Sleep Quality in Children and Adults with Rett Syndrome.

BACKGROUND: Over 80% of individuals suffering from Rett syndrome (RTT) are affected over their life period by sleeping disorders. Little is known about the impact of those on the quality of life and a clinical approach to the treatment of sleep disturbances is lacking. AIMS: Primary aim was to assess sleep quality in children and adults. Secondary aim was to assess behavioral disorders and their relationship to sleep quality. The medication taken by the subjects was also included. METHODS: Sleep quality and medication were assessed using the sleeping questionnaire for children with neurological and other complex diseases (SNAKE). Behavioral disorders were assessed by the Rett Syndrome Behavior Questionnaire (RSBQ). Questionnaires were sent to the 700 members of the Elternhilfe für Kinder mit Rett Syndrom in Deutschland e.V. (Rett Aid) of which 287 were included. Questionnaires were filled out by the primary caregivers. RESULTS: Sleep quality was rated as very good to good by over 60% of caregivers in contrast to data available in the literature. Behavioral disorders related to regression such as loss of acquired hand skills (p = 0.046) and isolation (p = 0.002) were found to be associated with sleep quality. Melatonin showed a significant association (p = 0.007) with sleep quality. CONCLUSION: Our study showed sleep dysfunction to be less prevalent in RTT-affected individuals than evidence from past studies has suggested. Nevertheless, this remains a subjective assessment of sleep quality and therefore the need to find objective, disorder-specific parameters that measure sleep quality in RTT patients persists.

Intraperitoneal and subcutaneous injections of the TLR9 agonist ODN 1668 in rats: brain inflammatory responses are related to peripheral IL-6 rather than interferons.

Subcutaneous or intraperitoneal administration of Toll-like receptor (TLR)-9 agonist, ODN 1668 caused moderate fever and anorexia. In comparison to stimulation of other intracellular TLRs, activation of TLR9 did not result in pronounced peripheral induction of interferons, but rather induced interleukin-6. Expression of cytokines (TNFα, IL-1ß) and inducible forms of enzymes for prostaglandin E2 synthesis occurred in the brain, in conjunction with a moderate activation of the transcription factors STAT3 and NF-IL6 in brain endothelial cells. The lack of a septic-like state in ODN 1668-treated rats reinforces the therapeutic value of this drug.

Fever, sickness behavior, and expression of inflammatory genes in the hypothalamus after systemic and localized subcutaneous stimulation of rats with the Toll-like receptor 7 agonist imiquimod.

The Toll-like receptor 7 (TLR7) agonist imiquimod is used for topical treatment of skin cancers. We studied the consequences of injections of imiquimod into a subcutaneous (s.c.) air pouch or of intraperitoneal (i.p.) injections on the manifestation of fever, sickness behavior, and the peripheral and brain-intrinsic induction of a variety of inflammatory molecules. Rats were given imiqimod s.c. or i.p. (1 or 5 mg/kg). Body temperature, motor activity, and food and water intake were recorded by telemetric devices. Peripheral and brain-intrinsic induction of inflammatory mediators was analyzed by real-time polymerase chain reaction (RT-PCR), bioassays, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemistry. Imiquimod is the first TLR-agonist to produce more potent effects with s.c. than i.p. administration. Peripheral induction of interferons (IFNs) and putative circulating pyrogens corresponded to the magnitude of the illness responses. In the brain, an expression of cytokines (TNFα, IL-1ß, and IL-6) and inducible forms of enzymes for prostaglandin E2 synthesis (COX-2 and mPGES) occurred, which was accompanied by a moderate activation of the transcription factors NFκB and STAT3, and a strong activation of the transcription factor NF-IL6, in cells of specific areas with an open blood-brain barrier. These inflammatory responses noted within the brain were more marked after s.c. administration, than i.p. administration of imiquimod. At a dose of 5 mg/kg, imiquimod causes rather moderate brain-inflammatory responses, which are related to peripheral IFN-expression and possibly mediated by brain-intrinsic activation of NF-IL6 and induction of a proinflammatory cocktail. The lack of a septic-like state in imiquimod-treated rats reinforces the therapeutic use of this drug.

A pilot study of topiramate in childhood absence epilepsy.

OBJECTIVE: Evaluate the antiepileptic effect of topiramate monotherapy in childhood absence epilepsy (CAE). MATERIALS AND METHODS: Childhood absence epilepsy patients aged 4-9 years were initiated with topiramate 15 or 25 mg/day, which was titrated upwards until patients were free of absence seizures. The primary efficacy outcome was seizure-free rates after a 12-week maintenance period. RESULTS: The study was terminated early due to lack of efficacy after enrollment of 12 patients. Four patients completed the study; two became clinically seizure-free, but without a significant reduction in the number of electrographic seizures. Six patients discontinued for lack of efficacy, none due to adverse events (AEs). Mean reduction in seizure count was seen on Days 22 (P = 0.0391) and 36 (P = 0.0156) and percentage of days with seizures decreased from baseline. Most AEs were mild. CONCLUSIONS: Although well-tolerated, this pilot study did not demonstrate an antiepileptic effect of topiramate monotherapy for treatment of CAE.

Topiramate dose effects on cognition: a randomized double-blind study.

BACKGROUND: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. OBJECTIVE: To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). METHODS: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. RESULTS: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. CONCLUSIONS: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

Distinct physiologic properties of microglia and blood-borne cells in rat brain slices after permanent middle cerebral artery occlusion.

The authors investigated the time course of leukocyte infiltration compared with microglial activation in adult rat brain slices after permanent middle cerebral artery occlusion (MCAO). To distinguish peripheral leukocytes from microglia, the blood cells were prelabeled in vivo with Rhodamine 6G (Rhod6G) i.v. before induction of ischemia. At specific times after infarct, invading leukocytes, microglia, and endothelial cells were labeled in situ with isolectin (IL)B4-FITC (ILB4). Six hours after MCAO only a few of the ILB4+ cells were colabeled by Rhod6G. These cells expressed the voltage-gated inwardly and outwardly rectifying K+ currents characteristic of macrophages. The majority of the ILB4+ cells were Rhod6G- and expressed a lack of voltage-gated channels, recently described for ramified microglial cells in brain slices, or exhibited only an inward rectifier current, a unique marker for cultured (but unstimulated) microglia. Forty-eight hours after MCAO, all blood-borne and the majority of Rhod6G- cells expressed outward and inward currents indicating that the intrinsic microglial population exhibited physiologic features of stimulated, cultured microglia. The ILB4+/Rhod6G- intrinsic microglial population was more abundant in the border zone of the infarct and their morphology changed from radial to ameboid. Within this zone, the authors observed rapidly migrating cells and recorded this movement by time-lapse microscopy. The current findings indicate that microglial cells acquire physiologic features of leukocytes at a later time point after MCAO.

Hyperbaric oxygenation induced tolerance against focal cerebral ischemia in mice is strain dependent.

SV129 or C57BL/6 mice were exposed to hyperbaric oxygenation (HBO, 5 days, 1 h every day, 100% O(2) at 3 atm absolute). One day after the 5th HBO session focal cerebral ischemia was induced. In SV129 mice, HBO induced tolerance against permanent focal cerebral ischemia (n=42, mean infarct volume reduction 27%, P=0.001), but not against transient (30 or 60 min) focal cerebral ischemia. In the C57BL/6 strain of mice, HBO did not induce tolerance against focal cerebral ischemia, even when the duration of ischemia or the HBO protocol were modified. For the first time we demonstrate that HBO can induce tolerance to focal cerebral ischemia, but this effect is strain dependent.

Acute treatment of hypertension increases infarct sizes in spontaneously hypertensive rats.

We studied the effect of dihydralazine treatment of hypertension in spontaneously hypertensive stroke-prone rats in a model of permanent focal cerebral ischemia (stroke). After occlusion of the middle cerebral artery systemic arterial pressure (SAP) was lowered with a computer controlled infusion device from 163 to 135 or 117 mm Hg for 24h. In the control group SAP was not manipulated. Reduction of SAP to normotension (117 mm Hg) significantly worsened outcome and increased infarct volume measured 7 days after induction of ischemia, whereas a mild reduction of SAP (to 137 mm Hg) had no statistically significant effect on outcome or infarct volume. We conclude that pharmacological treatment of hypertension may negatively affect neurological outcome and infarct volume in a rat stroke model.

Respiratory chain inhibition induces tolerance to focal cerebral ischemia.

The authors show that the inhibitor of the succinate dehydrogenase, 3-nitroproprionic acid (3-NPA), which in high doses and with chronic administration is a neurotoxin, can induce profound tolerance to focal cerebral ischemia in the rat when administered in a single dose (20 mg/kg) 3 days before ischemia. Infarcts were approximately 70% and 35% smaller in the 3-NPA preconditioned groups of permanent and transient focal cerebral ischemia, respectively. This regimen of 3-NPA preconditioning neither induced necrosis, apoptosis, or any other histologically detectable damage to the brain, nor did it affect behavior of the animals. 3-NPA led to an immediate (1-hour) and long-lasting (3-day) decrease in succinate dehydrogenase activity (30% reduction) throughout the brain, whereas only a short metabolic impairment occurred (ATP decrease of 35% within 30 minutes, recovery within 2 hours). The authors found that 3-NPA induces a burst of reactive oxygen species and the free radical scavenger dimethylthiourea, when administered shortly before the 3-NPA stimulus, completely blocked preconditioning. Inhibition of protein synthesis with cycloheximide given at the time of 3-NPA administration completely inhibited preconditioning. The authors were unsuccessful in showing upregulation of mRNA for the manganese superoxide dismutase, and did not detect increased activities of the copper-zinc and manganese superoxide dismutases, prototypical oxygen free radicals scavenging enzymes, after 3-NPA preconditioning. The authors conclude that it is possible to pharmacologically precondition the brain against focal cerebral ischemia, a strategy that may in principal have clinical relevance. The data show the relevance of protein synthesis for tolerance, and suggests that oxygen free radicals may be critical signals in preconditioning.

[Neurocysticercosis. Current review of the literature based on a long-term study of 2 clinically distinct German cases]. / Neurozystizerkose. Aktuelle Literaturübersicht anhand einer Langzeitbeobachtung zweier klinisch distinkter deutscher Erkankungsfälle.

Neurocysticercosis, caused by Taenia solium larvae (cysticerci), is the most common parasitic infection of the human CNS Worldwide. In Germany its appearance is rare. Here we report two cases of neurocysticercosis which we followed over a period of 4-6 years. The first patient acquired neurocysticercosis in Germany. On admission he suffered from papilledema, partial seizures and a mild psychotic disorder. MR-tomography showed an internal hydrocephalus and multiple contrast enhancing parenchymal cysts. In the course of the disease a giant cyst within the left temporal pole developed and was exstirpated neurosurgically. The persistent internal hydrocephalus required ventriculoperitoneal shunting. Therapy with Praziquantel led to a clinical improvement, however, repeated analysis of the cerebrospinal fluid documented persistent inflammation. With the aid of a contrast enhanced three-dimensional (3D) ultrasound imaging technique we demonstrated increased cerebral perfusion surrounding one cyst. This may be interpreted as evidence for persistent disease activity. The second patient presented with repeated episodes of cysticercotic encephalitis, which is rarely described in the literature (incidence 1%). Clinical features, laboratory findings, diagnosis, and therapy of neurocysticercosis will be presented together with the pitfalls of the two described cases. Our cases will be compared to previous reports on clinical findings in neurocysticercosis.

ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma.

Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-aspartate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.

Beneficence toward whom? Ethical decision-making in a maternal-fetal conflict.

Ethical dilemmas and conflicts occur frequently in critical care units. When these dilemmas involve a pregnant patient, the conflicts are further complicated, because they also involve the interests of the fetus. Using an ethical decision-making process facilitates the analysis of ethical dilemmas and their resolutions. This process is used to analyze the dilemma of selecting appropriate treatment for a woman at 30 weeks' gestation, diagnosed with acute lymphocytic leukemia. The case is examined from the perspective of the mother and the fetus, using the decision-making process. The medical indications include the patient's physical state, disease process, and treatment options. Patient preferences are the ethical and legal center of the patient-physician, and patient-nurse relationship. Contextual features include religious beliefs, cultural values, family dynamics, and financial and legal aspects of the care options. Finally, the ethical principles, relevant and in conflict, are assessed. Exploring these areas clarifies the best treatment option in consideration of the issues and facts of the case.

Induction of tolerance in rat cortical neurons: hypoxic preconditioning.

Sublethal ischemia leads to increased tolerance against subsequent prolonged cerebral ischemia in vivo. In the present study we modeled preconditioning mechanisms in a neuronal-enriched culture. Damage was significantly reduced (up to 72%) with 1.5 h of oxygen-glucose deprivation 48-72 h before 3 h oxygen-glucose deprivation. Tolerance was also elicited by Na+-K+-ATPase inhibition. No damage was observed when astroglial or endothelial cells were exposed to hypoxia for 3 and 6 h, respectively. We conclude that hypoxic preconditioning is a robust neuronal phenomenon in vitro with a similar temporal pattern and selective cellular vulnerability as the ischemic tolerance phenomenon shown in vivo.

Macrophage-generated nitric oxide as cytotoxic factor in destruction of alginate-encapsulated islets. Protection by arginine analogs and/or coencapsulated erythrocytes.

Isolated rat islets were microencapsulated in alginate beads of about 1.5 mm in diameter. These were cocultured with activated or resident peritoneal macrophages of syngeneic rats for 24 hr. Examination of the encapsulated islets by transmission electron microscopy showed that the islets were lysed by activated (80.0 +/- 12.8% of islets lysed), but not by resident, macrophages (17.5 +/- 12.2% lysis) despite encapsulation. Islet lysis was inhibited in a concentration-dependent manner by a specific nitric oxide-synthase inhibitor (0.5 mM NG-methyl-L-arginine: 5.9 +/- 3.9% lysis) in an L-arginine-reversible manner (0.5 mM NG-methyl-L-arginine + 10 mM L-arginine: 55.1 +/- 16.6% lysis). Incubation of encapsulated islets with 3 different nitric oxide-generating compounds also resulted in a concentration-dependent islet lysis. Coencapsulation of autologous erythrocytes was found to be an effective and easy way of protection from macrophage-mediated lysis. Protection was dependent upon the number of erythrocytes coencapsulated. This in vitro study demonstrates that nitric oxide secreted by activated macrophages is able to destroy islets despite encapsulation in alginate, and that both, inhibition of nitric oxide formation using enzyme inhibitors and scavenging of nitric oxide once formed exploiting the hemoglobin of autologous erythrocytes, protect encapsulated islets from destruction.

Efficacy and distribution of single-dose preoperative antibiotic prophylaxis in high-risk gastroduodenal surgery.

Although a single preoperative dose of antibiotic is now the accepted means of preventing postoperative surgical infection, the method has not been investigated adequately. In patients at high risk of infection who underwent gastroduodenal operations, the authors compared single-dose prophylaxis by intravenous cefotaxime (26 patients) with short-course perioperative prophylaxis (27 patients). No wound infection occurred, but in one patient in each group a subphrenic abscess developed after leakage at the anastomosis. The half-life of cefotaxime (1.23 +/- 0.12 hours) and its apparent volume of distribution (16.7 +/- 2.6 L/1.73 m2 resulted in perioperative levels of the antibiotic in blood (34.76 +/- 4.21 micrograms/mL), gastric mucosa (32.04 +/- 5.22 micrograms/mL) and subcutaneous fat (24.98 +/- 5.89 micrograms/mL) more than twice the usual minimal inhibitory concentration of the drug for organisms grown from the stomach contents and wound fat. These clinical and pharmacologic findings validate the efficacy of a single preoperative intravenous dose of the antibiotic in preventing postoperative infection in high-risk patients who undergo gastroduodenal surgery.

Simple elective cholecystectomy: to drain or not.

We performed a large single-center prospective randomized controlled study to assess the role of peritoneal drainage in simple elective cholecystectomy. In 248 patients, drains were omitted; 122 patients had closed suction drains and 124 had Penrose drains. There were no deaths, and no patient required reoperation or drainage of a subhepatic collection. Wound infections occurred in eight patients with drains and in six patients without. Most infections were staphylococcal. Postoperative pulmonary complications and hospital stays were similar in patients with and without drains. Statistical analysis of the 10 available prospective controlled randomized studies (1,920 patients) by the method of odds ratios supported our findings. Simple elective cholecystectomy is safe without peritoneal drainage, but short-term drains do not increase morbidity.

Is neomycin necessary for bowel preparation in surgery of the colon? Oral neomycin plus erythromycin versus erythromycin-metronidazole.

In 132 patients who underwent elective surgery of the colon, the value of bowel preparation with a conventional oral antibiotic preparation of neomycin-erythromycin (N-E) was compared with erythromycin-metronidazole (E-M). Of 125 patients who were available for assessment, 61 received N-E and 64 E-M. The two groups were evenly matched. Two wound infections occurred in patients receiving E-M, neither due to anaerobic bacteria, but seven wound infections developed in patients given N-E (p = 0.057), five of them caused by anaerobic bacteria. Anaerobic bacteria of the colon are the dominant cause of postoperative wound infection in elective surgery of the colon. Adequate antibiotic preparation directed against these bacteria makes the use of neomycin unnecessary.

Natural history of vertical abdominal parietal closure: Prolene versus Dexon.

The long-term outcome of laparotomy incisions after mass closure (taking large tissue bites through all layers) with continuous polypropylene (Prolene) in 95 patients or interrupted polyglycolic acid (Dexon) sutures in 105 patients was compared by randomized prospective study. Of the 200 patients, 194 incisions were median and 2 were paramedian (4 patients were excluded). There was one wound dehiscence (0.51%) due to slippage of a polypropylene knot. At 5-year follow-up, 4 hernias were found in incisions repaired with polypropylene, compared with 11 in the polyglycolic acid group; 10 of the 11 occurred after the first year (p = 0.01). Wound infections were slightly more frequent in patients whose incision was closed with polypropylene. Only two hernias in each group occurred in patients who had had wound infections. Polypropylene and polyglycolic acid both allow rapid and secure closure of vertical laparotomy incisions, but late herniation is more common when polyglycolic acid sutures are used.

Simulations for parallel processing of ultrasound reflection-mode tomography with applications to two-phase flow measurement.

An evaluation of the application of a parallel-processing array to the measurement of two-phase flow, such as bubbly oil flow through a pipe, in real-time is described. Pulse-echo ultrasound tomography is used to generate a cross-sectional image of the flow that forms the basis for the deduction of flow parameters, such as the void fraction. The tomographic algorithm used is backprojection adapted for execution on an array of parallel-processing devices. It is shown that real-time reconstruction is feasible using the concepts of parallel processing. Different sensor arrangements were investigated by computer simulation. It is shown that a special multisegment sensor results in a significant improvement in signal-to-noise ratio and image quality and that the reconstructed image benefits from the concurrent activation of multiple receivers per transmitted pulse. The findings may also be useful for nondestructive testing and medical applications.

Biliary bacteria, antibiotic use, and wound infection in surgery of the gallbladder and common bile duct.

That clinical risk groups predict postoperative infection in biliary operations has recently been challenged. To reevaluate the risk of infection, we studied 215 patients stratified by clinical risk factors. Of 100 patients having simple "low-risk" cholecystectomy, 11 had positive bile cultures (90% pure), and one with sterile bile got a staphylococcal wound infection (WI). Among 92 "high-risk" patients with acute cholecystitis, obstructive jaundice, or choledochal stones, 42 had positive bile cultures (44% pure, 12% anaerobes). One of 52 patients who received preoperative cefazolin got a staphylococcal WI, but ten of 40 patients without antibiotic therapy developed WIs, nine caused by organisms that also grew from the bile. Of 23 patients with obstructive cholangitis, 22 had positive bile cultures (88% mixed, 23% anaerobes). Despite antibiotic therapy, four developed WIs caused by these organisms. The concept of clinical risk factors is validated.