Modelling the effect of race surface and racehorse limb parameters on in silico fetlock motion and propensity for injury.

BACKGROUND: The metacarpophalangeal joint (fetlock) is the most commonly affected site of racehorse injury, with multiple observed pathologies consistent with extreme fetlock dorsiflexion. Race surface mechanics affect musculoskeletal structure loading and injury risk because surface forces applied to the hoof affect limb motions. Race surface mechanics are a function of controllable factors. Thus, race surface design has the potential to reduce the incidence of musculoskeletal injury through modulation of limb motions. However, the relationship between race surface mechanics and racehorse limb motions is unknown. OBJECTIVE: To determine the effect of changing race surface and racehorse limb model parameters on distal limb motions. STUDY DESIGN: Sensitivity analysis of in silico fetlock motion to changes in race surface and racehorse limb parameters using a validated, integrated racehorse and race surface computational model. METHODS: Fetlock motions were determined during gallop stance from simulations on virtual surfaces with differing average vertical stiffness, upper layer (e.g. cushion) depth and linear stiffness, horizontal friction, tendon and ligament mechanics, as well as fetlock position at heel strike. RESULTS: Upper layer depth produced the greatest change in fetlock motion, with lesser depths yielding greater fetlock dorsiflexion. Lesser fetlock changes were observed for changes in lower layer (e.g. base or pad) mechanics (nonlinear), as well as palmar ligament and tendon stiffness. Horizontal friction and fetlock position contributed less than 1° change in fetlock motion. MAIN LIMITATIONS: Simulated fetlock motions are specific to one horse's anatomy reflected in the computational model. Anatomical differences among horses may affect the magnitude of limb flexion, but will likely have similar limb motion responses to varied surface mechanics. CONCLUSIONS: Race surface parameters affected by maintenance produced greater changes in fetlock motion than other parameters studied. Simulations can provide evidence to inform race surface design and management to reduce the incidence of injury.

Treatment with corticosteroids--a risk factor for the development of clinical cytomegalovirus disease in AIDS.

OBJECTIVE: To assess the frequency with which HIV-seropositive patients treated with corticosteroids develop cytomegalovirus (CMV) disease. DESIGN: Retrospective case-controlled study. METHODS: All 130 patients receiving systemic corticosteroids over a 20-month period at the HIV Unit, Westminster Hospital, London, UK were reviewed for the development of clinical CMV disease within 28 days. The incidence of CMV disease in this group was compared with that in a cohort admitted during the same period, which was matched for admission diagnosis, HIV risk group, antiretroviral therapy and CD4 lymphocyte subset count (+/- 20%) at admission. RESULTS: Eleven of the 130 patients given corticosteroids developed CMV disease within 28 days, compared with two patients in the case-controlled cohort. All patients who developed CMV disease had a CD4 count < 50 x 10(6)/l on admission. CONCLUSION: The use of corticosteroids in patients with advanced immunosuppression due to HIV infection should be reviewed carefully in view of the possible increased incidence of CMV disease.

Pseudomonas septicaemia associated with HIV.

Between July 1985 and January 1990, pseudomonas scepticaemia occurred in 19 out of 584 patients with AIDS attending the Westminster and St Stephen's AIDS Unit, London, UK. Ten of these 19 were being treated for active cytomegalovirus infection. Fourteen of the 19 patients had a central venous catheter in situ, which was the source of infection in 11. Seven patients died. Mortality was significantly greater in those patients infected with Pseudomonas aeruginosa, in those patients whose source of infection was not the central venous line, and in those patients whose central line was not removed.

Salmonella, Campylobacter and Shigella in HIV-seropositive patients.

OBJECTIVE: To study the incidence, clinical features, treatment and outcome of patients with Salmonella, Shigella or Campylobacter infection. DESIGN: Retrospective analysis. SETTING: Two dedicated HIV units within a London teaching hospital. METHODS: All patients with Salmonella, Shigella or Campylobacter infection were reviewed retrospectively by correlating the records of the gastrointestinal and microbiology departments with the computerized records of all HIV-positive patients attending the two clinics. RESULTS: Between July 1985 and June 1991, 56 episodes of Salmonella, 37 of Campylobacter and eight of Shigella infection were documented in HIV-seropositive patients. Shigella was most likely to occur early in HIV disease, whilst patients with Campylobacter or Salmonella were more likely to have had a previous AIDS diagnosis. Septicaemica was most common in patients with Salmonella and was especially likely to occur in individuals with an AIDS diagnosis. Relapse of infection was common in patients with Salmonella, especially in those with low CD4 lymphocyte counts, those with an initial septicaemic illness and those not treated with ciprofloxacin. CONCLUSIONS: Patients with Salmonella who have low CD4 lymphocytes counts and/or a septicaemic illness should be considered for life-long secondary prophylaxis with ciprofloxacin because of the high rate of relapse observed. Administration of zidovudine or cotrimoxazole as prophylaxis against Pneumocystis carinii pneumonia may prevent the development of salmonellosis: significantly fewer patients with this infection were taking these drugs than patients with Campylobacter.

Treatment of HIV-related fluconazole-resistant oral candidosis with D0870, a new triazole antifungal.

OBJECTIVES: To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal candidosis. DESIGN: Multicentre open study. PATIENTS: HIV-seropositive patients with oro-oesophageal candidosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more. METHODS: Patients received an initial dose of D0870 (150 mg), then 25 mg per day for 6 days. Symptoms and signs of candidosis were compared at entry and on days 3 and 7 of treatment. At each visit, samples were taken for safety monitoring and for in vitro susceptibility testing of Candida isolates. Limited pharmacokinetic samples were taken on days 1 and 7. RESULTS: Of 26 evaluable patients, 16 showed partial improvement, nine showed no improvement, and only one had full clearance of thrush by day 7. In vitro testing of the cleared patient's isolate suggested that it was susceptible to fluconazole. Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry. Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 (range, 0.07-0.34 mg/l) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 (range, < 0.06-8 mg/l; median, 0.25 mg/l). When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates. Six patients were noted to have a fall in haemoglobin, three of whom were receiving concomitant therapy known to suppress bone marrow. Three patients reported headaches as adverse events that were attributed to study medication, but D0870 was well tolerated overall. CONCLUSIONS: D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal candidosis and was well tolerated, although efficacy in this difficult-to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered.

A dose comparison study of a new triazole antifungal (D0870) in HIV-positive patients with oral candidiasis.

OBJECTIVE: This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal candidiasis in HIV-positive patients who had no history of clinical resistance to fluconazole. METHODS: Three regimens were evaluated in two phases. In phase I a 50 mg initial dose was followed by 10 mg for 4 days (Group 1). In phase II a 100 mg initial dose was followed by 25 mg for 4 days (Group 2), or 10 mg for 5 days (Group 3). RESULTS: Clinical cure was obtained in 27 patients of a total of 35 (77%) and six other patients improved (17%). Two patients at the lowest dose failed and both had very low plasma concentration of D0870. No association was found between clinical outcome; minimum inhibitory concentration of D0870 pre-therapy for Candida albicans, maximum recorded plasma D0870 concentration, cfu of culture or CD4 cell count at entry. Overall, 37% of the patients experienced relapse during the 2 weeks post therapy. Tolerance was excellent. Mild adverse events possibly related to the study drug were recorded in five patients. CONCLUSION: D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile.

Clinical, immunological, and virological effects of sodium fusidate in patients with AIDS or AIDS-related complex (ARC): an open study.

Fusidic acid has previously been noted to prevent syncytial formation by human immunodeficiency virus (HIV) in vitro. Since this drug is a cheap, usually well-tolerated substance with known toxicity profile, an open, uncontrolled trial was undertaken to evaluate its possible efficacy in HIV disease. Twenty HIV antibody positive patients (10 with AIDS and 10 with ARC) were treated with sodium fusidate 500 mg every 8 h for up to 3 months. One patient died during therapy and six ceased treatment due to adverse events. Rash, nausea, diarrhea, and/or abdominal pain caused difficulties in all patients. There was no significant improvement in clinical state or T-helper cell levels, and no observed decrease in HIV p24 antigen during treatment. We conclude that in this open trial, sodium fusidate had no observable beneficial clinical, virological, or immunological effects.

A double-blind placebo-controlled phase II trial of thalidomide in asymptomatic HIV-positive patients: clinical tolerance and effect on activation markers and cytokines.

A randomized double-blind, placebo-controlled study was performed to determine the safety, efficacy, and effect of thalidomide on a variety of immunological and biochemical parameters in asymptomatic human immunodeficiency virus (HIV)-positive patients. Nineteen male patients with elevated markers of immune activation and CD4 cell counts above 400/mm3 were randomized to either placebo or thalidomide at 100 mg/day for 24 weeks. However, only 3 (of 10) patients receiving thalidomide completed all 24 weeks compared to 6 (of 9) patients receiving placebo. This was mainly due to fatigue (somnolence is a recognized side effect), although this was also seen to a lesser extent in the placebo group and so may not be drug attributable. No significant changes in CD4/CD8 count, activation markers, TNF-alpha, or TNFR1 were observed. However, a nonsignificant trend toward inhibition of mitogen-induced TNF-alpha production was observed in the thalidomide arm. The lack of systemic effect and the lower tolerance of thalidomide (at this dose) in asymptomatic patients highlights the need for pharmacokinetic analysis to address possible absorption problems and the need for more potent and less toxic TNF-alpha inhibitors to be developed for use in this type of study.

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

Biochemical assessment of pancreatic disease in human immunodeficiency virus infected men.

AIM: To determine the usefulness of measuring amylase activity as an indicator of pancreatic disease in human immunodeficiency virus (HIV) positive patients. METHODS: A prospective study of 129 ambulant HIV positive males. Total amylase, pancreatic amylase, and lipase activities were assayed using commercial test kits on an automated analyser. Samples with raised amylase were examined for the presence of macroamylasaemia using cellulose acetate electrophoresis. RESULTS: Thirty six (28%) of the subjects had raised total amylase activities compared with healthy, age matched blood donors. However, almost half of these were because of an increase of the salivary fraction. Four subjects were found to have macroamylasaemia. Pancreatic amylase and lipase assays, more specific indicators of pancreatic disease, produced significantly fewer abnormal results. There was no association between abdominal symptoms and elevated enzyme levels. CONCLUSIONS: Total amylase is a poor indicator of pancreatic disease in HIV infected outpatients. Specific assays for pancreatic amylase offer advantages over the traditional total amylase assay. The lipase assay produced the least number of abnormal results and its use could improve the biochemical identification of patients with possible pancreatic disease and allow a more selective investigation of these cases.

Sensitivity of detecting Chlamydia trachomatis elementary bodies in smears by use of a fluorescein labelled monoclonal antibody: comparison with conventional chlamydial isolation.

Commercially produced fluorescein labelled monoclonal antibodies for the detection of Chlamydia trachomatis have recently become available. One is for detecting inclusions in cell culture (culture confirmation) and the other for detecting elementary bodies in smears from potentially infected sites. We have compared the two monoclonal antibodies with our routine isolation method, which utilises Giemsa staining of cycloheximide treated McCoy cell cultures. The culture confirmation system offered no advantages over Giemsa staining for the detection of inclusions in cell monolayers. By contrast, using monoclonal antibody to detect elementary bodies in smears was much quicker and simpler and slightly more sensitive than isolation of chlamydiae in cell culture. For specimens from seven babies with conjunctivitis and from 35 female contacts of men with non-gonococcal urethritis, there was complete agreement between the results of detecting inclusions in culture and those of seeking elementary bodies in smears. For samples from 100 men with non-gonococcal urethritis and from 100 men with gonorrhoea there was 99% and 94% agreement, respectively, between the results of the two tests. Other aspects and possible uses of the new detection system are discussed.

Management of pulmonary aspergillosis in AIDS: an emerging clinical problem.

AIMS: To review the clinical, radiographic, and therapeutic features of 11 cases of respiratory Aspergillus infection in patients with AIDS. METHODS: All induced sputum and bronchoalveolar lavage samples obtained from HIV seropositive patients between January 1985 and March 1993 were analysed for Aspergillus species. Additionally, where appropriate, bronchial or renal biopsy specimens, or both, were taken before treatment had started. RESULTS: In 11 patients Aspergillus fumigatus was identified in alveolar samples obtained by sputum induction. This was confirmed by bronchoalveolar lavage in eight. Three patients had Aspergillus plaques in the trachea and bronchus, while a fourth patient had an aspergilloma. Risk factors for Aspergillus infection were present in all patients, including corticosteroid treatment in three cases and neutropenia in four, three of whom had received chemotherapy for Kaposi's sarcoma. Four patients had concomitant cytomegalovirus infection. Ten patients had a CD4 count of less than 50 cells/mm3 while one patient had a disseminated T cell lymphoma with a CD4 count of 242 cells/mm3. Of the three patients with samples obtained by sputum induction who did not undergo bronchoscopy, two had a normal chest x ray picture and the third had a right lobar pneumonia complicating an aggressive lymphoma. All three were treated with itraconazole 200 mg twice a day without further investigation. Survival from the time of diagnosis of Aspergillus infection was short: seven patients died within six weeks, although only one death was directly attributed to pulmonary aspergillosis. At six monthly follow up, one patient, who initially had a positive Aspergillus culture from bronchial washings and a normal chest radiograph, developed a renal aspergilloma despite the disappearance of Aspergillus sp from the sputum. CONCLUSION: Pulmonary aspergillosis is an important clinical problem in patients with AIDS with a CD4 count of less than 50 cells/mm. Furthermore, patients with Aspergillus sp in sputum induction or bronchial washings may develop disseminated disease despite adequate treatment of the primary infection.

Investigation into the value of Papanicolaou stained cervical smears for the diagnosis of chlamydial cervical infection.

Forty five (37%) of 121 female contacts of men with non-gonococcal urethritis or gonorrhoea were chlamydia positive, as judged by isolation or by detecting elementary bodies in smears with a fluorescein labelled chlamydial monoclonal antibody. Only six (13%) of these, however, had Papanicolaou stained smears in which there were inclusion like changes suggestive of chlamydial infection. Furthermore, of 15 patients who had such cytological changes, chlamydiae were detected in only six and the abnormalities were found also in Papanicolaou stained smears from 10 (13%) of the 76 chlamydia negative patients. Modifying the Papanicolaou stained smears by including endocervical material did not increase sensitivity. In addition, destaining and restaining them with the monoclonal antibody was time consuming and the results were unreliable. The staining of cervical smears with Papanicolaou reagent is a technique of low sensitivity and specificity for diagnosing or screening for chlamydial cervical infection and cannot be recommended.

Immunohistochemical markers of uterine receptivity in the human endometrium.

The factors responsible for the initial interaction between maternal and fetal epithelium leading to the establishment of pregnancy remain poorly understood. Temporal and spatial expression of specific endometrial peptides in response to ovarian steroids is thought to contribute to the development of a period of uterine receptivity, whereby the endometrium becomes hospitable to the implanting blastocyst. The failure to establish receptivity may account for a significant percentage of the cases of infertility in the female, especially affecting women with luteal phase deficiency, leiomyomata uteri, endometriosis, habitual abortion, and unexplained infertility. In addition, despite increasing global experience with advanced reproductive technologies, the majority of In Vitro Fertilization (IVF) attempts remain unsuccessful, most likely on the basis of implantation failure. In this article, we review the concepts involved in the study of uterine receptivity in the human, highlight potential immunohistochemical (IHC) markers that have recently been discovered, and discuss how IHC assessment of the endometrium is a potentially valuable method for the evaluation of the receptive endometrial state. Using this approach we have examined several new potential markers of uterine receptivity. Endometrial progesterone receptors and one of the integrin cell adhesion molecules appear to undergo changes in expression around the time of implantation, and may be sensitive indicators of the receptive state. Further, these markers are delayed in women with infertility and luteal phase deficiency. These studies illustrate the utility of IHC diagnosis for the evaluation of endometrial function.

Efficacy and safety of combination therapy with delavirdine and zidovudine: a European/Australian phase II trial.

The objective of the study was to investigate the safety and antiviral effect of three delavirdine dose regimens or placebo in combination with zidovudine in patients who were already taking zidovudine. Eighty-nine symptomatic HIV-1 seropositive individuals with CD4 cell counts between 50 and 350 cells/microl were included in this trial The influence of combination therapy on viral susceptibility to both zidovudine and delavirdine was investigated. Death or the occurrence, or re-occurrence of an AIDS-defining illness was considered as a clinical endpoint. The addition of delavirdine to the antiretroviral treatment regimen resulted in a significant, but transient, reduction in virus load, as determined by quantitative RNA measurements. CD4+ cell count did not change significantly. Susceptibility to zidovudine remained unchanged after 12 weeks of combination therapy, while 70% of the patients demonstrated a substantial decrease (> 10-fold) in sensitivity to delavirdine. Two patients suffered from an AIDS-defining disease during the study. No deaths occurred. Generally, the drug appeared to be safe. Skin rash was the most frequently observed adverse event (52%). In most patients the rash either resolved spontaneously or was treated successfully with a short course of antihistamines. The definite place of the compound in the management of HIV disease, in particular when given in combination with other antiretroviral agents, remains to be further explored.

Electromyographic study of the anterior cruciate ligament-hamstrings synergy during isometric knee extension.

The purpose of this investigation was to determine the role the hamstrings group may play in augmenting passive articular mechanisms during activity in which anterior drawer force may detrimentally affect the anterior cruciate ligament (ACL). Nine male subjects performed non-weight-bearing isometric knee extension at 10% increments of maximum voluntary contraction (MVC). Electromyographic (EMG) signals were detected and recorded from the vastus lateralis, vastus medialis oblique, vastus medialis longus, and the long head of the biceps femoris. The EMG signals were rectified and integrated over 1000 ms and normalized to subject-specific values. The data were subjected to a repeated-measures analysis of variance. The results demonstrated that expected significant increases in quadriceps excitation accompanied increases in knee extensor torque. Hamstrings excitation was not found to change significantly (total change = 3.4%). It was concluded that functionally adequate knees do not require posterior drawer force in excess of that provided passively by articular structures.

Hospital infection control in an era of HIV infection and multi-drug resistant tuberculosis.

Tuberculosis infection control in hospitals has received renewed interest after decades of low prominence following the occurrence of multiply drug-resistant strains in populations of patients with immune systems affected by HIV. This paper examines the history of tuberculosis infection control in hospitals and how recent outbreaks have influenced contemporary measures. The principal infection control measure must always be early recognition and isolation of patients in HIV-care situations who may be dispersing Mycobacterium tuberculosis, in both ward and outpatient areas. If there is either a high degree of suspicion or proven TB, patients should be housed in negative pressure isolation rooms whilst undergoing treatment and investigation. Procedures which may generate infectious aerosols should be carried out in similarly ventilated rooms. The quality assurance in such infection control is through the administrative systems put in place, staff training and the engineering controls of isolation room ventilation.

Rapid, reliable diagnosis of chlamydial ophthalmia by means of monoclonal antibodies.

The use of fluorescein-conjugated monoclonal antibody (Syva, UK) provided a rapid reliable diagnostic test for Chlamydia trachomatis in conjunctival samples from 100 adults with acute follicular conjunctivitis and seven babies with suspected chlamydial ophthalmia neonatorum. Elementary bodies (EBs) were seen in smears from 11 of the adults, and culture confirmed C. trachomatis infection in nine of them. Both tests were positive with specimens from four of the neonates. No specimens from either group of patients produced a negative result in the smear test but a positive result by culture. However, the two adult patients with chlamydial ophthalmia who had negative cultures but were EB-positive had both had prior topical tetracycline therapy.

Neuropsychiatric aspects of HIV-1 infection in gay men: controlled investigation of psychiatric, neuropsychological and neurological status.

The aim of this study was to determine whether HIV infection is associated with psychiatric morbidity or neuropsychological impairment in asymptomatic and early symptomatic stages of disease in gay men. The subjects were 100 gay men (68 HIV-ve, 32 HIV+ve, 6 being CDC IV). All subjects were recruited at the time of requesting their first HIV test and the assessment was double-blind to HIV serostatus. There were no differences in psychiatric status or neuropsychological performance between the HIV-ve and HIV+ve groups. Multiple regression analysis and logistic regression were used to identify factors associated with psychiatric morbidity, neuropsychological impairment and subjective reporting of memory problems and physical symptoms for all 100 subjects. Previous psychiatric history and current illegal (non-dependent) drug use were associated with psychiatric morbidity, poor education was associated with neuropsychological impairment and psychiatric status (score on HAD and PSE) was associated with subjective reporting of memory problems and physical symptoms.

Seroconversion to HIV-1 following a needlestick injury despite combination post-exposure prophylaxis.

Post-exposure prophylaxis with antiretroviral drugs for at-risk needlestick injuries has become routine practice and is usually empirical. With increasing numbers of treatment-experienced patients, the choice of antiretroviral may need to be individually tailored. Infection can still occur despite attempts to optimize the drug combination used.