Stratification of atopic dermatitis patients by patterns of response to proactive therapy with topical tacrolimus: low serum IgE levels and inadequately controlled disease activity at the start of treatment predict its failure

PurposeTopical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy).MethodsA single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients’ clinical and laboratory findings.ResultsOf the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (p = 0.049). At the beginning of proactive therapy, the mean-SCORing Atopic Dermatitis (SCORAD) score was significantly different between the proactive-completed (11.7 ± 4.6) and proactive-dropout (16.6 ± 4.2) groups (p = 0.025). In proactive-dropout group patients, worsened disease activity correlated well with the elevation of serum lactate dehydrogenase (LDH) and Thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil count.ConclusionAD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.

Key messages

• AD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy.
• The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels.
• TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.

     

HPLC with electrochemical detection for determining the distribution of free fatty acids in skin surface lipids from the human face and scalp

Free fatty acids (FFAs) in human skin surface lipids were determined by high-performance liquid chromatography with electrochemical detection. The amperometric detection of FFAs was based on electrochemical reduction of quinone, 2-methyl-1,4-naphthoquinone (vitamin K(3), VK(3)) in unbuffered solution. The peak heights for lauric, myristic, palmitic, palmitoleic, stearic, oleic, linoleic, linolenic, and arachidonic acids at a detection potential of -415 mV vs a saturated calomel electrode showed a linear relationship with the amounts of acid in the range of 50-1600 pmol. Standard acids at 200 pmol were determined ten times with a relative standard deviations (RSD) of less than 1.5%. FFAs from about 1 mg of skin surface lipids absorbed on 5 x 5 mm pieces of oil-absorbing paper were extracted with 200 microl ethanol-acetonitrile (20:80) to prepare the test solution, of which 20 microl was injected into the octadecylsilica column. The results of the analysis of skin surface lipids from the forehead of a male subject were measured within 15 min of obtaining the sample. The RSD ( n=5) in all cases was less than 4.5%, and the recovery of FFAs was more than 94%. Since the size of the lipid samples was very small for the analytical method, FFAs were determined in skin surface lipids from 50 points on the head of a male volunteer and the FFA distribution on the face and scalp were mapped. The present method is noninvasive, sensitive, selective for FFAs and suitable for the determination of FFAs in skin surface lipids of humans, and has the potential to help in the diagnosis and treatment of various skin disorders.     

Comparison of gadobenate dimeglumine and gadopentetate dimeglumine: a study of MR imaging and inductively coupled plasma atomic emission spectroscopy in rat brain tumors

BACKGROUND AND PURPOSE: After the advent of extracellular contrast media, hepatobiliary-specific gadolinium chelates were developed to improve the diagnostic value of MR imaging of the liver. Gadobenate dimeglumine (Gd-BOPTA) is a new paramagnetic contrast agent with partial biliary excretion that produces prolonged enhancement of liver parenchyma on T1-weighted images. However, whether Gd-BOPTA is useful as a contrast agent in central nervous system disease, particularly in brain tumors, is unclear. METHODS: The behavior of Gd-BOPTA as a brain tumor-selective contrast agent was compared with that of gadopentetate dimeglumine (Gd-DTPA), an MR contrast agent used in central nervous system disease, in a common dose of 0.1 mmol/kg. An MR imaging study of these two contrast agents was performed, and tissue concentrations were measured with inductively coupled plasma atomic emission spectroscopy (ICP-AES). RESULTS: Gd-BOPTA showed better MR imaging enhancement in brain tumors than did Gd-DTPA at every time course until 2 hours after administration and no enhancement in peritumoral tissue and normal brain. Corresponding results with ICP-AES showed significantly greater uptake of Gd-BOPTA in tumor samples than that in peritumoral tissue and normal brain 5 minutes after administration. Gadolinium was retained for a longer time in brain tumors when Gd-BOPTA rather than Gd-DTPA was administered. CONCLUSION: Gd-BOPTA is a useful contrast agent for MR imaging in brain tumors and possibly an effective absorption agent for neutron capture therapy.     

Rotational acetabular osteotomy for osteonecrosis with collapse of the femoral head in young patients

BACKGROUND: While rotational acetabular osteotomy has been reported to be successful for the treatment of osteoarthritis of the dysplastic hip, little is known about its efficacy in the treatment of osteonecrosis of the femoral head. METHODS: We retrospectively reviewed the results for a consecutive series of twenty-one patients (twenty-five hips) who had undergone rotational acetabular osteotomy between 1995 and 2001 for the treatment of extensive osteonecrosis of the femoral head associated with collapse. All but two of the patients had a history of steroid therapy as part of a treatment regimen for various diseases. At the time of surgery, the mean age of the five men and sixteen women was 29.0 years. The mean duration of follow-up was forty-nine months. No patient was lost to follow-up. The lesions were classified according to the staging system described by Steinberg et al., and the extent of necrosis was measured with use of the criteria described by Kerboul et al. Clinical evaluation was performed with use of the scoring system of Merle d'Aubigne and Postel. Radiographic evaluation was performed with use of yearly serial anteroposterior and lateral plain radiographs. RESULTS: The mean Merle d'Aubigne and Postel score improved from 11.3 points preoperatively to 14.9 points at the time of the final follow-up (p < 0.001). The mean pain score improved from 3.0 to 5.6 points (p < 0.001). However, the mean mobility score was 5.3 points preoperatively but only 4.9 points postoperatively (p = 0.1). All of the osteotomy sites showed radiographic evidence of osseous union at the time of the latest follow-up. Collapse of the femoral head progressed in seven hips, but in six of these hips the change in the extent of collapse was <2 mm. CONCLUSIONS: In the present study of young patients with extensive osteonecrosis and collapse of the femoral head, rotational acetabular osteotomy was associated with symptomatic relief and absence of substantial collapse of the femoral head at the time of early to intermediate-term follow-up.     

Pathophysiology and diagnosis of congenital periodic alternating nystagmus

PURPOSE: Not many cases of congenital periodic alternating nystagmus have been reported in Japan. We investigated the pathophysiology and diagnosis of congenital periodic alternating nystagmus noting the age when this disease began, which had not been reported previously. SUBJECTS: Ninety-one patients with congenital nystagmus who were seen in our department in Teikyo University School of Medicine between July 1994 and January 2002 were studied. RESULTS: Eighteen patients(19.8%) among the 91 congenital nystagmus patients were diagnosed with congenital periodic alternating nystagmus. A manifestation of the periodic face turning was seen between the age of three and nine. Visual acuity over 0.6 with correction was obtained in all patients. Almost all the patients had an asymmetric cycle of null point shifting and the face turning was seen at one side for a long time. CONCLUSION: When we see congenital nystagmus patients whose face turning alters periodically with fairly good vision over the age of three, we must check out the direction of jerk nystagmus changes at the same gazing point using electronystagmography or video cassette recording to detect the possibility of congenital periodic alternating nystagmus.     

Senescence of chondrocytes in aging articular cartilage: GADD45β mediates p21 expression in association with C/EBPβ in senescence-accelerated mice

Growth arrest and DNA damage-inducible protein 45β (GADD45β) is expressed in normal and early osteoarthritic articular cartilage. We recently reported that GADD45β enhances CCAAT/enhancer binding protein β (C/EBPβ) activation in vitro. This study was undertaken in order to determine whether GADD45β is expressed with C/EBPβ in aging articular cartilage. We also investigated whether the synergistic expression of GADD45β and C/EBPβ may be involved in the mechanism of chondrocyte senescence. Senescence-accelerated mice (SAMP1) were used as a model of aging. GADD45β, C/EBPβ, and p21 were analyzed by immunohistochemistry. A luciferase reporter assay using ATDC5 cells was performed in order to examine p21 as a target gene of the GADD45β/C/EBPβ cascade. GADD45β exhibited increased expression in the aging articular cartilage of SAMP1 mice compared to that in control mice. The co-localization of GADD45β and C/EBPβ was confirmed by double immunostaining. The synergistic mechanisms of GADD45β and C/EBPβ on the gene regulation of p21, a molecule related to cellular senescence, were verified by a p21-luciferase reporter assay. Co-expression of C/EBPβ and p21 was confirmed. These observations suggest that the synergism between GADD45β and C/EBPβ may play an important role in cellular senescence in the aging articular cartilage.     

Disruption of the midkine gene (Mdk) delays degeneration and regeneration in injured peripheral nerve

Midkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. MK acts as a reparative neurotrophic factor in damaged peripheral nerves. A postulated role of MK in the degeneration and regeneration of sciatic nerves was explored by comparing wild‐type (Mdk^+/+) mice with MK‐deficient (Mdk^?/?) mice after freezing injury. In the Mdk^?/? mice, a regenerative delay was observed, preceded by a decelerated Wallerian degeneration (WD). The relative wet weight of the soleus muscle slowly declined, and recovery was delayed compared with that in the Mdk^+/+ mice. In the regenerating nerve, unmyelinated axons were unevenly distributed, and some axons contained myelin‐like, concentrically lamellated bodies. In the endplates of soleus muscles, nerve terminals containing synaptic vesicles disappeared in both mice. In Mdk^?/? mice, the appearance of nerve terminals was delayed in synaptic vesicles of terminal buttons after injury. The recovery of evoked electromyogram was delayed in Mdk^?/? mice compared with Mdk^+/+ mice. Our results suggested a delay in axonal degeneration and regeneration in Mdk^?/? mice compared with Mdk^+/+ mice, and the delayed regeneration was associated with a delayed recovery of motor function. These findings show that a lack of MK following peripheral nerve injury is a critical factor in degeneration and regeneration, and manipulation of the supply of MK may offer interesting therapeutic options for the treatment of peripheral nerve damage. © 2009 Wiley‐Liss, Inc.     

Difference of ITS sequences of Akebia plants growing in various parts of Japan

The stem of the Akebia plant, “Mokutsu”, is a crude diuretic and antiphlogistic drug. Japanese products prepared from wild Akebia plants cover most of the Mokutsu market. Two Akebia plants, Akebia quinata Decaisne (Aq) and A. trifoliata Koidzumi (At) of Lardizabalaceae, are standardized as Mokutsu in Japanese pharmacopoeia. These two Akebia plants along with A. × pentaphylla Makino (Ap), which is considered a hybrid with the morphology of Aq and At, can be distinguished by DNA sequence analysis of internal transcribed spacers 1 and 2 (ITS) of nuclear ribosome DNA. Here, we report the results of molecular genetic analysis of Akebia plants grown in various wild habitats in Japan. We found that each of three Akebia plants could be distinguished in terms of their locality according to their nucleotide sequence in ITS, specifically at positions 91, 128, 133, 134, and 221. Plants with a comparable habitat had similar nucleotide sequences at these five points. We also found Aq with ITS and nucleotide deletion at position 86 that was distributed only around Awajishima in Shikoku (A), Harimanada (B), and Kinki (C), including the chief production center of Akebia Caulis. The results of these ITS sequences enabled discrimination of plants originating from Akebia Caulis.