Background

Treatment of patients with acute mania remains a considerable medical challenge since onset of action of antimanic medication is delayed for several days. Psychostimulants could have an earlier onset of action. This assumption is based on the ‘vigilance regulation model of mania’ which postulates that vigilance is unstable in manic patients. Accordingly, vigilance-stabilising psychostimulants could be more useful than conventional treatment in acute mania. We present here the study protocol of a trial intended to study the efficacy and safety of methylphenidate in the initial treatment of acute mania.

Methods/design

A multi-centre, randomised, double-blind, placebo-controlled clinical trial will be conducted in 88 bipolar inpatients with acute mania. Male and female patients older than 18 years will be randomised to treatment with either methylphenidate (20 to 40 mg/day) or placebo for 2.5 days, given once or twice daily. The main outcome measure is the reduction in the Young Mania Rating Scale (YMRS) after 2.5 days of treatment. Other outcome measures include the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) the Clinical Global Impression–Bipolar Scale (CGI-BP), the Screen for Cognitive Impairment in Psychiatry (SCIP), actigraphy and the EEG-‘Vigilance Algorithm Leipzig’ (VIGALL).

Discussion

A positive study outcome of the proposed study could substantially impact our understanding of the etiopathogenesis of mania and open new treatment perspectives.

Trial registration

ClinicalTrials.gov: NCT 01541605

Background

Inflammatory cytokines play an important role in the pathogenesis of heart failure. We have recently found the cytokine TWEAK (tumor necrosis factor (TNF)-like weak inducer of apoptosis), a member of the TNF superfamily, to be increased in patients with cardiomyopathy and result in the development of heart failure when overexpressed in mice. The molecular mechanisms underlying TWEAK-induced cardiac pathology, however, remain unknown.

Methodology and Critical Finding

Using mouse models of elevated circulating TWEAK levels, established through intravenous injection of adenovirus expressing TWEAK or recombinant TWEAK protein, we find that TWEAK induces a progressive dilated cardiomyopathy with impaired contractile function in mice. Moreover, TWEAK treatment is associated with decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1α requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1α gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFκB signaling pathways. Maintaining PGC1α levels through adenoviral-mediated gene expression is sufficient to protect against TWEAK-induced cardiomyocyte dysfunction.

Conclusion

Collectively, our data suggest that TWEAK induces cardiac dysfunction via downregulation of PGC1α, through FN14-TRAF2-NFκB-dependent signaling. Selective targeting of the FN14-TRAF2-NFκB-dependent signaling pathway or augmenting PGC1α levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure.

Background

Monitoring hepatic blood flow and function might be crucial in treating critically ill patients. Intra-abdominal hypertension is associated with decreased abdominal blood flow, organ dysfunction, and increased mortality. The plasma disappearance rate (PDR) of indocyanine green (ICG) is considered to be a compound marker for hepatosplanchnic perfusion and hepatocellular membrane transport and correlates well with survival in critically ill patients. However, correlation between PDRICG and intra-abdominal pressure (IAP) remains poorly understood. The aim of this retrospective study was to investigate the correlation between PDRICG and classic liver laboratory parameters, IAP and abdominal perfusion pressure (APP). The secondary goal was to evaluate IAP, APP, and PDRICG as prognostic factors for mortality.

Methods

A total of 182 paired IAP and PDRICG measurements were performed in 40 critically ill patients. The mean values per patient were used for comparison. The IAP was measured using either a balloon-tipped stomach catheter connected to an IAP monitor (Spiegelberg, Hamburg, Germany, or CiMON, Pulsion Medical Systems, Munich, Germany) or a bladder FoleyManometer (Holtech Medical, Charlottenlund, Denmark). PDRICG was measured at the bedside using the LiMON device (Pulsion Medical Systems, Munich, Germany). Primary endpoint was hospital mortality.

Results

There was no significant correlation between PDRICG and classic liver laboratory parameters, but PDRICG did correlate significantly with APP (R = 0.62) and was inversely correlated with IAP (R = -0.52). Changes in PDRICG were associated with significant concomitant changes in APP (R = 0.73) and opposite changes in IAP (R = 0.61). The IAP was significantly higher (14.6 ± 4.6 vs. 11.1 ± 5.3 mmHg, p = 0.03), and PDRICG (10 ± 8.3 vs. 15.9 ± 5.2%, p = 0.02) and APP (43.6 ± 9 vs. 57.9 ± 12.2 mmHg, p < 0.0001) were significantly lower in non-survivors.

Conclusions

PDRICG is positively correlated to APP and inversely correlated to IAP. Changes in APP are associated with significant concomitant changes in PDRICG, while changes in IAP are associated with opposite changes in PDRICG, suggesting that an increase in IAP may compromise hepatosplanchnic perfusion. Both PDRICG and IAP are correlated with outcome. Measurement of PDRICG may be a useful additional clinical tool to assess the negative effects of increased IAP on liver perfusion and function.

Objective

Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li).

Methods

We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15–30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction.

Results

The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls.

Conclusions

Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients without Li exposure, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Objective

Although bipolar disorder has high heritability, the onset occurs during several decades of life, suggesting that social and environmental factors may have considerable influence on disease onset. This study examined the association between the age of onset and sunlight at the location of onset.

Method

Data were obtained from 2414 patients with a diagnosis of bipolar I disorder, according to DSM-IV criteria. Data were collected at 24 sites in 13 countries spanning latitudes 6.3 to 63.4 degrees from the equator, including data from both hemispheres. The age of onset and location of onset were obtained retrospectively, from patient records and/or direct interviews. Solar insolation data, or the amount of electromagnetic energy striking the surface of the earth, were obtained from the NASA Surface Meteorology and Solar Energy (SSE) database for each location of onset.

Results

The larger the maximum monthly increase in solar insolation at the location of onset, the younger the age of onset (coefficient= −4.724, 95% CI: −8.124 to −1.323, p = 0.006), controlling for each country’s median age. The maximum monthly increase in solar insolation occurred in springtime. No relationships were found between the age of onset and latitude, yearly total solar insolation, and the maximum monthly decrease in solar insolation. The largest maximum monthly increases in solar insolation occurred in diverse environments, including Norway, arid areas in California, and Chile.

Conclusion

The large maximum monthly increase in sunlight in springtime may have an important influence on the onset of bipolar disorder.

Rationale

Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear.

Objective

Herein, we investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions.

Methods and Results

CSP cells isolated from C57BL/6J mice were utilized to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested following injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its anti-proliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a following myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury.

Conclusions

Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states.

Complement activation represents a crucial innate defense mechanism to invading microorganisms, but there is an eminent lack of understanding of the separate contribution of the different complement activation pathways to the host response during sepsis. We therefore investigated different innate host immune responses during cecal ligation and puncture (CLP)-induced sepsis in mice lacking either the alternative (fD−/−) or classical (C1q−/−) complement activation pathway. Both knockout mice strains showed a significantly reduced survival and increased organ dysfunction when compared with control mice. Surprisingly, fD−/− mice demonstrated a compensated bacterial clearance capacity as control mice at 6 h post CLP, whereas C1q−/− mice were already overwhelmed by bacterial growth at this time point. Interestingly, at 24 h after CLP, fD−/− mice failed to clear bacteria in a way comparable to control mice. However, both knockout mice strains showed compromised C3 cleavage during sepsis. Investigating potential causes for this discrepancy, we were able to demonstrate that despite normal bacterial clearance capacity early during the onset of sepsis, fD−/− mice displayed increased inflammatory cytokine generation and neutrophil recruitment into lungs and blood when compared with both control- and C1q−/− mice, indicating a potential loss of control over these immune responses. Further in vitro experiments revealed a strongly increased Nf-κB activation capacity in isolated neutrophils from fD−/− mice, supporting this hypothesis. Our results provide evidence for the new concept that the alternative complement activation pathway exerts a distinctly different contribution to the innate host response during sepsis when compared with the classical pathway.

Background

A major hurdle in the use of exogenous stems cells for therapeutic regeneration of injured myocardium remains the poor survival of implanted cells. To date, the delivery of stem cells into myocardium has largely focused on implantation of cell suspensions.

Methodology and Principal Findings

We hypothesize that delivering progenitor cells in an aggregate form would serve to mimic the endogenous state with proper cell-cell contact, and may aid the survival of implanted cells. Microwell methodologies allow for the culture of homogenous 3D cell aggregates, thereby allowing cell-cell contact. In this study, we find that the culture of cardiac progenitor cells in a 3D cell aggregate augments cell survival and protects against cellular toxins and stressors, including hydrogen peroxide and anoxia/reoxygenation induced cell death. Moreover, using a murine model of cardiac ischemia-reperfusion injury, we find that delivery of cardiac progenitor cells in the form of 3D aggregates improved in vivo survival of implanted cells.

Conclusion

Collectively, our data support the notion that growth in 3D cellular systems and maintenance of cell-cell contact improves exogenous cell survival following delivery into myocardium. These approaches may serve as a strategy to improve cardiovascular cell-based therapies.

Experimental studies in a rat model of fecal peritonitis conducted by Michael Bauer and colleagues show that in this model, changes in liver function occur early in the development of sepsis, with potential implications for prognosis and development of new therapeutic approaches.

Background

Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests.

Methods and Findings

In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87).

Conclusions

Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Sepsis (blood poisoning)—a life-threatening condition caused by an inappropriate immune response to an infection—is a major global cause of death. Normally, when bacteria or other microbes enter the human body, the immune system efficiently destroys the invaders. In sepsis the immune system goes into overdrive, and the chemicals it releases into the blood to combat the infection trigger widespread inflammation (swelling). This leads to the formation of small blood clots and leaky blood vessels that block the flow of blood to vital organs such as the kidneys and liver. In the most severe cases, multiple organs fail and the patient dies. Anyone can get sepsis, but people with weakened immune systems, the very young, and the elderly are most vulnerable. Symptoms of sepsis include fever, chills, rapid breathing, a fast heart rate, and confusion. In its early stages, sepsis can be treated with antibiotics alone, but people with severe sepsis need to be admitted to an intensive care unit where the vital organs can be supported while the infection is treated.

Why Was This Study Done?

Thirty to fifty percent of people who develop severe sepsis die. If sepsis could be diagnosed in its early stages, it might be possible to save more people. Unfortunately, the symptoms of sepsis mimic those of other conditions, and, because sepsis tends to develop very quickly, it is often not diagnosed until it is too late to save the patient's life. The development of liver (hepatic) dysfunction and jaundice are both regarded as late features of sepsis (jaundice is yellowing of the skin and eyes caused by a build-up of bilirubin in the blood). However, the researchers hypothesized that changes in liver function occur early in sepsis and could, therefore, be used to improve the diagnosis and management of sepsis.

What Did the Researchers Do and Find?

The researchers induced sepsis in rats by injecting bacteria into the peritoneal cavity (the gap between the abdominal wall and the abdominal organs), separated the infected animals into predicted survivors and non-survivors based on their heart stroke volume measured using cardiac ultrasound, and then examined their liver function. The expression of genes encoding proteins involved in “biotransformation” and “hepatobiliary transport” (the processes that convert waste products and toxic chemicals into substances that can be conjugated to increase solubility and then excreted) was down-regulated within six hours of sepsis induction in the predicted non-survivors compared to the predicted survivors. Functional changes such as bilirubin and bile acid accumulation in the liver (cholestasis), poor excretion of xenobiotics (molecules not usually found in the body such as antibiotics), and disturbed bile acid conjugation were also seen in predicted non-survivors but not in survivors. Moreover, phosphatidylinositol-3-kinase (PI3K) signaling (which is involved in several immune processes) increased soon after sepsis induction in non-survivor but not in survivor animals. Notably, mice lacking the PI3Kγ gene did not develop cholestasis or show impaired bile acid conjugation after induction of sepsis. Finally, in human patients, plasma bile acids were increased in 48 patients on the day that severe sepsis was diagnosed, and these increases accurately predicted death in these patients.

What Do These Findings Mean?

These findings show that liver dysfunction is an early event in animal models of sepsis and that PI3K signalling plays a crucial role in the development of liver dysfunction. They show that all aspects of liver biotransformation are affected during sepsis and suggest that outcomes are related to the severity of these changes. The limited clinical data included in this study also support the hypothesis that changes in liver function occur early in sepsis, although these data need confirming and extending. Taken together, these findings suggest that liver function tests might aid early diagnosis of sepsis and might also provide information about likely outcomes. They also have important implications for the use of drugs in patients who are critically ill with sepsis, in that some of the drugs routinely administered to such patients may not be adequately detoxified and may, therefore, contribute to organ injury. Finally, these findings suggest that inhibition of PI3Kγ may alleviate sepsis-associated cholestasis.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001338.

This study is further discussed in a PLOS Medicine Perspective by John Marshall

The US National Institute of General Medical Sciences has a fact sheet on sepsis

The UK National Health Service Choices website has information about sepsis and about jaundice

The Surviving Sepsis Campaign, which was developed to improve the management, diagnosis, and treatment of sepsis, provides basic information about sepsis

The Sepsis Alliance, a US not-for-profit organization, also provides information about sepsis for patients and their families, including personal stories about sepsis

The not-for profit UK Sepsis Trust is another useful source of information about sepsis that includes patient stories

MedlinePlus provides links to additional resources about sepsis and jaundice (in English and Spanish)

A recent paper by McKnight et al. in The Lancet has provided the first formal meta-analysis of the more common adverse reactions to lithium. The authors analyzed 385 studies and focused mainly on the harmful effects of lithium on the kidney, the thyroid and parathyroid glands, body weight, skin and congenital malformations. Their contribution is important and welcome, but as a guide for practice, it needs to be complemented by other relevant observations and individual patient-focused perspectives.

The findings from that meta-analysis somewhat underestimate the renal side-effects, and distort to some degree or exclude other adverse effects. The glomerular filtration rate is reduced but not more than 0 to 5 ml/min/year of observation; this may not fully reflect the present state of knowledge. A quarter of patients in the study had abnormalities of the thyroid and/or parathyroid gland, and lithium was found to increase body weight significantly less than did olanzapine. Unfortunately, the authors did not consider the observations from spontaneous reporting systems, which may have changed the picture.

We feel that some specific limitations of the study were related to the inclusion of patients regardless of adequacy of treatment, quality of monitoring, drug combinations, age and sex, and stabilization response.

Exposure to inorganic arsenic induces skin cancer and abnormal pigmentation in susceptible humans. High-throughput gene transcription assays such as DNA microarrays allow for the identification of biological pathways affected by arsenic that lead to initiation and progression of skin cancer and abnormal pigmentation. The overall purpose of the reported research was to determine knowledge building insights on biomarker genes for arsenic toxicity to human epidermal cells by integrating a collection of gene lists annotated with biological information. The information sets included toxicogenomics gene-chemical interaction; enzymes encoded in the human genome; enriched biological information associated with genes; environmentally relevant gene sequence variation; and effects of non-synonymous single nucleotide polymorphisms (SNPs) on protein function. Molecular network construction for arsenic upregulated genes TNFSF18 (tumor necrosis factor [ligand] superfamily member 18) and IL1R2 (interleukin 1 Receptor, type 2) revealed subnetwork interconnections to E2F4, an oncogenic transcription factor, predominantly expressed at the onset of keratinocyte differentiation. Visual analytics integration of gene information sources helped identify RAC1, a GTP binding protein, and TFRC, an iron uptake protein as prioritized arsenic-perturbed protein targets for biological processes leading to skin hyperpigmentation. RAC1 regulates the formation of dendrites that transfer melanin from melanocytes to neighboring keratinocytes. Increased melanocyte dendricity is correlated with hyperpigmentation. TFRC is a key determinant of the amount and location of iron in the epidermis. Aberrant TFRC expression could impair cutaneous iron metabolism leading to abnormal pigmentation seen in some humans exposed to arsenicals. The reported findings contribute to insights on how arsenic could impair the function of genes and biological pathways in epidermal cells. Finally, we developed visual analytics resources to facilitate further exploration of the information and knowledge building insights on arsenic toxicity to human epidermal keratinocytes and melanocytes.

We report a nanoparticulate system capable of targeting the heart after myocardial infarction (MI). Targeting is based on overexpression of angiotensin II type 1 receptor (AT1) in the infarcted heart. Liposomes 142 nm in diameter were conjugated with a ligand specific to AT1. The nanoparticles were able to specifically target cardiac cells in vitro, and in the infarcted heart after intravenous injection in vivo. This system may be useful for delivering therapeutic agents specifically to the infarcted heart.

Background

Treatment of septic shock relies on appropriate antimicrobial therapy. Current culture based methods deliver final results after days, which may delay potentially lifesaving adjustments in antimicrobial therapy. This study was undertaken to compare PCR with blood culture results under routine conditions regarding 1. impact on antimicrobial therapy, and 2. time to result, in patients with presumed sepsis.

Methodology/Principal Findings

This was an observational study in a 50 beds ICU of a university hospital. In 245 patients with suspected sepsis, 311 concomitant blood cultures and blood for multiplex PCR (VYOO®) were obtained. 45 of 311 blood cultures (14.5%) and 94 of 311 PCRs (30.1%) were positive. However, blood culture or microbiological sampling from the presumed site of infection rarely confirmed PCR results and vice versa. Median time to positivity and interquartile range were 24.2 (18.0, 27.5) hours for the PCR and 68 (52.2, 88.5) hours for BC (p<0.01). PCR median time to result was dependent on technician availability (53.5 hours on Saturdays, 7.2 hours under optimal logistic conditions). PCR results showed good correlation with procalcitonin (p<0.001). In 34% of patients with positive PCRs antimicrobial therapy was considered inadequate according to assessment of clinical arbitrators including 5 patients with vancomycin-resistant enterococci (VRE), 3 cases with multiresistant staphylococci, and 4 patients with fungi.

Conclusions

The results of this observational study support the hypothesis that PCR results are available faster, are more frequently positive, and may result in earlier adjustment of antimicrobial therapy. However, shorter time to result can only be fully exploited when the laboratory is adequately staffed for a 24 hour/7 day service, or when point of care/automated assay systems become available.

Experimental models, mimicking physiology, and molecular dynamics of diseases in human, harbor the possibility to study the effect of interventions and transfer results from bench to bedside. Recent advances in high-throughput technologies, standardized protocols, and integration of knowledge from databases yielded rising consistency and usability of results for inter-species comparisons. Here, we explored similarities and dissimilarities in gene expression from blood samples of a murine sepsis model (peritoneal contamination and infection, PCI) and patients from the pediatric intensive care unit (PICU) measured by microarrays. Applying a consistent pre-processing and analysis workflow, differentially expressed genes (DEG) from PCI and PICU data significantly overlapped. A major fraction of DEG was commonly expressed and mapped to adaptive and innate immune response related pathways, whereas the minor fraction, including the chemokine (C–C motif) ligand 4, exhibited constant inter-species disparities. Reproducibility of transcriptomic observations was validated experimentally in PCI. These data underline, that inter-species comparison can obtain commonly expressed transcriptomic features despite missing homologs and different protocols. Our findings point toward a high suitability of an animal sepsis model and further experimental efforts in order to transfer results from animal experiments to the bedside.

Background

Approximately 25% of so-called high utilizers of medical care are estimated to suffer from depression. A large proportion of these individuals remain undiagnosed and untreated. This study aims to examine the effects of a systematic screening and collaborative treatment program on depression severity in small primary care practices of the German outpatient health care system.

Method

High utilizers of primary care who screened positive for depressive symptoms on the Brief Psychiatric Health Questionnaire (B-PHQ) were further diagnosed using the DIA-X, a standardized diagnostic interview, performed by trained and supervised interviewers. Patients with major depression were randomized (cluster randomization by practice) to (a) a six-month treatment program of pharmacotherapy, standardized patient and provider education, and physician and patient counseling or (b) six months of usual medical care. All subjects were followed for a 12-month observation period using the 17-item Hamilton Depression Rating scale (HAMD-17) rated by the treating physicians and the B-PHQ-9 rated by the patients.

Results

A total of 63 high utilizer patients were included in the trial (17 male, 46 female), 19 randomized to intervention, 44 to usual care. The mean age was 49.7 (SD 13.8). Most patients had one or more somatic co-morbidities. There was no significant difference in response (defined as a decrease in the HAMD-17 sum score of at least 50%) after six months of treatment (50% vs. 42%, p = 0.961, all analyses adjusted for age) and after 12 months of treatment (83% vs. 54%, p = 0.282) between groups. Using patient self-rating assessments with the B-PHQ-9 questionnaire the intervention was superior to treatment as usual at six months (83% vs. 16%, p = 0.000).

There was no significant difference in HAMD-17 depression severity at six months between the groups (10.5 (SD 7.6) vs. 12.3 (SD 7.8), p = 0.718), but a trend at 12 months (4.7 (SD 8.0) vs. 11.2 (SD 7.4), p = 0.083). Again, using B-PHQ-9 sum scores depression severity was significantly lower in the intervention group than in the treatment as usual group after six months (6.4 (SD 5.2) vs. 11.5 (SD 5.8), p = 0.020), but not at 12 months (7.9 (SD 8.7) vs. 9.0 (SD 5.2), p = 0.858).

Conclusion

A systematic collaborating treatment program for depression in high utilizers in primary care showed superiority to treatment as usual only in terms of patients´ self-assessment but not according to physicians´ assessment. The advance of the intervention group at 6 months was lost after 12 months of follow-up. Overall, positive results from similar trials in the US health care systems could not be confirmed in a German primary care setting.

We live in an age of access to more information than ever before. This can be a double-edged sword. Increased access to information allows for more informed and empowered researchers, while information overload becomes an increasingly serious risk. Thus, there is a need for intelligent information retrieval systems that can summarize relevant and reliable textual sources to satisfy a user's query. Question answering is a specialized type of information retrieval with the aim of returning precise short answers to queries posed as natural language questions. We present a review and comparison of three biomedical question answering systems: askHERMES (http://www.askhermes.org/), EAGLi (http://eagl.unige.ch/EAGLi/), and HONQA (http://services.hon.ch/cgi-bin/QA10/qa.pl).

Background

Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection.

Discussion

To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population.

Summary

We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.

Rationale

High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice.

Objective

To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models.

Methods and Results

Herein, we describe a modified echocardiographic technique that utilizes speckle-tracking based strain analysis for the non-invasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared to conventional echocardiographic measures of LV structure and function, peak longitudinal strain and strain rate were able to detect changes in adult mouse hearts at an earlier time point following myocardial infarction (post-MI) and predicted the later development of adverse LV remodeling. Moreover, speckle-tracking based strain analysis was able to clearly identify subtle improvement in LV function that occurred early in response to standard post-MI cardiac therapy.

Conclusions

Our results highlight the utility of speckle-tracking based strain imaging for detecting discrete functional alterations in mouse models of cardiovascular disease in an efficient and comprehensive manner. Echocardiography speckle-tracking based strain analysis represents a method for relatively high-throughput and sensitive cardiac phenotyping, particularly in evaluating emerging cardiac agents and therapies in mice.

Background

Neuroprotective effects of lithium (Li) have been well documented in tissue cultures and animal models, whereas human data continue to be limited. Previous studies investigating the association between Li treatment and brain N-acetylaspartate (NAA), a putative neuronal marker, showed mixed results because of methodological heterogeneity.

Methods

To investigate the effects of Li on prefrontal cortex NAA levels, we compared patients with bipolar disorder from specialized Li clinics in Berlin and Halifax with at least 2 years of ongoing Li treatment (Li group), patients with lifetime Li exposure of less than 3 months more than 2 years ago (non-Li group) and healthy controls. Participants in both patient groups had at least 10 years of illness and 5 episodes. We measured left prefrontal NAA levels using 1.5-T magnetic resonance spectroscopy.

Results

We enrolled 27 participants in the Li, 16 in the non-Li and 21 in the healthy control groups. The non-Li group had lower prefrontal NAA levels than the Li group (t41 = −3.44, corrected p < 0.01) or control participants (t35 = −2.91, corrected p < 0.05), who did not differ from the Li group (t46 = −0.14, p = 0.89). The same pattern of prefrontal NAA differences was replicated in both sites. In addition, there was a negative correlation between prefrontal NAA and duration of illness in the non-Li group (r = −0.60, p = 0.019) but not in the Li group (r = 0.07, p = 0.74).

Limitations

Study limitations include the cross-sectional design and exposure to other medications.

Conclusion

Whereas patients with bipolar disorder, substantial illness burden and limited lifetime Li exposure had significantly lower prefrontal NAA levels than controls, Li-treated patients with similar illness burden showed prefrontal NAA levels comparable to those of healthy controls. These findings provide indirect support for neuroprotective effects of Li and for negative effects of illness burden on prefrontal NAA levels in patients with bipolar disorder.

Platelet activation has been implicated in microvascular thrombosis and organ failure in critically ill patients. In the first part the present paper summarises important data on the role of platelets in systemic inflammation and sepsis as well as on the beneficial effects of antiplatelet drugs in animal models of sepsis. In the second part the data of retrospective and prospective observational clinical studies on the effect of aspirin and other antiplatelet drugs in critically ill patients are reviewed. All of these studies have shown that aspirin and other antiplatelet drugs may reduce organ failure and mortality in these patients, even in case of high bleeding risk. From the data reviewed here interventional prospective trials are needed to test whether aspirin and other antiplatelet drugs might offer a novel therapeutic option to prevent organ failure in critically ill patients.

Rationale

Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation.

Objective

In this study, we tested whether the mouse heart possesses at birth a pool of cardiac stem cells (CSCs) which differentiate into myocytes contributing to the expansion of the parenchymal cell compartment postnatally.

Methods and Results

We have found that the newborn heart contains a population of c-kit-positive CSCs which are lineage negative, self-renewing and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5 indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs expanded significantly the proportion of transit amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a γ-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes which resulted in a 54% decrease in myocyte number. Following cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored.

Conclusions

Notch1 signaling is a critical determinant of CSC growth and differentiation and when this cascade of events is altered cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented and a life threatening myopathy supervenes.

Abstract

Thyroid hormones play a critical role in brain development but also in the adult human brain by modulating metabolic activity. Hypothyroid states are associated with both functional and structural brain alterations also seen in patients with major depression. Recent animal experimental and preclinical data indicate subtle changes in myelination, microvascular density, local neurogenesis, and functional networks. The translational validity of such studies is obviously limited. Clinical evidence for neurobiological correlates of different stages and severities of hypothyroidism and effects of pharmacological intervention is lacking but may be achieved using advanced imaging techniques, e.g. functional and quantitative MRI techniques applied to patients with hypothyroidism before and after hormone replacement therapy.

Introduction

Recent models capturing the pathophysiology of sepsis and ex-vivo data from patients are speculating about immunosuppression in the so-called late phase of sepsis. Clinical data regarding survival and microbiological burden are missing. The aim of this study was to determine the clinical significance of the 'late phase' of sepsis with respect to overall survival and occurrence of microbiological findings.

Methods

In a retrospective trial, 16,041 patient charts from a university intensive care unit were screened, and 999 patients with severe sepsis or septic shock were identified. Three phases were established according to the mortality peaks which were separated by two distinct nadirs: phase I (days 1 to 5), phase II (days 6 to 15) and phase III (days 16 to 150). Patients were analyzed for outcome, SOFA scores, procalcitonin levels, antimicrobial treatment, dialysis, mechanical ventilation and results of blood cultures during their hospital stay.

Results

Out of 999 enrolled patients, 308 died during the course of sepsis presenting a characteristic mortality rate (30.8%) with three distinct mortality peaks (at days 2, 7 and 17). Overall 36.7% of all deaths occurred in the early phase (phase I) and 63.3% during the later phases (phase II + III). In total 2,117 blood cultures were drawn. In phase I, 882 blood cultures were drawn, representing a sampling rate of 88% with a positive rate of 14.9%. In phase II, 461 samples were taken, indicating a sampling rate of 52% and a positive rate of 11.3%. Within phase III, 524 samples were obtained representing a sampling rate of 66% with a positive rate of 15.3%, which was significantly higher compared to the positive rate of phase II and similar to phase I. In particular, the rate of typically opportunistic bacteria increased significantly from 9% in phase I up to 18% in phase III. The same is true for Candida spp. (phase I 13%, phase III 30%).

Conclusions

The later phase of sepsis is associated with a significant re-increase of positive blood culture results, especially regarding opportunistic bacteria and fungi. These observations warrant further studies focusing on the underlying mechanisms resulting in this outcome burden in the later phase of sepsis.

Disrupted sleep is prevalent in both mood and thyroid disorders. Given the emerging use of thyroid hormones in the treatment of mood disorders, we investigated the effects of supraphysiological doses of levothyroxine (L-T4) on sleep. In an open-label design, 13 healthy subjects received up to 500 μg/day for an eight-week period. A baseline night was polysomnographically recorded (PSG) followed by PSG under the maximum tolerated dose of L-T4. All subjects developed hyperthyroxinemia. The heart rate and respiration rate increased significantly with treatment; a significant increase in body temperature was observed in men but not in women. Surprisingly, treatment with supraphysiological doses of L-T4 did not cause significant effects on sleep architecture. However, the increase in body movements and REM density was close to reaching statistical significance. Here, we report on the sleep data, thyroid hormone levels, and physiological parameters during sleep. We conclude that experimentally induced hyperthyroidism does not profoundly change the sleep structure in healthy individuals underlining the good tolerability of treatment with supraphysiological doses of L-T4 in patients with mood disorders.