Genetic variation of the alpha subunit of the epithelial Na+ channel influences exhaled Na+ in healthy humans

Epithelial Na(+) channels (ENaC) are located in alveolar cells and are important in β(2)-adrenergic receptor-mediated lung fluid clearance through the removal of Na(+) from the alveolar airspace. Previous work has demonstrated that genetic variation of the alpha subunit of ENaC at amino acid 663 is important in channel function: cells with the genotype resulting in alanine at amino acid 663 (A663) demonstrate attenuated function when compared to genotypes with at least one allele encoding threonine (T663, AT/TT). We sought to determine the influence of genetic variation at position 663 of ENaC on exhaled Na(+) in healthy humans. Exhaled Na(+) was measured in 18 AA and 13 AT/TT subjects (age=27±8 years vs. 30±10 years; ht.=174±12 cm vs. 171±10 cm; wt.=68±12 kg vs. 73±14 kg; BMI=22±3 kg/m(2) vs. 25±4 kg/m(2), mean±SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90 min following the administration of a nebulized β(2)-agonist (albuterol sulfate, 2.5 mg diluted in 3 ml normal saline). The AA group had a higher baseline level of exhaled Na(+) and a greater response to β(2)-agonist stimulation (baseline=3.1±1.8 mmol/l vs. 2.3±1.5 mmol/l; 30 min-post=2.1±0.7 mmol/l vs. 2.2±0.8 mmol/l; 60 min-post=2.0±0.5 mmol/l vs. 2.3±1.0 mmol/l; 90 min-post=1.8±0.8 mmol/l vs. 2.6±1.5 mmol/l, mean±SD, for AA and AT/TT, respectively, p<0.05). The results are consistent with the notion that genetic variation of ENaC influences β(2)-adrenergic receptor stimulated Na(+) clearance in the lungs, as there was a significant reduction in exhaled Na(+) over time in the AA group.     

Compassion in healthcare – lessons from a qualitative study of the end of life care of people with dementia

Objectives

A lack of compassion in UK healthcare settings has received much recent attention. This study explores the experiences of people with dementia in the last year of life and time surrounding death and how the presence and lack of compassion, kindness and humanity influenced the experience of care.

Design

Qualitative in-depth interviews with bereaved informal carers of people with dementia.

Setting

United Kingdom.

Participants

Forty bereaved carers – 31 women and nine men – with an age range of 18–86 years and from wide socioeconomic backgrounds participated.

Main outcome measures

Experiences of carers of care for person with dementia during last year of life.

Results

The interviews highlighted differences and challenges in care settings in providing compassionate, humanistic care and the impact of the care experienced by the person with dementia during the last year of life on informal carers during the bereavement period and beyond. Excellent examples of compassionate care were experienced alongside very poor and inhumane practices.

Conclusion

The concepts of compassion, kindness and humanity in dementia care are discussed within the paper. The ability to deliver care that is compassionate, kind and humanistic exists along a continuum across care settings – examples of excellent care sit alongside examples of very poor care and the reasons for this are explored together with discussion as to how health and social care staff can be trained and supported to deliver compassionate care.     

Low-Carbohydrate Diet Versus Caloric Restriction: Effects on Weight Loss,Hormones, and Colon Tumor Growth in Obese Mice

Our objective was to compare the effects of a low-carbohydrate diet to a high-carbohydrate/calorie-restricted diet on weight loss, hormones, and transplanted colon tumor growth. Eighty male C57BL/6 mice consumed a diet-induced obesity regimen (DIO) ad libitum for 7 weeks. From Weeks 8 to 14, the mice consumed a 1) DIO diet ad libitum (HF); 2) low-carbohydrate diet ad libitum (LC); 3) high-carbohydrate diet ad libitum (HC); or 4) HC calorie restricted diet (HC–CR). MC38 cells were injected at Week 15. At the time of injection, the HC–CR group displayed the lowest body weight (25.5 ± 0.57 g), serum insulin-like growth factor I (IGF-I; 135 ± 56.0 ng/ml), and leptin (1.0 ± 0.3 ng/ml) levels. This group also exhibited the longest time to palpable tumor (20.1 ± 0.9 days). Compared to the HF group, the HC group exhibited lower body weight (39.4 ± 1.4 vs. 32.9 ± 0.7 g, respectively), IGF-I (604 ± 44.2 vs. 243.4 ± 88.9 ng/ml, respectively), and leptin (15.6 ± 2.2 vs. 7.0 ± 0.7 ng/ml, respectively) levels but similar tumor growth. IGF-I levels were lower in the LC group (320.0 ± 39.9 ng/ml) than the HF group, but tumor growth did not differ. These data suggest LC diets do not slow colon tumor growth in obese mice.     

Is morality unified? Evidence that distinct neural systems underlie moral judgments of harm, dishonesty, and disgust

Much recent research has sought to uncover the neural basis of moral judgment. However, it has remained unclear whether "moral judgments" are sufficiently homogenous to be studied scientifically as a unified category. We tested this assumption by using fMRI to examine the neural correlates of moral judgments within three moral areas: (physical) harm, dishonesty, and (sexual) disgust. We found that the judgment of moral wrongness was subserved by distinct neural systems for each of the different moral areas and that these differences were much more robust than differences in wrongness judgments within a moral area. Dishonest, disgusting, and harmful moral transgression recruited networks of brain regions associated with mentalizing, affective processing, and action understanding, respectively. Dorsal medial pFC was the only region activated by all scenarios judged to be morally wrong in comparison with neutral scenarios. However, this region was also activated by dishonest and harmful scenarios judged not to be morally wrong, suggestive of a domain-general role that is neither peculiar to nor predictive of moral decisions. These results suggest that moral judgment is not a wholly unified faculty in the human brain, but rather, instantiated in dissociable neural systems that are engaged differentially depending on the type of transgression being judged.     

Physiological origin for the BOLD poststimulus undershoot in human brain: vascular compliance versus oxygen metabolism

The poststimulus blood oxygenation level-dependent (BOLD) undershoot has been attributed to two main plausible origins: delayed vascular compliance based on delayed cerebral blood volume (CBV) recovery and a sustained increased oxygen metabolism after stimulus cessation. To investigate these contributions, multimodal functional magnetic resonance imaging was employed to monitor responses of BOLD, cerebral blood flow (CBF), total CBV, and arterial CBV (CBV_a) in human visual cortex after brief breath hold and visual stimulation. In visual experiments, after stimulus cessation, CBV_a was restored to baseline in 7.9±3.4 seconds, and CBF and CBV in 14.8±5.0 seconds and 16.1±5.8 seconds, respectively, all significantly faster than BOLD signal recovery after undershoot (28.1±5.5 seconds). During the BOLD undershoot, postarterial CBV (CBV_pa, capillaries and venules) was slightly elevated (2.4±1.8%), and cerebral metabolic rate of oxygen (CMRO₂) was above baseline (10.6±7.4%). Following breath hold, however, CBF, CBV, CBV_a and BOLD signals all returned to baseline in ∼20 seconds. No significant BOLD undershoot, and residual CBV_pa dilation were observed, and CMRO₂ did not substantially differ from baseline. These data suggest that both delayed CBV_pa recovery and enduring increased oxidative metabolism impact the BOLD undershoot. Using a biophysical model, their relative contributions were estimated to be 19.7±15.9% and 78.7±18.6%, respectively.     

Influence of alginate cross-linking method on neurite response to microencapsulated neurotrophin-producing fibroblasts

Transplantation of cells genetically modified to produce neurotrophins is a promising spinal cord repair strategy. Previously we showed that fibroblasts engineered to produce brain-derived neurotrophic factor (Fb/BDNF) microencapsulated in alginate survive, continue to grow and express bioactive BDNF. We here compared the effects of different alginate crosslinkers on dorsal root ganglia (DRG) neurite growth using alginate-encapsulated Fb/BDNF. Aqueous sodium alginate (±Fb/BDNF) was contacted with different calcium salts, and used as substrate for DRG growth. Length, number and orientation of neurites were measured. Chloride or carbonate salts promoted significantly more neurite growth than sulphate, with or without Fb/BDNF, although encapsulated Fb/BDNF stimulated significantly more neurite growth than cell-free. An Fb/BDNF-derived neurotrophin concentration gradient directionally guided DRG neurite growth. This positive effect of alginate-encapsulated Fb/BDNF on neurite growth/guidance shows promise for enhanced regeneration and guidance of axons towards a specific target in the injured spinal cord.