Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review.

BACKGROUND: Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours. PATIENTS AND METHODS: Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy. RESULTS: In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis.

BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management.

Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.

OBJECTIVE: To examine the prevalence, incidence and risk factors associated with visual hallucinations (VHs) amongst people suffering from Parkinson's disease (PD). METHODS: We recruited 513 patients with PD from movement disorder and PD clinics within three sites in the UK. Patients were interviewed using a series of standardised clinical rating scales at baseline, 12, 24 and 36 months. Data relating to VHs were collected using the North-East Visual Hallucinations Interview. Prevalence rates for VHs at each assessment were recorded. Associations were determined using multiple regression analysis. RESULTS: Cross-sectional prevalence rates for VHs at baseline, 12, 24 and 36 months indicated VHs in approximately 50% of patients. A cumulative frequency of 82.7% of cases at the end of the study period exhibited VHs. The incidence rate for VHs was 457 cases per 1000 population. Longer disease duration, greater impairment in activities of daily living and higher rates of anxiety were most commonly associated with VHs. No factors predictive of VHs could be ascertained. CONCLUSIONS: When examined longitudinally, VHs affect more patients than is commonly assumed in cross-sectional prevalence studies. Clinicians should routinely screen for VHs throughout the disease course. Disease duration, impairment in activities of daily living and anxiety presented as co-morbidities associated with VHs in PD, and therefore those presenting with VHs should be screened for anxiety disorder and vice versa.

Phosphorylation of Caldesmon by PFTAIRE1 kinase promotes actin binding and formation of stress fibers.

Caldesmon (CaD) is an actin-binding protein that is capable of stabilizing actin filaments. Phosphorylation of CaD is widely accepted in the actin cytoskeletal modeling and promotion of cell migration. In this study, we show that CaD is a downstream phosphorylation substrate of PFTK1, a novel Cdc-2-related ser/thr protein kinase. Our study stemmed from an earlier investigation where we demonstrated that PFTK1 kinase conferred cell migratory advantages in human hepatocellular carcinoma (HCC) cells. Here, we showed that PFTK1-knockdown cells exhibited much reduced CaD phosphorylation and consequently caused dissociation of CaD from the F-actin fibers. The cellular localization of CaD was also altered in the absence of PFTK1. Immunofluorescence analysis revealed that PFTK1-abrogated cells exhibited a diffused and blurred appearance of CaD localization, whereas intact co-localization with F-actins was apparent in PFTK1-expressing cells. Without the binding of CaD to actin, disappearance of actin stress fibers was also evident in PFTK1-abrogated cells. In addition, we found that CaD is also commonly up-regulated in HCC tumors when compared to adjacent non-malignant liver (P = 0.022). Taken together, our results highlight a novel biological cascade that involved the phosphorylation activation of CaD by PFTK1 kinase in promoting formation of actin stress fibers.

Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

BACKGROUND: Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. METHODS: Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. RESULTS: Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. CONCLUSION: The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

Pre-clinical evaluation of ceramic femoral head resurfacing prostheses using computational models and mechanical testing.

Ceramic-on-ceramic hip resurfacing can potentially offer the bone-conserving advantages of resurfacing while eliminating metal ion release. Thin-walled ceramic resurfacing heads are conceivable following developments in the strength and reliability of ceramic materials, but verification of new designs is required. The present study aimed to develop a mechanical pre-clinical analysis verification process for ceramic resurfacing heads, using the DeltaSurf prosthesis design as a case study. Finite element analysis of a range of in vivo scenarios was used to design a series of physiologically representative mechanical tests, which were conducted to verify the strength of the prosthesis. Tests were designed to simulate ideal and worst-case in vivo loading and support, or to allow comparison with a clinically successful metallic device. In tests simulating ideal loading and support, the prosthesis sustained a minimum load of 39 kN before fracture, and survived 10 000 000 fatigue cycles of 0.534 kN to 5.34 kN. In worst-case tests representing a complete lack of superior femoral head bone support or pure cantilever loading of the prosthesis stem, the design demonstrated strength comparable to that of the equivalent metal device. The developed mechanical verification test programme represents an improvement in the state of the art where international test standards refer largely to total hip replacement prostheses. The case study's novel prosthesis design performed with considerable safety margins compared with extreme in vivo loads, providing evidence that the proposed ceramic resurfacing heads should have sufficient strength to perform safely in vivo. Similar verification tests should be designed and conducted for novel ceramic prosthesis designs in the future, leading the way to clinical evaluation.

Psychotherapeutic treatments for older depressed people.

BACKGROUND: Despite a number of reviews advocating psychotherapy for the treatment of depression, there is relatively little evidence based on randomised controlled trials that specifically examines its efficacy in older people. OBJECTIVES: To examine the efficacy of psychotherapeutic treatments for depression in older people. SEARCH STRATEGY: CCDANCTR-Studies and CCDANCTR-References were searched on 11/9/2006. The International Journal of Geriatric Psychiatry and Irish Journal of Psychiatry were handsearched. Reference lists of previous published systematic reviews, included/excluded trial articles and bibliographies were scrutinised. Experts in the field were contacted.. SELECTION CRITERIA: All randomised controlled trials that included older adults diagnosed as suffering from depression (ICD or DSM criteria) were included. All types of psychotherapeutic treatments were included, categorised into cognitive behavioural therapies (CBT), psychodynamic therapy, interpersonal therapy and supportive therapies. DATA COLLECTION AND ANALYSIS: Meta-analysis was performed, using odds ratios for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes, with 95% confidence intervals. Primary outcomes were a reduction in severity of depression, usually measured by clinician rated rating scales. Secondary outcomes, including dropout and life satisfaction, were also analysed. MAIN RESULTS: The search identified nine trials of cognitive behavioural and psychodynamic therapy approaches, together with a small group of 'active control' interventions. No trials relating to other psychotherapeutic approaches and techniques were found. A total of seven trials provided sufficient data for inclusion in the comparison between CBT and controls. No trials compared psychodynamic psychotherapy with controls. Based on five trials (153 participants), cognitive behavioural therapy was more effective than waiting list controls (WMD -9.85, 95% CI -11.97 to -7.73). Only three small trials compared psychodynamic therapy with CBT, with no significant difference in treatment effect indicated between the two types of psychotherapeutic treatment. Based on three trials with usable data, CBT was superior to active control interventions when using the Hamilton Depression Rating Scale (WMD -5.69, 95% CI -11.04 to -0.35), but equivalent when using the Geriatric Depression Scale (WMD -2.00, 95% CI -5.31 to 1.32). AUTHORS' CONCLUSIONS: Only a small number of studies and patients were included in the meta-analysis. If taken on their own merit, the findings do not provide strong support for psychotherapeutic treatments in the management of depression in older people. However, the findings do reflect those of a larger meta-analysis that included patients with broader age ranges, suggesting that CBT may be of potential benefit.

Association of Markers of Proinflammatory Phenotype and Beige Adipogenesis with Metabolic Syndrome in Chinese Centrally Obese Adults.

BACKGROUND: Visceral adiposity is associated with higher productions of C-reactive protein (CRP) and interleukin-6 (IL-6). Inflammation of obese adipose tissues could contribute to systemic metabolic dysregulation, especially thermogenic activity of white adipose tissues, namely, beige adipogenesis, characterized by altered irisin expression. Thus, we investigated the roles of inflammation and adipocyte beiging in Chinese centrally obese (CO) adults with metabolic syndrome (MetS). METHODS: This cross-sectional study was conducted on 54 CO and 58 non-CO subjects drawn from 1492 Chinese people with age and sex matched during November 2010 and August 2013. Twenty (37.0%) of the CO subjects fulfilled the IDF worldwide definition of MetS. Serum CRP, IL-6, and irisin levels were examined. RESULTS: Higher CRP and IL-6, but lower irisin, levels were manifested in MetS versus non-MetS subjects with or without CO. Multiple linear regression identified high-density lipoprotein cholesterol level as the only independent risk factor for irisin level. Categorized by median of CRP and IL-6 levels, a lower irisin level was only observed in high CRP group. CONCLUSION: Under the condition of central obesity, chronic inflammation and impaired beige adipogenesis are associated with MetS in Chinese adults.

Sonographic evaluation of the immediate effects of eccentric heel drop exercise on Achilles tendon and gastrocnemius muscle stiffness using shear wave elastography.

BACKGROUND: Mechanical loading is crucial for muscle and tendon tissue remodeling. Eccentric heel drop exercise has been proven to be effective in the management of Achilles tendinopathy, yet its induced change in the mechanical property (i.e., stiffness) of the Achilles tendon (AT), medial and lateral gastrocnemius muscles (MG and LG) was unknown. Given that shear wave elastography has emerged as a powerful tool in assessing soft tissue stiffness with promising intra- and inter-operator reliability, the objective of this study was hence to characterize the stiffness of the AT, MG and LG in response to an acute bout of eccentric heel drop exercise. METHODS: Forty-five healthy young adults (36 males and nine females) performed 10 sets of 15-repetition heel drop exercise on their dominant leg with fully-extended knee, during which the AT and gastrocnemius muscles, but not soleus, were highly stretched. Before and immediately after the heel drop exercise, elastic moduli of the AT, MG and LG were measured by shear wave elastography. RESULTS: After the heel drop exercise, the stiffness of AT increased significantly by 41.8 + 33.5% (P < 0.001), whereas the increases in the MG and LG stiffness were found to be more drastic by 75 + 47.7% (P < 0.001) and 71.7 + 51.8% (P < 0.001), respectively. Regarding the AT, MG and LG stiffness measurements, the inter-operator reliability was 0.940, 0.987 and 0.986, and the intra-operator reliability was 0.916 to 0.978, 0.801 to 0.961 and 0.889 to 0.985, respectively. DISCUSSION: The gastrocnemius muscles were shown to bear larger mechanical loads than the AT during an acute bout of eccentric heel drop exercise. The findings from this pilot study shed some light on how and to what extent the AT and gastrocnemius muscles mechanically responds to an isolated set of heel drop exercise. Taken together, appropriate eccentric load might potentially benefit mechanical adaptations of the AT and gastrocnemius muscles in the rehabilitation of patients with Achilles tendinopathy.

Wnt/ß-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion.

Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.

Psychosocial morbidity in bone marrow transplant recipients: a prospective study.

Previous work has demonstrated that psychosocial morbidity may occur following bone marrow transplantation (BMT), but few prospective quantitative data are available, especially in adults. We have conducted a prospective psychological assessment of 36 patients accepted onto our BMT programme, of whom 31 proceeded to transplant. Patients were assessed shortly before admission for BMT and again at about 4 and 8 months after the procedure, using the following tools: Hospital Anxiety and Depression Scale (HAD), Social Adjustment Scale-Self Report and the Present State Examination (PSE). A 54% incidence of psychosocial morbidity (as assessed by either an abnormal HAD or PSE result) was found among those cases assessed both before and at least once after BMT. Significant psychosocial morbidity was still present 6-9 months following BMT. Cases scoring abnormally following BMT in general also scored abnormally before transplant, suggesting a predictive value of pre-BMT psychological assessment. Psychological morbidity was unrelated to the type of transplant. Patients with chronic myeloid leukaemia had a higher incidence of post-BMT psychosocial morbidity than patients with other diagnoses; it is suggested that this may be due to their lack of previous experience of intensive haematological therapy. Psychological evaluation may help in identifying patients at risk of post-BMT psychosocial problems.

Age-related changes in the neurosensory epithelium of the mouse vomeronasal organ: extended period of postnatal growth in size and evidence for rapid cell turnover in the adult.

The total number of neurosensory cells in the mouse vomeronasal organ was estimated during postnatal development by counting the cell density and measuring the total volume of the neurosensory cell layer. There is a 43% increase in neurosensory cell number between 1 and 4 months of age, followed by a 21% fall in cell number between 4 and 8 months. There is no further significant change in cell number between 8 and 18 months of age. Cell division was shown to be occurring in the vomeronasal organ of animals at 7 months of age by labelling dividing cells with [3H]thymidine continuously administered by means of implanted 'osmotic pumps'. At least 1 in 6 cells were labelled by 12 days of thymidine administration, indicating a turnover time of 2--3 months for the whole epithelium. This raises the general problem of how a fixed central nervous system accommodates a changing peripheral input.

Passive membrane properties of neurones in the dorsal raphe and periaqueductal grey recorded in vitro.

A slice preparation of the rat mesencephalon containing the dorsal and medial raphe nucleus, the periaqueductal grey, the superior colliculi and the reticular formation is described. Intracellular recordings showed marked differences in the passive membrane properties of neurones of the dorsal raphe. Serotonin-containing neurons were characterized by a high membrane input resistance, a very long time constant and by the presence of membrane rectification only in a very hyperpolarized (less than -120 mV) region of their voltage-current relationship. In most of the neurones in and around the dorsal raphe area a brief pulse of depolarizing current was followed by a pronounced after-hyperpolarization, which appeared to be mediated by the activation of a Ca2+ dependent-K+ conductance.

The limitation of pulsatile flow through the aqueduct of Sylvius as a cause of hydrocephalus.

The concept is advanced that hydrocephalus results from limitation in the pulsatile flow of CSF downwards through the aqueduct of Sylvius during systole which is necessary to accommodate for the pulsatile pressure and volume increase that accompanies the propagation of the arterial pulse through the brain. Evidence is given to show that flow through the fixed human aqueduct is disturbed and not laminar. Further, with the pressures availalbe, the aqueduct is only just large enough to pass the quantity of fluid which must be vented extracranially during systole. Should the capacity of this systolic venting mechanism be exceeded, physical strain will cause cellular damage in the periventricular and periaqueductal regions which, if prolonged, will lead to tissue destruction and hydrocephalus. There appear to be two main causes for hydrocephalus resulting from this mechanism. Firstly, structural lesions, restricting the lumina of the CSF-venting pathways, especially the aqueduct, will reduce the volume of CSF that can flow through these pathways during systole. The hydrocephalic process will then be continuous and only limited when tissue destruction reduces the systolic volume expansion of the brain such that it can be accomodated by the restricted CSF venting pathways. Secondly, conditions which may increase the amount of the systolic volume expansion of the brain beyond the capacity of the CSF venting pathways. Raised mean intracranial pressure is the most important of these conditions. In such cases the hydrocephalus will be limited by the duration of the causal process and possibly also by the enlargement of the venting pathways, as a result of tissue destruction. This hypothesis also accounts for hydrocephalus resulting from obliteration of the cortical subarachnoid space, obstruction to the cranial venous drainage, deformities in the region of the foramen magnum and arterial encroachment upon the ventricular system.

Aspects of personality of soldiers presenting to an endoscopy clinic.

Eysenck Personality Questionnaires were completed by a consecutive series of 60 soldiers attending a military endoscopy clinic. Each individual was pair-matched with a non-endoscoped soldier from a medical ward and a soldier from the hospital alcohol treatment unit. Alcohol dependence and related disabilities were measured using the MAST, CAGE and SADQ questionnaires and liver function tests and MCV estimates were performed. Alcohol questionnaire scores and laboratory tests were analysed by discriminant function analysis and by applying 'cut-off' scores of the questionnaires. Analyses of the personality dimensions were carried out by analyses of variance and were examined in relation to sample, alcohol questionnaire scores and endoscopic findings. The soldiers from the alcohol treatment unit had the highest neuroticism score, followed by the soldiers attending the endoscopy clinic. Of the endoscoped soldiers, those diagnosed as non-ulcer dyspeptics had higher neuroticism scores than soldiers with ulcers. This finding was not associated with increased prevalence of alcohol dependence and related disabilities.

A study of patellofemoral plain in a junior infantry training unit.

The incidence of patellofemoral pain in a Junior Unit was assessed retrospectively over a 4 year period and prospectively by studying an annual intake of recruits during their initial training year. An average of 3.5% per intake were found to have been discharged due to the disease between 1977 and 1980. 4.5% of the intake prospectively studied were discharged and 75% of those presenting with symptoms were cured. The clinical characteristics of recruits presenting with the the disorder were prospectively studied in a controlled, blind, consecutive series of 45 patients. Two groups of characteristics were identified; those with an early, insidious onset in training, a pre-Service history and a poor response to physiotherapy and those with an acute, traumatic onset, presenting later in training and responding well to physiotherapy. The aetiology of patellofemoral pain in a Junior Recruit is discussed and attention drawn to specific problems encountered by these patients.

Palliative care for dementia--time to think again?

It is estimated that there are 35.6 million people with dementia worldwide and this is projected to increase to over 115 million by the year 2050. Dementia is a progressive neurodegenerative disease that significantly reduces survival. End-of-life care received by this group is often poor and does not equate to that offered in other life limiting illnesses. This review highlights results from a large UK study of informal carers of people with dementia to explore what are determinants of care for people with dementia and their family carers. New perspectives as to models of care for end-of-life care for patients with dementia are discussed together with how these may be implemented and delivered within wider community settings and contexts, where many people with dementia may be cared for in the future.

Novel therapeutic potential in targeting microtubules by nanoparticle albumin-bound paclitaxel in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) shows low response to most conventional chemotherapies. To facilitate target identification for novel therapeutic development, we deployed gene expression profiling on 43 paired HCC tumors and adjacent non-tumoral liver, which is also considered as the pre-malignant liver lesion. In conjunction with ontology analysis, a major functional process found to play a role in the malignant transformation of HCC was microtubule-related cellular assembly. We further examined the potential use of microtubule targeting taxane drugs, including paclitaxel and docetaxel, and compared with findings to results from doxorubicin, a common chemotherapeutic agent used in HCC. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, the nanoparticle albumin-bound (nab)-paclitaxel was also examined. In a panel of HCC cell lines studied, a high sensitivity towards taxane drugs was generally found, although the effect from nab-paclitaxel was most profound. The nab-paclitaxel showed an effective IC50 dose at 15-fold lower than paclitaxel alone or the derivative analogue docetaxel, and ~450-fold less compared to doxorubicin. Flow cytometric analysis confirmed a cell cycle blockade at the G2/M phase and increased apoptosis following nab-paclitaxel treatment. In vivo animal studies also showed that nab-paclitaxel readily inhibited xenograft growth with less toxicity to host cells compared to other anti-microtubule drugs and doxorubicin. Gene silencing of the microtubule regulatory gene STMN1 by RNAi suggested a distinct synergistic effect in the combined treatment with nab-paclitaxel. Our findings in this study highly suggest that the microtubule assembly represents a promising therapeutic target development in HCC.