Developing a vaccine for HIV may be aided by a complete understanding of those rare cases where some HIV-infected individuals control replication of the virus1–3. The majority of these elite controllers (ECs) express HLA-B*57 or HLA-B*273. These alleles remain by far the most robust associations with low concentrations of plasma virus4,5, yet the mechanism of control in these individuals is not entirely clear. Here we vaccinated Indian rhesus macaques that express Mamu-B*08, an animal model for HLA-B*27-mediated elite control6, with three Mamu-B*08-restricted CD8+ T cell epitopes and demonstrate that these vaccinated animals controlled replication of the highly pathogenic SIVmac239 clonal virus. High frequencies of CD8+ T cells against these Vif and Nef epitopes in the blood, lymph nodes and colon, were associated with viral control. Moreover, the frequency of the Nef RL10-specific response correlated significantly with reduced acute phase viremia. Finally, two of the eight vaccinees lost control of viral replication in the chronic phase, concomitant with escape in all three targeted epitopes, further implicating these three CD8+ T cell responses in control of viral replication. Our findings indicate that narrowly targeted vaccine-induced virus-specific CD8+ T cell responses can control replication of the AIDS virus.
A small number of HIV-infected individuals known as elite controllers experience low levels of chronic phase viral replication and delayed progression to AIDS. Specific HLA class I alleles are associated with elite control, implicating CD8+ T lymphocytes in the establishment of these low levels of viral replication. Most HIV-infected individuals that express protective HLA class I alleles, however, do not control viral replication. Approximately 50% of Mamu-B*00801+ Indian rhesus macaques control SIVmac239 replication in the chronic phase in a manner that resembles elite control in humans. We followed both the immune response and viral evolution in SIV-infected Mamu-B*00801+ animals to better understand the role of CD8+ T lymphocytes during the acute phase of viral infection, when viral control status is determined. The virus escaped from immunodominant Vif and Nef Mamu-B*00801–restricted CD8+ T lymphocyte responses during the critical early weeks of acute infection only in progressor animals that did not control viral replication. Thus, early CD8+ T lymphocyte escape is a hallmark of Mamu-B*00801+ macaques who do not control viral replication. By contrast, virus in elite controller macaques showed little evidence of variation in epitopes recognized by immunodominant CD8+ T lymphocytes, implying that these cells play a role in viral control.
We compared the psychometric performance of two validated self-report anxiety- symptom measures when rated by people with dementia versus collaterals (as proxies). Forty-one participants with mild-to-moderate dementia and their respective collaterals completed the Geriatric Anxiety Inventory, the Penn State Worry Questionnaire-Abbreviated, and a structured diagnostic interview. We used descriptive and nonparametric statistics to compare scores according to respondent characteristics. Receiver operating characteristic (ROC) curves were calculated to establish the predictive validity of each instrument by rater type against a clinical diagnosis of an anxiety disorder. Participant and collateral ratings performed comparably for both instruments. However, collaterals tended to give more severe symptom ratings, and the best-performing cut-off scores were higher for collaterals. Our findings suggest that people with mild-to-moderate dementia can give reliable self-reports of anxiety symptoms, with validity comparable to reports obtained from collaterals. Scores obtained from multiple informants should be interpreted in context.
worry; anxiety; elders; dementia; self-ratings; proxy ratings
The Pittsburgh Sleep Quality Index (PSQI) is a widely used, comprehensive self-report measure of sleep quality and impairment, which has demonstrated good psychometric properties within various populations, including older adults. However, the psychometric properties of the PSQI and its component scores have not been evaluated for older adults with generalized anxiety disorder (GAD). Additionally, changes in PSQI global or component scores have not been reported following cognitive-behavioral treatment (CBT) of late-life GAD. This study examined (1) the psychometric properties of the PSQI within a sample of 216 elderly primary care patients age 60 or older with GAD who were referred for treatment of worry and/or anxiety; as well as (2) response to CBT, relative to usual care, for 134 patients with principal or coprincipal GAD. The PSQI demonstrated good internal consistency reliability and adequate evidence of construct validity. Those receiving CBT experienced greater reductions in PSQI global scores at post-treatment, relative to those receiving usual care. Further, PSQI global and domain scores pertaining to sleep quality and difficulties falling asleep (i.e., sleep latency and sleep disturbances) demonstrated response to treatment over a 12-month follow-up period. Overall, results highlight the usefulness of the PSQI global and component scores for use in older adults with GAD.
Pittsburgh Sleep Quality Index; psychometrics; generalized anxiety disorder; elderly; cognitive behavioral therapy
We hypothesized that Nox2, the classical phagocytic NADPH oxidase, plays an important role in calcineurin inhibitor (CNI)-induced renal fibrosis. We tested this hypothesis in vitro, in animal and in human studies. Cyclosporine A (CsA) and tacrolimus (TAC) were associated with greater levels of Nox2 mRNA and epithelial to mesenchymal transition (EMT) in NRK52E cells. CsA increased Nox2, α-SMA and phosphorylated-p38MAPK, Smad3, and NFκB proteins. Nox2 upregulation and EMT were inhibited in TGF-β1 knockout cells suggesting that TGF-β1 is required for Nox2 activation. Fisher344 rats treated with high dose CsA showed increased Nox2 in the tubulointerstitium and greater Nox2, α-SMA, phosphorylated Smad3 and nitrotyrosine by immunoblot analyses. Inhibition of Nox2 by coadministration of apocynin or diphenyleneiodonium was associated with reduced fibrogenesis. We validated these findings by treating wild type and Nox2 null (B6.129S-CybbTm1Din/J) mice with high dose CsA. Western blot analyses confirmed the absence of Nox2 and significantly lower levels of α-SMA and 4-hydroxynonenal in CsA-treated knockout mice. These findings were clinically relevant since Nox2 and α-SMA were increased in the tubulointerstitium of kidneys from 15 liver transplant recipients with biopsy-confirmed chronic CsA or TAC nephrotoxicity. In conclusion, specific Nox2 inhibition strategies may improve chronic CNI nephrotoxicity in solid organ transplantation.
CsA; Nox2; Fibrosis; EMT; Oxidative Stress
Virus-specific CD8+ T cells play an important role in controlling HIV/SIV replication. These T cells recognize intracellular pathogen-derived peptides displayed on the cell surface by individual MHC class I molecules. In the SIV-infected rhesus macaque model, five Mamu class I alleles have been thoroughly characterized with regard to peptide binding, and a sixth was shown to be uninvolved. In this study, we describe the peptide binding of Mamu-A1*007:01 (formerly Mamu-A*07), an allele present in roughly 5.08% of Indian-origin rhesus macaques (n=63 of 1240). We determined a preliminary binding motif by eluting and sequencing endogenously bound ligands. Subsequently, we used a positional scanning combinatorial library and panels of single amino acid substitution analogs to further characterize peptide binding of this allele and derive a quantitative motif. Using this motif, we selected and tested 200 peptides derived from SIVmac239 for their capacity to bind Mamu-A1*007:01, 33 were found to bind with an affinity of 500nM or better. We then used PBMC from SIV-infected or vaccinated but uninfected, A1*007:01-positive rhesus macaques in IFN-γ Elispot assays to screen the peptides for T cell reactivity. In all, eleven of the peptides elicited IFN-γ+ T cell responses. Six represent novel A1*007:01-restricted epitopes. Furthermore, both Sanger and ultra-deep pyrosequencing demonstrated the accumulation of amino acid substitutions within four of these six regions, suggestive of selective pressure on the virus by antigen-specific CD8+ T cells. Thus, it appears that Mamu-A1*007:01 presents SIV-derived peptides to antigen-specific CD8+ T cells and is part of the immune response to SIVmac239.
SIV; MHC; Macaque; Epitope; Escape
The Rating Anxiety in Dementia (RAID; Shankar et al, 1999)is a clinical rating scale developed to evaluate anxiety in persons with dementia. This report explores the psychometric properties and clinical utility of a new structured interview format of the RAID (RAID-SI), developed to standardize administration and scoring based on information obtained from the patient, an identified collateral, and rater observation.
The RAID-SI was administered by trained master’s level raters. Participants were 32 persons with dementia who qualified for an anxiety treatment outcome study. Self-report anxiety, depression, and quality of life measures were administered to both the person with dementia and a collateral.
The RAID-SI exhibited adequate internal consistency reliability and inter-rater reliability. There was also some evidence of construct validity as indicated by significant correlations with other measures of patient-reported and collateral-reported anxiety, and non-significant correlations with collateral reports of patient depression and quality of life. Further, RAID-SI scores were significantly higher in persons with an anxiety diagnosis compared to those without an anxiety diagnosis.
There is evidence that the RAID-SI exhibits good reliability and validity in older adults with dementia. The advantage of the structured interview format is increased standardization in administration and scoring, which may be particularly important when RAID raters are not experienced clinicians.
dementia; anxiety; clinical interview; assessment; Rating for Anxiety in Dementia
Morphological changes that occur during kidney injury involve actin skeleton remodeling. Here we tested whether heat shock protein 27 (HSP27), a small stress response protein involved in cytoskeletal remodeling, protects the kidney from tubulointerstitial fibrosis in obstructive nephropathy. Tubular cell HSP27 immunostaining was significantly increased in human kidneys with ureteropelvic junction obstruction; supporting the clinical relevance of our studies. To develop an animal model for mechanistic studies we generated transgenic mice that specifically overexpress human HSP27 in renal tubules, under the kidney androgen-regulated protein promoter, and determined the effects of HSP27 overexpression on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis following unilateral ureteral obstruction. This was associated with decreased fibrogenesis as evidenced by significant declines in phosphorylated p38MAPK, collagen III, α-smooth muscle actin, 4-hydroxynonenal, and reduced trichrome staining following obstruction. Notably, E-cadherin and β-catenin remained at the cell membrane of tubular cells in transgenic mice with an obstructed ureter. Monocyte/macrophage infiltration, however, was not significantly affected in these transgenic mice. Thus, tubular HSP27 inhibits fibrogenesis in obstructive nephropathy. Further studies are needed to determine pathways regulating the interactions between HSP27 and the E-cadherin-β-catenin complex.
It has been suggested that poor immunogenicity may explain the lack of vaccine efficacy in preventing or controlling HIV infection in the Step trial. To investigate this issue we vaccinated eight Indian rhesus macaques with a trivalent replication-incompetent adenovirus serotype 5 vaccine expressing SIV Gag, Pol, and Nef using a regimen similar to that employed in the Step trial. We detected broad vaccine-induced CD8+ (2–7 pool-specific responses) and CD4+ (5–19 pool-specific responses) T-cell responses in IFN-γ ELISPOT assays at one week post-boost using fresh PBMC. However, using cryopreserved cells at one and four weeks post-boost we observed a reduction in both the number and magnitude of most vaccine-induced responses. This demonstrates that the time points and conditions chosen to perform immune assays may influence the observed breadth and frequency of vaccine-induced T-cell responses. To evaluate protective efficacy, we challenged the immunized macaques, along with naïve controls, with repeated, limiting doses of the heterologous swarm isolate SIVsmE660. Vaccination did not significantly affect acquisition or control of virus replication in vaccinees compared to naïve controls. Post-infection we observed an average of only two anamnestic CD8+ T-cell responses per animal, which may not have been sufficiently broad to control heterologous virus replication. While the trivalent vaccine regimen induced relatively broad T-cell responses in rhesus macaques, it failed to protect against infection or control viral replication. Our results are consistent with those observed in the Step trial and indicate that SIV immunization and challenge studies in macaque models of HIV infection can be informative in assessing pre-clinical HIV vaccines.
HIV vaccine; Adenovirus serotype 5; Simian Immunodeficiency Virus; CD8+ T cells; CD4+ T cells; Step trial
APOBEC3 proteins mediate potent antiretroviral activity by hypermutating the retroviral genome during reverse transcription. To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation. However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surfaces of lentivirus-infected cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that these T cell responses may be part of the larger antiretroviral immune response.
CD8+ T Lymphocytes (CTL) can control AIDS virus replication. However, natural selection favoring viral variants that escape CTL recognition is a common feature of both simian immunodeficiency virus (SIV) infection of macaques and HIV infection of humans. Emerging data indicate that CTL directed against alternate reading frame (ARF)-derived epitopes (a.k.a. cryptic epitopes) are important components of the total virus-specific response in SIV and HIV infection but the contributions of these responses during the critical first several weeks of infection have not been determined. We used a focused deep sequencing approach to examine acute phase viral evolution in response to CTL targeting two polypeptides encoded by ARFs of SIVmac239 in SIV-infected rhesus macaques. We report high magnitude CTL responses as early as three weeks post-infection against epitopes within both ARFs, which both overlap the 5′ end of the env gene. Further, mutations accumulated in the epitopes by three to four weeks post infection consistent with viral escape. Interestingly, these mutations largely maintained the primary amino acid sequence of the overlapping Envelope protein. Our data show that high frequency CTL target cryptic epitopes and exert selective pressure on SIV during the acute phase, underscoring the importance of these unique immune responses.
An effective vaccine remains the best solution to stop the spread of human immunodeficiency virus (HIV). Cellular immune responses have been repeatedly associated with control of viral replication and thus may be an important element of the immune response that must be evoked by an efficacious vaccine. Recombinant viral vectors can induce potent T-cell responses. Although several viral vectors have been developed to deliver HIV genes, only a few have been advanced for clinical trials. The live-attenuated yellow fever vaccine virus 17D (YF17D) has many properties that make it an attractive vector for AIDS vaccine regimens. YF17D is well tolerated in humans and vaccination induces robust T-cell responses that persist for years. Additionally, methods to manipulate the YF17D genome have been established, enabling the generation of recombinant (r)YF17D vectors carrying genes from unrelated pathogens. Here, we report the generation of seven new rYF17D viruses expressing fragments of simian immunodeficiency virus (SIV)mac239 Gag, Nef, and Vif. Studies in Indian rhesus macaques demonstrated that these live-attenuated vectors replicated in vivo, but only elicited low levels of SIV-specific cellular responses. Boosting with recombinant Adenovirus type-5 (rAd5) vectors resulted in robust expansion of SIV-specific CD8+ T-cell responses, particularly those targeting Vif. Priming with rYF17D also increased the frequency of CD4+ cellular responses in rYF17D/rAd5-immunized macaques compared to animals that received rAd5 only. The effect of the rYF17D prime on the breadth of SIV-specific T-cell responses was limited and we also found evidence that some rYF17D vectors were more effective than others at priming SIV-specific T-cell responses. Together, our data suggest that YF17D – a clinically relevant vaccine vector – can be used to prime AIDS virus-specific T-cell responses in heterologous prime boost regimens. However, it will be important to optimize rYF17D-based vaccine regimens to ensure maximum delivery of all immunogens in a multivalent vaccine.
Overlap of cognitive and anxiety symptoms (i.e., difficulty concentrating, fatigue, restlessness) contributes to inconsistent, complicated assessment of generalized anxiety disorder (GAD)in persons with dementia.
Anxious dementia patients completed a psychiatric interview, the Penn State Worry Questionnaire-Abbreviated, and the Rating for Anxiety in Dementia scale. Analyses to describe the 43 patients with and without GAD included the Wilcoxon Mann-Whitney two-sample test, Fisher’s exact test. Predictors of GAD diagnosis were identified using logistic regression.
Those with GAD were more likely to be male, have less severe dementia and endorsed more worry, and anxiety compared to patients without GAD. Gender, muscle tension and fatigue differentiated those with GAD from those without GAD.
Although this study is limited by a small sample, it describes clinical characteristics of GAD in dementia, highlighting the importance of muscle tension and fatigue in recognizing GAD in persons with dementia.
Generalized anxiety disorder; dementia; anxiety symptoms; dementia symptoms; differential diagnosis for generalized anxiety disorder/dementia
The goals of a T cell-based vaccine for HIV are to reduce viral peak and setpoint and prevent transmission. While it has been relatively straightforward to induce CD8+ T cell responses against immunodominant T cell epitopes, it has been more difficult to broaden the vaccine-induced CD8+ T cell response against subdominant T cell epitopes. Additionally, vaccine regimens to induce CD4+ T cell responses have been studied only in limited settings. In this study, we sought to elicit CD8+ T cells against subdominant epitopes and CD4+ T cells using various novel and well-established vaccine strategies. We vaccinated three Mamu-A*01+ animals with five Mamu-A*01-restricted subdominant SIV-specific CD8+ T cell epitopes. All three vaccinated animals made high frequency responses against the Mamu-A*01-restricted Env TL9 epitope with one animal making a low frequency CD8+ T cell response against the Pol LV10 epitope. We also induced SIV-specific CD4+ T cells against several MHC class II DRBw*606-restricted epitopes. Electroporated DNA with pIL-12 followed by a rAd5 boost was the most immunogenic vaccine strategy. We induced responses against all three Mamu-DRB*w606-restricted CD4 epitopes in the vaccine after the DNA prime. Ad5 vaccination further boosted these responses. Although we successfully elicited several robust epitope-specific CD4+ T cell responses, vaccination with subdominant MHC class epitopes elicited few detectable CD8+ T cell responses. Broadening the CD8+ T cell response against subdominant MHC class I epitopes was, therefore, more difficult than we initially anticipated.
Response to treatment for late-life generalized anxiety disorder has been defined by a variety of methods, all based on statistically significant reductions in symptom severity. However, it is unknown whether these improvements in symptom severity are associated with meaningful differences in everyday functioning. The current study used four methods to define response to treatment for 115 primary care patients, age 60 and older, with a principal or co-principal diagnosis of generalized anxiety disorder. The methods examined included percent improvement, reliable change index and minimal clinically significant differences. Agreement among classification methods and their associations with general and mental health related quality of life were assessed. Results indicated moderate agreement among symptom-based classification methods and significant associations with measures of quality of life.
GAD; older adults; treatment response; quality of life
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) primarily infect activated CD4+ T cells but can infect macrophages. Surprisingly, ex vivo tetramer-sorted SIV-specific CD8+ T cells that eliminated and suppressed viral replication in SIV-infected CD4+ T cells failed to do so in SIV-infected macrophages. It is possible, therefore, that while AIDS virus-infected macrophages constitute only a small percentage of all virus-infected cells, they may be relatively resistant to CD8+ T cell-mediated lysis and continue to produce virus over long periods of time.
The presentation of identical peptides by different major histocompatibility complex class I (MHC-I) molecules, termed promiscuity, is a controversial feature of T cell-mediated immunity to pathogens. The astounding diversity of MHC-I molecules in human populations, presumably to enable binding of equally diverse peptides, implies promiscuity would be a rare phenomenon. However, if it occurs, it would have important implications for immunity. We screened 77 animals for responses to peptides known to bind MHC-I molecules that were not expressed by these animals. Some cases of supposed promiscuity were determined to be the result of either non-identical optimal peptides or were simply not mapped to the correct MHC-I molecule in previous studies. Cases of promiscuity, however, were associated with alterations of immunodominance hierarchies, either in terms of the repertoire of peptides presented by the different MHC-I molecules or in the magnitude of the responses directed against the epitopes themselves. Specifically, we found that the Mamu-B*017:01-restricted peptides Vif HW8 and cRW9 were also presented by Mamu-A2*05:26 and targeted by an animal expressing that allele. We also found that the normally subdominant Mamu-A1*001:01 presented peptide Gag QI9 was also presented by Mamu-B*056:01. Both A2*05:26 and B*056:01 are molecules typically or exclusively expressed by animals of Chinese origin. These data clearly demonstrate that MHC-I epitope promiscuity, though rare, might have important implications for immunodominance and for the transmission of escape mutations, depending on the relative frequencies of the given alleles in a population.
Simian immunodeficiency virus; Epitope promiscuity; Major histocompatibility complex; CD8+ T lymphocyte; Macaca mulatta
Virus-specific CD8+ T lymphocytes select for escape mutations in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). To assess the effects of these mutations on viral fitness, we introduced escape mutations into 30 epitopes (bound by five major histocompatibility complex class I [MHC-I] molecules) in three different viruses. Two of these MHC-I alleles are associated with elite control. Two of the three viruses demonstrated reduced fitness in vivo, and 27% of the introduced mutations reverted. These findings suggest that T cell epitope diversity may not be such a daunting problem for the development of an HIV vaccine.
CD8+ T cells play a major role in the containment of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. CD8+ T cell-driven variations in conserved regions under functional constraints result in diminished viral replicative capacity. While compensatory mutations outside an epitope can restore replicative capacity, the kinetics with which they arise remains unknown. Additionally, certain patterns of linked mutations associated with CD8+ T cell epitope escape in these highly conserved regions may lead to variable levels of viral fitness. Here, we used pyrosequencing to investigate the kinetics and patterns of mutations surrounding the Mamu-A1*00101-bound Gag181-189CM9 CD8+ T cell epitope. We obtained more than 400 reads for each sequencing time point, allowing us to confidently detect the emergence of viral variants bearing escape mutations with frequencies as low as 1% of the circulating virus. With this level of detail, we demonstrate that compensatory mutations generally arise concomitantly with Gag181-189CM9 escape mutations. We observed distinct patterns of linked flanking mutations, most of which were found downstream of Gag181-189CM9. Our data indicate that, whereas Gag181-189CM9 escape is much more complex that previously appreciated, it occurs in a coordinated fashion, with very specific patterns of flanking mutations required for immune evasion. This is the first detailed report of the ontogeny of compensatory mutations that allow CD8+ T cell epitope escape in infected individuals.
Heat shock protein 27 (HSP27) is a multidimensional protein which acts as a protein chaperone and an antioxidant and plays a role in the inhibition of apoptosis and actin cytoskeletal remodeling. In each of these capacities, HSP27 has been implicated in different disease states playing both protective and counter-protective roles. The current review presents HSP27 in multiple disease contexts: renal injury and fibrosis, cancer, neuro-degenerative and cardiovascular disease, highlighting its role as a potential biomarker and therapeutic target.
Cognitive behavior therapy (CBT) is effective for late-life generalized anxiety disorder (GAD), but, only pilot studies have been conducted in primary care, where older adults most often seek treatment. .
To examine effects of CBT relative to enhanced usual care (EUC) in older adults with GAD in primary care.
Design, Setting, and Participants
A randomized clinical trial with 134 older adults (mean age, 66.9 years) recruited from March 2004 to August 2006 in two primary care settings. Treatment was provided for 3 months; assessments were conducted at baseline, post-treatment (3 months), and over a 12-month follow-up (6, 9, 12, and 15 months).
CBT (n = 70) was conducted in the primary care clinics. Treatment included education and awareness, relaxation training, cognitive therapy, exposure, problem-solving skills training, and behavioral sleep management. Patients assigned to EUC (n = 64) received biweekly calls to ensure patient safety and provide minimal support.
Main Outcome Measures
Primary outcomes included worry severity (Penn State Worry Questionnaire) and GAD severity (GAD Severity Scale).. Secondary outcomes included anxiety (Hamilton Anxiety Rating Scale, Beck Anxiety Inventory), coexistent depressive symptoms (Beck Depression Inventory II), and physical/mental health quality of life (SF-12).
CBT significantly improved worry severity [45.6; 95% CI 44.4 to 47.8; vs. 54.4; 95% CI 51.4 to 57.3; p < .0001), depressive symptoms (10.2; 95% CI 8.5 to 11.9; vs. 12.8; 95% CI 10.5 to 15.1; p = .02), and general mental health (49.6; 95% CI 47.4 to 51.8; vs. 45.3; 95% CI 42.6 to 47.9; p=.008) compared with EUC. . According to intent-to-treat analyses, response rates defined according to worry severity were higher following CBT than EUC at 3 months (40.0% [28/70] vs. 21.9% [14/64], p = .02).
Compared to EUC, CBT resulted in greater improvement in worry severity, depressive symptoms, and general mental health for older patients with GAD in primary care.
To determine the association of early and long-term reductions in worry symptoms after cognitive behavioral therapy for generalized anxiety disorder (GAD) in older adults.
Substudy of larger randomized controlled trial
Family medicine clinic and large multi-specialty health organization in Houston, TX, between March 2004 and August 2006
Patients (N=76) 60 years or older with a principal or coprincipal diagnosis of GAD, excluding those with significant cognitive impairment, bipolar disorder, psychosis or active substance abuse.
Cognitive behavioral therapy, up to 10 sessions over 12 weeks, or enhanced usual care (regular, brief telephone calls and referrals to primary care provider as needed)
Penn State Worry Questionnaire (PSWQ) administered by telephone at baseline, 1 month (mid-treatment), 3 months (post-treatment), and at 3-month intervals through 15 months (1-year follow-up). We used binary logistic regression analysis to determine the association between early (1-month) response and treatment responder status (reduction of more than 8.5 points on the PSWQ) at 3 and 15 months. We also used hierarchical linear modeling to determine the relationship of early response to the trajectory of score change after post-treatment.
Reduction in PSWQ scores after the first month predicted treatment response at post-treatment and follow-up, controlling for treatment arm and baseline PSWQ score. The magnitude of early reduction also predicted the slope of score change from post-treatment through the 15-month assessment.
Early symptom reduction is associated with long-term outcomes after psychotherapy in older adults with GAD.
psychotherapy; generalized anxiety disorder; older adults
Peaceful Mind, a cognitive-behavioral therapy for treating anxiety in persons with dementia, is a promising new treatment currently under investigation. This article reports results of our examination of a modification of the treatment protocol in two cases that included multiple caregivers in treating two persons with dementia.
Two case presentations of the benefits and challenges of including multiple caregivers in treatment are discussed. Treatment outcome data for these cases were collected as part of a larger investigation of Peaceful Mind.
The involvement of multiple collaterals resulted in several benefits, including increased family communication, as well as increased opportunities for the practice of new skills. These cases have also presented unique challenges requiring alterations in therapy structure and attention to issues of family conflict.
Including multiple collaterals in cognitive-behavioral therapy for treating anxiety in persons with dementia is feasible and may be beneficial in maximizing treatment gains and increasing the family’s investment in therapy.
cognitive-behavioral therapy; anxiety; dementia
It has recently been shown that polymorphism at the rhesus macaque TRIM5 locus can affect simian immunodeficiency virus (SIV) replication. Here we show that TRIM5 alleles can also affect acquisition of SIVsmE660. Animals coexpressing the TRIM5TFP and TRIM5CypA alleles took significantly longer to become infected with SIVsmE660, but not SIVmac239, after repeated limiting-dose intrarectal challenge than did animals expressing other TRIM5 allele combinations. Our results indicate that the TRIM5 alleles can be a barrier to productive infection and that this should be taken into account when designing acquisition studies using SIVsmE660 or related viruses.
The SIV-infected rhesus macaque (Macaca mulatta) is the most established model of AIDS disease systems, providing insight into pathogenesis and a model system for testing novel vaccines. The understanding of cellular immune responses based on the identification and study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide-binding motif, provides valuable information to decipher outcomes of infection and vaccine efficacy. Detailed characterization of Mamu-B*039:01, a common allele expressed in Chinese rhesus macaques, revealed a unique MHC:peptide-binding preference consisting of glycine at the second position. Peptides containing a glycine at the second position were shown to be antigenic from animals positive for Mamu-B*039:01. A similar motif was previously described for the Dd mouse MHC allele, but for none of the human HLA molecules for which a motif is known. Further investigation showed that one additional macaque allele, present in Indian rhesus macaques, Mamu-B*052:01, shares this same motif. These “G2” alleles were associated with the presence of specific residues in their B pocket. This pocket structure was found in 6% of macaque sequences but none of 950 human HLA class I alleles. Evolutionary studies using the “G2” alleles points to common ancestry for the macaque sequences, while convergent evolution is suggested when murine and macaque sequences are considered. This is the first detailed characterization of the pocket residues yielding this specific motif in nonhuman primates and mice, revealing a new supertype motif not present in humans.
Electronic supplementary material
The online version of this article (doi:10.1007/s00251-011-0598-5) contains supplementary material, which is available to authorized users.
HLA supertype; MHC; Peptide-binding motif; Rhesus macaque