Aneurysm formation appears to be related to tumor size, and large aneurysms confer a higher probability of rupture.

Isoniazid (INH) is associated with serious liver injury and autoimmunity. Classic studies in rats indicated that a reactive metabolite of acetylhydrazine is responsible for the covalent binding and toxicity of INH. Studies in rabbits suggested that hydrazine might be the toxic species. However, these models involved acute toxicity with high doses of INH, and INH-induced liver injury in humans has very different features than such animal models. In this study, we demonstrated that a reactive metabolite of INH itself can covalently bind in the liver of mice and also to human liver microsomes. Covalent binding also occurred in rats, but it was much less than that in mice. We were able to trap the reactive metabolite of INH with N-α-acetyl-l-lysine in incubations with human liver microsomes. This suggests that the reactive intermediate of INH that leads to covalent binding is a diazohydroxide rather than a radical or carbocation because those reactive metabolites would be too reactive to trap in this way. Treatment of mice or rats with INH for up to 5 weeks did not produce severe liver injury. The alanine transaminase assay (ALT) is inhibited by INH, and other assays such as glutamate and sorbitol dehydrogenase (SDH) were better biomarkers of INH-induced liver injury. High doses of INH (200 and 400 mg/kg/day) for one week produced steatosis in rats and an increase in SDH, which suggests that it can cause mitochondrial injury. However, steatosis was not observed when INH was given at lower doses for longer periods of time to either mice or rats. We propose that covalent binding of the parent drug can contribute to INH-induced hepatotoxicity and autoimmunity. We also propose that these are immune-mediated reactions, and there are clinical data to support these hypotheses.

Isoniazid (INH)‐induced hepatotoxicity remains a significant clinical problem, and the current mechanistic hypothesis is incomplete; it is simply referred to as metabolic idiosyncrasy,1 which is believed to involve cytotoxicity caused by bioactivation of acetylhydrazine,2 a metabolite of INH. However, this hypothesis is based on animal studies, involving characteristics that are very different from those that pertain to hepatotoxicity in humans, such as delayed onset. This issue therefore deserves a fresh look. Clinical Pharmacology & Therapeutics (2011) 89 6, 911–914. doi:

The importance of early detection by various radiological techniques of asymptomatic, unruptured aneurysms as a means of preventing subarachnoid hemorrhage (SAH) is discussed in this report. Four hundred volunteers underwent clinical and radiological evaluations between March, 1988, and September, 1992. Studies included a neurological examination as well as digital subtraction cerebral angiography via a femoral arterial catheter, computerized tomography, T1- and T2-weighted magnetic resonance (MR) imaging of the whole brain, and MR angiography. The evaluation revealed 27 asymptomatic, unruptured intracranial aneurysms in 26 volunteers, for an incidence of 6.5%. The subjects ranged in age from 39 to 71 years, with an average of 55 years. The aneurysms were located on the internal carotid artery in 13 cases (48%), the anterior communicating artery in six (22%), the middle cerebral artery in six (22%), and the basilar artery in two (7%). Aneurysms ranged in size from 5 mm or less in 16 cases, 6 to 10 mm in nine, and 11 to 15 mm in one; one aneurysm was more than 15 mm, with a maximum diameter of 2 cm. Volunteers with a family history of SAH within the second degree of consanguinity showed a higher incidence of aneurysms (17.9%). Aneurysm clipping was performed on 20 of the 26 cases with no significant morbidity or mortality. These findings support the contention that aggressive early detection of unruptured aneurysms may improve the outcome in patients harboring cerebral aneurysms by preventing the devastating effects of SAH.

Background: The gait speed and handgrip strength represented the core determinants of physical frailty and sarcopenia, which were reported to be associated with cognitive impairment and decline. Different physical measures might differentially affect cognitive changes, such as higher-level cognitive change and global cognitive decline. This study examined the differential associations of gait speed and handgrip strength with 10-year cognitive changes among community-dwelling older people. Methods: Participants aged 60 years and over living in the community were invited for study. Gait speed and handgrip strength were classified into 5 groups based on quintiles at baseline. Cognitive functions were assessed using the Mini-Mental State Examination (MMSE) and Digit Symbol Substitution Test (DSST) every 2 years from baseline for a period of 10 years. Linear mixed effects models were used to determine the role of gait speed and handgrip strength in the prediction of 10-year cognitive changes by adjusting covariates, including age, gender, education, depressive symptoms, marital status, smoking status, instrumental activities of daily life (IADL), Charlson Comorbidity Index (CCI), and body mass index (BMI) at baseline. Results: A total of 1096 participants were enrolled in the study. The mean age was 69.4 ± 5.8 years and 50.9% were male. The slowest gait speed group showed a significantly greater decline in the DSST scores over 10 years than the highest group (estimate = 0.28 and P = 0.003), but not in the MMSE scores (estimate = 0.05 and P = 0.078). The lowest handgrip strength group showed a significantly greater decline in the MMSE scores than the highest group (estimate = 0.06 and P = 0.039) and in the DSST scores than the highest two quintiles (estimate = 0.20 and P = 0.033 for the fourth quintile; estimate = 0.20 and P = 0.040 for the highest quintile) over 10-year follow-up. Conclusions: A slow gait speed could predict 10-year cognitive decline using DSST, and a low handgrip strength could predict 10-year cognitive decline using MMSE in addition to DSST. Thus both physical measures are lined to cognitive decline but there may be different mechanisms between brain and physical functions.

Amodiaquine (AQ) treatment is associated with a high incidence of idiosyncratic drug-induced liver injury (IDILI) and agranulocytosis. Evidence suggests that AQ-induced IDILI is immune mediated. A significant impediment to mechanistic studies of IDILI is the lack of valid animal models. This study reports the first animal model of IDILI with characteristics similar to mild IDILI in humans. Treatment of female C57BL/6 mice with AQ led to liver injury with delayed onset, which resolved despite continued treatment. Covalent binding of AQ was detected in the liver, which was greater in female than in male mice, and higher in the liver than in other organs. Covalent binding in the liver was maximal by Day 3, which did not explain the delayed onset of alanine aminotransferase (ALT) elevation. However, coincident with the elevated serum ALT, infiltration of liver and splenic mononuclear cells and activation of CD8 T-cells within the liver were identified. By Week 7, when ALT levels had returned close to normal, down-regulation of several inflammatory cytokines and up-regulation of PD-1 on T-cells suggested induction of immune tolerance. Treatment of Rag1 À/À mice with AQ resulted in higher ALT activities than C57BL/6 mice, which suggested that the adaptive immune response was responsible for immune tolerance. In contrast, depletion of NK cells significantly attenuated the increase in ALT, which implied a role for NK cells in mild AQ-induced IDILI. This is the first example of a delayed-onset animal model of IDILI that appears to be immune-mediated.

Large Magnitude (6-8) Late Quaternary Japanese volcanic eruptions are responsible for widespread ash (tephra) dispersals providing key isochrons suitable for the synchronisation and dating of palaeoclimate archives across East Asia, the NW Pacific and beyond. The transfer of geochronological information using these eruption deposits demands robust tephra correlations underpinned by detailed and precise volcanic glass geochemical data. Presented here is a major (electron microprobe; EMP) and trace element (Laser ablation inductively coupled plasma mass spectrometry; LA-ICP-MS) characterisation of near-source deposits from a series of large magnitude Japanese eruptions spanning approximately the last 150 ka. These data offer new insights into diagnostic compositional variations of the investigated volcanic sources spanning the Japanese islands. Whilst in the case of the highly productive Aso caldera (Kyushu), we are able to explore compositional variations through successive large magnitude eruptions (50-135 ka). These near-source volcanic glass data are used to validate and refine the visible tephrostratigraphy of the intensely dated Lake Suigetsu sedimentary record (SG06 core), Honshu Island, whilst also illustrating key tephrostratigraphic tie points to other East Asian palaeoclimate records (e.g. Lake Biwa). The identification of widespread Japanese tephrostratigraphic markers in the SG06 sediment record enables us to place chronological constraints on these ash dispersals, and consequently explosive volcanism at source volcanoes situated along the Kyushu Arc, including Kikai, Ata and Aso calderas. The proximal Aso-4 Ignimbrite (Magnitude 7.7) deposit is dated here by 40Ar/39Ar at 86.4 ± 1.1 ka (2σ), and provides a chronological anchor (SG06-4963) for the older sediments of the Lake Suigetsu record. Finally, trace element glass data verify visible ash fall layers derived from other compositionally distinct source regions of Japanese volcanism, including activity along the northern Izu-Bonin arc and North East Japan Arcs. These findings underline the Lake Suigetsu record as central node in the Japanese tephrostratigraphic framework.

We prospectively evaluated the usefulness of a new pain provocation test to diagnose superior labral tears in 32 patients with diagnosed throwing injuries of the shoulder. Results of the pain provocation test were compared with findings on magnetic resonance arthrography (all 32 patients) and arthroscopic examination (15 patients). In 22 patients, detachment of the superior labrum was observed on arthrograms, and all of them had positive results on the new pain provocation test. Nine of the other 10 patients had negative results on the new pain provocation test. However, 1 of the 10 patients had a positive result. Eleven of 15 patients were found to have superior labral lesions arthroscopically, and all of them were classified as type II superior labral anterior posterior lesions. All the 11 patients had positive pain provocation tests. The other four patients without superior labral tears on arthroscopic findings had negative results on the new pain provocation test. The new pain provocation test identified all patients with detachment of the superior labrum confirmed by magnetic resonance arthrography, for a sensitivity of 100%, a specificity of 90%, and an accuracy of 97%. Results of the new pain provocation test were in accord with arthroscopic findings in the 15 patients who underwent arthroscopic examination.