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IntroductionIn 2019, Camp Qargha (QAA), a British-led multinational military camp in Kabul, had three of the largest outbreaks of gastrointestinal illness (GI) experienced by the British Military since 2003. This paper discusses the incidence, the response of the British-led Role 1 (R1) medical treatment facility, identifies potential causative and exacerbating factors, and explains the control measures initiated.MethodGI in QAA results in local and UK military-wide data collection including in the form of local GI questionnaires, FMed85 forms and EpiNATO returns. The data from these was used to identify trends during and after outbreaks and produce environmental health (EH) and local outbreak reports.ResultsOverall, among the outbreaks 56% of stool samples tested positive for norovirus. In each outbreak incidence peaked within the first 3 days, and hardened multiperson rooms were worst affected. 206 patient presentations occurred during the three outbreaks, 706 working days were lost in isolation, with QAA shut down while in quarantine for 27 days.DiscussionSignificant strain was placed on QAA and the R1. Causative factors may include close interaction with the local national (LN) population, a high population density and accommodation being limited by specific national infrastructure protocols in an operational environment.ConclusionEarly recognition of GI, positive standard operating procedures and good hygiene habits are essential to prevent the spread of GI such as norovirus. An early awareness of LN population illness patterns will allow the R1 and command to be better prepared for outbreaks in the future.

IntroductionInfectious diseases are a frequent cause of morbidity among British troops. The aim of this paper is to describe the spectrum of infectious diseases seen when UK service personnel are evacuated for definitive care to the Role 4 Medical Treatment Facility based at Birmingham Heartlands Hospital.MethodA retrospective analysis of all military patients presenting with infectious diseases and treated at Birmingham Heartlands Hospital between 14 April 2005 and 31 December 2013 was undertaken.ResultsDuring this period, 502 patients were identified. Infections originated in 49 countries, most commonly Afghanistan (46% cases), the UK (10% cases) and Belize (9% of cases). The most common presentations were dermatological conditions, gastroenterological illnesses and undifferentiated fevers.ConclusionUK service personnel in significant numbers continue to suffer a wide range of infectious diseases, acquired throughout the globe, which often require specialist tertiary infection services to diagnose and manage. Future prospective data collection is recommended to identify trends, which in turn will inform military training needs and future research priorities in the Defence Medical Services (DMS) and allows development of appropriate policies and clinical guidelines for management of DMS personnel with infectious diseases.

Many human tumors express high levels of the p53 inhibitor Mdm2, resulting from amplification of the Mdm2 locus or aberrant post-translational regulation of the Mdm2 protein. While the importance of Mdm2 in regulating p53 is clear, Mdm2 also has p53-independent roles. For example, overexpression of Mdm2 results in genomic instability in a p53-independent manner. In addition, Mdm2 has many additional binding partners, some of which, such as the tumor suppressor p73, have also been implicated in genomic instability. In this study, cells and tumors with Mdm2 overexpression and p73 loss exhibit increased genomic instability as compared with either alteration alone and cooperate in development of B-cell lymphomagenesis. Cytogenetic analysis of mouse embryonic fibroblasts and pre-malignant B cells demonstrates that loss of p73 exacerbates the chromosome breaks and fusions observed in Mdm2(Tg) cells. B-cell lymphomas from Mdm2(Tg);p73(+/-) mice retain the remaining p73 allele, exhibit elevated levels of the antiapoptotic protein Bcl2 and thus dampen apoptosis. In summary, Mdm2 overexpression and p73 loss cooperate in genomic instability and tumor development, indicating that the oncogenic function of Mdm2 is a combined effect of inhibiting p53 and p73 functions. Given that p73 is lost or silenced in human B-cell lymphomas, the Mdm2(Tg);p73(+/-) mouse serves as a model for human disease and may provide additional insight into the pathways that contribute to B-cell lymphomagenesis.

Study Design Prospective consecutively enrolled cohort. Objectives To evaluate paraspinal muscle concentration of intravenously administered vancomycin, at predetermined time points, during posterior spinal fusion (PSF) with instrumentation in neuromuscular scoliosis (NMS). Summary Surgical site infection (SSI) after PSF for NMS can be a devastating complication, which may lead to prolonged antibiotic use, multiple additional surgical procedures, pseudarthroses, and sepsis. Because of significant morbidity of SSIs in NMS, the prophylactic use of vancomycin has been adopted at our institution as standard wound prophylaxis, despite any high-level evidence of its efficacy. Methods A prospective study of 20 patients who underwent definitive PSF for NMS and received vancomycin infusion preoperatively per institutional protocol. Serum levels were obtained immediately after infusion, at surgical incision, and then at 1, 2, and 4 hours post incision. Muscle tissue samples were simultaneously obtained at incision and at 1, 2, and 4 hours post incision. Samples were analyzed by a validated liquid chromatography–tandem mass spectrometry method. Results 10 males and 10 females with a mean age of 14+11 years (9–20 years) received a mean infusion of 15.0 mg/kg vancomycin. Mean serum levels were 26.7 μg/mL after infusion, 18.1 at incision, 13.2 at 1 hour, 11.8 at 2 hours, and 7.6 at 4 hours post infusion. Mean muscle levels were 0.5 μg/mL at incision, 0.6 at 1 hour, 0.5 at 2 hours, and 0.7 at 4 hours post infusion. Mean serum levels reached minimum inhibitory concentration (MIC) for Staphylococcus aureus at incision and at all timepoints during surgery. Mean muscle vancomycin levels never reached MIC. No patients had any cardiac or kidney disease, and all patients had normal kidney function according to their preoperative laboratory values. Conclusions Using accepted guidelines for the administration of intravenous vancomycin preoperatively, serum levels reached MIC at incision and at all timepoints tested during PSF for neuromuscular scoliosis. At no timepoint tested did muscle levels reach MIC. Level of Evidence Level II.

Research shows that prescription drug labels are often difficult for patients to understand, which contributes to medication errors and nonadherence. In this study, the authors developed and qualitatively evaluated an evidence-based bilingual prescription container label designed to improve understanding. The authors developed several prototypes in English only or in English and Spanish. The labels included an image of the drug, an icon to show its purpose, and plain-language instructions presented in a 4-time-of-day table. In 5 focus groups and interviews that included 57 participants, patients and pharmacists critically reviewed the designs and compared them with traditional medication labels and reformatted labels without illustrations. Patients strongly preferred labels that grouped patient-relevant content, highlighted key information, and included drug indication icons. They also preferred having the 4-time-of-day table and plain-language text instructions as opposed to either one alone. Patients preferred having pertinent warnings on the main label instead of auxiliary labels. Pharmacists and Latino patients valued having Spanish and English instructions on the label, so both parties could understand the content. The final label design adheres to the latest national- and state-level recommendations for label format and incorporates additional improvements on the basis of patient and pharmacist input. This design may serve as a prototype for improving prescription drug labeling.

Whether natural product drug discovery programs should rely on wild plants collected "randomly" from the natural environment, or whether they should also include plants collected on the basis of use in traditional medicine remains an open question.This study analyzes whether plants with ethnomedical uses from Vietnam and Laos have a higher hit rate in bioassay testing than plants collected from a national park in Vietnam with the goal of maximizing taxonomic diversity ("random" collection).All plants were extracted and subjected to bioassay in the same laboratories. Results of assays of plant collections and plant parts (samples) were scored as active or inactive based on whether any extracts had a positive result in a bioassay. Contingency tables were analyzed using χ(2) statistics.Random collections had a higher hit rate than ethnomedical collections, but for samples, ethnomedical plants were more likely to be active. Ethnomedical collections and samples had higher hit rates for tuberculosis, while samples, but not collections, had a higher hit rate for malaria. Little evidence was found to support an advantage for ethnomedical plants in HIV, chemoprevention and cancer bioassays. Plants whose ethnomedical uses directly correlated to a bioassay did not have a significantly higher hit rate than random plants.Plants with ethnomedical uses generally had a higher rate of activity in some drug discovery bioassays, but the assays did not directly confirm specific uses.Ethnomedical uses may contribute to a higher rate of activity in drug discovery screening.

Background Insufficient tissue oxygenation is a likely contribution to weak, inco-ordinate human uterine contractile activity characteristic of prolonged, dysfunctional labour. However, the direct effects of hypoxia on human myometrial contractility has, surprisingly, not yet been detailed. Therefore, we report the influence of hypoxia on spontaneous and agonist-induced carbachol, prostaglandin (PGF2alpha), and oxytocin contractions of myometria from nonpregnant and pregnant women. Materials and methods Uterine biopsies were obtained from pregnant women at term undergoing elective Caesarean section and nonpregnant women undergoing hysterectomy. Myometrial strips were equilibrated at 37 degrees C in normoxic physiological salt solution (95% air/5% CO(2)) and the influence of hypoxia (95% N(2)/5% CO(2)) on contractility was investigated. Results Hypoxia resulted in a significant reduction in spontaneous contractile function; nonpregnant tissue was less resistant to the deleterious effects of hypoxia. Agonist-induced contractions, while being more resistant to hypoxia than spontaneous contractions, were also significantly inhibited. In myometria of pregnant women the PGF2alpha- or oxytocin-induced contractility was more resistant to hypoxia than carbachol. Finally, the inhibitory actions of hypoxia were exacerbated with repeated oxytocin administration with a more severe effect on contractile integral than on initial phasic contraction amplitude. Conclusions We detail, for the first time, the effects of hypoxia on contractility of human myometria from nonpregnant and pregnant women. Physiologically important uterotonic agents are more resistant to the effects of hypoxia than spontaneous contractions although repeated stimulation with oxytocin during hypoxia results in progressively less force. The results indicate that if significant hypoxia occurs in vivo then it is a likely contributory factor to the pathways underlying prolonged dysfunctional labour.

Ethnobotany/ethnopharmacology has contributed to the discovery of many important plant-derived drugs. Field explorations to seek and document indigenous/traditional medical knowledge (IMK/TMK), and/or the biodiversity with which the IMK/TMK is attached, and its conversion into a commercialized product is known as bioprospecting or biodiversity prospecting. When performed in a large-scale operation, the effort is referred to as mass bioprospecting. Experiences from the mass bioprospecting efforts undertaken by the United States National Cancer Institute, the National Cooperative Drug Discovery Groups (NCDDG) and the International Cooperative Biodiversity Groups (ICBG) programs demonstrate that mass bioprospecting is a complex process, involving expertise from diverse areas of human endeavors, but central to it is the Memorandum of Agreement (MOA) that recognizes issues on genetic access, prior informed consent, intellectual property and the sharing of benefits that may arise as a result of the effort. Future mass bioprospecting endeavors must take heed of the lessons learned from past and present experiences in the planning for a successful mass bioprospecting venture.

BACKGROUND—Resection is the treatment of choice for lung cancer, but may cause impaired cardiopulmonary function with an adverse effect on quality of life. Few studies have considered the effects of thoracotomy alone on lung function, and whether the operation itself can impair subsequent exercise capacity. METHODS—Patients being considered for lung resection (n = 106) underwent full static and dynamic pulmonary function testing which was repeated 3-6 months after surgery (n =53). RESULTS—Thoracotomy alone (n = 13) produced a reduction in forced expiratory volume in one second (FEV1; mean (SE) 2.10 (0.16) versus 1.87 (0.15) l; p

The Ins(1,4,5)P3 regioisomers, Ins(1,4,6)P3 and Ins(1,3,6)P3, which can mimic the 1,4,5-arrangement on the inositol ring of Ins(1,4,5)P3, were examined for Ca2+ release by using four types of saponin-permeabilized cell possessing various abundances of receptor subtypes, with special reference to the relation of potency to receptor subtype. Ins(1,4,6)P3 and Ins(1,3,6)P3 were weak agonists in rat basophilic leukaemic cells (RBL cells), which possess predominantly subtype II receptors, with respective potencies of 1/200 and less than 1/500 that of Ins(1,4,5)P3 [the EC50 values were 0.2, 45 and more than 100 microM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively]. Similar rank order potencies were also evaluated for the displacement of [3H]Ins(1,4,5)P3 bound to RBL cell membranes by these regioisomers. However, they caused Ca2+ release from GH3 rat pituitary cells possessing predominantly subtype I receptors more potently; Ins(1,4,6)P3 and Ins(1,3,6)P3 evoked release at respective concentrations of only one-third and one-twentieth that of Ins(1,4,5)P3 (the EC50 values were 0.4, 1.2 and 8 microM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). In COS-1 African green-monkey kidney cells, with the relative abundances of 37% of the subtype II and of 62% of the subtype III receptor, potencies of 1/40 and approx. 1/200 for Ins(1, 4,6)P3 and Ins(1,3,6)P3 respectively were exhibited relative to Ins(1,4,5)P3 (the EC50 values were 0.4, 15 and approx. 80 microM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). In HL-60 human leukaemic cells, in spite of the dominant presence of subtype I receptors (71%), similar respective potencies to those seen with COS-1 cells were exhibited (the EC50 values were 0.3, 15 and approx. 100 microM for Ins(1,4,5)P3, Ins(1,4,6)P3 and Ins(1,3,6)P3 respectively). These results indicate that these regioisomers are the first ligands that distinguish between receptor subtypes; the present observations are of significance for the future design of molecules with enhanced selectivity.

The ventilatory response to exercise in patients with chronic heart failure (CHF) is greater than normal for a given work or metabolic rate (VO2). The factors that determine the ventilatory response to exercise are: 1) the CO2 production (VCO2), 2) the arterial CO2 set-point (arterial PCO2 (PaCO2) at rest), 3) the physiological dead space/tidal volume ratio (VD/VT), and 4) the change in PaCO2 during exercise. This report illustrates how each of these factors might influence the ventilatory response to exercise in CHF patients. Thirty-one CHF patients (New York Heart Association, Classes 2 and 3) were studied, 18 from Harbor-UCLA Medical Center (cycle-ergometer exercise) and 13 from Queen's University at Belfast (treadmill exercise). A group of healthy subjects matched for size, age and gender served as control subjects. Minute ventilation (VE) was 48, 88 and 43% greater in the CHF groups compared to the control population at 6 min of the 25w and 60w cycle and low level (2.5 km h-1 and 5% grade) treadmill exercise, respectively. VO2 kinetics were slower in CHF patients than the control group, the slowing being proportional to the lactate increase. However, the increase in VO2 above rest at 6 min of exercise was approximately the same for CHF and control subjects. VCO2 at 6 min increased in the CHF patients by 7% and 34% for 25 and 60 watts cycle and 19% for treadmill exercise, respectively, compared to the control group. Because PaCO2 was not measured in this study, neither CO2 set-point nor the VD/VT could be individually calculated. Because end-tidal PCO2 will decrease when PaCO2 decreases or VD/VT increases, the combined effect of PaCO2 change and increase in VD/VT could be assessed from the difference between the patient and the control group. Since PETCO2 was significantly reduced in the patient population at the end of 60w cycle exercise (32 versus 41 mm Hg), either the VD/VT was increased and/or the PaCO2 was reduced. Because the resting PaCO2 is generally normal in CHF patients, the increase in the ventilatory response to exercise in patients with CHF can best be accounted for by three physiological mechanisms: 1) an increase in VCO2 secondary to CO2 release from bicarbonate as it buffers lactic acid, 2) the reduction in PaCO2 secondary to the lactic acidosis-induced hyperventilation, and 3) an increase in the fraction of breath that is wasted (dead space). Mathematically, these factors interact so that relatively small changes in each cause large changes in VE.

Although illustrated medication instructions may improve medication management among vulnerable populations, little prior research has evaluated their use among Latinos. We conducted focus groups and interviews with Latino patients with diabetes at two safety net clinics in Tennessee to understand medication taking practices and perceptions of illustrated medication instructions. Patients reported confidence in being able to take medications, but demonstrated a lack of understanding of medication instructions. On further probing, they described several barriers to effective medication management rooted in poor communication. Patients expressed preference for illustrated medication instructions which could address several of the challenges raised by patients.

An ethnobotany-based approach in the selection of raw plant materials to study was implemented.To acquire raw plant materials using ethnobotanical field interviews as starting point to discover new bioactive compounds from medicinal plants of the Lao People's Democratic Republic.Using semi-structured field interviews with healers in the Lao PDR, plant samples were collected, extracted, and bio-assayed to detect bioactivity against cancer, HIV/AIDS, TB, malaria. Plant species demonstrating activity were recollected and the extracts subjected to a bioassay-guided isolation protocol to isolate and identify the active compounds.Field interviews with 118 healers in 15 of 17 provinces of Lao PDR yielded 753 collections (573 species) with 955 plant samples. Of these 955, 50 extracts demonstrated activity in the anticancer, 10 in the anti-HIV, 30 in the anti-TB, and 52 in the antimalarial assay. Recollection of actives followed by bioassay-guided isolation processes yielded a series of new and known in vitro-active anticancer and antimalarial compounds from 5 species.Laos has a rich biodiversity, harboring an estimated 8000-11,000 species of plants. In a country highly dependent on traditional medicine for its primary health care, this rich plant diversity serves as a major source of their medication.Ethnobotanical survey has demonstrated the richness of plant-based traditional medicine of Lao PDR, taxonomically and therapeutically. Biological assays of extracts of half of the 955 samples followed by in-depth studies of a number of actives have yielded a series of new bioactive compounds against the diseases of cancer and malaria.

During normal progressive exercise, the gas exchange anaerobic threshold occurs when CO2 production (VCO2) and ventilation (VE) increase so as to depart from a linear relationship to O2 consumption (VO2). This is thought to represent a gas exchange response to metabolic acidosis due to lactate accumulation. Patients with McArdle's disease have previously been reported to exhibit a steepened ventilatory response relative to VCO2, despite an inability to produce lactate. However, the VCO2 response has not been studied. We therefore investigated the VCO2-VO2 and VE-VO2 relationships in seven McArdle's disease patients and seven control subjects during symptom-limited maximal treadmill exercise. Analysis of gas exchange showed that whereas all control subjects had an easily identifiable anaerobic threshold, four of the patients had none and the other three displayed an attenuated threshold. The occurrence of the threshold in one patient was associated with a small rise in lactate and in another patient with an abrupt rise in leg discomfort, suggesting a pain response. Ammonia and the purine metabolite hypoxanthine were elevated during exercise in all patients, suggesting that ammonia may be a product of adenosine monophosphate degradation. Free fatty acid levels were also elevated, and a shift toward utilization of lipid may contribute to abnormal gas exchange responses. It is concluded that lactic acidosis contributes to the gas exchange anaerobic threshold but that other factors, such as discomfort, may be involved in the excess Ve seen during heavy exercise.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE) infections cause significant morbidity and mortality among liver transplant candidates and recipients. To assess rates of MRSA and VRE colonization, we obtained active surveillance cultures from 706 liver transplant candidates and recipients within 24 h of admission to an 11-bed liver transplant ICU from October 2000 to December 2005. Patients were followed prospectively to determine the cumulative risk of MRSA or VRE infection or death by colonization status. Outcomes were assessed by Kaplan-Meier survival analysis and Cox regression and multivariate logistic regression adjusting for covariates. The prevalence of newly detected MRSA nasal and VRE rectal colonization was 6.7% and 14.6%, respectively. Liver transplant candidates and recipients with MRSA colonization had an increased risk of MRSA infection (adjusted OR = 15.64, 95% CI 6.63-36.89) but not of death (adjusted OR = 1.00, 95% CI 0.43-2.30), whereas those with VRE colonization had an increased risk both of VRE infection (adjusted OR = 3.61, 95% CI 2.01-6.47) and of death (adjusted OR = 2.12, 95% CI 1.27-3.54) compared with noncolonized patients. Prevention and control strategies, including use of active surveillance cultures, should be implemented to reduce the rates of both MRSA and VRE colonization in this high-risk patient population.

Objective: To determine the sensitivity of seven over-the-counter pregnancy tests (OTC-PTs) using urine containing a mixture of human chorionic gonadotropin (hCG)-related molecules as found on the first day of missed menstrual period. Design: Blinded in vitro sensitivity analysis. Setting: Medical school laboratory. Participants: None. Interventions: Urine was tested with OTC-PT devices at titers of 100, 50, 25, 12.5, 6.3, and 0 mIU/mL hCG immunoreactivity, and laboratory workers rated their confidence in the test result based on whether the test result was a clear, sharp, and unquestionable band in the test window. Main Outcome Measures: Analytical sensitivity, defined as the urine concentration at which all OTC-PTs tested gave a positive result regardless of operator confidence score; clinical sensitivity of OTC-PTs, defined as the proportion of pregnancies likely to be detected on the first day of a missed period and calculated from the analytical sensitivity and a recently published regression curve for total urine hCG immunoreactivity in 25 urine samples from this period of gestation; percentage of tested devices showing a band in the test window at a specific hCG concentration measured devices positive; percentage faulty devices, defined as the proportion of tested devices failing to yield a band in the control window; and confidence score, determined from operator ratings for each device at each concentration of hCG. Results: First Response Early Result had an analytical sensitivity of 6.3 mIU/mL, which was estimated to detect greater than 95% of pregnancies on the day of missed period. The sensitivity of Clearblue Easy Earliest Results was 25 mIU/mL, which indicated detection of 80% of pregnancies. The sensitivity of the five other products was 100 mIU/mL or greater, indicating detection of 16% or less of pregnancies. Three of these last products included faulty devices. Conclusion: Universal claims for OTC-PTs of more than 99% laboratory accuracy and use as early as the first day of missed period, while cleared for use by the U.S. Food and Drug Administration, are ambiguous and inappropriate for many products, according to these data. The majority of products tested were found to detect only a small percentage of pregnancies on the first day of a missed menstrual period. Until more data become available on the actual clinical sensitivity of these products, pharmacists should advise consumers to be cautious in interpreting test results.

Objectives: Current testing to determine a failing pregnancy requires two separate clinic visits to measure the hCG doubling rate. Diagnosing a failing pregnancy is often done in emergency departments where simplified and accelerated testing methods are needed. Here, we investigated hyperglycosylated hCG (hCG-H) for predicting pregnancy failure. Design and methods: We studied two independent sets of patient samples collected in the early weeks of gestation. One set was urine samples, and the other was serum samples. In all cases, hCG and hCG-H were measured using automated chemiluminescence immunoassays. Concentrations of hCG and hCG-H were plotted on a scattergram, and levels in failing pregnancies were compared to those in continuing pregnancies. Results: Data indicated that a threshold level of hCG-H (13 μg/L) in both serum and urine samples defined the concentration below where pregnancies were likely to fail. This cut-off corresponded to 73% detection of failures at a 2.9% false positive rate using serum and 75% detection at a 15% false positive rate using urine. Using an hCG cut-off that corresponded to the same false positive rates, hCG detected only 42% of failures using serum and 43% of failures using urine. Conclusions: Our data indicate that hCG-H provides a much more accurate single test than hCG for assessing pregnancy outcome. Compatible with the use of serum or urine samples, a single hCG-H test might provide simpler, faster, and more accurate results for predicting the progress of a pregnancy than standard hCG testing.

Successful parturition requires the co-ordination of numerous myometrial signalling events to allow for timely and efficient uterine contractions. Late pregnancy and labour onset in humans may be associated with changes in the expression of myometrial proteins implicated in such uterine contractile signal integration. Accordingly, in myometria from non-pregnant women and pregnant women, not in labour or in labour, we examined the content of putative plasmalemmal scaffolding proteins (caveolin-1 and -2) and compared these to the proportions of signal transducing rho-associated kinases (ROKalpha and beta) and contractile filament-associated proteins alpha-actin, myosin regulatory light chain (MLC(20)) and h-caldesmon. There was no effect of pregnancy or labour on the proportion of caveolin, ROK betaor alpha-actin. However, pregnancy was associated with a decrease in ROKalpha and MLC(20) such that ROK alpha: alpha-actin and MLC(20): alpha-actin ratios were reduced compared to myometria of non-pregnant women. In contrast, h-caldesmon was up-regulated in pregnancy resulting in an elevated h-caldesmon: alpha-actin ratio. There were, however, no further significant changes in ROK alpha, MLC(20) or h-caldesmon expression with spontaneous or oxytocin-induced labour. These data suggest that the mechanism(s) integrating myometrial signalling events with the onset of human labour does not involve differential alterations of the cellular expressions of caveolins, ROK, alpha-actin, MLC(20) or h-caldesmon.

A rare case of idiopathic bilateral ossification of the auricular cartilage and cartilage of the external ear canal is reported. The hardening and thickening of the external ear canals with subsequent narrowing and impaired exposure resulted in symptomatic hearing loss because of the recurrent impediment of inspissated cerumen, the removal of which finally became impossible. Surgical resection of the cartilage external ear canal and tragus was indicated to provide a more permanent treatment of conductive hearing loss. Histological examination revealed complete replacement of the fibroelastic cartilage by normal bone structures showing Haversian canals and bone marrow. The present case report is unique because of the involvement of both the auricles and external ear canals, the symptomatic hearing loss and the surgical treatment to relieve symptoms.

This article discusses biochemical screening for congenital defects. Biochemical screening remains the standard for estimating the risk of aneuploidy in pregnancy. The combination of first and second trimester markers promises to further improve diagnostic accuracy for anomaly detection.

*Corresponding author Recently, crystallization of the prion protein in a dimeric form was reported. Here we show that native soluble homogenous FLAG-tagged prion proteins from hamster, man and cattle expressed in the bac- ulovirus system are predominantly dimeric. The PrP/PrP interaction was confirmed in Semliki Forest virus-RNA transfected BHK cells co-expressing FLAG- and oligohistidine-tagged human PrP. The yeast two-hybrid system identified the octarepeat re- gion and the C-terminal structured domain (aa90- aa230) of PrP as PrP/PrP interaction domains. Addi- tional octarepeats identified in patients suffering from fCJD reduced (wtPrP versus PrP+9OR) and completely abolished (PrP+9OR versus PrP+9OR) the PrP/PrP interaction in the yeast two-hybrid sys- tem. In contrast, the Met/Val polymorphism (aa129), the GSS mutation Pro102Leu and the FFI mutation Asp178Asn did not affect PrP/PrP interactions. Proof of interactions between human or sheep and bovine PrP, and sheep and human PrP, as well as lack of in- teractions between human or bovine PrP and ham- ster PrP suggest that interspecies PrP interaction studies in the yeast two-hybrid system may serve as a rapid pre-assay to investigate species barriers in prion diseases.

Pharmaceutical companies can direct scientific agendas and scientific opinion, and their role in sustaining medical research in Canada is considerable. Apart from this, however, the methods of science may come into conflict with patient-care.Using a model of the randomized controlled trial, we describe the types of conflicts that occur between science and patient-care. Such conflicts exist at the level of recruitment, adherence, drop-outs, outcome measures, and toxicity when science clashes with patient-care. These conflicts are illustrated by references to the literature and descriptions of personal experiences. Many of these conflicts are built into study protocols, are potentially avoidable, and are independent of trial sponsorship.Those involved in clinical trials must be aware of the conflicts between patient-care and science. When such conflicts occur, patients' needs must take precedence.

When the coincidence of a limb's spatial axes and inertial eigenvectors is broken, haptic proprioception of the limb's position conforms to the eigenvectors. Additionally, when prisms break the coincidence between an arm's visual and actual positions, haptic proprioception is shifted toward the visual-spatial direction. In 3 experiments, variation of the arm's mass distribution was combined with prism adaptation to investigate the hypothesis that the proprioceptive effects of inertial and visual manipulations are additive. This hypothesis was supported across manipulations of plane of motion, body posture, proprioceptive target, and proprioceptive experience during prism adaptation. Haptic proprioception seems to depend on local, physical reference frames that are relative to the physical reference frames for the body's environmental position and orientation.

This study was performed to compare a novel three-dimensional echocardiography (3DE) system to clinical two-dimensional echocardiography (2DE) and magnetic resonance imaging (MRI) for determination of left ventricular mass (LVM) in humans. LVM is an independent predictor of cardiac morbidity and mortality. Echocardiography is the most widely used clinical method for assessment of LVM, as it is non-invasive, portable and relatively inexpensive. However, when measuring LVM, 2DE is limited by assumptions about ventricular shape which do not affect 3D echo.A total of 25 unselected patients underwent 3DE, 2DE and MRI. Three-dimensional echo used a magnetic scanhead tracker allowing unrestricted selection and combination of images from multiple acoustic windows. Mass by quantitative 2DE was assessed using seven different geometric formulas.LVM by MRI ranged from 91 to 316 g. There was excellent agreement between 3DE and MRI (r = 0.99, SEE = 6.9 g). Quantitative 2D methods correlated well with but underestimated MRI (r = 0.84-0.92) with SEEs over threefold greater (22.5-30.8 g). Interobserver variation was 7.6% for 3DE vs. 17.7% for 2DE.LVM in humans can be measured accurately, relative to MRI, by transthoracic 3D echo using magnetic tracking. Compared to 2D echo, 3D echocardiography significantly improves accuracy and reproducibility.

Two evolutionary mechanisms have been proposed in the process of protein diversification of the large family of antimicrobial toxins of Escherichia coli, known as the colicins. Data from previous studies suggest that the relatively rare nuclease colicins appear to diversify primarily through the action of positive selection, whilst the more abundant pore-former colicins appear to diversify through the action of recombination. The complete DNA sequence of the newly characterized colicin plasmid, pCol-Let, isolated from a Yanomama Indian of South America, is presented here. This plasmid encodes a newly identified pore-former colicin, colicin Y. DNA and protein sequence comparisons of the colicin Y gene cluster and the encoded proteins with those of published pore-former colicins provide the first evidence that positive selection may also act to increase pore-former colicin diversity.

Home intravenous therapy requires knowledge and understanding for successful outcomes. This article presents the ideas of attachment, guidance, and culturally sensitive nursing practice interventions when caring for patients who require home i.v. therapy. Culturally sensitive nursing interventions can increase a patient's ability to comprehend the treatment plan if they are presented in a familiar context. As trust is built, barriers to accurate communication between the nurse and the patient and family are removed, resulting in increased patient compliance and learning. Four case studies are presented to illustrate how nursing interventions use the cultural backgrounds of patients to develop culturally sensitive nursing interventions and to show how decisions are made based on information regarding cultural norms.

Arterial desaturation as measured using pulse oximetry may not reflect cardiorespiratory disease; other possible causes, including certain drugs, should be sought. Within the literature, examples exist of dapsone-induced methaemoglobinaemia causing diagnostic confusion, particularly where respiratory disease is a feature. Few cases have been reported that demonstrate the potential of relatively low levels of methaemoglobinaemia to upset pulse oximetry readings. We describe three examples of dapsone-induced methaemoglobinaemia emphasising the potential for low-grade methaemoglobinaemia to cause diagnostic confusion. Widespread use of the pulse oximeter indicates this problem may occur more regularly, hence there is a need for increased awareness.

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols. The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO(2) [35.1 (S.D. 3. 1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (V(D)/V(T)) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml. min(-1).beat(-1); exercise, 4.7 (1.4) to 16.1 (4.6) ml.min(-1). beat(-1) (P0.0001 compared with baseline); difference between peak responses: P0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.

Nitric oxide (NO) is present in exhaled breath and produced by the pulmonary vascular endothelium as a potent vasodilator. Exercise is normally associated with pulmonary vasodilatation and a decrease in pulmonary vascular resistance to accommodate the increase in cardiac output. If production of NO is impaired in patients with chronic congestive cardiac failure (CCF), this might contribute to their exercise intolerance.We quantified NO production (V NO) in 12 patients with chronic stable CCF and 12 controls, at rest and during incremental cardiopulmonary exercise on a treadmill, and at a later date during constant workload exercise.Patients had reduced V NO compared with controls during incremental exercise [381 (180) vs. 777 (275) nL min-1; mean (SD); P0.0001] but at constant workload V NO was similar between the two groups [353 (124) vs. 389 (189) nL min-1; P = 0.25]. Plasma levels of nitrate, the stable end-product of NO production, were significantly higher in patients [resting value 46.1 (21.6) vs. 23.0 (10.0) microM; P = 0.004] and were not influenced by exercise.Impaired NO-mediated pulmonary vasodilatation does not appear to contribute to exercise limitation in CCF. Alternatively, the lower NO production observed during maximal exercise in the patient group compared with controls may reflect a reduced incremental response of a system that is already abnormally activated in heart failure.

This study sought to determine the concordance between biplane and volumetric echocardiography and magnetic resonance imaging (MRI) strategies and their impact on the classification of patients according to left ventricular (LV) ejection fraction (EF) (LVEF).Transthoracic echocardiography and MRI are noninvasive imaging modalities well suited for serial evaluation of LV volume and LVEF. Despite the accuracy and reproducibility of volumetric methods, quantitative biplane methods are commonly used, as they minimize both scanning and analysis times.Thirty-five adult subjects, including 25 patients with dilated cardiomyopathies, were evaluated by biplane and volumetric (cardiac short-axis stack) cine MRI and by biplane and volumetric (three-dimensional) transthoracic echocardiography. Left ventricular volume, LVEF and LV function categories (LVEFor =55%,35% to55% andor =35%) were then determined.Biplane echocardiography underestimated LV volume with respect to the other three strategies (p0.01). There were no significant differences (p0.05) between any of the strategies for quantitative LVEF. Volumetric MRI and volumetric echocardiography differed by a single functional category for 2 patients (8%). Six to 11 patients (24% to 44%) differed when comparing biplane and volumetric methods. Ten patients (40%) changed their functional status when biplane MRI and biplane echocardiography were compared; this comparison also revealed the greatest mean absolute difference in estimates of EF for those subjects whose EF functional category had changed.Volumetric MRI and volumetric echocardiographic measures of LV volume and LVEF agree well and give similar results when used to stratify patients with dilated cardiomyopathy according to systolic function. Agreement is poor between biplane and volumetric methods and worse between biplane methods, which assigned 40% of patients to different categories according to LVEF. The choice of imaging method (volumetric or biplane) has a greater impact on the results than does the choice of imaging modality (echocardiography or MRI) when measuring LV volume and systolic function.

Nuclear respiratory factor 2 (NRF-2) has been shown to contribute to the transcriptional regulation of a number of subunits of respiratory chain enzymes, including cytochrome c oxidase (CO). Our recent study demonstrated a parallel distribution of the alpha subunit proteins of NRF-2 (NRF-2 alpha) with CO in the monkey striate cortex, and that it can be regulated by neuronal activity. To determine whether this regulation is at the transcriptional level, the present study examined the expression of NRF-2 alpha mRNA in normal and monocularly deprived adult monkeys. A partial NRF-2 alpha cDNA was isolated from a human brain cDNA library. Sequence analysis revealed that it shared 99% identity with the published sequence from human HeLa cells. Riboprobes of NRF-2 alpha was generated and labeled with digoxigenin-11-UTP for in situ hybridization. The expression pattern of NRF-2 alpha mRNA in the normal striate cortex paralleled that of CO activity. It was highly expressed in layers IVC and VI, which contained high levels of CO, and more densely expressed in puffs of layers II and III than in interpuffs. In monkeys monocularly treated with tetrodotoxin for 1 day to 2 weeks, both NRF-2 alpha expression and CO activity were reduced in deprived ocular dominance columns of the visual cortex and in deprived layers of the lateral geniculate nucleus. These data indicate that, in the normal and visually deprived adult monkeys, NRF-2 alpha is regulated by neuronal activity at the transcriptional level.

The aim of this study was to determine the mechanisms of failure of magnets used for denture retention.Magnets were retrieved from dentures that had failed after 4 to 18 months of clinical use. The magnets were sectioned and the failure modes were evaluated using optical or scanning electron microscopy.The magnetic retention system investigated consists of a neodymium-iron-boron magnet sandwiched in a stainless steel keeper, capped with a titanium dome, and sealed with epoxy resin. The diffusion of moisture through the epoxy seal and the breakdown of the encapsulating material led to corrosion of the magnet. In both cases, a loss in retention occurred as the corrosion products weakened the overall magnetic attraction.The failure of magnets may occur by either breakdown of the epoxy seal or breakdown of the encapsulating material. Both problems need to be addressed to prolong the life span of these magnets.

Molecular characterization of male and female rat liver aldehyde oxidase is reported. As described for the mouse liver, male and female rat liver expressed kinetically distinct forms of aldehyde oxidase. Our data suggest that the two forms arise as a result of differences in redox state and are most simply explained by expression of a single gene encoding aldehyde oxidase in rats. In support of this argument we have sequenced cDNAs from male and female rat liver. We examined mRNA expression by Northern blot analysis with RNA from males and females, from several tissues, and following androgen induction. Purified rat liver enzyme from males or females revealed a single 150-kDa species consistent with cDNA sequence analysis. Both male and female forms were reactive to the same carboxyl-terminal directed antisera. Km(app) values obtained in crude extracts of male or female rat liver and post-benzamidine-purified aldehyde oxidase differed substantially from each other but could be interconverted by chemical reduction with dithiothreitol or oxidation with 4,4'-dithiodipyridine. Our data indicate that a single gene is most likely expressed in male or female rat liver and that the kinetic differences between male and female rat liver aldehyde oxidases are sensitive to redox manipulation.

The authors describe the efforts involved in improving cancer screening of an underserved population using a mobile clinic to bring these services to the community. The background, methods, results, and implications are discussed, as are the logistics of packing, scheduling, and providing follow-up.Members of the University of Pittsburgh Cancer Institute Cancer Prevention and Early Detection Program developed a cancer screening program to serve the underserved communities in the Pittsburgh area. The African American Cancer Screening Program has presented the staff with significant challenges. The most significant of those challenges has been taking the most comprehensive screening program to the areas convenient to clients. Although coordinating staff, materials, and transportation was a challenge, the logistical problems involved were resolved, allowing for the opportunity to "take the show on the road".Because the mortality rate from some cancers is higher in black Americans, early cancer screening and detection is crucial in this population. The establishment of a mobile cancer screening clinic allows underserved communities access to these services. The physical screening, educational counseling, scheduling of mammographies and flexible sigmoidoscopies, and meticulous follow-up provided through the mobile clinic may lead to a greater awareness and reduced morbidity and mortality from cancer in these communities.

The purpose of this blinded study was to test the value of primary and secondary signs, independent of each other, for diagnosis of a tear of the anterior cruciate ligament (ACL) by means of MR imaging.MR images of the knee in 74 patients who had the status of the ACL confirmed arthroscopically were blindly reviewed for status of the ACL three times: with primary signs masked, with secondary signs masked, and with no signs masked. On the basis of the observed signs at each session, the status of the ACL was predicted and the confidence in that prediction was noted. The MR imaging predictions were compared with the arthroscopic findings. The results were analyzed with receiver operating characteristic curves and stepwise discriminant analysis.We found no difference in diagnostic performance when only primary signs were used and when both primary and secondary signs were used. When using primary signs only, our observers performed significantly better than when using secondary signs alone. However, with secondary signs alone, our observers performed better than if left to chance for predicting ACL status. Of the secondary signs, our statistical analysis found bone contusion, anterior translation of the tibia, and an uncovered posterior horn of the lateral meniscus to be the most useful for diagnosis.Secondary signs do have value for deciding ACL status independent of primary signs. However, our observers performed much better when using primary signs instead of secondary signs. In the clinical setting, secondary signs do not help significantly in the diagnosis of ACL tears by means of MR imaging.

Autologous stem cell transplantation increasingly is used as a treatment modality for selected hematologic and solid tumors. Autologous stem cell transplant comprises either autologous bone marrow transplant (ABMT) or peripheral blood stem cell transplant (PBSCT). ABMT and PBSCT enable patients to receive potentially lethal doses of chemotherapy or radiation therapy and rescue them with a viable source of new blood cells. Supportive measures, including blood product, growth factor, and antibiotic administration, and the expanded clinical expertise of ambulatory and home care nurses have allowed an increasing portion of this process to be performed outside of an acute care setting. The shift of care to an ambulatory or home setting will become the standard, rather than the exception, in the near future. A brief review of major implications for nurses is delineated.

Hydrogen peroxide is an effective and commonly used contact lens disinfectant that is also used as a preservative in certain ocular medications. We describe the effects of hydrogen peroxide on the cornea and anterior chamber following its topical application via a contact lens or as drops. The conditions for interaction of hydrogen peroxide with corneal and palpebral tissues and its accumulation within the aqueous humor are detailed. Values are given for thresholds at which hydrogen peroxide in specified concentrations, volumes, locations, and durations of exposure can cause ocular pain, swelling of the corneal stroma, damage to the endothelium, and penetration of the compound to the anterior chamber. The cornea and the palpebral tissues, together with the tear film, form a highly effective barrier and detoxifying system that, except under extreme, accidental circumstances, prevents both extra- and intraocular damage from use of hydrogen peroxide in contact lens care or in medications.

Chronic Fatigue Syndrome appears to represent a spectrum of disorders in which a variety of pathophysiological mechanisms may operate. While the initiating event in the majority of patients is a pyrexial illness, possibly due to enterovirus infection, evidence of persisting infection or inflammatory changes in muscle and/or brain remain unconvincing. CFS patients display a definite reduced aerobic work capacity compared to normal control subjects, but this may reflect a state of deconditioning resulting from prolonged physical inactivity. They also have an altered perception of their level of exertion and premorbid fitness. The characteristic fluctuation in symptoms, with periods of relapses and partial remissions, may indicate that some central disorder of sensory perception is operational. It may be that a primary sleep disorder results in a reduced sensory threshold for afferent stimuli from muscle. This could well account for many of the subjective symptoms which patients experience. Much more research is clearly necessary if we are to achieve a better understanding of this distressing and at present enigmatic disorder.

Existing breast self-examination (BSE) educational approaches have not been successful in gaining older women's compliance in proficient BSE. The experimental study detailed in this article was designed to determine whether there is a difference in BSE performance between women taught BSE individually using self-modeling in addition to a breast model (experimental group) and women taught BSE in a group using only a breast model (control group). Seventy-nine women, age 50 and older, randomly were assigned to the experimental and the control group. A pretest, a post-test immediately after the instruction, and a second post-test three months later involved BSE specialists observing each woman performing examinations on her own breast and on a breast model. A paired comparisons study yielded a set of weights that was used in calculating performance scores. Repeated measures analysis indicated that women in the experimental group performed BSE significantly more proficiently than women in the control group (F = 3.27, df = 2, 140, p = 0.041).

Several enzymatic and nonenzymatic reactions play important roles in the physiologic neutralization of hydrogen peroxide (H2O2) in the anterior segment of the eye. The nonenzymatic reactions are particularly important in the aqueous humor, where enzymes are normally absent and high levels of ascorbate are present. One of ascorbate's presumed functions is to protect the lens and retina from the damaging effects of ultraviolet radiation. It also appears to act as an antioxidant for the removal of H2O2. Although H2O2 is frequently a product of antioxidant reactions, the low oxygen tension of the aqueous humor and the absence of trace elements apparently account for the relatively low concentrations of H2O2. This property of aqueous humor is important because high concentrations of H2O2 are toxic to both the lens and the cornea. This damage is exacerbated by the removal of glucose or by inhibition of glutathione reductase--an indication of the importance of the glutathione redox cycle in protecting against endothelial damage induced by H2O2. Catalase also protects the tissues bordering the anterior chamber from H2O2-induced damage. Decreasing catalase activity by treatment with 3-aminotriazole increases the time required for H2O2 clearance from the anterior chamber, thereby allowing more time for H2O2 to produce damage. A decline of catalase activity with age has been observed in the iris and corneal endothelium of rabbits.