Cryptosporidiosis after treatment with fingolimod: a case report and pharmacovigilance review.

BACKGROUND: Cryptosporidium sp. are common intracellular parasites responsible of severe diarrhea in T-cell-immunocompromised patients. We report the first case of a woman who contracted cryptosporidiosis after treatment with fingolimod, a drug labeled for multiple sclerosis and responsible for marked lymphopenia. CASE PRESENTATION: A 60-year-old woman was admitted for abdominal pain diarrhea and fever. The patient suffered from multiple sclerosis and had been treated with fingolimod from august 2017 to september 2018 time of occurrence of the first digestive symptoms. Stool culture was negative but parasitological examination was positive for Cryptosporidium sp. Blood biological examination profound lymphopenia of 240/mm3 [17 CD4/mm3 (7%) and 32 CD8/mm3 (14%)]. Fingolimod was stopped, and the patient was put on nitazoxanide 500 mg bid for 7 days. The diarrhea resolved and no relapse was observed. Six other cases were found in the Pharmacovigilance database. CONCLUSION: Physicians should be aware of this association and screen for Cryptosporidium in cases of diarrhea in patients treated with fingolimod. Patients should be aware of this risk and advise to take appropriate measures to avoid such contamination.

Patient safety ward round checklist via an electronic app: implications for harm prevention.

INTRODUCTION: Patient safety is a value at the core of modern healthcare. Though awareness in the medical community is growing, implementing systematic approaches similar to those used in other high reliability industries is proving difficult. The aim of this research was twofold, to establish a baseline for patient safety practices on routine ward rounds and to test the feasibility of implementing an electronic patient safety checklist application. METHODS: Two research teams were formed; one auditing a medical team to establish a procedural baseline of "usual care" practice and an intervention team concurrently was enforcing the implementation of the checklist. The checklist was comprised of eight standard clinical practice items. The program was conducted over a 2-week period and 1 month later, a retrospective analysis of patient charts was conducted using a global trigger tool to determine variance between the experimental groups. Finally, feedback from the physician participants was considered. RESULTS: The results demonstrated a statistically significant difference on five variables of a total of 16. The auditing team observed low adherence to patient identification (0.0%), hand decontamination (5.5%), and presence of nurse on ward rounds (6.8%). Physician feedback was generally positive. CONCLUSIONS: The baseline audit demonstrated significant practice bias on daily ward rounds which tended to omit several key-proven patient safety practices such as prompting hand decontamination and obtaining up to date reports from nursing staff. Results of the intervention arm demonstrate the feasibility of using the Checklist App on daily ward rounds.

History rather than hybridization determines population structure and adaptation in Populus balsamifera.

Hybridization between species is known to greatly affect their genetic diversity and, therefore, their evolution. Also, within species, there may be genetic clusters between which gene flow is limited, which may impact natural selection. However, few studies have looked simultaneously at the influence of among-species and within-species gene flow. Here, we study the influence of hybridization between Populus balsamifera and Populus trichocarpa on population structure and adaptation in P. balsamifera. We did this by sampling a total of 1517 individuals from across the ranges of these two species, and by genotyping them using a combination of 93 nuclear and 17 cpDNA SNPs. We found that hybridization is mostly limited to the contact zone where the species' distributions overlap. Within P. balsamifera, we found multiple levels of population structure. Interestingly, the border between the Eastern and Central clusters is very sharp, whereas the border between the Central and Western clusters is diffuse. Outlier analysis revealed that three loci associated with the sharp border were also associated with climate. We hypothesize that the observed clusters derive from three refugia during the Pleistocene ice ages. Between the Central and Western clusters, post-glacial long-distance gene flow has led to the diffusion of their border. In the Eastern cluster, we hypothesize that endogenous genomic barriers have developed, leading to the sharp border and a spurious climate association. We conclude that the large-scale genetic structure of P. balsamifera is mostly shaped by historical factors and the influence of interspecific hybridization is limited.

Ruminally undegradable protein content and digestibility for forages using the mobile bag in situ technique.

Four experiments were conducted to evaluate RUP content and digestibility for smooth bromegrass, subirrigated meadow, upland native range, and warm-season grasses. Samples were collected from esophageally cannulated cows or ruminally cannulated steers. Forages were ruminally incubated in in situ bags for durations of time based on 75% of total mean retention time, which was based on IVDMD and rate of passage calculations. One-half of the bags were duodenally incubated and excreted in the feces, and NDIN was analyzed on all bags for RUP calculations. Crude protein was numerically greater early in the growing cycle for grasses compared with later as grasses matured (P ≤ 0.32). The RUP was 13.3%, 13.3%, and 19.7% of CP for smooth bromegrass, subirrigated meadow, and upland native range, respectively. These values tended to be lower early in the growth cycle and increased (linear P ≤ 0.13) as forages matured for warm-season grasses and subirrigated meadows. Because both CP and RUP content change throughout the growing season, expressing RUP as a percentage of DM gives more consistent averages compared with RUP as a percentage of CP. Coefficient of variation values for RUP as a percentage of DM averaged 0.21 over all 4 experiments compared with 0.26 for RUP as a percentage of CP. Average RUP as a percentage of DM was 2.03%, 1.53%, and 1.94% for smooth bromegrass, subirrigated meadow, and upland native range, respectively. Total tract indigestible protein (TTIDP) linearly increased with maturity for subirrigated meadow samples (P < 0.01). A quadratic response (P ≤ 0.06) for TTIDP was observed in smooth bromegrass and warm-season grass samples. Digestibility of RUP varied considerably, ranging from 25% to 60%. Subirrigated meadow, native range, and smooth bromegrass samples tended to have linear decreases (P ≤ 0.11) in RUP digestibility throughout the growing season. The amount of digested RUP was fairly consistent across experiments and averages for smooth bromegrass, subirrigated meadow, and upland native range were 0.92%, 0.64%, and 0.49% of DM, respectively. Warm-season grasses in Exp. 2 had greater RUP (4.31% of DM) and amount of RUP digested (2.26% of DM), possibly because of cattle selecting for leadplant that contains more CP than the grasses. Forages can vary in CP, RUP, TTIDP, and RUP digestibility depending on the forage type, year, and time within year, but RUP digestibility is likely less than what previous sources have reported.

Estimation of undegradable intake protein in forages using neutral detergent insoluble nitrogen at a single in situ incubation time point.

Two experiments were conducted to evaluate the use of neutral detergent insoluble nitrogen (NDIN) at a single in situ incubation time point to estimate the undegradable intake protein (UIP) in forages as well as to compare rates of NDIN degradation. Forage samples in Exp. 1 comprised diet samples collected from range and meadow pastures monthly from May through September. In Exp. 2, clipped samples of alfalfa, birdsfoot trefoil, kura clover, and smooth bromegrass, and diet samples of the mixed legume-grass and smooth bromegrass were evaluated. Forage samples were incubated in situ for their mean retention time (MRT) estimated from IVDMD plus a 10-h passage lag to yield the total MRT (TMRT). Samples were also incubated for 0 h, 10 h, 75% TMRT, and 96 h. Undegradable intake protein was measured at 75% TMRT and TMRT, and calculated using fractional rates of degradation and passage with a 10-h passage lag. Rates of ruminal NDIN degradation were calculated using the slope of the regression of the natural logarithm of the potentially degradable NDIN remaining (96-h undegradable fraction subtracted) against time. The estimated UIP values obtained using 75% TMRT were highly correlated with those obtained using fractional rates of degradation and passage plus accounting for a 10-h passage lag in Exp. 1 (R2 = 0.95) and Exp. 2 (R2 = 0.98). Rates of NDIN degradation of range and meadow samples in Exp. 1 were slower (P < 0.05) from 0 to 10 h in May and June compared with rates from 10 h to 75% TMRT, but rates of degradation were not different (P = 0.34 to 0.71) for the rest of the collection periods. Rates of degradation were not different from 0 to 10 h and 10 h to 75% TMRT in Exp. 2 for diet (P = 0.82) or clipped samples (P = 0.86). The UIP of the forages in these experiments was accurately estimated using NDIN at a single in situ incubation time point equivalent to 75% of the TMRT, and rates of protein degradation can be obtained at this time point when 0- and 96-h incubations are included.

Concepts and approaches to in situ luminescence dating of Martian sediments.

In this paper we present the concept of a robotic instrument for in situ luminescence dating of near-surface sediments on Mars. The scientific objectives and advantages to be gained from the development of such an instrument are described, and the challenges presented by the Mars surface environment to the design and operation of the instrument are outlined.

Recent progress in protein farnesyltransferase inhibition.

This review aims to provide a recent update on protein farnesyltransferase inhibition, covering the period 1999 to mid 2000. A brief overview of the project rationale and its most recent evolution is also presented. For each inhibitor series, the most advanced molecules are presented along with a short description of the patent environment, focusing on second generation patents that cover new applications for protein farnesyltransferase inhibitors (PFTIs).

Characterization of endoglin on mouse uterine stromal cells.

During the oestrous cycle and early pregnancy, the uterus undergoes a variety of morphological and physiological modifications involving uterine cell proliferation and differentiation as well as extensive tissue remodelling. Transforming growth factor beta (TGF-beta) has powerful effects on these events and thus is thought to have a critical role in uterine physiology. Endoglin is a transmembrane glycoprotein that binds TGF-beta 1 and -beta 3 and interacts with TGF-beta signalling receptors to modulate many effects of this growth factor in different types of cell. Studies in mice revealed the highest concentrations of endoglin in the reproductive tract, notably on stromal cells of cyclic and pregnant uteri. The objective of the present study was to investigate the role of endoglin expressed on uterine stromal cells in binding TGF-beta and in the cellular responses induced by this growth factor. Highly purified populations of uterine stromal cells were isolated by cell affinity to the monoclonal antibody MJ7/18, which is specific to mouse endoglin. Affinity labelling of these cells with 125I-labelled TGF-beta followed by immunoprecipitation with endoglin-specific polyclonal 1256:4b antiserum indicated that endoglin expressed at the surface of uterine stromal cells binds TGF-beta 1 and interacts with TGF-beta signalling receptors. Treatment of uterine stromal cells with different concentrations of TGF-beta 1 induced a biphasic proliferative response and addition of MJ7/18 as well as neutralizing TGF-beta antibodies showed endoglin to be a modulator of TGF-beta-induced stromal cell proliferation. Given the importance of TGF-beta in the regulation of uterine physiology, these results indicate a role for endoglin during uterine tissue remodelling and decidualization.

Differentiation between partial agonists and neutral 5-HT1B antagonists by chemical modulation of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (GR-55562).

The synthesis and binding affinity at cloned h5-HT1D, h5-HT1D, and h5-HT1A receptors of 3-[3-(N,N-dimethylamino)propyl]-4-hydroxy- N-[4-(pyridin-4-yl)phenyl]benzamide (2, GR-55562) and four O-methylated analogs are described. The functional activity of these compounds was determined at the h5-HT1B receptor using a [35S]GTP gamma S binding assay. The four analogs have been prepared in order to evaluate the influence of the alkylamino side chain conformation on binding and intrinsic activity. Whereas 2 and its derivatives display a similar binding affinity profile, major differences arise from analysis of the intrinsic activity data at h5-HT1B receptors. The O-methylated analog of 2, 3-[3-(N,N-dimethylamino)propyl]-4-methoxy- N-[4-(pyridin-4-yl)phenyl]benzamide (3a), and the (1Z)-3-(N,N-dimethylamino)prop-1-enyl derivative (3c) act as neutral and potent antagonists (in a similar way to 2), while the 3-(N,N-dimethylamino)-prop-1-ynyl (3b) and (1E)-3-(N,N-dimethylamino)prop-1-enyl (3d) analogs display nonnegligible agonist activity. Molecular modeling studies show that, when the common triaryl portions of the molecules are overlapped, the partial agonists and the neutral antagonists differ by a near-orthogonal orientation of the NH+ projection to the hydrogen-bond receptor site.

Multistep phase difference phase contrast imaging.

A new technique for multistep phase-contrast image processing is presented. The N-step method consists of simply forming the linear average of the N-1 adjacent phase-difference signals. It has similar noise reduction properties as other multistep techniques, but the simplicity of the noise variance of the N-step technique allows intuitive insight into phase-difference phase-contrast processing and noise reduction, which can aid in the design of efficient and improved phase-contrast imaging sequences. As well, the computational simplicity of the N-step phase-difference technique compared with any other known multistep technique is advantageous. Like other multistep techniques, it has far more efficient noise reduction properties than simple two-step, multiple average phase-contrast imaging, even when normalized for total scan time. A three-step phase-difference velocity image has 50% less variance than an image acquired with two steps and two scans averaged but is obtained in 25% less scan time. Given its advantages, it should now be the chosen technique for increasing velocity-to-noise and contrast-to-noise ratios in all phase-difference phase-contrast clinical applications.

Suggestive linkages between markers on human 1p32-p22 and body fat and insulin levels in the Quebec Family Study.

A single-gene rodent mutation (diabetes) and a quantitative trait locus (dietary obese 1) mapped to the mid portion of mouse chromosome 4 have been related to obesity and/or insulin levels. Synteny relationships place their putative human homologs on 1p31 and 1p35-p31, respectively. In 137 sibships of adult brothers and sisters from the Québec Family Study, genetic linkages between seven microsatellite markers from 1p32-p22 and various obesity- and diabetes-related quantitative phenotypes were examined using single locus sibpair linkage analysis. Suggestive linkages were observed between markers D1S476 and body mass index (p = 0.05), fat mass (p = 0.02), the sum of six skinfolds (p = 0.02), the insulin area after an oral glucose tolerance test (p = 0.02), and between the neighboring marker D1S200 and body mass index (p = 0.03), and fat mass (p = 0.009). Suggestive linkages were also observed between the more telomeric markers D1S193 and body mass index (p = 0.03), and between the neighboring marker D1S197 and fasting insulin level (p = 0.05). No linkage was observed with the trunk to extremity skinfolds ratio. These linkages suggest that human homologs of the mouse diabetes or dietary obese 1 and/or other genes in this interval on chromosome 1 play a role in the regulation of body mass, body composition, and insulin levels, but not of subcutaneous fat distribution.

Dapsone in rheumatoid arthritis.

Dapsone, a synthetic sulfone with chemical similarities to sulfapyridine, has been used for a number of years to treat leprosy and dermatitis herpetiformis. Recently, a number of prospective, randomized, double-blind trials have shown their success in the management of rheumatoid arthritis, with dapsone being superior to placebo and comparable to chloroquine and hydroxychloroquine. Its mode of anti-inflammatory actions in rheumatoid arthritis is not clearly understood, but modulation of neutrophil activity or inhibition of neutrophil inflammatory product formation or release appear to play a role. The major limiting side effect is hemolytic anemia, which may be mitigated through careful patient selection, conservative drug dosing, close monitoring, and possibly, concurrent administration of antioxidants or cytochrome P450 inhibitors. Methemoglobinemia is another common finding among patients receiving dapsone therapy, but rarely does it result in prominent symptoms other than transient pallor. Less common adverse events to dapsone include the idiosyncratic reactions of leukopenia and agranulocytosis, cutaneous eruptions, peripheral neuropathy, psychosis, toxic hepatitis, cholestatic jaundice, nephrotic syndrome, renal papillary necrosis, severe hypoalbuminemia without proteinuria, an infectious mononucleosis-like syndrome, and minor neurological and gastrointestinal complaints. In this report, two patients with advanced rheumatoid arthritis, who were safely and effectively treated with dapsone after failure with other second-line agents, are described and the literature is reviewed. We suggest that dapsone is an effective second-line agent in the treatment of rheumatoid arthritis.

What women want from hormone replacement therapy: results of an international survey.

OBJECTIVES: To find out what women in France, Germany and the UK want from hormone replacement therapy (HRT). METHODS: A questionnaire sent to almost 2000 women in France, Germany and the UK followed up by more detailed interviews with 100 women from each country. RESULTS: From the questionnaire sent to 1871 women aged 48-55 years in France, Germany and the UK, it was found that 72% had not used HRT. The main reason for this seemed to be the prescribing physician who did not mention or recommend HRT. Some cultural differences were apparent. For example, in the UK 10% of the women did not use HRT because of perceived contraindications while the corresponding figures in France and Germany were 20% and 23%, respectively. Fear of side-effects was most common in Germany (20%), followed by the UK (14%) and much less in France (8%). In the detailed interviews with 100 women from each country, based on their menopausal status and the fact that they had received HRT, it was found that the main motivating factor was a desire to avoid the effects of ageing and prevent osteoporosis. In spite of their expectations being largely met, about one-third of the women sampled stopped taking HRT, mainly due to a dislike of breakthrough bleeding. CONCLUSIONS: The women who took HRT generally found it a positive experience and women who did use it derived considerable benefit. However, the main determinant whether HRT was used or not was the attitude of the patient's physician.

Body surface potential mapping of a patient with Wolff-Parkinson-White syndrome with two accessory pathways and two atrial pacemaker complexes.

As part of an ongoing research protocol, a patient with Wolff-Parkinson-White syndrome underwent body surface potential mapping and electrophysiologic studies before radiofrequency ablation therapy. Careful analysis of the body surface potential mapping data made it possible to distinguish four different map sequences representing four different cardiac complexes. Analysis of these maps is consistent with two accessory pathways, with the additional pathology of two distinct atrial pacemaker sites. A right anterosuperior pathway was found to conduct continuously. The second pathway is consistent with a right inferior pathway conducting intermittently. The analysis demonstrates the type of information that can be extracted from body surface potential maps, even in the presence of complex pathologies.

Quality of life after the menopause: influence of hormonal replacement therapy.

OBJECTIVE: Our purpose was to demonstrate the clinical efficacy and effect of hormone replacement therapy in menopause on quality of life. STUDY DESIGN: A randomized, open, 6-month comparison of hormone replacement therapy (estradiol transdermal system [Estraderm TTS] plus chlormadinone) and symptomatic treatment (verapipride) was performed. Analysis was by intention to treat. RESULTS: In 499 postmenopausal women with moderate and severe symptoms enrolled by 101 physicians, hormone replacement therapy was superior to symptomatic treatment on all assessments of quality of life and clinical efficacy. The effects were independent of the incidence of hot flushes. CONCLUSION: The effect of hormone replacement therapy on the quality of life of postmenopausal women was significantly superior to symptomatic treatment.

[Respective importance of the different risk factors for osteoporosis]. / Importance respective des différents facteurs de risque d'ostéoporose.

Among the factors which influence accumulation of bone mass, genetic factors related to race and family are preponderant: they account for approximately 80% of the variance observed in adulthood. At puberty, nutritional factors and physical activity modulate the accumulation of bone and determine whether or not optimal bone mass is achieved. In women, estrogen deprivation following menopause, and also more minor disorders of gonad function, are the main causes of decreased bone mass; their respective contributions are analyzed.

Listeria monocytogenes causing endovascular infection.

Listeria monocytogenes is an uncommon cause of mycotic aneurysms, endocarditis, and other endovascular infections. When they occur, these infections usually involve patients with relatively normal host defenses, but with abnormal vascular intima or cardiac valves. We have reported a Listeria monocytogenes infection at the site of a posttraumatic aortic aneurysm.

[Delayed hemolytic transfusion reaction caused by an anti-U]. / Réaction transfusionnelle hémolytique retardée due à un anti-U.

Delayed hemolytic transfusion reactions due to anti-U are rare, only two (2) cases having been reported in the literature. We now report a third case: a multiparous black woman without any transfusion history was admitted to hospital for severe microlytic anemia (31 g/l). The patient was group AB negative, the direct antiglobulin test was negative and an anti P1 cold allo-antibody was present in her serum. Five A, Rh negative, P2 packed red cells were cross-marched with the sample obtained at admission on January 8, 1988. She was transfused on January 8, 9, 10, 11 and 12. On the 12th of January her hemoglobin level reached 125 g/l. On January 13, the patient presented clinical signs of hemolysis and her hemoglobin fell to 60 g/l within 24 hours. On January 15, the direct antiglobulin test was positive and an antibody found in her serum was reactive with all the red cells of the commercial panel. The sample was referred to our red cell serology reference laboratory. The phenotype of the pre-transfusion sample was found to be Fy(a-b-) M, N, S-s-U-. An anti-U was detected in the eluate and the serum. The patient was transfused with two (2) units of O-P2, U-red cells obtained from the American Red Cross, Syracuse, and her hemoglobin reached 90 g/l within 48 hours. This is the third reported case of a delayed hemolytic transfusion reaction due to anti-U. This case illustrates the need to perform cross-matches with samples obtained within 48 hours of the scheduled transfusion for patients who have been transfused with blood in the preceding 3 months. Also, this case emphasises the need to recruit U negative blood donors for the Canadian rare donor file.