Visuo-spatial memory deficits following medial temporal lobe damage: A comparison of three patient groups.

The contributions of the hippocampal formation and adjacent regions of the medial temporal lobe (MTL) to memory are still a matter of debate. It is currently unclear, to what extent discrepancies between previous human lesion studies may have been caused by the choice of distinct patient models of MTL dysfunction, as disorders affecting this region differ in selectivity, laterality and mechanisms of post-lesional compensation. Here, we investigated the performance of three distinct patient groups with lesions to the MTL with a battery of visuo-spatial short-term memory tasks. Thirty-one subjects with either unilateral damage to the MTL (postsurgical lesions following resection of a benign brain tumor, 6 right-sided lesions, 5 left) or bilateral damage (10 post-encephalitic lesions, 10 post-anoxic lesions) performed a series of tasks requiring short-term memory of colors, locations or color-location associations. We have shown previously that performance in the association task critically depends on hippocampal integrity. Patients with postsurgical damage of the MTL showed deficient performance in the association task, but performed normally in color and location tasks. Patients with left-sided lesions were almost as impaired as patients with right-sided lesions. Patients with bilateral post-encephalitic lesions showed comparable damage to MTL sub-regions and performed similarly to patients with postsurgical lesions in the association task. However, post-encephalitic patients showed additional impairments in the non-associative color and location tasks. A strikingly similar pattern of deficits was observed in post-anoxic patients. These results suggest a distinct cerebral organization of associative and non-associative short-term memory that was differentially affected in the three patient groups. Thus, while all patient groups may provide appropriate models of medial temporal lobe dysfunction in associative visuo-spatial short-term memory, additional deficits in non-associative memory tasks likely reflect damage of regions outside the MTL. Importantly, the choice of a patient model in human lesion studies of the MTL significantly influences overall performance patterns in visuo-spatial memory tasks.

Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock.

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) controls tryptophan metabolism and is induced by pro-inflammatory stimuli. We investigated whether immunostimulatory treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) influences IDO activity and tryptophan metabolism in sepsis. Thirty-six patients with severe sepsis/septic shock and sepsis-associated immunosuppression (assessed using monocytic human leukocyte antigen-DR (mHLA-DR) expression) were assessed in a controlled trial of GM-CSF or placebo treatment for 8 days. Using tandem mass spectrometry, levels of tryptophan, kynurenine, kynurenic acid, quinolinic acid, 5-hydroxytryptophan, serotonin, and estimated IDO activity were determined in a blinded fashion over a 9-day interval. At baseline, tryptophan and metabolite levels did not differ between the study groups. Although tryptophan levels were unchanged in both groups over the treatment interval (all p>0.8), IDO activity was markedly reduced after GM-CSF treatment (35.4 +/- 21.0 vs 21.6 +/-9.9 (baseline vs day 9), p = 0.02). IDO activity differed significantly between the 2 groups after therapy (p = 0.03). Metabolites downstream of IDO (kynurenine, quinolinic acid, kynurenic acid) were all induced in sepsis and declined in the GM-CSF group, but not in controls. Serotonin pathway metabolites remained unchanged in both groups (all p>0.15). Moreover, IDO activity correlated with procalcitonin (p< 0.0001, r = 0.56) and mHLA-DR levels (p = 0.005, r = -0.28) in the overall samples group. Thus, GM-CSF therapy is associated with decreased IDO activity and reduced kynurenine pathway catabolites in sepsis. This may be due to an improved antibacterial defence.

A rare case of neuroleptic malignant syndrome presenting with serious hyperthermia treated with a non-invasive cooling device: a case report.

INTRODUCTION: A rare side effect of antipsychotic medication is neuroleptic malignant syndrome, mainly characterized by hyperthermia, altered mental state, haemodynamic dysregulation, elevated serum creatine kinase and rigor. There may be multi-organ dysfunction including renal and hepatic failure as well as serious rhabdomyolysis, acute respiratory distress syndrome and disseminated intravascular coagulation. The prevalence of neuroleptic malignant syndrome is between 0.02% and 2.44% for patients taking neuroleptics and it is not necessary to fulfil all cardinal features characterizing the syndrome to be diagnosed with neuroleptic malignant syndrome. Because of other different life-threatening diseases matching the various clinical findings, the correct diagnosis can sometimes be hard to make. A special problem of intensive care treatment is the management of severe hyperthermia. Lowering of body temperature, however, may be a major clinical problem because hyperthermia in neuroleptic malignant syndrome is typically unresponsive to antipyretic agents while manual cooling proves difficult due to peripheral vasoconstriction. CASE PRESENTATION: A 22-year-old Caucasian man was admitted unconscious with a body temperature of 42 degrees C, elevated serum creatine phosphokinase, tachycardia and hypotonic blood pressure. In addition to intensive care standard therapy for coma and shock, a non-invasive cooling device (Arctic Sun 2000((R)), Medivance Inc., USA), originally designed to induce mild therapeutic hypothermia in patients after cardiopulmonary resuscitation, was used to lower body temperature. After successful treatment it became possible to obtain information from the patient about his recent ambulant treatment with Olanzapin (Zyprexa(R)) for schizophrenia. CONCLUSION: Numerous case reports have been published about patients who developed neuroleptic malignant syndrome due to Olanzapin (Zyprexa(R)) medication. Frequently hyperthermia has been observed in these cases with varying outcomes. In our case the only residual impairment for the patient is dysarthria with corresponding symmetric cerebellar pyramidal cell destruction demonstrated by increased signal intensity in T2-weighted magnetic resonance imaging, most likely caused by the excessive hyperthermia.

Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

RATIONALE: Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. OBJECTIVES: In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. METHODS: In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. MEASUREMENTS AND MAIN RESULTS: Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. CONCLUSIONS: Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).

Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms.

BACKGROUND: Tryptophan (Trp) is catabolized by indoleamine 2,3-dioxygenase (IDO). Changes in Trp metabolism and IDO activity in chronic kidney disease (CKD) have not been widely studied, and the impact of haemodialysis is uncertain. Here we investigate Trp catabolism, IDO activity and the role of inflammation in moderate to very severe CKD and haemodialysis. METHODS: Eighty individuals were included in a prospective blinded endpoint analysis. Using tandem mass spectrometry, serum levels of Trp, kynurenine (Kyn), kynurenic-acid (Kyna), quinolinic-acid (Quin), 5-hydroxytryptophan (OH-Trp), serotonin (5-HT), estimated IDO activity and inflammatory markers were assessed in 40 CKD patients (age 57 +/- 14 years, 21 male, creatinine 4.5 +/- 2.7, n = 17 receiving haemodialysis), and in 40 healthy controls (age 34 +/- 9 years, 26 male). RESULTS: Trp levels were unchanged in CKD (P = 0.78 versus controls). Serum levels of Kyn, Kyna and Quin increased with CKD severity (stages 4, 5 versus controls all P < or = 0.01). IDO activity was significantly induced in CKD and correlated with disease severity (stages 3-5 versus controls, all P < or = 0.01) and inflammatory markers [high-sensitivity C-reactive protein (hsCRP), soluble TNF-receptor-1 (sTNFR-I); both P < or = 0.03]. IDO products (Kyn, Kyna, Quin) correlated also with hsCRP and sTNFR-I (all P < or = 0.04). Haemodialysis did not influence IDO activity (P = 0.26) and incompletely removed Kyn, Kyna, Quin, OH-Trp and 5-HT by 22, 26, 50, 44 and 34%, respectively. In multiple regression, IDO activity correlated with hsCRP and sTNFR-I (both P < or = 0.03) independent of serum creatinine, age and body weight. CONCLUSIONS: IDO activity and serum levels of tryptophan catabolites of the kynurenine pathway increase with CKD severity. In CKD, induction of IDO may primarily be a consequence of chronic inflammation.

Interleukin-6 serum level assessment using a new qualitative point-of-care test in sepsis: A comparison with ELISA measurements.

OBJECTIVES: Interleukin-6 (IL-6) is involved in inflammatory diseases, provides prognostical information, and allows the early identification and monitoring of septic patients. We investigated whether IL-6 can be assessed using a new densitometric point-of-care (POC) bedside assay. DESIGN AND METHODS: 392 samples were prospectively collected from 57 intensive care unit patients (38 male, age: 45.2 +/- 16.9years, APACHE II score: 25.4 +/- 4.8). Blinded IL-6 measurements were performed using conventional semiautomatic enzyme-linked immunosorbent assays (ELISA) and the POC test. RESULTS: Mean IL-6 levels were 102.9 +/- 388.6pg/mL (ELISA) and 97.0 +/- 535.5 (POC). A significant correlation was found (p < 0.0001, r = 0.92). The sensitivity/specificity for sepsis was 82.6%/86.5% (ELISA, AUC: 0.881), and 76.4%/95.0% (POC, AUC: 0.868). CONCLUSIONS: Here we demonstrate significant correlations of IL-6 levels determined using a POC test and semiautomatic ELISA. ROC analyses revealed no significant differences between the two tests. With a turn-around time of 20min, the bedside IL-6 test is a new tool that may help to initiate early goal-directed therapy.

Therapy-refractory Panton Valentine Leukocidin-positive community-acquired methicillin-sensitive Staphylococcus aureus sepsis with progressive metastatic soft tissue infection: a case report.

We report a case of fulminant multiple organ failure including the Acute Respiratory Distress Syndrome (ARDS), haemodynamic, and renal failure due to community-acquired methicillin-sensitive Panton Valentine Leukocidin (PVL) positive spa-type 284 (ST121) Staphylococcus aureus septic shock. The patient's first clinical symptom was necrotizing pneumonia. Despite organism-sensitive triple antibiotic therapy with linezolid, imipenem and clindamycin from the first day of treatment, progressive abscess formation in multiple skeletal muscles was observed. As a result, repeated surgical interventions became necessary. Due to progressive soft tissue infection, the anti-microbial therapy was changed to a combination of clindamycin and daptomycin. Continued surgical and antimicrobial therapy finally led to a stabilisation of the patients' condition. The clinical course of our patient underlines the existence of a "PVL-syndrome" which is independent of in vitro Staphylococcus aureus susceptibility. The PVL-syndrome should not only be considered in patients with soft tissue or bone infection, but also in patients with pneumonia. Such a condition, which may easily be mistaken for uncomplicated pneumonia, should be treated early, aggressively and over a long period of time in order to avoid relapsing infection.