EGFR Tyrosine Kinase Inhibitor Efficacy in Older Adult Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer: A Meta-Analysis and Systematic Review.

Background and Objectives: Lung cancer remains the most common malignancy worldwide. As the global population ages, the prevalence of epidermal growth factor receptor (EGFR)-mutation-positive non-small cell lung cancer (NSCLC) is increasing. Materials and Methods: We performed a meta-analysis and a systematic review of randomized, controlled trials to evaluate the efficacy of EGFR TKIs on progression-free survival (PFS) and overall survival (OS) in older adult patients with advanced EGFR-mutated NSCLC. A total of 1327 patients were included; among these, 662 patients were >65 years of age. Results: A pooled analysis indicated (1) an overall improvement in higher PFS for dacomitinib and osimetinib than that for other drugs (hazard ratio [HR] = 0.654, 95% CI: 0.474 to 0.903; p = 0.01) and (2) and no significant difference in the OS between the EGFR TKIs (HR = 0.989, 95% CI: 0.796 to 1.229; p = 921). Conclusion: Our study found that osimertinib achieved a higher PFS than all other EGFR TKIs did. Osimertinib is the preferred EGFR TKI for treatment of older adult patients with advanced EGFR-mutated NSCLC.

Targeting antigens through blood dendritic cell antigen 2 on plasmacytoid dendritic cells promotes immunologic tolerance.

The C-type lectin receptor blood dendritic cell Ag 2 (BDCA2) is expressed exclusively on human plasmacytoid DCs (pDCs) and plays a role in Ag capture, internalization, and presentation to T cells. We used transgenic mice that express human BDCA2 and anti-BDCA2 mAbs to deliver Ags directly to BDCA2 on pDCs in vivo. Targeting Ag to pDCs in this manner resulted in significant suppression of Ag-specific CD4(+) T cell and Ab responses upon secondary exposure to Ag in the presence of adjuvant. Suppression of Ab responses required both a decrease in effector CD4(+) T cells and preservation of Foxp3(+) regulatory T cells (Tregs). Reduction in Treg numbers following Ag delivery to BDCA2 restored both CD4(+) T cell activation and Ab responses, demonstrating that Tregs were required for the observed tolerance. Our results demonstrate that Ag delivery to pDCs through BDCA2 is an effective method to induce immunological tolerance, which may be useful for treating autoimmune diseases or to inhibit unwanted Ab responses.

Antiphospholipid antibodies and cerebellar ataxia: a clinical analysis and literature review.

BACKGROUND: Although it has been established that antiphospholipid antibodies (APAbs) bind to and modulate the signaling of cerebellar neurons in vitro, the clinical correlation between increased APAbs and cerebellar ataxia has rarely been investigated. METHODS: We reviewed 10 patients presenting with cerebellar ataxia with increased blood APAbs from our database along with 3 APAb-associated cerebellar ataxia patients in the literature. RESULTS: Of these 10 patients, 4 exhibited a subacute onset of progressive ataxia, and there were no significant structural changes in their brains that appeared to be responsible for the symptoms. Another 6 showed a chronic course of ataxia, and shared similar morphological changes that included symmetrical lesions in bilateral hemispheres, periventricular lucency and central and temporal atrophy of varying severity; the cerebellum was spared. The predominant APAbs for subacute and chronic ataxia were the anti-beta2-glycoprotein I antibody and anticardiolipin antibody, respectively. Cancer was found in 1 patient with subacute ataxia and in 4 with chronic ataxia. The removal of the cancer, the plasmapheresis and immunosuppressive therapy successfully abolished the ataxia and increased APAb levels in all 5 patients. CONCLUSIONS: The relation between APAbs and nonvascular neurological disorders, such as cerebellar ataxia, should be further studied. APAbs may mediate neurological deficits via different mechanisms such as structural damage or functional neurotoxicity. Clinically, the examination of blood APAb levels is recommended for patients with cerebellar ataxia without a determined cause, and the further survey of systemic cancers in the case of APAb positivity is also recommended. Finally, plasmapheresis is a reasonable and effective treatment for APAb-associated cerebellar ataxia.

A turn-on and reversible Schiff base fluorescence sensor for Al3+ ion.

A simple Schiff-base receptor 2 was prepared. It exhibits an "off-on-type" mode with high sensitivity in the presence of Al3+. The receptor 2 exhibited a high association constant with submicromolar detection for Al3+ in EtOH­H2O (95:5 v/v) solution. The addition of EDTA quenches the fluorescence of the receptor 2·Al3+ complex offering receptor 2 as a reversible chemosensor.

A turn-on and reversible fluorescence sensor for Al3+ ion.

A simple 2-hydroxy-1-naphthaldehyde (receptor 1) serves as a selective chemosensor for Al(3+) based on chelation-enhanced fluorescence (CHEF). The receptor 1 exhibited a high association constant with micromolar detection for Al(3+) in EtOH-H(2)O solution.

Neuro-psychological sequelae in HIV-negative cryptococcal meningitis after complete anti-fungal treatment.

PURPOSES: The cognitive sequelae and influence of depression in patients with cryptococcal meningitis (CM) after complete anti-fungal treatment has not been completely surveyed in literature. METHODS: Seventeen HIV-negative CM patients and 26 health y controls were enrolled in this prospective study. Neuro-psychological evaluation was performed to assess the attention, execution, speech and language, semantic and visuo-construction function, and depression. These were correlated with longitudinal magnetic resonance imaging (MRI) through the following checklists: dilated Virchow-Robin spaces, pseudo-cysts, intra-cerebral nodule or mass, meningeal enhancement, hydrocephalus, and hyper-intensity of white matter. For cognitive outcome measurement, initial clinical and biochemical markers were collected and analyzed. RESULTS: The mean follow-up duration in CM patients was 69.6 months. They had impairments in attention, execution, speech and language, and visuo-construction function, while six (35%) patients fulfilled the depression criteria. Initial cryptococcal antigen titer was inversely correlated with block design score (ρ=-0.54, p<0.05), after adjustment for depression. Patients with two or more CM-related lesions (mean, 19.2; SD, 12.6) (p=0.04). CM with depression is highly associated with poor cognitive performance and higher likelihood of two or more lesions in MRI (likelihood ratio=6.012, p=0.014). CONCLUSION: Cognitive deficits persist in CM patients even after complete treatment. The number of lesions plays an important role in cognitive performance and depression. Extensive involvement of the cognitive domains with wide radiographic presentations suggests a disseminated nature of cryptococcus.

Pallidoreticular lesion in carbon monoxide intoxication by gradient echo: report of a case with parkinsonism features and review of the literature.

PURPOSE: Pallidoreticular damage was defined by lesions involving both the pallidum and the substantia nigra and was only reported in four cases after CO intoxication. CASE REPORT: We report a patient with initial consciousness disturbances followed by parkinsonian features after carbon monoxide intoxication. The unique features in this patient included primary globus pallidus hemorrhage followed by delayed hemorrhage in pallidoreticular topography demonstrated by T1- and T2-weighted imaging. In the follow-up study 7 months later, the patient still presented with parkinsonism features and executive dysfunction while the pallidoreticular signal was only visible by gradient echo sequences but not the other MR conventional sequences. Hypometabolism in the frontal and basal ganglion regions were evident from 99mTc-TRODAT-1 study and partial responsiveness to levodopa in alleviating parkinsonian features was considered. CONCLUSION: This case highlights the delayed development of pallidoreticular damages and its linkage in modulating prefrontal-subcortical neuronal circuits.

Montreal cognitive assessment in assessing clinical severity and white matter hyperintensity in Alzheimer's disease with normal control comparison.

PURPOSE: Use Taiwanese version of the Montreal Cognitive Assessment (MoCA) in evaluating patients in different stages of Alzheimer's disease (AD) and correlate with white matter change. METHODS: Ninety-seven normal controls (NC), 52 very-mild AD (clinical dementia rating [CDR] = 0.5), 48 mild AD (CDR = 1) and 38 moderate AD (CDR = 2) patients were enrolled for the MoCA, Mini- Mental State Examination (MMSE) and the Cognitive Assessment Screening Instrument (CASI). White matter hyperintensities (WMHs) on brain MRI were visually rated and classified as deep or periventricular WMHs. RESULTS: In NC group, education (ß = 0.326) but not age (ß = -0.183, p = 0.069), was significantly related to MoCA score. However, while we added two points to the AD patients with less than 6 years education, the effects of education disappeared as compared with those of 7 years of education. For all educational levels, the cutoff value of MoCA for very-mild AD was 22/23 (sensitivity = 82.7%, specificity = 87.6%). No significant differences were found in the areas under the curves that differentiated NC from the patients with AD for MoCA and MMSE (differences = 0.008, p = 0.490), or for MoCA and CASI (differences = 0.023, p = 0.082). Total WMHs, frontal deep and periventricular WMHs were inversely correlated with the attention and delayed-recall subdomain. CONCLUSION: The MoCA is a good clinical tool for screening very-mild stage AD if the educational effects are carefully considered. The correlation between the executive subdomains with the frontal WMHs also makes it a useful tool for detecting subtle WMHs.

The association of metabolic risk factors and silent brain infarctions in healthy Taiwanese.

PURPOSE: Silent brain infarctions (SBI) commonly go unnoticed due to the subtlety of their neurological signs. However, there is the risk of subsequent symptomatic stroke and dementia. A better understanding of the risk factors of SBI may help accurately predict those who will require treatment. METHODS: This one-year retrospective study enrolled 199 adult healthy Taiwanese. Multiple logistic regression analysis was used to evaluate the relationships between baseline clinical factors and the presence of SBI during the study period. RESULTS: Fifteen (7.5%) healthy subjects had SBI, including 4.9% (5/103) males and 10.4% (10/96) females. Multiple logistic regression analysis revealed that both mean age and hypertension were independently associated with SBI, such that any increase of one year in mean age increased the SBI rate by 7.3%. CONCLUSION: In the present study, there is a close relationship between elderly patients and SBI and any increase of one year in mean age increases the SBI rate by 7.3%. Aside from age, hypertension is by far the strongest modifiable risk factor identified to date. Prospective, longitudinal observational studies are warranted to evaluate the relationship between control of hypertension and SBI in this specific population to determine how to prevent subsequent symptomatic stroke.

Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation.

Transforming growth factor (TGF)-beta inhibits T cell proliferation and differentiation. TGF-beta has been shown to inhibit the expression of transcription factors such as GATA-3 and T-bet that play important roles in T cell differentiation. Here we show that TGF-beta inhibits T cell differentiation at a more proximal step. An early event during T cell activation is increased intracellular calcium levels. Calcium influx in activated T cells and the subsequent activation of transcription factors such as NFATc, events essential for T cell differentiation, are modulated by the Tec kinases that are downstream of the T cell receptor and CD28. We show that in stimulated CD4+ T cells, TGF-beta inhibits phosphorylation and activation of the Tec kinase Itk, increase in intracellular Ca2+ levels, NFATc translocation, and activation of the mitogen-activated protein kinase ERK that together regulate T cell differentiation. Our studies suggest that by inhibiting Itk, and consequently Ca2+ influx, TGF-beta limits T cell differentiation along both the Th1 and Th2 lineages.

Adult-onset Still's disease complicated with hemophagocytic syndrome.

Hemophagocytic syndrome (HS) that occurs in the course of adult-onset Stills disease (AOSD) has been reported only rarely in the literature. HS and AOSD share overlapping clinical and laboratory features, therefore, it is difficult to recognize HS as a complication of AOSD. Here, we report the case of a 46-year old woman with classical features of AOSD. Severe pancytopenia and jaundice associated with extreme hyperferritinemia occurred during high-dose steroid treatment. Bone marrow biopsy showed typical pathological features of hemophagocytosis, which confirmed the coexistence of HS with AOSD. The patient was treated with methylprednisolone pulse therapy of 500 mg/day for 3 days, as recommended in cases of HS complicating AOSD, and her condition improved gradually. During the disease course, extensive studies could not identify any viral infection or other known underlying etiology for the reactive hemophagocytosis. Currently, the patient is in remission on low-dose prednisolone and azathioprine.

Walking ability and functional status after post-acute care for stroke rehabilitation in different age groups: a prospective study based on propensity score matching.

Few studies have compared how rehabilitative post-acute care affects recovery of walking ability and other functions after stroke in different age groups. After propensity score matching (1:1), 316 stroke patients were separated into an aged group (age ≥65 years, n=158) and a non-aged group (age <65 years, n=158). Both groups significantly improved in Barthel index, EuroQol-5 dimension, Berg balance scale, 6-minute walking distance and 5-meter walking speed (P<0.001). The non-aged group had significantly larger improvements in Berg balance scale, instrumental activities of daily living, EuroQol-5 dimension and 6-minute walking distance (P<0.001) compared to the aged group. The two groups did not significantly differ in Barthel index, 5-meter walking speed, length of stay, and cost. The aged group had poorer walking ability and poorer instrumental activities of daily living compared to the non-aged group. After intensive rehabilitative post-acute care, however, the aged group improved in walking ability, functional performance and mental health. Intensive strength training for unaffected lower limbs in the stroke patients achieved good recovery of walking ability and other functions. Overall, intensive rehabilitative post-acute care improved self-care ability and decreased informal care costs. Rehabilitative PAC under per-diem reimbursement is efficient and economical for stroke patients in an aging society.

Patch clamping on plane glass-fabrication of hourglass aperture and high-yield ion channel recording.

Planar patch-clamp has revolutionized ion-channel measurement by eliminating laborious manipulation from the traditional micropipette approach and enabling high throughput. However, low yield in gigaseal formation and/or relatively high cost due to microfabricated processes are two main drawbacks. This paper presents patch clamping on glass substrate-an economical solution without sacrificing gigaseal yield rate. Two-stage CO(2) laser drilling methodology was used to generate an hourglass, funnel-like aperture of a specified diameter with smooth and debris-free surfaces on 150 microm borosilicate cover glass. For 1-3 microm apertures as patch-clamp chips, seal resistance was tested on human embryonic kidney, Chinese hamster ovary, and Jurkat T lymphoma cells with a gigaseal success rate of 62.5%, 43.6% and 66.7% respectively. Results also demonstrated both whole-cell and single channel recording on endogenously expressed ion channels to confirm the capability of different patch configurations.

Reversible and Precisely Controllable p/n-Type Doping of MoTe2 Transistors through Electrothermal Doping.

Precisely controllable and reversible p/n-type electronic doping of molybdenum ditelluride (MoTe2 ) transistors is achieved by electrothermal doping (E-doping) processes. E-doping includes electrothermal annealing induced by an electric field in a vacuum chamber, which results in electron (n-type) doping and exposure to air, which induces hole (p-type) doping. The doping arises from the interaction between oxygen molecules or water vapor and defects of tellurium at the MoTe2 surface, and allows the accurate manipulation of p/n-type electrical doping of MoTe2 transistors. Because no dopant or special gas is used in the E-doping processes of MoTe2 , E-doping is a simple and efficient method. Moreover, through exact manipulation of p/n-type doping of MoTe2 transistors, quasi-complementary metal oxide semiconductor adaptive logic circuits, such as an inverter, not or gate, and not and gate, are successfully fabricated. The simple method, E-doping, adopted in obtaining p/n-type doping of MoTe2 transistors undoubtedly has provided an approach to create the electronic devices with desired performance.

Lymphocytic pleural effusion in acute melioidosis.

An endemic outbreak of melioidosis developed in southern Taiwan following a flood caused by a typhoon in July 2005. A total of 27 patients were diagnosed with the acute and indigenous form of pulmonary melioidosis. Parapneumonic pleural effusions were noted on chest X-rays in six patients. Thoracentesis was done in three patients and all revealed lymphocyte predominance in differential cell count. Burkholderia pseudomallei was isolated in the pleural effusion in one of them. All three patients survived after antibiotic treatment. Lymphocytic pleural effusion is generally seen in tuberculosis or malignancy. However, our findings suggest that melioidosis should be considered in the differential diagnosis of lymphocytic pleural effusion.

Bacteremic melioidosis in southern Taiwan: clinical characteristics and outcome.

BACKGROUND/PURPOSE: In recent years, the number of cases of melioidosis has increased substantially in Taiwan. However, there have been no publications specifically studying patients who have bacteremic melioidosis in Taiwan. This study aimed to determine the clinical characteristics and outcome of patients with bacteremic melioidosis in Taiwan. METHODS: We retrospectively reviewed the records of 30 patients (mean age, 65 years) with blood culture-confirmed melioidosis who were managed at Tainan Municipal Hospital between June 2004 and January 2007. Nineteen out of 30 patients were identified within 1 month after Typhoon Haitang struck in mid-July 2005. A comparison of demographic characteristics, underlying conditions, biochemistry results, and clinical presentations between survivors (n = 21) and non-survivors (n = 9) was analyzed. RESULTS: Underlying conditions were identified in 90% of patients, diabetes mellitus being the commonest (50%). The most common site of infection was the lung (70%), followed by the genitourinary tract (13.3%), peritoneum (6.7%), meninges (3.3%), skin (3.3%), and aorta (3.3%). There were also 20% of cases without a primary site of infection being identified. Twenty percent of patients had multiple sites of infection. The number of bacteremic melioidosis with pneumonia was significantly higher in the post-typhoon outbreak (p = 0.001). Comparing survivors and non-survivors, there were no significant differences in age, gender, underlying conditions, and presence of pneumonia. Significant differences were evident in elevated serum creatinine (p = 0.038) and pH (p = 0.004). Fifty-six percent (5/9) of deaths occurred within 48 hours after presentation to hospital and 67% (6/9) of deaths occurred in the post-typhoon outbreak. Patients with septic shock (p < 0.001), acute renal failure (p = 0.013), and respiratory failure (p = 0.001) had significantly higher mortality. The in-hospital mortality rate was 27% and the relapse rate was 14%. CONCLUSION: The lungs were the most common site of infection in patients with bacteremic melioidosis and rapidly progressive community-acquired pneumonia (CAP) was the major cause leading to mortality. Patients with septic shock, acute renal failure, and acute respiratory failure had a much higher mortality rate. Typhoon Haitang was associated not only with higher numbers of cases and deaths but also with pneumonic presentations. Locally adapted guidelines need to be developed for the treatment of CAP in an endemic area of melioidosis in southern Taiwan and after extreme weather events such as typhoons or heavy rains.

Broadband Omnidirectional Light Trapping in Gold-Decorated ZnO Nanopillar Arrays.

The photoluminescence (PL) and reflectivity characteristics of zinc oxide nanopillars (ZnO-NPs) grown on indium-tin-oxide (ITO)-coated glasses were investigated. The room temperature PL showed bright white-light emission for the undoped ZnO-NPs grown at 600 °C, suggesting the close relation between the optical characteristic and the growth conditions being carried out for obtaining the present ZnO-NPs. The reflectivity of the as-grown ZnO-NPs array was about ∼29% with the wavelength of the incident light ranging from 200 to 1800 nm. Nevertheless, the reflectance reduced significantly to less than 9.9% when a layer of gold (Au) was deposited on ZnO-NPs by sputtering for 5 min, corresponding to more than 65% reduction in Au-coated ZnO-NPs (Au/ZnO-NPs). Moreover, the angle-resolved reflectance measurements on the present Au/ZnO-NPs array show an omnidirectional light-trapping characteristic. These remarkable characteristics, broadband and omnidirectional light-trapping of Au/ZnO-NPs, are attributed to the extended effective optical path of the incident light due to subwavelength scattering resulting from the presence of Au nanoparticles.

Tsukamurella tyrosinosolvens bacteremia with coinfection of Mycobacterium bovis pneumonia: case report and literature review.

INTRODUCTION: We describe an immunocompromised patient with Tsukamurella tyrosinosolvens bacteremia and coinfection of Mycobacterium bovis pneumonia. CASE DESCRIPTION: A 75-year-old male was admitted to our hospital complaining of persistent fever with general malaise. His medical history showed that he had diabetes mellitus (HbA1C 9.2%). A chest computed tomography (CT) showed left upper lung consolidation . Two sets of blood culture at admission finally showed Tsukamurella tyrosinosolvens. Moreover, three transbronchoscopy washing specimen cultures revealed Mycobacterium bovis. DISCUSSION AND EVALUATION: The organism Tsukamurella tyrosinosolvens was identified using conventional biochemical identification methods, PCR-restriction DNA fragment analysis, and 16S rRNA gene sequencing. The clinical mycobacterial isolates were identified to the species level by combining Polymerase Chain Reaction (PCR) with an oligonucleotide microarray to detect the M. bovis amplicons. CONCLUSION: According to our literature review, our patient's case was the first of a coinfection with Tsukamurella tyrosinosolvens and Mycobacterium bovis. Prolonged antibiotic treatment and underlying disease control are necessary for this type of patient.

Electrical isolation and characteristics of permanent magnet-actuated valves for PDMS microfluidics.

This paper presents a magnetically driven valve via a permanent magnet pressing a spacer against deformable polydimethylsiloxane (PDMS) to fully close a microchannel. Its ability for electrical isolation, time response, and resistance to backpressure are interrogated. Simulation of the valve closing process was commenced along with experimental verification. Effects of PDMS thickness, and dimension and aspect ratio of microchannels were characterized. Up to 10 GΩ electrical isolation was demonstrated, as well as 50-70 ms valve response and ∼200 kPa resistible pressure. On-demand actuation for arbitrary flow patterns further quantifies its utility. With advantages of simple fabrication, flexible valving location, and no external power requirement, the on/off valve could be leveraged for proof-of-concept microfluidic devices and other applications.

Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production.

Dendritic-cell (DC)-associated C-type lectin receptors (CLRs) take up antigens to present to T cells and regulate DC functions. DCAL-2 is a CLR with a cytosolic immunoreceptor tyrosine-based inhibitory motif (ITIM), which is restricted to immature DCs (iDCs), monocytes, and CD1a+ DCs. Cross-linking DCAL-2 on iDCs induced protein tyrosine phosphorylation and MAPK activation as well as receptor internalization. To test if DCAL-2 is involved in DC maturation and cytokine expression, we stimulated iDCs with anti-DCAL-2 mAb with or without LPS, zymosan, or CD40L. While anti-DCAL-2 did not induce iDCs to mature, it did up-regulate CCR7 expression and IL-6 and IL-10 production. DCAL-2 signals augmented DC maturation induced by LPS or zymosan, increasing both CCR7 and DC-LAMP expression. Of interest, DCAL-2 ligation had the opposite effects on TLR versus CD40L signaling: anti-DCAL-2 suppressed TLR-induced IL-12 expression, but significantly enhanced CD40L-induced IL-12 production. DCAL-2 ligation also suppressed the ability of TLR-matured DCs to induce IFN-gamma-secreting Th1 cells but augmented the capacity of CD40L-matured DCs to polarize naive T cells into Th1 cells. Thus, DCAL-2 may program DCs differently depending on whether DCs are signaled via TLRs or by T cells. DCAL-2 may be a potential immunotherapeutic target for modulating autoimmune diseases or for developing vaccines.