Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

Predictive performance of dual modality of computed tomography angiography and intravascular ultrasound for no-reflow phenomenon after percutaneous coronary stenting in stable coronary artery disease.

Attenuated plaque on intravascular ultrasound (IVUS) and low attenuation plaque on computed tomography angiography (CTA) are associated with no-reflow phenomenon during percutaneous coronary intervention (PCI). However, evaluation by a single modality has been unable to satisfactorily predict this phenomenon. We investigated whether the combination of IVUS and CTA findings can ameliorate the predictive potential for no-reflow phenomenon after stent implantation during PCI in stable coronary artery disease (CAD). A total of 988 lesions of 707 stable CAD patients who underwent coronary CTA before PCI were enrolled. PCI was performed with preprocedural IVUS and stent implantation. As for plaque characters, very low attenuation plaque (CTA v-LAP) whose minimum density was < 0 Hounsfield units on CTA and attenuated plaque (IVUS AP) on IVUS were evaluated. No-reflow phenomenon was observed in 22 lesions (2.2%) of 19 patients (2.7%). Both CTA v-LAP and IVUS AP were much more frequently observed in patients with no-reflow phenomenon. Positive (PPV) and negative predictive values (NPV) and accuracy for prediction of no-reflow were almost equivalent between CTA v-LAP (13.2, 99.6, and 87.0%) and IVUS AP (15.7, 99.8, and 89.0%). The combination of CTA v-LAP and IVUS AP markedly ameliorated PPV (31.7%) without deterioration of NPV (99.7%) and increased the diagnostic accuracy (95.5%). These findings showed that the combination of CTA v-LAP and IVUS AP improved the predictive power for no-reflow phenomenon after coronary stenting in stable CAD patients, suggesting the usefulness of combined estimation by using CTA and IVUS for predicting no-reflow phenomenon during PCI in clinical practice.

[A case of MPO-ANCA-related nephritis caused by an anti-tuberculosis drug].

We report a rare case of MPO-ANCA-related nephritis induced by an anti-tuberculosis drug. The patient was a 67-year-old woman who was admitted to our hospital because of proteinuria and renal dysfunction. She had been under treatment with rifampicin (RFP) and ethambutol hydrochloride (EB) for pulmonary nontuberculous mycobacteriosis. Her serum myeloperoxidase (MPO)-ANCA titer was high. Drug-induced MPO-ANCA-related nephritis was suspected. When medication with RFP and EB was terminated, the levels of serum Cr and MPO-ANCA decreased. Renal biopsy examination revealed cell infiltration and fibrosis in the interstitium as well as crescent formations and necrotization of the capillary wall in the glomeruli. These findings were compatible with the diagnosis of ANCA-related nephritis. The standard treatment for ANCA-related glomerular nephritis (GN)is generally steroid pulse therapy, steroid therapy and immunosuppressive drugs. The lymphocyte stimulation test was positive for EB and negative for RFP, suggesting that in our patient EB was the cause of ANCA-related GN. After withdrawal of RFP and EB, the titer of MPO-ANCA decreased and the patient's renal function improved. This outcome is characteristic of drug-induced ANCA-related vasculitis.

A patient undergoing chronic dialysis whose renal anemia was successfully corrected by treatment with cinacalcet.

A 62-year-old female dialysis patient with chronic glomerulonephritis had been receiving hemodialysis therapy for 32 years. In 1985 she underwent a parathyroidectomy for secondary hyperparathyroidism (HPT); however, her parathyroid hormone (PTH) levels gradually increased. Her serum calcium level ranged from 9.0 to 10.0 mg/dL, which caused difficulties in performing vitamin D injection therapy. No parathyroid glands were seen by echography or scintigraphy. On 31 March 2008 her intact PTH (iPTH) level was 895 pg/mL so treatment with cinacalcet 25 mg/day was started. After 3 months her iPTH level decreased to 269 pg/mL and her hemoglobin level increased from 9.3 to 12.9 g/dL. In some cases of severe HPT, anemia improves after parathyroidectomy; however, in this case, cinacalcet improved not only secondary HPT but also anemia.

Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities.

Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age. At this stage, the plp1(tg/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(tg/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia.

Partial remission by cyclosporine monotherapy in a patient with membranous nephropathy superimposed diabetic nephropathy.

It has been noted that cyclosporine A (CsA) is an effective drug for membranous nephropathy (MN). Diabetes is a common disease that sometimes causes nephrotic syndrome. We report the case of an 89-year-old woman with type 2 diabetes mellitus who exhibited nephrotic syndrome. Examination of a renal biopsy indicated MN and she was prescribed CsA as monotherapy. Her edema subsided and she achieved partial remission. This is the first report of a patient in diabetic condition with MN having achieved partial remission after CsA monotherapy without steroid therapy. The use of steroid in patients with diabetes may worsen their diabetic condition, especially if they are of very advanced age. CsA monotherapy may be useful for diabetic patients with MN.

Conduction properties of identified neural pathways in the central nervous system of mice in vivo.

Various lines of transgenic or knockout mice are now available that have abnormalities in neuron, glial cells or neuron-glial interaction. However, the techniques for quantitative analysis of their pathophysiological functions are still limited. We established an experimental model system to measure the properties of nerve conduction of identified neural pathways in the CNS using anesthetized and immobilized mice. Dorsal column (DC), vestibulospinal/reticulospinal tracts (VRST) and pyramidal tract (PT) were stimulated by inserting stimulating electrodes into the dorsal column nuclei, medial longitudinal fasciculus, and the medullary pyramid, respectively. Volleys were recorded at various segments in the cervical spinal cord with surface electrodes, and their conduction velocities (CVs) and relative refractory periods (RRPs) were measured. The CVs of the DC, VRST and PT were 26.25 +/- 4.96 m/s (n = 7), 51.55 +/- 4.65 m/s (n = 7), 8.89 +/- 1.81 m/s (n = 7), respectively. Data from paired stimulation indicated that the median values of RRPs of the DC, VRST and PT were 10, 2 and 4 ms, respectively, which suggested marked difference among individual tracts. This is the first attempt to measure the conduction properties of the central tracts in mice in vivo. This experimental procedure will give us a physiological measure of CNS functions in normal and genetically manipulated mice and contribute to clarifying the molecular mechanisms and pathophysiology of neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

Electrophysiological abnormalities precede apparent histological demyelination in the central nervous system of mice overexpressing proteolipid protein.

Myelin proteolipid protein (plp), a major myelin protein in the CNS, has been proposed to function in myelin assembly. Transgenic mice overexpressing the plp gene by introduction of two extra wild-type (Wt) mouse plp genes (plp(tg/-)) exhibit normal myelination and ion channel clustering at the age of 2 months. However, at the age of 5 months, demyelination becomes observable, accompanied by a reduction in the number of K+ channel clusters at Ranvier's node and a progressive increase in motor deficit. To clarify how these age-dependent changes are related to nerve conduction in the CNS, we analyzed the conduction velocity (CV) and relative refractory period (RRP) of identified spinal ascending or descending tracts, such as the dorsal column pathway, the vestibulospinal and reticulospinal tracts, and the pyramidal tract, in plp(tg/-) mice 2, 5, and 8 months of age. We found that CVs decreased as age increased. Importantly, CVs were significantly reduced and prolonged RRPs were observed in 2-month-old (2M) plp(tg/-) mice that had no apparent demyelination. Immunohistological examination revealed that densities of Na+ and K+ channel clusters decreased as plp(tg/-) and Wt mice aged. However, a clear correlation was not observed between CVs and mean channel cluster densities or between mean channel cluster densities and progress of demyelination. Performance in the rotarod test was normal in 2M plp(tg/-) mice but deteriorated in mice older than age 5 months. These results suggest that electrophysiological analysis can detect the abnormalities of the plp(tg/-) mice earlier than histological or behavioral measures.