The extrapyramidal syndromes of chronic kidney disease and dialysis (EPS-CKDD): diagnostic criteria, risk factors and prognosis.

BACKGROUND: Acute extrapyramidal movement disorders in dialysis patients are rare, inconsistently defined and have uncertain aetiology and prognosis. AIM: Define diagnostic criteria, prognosis and risk factors. DESIGN AND METHODS: Retrospective case series review of 20 patients (14 female, mean age 62 years) receiving dialysis for a median of 15 (interquartile range 4-35) months who presented with acute parkinsonism (AP = 11) or chorea/athetosis (CA = 9). RESULTS: All patients had type 2 diabetes (HbA1c 6.8 ± 1.0) and had received metformin. Lactic acidosis was present in 2 patients at presentation and serum lactate was elevated in 7/15 patients tested. No patient had abnormal copper or thyroid metabolism and 5/8 patients tested returned marginal abnormalities in heavy metal screening. Magnetic resonance imaging (MRI) revealed characteristic bilateral symmetric T2 hyperintensity of the basal ganglia (BG), predominantly putamen and globus pallidus (the lentiform nucleus) and more extensive involvement of the external and internal capsules in patients with AP presentation. Post-mortem demonstrated cytotoxic necrosis of the BG. Therapy included thiamine, intensive dialysis and cessation of metformin. Two patients died acutely, nine recovered and nine had residual symptoms. Median survival did not differ by presentation: AP 24 [95% confidence interval (CI) 21-27] and CA 33 (95% CI 32-35) months, P = 0.21. CONCLUSIONS: There are two distinct clinical extrapyramidal movement disorders associated with specific diagnostic MRI imaging that support the diagnosis of the extrapyramidal syndromes of chronic kidney disease and dialysis. The associations with diabetes, metformin and metabolic acidosis suggest a common pathogenic mechanism but require additional study. Early recognition and treatment may improve outcomes.

Bilirubin and bile acids may modulate their own metabolism via regulating uridine diphosphate-glucuronosyltransferase expression in the rat.

BACKGROUND AND AIMS: Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) is a critical enzyme in the elimination of bilirubin and it also plays a role in the metabolism of bile acids. The aim of this study was to determine whether bilirubin and bile acids could modulate their own metabolism by regulating UGT levels in cultured rat hepatocytes. METHODS AND RESULTS: Incubation of hepatocytes with bilirubin (48 micromol/L) for 24 h significantly increased the mRNA expression of UGT1A1 and UGT1A5, two UGT isoforms responsible for the conjugation of bilirubin. The induction of UGT1A1 and UGT1A5 by bilirubin was concentration and time dependent. Treatment with chenodeoxycholic acid, cholic acid, deoxycholic acid, hyodeoxycholic acid and lithocholic acid at a concentration of 100 micromol/L for 48 h significantly enhanced the mRNA expression of UGT2B1, a UGT isoform responsible for the glucuronidation of bile acids. The UGT2B3 mRNA level was also increased by hyodeoxycholic acid. The regulation of UGT2B1 mRNA by chenodeoxycholic acid and hyodeoxycholic acid was dose and time dependent. CONCLUSION: Our results suggest that bilirubin and bile acids can induce UGT expression and as a result, these compounds may modulate their own metabolism. Such regulation could play a compensatory role in the pathological increased concentrations of these compounds in some hepatobiliary diseases.

Alcohol up-regulates UDP-glucuronosyltransferase mRNA expression in rat liver and in primary rat hepatocyte culture.

The interactions between alcohol and cytochrome P-450 enzymes have been well investigated. However, the data regarding the effect of alcohol on the regulation of UDP-glucuronosyltranferase (UGT) activity are less clear. The aim of the present study was to determine the role of alcohol in the regulation of UGT mRNA expression by using whole animal and primary cultured hepatocytes. Chronic ethanol feeding of rats significantly increased the expression of liver UGT1A1 mRNA to 177% of control. The mRNA levels for UGT1A5, UGT2B1 and UGT2B3 were also enhanced, but did not reach statistical significance. In cultured hepatocytes, treatment with either ethanol or isopentanol significantly increased the expression of UGT1A1, UGT1A5, UGT2B1, and UGT2B3 mRNAs, but to different degrees. The induction of UGT1A1 and UGT2B1 mRNAs by ethanol or isopentanol was time-dependent and maximal changes occurred at 48 h. The expression of UGT1A6 mRNA was not significantly modified by either ethanol or isopentanol. In conclusion, ethanol and isopentanol have direct roles in the regulation of UGT.

The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes.

PURPOSE: To investigate the direct effects of sex hormones, growth hormone, thyroid hormones and dexamethasone on the regulation of UDP-glucuronosyltransferase (UGT). METHODS: Rat hepatocytes were cultured on matrigel and treated with various hormones. Northern blot analysis was carried out using cDNA probes to family 1 and family 2 isoforms. RESULTS: Treatment with 10(-5) M testosterone increased the mRNA levels of UGT 2B1 by 29% and UGT2B3 by 32%. Incubation of growth hormone (10 mU) with hepatocytes suppressed the expression of UGT2B1 and UGT2B3 by 17% and 38%, respectively. T3 administration resulted in a time and dose-dependent effect on the expression of UGT 1 isoforms, with increased UGT1A6 by 70%, and decreased UGT1A1 by 38% and UGT1A5 by 35%. All UGT isoforms except UGT 1A6 studied in this assay were up-regulated by dexamethasone, but to different degrees. The regulation of UGT1A1 and UGT2B1 by dexamethasone was dose and time dependent, and the induction of dexamethasone in the expression of UGT1A1 and UGT2B1 was blocked by cycloheximide but not dichloro-1-D-ribofuranosylbenzimidazole. CONCLUSIONS: This study demonstrates that multiple hormones take part in the regulation of UGT mRNA expression in the rat and individual genes can be differentially modulated.

Magnesium in cardiac arrest (the magic trial).

The prognosis of out of hospital cardiac arrest (OHCA) is dismal. Recent reports indicate that high dose magnesium may improve survival. A prospective randomized double blind placebo controlled trial was conducted at the emergency department (ED) of Royal Perth Hospital, a University teaching hospital. Patients with OHCA of cardiac origin received either 5 g MgSO4 or placebo as first line drug therapy. The remainder of their management was standard advanced cardiac life support (ACLS). Study endpoints were: (1) ECG rhythm 2 min after the trial drug; (2) return of spontaneous circulation; (3) survival to leave the ED; (4) survival to leave intensive care; and (5) survival to hospital discharge. Of 67 patients enrolled, 31 received magnesium and 36 placebo. There were no significant differences between groups for all criteria, except that there were significantly more arrests witnessed after arrival of EMS personnel in the magnesium group (11 or 35% vs 4 or 11%). Return of spontaneous circulation occurred in seven (23%) patients receiving magnesium and eight (22%) placebo. Four patients in each group survived to leave the ED and one from the magnesium group survived to hospital discharge. There were no survivors in the placebo group. In this study, the use of high dose magnesium as first line drug therapy for OHCA was not associated with a significantly improved survival. Early defibrillation remains the single most important treatment for ventricular fibrillation (VF). Further studies are required to evaluate the role of magnesium in cardiac and cerebral resuscitation.

Stathmin in mung bean leaves and rat brain.

Stathmin is a highly-conserved, cytosolic protein whose synthesis and phosphorylation is closely associated with growth and differentiation. Although conserved among vertebrates, stathmin has not been identified in plants. In the present study, anti-stathmin antibodies were generated against a synthetic peptide corresponding to amino-acid residues 32-44 of rat stathmin, and these antibodies were used to probe immunoblots of proteins from rat brain and mung bean. The antibodies recognized 12-kDa, 21-kDa and 22-kDa proteins in cytosolic fractions from mung bean leaves and a 12-kDa protein in cytosolic fractions from roots. The two larger proteins identified by the antibodies have apparent molecular weights and isoelectric points similar to those of rat brain stathmin. These results are the first to show that stathmin-like proteins are present in plants.

Pluralistic ignorance and alcohol use on campus: some consequences of misperceiving the social norm.

Four studies examined the relation between college students' own attitudes toward alcohol use and their estimates of the attitudes of their peers. All studies found widespread evidence of pluralistic ignorance: Students believed that they were more uncomfortable with campus alcohol practices than was the average student. Study 2 demonstrated this perceived self-other difference also with respect to one's friends. Study 3 traced attitudes toward drinking over the course of a semester and found gender differences in response to perceived deviance: Male students shifted their attitudes over time in the direction of what they mistakenly believed to be the norm, whereas female students showed no such attitude change. Study 4 found that students' perceived deviance correlated with various measures of campus alienation, even though that deviance was illusory. The implications of these results for general issues of norm estimation and responses to perceived deviance are discussed.

Prolactin-induced proliferation of the Nb2 T-lymphoma is associated with protein kinase-C-independent phosphorylation of stathmin.

Phosphorylation of stathmin, a 19-kDa protein found in many tissues, has been linked to cell differentiation and proliferation. This protein is present in lymphocytes, and both phosphorylation and expression of stathmin are regulated by lymphotropic agents. In this study an antibody specific for stathmin was used to examine phosphorylation in response to PRL. The results suggest that PRL stimulates stathmin phosphorylation in the Nb2 lymphoma and that phosphorylation correlates with PRL-induced cell proliferation. Stathmin expression does not change substantially as PRL-stimulated Nb2 cells move through the cell cycle and enter into the S-phase. Thus, stathmin phosphorylation, but not expression, is regulated by PRL. Activation of protein kinase-C (PKC) in Nb2 cells also induces phosphorylation of stathmin, but PKC does not appear to mediate phosphorylation in response to PRL. The pattern of phosphorylation in response to 12-O-tetradecanoylphorbol-13-acetate differs from that in response to PRL, and down-regulation of PKC does not inhibit PRL-induced phosphorylation or proliferation. In addition to stathmin, PRL increases phosphorylation of a group of stathmin-like proteins. Phosphorylation of these proteins also correlates well with PRL-induced proliferation. Taken together, the results suggest that phosphorylation of stathmin and stathmin-like proteins may mediate some actions of PRL in Nb2 cells. The results further suggest that activation of PKC is not an important early event in PRL-stimulated mitogenesis in Nb2 cells.

Is intravenous lidocaine clinically effective in acute migraine?

We performed a prospective, randomized, double-blind, placebo-controlled trial of intravenous lidocaine (1 mg/kg) in the treatment of acute migraine. Thirteen subjects were randomly allocated to receive intravenous lidocaine and 12 received intravenous normal saline. Subjects scored the intensity of headache and nausea on separate visual analogue scales before the injection and at 10 and 20 min after injection. At 20 min, the mean pain intensity score was 80% of initial intensity in the lidocaine group and 82% in the placebo group. The difference was not statistically significant; at 20 min, the 95% confidence interval for the difference between the two groups in mean percentage of initial pain score was 2 +/- 29%. At the dose studied, intravenous lidocaine has, at best, only a modest effect in acute migraine.

Increases in p11 and annexin II proteins correlate with differentiation in the PC12 pheochromocytoma.

Regulation of p11 and annexin II by nerve growth factor, staurosporine, and epidermal growth factor was examined in PC12 rat adrenal pheochromocytoma cells using immunoblot analysis. Nerve growth factor, which is known to induce neurite outgrowth in PC12 cells, stimulated a five-fold increase in p11 and the higher levels of p11 were characteristic of PC12 cells exposed to nerve growth factor for up to ten days. Nerve growth factor induced an even greater increase (13.6-fold) in annexin II. Staurosporine, a protein kinase inhibitor that at high concentrations induces neurite formation, was as effective as nerve growth factor in increasing the intracellular levels of p11 and annexin II. Epidermal growth factor was less effective than nerve growth factor and staurosporine, producing only a two-fold increase in p11 and a three-fold increase in annexin II. The ineffectiveness of epidermal growth factor in increasing intracellular levels of p11 and annexin II is consistent with the fact that epidermal growth factor does not stimulate neurite outgrowth in PC12 cells. Evidence presented here suggests that p11 and/or annexin II may play a role in PC12 cell differentiation.

Familiarity and differences in self- and other-representations.

Two studies compared representations of the self and of other people, guided by the hypothesis that self-other differences derive from one's greater familiarity with oneself than with others. For the first study, participants wrote open-ended descriptions of themselves, a familiar person, and an unfamiliar person, which were analyzed for the amount and types of information they contained and for consistency in specific content across stimulus people and situations. Participants returned for a second study 1 week later and made timed judgments of information taken from their written protocols. The response latencies for these judgments were used to infer how information is organized in self- and other-concepts. The results supported most of the predicted self-other differences, but almost all were matched by differences between familiar and unfamiliar others. Familiarity does provide a parsimonious explanation for many self-other differences.

Growth and protein phosphorylation in the Nb2 lymphoma: effect of prolactin, cAMP, and agents that activate adenylate cyclase.

The Nb2 T lymphoma is unique in that these lymphocytes proliferate in response to prolactin as well as in response to interleukin-2. In this study, we have examined the responsiveness of the adenylate cyclase system in Nb2 cells and the role of this signaling system in regulating proliferation and protein phosphorylation. An analog of cAMP inhibited prolactin-stimulated proliferation and blocked a prolactin-induced decrease in protein phosphorylation. Forskolin, a potent activator of adenylate cyclase in T lymphocytes, did not elevate cAMP levels in Nb2 cells and was not an effective inhibitor of prolactin-induced proliferation. In fact, one preparation of forskolin stimulated proliferation of quiescent Nb2 cells. Like forskolin, prostaglandin E2 did not stimulate cAMP production in Nb2 cells even though it increased cAMP in a preparation of rat peripheral blood lymphocytes. Cholera toxin appeared to ADP-ribosylate a stimulatory guanine nucleotide-binding protein in Nb2 cells, but the toxin did not increase intracellular levels of cAMP nor was it a potent anti-mitogenic agent. Pertussis toxin, an agent that can increase cAMP production through suppression of the inhibitory guanine nucleotide-binding protein, exerted only minor anti-proliferative actions on prolactin-stimulated Nb2 cells. These data suggest that cAMP inhibits Nb2 cell proliferation and prolactin-induced changes in protein phosphorylation but that the adenylate cyclase system in our clone of Nb2 cells responds poorly to agents that normally increase cAMP.

Angiographically demonstrated arterial spasm in a case of benign sexual headache and benign exertional headache.

Benign headaches related to sexual activity and exertion are being recognised with increasing frequency. We wish to report a case of benign sexual headache (Type 2) and benign exertional headache, occurring sequentially in the same patient. Multiple areas of cerebral arterial spasm were demonstrable on angiography. This observation would support the concept that benign sexual headache (Type 2) and benign exertional headache may have a similar pathophysiology.

Inhibition of Nb2 T-lymphoma cell growth by transforming growth factor-beta.

Transforming growth factor-beta (TGF-beta) inhibits proliferation of Nb2 cells, a rat T lymphoma, in response to lactogens and interleukin-2. Prostaglandins may play an important role in the pathway through which TGF-beta exerts its inhibitory actions, because prostaglandin E2 also inhibits proliferation of Nb2 cells, and indomethacin, an inhibitor of prostaglandin synthesis, reverses the inhibitory effects of TGF-beta on Nb2 cell proliferation.

Changes in the biological activity of autacoids during passage through the human perfused fetoplacental lobule.

Changes in the biological activities of a number of autacoids after a single passage through the human perfused fetoplacental lobule have been assessed by bioassay, whilst recording fetal vascular resistance. Bradykinin did not affect vascular resistance, but its biological activity on the superfused bioassay tissues fell by approximately 98%, whereas des-Asp1-angiotensin I activity increased at least 80-fold and the vascular resistance rose. All these effects were inhibited by captopril. Angiotensin II increased vascular resistance but its activity on the bioassay tissues was not changed. 5-Hydroxytryptamine activity was reduced by 67-90% and resistance to flow was not affected. The activities of prostaglandins D2, E2, and F2 alpha were slightly reduced. Prostaglandins D2 and F2 alpha caused vasoconstriction, their maximum effects being greater than those of either of the angiotensins. The TxA2-mimetic U46619 was approximately 90 times more potent than PGF2 alpha, as a vasoconstrictor, but the maximal effects were comparable. Thus, autacoid activity can be reduced, augmented or not affected during passage through the human perfused fetal placental vasculature.

Bilateral anterior interosseous nerve syndromes associated with cytomegalovirus infection.

The occurrence of bilateral brachial mononeuropathies presenting as anterior interosseous nerve syndromes in association with cytomegalovirus mononucleosis in an otherwise healthy adult is reported, a relationship not previously described.