Vertical mother-to-infant transmission of herpes simplex virus 2 is correlated with tropism due to mutations in viral UL13.

Although neonates are commonly exposed to vaginal herpes simplex virus (HSV)-2, neonatal herpes is rare. Therefore, we analyzed paired infant and maternal HSV-2 isolates from two cases of mother-to-infant transmission to identify viral factors contributing to vertical transmission. Sixteen infant isolates with neonatal herpes and 27 genital isolates in their third trimester were included. The infant isolates were significantly more temperature-independent than the maternal isolates. Sequence comparison revealed viral UL13 protein kinase (UL13-PK) mutation in the infant isolates in both cases. In the expanded cohort, infant isolates (5/18) had significantly more UL13-PK mutations than genital isolates (1/29). Isolates within 8 days post-birth (3/4) had a significantly higher frequency of UL13-PK mutation than those after 9 days (2/14), suggesting a close association between UL13-PK mutations and vertical transmission. Elongation factor 1-delta was identified as a target of UL13-PK by proteomic analysis of UL13-PK-positive and -negative HepG2 cells. The mixed infant isolates with the intact and mutated UL13-PK conferred altered cell tropism, temperature independence adapting to fetal temperature, and better growth properties in Vero and hepatoblastoma HepG2 cells than in HSV-2 with intact and mutated UL13-PK alone, indicating that viral UL13-PK mutation is essential for vertical HSV-2 transmission.

The second nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan.

The present study compared trends in antimicrobial resistance patterns in pathogens isolated from skin and soft-tissue infections (SSTIs) in Japan with those of a nationwide survey conducted in 2013. Three organisms that caused most of the SSTIs were collected from 12 dermatology departments in medical centers and 12 dermatology clinics across Japan between April 2019 and August 2020. A total of 390 strains, including 267 Staphylococcus aureus, 109 coagulase-negative staphylococci (CNS), and 14 Streptococcus pyogenes strains were submitted to a central laboratory for antimicrobial susceptibility testing. Patient demographic and clinical information was collated. Methicillin-resistant S. aureus (MRSA) was detected in 25.8% (69/267) of the S. aureus strains. The prevalence of MRSA between the present study and the 2013 survey did not differ significantly. Furthermore, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains to other agents, regardless of a history of hospitalization within 1 year or invasive medical procedures. Methicillin-resistant CNS (MRCNS) was detected in 48.6% (53/109) of CNS isolates, higher than the 35.4% prevalence in the 2013 survey. This difference could be attributed to the heterogeneity in the members of the MRCNS, which comprises multiple staphylococci species, between the 2013 and 2019 surveys. However, it was noted that the susceptibility profiles of the MRCNS to each antibiotic were not significantly different from those identified in the 2013 survey. Most strains of S. pyogenes were susceptible to each antibiotic, similar to the 2013 survey. Continuous monitoring of trends in pathogen and susceptibility profiles is important to advise local public health efforts regarding the appropriate treatment of SSTIs.

Patient satisfaction and efficacy of calcipotriol plus betamethasone dipropionate gel in plaque psoriasis patients with poor adherence.

Poor adherence to treatment makes achievement of expected therapeutic outcomes more difficult, especially in chronic disorders like psoriasis. There are several critical factors that affect adherence, including therapeutic efficacy, patient satisfaction, patient treatment preferences and ease of application, especially in topical therapy. The fixed combination of calcipotriol plus betamethasone dipropionate in a gel formulation (Cal/BDP gel) has been recommended as a first-line topical treatment for mild to moderate plaque. To examine whether Cal/BDP gel can effectively improve treatment adherence, we investigated the effects of once-daily Cal/BDP gel on factors affecting adherence at weeks 4, 8 and 12 in patients with plaque psoriasis who had poor adherence. A total of 46 subjects were enrolled and 41 subjects (26 men, 15 women; mean age, 50.5 years) were included in the analysis. The following items were evaluated: Patient Preference Questionnaire, nine-item Treatment Satisfaction Questionnaire for Medication, Physician's Global Assessment (PGA), modified Psoriasis Area and Severity Index (m-PASI), body surface area (BSA), pruritus, medication adherence and application time. In patients with poor adherence, many preferred treatment with Cal/BDP gel and evaluated its convenience as "excellent" at weeks 4 and 12. At week 12, the proportion of "clear"/"very mild" ratings using PGA reached 20.5%, the change from baseline on m-PASI was -61.3% and the change from baseline on BSA was -39.8%, suggesting that the skin symptoms of psoriasis had improved greatly. In most patients, the longer they used Cal/BDP gel, the greater their preference and satisfaction and the higher the therapeutic effect, which increased markedly over 12 weeks. These results suggest that Cal/BDP gel can effectively improve treatment adherence. Conversely, high adherence to Cal/BDP gel must enhance the therapeutic effect. Therefore, we expect that Cal/BDP gel could become the mainstay of topical psoriasis treatment in patients with poor adherence.

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

The wound/burn guidelines - 6: Guidelines for the management of burns.

Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures.

The wound/burn guidelines - 2: Guidelines for the diagnosis and treatment for pressure ulcers.

The Wound/Burn Guidelines Committee consists of members commissioned by the Board of Directors of the Japanese Dermatological Association (JDA). It held several meetings and evaluations in writing since October 2008, and drafted five guidelines for the diagnosis and treatment including commentaries on wounds in general and the Guidelines for the Diagnosis and Treatment for Pressure Ulcers by taking opinions of the Scientific Committee and Board of Directors of JDA into consideration.

The wound/burn guidelines - 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

The wound/burn guidelines - 1: Wounds in general.

The Japanese Dermatological Association determined to prepare the Wound/Burn Guidelines focusing on treatments, catering to needs for the clinical practice of dermatology. Among these guidelines, "Wounds in General" was intended to explain knowledge necessary "to heal wounds" without specifying particular disorders.

The wound/burn guidelines - 3: Guidelines for the diagnosis and treatment for diabetic ulcer/gangrene.

We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting evidence-based recommendations for clinical judgments by incorporating various viewpoints.

The wound/burn guidelines - 5: Guidelines for the management of lower leg ulcers/varicose veins.

Varicose veins are treated at multiple clinical departments, but as patients often visit the dermatology clinic first due to leg ulcers, the present Guidelines for the Management of Lower Leg Ulcers/Varicose Veins were prepared in consideration of the importance of the dermatologist's role. Also, the disease concept of chronic venous insufficiency or chronic venous disorders and the CEAP classification of these disorders are presented. The objective of the present guidelines is to properly guide the diagnosis and treatment of lower leg ulcers/varicose veins by systematically presenting evidence-based recommendations that support clinical decisions.

Subclinical generation of acyclovir-resistant herpes simplex virus with mutation of homopolymeric guanosine strings during acyclovir therapy.

BACKGROUND: Suppressive therapy in patients with genital herpes has been used in Japan since 2006. Susceptibility and resistance of herpes simplex virus (HSV)-2 to acyclovir were examined in genital isolates from patients receiving suppressive therapy and compared with those from those naïve to acyclovir and receiving episodic treatment with acyclovir. OBJECTIVE: The aim of this study was to analyze the effect of acyclovir use on the susceptibility to acyclovir and analysis of the thymidine kinase gene by acyclovir treatment. METHODS: Genital HSV isolates were obtained from three patients groups. Susceptibility to acyclovir, the frequency of acyclovir-resistant clones and mutations in the thymidine kinase gene of acyclovir-resistant clones were determined. RESULTS: Susceptibility to ACV was significantly higher in isolates from patients receiving suppressive therapy than those naïve to acyclovir and receiving episodic treatment, but the frequencies of resistant clones were similar among the three groups. Mutation in guanosine homopolymeric strings (G-string mutation) was significantly more frequent in clones during episodic treatment and suppressive therapy than clones from patients naïve to ACV. The frequency of G-string mutation was significantly less frequent in isolates from patients naïve to ACV than those experienced ACV therapy. CONCLUSION: The frequency of acyclovir-resistant mutants was not increased by episodic and suppressive therapy, but exposure to acyclovir significantly generated G-string mutations, possibly induced by acyclovir. Acyclovir therapy had no substantial effects on the susceptibility of HSV-2 or frequency of resistant virus but did generate subclinical G-string mutants in patients' HSV-2.

Examination of the correlation between the manual and automated serological testing methods for syphilis.

We evaluated the correlation between the conventional manual serological testing method for syphilis and a novel automated serological testing method and between six different reagents used in the automated method. Twenty-six serum samples, which were positive on non-treponemal manual serological testing, were obtained from 19 patients with early syphilis. The samples were manually analyzed using the non-treponemal serological test for syphilis kit and automatically analyzed using six different reagents approved by the Ministry of Health, Labor and Welfare in Japan. Statistically significant correlations were observed between most of the reagents used in the automated testing (r = 0.652-0.996, P < 0.001), except for one combination of the reagents. In the simple regression analysis, the slope of the simple regression line (range, 0.014-3.040) and some of the regression coefficients were not equal to 1.0. Therefore, it is recommended that when the automated serological testing method is used to test for syphilis, the same reagent should be consistently selected to evaluate the changes in antibody titers. Statistically significant correlations were also observed between the manual method and all the reagents used in the automated method (r = 0.682-0.811, P < 0.001). In this case, the regression coefficients ranged 0.375-6.270, and the simple regression line intercept ranged -71.926 to 4.184. The regression coefficient and the intercept between the manual method and some of the reagents used in the automated method were not similar to the values described in the documentation attached to the reagents used in this study.

Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma.

To clarify whether mutations in the large T gene encoded by Merkel cell polyomavirus affect the expression and function of large T antigen in Merkel cell carcinoma cases, we investigated the expression of large T antigen in vitro and in vivo. Immunohistochemistry using a rabbit polyclonal antibody revealed that large T antigen was expressed in the nuclei of Merkel cell carcinoma cells with Merkel cell polyomavirus infection. Deletion mutant analyses identified an Arg-Lys-Arg-Lys sequence (amino acids 277-280) as a nuclear localization signal in large T antigen. Sequence analyses revealed that there were no mutations in the nuclear localization signal in any of the eleven Merkel cell polyomavirus strains examined. Furthermore, stop codons were not observed in the upstream of the nuclear localization signal in any of the Merkel cell carcinoma cases examined. These data suggest that the nuclear localization signal is highly conserved and functional in Merkel cell carcinoma cases.

Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma.

Merkel cell carcinoma is a rare malignancy that sometimes occurs in the skin of elderly people. Recently, a new human polyomavirus, Merkel cell polyomavirus (MCPyV) was identified in Merkel cell carcinoma. In the present study, MCPyV-DNA was detected in 6 of 11 (55%) cases of Merkel cell carcinoma by nested PCR and real-time PCR. Histologically, MCPyV-positive cases showed round and vesicular nuclei with a fine granular chromatin and small nucleoli, whereas MCPyV-negative cases showed polygonal nuclei with diffusely distributed chromatin. Real-time PCR analysis to detect the MCPyV gene revealed that viral copy numbers ranged 0.04-0.43 per cell in cases of Merkel cell carcinoma. MCPyV was also detected in 3 of 49 (6.1%) cases of Kaposi's sarcoma (KS), but not in 192 DNA samples of other diseases including 142 autopsy samples from 20 immunodeficient patients. The MCPyV copy number in KS was lower than that in Merkel cell carcinoma. PCR successfully amplified a full-length MCPyV genome from a case of KS. Sequence analysis revealed that the MCPyV isolated from KS had 98% homology to the previously reported MCPyV genomes. These data suggest that the prevalence of MCPyV is low in Japan, and is at least partly associated with the pathogenesis of Merkel cell carcinoma.

Meningococcemia without meningitis in Japan.

We report a case of meningococcemia without meningitis, which is a rare infectious disease in Japan. A 32-year-old woman was referred to our hospital with fever and joint pain. Her clinical presentation and the results of laboratory examination on admission suggested viral infection. However, her condition rapidly progressed to septic shock with fulminans purpura. Blood culture grew Neisseria meningitidis. She received antimicrobial therapy and underwent localized therapy for skin lesions. Meningococcal infection should be considered in patients who have fever along with skin rash or petechiae even when there are no signs of meningitis. In this report, we also review case reports of meningococcemia without meningitis in Japan.