-central-to-the-dynamic-2volr851qf.pdf

Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation

Objective To examine risk factors for the prevalence of dry eye syndrome in a population-based cohort. Methods The prevalence of dry eye was determined by history at the second examination (1993-1995) of the Beaver Dam Eye Study cohort (N = 3722). Results The cohort was aged 48 to 91 years (mean ± SD, 65 ± 10 years) and 43% male. The overall prevalence of dry eye was 14.4%. Prevalence varied from 8.4% in subjects younger than 60 years to 19.0% in those older than 80 years ( P P Conclusion The results suggest several factors, such as smoking, caffeine use, and multivitamin use, could be studied for preventive or therapeutic efficacy.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/413594/eeb90020.pdf

Prevalence of and Risk Factors for Dry Eye Syndrome

Sjogren's syndrome is a chronic autoimmune disease affecting the lacrimal glands and other epithelia. It has been suggested that acinar cells of the lacrimal glands provoke local autoimmune responses, leading to Sjogren's syndrome when they begin expressing major histocompatibility complex (MHC) class II molecules. We used isopycnic centrifugation and phase partitioning to resolve compartments that participate in traffic between the basolateral membranes and the endomembrane system to test the hypothesis that MHC class II molecules enter compartments that contain potential autoantigens, i.e., La/SSB, and enzymes capable of proteolytically processing autoantigen, i.e., cathepsins B and D. A series of compartments identified as secretory vesicle membranes, prelysosomes, and microdomains of the trans-Golgi network involved in traffic to the basolateral membrane, to the secretory vesicles, and to the prelysosomes were all prominent loci of MHC class II molecules, La/SSB, and cathepsins B and D. These observations support the thesis that lacrimal gland acinar cells that have been induced to express MHC class II molecules function as autoantigen processing and presenting cells.

MHC class II molecules, cathepsins, and La/SSB proteins in lacrimal acinar cell endomembranes

Testes of fetal rats possess the enzymes necessary for converting radioactive acetate to radioactive testosterone as early as 15.5 days of intrauterine life. The fetal testis is, therefore, capable of formation do novo of testosterone through the period of sexual differentiation of the internal genitalia. Testosterone was measured in testicular tissue of fetal rats. Values ranged from as low as 0.09 ng/mg at 15.5 days of gestation to 2.76 ng/mg at 18.5 days of gestation. The sharp rise at 18.5 days of fetal age coincides with morphological evidence that relatively large amounts of testosterone are necessary for Wolifian duct stabilization at this time. Fetal testes were also incubated with [‘4C] acetate or [‘H] pregnenolone. Whereas conversion of both substrates to radioactive testosterone occurred at 15.5 and 16.5 days of gestation, no such conversion was evident at 14.5 days of fetal age with either substrate. Nonradioactive testosterone was, however, measurable in incubation from all three time periods. Neither radioactive nor nonradioactive testosterone was detectable in incubations of fetal ovaries with radioactive acetate or pregnenolone at 15 to 20 days of gestation. The influence of steroid androgens on

Testosterone in the Fetal Rat Testis

To evaluate the extent to which LH receptors may participate in the regulation of testosterone production by the fetal and neonatal rat testis, the gonadal content of LH receptors was determined and correlated with the gonadal content of testosterone and other steroids at daily intervals throughout the period of sexual differentiation and early neonatal life. Also, to determine if FSH has a potential role during fetal life, FSH receptors were measured from 14.5 until 21.5 days of gestation, just before birth. LH receptors were first detected in the fetal rat testis at 15.5 days of gestation, at a concentration of 0.072 ± 0.016 fmol/gonad. This is the time at which previous studies have shown a biological response to LH stimulation with increases in cAMP and testosterone production. LH receptor content remained constant from 15.5–17.5 days of gestation and then increased sharply at 18.5 days of gestation to 0.706 ± 0.046 fmol/gonad, coincident with a surge in the testosterone content of the fetal testis. L...

Ontogeny of Gonadotropin Receptors in The Fetal and Neonatal Rat Testis

Testicular LH, lactogen, and estrogen receptors and in vitro steroidogenic and cAMP responses were measured in rats between the ages of 1 and 60 days. Testicular LH and lactogen receptors increased gradually with advancing age, although there was no direct correlation between the concentrations of the two receptors. Cytosolic estrogen receptors were present in the testis at 6 days of age, but α-fetoprotein represented the major estrogen-binding component until 20 days of age. The basal and maximally stimulated in vitro production rates of testosterone, pregnenolone, and cAMP per unit weight were more than 10-fold higher in neonatal rats than in 60-dayold animals. These production rates decreased rapidly to a nadir at 15 days and increased again between 15 and 60 days of age. Treatment of 1-day-old rats with a low dose of hCG (10 IU/kg daily) for 3 days caused an increase of 91% (P < 0.01) -in LH receptors per testis. This effect of hCG diminished gradually with advancing age and became insignificant in an...

Acquisition of Regulatory Mechanisms for Gonadotropin Receptors and Steroidogenesis in the Maturing Rat Testis

In 9 euthyroid volunteers and 6 athyreotic subjects receiving replacement thyroxine therapy, a single dose of dexamethasone caused significant reduction in circulating concentrations of total serum triiodothyronine (T3). The fall was observed 24 hours following the administration of dexamethasone with return to pre-treatment concentrations evident by 48 hours. The reduction in serum T3 in the athyreotic group on replacement thyroxine therapy demonstrates a direct effect of glucocorticoids on the peripheral metabolism of T3 in man.

Dwight W. Warren

Papers

MHC class II molecules, cathepsins, and La/SSB proteins in lacrimal acinar cell endomembranes

Testosterone in the Fetal Rat Testis

Ontogeny of Gonadotropin Receptors in The Fetal and Neonatal Rat Testis

Acquisition of Regulatory Mechanisms for Gonadotropin Receptors and Steroidogenesis in the Maturing Rat Testis

Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man