Human Simplex Virus Research Articles

Abstract LB170: AND-gate dual-targeting EGFR and PD-L1 with a split prodrug converter enzyme for cancer treatment

Abstract Conventional cancer chemotherapies, while effective, often encounter "on-target, off-tissue" cytotoxicity linked to target prevalence. Although antibody-drug conjugates (ADCs) offer improved targeting, they face limitations in drug payload capacity. Therefore, a potent chemotherapy without off-tissue effects or payload limitations is in crucial need. To address the demand, we developed an AND-gate-based dual-targeting approach that minimizes off-tissue cytotoxicity with tune-able payload, exploiting a pair of split human simplex virus thymidine kinase (HSV-TK), which converts the prodrug ganciclovir (GCV) into a cytotoxic form with high specificity. We first successfully split a pair of HSV-TK (Split TK) to exhibit the possibility of an AND-gate drug activation system. HSV-TK was split into N-fragment (nTK) and C-fragment (cTK) with a 20 amino acid overlap, transduced into HEK293T cells, and treated with ganciclovir for 72 hours. Cells expressing one TK half showed IC50 >1000 µM, while co-expression of cTK and nTK reduced IC50 to ~3 µM, which is comparable to full-length TK. Successful splitting of HSV-TK demonstrated the feasibility of dual-targeting. We then validated this AND-gate targeting in cancer treatment. Split TK[HH1] was assessed in treatment of triple-negative breast cancer (TNBC) cells. TNBC lacks the overexpression of common breast cancer targets, which poses a significant challenge in treatment strategies. We designed a specific split TK pair to treat MDA-MD-231 TNBC, with MCF-7 cells as a control. MDA-MB-231 has upregulated epidermal growth factor receptor (EGFR) and programmed death-ligand 1(PD-L1) expression, while MCF-7 is high in EGFR but low in PD-L1. To enable a split TK pairs that selectively reconstituted HSV-TK activity in MDA-MB-231 cell, we choose epidermal growth factor (EGF) as the targeting ligand for EGFR, and PD-1 extracellular domain for PD-L1. We fused nTK to EGF (nTK-EGF), and the extracellular domain of programmed cell death protein 1 (PD-1) to cTK (PD-1-cTK). Fusion proteins were expressed in SHuffle E. coli, purified, and introduced into MDA-MB-231 and MCF-7 cells, together with 100 µM GCV. After 7 days of treatment, individual nTK-EGF and PD-1-cTK treatments with GCV showed minimal cytotoxicity. However, combined treatment of nTK-EGF and PD-1-cTK significantly decreased cell viability in MDA-MB-231 by ~20%, while MCF-7 remained healthy. In summary, we have successfully constructed and validated an AND-gate-based dual-targeting approach that minimizes off-tissue cytotoxicity with tune-able payload for cancer treatment. This versatile AND-gate dual-targeting system has the great potential of a paradigm-shifting strategy of cancer treatment, particularly for the cancers that cannot be treated by targeting a single antigen. The distinct cytotoxicity based on differential antigen expression introduces a novel cancer therapy category to overcome the targeting difficulties of triple-negative breast cancer (TNBC) and is potentially generalizable to other cancers. Citation Format: Mengrou Lu, Yunhui Xing, Keng-Jung Lee, Xi Ren, Justin R. Pritchard, Boyle C. Cheng, Hongzhang He, Siyang Zheng. AND-gate dual-targeting EGFR and PD-L1 with a split prodrug converter enzyme for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB170.

Chapter 23 - Infectious leukoencephalopathies

Leukoencephalopathy from infectious agents may have a rapid course, such as human simplex virus encephalitis; however, in many diseases, it may take months or years before diagnosis, such as in subacute sclerosing panencephalitis or Whipple disease. There are wide geographic distributions and susceptible populations, including both immunocompetent and immunodeficient patients. Many infections have high mortality rates, such as John Cunningham virus and subacute sclerosing panencephalitis, although others have effective treatments if suspected and treated early, such as herpes simplex encephalitis. This chapter will describe viral, bacterial, and protozoal infections, which predominantly cause leukoencephalopathy. We focus on the clinical presentation of these infectious agents briefly covering epidemiology and subtypes of infections. Next, we detail current pathophysiologic mechanisms causing white matter injury. Diagnostic and confirmatory tests are discussed. We cover predominantly MRI imaging features of leukoencephalopathies, and in addition, summarize the common imaging features. Additionally, we detail how imaging features may be used to narrow the differential of a leukoencephalopathy clinical presentation. Lastly, we present an outline of common treatment approaches where available.

The Case Files

The Case Files

Detection of Main Causative Agents among Young Children Suffering from Epiglottitis in Hilla City, Iraq.

Epiglottitis is a rapidly progressive epiglottis infection leading to upper airway edema. This study aimed to detect the main causative agent, viral infection, by immunofluorescence antibody technique and PCR technique and bacterial infection detection by specific gene among young children suffering from epiglottitis. This study included 85 young children aged 10-15 years. The virus was identified on 85 blood samples using the CER test Human simplex virus Card test; the results revealed that 12 (14.1%) specimens were related to virus infection, and the sera of patients showed anti-IgM to HSV-1 antibodies. HSV-1 was detected in blood samples by qPCR technique. Eighty-five saliva samples were collected from young children suffering from epiglottitis. The samples were cultured for 18-24 hours at 37°C. They were then cultivated for 18-24 hours on various selective media at 37°C. The colony morphology, microscopically, and biochemical testing were used to identify Haemophilus influenzae as a first Identification. Out of 85 clinical specimens, 63 (74.1%) were positive culture, while 22 (25.9%) had no growth on culture media; out of 63 specimens, only 22 (34.9%) isolates belonged to Haemophilus influenzae by biochemical tests, while 41 (65.1%) related to other types of microorganisms. VITEK 2 was used to validate bacteria isolates from young children suffering from epiglottitis. The findings indicate that 22 (34.9%) isolates related to Haemophilus influenzae have been confirmed with an excellent ID message confidence level (94 to 99.8% likelihood percentage). This method is characterized by quick bacterial detection. DNA was taken from all suspected isolates previously identified as Haemophilus influenzae using the vitek2 technology, and traditional PCR was used to amplify specific hel gene for Haemophilus influenzae primers utilizing these DNA samples. After that, when compared to an allelic ladder, gel electrophoresis revealed that all 22 (100%) samples of Haemophilus influenzae produced 101 bp DNA fragments. For isolates previously identified as Haemophilus influenzae, molecular identification of the ompP gene was performed. The results showed that 12 (or 54.5 percent) of the 22 isolates tested positive for this virulence gene. When compared to an allelic ladder, the presence of (459 bp) bands indicated positive results. In addition, the bexA gene was molecularly detected in 22 Haemophilus influenzae isolates, showing that only 8 (36.3 percent) of the isolates had this gene. When compared to an allelic ladder, the presence of a (343 bp) band indicated positive results for bexA gene pathogenicity; in conclusion, HSV (1) and Hib were considered almost causative agents of epiglottitis in young children.

Blue light irradiation exerts anti-viral and anti-inflammatory properties against herpes simplex virus type 1 infection.

The aim of this study was to investigate the antiviral and anti-inflammatory functions of blue light (BL) in cutaneous viral infections. Previously, we examined the photo-biogoverning role of 450nm BL in SARS-CoV-2-infected cells, which showed that photo-energy could inhibit viral activation depending on the number of photons. However, the communication network between photo-energy irradiation and immune cells involved in viral infections has not been clarified. We verified viral activation, inflammatory responses, and relevant downstream cascades caused by human simplex virus type I (HSV-1) after BL irradiation. To examine the antiviral effect of BL, we further tested whether BL could disturb viral absorption or entry into host cells. The results showed that BL irradiation, but not green light (GL) exposure, specifically decreased plaque-forming activity and viral copy numbers in HSV-1-infected cells. Accumulated BL irradiation inhibited the localization of viral proteins and the RNA expression of characteristic viral genes such as UL19, UL27, and US6, thus exerting to an anti-viral effect. The results also showed that BL exposure during viral absorption interfered with viral entry or destroyed the virus, as assessed by plaque formation and quantitative PCR assays. The levels of the pro-inflammatory mediators interleukin (IL)-18 and IL-1β in M1-polarized macrophages were increased by HSV-1 infection. However, these increases were attenuated by BL irradiation. Importantly, BL irradiation decreased cGAS and STING expression, as well as downstream NF-κB p65, in M1-polarized HSV-1-infected macrophages, demonstrating anti-viral and anti-inflammatory properties. These findings suggest that BL could serve as an anti-viral and anti-inflammatory therapeutic candidate to treat HSV-1 infections.

Primate Simplexviruses Differ in Tropism for Macaque Cells.

Primate simplexviruses are closely related neurotropic herpesviruses, which are largely apathogenic in their respective host species. However, cross-species transmission of Macacine alphaherpesvirus 1 (McHV1, also termed herpes B virus) from rhesus macaques to humans can cause fatal encephalomyelitis. In contrast, closely related viruses, such as Cercopithecine alphaherpesvirus 2 (CeHV2, also termed simian agent 8) or Papiine alphaherpesvirus 2 (PaHV2, also termed herpesvirus papio 2), have not been linked to human disease and are believed to be largely apathogenic in humans. Here, we investigated whether McHV1, PaHV2 and CeHV2 differ in their capacity to infect human and non-human primate (NHP) cells. For comparison, we included the human simplexviruses HSV1 and HSV2 in our analyses. All five viruses replicated efficiently in cell lines of human and African green monkey origin, and McHV1 and PaHV2 also showed robust replication in rhesus macaque cell lines. In contrast, the replication of CeHV2 and particularly HSV1 and HSV2 in cell lines of rhesus macaque origin were reduced or inefficient. Similarly, McHV1, but not CeHV2, efficiently infected rhesus macaque brain organoids. These results point towards the previously unappreciated partial resistance of certain rhesus macaque cells to HSV1/HSV2/CeHV2 infection and reveal similarities between the cell tropism of McHV1 and PaHV2 that might be relevant for risk assessment.

Cytotoxicity and Antiviral Activity of Kyllinga nemoralis Methanolic Extract

Herpes Simplex Virus (HSV) is a double-stranded DNA virus in the Herpesviridae family. The most prevalent in humans is Human Simplex Virus Type 1 (HSV-1). It can reach the brain without causing the symptoms [1]. Currently, the most antiviral drug used is Acyclovir (ACV); nucleotide analogues target DNA polymerase inhibiting viral replication. However, ACV drug-resistant occurs, especially in immunocompromised patients [2]. Therefore, alternate therapy for patients with established resistance was required. Plant extract is commonly used as antiviral agent. Kyllinga nemoralis is known as White Spike Head had antiviral, antibacterial, antibleeding and anti-poisoning properties [3]. It contains antiviral sources such as the highest flavonoid and flavonol concentrations [4].
 
 The objective of this experimental study was to investigate the potential of K. nemoralis methanolic extract as antiviral agent against HSV-1. The root of K. nemoralis methanolic plant extract, Vero Cells and HSV-1 were used in this study. The Cytotoxic Concentration (CC50) of the K. nemoralis methanolic extract against Vero Cells and the antiviral activity of K. nemoralis methanolic extract against HSV-1 by using post-treatment, pre-treatment and virucidal assay were performed in this study.
 
 Results showed that the percentage of cell population versus concentration of root of K. nemoralis methanolic extract (figure 1). The CC50 of this extract was determined at 0.91 mg/mL. This showed that the root of K. nemoralis methanolic extract was considered not toxic to the cells as the CC50 of extract showed more than 4 µg/mL [5].
 
 The results indicate that the root of K. nemoralis methanolic extract was more effective in protecting the Vero cells. In pre-treatment, the SI value of the extract was 8.27. This finding shows that the root of K. nemoralis methanolic extract had a moderate ability to bind to the Vero cells and inhibited the binding of HSV-1 to the cell surface of the Vero cells. In a virucidal test, the root extract towards HSV-1 showed the SI value was 8.125. This data suggests that the root of the extract was moderately inactivates the extracellular component of HSV-1.
 In conclusion, the findings of this study show that K. nemoralis methanolic extract was non-toxic to the Vero cells and has the potential to be an antiviral agent against HSV-1.

In Vitro Antineoplastic and Antiviral Activity and In Vivo Toxicity of Geum urbanum L. Extracts

This study evaluated the in vitro antineoplastic and antiviral potential and in vivo toxicity of twelve extracts with different polarity obtained from the herbaceous perennial plant Geum urbanum L. (Rosaceae). In vitro cytotoxicity was determined by ISO 10993-5/2009 on bladder cancer, (T-24 and BC-3C), liver carcinoma (HEP-G2) and normal embryonic kidney (HEK-293) cell lines. The antineoplastic activity was elucidated through assays of cell clonogenicity, apoptosis induction, nuclear factor kappa B p65 (NFκB p65) activation and total glutathione levels. Neutral red uptake study was applied for antiviral activity. The most promising G. urbanum extract was analyzed by UHPLC–HRMS. The acute in vivo toxicity analysis was carried out following OEDC 423. The ethyl acetate extract of aerial parts (EtOAc-AP) exhibited the strongest antineoplastic activity on bladder cancer cell lines (IC50 = 21.33–25.28 µg/mL) by inducing apoptosis and inhibiting NFκB p65 and cell clonogenicity. EtOAc and n-butanol extracts showed moderate antiviral activity against human adenovirus type 5 and human simplex virus type I. Seventy four secondary metabolites (gallic and ellagic acid derivatives, phenolic acids, flavonoids, etc.) were identified in EtOAc-AP by UHPLC–HRMS. This extract induced no signs of acute toxicity in liver and kidney specimens of H-albino mice in doses up to 210 mg/kg. In conclusion, our study contributes substantially to the detailed pharmacological characterization of G. urbanum, thus helping the development of health-promoting phytopreparations.

Eczema herpeticum subsequent to septic shock in early pregnancy: a first case report

BackgroundEczema herpeticum (EH) is a severe skin complication caused by human simplex virus (HSV) infection concomitant with immune dysfunction and dermatological conditions, mainly atopic dermatitis. We present the first case of EH subsequent to sepsis-related immunological suppression in pregnancy.Case presentationSeptic shock developed in a 30-year-old primiparous woman at 14 weeks of pregnancy during admission for hyperemesis gravidarum. Although her life-threatening status due to sepsis improved by prompt treatment, on day 3 of treatment in the intensive care unit, blisters suddenly erupted on her face and neck and spread over her body. EH was diagnosed according to HSV type-1 antigen positivity and a past medical history of EH and atopic dermatitis. Antiviral agents were administered immediately, with positive results. Her general condition improved quickly, without central nervous system defects. This is the first report of EH following septic shock in early pregnancy. At present, we speculate that EH develops as a complication due to immunological changes in the late phase of sepsis because sepsis is mainly characterized by both an inflammatory state in the acute phase and an immunosuppressive state in the late phase. Pregnancy can also contribute to its pathogenesis, as it causes an immunosuppressive state. Mortality due to EH is relatively high; in this case, a history of EH and atopic dermatitis contributed to the initiation of prompt medical interventions for the former, with improvement in the patient’s severe condition. The combination of immunological changes in sepsis and pregnancy can cause HSV reactivation, resulting in EH recurrence.ConclusionsIn conclusion, if dermatological symptoms develop in a pregnant woman with a history of EH and/or atopic dermatitis treated for sepsis, EH should be suspected based not only on clinical features but also on immunological changes along with sepsis, and prompt medical interventions should be initiated.

Studies On Invitro Analysis Of Sargassum Wightii Against Human Simplex Virus (HSV)

Introduction: Human simplex viruses are ulcerative diseased found in skin and genital organs dependingupon the strain. It affects an individual at least once in a lifetime by direct contact with an infected person.There are two strains of HSV predominantly found are HSV-1 and HSV-2. HSV-1 infects the pharynx andoral region, whereas HSV-2 infects the genital areas of sexual contact.Materials and Method: The crude extract of S. wightii on the proliferation of Vero cells was assessed bythe neutral dye uptake method. Various fold of serially diluted solvent crude extracts showed cytotoxicconcentration50 (CC50) at 750 and 500mg/mL of ethyl acetate and methanol extract, respectively.Results: The Antiviral activity of solvent crude extract against HSV-1 showed significant reduction of viruson Vero cells. Among the solvent crude tested, the ethyl acetate showed effective IC50 against HSV-1 at 300mg/mL.Conclusion: The seaweed S. wightii is a natural source in treating the pathogen HSV-1 and it clearlyindicated that, the marine brown algae S. wightii possess strong antiviral activity with slight cytotoxic effect.

Role of Adiponectin in Cervical Cancer.

Cervical Cancer (CC) is the most common leading cancer in women globally. This is considered to be the type of cancer that is restricted to women. Any women in the reproductive age range can develop CC. However, women between the ages of 25 and 39 are at a higher risk. In comparison with developed countries, the screening and awareness of CC in developing countries are significantly low. Infection with Human papillomavirus (HPV) is the main cause of CC, especially HPV-16 and HPV-18. Other than HPV, there are other factors that can contribute to CC, such as Human simplex virus (HSV) infection and immunocompromised patients with HIV. Cervical cancer can be detected by molecular techniques such as (1) PCR, (2) visual acetic acid method, (3) DNA Hybrid II test, (4) liquid-based cytology, (5) Pap-Smear techniques, and (6) colposcopy techniques. Early detection of CC is very much needed; cryotherapy or LEEP (Loop electro surgical excision procedure) can be conducted during the pre-invasive stage of CC. Some metabolic changes in the human body such as fluctuating levels of insulin and triglycerides and increased activity of adiponectin may lead to CC. These contributing factors, such as adipokines, can be used as biomarkers for CC detection.

Expression characteristics of signaling molecules associated with innate immune response induced by HSV1 and HSV2 in respiratory and vaginal epithelial cells

Objective To investigate the influences of herpes simplex virus 1 and 2(HSV1 and HSV2) infection on the expression of signaling molecules associated with innate immune response in respiratory and vaginal epithelial cells for bettering understanding of HSV infection and pathological characteristics in the primary infection site, namely mucosal epithelial tissues. Methods KMB17 and VK2 cells were infected with HSV. Changes in cell morphology and inner structure after HSV infection were observed under optical microscope and scanning electron microscope, respectively. Viral proliferation in KMB17 and VK2 cells was detected by plaque assay, microcytopathic assay and real-time quantitative PCR. Expression of signaling molecules associated with innate immune response in virus-infected KMB17 and VK2 cells were analyzed by real-time quantitative PCR. Results Both HSV1 and HSV2 could infect KMB17 and VK2 cells, and cause damage to cell morphology and inner structure after 12 hours. Both of the two viruses formed similar plaque on the single layer of KMB17 and VK2 cells, although HSV2 proliferated slower than HSV1. There were differences in the expression of signaling molecules associated with innate immune response induced by the two viruses in KMB17 and VK2 cells. Conclusion Both HSV1 and HSV2 could infect and proliferate in epithelial cells (KMB17 and VK2 cells). Although there were slight differences in viral proliferation between them, significant differences in the expression of signaling molecules associated with innate immune response induced by the two viruses were observed. Key words: Human herpes simplex virus; Epithelial cell; Signaling molecules associated with innate immune response

Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and macaque isolates using monoclonal antibodies.

Our overall aim is to develop epitope-based assays for accurate differential diagnosis of B virus zoonotic infections in humans. Antibodies to cross-reacting epitopes on human-simplexviruses continue to confound the interpretation of current assays where abundant antibodies exist from previous infections with HSV types 1 and 2. To find B virus-specific epitopes we cloned ten monoclonal antibodies (mAbs) from the hybridomas we produced. Our unique collection of rare human sera from symptomatic and asymptomatic patients infected with B virus was key to the evaluation and identification of the mAbs as reagents in competition ELISAs (mAb-CE). The analysis of the ten mAbs revealed that the target proteins for six mAbs was glycoprotein B of which two are reactive to simian simplexviruses and not to human simplexviruses. Two mAbs reacted specifically with B virus glycoprotein D, and two other mAbs were specific to VP13/14 and gE-gI complex respectively. The mAbs specific to VP13/14 and gE-gI are strain specific reacting with B virus isolates from rhesus and Japanese macaques and not with isolates from cynomolgus and pigtail macaques. The mAb-CE revealed that a high proportion of naturally B virus infected rhesus macaques and two symptomatic humans possess antibodies to epitopes of VP13/14 protein and on the gE-gI complex. The majority of sera from B virus infected macaques and simplexvirus-infected humans competed with the less specific mAbs. These experiments produced a novel panel of mAbs that enabled B virus strain identification and confirmation of B virus infected macaques by the mAb-CE. For human sera the mAb-CE could be used only for selected cases due to the selective B virus strain-specificity of the mAbs against VP13/14 and gE/gI.To fully accomplish our aim to provide reagents for unequivocal differential diagnosis of zoonotic B virus infections, additional mAbs with a broader range of specificities is critical.

Commercial sex and risk of HIV, syphilis, and herpes simplex virus-2 among men who have sex with men in six Chinese cities.

BackgroundMen who have sex with men (MSM) are at high risk of HIV and sexually transmitted infections (STIs) in China and globally. Engaging in commercial sex put them at even greater risk. This study estimated the prevalence of HIV/STIs among three subgroups of MSM: MSM who sold sex (MSM-selling), MSM who bought sex (MSM-buying), and non-commercial MSM (NC-MSM) and evaluated the relationship between commercial sex and HIV/STIs.MethodsWe conducted a cross-sectional survey among MSM in six Chinese cities (Shenyang, Ji’nan, Changsha, Zhengzhou, Nanjing, and Kunming) from 2012 to 2013. Data on socio-demographics and sexual behaviors were collected. Serological tests were conducted to detect HIV, syphilis, and human simplex virus type 2 (HSV-2).ResultsOf 3717 MSM, 6.8% were engaged in commercial sex. The overall prevalence of HIV, syphilis and HSV-2 infections was 11.1, 8.8 and 12.1%, respectively. MSM-selling had higher prevalence of HIV (13.4%), syphilis (12.1%) and HSV-2 (17.9%) than NC-MSM (10.9, 8.7 and 11.9% for HIV, syphilis and HSV-2, respectively), though the differences are not statistically significant. Among MSM-selling, HIV prevalence was significantly higher for those who found sex partners via Internet than those did not (19.4% vs. 8.1%, P = 0.04). Compared to NC-MSM, MSM-selling were more likely to use recreation drugs (59.3% vs. 26.3%), have unprotected anal intercourse (77.9% vs. 61.7%), and have ≥10 male sex partners (46.2% vs. 6.2%) in the past 6 months (each P < 0.05).ConclusionsAll three subgroups of MSM in six large Chinese cities have high prevalence of HIV/STIs. Those who sell sex only have a particularly high risk of acquiring and transmitting disease, and therefore, they should be considered as a priority group in HIV/STIs surveillance and intervention programs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-2130-x) contains supplementary material, which is available to authorized users.

Roles of nucleic acid substrates and cofactors in the vhs protein activity of pseudorabies virus.

Pseudorabies virus (PrV) belongs to the α-herpesvirinae of which human simplex virus (HSV) is the prototype virus. One of the hallmarks of HSV infection is shutoff of protein synthesis that is mediated by various viral proteins including vhs (virion host shutoff), which is encoded by the UL41 gene. However, the function of PrV vhs is poorly understood. Due to the low sequence similarity (39.3%) between the HSV and PrV UL41 proteins, vhs might not share the same biochemistry characteristics. The purpose of this study was to characterize the nuclease activity of the PrV vhs protein with respect to substrate specificity, its requirements in terms of cofactors, and the protein regions, as well as key amino acids, which contribute to vhs activity. Our results indicated that, similar to HSV vhs, PrV vhs is able to degrade ssRNA and mRNA. However, PrV vhs also targeted rRNA for degradation, which is novel compared to the HSV-1 vhs. Activity assays indicated that Mg2+ alone enhances RNA degradation mediated by PrV vhs, while K+ and ATP are not sufficient to induce activity. Finally, we demonstrated that each of the four highly conserved functional boxes of PrV vhs contributes to RNA degradation and that, in particular, residues 152, 169, 171, 172, 173 343, 345, 352 and 356, which are conserved among α-herpesviruses, are key amino acids needed for PrV vhs ribonuclease activity.

心臓交感神経過亢進が関連したと考えられた浸水性肺水腫の1例(Immersion pulmonary edema due to sympathetic over–activation of heart: a case report)

要旨浸水性肺水腫（Immersion Pulmonary Edema，以下IPE）とは潜水や水泳で急性発症する肺水腫であり，多くは速やかに改善するが死亡例の報告もある。IPEの発症機序は不明な点が多く，非心原性肺水腫であると報告されていたが，近年では一過性心筋障害が関与している可能性が報告されている。今回我々は，一過性の心筋トロポニン上昇と心臓壁運動低下を認め，心臓核医学検査で交感神経過亢進と考えられる所見を認めたIPE症例を経験したので報告する。【症例】52歳の女性。水温18°C，最大深度8.4m，平均深度5.5m，潜水時間20分のSCUBAダイビングを行った。潜水中にトラブルはなかったが，浮上後5分程度で呼吸困難が出現したため近医を受診し，減圧症の可能性が考えられ当院に転院搬送となった。来院時の胸部単純レントゲン及び胸部単純CTでは両側肺水腫を認めた。また心筋トロポニンの軽度上昇，心電図検査では非特異的STの変化，心臓超音波検査では軽度の瀰漫性壁運動低下を認めた。肺水腫に伴う低酸素血症の診断で人工呼吸器管理下に集中治療を行った。翌日，肺水腫と低酸素血症は著明に改善し呼吸器を離脱し，第11病日に合併症なく退院となった。入院中の検査では，冠動脈CTで有意狭窄はなく，第2，第3病日の心臓超音波検査は正常であった。また第9病日に行った心筋SPECT MIBGシンチグラフィでは明らかな心筋障害はなかったが，交感神経過亢進と考えられる所見があった。経過，検査結果より減圧症・動脈ガス塞栓・急性冠症候群などは否定的であった。来院時は心筋障害を示す検査結果であったが，症状軽快後の心臓核医学検査では心筋障害はないことから，本症例は交感神経過亢進に伴う一過性心筋障害が関与したIPEと考えた。ダイビングは運動負荷や冷水刺激等により交感神経が刺激されることからIPE発症機序の一つに交感神経過亢進による一過性心筋障害の可能性があると考える。

A Case of Asymptomatic Culture Positive Human Simplex Virus Duodenitis Treated with Acyclovir

A Case of Asymptomatic Culture Positive Human Simplex Virus Duodenitis Treated with Acyclovir

Evolutionary origins of human herpes simplex viruses 1 and 2.

Herpesviruses have been infecting and codiverging with their vertebrate hosts for hundreds of millions of years. The primate simplex viruses exemplify this pattern of virus–host codivergence, at a minimum, as far back as the most recent common ancestor of New World monkeys, Old World monkeys, and apes. Humans are the only primate species known to be infected with two distinct herpes simplex viruses: HSV-1 and HSV-2. Human herpes simplex viruses are ubiquitous, with over two-thirds of the human population infected by at least one virus. Here, we investigated whether the additional human simplex virus is the result of ancient viral lineage duplication or cross-species transmission. We found that standard phylogenetic models of nucleotide substitution are inadequate for distinguishing among these competing hypotheses; the extent of synonymous substitutions causes a substantial underestimation of the lengths of some of the branches in the phylogeny, consistent with observations in other viruses (e.g., avian influenza, Ebola, and coronaviruses). To more accurately estimate ancient viral divergence times, we applied a branch-site random effects likelihood model of molecular evolution that allows the strength of natural selection to vary across both the viral phylogeny and the gene alignment. This selection-informed model favored a scenario in which HSV-1 is the result of ancient codivergence and HSV-2 arose from a cross-species transmission event from the ancestor of modern chimpanzees to an extinct Homo precursor of modern humans, around 1.6 Ma. These results provide a new framework for understanding human herpes simplex virus evolution and demonstrate the importance of using selection-informed models of sequence evolution when investigating viral origin hypotheses.

Loss to follow-up and associated factors in a cohort study among men who have sex with men

To explore the associated factors on loss to follow-up among men who have sex with men (MSM) in a prospective cohort study. We recruited eligible HIV-negative MSM at baseline in eight cities from June to October 2009. Interviewer-administrated questionnaire and blood testings for HIV, syphilis and human simplex virus type 2, were accomplished upon enrollment, 6-month and 12-month follow-up visits in the program. Loss to follow-up was recorded at each visit in this cohort. Univariate and multivariate statistical analysis were conducted to examine the associated factors on loss to follow-up. A total of 3196 eligible MSM were enrolled at the baseline study. During one year of follow-up, 894 (28.0%) of them dropped out thoroughly while 2302 (72.1%) showed up at least on one visit. Factors as MSM who were at age 25 or younger, resided locally less than 1 year, being unemployed, self-recognized as heterosexuality or bisexuality, never taking HIV testing in the past year, having had sex with women in the past 6 months etc., were more likely to withdraw from the follow-up visits. Conclusion Age, length of residency, sex orientation and history of HIV testing were associated with the loss of follow-up among MSM cohort in our study. These factors should be considered in this kind of study design in the future.

Current knowledge and systematic review of viruses associated with Crohn's disease

The aetiology of Crohn's disease (CD) is currently unknown. A viral trigger was proposed more than 40 years ago and has been the focus of many investigations. We summarised the current literature surrounding the association between viruses and CD and conducted a systematic review of all studies investigating this association quantitatively. Studies were identified by searching for 13 specific virus names or the general term 'virus' and 'Crohn's disease' in search engines PubMed and OVID. A total of 1315 studies were identified, of which 78 studies had a laboratory result. Of the 78, 46 case-control studies met all the inclusion criteria for forest plot analysis. The most common viruses studied were EBV, CMV and measles virus (MV). Forest plot analysis for each virus was carried out (fitted using random effects) and identified evidence of an association between CD and CMV (risk ratio [RR] 1.602, 95% confidence interval [CI] 1.069 to 2.400) with some suggestion that EBV may also be associated with CD (RR 1.366, 95% CI 0.996 to 1.873). However, there was evidence of large heterogeneity in the results from the identified studies for EBV. There was little evidence of an association with CD for MV, human herpes virus 6, human herpes virus 8, human simplex virus, varicella-zoster virus, mumps virus, Rubella virus, rotavirus, norovirus and adenovirus. There is still some question around whether CD is associated with the presence of a currently known virus.