Diurnal blood pressure and urine production in acute spinal cord injury compared with controls.

STUDY DESIGN: This is a prospective observational study. OBJECTIVES: The objective of this study was to determine time-dependent changes in diurnal blood pressure (BP) and urine production in acute spinal cord injury (SCI). SETTING: This study was conducted in a specialist, state-based spinal cord service in Victoria, Australia. METHODS: Consenting patients admitted consecutively with acute SCI were compared with patients confined to bed rest while awaiting surgery and with mobilising able-bodied controls. Participants underwent ambulatory BP monitoring (ABPM), measurement of diurnal urine production and rated orthostatic symptoms over 1 year. Participants with night:day systolic BP (SBP) <90% were classified as dippers, 90-100% as non-dippers and >100% as reverse dippers. RESULTS: Participants comprised tetraplegics (n=47, 40.0±17.3 years), paraplegics (n=35, 34.4±13.9 years), immobilised (n=18, 30.9±11.3 years) and mobilising (n=44, 33.1±13.5 years) controls. At baseline, 24-h BP was significantly lower in tetraplegics (111.8±1.9/62.1±1.1 mm Hg) but not in paraplegics (116.7± 1.4/66.0±1.1 mm Hg), compared with controls (117.1 ±1.3/69.1±1.1 mm Hg), adjusting for gender. This difference was not observed at 1 year. The average night:day SBP in mobilising controls was 86.1±0.7%, differing from paraplegics (94.0±1.5%, P<0.001) and tetraplegics (101.5±1.5%, P<0.001). Urine production in tetraplegics and paraplegics did not fall at night compared with the day. Abnormal diurnal BP and orthostatic symptoms in tetraplegics persisted throughout the study. Nocturnal hypertension was observed in 27% (n=9) of tetraplegics, of whom only 2 had day hypertension. All mobilising controls with nocturnal hypertension (n=6, 14%) had day hypertension. CONCLUSION: People with SCI have a high prevalence of isolated nocturnal hypertension, reverse dipping, orthostatic intolerance and nocturnal polyuria. Cardiovascular risk management and assessment of orthostatic symptoms should include ABPM.

A retrospective review of the ambulatory blood pressure patterns and diurnal urine production in subgroups of spinal cord injured patients.

STUDY DESIGN: Retrospective study. OBJECTIVES: To quantify diurnal blood pressure (BP) patterns and nocturnal hypertension and to measure diurnal urine production in spinal cord injury (SCI) patients with clinically significant disorders of BP control. SETTING: A specialist state-based spinal cord service in Victoria, Australia. METHODS: Medical records of patients with traumatic SCI who were referred to a specialist service for management of a BP disorder were examined. Ambulatory BP and nocturnal urine production were compared between groups of patients classified according to level, completeness and chronicity of SCI. Patients with night:day systolic BP <90% were classified as dippers, 90-100% as non-dippers and >100% as reversed dippers. RESULTS: Patients (44 tetraplegic, 10 paraplegic) were predominantly males (92.6%) aged 41±2.5 years (mean±s.e.m.). Referral was for orthostatic intolerance (n=37), autonomic dysreflexia (n=6), nocturnal polyuria (n=4), elevated BP (n=1) and peripheral oedema (n=1). The average BP was 111.1±1.4/65.0±1.2 mm Hg. In 56% of patients (n=30), BP at night was higher than during the day and another 37% (n=20) were non-dippers. Nocturnal hypertension was present in 31% (n=17) of the patients. In the tetraplegic patients, urine flow rate was greater during the night than day (121±9.5 ml h(-1) vs 89±8.2 ml h(-1), P=0.025). CONCLUSION: Ambulatory BP monitoring in patients with SCI and clinically significant BP disorders detected a high incidence of reversed dipping and nocturnal hypertension. We postulate elevated nocturnal BP may contribute to nocturnal diuresis that might cause relative volume depletion and thereby contribute to daytime orthostatic hypotension.

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers.

STUDY DESIGN: Single centre, single ascending dose study. OBJECTIVES: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. SETTING: Local population from Victoria, Australia. METHODS: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. RESULTS: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0-∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. CONCLUSION: Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.

A preliminary study of mental and physical practice on the kayak wet exit skill.

Outdoor activities and high-risk water sports often create anxiety in participants who feel concern about danger. Relaxation and imagery, often used to enhance training, can improve performance of skills in a variety of sports. The aim of this study was to establish whether Mental Practice, Physical Practice, Combined Mental and Physical Practice, or No Practice would affect the acquisition of skill for a kayak wet exit. 60 postprimary girls aged 11-16 yr., competent swimmers but without previous experience in kayaking, gave their informed consent to be in the study. Each participant was randomly assigned to one of the four experimental groups. Following their practice periods, each group performed three kayak wet exit attempts (unseen by others); these were videotaped for later analysis by an observer. The participant and an independent observer, who was blind to the allocation of practice group, then used a 6-point rating scale to assess each performance. Participants' and the observer's ratings were analysed by separate Kruskal-Wallis one-way analysis of variance which indicated a significant practice effect. Subsequent chi-squared tests indicated significantly different distributions of groups, showing Physical Practice superior to No Practice and Mental Practice. While physical practice remained effective in improving technique, combinations of mental and physical practice were better than no practice.

Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis.

It is not known if a surgical lung biopsy is necessary in all patients for the diagnosis of idiopathic pulmonary fibrosis (IPF). We conducted a blinded, prospective study at eight referring centers. Initially, cases were evaluated by clinical history and examination, transbronchial biopsy, and high-resolution lung computed tomography scans. Pulmonologists at the referring centers then assessed their certainty of the diagnosis of IPF and provided an overall diagnosis, before surgical lung biopsy. The lung biopsies were reviewed by a pathology core and 54 of 91 patients received a pathologic diagnosis of IPF. The positive predictive value of a confident (certain) clinical diagnosis of IPF by the referring centers was 80%. The positive predictive value of a confident clinical diagnosis was higher, when the cases were reviewed by a core of pulmonologists (87%) or radiologists (96%). Lung biopsy was most important for diagnosis in those patients with an uncertain diagnosis and those thought unlikely to have IPF. These studies suggest that clinical and radiologic data that result in a confident diagnosis of IPF by an experienced pulmonologist or radiologist are sufficient to obviate the need for a lung biopsy. Lung biopsy is most helpful when clinical and radiologic data result in an uncertain diagnosis or when patients are thought not to have IPF.

Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.

Telomerase activation is a common feature of advanced human cancers and facilitates the malignant transformation of cultured human cells and in mice. These experimental observations are in accord with the presence of robust telomerase activity in more advanced stages of human colorectal carcinogenesis. However, the occurrence of colon carcinomas in telomerase RNA (Terc)-null, p53-mutant mice has revealed complex interactions between telomere dynamics, checkpoint responses and carcinogenesis. We therefore sought to determine whether telomere dysfunction exerts differential effects on cancer initiation versus progression of mouse and human intestinal neoplasia. In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas. That telomere dysfunction also contributes to human colorectal carcinogenesis is supported by the appearance of anaphase bridges (a correlate of telomere dysfunction) at the adenoma-early carcinoma transition, a transition recognized for marked chromosomal instability. Together, these data are consistent with a model in which telomere dysfunction promotes the chromosomal instability that drives early carcinogenesis, while telomerase activation restores genomic stability to a level permissive for tumor progression. We propose that early and transient telomere dysfunction is a major mechanism underlying chromosomal instability of human cancer.

Development and dissemination of minimum standards of care for asthma.

Asthma is a common illness in children and adults that is often associated with suboptimal outcomes, despite the existence and distribution of carefully considered national and international guidelines for diagnosis and treatment. The need to improve asthma care in North Texas motivated a coalition of health plans, employers, hospitals, academic medical centers, providers, and benefit consultants to collaborate in developing and implementing Minimum Standards of Care for Asthma. To gain consensus, the North Central Texas HEDIS Coalition used a panel of regional asthma experts and surveyed a large number of primary-care providers to construct a one-page document that was ultimately approved by regional stakeholders in healthcare participating in this coalition and also by specialty organizations in Texas. Adopting a minimum standard guideline, developed and supported by multiple stakeholders, may represent a more realistic intermediate goal when implementing "best practice" guidelines is limited by practical barriers.

Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion.

To explain the very high frequency of cystic fibrosis (CF) mutations in most populations of European descent, it has been proposed that CF heterozygotes have a survival advantage when infected with Vibrio cholerae or Escherichia coli, the toxins of which induce diarrhea by stimulation of active intestinal chloride secretion. Two assumptions underlie this hypothesis: (1) chloride conductance by the CF transmembrane conductance regulator (CFTR) is the rate-limiting step for active intestinal chloride secretion at all levels of expression, from approximately zero in patients with CF to normal levels in people who are not carriers of a mutation; and (2) heterozygotes have smaller amounts of functional intestinal CFTR than do people who are not carriers, and heterozygotes therefore secrete less chloride when exposed to secretagogues. The authors used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analogue. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less-than-normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results do not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal illnesses mediated by intestinal hypersecretion of chloride.

Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery.

Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR(-/-) mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of "telomerase therapy" for such diseases.

Impact of the national asthma guidelines on internal medicine primary care and specialty practice.

OBJECTIVE: To evaluate documentation of compliance with the National Asthma Education and Prevention Program publication Guidelines for the Diagnosis and Management of Asthma. DESIGN: A retrospective review of 114 charts coded as asthma. Fourteen chart evaluation questions were developed based on the 4 management components in the guidelines: assessment and monitoring of asthma, control of asthma factors, pharmacotherapy, and patient education. SETTING: A hospital-based asthma clinic, a private pulmonary group, and a general internal medicine group in Dallas, Texas. RESULTS: Nearly all physicians documented inquiries about daytime asthma symptoms, but only 64% of pulmonary group and 58% of internal medicine physicians documented inquiries about nighttime symptoms. In addition, in 14% of pulmonary group charts and 74% of internal medicine charts, no spirometry or peak flow data were documented. Most asthma clinic and pulmonary group charts (98% and 78%, respectively) included a history of triggers, but the pulmonary group and internal medicine group were more likely to document administration of the influenza vaccine than the asthma clinic (25% and 26% vs 13%). Of 38 patients with > or = 1 recorded forced expiratory volume in 1 second <60%, all but 1 were on inhaled steroids. However, many charts lacked adequate documentation to match drug selection to asthma severity. The asthma clinic group documented the 4 educational interventions 65% to 83% of the time, compared with the pulmonary group, at 17% to 50%, and the internal medicine group, at 5% to 18%. CONCLUSIONS: Results showed significant variation with the recommendations. Areas in particular need of improvement were objective diagnosis and assessment, control of asthma-associated factors, and patient education. Furthermore, the study demonstrated significant variation between specialists and primary care physicians, with the more specialized clinics demonstrating better guideline compliance.

School-based management of chronic asthma among inner-city African-American schoolchildren in Dallas, Texas.

Asthma, a chronic disease of the respiratory tract, affects approximately five percent of the U.S. population, including almost five million children. Childhood asthma has been identified as the leading cause of school absences. This study was to examined efficacy of a school-based program to prevent exacerbation of asthma symptoms and manage asthma in school children using measured doses of an inhaled anti-inflammatory medication. The sample consisted of 22 African-American children in one inner-city elementary school in Dallas, Texas, ages 5-12 years with confirmed diagnoses of asthma. For three months, each child came to the school clinic two times per day for medication administration and measurement of respiratory peak flow rates. Data were collected for a number of variables including bronchodilator use, school absences, self-report of asthma symptoms, and number of visits to the physician. During the study, mean peak flow rates improved approximately 15%, and bronchodilator use decreased 66%. Improvement also was evident in several other areas.

X-ray photoelectron spectroscopy surface analysis of aluminum ion stress in barley roots.

X-ray photoelectron spectroscopy (XPS) has been used to analyze root surface changes when Dayton barley (Hordeum vulgare) (Al tolerant) and Kearney barley (Al sensitive) seedlings were grown in nutrient solution in the presence and absence of 37.0 micromolar Al. The electron spectra from root surfaces contained strong lines in order of decreasing intensity from organic forms of carbon, oxygen, and nitrogen and weak lines due to inorganic elements in the form of anions and cations on the surface. The surface composition of root tips from Kearney was C, 65.6%; 0, 26.8%; N, 4.4% and tips from Dayton was C, 72.7%; O, 23.6%; N, 1.9%, grown in the absence of aluminum. Electron lines characteristic of nitrate, potassium, chloride, phosphate were also present in the spectra from those roots. Dayton roots grown in the presence of 37.0 micromolar aluminum contained 2.1% aluminum while Kearney contained 1.3% aluminum. The ratio of aluminum to phosphate was close to 1.0. Dayton roots usually contained twice as much aluminum phosphate in the surface region as Kearney. Dayton may be less susceptible to Al toxic effects by accumulation of aluminum phosphate on the root surface which then acts as a barrier to the transport of aluminum into the interior of the roots.

Isolation of highly purified fractions of plasma membrane and tonoplast from the same homogenate of soybean hypocotyls by free-flow electrophoresis.

A procedure is described whereby highly purified fractions of plasma membrane and tonoplast were isolated from hypocotyls of dark-grown soybean (Glycine max L. var Wayne) by the technique of preparative free-flow electrophoresis. Fractions migrating the slowest toward the anode were enriched in thick (10 nanometers) membranes identified as plasma membranes based on ability to bind N-1-naphthylphthalamic acid (NPA), glucan synthetase-II, and K(+)-stimulated, vanadate-inhibited Mg(2+) ATPase, reaction with phosphotungstic acid at low pH on electron microscope sections, and morphological evaluations. Fractions migrating farthest toward the anode (farthest from the point of sample injection) were enriched in membrane vesicles with thick (7-9 nanometers) membranes that did not stain with phosphotungstic acid at low pH, contained a nitrate-inhibited, Cl-stimulated ATPase and had the in situ morphological characteristics of tonoplast including the presence of flocculent contents. These vesicles neither bound NPA nor contained levels of glucan synthetase II above background. Other membranous cell components such as dictyosomes (fucosyltransferase, latent nucleosidediphosphate phosphatase), endoplasmic reticulum vesicles (NADH- and NADPH- cytochrome c reductase), mitochondria (succinate-2(p-indophenyl)-3-p-nitrophenyl)-5-phenyl tetrazolium-reductase and cytochrome oxidase) and plastids (carotenoids and monogalactosyl diglyceride synthetase) were identified on the basis of appropriate marker constituents and, except for plastid thylakoids, had thin (<7 nanometers) membranes. They were located in the fractions intermediate between plasma membrane and tonoplast after free-flow electrophoretic separation and did not contaminate either the plasma membrane or the tonoplast fraction as determined from marker activities. From electron microscope morphometry (using both membrane measurements and staining with phosphotungstic acid at low pH) and analysis of marker enzymes, both plasma membrane and tonoplast fractions were estimated to be about 90% pure. Neither fraction appeared to be contaminated by the other by more than 3%.

Inhibition of mouse embryo cleavage by a factor present in the human preovulatory follicular fluid.

Human follicular fluids (hFF) inhibited the in vitro cleavage of mouse embryo and fertilized oocytes. This inhibitory effect occurred at all stages of embryonal development and was reversible at low concentrations of FF. Gel chromatography of FF revealed inhibitory activity in two fractions, corresponding to mol wt of 20,000 and 50,000 daltons. This factor(s) might contain peptide components, since it was activated by heat treatment and trypsin digestion. In spontaneous cycles, late follicular phase hFF had significantly higher inhibitory activity than early follicular phase hFF. There was no significant difference in inhibitory activity of hFF aspirated from patients treated with clomiphene citrate alone, a combination of clomiphene citrate and gonadotropins, or gonadotropins alone. There was a positive correlation between hFF inhibitory activity and hFF estradiol and a negative correlation with progesterone in individual FF samples. These findings suggest that the hFF inhibitory activity of mouse embryo cleavage correlates with the differentiation state of the granulosa cells.

Giant invasive cholesteatoma. Report of a case with cerebellar invasion.

We present a case of epidermoid cholesteatoma that killed the patient by relentless invasion, despite radical surgery. An autopsy disclosed a focus of dural and cerebellar invasion, which dramatized the aggressive nature of this disease. In fact, the epithelial cells of this disease are not thought to possess the ability to invade. Instead, inflammation is believed to both stimulate the squamous epithelial cells to proliferate and destroy adjacent tissues, thereby providing a pathway for epithelial cell migration. Epidermoid cholesteatoma, then, is a disease in which the processes of inflammation and hyperplasia combine to mimic a neoplasm.

XPS analysis of 316 LVM corroded in serum and saline.

Surface chemical analysis by x-ray photoelectron spectroscopy (XPS) was undertaken on 316 LVM stainless steel in the attempt to better understand corrosion occurring in vivo. Samples were dipped in saline or in blood serum, corroded in serum or saline by the application of a 5 volt anodic potential, or corroded by fretting. The products produced by fretting corrosion were also examined. XPS analysis revealed rapid protein coating of the stainless steel surfaces exposed to serum, changes in the oxidation state of the surfaces, and changes in the chlorine on the surface. In addition it was demonstrated that the corrosion products generated by fretting in saline had an oxidation state similar to that of chronic chloride whereas the corrosion products generated in serum had an oxidation state similar to that of potassium dichromate. These findings may have important implications since the chromium in dichromate is more biologically active than that in chronic chloride.