Human cytomegalovirus seropositivity is associated with reduced patient survival during sepsis.

BACKGROUND: Sepsis is one of the leading causes of death. Treatment attempts targeting the immune response regularly fail in clinical trials. As HCMV latency can modulate the immune response and changes the immune cell composition, we hypothesized that HCMV serostatus affects mortality in sepsis patients. METHODS: We determined the HCMV serostatus (i.e., latency) of 410 prospectively enrolled patients of the multicenter SepsisDataNet.NRW study. Patients were recruited according to the SEPSIS-3 criteria and clinical data were recorded in an observational approach. We quantified 13 cytokines at Days 1, 4, and 8 after enrollment. Proteomics data were analyzed from the plasma samples of 171 patients. RESULTS: The 30-day mortality was higher in HCMV-seropositive patients than in seronegative sepsis patients (38% vs. 25%, respectively; p = 0.008; HR, 1.656; 95% CI 1.135-2.417). This effect was observed independent of age (p = 0.010; HR, 1.673; 95% CI 1.131-2.477). The predictive value on the outcome of the increased concentrations of IL-6 was present only in the seropositive cohort (30-day mortality, 63% vs. 24%; HR 3.250; 95% CI 2.075-5.090; p < 0.001) with no significant differences in serum concentrations of IL-6 between the two groups. Procalcitonin and IL-10 exhibited the same behavior and were predictive of the outcome only in HCMV-seropositive patients. CONCLUSION: We suggest that the predictive value of inflammation-associated biomarkers should be re-evaluated with regard to the HCMV serostatus. Targeting HCMV latency might open a new approach to selecting suitable patients for individualized treatment in sepsis.

Systemically administered ligands of Toll-like receptor 2, -4, and -9 induce distinct inflammatory responses in the murine lung.

OBJECTIVE: To determine whether systemically administered TLR ligands differentially modulate pulmonary inflammation. METHODS: Equipotent doses of LPS (20 mg/kg), CpG-ODN (1668-thioat 1 nmol/g), or LTA (15 mg/kg) were determined via TNF activity assay. C57BL/6 mice were challenged intraperitoneally. Pulmonary NFκB activation (2 h) and gene expression/activity of key inflammatory mediators (4 h) were monitored. RESULTS: All TLR ligands induced NFκB. LPS increased the expression of TLR2, 6, and the cytokines IL-1αß, TNF-α, IL-6, and IL-12p35/p40, CpG-ODN raised TLR6, TNF-α, and IL12p40. LTA had no effect. Additionally, LPS increased the chemokines MIP-1α/ß, MIP-2, TCA-3, eotaxin, and IP-10, while CpG-ODN and LTA did not. Myeloperoxidase activity was highest after LPS stimulation. MMP1, 3, 8, and 9 were upregulated by LPS, MMP2, 8 by CpG-ODN and MMP2 and 9 by LTA. TIMPs were induced only by LPS. MMP-2/-9 induction correlated with their zymographic activities. CONCLUSION: Pulmonary susceptibility to systemic inflammation was highest after LPS, intermediate after CpG-ODN, and lowest after LTA challenge.

Video vs. direct laryngoscopy for adult surgical and intensive care unit patients requiring tracheal intubation: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This systematic review and meta-analysis aimed to determine whether a specific videolaryngoscopy technique is superior to standard direct laryngoscopy using a Macintosh blade to reduce the risk of difficult intubation in surgical and intensive care unit patients. MATERIALS AND METHODS: We identified all randomized controlled trials comparing videolaryngoscopes (VLSs) to direct laryngoscopy in the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE (from inception to April 2020). The primary outcome was difficult intubation in adult surgical and intensive care unit patients. Secondary outcomes were successful intubation at the first attempt, airway trauma, sore throat, hoarseness, hypoxia, and mortality. RESULTS: We included 97 randomized controlled trials to evaluate 12775 patients. A high risk of bias was found in at least 50% of the included studies for each outcome. VLSs reduced the risk of difficult intubation compared to direct Macintosh laryngoscopy (RR 0.48, 95% CI from 0.35 to 0.65). VLSs increased the rate of successful intubation at the first attempt when compared to direct Macintosh laryngoscopy (RR 1.03, 95% CI from 1.00 to 1.07). Lower risks of airway trauma were found with VLSs (RR 0.69, 95% CI from 0.55 to 0.86). A decreased risk of hoarseness was associated with the use of VLSs (RR 0.67, 95% CI from 0.54 to 0.83). In addition, VLSs did not significantly reduce the risk of hypoxia compared with direct laryngoscopy (RR 0.83, 95% CI from 0.60 to 1.16). CONCLUSIONS: In this systematic review and meta-analysis, we found that the use of VLSs reduced the risk of difficult intubation and slightly increased the ratio of successful intubation at the first attempt among adult patients.

Antagonism of lipopolysaccharide-induced blood pressure attenuation and vascular contractility.

OBJECTIVE: Aim was to assess whether lipopolysaccharide (LPS)-induced decrease of total peripheral resistance depends on Toll-like receptor (TLR)4 signaling and whether it is sensitive to NO-synthase or TLR4 antagonists. METHODS AND RESULTS: C3H/HeN mice (control), expressing a functional, and C3H/HeJ mice, expressing a nonfunctional TLR4, were compared. LPS (20 mg/kg) was injected i.p. 6 hours before hemodynamic measurements. L-NAME and SMT, inhibitors of NO production, and Eritoran, a TLR4 antagonist, were tested for their impact on vascular contractility. Aortic rings were incubated for 6 hours with or without LPS (1 microg/mL), or with LPS+Eritoran (2 microg/mL) and their phenylephrine-induced contractility was measured using a myograph. The expression of cytokines in aortic tissue was examined by real-time polymerase chain reaction. In control mice LPS induced a significant decrease of blood pressure and an increase of heart rate, whereas C3H/HeJ remained unaffected. LPS induced an increase of cytokine expression and a depression of vascular contractility only in control mice but not in C3H/HeJ. L-NAME and SMT increased contractility in all rings and restored LPS-dependent depression of contractility. Eritoran prevented LPS-induced loss of contractility. CONCLUSIONS: LPS upregulates cytokine expression via TLR4 and induces attenuation of smooth muscle contractility which can be effectively antagonized.

Treatment of depression with methylphenidate in patients difficult to wean from mechanical ventilation in the intensive care unit.

BACKGROUND: Mechanical ventilation is often required to support patients in the intensive care unit (ICU) with life-threatening cardiovascular, respiratory, or neuromuscular disorders. Occasionally, difficulties related to weaning patients from this support occur owing to depression. The traditional and newer-generation antidepressant drugs have a relatively long latency of response that interferes with rehabilitation attempts in the ICU. Psychostimulants such as methylphenidate show a rapid onset of antidepressant activity and a benign side effect profile. METHOD: As consulting psychiatrists in the consultation-liaison service of a university hospital, we treated 7 patients with complex ICU courses presenting prolonged mechanical ventilation and psychomotor retardation associated with markedly depressed mood (DSM-IV criteria) by giving them methylphenidate. Methylphenidate was started on the first day at a dose of 2.5 mg p.o. in the morning and was increased by 2.5 mg each day with twice-a-day dosing in the morning and at noon until the patient responded or showed side effects. A maximum dose of 15 mg/day was not exceeded. Outcome evaluation was performed using the Clinical Global Impressions scale. RESULTS: Five (71 %) of 7 patients showed marked or moderate improvement in mood and activity within 3 to 4 days, and discontinuation of ventilator support was achieved within 8 to 14 days. Side effects with these 5 patients were not encountered. Of the remaining 2 patients (29%), 1 developed psychomotor agitation and anxiety within 4 days. Another patient showed only minimal improvement with regard to activity. CONCLUSION: Methylphenidate might be a rapidly effective and safe treatment for depression in difficult-to-wean patients hospitalized for life-threatening medical illness in the ICU. Implications for future research for this population of patients warrant formal randomized, prospective, clinical case-control evaluation.

Buspirone and lorazepam in the treatment of generalized anxiety disorder in outpatients.

In this double-blind, placebo-controlled 10-week trial, the anxiolytic properties of the nonbenzodiazepine buspirone were compared with the benzodiazepine lorazepam and placebo in 125 outpatients with generalized anxiety disorder according to DSM-III. After a 3- to 7-day wash-out period, patients were allocated at random to receive orally 3 x 5 mg buspirone (n=58), 3 x 1 mg lorazepam (n=57), or placebo (n=10) over a 4-week period. The study also comprised a 2-week taper period and a 4-week placebo-control period to assess the stability of clinical improvement. The patient's clinical state was estimated on entry and at weekly intervals by general practitioners using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression (CGI) assessment and by a self-rating scale (State Trait Anxiety Inventory X2=STAI-X2). Lorazepam treatment resulted in descriptively, but not significantly, greater improvement on the Hamilton Rating Scale for Anxiety during the whole treatment (week 0-4) and taper period (week 5, 6) than did buspirone. After treatment with active drugs had been discontinued, the 4-week placebo control period showed buspirone-treated patients to display a stability of clinical improvement, while the symptoms of lorazepam-treated patients worsened at week 7-10. Both buspirone and lorazepam were more efficacious in reducing anxiety symptoms than placebo during the treatment and taper period; however, in contrast to the active drugs (buspirone, lorazepam), patients of the placebo group showed further clinical improvement during the control period, especially in the HAM-A score, so differences between placebo and active drugs became smaller at the end of the study.

Changes in patterns of psychiatric referral in a German general hospital: results of a comparison of two 1-year surveys 8 years apart.

The aim of this study was to investigate the issues of changes in patterns of referral and interventions and of consistency of psychiatric diagnoses assigned by a psychiatric consultation-liaison service in a general hospital over an 8-year period. We compared two 1-year surveys 8 years apart. Survey A comprised 713 referrals in 1990, and Survey B included 1025 consecutive new consultations in 1998. Data pertained to demographic characteristics, source of referral, reason for referral, psychiatric diagnosis according to DSM-III-R, and intervention. Our study demonstrated significant changes in diagnostic characteristics and in patterns of referral and intervention over the years. Changes in source of referral and psychiatric diagnoses were associated with the increasing involvement of clinical psychologists and specialists in psychosomatic medicine. Also, surgeons and physicians were increasingly aware of psychiatric morbidity in medical-surgical populations. Modern psychopharmacological treatment approaches resulted in a higher rate of recommendation of psychotropic medication. To ameliorate the provision of psychiatric care for general hospital patients, the need for a biopsychosocial conceptual framework at the interface of psychiatry and medicine in general hospitals should be underscored.

The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study.

Survivors of acute respiratory distress syndrome (ARDS) are at risk for long-lasting cognitive decline due to hypoxemia, sepsis and/or psychological sequelae associated with aggressive supportive care in the intensive care unit (ICU). We conducted an exploratory study to assess cognitive performance in long-term survivors of ARDS and to investigate how cognitive functioning is related to employment status and health-related quality of life (HRQOL). At median time of 6.0 years after ICU discharge, forty-six ARDS survivors were tested with SKT, a short cognitive performance test for assessing deficits of memory and attention. A measure of HRQOL (SF-36 Health Status Questionnaire) was also administered, and in a brief psychiatric interview, employment status was rated. 23.9% (n=11) of the patients showed cognitive impairments. However, no extreme and severe cognitive deficits were recorded. They primarily revealed low levels of cognitive function in various tasks assessing attention skills. Disability was found in 41.3% (n=19) of the patients. All ARDS survivors with cognitive deficits were disabled, whereas only 22.9% (n=8) of the cognitively not impaired patients gave evidence of disability. The SF-36 values of the ARDS survivors indicated impaired health status on seven out of eight domains when compared to normative population data. Patients with cognitive deficits described the lowest HRQOL with major limitations in the domains role-physical and social functioning when compared to patients without cognitive impairments. In conclusion, long-term ARDS survivors exhibit impaired health status and the presence of cognitive deficits is associated with disability and considerable impairments in HRQOL. More detailed psychiatric research is required to establish the etiology of these cognitive impairments.

Fundamental role for HIF-1α in constitutive expression of human ß defensin-1.

Antimicrobial peptides are secreted by the intestinal epithelium to defend from microbial threats. The role of human ß defensin-1 (hBD-1) is notable because its gene (beta-defensin 1 (DEFB1)) is constitutively expressed and its antimicrobial activity is potentiated in the low-oxygen environment that characterizes the intestinal mucosa. Hypoxia-inducible factor (HIF) is stabilized even in healthy intestinal mucosa, and we identified that epithelial HIF-1α maintains expression of murine defensins. Extension to a human model revealed that basal HIF-1α is critical for the constitutive expression of hBD-1. Chromatin immunoprecipitation identified HIF-1α binding to a hypoxia response element in the DEFB1 promoter whose importance was confirmed by site-directed mutagenesis. We used 94 human intestinal samples to identify a strong expression correlation between DEFB1 and the canonical HIF-1α target GLUT1. These findings indicate that basal HIF-1α is critical for constitutive expression of enteric DEFB1 and support targeting epithelial HIF for restoration and maintenance of intestinal integrity.

U-2932: two clones in one cell line, a tool for the study of clonal evolution.

Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgVH4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.

Prolonged confusional state following electroconvulsive therapy--diagnostic clues from serial electroencephalography.

INTRODUCTION: Cognitive impairment occasionally occurs after electroconvulsive therapy (ECT) and usually resolves within a few days. Any prolonged cognitive alterations or confusional states may have additional causes and require extensive diagnostic effort. Since cognitive dysfunction can also be caused by ictal states, electroencephalography (EEG) is an essential tool for these conditions. METHODS: We report on a female patient with pharmacotherapy resistant major depression who had been treated by a series of ECT and subsequently developed severe confusion and fluctuating amnesia. RESULTS: Laboratory and neuroimaging examinations were normal, however, EEG revealed a severe intermittent slowing with rhythmic high amplitude delta-/theta-activity and sporadic bitemporal sharp waves. Oral application of 1 mg lorazepam led to a sudden improvement of EEG abnormalities. Consequently, non-convulsive status epilepticus (NCSE) was suspected and the patient was regularly treated with lorazepam, accordingly. Clinically the confusional and amnesic symptoms declined, whereas serial EEG recordings showed a further improvement and normalization of brain electric activity. CONCLUSION: Routine EEG is an indispensable tool in patients with sudden deterioration of cognitive functions and unclear neuropsychiatric symptomatology. A testing dose of lorazepam can help to classify EEG abnormalities in terms of ictal EEG patterns.

[Acute liver failure in nefazodone therapy? A case report]. / Akutes Leberversagen unter Nefazodon-Therapie? Ein Fallbericht.

Antidepressant-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. We report on a patient with recurrent major depression who was treated with nefazodone. Six weeks after initiation of therapy with nefazodone, he developed fatal liver failure. After cessation of the drug, the patient did not recover. He underwent liver transplantation but unfortunately died.