Two cases of low back pain of unknown etiology diagnosed as multiple myeloma.

We report two cases of patients complaining of lumbar back pain of unknown etiology which were finally diagnosed as multiple myeloma. The first case was a woman in her 80s with a chief complaint of lumbar back pain. The second case was a male in his 70s. He also consulted our institution because his pain did not subside despite receiving increased doses of oral medication and nerve blocks from his previous doctor. Both patients presented with compression fractures on plain radiography, and additionally with cytopenia, hyperproteinemia, and hypoalbuminemia in blood tests. Further tests were conducted due to suspected multiple myeloma, revealing a punched-out legion in the skull and elevated levels of ß2 microglobulin and Immunoglobulin G. Subsequently, both patients were transferred to the hematology department. In these two cases, we had predicted the presence of multiple myeloma from the results of initial testing and subsequently successfully provided definitive diagnoses following additional examinations.

Usefulness of low tidal volume ventilation strategy for patients with acute respiratory distress syndrome: a systematic review and meta-analysis.

The effects of lower tidal volume ventilation (LTV) were controversial for patients with acute respiratory distress syndrome (ARDS). This systematic review and meta-analysis aimed to evaluate the use of LTV strategy in patients with ARDS. We performed a literature search on MEDLINE, CENTRAL, EMBASE, CINAHL, "Igaku-Chuo-Zasshi", clinical trial registration sites, and the reference of recent guidelines. We included randomized controlled trials (RCTs) to compare the LTV strategy with the higher tidal volume ventilation (HTV) strategy in patients with ARDS. Two authors independently evaluated the eligibility of studies and extracted the data. The primary outcomes were 28-day mortality. We used the GRADE methodology to assess the certainty of evidence. Among the 19,864 records screened, 13 RCTs that recruited 1874 patients were included in our meta-analysis. When comparing LTV (4-8 ml/kg) versus HTV (> 8 ml/kg), the pooled risk ratio for 28-day mortality was 0.79 (11 studies, 95% confidence interval [CI] 0.66-0.94, I2 = 43%, n = 1795, moderate certainty of evidence). Subgroup-analysis by combined high positive end-expiratory pressure with LTV showed interaction (P = 0.01). Our study indicated that ventilation with LTV was associated with reduced risk of mortality in patients with ARDS when compared with HTV. Trial registration: UMIN-CTR (UMIN000041071).

Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Influence of p-glycoprotein on brain Bcl-2 family proteins and cytokines in transient cerebral ischemia.

OBJECTIVES: P-glycoprotein (P-gp), produced by the multidrug resistance (mdr1a) gene, is present in vascular endothelial cells, astrocytes, and microglia in the brain. We previously reported that P-gp aggravated cerebral infarct. Therefore, modulation of the function of P-gp is important for the treatment of brain ischemia. Here, we examined how P-gp exacerbates ischemic damage in the brain. METHODS: Experiments were performed using mdr1a knockout (KO) mice and wild-type mice. Mice of both groups were subjected to transient focal ischemia and Bcl-2 family proteins, p-glycoprotein and cytokines were measured. RESULTS: At 48 h after reperfusion, the expression of Bcl-2 protein in the brains of mdr1a KO mice was significantly greater compared with that of wild-type mice. The expression of brain Bax protein in mdr1a KO mice was significantly lower compared with that of wild-type mice. At 6 h after reperfusion, the expression of plasma IL-6 in mdr1a KO mice was significantly lower compared with that of wild-type mice. CONCLUSION: These results indicate that P-gp derived from the mdr1a gene has pro-apoptotic functions mediated through Bcl family proteins and increased IL-6, which exacerbates ischemic damage in the brain. In summary, the inhibition of P-gp function is an effective strategy to protect against brain damage caused by ischemic damage.

Retraction Note: Brain injury following cardiac arrest: pathophysiology for neurocritical care.

[This retracts the article DOI: 10.1186/s40560-016-0140-9.].

Brain injury following cardiac arrest: pathophysiology for neurocritical care.

Cardiac arrest induces the cessation of cerebral blood flow, which can result in brain damage. The primary intervention to salvage the brain under such a pathological condition is to restore the cerebral blood flow to the ischemic region. Ischemia is defined as a reduction in blood flow to a level that is sufficient to alter normal cellular function. Brain tissue is highly sensitive to ischemia, such that even brief ischemic periods in neurons can initiate a complex sequence of events that may ultimately culminate in cell death. However, paradoxically, restoration of blood flow can cause additional damage and exacerbate the neurocognitive deficits in patients who suffered a brain ischemic event, which is a phenomenon referred to as "reperfusion injury." Transient brain ischemia following cardiac arrest results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, peri-infarct depolarization, oxidative and nitrative stress, inflammation, and apoptosis. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. Mitochondrial dysfunction based on the mitochondrial permeability transition after reperfusion, particularly involving the calcineurin/immunophilin signal transduction pathway, appears to play a pivotal role in the induction of neuronal cell death. The aim of this article is to discuss the underlying pathophysiology of brain damage, which is a devastating pathological condition, and highlight the central signal transduction pathway involved in brain damage, which reveals potential targets for therapeutic intervention.

Hypnotic effect of volatile anesthetics is mediated by PKC-γ dynamics.

BACKGROUND: Although protein kinase C-γ (PKC-γ) is a target for the effects of volatile anesthetics, the molecular mechanisms of the kinase function remain unclear. We examined the effects of different types of anesthetics on PKC-γ knockout mice, and investigated the dynamics of the kinase in mouse brain. METHODS: We measured the required number of times for loss of righting reflex (rtfLORR) after administration of isoflurane, sevoflurane, and propofol on PKC-γ knockout mice and compared with those of wild-type mice. We also used immunoblotting to investigate the intracellular distribution of PKC-γ and phosphorylated PKC-γ (p-PKC-γ) in brain of wild-type mice anesthetized by these anesthetics. RESULTS: Isoflurane and sevoflurane significantly prolonged the rtfLORRs in PKC-γ knockout mice compared with those in wild-type mice, while no significant difference was observed between knockout and wild-type mice treated with propofol. Examination of the cellular fractions showed that PKC-γ was significantly decreased, whereas p-PKC-γ was significantly increased in the synaptic membrane fraction (P2). There was no significant change in the supernatant fraction (S). In propofol-treated mice, PKC-γ and p-PKC-γ showed no significant changes in P2 or S. CONCLUSION: Our results provide new evidence to support the possibility of the involvement of PKC-γ in the actions of volatile anesthetics.

Effects of different types of anesthetic agents on cellular protein kinase C-γ dynamics in mouse brain.

BACKGROUND/AIMS: Although protein kinase C-γ (PKC-γ) is a target for the effects of volatile anesthetics, the molecular mechanisms of the kinase function during their action remain unclear. We examined the effects of different types of anesthetics on PKC-γ knockout mice. Furthermore, we investigated the dynamics of the kinase in brain cells obtained from mice anesthetized with these anesthetics. METHODS: We measured the required times for loss of righting reflex (rtfLORR) after administration of isoflurane, sevoflurane, or propofol on PKC-γ knockout mice and compared the times with those of wild-type mice. We also used immunoblotting to investigate the intracellular distribution of PKC-γ and phosphorylated PKC-γ (p-PKC-γ) in brain cell fractions obtained from wild-type mice during the loss of righting reflex induced by these anesthetics. RESULTS: Isoflurane (2.6%) and sevoflurane (3.4%) used at twice the minimum alveolar concentration significantly prolonged the rtfLORRs in PKC-γ knockout mice compared to those in wild-type mice. On the other hand, no significant difference was observed between knockout and wild-type mice treated with propofol (200 mg/kg). Examination of the cellular fractions isolated from volatile anesthetic-treated mouse brains showed that PKC-γ was significantly decreased in the synaptic membrane fraction (P2), whereas p-PKC-γ was significantly increased in P2. There was no significant change in the supernatant fraction (S). In propofol-treated mice, PKC-γ and p-PKC-γ showed no significant changes in P2 or S. CONCLUSION: Our results provide new evidence to support the possibility of the involvement of PKC-γ in the actions of volatile anesthetics.

Changes in expression of GABAA alpha4 subunit mRNA in the brain under anesthesia induced by volatile and intravenous anesthetics.

We investigated changes in levels of GABAA receptor alpha4 subunit mRNA in the mouse brain after administration of volatile or i.v. anesthetic, by performing quantitative RT-PCR. We also performed immunohistochemical assays for c-fos-like protein. During deep anesthesia (which was estimated by loss of righting reflex) after administration of propofol, levels of GABAA receptor alpha4 subunit mRNA in the hippocampus, striatum and diencephalons were significantly greater than those observed after administration of pentobarbital, midazolam or GOI (5.0% isoflurane and 70% nitrous oxide in oxygen). Under incomplete anesthesia, levels of GABAA receptor alpha4 subunit mRNA were significantly increased by midazolam in all brain regions, and were significantly increased by pentobarbital in the posterior cortex and striatum. Expression of GABAA receptor alpha4 subunit mRNA closely correlated with expression of c-fos-like protein. These results indicate that the GABAA receptor alpha4 subunit plays an important role in regulating the anesthetic stage of i.v. anesthetics.