Low Testosterone,but Not Estradiol,Is Associated With Incident Falls in Older Men: The International MrOS Study

Fracture risk is determined by bone strength and the risk of falls. The relationship between serum sex steroids and bone strength parameters in men is well known, whereas the predictive value of sex steroids for falls is less studied. The aim of this study was to assess the associations between serum testosterone (T) and estradiol (E2) and the likelihood of falls. Older men (aged ≥65 years) from the United States (n = 1919), Sweden (n = 2495), and Hong Kong (n = 1469) participating in the Osteoporotic Fractures in Men Study had baseline T and E2 analyzed by mass spectrometry. Bioavailable (Bio) levels were calculated using mass action equations. Incident falls were ascertained every 4 months during a mean follow‐up of 5.7 years. Associations between sex steroids and falls were estimated by generalized estimating equations. Fall rate was highest in the US and lowest in Hong Kong (US 0.50, Sweden 0.31, Hong Kong 0.12 fall reports/person/year). In the combined cohort of 5883 men, total T (odds ratio [OR] per SD increase = 0.88, 95% confidence interval [CI] 0.86–0.91) and BioT (OR = 0.86, 95% CI 0.83–0.88) were associated with incident falls in models adjusted for age and prevalent falls. These associations were only slightly attenuated after simultaneous adjustment for physical performance variables (total T: OR = 0.94, 95% CI 0.91–0.96; BioT: OR = 0.91, 95% CI 0.89–0.94). E2, BioE2, and sex hormone‐binding globulin (SHBG) were not significantly associated with falls. Analyses in the individual cohorts showed that both total T and BioT were associated with falls in MrOS US and Sweden. No association was found in MrOS Hong Kong, and this may be attributable to environmental factors rather than ethnic differences because total T and BioT predicted falls in MrOS US Asians. In conclusion, low total T and BioT levels, but not E2 or SHBG, are associated with increased falls in older men. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

Determinants of evidence use in public health policy making: Results from a study across six EU countries

The knowledge-practice gap in public health is widely known. The importance of using different types of evidence for the development of effective health promotion has also been emphasized.Nevertheless, in practice, intervention decisions are often based on perceived short-term opportunities, lacking the most effective approaches, thus limiting the impact of health promotion strategies. This article focuses on facilitators and barriers in the use of evidence in developing health enhancing physical activity policies.Data was collected in 2012 by interviewing 86 key stakeholders from six EU countries (FI, DK, UK, NL, IT, RO) using a common topic guide. Content analysis and concept mapping was used to construct a map of facilitators and barriers.Barriers and facilitators experienced by most stakeholders and policy context in each country are analysed. A lack of locally useful and concrete evidence, evidence on costs, and a lack of joint understanding were specific hindrances. Also users’ characteristics and the role media play were identified as factors of influence.Attention for individual and social factors within the policy context might provide the key to enhance more sustainable evidence use. Developing and evaluating tailored approaches impacting on networking, personal relationships, collaboration and evidence coproduction is recommended.     

A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection

The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics .     

Concentration–Response Relationship of Hearing Impairment Caused by Quinine and Salicylate: Pharmacological Similarities but Different Molecular Mechanisms

This review has the purpose to summarize concentration–effect studies made with quinine and to compare the effects on hearing between quinine and salicylate. Quinine and salicylate have roles in experimental hearing research and may induce pronounced and reversible hearing impairment when administered in sizeable doses. The quinine‐induced increase in hearing threshold and its recovery can be analysed according to ‘the psychophysical power function’. The power function is a special case of the Hill equation when the stimulus (e.g. a drug concentration) is exceedingly small compared with the concentration that would elicit a half‐maximum response. Quinine and salicylate induce sensorineural hearing impairment and tinnitus when given in higher dose ranges in man. The drugs influence the presence, magnitude, and quality of audiological responses, such as spontaneous and evoked otoacoustic emissions. Quinine reversibly reduces frequency selectivity and hearing sensitivity, whereas the self‐attained most comfortable speech level and the acoustic stapedius reflex are not affected, that is the dynamic range of hearing is reversibly reduced. This observation supports the view that quinine acts on the outer hair cell of the cochlea. Both drugs share a protective effect against the permanent hearing damages caused by gentamicin. This action is interpreted as a request for functioning mechanoelectric transducer (MET) channels to elicit the ill effect of aminoglycosides. Both drugs may interfere with the cochlear amplifier through blocking MET channels and the motor protein prestin. This review finds considerable overlap between type and extent of pharmacological actions of quinine and salicylate, supposedly caused by partly shared mechanisms of action but performed with different molecular mechanisms.     

Dendrotoxin from the venom of the green mamba,Dendroaspis angusticeps

Summary The venom of the green mamba, Dendroaspis angusticeps has previously been shown to produce neuromuscular facilitation by increasing acetylcholine release. After gel filtration and ion-exchange chromatography of the whole venom, a basic polypeptide with facilitatory actions was isolated. This polypeptide, named dendrotoxin, has 59 amino acid residues, probably with only 3 disulphide bonds and a blocked N-terminus.When injected into conscious mice, dendrotoxin made the mice hypersensitive to external stimuli and subsequently produced respiratory paralysis. When tested on the isolated chick biventer cervicis nerve-muscle preparation, concentrations of dendrotoxin of 0.5 g/ml (7×10^–8 M) and greater, increased responses to indirect stimulation by 200–250%, without any increase in responses to submaximal concentrations of exogeneous acetylcholine, carbachol, KCl or direct stimulation. The augmentation was slow to develop, not reversed by washing, and could last several hours before slowly waning. Dendrotoxin did not produce spontaneous twitching or contractures.It is concluded that dendrotoxin is not an anticholinesterase, does not affect receptor sensitivity or muscle contractility, but produces twitch augmentation by increasing the amount of acetylcholine released by nerve stimulation. Thus, dendrotoxin appears to represent a snake venom neurotoxin with unusual chemical and pharmacological properties.     

Functional development of the visual system in normal and protein deprived rats. II. Morphometric and biochemical studies on adult optic nerve

The optic nerve of normal (C) and protein deprived (PD) adult rats was examined by morphometry and biochemistry. The mean cross-sectional area of the optic nerve was reduced by 15% and the number of axons per unit area increased by 17% in the PD rats. Calibre spectrum analysis of axons revealed a reduction in median diameter from 0.49 micron in controls to 0.45 micron in PD rats. The number of axons with a diameter larger than 1 micron was reduced by 35% in PD rats. These reductions were probably due to a general reduction in size, since the calculated total number of axons in the optic nerve was almost identical in C and PD rats (126 X 10(3) and 124 X 10(3), respectively). The increased packing density of axons in the nerve was not only due to thinner axons. The biochemical measurements showed a marked reduction in myelin basic protein in the optic nerves of PD rats, without an alteration in the composition of the total protein. This confirms the persistent hypomyelination which has been reported previously in other malnutrition models. The possible relations between the structural and biochemical changes affecting optic nerve fibres and physiological findings on cortical visual evoked response and on optic nerve in vitro in PD rats are discussed.     

Blood pressure response in relation to blood lactate during exercise in patients with essential hypertension

Thirty-four untreated patients with essential hypertension WHO I-II, 17 patients under treatment with beta-blockade, and 32 healthy controls with a wide range of exercise capacity were studied at loadless pedaling (W0) and at the work load eliciting a blood lactate concentration corresponding to 4 mmol X l-1 (onset of blood lactate accumulation or OBLA). At W0 the treated patients had approximately the same systolic blood pressure (SBP) as the healthy controls, while the untreated patients had a higher SBP than the controls. At WOBLA the SBP was higher in the untreated patients than in both the treated patients and the healthy controls. On an individual basis it was found in the healthy controls and the untreated patients that the SBP at WOBLA showed a slight and insignificant increase versus SBP at W0, whereas the difference in SBP between WOBLA and W0 ("exercise SBP increase") demonstrated an inverse relationship (P less than 0.001-0,01) versus W0. It was suggested that for both healthy controls and untreated patients the exercise SBP depended on a "basal" level as depicted by W0 and a further SBP increase due to the exercise load. The difference between the two groups was that the patients with untreated hypertension displayed their relationships at higher pressure levels indicating the presence of a hyperkinetic drive. The treated patients appeared to have a lower increase in SBP between W0 and WOBLA than any other group, suggesting an unfavorable effect of the beta-blockade.     

On the use of diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide), as adjunct antidotes in the treatment of organophosphorus intoxication in the guinea-pig

Diazepam and pro-diazepam (2-benzoyl-4-chloro-N-methyl-N-lysylglycin anilide) have been used as adjunct antidotes to pyridostigmine and atropine against the organophosphate, soman, in the guinea-pig. Both added significant protection to the pyridostigmine/atropine treatment. Animals pretreated with diazepam, 60 min before soman, were "better" protected than animals given an equimolar dose of pro-diazepam therapeutically 1 min after soman. A pretreatment with diazepam for three days further increased the protection. A therapeutic dose of pro-diazepam, 1 min after soman, gave no further protection, to the three day diazepam pretreatment. The serum concentrations of diazepam (given i.p.) and desmethyldiazepam (given i.m.) were determined by GLC after diazepam (i.p.) and pro-diazepam (i.m.) were given. The protection, relative to the control, provided by the diazepam pretreatment (60 min before and for three days before soman) correlated linearly, r = 0.9898, with the serum values of diazepam achieved at these times. Our data suggest that diazepam as adjunct to pyridostigmine and atropine administered as pretreatment gives a "safer" protection, than an equimolar dose of pro-diazepam given therapeutically.     

Ideas of caring in nursing practice

In nursing practice, awareness of ethical inner values and a common understanding of nursing and caring are needed. It is therefore important to highlight ideas of caring in nursing practice. The aim of this paper was to illuminate nursing, caring and ethical inner values in caring and caring in nursing practice. By being attentive, open, respectful and treating the patient as a person, nurses can enhance both their own and the patient's sense of personal meaning in the caring relationship. Nurses can use self‐reflection to create an awareness of nursing, caring and ethical inner values in caring.