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1.  Orbital apex syndrome: an unusual complication of herpes zoster ophthalmicus 
Background
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.
Case presentation
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.
Conclusions
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.
doi:10.1186/s12879-015-0760-z
PMCID: PMC4314774  PMID: 25636374
Herpes zoster ophthalmicus; Orbital apex syndrome; Varicella zoster virus
2.  Pediatric Primary Care Provider Practices, Knowledge and Attitudes of HIV Screening Among Adolescents 
The Journal of pediatrics  2013;163(6):1711-1715.e6.
Objectives
To evaluate pediatric primary care provider (PCP) HIV screening practices, knowledge, and attitudes.
Study design
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2013.08.023
PMCID: PMC3888239  PMID: 24084105
3.  Phase Ib Dose-escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-dose Dexamethasone in Relapsed or Progressive Multiple Myeloma 
Purpose
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.
Experimental Design
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.
Results
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.
Conclusion
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.
doi:10.1158/1078-0432.CCR-12-3352
PMCID: PMC4149337  PMID: 23447001
Multiple myeloma; carfilzomib; lenalidomide; hematologic neoplasm; clinical trial; phase 1
4.  Overcoming language barriers in community-based research with refugee and migrant populations: options for using bilingual workers 
Background
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.
Discussion
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.
Summary
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.
doi:10.1186/1472-698X-14-11
PMCID: PMC4016643  PMID: 24725431
Bilingual workers; Cross cultural research; Migrants; Refugees; Communication; Interpreting
5.  Emergence of sporadic non-clustered cases of hospital-associated listeriosis among immunocompromised adults in southern Taiwan from 1992 to 2013: effect of precipitating immunosuppressive agents 
BMC Infectious Diseases  2014;14:145.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2334-14-145
PMCID: PMC4003814  PMID: 24641498
Immunocompromised host; Listeria monocytogenes; Hospital-associated infection
6.  14-3-3β protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection 
BMC Research Notes  2014;7:97.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1756-0500-7-97
PMCID: PMC3932789  PMID: 24555778
Angiostrongylus cantonensis; Eosinophilic meningitis; 14-3-3β protein
9.  A phase I/II study of carfilzomib 2–10-min infusion in patients with advanced solid tumors 
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s00280-013-2267-x
PMCID: PMC3784064  PMID: 23975329
Proteasome inhibitor; Carfilzomib; Solid tumors; Pharmacokinetics; Pharmacodynamics
10.  Reading Affect in the Face and Voice 
Archives of general psychiatry  2007;64(6):698-708.
Context
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.
Objectives
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.
Results
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.
Conclusions
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.
doi:10.1001/archpsyc.64.6.698
PMCID: PMC3713233  PMID: 17548751
11.  Neural basis of irony comprehension in children with autism: the role of prosody and context 
Brain : a journal of neurology  2006;129(0 4):932-943.
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.
doi:10.1093/brain/awl032
PMCID: PMC3713234  PMID: 16481375
autism; brain development; fMRI; language pragmatics; social cognition
12.  Daydreamer, a Ras effector and GSK-3 substrate, is important for directional sensing and cell motility 
Molecular Biology of the Cell  2013;24(2):100-114.
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.
doi:10.1091/mbc.E12-04-0271
PMCID: PMC3541958  PMID: 23135995
13.  Minimally important differences of the gout impact scale in a randomized controlled trial 
Rheumatology (Oxford, England)  2011;50(7):1331-1336.
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.
doi:10.1093/rheumatology/ker023
PMCID: PMC3307519  PMID: 21372003
Gout assessment questionnaire; Gout impact scale; Minimally important difference; Minimal clinically important differences; Rilonacept; Clinical trial design; Health-related quality of life; Health status
16.  Ure(k)a! Sirtuins regulate mitochondria 
Cell  2009;137(3):404-406.
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.
doi:10.1016/j.cell.2009.04.036
PMCID: PMC3310393  PMID: 19410538
17.  Processing mechanism and substrate selectivity of the core NuA4 histone acetyltransferase complex 
Biochemistry  2011;50(5):727-737.
Esa1, an essential MYST histone acetyltransferase found in the yeast piccolo NuA4 complex (picNuA4), is responsible for genome-wide histone H4 and histone H2A acetylation. picNuA4 uniquely catalyzes the rapid tetra-acetylation of nucleosomal H4, though the molecular determinants driving picNuA4 efficiency and specificity have not been defined. Here, we show through rapid substrate-trapping experiments that picNuA4 utilizes a non-processive mechanism, where picNuA4 dissociates from substrate after each acetylation event. Quantitative mass spectral analyses indicate that picNuA4 randomly acetylates free and nucleosomal H4, with a small preference for lysines 5, 8, and 12 over 16. Using a series of 24 histone mutants of H4 and H2A, we investigated the parameters affecting catalytic efficiency. Most strikingly, removal of lysine residues did not substantially affect the ability of picNuA4 to acetylate remaining sites, and insertion of an additional lysine into the H4 tail led to rapid quintuple-acetylation. Conversion of the native H2A tail to an H4-like sequence resulted in enhanced multi-site acetylation. Collectively, the results suggest picNuA4’s site selectivity is dictated by accessibility on the nucleosome surface, the relative proximity from the histone fold domain, and a preference for intervening glycine residues with a minimal (n + 2) spacing between lysines. Functionally distinct from other HAT families, the proposed model for picNuA4 represents a unique mechanism of substrate recognition and multisite acetylation.
doi:10.1021/bi101355a
PMCID: PMC3038686  PMID: 21182309
18.  The interaction of Pcf11 and Clp1 is needed for mRNA 3′-end formation and is modulated by amino acids in the ATP-binding site 
Nucleic Acids Research  2011;40(3):1214-1225.
Polyadenylation of eukaryotic mRNAs contributes to stability, transport and translation, and is catalyzed by a large complex of conserved proteins. The Pcf11 subunit of the yeast CF IA factor functions as a scaffold for the processing machinery during the termination and polyadenylation of transcripts. Its partner, Clp1, is needed for mRNA processing, but its precise molecular role has remained enigmatic. We show that Clp1 interacts with the Cleavage–Polyadenylation Factor (CPF) through its N-terminal and central domains, and thus provides cross-factor connections within the processing complex. Clp1 is known to bind ATP, consistent with the reported RNA kinase activity of human Clp1. However, substitution of conserved amino acids in the ATP-binding site did not affect cell growth, suggesting that the essential function of yeast Clp1 does not involve ATP hydrolysis. Surprisingly, non-viable mutations predicted to displace ATP did not affect ATP binding but disturbed the Clp1–Pcf11 interaction. In support of the importance of this interaction, a mutation in Pcf11 that disrupts the Clp1 contact caused defects in growth, 3′-end processing and transcription termination. These results define Clp1 as a bridge between CF IA and CPF and indicate that the Clp1–Pcf11 interaction is modulated by amino acids in the conserved ATP-binding site of Clp1.
doi:10.1093/nar/gkr801
PMCID: PMC3273803  PMID: 21993299
19.  The LRRK2-related Roco kinase Roco2 is regulated by Rab1A and controls the actin cytoskeleton 
Molecular Biology of the Cell  2011;22(13):2198-2211.
A new pathway that controls pseudopod extension is identified. Results support a model in which Rab1A is required for chemoattractant-mediated Roco2 activation that functions through the F-actin cross-linker filamin to promote pseudopod extension.
We identify a new pathway that is required for proper pseudopod formation. We show that Roco2, a leucine-rich repeat kinase 2 (LRRK2)-related Roco kinase, is activated in response to chemoattractant stimulation and helps mediate cell polarization and chemotaxis by regulating cortical F-actin polymerization and pseudopod extension in a pathway that requires Rab1A. We found that Roco2 binds the small GTPase Rab1A as well as the F-actin cross-linking protein filamin (actin-binding protein 120, abp120) in vivo. We show that active Rab1A (Rab1A-GTP) is required for and regulates Roco2 kinase activity in vivo and that filamin lies downstream from Roco2 and controls pseudopod extension during chemotaxis and random cell motility. Therefore our study uncovered a new signaling pathway that involves Rab1A and controls the actin cytoskeleton and pseudopod extension, and thereby, cell polarity and motility. These findings also may have implications in the regulation of other Roco kinases, including possibly LRRK2, in metazoans.
doi:10.1091/mbc.E10-12-0937
PMCID: PMC3128523  PMID: 21551065
20.  Non-nosocomial healthcare-associated infective endocarditis in Taiwan: an underrecognized disease with poor outcome 
BMC Infectious Diseases  2011;11:221.
Background
Non-nosocomial healthcare-associated infective endocarditis (NNHCA-IE) is a new category of IE of increasing importance. This study described the clinical and microbiological characteristics and outcome of NNHCA-IE in Taiwan.
Methods
A retrospective study was conducted of all patients with IE admitted to the Kaohsiung Veterans General Hospital in Kaohsiung, Taiwan over a five-year period from July 2004 to July 2009. The clinical and microbiological features of NNHCA-IE were compared to those of community-acquired and nosocomial IE. Predictors for in-hospital death were determined.
Results
Two-hundred episodes of confirmed IE occurred during the study period. These included 148 (74%) community-acquired, 30 (15%) non-nosocomial healthcare-associated, and 22 (11%) nosocomial healthcare-associated IE. Staphylococcus aureus was the most frequent pathogen. Patients with NNHCA-IE compared to community-acquired IE, were older (median age, 67 vs. 44, years, p < 0.001), had more MRSA (43.3% vs. 9.5%, p < 0.001), more comorbidity conditions (median Charlson comorbidity index [interquartile range], 4[2-6] vs. 0[0-1], p < 0.001), a higher in-hospital mortality (50.0% vs. 17.6%, p < 0.001) and were less frequently recognized by clinicians on admission (16.7% vs. 47.7%, p = 0.002). The overall in-hospital mortality rate for all patients with IE was 25%. Shock was the strongest risk factor for in-hospital death (odds ratio 7.8, 95% confidence interval 2.4-25.2, p < 0.001).
Conclusions
NNHCA-IE is underrecognized and carries a high mortality rate. Early recognition is crucial to provide optimal management and improve outcome.
doi:10.1186/1471-2334-11-221
PMCID: PMC3179455  PMID: 21849057
21.  Gout disease-specific quality of life and the association with gout characteristics 
Purpose
Assess the association of gout characteristics with health-related quality of life (HRQoL) using a new gout-specific HRQoL instrument, the Gout Impact Scale (GIS).
Patients and methods
Gout patients completed the GIS (five scales [0–100 score each] representing impact of gout overall [three scales] and during an attack [two scales]) and other questions describing recent gout attacks, treatment, gout history, comorbidities, and demographics. Physicians confirmed gout diagnosis, presence of tophi, and most recent serum uric acid (sUA) level. Relationships between gout characteristics and GIS scores were examined using analysis of variance and correlation analyses.
Results
The majority of patients were male (90.2%) with a mean age of 62.2 (±11.8) years. Approximately one-half (49.7%) reported ≥3 gout attacks in the past year and the majority (57.9%) reported experiencing gout-related pain between attacks. Patients had appreciable concern about their gout (“gout concern overall” scale, 63.1 ± 28.0) but believed their treatment was adequate (“unmet gout treatment need” scale (38.2 ± 21.4) below scale mid-point). Significantly worse GIS scores were associated with increasing attack frequency and greater amount of time with pain between attacks (most scales, P < 0.001). Common objective measures such as sUA level, presence of tophi and the number of joints involved in a typical attack did not appear to be good indicators of the impact of gout on the patients' HRQoL.
Conclusion
Attack frequency and gout pain between attacks were important correlates of patients' ratings of gout impact on their HRQoL. Further studies are needed to determine the minimal important difference for each GIS scale and interpret our results relative to other patient populations with gout.
doi:10.2147/PROM.S8310
PMCID: PMC3113652  PMID: 21686040
Gout impact scale; GIS; patient-reported outcomes
22.  DIFFERENTIAL CALCIUM SIGNALING AND Kv1.3 TRAFFICKING TO THE IMMUNOLOGICAL SYNAPSE IN SYSTEMIC LUPUS ERYTHEMATOSUS 
Cell calcium  2009;47(1):19.
Systemic lupus erythematosus (SLE) T cells exhibit several activation signaling anomalies including defective Ca2+ response and increased NF-AT nuclear translocation. The duration of the Ca2+ signal is critical in the activation of specific transcription factors and a sustained Ca2+ response activates NF-AT. Yet, the distribution of Ca2+ responses in SLE T cells is not known. Furthermore, the mechanisms responsible for Ca2+ alterations are not fully understood. Kv1.3 channels control Ca2+ homeostasis in T cells. We reported a defect in Kv1.3 trafficking to the immunological synapse (IS) of SLE T cells that might contribute to the Ca2+ defect. The present study compares single T cell quantitative Ca2+ responses upon formation of the IS in SLE, normal and rheumatoid arthritis (RA) donors. Also, we correlated cytosolic Ca2+ concentrations and Kv1.3 trafficking in the IS by two-photon microscopy. We found that sustained [Ca2+]i elevations constitute the predominant response to antigen stimulation of SLE T cells. This defect is selective to SLE as it was not observed in RA T cells. Further, we observed that in normal T cells termination of Ca2+ influx is accompanied by Kv1.3 permanence in the IS, while Kv1.3 premature exit from the IS correlates with sustained Ca2+ responses in SLE T cells. Thus, we propose that Kv1.3 trafficking abnormalities contribute to the altered distribution in Ca2+ signaling in SLE T cells. Overall these defects may explain in part the T cell hyperactivity and dysfunction documented in SLE patients.
doi:10.1016/j.ceca.2009.11.001
PMCID: PMC2819652  PMID: 19959227
human; T cells; autoimmunity; systemic lupus erythematosus
23.  Adipose segmentation in small animals at 7T: a preliminary study 
BMC Genomics  2010;11(Suppl 3):S9.
Background
Small animal MRI at 7 Tesla (T) provides a useful tool for adiposity research. For adiposity researchers, separation of fat from surrounding tissues and its subsequent quantitative or semi- quantitative analysis is a key task. This is a relatively new field and a priori it cannot be known which specific biological questions related to fat deposition will be relevant in a specific study. Thus it is impossible to predict what accuracy and what spatial resolution will be required in all cases and even difficult what accuracy and resolution will be useful in most cases. However the pragmatic time constraints and the practical resolution ranges are known for small animal imaging at 7T. Thus we have used known practical constraints to develop a method for fat volume analysis based on an optimized image acquisition and image post processing pair.
Methods
We designed a fat segmentation method based on optimizing a variety of factors relevant to small animal imaging at 7T. In contrast to most previously described MRI methods based on signal intensity of T1 weighted image alone, we chose to use parametric images based on Multi-spin multi-echo (MSME) Bruker pulse sequence which has proven to be particularly robust in our laboratory over the last several years. The sequence was optimized on a T1 basis to emphasize the signal. T2 relaxation times can be calculated from the multi echo data and we have done so on a pixel by pixel basis for the initial step in the post processing methodology. The post processing consists of parallel paths. On one hand, the weighted image is precisely divided into different regions with optimized smoothing and segmentation methods; and on the other hand, a confidence image is deduced from the parametric image according to the distribution of relaxation time relationship of typical adipose. With the assistance of the confidence image, a useful software feature was implemented to which enhances the data and in the end results in a more reliable and flexible method for adipose evaluation.
Results
In this paper, we describe how we arrived at our recommended procedures and key aspects of the post-processing steps. The feasibility of the proposed method is tested on both simulated and real data in this preliminary research. A research tool was created to help researchers segment out fat even when the anatomical information is of low quality making it difficult to distinguish between fat and non-fat. In addition, tool is designed to allow the operator to make adjustments to many of the key steps for comparison purposes and to quantitatively assess the difference these changes make. Ultimately our flexible software lets the researcher define key aspects of the fat segmentation and quantification.
Conclusions
Combining the full T2 parametric information with the optimized first echo image information, the research tool enhances the reliability of the results while providing more flexible operations than previous methods. The innovation in the method is to pair an optimized and very specific image acquisition technique to a flexible but tuned image post processing method. The separation of the fat is aided by the confidence distribution of regions produced on a scale relevant to and dictated by practical aspects of MRI at 7T.
doi:10.1186/1471-2164-11-S3-S9
PMCID: PMC2999354  PMID: 21143791
24.  Immune reconstitution inflammatory syndrome presenting as chylothorax in a patient with HIV and Mycobacterium tuberculosis coinfection: a case report 
BMC Infectious Diseases  2010;10:321.
Background
Patients with human immunodeficiency virus (HIV) infection are at risk for Mycobacterium tuberculosis (TB) coinfection. The advent of antiretroviral therapy restores immunity in HIV-infected patients, but predisposes patients to immune reconstitution inflammatory syndrome (IRIS).
Case Presentation
A 25-year-old HIV-infected male presented with fever, productive cough, and body weight loss for 2 months. His CD4 cell count was 11 cells/μl and HIV-1 viral load was 315,939 copies/ml. Antituberculosis therapy was initiated after the diagnosis of pulmonary TB. One week after antituberculosis therapy, antiretroviral therapy was started. However, multiple mediastinal lymphadenopathies and chylothorax developed. Adequate drainage of the chylothorax, suspension of antiretroviral therapy, and continued antituberculosis therapy resulted in successful treatment and good outcome.
Conclusions
Chylothorax is a rare manifestation of TB-associated IRIS in HIV-infected patients. Careful monitoring for development of IRIS during treatment of HIV-TB coinfection is essential to minimize the associated morbidity and mortality.
doi:10.1186/1471-2334-10-321
PMCID: PMC2988055  PMID: 21059235
25.  Involvement of the Cytoskeleton in Controlling Leading-Edge Function during Chemotaxis 
Molecular Biology of the Cell  2010;21(11):1810-1824.
Cells activate signaling pathways at the site closest to the chemoattractant source that lead to pseudopod formation and directional movement up the gradient. We demonstrate that cytoskeletal components required for cortical tension, including MyoII and IQGAP/cortexillins help regulate the level and timing of leading-edge pathways.
In response to directional stimulation by a chemoattractant, cells rapidly activate a series of signaling pathways at the site closest to the chemoattractant source that leads to F-actin polymerization, pseudopod formation, and directional movement up the gradient. Ras proteins are major regulators of chemotaxis in Dictyostelium; they are activated at the leading edge, are required for chemoattractant-mediated activation of PI3K and TORC2, and are one of the most rapid responders, with activity peaking at ∼3 s after stimulation. We demonstrate that in myosin II (MyoII) null cells, Ras activation is highly extended and is not restricted to the site closest to the chemoattractant source. This causes elevated, extended, and spatially misregulated activation of PI3K and TORC2 and their effectors Akt/PKB and PKBR1, as well as elevated F-actin polymerization. We further demonstrate that disruption of specific IQGAP/cortexillin complexes, which also regulate cortical mechanics, causes extended activation of PI3K and Akt/PKB but not Ras activation. Our findings suggest that MyoII and IQGAP/cortexillin play key roles in spatially and temporally regulating leading-edge activity and, through this, the ability of cells to restrict the site of pseudopod formation.
doi:10.1091/mbc.E10-01-0009
PMCID: PMC2877640  PMID: 20375144

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