NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD.

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported ('Form A') and 8 patient-reported ('Form B') response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

What's in a label? An exploratory study of patient-centered drug instructions.

OBJECTIVE: To assess the efficacy of patient-centered label (PCL) instructions on the knowledge and comprehension of prescription drug use compared to standard instructions. METHODS: A total of 94 participants recruited from an outpatient clinic in Ireland were each randomly assigned to receive: (1) standard prescription instructions written as times per day (usual care), (2) PCL instructions that specify explicit timing with standard intervals (morning, noon, evening, bedtime) or with mealtime anchors (both PCL), or (3) PCL instructions with a graphic aid to visually depict dose and timing of the medication (PCL + Graphic). The outcome was correct interpretation of the instructions. RESULTS: PCL instructions were more likely to be correctly interpreted than the standard instructions [adjusted relative risk (RR) 1.08, 95% confidence interval (CI) 0.98-1.18]. The inclusion of the graphic aid (PCL + Graphic) decreased the rates of correct interpretation compared to PCL instructions alone (RR 0.98, 95% CI 0.91-1.05). There was a significant interaction between instruction type and health literacy (p = 0.01). Those with limited health literacy were more likely to correctly interpret the PCL labels (91%) than the standard labels (66%), and those with adequate health literacy performed equally well. CONCLUSION: The PCL approach may improve patients' understanding and use of their medication regimen.

HOpe for contrast-induced acute kidney injury.

Contrast-induced nephropathy (CIN) is a common cause of acute kidney injury in hospitalized patients. The mechanisms involved in the pathogenesis of CIN are incompletely understood. Goodman et al. have demonstrated for the first time that heme oxygenase-1, a 32-kilodalton protein with antioxidant, antiapoptotic, anti-inflammatory effects, is induced in the kidney and, importantly, provides a beneficial effect in CIN.

Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis.

Heme oxygenase-1 (HO-1) is a 32-kDa microsomal enzyme that catalyzes the conversion of heme to biliverdin, releasing iron and carbon monoxide. Induction of HO-1 occurs as a protective response in cells/tissues exposed to a wide variety of oxidant stimuli. The chemotherapeutic effects of cis-diamminedichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limited by significant nephrotoxicity, which is characterized by varying degrees of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induced renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (-/-), develop more severe renal failure and have significantly greater renal injury compared with wild-type (+/+) mice treated with cisplatin. In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition of HO-1 enzyme activity reversed the cytoprotective effect. Overexpression of HO-1 resulted in a significant reduction in cisplatin-induced cytotoxicity. These studies provide a basis for future studies using targeted gene expression of HO-1 as a therapeutic and preventive modality in high-risk settings of acute renal failure.

Distribution of Na,K-ATPase is normal in the inner ear of a mouse with a null mutation of the glucocorticoid receptor.

This study was performed in order to test the hypothesis that the glucocorticoid hormone stimulates the formation of Na,K-ATPase in the inner ear of the mouse. An immunohistochemical study with respect to the presence and distribution of glucocorticoid receptors (GR) and Na,K-ATPase in the vestibular and cochlear regions of the inner ear was performed on a C57BL mouse with a null mutation of the glucocorticoid receptor (GR mutant mouse). The wild type C57BL mouse and the CBA mouse served as normal controls. As expected, the homozygous GR mutant mouse showed no specific staining for GR in the inner ear. The heterozygous GR mutant mouse showed faint staining of GR in the spiral limbus, the spiral ganglion, the organ of Corti and the utricle. This staining was markedly less than in the wild type C57BL mouse. Antibody labelling of Na,K-ATPase in the inner ear showed no significant difference between the homozygous and the heterozygous GR mutant mouse as compared to the control wild type C57BL mouse or the CBA mouse. Although earlier studies have shown a positive correlation between levels of glucocorticoid hormone in serum and the concentration of Na,K-ATPase in the inner ear, the hypothesis that glucocorticoid hormones alone stimulate the formation of Na,K-ATPase in the inner ear could not be confirmed by this study. Thus other regulating substances must be considered.

Development of thermal inactivation models for Salmonella enteritidis and Escherichia coli O157:H7 with temperature, pH and NaCl as controlling factors.

The thermal inactivation of Salmonella enteritidis phage type 4 and Escherichia coli O157:H7 as affected by temperature (54.5-64.5 degrees C), pH (4.2-9.6 with HCl or NaOH) and NaCl concentration (0.5-8.5% w/w) was studied. Cell suspensions in modified tryptone soya broth were heated in a submerged-coil heating apparatus and survivors were enumerated on tryptone soya agar incubated aerobically. For most thermal inactivation data there was a logarithmic decrease in the viable cell concentration over the initial 4-6 log10 reduction and D-values were fitted. In some cases, tailing of the survivor curves was observed with cells surviving longer than the D-values predicted. Models describing the effect of temperature, pH and NaCl concentration on the thermal inactivation of S. enteritidis and E. coli O157:H7 were produced. For both organisms, predicted z-values of 4.6-7.0 C degrees were obtained depending on conditions, with larger z-values at higher levels of NaCl. Optimum survival occurred between pH 5 and pH 7 and increasing acidity or alkalinity caused a decrease in the predicted D-values. At equivalent pH, acetic acid and lactic acid (at 0.5, 1 and 2% w/w) generally had a similar, or increased, lethal effect compared with HCl, whereas in most cases citric acid had a less lethal effect. For E. coli O157:H7, increasing NaCl concentration had a protective effect up to the maximum tested (8.5% w/w), while for S. enteritidis optimal survival at a NaCl concentration of 5-7% w/w was predicted. The models were validated in foods by comparing predictions with published data. Most (80%) of the predicted D-values from the S. enteritidis model were within the 95% confidence interval (within 2.45-fold of the published data) for different Salmonella serotypes in whole egg, egg albumen, egg yolk, beef and milk. Most (93%) of the predicted D-values from the E. coli O157:H7 model were larger than the limited published data for this organism in meat, poultry, milk and apple juice with 42% within the 95% confidence interval (within 2.05-fold of the published data). The D-value models were incorporated into Version 1, and subsequent versions, of the predictive microbiology software program, Food MicroModel.

Ca(2+)-ATPases in the cochlear duct.

Differing levels of the Ca(2+)-ATPase enzymes that reside on the plasma membrane (PM) and on the endoplasmic reticulum (ER) were identified in individual rat cochlear tissues by the use of a semi-quantitative enzyme-linked immunosorbent assay (ELISA). Unlike other studies, a specific antibody to PM Ca(2+)-ATPase was used to detect significantly greater levels (about 2x) of PM Ca(2+)-ATPase in the stria vascularis (SV) than that in the spiral ligament (SL) and organ of Corti (OC) tissues. Similarly, levels of ER Ca(2+)-ATPase were also significantly higher in the SV than in the SL and OC tissues. The presence of ER Ca(2+)-ATPase in the tissues of the SV has not been demonstrated previously. Given the importance of Ca2+ homeostasis in the inner ear, the statistically significantly higher densities of both PM and ER Ca(2+)-ATPase measured in the SV relative to the SL and OC regions would indicate tissue-specific responses to fluctuations in systemic and local Ca2+ concentrations.

Electrochemical potentials and potassium concentration profiles recorded from perilymph, endolymph and associated inner ear tissues in adrenalectomized rats.

This study evaluated the electrochemical potentials and potassium concentration (Ck+) profiles in the perilymph, endolymph, marginal cells, and spiral ligament of adrenalectomized rats in which endogenous corticosteroids had been removed. Electrochemical potentials recorded at the four cochlear sites were not affected by adrenalectomy (ADX). Ck+ was greater in the endolymph of the ADX animals as compared to control animals. Additionally, there was an increase of Ck+ in the marginal cells, perilymph, and spiral ligament tissues of the ADX animals as compared to control animals, although the observed increases were not statistically significant. In a previous study (Ma et al., 1995a), it was found that potassium levels in the blood plasma of ADX animals were higher than those identified in normal rats; thus, ADX may have a systemic effect on Ck+ that is detectable in both tissues and fluids within the cochlea. Even though Ck+ was elevated within the cochlea in the ADX model, the functional response of the inner ear, as assessed electrophysiologically, was not altered.

Receptors for glucocorticoids in the human inner ear.

Glucocorticoid receptors were detected in the human inner ear. The highest concentration of glucocorticoid receptor protein was measured by enzyme-linked immunosorbent assay in the spiral ligament tissues; the lowest concentration of glucocorticoid receptors was measured in the macula of the saccule. The demonstration of the presence of glucocorticoid receptors in human Inner ear tissues provides a basis to consider the direct effects of glucocorticoid action on select inner ear cells, rather than assuming a systemic antiinflammatory or immunosuppressive effect during the therapeutic treatment of patients with given inner ear disorders.

In situ real-time sequential potentiometric determinations of potassium concentrations from three cochlear regions in noise-exposed rats.

Double-barrelled potassium selective microelectrodes (K-ISME) were used in situ for real-time sequential determinations of potassium concentrations (CK+) in endolymph, marginal cells and the spiral ligaments of rats exposed to moderate noise at 100 dB for 30 min (NE) and control (CTL) animals. CK+ in NE animals at these sites did not differ significantly when compared to CK+ in CTL animals. However, there was a slight decrease in CK+ in marginal cells in the noise-exposed animals.

Effect of stress on cochlear glucocorticoid protein. II. Restraint.

The effect of restraint stress via immobilization on rat cochlear glucocorticoid receptor (GR) levels was determined using an enzyme-linked immunosorbent assay (ELISA). Results demonstrated that GR levels in cochlear tissues exhibited tissue-specific and time-dependent responses to immobilization (6 hours daily). Similar responses of the GR were observed in rats restrained during two different times of the day. A significant quadratic trend (P = 0.019, R2 = 0.58) was observed in levels of GR in spiral ligament tissues of rats restrained from 10:00 to 16:00 h; levels of GR were elevated by day 2, and by day 21 GR levels had returned to near normal levels. GR levels in the spiral ligament tissues also were found to increase significantly after 2 days in response to repeated restraint stress administered from 06:00 to 12:00 h (P = 0.017, R2 = 0.34). Interestingly, a subtle, but statistically significant, decreasing trend in the organ of Corti's GR levels was detected when the daily restraint stress was applied from 06:00 to 12:00 h for up to 7 days. No significant trends (P > 0.05) were observed in GR levels of stria vascularis tissues regardless of the time of day of the restraint protocol. Stress has been implicated as an etiological factor in Ménière's disease and other ear pathologies. The data presented here indicate that the effect of stress is specific to tissue region and that, as in tissues of other systems, the GR of cochlear tissues are responsive to stress.

Combined effects of adrenalectomy and noise exposure on compound action potentials, endocochlear potentials and endolymphatic potassium concentrations.

The effects of removal of endogenous corticosteroids via bilateral adrenalectomy in combination with noise exposure (30 min at 100 dB) were determined by recording compound action potential (CAP) and endocochlear potentials (EP), and by measuring potassium concentrations (K+e) within the endolymph. Thirty-eight Long-Evans rats were divided into groups according to experimental treatments: adrenalectomy (ADX) or non-ADX and noise exposure or non-noise exposure. CAP thresholds, EP and K+e values were subjected to repeated-measures analysis of variance with group and time as factors classifying the measurements. Noise exposure resulted in significant elevations of CAP thresholds in both the ADX and non-ADX animals, but had no effect on either EP or endolymphatic K+e. Recovery was noted during all post-exposure measurement periods and was significantly faster for ADX animals. EP and K+e did not change during or after noise exposure. ADX animals showed a non-significant reduction of EP and a statistically significant increase of K+e during all measurement periods as compared to non-ADX animals.

Survival of Campylobacter jejuni in foods and comparison with a predictive model.

Campylobacter jejuni was inoculated into a range of raw and cooked foods and survival determined during storage at 2 degrees, 10 degrees and 20 degrees C for up to 56 d. To facilitate easy enumeration, two antibiotic-resistant strains of Camp. jejuni, which had similar survival characteristics to the parent strain, were used. Campylobacter jejuni survived for longer at lower temperatures in all foods and inactivation was most rapid in pâté. There was generally good agreement between the survival data and predictions from a Camp. jejuni survival model (Food MicroModel).

Expression of Na, K-ATPase alpha and beta isoforms in the neonatal rat cochlea.

The postnatal expression of five Na, K-ATPase alpha (alpha 1, alpha 2, alpha 3) and beta (beta 1, beta 2) subunit isoforms in the rat cochlea was investigated by immunocytochemistry. High levels of expression of the alpha 1 and beta 2 isoforms were observed in stria vascularis (SV) at all developmental stages. alpha 1 and beta 1 isoforms showed a distinct time-dependent developmental expression pattern in tissues of the spiral ligament (SL) and spiral limbus (SLi). Limited, temporary expression of alpha 2 and alpha 3 subunit isoforms were found in SV and SL. Expression of each isoform was also seen in organ of Corti (OC), spiral ganglion (SG), cochlear nerve (CN) and Kölliker's Organ (KO). These observations suggest that individual isoforms may exert specific actions postnatally during final cochlear maturation.

Glucocorticoid receptor expression in the postnatal rat cochlea.

The glucocorticoid receptor (GR) expression in the neonatal rat cochlea was investigated by utilization of a polyclonal antibody against GR, the immunoreactivity of which exhibited a distinct, age-dependent developmental pattern in tissues of the spiral ligament (SL). Immunostaining of GR appeared initially at the 7th postnatal day (PND), increased rapidly between the 14th and 21st PND, and reached adult-like expression levels by the 21st PND. Less pronounced, developmentally regulated expression patterns of GR were observed in cells of the spiral limbus (SLi), spiral ganglion (SG), organ of Corti (OC), and cochlear nerve (CN). For example, high expression levels of GR were observed in the SLi, SG and OC at 3 PND; subsequently, GR immunoreactivity levels decreased from 7 to 14 PND, and then GR immunoreactivity intensified in these regions by 21 PND. No remarkable changes in GR expression were observed in stria vascularis (SV). These data indicate that GR expression in the inner ear is tissue and age-specific, and that GR expression parallels both Na,K-ATPase expression and endocochlear potential development.

De novo synthesis of glucocorticoid hormone regulated inner ear proteins in rats.

Changes of rat inner ear de novo protein synthesis in response to dexamethasone (DEX), a synthetic glucocorticoid, have been analyzed by high resolution two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D-SDS-PAGE) and fluorography. Two proteins (M(r) 41,000 and 35,000) were amplified and one protein (M(r) 47,000) was suppressed by DEX in a cochlear culture medium. In the culture medium conditioned by vestibular tissue, three proteins (M(r) 67,000, 57,000 and 50,000) were amplified after DEX administration. In cochlear and vestibular tissues, glucocorticoid-responsive protein synthesis was down-regulated by DEX, including two proteins (M(r) 39,000 and 35,000) in the cochlea and five proteins (M(r) 80,000, 64,000, 59,000, 56,000 and 40,000) in the vestibule. The regulation of these inner ear proteins by DEX suggests that glucocorticoid may play an important role in normal inner ear microhomeostasis, as well as in the treatment of some inner ear disorders.

When do physician recruitment arrangements affect a hospital's tax-exempt status?--revisited.

Physician recruitment incentives by hospitals continue to be popular in today's competitive health-care environment. A physician in private practice may also seek a hospital's assistance in recruiting a new colleague. In Conn Med 1989; 10:605-6, the authors discussed the prohibitions against private benefit and private inurement and their effect on recruitment packages. This article highlights new developments and Medicare/Medicaid fraud and abuse issues which may affect a tax-exempt hospital's status and, therefore, will dictate many of the terms of these packages.

Effect of stress on cochlear glucocorticoid protein: acoustic stress.

Levels of glucocorticoid (GR) receptor protein were determined by a quantitative enzyme-linked immunosorbent assay (ELISA) technique in inner ear tissue of rats exposed daily to 85 dB SPL white noise for 4 hours on 3 consecutive days. GR levels in spiral ligament and organ of Corti tissues were detected using a monoclonal antibody to the GR receptor, BuGR2. A non-significant 13% decrease in GR levels of spiral ligament tissues was observed in the noise exposed animals relative to untreated animals. A statistically significant decrease of 27% in GR protein levels was seen in the organ of Corti region (P < 0.03), however. There was a concomitant increase of serum corticosterone levels (P < 0.03) in noise exposed animals as opposed to those of controls. These results indicate a tissue specific response of GR receptor to acoustic stress. Inner ear GR protein therefore may be a useful marker in determining the effect of stress on the inner ear. Finally, such data may be applicable to support the hypothesis that stress is an etiological agent in Ménière's disease.

Expression of Na+,K(+)-ATPase alpha 1 subunit mRNA in the developing rat cochlea.

The distribution of Na+,K(+)-ATPase alpha 1 subunit mRNA was identified using in situ hybridization in the developing rat cochlea. The expression of alpha 1 subunit mRNA in stria vascularis (SV) was observed in all time points studied, 1 to 30 postnatal day (pnd) rats. The adult expression level was attained between 11 to 14 pnd. Surprisingly, alpha 1 subunit mRNA in spiral ligament (SL) and spiral limbus (SLi) was expressed in a more distinct time-dependent manner. At 7 pnd, the alpha 1 subunit mRNA expression was observed initially in the tissues of the SL. At 11 pnd, alpha 1 subunit expression appeared in SLi. Between 11 and 14 pnd, an adult-like pattern of Na+,K(+)-ATPase alpha 1 subunit mRNA expression was attained in the SL and SLi. These data suggest that the expression of Na+,K(+)-ATPase alpha 1 subunit mRNA in these areas are closely related to the development of the rat EP, as its expression in the stria vascularis.