Mimics of primary ovarian cancer and primary peritoneal carcinomatosis - A pictorial review.

Numerous conditions can mimic ovarian malignancy. Identifying the origin of a pelvic mass or disseminated peritoneal abnormality on imaging is important to ensure that the patient receives optimal management by the appropriate clinical team. Ovarian cancer mimics include infections and other neoplastic processes, for example, actinomycosis, lymphoma, and sarcoma. We will illustrate intraperitoneal and extraperitoneal ovarian and non-ovarian mimics. Primary peritoneal carcinomatosis mimics include processes such as deep infiltrating endometriosis and rare causes such as gliomatosis peritonei and diffuse peritoneal leiomyomatosis. We aim to illustrate the multimodality key imaging appearances of common and rarer types of mimics.

Poststroke cognitive outcome is better accounted for by white matter abnormalities automated segmentation than visual analysis.

BACKGROUND AND AIMS: The association between white matter abnormalities (WMA) and cognitive decline previously reported in poststroke patients has been mainly documented using visual scales. However, automated segmentation of WMA provides a precise determination of the volume of WMA. Nonetheless, it is rarely used in the stroke population and its potential advantage over visual scales is still unsettled. The objective of this study was to examine whether automated segmentation of WMA provides a better account than the visual Fazekas and Wahlund scales of the decline in executive functions and processing speed in stroke patients. METHODS: The analyses were conducted on the 358 patients of the GRECogVASC cohort with an MRI performed at six months poststroke in the Amiens center. WMA were visually analyzed using the Fazekas (subcortical abnormalities) and Wahlund scales. Segmentation was performed using LST (3.0.3). Following preliminary studies to determine the optimal segmentation threshold, we examined the relationship between cognitive status and WMA volume computed at each threshold using receiver operating characteristic (ROC) curves. Finally, we assessed the ability of both Fazekas and Wahlund visual scores and WMA volume to account for cognitive scores by using a bivariate Pearson correlation analysis, comparing correlation coefficients with the Fisher transformation and repeating correlation analysis after adjustment for the lesion volume. RESULTS: Increasing the threshold led to an underestimation of WMA (P=0.0001) (significant for a threshold ≥0.2) and an improvement in correct rejection of signal changes in the stroke cavity (P=0.02) (significant for a threshold ≤0.5), susceptibility artifacts (P=0.002) (significant for a threshold ≤0.6), and corticospinal degeneration (P=0.03) (significant for a threshold ≤0.5). WMA volume decreased with increasing threshold (P=0.0001). Areas under the curve (AUC) did not differ according to the threshold (processing speed: P=0.85, executive cognitive functions: P=0.7). Correlation coefficients between cognitive scores and WMA were higher for WMA volume than the Fazekas (processing speed: Z=-3.442, P=0.001; executive functions: Z=-2.751, P=0.006) and Wahlund scores (processing speed: Z=-3.615, P=0.0001; executive functions: Z=-2.769, P=0.006). Adjustment for lesion volume did not alter the correlations with WMA volume (processing speed: r=-0.327 [95%CI: -0.416; -0.223], P=0.0001; executive functions: r=-0.262 [95%CI: -0.363; -0.150], P=0.0001). CONCLUSION: This study shows that WMA volume assessed by automated segmentation provides a better account of cognitive disorders than visual analysis. This should favor its wider use to refine imaging determinants of poststroke cognitive disorders.

Virtual reality as a countermeasure for astronaut motion sickness during simulated post-flight water landings.

Entry motion sickness (EMS) affects crewmembers upon return to Earth following extended adaptation to microgravity. Anticholinergic pharmaceuticals (e.g., Meclizine) are often taken prior to landing; however, they have operationally adverse side effects (e.g., drowsiness). There is a need to develop non-pharmaceutical countermeasures to EMS. We assessed the efficacy of a technological countermeasure providing external visual cues following splashdown, where otherwise only nauseogenic internal cabin visual references are available. Our countermeasure provided motion-congruent visual cues of an Earth-fixed scene in virtual reality, which was compared to a control condition with a head-fixed fixation point in virtual reality in a between-subject design with 15 subjects in each group. We tested the countermeasure's effectiveness at mitigating motion sickness symptoms at the end of a ground-based reentry analog: approximately 1 h of 2Gx centrifugation followed by up to 1 h of wave-like motion. Secondarily, we explored differences in vestibular-mediated balance performance between the two conditions. While Motion Sickness Questionnaire outcomes did not differ detectably between groups, we found significantly better survival rates (with dropout dictated by reporting moderate nausea consecutively over 2 min) in the visual countermeasure group than the control group (79% survival vs. 33%, t(14) = 2.50, p = 0.027). Following the reentry analogs, subjects demonstrated significantly higher sway prior to recovery (p = 0.0004), which did not differ between control and countermeasure groups. These results imply that providing motion-congruent visual cues may be an effective mean for curbing the development of moderate nausea and increasing comfort following future space missions.

Political communication, press coverage and public interpretation of public health statistics during the coronavirus pandemic in the UK.

This article examines the way numbers, often concerning risk, were communicated by politicians, covered by the news media and interpreted by the public during the early stages of the COVID-19 crisis in the United Kingdom. To explore this topic, we adopted a mixed-methods approach that included content analysis, comparative thematic analysis and a series of focus groups. Whilst coherency and consistency are touted as essentials in public health messaging, our textual analysis highlighted the disconnect between political communication and news media coverage. Whereas the UK government relied on vague references to curves and peaks to underpin a narrative of consistency and certainty in public health policy, the UK news media referred to specific numbers from within and outside the UK to criticise the government's approach as haphazard and lacking. This disconnect gained even more significance during our focus groups. When discussing numbers, participants referred to news media coverage rather than political messaging, using these figures to challenge the timing and nature of the UK lockdown. These findings present a significant critique of the UK government's communication during this health crisis. Instead of putting forward a coherent, homogenous and clear message to the public, the discourse around numbers and risk was diffracted, disconnected and opaque. This was largely due to the competing narratives presented by the news media.

Audit of eliminating biopsy for presumed fibroadenomas with benign ultrasound greyscale and shear-wave elastography findings in women aged 25-39 years.

AIM: To assess the safety of a policy of not biopsying presumed fibroadenomas with benign ultrasound and shear-wave elastography findings in women aged 25-39 years. MATERIALS AND METHODS: Patients aged 25-39 years were included after attending a one-stop clinic before 01/05/2019 where clinical and ultrasound greyscale findings suggested a benign mass and shear-wave elastography showed a mean stiffness of <50 kPa. Such patients were reassured and discharged without biopsy or follow-up. The archived ultrasound images were reviewed subsequently by a second radiologist who could recall patients for biopsy if he deemed the imaging findings to be not definitively benign. Local and national electronic records were reviewed to identify whether these patients later re-presented with breast problems. RESULTS: Seventy-six women with a mean age of 33 years were included. The minimum follow-up was 12 months and the mean follow-up was 2 years. Three (4%) of patients were recalled after review of the ultrasound images by a second radiologist. Five (7%) patients re-presented with the same lump. Three (4%) patients re-presented with a different benign problem. Two patients presented with breast cancer in the ipsilateral breast but at a different location from the assessed benign lesion. CONCLUSION: Early audit results of a policy of not biopsying or following up clinically benign masses with benign ultrasound greyscale appearances and shear wave stiffness <50 kPa in women aged 25-39 years suggest that this approach may be safe and acceptable.

Associations between the ultrasound features of invasive breast cancer and breast cancer specific survival.

AIM: To assess whether ultrasound features of breast cancer are associated with breast cancer specific survival (BCSS). MATERIALS AND METHODS: Within a single breast service, data was collected prospectively (April 2010-April 2012) from 319 consecutive women (mean age 63 years) with 335 ultrasound-visible invasive breast cancers. Ultrasound features were evaluated retrospectively from the recorded images according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon by a radiologist blinded to outcomes. Survival and cause of death were ascertained from local and national sources. Kaplan-Meier survival curves were generated, and statistical significance tested using the log-rank test. RESULTS: Mean follow-up in those alive was 80.9 months. Thirty breast cancer deaths and 45 non-breast cancer deaths occurred. Five-year BCSS in the presence of distal acoustic enhancement was 76% compared to 88%, 96%, and 100% for those with distal shadowing, no distal effect or combined effect respectively (p<0.0002). Patients with sonographic skin involvement had 73% 5-year BCSS compared to 92% for no skin involvement (p<0.0001). Focal oedema was associated with 56% 5-year BCSS compared to 89% for those without (p=0.0002). A significant association was demonstrated between ultrasound tumour size and BCSS (p<0.0001). At multivariate analysis, skin changes, distal enhancement, and focal oedema maintained prognostic significance. CONCLUSION: Distal enhancement, focal oedema, and skin involvement have strong associations with breast cancer death. These factors could be taken into account, along with lesion size and other commonly used preoperative prognostic features, when considering management of women with breast cancer.

Extension of the known distribution of a novel clade C betacoronavirus in a wildlife host.

Disease surveillance in wildlife populations presents a logistical challenge, yet is critical in gaining a deeper understanding of the presence and impact of wildlife pathogens. Erinaceus coronavirus (EriCoV), a clade C Betacoronavirus, was first described in Western European hedgehogs (Erinaceus europaeus) in Germany. Here, our objective was to determine whether EriCoV is present, and if it is associated with disease, in Great Britain (GB). An EriCoV-specific BRYT-Green® real-time reverse transcription PCR assay was used to test 351 samples of faeces or distal large intestinal tract contents collected from casualty or dead hedgehogs from a wide area across GB. Viral RNA was detected in 10.8% (38) samples; however, the virus was not detected in any of the 61 samples tested from Scotland. The full genome sequence of the British EriCoV strain was determined using next generation sequencing; it shared 94% identity with a German EriCoV sequence. Multivariate statistical models using hedgehog case history data, faecal specimen descriptions and post-mortem examination findings found no significant associations indicative of disease associated with EriCoV in hedgehogs. These findings indicate that the Western European hedgehog is a reservoir host of EriCoV in the absence of apparent disease.

Evaluating the validity and reliability of the Medical Interview Satisfaction Scale in South African primary care consultations.

BACKGROUND: Effective primary care is vital for improving health outcomes. Patient-centred consultations are important and one way of assessing this is to evaluate patient satisfaction. The Medical Interview Satisfaction Scale (MISS) has not been used in South Africa. AIM: To test validity and reliability of the MISS and evaluate patient satisfaction with consultations. SETTING: Primary care facilities in the Helderberg sub-district, South Africa. METHODS: The MISS tool was adapted and validated by a panel of experts. The internal consistency was evaluated on 150 consultations. The level of patient satisfaction on 23 items, in consultations by nurses and doctors, was measured. Respondents indicated agreement with each item on a scale (1 = very strongly disagree, 7 = very strongly agree). RESULTS: The wording of the items were adapted and translated into Afrikaans and Xhosa. There was good overall internal consistency (Cronbach alpha 0.889), but not in all subscales. Patients were most satisfied with rapport (Median score 6.2 (IQR 5.3-5.9)) and understanding of their concerns, fears and beliefs (5.7 (IQR 5.1-6.3)). They were less satisfied with the ability to foster an acceptable management plan (5.5 (IQR 4.5-6.5)) and with accuracy of information (5.0 (IQR 4.2-5.8)). Scores for nurses and doctors were not significantly different. CONCLUSION: Further work is needed to improve the reliability of MISS subscales in the South African context and the best internal consistency was found with 21 items. Patients showed high levels of satisfaction with primary care consultations, although other studies suggest this may reflect low expectations rather than high quality consultations.

Herpesvirus skin disease in free-living common frogs Rana temporaria in Great Britain.

Infectious disease is a significant driver of global amphibian declines, yet despite this, relatively little is known about the range of pathogens that affect free-living amphibians. Recent detection of the tentatively named Ranid herpesvirus 3 (RHV3), associated with skin disease in free-living common frogs Rana temporaria in Switzerland, helps to address this paucity in knowledge, but the geographic distribution and epidemiology of the pathogen remains unclear. Syndromic surveillance for ranid herpesvirus skin disease was undertaken throughout Great Britain (GB), January 2014 to December 2016. Reports of common frogs with macroscopic skin lesions with a characteristic grey appearance were solicited from members of the public. Post-mortem examination was conducted on one affected frog found dead in 2015 at a site in England. In addition, archived samples from an incident involving common frogs in England in 1997 with similar macroscopic lesions were further investigated. Transmission electron microscopy identified herpes-like virions in skin lesions from both the 1997 and 2015 incidents. RHV3, or RHV3-like virus, was detected in skin lesions from the 2015 case by PCR and sequencing. Our findings indicate that herpesvirus skin disease is endemic in common frogs in GB, with widespread distribution at apparently low prevalence. Further research into the role of host immunity, virus latency and the significance of infection to host survival is required to better understand the epidemiology and impact of cutaneous herpesvirus infections in amphibian populations.

Temporal association between home nursing and hospital costs at end of life in three provinces.

BACKGROUND: Research has demonstrated that increases in palliative homecare nursing are associated with a reduction in the rate of subsequent hospitalizations. However, little evidence is available about the cost-savings potential of palliative nursing when accounting for both increased nursing costs and potentially reduced hospital costs. METHODS: Our retrospective cohort study included cancer decedents from British Columbia, Ontario, and Nova Scotia who received any palliative nursing in the last 6 months of life. A Poisson regression analysis was used to determine the association of increased nursing costs (in 2-week blocks) on the relative average hospital costs in the subsequent 2-week block and on the overall total cost (hospital costs plus nursing costs in the preceding 2-week block). RESULTS: The cohort included 58,022 cancer decedents. Results of the analysis for the last month of life showed an association between increased nursing costs and decreased relative hospital costs in comparisons with a reference group (>0 to 1 hour nursing in the block): the maximum decrease was 55% for Ontario, 31% for British Columbia, and 38% for Nova Scotia. Also, increased nursing costs in the last month were almost always associated with lower total costs in comparison with the reference. For example, cost savings per person-block ranged from $376 (>10 nursing hours) to $1,124 (>4 to 6 nursing hours) in British Columbia. CONCLUSIONS: In the last month of life, increased palliative nursing costs (compared with costs for >0 to 1 hour of nursing in the block) were associated with lower relative hospital costs and a lower total cost in a subsequent block. Our research suggests a cost-savings potential associated with increased community-based palliative nursing.

Quality of end-of-life cancer care in Canada: a retrospective four-province study using administrative health care data.

BACKGROUND: The quality of data comparing care at the end of life (eol) in cancer patients across Canada is poor. This project used identical cohorts and definitions to evaluate quality indicators for eol care in British Columbia, Alberta, Ontario, and Nova Scotia. METHODS: This retrospective cohort study of cancer decedents during fiscal years 2004-2009 used administrative health care data to examine health service quality indicators commonly used and previously identified as important to quality eol care: emergency department use, hospitalizations, intensive care unit admissions, chemotherapy, physician house calls, and home care visits near the eol, as well as death in hospital. Crude and standardized rates were calculated. In each province, two separate multivariable logistic regression models examined factors associated with receiving aggressive or supportive care. RESULTS: Overall, among the identified 200,285 cancer patients who died of their disease, 54% died in a hospital, with British Columbia having the lowest standardized rate of such deaths (50.2%). Emergency department use at eol ranged from 30.7% in Nova Scotia to 47.9% in Ontario. Of all patients, 8.7% received aggressive care (similar across all provinces), and 46.3% received supportive care (range: 41.2% in Nova Scotia to 61.8% in British Columbia). Lower neighbourhood income was consistently associated with a decreased likelihood of supportive care receipt. INTERPRETATION: We successfully used administrative health care data from four Canadian provinces to create identical cohorts with commonly defined indicators. This work is an important step toward maturing the field of eol care in Canada. Future work in this arena would be facilitated by national-level data-sharing arrangements.

[Lower extremity venous thrombosis in Togo]. / La thrombose veineuse des membres inférieurs au Togo.

The purpose of this report was to describe epidemiologic, clinical, and paraclinical aspects and to identify etiologic factors associated with lower extremity venous thrombosis in Lome, Togo.

Efficacy of Coronary Computed Tomography Angiography for the De Novo Detection of Chronic Total Occlusion Prior to Coronary Angiography: A Preliminary and Retrospective Study.

Coronary computed tomography angiography (CCTA) offers high-resolution anatomic characterization of the coronary vasculature but may be suboptimal for lesions dependent on real-time visualization of flow including chronic total occlusion (CTO). In CTOs, heavy calcification and distal vessel opacification from collateralization may confound luminal assessment. Several studies have examined the role of CCTA in characterizing known CTOs to guide percutaneous coronary intervention (PCI). However, the efficacy of CCTA in the de novo diagnosis of CTOs prior to coronary angiography (CAG) has not been demonstrated. A total of 233 consecutive patients who presented for CAG within a 3-month period of having CCTA were retrospectively reviewed. Those patients with prior diagnosis of CTO or prior bypass of the occluded vessels were excluded. Sensitivity and specificity analysis of CCTA in identifying CTOs using CAG as the gold standard was performed. The prevalence of CTO was 21.11% in the population that met criteria for analysis ( n = 199). The sensitivity of CCTA in predicting CTO was 57.1%, while the specificity was 96.8%. The positive predictive value and negative predictive value of CCTA in detection of CTO were 82.8 and 89.4%, respectively. Our study shows that CCTA has excellent specificity but poor sensitivity in the detection of CTO thus limiting its clinical use in de novo diagnosis. Further studies to determine the effect of de novo CTO diagnosis on clinically important procedural factors, such as radiation exposure, contrast use, and need for repeat procedures, are warranted and may implicate a role for CCTA in this setting.

Aflatoxin and ochratoxin A residues in supplementary foods used for wild birds.

Provision of supplementary food for garden birds is practiced on a large scale in multiple countries. While this resource has benefits for wild bird populations, concern has been expressed regarding the potential for contamination of foodstuffs by mycotoxins, and the implications this might have for wildlife health. We investigated whether aflatoxin (AF) and ochratoxin A (OA) residues are present in foodstuffs sold for wild bird consumption at point of sale in Great Britain using high pressure liquid chromatography analyses. The hypothesis that production of these mycotoxins occurs in British climatic conditions, or under storage conditions after the point of sale, was tested under experimental conditions but was not proved by our study. While the majority of peanut samples were negative for AF residues, 10% (10/98) of samples at point of sale and 11% (13/119) of those across the storage and climate exposure treatment replicates contained AFB1 that exceeded the maximum permitted limit of 20 µg/kg. No significant difference was found in the detection of either mycotoxin between branded and non-branded products. The clinical significance, if any, of exposure of wild birds to mycotoxins requires further investigation. Nevertheless, the precautionary principle should be adopted and best practice steps to reduce the likelihood of wild bird exposure to mycotoxins are recommended.

Development of comparable algorithms to measure primary care indicators using administrative health data across three Canadian provinces.

INTRODUCTION: Performance measurement has been recognized as key to transforming primary care (PC). Yet, performance reporting in PC lags behind even though high-performing PC is foundational to an effective and efficient health care system. OBJECTIVES: We used administrative data from three Canadian provinces, British Columbia, Ontario and Nova Scotia, to: 1) identify and develop a core set of PC performance indicators using administrative data and 2) examine their ability to capture PC performance. METHODS: Administrative data used included Physician Billings, Discharge Abstract Database, the National Ambulatory Care and Reporting System database, Census and Vital Statistics. Indicators were compiled based on a literature review of PC indicators previously developed with administrative data available in Canada (n=158). We engaged in iterative discussions to assess data conformity, completeness, and plausibility of results in all jurisdictions. Challenges to creating comparable algorithms were examined through content analysis and research team discussions, which included clinicians, analysts, and health services researchers familiar with PC. RESULTS: Our final list included 21 PC performance indicators pertaining to 1) technical care (n=4), 2) continuity of care (n=6), and 3) health services utilization (n=11). Establishing comparable algorithms across provinces was possible though time intensive. A major challenge was inconsistent data elements. Ease of data access, and a deep understanding of the data and practice context, was essential for selecting the most appropriate data elements. CONCLUSIONS: This project is unique in creating algorithms to measure PC performance across provinces. It was essential to balance internal validity of the indicators within a province and external validity across provinces. The intuitive desire of having the exact same coding across provinces was infeasible due to lack of standardized PC data. Rather, a context-tailored definition was developed for each jurisdiction. This work serves as an example for developing comparable PC performance indicators across different provincial/territorial jurisdictions.

Seroprevalence and isolation of Toxoplasma gondii from free-range chickens in Ghana, Indonesia, Italy, Poland, and Vietnam.

The prevalence of Toxoplasma gondii in free-ranging chickens (Gallus domesticus) is a good indicator of the prevalence of the parasite's oocysts in soil because chicken feed from the ground. The prevalence of T. gondii in free-range chickens from Ghana, Indonesia, Italy, Poland, and Vietnam was determined using the modified agglutination test (MAT). Antibodies to T. gondii were found in 41 (64%) of 64 chickens from Ghana, 24 (24.4%) of 98 chickens from Indonesia, 10 (12.5%) of 80 chickens from Italy, 6 (30%) of 20 chickens from Poland, and 81 (24.2%) of 330 chickens from Vietnam. Hearts and brains of chickens were bioassayed for T. gondii. Viable T. gondii was isolated from 2 chickens from Ghana, 1 chicken from Indonesia, 3 chickens from Italy, 2 chickens from Poland, and 1 chicken from Vietnam. Toxoplasma gondii isolates from 9 chickens were genotyped using 10 PCR-RFLP markers including SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico. A total of 7 genotypes was identified; the 3 isolates from chickens from Italy were clonal type II, and the others were nonclonal. This is the first report of genetic characterization of T. gondii isolates from animals from these countries.

Quantum oscillations of electrical resistivity in an insulator.

In metals, orbital motions of conduction electrons on the Fermi surface are quantized in magnetic fields, which is manifested by quantum oscillations in electrical resistivity. This Landau quantization is generally absent in insulators. Here, we report a notable exception in an insulator-ytterbium dodecaboride (YbB12). The resistivity of YbB12, which is of a much larger magnitude than the resistivity in metals, exhibits distinct quantum oscillations. These unconventional oscillations arise from the insulating bulk, even though the temperature dependence of the oscillation amplitude follows the conventional Fermi liquid theory of metals with a large effective mass. Quantum oscillations in the magnetic torque are also observed, albeit with a lighter effective mass.

Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc.

IFN-gamma, a pleiotropic cytokine, is a key effector molecule in the pathogenesis of several autoimmune diseases, including lupus. Importantly, deletion of IFN-gamma or IFN-gammaR in several lupus-predisposed mouse strains resulted in significant disease reduction, suggesting the potential for therapeutic intervention. We evaluated whether intramuscular injections of plasmids with cDNA encoding IFN-gammaR/Fc can retard lupus development and progression in MRL-Fas(lpr) mice. Therapy significantly reduced serum levels of IFN-gamma, as well as disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality), when treatment was initiated at the predisease stage, particularly when IFN-gammaR/Fc expression was enhanced by electroporation at the injection site. Remarkably, disease was arrested and even ameliorated when this treatment was initiated at an advanced stage. This therapy represents a rare example of disease reversal and makes application of this nonviral gene therapy in humans with lupus (and perhaps other autoimmune/inflammatory conditions) highly promising.

Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).

The gene encoding C/EBP-homologous protein (CHOP), also known as growth arrest and DNA-damage-inducible gene 153 (GADD153), is activated by agents that adversely affect the function of the endoplasmic reticulum (ER). Because of the pleiotropic effects of such agents on other cellular processes, the role of ER stress in inducing CHOP gene expression has remained unclear. We find that cells with conditional (temperature-sensitive) defects in protein glycosylation (CHO K12 and BHK tsBN7) induce CHOP when cultured at the nonpermissive temperature. In addition, cells that are defective in initiating the ER stress response, because of overexpression of an exogenous ER chaperone, BiP/GRP78, exhibit attenuated inducibility of CHOP. Surprisingly, attenuated induction of CHOP was also noted in BiP-overexpressing cells treated with methyl methanesulfonate, an agent thought to activate CHOP by causing DNA damage. The roles of DNA damage and growth arrest in the induction of CHOP were therefore reexamined. Induction of growth arrest by culture to confluence or treatment with the enzymatic inhibitor N-(phosphonacetyl)-L-aspartate did not induce CHOP. Furthermore, both a DNA-damage-causing nucleoside analog (5-hydroxymethyl-2'-deoxyuridine) and UV light alone did not induce CHOP. These results suggest that CHOP is more responsive to ER stress than to growth arrest or DNA damage and indicate a potential role for CHOP in linking stress in the ER to alterations in gene expression.

In vivo expression of mammalian BiP ATPase mutants causes disruption of the endoplasmic reticulum.

BiP possesses ATP binding/hydrolysis activities that are thought to be essential for its ability to chaperone protein folding and assembly in the endoplasmic reticulum (ER). We have produced a series of point mutations in a hamster BiP clone that inhibit ATPase activity and have generated a species-specific anti-BiP antibody to monitor the effects of mutant hamster BiP expression in COS monkey cells. The enzymatic inactivation of BiP did not interfere with its ability to bind to Ig heavy chains in vivo but did inhibit ATP-mediated release of heavy chains in vitro. Immunofluorescence staining and electron microscopy revealed vesiculation of the ER membranes in COS cells expressing BiP ATPase mutants. ER disruption was not observed when a "44K" fragment of BiP that did not include the protein binding domain was similarly mutated but was observed when the protein binding region of BiP was expressed without an ATP binding domain. This suggests that BiP binding to target proteins as an inactive chaperone is responsible for the ER disruption. This is the first report on the in vivo expression of mammalian BiP mutants and is demonstration that in vitro-identified ATPase mutants behave as dominant negative mutants when expressed in vivo.