博莱霉素脂质体凝胶的制备和体外透皮性比较

目的：研制博莱霉素（BLM）脂质体凝胶,并对其皮肤靶向性进行体外评价。方法：采用逆相蒸发-冻融法制备BLM脂质体,再用卡渡姆940为基质制成BLM脂质体凝胶;以离心法测定BLM脂质体的包封率;以体外透皮渗透释药法,比较BLM脂质体凝胶与BLM普通凝胶的透过作用。结果：BLM脂质体平均粒径为（885．20±12．08）nm,平均包封率为（66．80±1．38）％。在24h内,BLM脂质体凝胶累积透过量（Q）及稳态透皮速率（J）与BLM普通脂质体相比,均明显提高,而在皮肤中的滞留药量也显著提高（P〈0．05）。结论：BLM脂质体凝胶在体外可显著增加BLM的透皮吸收,增加皮肤中的滞留量,值得进一步研究。     

The skin as a mirror of the aging process in the human organism--state of the art and results of the aging research in the German National Genome Research Network 2 (NGFN-2)

As our society is growing older, the consequences of aging have begun to gain particular attention. Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research. The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors. In particular, hormones are decisively involved in the generation of aging. Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease. Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes. Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed. Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20- and in 60-year-old women. Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20- and 60-year-old hormone mixture, respectively. Among them genes were regulated which are involved in biological processes which are all hallmarks of aging. The most significantly altered signaling pathway identified was that of the transforming growth factor-beta (TGF-beta). A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer. Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified. These data demonstrate that skin and its appendages may represent an adequate model for aging research. Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels. Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases. Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process.     

Assessment of lower limb ischemia with measurement of skin perfusion pressure in patients on hemodialysis

Measurement of skin perfusion pressure (SPP) using laser Doppler has become available for the assessment of peripheral arterial disease. We studied whether measurements of SPP can be used to identify hemodialyzed patients with peripheral arterial disease by comparing it with measurements of the ankle brachial pressure index (ABI). The ABI at rest and the SPP in the foot were measured in 59 Japanese hemodialyzed patients (118 limbs). Twenty-one patients had diabetes mellitus. Five had intermittent claudication; however, 20 patients were accompanied by other exertional leg symptoms. The SPP could not be measured in three limbs because of involuntary movement due to previous stroke or restless leg syndrome. The SPP was correlated with the ABI. Depending upon these results of the ABI, the 114 limbs from which both the ABI and the SPP could measured were divided into three groups: (A) ABI > or = 1.3, (B) 0.9 < or = ABI < 1.3, and (C) ABI < 0.9. The average SPP of group C was significantly decreased among the three groups. All subjects of the three groups were divided into an extra two groups according to the presence of diabetes (non-diabetes groups, -I; diabetes groups, -II). The average SPP of group B-II was significantly decreased compared with those of group B-I. The SPP measurement is a noninvasive, useful screening method for limb ischemia that can be applied to exercise tolerance limited patients. The SPP measurements are expected to be useful for the evaluation of limb ischemia in hemodialyzed patients at risk.     

Effects of inter-stimulus interval on skin conductance responses and event-related potentials in a Go/NoGo task

Skin conductance responses (SCRs) to NoGo stimuli have been found to be smaller than to Go stimuli, possibly due to their diminished task relevance. These findings have been obtained at inter-stimulus intervals (ISI) that were unusually short for SCR recordings. Therefore, we tested whether the same findings would also hold at longer ISIs. Simultaneously, effects of ISI duration on the NoGo-N2 and-P3 components of event-related brain potentials (ERPs) were assessed. Go and NoGo stimuli were equiprobable while ISI varied between 2, 5, and 8 s. Although increasing the ISI-enhanced SCR amplitudes in general, it did not modulate the attenuation of the response to NoGo relative to Go stimuli. When considered as difference between NoGo and Go conditions, neither the NoGo-N2 nor the NoGo-P3 was affected by ISI variation. Together, these data confirm the feasibility of co-registering ERPs and SCRs.     

Mustard oil enhances spinal neuronal responses to noxious heat but not cooling

The TRPA1 agonist mustard oil (allyl isothiocyanate = AITC) induces heat hyperalgesia and mechanical allodynia in human skin and sensitizes rat spinal wide dynamic range (WDR) neuronal responses to noxious skin heating. We presently used electrophysiological methods to investigate if AITC affects the responsiveness of individual spinal WDR neurons to intense skin cooling. Recordings were made from cold-sensitive WDR neurons in lamina I and deeper dorsal horn; 21/23 also responded to noxious skin heating. Topical application of AITC excited 8/18 units and significantly enhanced their responses to noxious heat while not significantly affecting responses to the cold stimulus. Vehicle (mineral oil) had no effect on thermal responses. The data confirm a role for the TRPA1 agonist AITC in enhancing heat nociception without significantly affecting cold sensitivity.     

Lymphohistiocytic anaplastic large cell lymphoma involving skin: A diagnostic challenge

Systemic anaplastic large cell lymphoma (ALCL) involving the skin should be differentiated from primary cutaneous CD30-positive T-cell lymphoproliferative disorders. The lymphohistiocytic variant of ALCL (LH-ALCL) is rich in reactive histiocytes with relatively few neoplastic cells, which pose a diagnostic challenge. We present a case of LH-ALCL involving skin mimicking granulomatous inflammation.     

IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not

Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-γ nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-γ and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-α potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations. Kerstin Wolk and Harald S. Haugen equally contributed to this work.     

Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women

Objectives

Hormone replacement therapy (HRT) increases skin elasticity in postmenopausal women. However, the effects of raloxifene, a selective estrogen receptor modulator (SERM), on skin degenerative changes in postmenopausal women remain unknown. We investigated whether raloxifene increases skin elasticity, similar to HRT, in postmenopausal women.

Methods

In a 12-month trial, 17 postmenopausal women (mean age, 66.4 ± 7.8 years) received continuous raloxifene treatment (60 mg/day), 19 women (56.2 ± 6.4 years) received continuous 17-β estradiol treatment using a patch (0.72 mg/2 days) plus cyclic medroxyprogesterone acetate (2.5 mg/day, for 12 days/month), and 11 women (58.1 ± 7.3 years) did not receive either therapy. In each subject, the skin elasticity of the forearm was measured using a suction device at baseline and at 12 months after the start of the study.

Results

Raloxifene and HRT significantly increased skin elasticity from 52.4 ± 3.8% and 64.1 ± 7.2% at baseline to 55.1 ± 4.7% and 67.4 ± 7.4% after 12 months, respectively (P < 0.05, each), but the untreated subjects did not exhibit any significant change in skin elasticity during the study. The delta value for skin elasticity was significantly higher among the raloxifene and HRT subjects than among the untreated subjects (P < 0.05, each).

Conclusions

These findings suggest that raloxifene may have a beneficial effect on skin elasticity, which undergoes degenerative changes in postmenopausal women, in addition to its effects on bone metabolism.     

原发性皮肤间变性大细胞淋巴瘤临床病理分析

目的 探讨原发性皮肤间变性大细胞淋巴瘤(C-ALCL)的临床病理特征、免疫表型及预后.方法 分析8例C-ALCL的临床病理资料,复习HE切片,进行T淋巴细胞、B淋巴细胞、活化淋巴细胞和细胞毒性等16种标记的免疫组织化学染色,原位杂交检测EB病毒.结果 8例中男3例,女5例,中位年龄49.5岁.临床上以皮肤无症状的单个红色结节、肿块为主要表现,组织学上肿瘤细胞在真皮与皮下脂肪内大片状、弥漫性浸润.瘤细胞以大细胞为主,异形性明显.8例C-ALCL的瘤细胞CD30阳性细胞数均大于75%.瘤细胞均表达1～3个T细胞标记(CD3、CD5或CD45RO)及1～3个细胞毒性标记[T细胞内抗原(TIA)-1、颗粒酶B或穿孔素].表达白细胞共同抗原(LCA)为8例、CIM为5例、CD8为1例、间变性淋巴瘤激酶(ALK)-1为1例、上皮细胞膜抗原(EMA)为3例,均不表达CD15、CD20、CK和HMB45.EBER 1/2原位杂交均为阴性.获随访的6例中5例存活,1例死亡(死因不详).结论 C-ALCL有独特的临床病理表现和免疫表型,预后较好.EB病毒与C-ALCL可能无明确的相关性.