The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of “iron immunology” as the synthesis of the iron metabolism and the immune response.
Gastric acid measurement is useful in assessing the effectiveness of antisecretory drugs, however, the conventional tests involve invasive nasogastric intubation. Orally administered 13C-labeled calcium carbonate (Ca13CO3) reacts with gastric acid to produce 13C-labeled carbon dioxide (13CO2), which is then excreted in the breath. The objective of this study was to evaluate the suitability of Ca13CO3 breath test for estimating gastric acid secretion in human noninvasively. First, the Ca13CO3 breath test and the measurement of pooled gastric acid under a fasting condition were performed in 6 healthy volunteers to evaluate the correlation between the two parameters. Next, endoscopic gastric acid collection and the Ca13CO3 breath test were performed on different days after pentagastrin injection in 20 subjects to evaluate the correlation between the tests and the reproducibility. Finally, the same studies were repeated in 4 subjects before and after 1-week rabeprazole, a proton pump inhibitor, administration. The maximum 13CO2 concentration (Cmax) correlated very well with the amount of pooled gastric acid (r = 0.95), suggesting that Ca13CO3 breath test values well reflected the fasting intragastric acidity. The 13CO2 concentration after pentagastrin injection correlated well with pentagastrin-stimulated maximal acid output (r = 0.79 at 20 min). The reproducibility of the Ca13CO3 breath test under pentagastrin-stimulation was good (coefficient of variation = 0.11). Rabeprazole administration markedly reduced the values of the Ca13CO3 breath test, suggesting that it can sensitively assess the efficacy of rabeprazole. The Ca13CO3 breath test can potentially be a useful method for non-invasive estimation for gastric acid secretion in human.
Galectin-9 (Gal-9) is a β-galactoside-binding protein involved in various biologic processes, including cell aggregation, adhesion, chemoattraction, and apoptosis. Little is known, however, about the regulation mechanisms of Gal-9 production. Recent studies reported high plasma Gal-9 levels in humans infected with human immunodeficiency virus-1 and dengue virus. Viral respiratory infections such as influenza are common human illnesses. A synthetic double-stranded RNA, polyinosinic-polycytidylic acid (PolyIC), mimics the effects of viruses in various cell types and induces the expression of Gal-9 in endothelial cells. To examine the potential link between viral infection and Gal-9 expression, we measured plasma Gal-9 concentrations in patients with influenza. Subjects were 43 patients with influenza virus infection, 20 with pneumococcal pneumonia, and 20 healthy adults. Gal-9 concentrations in the plasma and in culture supernatants of human airway epithelial cells were measured using an enzyme-linked immunosorbent assay. Plasma Gal-9 concentrations were higher in patients with influenza infection than in patients with pneumococcal pneumonia and healthy subjects (p < 0.05). Patients with influenza were effectively differentiated from those with pneumococcal pneumonia or healthy subjects, based on the plasma levels of Gal-9 (p < 0.0001). Furthermore, using a human airway epithelial cell line, we showed that the presence of PolyIC but not lipopolysaccharides increased the Gal-9 concentration in the culture medium (p < 0.05), suggesting that PolyIC enhanced Gal-9 production. These findings support our proposal that Gal-9 production is induced by influenza virus infection in humans. In conclusion, plasma Gal-9 could be a new biomarker for patients with influenza infection.
Cervical cancer is the third most common malignant disease of women worldwide. Despite advances in screening and treatment strategies, a significant number of patients have advanced and recurrent disease. These patients are not amenable to curative treatments, such as surgery and radiation, and have poor prognosis. Therefore, palliative treatment remains the standard of care for these patients. Several phase II/III trials have demonstrated that cisplatin is the most active single agent, and the combination of cisplatin and paclitaxel is considered a standard regimen for clinical practice and trials in these patients with improved response rates and progression-free intervals. Although other cisplatin doublet chemotherapy regimens were not superior to cisplatin plus paclitaxel, substituting topotecan or gemcitabine for paclitaxel might be helpful for some patients considering different toxicity profiles. Because the response to palliative chemotherapy is poor, several targeted agents including bevacizumab, erlotinib, pazopanib, lapatinib, sunitinib and cetuximab, each of which inhibits cell proliferation and angiogenesis, were evaluated in these patients. Of them, bevacizumab, targeting vascular endothelial growth factor, showed favorable results. Recent phase III trial showed that bevacizumab combined with chemotherapy was shown to significantly improve the response rate, progression-free interval, and overall survival compared to chemotherapy alone. These results suggest that targeted agents could significantly improve survival and affect practice guidelines in these patients showing poor prognosis. Thus, future trials using newly developed targeted agents are warranted to improve treatment strategies in these patients.
West syndrome (WS), an intractable epileptic encephalopathy of infancy, is refractory to many antiepileptic drugs; however, adrenocorticotropic hormone (ACTH) is an effective treatment for WS. The mechanism behind the efficacy of ACTH is mediated by biochemical processes that remain unknown. We examined the effects of ACTH therapy with tetracosactide (TCS), a synthetic ACTH analogue, on brain metabolism in patients with WS, using 1H magnetic resonance spectroscopy (1H-MRS). In six patients with cryptogenic WS, we performed single-voxel 1H-MRS at the occipital lobe cortex. Measurements were taken prior to TCS treatment, a few days after therapy, and several months after therapy. Data were also compared with subjects having only mild psychomotor delays. The metabolites measured were glutamine plus glutamate (Glx), N-acetylaspartate (NAA), choline (Cho), and myoinositol (mI); each was expressed as a ratio with creatine plus phosphocreatine (total creatine: tCr). The Glx/tCr ratio was significantly reduced after the TCS treatment. The NAA/tCr ratio was also significantly reduced after the treatment compared with the control group, although the change in NAA signal was heterogeneous among patients, correlating with respective outcomes. The Cho/tCr and mI/tCr ratios were not affected by TCS treatment. The reduction in Glx suggests a decrease in the glutamate-glutamine cycle, which plays a pivotal role in synthesizing neurotransmitters such as glutamate and GABA. TCS-induced Glx reduction may induce changes in synaptic signal transduction, thereby accounting for the effect of TCS on WS. The change in NAA indicates altered neuronal activity, which may be correlated with outcome in WS patients.
The relationship between hospital caseload or volume and the outcome of various surgical procedures has been well documented. However, such hospital caseload-outcome relationship (HCOR) has been seldom addressed in rare medical conditions, such as pleural infection, which is usually associated with pneumonia and may progress to systemic inflammation and severe sepsis. Pleural infection can be treated with medical or surgical pleural space drainage, but the treatment is still unstandardized. This population-based study, using Taiwan’s medical claim data, investigated the HCOR in patients with pleural infection. A total of 24,876 patients with pleural infection (median age of 65 years; men, 76.6%) were identified between 1997 and 2008. Hospital caseload was calculated with the average number of cases per hospital annually. The primary outcome is hospital mortality, and the secondary outcomes include hospital length of stay and charges. The risk of mortality among patients treated in hospitals with the highest caseload quartile (≥ 14 cases per hospital annually) is less than those treated in hospitals with the lowest caseload (1 case per hospital annually) by 27% (adjusted odds ratio = 0.73, 95% confidence interval = 0.55 to 0.96). Such beneficial effect disappeared after adjustment for therapeutic procedures. Hospital caseload explained only a small portion of variation in hospital mortality (−2 log likelihood % = 0.26%). These findings suggest that higher hospital caseload is associated with better outcomes of patients with pleural infection. The difference in therapeutic procedures for pleural infection contributes to the observed effect of hospital caseload on hospital mortality.
Measurement of the gastric acid secretion is useful for estimating the risk for various diseases in the upper gastro-intestinal tract; however, the procedure causes significant distress to the subjects. Pepsinogens I and II are secreted from the gastric fundic glands, and thus, the serum pepsinogen levels reflect the gastric functional statuses. The aim of this study is to establish appropriate serum pepsinogen cutoff points for predicting the gastric acid secretion status. In a total of 627 Japanese subjects, gastric acid secretion was measured with an endoscopic gastrin test, and the serum pepsinogen values and serum Helicobacter (H.) pylori-IgG antibody were also measured. After checking the correlation between gastric acid secretion and serum pepsinogen, the receiver operating characteristics analyses were employed for determining the most suitable cutoff points of serum pepsinogen for the gastric acid secretion status (i.e., hypochlorhydria, profound hypochlorhydria, and hyperchlorhydria). The pepsinogen I/II ratio and pepsinogen I showed the best correlation with gastric acid secretion in H. pylori-positive and H. pylori-negative subjects, respectively. The serum pepsinogen I/II ratio (or pepsinogen I in cases of H. pylori-negative subjects) was useful to determine the gastric acid secretion status with acceptable to outstanding diagnostic accuracy (the range of the area under the curve: 0.79-0.93). The diagnostic accuracy was further improved after stratifying the subjects by H. pylori-infection status. Estimating gastric acid secretion levels by simple measurement of serum pepsinogens will have significant clinical implications in estimating the risks for various diseases of the upper gastrointestinal tract.
Streptococcus (S.) pyogenes is well recognized as the most common pathogen causing pharyngotonsillitis in school-age children. In Japan, mucoid Streptococcus pneumoniae is well known as a causative agent of severe acute otitis media (AOM); however, mucoid S. pyogenes has rarely been reported. To the best of our knowledge, this is the first report of an AOM patient caused by mucoid S. pyogenes in Japan. A 36-year-old previously healthy female was referred to our hospital with suspicion of cerebrospinal otorrhea due to increasing otalgia accompanied by headache following myringotomy. Bacterial cultures of middle ear secretions were performed, and mucoid-form colonies surrounded by zones of complete β-hemolysis were produced on sheep’s blood agar. Antigen-agglutination test results were positive for S. pyogenes, and thus the patient received treatment with panipenem-betamipron 2.0 g/day for 10 days, which resolved nearly all symptoms. The bacteriological features of this strain were then investigated. The M-protein genotype encoded by the emm gene, the major virulence factor of S. pyogenes, was determined to be emm75. Generally, S. pyogenes forms colonies having non-mucoid matt appearances based on β-hemolysis of sheep’s blood agar. The mucoid phenotype results from abundant production of hyaluronic acid capsular polysaccharide, a key virulence determinant. emm75 is common in noninvasive, but less common in invasive disease. In conclusion, mucoid S. pyogenes can cause severe infection even in previously healthy persons. Emergence of mucoid S. pyogenes and drug resistance trends should be monitored in the future.