Is insulin the most effective injectable antihyperglycaemic therapy?

AIMS: The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once-daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c ∼8.3% (67 mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. METHODS: Descriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c. An analysis of covariance (ANCOVA) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles. RESULTS: At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP-1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP-1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c. Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP-1RAs. CONCLUSIONS: HbA1c reduction with the GLP-1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c. This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high (≥9.0%).

A forecast-based STDP rule suitable for neuromorphic implementation.

Artificial neural networks increasingly involve spiking dynamics to permit greater computational efficiency. This becomes especially attractive for on-chip implementation using dedicated neuromorphic hardware. However, both spiking neural networks and neuromorphic hardware have historically found difficulties in implementing efficient, effective learning rules. The best-known spiking neural network learning paradigm is Spike Timing Dependent Plasticity (STDP) which adjusts the strength of a connection in response to the time difference between the pre- and post-synaptic spikes. Approaches that relate learning features to the membrane potential of the post-synaptic neuron have emerged as possible alternatives to the more common STDP rule, with various implementations and approximations. Here we use a new type of neuromorphic hardware, SpiNNaker, which represents the flexible "neuromimetic" architecture, to demonstrate a new approach to this problem. Based on the standard STDP algorithm with modifications and approximations, a new rule, called STDP TTS (Time-To-Spike) relates the membrane potential with the Long Term Potentiation (LTP) part of the basic STDP rule. Meanwhile, we use the standard STDP rule for the Long Term Depression (LTD) part of the algorithm. We show that on the basis of the membrane potential it is possible to make a statistical prediction of the time needed by the neuron to reach the threshold, and therefore the LTP part of the STDP algorithm can be triggered when the neuron receives a spike. In our system these approximations allow efficient memory access, reducing the overall computational time and the memory bandwidth required. The improvements here presented are significant for real-time applications such as the ones for which the SpiNNaker system has been designed. We present simulation results that show the efficacy of this algorithm using one or more input patterns repeated over the whole time of the simulation. On-chip results show that the STDP TTS algorithm allows the neural network to adapt and detect the incoming pattern with improvements both in the reliability of, and the time required for, consistent output. Through the approximations we suggest in this paper, we introduce a learning rule that is easy to implement both in event-driven simulators and in dedicated hardware, reducing computational complexity relative to the standard STDP rule. Such a rule offers a promising solution, complementary to standard STDP evaluation algorithms, for real-time learning using spiking neural networks in time-critical applications.

Asthma knowledge and medication compliance among parents of asthmatic children in Nanjing, China.

Asthma knowledge and medication compliance among parents of 150 asthmatic children in Nanjing were assessed using a self-administered questionnaire. The results showed that 54.7% of parents had poor knowledge of asthma and its management. Parental compliance with medication was also suboptimal as only 43.3% of parents reported adherence with prescribed anti-asthmatic medication for their children. Reasons for non-compliance included fear of medication side-effects and tolerance, and forgetting to give the child's medication. Education and occupation were found to be associated with asthma knowledge, however there was no association between age or income with knowledge. Income was associated with compliance with asthma medication, however no association was found between parents' age, education, occupation, or asthma knowledge with compliance. This study has identified the need for accurate and up-to-date information on asthma for parents of asthmatic children as well as programs aimed at teaching parents skills in managing their child's asthma. There is also the need for strategies aimed at improving communication between the health provider and parents of asthmatic children.

The epidemiology of dog walking: an unmet need for human and canine health.

OBJECTIVE: To describe the prevalence of dog walking in New South Wales, and to identify potential health gains if more dogs were walked. DESIGN: Cross-sectional analytical survey. SETTING AND PARTICIPANTS: 894 adults in NSW in 1998 (among the owners of approximately two million domestic dogs in NSW who were potential participants in dog-walking behaviours). INTERVENTIONS: None yet. MAIN OUTCOME MEASURES: Dog walking hours per week; other DogEpi concepts to illustrate the public health gains include the DAF (dog attributable fraction), and the BBR (benefits to bites ratio). RESULTS: The response rate to the survey was 74%. 46% of households in NSW had a dog and, overall, dog owners walked 18 minutes per week more than non-dog owners. However, more than half of dog owners did not walk their dogs, and were less likely than non-owners to meet recommended levels of physical activity sufficient for health benefits. If all dog owners walked their dogs, substantial disease prevention and healthcare cost savings of $175 million per year might accrue. CONCLUSIONS: There are potential benefits of dog walking for human health; currently, among dog owners, much of this benefit remains to be realised. There are also likely benefits for canine health. Dog walking should be promoted through national strategies recommending "Walkies for all by the year 2010".

Spreading the word: Teaching health promotion to students from disciplines other than health.

Intersectoral collaboration has gained acceptance as a strategic approach in promoting health, based on the assumption that the main determinants of health are social, physical and politico-economic factors and not medical care utilization. However, the difficulties of collaborating intersectorally for better health have become apparent over the last two decades. This paper describes an attempt to address these difficulties through an awareness-raising educational initiative devised for undergraduate university students from disciplines other than health. The course aims to raise students' appreciation of the ways in which their future occupations could have an impact on the health of others through intersectoral collaboration and the creation of environments that are supportive of health. The evaluation of the course, which comprised a peer-review process, a questionnaire seeking student feedback, and a task exploring students' ideas on how they could influence the health of others, demonstrated that students recognized the value of working intersectorally for better health. If intersectoral collaboration is really expected to be the way forward that many public health theorists claim, then this small but effective contribution should best be seen as one of a series of incremental building blocks leading to the desired effects.

Progression and regression of low-grade epithelial abnormalities of the cervix.

The records of 738 women with low-grade cervical epithelial abnormalities were examined for changes in degree of cervical disease and lesion size, as well as sociodemographic and behavioural factors which influence the development of invasive cancer of the cervix. Survival analysis was used to determine the predictors and rates of progression and regression. The results suggest that about 80% of the low-grade epithelial abnormalities of the cervix will not progress within 2 years. The only predictors of progression were a biopsy diagnosis of CIN 1 and the size of the lesion. Predictors of regression were older age, older age at first intercourse, greater parity, fewer sexual partners, and absence of a past history of genital herpes. Although progression rates of low-grade abnormalities of the cervix were very low, CIN 1 lesions were 2.4 times (95% CI: 1.6 to 3.7) more likely to progress than lower-grade lesions and large lesions (> 1/2 ectocervix) were 2.0 times (95% CI: 1.2 to 3.3) more likely to progress than small ones (< 1/4 ectocervix).

Encouraging environmental awareness in renal units.

Humans have inhabited Earth for centuries, but unfortunately during the past two centuries we have caused untold damage and destruction to our planet, through pollution and waste of natural resources. Baxter Healthcare Ltd. is committed to a programme of environmental protection. The company adopted an Environmental policy in 1990 which applied to all Baxter operations world-wide. This policy stated that each area of the company would develop and implement its own environmental management programme.

Computer assisted learning (CAL) of oral manifestations of HIV disease.

General dental practitioners (GDPs) in the UK may wish additional education on relevant aspects of human immunodeficiency virus (HIV) disease. The aim of the present study was to develop and assess a computer assisted learning package on the oral manifestations of HIV disease of relevance to GDPs. A package was developed using a commercially-available software development tool and assessed by a group of 75 GDPs interested in education and computers. Fifty-four (72%) of the GDPs completed a self-administered questionnaire of their opinions of the package. The majority reported the package to be easy to load and run, that it provided clear instructions and displays, and that it was a more effective educational tool than videotapes, audiotapes, professional journals and textbooks, and of similar benefit as post-graduate courses. The GDPs often commented favourably on the effectiveness of the clinical images and use of questions and answers, although some had criticisms of these and other aspects of the package. As a consequence of this investigation the package has been modified and distributed to GDPs in England and Wales.

The cost of cervical cancer screening provided by a women's health nurse.

This study examines the cost of cervical cancer screening provided by a women's health nurse. Methods used to estimate the cost of taking a Pap smear were based on the economic principle of opportunity cost. Techniques for estimating the magnitude of some costs were developed specifically for this study because the cost of taking a Pap smear had to be isolated from the costs of other services provided by the women's health nurse. The cost of taking a Pap smear in 1989 was estimated to be between $17.68 and $17.95. A sensitivity analysis was carried out so that the results of this study could be adapted for practices which differ from the women's health nurse's practice in the Mount Druitt and Hawkesbury area of New South Wales. As a result of this analysis, the cost of taking a Pap smear ranged from $14.16 to $38.88, depending on whether the women's health nurse was a Clinical Nurse Consultant or Clinical Nurse Specialist, the number of Pap smears taken, the proportion of clients who come for postnatal examinations, length of consultations and the distance travelled. It should be noted that the cost of taking a Pap smear would rise considerably above $38.88 for women's health nurses working in remote areas.

Cell death of motoneurons in the chick embryo spinal cord. X. Synapse formation on motoneurons following the reduction of cell death by neuromuscular blockade.

Chronic treatment of chick embryos with neuromuscular blocking agents, such as curare, rescues motoneurons from naturally occurring cell death. In the present study, embryos treated with curare from E6 to E9 had 35% more motoneurons than controls on E10 and 42% more than controls on E16. Previous studies have shown that several aspects of motoneuron differentiation occur normally in curare-treated embryos. We report here that dendrite growth and arborization is also unaltered on E10 and E16 following curare treatment. A quantitative analysis of afferent synapses on motoneurons shows that the packing density of both axosomatic and axodendritic synapses is also normal on E10 in curare-treated embryos, despite the greater number of motoneurons present. This indicates that the interneurons that provide presynaptic input to motoneurons are able to compensate for the increased number of synaptic sites made available by curare treatment. However, by E16 the packing density of synapses is reduced by about half. Because motoneurons and their dendrites continue to grow between E10 and E16, the further increase in synaptic sites made available in curare-treated embryos apparently exceeds the compensatory capacity of presynaptic interneurons on E16. One can conclude from these results that the increased survival of motoneurons in curare-treated embryos is not owing to an increase in afferent synapses. Motoneurons in these embryos continue to survive in the face of either no change (E10) or a reduction (E16) in the number of axodendritic and axosomatic synapses. Therefore, increased motoneuron survival in this situation is very likely regulated primarily by motoneuron-target interactions.

Naturally-occurring neuron death in the ciliary ganglion of the chick embryo following removal of preganglionic input: evidence for the role of afferents in ganglion cell survival.

With only a few exceptions, most investigations of the mechanisms involved in naturally-occurring neuron death have focused on interactions between neurons and their targets, with much less attention having been paid to the possible role of the afferent inputs in this phenomenon. This is true of the avian ciliary ganglion (CG), which is composed of a population of peripheral autonomic neurons that project to smooth and striated musculature in the eye and which receive afferents from a single source, the accessory oculomotor nucleus (AON), which is the avian homolog of the Edinger-Westphal nucleus. Although several lines of evidence strongly support the important role of targets in regulating the death and survival of CG neurons, the role of afferents has not yet been systematically examined. Following the destruction of the AON on embryonic day (E) 4, which is several days before the onset of normal cell death in the CG, we have found that by the end of the normal cell death period (E14-E15), 85-90% of the CG neurons degenerate and die, compared to 50% in controls. This is comparable to the amount of induced cell loss that occurs following removal of the optic vesicle containing the CG targets. The neurons surviving after deafferentation appear to be sustained by some influence from their targets since combined deafferentation and eye removal results in the loss of virtually all neurons in the CG. Following deafferentation of the CG on E4, the ganglion develops normally up to about E10, after which a precipitous loss of cells occurs. Based on several kinds of evidence (e.g., axon counts, silver stain, retrograde labeling of the CG), we conclude that the deafferented neurons project to and innervate their muscular targets in the eye. Therefore, the increased cell death following deafferentation cannot be due to the failure of deafferented neurons to contact their targets. The deafferented neurons undergo a normal sequence of initial ultrastructural differentiation. When they do begin to degenerate, the type of fine structural changes they exhibit appears indistinguishable from the degenerative changes observed in control embryos. Neurons in deafferented ganglia were occasionally observed to receive synaptic contacts, which we attribute to aberrant intraganglionic connections induced by deafferentation. These contacts probably play little, if any, role in the maintenance of neurons since, as noted above, following combined deafferentation and target deletion virtually all neurons degenerate and die.(ABSTRACT TRUNCATED AT 400 WORDS)

Pathway formation and the terminal distribution pattern of the spinocerebellar projection in the chick embryo.

Pathway formation and the terminal distribution pattern of spinocerebellar fibers in the chick embryo were examined by means of an anterograde labelling technique with wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP). Spinocerebellar fibers, which originate in the lumbar spinal cord and are located in the marginal layer of the spinal cord, reach the dorsal part of the cerebellar plate on embryonic day (E)8. On the way to the cerebellum the fibers form one distinct bundle, that suggests that gross projection errors probably do not occur during the formation of the spinocerebellar pathway. On E10, labelled fibers are located mostly in the medullary zone of the anterior lobe. By E12, the number of labelled fibers increases greatly in the inner granular and molecular layers. In transverse sections labelling was distributed throughout the mediolateral extent of the medullary zone. By E14, sagittal strips of labelling were clearly recognized in lobules II-IV; however, labelled terminals were present throughout lobule I. Although the adult pattern of terminal distribution is attained by E14, the mossy fiber terminals are still quite immature. The density of labelling decreased greatly by E16, and small terminal varicosities were first recognized. Structural differentiation of mossy fiber terminals continues to the end of the embryonic or the newly posthatched period.

A Golgi study of the development of the inferior olivary nuclear complex in the chicken.

The present study is an examination of the qualitative and quantitative changes in the morphology of neurons in the inferior olivary nuclear complex ( IOC ) of the chicken. The development of the chicken IOC was studied with the Golgi technique between embryonic day 11 (E11) and posthatch day 35 ( P35 ). The olivary cells change most between E11 and E19 and are essentially mature (i.e., similar to P35 ) at E19 . These changes chiefly involve a gradual loss of features that typify immature growing cells (e.g., growth cones, growth buds, filopodia, beaded dendrites); from E11 to P35 there is an increase in the soma size by 42%, an increase in the dendritic field size by 49%, and a decrease in the number of dendritic branches by 47%. A minor but significant fall in the number of dendrites per neuron between E11 and E19 was observed, but as there is no significant difference between E11 and P35 , the relevance of this observed change, if any, is unclear. On the basis of dendritic branching, it appears that one type of olivary neuron is present in the chicken, which is similar to the type of neuron found in the caudal medial olive (MO) and the caudal dorsal olive (DO) of mammals ( Schiebel and Schiebel , '55; Rutherford and Gwyn , '80). This finding correlates with the proposal that the avian IOC corresponds mostly to the mammalian MO and DO and that only a small portion corresponds to the mammalian principal olive ( Furber , '83).

The organization of the olivocerebellar projection in the chicken.

The olivocerebellar pathway in the chicken was studied, using the horseradish peroxidase retrograde tracing technique. The inferior olivary nuclear complex (IOC) of the chicken comprises a dorsal and a ventral lamella and projects to the contralateral cerebellar hemisphere. In this paper the organization of the olivocerebellar pathways in the chicken is compared with the mammalian olivocerebellar pathway. The present results, taken in conjunction with data on the embryogenesis of the rat IOC, suggest that the avian dorsal lamella represents, from lateral to medial, the dorsal olivary nucleus, the principal olivary nucleus, and the rostral and a small part of the caudal medial nucleus (MO) of mammals, while the ventral lamella represents a larger part of the caudal MO of mammals.

Organization of the olivocerebellar projection in the rat.

The olivocerebellar projection has been studied in the rat using the horseradish peroxidase (HRP) retrograde tracing technique. All regions of the cerebellum, except for the flocculonodular lobe, were injected with small volumes of HRP. The overall organization of the rat olivocerebellar projection is similar in all major respects to that found in other mammals. For example, in the rat Crus 1 and Crus 2 receive afferents from the principal olive, medial part of the rostral dorsal olive, the rostral medial olive, the dorsal cap and the ventrolateral outgrowth which agrees with studies in the cat. The most notable difference between the present study and studies in other mammals is the finding of a projection in the rat from the dorsomedial cell column to all regions of the cerebellar hemispheres, except for the paraflocculus.

Ratio of inferior olivary cells to Purkinje cells in a marsupial (Trichosurus vulpecula).

An indirect estimate of the extent of branching of the olivary axons in the cerebellum in a marsupial (Trichosurus vulpecula) was carried out. The cells in the inferior olivary nuclear complex (IOC) of both sides were estimated (mean = 57,200), as were the cerebellar Purkinje cells (mean = 881,300). Assuming that all climbing fibers arise from IOC cells and that each Purkinje cell receives a climbing fiber input, each IOC cell sends climbing fiber terminals to 15 Purkinje cells.