Sexual reproduction evolved as a consequence of evolutionary requirement for diverse phenotypes that can cope with infectious parasites, which mutate much more rapidly than the hosts. Of great interest, we can understand complicated animal (and plant) behaviors as strategies to maximize their reproductive successes. Sexual selection was first advocated by Charles Darwin and is still regarded as one of the most important factors in intra-species evolution. In the present special issue, I have organized reviews of our recent understanding of sexual differentiation, sexual dysfunctions, sexual identity disorders, sexually transmitted infections and gender-related immune disorders. I appreciate the efforts of the contributors, all of whom are my old friends and colleagues, and dedicate this issue to my mentor, the late Dr. Susumu Ohno (1928-2000) who guided me to this field of reproductive genetics and immunology.

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Genetic sex is determined at the time of conception. In humans, the sexual phenotype is established in three steps (1) The sex chromosome complement of the embryo, (2) Gonadal differentiation, and (3) Differentiation of the internal duct and the external genitalia as female or male occurs as a response to hormones produced by the differentiated gonads. A number of genes, i.e., SRY, SOX9, SF1, DAX1, WT1, have been shown to influence these early and late sexual development processes. Mammalian gonads arise from the bilateral genital ridges and have the potential to develop into testes or ovaries. The Y chromosome (46, XY) is key to the differentiation of germ cells into testes. In the absence of a Y chromosome and the presence of a second X chromosome (46, XX) or in the absence of a gonad, development will be female in nature. The primary testis determinant is the SRY (Sex determining Region Y) gene, which is located on the short arm of the Y chromosome, and initiates the testicular differentiation from the Wolffian duct. Hormones produced from the testis (Müllerian inhibiting substance (MIS, MIF: Müllerian inhibiting factor, AMH: anti Müllerian hormone), secreted from the Sertoli cells, and testosterone, secreted from the Lydig cells steer the further development of the remainder of the genital tract. MIS mediates the regression of the Müllerian ducts (paramesonephric duct), whereas the androgens maintain the Wolffian ducts. In the absence of MIS, the internal ducts differentiate into fallopian tubes, the uterus, and the upper vagina from the Müllerian ducts. Unlike the internal genitalia, the external genitalia are neutral primordially, and can differentiate into either male or female structures depending on the gonadal steroid hormone signals. Gonadal differentiation involves a complex interplay of developmental pathways. Normal sexual differentiation will be considered in order to provide a basis for understanding the various types of abnormal development. This issue will present disorders of sexual development (DSD) as abnormal sexual development based on normal sexual development.

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Gender identity disorder (GID) is defined as a sexual disorder characterized by strong self-identification with the opposite gender, followed by unpleasant feelings due to the birth-given gender. This paper examines the current diagnostic criteria and treatment for GID. While the etiology of GID remains unknown, several hypotheses have been proposed. We describe the evolution of the hypotheses on the etiology of GID. The possible biological pathogenesis of GID is also discussed mainly from the viewpoint of brain science. Similar to animal studies, it has been reported that fetal or neonatal gonadal steroids are responsible for sexual differentiation of the human brain, which might be related to gender identity and sexual orientation. Based upon the findings of investigations into the biological basis of GID, valuable insights into GID are suggested.

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The objective this review is to present an overview of current practice in the management of erectile dysfunction and discuss the evidence supporting the clinical effectiveness of these pharmacological treatments. Since sildenafil was introduced more than 10 years ago, highly selective phosphodiesterase type 5 inhibitors (PDE5i) have changed the medical management of erectile dysfunction (ED). Effective treatment of ED may restore quality of life and allow patients to return to the sex life they had before. Current therapeutic management includes oral therapies. Oral administration of PDE5i is considered the first-line treatment for ED. PDE5i can elevate the levels of cGMP in the corpus cavernosum and effectively improve ED of various causes and degrees. Three types of PDE5i are currently available, sildenafil, vardenafil and tadalafil. All of them are effective, with similar efficacy and safety profiles. The use of sildenafil citrate (Viagra^®) resulted in a 76% successful intercourse rate with treatment, compared with 22% in a control group. Patients receiving 5, 10 or 20 mg vardenafil (Levitra^®) experienced significantly improved erections, with 85% of 20mg vardenafil cases reporting improved erectile function, compared with 28% of placebo cases. The characteristics of this treatment are well known for their immediate effect. On the other hand, management of ED with Tadalafil (Chalis^®) is characterized by long-term efficacy and easy acceptance by patients and their partners. Tadalafil is also efficacious in the improvement of male lower urinary tract symptoms, and has been licensed for such symptoms in Europe.

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Sexually transmitted infections (STI) are a great human public health concern. During the last decade, public surveys have revealed decreases in the number of syphilis, genital Chlamydia trachomatis, gonococcal, genital herpes virus and Condyloma acuminata infections, with a concomitant increase of HIV/AIDS patients in Japan. In this article, we review the current topics of STI including their epidemiology, prevention and treatment. Unprotected sexual behavior increases infection sites not only of the genital organs but also the pharynx and rectum, while the role of oral contraceptives remains controversial. The increase of antibiotic-resistant Neisseria gonorrhoeae has been reported in many countries. In the treatment of HIV/AIDS, antiretroviral therapy (ART) can suppress the viral load and reduce HIV-related morbidity and mortality. Recently, the new concept of “Treatment as prevention” has been raised because the suppression of viral load by ART significantly decreases the risk of HIV transmission. Cervical cancer and Condyloma acuminata occur after persistent infection with a specific subset of human papillomavirus (HPV) types. Two prophylactic HPV vaccines derived from HPV-16/18 and HPV-6/11/16/18 are presently available. These vaccines have dramatically decreased HPV-related genital neoplasms but do not cover all viral types. Due to the essential nature of sexual activities and human reproduction, it is quite difficult to eradicate STI completely. However, we believe that we can control most STIs with appropriate use of vaccines, antimicrobial drugs and educating the public about safer sex. Thus, STI specialists and general practitioners should be provided with sufficient information regarding recent trends of STI diagnosis and management.

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Autoimmune disorders occur more frequently in women. This predominance is attributed to gonadal steroids related to immunoactivation, fetal microchimerism and/or X chromosome inactivation. Both in vivo and in vitro experiments have shown that estrogen up-regulates humoral immune responses, which are suppressed by androgen and progesterone. The histopathological similarities between Scleroderma (SSc) and Graft versus host disease (GVHD) suggest its pathophysiology as chronic GVHD between fetal cells and maternal tissues. This hypothesis was confirmed using highly sensitive PCR and in situ hybridization. However, other reports have suggested that chimeric fetal cells can restore damaged maternal tissues. Finally, recent advances in molecular biology have revealed skewed X chromosomal inactivation in patients with autoimmune disorders. Females exhibit chimeric X chromosome activation status between Xp (paternal) and Xm (maternal) cells. If thymic antigen presentation cells become skewed for Xp or Xm, central T cell selection lacks Xp or Xm directed regulatory T cells. Other explanations suggest reactivation of silenced X chromosome and subsequent CD40L transcription and/or lack of pseudoautosomal region relatedimmunoregulation in Xo monosomy lymphocytes. From the evolutionary antiquity of sex over the acquired immune system, we suggest that viviparity is the ultimate cause of inconsistencies in autoimmune recognition.

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To study the elongation of Osborne’s ligament due to elbow flexion, 19 cadavers were dissected. The length of Osborne’s ligament from its point of attachment to the humerus to its point of attachment to the ulna was measured in 10° increments of elbow flexion angle from 20° to 140°. Up to 40° 3, the length decreased slightly, and then increased almost linearly to an average of 7.62 mm or 52.3%. Osborne’s ligament had a tendency to gradually elongate at a flexion angle of more than 90°. However, this distance was shortened in four elbows due to variations in the sites of attachment of Osborne’s ligament.

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エベロリムス (Everolimus) はラパマイシンの誘導体であり，根治切除不能腎細胞癌および転移性腎細胞癌に対する分子標的治療薬である．副作用として間質性肺炎発症頻度が高く両側性が多い．本症例はエベロリムス投与 1 か月後に片側性の浸潤影を認めた．気管支肺胞洗浄液中のリンパ球増加を認め，エベロリムスによる薬剤性間質性肺炎と診断した．ステロイド治療により自覚症状・画像所見ともに著明に改善した．

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多数の抗菌薬の開発にも関わらず，耐性菌による感染症は依然として臨床上の大きな問題になっています．中でもメチシリン耐性黄色ブドウ球菌 (Methicillin-Resistant Staphylococcus aureus: MRSA) は，耐性菌感染症の原因菌の大部分を占めています．MRSAの標準的な治療薬であるバンコマイシンの治療効果が低下してきている現在，限られた抗 MRSA 薬の特徴を十分に理解し，治療には最も適切な抗菌薬を選択することが求められます．

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HIV ウイルスの感染予防とその AIDS 発症予防法の開発は社会的にも解決されるべきプライオリティーの高い課題として残されている．HIV/AIDS の制圧には有効な感染予防ワクチンが最も効果的であることがこれまでのワクチン開発の成果から明らかになっている．近年，その成果と HIV ウイルス・感染・発症者の解析結果に基づいて候補ワクチンが作成され，いくつかの第 3 相臨床試行が世界的規模で行われたが，サルモデルでは効果が認められるものの，人での効果は得られていない．幸い，AIDS 治療薬開発による治療法の開発がすすんできたが，完治できる治療法の開発は今後に残されている．従って，感染予防ワクチンは，現在の HIV/AIDS の制圧には最も効果的な手段であり，その開発が求められている．本稿では直面しているワクチン開発の主な課題点と新規ワクチン開発の現状を我々の試みを交えて紹介する．

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主要歯周病原菌 Porphyromonas gingivalis などが大量に産生する酪酸は，T 細胞やマクロファージなどに顕著にアポトーシスを誘導し，歯肉局所の免疫応答低下を誘導することから，感染が促進される可能性を報告した．また，ヒト免疫不全ウイルス (HIV) 感染者の歯肉溝内 HIV 量と歯周病の進展とが深く関わっているため，歯周病原細菌の増殖が潜伏感染 HIV の再活性化に関与する可能性があると考え検討を行った．その結果，酪酸のエピジェネティック制御を介して HIV が再活性化し，歯周病患者血清内で増加している TNF-α との相乗作用によりエイズ発症の可能性が示唆された．また，酪酸産生能のある腸内細菌や女性生殖器内細菌によっても同様に潜伏感染 HIV が再活性化された．さらに，酪酸は Epstein-Barr ウイルスの再活性化や口腔がん細胞の転移にも影響する可能性がある．「微生物間相互作用」 という視点から得られたこれら結果は，“慢性炎症性疾患・歯周病” が新たな全身疾患に深く関与している可能性を強く示唆している．

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