Search

Objectives: To assess second‐line antiretroviral therapy (ART) virological failure and HIV drug resistance‐associated mutations (RAMs), in support of third‐line regimen planning in Asia. Methods: Adults > 18 years of age on second‐line ART for ≥ 6 months were eligible. Cross‐sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia‐Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3–6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS‐USA 2019 mutations list. VF risk factors were analysed using logistic regression. Results: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second‐line switch, median [interquartile range (IQR)] age was 37 (32–42) years and median (IQR) CD4 count was 103 (43.5–229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17–0.77 vs. CD4 ≤ 50) and HIV exposure through male–male sex (OR = 0.32, 95% CI: 0.17–0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12–0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more. Conclusions: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second‐line regimens. [ABSTRACT FROM AUTHOR]

Non-obstructive azoospermia is a severe condition because spermatogenesis per se is disrupted. Although microdissection testicular sperm extraction is the standard therapy for non-obstructive azoospermia, sperm retrieval is unsuccessful in approximately 50% of patients. For these patients, we conducted human chorionic gonadotropin-based salvage hormonal therapy, and sperm retrieval was possible in 10-20% of patients. The objectives of this study were to assess the changes in interstitial lesions in patients with non-obstructive azoospermia and to evaluate the effects of human chorionic gonadotropin on these tissues. Testicular biopsy specimens were obtained from 10 non-obstructive azoospermia patients who failed to obtain spermatozoa and from 10 obstructive azoospermia patients. All non-obstructive azoospermia patients received salvage hormonal therapy after microdissection testicular sperm extraction. Hematoxylin and eosin (H.E.) staining and immunohistochemical staining for steroidogenic acute regulatory protein antibody, the Leydig cell marker, and TE-7 antibody, the fibroblast marker, as well as picrosirius red staining to detect collagen fibers, were performed. We measured interstitial lesions, as Leydig cell area and the other area, with ImageJ software. Interstitial area, excluding Leydig cells, increased up to 12.5% in non-obstructive azoospermia compared with 1.2% in obstructive azoospermia ( p < 0.01), which was mainly because of fibrosis with TE-7-positive fibroblasts. The increase in interstitial lesions was correlated with Johnsen scores. Interstitial area, excluding the Leydig cells, decreased by 29% after salvage hormonal therapy ( p < 0.05), indicating improvement of interstitial fibrosis in non-obstructive azoospermia. There were no significant difference in total Leydig cell area and size of each Leydig cells between obstructive azoospermia and non-obstructive azoospermia. After the salvage hormonal therapy, a portion of the Leydig cells became hypertrophied and mean diameter of Leydig cell significantly increased ( p < 0.01). This study showed anti-fibrotic effects of human chorionic gonadotropin and hypertrophic change of Leydig cells after human chorionic gonadotropin administration. [ABSTRACT FROM AUTHOR]

Background and Purpose: Prefrontal dopamine release by the combined activation of 5-HT1A and sigma-1 (σ1 ) receptors is enhanced by the GABAA receptor antagonist picrotoxin in mice. Here, we examined whether this neurochemical event was accompanied by behavioural changes.Experimental Approach: Male mice were treated with picrotoxin to decrease GABAA receptor function. Their anhedonic behaviour was measured using the female encounter test. The expression of c-Fos was determined immunohistochemically.Key Results: Picrotoxin caused an anxiogenic effect on three behavioural tests, but it did not affect the immobility time in the forced swim test. Picrotoxin decreased female preference in the female encounter test and attenuated the female encounter-induced increase in c-Fos expression in the nucleus accumbens. Picrotoxin-induced anhedonia was ameliorated by fluvoxamine and S-(+)-fluoxetine, selective serotonin reuptake inhibitors with high affinity for the σ1 receptor. The effect of fluvoxamine was blocked by a 5-HT1A or a σ1 receptor antagonist, and co-administration of the σ1 receptor agonist (+)-SKF-10047 and the 5-HT1A receptor agonist osemozotan mimicked the effect of fluvoxamine. By contrast, desipramine, duloxetine and paroxetine, which have little affinity for the σ1 receptor, did not affect picrotoxin-induced anhedonia. The effect of fluvoxamine was blocked by a dopamine D2/3 receptor antagonist. Methylphenidate, an activator of the prefrontal dopamine system, ameliorated picrotoxin-induced anhedonia.Conclusion and Implications: Picrotoxin-treated mice show anhedonic behaviour that is ameliorated by simultaneous activation of 5-HT1A and σ1 receptors. These findings suggest that the increased prefrontal dopamine release is associated with the anti-anhedonic effect observed in picrotoxin-treated mice. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to assess the prevalence and characteristics associated with current smoking in an Asian HIV-positive cohort, to calculate the predictive risks of cardiovascular disease ( CVD), coronary heart disease ( CHD) and myocardial infarction ( MI), and to identify the impact that simulated interventions may have. Methods Logistic regression analysis was used to distinguish associated current smoking characteristics. Five-year predictive risks of CVD, CHD and MI and the impact of simulated interventions were calculated utilizing the Data Collection on Adverse Effects of Anti- HIV Drugs Study (D:A:D) algorithm. Results Smoking status data were collected from 4274 participants and 1496 of these had sufficient data for simulated intervention calculations. Current smoking prevalence in these two groups was similar (23.2% vs. 19.9%, respectively). Characteristics associated with current smoking included age > 50 years compared with 30-39 years [odds ratio ( OR) 0.65; 95% confidence interval ( CI) 0.51-0.83], HIV exposure through injecting drug use compared with heterosexual exposure ( OR 3.03; 95% CI 2.25-4.07), and receiving antiretroviral therapy ( ART) at study sites in Singapore, South Korea, Malaysia, Japan and Vietnam in comparison to Thailand (all OR > 2). Women were less likely to smoke than men ( OR 0.11; 95% CI 0.08-0.14). In simulated interventions, smoking cessation demonstrated the greatest impact in reducing CVD and CHD risk and closely approximated the impact of switching from abacavir to an alternate antiretroviral in the reduction of 5-year MI risk. Conclusions Multiple interventions could reduce CVD, CHD and MI risk in Asian HIV-positive patients, with smoking cessation potentially being the most influential. [ABSTRACT FROM AUTHOR]

P neumocystis jirovecii pneumonia ( PCP) remains an important cause of morbidity and mortality in immunocompromised renal transplant recipients. In recent years, PCP outbreaks in renal transplant centers have been reported in many countries. Person-to-person transmission between PCP patients and other recipients lacking prophylaxis is one of the possible sources of infection. To prevent infection, effective prophylaxis in susceptible patients is recommended. Trimethoprim-sulfamethoxazole ( TMP- SMX) is the most effective drug for PCP prophylaxis, but its recommended duration of use after transplantation varies among the different guidelines. The European Renal Association recommends a prophylaxis period of 4 months after transplantation, the American Society of Transplantation ( AST) 6-12 months, and the Kidney Disease Improving Global Outcomes guidelines 3-6 months. Lifelong prophylaxis with TMP- SMX is not recommended in renal transplant recipients; however, in many cases, PCP has occurred after the recommended prophylaxis periods after transplantation. In this minireview, we discuss the risk factors including environmental-nosocomial exposure; state-of-the-art diagnosis, treatment, prophylaxis and isolation; and references to the AST 2009 guidelines with the aim of integrating our experience with PCP outbreaks into recent reports, and we discuss how renal transplant recipients can be protected from PCP. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to examine the rates and predictors of treatment modification following combination antiretroviral therapy (cART) failure in Asian patients with HIV enrolled in the TREAT Asia HIV Observational Database (TAHOD). Methods Treatment failure (immunological, virological and clinical) was defined by World Health Organization criteria. Countries were categorized as high or low income by World Bank criteria. Results Among 2446 patients who initiated cART, 447 were documented to have developed treatment failure over 5697 person-years (7.8 per 100 person-years). A total of 253 patients changed at least one drug after failure (51.6 per 100 person-years). There was no difference between patients from high- and low-income countries [adjusted hazard ratio (HR) 1.02; P=0.891]. Advanced disease stage [Centers for Disease Control and Prevention (CDC) category C vs. A; adjusted HR 1.38, P=0.040], a lower CD4 count (≥51 cells/μL vs. ≤50 cells/μL; adjusted HR 0.61, P=0.022) and a higher HIV viral load (≥400 HIV-1 RNA copies/mL vs. <400 copies/mL; adjusted HR 2.69, P<0.001) were associated with a higher rate of treatment modification after failure. Compared with patients from low-income countries, patients from high-income countries were more likely to change two or more drugs (67% vs. 49%; P=0.009) and to change to a protease-inhibitor-containing regimen (48% vs. 16%; P<0.001). Conclusions In a cohort of Asian patients with HIV infection, nearly half remained on the failing regimen in the first year following documented treatment failure. This deferred modification is likely to have negative implications for accumulation of drug resistance and response to second-line treatment. There is a need to scale up the availability of second-line regimens and virological monitoring in this region. [ABSTRACT FROM AUTHOR]

Background and Objective: Several studies have shown that diabetes mellitus increases the severity of periodontitis. Conversely, periodontitis has been shown to have an impact on diabetes, although the underlying mechanisms of this are unclear. The aim of this study was to compare the inflammatory response to Porphyromonas gingivalis infection in normal and diabetic mice. Material and Methods: Porphyromonas gingivalis were inoculated adjacent to the periosteum, at a point on the midline of the skull located between the ears, in C57BL/6 (normal) and KKAy (diabetic) mice. After induction, the levels of tumor necrosis factor-α, interleukin-6 and adiponectin in the mice were measured using real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results: The KKAy mice showed significant increases in blood glucose, serum tumor necrosis factor-α and interleukin-6 levels after inoculation with Porphyromonas gingivalis, and a significant decrease in adiponectin to 35.7%. Similar results were observed at the mRNA level in liver and visceral adipose tissue. Conclusion: These observations suggest that tumor necrosis factor-α, interleukin-6 and adiponectin are an integral part of the link between diabetes mellitus and Porphyromonas gingivalis infection. [ABSTRACT FROM AUTHOR]

The article presents a study which describes the development and evaluation of a new toothbrush designed for patients with elbow joint arthropathy. It explores the custom-designed toothbrush for patients with limited movement. It also evaluates the toothbrush's usefulness and its ability to remove dental plaque safely and effectively.

Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infections. As several HIV-1 CTL epitopes restricted to many HLA types are already known, we aimed at identifying the CTL epitopes restricted by HLA-A*3101 in an effort to expand the epitope repertoire available for the development of potential T cell-mediated therapeutic measures and protective vaccines. Scanning of HIV-1 clade B SF2 strain proteins for the presence of peptides containing HLA-A*3101-binding motifs revealed 88 nine- to 11-mer peptides that had been synthesized and assayed for binding to HLA-A*3101 molecules. Peptides with medium to high HLA-binding affinity were tested for their ability to stimulate a CTL response in the peripheral blood mononuclear cells (PBMCs) from selected HIV-1-infected patients. Two of these binding peptides, Env769–779 (RLRDLLLIAAR) and Nef192–200 (KLAFHHMAR), induced peptide-specific CTLs in PBMCs from at least two of five HIV-1-seropositive individuals. CTL clones specific for the two peptides killed HLA-A*3101-expressing target cells infected with HIV-1 recombinant vaccinia virus, indicating that these peptides were naturally processed HLA-A*3101-restricted CTL epitopes. Identification of T-cell epitopes on HIV-1 proteins will increase our understanding of the role of CD8+ T cells in HIV-1 infections and assist in the design of new protective strategies. [ABSTRACT FROM AUTHOR]

: It is controversial as to whether the development of gastric cancer is influenced byHelicobacter pylorieradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate.: To investigate the morphological changes in the gastric neoplasm afterH. pylorieradication.: We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication.: Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels.: The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate. [ABSTRACT FROM AUTHOR]

In the present study, we measured the levels of the cytokines and gelatinase species in the fluids of ameloblastomas and odontogenic keratocysts, and showed that ameloblastomas can be distinguished from odontogenic keratocysts by the use of these biochemical data. We found that interleukin (IL)-1α and lL-1β levels in the intracystic fluids of ameloblastomas were significantly lower than those in the fluids of odontogenic keratocysts, while IL-6 levels in the fluids of ameloblastomas were significantly higher than those in the fluids of odontogenic keratocysts. On the other hand, no significant differences in tumor necrosis factor (TNF)-α levels of the fluids were detected between amelablastomas and odontogenic keratocysts. An immunohistochemical study revealed that the staining intensity of IL-1α, IL-1β and TNF-α in the tumor cells of ameloblastomas was significantly weaker than that in the epithelial cells of odontogenic keratocysts, while the staining intensity of IL-6 in the tumor cells was significantly stronger than that in the epithelial cells of odontogenic keratocysts. Gelatin zymography of the fluids showed that only a small amount of pro-MMP-9 was detected in ameloblastomas, while both pro-MMP-9 and the active form of MMP-9 were detected in 8 of 10 cases of odontogenic keratocysts. Thus, ameloblastomas can be distinguished from odontogenic keratocysts by measuring IL-1α and lL-6 levels, and gelatinase species in the fluids. [ABSTRACT FROM AUTHOR]

Summary B220 is the full-length splicing isoform of a tyrosine phosphatase CD45 and is predominantly expressed as a transmembrane protein on B cells. Other splicing isoforms of CD45 are yielded by alternative splicing of exons 4, 5 and 6. Recently, the expression of B220 on peripheral T cells during activation-induced cell death has been reported. To investigate whether B220 is implicated in apoptosis of immature T cells, we analysed (by flow cytometry using the anti-B220 monoclonal antibody, RA3-6B2) the expression of B220 on mouse thymocytes undergoing X-irradiation- and dexamethasone (DEX)-induced apoptosis. The expression of B220 on thymocytes positive for Thy-1 was induced by X-irradiation or DEX treatment and increased with length of incubation. The expression of B220 was pronounced on the apoptotic hypodiploid cells in the fraction showing lower forward scattering values. Reverse transcription–polymerase chain reaction detected mRNA containing exons 4, 5 and 6 of CD45 in normal thymocytes as well as those exposed to X-rays or DEX. Surprisingly, cytoplasmic B220 antigens were detected in a considerable fraction of normal thymocytes. Moreover, the expression level of the 220 000-MW protein in normal thymocytes was similar to that in the thymocytes undergoing apoptosis. During apoptosis, the expression level of B220 antigen was reduced in the cytoplasm but, conversely, up-regulated on the surface of thymocytes. These results suggest that B220 is constitutively expressed as a cytoplasmic form within thymocytes and possibly translocated to the cell membrane during apoptosis. [ABSTRACT FROM AUTHOR]

We prepared (2S,6S)-Z-Dpm(Z)(OMe) (4) by protease-mediated hydrolysis of (R,R/S,S)-Z-Dpm(Z)(OMe)-OMe (3), converted it to (2S,6S)-Dpm(Z)(OMe) (6) via PCl[sub 5] to an NCA intermediate and hydrolysis, protected the amino group with Boc to give (2S,6S)-Boc-Dpm(Z)(OMe) (7), which upon ammonolysis of the Me ester afforded (2S,6S)-Boc-Dpm(Z)(NH[sub 2]) (8). Hydrogenolysis of 8 and protection with Fmoc gave (2S,6S)-Boc-Dpm(Fmoc)(NH[sub 2]) (10). Using 10 and SPPS, we prepared three Dpm-containing peptides and their corresponding Lys peptides. Enzymatic studies with mLAP and cLAP showed that the Leu moiety in Ac-Gly-(2S,6S)-Dpm(Leu)(NH[sub 2])-Ala (14) was hydrolyzed 68-fold and> 1000-fold more rapidly, respectively, than that in Ac-Gly-Lys(Leu)-Ala (12). The enhanced rate of Leu formation from 14 compared to 12 was also observed with homogenates of mouse C3 sarcomas. This homogenate also hydrolyzed Ac-Gly-(2S,6S)-Dpm(Ac-Gly-Pro-Gln-Gly-Leu)(NH[sub 2])-Ala (16) to Ac-Gly-(2S,6S)-Dpm(NH[sub 2])-Ala (13), Leu and Ac-Gly-Pro-Gln-Gly (17). This implies the side chain is cleaved first by endopeptidases, such as matrix metalloproteinases (MMPs), and then the remaining Leu is cleaved by LAP-like exopeptidases. The rate of liberation of 17 from 16 and the corresponding Lys isopeptide, Ac-Gly-Lys(Ac-Gly-Pro-Gln-Gly-Leu)-Ala (15), was not significantly different. The rate of formation of 13 was faster from 16 than Ac-Gly-Lys-Ala (11) was from 15. Thus, the entire isopeptide side chain can be removed by the cooperative action of LAP-like and MMP-like peptidases present in tumor tissue, which occurs faster in the Dpm peptide 16 than in the Lys peptide 15. The rate of formation of 13 from 16 by lung, liver, and intestine homogenates (from the same C3 tumor-bearing mice) was comparable to or higher than from the tumor homogenates, but the rate by blood was only 4% the value of the tumor homogenates. Analogs of a bioadhesive fragment from the laminin α1 chain were prepared by replacing the essential Lys with Dpm(NH[sub 2]) (20) and Dpm(Leu)(NH[sub 2]) (21). Both Dpm-containing peptides were active, although considerably weaker than the corresponding Lys peptides 18 and 19, in a cell attachment assay with human fibrosarcoma HT-1080 cells. [ABSTRACT FROM AUTHOR]

IgA antibodies were analysed in sera and saliva from 40 HIV-1 seropositive individuals. The level of total IgA in serum was elevated according to the progress of the disease. IgA antibodies against p24 and gp160 were detected in the asymptomatic phase of infection. However, they declined in the symptomatic phases in contrast with IgG antibodies, interestingly, three patients in the symptomatic phase who showed high levels of IgA antibodies were all in relatively good clinical condition. The IgG and IgA antibodies in saliva declined in the symptomatic phase. The level of IgG anti-p24 antibodies in saliva correlated with that in serum, suggesting that IgG anti-p24 antibodies in saliva originated from those in the scrum. These results indicate that IgA antibodies are regulated independently from IgG antibodies and that the mucosal immune system is impaired early in the symptomatic phase of HIV infection, which starts with mucosal impairment. Detection of TgA antibodies may be useful for prognosis of the disease in HIV-infected individuals. The results indicate also that treatment for the impaired IgA mucosal immune system should be taken into consideration. [ABSTRACT FROM AUTHOR]

In this paper, we characterize a novel human leukocyte antigen ( HLA) DQB1*04:10 allele. [ABSTRACT FROM AUTHOR]

A novel HLA allele, HLA-DQB1*06:51, was identified in a Japanese rheumatoid arthritis patient. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 47-year-old man with HIV infection who was diagnosed with Kaposi's sarcoma and cytomegalovirus through colonoscopy and indigo carmine dye chromoendoscopy.

Purpose: Highly active anti-retroviral therapy (HAART) dramatically improves the prognosis of AIDS patients. However, some patients with opportunistic infections suffer from the hyperreactive inflammation (HRI) following HAART, which sometimes interferes with the continuation of HAART. In order to clarify the mechanism of HRI, we investigated the clinical course of these cases and performed in vitro and in vivo analyses. Materials and methods: AIDS patients with active opportunistic infections including miliary tuberculosis, Mycobacterium avium complex (MAC) bacteraemia, Pneumocystis carinii pneumonia (PCP), disseminated cryptococcosis were included in the present study. We started HAART after treatment of these opportunistic infections. Blood and clinical samples were obtained from infective sites to make the definitive diagnosis and to prove HRI. Peripheral blood mononuclear cells (PBMC) obtained and stored sequentially during lymphadenitis due to Mycobacterium tuberculosis were stimulated with purified protein derivative (PPD) in vitro and measured lymphocyte proliferation and cytokine production. Results and conclusions: Hyperreactive inflammation occurred 3 weeks on average after starting HAART in most patients who had these opportunistic infections. Discrimination between HRI and deterioration of the infection was sometimes very difficult. If we were able diagnose HRI, we treated the patients with corticosteroid to mitigate HRI. Two-thirds of the patients continued HAART, but the remaining cases had to have HAART suspended due to severe reactions including fever (> 40°C) and pain of lymphadenitis. In vitro study with the PPD stimulation revealed that proliferating lymphocytes existed in peripheral blood and γ-interferon was produced from such PBMC. These results might support the fact that the infective site must have the much stronger reaction to the opportunistic pathogen. If it was true, use of steroids makes sense to control the reaction. Actually, treatment with the steroid to HRI is successful. However, how to use the steroid (e.g. how much dose and how long) is to be elucidated from future clinical observations. Acknowledgements: The following doctors are acknowledged for their contribution to this study: M. Tanaka, C. Yasuoka, Y. Takahashi, S. Ida, N. Tachikawa, Y. Kikuchi, A. Yasuoka, and Y. Hirabayashi. This study was supported by a grant for AIDS Research from the Ministry of Health and Welfare of Japan. [ABSTRACT FROM AUTHOR]