A novel mutation in early-onset sarcoidosis/Blau syndrome: an association with Propionibacterium acnes.

BACKGROUND: Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are systemic inflammatory granulomatous diseases without visible pulmonary involvement, and are distinguishable from their sporadic and familial forms. The diseases are characterized by a triad of skin rashes, symmetrical polyarthritis, and recurrent uveitis. The most common morbidity is ocular involvement, which is usually refractory to conventional treatment. A gain-of-function mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene has been demonstrated in this disease; however, little is known about the relationship between the activation of NOD2 and the pathophysiology of EOS/BS. Here we describe EOS/BS with a novel mutation in the NOD2 gene, as well as detection of Propionibacterium acnes (P. acnes) in the granulomatous inflammation. CASE PRESENTATION: An 8-year-old Japanese girl presented with refractory bilateral granulomatous panuveitis. Although no joint involvement was evident, she exhibited skin lesions on her legs; a skin biopsy revealed granulomatous dermatitis, and P. acnes was detected within the sarcoid granulomas by immunohistochemistry with P. acnes-specific monoclonal (PAB) antibody. Genetic analyses revealed that the patient had a NOD2 heterozygous D512V mutation that was novel and not present in either of her parents. The mutant NOD2 showed a similar activation pattern to EOS/BS, thus confirming her diagnosis. After starting oral prednisolone treatment, she experienced an anterior vitreous opacity relapse despite gradual prednisolone tapering; oral methotrexate was subsequently administered, and the patient responded positively. CONCLUSIONS: We presented a case of EOS/BS with a novel D512V mutation in the NOD2 gene. In refractory granulomatous panuveitis cases without any joint involvement, EOS/BS should be considered as a differential diagnosis; genetic analyses would lead to a definite diagnosis. Moreover, this is the first report of P. acnes demonstrated in granulomas of EOS/BS. Since intracellular P. acnes activates nuclear factor-kappa B in a NOD2-dependent manner, we hypothesized that the mechanism of granuloma formation in EOS/BS may be the result of NOD2 activity in the presence of the ligand muramyl dipeptide, which is a component of P. acnes. These results indicate that recognition of P. acnes through mutant NOD2 is the etiology in this patient with EOS/BS.

Purpuric drug eruption without leukocytoclastic vasculitis associated with vancomycin.

Vancomycin (VCM) has been reported to elicit adverse cutaneous drug reactions. However, VCM-associated purpuric drug eruption has not been reported yet, except leukocytoclastic vasculitis. A 16-year-old Japanese girl was admitted with a respiratory infection. We initiated intravenous administration of VCM. After the start of treatment, impalpable purpuric eruption appeared on her trunk. The eruption gradually extended to her neck, legs, and arms. Skin biopsy showed vasculitis with lymphocyte infiltration in the superficial dermis. A drug lymphocyte stimulation test yielded positive results for VCM. Her cutaneous symptoms rapidly reversed after the withdrawal of VCM. To the best of our knowledge, this is the first reported case of VCM-associated purpuric drug eruption, which differs from leukocytoclastic vasculitis. We recommend that VCM-associated purpuric drug eruption should be considered in the differential diagnosis during the administration of VCM, and a drug lymphocyte stimulation test may be useful for assessment of pathogenesis.

Early canakinumab therapy for the sensorineural deafness in a family with Muckle-Wells syndrome due to a novel mutation of NLRP3 gene.

Cryopyrin-associated periodic syndrome (CAPS) is one of the autoinflammatory disorders caused by mutations in NLRP3 gene. The over-production of interleukin (IL)-1ß induced by NLRP3 gene mutations plays an important role in the pathophysiology of CAPS. We diagnosed 3 patients with CAPS, who were lineal family members having a novel mutation of NLRP3 gene. The objective of this report is to compare the characteristics of symptoms and differences in the therapeutic responses of them, who had the same mutation. In addition, we aimed to examine the usefulness of cytokine measurement for diagnosis or determination of treatment effect of CAPS. A 5-year-old Japanese boy (proband) came to our hospital because of short stature, reached the diagnosis of Muckle-Wells syndrome (MWS) due to a mutation in NLRP3 gene, which had not been reported so far (p.G328E, c.G983A). His mother and grandmother harbored the same mutation of NLRP3. We measured serum concentrations of cytokines in the proband assessed by flow-cytometric bead array. All of them had episodic skin eruptions with conjunctivitis, hearing loss, and arthralgia, but not periodic fever, cold-triggered episodes, and chronic aseptic meningitis. Only the proband had short stature. Canakinumab therapy led to a prompt relief of symptoms and normalized laboratory data in all patients. Audiograms demonstrated an improved hearing level in the proband, but not two others despite of the same mutation. All cytokines did not show any characteristic findings. Sensorineural hearing loss and itchless rash but not serum cytokine profile deserved attention to the diagnosis and treatment start of CAPS. The early intervention of IL-1ß blockade may reduce the chance of complete deafness in patients with CAPS.

[Home medical support at Jikei Medical University].

A clinical clerkship of home care has been introduced to third-year medical students since 1998 at our university. Visiting nurses from the regional visiting nursing stations would give actual trainings at patient's home to a lot of medical students every year. For the improvement of medical education, it is not sufficient to give actual trainings to the students from visiting nurses. Then what we can do for visiting nurses about the role of the medical University was to offer and introduce the programs of cardiac and respiratory assessment as lifelong learning for the visiting nurses. After these programs were finished, two kinds of questionnaires were given to all participants to examine the necessity and scheduling of these program: 1 ) The first questionnaires after the programs was of cardiac and respiratory assessment, 2 ) The second questionnaires was for the participants with the experience of these programs, 3 ) Last questionnaires was for all visiting nurses about our 41 regional visiting nursing stations to promote the new programs(eight programs: home hospice care and opioids, PEG for the nutrition, ICLS, management of respirator at home, management of IVH port, ECG, foreign body of the airway, and the anatomy of organs)for lifelong learning. 1 ) A total of 7 2 visiting nurses participated in our programs for about one year recently, and 100% of these attendants returned questionnaires. After the programs, almost all of visiting nurses agreed that these programs were meaningful for them and it should be continued. 2 ) A total of 2 10 visiting nurses participated in our programs for the past 5 years. Fifty seven percent(57. 1%)of visiting nurses returned questionnaires. After the programs, a lot of visiting nurses agreed that these programs were meaningful for them and it should be continued. 3 ) Nearly 50 percent (47. 8% or 213/446)of visiting nurses from 41 visiting nursing stations returned questionnaires. A lot of visiting nurses expressed that they would like to participate in the subject of hospice care and opioids, PEG for the nutrition, ICLS and management of respirator at home as new programs. For the role of the medical University to promote a home care, it is necessary to support a community-based home care with educational issues at the university and to offer the new program mentioned previously as lifelong learning with practical and essential issues for medical staffs at patients' homes.

Defect images in stress thallium-201 myocardial scintigraphy in patients with complete left bundle branch block: comparison of exercise stress and pharmacological stress.

OBJECTIVES: Stress thallium-201 (201Tl) myocardial scintigraphy can demonstrate perfusion abnormalities, especially in the septum in patients with complete left bundle branch block (CLBBB) even with angiographically normal coronary arteries. Differences in the images between exercise and pharmacological stress 201Tl myocardial scintigraphy were evaluated in patients with CLBBB and normal coronary arteries. METHODS: Forty-five patients with CLBBB underwent exercise stress using treadmill or pharmacological (adenosine triphosphate) stress 201Tl myocardial scintigraphy from October 1997 to February 2003. Patients with myocardial diseases were excluded, such as cardiomyopathy and coronary artery diseases detected by echocardiography and/or cardiac catheterization. The myocardial segment was classified according to the American Heart Association style for coronary artery disease. RESULTS: Peak blood pressure levels and heart rates were significantly higher in the exercise stress group than in the pharmacological stress group (p < 0.001). The rate of defects in stress images was significantly higher in the exercise stress group (72.4%; 21/29 cases) than in the pharmacological stress group (18.8%; 3/16 cases) (p < 0.01). The rate of redistribution of observed defects in delayed images was 76.2% (16/21 cases) in the exercise stress group, and 0% (0/3 cases)in the pharmacological stress group (p < 0.01). The myocardial segments showing defects were different between the exercise stress group and the pharmacological stress group. CONCLUSIONS: Patients with CLBBB showed different frequencies of defects by stress 201Tl myocardial scintigraphy according to the stress method. Moreover, defects also occured in areas other than the septum. Blood pressure and heart rate were involved in the mechanisms of defects in left bundle branch block.

Impaired Ca2+ handling in perfused hypertrophic hearts from Dahl salt-sensitive rats.

To clarify the correlation between intracellular Ca2+ dynamics and level of Ca2+-regulatory proteins, changes in Ca2+ handling and these proteins were investigated in a whole-heart experimental model of pressure-overload hypertrophy. We used 17-18-week-old male Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) fed a high-salt diet. We monitored the fura-2 fluorescence ratio, an index of cytoplasmic Ca2+ concentration ([Ca2+]i), using a Ca2+ analyzer in a retrograde perfused heart. Left ventricular pressure (LVP) and an electrocardiogram were simultaneously recorded. Ca2+ handling was assessed by exposing the hearts to 2 min of low-Na+ (70 mmol/l) perfusion to produce an increase in [Ca2+]i (n = 6), which was sensitive to Ni2+, a blocker of the Na+/Ca2+ exchanger (NCX). In another series, the hearts were stimulated at 2.5 to 5 Hz to determine the Ca2+-force-frequency relationship (n = 6). DS rats showed marked cardiac hypertrophy without any signs of failure. The time-to-peak Ca2+ transient was prolonged in DS compared with that in DR during normal beating. During low-Na+ exposure, the time-to-peak diastolic [Ca2+]i (TTP) and the decay-time from peak [Ca2+]i (DT) were prolonged in DS compared with DR (TTP, 43.3 +/- 4.0 vs. 32.5 +/- 2.5 s, p < 0.05; DT, 70.0 +/- 8.8 vs. 29.2 +/- 2.7 s, p < 0.005). Following pretreatment with 10 mmol/l caffeine to inhibit sarcoplasmic reticulum (SR) function, TTP and DT were still prolonged in DS compared with DR (TTP, 64.2 +/- 9.7 vs. 37.0 +/- 5.8 s, p < 0.05; DT, 55.8 +/- 12.6 vs. 26.0 +/- 5.7 s, p < 0.05). The force (LVP)-frequency relationship was initially positive in DR but was negative at all times in DS (%LVP/2.5 Hz: DS, 90.3 +/- 2.0%; DR, 112.2 +/- 4.5%; p < 0.05). Elevation of diastolic [Ca2+]i (percent increase of baseline) was greater in DS than in DR with increased stimulation (5 Hz: DS, 80.7 +/- 6.7%; DR, 52.1 +/- 5.9%; p < 0.05). In Western blot analysis, the protein level of NCX was equivalent, whereas that of SR Ca2+ ATPase (SERCA2) was significantly decreased in DS compared with DR. These results suggest that slowing of cellular Ca2+ mobilization and removal is related to impaired Ca2+ handling in late-phase cardiac hypertrophy. Both the activity of the NCX and that of the SR may be affected. The SR dysfunction may be associated with change in protein level of SERCA2.