An elevated PSA, which normalizes, does not exclude the presence of prostate cancer

The purpose of this study was to determine the incidence of prostate cancer in patients who have an elevated referral prostate-specific antigen (PSA), which subsequently falls to within their normal age-specific reference range prior to prostate biopsy. The study demonstrated that of the 160 patients recruited, 21 (13%) had a repeat PSA level which had fallen back to within their normal range. Five of these 21 patients (24%) were diagnosed with prostate cancer following biopsy, two of whom had a benign prostate examination. The study, therefore, demonstrates that normalisation of the PSA level prior to biopsy does not exclude the presence of prostate cancer even when the prostate feels benign.

PASSCLAIM - gut health and immunity

Background The gut and immune system form a complex integrated structure that has evolved to provide effective digestion and defence against ingested toxins and pathogenic bacteria. However, great variation exists in what is considered normal healthy gut and immune function. Thus, whilst it is possible to measure many aspects of digestion and immunity, it is more difficult to interpret the benefits to individuals of variation within what is considered to be a normal range. Nevertheless, it is important to set standards for optimal function for use both by the consumer, industry and those concerned with the public health. The digestive tract is most frequently the object of functional and health claims and a large market already exists for gut-functional foods worldwide. Aim To define normal function of the gut and immune system and describe available methods of measuring it. Results We have defined normal bowel habit and transit time, identified their role as risk factors for disease and how they may be measured. Similarly, we have tried to define what is a healthy gut flora in terms of the dominant genera and their metabolism and listed the many, varied and novel methods for determining these parameters. It has proved less easy to provide boundaries for what constitutes optimal or improved gastric emptying, gut motility, nutrient and water absorption and the function of organs such as the liver, gallbladder and pancreas. The many tests of these functions are described. We have discussed gastrointestinal well being. Sensations arising from the gut can be both pleasant and unpleasant. However, the characteristics of well being are ill defined and merge imperceptibly from acceptable to unacceptable, a state that is subjective. Nevertheless, we feel this is an important area for future work and method development. The immune system is even more difficult to make quantitative judgements about. When it is defective, then clinical problems ensure, but this is an uncommon state. The innate and adaptive immune systems work synergistically together and comprise many cellular and humoral factors. The adaptive system is extremely sophisticated and between the two arms of immunity there is great redundancy, which provides robust defences. New aspects of immune function are discovered regularly. It is not clear whether immune function can be "improved". Measuring aspects of immune function is possible but there is no one test that will define either the status or functional capacity of the immune system. Human studies are often limited by the ability to sample only blood or secretions such as saliva but it should be remembered that only 2% of lymphocytes circulate at any given time, which limits interpretation of data. We recommend assessing the functional capacity of the immune system by: measuring specific cell functions ex vivo, measuring in vivo responses to challenge, e. g. change in antibody in blood or response to antigens, determining the incidence and severity of infection in target populations during naturally occurring episodes or in response to attenuated pathogens.

Verb retrieval in fluent aphasia: a clinical study

Background: Problems with lexical retrieval are common across all types of aphasia but certain word classes are thought to be more vulnerable in some aphasia types. Traditionally, verb retrieval problems have been considered characteristic of non-fluent aphasias but there is growing evidence that verb retrieval problems are also found in fluent aphasia. As verbs are retrieved from the mental lexicon with syntactic as well as phonological and semantic information, it is speculated that an improvement in verb retrieval should enhance communicative abilities in this population as in others. We report on an investigation into the effectiveness of verb treatment for three individuals with fluent aphasia. Methods & Procedures: Multiple pre-treatment baselines were established over 3 months in order to monitor language change before treatment. The three participants then received twice-weekly verb treatment over approximately 4 months. All pre-treatment assessments were administered immediately after treatment and 3 months post-treatment. Outcome & Results: Scores fluctuated in the pre-treatment period. Following treatment, there was a significant improvement in verb retrieval for two of the three participants on the treated items. The increase in scores for the third participant was statistically nonsignificant but post-treatment scores moved from below the normal range to within the normal range. All participants were significantly quicker in the verb retrieval task following treatment. There was an increase in well-formed sentences in the sentence construction test and in some samples of connected speech. Conclusions: Repeated systematic treatment can produce a significant improvement in verb retrieval of practised items and generalise to unpractised items for some participants. An increase in well-formed sentences is seen for some speakers. The theoretical and clinical implications of the results are discussed.

An intronic growth hormone receptor mutation causing activation of a pseudoexon is associated with a broad spectrum of growth hormone insensitivity phenotypes

Context: Inherited GH insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Patients present with short stature associated with high GH and low IGF-I levels and may have midfacial hypoplasia ( typical Laron syndrome facial features). We previously described four mildly affected GHI patients with an intronic mutation in the GHR gene (A.(1) -> G.(1) substitution in intron 6), resulting in the activation of a pseudoexon (6 Psi) and inclusion of 36 amino acids. Objective: The study aimed to analyze the clinical and genetic characteristics of additional GHI patients with the pseudoexon (6 Psi) mutation. Design/Patients: Auxological, biochemical, genetic, and haplotype data from seven patients with severe short stature and biochemical evidence of GHI were assessed. Main Outcome Measures: We assessed genotype-phenotype relationship. Results: One patient belongs to the same extended family, previously reported. She has normal facial features, and her IGF-I levels are in the low-normal range for age. The six unrelated patients, four of whom have typical Laron syndrome facial features, have heights ranging from -3.3 to -6.0 SD and IGF-I levels that vary from normal to undetectable. We hypothesize that the marked difference in biochemical and clinical phenotypes might be caused by variations in the splicing efficiency of the pseudoexon. Conclusions: Activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes. Therefore, screening for the presence of this mutation should be performed in all GHI patients without mutations in the coding exons.

Iron and zinc status in multiple sclerosis patients with pressure sores

Measurements of weighted dietary intakes and plasma determinations of albumin, iron, zinc, ascorbic acid and TIBC were carried out on twenty female multiple sclerosis patients in a long-stay hospital for disabled people. The group included ten patients with a recent history of pressure sores, closely matched with ten patients without pressure sores. Mean daily intake of carbohydrate was found to be higher in the non-pressure sore group whilst intake of zinc was lower in this group. Intakes of all other nutrients were comparable between the two groups. For both groups, intakes of energy, folate, vitamin D, iron and zinc were less than recommended values. Mean plasma levels of albumin and iron were towards the lower limit of the normal range, whilst that for zinc was considerably less than the normal range. Plasma TIBC was slightly above the normal range. Levels of plasma iron and zinc were significantly lower in the pressure sore group. The data indicate that severely disabled hospitalized patients with multiple sclerosis may be at risk of poor nutritional status. The results suggest that in the presence of pressure sores, there are increased requirements for specific nutrients, notably zinc and iron. Consideration is given to the possible value of supplementation of these individuals.

Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function

Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.

Genetic heterogeneity in erythropoietic protoporphyria: a study of the enzymatic defect in nine affected families

Erythropoietic protoporphyria (EPP) is associated with a deficiency of protohaem ferrolyase. We have used a novel assay for this enzyme based on its ability to utilize zinc as a substrate to investigate the inheritance of EPP in nine affected families. Zinc chelatase activity was markedly reduced in peripheral blood mononuclear cells from 14 EPP patients (mean, 3.3 nmol Zn protohaem/h/mg protein; range, 0.3-8.0) when compared with 41 controls (16.8 +/- 3.6) p less than 0.01. In three families with parent-to-child transmission of disease, the asymptomatic parent had an enzymatic activity within the normal range. In three pedigrees where the parents were asymptomatic, enzymatic activities were below the 95% confidence limits in both. Zinc chelatase activity was below the mean control value in 17 of the 18 parents in nine affected pedigrees, and six of seven asymptomatic offspring of patients with protoporphyria. The findings suggest that EPP is not transmitted as a simple dominant trait and that inheritance of more than one gene may be required for disease expression.

Impairments in glucose tolerance can have a negative impact on cognitive function: a systematic research review

There is an increasing body of research investigating whether abnormal glucose tolerance is associated with cognitive impairments, the evidence from which is equivocal. A systematic search of the literature identified twenty-three studies which assessed either clinically defined impaired glucose tolerance (IGT) or variance in glucose tolerance within the clinically defined normal range (NGT). The findings suggest that poor glucose tolerance is associated with cognitive impairments, with decrements in verbal memory being most prevalent. However, the evidence for decrements in other domains was weak. The NGT studies report a stronger glucose tolerance-cognition association than the IGT studies, which is likely to be due to the greater number of glucose tolerance parameters and the more sensitive cognitive tests in the NGT studies compared to the IGT studies. It is also speculated that the negative cognitive impact of abnormalities in glucose tolerance increases with age, and that glucose consumption is most beneficial to individuals with poor glucose tolerance compared to individuals with normal glucose tolerance. The role of potential mechanisms are discussed.

Gut permeability in autism spectrum disorders

Objective To test whether gut permeability is increased in autism spectrum disorders (ASD) by evaluating gut permeability in a population-derived cohort of children with ASD compared with age- and intelligence quotient-matched controls without ASD but with special educational needs (SEN). Patients and Methods One hundred thirty-three children aged 10–14 years, 103 with ASD and 30 with SEN, were given an oral test dose of mannitol and lactulose and urine collected for 6 hr. Gut permeability was assessed by measuring the urine lactulose/mannitol (L/M) recovery ratio by electrospray mass spectrometry-mass spectrometry. The ASD group was subcategorized for comparison into those without (n = 83) and with (n = 20) regression. Results There was no significant difference in L/M recovery ratio (mean (95% confidence interval)) between the groups with ASD: 0.015 (0.013–0.018), and SEN: 0.014 (0.009–0.019), nor in lactulose, mannitol, or creatinine recovery. No significant differences were observed in any parameter for the regressed versus non-regressed ASD groups. Results were consistent with previously published normal ranges. Eleven children (9/103 = 8.7% ASD and 2/30 = 6.7% SEN) had L/M recovery ratio > 0.03 (the accepted normal range cut-off), of whom two (one ASD and one SEN) had more definitely pathological L/M recovery ratios > 0.04. Conclusion There is no statistically significant group difference in small intestine permeability in a population cohort-derived group of children with ASD compared with a control group with SEN. Of the two children (one ASD and one SEN) with an L/M recovery ratio of > 0.04, one had undiagnosed asymptomatic celiac disease (ASD) and the other (SEN) past extensive surgery for gastroschisis.

Parental responsibility beliefs: associations with parental anxiety and behaviours in the context of childhood anxiety disorders

Background: High levels of parental anxiety are associated with poor treatment outcomes for children with anxiety disorders. Associated parental cognitions and behaviours have been implicated as impediments to successful treatment. We examined the association between parental responsibility beliefs, maternal anxiety and parenting behaviours in the context of childhood anxiety disorders. Methods: Anxious and non-anxious mothers of 7-12 year old children with a current anxiety disorder reported their parental responsibility beliefs using a questionnaire measure. Parental behaviours towards their child during a stressor task were measured. Results: Parents with a current anxiety disorder reported a greater sense of responsibility for their child’s actions and wellbeing than parents who scored within the normal range for anxiety. Furthermore, higher parental responsibility was associated with more intrusive and less warm behaviours in parent-child interactions and there was an indirect effect between maternal anxiety and maternal intrusive behaviours via parental responsibility beliefs. Limitations: The sample was limited to a treatment-seeking, relatively high socio-economic population and only mothers were included so replication with more diverse groups is needed. The use of a range of stressor tasks may have allowed for a more comprehensive assessment of parental behaviours. Conclusions: The findings suggest that parental anxiety disorder is associated with an elevated sense of parental responsibility and may promote parental behaviours likely to inhibit optimum child treatment outcomes. Parental responsibility beliefs may therefore be important to target in child anxiety treatments in the context of parental anxiety disorders.

The biogeophysical climatic impacts of anthropogenic land use change during the Holocene

The first agricultural societies were established around 10 ka BP and had spread across much of Europe and southern Asia by 5.5 ka BP with resultant anthropogenic deforestation for crop and pasture land. Various studies (e.g. Joos et al., 2004; Kaplan et al., 2011; Mitchell et al., 2013) have attempted to assess the biogeochemical implications for Holocene climate in terms of increased carbon dioxide and methane emissions. However, less work has been done to examine the biogeophysical impacts of this early land use change. In this study, global climate model simulations with Hadley Centre Coupled Model version 3 (HadCM3) were used to examine the biogeophysical effects of Holocene land cover change on climate, both globally and regionally, from the early Holocene (8 ka BP) to the early industrial era (1850 CE). Two experiments were performed with alternative descriptions of past vegetation: (i) one in which potential natural vegetation was simulated by Top-down Representation of Interactive Foliage and Flora Including Dynamics (TRIFFID) but without land use changes and (ii) one where the anthropogenic land use model Kaplan and Krumhardt 2010 (KK10; Kaplan et al., 2009, 2011) was used to set the HadCM3 crop regions. Snapshot simulations were run at 1000-year intervals to examine when the first signature of anthropogenic climate change can be detected both regionally, in the areas of land use change, and globally. Results from our model simulations indicate that in regions of early land disturbance such as Europe and south-east Asia detectable temperature changes, outside the normal range of variability, are encountered in the model as early as 7 ka BP in the June–July–August (JJA) season and throughout the entire annual cycle by 2–3 ka BP. Areas outside the regions of land disturbance are also affected, with virtually the whole globe experiencing significant temperature changes (predominantly cooling) by the early industrial period. The global annual mean temperature anomalies found in our single model simulations were −0.22 at 1850 CE, −0.11 at 2 ka BP, and −0.03 °C at 7 ka BP. Regionally, the largest temperature changes were in Europe with anomalies of −0.83 at 1850 CE, −0.58 at 2 ka BP, and −0.24 °C at 7 ka BP. Large-scale precipitation features such as the Indian monsoon, the Intertropical Convergence Zone (ITCZ), and the North Atlantic storm track are also impacted by local land use and remote teleconnections. We investigated how advection by surface winds, mean sea level pressure (MSLP) anomalies, and tropospheric stationary wave train disturbances in the mid- to high latitudes led to remote teleconnections.

Prediction leaching of potassium using the convective-dispersive and the convective log-normal transfer function models

There is increasing concern about soil enrichment with K+ and subsequent potential losses following long-term application of poor quality water to agricultural land. Different models are increasingly being used for predicting or analyzing water flow and chemical transport in soils and groundwater. The convective-dispersive equation (CDE) and the convective log-normal transfer function (CLT) models were fitted to the potassium (K+) leaching data. The CDE and CLT models produced equivalent goodness of fit. Simulated breakthrough curves for a range of CaCl2 concentration based on parameters of 15 mmol l(-1) CaCl2 were characterised by an early peak position associated with higher K+ concentration as the CaCl2 concentration used in leaching experiments decreased. In another method, the parameters estimated from 15 mmol l(-1) CaCl2 solution were used for all other CaCl2 concentrations, and the best value of retardation factor (R) was optimised for each data set. A better prediction was found. With decreasing CaCl2 concentration the value of R is required to be more than that measured (except for 10 mmol l(-1) CaCl2), if the estimated parameters of 15 mmol l(-1) CaCl2 are used. The two models suffer from the fact that they need to be calibrated against a data set, and some of their parameters are not measurable and cannot be determined independently.

Acclimation of photosynthesis to elevated CO2 in onion (Allium cepa) grown at a range of temperatures

Onion (Allium cepa) was grown in the field within temperature gradient tunnels (providing about -2.5degreesC to +2.5degreesC from outside temperatures) maintained at either 374 or 532 mumol mol(-1) CO2. Plant leaf area was determined non-destructively at 7 day intervals until the time of bulbing in 12 combinations of temperature and CO2 concentration. Gas exchange was measured in each plot at the time of bulbing, and the carbohydrate content of the leaf (source) and bulb (sink) was determined. Maximum rate of leaf area expansion increased with mean temperature. Leaf area duration and maximum rate of leaf area expansion were not significantly affected by CO2. The light-saturated rates of leaf photosynthesis (A(sat)) were greater in plants grown at normal than at elevated CO2 concentrations at the same measurement CO2 concentration. Acclimation of photosynthesis decreased with an increase in growth temperature, and with an increase in leaf nitrogen content at elevated CO2. The ratio of intercellular to atmospheric CO2 (C-i/C-a ratio) was 7.4% less for plants grown at elevated compared with normal CO2. A(sat) in plants grown at elevated CO2 was less than in plants grown at normal CO2 when compared at the same C-i Hence, acclimation of photosynthesis was due both to stomatal acclimation and to limitations to biochemical CO2 fixation. Carbohydrate content of the onion bulbs was greater at elevated than at normal CO2. In contrast, carbohydrate content was less at elevated compared with normal CO2 in the leaf sections in which CO2 exchange was measured at the same developmental stage. Therefore, acclimation of photosynthesis in fully expanded onion leaves was detected despite the absence of localised carbohydrate accumulation in these field-grown crops.

Acclimation of photosynthesis to elevated CO2 in onion (allium cepa) grown at a range of temperatures

Onion (Allium cepa) was grown in the field within temperature gradient tunnels (providing about -2.5 degrees C to +2.5 degrees C from outside temperatures) maintained at either 374 or 532 mumol mol (-1) CO2. Plant leaf area was determined non-destructively at 7 day intervals until the time of bulbing in 12 combinations of temperature and CO2 concentration. Gas exchange was measured in each plot at the time of bulbing, and the carbohydrate content of the leaf (source) and bulb (sink) was determined. Maximum rate of leaf area expansion increased with mean temperature. Leaf area duration and maximum rate of leaf area expansion were not significantly affected by CO2. The light-saturated rates of leaf photosynthesis (A(sat)) were greater in plants grown at normal than at elevated CO2 concentrations at the same measurement CO2 concentration. Acclimation of photosynthesis decreased with an increase in growth temperature, and with an increase in leaf nitrogen content at elevated CO2. The ratio of intercellular to atmospheric CO2 (C-i/C-a ratio) was 7.4% less for plants grown at elevated compared with normal CO2. A(sat) in plants grown at elevated CO2 was less than in plants grown at normal CO2 when compared at the same C-i Hence, acclimation of photosynthesis was due both to stomatal acclimation and to limitations to biochemical CO2 fixation. Carbohydrate content of the onion bulbs was greater at elevated than at normal CO2. In contrast, carbohydrate content was less at elevated compared with normal CO2 in the leaf sections in which CO2 exchange was measured at the same developmental stage. Therefore, acclimation of photosynthesis in fully expanded onion leaves was detected despite the absence of localised carbohydrate accumulation in these field-grown crops.

Enhanced long-range forecast skill in boreal winter following stratospheric strong vortex conditions

There has been a great deal of recent interest in producing weather forecasts on the 2–6 week sub-seasonal timescale, which bridges the gap between medium-range (0–10 day) and seasonal (3–6 month) forecasts. While much of this interest is focused on the potential applications of skilful forecasts on the sub-seasonal range, understanding the potential sources of sub-seasonal forecast skill is a challenging and interesting problem, particularly because of the likely state-dependence of this skill (Hudson et al 2011). One such potential source of state-dependent skill for the Northern Hemisphere in winter is the occurrence of stratospheric sudden warming (SSW) events (Sigmond et al 2013). Here we show, by analysing a set of sub-seasonal hindcasts, that there is enhanced predictability of surface circulation not only when the stratospheric vortex is anomalously weak following SSWs but also when the vortex is extremely strong. Sub-seasonal forecasts initialized during strong vortex events are able to successfully capture the associated surface temperature and circulation anomalies. This results in an enhancement of Northern annular mode forecast skill compared to forecasts initialized during the cases when the stratospheric state is close to climatology. We demonstrate that the enhancement of skill for forecasts initialized during periods of strong vortex conditions is comparable to that achieved for forecasts initialized during weak events. This result indicates that additional confidence can be placed in sub-seasonal forecasts when the stratospheric polar vortex is significantly disturbed from its normal state.