Descriptive analysis of dosing and outcomes for patients with ibrutinib-treated relapsed or refractory chronic lymphocytic leukemia in a Canadian centre.

Background: Ibrutinib is an approved treatment for relapsed or refractory chronic lymphocytic leukemia (cll) and small lymphocytic lymphoma (sll). The effect of ibrutinib dose reduction compared with discontinuation in a population-based setting is unclear. Methods: To examine the patterns of ibrutinib use in a Canadian population-based setting, we analyzed a retrospective cohort of patients with relapsed or refractory cll or sll treated with ibrutinib. Results: The 64 patients diagnosed with cll or sll had a median age of 76.5 years. Most had unmutated ighv (immunoglobulin variable heavy chain). A hematologic response occurred in 39 patients regardless of the ibrutinib dose. The most common toxicities were infection, bruising or bleeding, and musculoskeletal problems, with a median time to first toxicity of 14 days. More than half the cohort experienced a dose reduction, with musculoskeletal problems, cytopenias, and infection being the leading causes; surgery was the most frequent indication for holding treatment. Only 26 of the 64 patients (40.6%) stayed on the recommended maximal dose of ibrutinib. No differences in reported toxicities or hematologic response rates were evident between the patients receiving maximal and submaximal therapy. At the end of the study period, 53 patients from the initial cohort remained on ibrutinib. Conclusions: More than half the study patients received ibrutinib therapy at a submaximal dose without evidence of increased frequency of toxicities or disease progression. The rate of ibrutinib discontinuation was lower in our cohort than has been reported in other settings. Submaximal ibrutinib dosing will have to be further systematically evaluated.

Evaluating interventions against Salmonella in broiler chickens: applying synthesis research in support of quantitative exposure assessment.

A scoping study and systematic review-meta-analyses (SR-MAs) were conducted to evaluate the effectiveness of various interventions for Salmonella in broiler chicken, from grow-out farm to secondary processing. The resulting information was used to inform a quantitative exposure assessment (QEA) comparing various control options within the context of broiler chicken production in Ontario, Canada. Multiple scenarios, including use of two separate on-farm interventions (CF3 competitive exclusion culture and a 2% lactose water additive), a package of processing interventions (a sodium hydroxide scald water disinfectant, a chlorinated post-evisceration spray, a trisodium phosphate pre-chill spray and chlorinated immersion chilling) a package consisting of these farm and processing interventions and a hypothetical scenario (reductions in between-flock prevalence and post-transport concentration), were simulated and compared to a baseline scenario. The package of on-farm and processing interventions was the most effective in achieving relative reductions (compared to baseline with no interventions) in the concentration and prevalence of Salmonella by the end of chilling ranging from 89·94% to 99·87% and 43·88% to 87·78%, respectively. Contaminated carcasses entering defeathering, reductions in concentration due to scalding and post-evisceration washing, and the potential for cross-contamination during chilling had the largest influence on the model outcomes under the current assumptions. Scoping study provided a transparent process for mapping out and selecting promising interventions, while SR-MA was useful for generating more precise and robust intervention effect estimates for QEA. Realization of the full potential of these methods was hampered by low methodological soundness and reporting of primary research in this area.

Occurrence and characterization of Salmonella from chicken nuggets, strips, and pelleted broiler feed.

Raw, frozen chicken nuggets and strips have been identified as a significant risk factor in contracting foodborne salmonellosis. Cases of salmonellosis as a result of consuming partly cooked chicken nuggets may be due in part to Salmonella strains originating in broiler feed. This study was undertaken to determine the occurrence and characterize the strains of Salmonella contaminating chicken nuggets, strips, and pelleted feeds, in an attempt to demonstrate whether the same Salmonella strains present in broiler feed could be isolated from raw, frozen chicken nuggets and strips available for human consumption. Salmonellae were recovered using the Health Canada MFHPB-20 method for the isolation and identification of Salmonella from foods. Strains were characterized by serotyping, phage typing, antimicrobial resistance typing (R-typing), and by pulsed-field gel electrophoresis (PFGE). Salmonellae were isolated from 25-g samples in 27% (n=92) of nugget and strip samples, 95% (n=20) of chicken nugget meat samples, and from 9% (n=111) of pelleted feed samples. Salmonella Heidelberg, Salmonella Enteritidis, and Salmonella Orion were the most commonly isolated serovars from chicken nuggets and strips, nugget and strip meat, and pelleted broiler feeds, respectively. Salmonella Enteritidis phage type (PT) 13a with PFGE pattern SENXAI.0006 and R-type sensitive as well as Salmonella Enteritidis PT13a with PFGE pattern SENXAI.0068 and R-type sensitive were isolated from pelleted feed, and chicken nugget and strip meat in two separate instances. Data showed that Salmonella strains isolated from broiler feed were indistinguishable from strains isolated from packaged raw, frozen chicken nuggets and strips. However, results did not rule out the possibility that breeding stock or contamination during processing may have contributed to chicken meat contamination by Salmonella.

Synthesis and characterization of a photoactivatable glycoaryldiazirine for surface glycoengineering.

Biological systems make considerable use of specific molecular interactions. Many biomolecules involved in biorecognition are glycosylated, the carbohydrate moiety playing an essential role. Controlled surface glycoengineering is thus of crucial importance in biosensing, cell guidance, and biomedical applications. This study describes the synthesis of an aryldiazirine-derivatized galactose and the functionalization of surfaces by carbohydrates using photochemical immobilization techniques. A photoactivatable glycosylated reagent was synthesized by addition of thiogalactopyranose to the maleimide group of N-[m-[3-(trifluoromethyl)diazirin-3-yl]phenyl]-4-maleimidobutyr amide (MAD) to give N-[m-[3-(trifluoromethyl)diazirin-3-yl]phenyl]-4-[3-thio (1-D-galactopyranosyl)succinimidyl]butyramide (MAD-Gal). The structure of the newly synthesized molecule was confirmed by UV spectroscopy, photoactivation, 1H NMR, and 13C NMR. MAD-Gal was immobilized on thin diamond films by photoactivation of the diazirine function (350 nm). Surface modification was investigated by XPS (X-ray photoelectron spectroscopy) and ToF-SIMS (time-of-flight secondary ion mass spectrometry). Imaging ToF-SIMS was applied to detect glycopatterns generated by mask-assisted lithography.

Failure of 84 cell pairs in 26 different heart-muscle cell cultures to build intercalated discs.

Cell contacts formed in cultures between embryonic chick-heart cells were studied. In young cultures, living muscle cells were photographed by phase contrast, each time before and after contact. After fixation the contact sites were observed in the electron microscope. One example where connected cells had beaten together for 3 hours is illustrated here. In the case of these four cell pairs, up to 22 subsequent levels of each contact site were examined. The other 80 cases belonged to 25 different cultures of 2nd, 3rd, 5th, 6th, 8th, 13th, 20th, 47th and 64th days of incubation and were collected within 5 years. On the contact sites of these synchronously-beating muscle cells, membrane specializations, such as intermediate junctions (zonula adhaerens) and gap-junctions (nexus-like), were found, seldom accompanied by desmosomes. Nowhere had these specializations developed an appearance necessary to identify an intercalated disc, i.e., with filament insertion on both sides. These contacts show that common pulsation does not suffice for the formation of an intercalated disc. A developing factor for the maturation of heart myocytes in vivo which is not present in most cultures is to be postulated.

Pericapsular smooth muscle cells in renal corpuscles of the Mongolian gerbil.

During the course of a systematic investigation of the renal corpuscles in various desert rodents (Meriones unguiculati, Meriones shawii, Psammomys obesus, and Dipodymis), a thickened Bowman's capsule was observed light microscopically in some kidneys of adult Meriones unguiculati (Mongolian gerbil). Electron microscopic studies show that this unusual finding may depend on the presence of one or two layers of typical smooth muscle cells adjacent to the outer surface of the basal lamina. In the kidneys of other species of desert rats examined, no pericapsular smooth muscle cells were observed.

Ultrastructural and morphometric aspects of the juxtaglomerular apparatus in the monkey kidney.

The authors describe the ultrastructure of the juxtaglomerular apparatus in five adult male Cebus apella monkeys and communicate morphometric data of the macula densa. In comparison with several species of rodents examined before, the macula cells of the monkey contain many more mitochondria and possess a particularly thick basal membrane. The relative volume of the nuclei is slightly smaller than in rodents. The Goormaghtigh cells of the monkey resemble those of the other animals investigated. The epithelioid (or juxtaglomerular) cells do not contain secretory granules. This observation reminds one of the behavior of the epithelioid cells of guinea pigs.

[Scanning electron microscopic study of the changes of the luminal surface of rat thyroid epithelial cells following exposure to cold for 6 to 48 hours (author's transl)]. / Rasterelektronenmikroskopische Untersuchung der Oberflächenveränderungen von Schilddrüsenepithelzellen der Ratte nach 6- bis 48-stündiger Kälteeinwirkung.

Scanning electron microscopic observations of thyroid follicle cells of rats exposed to 4 degrees C for 6 to 48 hours were found to show an increased number of apical microvilli in comparison to those of controls kept at 22 degrees C. These ultrastructural differences--which were statistically significant 48 hours after start of the experiments--are related to stimulation of thyroid gland activity by exposure to cold.

[Circadian changes of various enzyme activities in the kidney macula densa of gerbils (Meriones unguiculati)]. / Zirkadiane Veränderungen einiger Enzymaktivitäten in der Macula densa der Nieren von Wüstenratten (Meriones unguiculati).

Circadian Changes of the Activity of some Enzymes in the Macula densa of the Kidney of Mongolian Gerbilis.--The authors investigated the enzyme histochemical activity of some dehydrogenases in the macula densa of desert rodents killed respectively at 11 a.m. and at 11 p.m. The percentage of macula cells which, in comparison with the non specific distal convolution epithelial cells, showed the same or even enhanced enzyme activities was higher at 11 p. m., i.e. nightly (see Tab. 1).

Comparison of the activities of some dehydrogenases in the juxtaglomerular complex of kidneys of Wistar rats and desert rats (Meriones unguiculati).

The authors compared the enzyme histochemical activities of some dehydrogenases in the macula densa, the Goormaghtigh cells and the epithelioid (or juxtaglomerular cells in the kidneys of desert rodents (Mongolian Gerbils) with those of the Wistar rats. The macula cells (Table 1), which in the Wistar rats are clearly distinct from the non specific epithelial cells of the distal convolution, show, in the desert rats, noticeable fluctuations. Their enzyme histochemical reactions are often weaker than those of the distal convolution cells, with the exception of the NAD-tetrazolium-reductase activity. The Goormaghtigh cells (Table 2) in the kidneys of the Meriones have a much larger enzymatic spectrum than in the Wistar rats. Here also, we find functional variations in the examined desert species. In the epithelioid cells (Table 3) we observed a somewhat weaker enzymatic activity in the Meriones. These cells contain no secretion granules, this making their diagnosis difficult.

[Development of the intercalated disc in culture]. / Zur Discus intercalaria-Bildung in der Kultur.

A culture of separated chick embryo heart cells was observed for 48 hours. By electron microscopy it was observed that at the sites of contacts made during culture intercalated discs did not in general develop. Previous reports to the contrary are devoid of controls excluding the possibility that the intercalated discs found originated from the tissue with which the culture was started. Their electron micrographs, in any case, related to the mature state of the tissue used. In one part of the culture used here the site of a contact which had developed in culture shows a fascia adherens to which filaments (of up to myofilament diameter) insert on both sides. Their course, however, is irregular in one cell, and in the other they are very sparse. Z-lines are missing and only round Z-bodies are to be seen, so one can only speak of an intercalated disc at the earliest stage of development. These findings agree with the recently published statement of Gross and Müller (1977), according to which intercalated discs did not develop even during common pulsation of heart muscle cells for two and a half month, provided that during culture a certain mechanical momentum did not supervene. It is supposed that the intercalated disc Anlage here demonstrated represents one of the most advanced states to which spontaneous development, without mechanical momentum, can lead .

[Studies of the activity of various dehydrogenases in the desert rat (Meriones unguiculati) nephrons]. / Untersuchungen über die Aktivität einiger Dehydrogenasen in den Nephronen von Wüstenratten (Meriones unguiculati).

Researches about the Activity of some Dehydrogenases in the Nephrons of Desert Rats (Meriones unguiculati).--Our desert rats Meriones unguiculati (Mongolian Gerbils) show--also when held under the same experimental conditions as our other laboratory rodents (Wistar rats and white mice)--a somewhat different enzyme histchemical behaviour of these nephrons. The essential difference in the Meriones is that their distal convolutions display on the whole stronger enzyme activities compared as well with the proximal convolutions of the same kidneys, as with the distal convolutions of Wistar rats.

[Modification of the number and structure of certain cytoplasmic components of the renal tubules during compensatory hypertrophy]. / Modification du nombre et de la structure de certains composants cytoplasmiques des tubes rénaux au cours de l'hypertrophie compensatrice

In the remaining kidney of unilaterally nephrectomised three to six months old Wistar rats, the measurement of the external and internal diameters indicated an increase in size of both proximal and distal convoluted tubules, although less distinct in the latter. Stereomorphometric measurements of the chondriome and the cytoplasmic inclusions (lysosomes, phagosomes, peroxisomes, etc.) have shown, as compared with similar tests in shamoperated animals, changes in the volumes of these components which can be related to the increase of enzymatic activities reported earlier. However, no obvious changes of the general ultrastructure of the kidneys undergoing hypertrophy could be observed.

Morphometric and enzyme histochemical behaviour of the kidney of young rats before and after unilateral nephrectomy.

Four week old male Wistar rats were unilaterally nephrectomized, and one, two, four, fourteen, and twenty-eight days after the operation the remaining kidneys were removed for morphological examination--including measurement of diameters of the tubules--and for histochemical investigation of enzymatic activities in the nephrons. The following enzymes were examined: succinate DH, lactate DH, alpha-glycerophosphate DH, isocitrate DH, glucose-6-phosphate DH, cytochrome oxidase, adenosine triphosphatase, alkaline and acid phosphatases. In comparison with kidneys of control animals of the same age and sex, the hypertrophy of the remaining kidney was found to be, even in these young rats, entirely due to enlargement of preexisting nephrons. The measurements have indicated that the hypertrophy was most distinct between the second and fourth day after uninephrectomy. Four weeks after the operation the diameters of proximal and distal tubules were about 21% and 18% respectively bigger in the uninephrectomized animals than in the corresponding controls. This increase in size was accompanied by some changes in intensity of enzymatic staining reactions; after an initial diminishment, a graduate increase in activity of almost all the observed tubular enzymes was found; this seems to be the expression of the functional compensation by the remaining kidney.