Association between Comorbidity and Relative Dose Intensity in Patients with Diffuse Large B-Cell Lymphoma.

BACKGROUND: Comorbidities among cancer patients are becoming more common. Comorbidity and relative dose intensity (RDI)are 2 major host-dependent prognostic factors for diffuse large B-cell lymphoma(DLBCL), but the clinical evidence demonstrating a relationship between those 2 factors is limited. METHODS: We retrospectively analyzed the clinical records of patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone(R-CHOP) therapy at the Okitama Public General Hospital between January 2010 and October 2018 to evaluate the relationship between comorbidity and RDI. RESULTS: A total of 104 patients with a median age of 73 years(range, 36-90 years)were included. More than half of the patients(n=58, 55.8%)had at least one comorbidity. 3-year progression-free survival(p=0.043)and 3- year overall survival(p=0.049)were lower in the comorbidity group than in the no comorbidity group. The RDI was also lower in the comorbidity group than in the no comorbidity group(p=0.011). Univariate analysis of various factors influencing the RDI revealed that the presence of comorbidity was associated with insufficient RDI(p=0.016), but multivariate analysis revealed that only age ≥75(p<0.001)was independently associated with insufficient RDI. CONCLUSIONS: Our results demonstrated that the presence of comorbidity was associated with insufficient RDI and poor treatment outcome in DLBCL patients treated with R-CHOP. To optimize the RDI maintenance to achieve better outcomes for DLBCL patients, further investigation of comorbidities is required.

Successful high-dose dexamethasone treatment of acquired pure red cell aplasia following ABO major mismatched allogeneic hematopoietic stem cell transplantation.

A 46-year-old man was diagnosed with acute myelomonocytic leukemia involving inv(16)(p13.1q22) in August 2007. He received a human leukocyte antigen-identical, ABO major-mismatched (donor: A, recipient: O) bone marrow transplantation from an unrelated donor in June 2009. Cyclosporin A (CsA) and short-course methotrexate were used for graft versus host disease prophylaxis. Although granulocyte and platelet engraftment were achieved, the patient exhibited persistent anemia and was dependent on red blood cell (RBC) transfusions. Bone marrow aspiration on day 63 revealed the near absence of erythroid precursors, a finding consistent with pure red cell aplasia. No CBFß-MYH11 transcripts were detected. The recipient's anti-A IgM antibody titer was 1:64, and his anti-A IgG antibody titer was 1:1024. The discontinuation of CsA, and the initiation of rituximab and donor lymphocyte infusions were all ineffective against his anemia. He was treated with high-dose dexamethasone (DEXA) (40 mg/day DEXA, days 657-660, days 757-760; 20 mg/day DEXA, days 764-767, days 772-775) in April 2010. A follow-up examination performed at 7 months after the high-dose DEXA treatment showed the patient's anti-A antibody titer to have dropped to an undetectable level. His hemoglobin levels also returned to normal (Hb: 13.4 g/dl), and he no longer required RBC transfusions.

Management of erythropoiesis: cross-sectional study of the relationships between erythropoiesis and nutrition, physical features, and adiponectin in 3519 Japanese people.

Although erythroid abnormalities (anemia and polycythemia) are commonly observed pathological conditions, not much information about borderline abnormalities is available. In this study, a cross-sectional study to analyze the relationships between erythropoiesis and nutrition, physical features, and laboratory test findings was conducted in middle-aged and older men and women. The study included 3519 Japanese people (1579 men and 1940 women), age 40 years and over. Analysis of variance showed that the group with a tendency to anemia was older, had a lower body mass index and diastolic blood pressure, and had higher serum adiponectin and creatinine. Multiple regression analysis showed that adiponectin, triglycerides, and total protein were common factors that affected erythropoiesis in both men and women. Hepatic, renal, and cardiac functions were also factors involved in erythropoiesis in men and in postmenopausal women. In addition, nutrient factors such as alcohol, vitamins, and carbohydrates were also significantly involved in erythropoiesis in men, but there were no significant nutrient factors involved in erythropoiesis in either premenopausal or postmenopausal women. This study showed that factors that influence erythropoiesis differ between men, premenopausal women, and postmenopausal women, and it suggested that appropriately modifying erythropoiesis management for each group of people is essential.

Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage.

We studied the relationships between genetic and epigenetic alterations in gastrointestinal cancer by integrating DNA copy number changes determined by arbitrarily primed PCR (AP-PCR) with DNA methylation variations estimated by methylation-sensitive amplified fragment length polymorphism (MS-AFLP). We analyzed about 100 different chromosomal regions by AP-PCR and over 150 random CpG loci by MS-AFLP in human colon and gastric carcinomas. DNA hypomethylation and hypermethylation alterations distributed gradually and increased with cancer patient age, in contrast with the age-independent genomic alterations. Increased DNA hypomethylation and hypermethylation correlated with increased genomic damage, but only hypomethylation was highly significant in multivariate analyses. We conclude that age-dependent accumulation of DNA demethylation precedes diploidy loss in a significant subset of gastrointestinal cancers.

[Correlates of mental health in Japanese caseworkers employed at social welfare offices].

OBJECTIVES: The aim of this study was to evaluate the correlation between the mental health status of caseworkers at welfare offices and factors affecting mental health (i.e., working conditions, participation in training courses and workshops, lifestyle habits, presence of illness, social support, and self-efficacy). METHODS: The welfare offices in Japan (1,230 locations) were arranged in descending order according to their establishment and region. Systematic sampling was then conducted to select 20% (n =246) of the welfare institutions for this study. A total of 1,230 caseworkers on welfare (five from each institution) were administered anonymous self-completed questionnaires. The questionnaires involved the General Health Questionnaire (GHQ)-28 Japanese version and questions regarding basic attributes, working conditions, social support (i.e., family, friends, superiors, and colleagues), participation in training courses and workshops, presence of illness, lifestyle habits, mental health, and self-efficacy. Subjects were divided into the following 2 groups: low-score group (GHQ-28 score ≤5) and high-score group (GHQ-28 score ≥6). Data were analyzed using a t-test, χ(2) test, and Fisher's exact test. The GHQ-28 high- and low-score groups were considered gender-specific dependent variables due to the sex differences observed in the univariate analysis. Significant variables in the univariate analysis were considered independent variables in the multiple logistic regression analysis (forward stepwise selection). RESULTS: Five hundred and six people (410 male and 96 female) provided valid responses. Most respondents had poor mental health (66%, high-score group; 34%, low-score group). Both men and women who worked ≥10 hours/day had significantly poorer mental health than individuals who worked ≤9 hours/day. Individuals with low self-efficacy had significantly poorer mental health compared to people with high self-efficacy. Men who were able to maintain moderate hours of sleep and received support from colleagues, friends, and family had good mental health. Among women, mental health deteriorated with age. Furthermore, women who devoted most work time to home visit had good mental health. CONCLUSION: The mental health of caseworkers at welfare offices can be improved by reducing overtime work hours, ensuring sufficient hours of sleep for each worker, and fostering supportive communication and self-efficacy in the workplace. Furthermore, sex differences should be considered when assessing the mental health of workers at welfare offices in Japan.

Effects of exercise on the prevention of conditions leading to the need for long-term care.

BACKGROUND: Intervention strategies for 'prevention of conditions leading to the need for long-term care' (prevention of long-term care status) that have physically and mentally proven effects are needed. OBJECTIVE: The aim of this randomized controlled trial was to clarify the physical and psycho-social effects of an exercise program, easily performed at home and in communities using inexpensive equipments for prevention of long-term care status. METHODS: A cluster of 196 participants was randomly assigned to the intervention group that performed the exercise for 8 weeks and the control group. Both groups received tests for physical strength and endurance and interview surveys at baseline and 9 weeks later. The exercise consisted of six types of stretching exercises, six types of muscle strength training, two types of balance training and toe stretching in order to improve ambulatory, balance and stability ability of elderly. The physical aspects of the subjects were assessed by balance assessment, activities of daily living (ADL), timed up-and-go test (TUG), functional reach test (FRT), sit and reach. The psycho-social aspects were assessed by the fall prevention self-efficacy scale (FPSE), instrumental activities of daily living (IADL), degree of houseboundness, and assessment at the end of intervention. RESULTS: The intervention and control groups consisted of 101 and 81 persons at the baseline and 92 and 74 after intervention, respectively. The intervention group showed significantly higher values than the control group after exercise in the FRT, the FPSE and degree of houseboundness. CONCLUSION: This exercise program can promote physical and psycho-social aspects of the health in the elderly, and may reduce the amount of care that the elderly require.

Metabotropic glutamate receptor 5 contributes to inflammatory tongue pain via extracellular signal-regulated kinase signaling in the trigeminal spinal subnucleus caudalis and upper cervical spinal cord.

BACKGROUND: In the orofacial region, limited information is available concerning pathological tongue pain, such as inflammatory pain or neuropathic pain occurring in the tongue. Here, we tried for the first time to establish a novel animal model of inflammatory tongue pain in rats and to investigate the roles of metabotropic glutamate receptor 5 (mGluR5)-extracellular signal-regulated kinase (ERK) signaling in this process. METHODS: Complete Freund's adjuvant (CFA) was submucosally injected into the tongue to induce the inflammatory pain phenotype that was confirmed by behavioral testing. Expression of phosphorylated ERK (pERK) and mGluR5 in the trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) were detected with immunohistochemical staining and Western blotting. pERK inhibitor, a selective mGluR5 antagonist or agonist was continuously administered for 7 days via an intrathecal (i.t.) route. Local inflammatory responses were verified by tongue histology. RESULTS: Submucosal injection of CFA into the tongue produced a long-lasting mechanical allodynia and heat hyperalgesia at the inflamed site, concomitant with an increase in the pERK immunoreactivity in the Vc and C1-C2. The distribution of pERK-IR cells was laminar specific, ipsilaterally dominant, somatotopically relevant, and rostrocaudally restricted. Western blot analysis also showed an enhanced activation of ERK in the Vc and C1-C2 following CFA injection. Continuous i.t. administration of the pERK inhibitor and a selective mGluR5 antagonist significantly depressed the mechanical allodynia and heat hyperalgesia in the CFA-injected tongue. In addition, the number of pERK-IR cells in ipsilateral Vc and C1-C2 was also decreased by both drugs. Moreover, continuous i.t. administration of a selective mGluR5 agonist induced mechanical allodynia in naive rats. CONCLUSIONS: The present study constructed a new animal model of inflammatory tongue pain in rodents, and demonstrated pivotal roles of the mGluR5-pERK signaling in the development of mechanical and heat hypersensitivity that evolved in the inflamed tongue. This tongue-inflamed model might be useful for future studies to further elucidate molecular and cellular mechanisms of pathological tongue pain such as burning mouth syndrome.

[Physiology of the Vagus Nerve: Basic Medical Research from the Past to the Present].

The vagus nerve, which is the 10th cranial nerve, exits from the medulla and distributes widely to the visceral organs. Although it contains the motor, somatic, and sympathetic nerves, the main component is the parasympathetic nerve, which acts as the core of homeostasis. The vagal efferent regulates the cardiac muscle, striated muscle and glands, while the vagal afferent sends the information from the visceral organs to the brain. The vagus nerve is also responsible for the gut-brain axis.

Cell death induction in resting lymphocytes by pan-Cdk inhibitor, but not by Cdk4/6 selective inhibitor.

Immunosuppression is one of the common side effects of many anti-tumor agents targeting proliferating cells. We previously reported the development of a new class of pan-cyclin-dependent kinase (Cdk) inhibitor compounds that induce immunosuppression in rodents. Here, we demonstrated that a pan-Cdk inhibitor, Compound 1 very rapidly reduced white blood cells in mice, only 8 h after administration. Compound 1 induced death of peripheral blood cells or purified resting (non-stimulated) lymphocytes ex vivo. Cell death was induced very rapidly, after 4 h of incubation, suggesting that acute immunosuppression observed in rodents might be, at least in part, due to direct cytotoxic effects of Compound 1 on resting lymphocytes. While cell cycle-related Cdks were not activated, the carboxyl terminal domain (CTD) of the largest subunit of RNA polymerase II was phosphorylated, indicating activation of Cdk7 or Cdk9, which phosphorylates this domain, in resting lymphocytes. Indeed, the pan-Cdk inhibitor suppressed CTD phosphorylation in resting cells at the dose required for cell death induction. Inhibition of Cdk7 or Cdk9 by Compound 1 was also confirmed by suppression of nuclear factor-kappa B (NF-κB)-dependent transcription activity in the human cancer cell line U2OS. Interestingly, a Cdk4/6 inhibitor with selectivity against Cdk7 and Cdk9 did not induce cell death in resting lymphocytes. These results suggest that CTD phosphorylation possibly by Cdk7 or Cdk9 might be important for survival of resting lymphocytes and that Cdk inhibitors without inhibitory activity on these kinases might be an attractive agent for cancer chemotherapy.

Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms.

The aim of this study was to investigate whether astroglia in the medullary dorsal horn (trigeminal spinal subnucleus caudalis; Vc) may be involved in orofacial neuropathic pain following trigeminal nerve injury. The effects of intrathecal administration of the astroglial aconitase inhibitor sodium fluoroacetate (FA) were tested on Vc astroglial hyperactivity [as revealed by glial fibrillary acid protein (GFAP) labeling], nocifensive behavior, Vc extracellular signal-regulated kinase phosphorylation (pERK), and Vc neuronal activity in inferior alveolar nerve-transected (IANX) rats. Compared with sham-control rats, a significant increase occurred in GFAP-positive cells in ipsilateral Vc at postoperative day 7 in IANX rats, which was prevented following FA administration. FA significantly increased the reduced head withdrawal latency to high-intensity heat stimulation of the maxillary whisker pad skin in IANX rats, although it did not significantly affect the reduced escape threshold to low-intensity mechanical stimulation of the whisker skin in IANX rats. FA also significantly reduced the increased number of pERK-like immunoreactive cells in Vc and the enhanced Vc nociceptive neuronal responses following high-intensity skin stimulation that were documented in IANX rats, and glutamine administration restored the enhanced responses. These various findings provide the first documentation that astroglia is involved in the enhanced nociceptive responses of functionally identified Vc nociceptive neurons and in the associated orofacial hyperalgesia following trigeminal nerve injury.

Purinergic receptors are involved in tooth-pulp evoked nocifensive behavior and brainstem neuronal activity.

BACKGROUND: To evaluate whether P2X receptors are involved in responses to noxious pulp stimulation, the P2X3 and P2X2/3 receptor agonist α,ß-methyleneATP (α,ß-meATP) was applied to the molar tooth pulp and nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation in trigeminal spinal subnucleus caudalis (Vc), trigeminal spinal subnucleus interpolaris (Vi), upper cervical spinal cord (C1/C2) and paratrigeminal nucleus (Pa5) neurons were analyzed in rats. RESULTS: Genioglossus (GG) muscle activity was evoked by pulpal application of 100 mM α,ß-meATP and was significantly larger than GG activity following vehicle (phosphate-buffered saline PBS) application (p < 0.01). The enhanced GG muscle activity following 100 mM α,ß-meATP was significantly reduced (p < 0.05) by co-application of 1 mM TNP-ATP (P2X1, P2X3 and, P2X2/3 antagonist). A large number of pERK-LI cells were expressed in the Vc, Vi/Vc, C1/C2 and Pa5 at 5 min following pulpal application of 100 mM α,ß-meATP compared to PBS application to the pulp (p < 0.05). The pERK-LI cell expression and GG muscle activity induced by 100 mM α,ß-meATP pulpal application were significantly reduced after intrathecal injection of the MAPK/ERK kinase (MEK) inhibitor PD 98059 and by pulpal co-application of 1 mM TNP-ATP (p < 0.05). CONCLUSIONS: The present findings suggest that activation of P2X3 and P2X2/3 receptors in the tooth pulp is sufficient to elicit nociceptive behavioral responses and trigeminal brainstem neuronal activity.

Functional mapping of gustatory neurons in the insular cortex revealed by pERK-immunohistochemistry and in vivo optical imaging.

Neural plasticity in the gustatory area of the insular cortex (IC) plays a critical role in detecting novel taste and taste memory formation, which require extracellular signal-regulated kinase 1-2 (ERK1-2) phosphorylation. However, the distribution patterns of phosphorylated ERK1-2 (pERK) responses to gustatory stimulation remain unknown. This study examined distribution patterns of gustatory stimulation-driven pERK expression in the IC of anesthetized and alert rats. In both pentobarbital-anesthetized and alert rats, gustatory stimulation (10% sucrose) induced pERK-like immunoreactivity in pyramidal cells of all IC subdivisions: agranular (AI), dysgranular (DI), and granular IC (GI). Alert naïve rats exhibited approximately 10-fold larger number of pERK-like immunopositive (pERK-LI) cells than anesthetized naïve rats in response to sucrose application. Most pERK-LI cells were located in layers II/III but not deeper layers and almost no parvalbumin/somatostatin-immunopositive cells expressed pERK. In the AI, rostral regions exhibited more pERK-LI cells than caudal regions, whereas most pERK-LI cells existed in the DI/GI around the intersection of the rhinal fissure and middle cerebral artery (MCA), where in vivo optical imaging revealed activation during sucrose application in addition to the ventral primary and secondary somatosensory cortices. Gustatory experience affected the number of pERK-LI cells in the IC: sucrose stimulation induced more pERK-LI cells in the DI/GI of alert naïve rats than sucrose-exposed rats, which had received sucrose solution for 1 week. These results suggest that pyramidal cells in the upper layers of the gustatory region are highly susceptible to ERK1-2 phosphorylation by gustatory stimulation, which may induce neuroplastic changes in the IC.

Retraction: Effects of exercise on the prevention of conditions leading to the need for long-term care.

The paper entitled "Effects of Exercise on the Prevention of Conditions Leading to the Need for Long-term Care" by M. Ohtake et al, which was published online on 2 November 2010, has been withdrawn at the authors' request.

Metabolic indices related to leaf marginal necrosis associated with potassium deficiency in tomato using GC/MS metabolite profiling.

To clarify the physiological factors associated with the development of tomato leaf marginal necrosis associated with potassium deficiency, tomato leaf blades prior to development of the symptoms were collected, and profiles of water-soluble metabolites were analyzed using gas chromatography-mass spectrometry. Multivariate analysis was conducted to screen for a component that was related to potassium deficiency-induced leaf necrosis among the 60 metabolites detected in tomato leaves. Polyamines, sugars, and branched amino acids were ranked highly. Putrescine was most strongly and negatively correlated with potassium concentration and exhibited an exponential response, regardless of the site or plant body. In addition to putrescine, glucose, xylose and l-isoleucine are known to play important roles in stress response and ion balance control, and it is thought that changes in metabolite profiles are linked to tomato leaf marginal necrosis associated with a decrease in endogenous potassium concentration. These findings will be useful for cultivation management to mitigate this physiological disorder of tomato.

Impact of comorbidity and relative dose intensity on outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.

BACKGROUND: Comorbidity and relative dose intensity (RDI) have been associated with survival in diffuse large B-cell lymphoma (DLBCL) patients, but both relationships remain unaddressed in the same patients. METHODS: A retrospective review of consecutive DLBCL patients treated from January 2010 to October 2018 was performed. Data for the clinical characteristics of the patients, including the Charlson Comorbidity Index (CCI) and RDI, on their outcomes were evaluated. RESULTS: A total of 211 patients with a median age of 72 years (range 19-90 years) were analyzed. CCI ≥ 2 was associated with poor event-free survival (EFS) and overall survival (OS). RDI < 70% was associated with worse EFS and OS. A multivariate analysis revealed that RDI < 70% was only a poor risk factor for the reduction of OS in elderly DLBCL patients (65 years <) and independent from the presence of CCI. The relationship between CCI and RDI in elderly patients was analyzed in four groups, based on CCI ≥ 2 or less and RDI ≥ 70% or less. The group with CCI ≥ 2 and RDI < 70% had a poorer OS and EFS, as compared to the other three groups. The group with CCI < 2 and RDI ≥ 70% had a superior OS but an identical EFS, as compared to the two groups with CCI < 2 and RDI < 70% and CCI ≥ 2 and RDI ≥ 70%. CONCLUSIONS: CCI ≥ 2 was associated with a poorer outcome, but maintaining RDI ≥ 70% may improve the outcome, especially in elderly DLBCL patients.

Somatosensory regulation of resting muscle blood flow and physical therapy.

Somatosensory stimulation can affect skeletal muscle blood flow (MBF) at rest in anesthetized animals via pressor reflex response or antidromic and local vasodilation. Increase in MBF due to reflex pressor response occurs generally in the skeletal muscles of the entire body, while antidromic and local vasodilation are limited to the peripheral stimulation site. Since increased MBF improves several disorders (muscle stiffness, pain, etc.), it is reasonable to further explore the effective use of somatic stimulation in physical therapies, such as massage, acupuncture, anma, and shiatsu or acupressure, in treating skeletal muscle disorders.

Augmented brain 5-HT crosses the blood-brain barrier through the 5-HT transporter in rat.

The present study re-evaluated an existing notion that serotonin (5-hydroxytryptamine; 5-HT) could not cross the brain to the circulating blood via the blood-brain barrier (BBB). To elevate brain 5-HT alone, 5-hydroxytryptophan (5-HTP; 30-75 mg/kg) was administrated intravenously to anaesthetized rats that had undergone gastrointestinal and kidney resections along with liver inactivation (organs contributing to increasing blood 5-HT after 5-HTP administration). A microdialysis method and HPLC system were used to determine the brain 5-HT levels in samples collected from the frontal cortex. Blood 5-HT levels were determined from whole blood, not platelet-poor plasma, collected from the central vein. We found that blood 5-HT levels showed a significant augmentation whenever brain 5-HT levels were significantly elevated after the administration of 5-HTP in those rats with the abdominal surgical procedures. This elevation was abolished after pretreatment with a selective serotonin reuptake inhibitor (fluoxetine; 10 mg/kg i.v.), although brain 5-HT levels remained augmented. These results indicate that augmented brain 5-HT can cross the BBB through the 5-HT transporter from the brain to the circulating blood.

Attenuation of naloxone-induced Vc pERK hyper-expression following capsaicin stimulation of the face in aged rat.

In order to clarify the effect of age-related change in trigeminal nociception, phosphorylation of extracellular signal-regulated kinase (pERK) in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord neurons were studied in the aged rats following subcutaneous capsaicin injection into the whisker pad. A large number of pERK-LI cells was expressed in the superficial laminae of Vc and upper cervical spinal cord in adult and aged rats following subcutaneous capsaicin injection into the whisker pad region. The number of pERK-LI cells was largest at about 2.0mm caudal from the obex and gradually decreased in their numbers in more rostral and caudal sections. The rostro-caudal distribution profile of pERK-LI cells expressed after subcutaneous capsaicin injection into whisker pad was similar in adult and aged rats. The number of pERK-LI cells was slightly, but not significantly larger in aged rats compared with that of adults. Pretreatment with naloxone significantly increased the number of capsaicin-induced pERK-LI cells in adult rats but not in aged rats. The present findings suggest that the descending modulation system impaired with advancing age, resulting in the abnormal pain sensation in aged rats.