Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells ...into the circulation. We found thatPhd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate–glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower inPhd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo13C-labeled lactate incorporation assay revealed that the livers ofPhd2-LKOmice produce significantly more glucose derived from13C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate.Phd2-LKOmice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.
We present a life-threatening case of hemothorax resulting from right brachiocephalic vein perforation during right internal jugular vein catheterization. We considered that the guidewire had ...punctured the right brachiocephalic vein extraluminally and the catheter inserted over the guidewire had enlarged the size of the perforation. Despite the use of proper technique, an angle-tip guidewire may perforate the venous wall. Therefore, when there is negative aspiration after central venous catheterization, it is important to perform an emergency chest radiograph before proceeding with surgery; it is also important not to use an angle-tip guidewire.
Purpose
It has been reported some patients have opened eyes with low bispectral index (BIS) values immediately following electroconvulsive therapy (ECT). We investigated the time course of the ...recovery from amnesia and BIS values.
Methods
Five patients with depression requiring repeated ECT procedures were enrolled. The patients were asked to recall an object presented prior to anesthesia at four specific points (prior to induction, upon regaining consciousness following ECT, when they returned to their ward, and when their BIS values had returned to pre-anesthetic levels). BIS data were recorded continuously until BIS values returned to the pre-anesthetic levels at their ward. The area under a receiver-operating characteristic (ROC) curve was used to detect associations between the BIS values and disturbance of memory function.
Results
A total of 41 ECT stimuli were administered. After returning to their ward, patients generally fell asleep, with BIS values of between 50 and 70, and they woke up 1–2 h later. All the patients could recall the presented object prior to anesthesia and when the BIS values had returned to pre-anesthetic levels. The area under the ROC curve for the detection of memory disturbance was 0.902.
Conclusion
The present study demonstrated a high frequency of patients falling asleep and the frequent occurrence of prolonged periods of low BIS values following ECT. The results of memory testing showed that ECT procedures resulted in amnesia. The ROC curve findings suggest a strong association of memory disturbance with BIS values. In conclusion, patients generally fell asleep, with low BIS values, for 1–2 h after ECT, and a prolonged period of impairment of memory formation was associated with low BIS values.
Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic ...acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.
C1 inhibitor (INH) deficiency is characterized by the presence of angioedema of the extremities, face, airway and the gastrointestinal tract. Airway obstruction is the most common cause of mortality. ...A 78-year-old woman presented with repeated episodes of angioedema. These episodes were triggered by general anesthesia, dental extraction, venipuncture, vaccination and loxoprofen. The familiy history of similar symptoms was negative. C1 inhibitor concentrate was administered perioperatively for prophylaxis of attacks. Operation was performed under neurolept anesthesia and combined spinal-epidural anesthesia in order to avoid airway manipulation. Postoperative pain was controlled by patient-controlled epidural anesthesia to prevent attacks triggered by pain. The patient had angioedema on both lower extremities perioperatively but did not develop further attacks. Anesthesia was safely performed in a patient with C1 inhibitor deficiency scheduled for total hip arthroplasty.
The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus‐1 infection worldwide. However, malignant lymphoma is a severe and ...frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS‐related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS‐related lymphoma according to the revised classification. In this retrospective study, 207 AIDS‐related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B‐cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non‐GC type. Non‐GC‐type cases showed a significantly lower 1‐year survival rate (43%) than the GC‐type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B‐cell lymphoma arising in Kaposi sarcoma‐associated herpesvirus‐associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART‐naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL‐6 negativity, Epstein–Barr virus positivity, and Kaposi sarcoma‐associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.
In this study, the authors classified AIDS‐related lymphoma cases, diagnosed between 1987 and 2012 in Japan, according to the WHO classification of lymphomas, fourth edition. This study revealed the proportions and clincopathological features of each histological subtype of AIDS‐related lymphoma during the study period. The authors also propose a set of biological markers that can be used for the classification of AIDS‐related lymphoma.
Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the ...introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies.
A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985-2012 were retrospectively reviewed. Clinical data were collected from patient medical records.
Mean CD4 counts of patients were 77.0 cells/μL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/μL in naïve patients (ART (-) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026).
The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.
We conducted a pilot study to assess the feasibility and efficacy of immunotherapy for stage IV malignant melanoma patients resistant to conventional therapies involving vaccination with mature ...dendritic cells (mDCs) combined with administration of low dose interleukin-2. Autologous monocytes were harvested from a single apheresis and cultured for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4, yielding immature dendritic cells (iDCs), which were then cryopreserved until use. For 4 days prior to vaccination, iDCs were exposed to autologous tumour lysate combined with tumour necrosis factor-alpha to induce terminal differentiation into mDCs. Patients were then vaccinated weekly with 107 mDCs for 10 weeks and given 350-700 kIU of interleukin-2 three times per week. Of the 10 patients in the study, one showed stable disease, seven showed progressive disease, and two showed mixed responses, including partial tumour regression, and were therefore given 20 additional injections. Only minimal adverse events were noted, including localized skin reactions and mild fever (NIH-CTC grade 0-1). Median survival from the first vaccination was 240 days (range 31-735 days). In vitro, melanoma patient-derived dendritic cells (DCs) showed reduced cell surface expression of CD1a antigen on iDCs and reduced CD86 and HLA-DR expression on mDCs. In addition, antigen uptake, chemotaxis and antigen presentation were all attenuated in DCs from the patients. In summary, although improvement of clinical efficacy will require further research, autologous tumour lysate-pulsed monocyte-derived mDCs could be safely harvested, cryopreserved and administrated to patients without obvious complications.
Abstract
We have recently identified lipopolysaccharide tumor-induced tumor necrosis factor α factor (LITAF) as a novel transcription factor controlling necrosis factor (TNF)-α expression in the ...human monocytic cell line, THP-1. To characterize the human (h) LITAF promoter, we isolated a 1.2-kb DNA fragment and followed this by a screening of human genomic DNA with a hLITAF cDNA probe. A 34-bp sequence domain located from nucleotides −74 to −43 in the hLITAF promoter exhibited the highest basal reporter gene activity; however, the activity was not elevated by lipopolysaccharide (LPS) stimulation. The sequence domain included a consensus sequence for hepatocyte nuclear factor (HNF)-3α, regulating the transcription of many kinds of genes. Interestingly, the DNA sequence position between −542 and −538 in the hLITAF promoter contained the CTCCC motif, which has been reported to act as a specific binding site for hLITAF protein. Electrophoretic mobility shift assays demonstrated that LPS induced the binding of THP-1 nuclear factors to a 22 bp probe containing the CTCCC motif. In addition, hLITAF mRNA and nuclear hLITAF protein increased significantly in the THP-1 cells immediately after LPS stimulation. These results suggest that the consensus sequence for HNF-3α, or a nuclear binding protein to the CTCCC motif, may play an important role in regulating LPS-dependent LITAF transcription.
PDF
