Control of HIV-1 Replication by CD8+ T Cells Specific for Two Novel Pol Protective Epitopes in HIV-1 Subtype A/E Infection.

Although many HIV-1-specific CD8+ T cell epitopes have been identified and used in various HIV-1 studies, most of these epitopes were derived from HIV-1 subtypes B and C. Only 17 well-defined epitopes, none of which were protective, have been identified for subtype A/E infection. The roles of HIV-1-specific T cells have been rarely analyzed for subtype A/E infection. In this study, we identified six novel HLA-B*15:02-restricted optimal HIV-1 subtype A/E epitopes and then analyzed the presentation of these epitopes by HIV-1 subtype A/E virus-infected cells and the T cell responses to these epitopes in treatment-naive HIV-1 subtype A/E-infected HLA-B*15:02+ Vietnamese individuals. Responders to the PolTY9 or PolLF10 epitope had a significantly lower plasma viral load (pVL) than nonresponders among HLA-B*15:02+ individuals, whereas no significant difference in pVL was found between responders to four other epitopes and nonresponders. The breadth of T cell responses to these two Pol epitopes correlated inversely with pVL. These findings suggest that HLA-B*15:02-restricted T cells specific for PolTY9 and PolLF10 contribute to the suppression of HIV-1 replication in HLA-B*15:02+ individuals. The HLA-B*15:02-associated mutation Pol266I reduced the recognition of PolTY9-specific T cells in vitro but did not affect HIV-1 replication by PolTY9-specific T cells in Pol266I mutant virus-infected individuals. These findings indicate that PolTY9-specific T cells suppress replication of the Pol266I mutant virus even though the T cells selected this mutant. This study demonstrates the effective role of T cells specific for these Pol epitopes to control circulating viruses in HIV-1 subtype A/E infection. IMPORTANCE It is expected that HIV-1-specific CD8+ T cells that effectively suppress HIV-1 replication will contribute to HIV-1 vaccine development and therapy to achieve an HIV cure. T cells specific for protective epitopes were identified in HIV-1 subtype B and C infections but not in subtype A/E infection, which is epidemic in Southeast Asia. In the present study, we identified six T cell epitopes derived from the subtype A/E virus and demonstrated that T cells specific for two Pol epitopes effectively suppressed HIV-1 replication in treatment-naive Vietnamese individuals infected with HIV-1 subtype A/E. One of these Pol protective epitopes was conserved among circulating viruses, and one escape mutation was accumulated in the other epitope. This mutation did not critically affect HIV-1 control by specific T cells in HIV-1 subtype A/E-infected individuals. This study identified two protective Pol epitopes and characterized them in cases of HIV-1 subtype A/E infection.

Targeted gene disruption of ATP synthases 6-1 and 6-2 in the mitochondrial genome of Arabidopsis thaliana by mitoTALENs.

We recently achieved targeted disruptions of cytoplasmic male sterility (CMS)-associated genes in the mitochondrial genomes of rice and rapeseed by using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs). It was the first report of stable and heritable targeted gene modification of plant mitochondrial genomes. Here, we attempted to use mitoTALENs to disrupt two mitochondrial genes in the model plant Arabidopsis thaliana(Arabidopsis) using three different promoters and two types of TALENs. The targets were the two isoforms of the ATP synthase subunit 6 gene, atp6-1 and atp6-2. Each of these genes was successfully deleted and the mitochondrial genomes were recovered in a homoplasmic state. The nuclear genome also has a copy of atp6-1, and we were able to confirm that it was the mitochondrial gene and not the nuclear pseudogene that was knocked out. Among the three mitoTALEN promoters tried, the RPS5A promoter was the most effective. Conventional mitoTALENs were more effective than single-molecule mito-compactTALENs. Targeted mitochondrial gene deletion was achieved by crossing as well as by floral-dip transformation to introduce the mitoTALEN constructs into the nucleus. The gene disruptions were caused by large (kb-size) deletions. The ends of the remaining sequences were connected to distant loci, mostly by illegitimate homologous recombinations between repeats.

The mediating effect of resilience between family functioning and mental well-being in hemodialysis patients in Japan: a cross-sectional design.

BACKGROUND: End-stage kidney disease is highly prevalent worldwide. Currently, one of the most effective treatment modalities is dialysis therapy, which leads to serious side effects. Furthermore, psychiatric illnesses are prevalent among dialysis patients. Recently, researchers asserted that psychological resilience and family support could be helpful to maintain or improve patients' mental well-being. Therefore, the purpose of this study was to examine the mediating effects of resilience on the relationship between family functioning and mental well-being in these patients. METHODS: To investigate the aim of this study, a cross-sectional design was employed. A total of 110 hemodialysis patients, who were receiving outpatient treatment from dialysis units at the University of Fukuoka and St. Maria Health Care Center in Japan, participated. Only the patients who met the criteria and who were willing to participate in this 30-min study were given The General Health Questionnaire-12, Conner-Davidson Resilience Scale, and Family Assessment Device. Structural Equation Modeling (SEM) was performed to test the hypothesis that resilience would mediate the relationship between each subscale of family functioning, namely, cohesion, adaptability, communication, and mental well-being. Then Sobel's test was employed to examine the indirect effect. RESULTS: The results of the SEM showed that the model had an acceptable fit (RMSEA = .077; CFI = .93; and IFI = .94). According to the results, resilience fully mediated the relationship between family functioning, specifically family adaptability and communication, and mental health well-being of the dialysis patients. However, family cohesion was not associated with resilience. CONCLUSIONS: The present study revealed that higher family adaptability and communication resulted in greater resilience, thus associated with better mental health. Given that poor mental health among dialysis patients is significantly associated with a decreased likelihood to adhere to treatment plans, it may lead to a significant risk to therapeutic compliance. As such, patients may experience detrimental consequences, such as death. This study showed that in order to maintain healthy mental well-being, developing resilience is a vital factor for hemodialysis patients.

HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E.

HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control.IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1 subtype A/E infection which are different from those identified for cohorts infected with HIV-1 subtypes B and C.

The Mediating Effects of Resilience, Morale, and Sense of Coherence Between Physical Activity and Perceived Physical/Mental Health Among Japanese Community-Dwelling Older Adults: A Cross-Sectional Study.

The aim of this study was to examine the mediating effects of resilience, morale, and sense of coherence on the relationship between physical activity and respondents' perceived physical/mental health and depression among community-dwelling older adults in Japan. The study included 369 participants with an average age of 74 years from Kasuishimohara District in Fukuoka Prefecture, Japan. They completed a survey that included the Resilience Scale, the Sense of Coherence Scale, the Medical Outcomes Short Form 8, the Philadelphia Geriatric Center Morale Scale, the Geriatric Depression Scale (Short Form), and a demographic questionnaire. The results of the path mediation analyses revealed that resilience and morale fully mediated the relationship between physical activity and perceived physical/mental health and depression. However, sense of coherence was not a significant mediator. Some intervention programs are suggested to maximize the effects of physical activity on one's well-being. At-risk populations who need such programs are also discussed.

Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes.

UNLABELLED: Identification and characterization of CD8(+) T cells effectively controlling HIV-1 variants are necessary for the development of AIDS vaccines and for studies of AIDS pathogenesis, although such CD8(+) T cells have been only partially identified. In this study, we sought to identify CD8(+) T cells controlling HIV-1 variants in 401 Japanese individuals chronically infected with HIV-1 subtype B, in which protective alleles HLA-B*57 and HLA-B*27 are very rare, by using comprehensive and exhaustive methods. We identified 13 epitope-specific CD8(+) T cells controlling HIV-1 in Japanese individuals, though 9 of these epitopes were not previously reported. The breadths of the T cell responses to the 13 epitopes were inversely associated with plasma viral load (P = 2.2 × 10(-11)) and positively associated with CD4 count (P = 1.2 × 10(-11)), indicating strong synergistic effects of these T cells on HIV-1 control in vivo. Nine of these epitopes were conserved among HIV-1 subtype B-infected individuals, whereas three out of four nonconserved epitopes were cross-recognized by the specific T cells. These findings indicate that these 12 epitopes are strong candidates for antigens for an AIDS vaccine. The present study highlighted a strategy to identify CD8(+) T cells controlling HIV-1 and demonstrated effective control of HIV-1 by those specific for 12 conserved or cross-reactive epitopes. IMPORTANCE: HLA-B*27-restricted and HLA-B*57-restricted cytotoxic T lymphocytes (CTLs) play a key role in controlling HIV-1 in Caucasians and Africans, whereas it is unclear which CTLs control HIV-1 in Asian countries, where HLA-B*57 and HLA-B*27 are very rare. A recent study showed that HLA-B*67:01 and HLA-B*52:01-C*12:02 haplotypes were protective alleles in Japanese individuals, but it is unknown whether CTLs restricted by these alleles control HIV-1. In this study, we identified 13 CTLs controlling HIV-1 in Japan by using comprehensive and exhaustive methods. They included 5 HLA-B*52:01-restricted and 3 HLA-B*67:01-restricted CTLs, suggesting that these CTLs play a predominant role in HIV-1 control. The 13 CTLs showed synergistic effects on HIV-1 control. Twelve out of these 13 epitopes were recognized as conserved or cross-recognized ones. These findings strongly suggest that these 12 epitopes are candidates for antigens for AIDS vaccines.

[A Retrospective Analysis of Epiphora Due to Docetaxel].

Docetaxel is an antineoplastic agent used to treat breast cancer and several other types of cancer. Typical adverse drug reactions with docetaxel include myelosuppression and edema, but there have also been numerous reports of eye disorders, such as epiphora and lacrimal duct obstruction. Reports from Japan on such reactions, however, are limited; the duration and frequency of their appearance and other factors have not been elucidated. Since this information would be useful in routine medical practice, we conducted a retrospective analysis of epiphora due to docetaxel. Of the 48 breast cancer patients who commenced new 3-weekly docetaxel dosage regimens during the study period, 6 (12.5%) presented with epiphora. The patients with epiphora were receiving docetaxel at a significantly greater dose intensity (mg/m 2/3 weeks) than those in whom epiphora did not present (72.7 vs 67.1, p=0.0427). The timing of the reaction had no fixed pattern, and the symptoms were reversible in all cases, recorded as Grade 1 or 2. Thus, epiphora due to docetaxel during a 3-weekly dosage regimen presented rather frequently in Japanese patients, and the symptoms were reversible and mild. We found that greater dose intensity might be a risk factor for epiphora. More detailed studies that include data from a large number of facilities should be conducted in the future.

Host-specific adaptation of HIV-1 subtype B in the Japanese population.

UNLABELLED: The extent to which HIV-1 clade B strains exhibit population-specific adaptations to host HLA alleles remains incompletely known, in part due to incomplete characterization of HLA-associated HIV-1 polymorphisms (HLA-APs) in different global populations. Moreover, it remains unknown to what extent the same HLA alleles may drive significantly different escape pathways across populations. As the Japanese population exhibits distinctive HLA class I allele distributions, comparative analysis of HLA-APs between HIV-1 clade B-infected Japanese and non-Asian cohorts could shed light on these questions. However, HLA-APs remain incompletely mapped in Japan. In a cohort of 430 treatment-naive Japanese with chronic HIV-1 clade B infection, we identified 284 HLA-APs in Gag, Pol, and Nef using phylogenetically corrected methods. The number of HLA-associated substitutions in Pol, notably those restricted by HLA-B*52:01, was weakly inversely correlated with the plasma viral load (pVL), suggesting that the transmission and persistence of B*52:01-driven Pol mutations could modulate the pVL. Differential selection of HLA-APs between HLA subtype members, including those differing only with respect to substitutions outside the peptide-binding groove, was observed, meriting further investigation as to their mechanisms of selection. Notably, two-thirds of HLA-APs identified in Japan had not been reported in previous studies of predominantly Caucasian cohorts and were attributable to HLA alleles unique to, or enriched in, Japan. We also identified 71 cases where the same HLA allele drove significantly different escape pathways in Japan versus predominantly Caucasian cohorts. Our results underscore the distinct global evolution of HIV-1 clade B as a result of host population-specific cellular immune pressures. IMPORTANCE: Cytotoxic T lymphocyte (CTL) escape mutations in HIV-1 are broadly predictable based on the HLA class I alleles expressed by the host. Because HLA allele distributions differ among worldwide populations, the pattern and diversity of HLA-associated escape mutations are likely to be somewhat distinct to each race and region. HLA-associated polymorphisms (HLA-APs) in HIV-1 have previously been identified at the population level in European, North American, Australian, and African cohorts; however, large-scale analyses of HIV-1 clade B-specific HLA-APs in Asians are lacking. Differential intraclade HIV-1 adaptation to global populations can be investigated via comparative analyses of HLA-associated polymorphisms across ethnic groups, but such studies are rare. Here, we identify HLA-APs in a large Japanese HIV-1 clade B cohort using phylogenetically informed methods and observe that the majority of them had not been previously characterized in predominantly Caucasian populations. The results highlight HIV's unique adaptation to cellular immune pressures imposed by different global populations.

[A Retrospective Analysis of Eye Disorders Due to Oxaliplatin].

In recent years, the incidence of eye disorders due to antineoplastic agents such as S-1 has increased. Eye disorders including visual field defect, visual field impairment, optic neuritis, and visual acuity reduction have been reported as serious adverse effects of oxaliplatin, an agent that is frequently used as a standard therapy for colorectal cancer. However, specific details about these conditions, such as the timing relative to oxaliplatin administration and frequencies at which they appear, remain to be clarified; therefore, we conducted a retrospective analysis of patients with eye disorders due to oxaliplatin in order to obtain evidence that would be useful in routine medical practice. Of the 55 patients who were treated with oxaliplatin in this analysis 10 (18.2%) presented with eye disorders, including blepharoptosis (5 patients, 9.1%), visual field impairment (2 patients, 3.6%), visual acuity reduction (2 patients, 3.6%), eye pain (1 patient, 1.8%), congestion (1 patient, 1.8%), watering eyes (1 patient, 1.8%), and blurred vision (1 patient, 1.8%). These symptoms appeared during the early period of treatment, such as after the first or the second dose. We found that all patients had mild symptoms (Grade 1 or 2), and most improved spontaneously. Thus, eye disorders due to oxaliplatin affect Japanese patients somewhat frequently, although the symptoms are reversible and are mild in most cases. Detailed studies that include data from a larger number of facilities should be conducted in the future.

[A case of lacrimal duct obstruction caused by capecitabine].

In recent years, the incidence of adverse ocular reactions, including corneal problems and lacrimal duct obstruction, due to antineoplastic agents such as S-1 has increased. Very few reports of adverse ocular reactions caused by capecitabine, a fluorinated pyrimidine antineoplastic agent like S-1, exist, and consequently, the mechanism underlying these reactions is not well understood. This report describes our recent experience with a case of lacrimal duct obstruction caused by capecitabine. The patient was a 71-year-old woman who was being administered trastuzumab plus capecitabine combination chemotherapy for breast cancer-related bone metastasis. She complained of epiphora 7 days after capecitabine was initiated. Thereafter, her capecitabine dose was reduced owing to exacerbation of hand-foot syndrome, but the epiphora persisted. Capecitabine was discontinued 287 days after initiation owing to exacerbation of the hand-foot syndrome. However, because the epiphora persisted, the patient visited the ophthalmology department. The ophthalmologist diagnosed the patient with binocular nasolacrimal duct obstruction and cataract, and prescribed a 0.3% gatifloxacin ophthalmic solution and 0.1% fluorometholone ophthalmic suspension. Thereafter, the epiphora reduced. When the patient returned to the ophthalmology department, symptom improvement was confirmed. In this case, lacrimal duct obstruction likely developed due to capecitabine. The symptoms were reversible with discontinuation of capecitabine and ophthalmic treatment. We believe that reporting this case could be valuable in discussing capecitabine-induced lacrimal duct obstruction.

Selection and accumulation of an HIV-1 escape mutant by three types of HIV-1-specific cytotoxic T lymphocytes recognizing wild-type and/or escape mutant epitopes.

It is known that cytotoxic T lymphocytes (CTLs) recognizing HIV-1 escape mutants are elicited in HIV-1-infected individuals, but their role in the control of HIV-1 replication remains unclear. We investigated the antiviral ability of CTLs recognizing the HLA-A*24:02-restricted Gag28 -36 (KYKLKHIVW) epitope and/or its escape mutant (KYRLKHIVW) elicited in the early and chronic phases of the infection. Wild-type (WT)-epitope-specific CTLs, as well as cross-reactive CTLs recognizing both WT and K30R (3R) epitopes, which were predominantly elicited at early and/or chronic phases in HLA-A*24:02(+) individuals infected with the WT virus, suppressed the replication of the WT virus but failed to suppress that of the 3R virus, indicating that the 3R virus was selected by these 2 types of CTLs. On the other hand, cross-reactive and 3R-specific CTLs, which were elicited in those infected with the 3R virus, did not suppress the replication of either WT or 3R virus, indicating that these CTLs did not contribute to the control of 3R virus replication. High accumulation of the 3R mutation was found in a Japanese population recently recruited. The selection and accumulation of this 3R mutation resulted from the antiviral ability of these Gag28-specific CTLs and high prevalence of HLA-A*24:02 in a Japanese population. The present study highlighted the mechanisms for the roles of cross-reactive and mutant-epitope-specific CTLs, as well as high accumulation of escape mutants, in an HIV-1-infected population.

[A case of hepatitis B virus reactivation in a patient with prior resolved hepatitis B infection during bevacizumab plus FOLFIRI treatment].

Hepatitis Bvirus (HBV)reactivation induced by cancer chemotherapy is increasingly being observed. However, most reports of resolved HBV[hepatitis Bsurface antigen(HBs-Ag)negative and hepatitis Bsurface antibody(HBs-Ab)positive and/or hepatitis Bcore antibody(HBc-Ab)positive]infection involve patients with hematological malignancies, whereas few describe patients with solid cancers. In this study, we report our experience with a patient with resolved HBV infection who was undergoing bevacizumab plus FOLFIRI treatment for rectal cancer when HBV reactivation was noted. This 74-year-old man was HBs-Ag negative, HBs-Ab negative, HBcAb positive, hepatitis B e antigen(HBe-Ag)negative, and hepatitis Be antibody(HBe-Ab)negative and had HBV-DNA levels below the detection limit. Forty-two days after the 21st cycle of bevacizumab plus FOLFIRI treatment, his aspartate aminotransferase and alanine aminotransferase levels increased. At followup examination, he was HBs-Ag positive, HBs-Ab negative, HBc-Ab positive, HBe-Ag positive, and HBe-Ab positive, while his HBV-DNA levels had increased to>9.0 log copies/mL, confirming HBV reactivation. His treatment included entecavir(0.5mg/ day)administration and plasmapheresis, but he succumbed to liver failure 82 days after his final dose of bevacizumab plus FOLFIRI. Thus, HBV reactivation can occur during bevacizumab plus FOLFIRI treatment in rectal cancer patients with a resolved prior HBV infection. No similar report has been published to date, and we believe that this study will be important when discussing HBV reactivation in patients with resolved HBV infection. Future studies will require detailed investigations in a larger number of institutions.

Selection of escape mutant by HLA-C-restricted HIV-1 Pol-specific cytotoxic T lymphocytes carrying strong ability to suppress HIV-1 replication.

HIV-1 mutants escaping from HLA-A- or HLA-B-restricted CTL have been well studied, but those from HLA-C-restricted CTL have not. Therefore we investigated the ability of HLA-C-restricted CTL to select HIV-1 escape mutants. In the present study, we identified two novel HLA-Cw(*) 1202-restricted Pol-specific CTL epitopes (Pol328-9 and Pol463-10). CTL specific for these epitopes were detected in 25-40% of chronically HIV-1-infected HLA-Cw(*) 1202(+) individuals and had strong abilities to kill HIV-1-infected cells and to suppress HIV-1 replication in vitro, suggesting that these CTL may have the ability to effectively control HIV-1 in some HLA-Cw(*) 1202(+) individuals. Sequence analysis of these epitopes showed that a V-to-A substitution at the 9th position (V9A) of Pol 463-10 was significantly associated with the HLA-Cw(*) 1202 allele and that the V9A mutant was slowly selected in the HLA-Cw(*) 1202(+) individuals. Pol 463-10-specific CTL failed both to kill the V9A virus-infected cells and to suppress replication of the V9A mutant. These results indicate that the V9A mutation was selected as an escape mutant by the Pol463-10-specific CTL. The present study strongly suggests that some HLA-C-restricted CTL have a strong ability to suppress HIV-1 replication so that they can select HIV escape mutants as in the case of HLA-A-restricted or HLA-B-restricted CTL.

Targeted base editing in the plastid genome of Arabidopsis thaliana.

Bacterial cytidine deaminase fused to the DNA binding domains of transcription activator-like effector nucleases was recently reported to transiently substitute a targeted C to a T in mitochondrial DNA of mammalian cultured cells1. We applied this system to targeted base editing in the Arabidopsis thaliana plastid genome. The targeted Cs were homoplasmically substituted to Ts in some plantlets of the T1 generation and the mutations were inherited by their offspring independently of their nuclear-introduced vectors.

Systematic gene regulation involving miRNAs during neuronal differentiation of mouse P19 embryonic carcinoma cell.

MicroRNAs (miRNAs) are small noncoding RNA and play an essential role in gene regulation. In this study, we investigated regulation of gene expression during neuronal differentiation of mouse P19 embryonic carcinoma cells and described a systematic pathway of gene regulation involving miRNAs. In the pathway, downregulation of Lin28 involved in blocking the let-7 maturation and upregulation of let-7 occur following induction of the differentiation, thereby triggering suppression of the downstream High Mobility Group A2 (Hmga2) gene expression via activation of gene silencing mediated by let-7. Our data further suggest that miR-9, as well as miR-125b, participate in the reduction of the Lin28 expression. The gene regulation involving miRNAs likely contributes to a rapid and programmed change in gene expression in neuronal differentiation of P19 cells.

Variation of gene silencing involving endogenous microRNA in mammalian cells.

MicroRNAs (miRNAs) are small noncoding RNA and play a role in gene expression regulation by inhibiting translation of their target messenger RNAs (mRNAs). In this study, we investigated the effects of endogenous let-7 miRNA on the expression of target genes in various mammalian cells by means of two types of reporter plasmids possessing target sequences for let-7: one carries perfectly matched target sequence for let-7 in the 3'-untranslated region of the luciferase reporter gene to monitor RNA interference (RNAi) activity and the other has three bulged binding sites for let-7 to monitor translation-inhibition activity. The results indicate that different cells have different levels of gene silencing against the target reporter genes. The data presented here suggest that not only microRNA level but also target transcript level likely participate in the generation of a variety of gene silencing.

Islet cell transplantation for the treatment of type 1 diabetes in the USA.

Islet cell transplantation (ICTx) is one of the most effective treatments for type 1 diabetes and is less invasive compared to whole organ transplantation. The US has been the leader in the research and clinical applications of ICTx for the last 40 years. ICTx requires complex procedures, including pancreas procurement and preservation; pancreas digestion; islet purification; and transplantation. Even with the dramatic progresses in each of the procedures listed above, there are still challenges to make ICTx the standard therapy. These challenges are: (1) obtaining enough islets from a single donor and (2) preventing graft loss due to allogenic rejection and recurrence of autoimmune islet destruction. A new preservation strategy for pancreata and pancreatic ducts using ET-Kyoto solution as well as a new islet purification method using iodixanol has substantially improved islet yields. Continuous research to improve the efficacy of islet isolation will solve the issue of obtaining enough islets from a single donor. Immunological tolerance is an ideal solution for the issue of rejection and autoimmune recurrence and a regulatory T cell strategy seems promising. Moreover, the SUITO index is a simple and powerful tool to assess engrafted islet mass and is, therefore, useful for evaluating the efficacy of new immunosuppressant strategies. Once ICTx becomes a standard treatment, the donor shortage will become the next challenge. Marginal or living donor islet transplantations could help alleviate this issue; however, bio-artificial islet transplantation with animal islets could be the ultimate solution.

Effects of a novel method for enteral nutrition infusion involving a viscosity-regulating pectin solution: A multicenter randomized controlled trial.

BACKGROUND & AIMS: The initial complications associated with infusion of enteral nutrition (EN) for clinical and nutritional care are vomiting, aspiration pneumonia, and diarrhea. There are many recommendations to prevent these complications. A novel method involving a viscosity-regulating pectin solution has been demonstrated. In Japan, this method along with the other so-called "semi-solid EN" approaches has been widely used in practice. However, there has been no randomized clinical trial to prove the efficiency and safety of a viscosity-regulating pectin solution in EN management. Therefore, we planned and initiated a multicenter randomized controlled trial to determine the efficiency and safety. METHODS: This study included 34 patients from 7 medical institutions who participated. Institutional review board (IRB) approval was obtained from all participating institutions. Patients who required EN management were enrolled and randomly assigned to the viscosity regulation of enteral feeding (VREF) group and control group. The VREF group (n = 15) was managed with the addition of a viscosity-regulating pectin solution. The control group (n = 12) was managed with conventional EN administration, usually in a gradual step-up method. Daily clinical symptoms of pneumonia, fever, vomiting, and diarrhea; defecation frequency; and stool form were observed in the 2 week trial period. The dose of EN and duration of infusion were also examined. RESULTS: A favorable trend for clinical symptoms was noticed in the VREF group. No significant differences were observed in episodes of pneumonia, fever, vomiting, and diarrhea between the 2 groups. An apparent reduction in infusion duration and hardening of stool form were noted in the VREF group. CONCLUSIONS: The novel method involving a viscosity-regulating pectin solution with EN administration can be clinically performed safely and efficiently, similar to the conventional method. Moreover, there were benefits, such as improvement in stool form, a short time for EN infusion, and a reduction in vomiting episodes, with the use of the novel method. This indicates some potential advantages in the quality of life among patients receiving this novel method.

A strong association of human leukocyte antigen-associated Pol and Gag mutations with clinical parameters in HIV-1 subtype A/E infection.

OBJECTIVES: Identification of human leukocyte antigen-associated HIV-1 polymorphisms (HLA-APs) in different global populations furthers our understanding of HIV-1 pathogenesis and may help identify candidate immunogens for HIV vaccines targeted to these populations. Although numerous population-based studies identifying HLA-APs have been conducted in HIV-1 subtype B- and subtype C-infected cohorts, few have focused on subtype A/E. DESIGN: We investigated HLA-APs in a cohort of chronically HIV-1 subtype A/E-infected Vietnamese individuals. METHODS: HLA-APs in HIV-1 Gag, Pol, and Nef regions from 388 treatment-naive individuals chronically infected with HIV-1 subtype A/E were analyzed using phylogenetically informed approaches. RESULTS: A total of 303 HLA-APs were identified. HLA-APs occurring at six positions in Gag and six positions in Pol were significantly associated with higher plasma viral load (pVL), whereas HLA-APs occurring at two positions in Gag and 13 positions in Pol were significantly associated with lower CD4 T-cell counts. Furthermore, the proportion of Pol codons harboring an HLA-AP specific to the host's HLA correlated positively with HIV-1 pVL (R = 0.22; P < 0.0001) and inversely with CD4 T-cell counts (R = -0.32; P < 0.0001). Similarly, the proportion of HLA-associated Gag codons harboring host-specific HLA-AP correlated inversely with CD4 T-cell counts (R = -0.13; P = 0.01). CONCLUSION: These significant associations between HIV-1 amino acids adapted to Vietnamese HLA alleles and higher pVL and lower CD4 T-cell counts suggests that accumulation of cytotoxic T cells escape mutations may influence clinical outcomes in HIV-1 subtype A/E-infected Vietnamese individuals.

Association study of the chemokine, CXC motif, ligand 1 (CXCL1) gene with sporadic Alzheimer's disease in a Japanese population.

Inflammation is profoundly involved in the development of Alzheimer's disease (AD) and other neurodegenerative diseases. Chemokine, CXC motif, ligand 1 (CXCL1; or GRO1) is an inflammatory cytokine and appears to be implicated in the pathogenesis of AD. It is of interest and importance to see if the CXCL1 gene, mapped on chromosome 4q12-q13, has potential for conferring the predisposition to AD. Here we report on an association study of the CXCL1 gene with sporadic AD patients in a Japanese population; three single nucleotide polymorphisms (SNPs) in the CXCL1 locus were investigated in 103 AD patients and 130 healthy individuals. The results indicate that neither genotype frequencies nor allele frequencies of the examined SNPs attained statistical significance even after being stratified by the presence or absence of the Apolipoprotein E epsilon4 allele. Therefore, the data presented here suggests that the CXCL1 gene could not be associated with the susceptibility to AD in a Japanese population.