Henry Ford Hospital

Journal of Bone and Mineral ResearchVolume 2, Issue 6 p. 595-610 Article Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee A. Michael Parfitt M.D., Corresponding Author A. Michael Parfitt M.D. Chairman Bone and Mineral Research Laboratory, Department of Medicine, Henry Ford Hospital, Detroit, MIBone and Mineral Research Laboratory Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202Search for more papers by this authorMarc K. Drezner, Marc K. Drezner Bone and Mineral Metabolism Section, Division of Metabolism, Endocrinology and Genetics, Department of Medicine, Duke University Medical Center, Durham, NCSearch for more papers by this authorFrancis H. Glorieux, Francis H. Glorieux Genetics Unit, Shriners Hospital for Crippled Children, Montreal, Quebec, CanadaSearch for more papers by this authorJohn A. Kanis, John A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, UKSearch for more papers by this authorHartmut Malluche, Hartmut Malluche Department of Medicine, Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky College of Medicine, Lexington, KTSearch for more papers by this authorPierre J. Meunier, Pierre J. Meunier INSERM Unit 234, Faculte Alexis Carrel, Lyon, FranceSearch for more papers by this authorSusan M. Ott, Susan M. Ott Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WASearch for more papers by this authorRobert R. Recker, Robert R. Recker Metabolic Research Unit, Department of Internal Medicine, Creighton University School of Medicine, Omaha, NBSearch for more papers by this author A. Michael Parfitt M.D., Corresponding Author A. Michael Parfitt M.D. Chairman Bone and Mineral Research Laboratory, Department of Medicine, Henry Ford Hospital, Detroit, MIBone and Mineral Research Laboratory Henry Ford Hospital 2799 West Grand Boulevard Detroit, MI 48202Search for more papers by this authorMarc K. Drezner, Marc K. Drezner Bone and Mineral Metabolism Section, Division of Metabolism, Endocrinology and Genetics, Department of Medicine, Duke University Medical Center, Durham, NCSearch for more papers by this authorFrancis H. Glorieux, Francis H. Glorieux Genetics Unit, Shriners Hospital for Crippled Children, Montreal, Quebec, CanadaSearch for more papers by this authorJohn A. Kanis, John A. Kanis Department of Human Metabolism and Clinical Biochemistry, University of Sheffield, Sheffield, UKSearch for more papers by this authorHartmut Malluche, Hartmut Malluche Department of Medicine, Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky College of Medicine, Lexington, KTSearch for more papers by this authorPierre J. Meunier, Pierre J. Meunier INSERM Unit 234, Faculte Alexis Carrel, Lyon, FranceSearch for more papers by this authorSusan M. Ott, Susan M. Ott Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WASearch for more papers by this authorRobert R. Recker, Robert R. Recker Metabolic Research Unit, Department of Internal Medicine, Creighton University School of Medicine, Omaha, NBSearch for more papers by this author First published: December 1987 https://doi.org/10.1002/jbmr.5650020617Citations: 4,046AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume2, Issue6December 1987Pages 595-610 RelatedInformation

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

BACKGROUND: B-type natriuretic peptide is released from the cardiac ventricles in response to increased wall tension. METHODS: We conducted a prospective study of 1586 patients who came to the emergency department with acute dyspnea and whose B-type natriuretic peptide was measured with a bedside assay. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the B-type natriuretic peptide assay. RESULTS: The final diagnosis was dyspnea due to congestive heart failure in 744 patients (47 percent), dyspnea due to noncardiac causes in 72 patients with a history of left ventricular dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). B-type natriuretic peptide levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying congestive heart failure as the cause of dyspnea. The diagnostic accuracy of B-type natriuretic peptide at a cutoff of 100 pg per milliliter was 83.4 percent. The negative predictive value of B-type natriuretic peptide at levels of less than 50 pg per milliliter was 96 percent. In multiple logistic-regression analysis, measurements of B-type natriuretic peptide added significant independent predictive power to other clinical variables in models predicting which patients had congestive heart failure. CONCLUSIONS: Used in conjunction with other clinical information, rapid measurement of B-type natriuretic peptide is useful in establishing or excluding the diagnosis of congestive heart failure in patients with acute dyspnea.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

To ascertain the prevalence of posttraumatic stress disorder (PTSD) and risk factors associated with it, we studied a random sample of 1007 young adults from a large health maintenance organization in the Detroit, Mich, area. The lifetime prevalence of exposure to traumatic events was 39.1%. The rate of PTSD in those who were exposed was 23.6%, yielding a lifetime prevalence in the sample of 9.2%. Persons with PTSD were at increased risk for other psychiatric disorders; PTSD had stronger associations with anxiety and affective disorders than with substance abuse or dependence. Risk factors for exposure to traumatic events included low education, male sex, early conduct problems, extraversion, and family history of psychiatric disorder or substance problems. Risk factors for PTSD following exposure included early separation from parents, neuroticism, preexisting anxiety or depression, and family history of anxiety. Life-style differences associated with differential exposure to situations that have a high risk for traumatic events and personal predispositions to the PTSD effects of traumatic events might be responsible for a substantial part of PTSD in this population.

To date, no instruments exist to quantify the psychosocial consequences of voice disorders. The aim of the present investigation was the development of a statistically robust Voice Handicap Index (VHI). An 85-item version of this instrument was administered to 65 consecutive patients seen in the Voice Clinic at Henry Ford Hospital. The data were subjected to measures of internal consistency reliability and the initial 85-item version was reduced to a 30-item final version. This final version was administered to 63 consecutive patients on two occasions in an attempt to assess test-retest stability, which proved to be strong. The findings of the latter analysis demonstrated that a change between two administrations of 18 points represents a significant shift in psychosocial function.

Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.

Conventional vestibulometric techniques are inadequate for quantifying the impact of dizziness on everyday life. The 25-item Dizziness Handicap Inventory (DHI) was developed to evaluate the self-perceived handicapping effects imposed by vestibular system disease. The development of the preliminary (37 items) and final versions (25 items) of the DHI are described. The items were subgrouped into three content domains representing functional, emotional, and physical aspects of dizziness and unsteadiness. Cronbach's alpha coefficient was employed to measure reliability based on consistency of the preliminary version. The final version of the DHI was administered to 106 consecutive patients and demonstrated good internal consistency reliability. With the exception of the physical subscale, the mean values for DHI scale scores increased significantly with increases in the frequency of dizziness episodes. Test-retest reliability was high.

BACKGROUND: Prior unblinded studies have suggested that catheter-based renal-artery denervation reduces blood pressure in patients with resistant hypertension. METHODS: We designed a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo renal denervation or a sham procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. RESULTS: A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was -6.75±15.11 mm Hg in the denervation group and -4.79±17.25 mm Hg in the sham-procedure group, for a difference of -1.96 mm Hg (95% CI, -4.97 to 1.06; P=0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. CONCLUSIONS: This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.).

OBJECTIVE: To develop a self-report tinnitus handicap measure that is brief, easy to administer and interpret, broad in scope, and psychometrically robust. DESIGN: A standardization study of a self-report tinnitus handicap measure was conducted to determine its internal consistency reliability and convergent and construct validity. SETTING: Audiology clinics in tertiary care centers in two sites. PARTICIPANTS: In the first investigation, 84 patients reporting tinnitus as their primary complaint or secondary to hearing loss completed the 45-item alpha version of the Tinnitus Handicap Inventory (THI). In the second investigation, 66 subjects also reporting tinnitus completed the 25-item beta version. OUTCOME MEASURES: Convergent validity was assessed using another measure of perceived tinnitus handicap (Tinnitus Handicap Questionnaire). Construct validity was assessed using the Beck Depression Inventory, Modified Somatic Perception Questionnaire, symptom rating scales (annoyance, sleep disruption, depression, and concentration), and perceived tinnitus pitch and loudness judgments. RESULTS: From the alpha version of the THI, we derived a 25-item beta version with the items grouped into functional, emotional, and catastrophic subscales. The total scale yielded excellent internal consistency reliability (Cronbach's alpha = .93). No significant age or gender effects were seen. Weak correlations were observed between the THI and the Beck Depression Inventory, Modified Somatic Perception Questionnaire, and pitch and loudness judgments. Significant correlations were found between the THI and the symptom rating scales. CONCLUSION: The THI is a self-report measure that can be used in a busy clinical practice to quantify the impact of tinnitus on daily living.

BACKGROUND: Benign prostatic hyperplasia is commonly treated with alpha-adrenergic-receptor antagonists (alpha-blockers) or 5alpha-reductase inhibitors. The long-term effect of these drugs, singly or combined, on the risk of clinical progression is unknown. METHODS: We conducted a long-term, double-blind trial (mean follow-up, 4.5 years) involving 3047 men to compare the effects of placebo, doxazosin, finasteride, and combination therapy on measures of the clinical progression of benign prostatic hyperplasia. RESULTS: The risk of overall clinical progression--defined as an increase above base line of at least 4 points in the American Urological Association symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection--was significantly reduced by doxazosin (39 percent risk reduction, P<0.001) and finasteride (34 percent risk reduction, P=0.002), as compared with placebo. The reduction in risk associated with combination therapy (66 percent for the comparison with placebo, P<0.001) was significantly greater than that associated with doxazosin (P<0.001) or finasteride (P<0.001) alone. The risks of acute urinary retention and the need for invasive therapy were significantly reduced by combination therapy (P<0.001) and finasteride (P<0.001) but not by doxazosin. Doxazosin (P<0.001), finasteride (P=0.001), and combination therapy (P<0.001) each resulted in significant improvement in symptom scores, with combination therapy being superior to both doxazosin (P=0.006) and finasteride (P<0.001) alone. CONCLUSIONS: Long-term combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression of benign prostatic hyperplasia significantly more than did treatment with either drug alone. Combination therapy and finasteride alone reduced the long-term risk of acute urinary retention and the need for invasive therapy.

In this randomized, prospective, open-label trial, we studied 1233 patients with congestive heart failure or ischemic heart disease who were undergoing hemodialysis at 51 centers (see the Appendix). The institutional review boards at all centers approved the protocol, and all the patients gave written, informed consent. All the patients had end-stage renal disease and were undergoing longterm hemodialysis, and they had hematocrit values of 27 to 33 percent while receiving epoetin during the four weeks before enrollment. Ninety percent of the patients received epoetin intrave-

Abstract IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell–specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

BACKGROUND: In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS: To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS: A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS: The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.).

We devised a new method for examining the structural changes that occur in trabecular bone in aging and in osteoporosis. With simultaneous measurement of total perimeter and bone area in thin sections, indirect indices of mean trabecular plate thickness (MTPT) and mean trabecular plate density (MTPD) can be derived, such that trabecular bone volume = MTPD X MTPT. MTPD is an index of the probability that a scanning or test line will intersect a structural element of bone, and is the reciprocal of the mean distance between the midpoints of structural elements, multiplied by pi/2. We applied this method to iliac bone samples from 78 normal subjects, 100 patients with vertebral fracture, and 50 patients with hip fracture. The reduction in trabecular bone volume observed in normal subjects with increasing age was mainly due to a reduction in plate density, with no significant decrease in plate thickness. The further reduction in trabecular bone volume observed in patients with osteoporotic vertebral fracture was mainly due to a further reduction in plate density. There was a relatively smaller reduction in plate thickness that was statistically significant in males but not in females. Only in patients with hip fracture did trabecular thinning contribute substantially to the additional loss of trabecular bone in osteoporosis relative to age. These data indicate that age-related bone loss occurs principally by a process that removes entire structural elements of bone; those that remain are more widely separated and some may undergo compensatory thickening, but most slowly become reduced in thickness. We propose that the process of removal is initiated by increased depth of osteoclastic resorption cavities which leads to focal perforation of trabecular plates; this is followed by progressive enlargement of the perforations with conversion of plates to rods. The resulting structural changes are more severe in osteoporotic patients than in normal subjects, but have been completed in most patients before they develop symptoms.

BACKGROUND AND PURPOSE: Occluding a large intracranial artery in rats produces a brain lesion that grows in terms of an increase in both surface area and number of necrotic neurons. The present study investigated whether reperfusing the ischemic territory 30 to 60 minutes after the arterial occlusion would have a beneficial effect on either the clinical or the histological outcome of the lesion. METHODS: One hundred four adult rats (including appropriate controls) were used; 97 had a middle cerebral artery occluded by inserting a nylon monofilament via the right external carotid artery. The arterial occlusion was transient in two groups and permanent in another; survival times were comparable for all groups. Control animals were subjected to a sham operation during which the artery was occluded for less than 1 minute. The outcome was evaluated by measuring the extent of the neurological deficit and the severity of the histological injury. RESULTS: Mean neurological score and mean number of necrotic neurons in the cortex were more favorable after transient (30- to 60-minute) compared with permanent arterial occlusion (P < .005). Moreover, the correlation between mean neurological score and mean number of necrotic neurons was highly significant: r = .951; P < .001. CONCLUSIONS: The histological effects of an intracranial arterial occlusion in the adult rat can be predicted on day 1 by the neurological score described in this report. Significant improvement can be obtained in these animals by reestablishing arterial flow 60 minutes or sooner after the ictus. The pattern of cortical pannecrosis observed after permanent occlusion (> or = 72 hours) was transformed into incomplete ischemic injury in most instances of transient occlusion.

BACKGROUND: It has been hypothesized that asthma-related health problems are most severe among children in inner-city areas who are allergic to a specific allergen and also exposed to high levels of that allergen in bedroom dust. METHODS: From November 1992 through October 1993, we recruited 476 children with asthma (age, four to nine years) from eight inner-city areas in the United States. Immediate hypersensitivity to cockroach, house-dust-mite, and cat allergens was measured by skin testing. We then measured major allergens of cockroach (Bla g 1), dust mites (Der p 1 and Der f 1), and cat dander (Fel d 1) in household dust using monoclonal-antibody-based enzyme-linked immunosorbent assays. High levels of exposure were defined according to proposed thresholds for causing disease. Data on morbidity due to asthma were collected at base line and over a one-year period. RESULTS: Of the children, 36.8 percent were allergic to cockroach allergen, 34.9 percent to dust-mite allergen, and 22.7 percent to cat allergen. Among the children's bedrooms, 50.2 percent had high levels of cockroach allergen in dust, 9.7 percent had high levels of dust-mite allergen, and 12.6 percent had high levels of cat allergen. After we adjusted for sex, score on the Child Behavior Checklist, and family history of asthma, we found that children who were both allergic to cockroach allergen and exposed to high levels of this allergen had 0.37 hospitalization a year, as compared with 0.11 for the other children (P=0.001), and 2.56 unscheduled medical visits for asthma per year, as compared with 1.43 (P<0.001). They also had significantly more days of wheezing, missed school days, and nights with lost sleep, and their parents or other care givers were awakened during the night and changed their daytime plans because of the child's asthma significantly more frequently. Similar patterns were not found for the combination of allergy to dust mites or cat dander and high levels of the allergen. CONCLUSIONS: The combination of cockroach allergy and exposure to high levels of this allergen may help explain the frequency of asthma-related health problems in inner-city children.

BACKGROUND: The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects. METHODS: We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute). RESULTS: During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups. CONCLUSIONS: Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310.).

BACKGROUND AND PURPOSE: Human umbilical cord blood cells (HUCBC) are rich in stem and progenitor cells. In this study we tested whether intravenously infused HUCBC enter brain, survive, differentiate, and improve neurological functional recovery after stroke in rats. In addition, we tested whether ischemic brain tissue extract selectively induces chemotaxis of HUCBC in vitro. METHODS: Adult male Wistar rats were subjected to transient (2-hour) middle cerebral artery occlusion (MCAO). Experimental groups were as follows: group 1, MCAO alone (n=5); group 2, 3x10(6) HUCBC injected into tail vein at 24 hours after MCAO (n=6) (animals of groups 1 and 2 were killed at 14 days after MCAO); group 3, MCAO alone (n=5); group 4, MCAO injected with PBS at 1 day after stroke (n=8); and group 5, 3x10(6) HUCBC injected into tail vein at 7 days after MCAO (n=5). Rats of groups 3, 4, and 5 were killed at 35 days after MCAO. Behavioral tests (rotarod and Modified Neurological Severity Score [mNSS]) were performed. Immunohistochemical staining was used to identify cells derived from HUCBC. Chemotactic activity of ischemia brain tissue extracts toward HUCBC at different time points was evaluated in vitro. RESULTS: Treatment at 24 hours after MCAO with HUCBC significantly improved functional recovery, as evidenced by the rotarod test and mNSS (P<0.05). Treatment at 7 days after MCAO with HUCBC significantly improved function only on the mNSS (P<0.05). Some HUCBC were reactive for the astrocyte marker glial fibrillary acidic protein and the neuronal markers NeuN and microtubule-associated protein 2. In vitro, significant HUCBC migration activity was present at 24 hours after MCAO (P<0.01) compared with normal brain tissue. CONCLUSIONS: Intravenously administered HUCBC enter brain, survive, migrate, and improve functional recovery after stroke. HUCBC transplantation may provide a cell source to treat stroke.

Excessive daytime sleepiness and loud snoring are the major symptoms of obstructive sleep apnea, often leading to serious medical complications if unrecognized and untreated. Tracheostomy has been the only effective treatment in most adult cases. This paper reports on a new surgical approach to treat obstructive sleep apnea by uvulopalatopharyngoplasty designed to enlarge the potential airspace in the oropharynx. Twelve patients underwent this operation. In nine there was relief of symptoms and in eight there was objective improvement in nocturnal respiration and sleep pattern, demonstrated by polysomnography.