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We present a case of malignant change of an ovarian mature cystic teratoma. Our patient was a 48-year-old woman and she visited a primary care doctor presenting with abdominal pain. At her first visit, her pelvic tumor measured 70 × 50 mm by ultrasonography. She was diagnosed as rupture of the malignant tumor occurred secondary to mature cystic teratoma and she took the surgery (abdominal total hysterectomy, bilateral oophorectomy and partial omentectomy). Pathologic diagnosis was squamous cell carcinoma (SCC) occurred secondary to mature cystic teratoma. Treatment with paclitaxel/carboplatin (TC chemotherapy) and gemcitabine hydrochloride/carboplatin (GC chemotherapy) after operation was not effective, and the refractory ileus resulting from rapid progression of the disease continued. She was died of disease progression 7 months after the diagnosis of ovarian cancer. We discuss about the clinical characteristics of malignant transformation of mature cystic teratoma and considered about the treatment of the ovarian SCC.

Open wedge high tibial osteotomy (OWHTO) brings new complications such as screw breakages with or without correction loss and time-dependent increased posterior tibial slopes (PTS) due to the opening gap. For preventive purposes, we changed our OWHTO procedure from anteromedial plating without filling the gap (non-grafted group, n = 40, 2009-2012) to medial plating with bone-substitute insertion (grafted group, n = 45, 2012-2015). The objectives of this study were to evaluate the complication patterns and the effects of the modifications.Patients undergoing OWHTO with TomoFix plates were included in this retrospective study. Demographics, clinical outcomes (flexion range and Japanese Orthopaedic Association score) and radiological outcomes (femorotibial angle) were assessed in both groups pre-operatively and 2-years postoperatively. The plate installation angle [PIA] and screw insertion depth [SID] were measured on computed tomographic slices at 6 months. PIA/SID was defined as the angle between the tibial anteroposterior axis and plate-width axis/the distance between the proximal screw tip and the proximal tibiofibular joint. The non-grafted group was further divided into complication and non-complication subgroups. Screw breakages were assessed during plate removal (1.5-2.5 years postoperatively).There were no differences in baseline characteristics or radiological/clinical outcomes between the non-grafted and grafted groups. There were 0 and 11 complications in the grafted and non-grafted groups, respectively. Complications included 7 screw breakages, 4 correction losses, and 5 time-dependent increased PTS with some overlaps. PIA and SID were significantly lower (p 0.001) and higher (p 0.001), respectively, in the grafted group and significantly lower (p = 0.018) and higher (p = 0.040), respectively, in the non-complication subgroup within the non-grafted group. The cutoff value of PIA for complications was calculated at 48.0°.Medial plating OWHTO (PIA48°) using bone-substitute with deeper screw insertion reinforces the opening gap for better angular stability compared with anteromedial plating without bone-substitute.

Human T cell leukemia virus type 1 (HTLV-1) is mainly transmitted vertically through breast milk. The rate of mother-to-child transmission (MTCT) through formula feeding, although significantly lower than through breastfeeding, is approximately 2.4%-3.6%, suggesting the possibility of alternative transmission routes. MTCT of HTLV-1 might occur through the uterus, birth canal, or placental tissues; the latter is known as transplacental transmission. Here, we found that HTLV-1 proviral DNA was present in the placental villous tissues of the fetuses of nearly half of pregnant carriers and in a small number of cord blood samples. An RNA ISH assay showed that HTLV-1-expressing cells were present in nearly all subjects with HTLV-1-positive placental villous tissues, and their frequency was significantly higher in subjects with HTLV-1-positive cord blood samples. Furthermore, placental villous trophoblasts expressed HTLV-1 receptors and showed increased susceptibility to HTLV-1 infection. In addition, HTLV-1-infected trophoblasts expressed high levels of viral antigens and promoted the de novo infection of target T cells in a humanized mouse model. In summary, during pregnancy of HTLV-1 carriers, HTLV-1 was highly expressed in placental villous tissues, and villous trophoblasts showed high HTLV-1 sensitivity, suggesting that MTCT of HTLV-1 occurs through the placenta.

Background Percutaneous endoscopic gastrostomy may be performed in dysphagic stroke patients. However, some patients regain complete oral intake without gastrostomy. This study aimed to investigate the predictive factors of intake, thereby determining gastrostomy indications. Method Stroke survivors admitted to our convalescent rehabilitation ward who underwent gastrostomy or nasogastric tube placement from 2009 to 2015 were divided into 2 groups based on intake status at discharge. Demographic data and Functional Independence Measure (FIM), Dysphagia Severity Scale (DSS), National Institutes of Health Stroke Scale, and Glasgow Coma Scale (GCS) scores on admission were compared between groups. We evaluated the factors predicting intake using a stepwise logistic regression analysis. Results Thirty-four patients recovered intake, whereas 38 achieved incomplete intake. Mean age was lower, mean body mass index (BMI) was higher, and mean time from stroke onset to admission was shorter in the complete intake group. The complete intake group had less impairment in terms of GCS, FIM, and DSS scores. In the stepwise logistic regression analysis, BMI, FIM-cognitive score, and DSS score were significant independent factors predicting intake. The formula of BMI × .26 + FIM cognitive score × .19 + DSS score × 1.60 predicted recovery of complete intake with a sensitivity of 88.2% and a specificity of 84.2%. Conclusions Stroke survivors with dysphagia with a high BMI and FIM-cognitive and DSS scores tended to recover oral intake.

Among Tissue kallikrein genes (KLKs), KLK1 is abundantly expressed in human skin. Although its putative promoter is known to have various cis-elements, they have not been functionally tested. In the present study, the regulation mechanism of KLK1 promoter supporting such abundant expression was examined. Luciferase assay targeting the KLK1 promoter (nucleotide − 1153/+ 40 from the major transcriptional start site) was performed on NHEK human keratinocyte. − 954/− 855, − 428/− 236, and − 100/+ 40 had the induction activity. The motif search program failed to find unique binding motifs in − 428/− 236, whereas both − 954/− 855 and − 100/+ 40 had a unique GATAs binding motif. Electrophoretic mobility shift assay (EMSA) and DNA footprinting confirmed the binding of NHEK nuclear protein to these motifs that were supershifted by anti-GATA3 antibody. Among GATA isoforms, GATA3 alone could be amplified in RNA obtained from NHEK. Moreover, introduction of GATA3 into fibroblastic NIH3T3 cells enhanced the activity of KLK1 promoter containing − 954/+ 40, while that of GATA3 dominant negative mutant to NHEK cells impaired the same promoter's activity. Thus, GATA3 was found to bind the site located at − 954/− 855 and to be a key regulator of abundant KLK1 expression in human keratinocyte.

Desquamation of the stratum corneum is a serine protease-dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1–6 (rLEKTI(1–6)), domains 6–8 and partial domain 9 (rLEKTI(6–9′)), domains 9–12 (rLEKTI(9–12)), and domains 12–15 (rLEKTI(12–15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1–6), rLEKTI(6–9′), and rLEKTI(9–12) with Ki values in the range of 2.3–28.4 nm, 6.1–221 nm, and 2.7–416 nm for each respective fragment. Only KLK5 was inhibited by rLEKTI(12–15) (Ki = 21.8 nm). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca2+ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

We report a 6-day-old Japanese girl showing generalized erythroderma accompanied by yellowish, exfoliative scaling that was accentuated on the face and scalp. Histological analysis showed psoriasiform dermatitis with acanthotic epidermis and premature shedding of the stratum corneum. Measurement of trypsin-like hydrolytic activity in SC showed six-fold greater activity compared with age-matched controls. DNA analysis revealed two mutations, 375delAT and 966insC, in exons 5 and 11, respectively, of the SPINK5 gene. Although at 4 weeks the child was still too young to display characteristic hair abnormalities or atopic diathesis, we diagnosed Netherton syndrome based on enzyme assay and DNA analysis.

We describe a patient in whom pemphigus foliaceus developed after cutaneous squamous cell carcinoma (SCC) metastasized to regional lymph nodes. Immunologic analysis revealed that production of anti-desmoglein 1 autoantibodies started when SCC metastasized, and the SCC expressed desmoglein 1, suggesting a pathogenic role of metastasized SCC in developing pemphigus foliaceus. (J Am Acad Dermatol 2001;45:767-70.)

15歳,女性。10歳時に左足背に圧痛を伴う皮内結節が出現し,切除術を受けた。切除半年後,その近接した部位に疼痛を伴う紅褐色丘疹が出現したため九州大学皮膚科を受診,切除術を受けた。両病変組織とも,病理組織学的には,真皮上層から中層にかけて多数の神経線維を含んだ末梢神経構造が認められ,外傷既往もないことから自験例を異時性に多発した特発性の皮膚神経腫と診断した。

当院皮膚科で,1993～1996年及び1998年に,風疹,麻疹,溶連菌感染症などの典型的なウイルス性,細菌性発疹症などを除外し,中毒疹と診断した入院患者159人を対象に原因検索及びその解析を行った。薬剤性と推定された患者は91人(57.2%)と最も多く,次いで感染性が44人(27.7%)であった。感染性はウイルス性,細菌性,マイコプラズマ性などに分類し,その内,ウイルス性が最も多かった。薬剤性と推定された患者91人中21例は,薬剤の他,感染症など複数の要素が推定原因とされた。薬剤テストを施行した薬剤330種類中,77種類で薬剤テスト陽性であった。薬剤性と推定された患者91人中63人で,薬剤テスト陽性であった。薬剤テストが陽性であった被疑薬剤77種類のうち,69種類(89.6%)でスクラッチパッチテストが陽性を示し,薬剤テストの中で特にスクラッチパッチテストの有用性が示唆された。推定原因とされた薬剤は,消炎鎮痛剤,抗生物質,総合感冒薬など使用頻度が高く,かつ市販薬として入手が容易な薬剤が上位を占めた。また,病型は個々の症例で異なることが多く,病型から薬剤を推定することは困難と思われた。当院における中毒疹の実態調査から,薬剤テストが原因検索の検査法として有用であることが示唆された。中毒疹の原因の推定には各種検査を必要とし,最終的には検査結果や臨床経過,主治医の経験などから総合的に推定するしかなく,今後も薬疹の診断基準,検査方法などについて,症例を重ねさらに検討していく必要があると思われた。

Human tissue kallikreins are a family of 15 trypsin- or chymotrypsin-like secreted serine proteases (KLK1-KLK15). Many KLKs have been identified in normal stratum corneum (SC) and sweat, and are candidate desquamation-related proteases. We report quantification by enzyme-linked immunosorbent assay (ELISA) of KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of atopic dermatitis (AD) patients by ELISA, and examine their variation with clinical phenotype, correlation with blood levels of eosinophils, lactate dehydrogenase (LDH) and immunoglobulin E. The overall SC serine protease activities were also measured. In the SC of AD, all KLKs, except KLK11, were significantly elevated. The elevation of chymotrypsin-like KLK7 was predominant, compared with trypsin-like KLKs. The SC overall plasmin- and furin-like activities were significantly elevated, while trypsin- and chymotrypsin-like activities did not differ significantly. In the serum of AD patients, KLK8 was significantly elevated and KLK5 and KLK11 were significantly decreased. However, their serum levels were not modified by corticosteroid topical agents. The alterations of KLK levels in the SC of AD were more pronounced than those in the serum. KLK7 in the serum was significantly correlated with eosinophil counts in the blood of AD patients, while KLK5, KLK8 and KLK11 were significantly correlated with LDH in the serum. In conclusion, we report abnormal kallikrein levels in the SC and the serum of AD patients. KLKs might be involved in skin manifestation and/or focal/systemic inflammatory reactions in AD. Our data may contribute to a better understanding of the pathogenesis of AD.

Summary Background Human tissue kallikreins (KLKs) are a family of 15 trypsin-like or chymotrypsin-like secreted serine proteases (KLK1–KLK15). Multiple KLKs have been quantitatively identified in normal stratum corneum (SC) and sweat as candidate desquamation-related proteases. Objectives To quantify KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13 and KLK14 in the SC and serum of patients with psoriasis, and their variation between lesional and nonlesional areas and with phenotype, therapy and severity. The overall SC serine protease activities were also measured. Methods Enzyme-linked immunosorbent assays and enzymatic assays were used. Results The lesional SC of psoriasis generally contained significantly higher levels of all KLKs. KLK6, KLK10 and KLK13 levels were significantly elevated even in the nonlesional SC. The overall trypsin-like, plasmin-like and furin-like activities were significantly elevated in the lesional SC. Plasmin-like activity was significantly elevated also in the nonlesional SC. The SC chymotrypsin-like activity was only slightly elevated in psoriasis. KLK7 serum levels did not differ between normal volunteers and patients with psoriasis. Serum KLK6, KLK8, KLK10 and KLK13 levels in patients with untreated psoriasis significantly correlated with Psoriasis Area and Severity Index score. Serum KLK5 and KLK11 levels decreased in patients with psoriasis after therapy, especially with etretinate. Patients with erythrodermic psoriasis exhibited significantly higher serum KLK levels than normal subjects or patients with psoriasis vulgaris or arthropathic psoriasis. Conclusions We found aberrant KLK levels in the SC and serum of patients with psoriasis and suggest that KLKs might be involved in the pathogenesis of this disease.

Background Human growth hormone (hGH) is naturally present in numerous isoforms, some of which arise from proteolytic processing in both the pituitary and periphery. The nature of the enzymes that proteolytically cleave hGH and the regulation of this process are not fully understood. Our objective is to examine if members of a newly discovered human tissue kallikrein family (KLKs) are expressed in the pituitary and if these enzymes can cleave hGH in-vitro . Methods Expression of 12 of the KLKs ( KLKs 4-15) and serine protease inhibitor Kazal-type 5 (SPINK5) genes and their proteins in the pituitary was examined by RT-PCR and immunohistochemistry. Recombinant hGH was digested by various recombinant KLKs and fragments were characterized by N-terminal sequencing. SPINK5 recombinant fragments were used for inhibition of KLK activities. Results We here describe for the first time expression of numerous KLKs ( KLKs 5–8, 10–14) and SPINK5 in the pituitary. KLK6 and SPINK5 appeared to be localized to hGH-producing cells. KLKs 4–6, 8, 13 and 14 were able to cleave hGH, yielding various isoforms, in vitro . Inhibitor SPINK5 fragments were able to suppress activity of KLKs 4, 5 and 14 in vitro . Based on these data, we propose a model for the proteolytic processing of hGH in the pituitary and the regulation of this system by SPINK5 inhibitory domains. We speculate that loss of SPINK5 inhibitory domains, as in the case of Netherton syndrome, may lead to proteolytic over-processing of hGH and to growth retardation. Conclusion We conclude that many KLKs and SPINK5 are expressed in the pituitary. This serine protease-inhibitor system is likely to participate in the regulated proteolytic processing of hGH in the pituitary, leading to generation of hGH fragments. Our data suggest that KLKs 5, 6 and 14 might be involved in this process.

Publisher Summary Kallikreins are expressed in many organs, most prominently in endocrine-related tissues such as the prostate, breast, ovary, uterus, vagina, and testis. The coexpression of many kallikreins in several cancer types and other information pointing to the possibility of their involvement in a cascade-like pathway that may be associated with cancer pathogenesis or progression are presented in this chapter. Characterization and sequence analysis of human-tissue kallikrein gene locus are discussed in this chapter. A short historical perspective of the discovery of human-tissue kallikrein gene locus is presented in this chapter. Kallikreins in rodents and other species such as the mouse kallikrein gene family, the rat kallikrein gene family, and the dog kallikrein gene family are also described in this chapter. Structural features of human-tissue kallikrein genes and proteins such as common structural features and three-dimensional structure are also presented in this chapter. Sequence variations of human kallikrein genes, the tissue kallikreins in the context of other serine proteases in the human genome, tissue expression and cellular localization of the kallikrein genes, regulation of kallikrein activity (at the mRNA level, at the protein level, locus control of kallikrein expression, and epigenetic regulation of kallikrein gene expression), hormonal regulation of kallikreins, and evolution of kallikreins are also presented in this chapter. Prognostic and predictive value of kallikreins in hormone-dependent cancers such as ovarian cancer, breast cancer, and prostate cancer is also described in this chapter. The enzymatic activity of these serine proteases may initiate or terminate biological events. A third possible therapeutic approach involves immunotherapy or development of cancer vaccines. With increasing knowledge of the hormonal regulation of kallikreins, hormonal activation (or repression) of kallikrein activity could be investigated in the future.

Netherton syndrome is a congenital ichthyosis associated with erythroderma, hair shaft defects, and atopic features. The mutations of the secretory serine protease inhibitor Kazal-type 5 gene have been identified in Netherton syndrome patients; however, the actual physiologic substrates of the serine protease inhibitor Kazal-type 5 proprotein are unknown, and how the genetic defects cause characteristic skin phenotype remains uncertain. Here, we describe the serine protease inhibitor Kazal-type 5 gene mutations, including two novel non-sense mutations, and genotype–phenotype correlation in three Netherton syndrome patients in two unrelated Japanese families. Furthermore, based on the reappraisal of the structure of the serine protease inhibitor Kazal-type 5 proprotein, demonstration of the presence of carboxypeptidase in normal keratinocytes, and the observation of mRNA localization of the serine protease inhibitor Kazal-type 5 transcripts in the uppermost epidermis as well as pilosebaceous units, we propose a hypothetical model of proteolytic processing of the serine protease inhibitor Kazal-type 5 proprotein in the epidermis and inhibitory regulation of corneocyte desquamation by a set of serine protease inhibitor Kazal-type 5-derived peptides. This hypothesis is supported by the marked increase of trypsin-like hydrolytic activity demonstrated in stratum corneum samples from our Netherton syndrome patients. The findings in this study suggest that the defective inhibitory regulation of desquamation due to the serine protease inhibitor Kazal-type 5 gene mutations may cause over-desquamation of corneocytes in Netherton syndrome, leading to severe skin permeability barrier dysfunction.

Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by serine protease inhibitor Kazal-type 5 (SPINK5) mutations. Tissue kallikreins (KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 product) may contribute to the balance of serine proteases/inhibitors in skin and influence skin barrier function and desquamation. SPINK5 mutations, causing NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different length, depending on the location of mutations. This study aims to elucidate genotype/phenotype correlations in Japanese NS patients and to characterize the functions of each LEKTI domain. Since we were unable to demonstrate truncated proteins in tissue from patients with NS, we used recombinant protein to test the hypothesis that the length of LEKTI correlated with protease inhibitory activity. Genotype/phenotype correlations were observed with cutaneous severity, growth retardation, skin infection, stratum corneum (SC) protease activities, and KLK levels in the SC. Predominant inhibition by LEKTI domains against overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI domains 6-12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 12-15, chymotrypsin-like activity by all domains, and furin-like activity by none. KLK levels were significantly elevated in the SC and serum of NS patients. These data link LEKTI domain deficiency and clinical manifestations in NS patients and pinpoints to possibilities for targeted therapeutic interventions.

Human tissue kallikreins are a family of 15 trypsin or chymotrypsin-like secreted serine proteases (hK1–hK15). hK5, hK6, hK7, hK8, and hK13 have been identified in the stratum corneum (SC), stratum granulosum, and skin appendages. It has been reported that hK5 and hK7 degrade desmosomes/corneodesmosomes, suggesting that kallikreins are responsible for desquamation. We report the quantification of hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 in the SC by ELISA and their variation among age groups. The total SC trypsin and chymotrypsin-like activities were also measured. The amount of hK7, hK8, and hK11 (ng per mg dry weight) were high, and varied from 6 to 14, hK5 (2.0–4.0) was present at intermediate levels, and hK10 (0.65–1.0), hK14 (0.1–0.3), hK6 (0.1–0.3), and hK13 (0.02–0.1) were present at lower levels. hK6 and hK14 were significantly lower in females between 20 and 59 y. hK5, hK7, hK10, hK11, and hK14 were not significantly different across the age groups. hK8 was lowest at extremes of age (highest at 30–39 y), hK6 was lower at >30 y, and hK13 was lower at >20 y. Overall trypsin-like activity did not differ across age groups but was higher in subjects