We describe health and psychosocial outcomes of HIV+ Young transgender women (YTW) engaged in care across the United States. When compared to other behaviorally infected youth (BIY), YTW reported higher rates of unemployment (25% vs 19%), limited educational (42% vs 13%), and suboptimal ART adherence (51% vs 30%). There was no difference in likelihood of having a detectable viral load (38% vs 39%) between groups. However, particular isolating psychosocial factors (unstable housing, depression, and lack of social support for attending appointments) increased predicted probability of viral detection to a greater extent among YTW which may have important health implications for this marginalized youth population.
HIV/AIDS; Transgender; LGBT Youth; Gender Identity; Access to Care
BCL-2 is a negative regulator of apoptosis implicated in homeostatic and pathologic cell survival. The canonical anti-apoptotic mechanism involves entrapment of activated BAX by a groove on BCL-2, preventing BAX homo-oligomerization and mitochondrial membrane poration. The BCL-2 BH4 domain also confers anti-apoptotic functionality, but the mechanism is unknown. We find that a synthetic α-helical BH4 domain binds to BAX with nanomolar affinity and independently inhibits the conformational activation of BAX. Hydrogen-deuterium exchange mass spectrometry demonstrated that the N-terminal conformational changes in BAX induced by a triggering BIM BH3 helix were suppressed by the BCL-2 BH4 helix. Structural analyses localized the BH4 interaction site to a groove formed by residues of α1, α1–α2 loop, and α2–α3 and α5–α6 hairpins on the BAX surface. These data reveal a previously unappreciated binding site for targeted inhibition of BAX and suggest that the BCL-2 BH4 domain may participate in apoptosis blockade by a noncanonical interaction mechanism.
We postulated that proteasome inhibition (PI) may be useful in the treatment of SLE by targeting plasmacytoid dendritic cells (pDCs) and plasma cells (PCs), both critical to disease pathogenesis.
Lupus prone mice were treated with the non-selective PIs carfilzomib and bortezomib, the LMP7-selective immunoproteasome inhibitor ONX 0914, or vehicle control. Tissues were harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by proteinuria and kidney harvest. Serum anti-dsDNA levels were measured by ELISA and total IgG and dsDNA antibody secreting cells (ASC) by ELIspot. Human PBMCs or mouse bone marrow cells were incubated with TLR agonists and PIs and interferon α measured by ELISA and flow cytometry.
Early treatment of lupus prone mice with the dual targeting PIs carfilzomib or bortezomib or the immunoproteasome specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells with greater reductions in autoreactive than total IgG ASCs, an effect that became more pronounced with prolonged treatment, and was reflected in decreasing serum autoantibodies. Remarkably, proteasome inhibition efficiently suppressed production of interferon α by toll-like receptor activated pDCs in vitro and in vivo, an effect mediated by both an inhibition of pDC survival and function.
Inhibition of the immunoproteasome is equally efficacious to dual targeting agents in preventing lupus disease progression by targeting two critical pathways in disease pathogenesis, type I interferon activation and autoantibody production by plasma cells.
interferon; plasmacytoid dendritic cells; plasma cells; Systemic Lupus Erythematosus; autoimmunity
Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided.
Materials and Methods
A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/μL). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated.
Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49–15.90, P = 0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52–24.40, P = 0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587–0.798) for the study cohort and 0.792 (95% CI: 0.776–0.808) and 0.766 in the 2 validation cohorts.
A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system.
The risk factors, microbial etiology, differentiation, and clinical features of purulent and non-purulent cellulitis are not well defined in Taiwan.
We conducted a retrospective cohort study of hospitalized adults with cellulitis in Taiwan in 2013. The demographic characteristics, underlying diseases, clinical manifestations, laboratory and microbiological findings, treatments, and outcomes were compared for patients with purulent and non-purulent cellulitis.
Of the 465 patients, 369 had non-purulent cellulitis and 96 had purulent cellulitis. The non-purulent group was significantly older (p = 0.001) and was more likely to have lower limb involvement (p < 0.001), tinea pedis (p = 0.003), stasis dermatitis (p = 0.025), a higher Charlson comorbidity score (p = 0.03), and recurrence at 6 months post-infection (p = 0.001) than the purulent group. The purulent group was more likely to have a wound (p < 0.001) and a longer hospital stay (p = 0.001) and duration of antimicrobial therapy (p = 0.003) than the non-purulent group. The etiological agent was identified in 35.5 % of the non-purulent cases, with β-hemolytic streptococci the most frequent cause (70.2 %). The etiological agent was identified in 83.3 % of the purulent cases, with Staphylococcus aureus the predominant pathogen (60 %): 50 % of these were methicillin-resistant S. aureus (MRSA). In multivariable analysis, purulent group (odds ratio (OR), 5.188; 95 % confidence interval (CI), 1.995–13.493; p = 0.001) was a positive predictor of MRSA. The prescribed antimicrobial agents were significantly different between the purulent and non-purulent groups, with penicillin the most frequently used antimicrobial agent in the non-purulent group (35.2 %), and oxacillin the most frequent in the purulent group (39.6 %). The appropriate antimicrobial agent was more frequently prescribed in the non-purulent group than in the purulent group (83.2 % vs. 53.8 %, p < 0.001).
The epidemiology, clinical features, and microbiology of purulent and non-purulent cellulitis were significantly different in hospitalized Taiwanese adults. Purulence was a positive predictor of MRSA as the causal agent of cellulitis. These findings provide added support for the adoption of the IDSA guidelines for empirical antimicrobial therapy of cellulitis in Taiwan.
Cellulitis; Methicillin-resistant Staphylococcus aureus; Soft tissue infections; Staphylococcal skin infections
A youth-driven, social media-based campaign aimed at improving knowledge about and increasing testing for sexually transmitted infections (STIs)/HIV among youth 13–17 years old was assessed by: tracking website/social media use throughout the campaign; online survey of knowledge of and attitudes towards STI testing 9 months after campaign launch; and comparing rates of STI testing at affiliated family planning clinics during the 1 year period immediately prior versus 1 year immediately after campaign launch. Over 1,500 youth were reached via social media. Survey results showed 46 % of youth had never been tested, but 70 % intended to test in the next 6 months. While the total number of GC/CT tests conducted and positive results were not significantly different pre- and post-campaign, there was a large increase in the proportion of visits at which Syphilis (5.4 vs. 18.8 %; p <0.01) and HIV (5.4 vs. 19.0 %; p <0.01) testing was conducted post-campaign launch. Future campaigns should incorporate lessons learned about engaging younger adolescents, social media strategies, and specific barriers to testing in this age group.
Adolescents; HIV/AIDS; Sexually transmitted infections (STI); Social media; Mobile health
Almost all eukaryotic mRNAs must be polyadenylated at their 3′ ends to function in protein synthesis. This modification occurs via a large nuclear complex that recognizes signal sequences surrounding a poly(A) site on mRNA precursor, cleaves at that site, and adds a poly(A) tail. While the composition of this complex is known, the functions of some subunits remain unclear. One of these is a multidomain protein called Mpe1 in the yeast Saccharomyces cerevisiae and RBBP6 in metazoans. The three conserved domains of Mpe1 are a ubiquitin-like (UBL) domain, a zinc knuckle, and a RING finger domain characteristic of some ubiquitin ligases. We show that mRNA 3′-end processing requires all three domains of Mpe1 and that more than one region of Mpe1 is involved in contact with the cleavage/polyadenylation factor in which Mpe1 resides. Surprisingly, both the zinc knuckle and the RING finger are needed for RNA-binding activity. Consistent with a role for Mpe1 in ubiquitination, mutation of Mpe1 decreases the association of ubiquitin with Pap1, the poly(A) polymerase, and suppressors of mpe1 mutants are linked to ubiquitin ligases. Furthermore, an inhibitor of ubiquitin-mediated interactions blocks cleavage, demonstrating for the first time a direct role for ubiquitination in mRNA 3′-end processing.
The goal of this present study was to determine the proportion of CCR5-tropic and CXCR4-tropic viruses and impact of tropism test on clinical presentation, CD4 cell counts, viral load and genotypic drug resistance from drug-naïve, voluntary counselling and testing (VCT) clients in southern Taiwan.
This was a cross-sectional study. Plasma samples were collected from HIV-1-infected patients from January 2013 to December 2013; subjects were recruited from free VCT centres in southern Taiwan.
Plasma samples from 108 HIV-1-infected, treatment-naïve, VCT clients were analysed. HIV-1 strains were sequenced, genotype resistance was determined by a commercial kit (Viro-seq) and co-receptor tropism (CRT) was predicted by an internet tool geno2pheno[coreceptor], with a 10% false-positive rate as the cut-off. Differences in progression markers, patient characteristics, VCT questionnaires and HIV subtype distribution were evaluated statistically.
All the 108 VCT clients were male with 90% between the ages of 20 and 40 years. Eighty-eight per cent of the patients were men who have sex with men (MSM). The median (IQR) CD4 cell count was 342 cells/µL (221–454) and the viral load was 4.6 log (4.0–5.0). HIV-transmitted drug resistance was found in 9.3% (10/108) of the patients. CRT predictions indicated that 74% of the patients had only R5-tropic strains. CRT was not associated with CD4 cell counts, patient characteristics, VCT questionnaire and transmitted drug resistance. There was a significant difference with regard to viral load at the time of presentation, showing that patients with R5 more often had a higher viral load as compared with those with X4/DM strains (4.6±0.6 log vs 4.33±0.7 log, p=0.036).
We found that 74% of the VCT clients were infected with R5-tropic virus strains. HIV-transmitted drug resistance was not associated with CRT predictions. Higher viral load at presentation was predictive of R5 co-receptor usage.
Angiostrongylus cantonensis, the rat lungworm, is the major cause of eosinophilic meningitis worldwide. Rats serve as the definitive host of the nematode, but humans can be infected incidentally, leading to eosinophilic meningitis. A previous BALB/c animal study has demonstrated increased apoptotic proteins and decreased anti-apoptotic proteins in mice infected with A. cantonensis. Steroids may be an effective treatment option for eosinophilic meningitis caused by A. cantonensis, but the involved mechanism is unclear. This study hypothesized that the beneficial effects of steroids on eosinophilic meningitis are mediated by decreased apoptosis.
In a BALB/c animal model, mice were orally infected with 50 A. cantonensis L3 via an oro-gastric tube and were sacrificed every week for 3 consecutive weeks after infection or until the end of the study. Dexamethasone was injected intra-peritoneally from the 7th day post-infection until the end of the 21-day study. Evans blue method was used to measure changes in the blood brain barrier, while western blotting, immuno-histochemistry, and TUNEL assay were used to analyze brain homogenates expression of apoptotic and anti-apoptotic proteins.
There were increased amounts of Evans blue, apoptotic proteins (caspase-3, -8, and -9 and cytochrome C), and decreased anti-apoptotic proteins (bcl-2) after 2-3 weeks of infection. Dexamethasone administration significantly decreased Evans blue extravasations and apoptotic protein expressions.
Apoptosis of mice brain homogenates can be repressed by dexamethasone treatment.
Angiostrongylus cantonensis; Apoptosis; Blood brain barrier; Corticosteroid; Eosinophilic meningitis
Herpes zoster ophthalmicus is defined as herpes zoster involvement of the ophthalmic division of the trigeminal nerve. Ocular involvement occurs in 20–70% of patients with herpes zoster ophthalmicus and may include blepharitis, keratoconjunctivitis, iritis, scleritis, and acute retinal necrosis. Orbital apex syndrome is a rare but severe ocular complication of herpes zoster ophthalmicus. We present here the first reported case of herpes zoster ophthalmicus complicated by orbital apex syndrome in a patient from Taiwan.
A 78-year-old man initially presented with patchy erythema and herpetiform vesicles on his left forehead and upper eyelid. He subsequently developed left-sided ocular complications including reduced visual acuity, anisocoria, ptosis, and complete ophthalmoplegia. Orbital magnetic resonance imaging (MRI) was performed on day 6 of admission to search for signs of the common causes of orbital apex syndrome such as hemorrhage, neoplasm, and cavernous sinus thrombosis. The MRI showed only orbital myositis and enhancement of the retro-orbital optic nerve sheath. The patient was diagnosed with herpes zoster ophthalmicus complicated by orbital apex syndrome. Although the ocular complications partially resolved after systemic antiviral therapy for 15 days and steroid therapy tapered over 12 weeks, there was residual limitation of abduction and paralysis of the left upper eyelid at follow-up at 180 days after the onset of symptoms. The orbital MRI findings at 180 days showed no significant changes compared with the MRI findings on day 6 of admission.
Primary care physicians should be aware of this rare but potentially sight-threatening complication of herpes zoster ophthalmicus. The appropriate therapy for orbital apex syndrome due to herpes zoster ophthalmicus and the potential outcomes of this condition require further investigation.
Herpes zoster ophthalmicus; Orbital apex syndrome; Varicella zoster virus
To evaluate pediatric primary care provider (PCP) HIV screening practices, knowledge, and attitudes.
Anonymous cross-sectional, internet-based survey of pediatric PCPs from 29 primary care practices. Survey items assessed current HIV screening practices and knowledge, attitudes, and perceived barriers towards screening. Provider demographics and practice characteristics were analyzed for associations with screening through logistic regression.
Of 190 PCPs, there were 101 evaluable responses (response rate: 53.2%). PCPs reported a screening rate for HIV of 39.6% (“most” or “all of the time”) during routine adolescent visits compared with violence (60.4%), substance abuse (92.1%), and depression (94.1%) (p<0.001). Less than 10% of PCPs correctly answered questions related to CDC and state HIV screening recommendations. Of 20 potential HIV screening barriers assessed, mean number of reported barriers was 4.8 (SD +/− 2.9); with most concerns related to confidentiality, time for counseling, and follow up. In a multivariable model, the only factor significantly associated with HIV screening “most” or “all of the time” during routine adolescent visits was urban practice site (adjusted odds ratio 9.8, 95% CI 2.9, 32.9). Provider type, sex, years since training, HIV screening guideline knowledge, and endorsing ≤5 barriers were not associated with HIV screening.
Although providers practicing in urban areas were more likely to report screening adolescents for HIV than those in suburban areas, overall self-reported screening rates were low, and several barriers were identified commonly. Future interventions should target increasing providers’ knowledge and addressing concerns about confidentiality, requirements and counseling time, and follow-up of results.
Carfilzomib, a selective proteasome inhibitor, has demonstrated safety and efficacy in relapsed and/or refractory multiple myeloma. This Phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a Phase II expansion study.
Patients with multiple myeloma who relapsed after 1–3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15–27 mg/m2 on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10–25 mg on Days 1–21; and dexamethasone 40 mg weekly.
Forty patients enrolled in 6 cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the Phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no Grade 3/4 neuropathy reported. Proteasome inhibition 1 hour post-dose was >80% in Cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and median duration of response and progression-free survival were 11.8 and 10.2 months, respectively.
The maximum planned CRd dose—carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg—was recommended for further study, with promising safety and efficacy.
Multiple myeloma; carfilzomib; lenalidomide; hematologic neoplasm; clinical trial; phase 1
Although the challenges of working with culturally and linguistically diverse groups can lead to the exclusion of some communities from research studies, cost effective strategies to encourage access and promote cross-cultural linkages between researchers and ethnic minority participants are essential to ensure their views are heard and their health needs identified. Using bilingual research assistants is one means to achieve this. In a study exploring alcohol and other drug service use by migrant women in Western Australia, bilingual workers were used to assist with participant recruitment and administration of a survey to 268 women who spoke more than 40 different languages.
Professional interpreters, bilingual students, bilingual overseas-trained health professionals and community sector bilingual workers were used throughout the research project. For the initial qualitative phase, professional interpreters were used to conduct interviews and focus group sessions, however scheduling conflicts, inflexibility, their inability to help with recruitment and the expense prompted exploration of alternative options for interview interpreting in the quantitative component of the study. Bilingual mature-age students on work placement and overseas-trained health professionals provided good entry into their different community networks and successfully recruited and interviewed participants, often in languages with limited interpreter access. Although both groups required training and supervision, overseas-trained health professionals often had existing research skills, as well as understanding of key issues such as confidentiality and referral processes. Strategies to minimise social desirability bias and the need to set boundaries were discussed during regular debriefing sessions. Having a number of workers recruiting participants also helped minimise the potential for selection bias. The practical and educational experience gained by the bilingual workers was regarded as capacity building and a potentially valuable community resource for future health research projects.
The use of bilingual workers was key to the feasibility and success of the project. The most successful outcomes occurred with students and overseas-trained health professionals who had good community networks for recruitment and the required linguistic skills. By describing the advantages and disadvantages encountered when working with bilingual workers, we offer practical insights to assist other researchers working with linguistically diverse groups.
Bilingual workers; Cross cultural research; Migrants; Refugees; Communication; Interpreting
Sporadic non-clustered hospital-associated listeriosis is an emerging infectious disease in immunocompromised hosts. The current study was designed to determine the impact of long-term and precipitating immunosuppressive agents and underlying diseases on triggering the expression of the disease, and to compare the clinical features and outcome of hospital-associated and community-associated listeriosis.
We reviewed the medical records of all patients with Listeria monocytogenes isolated from sterile body sites at a large medical center in southern Taiwan during 1992–2013. Non-clustered cases were defined as those unrelated to any other in time or place. Multivariable regression analysis was used to determine factors associated with prognosis.
Thirty-five non-clustered cases of listeriosis were identified. Twelve (34.2%) were hospital-associated, and 23 (65.7%) were community-associated. The 60-day mortality was significantly greater in hospital-associated than in community-associated cases (66.7% vs. 17.4%, p = 0.007). Significantly more hospital-associated than community-associated cases were treated with a precipitating immunosuppressive agent within 4 weeks prior to onset of listeriosis (91.7% vs. 4.3%, respectively p < 0.001). The median period from the start of precipitating immunosuppressive treatment to the onset of listeriosis-related symptoms was 12 days (range, 4–27 days) in 11 of the 12 hospital-associated cases. In the multivariable analysis, APACHE II score >21 (p = 0.04) and receipt of precipitating immunosuppressive therapy (p = 0.02) were independent risk factors for 60-day mortality.
Sporadic non-clustered hospital-associated listeriosis needs to be considered in the differential diagnosis of sepsis in immunocompromised patients, particularly in those treated with new or increased doses of immunosuppressive agents.
Immunocompromised host; Listeria monocytogenes; Hospital-associated infection
Angiostrongylus cantonensis is a parasite endemic in the Southeast Asian and Pacific regions. Humans are incidentally infected either by eating uncooked intermediate hosts or by consuming vegetables containing the living third-stage larvae. The 14-3-3β protein is a cerebrospinal fluid (CSF) marker of neuronal damage during the development of Creutzfeldt-Jakob disease. In addition, increased 14-3-3β protein is also found in CSF from patients with a variety of neurological disorders. The goal of this study is to determine the roles of serum/CSF14-3-3β protein in patients with eosinophilic meningitis.
In a cohort study among nine Thai laborers with eosinophilic meningitis due to eating raw snails (Pomacea canaliculata), we examined the CSF weekly while patients were still hospitalized and followed up the serum for 6 months. The levels of 14-3-3β protein in CSF were analyzed by western blot and an in-house 14-3-3β enzyme-linked immunosorbent assay (ELISA) measurement was established and tested in an animal model of eosinophilic meningitis.
The elevated 14-3-3β level was detected in the CSF from eight out of nine (81%) patients After 2 weeks of treatment, all patients showed a declined level or cleared of 14-3-3β protein in the CSF. By developing an in-house ELISA for measurement of 14-3-3β protein, it was found that the serum 14-3-3β level was significantly increased in patients during initial visit. . This finding was consistent to the animal experiment result in which there was severe blood brain barrier damage three weeks after infection and increased 14-3-3β protein expression in the CSF and serum by western blot and in house ELISA. After treatment, the serum 14-3-3β level in meningitis patients was rapidly returned to normal threshold. There was a correlation between initial CSF 14-3-3β level with severity of headache (r = 0.692, p = 0.039), CSF pleocytosis (r = 0.807, p = 0.009) and eosinophilia (r = 0.798, p = 0.01) in the CSF of patients with eosinophilic meningitis (Spearman’s correlation test).
The serum 14-3-3β concentrations may constitute a useful marker for blood brain barrier damage severity and follow up in patients with eosinophilic meningitis caused by A. cantonensis.
Angiostrongylus cantonensis; Eosinophilic meningitis; 14-3-3β protein
NSAIDs; COX-2 inhibitor; colchicine; corticosteroid therapy; prednisone; intra-articular glucocorticosteroids; ACTH; anakinra; canakinumb; rilonacept; IL-1
Allopurinol; Febuxostat; Probenecid; Pegloticase; Uricosuric; Xanthine Oxidase; Tophi
Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2–10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.
Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m2 in week 1 of cycle 1 and 20, 27, or 36 mg/m2 thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.
Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m2 was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.
Carfilzomib 20/36 mg/m2 was well tolerated when administered twice weekly by 2–10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.
Proteasome inhibitor; Carfilzomib; Solid tumors; Pharmacokinetics; Pharmacodynamics
Understanding a speaker’s communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion.
To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity.
Design, Setting, and Participants
Eighteen boys with ASD (aged 7–17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles.
Main Outcome Measures
Blood oxygenation level– dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded.
Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group X condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region.
Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.
While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.
autism; brain development; fMRI; language pragmatics; social cognition
Daydreamer (DydA), a new Mig10/RIAM/lamellipodin family adaptor protein, is a Ras effector required for cell polarization and directional movement during chemotaxis. DydA is phosphorylated by glycogen synthase kinase-3, which is required for some, but not all, of DydA's functions. gskA− cells exhibit very strong chemotactic phenotypes, a subset of which are exhibited by dydA− cells.
How independent signaling pathways are integrated to holistically control a biological process is not well understood. We have identified Daydreamer (DydA), a new member of the Mig10/RIAM/lamellipodin (MRL) family of adaptor proteins that localizes to the leading edge of the cell. DydA is a putative Ras effector that is required for cell polarization and directional movement during chemotaxis. dydA− cells exhibit elevated F-actin and assembled myosin II (MyoII), increased and extended phosphoinositide-3-kinase (PI3K) activity, and extended phosphorylation of the activation loop of PKB and PKBR1, suggesting that DydA is involved in the negative regulation of these pathways. DydA is phosphorylated by glycogen synthase kinase-3 (GSK-3), which is required for some, but not all, of DydA's functions, including the proper regulation of PKB and PKBR1 and MyoII assembly. gskA− cells exhibit very strong chemotactic phenotypes, as previously described, but exhibit an increased rate of random motility. gskA− cells have a reduced MyoII response and a reduced level of phosphatidylinositol (3,4,5)-triphosphate production, but a highly extended recruitment of PI3K to the plasma membrane and highly extended kinetics of PKB and PKBR1 activation. Our results demonstrate that GSK-3 function is essential for chemotaxis, regulating multiple substrates, and that one of these effectors, DydA, plays a key function in the dynamic regulation of chemotaxis.
Objective. The Gout Impact Scale (GIS) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout. The GIS has five scales and each is scored from 0 to 100 (worse health). Our objective was to assess minimally important differences (MIDs) for the GIS administered in a randomized controlled trial (RCT) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy.
Methods. Trial subjects ( n = 83) included those with two or more gout flares (self-reported) in the past year. Of these, 73 had data for Weeks 8 vs 4 and formed the MID analysis group and were analysed irrespective of the treatment assignment. Subjects completed the GIS and seven patient-reported anchors. Subjects with a one-step change (e.g. from very poor to poor) were considered as the MID group for each anchor. The mean change in GIS scores and effect size (ES) was calculated for each anchor’s MID group. The average of these created the overall summary MID statistics for each GIS. An ES of 0.2–0.5 was considered to represent MID estimates.
Results. Trial subjects (n = 73) were males (96.0%), White (90.4%), with mean age of 50.5 years and serum uric acid of 9.0 mg/dl. The mean change score for the MID improvement group for scales ranged from −5.24 to −7.61 (0–100 scale). The ES for the MID improvement group for the four scales ranged from 0.22 to 0.38.
Conclusion. The MID estimates for GIS scales are between 5 and 8 points (0–100 scale). This information can aid in interpreting the GIS results in future gout RCTs.
Trial Registration. Clinicaltrials.gov, www.clinicaltrials.gov, NCT00610363.
Gout assessment questionnaire; Gout impact scale; Minimally important difference; Minimal clinically important differences; Rilonacept; Clinical trial design; Health-related quality of life; Health status
Increasing evidence suggests that multiple metabolic pathways are regulated by sirtuin-dependent protein deacetylation in the mitochondria. In this issue, Nakagawa et al. (2009) show that an uncharacterized sirtuin, SIRT5, deacetylates and activates a mitochondrial enzyme, carbamoyl phosphate synthetase 1, which mediates the first step in the urea cycle.