Blockade of IL-18Rα-mediated signaling pathway exacerbates neutrophil infiltration in imiquimod-induced psoriasis murine model.

Psoriasis is an immune-mediated inflammatory disease of the skin, which is characterized by epidermal hyperkeratosis and neutrophil infiltration. The interleukin (IL)-17/IL-23 pathway and associated cytokines play major roles in the pathogenesis and exacerbation of psoriasis. The IL-18/IL-18 receptor (R) α signaling pathway is important for Th1 cytokine production and differentiation of Th1 cells; however, its role in the pathogenesis of psoriasis remains unknown. In this study, we investigated the effect of the IL-18Rα-mediated signaling pathway in the pathogenesis of psoriasis in Il18ra-deficient mice (Il18ra-/-) and wild-type imiquimod (IMQ)-induced psoriatic dermatitis model mice. Blocking this pathway exacerbated IMQ-induced psoriatic skin inflammation. Il18ra deficiency led to significant increases in the levels of IL-1ß, IL-6, IL-8, IL-17A, IL-23, and chemokine (C-X-C motif) ligand 2 in skin lesions. Gr1-positive cells highly infiltrated psoriatic skin lesions in Il18ra-/- mice compared to those in wild-type mice. Citrullinated histone H3-positive area was relatively broad in Il18ra-/- mice. These results suggest that IL-18Rα-mediated signaling pathways may inhibit psoriatic skin inflammation by regulating infiltration and activation of neutrophil and other innate immune cells.

Visualization of cross-resistance between antimicrobial agents by asymmetric multidimensional scaling.

WHAT IS KNOWN AND OBJECTIVE: In our previous studies, we developed a cross-resistance rate (CRR) correlation diagram (CRR diagram) that visually captures the magnitude of CRRs between antimicrobials using scatter plots. We used asymmetric multidimensional scaling (MDS) to transform cross-resistance similarities between antimicrobials into a 2-dimensional map and attempted to visually express them. We also explored the antibiograms of Pseudomonas aeruginosa before and after the transfer to newly built hospitals, and we determined by the CRR diagram that the CRRs among ß-lactam antimicrobials other than carbapenems decreased substantially with the facility transfer. The present study tests whether the analysis of CRRs by asymmetric MDS can be used as new visual information that is easy for healthcare professionals to understand. METHOD: We tested the impact of changes in the nosocomial environment due to institutional transfers on CRRs among antimicrobials in asymmetric MDS, as well as contrasted the asymmetric MDS map and CRR diagram. RESULTS AND DISCUSSION: In the asymmetric MDS map, antimicrobial groups with the same mechanism of action were displayed close together, and antimicrobial groups with different mechanisms of action were displayed separately. The asymmetric MDS map drawn solely for antimicrobials belonging to the group with the same mechanism of action showed similarities to the CRR diagram. Also, the distance of each antimicrobial to other antimicrobials shown in the asymmetric MDS map was negatively correlated with the CRRs for them against that antimicrobial. WHAT IS NEW AND CONCLUSION: The asymmetric MDS map expresses the dissimilarity as distances between agents, and there are no meanings or units on the ordinate and abscissa axes of the output map. In contrast, the CRR diagram expresses the antimicrobials' resistance status as values, such as resistance rate and CRR. By analysing the CRRs in the asymmetric MDS, it is feasible to visually recognize cross-resistance similarities between antimicrobial groups as distances. The use of the asymmetric MDS combined with the CRR diagram allows us to visually understand the resistance and cross-resistance status of each antimicrobial agent as a 2-dimensional map, as well as to understand the trends and characteristics of the data by means of quantitative values.

Antiretroviral Therapy Improves Acquired Immunodeficiency Syndrome with Systemic Lupus Erythematosus.

A 35-year-old male was referred to our hospital with dysesthesia of the lower extremities that had begun six months earlier. A blood test revealed the presence of various antibodies, suggesting a collagen-related peripheral neuropathy. However, a history of repeated shingles and sex with males was noted, and the patient was tested for and diagnosed with human immunodeficiency virus (HIV) infection. Based on the manifestations and laboratory data, including the results of immunological and urinary tests, he was further diagnosed with concomitant systemic lupus erythematosus (SLE). The activity of SLE improved with antiretroviral therapy. There is currently no established treatment for AIDS complicated with SLE. Indeed, because HIV treatment involves the activation of immune function and SLE treatment involves immunosuppression, any treatments for the two conditions would be in conflict. It is thus necessary to select a treatment strategy based on the condition of the individual patient. In addition, because HIV infection is relatively rare in Japan compared to other countries, rheumatologists in Japan must keep HIV infection in mind as a differential diagnosis for autoimmune diseases.

Real-World Methotrexate Dose on Clinical Effectiveness and Structural Damage of Certolizumab Pegol With Rheumatoid Arthritis.

Objective: Rheumatoid arthritis (RA) treatments have markedly advanced with the introduction of biological agents, e. g., tumor necrosis factor (TNF) inhibitors. TNF inhibitors are demonstrated to be quite effective in combination with methotrexate (MTX), and sufficient doses of both agents are important to control RA's disease activity. However, not all RA patients can be treated with high-dose MTX due to contraindications related to the antimetabolite action of MTX or to tolerability concerns. In daily practice, this has resulted in reduced effectiveness of TNF inhibitors. We sought to determine whether the concomitant use of dose of MTX affected the clinical effectiveness, retention rate, and side effects of certolizumab pegol (CZP) for treating RA in a real-world setting. CZP is a pegylated-conjugated Fab' fragment of a humanized anti-TNF antibody that has high affinity to TNF. Patients and Methods: We divided Japanese RA patients treated with CZP (n = 95, 25-83 years old) into groups based on those with (n = 65) and without (n = 30) concomitant MTX and those treated with a high dose (≥8 mg, n = 41) or low dose (1- <8 mg, n = 24) of MTX. We retrospectively analyzed the concomitant MTX doses' effects and side effects and the patient retention rate. Results: There were no significant differences among the CZP groups with and without MTX or the groups receiving the high vs. low MTX doses in the retention rate, the low disease activity rate, or the inhibitory effect in radiographic joint damage. Conclusion: CZP has the potential to be a useful biological agent to control RA's disease activity and the bone destruction in patients who cannot tolerate a sufficient MTX dose.

Infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results.

PURPOSE: We evaluated the clinical responses and radiographic outcomes of 90 patients with rheumatoid arthritis (RA) undergoing continuous or dose-adjusted infliximab treatment over 104 weeks. PATIENTS AND METHODS: Patients received 3 mg/kg infliximab continuously (the contin group; n=50), or the dose escalation and de-escalation of infliximab (3, 6, and 10 mg/kg) from week 14 (the adjusted group; n=40) based on the patient's Disease Activity Score in 28 joints (DAS28). The retention rate, clinical response, and radiographic assessment were determined at week 104. RESULTS: The contin and adjusted groups' retention rates at week 104 were 56.8 and 66.7%, and the groups' low disease activity in the DAS28 was 39.1 and 66.7%, respectively. Remission based on the DAS28 and the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) Boolean-based criteria was significantly increased in the adjusted group. In the radiographic assessment, there was also a significant reduction in the mean changes in total Sharp score. The cumulative rates of any adverse effects showed no significant difference between the groups. CONCLUSION: In an assessment of adequate DAS28 results, the RA patients who did not respond to the initial dose of infliximab showed improved clinical responses and radiographic assessment after a dose adjustment of infliximab, without an increased risk of serious adverse events.

Impaired Pain Processing Correlates with Cognitive Impairment in Parkinson's Disease.

Objective Pain and cognitive impairment are important clinical features in patients with Parkinson's disease (PD). Although pain processing is associated with the limbic system, which is also closely linked to the cognitive function, the association between pain and cognitive impairment in PD is still not well understood. The aim of the study was to investigate the association between pain processing and cognitive impairment in patients with PD. Methods Forty-three patients with PD and 22 healthy subjects were studied. Pain-related somatosensory evoked potentials (SEPs) were generated using a thin needle electrode to stimulate epidermal Aδ fibers. Cognitive impairment was evaluated using the Mini-Mental State Examination (MMSE), the Frontal Assessment Battery, and Japanese version of the Montreal Cognitive Assessment (MoCA-J), and their correlation with pain-related SEPs was investigated. Results The N1/P1 amplitude was significantly lower in PD patients than the controls. N1/P1 peak-to-peak amplitudes correlated with the MMSE (r=0.66, p<0.001) and MoCA-J scores (r=0.38, p<0.01) in patients with PD. These amplitudes also strongly correlated with the domains of attention and memory in the MMSE (attention, r=0.52, p<0.001; memory, r=0.40, p<0.01) and MoCA-J (attention, r=0.45, p<0.005; memory, r=0.48, p<0.001), but not in control subjects. Conclusion A good correlation was observed between the decreased amplitudes of pain-related SEPs and an impairment of attention and memory in patients with PD. Our results suggest that pathological abnormalities of the pain pathway are significantly linked to cognitive impairment in PD.

Association of leptin with orthostatic blood pressure changes in Parkinson's disease.

INTRODUCTION: Leptin is involved in the regulation of blood pressure; however, no studies have evaluated the role of leptin in blood pressure changes during orthostatic stress in PD patients. The aim of this study was to determine whether plasma leptin levels influence orthostatic blood pressure changes in PD patients. METHODS: We enrolled 55 patients and 25 age-matched healthy controls in this study. Associations between head-up tilt test measurements and leptin levels were evaluated. RESULTS: Systolic blood pressure changes during the head-up tilt tests were strongly correlated with leptin levels at baseline and at a 60-degree head-up tilt in PD patients, but not in control subjects. Multiple regression analysis also demonstrated that leptin levels were associated with orthostatic blood pressure changes. CONCLUSION: These observations suggest that low leptin levels may be associated with orthostatic hypotension during the head-up tilt test in patients with PD. © 2016 International Parkinson and Movement Disorder Society.

Impaired peripheral vasoconstrictor response to orthostatic stress in patients with multiple system atrophy.

BACKGROUND AND PURPOSE: Most patients with multiple system atrophy (MSA) develop autonomic dysfunction; however, orthostatic hypotension is not always present. Failure of the vasoconstrictor response is thought to be responsible for orthostatic hypotension, but the degree of impairment of this response in patients with MSA is unclear. We assessed autonomic function in patients with MSA by evaluating the vasoconstrictive response during a head-up tilt test and determining its relationship to orthostatic hypotension. As an additional examination, the efficacy of norepinephrine in treating orthostatic hypotension was also assessed. METHODS: The study included 82 patients with MSA and 28 controls. Measures of total peripheral resistance were obtained during a head-up tilt test. Norepinephrine was administered to the patients lacking a vasoconstrictive response to evaluate its ability to treat orthostatic hypotension. RESULTS: At a 60° tilt, orthostatic hypotension occurred in 47.6% of the patients and 0% of controls. Reduction in total peripheral resistance from baseline at a 60° tilt was observed in 69.5% of the patients and 0% of controls. In patients with MSA, changes in systolic blood pressure from the baseline at a 60° tilt correlated positively with changes in the total peripheral resistance (r = 0.69, p < 0.0001). Norepinephrine prevented the reduction of total peripheral resistance and development of orthostatic hypotension. CONCLUSIONS: A large number of patients with MSA with and without orthostatic hypotension have an impaired peripheral vasoconstrictive response, suggesting a high frequency of cardiovascular dysautonomia with an associated risk of developing orthostatic hypotension. A norepinephrine infusion was effective for treating orthostatic hypotension.

Efficacy of intravenous immunoglobulin for treatment of Lambert-Eaton myasthenic syndrome without anti-presynaptic P/Q-type voltage-gated calcium channel antibodies: a case report.

We evaluated the efficacy of intravenous immunoglobulin (IVIg) in a patient with Lambert-Eaton myasthenic syndrome (LEMS). Comprehensive clinical and electrophysiological testing was performed on a 34-year-old woman with progressive limb weakness, before and after IVIg treatment. Neurological examination revealed muscle weakness, predominantly in the proximal parts of the limbs. Muscle weakness improved following a short period of maximum voluntary muscle contraction. A repetitive low-rate (3-Hz) nerve stimulation test of the abductor hallucis was normal, but high-rate (20-Hz) stimulation induced an incremental response. Anti-presynaptic P/Q-type voltage-gated calcium channel (P/Q-VGCC) antibodies were absent in the patient's serum. Whole body computed tomography revealed no tumors. We diagnosed seronegative LEMS without tumor and treated the patient with IVIg. Both clinical and electrophysiological indices improved gradually after treatment. This case study indicates that treatment with IVIg is equally effective for LEMS that is seronegative or seropositive for P/Q-VGCC antibodies.

Difference in Physiological Components of VO2 Max During Incremental and Constant Exercise Protocols for the Cardiopulmonary Exercise Test.

[Purpose] VO2 is expressed as the product of cardiac output and O2 extraction by the Fick equation. During the incremental exercise test and constant high-intensity exercise test, VO2 results in the attainment of maximal O2 uptake at exhaustion. However, the differences in the physiological components, cardiac output and muscle O2 extraction, have not been fully elucidated. We tested the hypothesis that constant exercise would result in higher O2 extraction than incremental exercise at exhaustion. [Subjects] Twenty-five subjects performed incremental exercise and constant exercise at 80% of their peak work rate. [Methods] Ventilatory, cardiovascular, and muscle oxygenation responses were measured using a gas analyzer, Finapres, and near-infrared spectroscopy, respectively. [Results] VO2 was not significantly different between the incremental exercise and constant exercise. However, cardiac output and muscle O2 saturation were significantly lower for the constant exercise than the incremental exercise at the end of exercise. [Conclusion] These findings indicate that if both tests produce a similar VO2 value, the VO2 in incremental exercise would have a higher ratio of cardiac output than constant exercise, and VO2 in constant exercise would have a higher ratio of O2 extraction than incremental exercise at the end of exercise.

Hyposmia and cardiovascular dysautonomia correlatively appear in early-stage Parkinson's disease.

OBJECTIVE: Olfactory dysfunction is considered to precede motor symptoms and early markers of Parkinson's disease (PD), while the relative time at which cardiovascular dysautonomia appears in PD is not well understood. To assess the appearance of cardiovascular dysautonomia in PD, we evaluated its relation to olfactory dysfunction in early-stage PD patients. METHODS: Twenty-three non-demented PD patients within 2 years from the onset of motor symptoms were enrolled. We evaluated olfactory dysfunction by the Odor Stick Identification Test for Japanese (OSIT-J) and analyzed its relationship to the results of other cardiovascular autonomic tests and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: There was a correlation between olfactory scores and increased blood pressure in both the norepinephrine (r = 0.75, p < 0.0001, n = 21) and dobutamine (r = 0.57, p = 0.0087, n = 20) infusion tests and cardiac MIBG uptake (r = 0.42, p = 0.049, n = 23). The fall in orthostatic blood pressure during the head-up tilt test was not correlated with the olfactory scores, but the Valsalva maneuver revealed that OSIT-J scores correlated with the pressure recovery time from phase III to the return of blood pressure to baseline (r = 0.54, p = 0.037, n = 15) and with the magnitude of blood pressure overshoot during phase IV (r = 0.67, p = 0.0016, n = 20). CONCLUSION: Our results demonstrate that extensive components of the cardiovascular sympathetic system as well as the olfactory system are correlatively impaired in the early stage of PD, suggesting that degeneration of broad aspects of the cardiovascular sympathetic system occurs concurrently with olfactory system degeneration during the premotor phase of PD.

Slowly progressive folate-deficiency myelopathy: report of a case.

BACKGROUND: Folate deficiency is known to be associated with subacute combined degeneration of the spinal cord; however, reports of long-standing cases are rare. Although neurological deficits due to folate deficiency have been reported to respond to folic acid supplementation, the functional outcomes have not been fully elucidated. OBJECTIVE: The aim of the study was to evaluate the clinical features and response to folate supplementation in a patient with folate deficiency manifested over 10 years as a slowly progressive myelopathy. METHODS: We performed comprehensive clinical screening, electrophysiological testing, and posturography before and after folate supplementation. RESULTS: A 49-year-old man had a slowly progressive gait disturbance for 10 years. He had not eaten fresh green vegetables for more than 10 years. Neurological examination revealed spastic paraplegia and absence of any vibration sense in the lower limbs accompanied by a positive Romberg's sign. Serum folate level was low, and plasma homocysteine level was elevated. Levels of blood thiamine and serum cobalamin were normal. We diagnosed the patient with myelopathy due to folate deficiency. Folic acid supplementation led to improvement of his symptoms; posturography and walking speed tests showed partial improvement, while the somatosensory-evoked potentials and central motor conduction time remained unchanged. CONCLUSIONS: Folate deficiency should be considered as a differential diagnosis of chronic slowly progressive myelopathy. The present case suggests the importance of early diagnosis and treatment before the adverse neurological manifestations of folate deficiency become irreversible.