Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review.

Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive somnolence, modafinil is thought to be used widely off-prescription for cognitive enhancement. However, despite this popularity, there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy, non-sleep-deprived humans. This problem is compounded by methodological discrepancies within the literature, and reliance on psychometric tests designed to detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date systematic evaluation that addresses these concerns, we searched MEDLINE with the terms "modafinil" and "cognitive", and reviewed all resultant primary studies in English from January 1990 until December 2014 investigating the cognitive actions of modafinil in healthy non-sleep-deprived humans. We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.

Seasonal photosynthetic responses of European oaks to drought and elevated daytime temperature.

Oaks are commonly considered as drought- and heat-tolerant trees that might benefit from a warmer and drier climate. Their tolerance to drought has been frequently studied in the past, whereas studies dealing with elevated temperature or its combination with drought are very limited in number. In this study we investigated seasonal photosynthetic patterns in three European oak species (Quercus robur, Q. petraea, Q. pubescens) exposed in lysimeter-based open-top chambers (OTC) to elevated daytime temperature, drought and their combination. Stomatal and non-stomatal traits of photosynthesis were followed over an entire growing season and related to changes in daytime temperature, soil moisture and pre-dawn leaf water potential (Ψ(PD) ). Elevated daytime temperature enhanced net photosynthesis (P(N) ) in a season-dependent manner, with higher mid-summer rates than in controls exposed to ambient temperature. Drought imposed in early and mid-summer reduced the soil moisture content and caused a gradual decline in Ψ(PD) , stomatal conductance (g(S) ) and P(N) . Drought effects on Ψ(PD) and P(N) were exacerbated when drought was combined with elevated daytime temperature. In general, P(N) tended to be more affected by low soil moisture content or low Ψ(PD) in Q. robur than in Q. petraea and Q. pubescens. Non-stomatal limitations may have contributed to the drought-induced decline of P(N) in Q. robur, as indicated by a down-regulation of PSII photochemistry (F(V) /F(M) ) and decreased chlorophyll content. Taken together, our findings show that European oaks may benefit from elevated temperature, but detrimental effects can be expected when elevated temperature occurs simultaneously with drought.

Endogenous inhibitors (GALFs) of 11beta-hydroxysteroid dehydrogenase isoforms 1 and 2: derivatives of adrenally produced corticosterone and cortisol.

Two isoforms of 11beta-HSD exist; 11beta-HSD1 is bi-directional (the reductase usually being predominant) and 11beta-HSD2 functions as a dehydrogenase, conferring kidney mineralocorticoid specificity. We have previously described endogenous substances in human urine, "glycyrrhetinic acid-like factors (GALFs)", which like licorice, inhibit the bi-directional 11beta-HSD1 enzyme as well as the dehydrogenase reaction of 11beta-HSD2. Many of the more potent GALFs are derived from two major families of adrenal steroids, corticosterone and cortisol. For example, 3alpha5alpha-tetrahydro-corticosterone, its derivative, 3alpha5alpha-tetrahydro-11beta-hydroxy-progesterone (produced by 21-deoxygenation of corticosterone in intestinal flora); 3alpha5alpha-tetrahydro-11beta-hydroxy-testosterone (produced by side chain cleavage of cortisol); are potent inhibitors of 11beta-HSD1 and 11beta-HSD2-dehydrogenase, with IC50's in range 0.26-3.0 microM, whereas their 11-keto-3alpha5alpha-tetrahydro-derivatives inhibit 11beta-HSD1 reductase, with IC50's in range 0.7-0.8 microM (their 3alpha5beta-derivatives being completely inactive). Inhibitors of 11beta-HSD2 increase local cortisol levels, permitting it to act as a mineralocorticoid in kidney. Inhibitors of 11beta-HSD1 dehydrogenase/11beta-HSD1 reductase serve to adjust the set point of local deactivation/reactivation of cortisol in vascular and other glucocorticoid target tissues, including adipose, vascular, adrenal tissue, and the eye. These adrenally derived 11-oxygenated C21- and C19 -steroidal substances may serve as 11beta-HSD1- or 11beta-HSD2-GALFs. We conclude that adrenally derived products are likely regulators of local cortisol bioactivity in humans.

Clinical morbidity in pediatric dialysis patients: data from the Network 1 Clinical Indicators Project.

The Health Care Financing Administration (HCFA) has gathered clinical data on end stage renal disease (ESRD) patients since 1994, but details are only available on patients >/=18 years. In this report, we present morbidity data collected prospectively over 12 months from all children (1-18 years) maintained on either hemodialysis (HD) or peritoneal dialysis (PD) within the six-state New England area. During this year, 17 observations were recorded on 14 HD patients (age 13.4+/- 11.3 years) and 36 observations were made on 25 PD patients (age 11.5+/-4.8 years; mean +/- SD). These patients were generally highly functional, attending school at least part time in nearly all cases. Dialysis adequacy index (DAI), defined as the delivered KT/V divided by DOQI guideline values, indicated that patients were well dialyzed (HD 1.41+/-0.1 and PD 1.10+/-0.1; mean +/- SE). When all dialysis patients were grouped and analyzed, the DAI did not correlate with number of hospitalizations, degree of anemia, serum albumin, or type of dialysis. The number of hospitalizations were greater the younger the patient (P<0.01). The need for antihypertensive medications was higher in the children maintained on HD (94%) compared to children on PD (58%) (P<0.01). Lastly, while serum ferritin did not correlate with serum iron, hematocrit or Epo dosage, it was inversely related to serum albumin (P<0.03). We conclude that, in children, (1) exceeding suggested dialysis adequacy may not improve patient morbidity, (2) the need for antihypertensive medications appears greater in children maintained on HD, and (3) inflammation may play a role in determining serum albumin independent of nutrition.

Insights Into Glucocorticoid-Associated Hypertension.

The association between excess glucocorticoids and hypertension has been much discussed but poorly understood. From both clinical observations and laboratory studies, it is clear that glucocorticoids exert their effects at many different sites responsible for blood pressure regulation. Isoforms of the enzyme 11ss-hydroxysteroid dehydrogenase (11ss-HSD), located in steroid-responsive tissues, metabolize endogenously produced glucocorticoids. These enzymes limit steroid access to mineralocorticoid and/or glucocorticoid receptors. In the kidney, synthetic and endogenous glucocorticoids are capable of enhancing transepithelial sodium transport in the presence of 11ss-HSD inhibition. Proximal tubule reabsorption of sodium can be indirectly augmented after chronic exposure to glucocorticoids. In this segment, steroids have a permissive effect, increasing the expression of both Na(+), K(+) adenosine triphosphatase along the basolateral membrane and Na(+)-H(+) exchanger along the apical membrane of epithelial cells. Although glucocorticoids themselves produce no increase in sodium reabsorption in this segment, angiotensin II-stimulated sodium transport is significantly greater in proximal tubular cells pretreated with glucocorticoids. The increased transport in distal renal segments is more direct and stems in part from glucocorticoid cross-over binding to mineralocorticoid receptors. In vascular tissue, synthetic and endogenous glucocorticoids, after inhibition of the dehydrogenase reaction, magnify the response to circulating vasoconstrictors. The effects of glucocorticoids in vascular tissue is indirect, upregulating the expression of receptors to many vasoconstrictors and downregulating the effects of potential vasodilators. Thus, glucocorticoids have the potential to alter both circulating volume and vascular resistance.

Outcome data on pediatric dialysis patients from the end-stage renal disease clinical indicators project.

Network 1 (New England) initiated the Clinical Indicator Project to survey dialysis adequacy (Kt/V), nutrition (serum albumin level), and anemia management in patients maintained on chronic dialysis. Because little information is available in children, data were specifically recorded covering these variables in patients (age, 1 to 18 years) maintained on either hemodialysis (HD) or peritoneal dialysis (PD). During the 18 months of data collection, 29 observations were recorded on 23 HD patients (age, 14.3 +/- 3.6 years), and 43 observations were made on 30 PD patients (age,10.6 +/- 4.7 years). Kt/V correlated inversely with the age of the patient (HD, P < 0.004; PD, P < 0.0007). Although serum albumin level was not associated with dialysis adequacy in HD patients, there was a strong inverse relationship between albumin level and Kt/V in PD patients (P < 0.002). Hematocrit values were not significantly different in the two groups (HD, 31.0% +/- 5.5% versus PD, 32.9% +/- 4.8%) and could not be correlated with weekly erythropoietin dose. Weekly erythropoietin dose was directly related to patient age in both groups (HD, P < 0.05; PD, P < 0.02). The weekly erythropoietin dosage needed to maintain the hematocrit was greater in HD patients (HD, 11,211 +/- 7,484 U versus PD, 3,790 +/- 1,968 U; P < 0.0001). We conclude that (1) smaller children in both groups tend to have a greater Kt/V, (2) Kt/V greater than 2.75 in PD patients may not improve nutrition per se and could result in increased albumin losses, and (3) erythropoietin dosing appears to correlate best with patient size (age) rather than degree of anemia.

Interactions of mineralocorticoids and glucocorticoids in epithelial target tissues.

BACKGROUND: : In Na+-transporting epithelial target tissues, such as mammalian kidney and the isolated toad bladder, glucocorticoids (GCs) do not normally elicit Na+ retention. In mammalian kidney, however, they do cause kaliuresis. The presence of 11beta-hydroxysteroid dehydrogenase isoform 2 (11beta-HSD2) in these target tissues inactivates the GCs, preventing them from accessing mineralocorticoid receptors (MRs) and stimulating Na+ transport. RESULTS: : The usually observed Na+ retention elicited by the mineralocorticoid aldosterone was blunted when the GC corticosterone was coadministered along with aldosterone. However, when corticosterone was administered along with a 11beta-HSD2 inhibitor, a strong Na+ transport was elicited by an MR-mediated mechanism. 11-Dehydrocorticosterone also blunted aldosterone-elicited Na+ transport in these target tissues. CONCLUSIONS: : 11beta-HSD2 appears to play two important roles in the epithelial target tissues, kidney and toad bladder. The first is to protect GC access to MR, and the second involves the product of the enzyme to regulate the magnitude of aldosterone-induced Na+ retention.

Primary laparoscopic placement of peritoneal dialysis catheters in children and young adults.

BACKGROUND: Primary placement of peritoneal dialysis catheters in children often requires suturing of the catheter into the pelvis. We describe our experience with a gasless laparoscopy technique in children and young adults. METHODS: During an 18-month period, 12 patients (mean age, 14 years) underwent primary laparoscopic placement of peritoneal dialysis catheters. A single umbilical port was used for abdominal wall elevation, telescope, and catheter. A needleholder was introduced via an accessory port at the future catheter exit site or through the umbilical port. Omentectomy was performed through the umbilical incision. The catheter was tunneled to the lateral abdominal wall. Follow-up data (>/= 15 months) included time to initiation of dialysis, hospitalization, and outcome. End points were cure, transplantation, or death. RESULTS: Diet was started on the day of surgery and dialysis on the following day. Four patients had seven complications, including leakage and entanglement of the catheter in tubal fimbriae. Long-term revision-free catheter survival was 67% at 24 months. CONCLUSIONS: This minimal access technique for primary placement of peritoneal dialysis catheters includes securing of the catheter tip in a dependent location and omentectomy. It allows nearly immediate use of the catheter, leads to a minimal hospital stay, and has acceptable long-term patency.

Glucocorticoid metabolism in proximal tubules modulates angiotensin II-induced electrolyte transport.

The hormonal interactions that regulate electrolyte transport in the proximal tubule are complex and incompletely understood. Since endogenous glucocorticoids and angiotensin II each can affect electrolyte transport in this renal segment, we hypothesized that local metabolism of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) might alter the response to angiotensin II. Studies were conducted in cultured origin defective SV-40 transformed immortalized renal proximal tubule cells (IRPTC) derived from weanling Wistar rat kidney. The 11beta-HSD contained in these cells uses NADP+, has an apparent Km for corticosterone of 1.6 microM, but functions only as a dehydrogenase (corticosterone --> 11-dehydro-corticosterone). When mounted in modified Ussing chambers, IRPTC generate a transmembrane current, and angiotensin II (10 pM to 10 microM) increases this sodium-dependent current. Cells incubated with corticosterone (100 nM) and the 11beta-HSD inhibitor carbenoxolone (CBX) (1 microM) for 24 hr and then acutely stimulated with angiotensin (10 nM) show a greater rise in current than do cells exposed to corticosterone alone and stimulated with angiotensin (corticosterone + CBX: 64.2% +/- 20.5% vs. corticosterone: 18.8% +/- 5.9%; P < 0.02 at 180 min)[mean +/- SE percentage above baseline, n = 8/group]. Cells exposed to corticosterone (100 nM) or CBX (1 microM) alone for 24 hr and then stimulated with angiotensin II (10 nM) had responses similar to controls. Thus glucocorticoids can enhance angiotensin II-induced electrolyte transport in proximal tubule epithelial cells when local 11beta-HSD is inhibited.

Glucocorticoids inhibit the expression of calcium-dependent potassium channels in vascular smooth muscle.

Increased calcium-activated potassium channel (KCa) activity in vascular smooth muscle (VSM) cells leads to a relaxation response counteracting the effects of high blood pressure. Since chronic exposure to glucocorticoids (GC) can be associated with an increase in blood pressure, we reasoned that GCs might modify the expression of KCa channels resulting in a net rise in vascular tone. To test this hypothesis, primary cultures of rat VSM cells were exposed to (a) RU 28362 (a pure glucocorticoid receptor agonist), 1 microM; (b) corticosterone 10 nM + carbenoxolone (an inhibitor of bidirectional VSM 11beta-OH steroid dehydrogenase), 1 microM; (c) 11-dehydrocorticosterone (a biologically inactive metabolite), 10 nM + carbenoxolone; (d) carbenoxolone alone; or (e) aldosterone 10 nM for periods of up to 72 h. Proteins were then extracted and Western blots prepared. Gels were probed with a rabbit-derived polyclonal antibody directed against KCa channel protein. The experimental procedure was repeated on separate sets of VSM cells to ensure reproducibility. Expression of KCa channel protein was diminished in VSM cells incubated with corticosterone + carbenoxolone and with RU 28362 after 24 h and remained low at 72 h. Expression of KCa protein in cells exposed to 11-dehydrocorticosterone + carbenoxolone, carbenoxolone alone, and aldosterone was either similar to controls or mildly increased over the 72 h. These data are consistent with the hypothesis that GCs diminish the expression of KCa protein. Diminished KCa expression could contribute to the observed increase in vascular tone following chronic GC exposure.

Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANG II feedback.

The renal proximal tubule (PT) is a major site for a complete tissue renin-angiotensin system (RAS) and produces endogenous angiotensin II (ANG II). The present studies demonstrate autocrine RAS feedback in a line of origin-defective SV40 plasmid transformed immortalized rat PT cells (IRPTC) designated as line 93-p-2-1, which are highly differentiated and express all RAS components. Receptor competition assays and Southern blot following RT-PCR demonstrated that these IRPTC express AT1 and AT2 angiotensin receptor subtypes. Autocrine RAS feedback was examined following exposure to ANG II (10(-8) M), and it was noted that angiotensinogen mRNA increases significantly by 1 h and remains elevated through 24 h. The AT1 blocker losartan prevents this increase. Moreover, ANG II upregulates expression of ANG II receptor mRNA (both AT1 and AT2). Thus the present studies demonstrate positive ANG II feedback with angiotensinogen and ANG II receptors in PTC, suggesting that the main site of such intrarenal feedback in vivo is within PT. ANG II secreted by line 93-p-2-1 is increased by isoproterenol, suggesting beta-adrenergic regulation in IRPTC.

Effect of serum on vascular smooth muscle function.

Serum contains many biologically active factors influencing cell growth and is commonly used as a culture medium supplement. It has not generally been appreciated that serum can affect vascular tone. We have observed that the contractile response of aortic rings previously exposed to 10% fetal bovine serum (FBS) for 24 hours and then stimulated with phenylephrine (0.01-1microM) or angiotensin II (1microM) is significantly diminished compared to 1) rings incubated in FBS for only 6 hours, 2) aortic rings previously incubated in 1% FBS or 3) aortic rings incubated in 10% bovine serum albumin for 24 hours. A similar attenuated response was also seen when the vascular aortic rings were incubated in heat inactivated adult bovine serum. To test whether prostaglandins might be induced by factors contained in serum and account for the diminished stimulated contractile response, rings were incubated for 24 hours in media containing 10% FBS with either indomethacin 10microM, corticosterone 100nM or 11-dehydrocorticosterone 100nM. These agents are known to affect prostaglandin synthesis. Contractile responses were then measured accordingly. In each series, the previously attenuated contractile response to phenylephrine and to angiotensin II was fully restored with prostaglandin synthesis inhibition. Thus, factors contained in serum are capable of blunting the stimulated contractile response of rat aortic vessels. These serum factors appear to act by inducing prostaglandin synthesis in vascular tissue.

Localization of 2 11beta-OH steroid dehydrogenase isoforms in aortic endothelial cells.

11Beta-hydroxysteroid dehydrogenase (11beta-HSD) is expressed in vascular smooth muscle cells (VSMC) but has not been reported to be present in vascular endothelial cells. This enzyme assists in regulating the cellular concentration of active endogenous glucocorticoids (GCs). We have observed that endothelium intact rat aortic rings express message for both Type 1 and Type 2 11beta-HSD whereas primary cultures of VSMC express only mRNA for the Type I isoform. Since GCs diminish prostacyclin synthesis in endothelial cells, we hypothesized that 11beta-HSD is present in vascular endothelial cells. In primary cultures of rat aortic endothelial (RAE) cells, mRNA from both isoforms of 11beta-HSD could be detected by RT-PCR with higher levels of the Type 1 isoform. The oxo-reductase reaction "activating" 11-dehydro metabolites back to the parent steroid is the preferred enzyme direction (12:1 after a 120 minutes steroid incubation) in intact RAE cells. When RAE cells are grown in the presence of antisense oligonucleotides specific for Type 1 11beta-HSD, oxo-reductase activity is decreased by approximately 50% but the dehydrogenase reaction, which inactivates endogenous GCs and is characteristic of the Type 2 isoform, is unaffected. Thus endothelial cells appear to express both isoforms of 11beta-HSD; the Type 1 isoform dominates functioning in the oxo-reductase mode. Inhibition of the oxo-reductase reaction may lower the local concentrations of GC and indirectly allow for increased production of prostacyclin in endothelial cells.

Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.

Analysis of patients with inherited hypokalaemic alkalosis resulting from salt-wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood-pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss-of-function mutations that impair renal chloride reabsorption in the thick ascending limb of Henle's loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt-wasting, low blood pressure, normal magnesium and hyper- or normocalciuria; they define a distinct subset of patients with Bartter's syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood-pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.

11BetaOH-progesterone affects vascular glucocorticoid metabolism and contractile response.

Vascular smooth muscle (VSM) contains a bidirectional isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the enzyme that can metabolize endogenous glucocorticoids to their respective 11-dehydro derivatives. 11BetaOH-progesterone (11betaOH-P), a compound that can be produced in vivo, is as potent or more potent than licorice derivatives in inhibiting renal and hepatic 11beta-HSD. When studied in homogenates prepared from primary cultures of rat VSM, 11betaOH-P and its derivative, 11-keto-progesterone (11-keto-P), proved to be potent, directionally specific inhibitors of vascular 11beta-HSD. 11BetaOH-P selectively inhibited the forward dehydrogenase reaction (corticosterone-->11-dehydrocorticosterone), whereas 11-keto-P selectively blocked the reverse oxidoreductase reaction. To test the physiological effects, vascular rings were prepared from rat aorta. Rings were incubated in culture media containing either a submaximal concentration of corticosterone (10 nmol/L), 11-dehydrocorticosterone (100 nmol/L), 11betaOH-P (1 micromol/L), 11-keto-P (1 micromol/L), or a combination of glucocorticoid and inhibitor for 24 hours. After the 24-hour incubation, rings were briefly stimulated sequentially with phenylephrine (10 nmol/L to 1 micromol/L) and angiotensin II (1 micromol/L). The immediate contractile response in rings incubated with both corticosterone and 11betaOH-P was greater than in rings previously incubated with either the corticosterone or 11betaOH-P alone (eg, response to 100 nmol/L phenylephrine in milligrams of force, mean+/-SE: corticosterone, 728+/-56, n=9; 11betaOH-P, 325+/-105, n=4; both, 1132+/-122, n=8; corticosterone versus both, P<.01). In contrast, the immediate contractile responses to phenylephrine and to angiotensin II were attenuated in rings exposed previously to both 11-dehydrocorticosterone and 11-keto-P. Thus, 11betaOH-P and 11-keto-P (and possibly structurally similar compounds) alter the vascular effects of glucocorticoids and may play a role in glucocorticoid-induced hypertension.

Influence of dietary sodium on the renal isoforms of 11 beta-hydroxysteroid dehydrogenase.

Endogenous glucocorticoids are converted to their biologically inert 11-dehydroderivatives by isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). The low-K(m), NAD(+)-dependent renal isoform (Type 2) identified in the distal nephron protects mineralocorticoid receptors from activation by endogenous glucocorticoids. The function of high-K(m), NADP(+)-dependent renal isoform (Type 1) is less well understood. Since glucocorticoids may modulate sodium transport in renal proximal tubules (PT), we hypothesized that Type 1 activity in this segment may be regulated by dietary Na(+)-11 beta-HSD activity was assessed in homogenates of canine PT by the conversion of cortisol to cortisone in the presence of NADP+ 200 microM. A high-Na+ diet for 4 days increased the Vmax 4-fold, with no change in the Type 1 K(m) (40 mEq/day Na+ diet: K(m) 0.959 microM, Vmax 3.40 pmoles/min/mg protein versus 150 mEq/day Na+ diet: K(m) 0.962 microM, Vmax 14.8 pmoles/min/mg protein). Type 1 mRNA also rose in the salt repleted animals. The high-Na+ diet produced no detectable change in the Type 2 isoform enzyme kinetics and mRNA level. No reverse oxo-reductase activity was noted with either renal isoform. Thus, renal Type 1 11 beta-HSD can be regulated by dietary Na+ independent of changes in the renal Type 2 isoform.