Chemotherapy-induced cognitive impairments: A systematic review of the animal literature.

Whilst chemotherapy is a widely used anti-cancer treatment, a subset of patients experience cognitive decline. However, cancer type, treatment regimen, fatigue and anxiety can influence cognitive status. Rodent research has overcome these confounds to systematically evaluate cognitive domains and underlying neural mechanisms disrupted by chemotherapy treatment. Therefore, a systematic review was conducted in June 2017 to examine the relationship between chemotherapy and cognitive decline in animal models. A comprehensive literature search was performed in PubMed, PsycInfo, Web of Science, Scopus and Medline databases. A quality assessment yielded a total of 83 papers to be considered for the review. A critical assessment of research papers indicated that cisplatin, CMF and MTX + 5-FU chemotherapy regimens produced strong deficits in short term memory, long term memory and executive control. An assessment of specific cognitive domains illustrated that short term memory was strongly impaired by chemotherapy treatment, often associated with impaired neurogenesis, inflammation and mitochondrial dysfunction in the hippocampus. Pharmacological treatments were the most common intervention to reduce the prevalence of chemobrain.

Invited review: The evolution of cattle bioacoustics and application for advanced dairy systems.

Vocalisations are commonly expressed by gregarious animals, including cattle, as a form of short- and long-distance communication. They can provide conspecifics with meaningful information about the physiology, affective state and physical attributes of the caller. In cattle, calls are individually distinct meaning they assist animals to identify specific individuals in the herd. Consequently, there is potential for these vocalisations to be acoustically analysed to make inferences about how individual animals or herds are coping with their external surroundings, and then act on these signals to improve feed conversion efficiency, reproductive efficiency and welfare. In the case of dairy farming, where herd sizes are expanding and farmers are becoming more reliant on technologies to assist in the monitoring of cattle, the study of vocal behaviour could provide an objective, cost effective and non-invasive alternative to traditional measures of welfare. The vocalisations of cattle in response to calf separation, social isolation and painful husbandry procedures, alongside changes to feeding and oestrous activity are here reviewed. For future application of sound technology, research is first necessary to analyse the acoustic structure of cattle vocalisations and determine the specific information they encode. This review draws together the latest research in field of cattle bioacoustics highlighting how the source-filter theory and affective state dimensional approach can be adopted to decode this information and improve on-farm management.

Chemotherapy-induced cognitive impairments: White matter pathologies.

Whilst chemotherapeutic agents show promising results in the amelioration of cancerous tumors, patients often experience cognitive disturbances associated with chemotherapy long after treatment has ceased. Research has suggested that the structural integrity of white matter fibres in the brain are susceptible to the harmful effects of chemotherapy. Post-chemotherapy, white matter tracts often display altered morphology with a reduction in glial cells such as oligodendrocytes. Demyelination, gliosis and leukoencephalopathy during or post chemotherapy is associated with changes in processing speed and IQ. Thus, understanding the relationship between chemotherapy, white matter damage and cognition is warranted. This review presents evidence for chemotherapy induced white matter damage highlighting the importance of implementing behavioral and pharmological strategies to prevent or reverse such acute toxicity in the brain.

mtDNA diversity in human populations highlights the merit of haplotype matching in gene therapies.

STUDY QUESTION: Does mitochondrial DNA (mtDNA) diversity in modern human populations potentially pose a challenge, via mtDNA segregation, to mitochondrial replacement therapies? SUMMARY ANSWER: The magnitude of mtDNA diversity in modern human populations is as high as in mammalian model systems where strong mtDNA segregation is observed; consideration of haplotype pairs and/or haplotype matching can help avoid these potentially deleterious effects. WHAT IS KNOWN ALREADY: In mammalian models, substantial proliferative differences are observed between different mtDNA haplotypes in cellular admixtures, with larger proliferative differences arising from more diverse haplotype pairings. If maternal mtDNA is 'carried over' in human gene therapies, these proliferative differences could lead to its amplification in the resulting offspring, potentially leading to manifestation of the disease that the therapy was designed to avoid-but existing studies have not investigated whether mtDNA diversity in modern human populations is sufficient to permit significant amplification. STUDY DESIGN, SIZE, DURATION: This theoretical study used over 7500 human mtDNA sequences from The National Center for Biotechnology Information (NCBI), a range of international and British mtDNA surveys, and 2011 census data. PARTICIPANTS/MATERIALS, SETTING, METHODS: A stochastic simulation approach was used to model random haplotype pairings from within different regions. In total, 1000 simulated pairings were analysed using the basic local alignment search tool (BLAST) for each region. Previous data from mouse models were used to estimate proliferative differences. MAIN RESULTS AND THE ROLE OF CHANCE: Even within the same haplogroup, differences of around 20-80 single-nucleotide polymorphisms (SNPs) are common between mtDNAs admixed in random pairings. These values are sufficient to lead to substantial segregation in mouse models over an organismal lifetime, even given low starting heteroplasmy, inducing increases from 5% to 35% over 1 year. Substantial population mixing in modern UK cities increases the expected genetic differences. Hence, the likely genetic differences between humans randomly sampled from a population may well allow substantial amplification of a disease-carrying mtDNA haplotype over the timescale of a human lifetime. We report ranges and mean differences for all statistics to quantify uncertainty in our results. LIMITATIONS/REASONS FOR CAUTION: The mapping from mouse and other mammalian models to the human system is challenging, as timescales and mechanisms may differ. Reporting biases in NCBI mtDNA data, if present, may affect the statistics we compute. We discuss the robustness of our findings in the light of these concerns. WIDER IMPLICATIONS OF THE FINDINGS: Matching the mtDNA haplotypes of the mother and third-party donor in mitochondrial replacement therapies is supported as a means of ameliorating the potentially deleterious results of human mtDNA diversity. We present a chart of expected SNP differences between mtDNA haplogroups, allowing the selection of optimal partners for therapies. LARGE SCALE DATA: N/A STUDY FUNDING/COMPETING INTERESTS: The authors report no external funding sources or conflicts of interest.

The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.

The Pseudotumor Cerebri Syndrome: A Unifying Pathophysiological Concept for Patients with Isolated Intracranial Hypertension with Neither Mass Lesion Nor Ventriculomegaly.

In 1991 we proposed that while the syndrome of isolated intracranial hypertension might have many definite and probable causes, it has nonetheless a single unifying pathophysiological mechanism: namely, impairment of cerebrospinal fluid (CSF) reabsorption. For that reason, we also proposed then that it is best described by a single, unifying, inclusive term, namely, pseudotumor cerebri syndrome. Although it appears that there is, as far as nomenclature is concerned, now international agreement, there is as yet no agreement on pathophysiology and classification. Herein we outline our views on these matters and give our reasons.

Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention.

BACKGROUND: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis. AIM: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea. METHODS: One hundred and fifty-two consecutive patients were grouped according to (75) Se-homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; ≤15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7α-hydroxy-4-cholesten-3-one (C4) and total bile acids. RESULTS: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 ≤ 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy. CONCLUSIONS: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy.

Chemotherapy and cognitive impairment: treatment options.

Chemotherapy has improved survival rates in patients with many of the common cancers. However, there is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years after the completion of chemotherapy. The etiology of this phenomenon is largely unknown, and currently there are no proven treatments. This article explores the clinical and preclinical literature on potential therapies for chemotherapy-induced cognitive impairments. Emerging results suggest that both pharmacological and behavioral approaches may offer patients some benefits. However, research in this area has been limited and is sometimes fraught with methodological flaws. As a result, it is difficult to draw definite conclusions regarding treatment efficacy. These issues, along with predictors of cognitive decline, are discussed in the light of possible interventions.

Self-assembly, modularity, and physical complexity.

We present a quantitative measure of physical complexity, based on the amount of information required to build a given physical structure through self-assembly. Our procedure can be adapted to any given geometry, and thus, to any given type of physical structure that can be divided into building blocks. We illustrate our approach using self-assembling polyominoes, and demonstrate the breadth of its potential applications by quantifying the physical complexity of molecules and protein complexes. This measure is particularly well suited for the detection of symmetry and modularity in the underlying structure, and allows for a quantitative definition of structural modularity. Furthermore we use our approach to show that symmetric and modular structures are favored in biological self-assembly, for example in protein complexes. Lastly, we also introduce the notions of joint, mutual and conditional complexity, which provide a useful quantitative measure of the difference between physical structures.

Whole blood pumping with a microthrottle pump.

We have previously reported that microthrottle pumps (MTPs) display the capacity to pump solid phase suspensions such as polystyrene beads which prove challenging to most microfluidic pumps. In this paper we report employing a linear microthrottle pump (LMTP) to pump whole, undiluted, anticoagulated, human venous blood at 200 µl min(-1) with minimal erythrocyte lysis and no observed pump blockage. LMTPs are particularly well suited to particle suspension transport by virtue of their relatively unimpeded internal flow-path. Micropumping of whole blood represents a rigorous real-world test of cell suspension transport given blood's high cell content by volume and erythrocytes' relative fragility. A modification of the standard Drabkin method and its validation to spectrophotometrically quantify low levels of erythrocyte lysis by hemoglobin release is also reported. Erythrocyte lysis rates resulting from transport via LMTP are determined to be below one cell in 500 at a pumping rate of 102 µl min(-1).

Cryptogenic fibrosing alveolitis and lung cancer: the BTS study.

BACKGROUND: The risk of lung cancer is often reported to be increased for patients with cryptogenic fibrosing alveolitis (CFA). METHODS: Vital status was sought for all 588 members of the British Thoracic Society (BTS) cryptogenic fibrosing alveolitis (CFA) study 11 years after entry to the cohort. Observed deaths due to lung cancer were compared with expected deaths using age-, sex- and period-adjusted national rates. The roles of reported asbestos exposure and smoking were also investigated. RESULTS: 488 cohort members (83%) had died; 46 (9%) were certified to lung cancer (ICD9 162). The standardised mortality ratio (SMR) was 7.4 (95% CI 5.4 to 9.9). Stratified analysis showed increased lung cancer mortality among younger subjects, men and ever smokers. Using an independent expert panel, 25 cohort members (4%) were considered to have at least moderate exposure to asbestos; the risk of lung cancer was increased for these subjects (SMR 13.1 (95% CI 3.6 to 33.6)) vs 7.2 (95% CI 5.2 to 9.7) for those with less or no asbestos exposure). Ever smoking was reported by 448 (73%) of the cohort and was considerably higher in men than in women (92% vs 49%; p<0.001). Most persons who died from lung cancer were male (87%), and all but two (96%) had ever smoked. Ever smokers presented at a younger age (mean 67 vs 70 years; p<0.001) and with less breathlessness (12% smokers reported no breathlessness vs 5% never smokers; p = 0.02). CONCLUSIONS: These findings confirm an association between CFA and lung cancer although this relationship may not be causal. The high rate of smoking and evidence that smokers present for medical attention earlier than non-smokers suggest that smoking could be confounding this association.

'Liver function tests' on the intensive care unit: a prospective, observational study.

AIMS: To evaluate the prevalence, patterns and significance of deranged liver function tests (LFT) in critically ill patients. METHODS: A prospective, observational data collection of the LFT [bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (AKP), gamma glutaryl transferase (gammaGT)] and critical care parameters in all admissions to the general intensive care unit (ICU) of our institution. Prevalence of abnormal LFT on the day of ITU admission is described and the relationship of abnormal LFT to clinical events and 30-day mortality analysed. RESULTS: Of 263 first admissions without hepatobiliary disease, 61% demonstrated an abnormal LFT at the point of admission. The majority of abnormalities were less than twice the upper limit of normal. Episodes of ventilation, haemofiltration and hypotension during the first 48 h were associated with an abnormal ALT on day 3. The presence of an abnormal ALT [odds ratio 2.7 (1.2-6.0)], AKP [OR 2.8 (1.1-7.3)] or gammaGT [OR 3.9 (1.9-8.3)] was associated with an increased risk of death within 30 days of admission. When adjusted for APACHE II score, LFTs were not independent predictors of mortality. DISCUSSION: Low-grade abnormalities of LFT are a significant entity in critically ill patients and show an association with mortality outcomes and clinical events on ICU. They are likely to represent part of a spectrum of liver injury associated with critical illness and should not be disregarded.

The pulmonary artery catheter in Australasia: a survey investigating intensive care physicians' knowledge and perception of future trends in use.

A survey was conducted to assess the knowledge and trends of use of the pulmonary artery catheter amongst intensive care practitioners in Australasia. A 31-item multiple choice questionnaire, identical to one previously trialled in studies in the United States and Europe, was distributed to all registered intensive care specialists and trainees working in intensive care units in Australasia. Five-hundred-and-forty-one questionnaires were distributed and 151 (27.9%) were returned, with an average mark of 82.7% +/- 9.3% and a range of 53.3 to 100%. Total score was significantly associated with years of experience in intensive care (P < 0.04), number of pulmonary artery catheters inserted (P < 0.015) and whether or not the respondent had passed the Joint Faculty of Intensive Care Medicine examination (P < 0.01). Scores were significantly higher amongst trainees (P < 0.0001) and physicians who had passed the Joint Faculty of Intensive Care Medicine examination (P < 0.0001). Overall, 44.9% of respondents indicated their use of the pulmonary artery catheter was decreasing, with 42.6% indicating their use was the same over the past five years. Sixty-one percent of respondents indicated they either agreed or strongly agreed with the statement that the use of echocardiography should supersede the use of the pulmonary artery catheter by intensive care specialists in the future. We concluded that in this study, knowledge of the pulmonary artery catheter and its use is better in Australasia than in previous studies in North America and Europe. The majority of respondents in Australasia believe that echocardiography will supersede the use of the pulmonary artery catheter in the future.

Individual and group-based parenting programmes for the treatment of physical child abuse and neglect.

BACKGROUND: Child physical abuse and neglect are important public health problems and recent estimates of their prevalence suggest that they are considerably more common than had hitherto been realised. Many of the risk factors for child abuse and neglect are not amenable to change in the short term. Intervening to change parenting practices may, however, be important in its treatment. Parenting programmes are focused, short-term interventions aimed at improving parenting practices in addition to other outcomes (many of which are risk factors for child abuse e.g. parental psychopathology, and parenting attitudes and practices), and may therefore be useful in the treatment of physically abusive or neglectful parents. OBJECTIVES: To assess the efficacy of group-based or one-to-one parenting programmes in addressing child physical abuse or neglect. SEARCH STRATEGY: A range of biomedical and social science databases were searched including MEDLINE, EMBASE, CINAHL, PsychINFO, Sociofile, Social Science Citation Index, ASSIA, the Cochrane Library, Campbell Library (including SPECTR and CENTRAL), National Research Register (NRR) and ERIC, from inception to May 2005. SELECTION CRITERIA: Only randomised controlled trials or randomised studies that compared two treatments were included. Studies had to include at least one standardised instrument measuring some aspect of abusive or neglectful parenting. In the absence of studies using objective assessments of child abuse, studies reporting proxy measures of abusive parenting were included. Only studies evaluating the effectiveness of standardised group-based or one-to-one parenting programmes aimed at the treatment of physical child abuse or neglect were included. Studies were also only eligible for inclusion if they had targeted parents of children aged 0-19 years who had been investigated for physical abuse or neglect. DATA COLLECTION AND ANALYSIS: The treatment effect for each outcome in each study was standardised by dividing the mean difference in post-intervention scores for the intervention and treatment group by the pooled standard deviation, to obtain an effect size. The results for each outcome in each study have been presented, with 95% confidence intervals. It was not possible to combine any results in a meta-analysis. MAIN RESULTS: A total of seven studies of variable quality were included in this review. Only two studies assessed the effectiveness of parenting programmes on the incidence of child abuse or number of injuries. One study showed that there were no reports of abuse in the intervention group compared with one report of abuse in the control group. In the second study the small number of injuries sustained precluded the possibility of statistical analysis. Data were also extracted on over fifty outcomes that are used as proxy measures of abusive parenting. These were on the whole diverse and measured a range of aspects of parenting (e.g. parental child management, discipline practices, child abuse potential and mental health), child health (e.g. emotional and behavioural adjustment) and family functioning, thereby precluding the possibility of undertaking a meta-analysis for most outcomes for which data were extracted. While none of the programmes were effective across all of the outcomes measured, many appeared to have improved some outcomes for some of the participating parents, although many failed to achieve statistical significance. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of parenting programmes to treat physical abuse or neglect (i.e. such as the incidence of child abuse using reports of child abuse/linjuries or children on the children protection register). There is, however, limited evidence to show that some parenting programmes may be effective in improving some outcomes that are associated with physically abusive parenting. There is an urgent need for further rigorous evaluation of the effectiveness of parenting programmes that are specifically designed to treat physical abuse and neglect, either independently or as part of broader packages of care. Such evaluation should include the use of objective measures of outcome such as independent assessments of parenting and the number of instances of physical abuse. In order to do this, future studies need to include long-term follow-up.

Cranial venous outflow obstruction and pseudotumor Cerebri syndrome.

The pathophysiology of PTS including idiopathic intracranial hypertension or 'BIH', remains controversial. The older literature frequently referred to pathology in the cerebral venous drainage but more modern imaging techniques (CT and early MR) failed to reveal gross venous pathology. The role of impaired cranial venous outflow has recently been re-examined in the light of new methods of investigation (advanced MR venography and direct microcatheter venography with manometry) and of treatment (venous sinus stenting). Venous sinus obstruction in PTS is a more common factor in the pathogenesis of the condition than previously recognised. Venous obstruction may be primary, that is, it is the underlying aetiological factor in PTS. Venous sinus obstruction may also be secondary to raised CSF pressure which may exacerbate problems with intracranial compliance and raised CSF pressure. Early experience with venous stenting suggests that it may be a helpful treatment for patients with PTS but more experience and longer follow-up is required to define the subgroups of patients for whom it is most appropriate.

The molecular regulation of exercised-induced muscle fibre hypertrophy in the common carp: expression of MyoD, PCNA and components of the calcineurin-signalling pathway.

Growth was investigated over 16 d in juvenile common carp (Cyprinus carpio L.) held in either static water (tank rested, TR16) or exercised in a flume at 2.5-3.2 body lengths s-1 for 18 h a day (exercised, E16). Relative to the start of the experiment (TR0), the TR16 group showed a 31% increase in body mass (specific growth rate, 1.57% d-1), whereas there was no net change in the E16 group. There was, however, a significant exercise-induced hypertrophy of slow muscle fibres with average fibre cross-sectional area (FCSA) increasing by 35% in the E16 group, compared with 11% in the TR16 group. In contrast, FCSA of fast muscle fibres increased by 34% in the TR16 group compared to just 18% in the E16 group. The relative concentrations and subcellular localisation of proteins hypothesised to play a role in the regulation of muscle growth were measured. MyoD concentration was similar in the TR0, TR16 and E16 groups in both slow and fast muscle. However, there was a small (5%-10%) but statistically significant increase in nuclear localisation of MyoD in those groups showing a significant increase in FCSA over the time course of the experiment. PCNA concentration was 31% and 12% higher in the TR16 than in either the TR0 or E16 groups for slow and fast muscle, respectively. Exercise resulted in a approximately 10% increase in nuclear factor of T-cells (NFAT2) concentration in slow muscle but no change in NFAT2 localisation. Calcineurin B concentration was similar in tank rested and exercised groups. The results do not support a major role for the calcineurin-signalling pathway in the regulation of muscle hypertrophy in the common carp.

The role of myostatin and the calcineurin-signalling pathway in regulating muscle mass in response to exercise training in the rainbow trout Oncorhynchus mykiss Walbaum.

Rainbow trout Oncorhynchus mykiss Walbaum were exercised at 0.8 and 1.6 body lengths s(-1) for 18 h a day over a 30 day period. Exercise resulted in a 24-30% increase in the average cross-sectional area of fast muscle fibres relative to tank-rested controls. The concentrations of growth factors and transcription factors hypothesised to play a role in regulating exercise-induced muscle fibre hypertrophy were measured. Exercise training resulted in a minor increase in calcineurin localisation in the nucleus. However, nuclear factor of T-cells 2 (NFAT2) nuclear localisation did not follow a pattern that was consistent with NFAT2-mediated transcriptional activity and changes in calcineurin signaling. The active peptide of myostatin, a negative regulator of muscle growth in mammals, was downregulated in exercise groups relative to tank-rested controls, but only by 6-7%. It was concluded that myostatin and calcineurin signaling do not play a major role in regulating exercise-induced muscle hypertrophy in trout.