Grey matter structural differences in alcohol-dependent individuals with and without comorbid depression/anxiety-an MRI study.

Although depression and anxiety disorders are common comorbid conditions in alcohol dependence, few structural brain imaging studies have compared alcohol-dependent subjects with and without such comorbidity. In the current study, brain scans of 35 alcohol-dependent with and 40 individuals without diagnosis of a comorbid ICD-10 depressive or anxiety disorder receiving detoxification inpatient treatment were evaluated. Thickness and volumes of automatically segmented neuroanatomical structures were measured in FreeSurfer. Furthermore, associations of brain structure with biological markers and clinical severity markers of alcohol dependence were assessed. Despite comparable addiction severity, the non-comorbid group had evidence of higher cytotoxic effects of alcohol use on hepatic and haematological markers, and showed significantly smaller volumes of total cerebral, and cerebellar grey matter. Similarly, they showed unexpected smaller hippocampal and nucleus accumbens volumes, and thinner frontal, temporal and occipital cortices. Smaller brain volumes correlated with increased markers of hepatic and haematological dysfunction, and with longer duration of alcohol dependence in the non-comorbid group. Evidence of higher biomarkers of alcohol use may be indicative of more severe alcohol dependence or higher vulnerability to ethanol toxicity in this group. Furthermore, psychopathology-related drug treatment, which occurred in 53% of the comorbid group over the recent years, or tissue inflammation may have a moderate effect on the grade of cerebral atrophy in alcohol-dependent patients. Longitudinal studies are needed to investigate this issue more fully.

Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs.

RATIONALE: The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs. OBJECTIVES: To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro. METHODS: In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined. MEASUREMENTS AND MAIN RESULTS: Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-ß (TGF-ß) responses in C2C12 cells, suggesting increased sensitivity to TGF-ß in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle. CONCLUSIONS: GDF-15 may increase sensitivity to TGF-ß signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets.

Group music therapy for severe mental illness: a randomized embedded-experimental mixed methods study.

OBJECTIVE: Music therapy is an innovative approach to support people with severe mental illness (SMI). The aim of the study was to determine whether group music therapy (GMT) positively impacted on quality of life (QoL), social enrichment, self-esteem, spirituality and psychiatric symptoms of participants with SMI and how they experienced the intervention. METHOD: The primary outcome was QoL; secondary measures assessed social enrichment, self-esteem, spirituality and psychiatric symptoms. The 13-week intervention comprised singing familiar songs and composing original songs recorded in a professional studio. Qualitative data were generated from focus group interviews and song lyric analysis. RESULTS: Ninety-nine adults (57 female) were recruited, with an initial cohort (n = 75) randomized to either: weekly GMT followed by standard care (SC) or SC followed by GMT. Crossover occurred after 13 weeks. Measures were conducted at baseline, 13, 26 and 39 weeks. A second cohort (n = 24) could not be randomized and were assigned to GMT followed by SC. Intention-to-treat analysis showed a significant difference between GMT and SC on QoL and spirituality. This was robust to different assumptions about missing data (listwise deletion, last observation carried forward or multiple imputation). Per-protocol analysis suggested greater benefit for those receiving more sessions. Focus group interview and song lyric analyses suggested that GMT was enjoyable; self-esteem was enhanced; participants appreciated therapists and peers; and although challenges were experienced, the programme was recommended to others. CONCLUSION: Group music therapy may enhance QoL and spirituality of persons with SMI.

Clinical consequences of aspirin and clopidogrel resistance: an overview.

The aim of this review is to introduce the concept of personalized medicine in secondary stroke prevention with antiplatelet medication. In the last years, many studies have been conducted regarding aspirin resistance and genotyping of clopidogrel metabolism. A review of the currently published data on this issue emphasizes the importance of focusing on the individualizing approach in antiplatelet therapy to achieve maximal therapeutic beneficial effect. However, many authors suggest that, before new information from ongoing trials become available, good clinical practice should dictate the use of low dose of aspirin that was shown to be effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, because higher doses do not have significantly better efficacy than lower doses in secondary stroke prevention, but lower-dose aspirin is associated with less side effects. On the other hand, many factors are associated with clopidogrel resistance, and recent genetic studies showed that the CYP2C19*2 genotype (loss-of-function allele) is related to poor metabolism of clopidogrel, but larger studies are needed to definitively confirm or rule out the clinical significance of this genetic effect. The aim of personalized approach in secondary stroke prevention is to take the most appropriate medicine in the right dose in accordance with the clinical condition of the patient and associated risk factors.

Molecular mechanisms of intensive care unit-acquired weakness.

Intensive care unit-acquired weakness (ICUAW) is an increasingly recognised and important clinical consequence of critical illness. It is associated with significant morbidity and mortality. The aetiology of this disease is not well understood. The purpose of this article is to review our understanding of the molecular pathogenesis of ICUAW in the context of current knowledge of clinical risk factors and aetiology. Key features of the disease are loss of muscle mass resulting from a shift in the dynamic balance of muscle protein synthesis and breakdown and a reduction in force-generating capacity. These alternations are secondary to neuropathy, disruption of the myofilament structure and function, a disrupted sarcoplasmic reticulum, electrical inexcitability and bioenergenetic failure. As knowledge and understanding of ICUAW grows, potential therapeutic targets will be identified, hopefully leading to multiple strategies for prevention and treatment of this important condition.

Fluorescence lifetime imaging microscopy using near-infrared contrast agents.

Although single-photon fluorescence lifetime imaging microscopy (FLIM) is widely used to image molecular processes using a wide range of excitation wavelengths, the captured emission of this technique is confined to the visible spectrum. Here, we explore the feasibility of utilizing near-infrared (NIR) fluorescent molecular probes with emission >700 nm for FLIM of live cells. The confocal microscope is equipped with a 785 nm laser diode, a red-enhanced photomultiplier tube, and a time-correlated single photon counting card. We demonstrate that our system reports the lifetime distributions of NIR fluorescent dyes, cypate and DTTCI, in cells. In cells labelled separately or jointly with these dyes, NIR FLIM successfully distinguishes their lifetimes, providing a method to sort different cell populations. In addition, lifetime distributions of cells co-incubated with these dyes allow estimate of the dyes' relative concentrations in complex cellular microenvironments. With the heightened interest in fluorescence lifetime-based small animal imaging using NIR fluorophores, this technique further serves as a bridge between in vitro spectroscopic characterization of new fluorophore lifetimes and in vivo tissue imaging.

Multifunctional Thio-Stabilized Gold Nanoparticles for Near-Infrared Fluorescence Detection and Imaging of Activated Caspase-3.

BACKGROUND: Gold nanoparticles (AuNPs) are commonly used in nanomedicine because of their unique spectral properties, chemical and biological stability, and ability to quench the fluorescence of organic dyes attached to their surfaces. However, the utility of spherical AuNPs for activatable fluorescence sensing of molecular processes have been confined to resonance-matched fluorophores in the 500 nm to 600 nm spectral range to maximize dye fluorescence quenching efficiency. Expanding the repertoire of fluorophore systems into the NIR fluorescence regimen with emission >800 nm will facilitate the analysis of multiple biological events with high detection sensitivity. OBJECTIVE: The primary goal of this study is to determine if spherical AuNP-induced radiative rate suppression of non-resonant near-infrared (NIR) fluorescent probes can serve as a versatile nanoconstruct for highly sensitive detection and imaging of activated caspase-3 in aqueous media and cancer cells. This required the development of activatable NIR fluorescence sensors of caspase-3 designed to overcome the nonspecific degradation and release of the surface coatings in aqueous media. METHOD: We harnessed the fluorescence-quenching properties and multivalency of spherical AuNPs to develop AuNP-templated activatable NIR fluorescent probes to detect activated caspase-3, an intracellular reporter of early cell death. Freshly AuNPs were coated with a multifunctional NIR fluorescent dye-labeled peptide (LS422) consisting of an RGD peptide sequence that targets αvß3-integrin protein (αvß3) on the surface of cancer cells to mediate the uptake and internalization of the sensors in tumor cells; a DEVD peptide sequence for reporting the induction of cell death through caspase-3 mediated NIR fluorescence enhancement; and a multidentate hexacysteine sequence for enhancing self-assembly and stabilizing the multifunctional construct on AuNPs. The integrin binding affinity of LS422 and caspase-3 kinetics were determined by a radioligand competitive binding and fluorogenic peptide assays, respectively. Detection of intracellular caspase-3, cell viability, and the internalization of LS422 in cancer cells were determined by confocal NIR fluorescence spectroscopy and microscopy. RESULTS: Narrow size AuNPs (13 nm) were prepared and characterized by transmission electron microscopy and dynamic light scattering. When assembled on the AuNPs, the binding constant of LS422 for αvß3 improved 11-fold from 13.2 nM to 1.2 nM. Whereas the catalytic turnover of caspase-3 by LS422-AuNPs was similar to the reference fluorogenic peptide, the binding affinity for the enzyme increased by a factor of 2. Unlike the αvß3 positive, but caspase-3 negative breast cancer MCF-7 cells, treatment of the αvß3 and caspase-3 positive lung cancer A549 cells with Paclitaxel showed significant fluorescence enhancement within 30 minutes, which correlated with caspase-3 specific activation of LS422-AuNPs fluorescence. Incorporation of a 3.5 mW NIR laser source into our spectrofluorometer increased the detection sensitivity by an order of magnitude (limit of detection ~0.1 nM of cypate) and significantly decreased the signal noise relative to a xenon lamp. This gain in sensitivity enabled the detection of substrate hydrolysis at a broad range of inhibitor concentrations without photobleaching the cypate dye. CONCLUSION: The multifunctional AuNPs demonstrate the use of a non-resonant quenching strategy to design activatable NIR fluorescence molecular probes. The nanoconstruct offers a selective reporting method for detecting activated caspase-3, imaging of cell viability, identifying dying cells, and visualizing the functional status of intracellular enzymes. Performing these tasks with NIR fluorescent probes creates an opportunity to translate the in vitro and cellular analysis of enzymes into in vivo interrogation of their functional status using deep tissue penetrating NIR fluorescence analytical methods.

Psychosocial adaptation in female partners of men with prostate cancer.

The objective was to explore the psychosocial adaptation of female partners living with men with a diagnosis of either localized or metastatic prostate cancer. Semi-structured qualitative interviews were conducted with 50 women at two time points (baseline and 6 months later). The interviews examined emotions, experiences, attitudes to sexual and continence issues and treatment decision making. As part of a larger prospective observational study, demographic data and scores for depression and anxiety were collected. Initial analysis demonstrated that the group of 11 women assessed as distressed on the anxiety and depression measures described reduced coping skills and poorer adaptation after 6 months. In contrast, the 39 women in the non-distressed group reported emotional adaptation that fitted the Lazarus and Folkman pattern of coping through appraisal of the impact of the diagnosis on their partner and themselves, appraisal of coping strategies and reappraisal of the situation. A surprise finding was the high level of resilience displayed by majority of these women. Results suggest that a psychosocial intervention could strengthen healthy adaptation and provide better coping skills for distressed couples.

Difference in brain densities between chronic alcoholic and normal control patients.

The densities of the brains of 11 chronic alcoholics were compared with those of 11 age-matched normal control subjects. Densities were determined from the density numbers generated by computerized tomography at three levels of the brain-the highest level of the lateral ventricles and the next two higher levels-with adjustments made to control for possible artifacts in the data. The advantage of the dominant hemisphere over the nondominant hemisphere was lessened in alcoholics.

The ethical imperative to scale up health care services for people with severe mental disorders in low and middle income countries.

Most mentally ill people in low and middle income countries, where clinical services are typically scarce and mental health legal provisions often inadequate, do not receive requisite evidence based treatment. The unfortunate consequence is compromised health and well-being and lack of social integration in the community. Recent initiatives, such as the Movement for Global Mental Health, aim to improve the situation and, in so doing, take into account ethical factors that play a role in the face of inadequate care and mental health legislative frameworks. Two composite case vignettes based on the narratives of actual patients living in India are used to show how family carers resort to measures like deception, coercion and physical restraint in order to deal with challenging behaviours stemming from severe and enduring mental disorders. These actions, while violating patients' fundamental human rights, are also the consequence of the utter frustration and despair experienced by families. Scaling up mental health care based on the principle of cost effectiveness is not only a clinical imperative, but also a pivotal means to ensure that the severely mentally ill are accorded the same universal rights as those enjoyed by others.

Charge-transfer excitons in DNA.

There have been a number of theoretical treatments of excitons in DNA, most neglecting both the intrachain and interchain wavefunction overlaps of the electron and hole, treating them as Frenkel excitons. Recently, the importance of the intrachain and interchain coupling has been highlighted. Experiments have shown that in (dA)n oligomers and in duplex (dA)n.(dT)n, to be abbreviated (A/T), where A is adenine and T is thymine, the exciton wavefunction is delocalized over several bases. In duplexes it is possible to have charge-transfer (CT) excitons. Theoretical calculations have suggested that CT excitons in DNA may have lower energy than single chain excitons. In all the calculations of excitons in DNA, the polarization of the surrounding water has been neglected. Calculations have shown, however, that polarization of the water by an excess electron or a hole in DNA lowers its energy by approximately 1/2 eV, causing it to become a polaron. It is therefore to be expected that polarization charge induced in the surrounding water has a significant effect on the properties of the exciton. In what follows, we present calculations of some properties CT excitons would have in an A/T duplex taking into account the wavefunction overlaps, the effect of the surrounding water, which results in the electron and hole becoming polarons, and the ions in the water. As expected, the CT exciton has lowest energy when the electron and hole polarons are directly opposite each other. By appropriate choice of the dielectric constant, we can obtain a CT exciton delocalized over the number of sites found in photoinduced absorption experiments. The absorption threshold that we then calculate for CT exciton creation in A/T is in reasonable agreement with the lowest singlet absorption deduced from available data.

Immune response profiling of primary monocytes and oral keratinocytes to different Tannerella forsythia strains and their cell surface mutants.

The oral pathogen Tannerella forsythia possesses a unique surface (S-) layer with a complex O-glycan containing a bacterial sialic acid mimic in the form of either pseudaminic acid or legionaminic acid at its terminal position. We hypothesize that different T. forsythia strains employ these stereoisomeric sugar acids for interacting with the immune system and resident host tissues in the periodontium. Here, we show how T. forsythia strains ATCC 43037 and UB4 displaying pseudaminic acid and legionaminic acid, respectively, and selected cell surface mutants of these strains modulate the immune response in monocytes and human oral keratinocytes (HOK) using a multiplex immunoassay. When challenged with T. forsythia, monocytes secrete proinflammatory cytokines, chemokines and vascular endothelial growth factor (VEGF) with the release of interleukin-1ß (IL-1ß) and IL-7 being differentially regulated by the two T. forsythia wild-type strains. Truncation of the bacteria's O-glycan leads to significant reduction of IL-1ß and regulates macrophage inflammatory protein-1. HOK infected with T. forsythia produce IL-1Ra, chemokines and VEGF. Although the two wild-type strains elicit preferential immune responses for IL-8, both truncation of the O-glycan and deletion of the S-layer result in significantly increased release of IL-8, granulocyte-macrophage colony-stimulating factor and monocyte chemoattractant protein-1. Through immunofluorescence and confocal laser scanning microscopy of infected HOK we additionally show that T. forsythia is highly invasive and tends to localize to the perinuclear region. This indicates, that the T. forsythia S-layer and attached sugars, particularly pseudaminic acid in ATCC 43037, contribute to dampening the response of epithelial tissues to initial infection and hence play a pivotal role in orchestrating the bacterium's virulence.

Peritoneal mucinous cystadenocarcinoma of probable urachal origin: a challenging diagnosis.

This report describes the case of a mucinous cystadenocarcinoma of probable urachal origin that presented with mass effect, precipitating deep venous thrombosis and pulmonary embolism. The patient presented with acute symptoms of leg swelling, pain and dyspnoea, and a vague awareness of lower abdominal distension. Computer tomography showed a cystic mass closely related to the anterior abdominal wall and the superior aspect of the bladder. A 1500 cm(3) cyst adherent to the dome of the urinary bladder was resected on laparotomy. Partial cystectomy was not carried out in the belief that the cyst represented a benign lesion. Subsequent imaging has shown cystic changes in the anterior bladder wall, and the patient has been referred for partial cystectomy.

The written summary as a group psychotherapy technique.

During the past 18 months, we have been preparing detailed written summaries of the events of group therapy meetings, which have then been mailed to the group members. This technique was introduced initially as a device to provide structure in a very anxious group. We soon realized that the summary had a great potential for enhancing therapist effectiveness and it came to assume a number of other functions. In this report, we describe our experience with this technique, emphasizing its importance as a tool to improve the cognitive integration of the group therapy experience for both patient and therapist.

Therapeutic factors in group psychotherapy. A review.

This is a review of theoretical, empirical, and clinical research on therapeutic factors (TFs) in group psychotherapy covering the period 1955 to 1979. Therapeutic factors are processes that contribute to improvement in the patient's condition; they are different from conditions for change and from techniques. The following TFs are examined: self-disclosure, interaction, acceptance (cohesiveness), insight, catharsis, guidance, altruism, vicarious learning, instillation of hope, and an existential factor. Criteria for adequate experimental design in group research are proposed. About 40% of the works reviewed contain empirical studies; the quality of these studies is variable both conceptually and methodologically. It is difficult to assess the extent to which clinical practice has actually been influenced by this work on TFs.

Alcoholics in interactional group therapy: an outcome study.

Three interactional therapy groups of alcoholic patients (N = 20) were formed, and treatment outcome after eight months and again after 12 months of therapy was compared with the outcome of 17 neurotic patients in comparable therapy. Outcome assessment was obtained from three sources: patient, therapist, and independent judge, using both nomothetic and ideographic measures. The results indicated that although more alcoholic than neurotic patients terminated therapy within the first six sessions, a higher percentage of alcoholic patients remained in therapy for 12 months. At the end of 12 months, both samples had improved along a wide variety of variables, and there were no significant differences between the alcoholic and neurotic population in degree of improvement.

The impact of a weekend group experience on individual therapy.

Thirty-three patients in long-term individual therapy were referred to one of three weekend groups: two experimental (affect-arousing, gestalt therapy) groups and one control (meditation-Tai Chi) group. The impact of the weekend group experience (WGE) on individual therapy was examined six and 12 weeks later. At six weeks the patients in the experimental groups showed, on some measures, a significantly greater improvement in their individual therapy than did controls. By 12 weeks, there were no demonstrable differences. The WGE was not without risk: even though the group leaders were highly trained, responsible clinicians, two patients suffered considerable psychological damage. The control (meditation-Tai Chi) group offered a relatively innocuous experience; there was no risk, but few members found the specific procedures useful in their lives. Intense affect arousal in the WGE was not related to positive change in subsequent individual therapy. Those expressing the greatest affect in either experimental group were no more likely to have had a measurable positive impact on their subsequent individual therapy than patients expressing little or no measurable affect.

Structural brain deficits in schizophrenia. Identification by computed tomographic scan density measurements.

Research has suggested the presence of brain damage as a cause or concomitant of chronic schizophrenia. The most recent research in this area has been the identification of abnormalities in schizophrenia by computed tomographic (CT) scans. A study was done to investigate localized changes in CT scan density numbers in the brains of schizophrenic patients, as opposed to the brains in normal control subjects. Twenty-four normal subjects and 23 schizophrenic patients were tested with CT scans. Density measurements in each area of the brain (left, right, anterior and posterior) were compared to three separate CT scan levels. Of six measurements of anterior left-hemisphere density, it was found that five showed lower density in schizophrenic brains, as compared with normal brains. Of the remaining 18 measurements that evaluated other areas of the brain, only three differentiated between schizophrenic patients and normal subjects. The results support the hypothesis that there are primary structural deficits in some schizophrenic patients, and these deficits are centered in and around the anterior area of the left (dominant) hemisphere. The results also demonstrated further implications.

Characterization of antihuman chorionic gonadotropin serum antibody appearing after ovulation induction.

After repeated im courses of menopausal gonadotropins and hCG, a factor was found in a woman's serum which preferentially bound the intact hCG molecule (nanograms or milliinternational units required for 50% displacement of [125I] hCG: hCG, 9.2 ng; APL, 74 mIU; Pergonal, 400 mIU; LER 960, 900 ng; and FSH and TSH alpha-subunits, hCG beta-subunit, and LH beta-subunit, greater than 1000 ng). This factor had a low affinity (Ka = 5.8 X 10(9) liters/M) and high capacity (binding capacity, 5.5 X 10(-11) M/liter) for hCG, was isolated with the immunoglobulin G fraction of the patient's serum, and coeluted with immunoglobulin G from a Sepharose CL-6B-200 column. Preincubation of hCG with this fraction did not reduce the in vitro biological activity of the hCG in the hypophysectomized rat ventral prostate weight assay. Similarly, there was no gonadal resistance to hCG in the patient, since ovulation could still be induced with hCG, and both progesterone and 17-hydroxyprogesterone levels as well as duration of the luteal phase increased after repeated hCG injections. This serum factor prolonged the half-life of injected hCG in the patient's circulation (t 1/2 = 9.4 days in patient vs. 1.3 days in controls). The titer of the factor transiently decreased with the exogenous administration of hCG. No binding of the serum factor to human placental tissue could be demonstrated by immunohistochemical techniques. Thus, this factor behaves similarly to the antibodies frequently found after the injection of other polypeptide hormones, in that it serves as a high capacity reservoir of the hormone but does not significantly reduce its biological activity. These results also indicate that the factor requires the intact tertiary structure of the hCG molecule for immune recognition.

The regulation and regulatory role of collagenase in bone.

Interstitial collagenase plays an important role in both the normal and pathological remodeling of collagenous extracellular matrices, including skeletal tissues. The enzyme is a member of the family of matrix metalloproteinases. Only one rodent interstitial collagenase has been found but there are two human enzymes, human collagenase-1 and -3, the latter being the homologue of the rat enzyme. In developing rat and mouse bone, collagenase is expressed by hypertrophic chondrocytes, osteoblasts, and osteocytes, a situation that is replicated in a fracture callus. Cultured osteoblasts derived from neonatal rat calvariae show greater amounts of collagenase transcripts late in differentiation. These levels can be regulated by parathyroid hormone (PTH), retinoic acid, and insulin-like growth factors, as well as the degree of matrix mineralization. Much of the work on collagenase in bone has been derived from studies on the rat osteosarcoma cell line, UMR 106-01. All bone-resorbing agents stimulate these cells to produce collagenase mRNA and protein, with PTH being the most potent stimulator. Determination of secreted levels of collagenase has been difficult because UMR cells, normal rat osteoblasts, and rat fibroblasts possess a scavenger receptor that removes the enzyme from the extracellular space, internalizes and degrades it, thus imposing another level of control. PTH can also regulate the abundance of the receptor as well as the expression and synthesis of the enzyme. Regulation of the collagenase gene by PTH appears to involve the cAMP pathway as well as a primary response gene, possibly Fos, which then contributes to induction of the collagenase gene. The rat collagenase gene contains an activator protein-1 sequence that is necessary for basal expression, but other promoter regions may also participate in PTH regulation. Thus, there are many levels of regulation of collagenase in bone perhaps constraining what would otherwise be a rampant enzyme.