Multidimensional spectroscopy of magneto-excitons at high magnetic fields.

We perform two-dimensional Fourier transform spectroscopy on magneto-excitons in GaAs at magnetic fields and observe Zeeman splitting of the excitons. The Zeeman components are clearly resolved as separate peaks due to the two-dimensional nature of the spectra, leading to a more accurate measurement of the Zeeman splitting and the Landé g factors. Quantum coherent coupling between Zeeman components is observed using polarization dependent one-quantum two-dimensional spectroscopy. We use two-quantum two-dimensional spectroscopy to investigate higher four-particle correlations at high magnetic fields and reveal the role of the Zeeman splitting on the two-quantum transitions. The experimental two-dimensional spectra are simulated using the optical Bloch equations, where many-body effects are included phenomenologically.

Optical Coherence in Atomic-Monolayer Transition-Metal Dichalcogenides Limited by Electron-Phonon Interactions.

We systematically investigate the excitonic dephasing of three representative transition-metal dichalcogenides, namely, MoS_{2}, MoSe_{2}, and WSe_{2} atomic monolayer thick and bulk crystals, in order to gain a proper understanding of the factors that determine the optical coherence in these materials. Coherent nonlinear optical spectroscopy and temperature dependent absorption, combined with theoretical calculations of the phonon spectra, indicate electron-phonon interactions, to be the limiting factor. Surprisingly, the excitonic dephasing, differs only slightly between atomic monolayers and high quality bulk crystals, which indicates that material imperfections are not the limiting factor in atomically thin monolayer samples. The temperature dependence of the electronic band gap and the excitonic linewidth combined with "ab initio" calculations of the phonon energies and the phonon density of states reveal a strong interaction with the E' and E" phonon modes.

Strong Quantum Coherence between Fermi Liquid Mahan Excitons.

In modulation doped quantum wells, the excitons are formed as a result of the interactions of the charged holes with the electrons at the Fermi edge in the conduction band, leading to the so-called "Mahan excitons." The binding energy of Mahan excitons is expected to be greatly reduced and any quantum coherence destroyed as a result of the screening and electron-electron interactions. Surprisingly, we observe strong quantum coherence between the heavy hole and light hole excitons. Such correlations are revealed by the dominating cross-diagonal peaks in both one-quantum and two-quantum two-dimensional Fourier transform spectra. Theoretical simulations based on the optical Bloch equations where many-body effects are included phenomenologically reproduce well the experimental spectra. Time-dependent density functional theory calculations provide insight into the underlying physics and attribute the observed strong quantum coherence to a significantly reduced screening length and collective excitations of the many-electron system.

Biexciton formation and exciton coherent coupling in layered GaSe.

Nonlinear two-dimensional Fourier transform (2DFT) and linear absorption spectroscopy are used to study the electronic structure and optical properties of excitons in the layered semiconductor GaSe. At the 1s exciton resonance, two peaks are identified in the absorption spectra, which are assigned to splitting of the exciton ground state into the triplet and singlet states. 2DFT spectra acquired for co-linear polarization of the excitation pulses feature an additional peak originating from coherent energy transfer between the singlet and triplet. At cross-linear polarization of the excitation pulses, the 2DFT spectra expose a new peak likely originating from bound biexcitons. The polarization dependent 2DFT spectra are well reproduced by simulations using the optical Bloch equations for a four level system, where many-body effects are included phenomenologically. Although biexciton effects are thought to be strong in this material, only moderate contributions from bound biexciton creation can be observed. The biexciton binding energy of ∼2 meV was estimated from the separation of the peaks in the 2DFT spectra. Temperature dependent absorption and 2DFT measurements, combined with "ab initio" theoretical calculations of the phonon spectra, indicate strong interaction with the A1 (') phonon mode. Excitation density dependent 2DFT measurements reveal excitation induced dephasing and provide a lower limit for the homogeneous linewidth of the excitons in the present GaSe crystal.

Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match.

Manifestations of and risk factors for graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age, 37 years) who underwent transplantation for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor/mycophenolate mofetil immunosuppression. Incidence of day 180 grades II to IV and III to IV acute GVHD (aGVHD) were 53% (95% confidence interval, 44 to 62) and 23% (95% confidence interval, 15 to 31), respectively, with a median onset of 40 days (range, 14 to 169). Eighty percent of patients with grades II to IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD, with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome. Late GVHD in the form of classic chronic GVHD was uncommon. Notably, grades III to IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A, -B, -DRB1 allele match was >4/6 to the recipient (hazard ratio, 0.385; P = .031), whereas engrafting unit infused nucleated cell dose and unit-to-unit HLA match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, and had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

Molecular biomarkers for assessing the heat-adapted phenotype: a narrative scoping review.

Heat acclimation/acclimatisation (HA) mitigates heat-related decrements in physical capacity and heat-illness risk and is a widely advocated countermeasure for individuals operating in hot environments. The efficacy of HA is typically quantified by assessing the thermo-physiological responses to a standard heat acclimation state test (i.e. physiological biomarkers), but this can be logistically challenging, time consuming, and expensive. A valid molecular biomarker of HA would enable evaluation of the heat-adapted state through the sampling and assessment of a biological medium. This narrative review examines candidate molecular biomarkers of HA, highlighting the poor sensitivity and specificity of these candidates and identifying the current lack of a single 'standout' biomarker. It concludes by considering the potential of multivariable approaches that provide information about a range of physiological systems, identifying a number of challenges that must be overcome to develop a valid molecular biomarker of the heat-adapted state, and highlighting future research opportunities.

An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis.

A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.

Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract.

Local mucosal cellular immunity is critical in providing protection from HSV-2. To characterize and quantify HSV-2-reactive mucosal T cells, lymphocytes were isolated from endocervical cytobrush and biopsy specimens from 17 HSV-2-infected women and examined ex vivo for the expression of markers associated with maturation and tissue residency and for functional T-cell responses to HSV-2. Compared with their circulating counterparts, cervix-derived CD4+ and CD8+ T cells were predominantly effector memory T cells (CCR7-/CD45RA-) and the majority expressed CD69, a marker of tissue residency. Co-expression of CD103, another marker of tissue residency, was highest on cervix-derived CD8+ T cells. Functional HSV-2 reactive CD4+ and CD8+ T-cell responses were detected in cervical samples and a median of 17% co-expressed CD103. HSV-2-reactive CD4+ T cells co-expressed IL-2 and were significantly enriched in the cervix compared with blood. This first direct ex vivo documentation of local enrichment of HSV-2-reactive T cells in the human female genital mucosa is consistent with the presence of antigen-specific tissue-resident memory T cells. Ex vivo analysis of these T cells may uncover tissue-specific mechanisms of local control of HSV-2 to assist the development of vaccine strategies that target protective T cells to sites of HSV-2 infection.

Persistence of mucosal T-cell responses to herpes simplex virus type 2 in the female genital tract.

Relatively little is known about the human T-cell response to herpes simplex virus type 2 (HSV-2) in the female genital tract, a major site of heterosexual HSV-2 acquisition, transmission, and reactivation. In order to understand the role of local mucosal immunity in HSV-2 infection, T-cell lines were expanded from serial cervical cytobrush samples from 30 HSV-2-infected women and examined for reactivity to HSV-2. Approximately 3% of the CD3+ T cells isolated from the cervix were HSV-2 specific and of these, a median of 91.3% were CD4+, whereas a median of 3.9% were CD8+. HSV-2-specific CD4+ T cells expanded from the cervix were not only more frequent than CD8+ T cells but also exhibited greater breadth in terms of antigenic reactivity. T cells directed at the same HSV-2 protein were often detected in serial cervical cytobrush samples and in blood. Thus, broad and persistent mucosal T-cell responses to HSV-2 were detected in the female genital tract of HSV-2+ women suggesting that these cells are resident at the site of HSV-2 infection. Understanding the role of these T cells at this biologically relevant site will be central to the elucidation of adaptive immune mechanisms involved in controlling HSV-2 disease.

The feasibility of HIV-1 vaccine efficacy trials among gay/bisexual men in New York City: Project ACHIEVE. AIDS Community Health Initiative Enroute to the Vaccine EFfort.

OBJECTIVE: Candidate populations for HIV-1 vaccine efficacy trials need to be at high risk of infection, adhere to study protocols and be willing to participate. The goal of Project ACHIEVE is to collect baseline data needed in order to prepare for vaccine efficacy trials among gay/bisexual men in New York City. DESIGN AND METHODS: HIV-1 antibody-negative men were recruited into a cohort study with follow-up visits every 3 months (n = 622). Frequency of high-risk behaviors and incidence of HIV-1 seroconversion were measured. RESULTS: Of 544 men reporting having had at least one partner in the previous 3 months who was HIV-1 antibody-positive or of unknown status at baseline, 49% reported receptive anal sex encounters. Thirty-two per cent of these men reported the highest risk behavior, unprotected receptive anal sex. The follow-up rate at 12 months was 81%. The incidence rate of infection was 2.9 per 100 person-years (95% confidence interval: 1.7, 4.9). During follow-up, declines were observed in the proportion of men with an HIV-1 antibody-positive partner and the proportion reporting unprotected receptive or insertive anal sex. HIV-1 infection rates declined from 4.3 per 100 person-years in the first 6 months to 1.6 per 100 person-years by the 12-month visit. CONCLUSIONS: Gay/bisexual men in New York City are still placing themselves at risk of HIV-1 infection and may be a suitable population for future vaccine trials. Continued follow-up is needed to further define the incidence over time, especially for the period after the initial 3 to 6 months when vaccines are most likely to be effective. Immediate prevention efforts need to target this population more effectively.

Physiological implications of microbial digestion in the large intestine of mammals: relation to dietary factors.

The rate of digesta marker passage through the large intestine of the dog, pig, and pony correlated with the relative length and degree of sacculation of the colon. Volatile fatty acids (VFA), the end products of microbial digestion of all forms of carbohydrate, were the major anions present in large intestinal contents of all three species. Total VFA concentration was little affected by the feeding of high-versus low-fiber diets. VFA were rapidly transported across colonic mucosa of all three species. Results of comparative studies indicate that production and absorption of VFA are important to the nutrition of some mammals and to the normal secretory and absorptive functions of the large intestine of most mammals.

Prospects for control of hepatitis B virus infection: implications of childhood vaccination and long-term protection.

Hepatitis B vaccine has been recommended for high-risk individuals in the United States for more than a decade. This targeted strategy, however, has failed to control hepatitis B virus (HBV) infection. Universal immunization is being considered as an alternative approach, in particular the inclusion of hepatitis B vaccine with routine childhood vaccinations. Data presented herein demonstrate a high degree of efficacy for hepatitis vaccine with hepatitis B immune globulin in preventing perinatal HBV infection in newborns. Immune response to vaccine was dependent in part on the dose administered, with some enhancement of response if the infant was older at the time of initial injection or if the booster dose was given later. Long-term follow-up showed persistence of vaccine-induced antibody for 5 to 10 years in 90% of immunized infants and adults. Only 3% to 5% of these high-risk individuals had serologic evidence of an HBV infection. None of the infections had been symptomatic and none resulted in a chronic HBV carrier state. Thus, immune responses and efficacy of hepatitis B vaccine in infants were excellent, and immunity and protection against clinically significant HBV infection persisted for at least 5 to 10 years, features essential to success of a program of universal childhood immunization against HBV.

Search for epitope-specific antibody responses to the human immunodeficiency virus (HIV-1) envelope glycoproteins signifying resistance to disease development.

It is essential for the development of strategies for prevention and therapy of human immunodeficiency virus (HIV-1) infections to define host factors playing a dominant role in determining the clinical outcome of infection. Antibodies directed against restricted regions of the HIV-1 glycoproteins gp120 and gp41 are likely to represent important factors involved in host defense against HIV-1. Definition of qualitative and quantitative differences in the spectrum of anti-gp120 and anti-gp41 antibodies between two vastly different groups of HIV-1-infected individuals, long-term asymptomatic carriers, and individuals with acquired immunodeficiency syndrome (AIDS) who died, might reveal the epitope specificity of antibodies contributing to prevention of clinical disease. To accomplish this goal, sera from both groups were assayed for antibodies recognizing synthetic peptides from gp120/gp41 which were shown in earlier experiments to mimic epitopes on the two HIV-1 glycoproteins. None of the sera recognized all of the distinct 27 peptides from gp120 and gp41. The spectrum of antibodies was distinct for each of the sera from both groups of HIV-1-infected individuals. Nevertheless, antibody responses distinguishing the two groups from each other were discerned. In particular, it was possible to predict the unfavorable outcome of disease by comparative measurements of levels of antibodies to a peptide (303-338), corresponding to the entire V3 hypervariable loop of gp120 and/or by providing evidence for declining levels of these antibodies during the course of infection. Antibodies recognizing additional peptides [(219-245), (280-306), (425-452), (658-682), (729-758), (808-845), and (845-862)] were significantly less prevalent in AIDS patients than in asymptomatic carriers. It appears possible that maintenance of high levels of the respective antibodies would contribute to preventing AIDS in HIV-1-infected individuals. Active immunization with antigens containing epitopes defined by the respective peptides and/or administration of the corresponding antibodies may be considered as a modality for therapy of HIV-1 infections.

Group specific component (Gc) and HIV diseases.

A previous report suggested a relationship between particular phenotypes of group specific component (Gc), and susceptibility or resistance to HIV infection, whereas other recent investigations failed to corroborate this finding. The present study demonstrated that Gc allele frequencies in white homosexual men corresponded to those expected, regardless of HIV serology and related disease. Assignment of phenotype was not influenced by Gc complexing secondary to tissue damage, or the process of infection per se. However, Gc allele frequencies in black patients with AIDS were significantly different from those in black control subjects, suggesting that the previously observed results might be in part explicable on the basis of gene admixture in ethnically mixed populations.

Graft-versus-leukemia-induced complete remission following unrelated umbilical cord blood transplantation for acute leukemia.

A 15-year-old female received an unrelated three of six HLA antigen matched umbilical cord blood (UCB) transplant for refractory, relapsed T-cell ALL. Conditioning consisted of TBI, melphalan, and anti-thymocyte globulin (ATG), with cyclosporin A (CsA) and solumedrol for GVHD prophylaxis. She engrafted and a day 34 bone marrow aspirate showed 100% donor cells and no evidence of leukemia. The post-transplant course was complicated by mild grade I acute GVHD involving skin, and limited chronic GVHD of the gut which resolved with the addition of 1 mg/kg/day of steroids to her CsA prophylaxis. One hundred and ninety days after transplantation the patient developed pancytopenia and was subsequently found to have a leukemic relapse. Immunosuppression was discontinued and she was started on G-CSF and erythropoietin. Moderate skin and gut GVHD developed which was treated with both topical and low-dose oral steroids. Over the next few weeks she became transfusion independent and a follow-up bone marrow aspirate showed complete remission. She continued in complete remission for 4 months, at which time localized leukemic relapse was found in a soft tissue breast mass in spite of continued bone marrow remission. While the patient ultimately died of progressive disease, this case demonstrates that mismatched UCB in conjunction with G-CSF is capable of generating a GVL effect that can induce a complete remission.

Comparison of Southern transfer hybridization and dot filter hybridization for detection of cervical human papillomavirus infection with types 6, 11, 16, 18, 31, 33, and 35.

A commercial dot filter hybridization kit (Virapap Kit) was compared with Southern transfer hybridization for the detection of seven types of human papillomavirus (HPV) in cervical specimens from 450 consecutive females attending a sexually transmitted diseases clinic. In comparison with Southern transfer hybridization, performed with the same probes used in the dot filter kit, the sensitivity, specificity, and positive and negative predictive values of dot filter hybridization were 90%, 94%, 74%, and 98%, respectively. Among patients with cervical cytologic dysplasia, HPV DNA was detected in 44% by dot filter hybridization and in 35% by Southern transfer hybridization. Although 26% of specimens positive by dot filter hybridization were not confirmed by Southern transfer hybridization, cervical dysplasia was detected in 5 (25%) of 20 with HPV DNA detected by dot filter hybridization alone, compared with 25 (8%) of those with no definitive evidence of HPV by either method (P = 0.009) and with 16 (30%) of 53 with HPV DNA detected by both methods (P = 0.7). The kappa statistic for interobserver and intraobserver reproducibility for interpretation of blots was similar for the two methods. The dot filter hybridization method evaluated appears to be a satisfactory alternative to Southern transfer hybridization for detection of HPV DNA.

The inflammatory Papanicolaou smear: what does it mean?

OBJECTIVE: To determine the correlation between inflammation detected on Papanicolaou smear and specific lower genital tract agents, and, based on these findings, to develop recommendations for follow-up tests and treatment of young women with inflammation on smears. METHODS: A high-risk population of 779 randomly selected women attending a sexually transmitted disease (STD) clinic and a low-risk population of 1050 consecutive women presenting for annual examination at a university student health center underwent a standardized history and gynecologic examination. Univariate and multivariate analyses, focusing on the association between dense inflammation on Papanicolaou smear and specific lower genital tract pathogens or findings on cervical examination, were done for each population. RESULTS: Dense inflammation was present on the Papanicolaou smear of 256 (33%) of the 779 women in the STD clinic and 200 (19%) of 1050 students. Dense inflammation on Papanicolaou smear was independently associated with mucopus, cervical ectopy, cervical infection with Neisseria gonorrhoeae, Chlamydia trachomatis, herpes simplex virus (HSV), and vaginal infection by Trichomonas vaginalis in the STD population; in the student population, it was associated with cervical ectopy, C trachomatis, and mucopus. CONCLUSION: Although dense inflammation on Papanicolaou smear was a common finding in both the high- and low-risk populations, about half of the inflammation detected in the high-risk setting was associated with a specific microbial organism (C trachomatis, N gonorrhoeae, HSV, or T vaginalis), whereas less than 10% of the dense inflammation detected in the low-risk setting was linked with a specific pathogen (C trachomatis). In both settings, a substantial population of sexually active women had dense inflammation associated with cervical ectopy but none of the specific organisms evaluated in this study.

Vulvovaginal candidiasis: clinical manifestations, risk factors, management algorithm.

OBJECTIVE: To correlate symptoms, signs, and risk factors with positive wet mounts or cultures for Candida albicans and to develop an algorithm to diagnose vulvovaginal candidiasis. METHODS: This cross-sectional study of 774 randomly selected women from an urban sexually transmitted disease (STD) clinic evaluated symptoms, signs, and risk factors associated with C albicans, detected by wet mount and culture, and constructed an algorithm. RESULTS: C albicans, recovered from 186 (24%) of the 774 women, was associated with chief complaints of vulvar pruritus or burning. Elicited symptoms were vulvar pruritus, pain or burning, and external dysuria; signs were vulvar erythema, edema, fissures, vaginal erythema, and thick, curdy vaginal discharge. Among 545 women with symptoms of either increased vaginal discharge or vulvar pruritus or burning, only 155 (28%) had positive C albicans cultures, whereas bacterial vaginosis or other sexually transmitted infections were found in 288 (53%). In multivariate analysis, risk factors for positive C albicans culture included condom use, presentation after the 14th menstrual cycle day, sexual intercourse more than four times per month, recent antibiotic use, young age, past gonococcal infection, and absence of current gonorrhea or bacterial vaginosis. A clinical algorithm based on symptoms, signs, and selective use of wet mounts and cultures would have provided prompt treatment to 150 of 167 (90%) women with vulvovaginal candidiasis while minimizing the number of cultures performed. CONCLUSION: A simple algorithm using symptoms, signs, wet mounts, and selective cultures can identify 90% of women with vulvovaginal candidiasis. In this STD clinic, vulvovaginal symptoms also require assessment for bacterial vaginosis, trichomoniasis, and cervical infection.

Radioimmunoassay and enzyme-linked immunoassay of antibodies to the core protein (P24) of human T-lymphotropic virus (HTLV III).

Human T-cell lymphotropic viruses designated HTLV III or LAV are considered to represent the causative agent(s) of the acquired immunodeficiency syndrome (AIDS). Individuals who have been infected with these viruses may generally be identified on the basis of a positive serological test for antibodies against the protein components of these viruses. Purified viruses or viral proteins have been utilized for developing such tests. Since AIDS may be transmitted by blood transfusion and by blood products, screening of donors for antibodies to HTLV III/LAV has become a necessity. Such screening may be facilitated by the application of assays based on the use of crude virus-infected tissue culture media avoiding elaborate, expensive and potentially hazardous virus purification steps. Serum specimens were mixed with an appropriate dilution of an HTLV III-infected tissue culture-derived fraction, obtained by precipitation with polyethylene glycol 6000 and treatment with Tween 80 and tri-n-butylphosphate (to disrupt virus particles), and incubated with polystyrene beads coated with antibodies to HTLV III/LAV (anti-HTLV III). Subsequently, washed beads were incubated with either 125I- or beta-lactamase-labeled anti-HTLV III. The radioactivity or enzymatic activity associated with the beads was proportionate to the quantity of HTLV III antigen originally added to the beads. The presence of anti-HTLV III in serum specimens resulted in decreased antigen binding and thus in decreased radioactivity or diminished beta-lactamase activity associated with the beads. The test was specific for antibodies to the approximately equal to 24 kDa core protein of HTLV III. The prevalence of these antibodies (given in parentheses) in distinct populations was as follows: random blood donors (0.33%); hemophiliacs (36.4%); random homosexual males (25.1%); homosexual males preselected on the basis of positive markers for infection with hepatitis B virus (50%); and those with persistent lymphadenopathy (70%).

Radioimmunoassay and enzyme-linked immunoassay of antibodies directed against lymphadenopathy-associated virus (LAV) proteins larger than the core protein (P24).

The acquired immunodeficiency syndrome (AIDS) may be transmitted by blood transfusions and by blood products from donors who have been infected with the lymphadenopathy-associated virus (LAV). Such donors may generally be identified on the basis of a positive test for antibodies-against LAV proteins. We have already described an anti-LAV assay based on the use of crude virus-infected tissue culture medium, which avoids elaborate, expensive and potentially hazardous virus purification steps. This test was operationally specific for antibodies to the approximately 24 kD core protein of the virus (P24; Neurath et al. J. Virol. Methods 11, 75, 1985). Molecular exclusion chromatography of crude LAV antigen preparations allows separation of most of P24 from larger proteins of LAV (PL). PL and 125I- or beta-lactamase-labeled anti-LAV were used as reagents for radioimmunoassay (RIA)--or enzyme-linked immunoassay (ELISA)--inhibition tests to detect antibodies directed predominantly against PL (anti-PL). Among 257 individuals belonging to groups at high risk of developing AIDS, 117 (45.5%) were positive for anti-PL and 108 (42%) for anti-P24, respectively. The 2 individuals among 600 random blood donors found to be anti-P24-positive in the preceding study also had anti-PL in their serum. Sera from 500 additional blood donors were screened for anti-PL and 1 of these was positive. The implication of these findings for screening of blood donors is discussed.