“You’ve Got to Pick Your Battles”: A Mixed-Methods Investigation of Physical Activity Counselling and Referral within General Practice

One in four people say they would be more active if advised by a general practitioner (GP), yet 72% of GPs do not discuss physical activity (PA) with patients and 80% of GPs are unaware of the PA guidelines. The aim of this study was therefore to investigate GP perspectives on PA counselling and referral and interpret these within the context of the socio-ecological model (SEM). Fifty-six GPs completed an online survey to investigate factors influencing PA counselling and referral. Semi-structured interviews were then conducted with seven GPs to explore topics in more depth. Interview data were analysed thematically and mapped to the SEM. GPs were more likely to discuss PA with patients if they were physically active themselves (p = 0.004). Influences on PA counselling and referral were identified at the policy (provision of education, priority), organisational (feedback, e-referral), interpersonal (PA as everybody’s business, patient factors) and intrapersonal (knowledge, GP PA levels) levels of the SEM. Multi-level strategies are required to help GPs promote PA and make use of exercise referral schemes, including making PA a strategic priority, introducing systems for feedback from referrals, and involving other members of the care team in PA counselling and referral

Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens

Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein with a lethal effect on livestock, producing severe enterotoxemia characterized by general edema and neurological alterations. Site-specific mutations of the toxin are valuable tools to study the cellular and molecular mechanism of the toxin activity. In particular, mutants with paired cysteine substitutions that affect the membrane insertion domain behaved as dominant-negative inhibitors of toxin activity in MDCK cells. We produced similar mutants, together with a well-known non-toxic mutant (Etx-H106P), as green fluorescent protein (GFP) fusion proteins to perform in vivo studies in an acutely intoxicated mouse model. The mutant (GFP-Etx-I51C/A114C) had a lethal effect with generalized edema, and accumulated in the brain parenchyma due to its ability to cross the blood-brain barrier (BBB). In the renal system, this mutant had a cytotoxic effect on distal tubule epithelial cells. The other mutants studied (GFP-Etx-V56C/F118C and GFP-Etx-H106P) did not have a lethal effect or cross the BBB, and failed to induce a cytotoxic effect on renal epithelial cells. These data suggest a direct correlation between the lethal effect of the toxin, with its cytotoxic effect on the kidney distal tubule cells, and the ability to cross the BBB

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine

Ku Regulates the Non-Homologous End Joining Pathway Choice of DNA Double-Strand Break Repair in Human Somatic Cells

The repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genomic integrity and viability for all organisms. Mammals have evolved at least two genetically discrete ways to mediate DNA DSB repair: homologous recombination (HR) and non-homologous end joining (NHEJ). In mammalian cells, most DSBs are preferentially repaired by NHEJ. Recent work has demonstrated that NHEJ consists of at least two sub-pathways—the main Ku heterodimer-dependent or “classic” NHEJ (C-NHEJ) pathway and an “alternative” NHEJ (A-NHEJ) pathway, which usually generates microhomology-mediated signatures at repair junctions. In our study, recombinant adeno-associated virus knockout vectors were utilized to construct a series of isogenic human somatic cell lines deficient in the core C-NHEJ factors (Ku, DNA-PKcs, XLF, and LIGIV), and the resulting cell lines were characterized for their ability to carry out DNA DSB repair. The absence of DNA-PKcs, XLF, or LIGIV resulted in cell lines that were profoundly impaired in DNA DSB repair activity. Unexpectedly, Ku86-null cells showed wild-type levels of DNA DSB repair activity that was dominated by microhomology joining events indicative of A-NHEJ. Importantly, A-NHEJ DNA DSB repair activity could also be efficiently de-repressed in LIGIV-null and DNA-PKcs-null cells by subsequently reducing the level of Ku70. These studies demonstrate that in human cells C-NHEJ is the major DNA DSB repair pathway and they show that Ku is the critical C-NHEJ factor that regulates DNA NHEJ DSB pathway choice

Non-pharmacological management of hypertension

The importance of a healthy lifestyle is well understood for the primary and secondary prevention of cardiovascular disease. Numerous studies have emphasised the importance of lifestyle changes as an integral component of lowering blood pressure in both patients with hypertension and prehypertension. Non-pharmacological interventions are an integral part of preventing and managing not only hypertension but also in reducing cardiovascular mortality and morbidity. The importance of physical activity, exercise training, and a healthy diet need to be reemphasised as powerful primary and secondary preventive tools. Therefore, physicians and other healthcare practitioners must allow time with patients to discuss patient goals related to non-pharmacological/lifestyle modifications

DIODE-ARRAY UV SPECTROMETRIC EVIDENCE FOR A CONCENTRATION-DEPENDENT PHASE-TRANSITION IN DILUTE AQUEOUS-SOLUTIONS OF PLURONIC F87 (POLOXAMER-237)

Incubation of dilute polymer solutions with a KI-I-2 standard shows the presence of a concentration dependent phase transition for the poly(oxyethylene) + poly(oxypropylene) + poly(oxyethylene) block copolymer F87 (P237) using diode-array UV spectrometry; the transition is shown to be reversible and reproducible and is in agreement with previous data obtained via high-sensitivity differential scanning microcalorimetry (HSDSC)

DIODE-ARRAY UV SPECTROMETRIC EVIDENCE FOR A CONCENTRATION-DEPENDENT PHASE-TRANSITION IN DILUTE AQUEOUS-SOLUTIONS OF PLURONIC F87 (POLOXAMER-237)

Incubation of dilute polymer solutions with a KI-I-2 standard shows the presence of a concentration dependent phase transition for the poly(oxyethylene) + poly(oxypropylene) + poly(oxyethylene) block copolymer F87 (P237) using diode-array UV spectrometry; the transition is shown to be reversible and reproducible and is in agreement with previous data obtained via high-sensitivity differential scanning microcalorimetry (HSDSC).181843184