The prevalence of cancer in patients with multiple sclerosis (MS) who received rituximab: a systematic review and meta-analysis.

OBJECTIVE: To estimate the pooled prevalence of cancer in patients with multiple sclerosis (MS) cases who were under treatment with rituximab. METHODS: We searched PubMed, Scopus, EMBASE, Web of Science, and google scholar along with gray literature up to April 2021. The search strategy included the MeSH and text words as (("CD20 Antibody" AND Rituximab) OR "Rituximab CD20 Antibody" OR Mabthera OR "IDEC-C2B8 Antibody" OR "IDEC C2B8 Antibody" OR IDEC-C2B8 OR "IDEC C2B8" OR GP2013 OR Rituxan OR rituximab) AND ((Sclerosis AND multiple) OR (sclerosis AND disseminated) OR "disseminated sclerosis" OR "multiple sclerosis" OR "acute fulminating"). RESULTS: The literature search revealed 3577 articles, after deleting duplicates 2066 remained. For the meta-analysis, 22 studies were included. Totally, 15599 patients were enrolled while 133 cancers were detected. The pooled prevalence of cancer in MS patients under treatment with rituximab is 1in 100,000 (I2 = 99.9%, p < 0.001). CONCLUSION: The results of this systematic review and meta-analysis show that the pooled prevalence of cancer in MS patients who received rituximab is 1 in 100,000 cases.

Water vapor capturing using an array of traveling liquid beads for desalination and water treatment.

Growing concern over the scarcity of freshwater motivates the development of compact and economic vapor capture methods for distributed thermal desalination or harvesting of water. We report a study of water vapor condensation on cold liquid beads traveling down a massive array of vertical cotton threads that act as pseudo-superhydrophilic surfaces. These liquid beads form through intrinsic flow instability and offer localized high-curvature surfaces that enhance vapor diffusion toward the liquid surface, a critical rate-limiting step. As the liquid flow rate increases, the bead spacing decreases, whereas the bead size and speed stay nearly constant. The resulting increase in the spatial bead density leads to mass transfer conductances and hence condensation rates per volume that are almost three times higher than the best reported values. Parallel and contiguous gas flow paths also result in a substantial reduction in gas pressure drop and hence electric fan power consumption.

Phenotyping and long-term follow up of patients with hyper IgE syndrome

Introduction and objectives: Long-term follow up of patients with hyper IgE syndrome (HIES), as a primary immunodeficiency disorder, has been poorly investigated. This study describes common clinical and immunological features of patients with HIES in the last 10 years in Shiraz University of Medical Sciences, Shiraz, Iran. Methods and patients: In this cross-sectional study, the symptoms and medical records of 18 patients, who were diagnosed with HIES, were observed. Genetic and immunologic study was also performed. Results: Eighteen patients with the mean age of 13 years old were investigated. Ten patients were detected to have mutations in DOCK8 gene and autosomal recessive HIES (AR-HIES); and four patients were found with STAT3 mutation and autosomal dominant HIES (AD-HIES). So, 14 patients with known genetic results were considered for further data analysis. Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. Food allergy and viral infection were significantly higher in DOCK8 deficient patients. The most common causes of hospitalization in both AR-HIES and AD-HIES patients were pneumonia, skin infections and sepsis. The most common cause of death was found to be sepsis. Conclusions; AD-HIES and AR-HIES cannot be differentiated only based on the clinical presentations. Genetic features are also necessary for better diagnosis. This study, summarizing the clinical, immunological and genetic information of the patients with AD-HIES and AR-HIES, may open a way for better diagnosis and management of HIES

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Phenotyping and long-term follow up of patients with hyper IgE syndrome.

INTRODUCTION AND OBJECTIVES: Long-term follow up of patients with hyper IgE syndrome (HIES), as a primary immunodeficiency disorder, has been poorly investigated. This study describes common clinical and immunological features of patients with HIES in the last 10 years in Shiraz University of Medical Sciences, Shiraz, Iran. METHODS AND PATIENTS: In this cross-sectional study, the symptoms and medical records of 18 patients, who were diagnosed with HIES, were observed. Genetic and immunologic study was also performed. RESULTS: Eighteen patients with the mean age of 13 years old were investigated. Ten patients were detected to have mutations in DOCK8 gene and autosomal recessive HIES (AR-HIES); and four patients were found with STAT3 mutation and autosomal dominant HIES (AD-HIES). So, 14 patients with known genetic results were considered for further data analysis. Food allergy, eczema, viral and skin infections were the major complications of AR-HIES patients. The major clinical complications of AD-HIES patients were pneumonia, skin infections and eczema. Food allergy and viral infection were significantly higher in DOCK8 deficient patients. The most common causes of hospitalization in both AR-HIES and AD-HIES patients were pneumonia, skin infections and sepsis. The most common cause of death was found to be sepsis. CONCLUSIONS: AD-HIES and AR-HIES cannot be differentiated only based on the clinical presentations. Genetic features are also necessary for better diagnosis. This study, summarizing the clinical, immunological and genetic information of the patients with AD-HIES and AR-HIES, may open a way for better diagnosis and management of HIES.

Bayesian framework for parametric bivariate accelerated lifetime modeling and its application to hospital acquired infections.

Infectious diseases that can be spread directly or indirectly from one person to another are caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi. Infectious diseases remain one of the greatest threats to human health and the analysis of infectious disease data is among the most important application of statistics. In this article, we develop Bayesian methodology using parametric bivariate accelerated lifetime model to study dependency between the colonization and infection times for Acinetobacter baumannii bacteria which is leading cause of infection among the hospital infection agents. We also study their associations with covariates such as age, gender, apache score, antibiotics use 3 months before admission and invasive mechanical ventilation use. To account for singularity, we use Singular Bivariate Extreme Value distribution to model residuals in Bivariate Accelerated lifetime model under the fully Bayesian framework. We analyze a censored data related to the colonization and infection collected in five major hospitals in Turkey using our methodology. The data analysis done in this article is for illustration of our proposed method and can be applied to any situation that our model can be used.

Optimizing Trehalose-Based Quantification of Live Eggs in Potato Cyst Nematodes (Globodera rostochiensis and G. pallida).

Integrated management of potato cyst nematodes (PCN; Globodera rostochiensis and G. pallida) relies heavily on the determination of cyst population densities in soil as well as the viability of the eggs inside the cysts. This study aimed to optimize a quantitative method to determine the number of viable eggs of PCN based on trehalose present in live eggs. Trehalose was extracted from cysts and from a dilution series of eggs and quantified. More trehalose was detected when cysts were crushed than when left intact. Reaction volumes were adapted to the number of eggs because small reaction volumes hampered an accurate extraction of trehalose. A maximum of 10.5 eggs/µl of reaction volume should be used to obtain a significant linear relationship between detected trehalose content and egg numbers. The sensitivity of the trehalose-based method was evaluated by determining the lowest egg detection limit and was defined as five viable eggs. The reliability of this method was tested by comparing efficacy with that of two commonly used assays, visual assessment and hatching test. The trehalose-based method gave viability results similar to those of the visual assessment, which is time consuming, requires trained personnel, and can involve some subjectivity. The hatching test identified fewer viable eggs than the other two methods. In addition, the viability of dead eggs (heated and naturally dead) was tested. No false-positive results (dead eggs declared viable) were obtained with the trehalose-based method. The robustness of the test was demonstrated by measuring the viability of eggs of PCN in different experiments repeated in time. The viability assessment method based on trehalose proved to be an objective as well as sensitive, reliable, robust, fast, and cheap technique for assessing the number of viable eggs in PCN cysts.

An audit of the efficacy of a structured handover tool in obstetric anaesthesia.

INTRODUCTION: The SAFE handover tool was developed to reduce critical omissions during handovers in obstetric anaesthesia. It comprises a simple proforma onto which the outgoing team documents patients who fall into one of four anaesthetically relevant categories: Sick patients; At-risk patients (of emergency caesarean section, major haemorrhage or anaesthetic problems); Follow-ups; and Epidurals. We hypothesised that its use would reduce the number of critical omissions at handover. METHODS: The efficacy of the SAFE handover tool was assessed through several audit cycles in a single maternity unit. The four SAFE categories were considered the gold standard, since they encompassed the consensus opinion of senior obstetric anaesthetists with respect to parturients they most wanted to know about at handover. Against these criteria it was possible to compare the number of cases that should have been handed-over against the number that were actually handed-over. RESULTS: After implementation of the handover tool, patients were four times more likely to be handed-over than without the use of the tool: an increase from 49% to 79% of relevant cases (P<0.0001, OR 4.1, 95% CI 2.19-7.6). The handover tool was particularly effective at increasing the handover rates of Sick and At-risk parturients, which increased from 21% to 67% (P<0.0001, OR 7.7, 95% CI 2.7-21.7) and 25% to 78% (P<0.01, OR 9.9, 95% CI 1.6-61.6), respectively. CONCLUSION: The SAFE handover tool significantly increased handover rates of anaesthetically relevant parturients. It is easy to remember and consistent with UK National Health Service Litigation Authority's guidance on risk management in maternity units.

Comparative study on corrosion behaviour of Nitinol and stainless steel orthodontic wires in simulated saliva solution in presence of fluoride ions.

Localized corrosion and effects of pre-passivation treatment of Nitinol and SS304 orthodontic wires in simulated saliva solution in the presence and absence of fluoride ions were investigated by means of potentiodynamic and potentiostatic polarisations. Results revealed that Nitinol does not show pitting corrosion in saliva solution however, SS304 shows pitting corrosion. Meanwhile fluoride ion has deteriorative effect on pitting corrosion of Nitinol, while its effect on SS304 was marginally constructive. Additionally, the presence of artificial crevice has no effect on corrosion behaviour in the presence of fluoride. Pre-passivation treatment has positive influence on pitting corrosion of both alloys in the presence of F(-) ions.

Stent conformity in curved vascular models with simulated aneurysm necks using flat-panel CT: an in vitro study.

BACKGROUND AND PURPOSE: Radiographic visibility of self-expandable intracranial stents is insufficient for assessment of conformability and deployment characteristics. The purpose of this study was to evaluate stent mechanics in a curved vessel model by using Flat-Panel CT (FPCT). MATERIALS AND METHODS: The following stents were used: Neuroform 2, Neuroform Treo, Enterprise, and LEO. All stents were bent in the same polytetrafluoroethylene tubes with various angles ranging from 150 degrees to 30 degrees . To visualize potential prolapse of the stent struts, 4-, 5-, and 8-mm openings were created. FPCTs were obtained using a C-arm with flat detector. RESULTS: FPCT scans provided excellent visualization of deployment characteristics and stent mechanics and was superior to digital subtraction angiography (DSA) and digital radiography (DR). The Neuroform2/Treo showed, with increasing angle and diameter of the opening, a continuous increase in cell size. These stents also showed an outward prolapse at the convexity and an inwards prolapse of struts at the concavity of the curvature. The Enterprise showed an increasing trend to flatten and to kink with curvatures that are more acute. The LEO showed fewer trends to kink but an inward crimping of its ends with more acute angles. CONCLUSIONS: Deployment characteristics and conformability to a curved vessel model vary considerably, depending on the angle and the stent design. Adverse mechanics such as increased cell opening, strut prolapse, flattening, and kinking occur during stent placement in a curved vessel model, and may gain clinical importance. FPCT is superior to DSA and DR in visualizing small metallic stents and enables accurate detection of adverse stent mechanics.

Topical H2 antagonist prevents periodontitis in a rabbit model.

Cimetidine is a powerful H2 receptor antagonist that eliminates histamine's effects on chemotaxis, phagocytosis, and superoxide anion production by phagocytes. The purpose of this study was to analyze the clinical and histopathological changes associated with experimental periodontitis in rabbits in response to topically applied cimetidine. Experimental periodontitis was induced in 21 New Zealand White rabbits using Porphyromonas gingivalis (10(9) CFU) topically applied three times a week for a 6-week period to previously ligatured teeth. Topical application of cimetidine in a liposome carrier for the prevention of periodontitis was evaluated in four groups of four animals each: 1, 10, and 100 mg/ml and no treatment (positive control). In addition, there was a vehicle group (n = 3) that received liposome preparation (carrier) only, and two animals with ligature application alone served as negative controls. Periodontal disease was quantified by direct visualization and radiographical evaluation of bone loss on defleshed skulls and by histological analyses of sections stained with hematoxylin-eosin and tartrate-resistant acid phosphatase. In the no-treatment (positive control) and liposome (vehicle) groups, direct visualization and radiological measurements revealed statistically significant bone loss compared to the negative control. Application of cimetidine at all concentrations tested inhibited inflammation and bone loss by >90%. Histological findings revealed that ligated sites of the positive control and vehicle groups showed significant reduction in bone level (P < 0.05) compared to the three cimetidine groups, with a marked decrease in inflammation. The findings of this study provide morphological and histological evidence that topically active cimetidine is a potent inhibitor of P. gingivalis-elicited periodontal inflammation, arresting and/or preventing tissue destruction and influencing cell populations present in the inflammatory cell infiltrate.

RvE1 protects from local inflammation and osteoclast- mediated bone destruction in periodontitis.

Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation that has pathogenic features similar to those observed in other inflammatory diseases such as arthritis. Resolvins are a new family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammatory signals. Because it is now increasingly apparent that local inflammation plays a critical role in many diseases, including cardiovascular disease, atherosclerosis, and asthma, experiments were undertaken to evaluate the actions of the newly described EPA-derived Resolvin E1 (RvE1) in regulation of neutrophil tissue destruction and resolution of inflammation. The actions of an aspirin-triggered lipoxin (LX) analog and RvE1 in a human disease, localized aggressive periodontitis (LAP), were determined. Results indicate that neutrophils from LAP are refractory to anti-inflammatory molecules of the LX series, whereas LAP neutrophils respond to RvE1. In addition, RvE1 specifically binds to human neutrophils at a site that is functionally distinct from the LX receptor. Consistent with these potent actions, topical application of RvE1 in rabbit periodontitis conferred dramatic protection against inflammation induced tissue and bone loss associated with periodontitis.

First Report of Pratylenchus neglectus and P. thornei Infecting Canola and Weeds in Iran.

Cultivation of canola (Brassica napus L.) is relatively new in Iran. Because nearly 90% of Iran's edible oil is imported, farmers are subsidized and encouraged to grow this crop. Except for the sugar beet cyst nematode, Heterodera schachtii, to which susceptibility of some canola cultivars has been established (1), information on other nematode pests of canola is lacking. During a survey from April-May 2002 and repeated in 2003, soil and root samples of winter canola and weeds were collected at harvest of canola from research stations and farmers' fields in the south, west, and northwest of Tehran Province. Each sample was a composite of 25 roots and 2 kg of soil per hectare, collected from the rhizosphere of canola with a 2.5-cm-diameter soil corer. Samples were put in plastic bags and kept at 5°C until they were processed, within 2 weeks from sampling. Samples were sieved through a 0.840-cm aperture sieveand mixed thoroughly. Nematodes were extracted from subsamples of 5 g of roots and 250 g of soil with a modification of the sugar centrifugal flotation method (2), counted, and identified. Two species of root lesion nematodes, Pratylenchus neglectus and P. thornei, were found. When they were present in the same field, they occurred in the roots of both Regents × Cobra and Orient cultivars. Averages of 28 and 321 P. thornei per gram were found in the roots of cvs. Regents × Cobra and Orient, respectively. Averages of 30, 1,026, 626, and 450 P. neglectus per gram of roots of cvs. Regents × Cobra, Orient, Ocapi, and GLSIO were detected, respectively, in different fields. Heavily infected plants were stunted and had roots with dark lesions, a symptom typical of the attacks by these nematodes. Generally, greater nematode densities were in the roots than in the soil and both nematode species were more abundant in cooler than in warmer areas of the province. Since these nematodes are also severe pests of wheat, which is also grown in the province, they could pose a potential threat to both crops. Weeds that were present in the sampled fields belonged to the botanical families Scrophulariaceae, Gramineae, Euphorbiaceae, Crucifereae, and Compositeae. Between 22 and 1,500 P. thornei and 17 P. neglectus per gram of roots of Crucifereae and 280 P. thornei per gram of roots of Gramineae were found. To our knowledge, this is the first report of lesion nematodes infecting canola plants in Iran. References: (1) S. Fatemy and E. Abootorabi. Nematol. Mediterr. 30:163, 2002. (2) W. R. Jenkins. Plant Dis. Rep. 48:692, 1964.

Occurrence of plant parasitic nematodes (Tylenchina) in sugar beet fields in Fars province, Iran.

On a survey of plant parasitic nematode fauna, belonging to the suborder Tylenchina, about 110 soil and root samples were collected from different sugar beet field in fars Province in Iran. The samples were washed and the nematodes were extracted by Centrifugal Flotation Technique according to the modified method by De Grisse, 1969. They were fixed and transferred to glycerine, then permanent slides were mounted. Morphological and morphometrical characters of collected species were carefully studied and the characters were compared with the original descriptions and differences were discussed. In this study 18 species belonging to 11 different genera of subordes Tylenchina were identified as follows. Boleodorus thylactus, Ditylenchus destructor, D. dipsaci Geocenamus brevidens, G. rugosus, Helicotylenchus digonicus, H. pseudorobustus, H. vulgaris, Heterodera filipjevi, H. schachtii, Pratylenchus neglectus, P. thornei, Psilenchus hilarulus, P. hilarus, Stictylus mucronatus, Tylenchorhynchus ventrosinatus, Tylenchus davainei and Zygotylenchus guevarai. The species of the genera Ditylenchus, Heterodera, Pratylenchus and Psilenchus were comparatively more distributed than the others. This investigation revealed that sugar beet cyst nematode (Heterodera schachti) was found already in most sugar beet fields in this Province. Fathabod, Marvdasht and Tasuj-kwar were the most infested areas. Cysts collected from 100 gr. Of soil samples were 120 to 121 in number and the eggs and second stage larvae in each gr. of soil were 104.1 to 104.5 respectively.

Initial outcomes in the Multicenter Study of Epilepsy Surgery.

OBJECTIVE: To obtain prospective data regarding seizures, anxiety, depression, and quality of life (QOL) outcomes after resective epilepsy surgery. METHODS: The authors characterized resective epilepsy surgery patients prospectively at yearly intervals for seizure outcome, QOL, anxiety, and depression, using standardized instruments and patient interviews. RESULTS: Of 396 patients who underwent resective surgical procedures, 355 were followed for at least 1 year. Of these, 75% achieved a 1-year remission at some time during follow-up; patients with medial temporal (77%) were more likely than neocortical resections (56%) to achieve remission (p = 0.01). Relapse occurred in 59 (22%) patients who remitted, more often in medial temporal (24%) than neocortical (4%) resected patients (p = 0.02). QOL, anxiety, and depression all improved dramatically within 3 months after surgery (p < 0.0001), with no significant difference based on seizure outcome. After 3 months, QOL in seizure-free patients further improved gradually, and patients with seizures showed gradual declines. By 12 and 24 months, overall QOL and its epilepsy-targeted and physical health domains were significantly different in the two outcome groups. (Anxiety and depression scores also gradually diverged, with improvements in seizure-free and declines in continued seizure groups, but differences were not significant.) CONCLUSION: Resective surgery for treatment of epilepsy significantly reduces seizures, most strikingly after medial temporal resection (77% 1 year remission) compared to neocortical resection (56% 1 year remission). Resective epilepsy surgery has a gradual but lasting effect on QOL, but minimal effects on anxiety and depression. Longer follow-up will be essential to determine ultimate seizure, QOL, and psychiatric outcomes of epilepsy surgery.

Defining early seizure outcomes in pediatric epilepsy: the good, the bad and the in-between.

PURPOSE: To examine different approaches to classifying seizure outcomes. METHODS: In a prospective cohort study of children (N=613) with newly diagnosed epilepsy, seizure outcomes at 2 years were classified as 'good' (> or =1 year remission), 'bad' or 'intractable' (> or = AED failures, > or =1 seizure/month over > or =18 months), and 'indeterminate' (neither 'good' nor 'bad'). Outcomes at 2 years were compared to outcomes in those followed 4 or more years. The associations of three commonly studied prognostic factors, etiology, age at onset, and syndromic grouping with the three-level outcome were assessed. RESULTS: 595 (97.1%) children were followed > or =2 years. A 'good', indeterminate, and 'bad' outcome was present in 314 (52.8%), 235 (38.3%), and 46 (7.7%) children. Problems with treatment were recorded in 64.7% of the indeterminate group. In 390 children followed > or =4 years, early 'good' and 'bad' outcomes persisted in approximately 80%. About half of those with indeterminate 2-year outcomes later achieved remission, 8% met criteria for intractability, and 37% remained indeterminate. Most of the associations with etiology, age, and syndrome were due to variation in the proportion that met criteria for intractability and not remission. CONCLUSIONS: Many children have indeterminate outcomes, often in association with treatment issues. Clearly 'good' and 'bad' early outcomes can be identified and persist > or =2 years later. In the absence of pharmaco-resistance, lack of early remission (indeterminate outcome) is usually not associated with a bad outcome, at least over the next few years.

Two-year remission and subsequent relapse in children with newly diagnosed epilepsy.

PURPOSE: Although remission is the ultimate measure of seizure control in epilepsy, and epilepsy syndrome should largely determine this outcome, little is known about the relative importance of syndrome versus other factors traditionally examined as predictors of remission or of relapse after remission. The purpose of this study was to examine remission and relapse with respect to the epilepsy syndrome and other factors traditionally considered with respect to seizure outcome. METHODS: A prospectively identified cohort of 613 children with newly diagnosed epilepsy was assembled and is actively being followed to determine seizure outcomes. Epilepsy syndrome and etiology were classified at diagnosis and again 2 years later. Remission was defined as 2 years completely seizure-free, and relapse as the recurrence of seizures after remission. Multivariable analysis was performed with the Cox proportional hazards model. RESULTS: Five hundred ninety-four of the original 613 children were followed > or = 2 years (median follow-up, 5 years). Remission occurred in 442 (74%), of whom 107 (24%) relapsed. On multivariable analysis, idiopathic generalized syndromes and age at onset between 5 and 9 years were associated with a substantially increased remission rate, whereas remote symptomatic etiology, family history of epilepsy, seizure frequency, and slowing on the initial EEG were associated with a decreased likelihood of attaining remission. Young onset age (<1 year) and seizure type were not important after adjustment for these predictors. Relapses occurred more often in association with focal slowing on the initial EEG and with juvenile myoclonic epilepsy. Benign rolandic epilepsy and age at onset <1 year were associated with markedly lower risks of relapse. About one fourth of relapses were apparently spontaneous while the child was taking medication with good compliance, and more than half occurred in children who were tapering or had fully stopped medication. CONCLUSIONS: A large proportion of children with epilepsy remit. Symptomatic etiology, family history, EEG slowing, and initial seizure frequency negatively influence, and age 5-9 years and idiopathic generalized epilepsy positively influence the probability of entering remission. Factors that most influence relapse tend to be different from those that influence remission.

The effects of misclassification of the actual cause of death in competing risks analysis.

The problem of competing risks analysis arises often in public health, demography, actuarial science, industrial reliability applications, and experiments in medical therapeutics. In the classical competing risks scenario one models the risks with a vector (T = (T1, ..., Tk) of non-negative random variables that represents the potential times to death of k risks. One cannot see T directly but sees instead Y = min (T1, ..., Tk) and the actual cause of death. The major difficulty with this analysis is the requirement for the expert to specify the single cause of death that, in fact, may not be the actual cause. This paper addresses competing risks analysis for the situations where one observes Y and the set of several possible causes of death specified by the expert. Many times there are several causes that act together and realistically it is impossible for the expert to assign a death to a single cause. In particular, I provide a likelihood for parametric competing risks analysis when the actual cause of death is possibly misclassified. The data include time to death, Y, and a set of possible causes of death. If misclassification probabilities are unknown, I propose a Baysian analysis based on a prior distribution for the parameters of interest and for the misclassification probabilities.

Estimation of two ordered mean residual lifetime functions.

In many statistical studies involving failure data, biometric mortality data, and actuarial data, mean residual lifetime (MRL) function is of prime importance. In this paper we introduce the problem of nonparametric estimation of a MRL function on an interval when this function is bounded from below by another such function (known or unknown) on that interval, and derive the corresponding two functional estimators. The first is to be used when there is a known bound, and the second when the bound is another MRL function to be estimated independently. Both estimators are obtained by truncating the empirical estimator discussed by Yang (1978, Annals of Statistics 6, 112-117). In the first case, it is truncated at a known bound; in the second, at a point somewhere between the two empirical estimates. Consistency of both estimators is proved, and a pointwise large-sample distribution theory of the first estimator is derived.