Ultrasound-detected joint inflammation and B cell count: related variables for rituximab-treated RA patients?

This cross-sectional observational study aimed to explore the relationship between B cell count and ultrasound (US)-detected synovitis, in patients with rheumatoid arthritis treated with rituximab. Thirty-seven consecutive RA patients treated with RTX were recruited for the study. The patients underwent clinical [i.e., Disease Activity Score 28 joints (DAS28)], laboratory, and US assessment of 12 joints. Each joint was semiquantitatively (0–3) scored on B-mode and power Doppler mode. The scores were summed, and a global index was created for BM (BMS) and PD scores (PDI) synovitis. BM subclinical synovitis was evident in all patients, with PD synovial signal detected in 16 patients (43.2 %). No correlation was found between DAS28 and US scores. B cells were detected in 27 (72.9 %) patients, but there was no association in the mean B cell count and disease activity as measured by DAS28 (DAS28 < 2.6 = 34.53, DAS28 > 2.6 = 49.45, p = 0.52) and PDI score (PDI < 1 = 49.48, PDI > 1 = 35.44, p = 0.54). There was no correlation between the B cell count and DAS28, BMS, and PDI (r = 0.020, p = 0.907; r = ?0.151, p = 0.371; r = ?0.099, p = 0.558, respectively). In RTX-treated RA patients, no relationship could be established between US-detected synovitis and peripheral blood B cell count.     

Multiscale photonic imaging of the native and implanted cochlea

The cochlea of our auditory system is an intricate structure deeply embedded in the temporal bone. Compared with other sensory organs such as the eye, the cochlea has remained poorly accessible for investigation, for example, by imaging. This limitation also concerns the further development of technology for restoring hearing in the case of cochlear dysfunction, which requires quantitative information on spatial dimensions and the sensorineural status of the cochlea. Here, we employed X-ray phase-contrast tomography and light-sheet fluorescence microscopy and their combination for multiscale and multimodal imaging of cochlear morphology in species that serve as established animal models for auditory research. We provide a systematic reference for morphological parameters relevant for cochlear implant development for rodent and nonhuman primate models. We simulate the spread of light from the emitters of the optical implants within the reconstructed nonhuman primate cochlea, which indicates a spatially narrow optogenetic excitation of spiral ganglion neurons.

In the case of profound sensorineural hearing impairment, cochlear implants (CIs) partially restore hearing by providing auditory information to the brain via electrical stimulation of the spiral ganglion neurons (SGNs). CIs enable speech understanding in the majority of the ∼700,000 users worldwide. However, current clinical CIs are limited by their wide current spread (1) resulting in poor coding of spectral information (2). Recently, cochlear optogenetics was proposed for stimulating the auditory nerve by light (3–10). As light can be better confined in space, the spread of excitation in the cochlea is lower (3, 9–11) and, hence, future optical CIs (oCIs) promise improved speech comprehension—especially in noisy background—as well as greater music appreciation.For the technical development of oCIs toward a future medical device, major efforts are currently being undertaken to devise multichannel optical stimulators for the cochlea (10, 12–17). As is the case for the electrodes of current CIs, future oCIs will place multiple stimulation channels, here microscale emitters, along the tonotopic axis of the cochlea. Further development of the oCIs requires precise estimates of parameters such as scala tympani size, optimal probe stiffness, and bending radius. Moreover, cochlear optogenetics employs gene transfer to the SGNs for which adeno-associated viruses (AAVs) seem promising candidate vectors (3–5, 8). AAV delivery has used injection of virus suspension via the round window (4, 8) or directly into Rosenthal’s canal (5, 9, 10). Therefore, the volumes of Rosenthal’s canal and the scalae tympani, vestibuli and media needed to be evaluated in order to estimate the required virus load for injection. Finally, the sensorineural status of the cochlea is highly relevant for future gene therapy and CI stimulation, and hence, quantitative imaging of sensory cells and neurons is an important objective.Here, we employed multiscale X-ray phase-contrast tomography (XPCT) and light-sheet fluorescence microscopy (LSFM) and provide an analysis of cochlear morphology for mice, rats, gerbils, guinea pigs, and marmosets. Each of these animal models offers unique advantages for auditory research. The mouse is readily available for genetic manipulation (e.g., ref. 18). Channelrhodopsin-expressing transgenic lines are available also for rats (19, 20) that offer a larger cochlea and can carry heavier implants than mice (21–24). Similarly, gerbils and guinea pigs are established rodent models for auditory research with larger-sized cochleae. Moreover, gerbils, which have low-frequency hearing more similar to humans, have already been employed for cochlear optogenetics (5, 9, 10, 24). Finally, we analyzed the cochlea of the common marmoset, as an established nonhuman primate model for auditory research (e.g., refs. 25, 26). Marmosets possess a rich vocalization repertoire and share a pitch perception mechanism with humans (27). Therefore, we compared cochlear insertion of newly designed oCIs with electrical cochlear implants (eCI) and modeled the optical spread of excitation in the marmoset cochlea.     

Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.     

Myocardial perfusion in real-time using power modulation. In vivo evidence for microcirculatory damage after acute myocardial infarction

BACKGROUND: The effect of beta-radiation on extra-stent vascular remodeling in patients with in-stent restenosis has not been studied. The correlation between the extent of extra-stent plaque proliferation and that of intimal hyperplasia (IH) in in-stent restenosis in patients who received beta-radiation therapy as well as conventional therapy has also not been studied. METHODS: We evaluated the extra-stent remodeling in diffuse in-stent restenosis between a beta-radiation therapy patient group (188Re-MAG3, n=50) and a control group (n=9) by applying serial intravascular ultrasound (IVUS) analysis. Matching (post-intervention and follow-up) images were acquired at the follow-up lesion site and were available in 44 of 50 patients who received radiation therapy and in seven of nine control patients. RESULTS: There was a significant increase of the external elastic membrane (EEM) area in both groups: 16.4 +/- 3.3 mm2 post-intervention to 17.1 +/- 3.3 mm2 at follow-up, P=0.001 in the radiation therapy group, and 16.8 +/- 4.0 mm2 post-intervention to 17.4 +/- 4.1 mm2 at follow-up, P=0.008 in the control group. There were no statistically significant differences of the Delta EEM area between the two groups: 0.7 +/- 0.4 mm2 in the radiation therapy group vs. 0.6 +/- 0.4 mm2 in the control group, P=0.389. The Delta IH area correlated with the Delta EEM area in the control group (r=0.826, P=0.022), but not in the radiation therapy group (r=0.016, P=0.919). CONCLUSIONS: The findings of this IVUS study were that positive remodeling (increased EEM area) occurred equally in both control and irradiated patients with in-stent restenosis. The extent of remodeling was directly in proportion to IH in the control group, but no such relationship existed in the irradiated patient group.     

Postexercise blood pressure reduction in elderly hypertensive patients

OBJECTIVES: We sought to study: 1) the impact of hemodynamic and left ventricular function on short-term postexercise blood pressure reduction in elderly hypertensive patients; and 2) the 22-h postexercise effects on ambulatory blood pressure in elderly hypertensive patients. BACKGROUND: Although early exercise provokes postexercise blood pressure reduction, the mechanisms underlying this response are not completely understood. Besides, it is unclear whether the reduction in blood pressure after exercise lasts long enough to have clinical relevance in elderly hypertensive patients. METHODS: We studied 24 elderly hypertensive patients (age 68.9 +/- 1.5 years) and 18 age-matched normotensive control subjects (age 68.1 +/- 1.2 years). Cardiac output (carbon dioxide rebreathing) and blood pressure (auscultatory) were measured at rest and after a 45-min period of low-intensity bicycle exercise (50% maximal oxygen uptake) and at 15, 30, 60 and 90 min after exercise. Left ventricular function (by Doppler echocardiography) was also evaluated. Ambulatory blood pressure monitoring was evaluated after 45 min of exercise or 45 min of rest, in a randomized order. RESULTS: In the hypertensive patients, exercise provoked a significant reduction in blood pressure, cardiac output, stroke volume and left ventricular end-diastolic volume. It also provoked a significant reduction in systolic, mean and diastolic blood pressure during a 22-h period, at daytime and nighttime. CONCLUSIONS: The short-term reduction in blood pressure after exercise in elderly hypertensive patients is associated with a decrease in stroke volume and left ventricular end-diastolic volume. The 22-h postexercise reduction in blood pressure demonstrates the clinical relevance of low-intensity exercise in elderly hypertensive patients.     

Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.