The direction of tissue strain affects the neovascularization in the fracture-healing zone.

Sufficient vascularization of the fracture-healing zone is a prerequisite for undisturbed bone healing. One important factor affecting the vascularization is the interfragmentary movement in the fracture-healing zone. Many studies have demonstrated that stable fixation with predominatly moderate interfragmentary compression movement can stimulate vascularization and the healing process whereas unstable fracture fixation delays the vascularization and bone healing process. Instability of fracture fixation, in particular large shearing interfragmentary movement, can cause delayed healing or non-unions. We hypothesize that the direction of interfragmentary movement affects vascularization in the fracture-healing zone. Cyclic compressive strain stimulates greater vessel formation than tensile or shearing strain. This is due to differences in the local mechanical environment which are not delineated by the direction-independent characterization of interfragmentary movement typically reported. We propose that new vessel formations buckle under compressive loading without significant load transfer across endothelial cell junctions while both tensile and shearing deformations result in disruptive loads despite a biochemically angiogenic environment. From a clinical perspective, this means that the optimal conditions for rapid vascularization result from fracture fixation that minimizes cyclic tensile and shearing movements in the healing zone while allowing moderate compressive movements.

Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study.

BACKGROUND: Renzapride, a 5-hydroxytryptamine type-4 (5-HT(4)) receptor agonist and 5-HT(3) receptor antagonist, has been proposed as a new treatment of irritable bowel syndrome with constipation (IBS-C). AIM: To assess the efficacy and safety of renzapride in women with IBS-C. METHODS: Women with IBS-C were randomized to renzapride 4 mg daily, 2 mg b.d. or placebo for 12 weeks. The primary outcome measure was global relief of IBS symptoms. A subset of patients were enrolled in a 12-month, open-label study of renzapride 4 mg daily. RESULTS: A total of 1798 patients were included in the efficacy analysis and 971 patients entered the long-term study. The mean (S.E.M.) number of months with relief of overall IBS symptoms was 0.55 (0.04), 0.60 (0.04) and 0.44 (0.04) in the renzapride 4 mg daily, 2 mg b.d. and placebo groups (P = 0.027 and P = 0.004 respectively). Small yet statistically significant differences in favour of renzapride were observed on stool consistency and frequency, and bloating/abdominal distension scores. Renzapride was generally well tolerated; however, three episodes of ischaemic colitis were reported in the long-term study. CONCLUSION: Given the limited increase in efficacy over placebo and the incidence of ischaemic colitis observed, our data suggest that the benefit/risk ratio of renzapride is not sufficient to warrant further study in IBS-C.

Identification of patients with non-d, non-C irritable bowel syndrome and treatment with renzapride: an exploratory, multicenter, randomized, double-blind, placebo-controlled clinical trial.

This was an exploratory study of renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on renzapride versus placebo of 18.2% (95% CI -5% to 42%; P = 0.066) during weeks 1-4 and 6% (95% CI -21% to 33%; P = 0.339) during weeks 5-8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether renzapride is beneficial in this patient population.

All creatures great and minute: a public policy primer for companion animal zoonoses.

Approximately 63% of US households have at least one pet, a large percentage of which are considered family members. Pet owners can derive substantial physical and psychological benefits from interaction with companion animals. However, pet ownership is not without risks; zoonotic diseases are increasingly drawing the attention of healthcare professionals, policy makers and the general public. While zoonoses of 'traditional' pets are widely recognized and their prevention and treatment factors are generally known, the growing popularity of 'non-traditional' pets has the potential to facilitate human exposure to novel zoonoses. However, the greatest risk of zoonoses probably arises from animals taken directly from the wild to serve as pets. Non-governmental organizations, state veterinary associations and others have been calling for increased regulation of animal imports, some proposing that all 'exotics' be banned from the pet trade. Because zoonotic diseases of companion animals are influenced by interacting factors of ecological, technical, socio-economic, and political origin, efforts to minimize their impact need be multi-dimensional, simultaneously addressing both the ecological and socio-political drivers of disease emergence and transmission. This study is intended to serve as a primer for animal care professionals seeking to engage with policy makers and the pet industry on the prevention of companion animal zoonoses. We provide background on the human-animal bond, risks of zoonoses associated with groups of companion animals, and the public policy context, as well as identify the factors needed to build a comprehensive approach to companion animal zoonoses risk management. Also included are examples of innovative, non-regulatory initiatives designed to limit the spread and impact of companion animal zoonoses, including a reptile salmonella poster, the National Reptile Improvement Plan, Habitattitude campaign, Pet Zoonoses Committee, and a wildlife disease surveillance initiative known as Project TripWire.

Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting.

BACKGROUND: Relatively few pharmacological treatment options are available for treating patients with irritable bowel syndrome. New and effective medicines are urgently required. AIM: To identify an appropriate dosage of renzapride (a 5-HT(4) receptor full agonist/5-HT(3) receptor antagonist) to treat abdominal pain/discomfort in patients with constipation-predominant irritable bowel syndrome. METHODS: In this randomized, placebo-controlled, phase IIb study in the primary care setting, men and women were randomized to placebo or renzapride (1, 2 or 4 mg/day) for 12 weeks. The primary outcome measure was patient self-assessed relief of abdominal pain/discomfort during weeks 5-12. Secondary efficacy measures included patients' assessment of their bowel habits, stool consistency and quality of life. RESULTS: Although there were no statistically significant differences between renzapride and placebo for relief from abdominal pain/discomfort, responder rates in the renzapride treatment groups increased dose dependently, with the 4 mg/day group being consistently numerically greater than placebo. Importantly, a larger numerical treatment difference vs. placebo was observed in women (8% and 12% respectively). Statistically significant improvements in bowel movement frequency and stool consistency were observed in the 4 mg/day group relative to placebo. Renzapride was well tolerated at all doses. CONCLUSIONS: This study confirms the gastrointestinal prokinetic effects of renzparide. The data also suggested a potentially beneficial effect on abdominal pain/discomfort in women with constipation-predominant irritable bowel syndrome.

The cardiovascular safety profile of renzapride, a novel treatment for irritable bowel syndrome.

The cardiac safety of renzapride, a novel benzamide currently under clinical development for the treatment of irritable bowel syndrome, was investigated in a four-way randomized crossover electrocardiographic clinical study in healthy human subjects and also in an in vitro cardiac conductivity study in sheep isolated Purkinje fibres. The primary endpoint in the clinical study was prolongation of the individually corrected QT interval (QTci). No clinically or statistically significant prolongation of QTci after 4 or 20 mg renzapride compared with placebo was observed. The relative effects of renzapride and cisapride in the in vitro study showed that the cardiac action potential duration was unaltered by 0.2 and 2 microM renzapride, shortened by 20 microM renzapride, and prolonged by 1 microM cisapride. Cisparide was also a 1000-fold more potent inhibitor of human ether-a-go-go related gene (hERG) channels in HEK293 cells than renzapride. These studies indicate that therapeutic doses of renzapride are unlikely to prolong cardiac action potentials and, therefore, are also unlikely to cause cardiac arrhythmias in clinical use.

Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome.

AIM: To investigate the efficacy and safety of renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. METHODS: In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, renzapride 2 mg o.d. and renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. RESULTS: Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; renzapride 2 mg o.d., 2.6 +/- 1.4 days; renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on renzapride and placebo. CONCLUSIONS: Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of renzapride in patients with constipation-predominant irritable bowel syndrome.

Communication, information and well-being for Australians with physical disabilities.

PURPOSE: This paper is a literature review, the purpose of which was to examine the legislative framework and the Australian Government Information Policy and how this has impacted on virtual communication and the well-being of Australians with disabilities. METHOD: This has been a systematic review of current Australian literature that considers especially how communication and information can contribute positively towards connecting people with disabilities with other people during and post-rehabilitation. RESULTS: The results of this systematic literature review has been encouraging in that Australians with disabilities are being taken account of in the planning processes and evaluation of communications technologies. CONCLUSION: The paper also deals with how these interactive telecommunications may play an important role by assisting persons with disabilities in dealing with the loss of a sense of control over one's destiny, which is often prevalent during the acute phase of injury in persons with disabilities.

Randomized controlled study of in-hospital exercise training programs in children with cystic fibrosis.

The aim of this study was to compare aerobic and resistance training in children with cystic fibrosis (CF) admitted to hospital with an intercurrent pulmonary infection with a control group. The subjects were randomized into three groups on the first day of admission. The fat-free mass (FFM) was calculated, using the skin fold thickness from four sites (biceps, triceps, subscapular, and iliac crest). Pulmonary function tests were performed within 36 hr of admission and repeated on discharge from the hospital, and again at 1 month after discharge. All subjects performed an incremental treadmill exercise test, using a modified Bruce protocol. Lower limb strength was measured using a Cybex dynamometer. An assessment of quality of life was made using the Quality of Well Being Scale, as previously reported. Activity levels were measured using a 7-day activity diary, and subjects also wore an accelerometer on their hips. There were no significant differences between the three groups in terms of disease severity, and length of stay in hospital. Subjects in all three groups received intravenous antibiotics and nutritional supplementation as determined by the physician. Children randomized to the aerobic training group participated in aerobic activities for five sessions, each of 30-min duration, a week. The children randomized to the resistance training group exercised both upper and lower limbs against a graded resistance machine. Subjects in the control group received standard chest physiotherapy. Our study demonstrated that children who received aerobic training had significantly better peak aerobic capacity, activity levels, and quality of life than children who received the resistance training program. Children who received resistance training had better weight gain (total mass, as well as fat-free mass), lung function, and leg strength than children who received aerobic training. A combination of aerobic and resistance training may be the best training program, and future studies to assess optimal training programs for CF patients are indicated.

Leucocyte entry and endothelial E-selectin expression following intradermal Propionibacterium acnes administration.

Immune responses in porcine skin to intradermal inoculation of heat-killed Propionibacterium acnes (HKPA), the major bacterial agent associated with human inflammatory acne, were studied. Pigs were chosen as experimental animals because their skin is similar in structure and composition to that of man and because the use of genetically inbred pigs enables leucocytes to be transferred between animals without eliciting rejection responses. Two pigs were sensitized intradermally with 10 mg of HKPA and were challenged 2 weeks later with doses ranging from 1-100 microg of HKPA in various intradermal sites on the ventral aspect of the abdomen. Four further pigs, previously sensitized with Bacillus Calmette-Guérin (BCG) but not HKPA, were challenged with purified protein derivative (PPD) of bovine tuberculin and HKPA. Entry of(51)Cr-labelled peripheral blood lymphocytes (PBLs) over 48 h was studied in all the challenge sites. Peak PBL entry occurred at 4 h, remaining sustained up to 24 h. There was a dose-dependent effect of HKPA on the level of PBL entry, which was antigen-specific, as few leucocytes were seen in PPD-challenge sites in HKPA-sensitized pigs or in HKPA-challenged sites in BCG-sensitized pigs. There was also a substantial influx of(111)Indium-labelled neutrophils into the lesions. Lymphocytes present were predominantly of the CD3(+)CD2(+)T-cell subset, although gammadelta TCR(+)cells were present also, particularly after 24 h. E-selectin was markedly upregulated on dermal endothelium in the P. acnes sites. The histological infiltration and kinetics were similar to those reported in human inflammatory acne.

The impact of OBRA '87 on psychiatric services in nursing homes. Joint testimony of the American Psychiatric Association and the American Association for Geriatric Psychiatry.

The Institute of Medicine has formed a Committee on Improving Quality in Long-Term Care, which is examining the legislative and quality-of-care impact that the Omnibus Budget Reconciliation Act of 1987 (OBRA '87) had on long-term care. The American Psychiatric Association and the American Association for Geriatric Psychiatry were asked to provide written and oral testimony before the Committee in March 1998. The two organizations summarized the key outcomes of OBRA '87 on the psychiatric needs of individuals who receive services in long-term care settings. The written testimony also encouraged the Committee to insist that the long-term care industry develop, test, and refine psychiatric and mental health quality outcome measures for nursing facilities and other long-term care settings.

Mucosal or targeted lymph node immunization of macaques with a particulate SIVp27 protein elicits virus-specific CTL in the genito-rectal mucosa and draining lymph nodes.

The major routes of HIV transmission are through the rectal and cervico-vaginal mucosa. To prevent dissemination of HIV to the regional lymph nodes (LNs), an effective vaccine may need to stimulate CTL in the rectal or genital tract and the draining LNs. We report that mucosal immunization by the recto-oral and vagino-oral route or s.c. immunization targeting the iliac LNs with a particulate SIVp27:Ty-VLP vaccine elicits SIVgag-specific CTL in the regional LNs as well as in the spleen and PBMC. Targeted LN immunization with this vaccine elicited MHC class I-restricted CD8+ CTL responses, and the highest frequency of CTL was found in the iliac LNs. Moreover, SIVgag-specific CTL activity was detected in short term T cell lines established in mononuclear cells eluted from the rectal and cervico-vaginal mucosa. The relative frequency of CTL in short term cell lines prepared from the rectal mucosa (21/113 or 18.6%) was similar to that obtained from the cervico-vaginal mucosa (16/79 or 20.3%). Examination of the relative frequency of CTL to the T cell epitopes residing within SIVp27 showed a higher frequency in iliac LN cells to peptide aa 41-70 than in that to peptide aa 121-150, and this was significant after both recto-oral (chi-squared 6.500, p < 0.02) and vagino-oral (chi-squared = 10.391, p < 0.01) immunization. In contrast, the relative frequency of CTL in PBMC to peptide aa 41-70 (15.5%) was comparable to that elicited by peptide aa 121-150 (17.6%). This study provides novel evidence that mucosal or targeted LN immunization can generate anti-SIV CTL in the rectal and genital mucosa, in the draining LNs, and in the central lymphoid system.

Induction of single and dual cytotoxic T-lymphocyte responses to viral proteins in mice using recombinant hybrid Ty-virus-like particles.

The induction of cytotoxic T-lymphocyte (CTL) responses to viral proteins is thought to be an essential component of protective immunity against viral infections. Methods for generating such responses in a reproducible manner would be of great value in vaccine development. We demonstrate here that the recombinant antigen-presentation system based on the yeast transposon (Ty) particle-forming p1 protein is a potent means of inducing CTL responses to a variety of viral CTL epitopes, including influenza virus nucleoprotein (two epitopes), Sendai virus and vesicular stomatitis virus nucleoproteins, and the V3 loop of human immunodeficiency virus type-1 (HIV-1) gp120. CTL were primed by hybrid Ty-virus-like particles (VLP) carrying the minimal epitope or as much as 19,000 MW of protein. Ty-VLP carrying two different epitopes (dual-epitope Ty-VLP) were capable of priming CTL responses in two different strains of mice or against two epitopes in the same individual. Furthermore, co-administration of a mixture of two different Ty-VLP carrying single epitopes could induce responses to both epitopes in the same individual. Ty-VLP appear to represent a reproducible and flexible system for inducing CTL responses in mice, and warrant further evaluation in primates.

Health enhancement and companion animal ownership.

The relationship between people and companion animals, on the one hand, explains the bites and zoonotic diseases that occur among those with companion animals and, on the other hand, appears to enhance the psychological and physiological well-being of many people. Presently, no less than 56% of households in the United States have animals, typical of developed countries around the world. It is well documented that people denied human contact do not thrive well. All indications are that companion animals play the role of a family member, often a member with the most desired attributes. Animals play special roles for children, aiding the teaching of nurturing behavior and appreciation of nonverbal communication. Ordinary interactions with animals can reduce blood pressure and alter survival after a heart attack. For some, pets increase the opportunities to meet people, while for others pets permit them to be alone without being lonely.

Generation of diversity in the hierarchy of T-cell epitope responses following different routes of immunization with simian immunodeficiency virus protein.

OBJECTIVES: To examine whether the route of immunization determines the hierarchy of T-cell epitope proliferative responses in macaques. DESIGN: Macaques were immunized with a recombinant simian immunodeficiency virus (SIV) p27 core protein by the intramuscular, male and female genital or rectal route, each of which was augmented by oral immunization, and by the novel targeted lymph-node immunization route. Overlapping peptides were used to identify the proliferative T-cell epitopes and to determine their hierarchy in the circulation, spleen and lymph nodes. METHODS: T-cell epitope mapping of the proliferative responses was studied in short-term cell lines. Dendritic cells and macrophages were enriched by metrizamide gradient and adherence to plastic, respectively. RESULTS: Intramuscular immunization elicited in the circulating T cells a hierarchy of T-cell epitopes within four peptides in the following descending order of frequency: peptides 121-140 (57.9%), 41-60 (28.9%), 61-80 (18.9%) and 101-120 (5.4%). The hierarchy of these four T-cell epitope responses differed significantly with each of the five routes of immunization, when circulating (P < 0.001), splenic (P < 0.02-< 0.001) or iliac lymph-node cells (P < 0.001) were analysed. The effect of antigen-presenting cells was then investigated and enriched dendritic cells were more effective than macrophages in processing and presenting the p27 antigen and the immunodominant (121-140) and 61-80 T-cell epitopes. CONCLUSIONS: The route of immunization may determine the hierarchy of T-cell epitopes in the lymph nodes draining the mucosa in the circulating and splenic lymphocytes. The diversity of T-cell epitopes may affect the control of HIV at different anatomical sites, the administration route of the vaccine, and selection of polypeptides or recombinant antigens for immunization.

Experimental herpes simplex virus type 1 (HSV-1) infection of the spinal cord and dorsal root ganglia.

Host factors determining the outcome of herpes simplex virus type 1 (HSV-1) infection within neurons are poorly understood. This paper aims to identify regional differences in the behaviour of HSV-1 within the nervous system as an approach to investigating the role of the host environment in determining the outcome of infection. We describe a mouse model of HSV infection focused on motor neurons of the spinal cord, resulting from intramuscular injection (i.m.) and compare this with the behaviour of virus within sensory neurons following scarification of virus on to skin. Viral antigen was detectable immunohistochemically by 2 days in both models and disappeared by 9-11 days. The time course of acute infection was reflected in the i.m. group by quantitative plaque assay for virus. Inflammation and cell destruction occurred in both models, but clinical features and histological destruction were greater in the group infected via the intramuscular route. In the sensory ganglia, a latent state from which virus could be reactivated by explanation, was established with LATS expression detectable in many neurons at 35 days post-infection (p.i.), but not in non-neuronal cells. Expression of latency associated transcript (LATS) was detected in motor neutrons in spinal cords at 35 days p.i. providing evidence for establishment of a LATS-positive latent state at this site, and continued to be detectable up to 6 months post-infection. In addition, LATS was detected in white matter at late times, suggesting a non-neuronal site of latency. In contrast to the behaviour in sensory ganglia, induced reactivation from spinal cords, by explanation and nerve section, was a very rare event. We have shown that a LATS-positive latent state can be established within motor neurons of the CNS, but that there are regional differences in the biology and outcome of infection between the CNS and peripheral nervous system. We propose that this may be a useful model to study reproducibly, the behaviour of HSV-1 in a CNS environment and, by comparison with sensory ganglion infection, to explore host factors which may underlie these regional differences. The relevance of this model for using HSV-1 as a therapeutic vector for motor neurons is also discussed.

Beneficial wound healing and metabolic effects of clenbuterol in burned and nonburned rats.

Clenbuterol is known to increase muscle mass in nonburned and burn-injured subjects. The effects of clenbuterol on wound healing and the postburn response were examined in both nutritionally matched and free-feeding groups of rats. Rats received either a sham or 30% total body surface area scald burn and then a dorsal incision. Clenbuterol (2 mg/kg/day) was administered subcutaneously via a miniosmotic pump. The burn injury resulted in a sustained non-temperature-dependent hypermetabolism that was not altered by clenbuterol. Clenbuterol induced muscle anabolism and body growth in sham and burned-injured animals. Treated sham animals demonstrated increased wound breaking strength. Matched nutritional intake attenuated the body weight gain, although muscle anabolism was still evident in treated animals. Clenbuterol elevated RNA concentration in the tibialis muscle and reduced it in the liver. There was no statistical difference in wound strength when nutritional intake was matched. Clenbuterol's actions appear to be dependent on substrate availability. Clenbuterol may prove beneficial in patients with severe prolonged catabolic state, such as that associated with burn injury, by promoting protein anabolism and enhancing wound healing.

Structural similarity between the p17 matrix protein of HIV-1 and interferon-gamma.

The human immunodeficiency virus (HIV) matrix protein, p17, forms the outer shell of the core of the virus, lining the inner surface of the viral membrane. The protein has several key functions. It orchestrates viral assembly via targeting signals that direct the gag precursor polyprotein, p55, to the host cell membrane and it interacts with the transmembrane protein, gp41, to retain the env-encoded proteins in the virus. In addition, p17 contains a nuclear localization signal that directs the preintegration complex to the nucleus of infected cells. This permits the virus to infect productively non-dividing cells, a distinguishing feature of HIV and other lentiviruses. We have determined the solution structure of p17 by nuclear magnetic resonance (NMR) with a root-mean square deviation for the backbone of the well-defined regions of 0.9 A. It consists of four helices connected by short loops and an irregular, mixed beta-sheet which provides a positively charged surface for interaction with the inner layer of the membrane. The helical topology is unusual; the Brookhaven protein database contains only one similar structure, that of the immune modulator interferon-gamma.