The circadian system and mood related behavior in mice.

Most organisms on earth have evolved an internal clock in order to predict daily recurring events. This clock called circadian clock has a period of about 24 h and allows organisms to organize biochemical and physiological processes over one day. Changes in lighting conditions as they occur naturally over seasons, or man made by jet lag or shift work, advance or delay clock phase in order to synchronize an organism's physiology to the environment. A misalignment of the clock to its environment results in sleep disturbances and mood disorders. Although there are strong associations between the circadian clock and mood disorders such as depression, the underlying molecular mechanisms are not well understood. This review describes the currently known molecular links between circadian clock components and mood related behaviors in mice, which will help to understand the causal links between the clock and mood in humans in the future.

[Identification of rheumatological health apps in the Apple app store applying the "semiautomatic retrospective app store analysis" method : A longitudinal observation]. / Identifikation rheumatologischer Gesundheits-Apps im Apple App Store mit der Methode der "semiautomatischen retrospektiven App Store-Analyse" : Eine longitudinale Betrachtung.

BACKGROUND: The Apple and Google app stores offer a wide range of health apps. It is still a challenge to find valuable and qualified apps. OBJECTIVE: Can German language apps be identified using the "semiautomated retrospective app store analysis" (SARASA) method for the field of rheumatology? MATERIAL AND METHOD: The SARASA is a semiautomated method to select and characterize apps listed in the app store. After the first application in February 2018 SARASA was applied again to the Apple app store in February 2020. RESULTS: In February 2018 it was possible to acquire metadata for 103,046 apps and in February 2020 data for 94,735 apps that were listed in the category "health and fitness" or "medicine" in Apple's app store frontend for Germany. After applying the search terms 59 apps with a German language app description were identified for the field of rheumatology in 2018 and 53 apps in 2020. For these, more detailed manual reviews seem worthwhile. In 2018, the apps found were more likely to address patients than physicians and this was more balanced in 2020. In addition, it became apparent that for certain diseases there was no app developer activity. The percentage breakdown of matches by search term revealed substantial fluctuations in the app market when comparing 2018 to 2020. DISCUSSION: The SARASA method provides a useful tool to identify apps from app stores that meet predefined, formal criteria. Subsequent manual checks of the quality of the contents are still necessary. Further development of the SARASA method and consensus and standardization of quality criteria are worthwhile. Quality criteria should be considered for offers of mobile health apps in app stores.

Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported. CASE PRESENTATION: We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness. CONCLUSION: KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.

Visual Impairment and Functional Classification in Children with Cerebral Palsy.

BACKGROUND: Cerebral palsy (CP) is the most common motor impairment in childhood and often accompanied by a broad spectrum of comorbidities. Data are sparse concerning visual impairment (VI) and functional classification among CP children. OBJECTIVE: The objective of this study was to analyze the prevalence of VI among children with CP and to investigate a possible association between VI and Gross Motor Function Classification System (GMFCS) and the Bimanual Fine Motor Function (BFMF). METHODS: In this hospital-based study, records of 200 children with CP aged 2 to 17 years were reviewed. RESULTS: Overall, VI was found in 59.5% of children with CP. Prevalence of VI was higher when compared with non-CP children. A correlation between GMFCS as well as BFMF and severity of VI was found. Children with severe CP were at greater risk for severe VI, especially cerebral VI compared with children with mild CP. CONCLUSION: VI is a significant problem in children with CP and is correlated with motor function. Children with CP should undergo detailed ophthalmologic and orthoptic assessment to enable early intervention.

The circadian clock, metabolism and obesity.

In the last decades, obesity has been on the rise becoming a burden for health care systems. The reasons behind this rise are most likely caused by lifestyle rather than by an increase in gene mutations, because manifestations of genetic alterations would take longer than just a few decades. Lifestyle has a great impact on the circadian system and therefore on the body internal organization of physiological and biochemical processes, regulating various aspects of behavior and metabolism. In the following, I will discuss recent studies delineating relationships between metabolic processes and the circadian system, how metabolites and nutrients regulate the circadian clock and how nuclear receptors can act as metabolic sensors and clock regulators. Finally, I will discuss how clock modulation and feeding patterns influence the development of obesity.

Piroxicam inhibits herpes simplex virus type 1 infection in vitro.

Piroxicam is a potent, nonsteroidal, anti-inflammatory agent (NSAID) which also exhibits antipyretic activity. The antiviral effect of piroxicam against herpes simplex virus type 1 (HSV-1) was examined in vitro on RC-37 monkey kidney cells using a plaque reduction assay. Piroxicam was dissolved in ethanol or dimethylsulfoxide (DMSO) and the 50% inhibitory concentration (IC50) was determined at 4 µg/ml and 75 µg/ml, respectively. The IC50 for the standard antiherpetic drug acyclovir was determined at 1.6 µM. At non-cytotoxic concentrations of these piroxicam solutions, plaque formation was significantly reduced by 62.4% for ethanolic piroxicam and 72.8% for piroxicam in DMSO. The mode of antiviral action of these drugs was assessed by time-on-addition assays. No antiviral effect was observed when cells were incubated with piroxicam prior to infection with HSV-1 or when HSV-1 infected cells were treated with dissolved piroxicam. Herpesvirus infection was, however, significantly inhibited when HSV-1 was incubated with piroxicam prior to the infection of cells. These results indicate that piroxicam affected the virus before adsorption, but not after penetration into the host cell, suggesting that piroxicam exerts a direct antiviral effect on HSV-1. Free herpesvirus was sensitive to piroxicam in a concentration-dependent manner and the inhibition of HSV-1 appears to occur before entering the cell but not after penetration of the virus into the cell. Considering the lipophilic nature of piroxicam, which enables it to penetrate the skin, it might be suitable for topical treatment of herpetic infections.

Modeling the LPS-induced effects on transcription factor activation and gene expression in murine macrophages.

Macrophages within the liver are of particular importance for a functional defense against bacterial infection. They exhibit a complex response to lipopolysaccharide and secrete a variety of pro-inflammatory cytokines and chemokines that both coordinate the immune response and regulate activity of the macrophages, themselves. In this context, the dynamic of pathway activation and gene expression is important for a better understanding of the role of activated macrophages in healthy and diseased states. Therefore, we present a representative model of LPS-induced macrophage activation that covers the principle regulatory motifs. Based on that, we propose a simplified model with a reduced number of states and parameters that allows estimation of transcription factor activity from gene expression data and can be easily extended to describe the full spectrum of gene regulation in LPS-activated macrophages.

[Future trend medical apps. From the apps store directly into medical practice?]. / Zukunftstrend "Medical Apps". Vom App-Store direkt in die medizinische Anwendung?

In day to day medical care, patients, nursing staff and doctors currently face a bewildering and rapidly growing number of health-related apps running on various "smart" devices and there are also uncountable possibilities for the use of such technology. Concerning regulation, a risk-based approach is applied for development and use (including safety and security considerations) of medical and health-related apps. Considering safety-related issues as well as organizational matters, this is a sensible approach but requires honest self-assessment as well as a high degree of responsibility, networking and good quality management by all those involved. This cannot be taken for granted. Apart from regulatory aspects it is important to not only consider what is reasonable, helpful or profitable. Quality aspects, safety matters, data protection and privacy as well as liability issues must also be considered but are often not adequately respected. If software quality is compromised, this endangers patient safety as well as data protection, privacy and data integrity. This can for example result in unwanted advertising or unauthorized access to the stored data by third parties; therefore, local, regional and international regulatory measures need to be applied in order to ensure safe use of medical apps in all possible areas, including the operating room (OR) with its highly specialized demands. Lawmakers need to include impulses from all stakeholders in their considerations and this should include input from existing private initiatives that already deal with the use and evaluation of apps in a medical context. Of course, this process needs to respect pre-existing national, European as well as international (harmonized) standards.

Sports in LCHAD Deficiency: Maximal Incremental and Endurance Exercise Tests in a 13-Year-Old Patient with Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD) and Heptanoate Treatment.

Exercise and subsequent catabolism is a potential trigger for creatine kinase (CK) concentration increase (rhabdomyolysis) in patients with LCHADD, therefore we evaluated the clinical and biochemical stability under physical exertion conditions at the age of 13 years in a currently 14-year-old LCHADD patient treated with heptanoate.LCHADD was diagnosed during first decompensation at age 20 months. In the following 2 years, the patient had several episodes of rhabdomyolysis. Heptanoate 0.5-1 g/kg/day was started at 4 years, with no further CK elevations since. He is clinically stable, has retinopathy without vision impairment or polyneuropathy. Maximal incremental and endurance exercise tests were performed to evaluate both clinical and metabolic stability during and after exertion.Physical fitness was adequate for age (maximum blood lactate 7.0 mmol/L, appropriate lactate performance curve, maximum heart rate of 196 bpm, maximum power 139 Watt = 2.68 Watt/kg body weight). There were no signs of clinical (muscle pain, dark urine) or metabolic derangement (stable CK, acyl carnitine profiles, blood gas analyses) - neither after maximal incremental nor endurance exertion.This case illustrates that both under maximal incremental and endurance exertion, clinical and biochemical parameters remained stable in this currently 14-year-old LCHADD patient receiving heptanoate treatment.

Randomised clinical trial: a herbal preparation of myrrh, chamomile and coffee charcoal compared with mesalazine in maintaining remission in ulcerative colitis--a double-blind, double-dummy study.

BACKGROUND: The herbal treatment with myrrh, dry extract of chamomile flowers and coffee charcoal has anti-inflammatory and antidiarrhoeal potential and might benefit patients with UC. Aminosalicylates are used as standard treatment for maintaining remission in ulcerative colitis (UC). AIM: To compare the efficacy of the two treatments in maintaining remission in patients with ulcerative colitis. METHODS: We performed a randomised, double-blind, double-dummy study over a 12-month period in patients with UC. Primary endpoint was non-inferiority of the herbal preparation as defined by mean Clinical Colitis Activity Index (CAI-Rachmilewitz). Secondary endpoints were relapse rates, safety profile, relapse-free times, endoscopic activity and faecal biomarkers. RESULTS: A total of 96 patients (51 female) with inactive UC were included. Mean CAI demonstrated no significant difference between the two treatment groups in the intention-to-treat (P = 0.121) or per-protocol (P = 0.251) analysis. Relapse rates in total were 22/49 patients (45%) in the mesalazine treatment group and 25/47 patients (53%) in the herbal treatment group (P = 0.540). Safety profile and tolerability were good and no significant differences were shown in relapse-free time, endoscopy and faecal biomarkers. CONCLUSIONS: The herbal preparation of myrrh, chamomile extract and coffee charcoal is well tolerated and shows a good safety profile. We found first evidence for a potential efficacy non-inferior to the gold standard therapy mesalazine, which merits further study of its clinical usefulness in maintenance therapy of patients with ulcerative colitis. EudraCT-Number 2007-007928-18.

Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range.

Circadian clocks are internal timekeepers present in almost all organisms. Driven by a genetic network of highly conserved structure, they generate self-sustained oscillations that entrain to periodic external signals such as the 24 h light-dark cycle. Vertebrates possess multiple, functionally overlapping homologues of the core clock genes. Furthermore, vertebrate clocks entrain to a range of periods three times as narrow as that of other organisms. We asked whether genetic redundancies play a role in governing entrainment properties and analysed locomotor activity rhythms of genetically modified mice lacking one set of clock homologues. Exposing them to non-24 h light-dark cycles, we found that the mutant mice have a wider entrainment range than the wild types. Spectral analysis furthermore revealed nonlinear phenomena of periodically forced self-sustained oscillators for which the entrainment range relates inversely to oscillator amplitude. Using the forced oscillator model to explain the observed differences in entrainment range between mutant and wild-type mice, we sought to quantify the overall oscillator amplitude of their clocks from the activity rhythms and found that mutant mice have weaker circadian clocks than wild types. Our results suggest that genetic redundancy strengthens the circadian clock leading to a narrow entrainment range in vertebrates.

Anatomic double-bundle ACL reconstruction restricts knee extension in knees with hyperextension.

PURPOSE: Double-bundle ACL reconstruction has been demonstrated to be at least as effective as single-bundle reconstruction in terms of restoring knee rotational and translational stability. Until now, the influence on knees with hyperextension has not been evaluated. It was the purpose of this study to evaluate whether double-bundle ACL reconstruction restricts extension in hyperextendable knees. METHODS: Hamstring tendon reconstructions of 10 human cadaveric knees with the ability of hyperextension (age: 48 ± 14 years) were performed as single bundle (SB) on one side and double bundle (DB) on the other side. A surgical navigation system (BrainLab, Germany) was used to assess the kinematics of each knee at the intact and reconstructed state. A difference with regard to the anterior-to-posterior translation (AP) and rotational stability at 30° of knee flexion, 90° of flexion and the hyperextension capability of each specimen was analysed. RESULTS: The difference in AP translation before and after the reconstruction was not significantly different in 30° and 90° of flexion (n.s). Both single- and double-bundle reconstructions restored the preoperative kinematics at 30° and 90° of knee flexion (n.s). The knee extension was 4° ± 1.8° with the intact ACL and 4° ± 1.7° after reconstruction in the SB group (n.s). The knee extension was 5° of hyperextension ± 1.1° with the intact ACL and 0° ± 0.4° after reconstruction in the DB group; the limitation of the extension was significantly larger in this group (p = 0.013). CONCLUSION: Both single- and double-bundle ACL reconstruction techniques are capable of restoring knee anteroposterior and rotational stability. Double-bundle reconstructions significantly reduce knee extension in knees with hyperextension capability. Care must be taken when using double-bundle techniques in patients with knee hyperextension as this procedure may limit the knee extension after double-bundle ACL reconstruction.

[Implant-free tibial fixations of the posterior cruciate ligament. Development and biomechanical testing]. / Implantatfreie tibiale Fixierung des hinteren Kreuzbandes. Entwicklung und biomechanische Testung.

BACKGROUND: A secure tibial press fit technique in posterior cruciate ligament reconstructions may be a relevant alternative to common techniques because no hardware is necessary. Up to the present point in time no biomechanical data exist for a tibial press fit posterior cruciate ligament (PCL) reconstruction. This study compares the biomechanical properties of hamstring and quadriceps tendon grafts using a press fit technique with those of an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age 49.2±18.5 years) were used. A press fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 27 porcine tibiae. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518±157 N (387-650 N) for the K group, 558±119 N (466-650 N) for the I group and 620±102 N (541-699 N) for the Q group. The stiffness was 55±27 N/mm (18-89 N/mm) for the K group, 117±62 N/mm (69-165 N/mm) for the I group and 65±21 N/mm (49-82 N/mm) for the Q group. The stiffness of the I group was significantly larger (ANOVA on ranks, P=0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th and the 20th cycle (P<0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness were significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. The results of group K were inferior. All three investigated fixation techniques exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Future randomized, clinical trials have to investigate the biological effectiveness of these fixation techniques.

The fixation strength of tibial PCL press-fit reconstructions.

PURPOSE: A secure tibial press-fit technique in posterior cruciate ligament reconstructions is an interesting technique because no hardware is necessary. For anterior cruciate ligament (ACL) reconstruction, a few press-fit procedures have been published. Up to the present point, no biomechanical data exist for a tibial press-fit posterior cruciate ligament (PCL) reconstruction. The purpose of this study was to characterize a press-fit procedure for PCL reconstruction that is biomechanically equivalent to an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age: 49.2 ± 18.5 years) were used. A press-fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 30 porcine femora. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness, and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518 ± 157 N (387-650 N) for the (K) group, 558 ± 119 N (466-650 N) for the (I) group, and 620 ± 102 N (541-699 N) for the (Q) group. The stiffness was 55 ± 27 N/mm (18-89 N/mm) for the (K) group, 117 ± 62 N/mm (69-165 N/mm) for the (I) group, and 65 ± 21 N/mm (49-82 N/mm) for the (Q) group. The stiffness of the (I) group was significantly larger (P = 0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th to the 20th cycle (P < 0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness was significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. All three fixation techniques that were investigated exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Clinical trials have to investigate the biological effectiveness of these fixation techniques.

The role of clock genes and rhythmicity in the liver.

The liver is the important organ to maintain energy homeostasis of an organism. To achieve this, many biochemical reactions run in this organ in a rhythmic fashion. An elegant way to coordinate the temporal expression of genes for metabolic enzymes relies in the link to the circadian timing system. In this fashion not only a maximum of synchronization is achieved, but also anticipation of daily recurring events is possible. Here we will focus on the input and output pathways of the hepatic circadian oscillator and discuss the recently found flexibility of its circadian transcriptional networks.

Comparison of three suture techniques and three suture materials on gap formation and failure load in ruptured tendons: a human cadaveric study.

INTRODUCTION: There is a large variety of ruptures of tendons and ligaments in trauma surgery. Reliable data about the most appropriate suture technique and suture material for ruptured tendons are sparse. This human cadaveric study compares the biomechanical properties of three suture materials and three suture techniques for semitendinosus tendon repair. METHOD: Sixty-three human cadaver hamstring tendons underwent tenotomy and repair with either Baseball suture, Kessler suture, or a novel "Hannover" suture, using either PDS 2-0, Ethibond 2-0, or Fiberwire 2-0. Biomechanical analysis included pretensioning the constructs with 2 N for 50 s, then cyclic loading of 500 cycles between 2 and 15 N at 1 Hz in a servohydraulic testing machine with measurement of elongation. After this, ultimate failure load and failure mode analysis was performed. RESULTS: Ruptures repaired by Fiberwire™ as suture material and the Baseball suture technique were able to withstand significantly higher maximum failure loads (72.8 ± 22.0 N, p < 0.001) than the Kessler suture and the Hannover suture, while ruptures repaired by Fiberwire and the Kessler suture technique showed the lowest elongation after cyclic loading (14.6 ± 3.8 mm, p = 0.15). CONCLUSION: These findings may be of relevance for the future clinical treatment of tendon ruptures. Further in vivo clinical application studies are desirable for the future.

[The unrecognized myocardial infarction]. / Der nicht erkannte Myokardinfarkt.

BACKGROUND AND OBJECTIVES: despite the improved quality of diagnostic technology, myocardial infarction still belongs to the diseases that are most frequently overlooked. Especially asymptomatic patients or patients with atypical symptoms are more common to be misdiagnosed. Failure to correctly diagnose is the leading cause of malpractice claims. It was the aim of this study to evaluate the records of patients who died from myocardial infarction and to analyse whether medical malpractice had occured in those who had undergone a medical examination shortly before their death. METHODS: in the years 2008 and 2009 myocardial infarction had been diagnosed in 109 auotopsies performed at the Institute of Legal Medicine of the Hanover Medical School. The records of these patients who had died from myocardial infarction were retrospectively analysed with particular emphasis on an antemortem medical consultation, reported symptoms and diagnostic measures. RESULTS: in 38 persons (34.9 %) an antemortem medical consultation or hospitalisation has taken place, whereby in five persons the diagnosis of myocardial infarction was suspected. In 33 persons, a myocardial infarction could not be diagnosed antemortem. In two cases an additionally cardiologic assessment was recommended to estimate if medical malpractice was present and in another two cases with insufficient diagnostic measures medical malpractice was reproached from forensic pathologists. CONCLUSION: autopsy give the most accurate diagnostic information. On the other hand, it may provide an effective defence against medical malpractice litigation.

Behavioural food anticipation in clock genes deficient mice: confirming old phenotypes, describing new phenotypes.

Animals fed daily at the same time exhibit circadian food-anticipatory activity (FAA), which has been suggested to be driven by one or several food-entrainable oscillators (FEOs). FAA is altered in mice lacking some circadian genes essential for timekeeping in the main suprachiasmatic clock (SCN). Here, we confirmed that single mutations of clock genes Per1(-/-) and Per2(Brdm1) alter FAA expression in constant darkness (DD) or under a light-dark cycle (LD). Furthermore, we found that Per1(-/-);Per2(Brdm1) and Per2(Brdm1);Cry1(-/-) double mutant animals did not display a stable and significant FAA either in DD or LD. Interestingly, rescued behavioural rhythms in Per2(Brdm1);Cry2(-/-) mice in DD were totally entrained to feeding time and re-synchronized after phase-shifts of mealtime, indicating a higher SCN sensitivity to feeding cues. However, under an LD cycle and restricted feeding at midday, FAA in double Per2(Brdm1);Cry2(-/-) mutant mice was absent. These results indicate that shutting down one or two clock genes results in altered circadian meal anticipation. Moreover, we show that in a genetically rescued SCN clock (Per2(Brdm1);Cry2(-/-)), food is a powerful zeitgeber to entrain behavioural rhythms, leading the SCN to be more sensitive to feeding cues than in wild-type littermates.

Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation.

Propionic acidemia caused by propionyl-CoA carboxylase deficiency frequently leads to neurologic complications. Herein we report an eleven-year-old patient with propionic acidemia having three stroke-like episodes during a period of 13 months characterized by acute reversible hemiplegia and vegetative symptoms like bradycardia or drowsiness. No biochemical signs of severe metabolic decompensation were detectable in plasma. At all three episodes, EEG was not indicative for status epilepticus, but in the acute episode it showed slowing of background activity emphasized on one side. MRI revealed reversible hyperintensities in cortical grey matter and basal ganglia. During the third episode a lumbar puncture was done in parallel with venous puncture. Concentrations of glutamine (902 micromol/L), glycine (24 micromol/L) and alanine (78 micromol/L) were elevated in CSF. In plasma glycine (1 859 micromol/L) and alanine (608 micromol/L) concentrations were also elevated, whereas the glutamine (458 micromol/L) concentration was normal. CSF/plasma ratios were elevated for glutamine (1.97) and alanine (0.13) and normal for glycine (0.01). We assume that the stroke-like episodes in our patient may be caused by an acute focal cerebral metabolic decompensation, which is detectable by unspecific changes in MRI and by measuring amino acids and lactate in CSF versus plasma.