Hypoxia-induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis.

INTRODUCTION: Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo. METHODS: Cystic fibrosis bronchoepithelial cells expressing wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24 h. Time-dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole-cell and cell-attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro-optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF-1α, pH, sinus potential difference (SPD), and MCT were determined. RESULTS: Ussing chamber (p < 0.05), whole-cell (p < 0.001), and single channel patch-clamp (p < 0.0001) showed significant inhibition of Cl- currents in hypoxic cells. Cytoplasmic free radicals showed time-dependent elevation peaking at 4 h (p < 0.0001). Airway surface liquid (p < 0.0001), periciliary liquid (p < 0.001), and MCT (p < 0.01) were diminished. Co-incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p < 0.0001), increased HIF1α mRNA (p < 0.05), reduced pH (p < 0.01), and decreased MCT (p < 0.001). SPD measurements demonstrated markedly diminished transepithelial Cl- transport (p < 0.0001). CONCLUSION: Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.

Advances in Sinus Surgery for Nasal Polyps.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is comprised of a diverse group of endotypes that cause significant morbidity for afflicted patients. While endoscopic sinus surgery helps ameliorate the disease, polyps frequently recur. Newer strategies are intended to provide access for topical steroid irrigations in attempts to improve the disease process and quality of life, and decrease overall recurrence of polyps. OBJECTIVE: To review the current literature examining the latest surgical approaches for CRSwNP. METHODS: Review article. RESULTS: In dealing with the recalcitrant nature of CRSwNP, surgical techniques have simultaneously become more nuanced and aggressive. Bony resection in anatomically unfavorable areas such as the frontal, maxillary, and sphenoid outflow regions, replacing diseased or denuded mucosa with healthy grafts or flaps at the neo-ostia, and introducing drug-eluting biomaterials to newly opened sinus outflow tracts are highlights in the recent advancements in sinus surgery for CRSwNP. The Draf 3 or modified endoscopic Lothrop procedure has become a standard technique and demonstrated to improve quality of life and decrease polyp recurrence. A number of mucosal grafting or mucosal flap techniques have been described that cover exposed bone of the neo-ostium and evidence shows that this improves healing and diameter of the Draf 3. Partial middle turbinectomy, while controversial, appears to help decrease polyp recurrence in long-term follow-up studies. Modified endoscopic medial maxillectomy improves access to the maxillary sinus mucosa, facilitates debridement and, particularly, in the cystic fibrosis nasal polyp patient, improves overall management of the disease. Sphenoid drill-out procedure provides wider access for topical steroid irrigations and also may improve management of CRSwNP. CONCLUSION: Surgical intervention remains a mainstay of therapy for CRSwNP. Newer techniques revolve around improving access for topical steroid therapy.

Optimal timing and technique for endoscopic management of dysphagia in pediatric aerodigestive patients.

INTRODUCTION: The best strategy to manage an interarytenoid defect [Type 1 laryngeal cleft (LC-1) or deep interarytenoid groove (DIG)] in pediatric aerodigestive patients with dysphagia remains uncertain. This study compared benefit of interarytenoid augmentation (IAA) to suture repair or clinical observation alone in pediatric patients. METHODS: A 3-year retrospective, single-center analysis of children with dysphagia undergoing endoscopic airway evaluation was performed. Physician preference guided treatment plan: suture repair with CO2 laser, IAA (carboxy methylcellulose or calcium hydroxyapatite), or observation. Primary outcome was improved post-operative diet. Significance was assumed at p < 0.05. RESULTS: 449 patients underwent diagnostic endoscopy. Mean age (±SD) at procedure was 21 ± 13 months, with nearly one fourth (28 %) of children ≤ 12 months. Eighty (18 %) had either an LC-1 (n = 55) or DIG (n = 25). Of these, 35 (42 %) underwent suture repair, 22 (28 %) IAA, and 23 (30 %) observation only. Aspiration improved overall in the interventional groups compared to observational controls (58 % vs. 9 %, p < 0.05), with no change in benefit observed by age of intervention. IAA was as effective as suture repair (59 % vs 55 %, p = 0.46). In patients with only a DIG, IAA intervention alone significantly improved swallow function (66.6 % vs. 0 %, p < 0.05). CONCLUSION: In pediatric aerodigestive patients with dysphagia, 18 % of children have an addressable lesion. IAA or suture repair similarly improves dietary advancement. IAA improves swallow function in patients with DIG. These findings support a novel protocol to intervene in dysphagia patients with LC-1 or DIG via IAA at the initial operative evaluation.

Combination checkpoint inhibitor therapy induces multiple immune major related adverse events in the treatment of vaginal melanoma: A cautionary case report.

BACKGROUND: Immune checkpoint inhibitors (ICI) eliminate cancer cells through release of inhibition of cytotoxic CD8+ lymphocytes. Potent systemic activation of immune cells provides unprecedented efficacy in some types of advanced cancer therapy, but also often induces serious immune related adverse events (irAEs) that can be devastating if not promptly identified and properly managed. Herein, we describe the case of multiple major irAEs manifesting after administration of combination ICI therapy in a patient with vaginal melanoma.Case:A 54-year-old, G2P0 woman with recurrent metastatic vaginal melanoma, following three doses of combination nivolumab-ipilimumab immunotherapy, presented for admission at our tertiary care center for the work-up of sudden-onset of colitis of unknown etiology. Prior to admission at our facility, the patient was diagnosed with a severe maculopapular rash, headaches and hyponatremia in the weeks immediately following initiation of therapy. During work up of the colitis, infectious etiologies were ruled out, and the patient was discharged on a steroid taper for treatment of presumed immune-related colitis. Consideration of salt-supplement resistant hyponatremia with new onset frontal headache in the setting of immune-related colitis indicated possible hypophysitis. With high suspicion for multiple high grade irAEs, ICI was discontinued, and the patient was given high dose intravenous steroids prior to discharge with a prednisone dose taper for outpatient management. After control of irAEs was achieved, ipilimumab therapy was subsequently discontinued to minimize the chance of recurrent irAEs, yet nivolumab monotherapy was resumed in an attempt to control disease progression that could occur in with iatrogenic immunosuppression. CONCLUSION: ICIs have demonstrated the ability to induce improved long-term survival in metastatic cutaneous or mucosal melanomas, including those of gynecologic origin. As ICI therapy becomes more widespread, healthcare providers across all fields of medicine need be vigilant to recognize the symptoms of irAEs that can often masquerade as common illnesses to prevent potentially dangerous irreversible immune toxicities.

Estimating micro area behavioural risk factor prevalence from large population-based surveys: a full Bayesian approach.

BACKGROUND: An important public health goal is to decrease the prevalence of key behavioural risk factors, such as tobacco use and obesity. Survey information is often available at the regional level, but heterogeneity within large geographic regions cannot be assessed. Advanced spatial analysis techniques are demonstrated to produce sensible micro area estimates of behavioural risk factors that enable identification of areas with high prevalence. METHODS: A spatial Bayesian hierarchical model was used to estimate the micro area prevalence of current smoking and excess bodyweight for the Erie-St. Clair region in southwestern Ontario. Estimates were mapped for male and female respondents of five cycles of the Canadian Community Health Survey (CCHS). The micro areas were 2006 Census Dissemination Areas, with an average population of 400-700 people. Two individual-level models were specified: one controlled for survey cycle and age group (model 1), and one controlled for survey cycle, age group and micro area median household income (model 2). Post-stratification was used to derive micro area behavioural risk factor estimates weighted to the population structure. SaTScan analyses were conducted on the granular, postal-code level CCHS data to corroborate findings of elevated prevalence. RESULTS: Current smoking was elevated in two urban areas for both sexes (Sarnia and Windsor), and an additional small community (Chatham) for males only. Areas of excess bodyweight were prevalent in an urban core (Windsor) among males, but not females. Precision of the posterior post-stratified current smoking estimates was improved in model 2, as indicated by narrower credible intervals and a lower coefficient of variation. For excess bodyweight, both models had similar precision. Aggregation of the micro area estimates to CCHS design-based estimates validated the findings. CONCLUSIONS: This is among the first studies to apply a full Bayesian model to complex sample survey data to identify micro areas with variation in risk factor prevalence, accounting for spatial correlation and other covariates. Application of micro area analysis techniques helps define areas for public health planning, and may be informative to surveillance and research modeling of relevant chronic disease outcomes.

Estimating cancer risk in relation to tritium exposure from routine operation of a nuclear-generating station in Pickering, Ontario.

INTRODUCTION: Evidence suggests that current levels of tritium emissions from CANDU reactors in Canada are not related to adverse health effects. However, these studies lack tritium-specific dose data and have small numbers of cases. The purpose of our study was to determine whether tritium emitted from a nuclear-generating station during routine operation is associated with risk of cancer in Pickering, Ontario. METHODS: A retrospective cohort was formed through linkage of Pickering and north Oshawa residents (1985) to incident cancer cases (1985-2005). We examined all sites combined, leukemia, lung, thyroid and childhood cancers (6-19 years) for males and females as well as female breast cancer. Tritium estimates were based on an atmospheric dispersion model, incorporating characteristics of annual tritium emissions and meteorology. Tritium concentration estimates were assigned to each cohort member based on exact location of residence. Person-years analysis was used to determine whether observed cancer cases were higher than expected. Cox proportional hazards regression was used to determine whether tritium was associated with radiation-sensitive cancers in Pickering. RESULTS: Person-years analysis showed female childhood cancer cases to be significantly higher than expected (standardized incidence ratio [SIR] = 1.99, 95% confidence interval [CI]: 1.08-3.38). The issue of multiple comparisons is the most likely explanation for this finding. Cox models revealed that female lung cancer was significantly higher in Pickering versus north Oshawa (HR = 2.34, 95% CI: 1.23-4.46) and that tritium was not associated with increased risk. The improved methodology used in this study adds to our understanding of cancer risks associated with low-dose tritium exposure. CONCLUSION: Tritium estimates were not associated with increased risk of radiationsensitive cancers in Pickering.

TITRE: Estimation du risque de cancer lié à l'exposition au tritium dans le cadre des activités courantes de la centrale nucléaire de Pickering (Ontario). INTRODUCTION: D'après les données dont nous disposons, les niveaux actuels des émissions de tritium provenant des réacteurs CANDU au Canada n'entraîneraient pas d'effets néfastes sur la santé. Toutefois, les études ne précisent pas les doses spécifiques au tritium, et reposent sur un petit nombre de cas. La présente étude avait pour but de déterminer si le tritium émis par la centrale nucléaire de Pickering, en Ontario, lors de ses activités courantes, est associé à un risque de cancer. MÉTHODOLOGIE: Nous avons constitué une cohorte rétrospective en couplant les données sur les résidents de Pickering et de North Oshawa (1985) à celles sur les nouveaux cas de cancer (1985-2005). Nous avons examiné les cas de cancer tous sièges combinés, ainsi que les cas de leucémie, de cancer du poumon, de cancer de la thyroïde et de cancer infantile (6-19 ans) pour les sujets de sexe masculin et féminin, de même que les cas de cancer du sein chez la femme. Les estimations de la concentration de tritium reposaient sur un modèle de dispersion atmosphérique qui intégrait les caractéristiques des émissions annuelles de tritium et les données météorologiques. Chaque membre de la cohorte s'est vu assigner une estimation de la concentration de tritium, en fonction de son lieu précis de résidence. Une analyse des années-personnes a permis de déterminer si les cas de cancer observés étaient plus nombreux que prévus. Un modèle de régression des risques proportionnels de Cox a servi à établir si le tritium était associé à des cancers radiosensibles à Pickering. RÉSULTATS: Une analyse des années-personnes a révélé que le nombre de cas de cancer chez les jeunes filles était significativement plus élevé que prévu (rapport standardisé d'incidence [RSI] = 1,99, intervalle de confiance [IC] à 95 % : 1,08 à 3,38). L'explication la plus plausible de cette observation est le recours à des comparaisons multiples. Les modèles de Cox ont révélé que le cancer du poumon chez la femme était significativement plus élevé à Pickering qu'à North Oshawa (RR = 2,34; IC à 95 % : 1,23 à 4,46) et que le tritium n'était pas associé à une augmentation du risque. La méthodologie améliorée de la présente étude nous permet de mieux comprendre les risques de cancer associés à une exposition à de faibles doses de tritium. CONCLUSION: Les doses estimées de tritium n'ont pas été associées à une augmentation du risque de cancers radiosensibles à Pickering.

The risk of peri-prosthetic fracture after primary and revision total hip and knee replacement.

Peri-prosthetic fracture after joint replacement in the lower limb is associated with significant morbidity. The primary aim of this study was to investigate the incidence of peri-prosthetic fracture after total hip replacement (THR) and total knee replacement (TKR) over a ten-year period using a population-based linked dataset. Between 1 April 1997 and 31 March 2008, 52,136 primary THRs, 8726 revision THRs, 44,511 primary TKRs, and 3222 revision TKRs were performed. Five years post-operatively, the rate of fracture was 0.9% after primary THR, 4.2% after revision THR, 0.6% after primary TKR and 1.7% after revision TKR. Comparison of survival analysis for all primary and revision arthroplasties showed peri-prosthetic fractures were more likely in females, patients aged > 70 and after revision arthroplasty. Female patients aged > 70 should be warned of a significantly increased risk of peri-prosthetic fracture after hip or knee replacement. The use of adjuvant medical treatment to reduce the effect of peri-prosthetic osteoporosis may be a direction of research for these patients.

Rates of infection and revision in patients with renal disease undergoing total knee replacement in Scotland.

We undertook a study to determine the rates of infection and revision of total knee replacement (TKR) in patients with renal failure, renal transplantation and those undergoing renal dialysis in Scotland. The overall early and late infection rates were 1.10% and 2.19% compared with 1.06% and 2.01%, respectively, for non-renal patients. Patients with renal failure had a significantly increased risk of early infection (1.6%, relative risk 1.52, p = 0.002) and late infection (4.47%, relative risk 2.22, p < 0.001). Those on renal dialysis had significantly increased risks of late infection (8.03%, relative risk 3.99, p < 0.001) and early revision (3.70%, relative risk 4.40, p < 0.001). Renal transplant patients had a significantly increased risk of late infection, regardless of whether renal transplantation occurred before TKR (9.09%, relative risk 4.517, p = 0.027) or at any time (8.0%, relative risk 3.975, p = 0.047). There were significantly increased rates of comorbidities associated with infection for all the renal patient groups. Logistic regression analysis showed that renal failure and renal dialysis were independent risk factors for early infection and revision, respectively.

Deaths from violence in North Carolina, 2004: how deaths differ in females and males.

OBJECTIVE: To identify gender differences in violent deaths in terms of incidence, circumstances, and methods of death. DESIGN: Analysis of surveillance data. SETTING: North Carolina, a state of 8.6 million residents on the eastern seaboard of the US. SUBJECTS: 1674 North Carolina residents who died from violence in the state during 2004. METHODS: Information on violent deaths was collected by the North Carolina Violent Death Reporting System using data from death certificates, medical examiner reports, and law enforcement agency incidence reports. RESULTS: Suicide and homicide rates were lower for females than males. For suicides, females were more likely than males to have a diagnosis of depression (55% v 36%), a current mental health problem (66% v 42%), or a history of suicide attempts (25% v 13%). Firearms were the sole method of suicide in 65% of males and 42% of females. Poisonings were more common in female than male suicides (37% v 12%). Male and female homicide victims were most likely to die from a handgun or a sharp instrument. Fifty seven percent of female homicides involved intimate partner violence, compared with 13% of male homicides. Among female homicides involving intimate partner violence, 78% occurred in the woman's home. White females had a higher rate of suicide than African-American females, but African-American females had a higher rate of homicide than white females. CONCLUSIONS: The incidence, circumstances, and methods of fatal violence differ greatly between females and males. These differences should be taken into account in the development of violence prevention efforts.

A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication.

In a 5-year survey of nonpromyelocytic/nonmonocytic acute myeloid leukemias (AMLs) diagnosed in the University of Washington Hematopathology Laboratory, we identified 19 cases containing distinctive, cup-like nuclear indentation in 10% or more of the blasts ('AML-cuplike'). Fourteen of these cases (74%) demonstrated near-complete loss of HLA-DR expression, while the other five cases showed partial loss of HLA-DR. A total of 16 of the cases (84%) demonstrated internal tandem duplication (ITD) of the Flt3 gene. When compared to a selected set of AMLs lacking this nuclear morphology, AML-cuplike was significantly more likely to lack HLA-DR and CD34 expression, to express CD123 without CD133, to have a normal karyotype, and to harbor the Flt3 ITD. To characterize AML-cuplike in an unselected series of AMLs, we analyzed 42 consecutive nonpromyelocytic/nonmonocytic AMLs diagnosed in our laboratory during a 6-month period in 2002. Strikingly, in this unselected series, there was a statistically significant coincidence of invaginated nuclear morphology, loss of HLA-DR, and presence of the Flt3 ITD beyond that expected if these three features were unrelated, suggesting that AMLs with these three features may represent a distinct AML subset.

Satellite 2 methylation patterns in normal and ICF syndrome cells and association of hypomethylation with advanced replication.

Mutation in the DNMT3B DNA methyltransferase gene is a common cause of ICF (immunodeficiency, centromeric heterochromatin, facial anomalies) immunodeficiency syndrome and leads to hypomethylation of satellites 2 and 3 in pericentric heterochromatin. This hypomethylation is associated with centromeric decondensation and chromosomal rearrangements, suggesting that these satellite repeats have an important structural role. In addition, the satellite regions may have functional roles in modifying gene expression. The extent of satellite hypomethylation in ICF cells is unknown because methylation status has only been determined with restriction enzymes that cut infrequently at these loci. We have therefore developed a bisulfite conversion-based method to determine the detailed cytosine methylation patterns at satellite 2 sequences in a quantitative manner for normal and ICF samples. From our sequence analysis of unmodified DNA, the internal repeat region analyzed for methylation contains an average of 17 CpG sites. The average level of methylation in normal lymphoblasts and fibroblasts is 69% compared with 20% in such cells from ICF patients with DNMT3B mutations and 29% in normal sperm. Although the mean satellite 2 methylation values for these groups do not overlap, there is considerable overlap at the level of individual DNA strands. Our analysis has also revealed a pattern of methylation specificity, suggesting that some CpGs in the repeat are more prone to methylation than other sites. Variation in satellite 2 methylation among lymphoblasts from different ICF patients has prompted us to determine the frequency of cytogenetic abnormalities in these cells. Although our data suggest that some degree of hypomethylation is necessary for pericentromeric decondensation, factors other than DNA methylation appear to play a major role in this phenomenon. Another such factor may be altered replication timing because we have discovered that the hypomethylation of satellite 2 in ICF cultures is associated with advanced replication.

Chromosomal changes in a dedifferentiated chondrosarcoma: a case report and review of the literature.

The chromosome abnormalities observed in a dedifferentiated chondrosarcoma are reported. A new molecular cytogenetic technique, spectral karyotyping, was used to identify and confirm structural rearrangements in this case. A review of the literature revealed that nine cases have been reported, in eight of which a complete description of the cytogenetic abnormalities was described. Structural aberrations were most frequently reported in chromosomes 1 and 9, and chromosomes 7 and 19 were most frequently observed to be involved in numerical aberrations (trisomy and tetrasomy). In chondrosarcomas, structural aberrations in chromosomes 1 and 9 and trisomy or tetrasomy of chromosome 7 are among the more frequently observed aberrations.

Familial cryptic (20;21) translocation identified by in situ hybridization technologies.

We report on a familial cryptic (20;21) translocation [(t20;21)] that was initially suspected with the observation of a single chromosome 21 specific signal in an interphase nuclei by in situ hybridization (FISH) study performed on a 34-week gestation amniotic fluid specimen. The genetic amniocentesis was prompted by the presence of fetal anomalies detected by ultrasound. In addition, there was a family history of a maternal uncle with mental retardation and multiple malformations and an apparently normal karyotype. No obvious aberration could be detected in the G-banded karyotype prepared from the amniotic fluid specimen. A FISH study using a chromosome 21 specific long arm probe and chromosome 20 whole chromosome paint, however, showed an unbalanced rearrangement in the fetus [46,XY, der(21)t(20;21)(q13.2;q22.13 or 22.2) mat]. The mother and maternal grandmother were demonstrated to be balanced translocation carriers. These results were confirmed by multicolor karyotyping. This familial aberration was discovered by chance in the interphase FISH analysis. Our experience with this case, however, serves to emphasize the importance of the reevaluation of patients with mental retardation and congenital malformations of unknown cause and prudent use of multicolor karyotyping in the detection of cryptic cytogenetic rearrangements.

Overall rotational diffusion and internal mobility in domain II of protein G from Streptococcus determined from 15N relaxation data.

The backbone dynamics and overall tumbling of protein G have been investigated using 15N relaxation. Comparison of measured R2/R1 relaxation rate ratios with known three-dimensional coordinates of the protein show that the rotational diffusion tensor is significantly asymmetric, exhibiting a prolate axial symmetry. Extensive Monte Carlo simulations have been used to estimate the uncertainty due to experimental error in the relaxation rates to be D(parallel)/D(perpendicular) = 1.68 +/- 0.08, while the dispersion in the NMR ensemble leads to a variation of D(parallel)/D(perpendicular) = 1.65 +/- 0.03. Incorporation of this tensorial description into a Lipari-Szabo type analysis of internal motion has allowed us to accurately describe the local dynamics of the molecule. This analysis differs from an earlier study where the overall rotational diffusion was described by a spherical top. In this previous analysis, exchange parameters were fitted to many of the residues in the alpha helix. This was interpreted as reflecting a small motion of the alpha helix with respect to the beta sheet. We propose that the differential relaxation properties of this helix compared to the beta sheet are due to the near-orthogonality of the NH vectors in the two structural motifs with respect to the unique axis of the diffusion tensor. Our analysis shows that when anisotropic rotational diffusion is taken into account NH vectors in these structural motifs appear to be equally rigid. This study underlines the importance of a correct description of the rotational diffusion tensor if internal motion is to be accurately investigated.

Chimeric del20q in a case of chronic neutrophilic leukemia.

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative disorder in which recurrent abnormalities of chromosome 20 have been reported. We report the case of a 76-year-old woman with CNL with partial deletion of the long arm of chromosome 20 in a subset of bone marrow metaphases, suggesting coexistence of a clonal stem cell disorder and normal hematopoiesis. Review of the literature suggests that such mosaicism is common in CNL, possibly accounting for the favorable prognosis observed in many patients with this disorder.

A phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia.

PURPOSE: The Southwest Oncology Group performed a Phase II study to investigate the effectiveness of an induction regimen of high dose cytosine arabinoside (ara-C) with high dose mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients at least 16-years-old with ALL that was in relapse after, or was refractory to, standard induction therapy including at least vincristine and prednisone were eligible, as long as they had no prior treatment with high dose ara-C. The induction regimen included high dose ara-C (3 g/m2 by 3-h i.v. days 1-5) and mitoxantrone (80 mg/m2 by 15-30 min i.v. 12-20 h after the first dose of ara-C). The study design called for a maximum of 55 patients, with early termination if less than nine of the first 30 achieved complete remission. RESULTS: Thirty-three patients entered the study, and 31 were included in the analysis. All 31 completed one course of induction therapy. Four patients died of infection and a fifth of cardiomyopathy with possible sepsis. Seven patients achieved complete remission (23%; 95% confidence interval 10-41%). One of the seven received syngeneic bone marrow transplantation while in remission, and the other six all relapsed within 10 months. All 31 patients died within 25 months after entering the study. CONCLUSIONS: The regimen of high dose ara-C and mitoxantrone was found to be insufficiently effective to warrant further investigation.

In-phase selective excitation of overlapping multiplets.

An editing experiment is presented that selects for a peak on the basis of its chemical shift and that of one of its scalar coupling partners. The selected multiplet is pure in-phase. The editing procedure can be used in conjunction with 1D TOCSY/HOHAHA and NOE measurements. The pulse sequence described is particularly suitable for small molecules; data is presented for Gramicidin S and dehydrotestosterone.

A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins.

Cyclin E-Cdk2 is an evolutionary conserved cyclin-dependent kinase (CDK) complex that drives the G1 to S phase transition of the cell cycle. A novel cDNA encoding a HECT family protein also containing RCC1-like repeats was isolated by a yeast two-hybrid screening using both cyclin E and its inhibitor p21. The protein product of this cDNA, Ceb1, interacts with various cyclin subunits of CDKs in mammalian cells. Expression of Ceb1 is specifically detected in testis and ovary and is highly elevated when the functions of the tumor suppressor proteins, p53 and RB, are compromised by mutations or viral oncoproteins. The present results suggest that Ceb1 may play a critical role when its expression and the CDK activity are upregulated by inactivation of p53 and RB.

Quantitative measurement of long range nuclear Overhauser enhancement.

Measurement of nuclear Overhauser enhancement is one of the mainstays of structural studies of molecules in solution. Measurements, particularly over long distances, are often compromised by spin diffusion. A robust and accurate method for measuring nuclear Overhauser enhancements that are largely free of spin diffusion effects is presented. The effects of using imperfect radiofrequency pulses are considered and experimental data are presented for Amphotericin B.