Autonomic responses to orthostatic stress in head-up tilt testing: Relationship to test-induced prolonged asystole

Background: Prolonged asystole is sometimes an extreme manifestation of neurally mediated syncope. Hypothesis: To investigate the mechanism of head-up tilt testing-induced prolonged (life-threatening) cardiac asystole, we measured temporal changes in frequency domain heart rate variability indices in 25 patients with syncope of undetermined etiology. Methods: Head-up tilt testing (80°) was performed in 25 patients for up to 40 min or until asystole or syncope occurred. Three patients (Group 1; 37 ±13 years, 1 man, 2 women) had an episode of prolonged cardiac asystole (≥ 10 s) during testing, necessitating cardiopulmonary resuscitation. Syncope, but no asystole, was induced in 10 patients (Group 2; 48 ± 31 years, 6 men, 4 women), and 12 patients (Group 3; 55 ± 20 years, 5 men, 7 women) failed to show asystole or syncope during testing. Power spectra of low (0.04–0.15 Hz) and high (0.15–0.40 Hz) frequency, and total (0.01–1.00 Hz) frequency spectra were measured in consecutive 2 min segments throughout the test. Results: Maximally changed values in heart rate, systolic blood pressure, and heart rate variability indices during testing were compared among the three groups (maximally changed values did not include the values during tilt-induced symptoms). High frequency spectra in Groups 2 and 3, but not in Group 1, decreased during the test. High frequency spectra, low frequency spectra, and total spectra in Group 1 were significantly higher than those in Groups 2 and 3 during testing. In Group 1 patients, findings at test-induced asystole were consistent with exaggerated sympathetic and concurrent persistent parasympathetic activity. Conclusion: Unusual autonomic responses to orthostatic stress can cause prolonged asystole, and this autonomic nerve dysregulation may relate to asystolic episodes associated with cardiovascular collapse.     

Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome

JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL). However, functional consequences of the JAK3 mutations in TMD patients remain undetermined. To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation. JAK3 mutations were not detected in 10 TMD samples that had not previously been studied. Together with our previous report we detected JAK3 mutations in one in 11 TMD patients. Furthermore, this study showed for the first time that a TMD patient-derived JAK3 mutation (JAK3(I87T)), as well as two novel JAK3 mutations (JAK3(Q501H) and JAK3(R657Q)) identified in an MGS cell line, were activating mutations. Treatment of MGS cells and Ba/F3 cells expressing the JAK3 mutants with JAK3 inhibitors significantly decreased their growth and viability. These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.     

Emetic Potentials of Newly Identified Staphylococcal Enterotoxin-Like Toxins

Staphylococcal enterotoxins (SEs) are a common causative agent of food poisoning. Recently, many new SE-like (SEl) toxins have been reported, although the role of SEls in food poisoning remains unclear. In this study, the emetic potentials of SElK, SElL, SElM, SElN, SElO, SElP, and SElQ were assessed using a monkey-feeding assay. All the SEls that were tested induced emetic reactions in monkeys at a dose of 100 μg/kg, although the numbers of affected monkeys were significantly smaller than the numbers that were affected after consuming SEA or SEB. This result suggests that these new SEs may play some role in staphylococcal food poisoning.     

Monte Carlo simulation of the acquisition conditions for 177Lu molecular imaging of hepatic tumors

Annals of Nuclear Medicine - To examine the impact of acquisition time on Lutetium-177 (177Lu) single-photon emission computed tomography (SPECT) images using Monte Carlo simulation. A gamma camera...     

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with ‘capsulomas’ without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt–Hogg–Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small‐sized capsular angiomyolipomas known as ‘capsulomas’ in a 39‐year‐old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and ‘capsulomas’ developing in a patient without genetic features, having potential for novel genetic variation.     

Longest neurite‐specific activation of Rap1B in hippocampal neurons contributes to polarity formation through RalA and Nore1A in addition to PI3‐kinase

In a developing nervous system, axon‐dendrite formation is instructed by extrinsic cues, and the mechanism whereby a developing neuron interprets these cues using intracellular signaling is particularly important. Studies using dissociated hippocampal neurons have identified many signaling pathways underlying neuronal polarization. Among the components of these pathways, Rap1B is essential for axon specification in hippocampal cultures. However, spatiotemporal regulation of Rap1B activity in polarizing neurons and how it affects neuronal polarization remain unclear. Herein, we investigated spatiotemporal activity‐change of Rap1B and its target molecules in hippocampal neurons. FRET imaging showed that specific activation of Rap1B was observed at the tip of a future axon. To dissect downstream signaling, we used three effector mutants of Rap1B. Expression of Rap1B‐G12V/E37G and G12V/Y40C mutants resulted in supernumerary axons. The targets of Rap1B‐G12V/E37G were RalA and Nore1A, whereas Rap1B‐G12V/Y40C activated PI3‐kinase. RalA was activated in the tip of stage 3 axons, and RalA‐S28N expression reduced the fraction of neurons with supernumerary axons induced by Rap1B‐G12V/E37G. Furthermore, Nore1A depletion reduced the number of cells without axons. These results indicate that specific activation of Rap1B contributes to neuronal polarization via interaction with RalA and Nore1A in addition to PI3‐kinase.     

Alanine Aminotransferase Elevation during Peginterferon Alpha-2a or Alpha-2b plus Ribavirin Treatment

Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients.