Clinical Characteristics of Voice, Speech, and Swallowing Disorders in Oromandibular Dystonia.
To better define the clinical characteristics of idiopathic oromandibular dystonia, we studied voice, speech, and swallowing disorders and their impact on activities of daily living. Fourteen consecutive patients with idiopathic oromandibular dystonia and 14 matched, healthy control subjects were included in the study. Dysarthria was the most common disorder and its characteristics varied from one patient to another. However, we frequently observed a hyperkinetic, dysarthric profile characterized by imprecise consonants, a rough voice, changes in intensity, and hypernasality. Dysphagia appeared to be slightly less frequent and less disabling than dysarthria. Most patients had difficulty swallowing solids, and the oral phase was particularly problematic. Dysarthria and dysphagia affected activities of daily living in general and the psychological/emotional domain in particular. The characteristics of dysarthria in oromandibular dystonia vary significantly from one patient to another due to differences in the set of affected muscles, so each patient should receive a personalized rehabilitation program. Dysarthria was the most prominent symptom, although spasmodic dysphonia was more frequent than expected. Further laboratory-based studies are needed to clarify the mechanisms and consequences of dysphagia in oromandibular dystonia.


Coalescence of 3-phenyl-propynenitrile on Cu(111) into interlocking pinwheel chains.
3-phenyl-propynenitrile (PPN) adsorbs on Cu(111) in a hexagonal network of molecular trimers formed through intermolecular interaction of the cyano group of one molecule with the aromatic ring of its neighbor. Heptamers of trimers coalesce into interlocking pinwheel-shaped structures that, by percolating across islands of the original trimer coverage, create the appearance of gear chains. Density functional theory aids in identifying substrate stress associated with the chemisorption of PPN's acetylene group as the cause of this transition.


Cinnamon extracts' inhibitory effect on Helicobacter pylori.
Ethanol and methylene chloride extracts of cinnamon were compared for their effect on Helicobacter pylori growth and urease activity. Methylene chloride extract was found to inhibit growth of H. pylori, while ethanol extract counteracted its urease activity. Cinnamon extract (from methylene chloride) inhibited H. pylori at concentration range of common antibiotics. Complete inhibition in vitro was achieved by 50 microg/ml in solid medium (egg yolk emulsion agar) and by 15 microg/ml in liquid medium (supplemented brain heart infusion broth). The cinnamon extracts were more inhibitory on free urease than on whole cell urease.


Group IIa secretory phospholipase A2 (sPLA2IIa) and progression in patients with lung cancer.
Group IIa secretory phospholipase A2 (sPLA2 IIa) plays a role in the malignant potential of several epithelial cancers. It is overexpressed in many cancer specimens and its elevated levels are correlated with high tumor grade and metastasis. Here, we evaluate the clinical significance of sPLA2 IIa in lung adenocarcinoma and the role of sPLA2 IIa in the process of cancer cell invasion and metastasis. Immunohistochemistry was used to investigate sPLA2 IIa in surgically resected lung adenocarcinoma of 180 patients and its correlation with survival. We overexpressed sPLA2 IIa in a lung adenocarcinoma cell line with very low sPLA2 IIa levels and investigated the in vitro and in vivo effects of sPLA2 IIa expression. High expression of sPLA2 IIa in lung cancer tissue was significantly associated with clinical stage, metastasis, postoperative relapse and shorter patient survival. The overexpression of sPLA2 IIa enhanced xenograft tumor growth and invasion in vitro. sPLA2 IIa expression can predict the clinical outcome of lung adenocarcinoma patients. sPLA2 IIa is a novel invasion-promoting gene in lung adenocarcinoma.


Population dynamics of HIV-1 subtype B in a cohort of men-having-sex-with-men in Rome, Italy.
A recent increase in HIV diagnoses among men-having-sex-with-men (MSM) has been shown by surveillance data from Europe and Italy, and new approaches to inferring viral population dynamics from heterochronously sampled gene sequences have been developed. The aim of this study was to reconstruct the epidemiological history of HIV-1 subtype B in a homogeneous group of Italian MSM using a coalescent-based Bayesian framework. A total of 125 HIV-1 subtype B pol sequences were analyzed using Bayesian methods and a relaxed molecular clock to reconstruct their dated phylogeny and estimate population dynamics. At least 10 epidemiological clusters of 3-9 isolates were identified: half including the largest clades originated in the early 1990s and the other half radiated from 1999. Demographic analysis showed that the HIV epidemic grew in accordance with a logistic model characterized by a rapid exponential increase in the effective number of infections (r = 1.54 year) starting from the early 1980s and reaching a plateau 10 years later. Our data suggest that the HIV B epidemic entered our MSM population through multiple transmission chains about 20 years later than in other Western European country. Epidemiological clusters originating in the early 2000s suggest a recent re-emergence of HIV in Italian MSM.


Clot Extraction With the FlowTriever Device in Acute Massive Pulmonary Embolism.
Clinical guidelines support the use of systemic thrombolytic therapy for acute massive pulmonary embolism (PE). When anticoagulation and thrombolysis fail or are contraindicated, options become limited. We report an acute PE case in which treatment options were limited, and a novel device, the FlowTriever (Inari Medical, Irvine, California), was successfully used. This is the first case report of the use of this device that we are aware of.


Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach.
Aspirin-intolerant asthma (AIA) is a subtype of bronchial asthma characterized by development of bronchoconstriction evoked by non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the cyclooxygenase pathway, leading to enhancement of the lipoxygenase pathway. We evaluated allelic association of 370 single nucleotide polymorphisms (SNPs) of 63 candidate genes, mostly from the arachidonic acid metabolic cascade, with AIA. After two rounds of screening with 198 AIA patients, multiple SNPs in the prostaglandin E(2) receptor subtype 2 (EP2) gene were associated with AIA (P<0.05). Among the 77 SNPs identified in the EP2 gene, we selected 17 SNPs on the basis of linkage disequilibrium and allelic frequencies (minor allele frequency >0.1) for further association study. SNPs in the promoter region of the EP2 gene, uS5, uS5b, and uS7, were significantly associated with AIA (permutation P=0.039-0.001). Analysis of haplotypes constructed according to the LD pattern showed a significant association with AIA (permutation P=0.001). The most significantly associated SNP, uS5, located in the regulatory region of the EP2 gene, was in a STATs-binding consensus sequence [AIA 31.1% versus control 22.1% (permutation P=0.0016) or versus aspirin-tolerant asthma 22.2% (permutation P=0.0017)]. Although STAT1 binding was not observed in gel mobility shift assay with HeLa nuclear extract, an unidentified protein was specifically bound to the allelic sequence. In in vitro reporter assay in HCT116 cells, the site containing the uS5 allele showed reduced transcription activity. Taken together, these results suggest that uS5 allele serves as a target of a transcription repressor protein. A functional SNP of the EP2 gene associated with risk of AIA should decrease the transcription level, resulting in reduction of the PGE(2) braking mechanism of inflammation and involvement in the molecular mechanism underlying AIA.


Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia.
The Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. A single-nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. This study investigated the association between the Bcl-2 rs956572 SNP and brain structural abnormalities in non-demented elders, and to test the relationship between neuropsychological performance and regional gray matter (GM) volumes. Our sample comprised 97 non-demented elderly men with a mean age of 80.6 ± 5.6 years (range, 65 to 92 years). Cognitive test results, magnetic resonance imaging, and genotyping of Bcl-2 rs956572 were examined for each subject. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. Subjects with G homozygotes exhibited significantly worse performance in the language domain of the Cognitive Abilities Screening Instrument (CASI; p = 0.009). They also showed significantly smaller GM volumes in the right middle temporal gyrus (MTG) (BA 21), but larger GM volumes in the left precuneus (BA 31), right lingual gyrus (BA 18), and left superior occipital gyrus (BA 19) relative to A-allele carriers (p < 0.001). A trend toward a positive correlation between right MTG GM volumes and the language domain of CASI was also evident (r = 0.181; p = 0.081). The findings suggest that Bcl-2 rs956572 SNP may modulate cognitive function and regional GM volume in non-demented elderly men, and that this polymorphism may affect language performance through its effect on the right MTG.


Abnormal hippocampal development in children with medulloblastoma treated with risk-adapted irradiation.
Children with medulloblastoma demonstrate post-treatment neurocognitive deficits in a number of areas, including memory performance. However, there is no definitive understanding of the neuropathology underlying these functional deficits. Previous literature has reported that hippocampal integrity is crucial to the acquisition of new episodic memories. Therefore, we hypothesized that longitudinal hippocampal volume measurements are abnormal in patients with medulloblastoma and thereby provide a possible substrate for explaining memory dysfunction. Twenty-five pediatric patients underwent 159 serial MR imaging examinations (mean = six examinations per patient) for up to 5 years after irradiation and chemotherapy treatment for medulloblastoma. Right and left hippocampal volumes were obtained by manually tracing 1.5-mm contiguous coronal sections through the structure. Random coefficient models were used to examine longitudinal change in hippocampal volume as a function of time after diagnosis. Both right and left hippocampal volumes initially decreased after treatment. This abnormal volume pattern continued until approximately 2-3 years after diagnosis, when hippocampal volumes returned toward a normal positive growth pattern. Volume loss occurred predominately in the posterior regions. Female sex, low parental education, shunt placement, and positive seizure history all had a significant negative impact on hippocampal volume. Pediatric medulloblastoma survivors demonstrate an abnormal pattern of hippocampal volume development after treatment. Radiation dose mapping may expand our understanding of region-specific changes in hippocampal volume. Further exploration of the relationships between radiation therapy, memory dysfunction, and hippocampal pathology in this population is warranted.


Molecular evidence that the genes for dioecism and monoecism in Spinacia oleracea L. are located at different loci in a chromosomal region.
Spinach (Spinacia oleracea L.) is widely known to be dioecious. However, monoecious plants can also occur in this species. Sex expression in dioecious spinach plants is controlled by a single gene pair termed X and Y. Our previous study showed that a single, incompletely dominant gene, which controls the monoecious condition in spinach line 03-336, should be allelic or linked to X/Y. Here, we developed 19 AFLP markers closely linked to the monoecious gene. The AFLP markers were mapped to a 38.2-cM chromosomal region that included the monoecious gene, which is bracketed between flanking markers with a distance of 7.1 cM. The four AFLP markers developed in our studies were converted into sequence-characterized amplified region (SCAR) markers, which are linked to both the monoecious gene and Y and are common to both populations segregating for the genes. Linkage analysis using the SCAR markers suggested that the monoecious gene (M) and Y are located in different intervals, between different marker pairs. Analysis of populations segregating for both M and Y also directly demonstrates linkage of the genes at a distance of ~12 cM. The data presented in this study may be useful for breeding dioecious and highly male monoecious lines utilized as the pollen parents for hybrid seed production, as well as for studies of the evolutionary history of sexual systems in this species, and can provide a molecular basis for positional cloning of the sex-determining genes.


Is adult separation anxiety associated with offspring risk for internalizing psychiatric problems?
Awareness of adult separation anxiety (ASA) is growing, but there is a dearth of knowledge about how separation anxiety aggregates in families. We examined the intergenerational associations of separation anxiety and other forms of internalizing problems in an American community sample of 515 predominantly white children and their parents. Children's separation anxiety (CSA), depression, and other anxiety disorders were modeled as latent factors using diagnoses from interviews and symptom scores from questionnaires completed by mothers, fathers, and children when children were 9 years old and again 3 years later. Parents' separation anxiety was assessed via a questionnaire and parents' other anxiety, depressive, and substance use disorders were assessed with a diagnostic interview when children were nine. Relationships between parents' and children's psychopathology were modeled using s.e.m. Mothers' and fathers' ASA were related to all three psychopathology factors in offspring, over and above other parental disorders, in concurrent and prospective analyses. CSA was also related to maternal depression concurrently and prospectively and to maternal anxiety prospectively. Of all paternal psychopathology variables, only ASA was significantly related to children's psychopathology in either model. Results indicate that parental separation anxiety is an important, but non-specific, risk factor for children's psychopathology. The pathway by which this risk is transmitted may be genetic or environmental, and the observed statistical associations likely also encompass child-to-parent effects.


Rapidly Growing Facial Tumor in a 5-Year-Old Girl.
The aim of this study is to describe the clinical, radiological and histological characteristics that define lipoblastomas with special emphasis on differential diagnosis. The patient is a 5-year-old girl who consulted for a rapidly growing lower cheek tumor. This study analyzes, evaluates, and discusses the issues that need to be addressed throughout the process that affect treatment planning and provides an updated review of these rare head-and-neck tumors.


Optimization of the SPME parameters and its online coupling with HPLC for the analysis of tricyclic antidepressants in plasma samples.
Solid-phase microextraction (SPME)-liquid chromatography (LC) is used to analyze tricyclic antidepressant drugs desipramine, imipramine, nortriptyline, amitriptyline, and clomipramine (internal standard) in plasma samples. Extraction conditions are optimized using a 2(3) factorial design plus a central point to evaluate the influence of the time, temperature, and matrix pH. A Polydimethylsiloxane-divinylbenzene (60-mum film thickness) fiber is selected after the assessment of different types of coating. The chromatographic separation is realized using a C(18) column (150 x 4.6 mm, 5-microm particles), ammonium acetate buffer (0.05 mol/L, pH 5.50)-acetonitrile (55:45 v/v) with 0.1% of triethylamine as mobile phase and UV-vis detection at 214 nm. Among the factorial design conditions evaluated, the best results are obtained at a pH 11.0, temperature of 30 degrees C, and extraction time of 45 min. The proposed method, using a lab-made SPME-LC interface, allowed the determination of tricyclic antidepressants in in plasma at therapeutic concentration levels.


Approaches to learning of student nurses.
This paper presents findings from a study of student nurses' learning styles in an Institution of Higher Education in South Wales, United Kingdom (UK). The aim of the research was to evaluate students' approaches to learning as measured by a study process questionnaire (SPQ). The questionnaire is viewed as a reliable and valid measure of students' learning, and has been used extensively with students in higher education in Australia. The SPQ is a 42-item questionnaire measuring surface, deep and achieving approaches to learning. It was distributed to 300 student nurses attending the common foundation program of a preregistration-nursing course. Data were entered into SPSS Windows Release 10. The results indicated that many of the students were taking a surface approach or surface-achieving approach to their studies. There was little difference in results between undergraduates and diploma students or between students majoring in different nursing specialties. The deep and achieving approaches to learning scores correlated positively and significantly with overall mean assessment scores of students, the deep approach with Sociology scores and negatively and significantly with Psychology scores. The implications of these results are discussed in relation to curriculum design and the demands of higher education.


Heterologous Expression of a Thermostable α-Glucosidase from Geobacillus sp. Strain HTA-462 by Escherichia coli and Its Potential Application for Isomaltose⁻Oligosaccharide Synthesis.
Isomaltose-oligosaccharides (IMOs), as food ingredients with prebiotic functionality, can be prepared via enzymatic synthesis using α-glucosidase. In the present study, the α-glucosidase (GSJ) from Geobacillus sp. strain HTA-462 was cloned and expressed in Escherichia coli BL21 (DE3). Recombinant GSJ was purified and biochemically characterized. The optimum temperature condition of the recombinant enzyme was 65 °C, and the half-life was 84 h at 60 °C, whereas the enzyme was active over the range of pH 6.0-10.0 with maximal activity at pH 7.0. The α-glucosidase activity in shake flasks reached 107.9 U/mL and using 4-Nitrophenyl β-D-glucopyranoside (pNPG) as substrate, the Km and Vmax values were 2.321 mM and 306.3 U/mg, respectively. The divalent ions Mn2+ and Ca2+ could improve GSJ activity by 32.1% and 13.8%. Moreover, the hydrolysis ability of recombinant α-glucosidase was almost the same as that of the commercial α-glucosidase (Bacillus stearothermophilus). In terms of the transglycosylation reaction, with 30% maltose syrup under the condition of 60 °C and pH 7.0, IMOs were synthesized with a conversion rate of 37%. These studies lay the basis for the industrial application of recombinant α-glucosidase.


Is a Chlamydia vaccine a reality?
Chlamydia trachomatis is a leading cause of sexually transmitted bacterial infections with severe sequelae such as tubal factor infertility and ectopic pregnancy; infections can also be asymptomatic. So far no vaccine has been developed but studies that may lead to the development of a highly warranted vaccine have been performed. The first attempt to vaccinate children with a whole-cell vaccine initially resulted in protection but the protection was short-lived. In animal models whole-cell vaccination resulted in hypersensitivity reactions, so that new strategies were devised. The first immunogenic molecule described was the major outer membrane protein (MOMP), and this molecule has therefore been studied in great detail as a candidate vaccine. Even though complete protection was not obtained, reduced shedding was observed and vaccine trials in animal models using naked DNA as a vaccine resulted in stimulation of both the humoral and cellular immune response, indicating progress in the development of a vaccine.


Guidelines for management of patients with methicillin-resistant Staphylococcus aureus in acute care hospitals and long-term care facilities. The MRSA Interagency Advisory Committee in conjunction with the Connecticut Department of Public Health and Addiction Services, July 1993.
Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that can colonize or infect people. MRSA strains are not more virulent than methicillin susceptible strains. Colonized and infected patients represent the most important reservoir of MRSA in hospitals. MRSA is transmitted by direct person-to-person contact, usually on the hands of health care workers. Limiting the spread of MRSA is desirable because the organism is resistant to oxacillin, nafcillin, cephalosporins, and imipenem. Treatment of choice for MRSA infection is usually intravenous vancomycin. The preferred methods for antimicrobial susceptibility testing of S. aureus include oxacillin-salt screening plates, microdilution broth tests with 2% NaCI, and disk diffusion tests incubated for 24 hours at 35 degrees C. Hospitals and LTCFs should monitor the incidence of nosocomial transmission of MRSA in their facility. Hospital admission because of MRSA infection is acceptable medical practice because treatment can best be accomplished in an acute care setting. However, given special circumstances, treatment of MRSA infection can be accomplished in an extended care facility or at home. This decision is based on the clinical judgement of the attending physician. Hospital admission solely because of MRSA colonization is unwarranted. MRSA colonization is not a contraindication to discharge from an acute care hospital to home or another facility. When a hospitalized patient who is colonized with MRSA no longer needs to receive acute nursing care (i.e. their MRSA infection and/or other acute medical problems are under control), they can be discharged. If they are discharged to another institution, that institution should be notified in advance that the patient is colonized with MRSA.


Radical scavenging and chemical repair of rutin observed by pulse radiolysis: as a basis for radiation protection.
Pulse radiolysis was conducted to investigate: several fundamental reactions of a natural flavonoid, rutin, and its glycosylated form (αG-rutin) as a basis for their radiation protection properties; the reactions with •OH (radical scavenging) and dGMP radical, dGMP• (chemical repair), which was used as a model of initial and not yet stabilised damage on DNA. Three absorption peaks were commonly seen in the reactions of the flavonoids with •OH, showing that their reactive site is the common structure, i.e. aglycone. One among the three peaks was attributed to the flavonoid radical produced as a result of the removal of a hydrogen atom. The same peak was found in their reactions with dGMP•, showing that dGMP• is chemically repaired by obtaining a hydrogen atom supplied from the flavonoids. Such a spectral change due to the chemical repair was as clear as never reported. The rate constants of the chemical repair reaction were estimated as (9 ± 2)×108 M-1 s-1 and (6 ± 1)×108 M-1 s-1 for rutin and αG-rutin, respectively. The rate constants of the radical scavenging reactions towards •OH were estimated as (1.3 ± 0.3)×1010 M-1 s-1 and (1.0 ± 0.1)×1010 M-1 s-1 for rutin and αG-rutin, respectively. In addition, there was no obvious difference between rutin and αG-rutin, indicating that the glycosylation does not change early chemical reactions of rutin.


Growth inhibition and ultrastructural alterations induced by Delta24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms.
Although Candida species are commensal microorganisms, they can cause many invasive fungal infections. In addition, antifungal resistance can contribute to failure of treatment.The purpose of this study was to evaluate the antifungal activity of inhibitors of Delta24(25)-sterol methyltransferase (24-SMTI), 20-piperidin-2-yl-5alpha-pregnan-3beta-20(R)-diol (AZA), and 24(R,S),25-epiminolanosterol (EIL), against clinical isolates of Candida spp., analysing the ultrastructural changes. AZA and EIL were found to be potent growth inhibitors of Candida spp. isolates. The median MIC50 was 0.5 microg.ml-1 for AZA and 2 microg.ml-1 for EIL, and the MIC90 was 2 microg.ml-1 for both compounds. All strains used in this study were susceptible to amphotericin B; however, some isolates were fluconazole- and itraconazole-resistant. Most of the azole-resistant isolates were Candida non-albicans (CNA) species, but several of them, such as C. guilliermondii, C. zeylanoides, and C. lipolytica, were susceptible to 24-SMTI, indicating a lack of cross-resistance. Reference strain C. krusei (ATCC 6258, FLC-resistant) was consistently susceptible to AZA, although not to EIL. The fungicidal activity of 24-SMTI was particularly high against CNA isolates. Treatment with sub-inhibitory concentrations of AZA and EIL induced several ultrastructural alterations, including changes in the cell-wall shape and thickness, a pronounced disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, mitochondrial swelling, and the presence of electron-dense vacuoles. Fluorescence microscopy analyses indicated an accumulation of lipid bodies and alterations in the cell cycle of the yeasts. The selectivity of 24-SMTI for fungal cells versus mammalian cells was assessed by the sulforhodamine B viability assay. Taken together, these results suggest that inhibition of 24-SMT may be a novel approach to control Candida spp. infections, including those caused by azole-resistant strains.


Combination study of 1,24(S)-dihydroxyvitamin D2 and chemotherapeutic agents on human breast and prostate cancer cell lines.
Vitamin D compounds are important modulators of cellular proliferation and differentiation, with potential utility as anticancer drugs. 1,24(S)-Dihydroxyvitamin D2 [1,24(OH)2D2] is a naturally occurring active vitamin D compound with low calcemic activity. We evaluated the growth inhibitory effects of 1,24(OH)2D2 on LNCaP prostate cancer and MCF-7 breast cancer cells. 1,24(OH)2D2 was evaluated alone and in paired combination with nine chemotherapeutic agents. Drug interactions were analyzed using the median-effect/isobologram method. Combination index values were used to characterize the interactions as synergistic, additive, or antagonistic. In MCF-7 cells, 1,24(OH)2D2 produced synergistic effects with doxonrubicin and cisplatin and additive effects with busulfan, etoposide, tamaxifen, 5-fluorouracil and carboplatin. In LNCaP cells, 1,24(OH)2D2 produced a synergistic effect with carboplatin and additive effects with doxorubicin, busulfan, paclitaxel and etoposide. We conclude that 1,24(OH)2D2 may have therapeutic value in the treatment of prostate and breast cancers, alone or in combination with chemotherapeutic agents.


[Dieulafoy ulcer associated with acute drug-induced gastritis: a rare case].
The lesion in Dieulafoy's disease consists of an unusually large and tortuous artery in the base of an ulcer. The disease is underdiagnosed rather than truly rare and often presents with a massive and potentially fatal, usually repeated, haematemesis. The authors describe a case of Dieulafoy's disease associated with acute drug-induced gastritis whose gravity required, in the case reported, a very serious emergency treatment.


[Fatty acid variation in yellowfin tuna, spotted weakfish and Florida pompano when submitted to six cooking techniques].
The aim of the present study was to analyze the effect of six cooking techniques (steamed, foiled, foiled with banana leaf, baked, microwave-cooked and light frying) in the fatty acid content of Thunnus albacore (yellowfin tuna), Cynoscionnebulosus (spotted weakfish) and Trachinotuscarolinus (Florida pompano). After cooking the fish fillets, fatty acid analyses were performed using gas chromatography. Total lipids increased in all cooking techniques in tunaand spotted weakfish. Saturated fatty acids of tuna and spotted weakfish increased in three cooking techniques, while in Florida pompano only gas oven raised their content. Lightly frying generated the highest content of n-3 in tuna and spotted weakfish, and the lowest in Florida pompano, specie that presented less variation. In tuna fish, the most recommended cooking techniques are foiled with aluminum and microwave oven; for spotted weakfish, foiled with banana leaf; while Florida pompano can be prepared using all cooking methods except gas oven. This information is useful to enrich data from chemical composition tables, in which concentrations are usually presented in raw food.


Positively Charged Combinatory Drug Delivery Systems against Multi-Drug-Resistant Breast Cancer: Beyond the Drug Combination.
The formation and development of cancer is usually accompanied by angiogenesis and is related to multiple pathways. The inhibition of one pathway by monotherapy might result in the occurrence of drug resistance, tumor relapse, or metastasis. Thus, a combinatory therapeutic system that targets several independent pathways simultaneously is preferred for the treatment. To this end, we prepared combinatory drug delivery systems consisting of cytotoxic drug SN38, pro-apoptotic KLAK peptide, and survivin siRNA with high drug loading capacity and reductive responsiveness for the treatment of multi-drug-resistant (MDR) cancer. With the help of positive charge and the synergistic effect of different drug, the combinatory systems inhibited the growth of doxorubicin-resistant breast cancer cells (MCF-7/ADR) efficiently. Interestingly, the systems without siRNA showed more superior in vivo anticancer efficacy than those with siRNA which exhibited enhanced in vitro cytotoxicity and pro-apoptotic ability. This phenomenon could be attributed to the preferential tumor accumulation, strong tumor penetration, and excellent tumor vasculature targeting ability of the combinatory micelles of SN38 and KLAK. As a result, a combinatory multitarget therapeutic system with positive charge induced tumor accumulation and vasculature targeting which can simultaneously inhibit the growth of both tumor cell and tumor vasculature was established. This work also enlightened us to the fact that the design of combinatory drug delivery systems is not just a matter of simple drug combination. Besides the cytotoxicity and pro-apoptotic ability, tumor accumulation, tumor penetration, or vascular targeting may also influence the eventual antitumor effect of the combinatory system.


Isolation and characterization of Nrf1p, a novel negative regulator of the Cdc42p GTPase in Schizosaccharomyces pombe.
The Cdc42p GTPase and its regulators, such as the Saccharomyces cerevisiae Cdc24p guanine-nucleotide exchange factor, control signal-transduction pathways in eukaryotic cells leading to actin rearrangements. A cross-species genetic screen was initiated based on the ability of negative regulators of Cdc42p to reverse the Schizosaccharomyces pombe Cdc42p suppression of a S. cerevisiae cdc24(ts) mutant. A total of 32 S. pombe nrf (negative regulator of Cdc forty two) cDNAs were isolated that reversed the suppression. One cDNA, nrf1(+), encoded an approximately 15 kD protein with three potential transmembrane domains and 78% amino-acid identity to a S. cerevisiae gene, designated NRF1. A S. pombe Deltanrf1 mutant was viable but overexpression of nrf1(+) in S. pombe resulted in dose-dependent lethality, with cells exhibiting an ellipsoidal morphology indicative of loss of polarized cell growth along with partially delocalized cortical actin and large vacuoles. nrf1(+) also displayed synthetic overdose phenotypes with cdc42 and pak1 alleles. Green fluorescent protein (GFP)-Cdc42p and GFP-Nrf1p colocalized to intracellular membranes, including vacuolar membranes, and to sites of septum formation during cytokinesis. GFP-Nrf1p vacuolar localization depended on the S. pombe Cdc24p homolog Scd1p. Taken together, these data are consistent with Nrf1p functioning as a negative regulator of Cdc42p within the cell polarity pathway.


Efficient clearance of poly(ethylene glycol)-modified immunoenzyme with anti-PEG monoclonal antibody for prodrug cancer therapy.
The F(ab')(2) fragment of the anti-TAG-72 antibody, B72.3, was covalently linked to Escherichia coli-derived beta-glucuronidase that was modified with methoxypoly(ethylene glycol). The conjugate (B72.3-betaG-PEG) localized to a peak concentration in LS174T xenografts within 48 h after injection, but enzyme activity persisted in plasma such that prodrug administration had to be delayed for at least 4 days to avoid systemic prodrug activation and associated toxicity. Conjugate levels in tumors decreased to 36% of peak levels at this time. Intravenous administration of AGP3, an IgM mAb against methoxypoly(ethylene glycol), accelerated clearance of conjugate from serum and increased the tumor/blood ratio of B72. 3-betaG-PEG from 3.9 to 29.6 without significantly decreasing the accumulation of conjugate in tumors. Treatment of nude mice bearing established human colon adenocarcinoma xenografts with B72. 3-betaG-PEG followed 48 h later with AGP3 and a glucuronide prodrug of p-hydroxyaniline mustard significantly (p< or =0.0005) delayed tumor growth with minimal toxicity compared to therapy with a control conjugate or conventional chemotherapy.


AIDS cholangiopathy as initial presentation of HIV infection.
AIDS related cholangiopathy is a known clinical entity, but most cases described in literature are known cases of HIV infection who have presented with pain abdomen. AIDS cholangiopathy as the initial presentation of HIV infection is very rare. Here we report such a case.


Social Media in Neurosurgery: Using ResearchGate.
Neurosurgery is a unique field, which would benefit greatly from increased global collaboration, furthering research efforts. ResearchGate is a social media platform geared toward scientists and researchers. This study evaluated the use of ResearchGate for neurosurgical research collaboration and compared the ResearchGate score with more classic bibliometrics. ResearchGate is a unifying social platform that can strengthen global research collaboration (e.g., data sharing) in the neurosurgery community. Publicly available metrics on 3718 neurosurgery clinical faculty and residents in Canada and the United States were obtained from the American Association of Neurological Surgeons Web site. The following metrics were collected: program name, clinician name, sex, attending (yes or no), resident (yes or no), postgraduate year (if resident), and ResearchGate profile (yes or no). ResearchGate score and its components and h index excluding self-citations were collected. Fellows were not included. Of the 3718 total individuals included, 1338 (36.0%) were present on ResearchGate, comprising 181 women (13.5%) and 1157 men (86.5%). Women and men were present in similar proportions (33.8% of women and 36.3% of men) (χ2 [1, N = 3718] = 1.26; P = 0.26). More faculty were present on ResearchGate than residents (62.4%) (χ2 [1, N = 3718] = 11.42; P = 0.001). A strong positive monotonic correlation between h index and ResearchGate score was shown (rs [1292] = 0.93; P < 0.0005). More than 400 international departments were determined. ResearchGate may be a useful platform to increase neurosurgical networking and research collaboration. Its novel bibliometrics are strongly correlated with more classic platforms.


Signal detection for vaccine side effects that have not been specified in advance.
An information-theoretic definition of similarity proposed by Dekang Lin in 1998 appears to have attractive properties for identifying medically similar cases in a large database. Examination of similar cases that appear following vaccination may provide a way of detecting previously unexpected associations. A key element here is the inclusion of shared time-since-vaccination as a dimension of similarity while considering concordance on many other features. The system is potentially much more sensitive to patterns with multiple features than are very large, high-dimension contingency tables.


Response to: 'Why medical professionals have no moral claim to conscientious objection accommodation in liberal democracies' by Schuklenk and Smalling.
The recent essay by Schuklenk and Smalling opposing respect for physicians' conscientious objections to providing patients with medical services that are legally permitted in liberal democracies is based on several erroneous assumptions. Acting in this manner would have serious harmful effects on the ethos of medicine and of bioethics. A much more nuanced and balanced position is critical in order to respect physicians' conscience with minimal damage to patients' rights.


Work environment effects on labor productivity: an intervention study in a storage building.
Although increased attention has been focused on the relationship between occupational health and productivity, solid scientific data on this topic are sparse. The purpose of the present case study was to assess the relationship between productivity and work environment in a storage building. The study was implemented as an intervention consisting of the renovation of a harbor storage facility. The study design consisted of a single group of employees working in the storage hall. The physical and chemical factors, perceived environment, and labor productivity were measured before and after the renovation. As a result of the renovation, thermal conditions, air quality, and lighting conditions improved notably. In addition, the employees' subjective evaluations showed the significant decrease in dissatisfaction ratings. The direct measure for the labor productivity, expressed as zinc tons/work-hour (tn) increased about 9% after the renovation. We conclude that increased productivity is most likely related to the combined effect of the improved work environment, i.e., better thermal climate, reduced contaminant concentrations, and better lighting conditions.


Financial implications and recommendations for care of ventilator-dependent patients.
Patients who require prolonged mechanical ventilation consume a disproportionately large share of healthcare resources and represent a significant financial burden for traditional acute care institutions. When these patients are evaluated as a population, trends that may facilitate medical and financial management emerge. This report examines the demographics, cost/reimbursement, and current management of patients who require prolonged mechanical ventilation. Recommendations for potential reduction of costs, revenue producing alternatives, or both in delivering healthcare to this aggregate are also explored.


Clinical Features and Changes in Insulin Requirements in People with Type 2 Diabetes Requiring Insulin When Hospitalised with SARS-CoV-2 Infection.
Uncontrolled hyperglycaemia before and during hospitalisation is a risk factor for adverse outcomes in people with diabetes and SARS-CoV-2 infection. Insulin often at high doses is frequently required to manage hyperglycaemia associated with SARS-CoV-2 infection during hospitalisation. However, there is limited information on the clinical features and sequelae of people with type 2 diabetes (T2DM) not previously on insulin that require insulin as a new treatment when hospitalised with SARS-CoV-2 infection. To describe the clinical features and insulin treatment sequelae of 113 people with T2DM that required insulin as a new treatment when hospitalised with SARS-CoV-2 infection. A single-centre study of 113 people with T2DM who were not on insulin before their admission for SARS-CoV-2 infection. The primary aim of our study was to identify clinical and biochemical features that were associated with the need for insulin as a new treatment in people with known T2DM not on insulin treatment at the time of hospitalisation for SARS-CoV-2 infection. We also describe changes in insulin requirements at time of discharge from hospital and 6 weeks later during the first wave of SARS-CoV-2 infection (April-March 2020) in the UK. Clinical, biochemical, and anthropometric data were collected from electronic health records. We observed that of 113 people with T2DM, 35% (n = 39) needed insulin as a new treatment during their hospitalisation for SARS-CoV-2 infection. People requiring insulin were younger, had a higher preadmission HbA1c, were more frequently on oral medication for diabetes before the admission, and were more likely to be obese (body mass index ≥30 kg/m2), with p ≤ 0.001 for all. In multivariable logistic regression analyses, we observed that younger age and higher HbA1c before admission were independently associated with needing insulin, with one-year increase in age associated with decreased odds of needing insulin initiation (OR 0.91, 95% CI 0.83-0.99), and increasing preadmission HbA1c by 1 mmol/mol associated with an increased odds of insulin initiation (OR 1.05, 95% CI 1.002-1.11) (p < 0.05 for both). Of the 39 people with T2DM who required insulin as a new treatment, 28% remained on insulin at the time of discharge with their insulin dose falling from 1.26 U/kg within the first 7 days of admission to 0.39 U/kg at discharge. At 6 weeks after discharge, 24% of people remained on insulin. More than one-third of people with T2DM not previously treated with insulin required new insulin treatment when hospitalised with SARS-CoV-2 infection, and of this group, 24% remained on insulin at 6 weeks after discharge. This study highlights the important variations of insulin requirements in people with T2DM new to insulin and the importance of a dedicated team for patient education and close follow-up.


Altered compensatory cytokine signaling underlies the discrepancy between Flt3-/- and Flt3l-/- mice.
The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in Flt3l-/- mice than in Flt3-/- mice. This has led to speculation that Flt3L binds to another receptor that also supports DC development. However, we found that Flt3L administration does not generate DCs in Flt3-/- mice, arguing against a second receptor. Instead, Flt3-/- DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of Csf1r in Flt3-/- mice further reduced DC development, indicating that these cytokines could compensate for Flt3. Surprisingly, Flt3-/- DC progenitors displayed enhanced M-CSF signaling, suggesting that loss of Flt3 increased responsiveness to other cytokines. In agreement, deletion of Flt3 in Flt3l-/- mice paradoxically rescued their severe DC deficiency. Thus, multiple cytokines can support DC development, and the discrepancy between Flt3-/- and Flt3l-/- mice results from the increased sensitivity of Flt3-/- progenitors to these cytokines.


Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.
The issue of whether regular use of an inhaled beta2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication. Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.


Maxillary and sphenoid sinus aplasia in Turkish individuals: a retrospective review using computed tomography.
The absence of a maxillary or sphenoid sinus in an adult is an extremely rare condition. We investigated maxillary and sphenoid sinus aplasia in adult Turkish individuals using computed tomography (CT). We examined CT scans in the axial and coronal planes of the paranasal sinuses in 1,526 patients. The CT scans of a 21-year-old male were notable for bilateral maxillary sinus aplasia. Another patient, a 20-year-old female, had CT scans that showed the unilateral absence of a maxillary sinus. Two additional cases showed the unilateral absence of one sphenoid sinus. Bilateral absence of the sphenoid sinuses was not observed in our study. The clinical implications of maxillary and sphenoid sinus aplasia will be further discussed.


Pharmacokinetic-pharmacodynamic integration of enrofloxacin and its metabolite ciprofloxacin in buffalo calves.
The present study was planned with an objective to test the pharmacokinetics of a new formulation of enrofloxacin (Flobac® SA) in buffalo calves. The drug was administered at the dose rate of 7.5 mg kg-1 body weight through the intravenous (i.v.) and intramuscular (i.m.) route followed by plasma collection and analysis at different time intervals. After analysis, using High Performance Liquid Chromatography - Ultraviolet, various pharmacokinetic parameters were calculated using visual fit for compartmental analysis, followed by integration with pharmacodynamic parameters against Escherichia coli and Pasteurella multocida. Although total area under plasma drug concentration time curve was higher through the i.v. route, mean residence time and metabolic conversion ratio was higher following administration by the i.m. route indicating longer persistence of the drug in body. Overall i.m. bioavailability of the parent compound with its metabolite was found to be 91%. Upon, Pharmacokinetic-Pharmacodynamic integration, all the parameters indicated significant antibacterial activity. It can be concluded that the dose of enrofloxacin used in the present study can be administered to contain infections caused by P. multocida and E. coli in buffalo calves.


Mental illness in nursing homes.
This report presents statistics on residents of nursing homes who had at least one condition that can be classified as a mental illness. Data for this major subgroup of nursing home residents are presented by length of stay since admission, source of payment in the month before the survey, functional dependencies in the activities of daily living, usual living arrangements prior to admission, and reasons for admission, according to major demographic and facility characteristics. This report also includes selected comparisons between residents with and without mental disorders. Estimates are based on data collected in the 1985 National Nursing Home Survey.


The Influence of Probiotics on the Firmicutes/Bacteroidetes Ratio in the Treatment of Obesity and Inflammatory Bowel disease.
The two most important bacterial phyla in the gastrointestinal tract, Firmicutes and Bacteroidetes, have gained much attention in recent years. The Firmicutes/Bacteroidetes (F/B) ratio is widely accepted to have an important influence in maintaining normal intestinal homeostasis. Increased or decreased F/B ratio is regarded as dysbiosis, whereby the former is usually observed with obesity, and the latter with inflammatory bowel disease (IBD). Probiotics as live microorganisms can confer health benefits to the host when administered in adequate amounts. There is considerable evidence of their nutritional and immunosuppressive properties including reports that elucidate the association of probiotics with the F/B ratio, obesity, and IBD. Orally administered probiotics can contribute to the restoration of dysbiotic microbiota and to the prevention of obesity or IBD. However, as the effects of different probiotics on the F/B ratio differ, selecting the appropriate species or mixture is crucial. The most commonly tested probiotics for modifying the F/B ratio and treating obesity and IBD are from the genus Lactobacillus. In this paper, we review the effects of probiotics on the F/B ratio that lead to weight loss or immunosuppression.


Predictors of incident heart failure in a large insured population: a one million person-year follow-up study.
Studies on the incidence and predictors of heart failure (HF) are often restricted to elderly persons or identify only inpatient cases. We determined the incidence and predictors of new HF diagnosed in either outpatient or inpatient settings, among 359 947 women and men (age ≥18 years) insured by Kaiser Permanente Georgia at any time during calendar years 2000 to 2005. Subjects were free of HF at baseline, and incident HF was identified with ICD-9 codes (1 inpatient or 2 outpatient HF visits). We developed multivariable Cox models to assess the association of antecedent factors (coronary heart disease, hypertension, diabetes mellitus, atrial fibrillation, and valvular heart disease) with incident HF. Separate models were created for each sex and for newly diagnosed HF in outpatient or inpatient settings. There were 4001 incident HF cases (50% women and 48% in subjects <65 years old), during 1 015 794 person-years of follow-up. The incidence rate of HF was greater in men than in women (4.24 versus 3.68 per 1000 person-years) but was stable across the study interval in both sexes. Two thirds of incident HF cases from this population occurred in outpatients. These 5 antecedent factors and age yielded excellent discrimination for incident HF in both outpatients and inpatients and in both sexes (C >0.85 in all models). Common modifiable risk factors accurately discriminate women and men at risk for HF diagnosed in either outpatient or inpatient settings. Approximately two thirds of new HF cases in our insured population were diagnosed in outpatients; more research is needed to characterize these subjects and their prognosis.


Communication between researchers and practitioners: findings from a qualitative evaluation of a large-scale college intervention.
Many community-based intervention studies experience problems with collaboration between researchers and practitioners. A preferred strategy appears to be to form community coalitions to carry out the proposed interventions in the community, but doing so risks shifting the focus from intervention objectives to coalition process. As a by-product, coalitions often lack understanding of the project goals and are not given specific instructions on how to implement the intervention. In contrast to conventional wisdom, the Safer California Universities study implemented a very directive approach in collaboration with local liaisons on the participating campuses, even though this approach is seen to risk cooperation or commitment from collaborators. This paper reports on the findings of a qualitative study based on interviews with campus liaisons of how the directive approach was perceived on the participating campuses. Findings indicate that the strategy was successful in terms of "getting things done" but could have been improved in terms of liaison involvement in setting objectives, and in finding the optimal level of specificity.


FoxK1 is Required for Ectodermal Cell Differentiation During Planarian Regeneration.
Forkhead box (Fox) genes belong to the "winged helix" transcription factor superfamily. The function of some Fox genes is well known, such as the role of foxO in controlling metabolism and longevity and foxA in controlling differentiation of endodermal tissues. However, the role of some Fox factors is not yet well characterized. Such is the case of FoxK genes, which are mainly studied in mammals and have been implicated in diverse processes including cell proliferation, tissue differentiation and carcinogenesis. Planarians are free-living flatworms, whose importance in biomedical research lies in their regeneration capacity. Planarians possess a wide population of pluripotent adult stem cells, called neoblasts, which allow them to regenerate any body part after injury. In a recent study, we identified three foxK paralogs in the genome of Schmidtea mediterranea. In this study, we demonstrate that foxK1 inhibition prevents regeneration of the ectodermal tissues, including the nervous system and the epidermis. These results correlate with foxK1 expression in neoblasts and in neural progenitors. Although the triggering of wound genes expression, polarity reestablishment and proliferation was not affected after foxK1 silencing, the apoptotic response was decreased. Altogether, these results suggest that foxK1 would be required for differentiation and maintenance of ectodermal tissues.


Rationally Constructed Surface Energy and Dynamic Hard Domains Balance Mechanical Strength and Self-Healing Efficiency of Energetic Linear Polymer Materials.
Polymeric materials that simultaneously possess excellent mechanical properties and high self-healing ability at room temperature, convenient healing, and facile fabrication are always a huge challenge. Herein, we report on surface-energy-driven self-healing energetic linear polyurethane elastomers (EPU) that were facilely fabricated by two-step methods to acquire high healing efficiency and mechanical properties. By constructing surface energy and dynamic hard domains, energetic linear polyurethane elastomers not only obtained high healing ability and mechanical properties at high or room temperature but also avoid the use of some assisted healing conditions and complex chemical structure design and decrease manufacturing difficulty. Based on the interfacial healing physical model, various trends of surface tension, radius, and depth of the crack bottom were calculated to analyze the healing mechanism. We propose that polyurethane elastomers with low junction density could generate excess surface energy resulting from damage and drive self-healing, and incorporating a small amount of disulfide bonds increases the slightly packed hard phase and decreases the healing energy barrier. This work may offer a novel strategy for improving mechanical tensile and healing ability in the field of self-healing material application.


Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals.
During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.


Spatial distribution of tumor-specific monoclonal antibodies in human melanoma xenografts.
The time-dependent (1-72-h) spatial distribution of three biotinylated anti-melanoma monoclonal antibodies (MAbs), a control MAb, and several macromolecular tracers was studied in two small (4-12-mg), well-characterized human melanoma xenografts (SK-MEL-2, M21) growing in the s.c. space of athymic nude mice. The specific MAbs (436, IND1, and 9.2.27) recognize two different melanoma cell surface antigens (Mr 125,000 glycoprotein melanoma-associated antigen and high molecular weight melanoma-associated antigen) and have equilibrium association constants differing by two orders of magnitude (10(8)-10(10) M-1). SK-MEL-2 tumors were poorly vascularized and were composed of one or several collections of tumor cells with few intratumor blood vessels. In contrast, M21 tumors induced a strong angiogenic response and were organized into multiple small tumor cell nests separated from each other by fine blood vessels. Neither tumor developed extensive connective tissue stroma. In both tumors, hyperpermeable blood vessels were concentrated at the tumor-host interface but some intratumor vessels in M21 tumors were also leaky. Macromolecular tracers extravasated extensively from leaky vessels into tumor stroma but penetrated poorly into tumor parenchyma. All three tumor-specific MAbs stained tumor cell surfaces in a time-dependent fashion such that one-half or more of all tumor cells were stained by 24-48 h. Tumor cell staining was favored by increased density of tumor cell antigens but, at the doses studied, was little affected by differences in affinity among tumor-specific antibodies. The distribution of MAb staining was nonuniform in two respects: (a) peripherally situated tumor cells were more likely to be stained than centrally placed cells, and only in the smallest tumors did MAb reach centrally placed tumor cells; and (b) staining was nonuniform in different parts of the same tumor. The inhomogeneity of tumor cell staining by tumor-specific MAb was attributable to several factors, including: tumor blood vessel number, distribution, perfusion and permeability; distribution of tumor connective tissue stroma; small volume of the parenchymal interstitial space and relatively impaired diffusion of macromolecules in that space (low effective diffusivity of MAb); and interactions between specific MAbs and tumor cells. Of these factors, those associated with the parenchymal compartment apparently were rate limiting, and strategies that enhance parenchymal penetration are likely to improve solid tumor therapy with MAbs.


Validity and Reliability of Pre-matriculation and Institutional Assessments in Predicting USMLE STEP 1 Success: Lessons From a Traditional 2 x 2 Curricular Model.
We have observed that students' performance in our pre-clerkship curriculum does not align well with their United States Medical Licensing Examination (USMLE) STEP1 scores. Students at-risk of failing or underperforming on STEP1 have often excelled on our institutional assessments. We sought to test the validity and reliability of our course assessments in predicting STEP1 scores, and in the process, generate and validate a more accurate prediction model for STEP1 performance. Student pre-matriculation and course assessment data of the Class of 2020 (n = 76) is used to generate a stepwise STEP1 prediction model, which is tested with the students of the Class of 2021 (n = 71). Predictions are developed at the time of matriculation and subsequently at the end of each course in the programing language R. For the Class of 2021, the predicted STEP1 score is correlated with their actual STEP1 scores, and data agreement is tested with means-difference plots. A similar model is generated and tested for the Class of 2022. STEP1 predictions based on pre-matriculation data are unreliable and fail to identify at-risk students (R2 = 0.02). STEP1 predictions for most year one courses (anatomy, biochemistry, physiology) correlate poorly with students' actual STEP1 scores (R2 = 0.30). STEP1 predictions improve for year two courses (microbiology, pathology, and pharmacology). But integrated courses with customized NBMEs provide more reliable predictions (R2 = 0.66). Predictions based on these integrated courses are reproducible for the Class of 2022. MCAT and undergraduate GPA are poor predictors of student's STEP1 scores. Partially integrated courses with biweekly assessments do not promote problem-solving skills and leave students' at-risk of failing STEP1. Only courses with integrated and comprehensive assessments are reliable indicators of students' STEP1 preparation.


Bis(1-benzoyl-7-meth-oxy-naphthalen-2-yl) terephthalate.
The title molecule, C44H30O8, lies about a crystallographic inversion centre located at the centre of the central benzene ring. The benzene rings in the benzoyl and the terephthalate units make dihedral angles of 67.05 (7)° and 57.57 (7)°, respectively, with the naphthalene ring system. There is an intra-molecular C-H⋯O inter-action between the ketonic carbonyl O atom and an H atom on the naphthalene ring system. In the crystal, C-H⋯O inter-action of the benzene ring in the benzoyl group and weak C=O⋯π inter-action [O⋯centroid = 3.375 (2) Å] of the naphthalene ring with the O atom in the ketonic carbonyl group are observed. These inter-actions form layers parallel to the bc plane.


Dynamic-range compression affects the lateral position of sounds.
Dynamic-range compression acting independently at each ear in a bilateral hearing-aid or cochlear-implant fitting can alter interaural level differences (ILDs) potentially affecting spatial perception. The influence of compression on the lateral position of sounds was studied in normal-hearing listeners using virtual acoustic stimuli. In a lateralization task, listeners indicated the leftmost and rightmost extents of the auditory event and reported whether they heard (1) a single, stationary image, (2) a moving/gradually broadening image, or (3) a split image. Fast-acting compression significantly affected the perceived position of high-pass sounds. For sounds with abrupt onsets and offsets, compression shifted the entire image to a more central position. For sounds containing gradual onsets and offsets, including speech, compression increased the occurrence of moving and split images by up to 57 percentage points and increased the perceived lateral extent of the auditory event. The severity of the effects was reduced when undisturbed low-frequency binaural cues were made available. At high frequencies, listeners gave increased weight to ILDs relative to interaural time differences carried in the envelope when compression caused ILDs to change dynamically at low rates, although individual differences were apparent. Specific conditions are identified in which compression is likely to affect spatial perception.


Mechanism of metalloid-induced death in Leishmania spp.: role of iron, reactive oxygen species, Ca2+, and glutathione.
There is growing evidence that metalloid-induced cell death in protozoan parasites is due to oxidative injury; however, the biochemical changes related to this event are not fully understood. Leishmania spp. demonstrated cross-resistance to two related metalloids, arsenic and antimony, and both metalloids induced cell death accompanied by cell shrinkage and DNA fragmentation that was preceded by an increase in reactive oxygen species. Both drugs caused mitochondrial dysfunction in terms of loss of membrane potential and a drop in ATP levels. Arsenic treatment resulted in an elevation of intracellular Ca2+ levels that did not occur with antimony exposure. Cellular glutathione level was reduced after antimony treatment but arsenic did not affect glutathione. Inhibition of Ca2+ influx during arsenic treatment reduced cell death, whereas supplementation of glutathione during antimony treatment rescued cell loss. Under iron-depleted conditions, the cytotoxic effects of arsenic and antimony did not occur and cell survival increased; in contrast, the presence of excess iron resulted in higher cell death. Therefore, this study provides a new possibility that iron can potentiate parasite death induced by metalloids like arsenic and antimony. In addition, an important observation is that the two similar metalloids produce toxicity by very different mechanisms.


Interpretation of results for tumor markers on the basis of analytical imprecision and biological variation.
Interpretation of results for CA 15.3, carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) during breast cancer monitoring requires data on intra- (CVP) and inter- (CVG) individual biological variation, analytical imprecision (CVA), and indices of individuality. The average CVP and CVG obtained from 22 healthy women were, respectively, 6.2% and 62.9% (CA 15.3), 9.3% and 86.8% (CEA), and 28.3% and 133% (TPA). The indices of individuality were all < 0.6: 0.2 (CA 15.3), 0.15 (CEA), and 0.2 (TPA). CVA depended on the concentration of the analytes. CVP and CVA determine what constitutes a significant difference between sequential results. Assuming a CVA of 11.2% (CA 15.3), 9.5% (CEA), or 11.9% (TPA), results must differ by 30%, 31%, or 72%, respectively, for P < or = 0.05. We found that CVP and CVA contribute considerably to the variation during breast cancer monitoring. Consequently, both CVP and CVA should be considered in criteria for marker evaluation. Because of low indices of individuality, conventional cutoff limits are inappropriate both for initial identification and for follow-up of breast cancer.


Clonal similarity of salivary and nasopharyngeal Fusobacterium nucleatum in infants with acute otitis media experience.
The environment of an infant's nasopharynx during acute otitis media (AOM) favours the growth of anaerobic bacteria, which can be recovered frequently during infection, but hardly at all if the infant is healthy. The aim of this investigation was to identify the potential source and inoculation route of anaerobes that were present in the nasopharynx. Eleven Fusobacterium nucleatum isolates that were collected through the nasal cavity from the nasopharynx of eight infants with a history of AOM, and 161 F. nucleatum isolates from the saliva of the same infants, were typed to the clonal level by using arbitrarily primed PCR (AP-PCR). In five of the eight infants examined, identical AP-PCR types were found among nasopharyngeal and salivary isolates. As anaerobes seem to be present only transiently in the nasopharynx and salivary contamination of the nasopharyngeal samples can be excluded, this observation indicates that the source of nasopharyngeal anaerobes is the oral cavity and that saliva is their transmission vehicle.


Obtaining Natural Sit-to-Stand Motion with a Biomimetic Controller for Powered Knee Prostheses.
Standing up from a seated position is a common activity in people's daily life. However, for transfemoral (i.e., above-knee) amputees fitted with traditional passive prostheses, the sit-to-stand (STS) transition is highly challenging, due to the inability of the prosthetic joints in generating torque and power output. In this paper, the authors present a new STS control approach for powered lower limb prostheses, which is able to regulate the power delivery of the prosthetic knee joint to obtain natural STS motion similar to that displayed by healthy subjects. Mimicking the dynamic behavior of the knee in the STS, a unified control structure provides the desired control actions by combining an impedance function with a time-based ramp-up function. The former provides the gradual energy release behavior desired in the rising phase, while the latter provides the gradual energy injection behavior desired in the loading phase. This simple and intuitive control structure automates the transition between the two phases, eliminating the need for explicit phase transition and facilitating the implementation in powered prostheses. Human testing results demonstrated that this new control approach is able to generate a natural standing-up motion, which is well coordinated with the user's healthy-side motion in the STS process.


In Vitro Activity of KBP-7072 against 536 Acinetobacter baumannii Complex Isolates Collected in China.
Acinetobacter baumannii has emerged globally as a difficult-to-treat nosocomial pathogen and become resistant to carbapenems, resulting in limited treatment options. KBP-7072 is a novel semisynthetic aminomethylcycline, expanded spectrum tetracycline antibacterial agent with completed phase 1 clinical development studies. This study aimed to evaluate the in vitro activity of KBP-7072 and several comparators against clinical A. baumannii isolates collected from China. A collection of 536 A. baumannii clinical isolates were isolated from 20 hospitals across 13 provinces and cities in China between 2018 and 2019. Antimicrobial susceptibility testing of 12 antimicrobial agents was performed utilizing the broth microdilution method recommended by CLSI. KBP-7072 has shown active antibacterial activity against 536 A. baumannii isolates. It inhibited the growth of all isolates at 4 mg/liter, including 372 carbapenem-resistant isolates, 37 tigecycline MIC ≥ 4 mg/liter isolates, and 138 omadacycline MIC ≥ 4 mg/liter isolates. Compared with other expanded spectrum tetracyclines, KBP-7072 (MIC90, 1 mg/liter) outperformed 2-fold and 4-fold more active against 536 A. baumannii isolates than tigecycline (MIC90, 2 mg/liter) and omadacycline (MIC90, 4 mg/liter). KBP-7072 was as equally active as colistin (MIC90, 1 mg/liter, 99.4% susceptible). Doxycycline (33.4% susceptible), gentamicin (31.3% susceptible), meropenem (30.6%, susceptible), imipenem (30.2% susceptible), ceftazidime (27.8% susceptible), piperacillin-tazobactam (27.2% susceptible), and levofloxacin (27.2% susceptible) showed marginally poor antibacterial activity against tested isolates according to CLSI breakpoints, except for minocycline (73.7% susceptible). KBP-7072 is a potential alternative agent for the treatment of infection caused by A. baumannii, including carbapenem-resistant species. IMPORTANCE It is reported that A. baumannii has emerged as an intractable nosocomial pathogen in hospitals especially when it develops resistance to carbapenems and other antibiotics, which limits treatment options and leads to high mortality. In February 2017, the WHO published a list of ESKAPE pathogens designated "priority status" for which new antibiotics are urgently needed. Therefore, the epidemiological surveillance and new therapeutic development of A. baumannii must be strengthened to confront an emerging global epidemic. KBP-7072 is a novel, expanded spectrum tetracycline antibacterial and has demonstrated good in vitro activity against recent geographically diverse A. baumannii isolates collected from North America, Europe, Latin America, and Asia-Pacific. This study has shown excellent in vitro activity of KBP-7072 against clinical A. baumannii isolates collected from different regions of China, regarded as supplementary to KBP-7072 pharmacodynamics data, which is of great significance, as it is promising an alternative treatment in CRAB isolates infections in China.


The use of hormone replacement therapy in women with acute myocardial infarction: an audit of current practice.
We undertook criterion-based audit of the current practice of prescribing hormone replacement therapy for women with acute myocardial infarction; the audit included 181 consecutive women admitted to one hospital with this diagnosis in one calendar year. The set standard was that, barring any contraindication, all postmenopausal women with acute myocardial infarction should be prescribed hormone replacement therapy before discharge from hospital. The evidence base of this standard derives from more than 30 epidemiological and clinical studies and a large body of biological data. Only 4.7% of the women were current users of hormone replacement therapy and the set standard was met in only 3% of eligible nonusers. Professionals caring for women who have had a myocardial infarction need to consider hormone replacement therapy as a secondary prophylaxis of myocardial infarction. Gynaecologists should liaise with colleagues in other specialties and general practice to ensure that information on the nongynaecological benefits of hormone replacement therapy is widely disseminated.


Role of MAP kinases in the 1,25-dihydroxyvitamin D3-induced transactivation of the rat cytochrome P450C24 (CYP24) promoter. Specific functions for ERK1/ERK2 and ERK5.
The current study investigated the action of 1,25-dihydroxyvitamin D(3) (1,25D) at the genomic and signal transduction levels to induce rat cytochrome P450C24 (CYP24) gene expression. A rat CYP24 promoter containing two vitamin D response elements and an Ets-1 binding site was used to characterize the mechanism of actions for the 1,25D secosteroid hormone. The Ets-1 binding site was determined to function cooperatively with the most proximal vitamin D response element in a hormone-dependent fashion. Evidence was obtained for distinct roles of ERK1/ERK2 and ERK5 in the 1,25D-inductive actions. Specifically, 1,25D stimulated the activities of ERK1/ERK2 and ERK5 in a Ras-dependent manner. Promoter induction was inhibited by mitogen-activated protein (MAP) kinase inhibitors (PD98059 and U0126) and a dominant-negative Ras mutant (Ras17N). Induction of CYP24 by 1,25D was also inhibited by overexpression of dominant-negative mutants of ERK1 and MEK5 (ERK1K71R and MEK5(A)). The p38 and JNK MAP kinases were not required for the action of 1,25D. 9-cis retinoid X receptor alpha (RXR alpha) interacted with ERK2 but not ERK5 in intact cells, whereas Ets-1 interacted preferentially with ERK5. Increased phosphorylation of RXR alpha and Ets-1 was detected in response to 1,25D. Activated ERK2 and ERK5 specifically phosphorylated RXR alpha and Ets-1, respectively. Mutagenesis of Ets-1 (T38A) reduced CYP24 promoter activity to levels observed with the dominant-negative MEK5(A) and inhibited ERK5-directed phosphorylation. Mutated RXR alpha (S260A) inhibited 1,25D-induced CYP24 promoter activity and abolished phosphorylation by activated ERK2. The 1,25D-inductive action through ERK5 involved Ets-1 phosphorylation at threonine 38, whereas hormone stimulation of ERK1/ERK2 required RXR alpha phosphorylation on serine 260. The ERK1/ERK2 and ERK5 modules provide a novel mechanism for linking the rapid signal transduction and slower transcription actions of 1,25D to induce CYP24 gene expression.


Case Report: Primary Pulmonary Angiosarcoma With Brain Metastasis.
Primary pulmonary angiosarcoma (PPA) is a rare malignant vascular tumor, of which early diagnosis is challenging due to lack of specific clinical manifestations and a low level of suspicion. Here, we report a case of PPA presented with advanced brain metastasis. A 21-year-old patient with 1 week history of headache and mild cough was hospitalized for a head injury. Head MRI showed multiple intracranial lesions with brain edema. Chest CT displayed bilateral pulmonary infiltrates with mediastinal lymph node enlargement. After 2 months of anti-tuberculosis treatment, the patient was readmitted for persistent headache and cough with occasional hemosputum along with worsening pulmonary and intracranial lesions. Despite seizure prophylaxis and control of intracranial pressure and brain edema, his symptoms progressively aggravated, accompanied by cough with bloody sputum, frequent epileptic seizures, and hypotension. He eventually developed coma and died within 3 months of onset of symptoms. An autopsy confirmed PPA with brain metastasis.


The yeast H+-ATPase Pma1 promotes Rag/Gtr-dependent TORC1 activation in response to H+-coupled nutrient uptake.
The yeast Target of Rapamycin Complex 1 (TORC1) plays a central role in controlling growth. How amino acids and other nutrients stimulate its activity via the Rag/Gtr GTPases remains poorly understood. We here report that the signal triggering Rag/Gtr-dependent TORC1 activation upon amino-acid uptake is the coupled H+ influx catalyzed by amino-acid/H+ symporters. H+-dependent uptake of other nutrients, ionophore-mediated H+ diffusion, and inhibition of the vacuolar V-ATPase also activate TORC1. As the increase in cytosolic H+ elicited by these processes stimulates the compensating H+-export activity of the plasma membrane H+-ATPase (Pma1), we have examined whether this major ATP-consuming enzyme might be involved in TORC1 control. We find that when the endogenous Pma1 is replaced with a plant H+-ATPase, H+ influx or increase fails to activate TORC1. Our results show that H+ influx coupled to nutrient uptake stimulates TORC1 activity and that Pma1 is a key actor in this mechanism.


The phagocytic capability of the various zones of the guinea pig conjunctival epithelium: an electron microscopic study.
The phagocytic capacity of the different zones of the guinea pig conjunctival epithelium from the corneal limbus to the lid margin was investigated using latex microspheres as tracers. After 24 h exposure to a suspension of microspheres, the phagocytic capability of the epithelium could be estimated, zonal differences compared, and the kinetics of the internalized particles followed. The epithelial cells of the perilimbal zone contained the highest number of intracellular microspheres, followed by the cells of the supranodular zone. The phagocytic capability of the other zones was low. In the perilimbal zone a significant number of microspheres seemed to be transferred to the epithelial cells in the deeper layers, but not to the basal cells. In the supranodular zone the phagocytized and apparently transcellularly transported microspheres were secondarily taken up, mainly by polymorphonuclear leukocytes that infiltrated the epithelium.


Ultrastructure of the ovarian follicles in the placentotrophic Andean lizard of the genus Mabuya (Squamata: Scincidae).
We studied the ultrastructural organization of the ovarian follicles in a placentotrophic Andean lizard of the genus Mabuya. The oocyte of the primary follicle is surrounded by a single layer of follicle cells. During the previtellogenic stages, these cells become stratified and differentiated in three cell types: small, intermediate, and large globoid, non pyriform cells. Fluid-filled spaces arise among follicular cells in late previtellogenic follicles and provide evidence of cell lysis. In vitellogenic follicles, the follicular cells constitute a monolayered granulosa with large lacunar spaces; the content of their cytoplasm is released to the perivitelline space where the zona pellucida is formed. The oolemma of younger oocytes presents incipient short projections; as the oocyte grows, these projections become organized in a microvillar surface. During vitellogenesis, cannaliculi develop from the base of the microvilli and internalize materials by endocytosis. In the juxtanuclear ooplasm of early previtellogenic follicles, the Balbiani's vitelline body is found as an aggregate of organelles and lipid droplets; this complex of organelles disperses in the ooplasm during oocyte growth. In late previtellogenesis, membranous organelles are especially abundant in the peripheral ooplasm, whereas abundant vesicles and granular material occur in the medullar ooplasm. The ooplasm of vitellogenic follicles shows a peripheral band constituted by abundant membranous organelles and numerous vesicular bodies, some of them with a small lipoprotein core. No organized yolk platelets, like in lecithotrophic reptiles, were observed. Toward the medullary ooplasm, electron-lucent vesicles become larger in size containing remains of cytoplasmic material in dissolution. The results of this study demonstrate structural similarities between the follicles of this species and other Squamata; however, the ooplasm of the mature oocyte of Mabuya is morphologically similar to the ooplasm of mature oocytes of marsupials, suggesting an interesting evolutionary convergence related to the evolution of placentotrophy and of microlecithal eggs.


Effect of van der Waals interaction on the geometric and electronic properties of DNA nucleosides adsorbed on Cu(111) surface: a DFT study.
The geometrical properties and electronic structure of DNA nucleosides (deoxyadenosine, thymidine, deoxyguanosine, deoxycytidine) adsorbed on a metallic surface of Cu(111) are determined using density functional theory computations. In order to assess the effect of the long-range interaction upon the results of the DFT simulations, we compare the results of a standard GGA exchange-correlation functional with those produced by the newly developed van der Waals exchange-correlation functional. The most striking difference between the two sets of results occurs for the adsorption energies: standard functional predicts values representing about 30% of those obtained when van der Waals interaction is taken into account. The standard GGA functional favors slightly tilted orientation of the DNA bases with respect to the surface, while the inclusion of the van der Waals effect leads to an almost parallel orientation of the bases with the surface. On the other hand, the position of the sugar pucker is less influenced by the type of the exchange-correlation used. According to our studies, in the presence of long-range interactions, the molecule-surface charge transfer is qualitatively affected. Standard functional predicts a decrease of the electronic population of the adsorbate, while the presence of long-range interaction leads to an opposite effect.


PPARγ Alleviates Sepsis-Induced Liver Injury by Inhibiting Hepatocyte Pyroptosis via Inhibition of the ROS/TXNIP/NLRP3 Signaling Pathway.
Sepsis is a systemic inflammatory response syndrome caused by a dysregulated host response to infection. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts anti-inflammatory and antioxidative properties. To investigate the potential effects of PPARγ on sepsis-induced liver injury and determine the related mechanisms, C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to create a sepsis model which was treated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulation of PPARγ decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), and liver pathological damage and improved the 5-day survival rate. Increased expression of PPARγ also decreased sepsis-induced reactive oxygen species (ROS) by promoting the expression of Nrf2. In addition, upregulated PPARγ inhibited the expression of the TXNIP/NLRP3 signaling pathway by reducing ROS-induced injury in the liver during sepsis, which further reduced NLRP3-mediated pyroptosis and the inflammatory response. The role of PPARγ was further examined in in vitro experiments, where lipopolysaccharide- (LPS-) treated HepG2 and Hep3B cells were incubated with GW1929 or GW9662 to upregulate or downregulate the expression of PPARγ. We found that upregulated PPARγ ameliorated LDH release and improved cell viability. Our results indicated that increased expression of PPARγ reduced ROS levels and inhibited the TXNIP/NLRP3 signaling pathway, resulting in decreased pyroptosis and reduced liver dysfunction during sepsis.


[Construction and significance of recombinant hF9 minigene and its stable nonsense mutant cell lines].
This study was purposed to construct the recombinant hF9 minigene and its stable nonsense mutant cell lines, and to investigate its significance. Minigene hF9 was cloned into the mammalian expression vector pCMV-Tag3B; a nonsense mutant containing a premature termination codon (PTC) in the 121(st) amino acid residue was obtained by PCR site-directed mutagenesis; minigene hF9 and nonsense mutant were respectively transfected into HepG2 cells with G418 treatment to get stable HepG2-WT and HepG2-N cell lines. The results confirmed that the minigene hF9 and nonsense mutant were constructed successfully. The gene of interest was amplified by RT-PCR from the stable cell lines, and the minigene hF9 was expressed in the stable cell lines. It is concluded that the recombinant hF9 minigene and its stable nonsense mutant cell lines are constructed successfully. The cell lines can be used to screen the drugs treating the nonsense mutation-caused hemophilia according to PTC read-through approaches.


Burned Ear Reconstruction Using the Combination of an Expanded Postauricular Scar Skin Flap and a Postauricular Fascial Flap.
The external ear is highly vulnerable to burn injury due to its location and thin integument. Reconstruction of the external ear after burns is a major challenge to undertake, and surgeons face many problems, including excessive scar tissue, poor blood supply, a paucity of available skin, and a high infection rate, when designing an operative plan for patients with postburn auricular deformity. In this article, the authors describe their experience of using an expanded postauricular scar flap combined with a postauricular fascial flap as the coverage for the framework for subtotal and total ear reconstruction in 27 burned patients. Four patients developed expander exposure and two developed framework exposure, which were resolved with good results after further repair. After an average follow-up time of 6 months, all of the patients experienced very good cosmetic outcomes, high satisfaction, and low morbidity.


Immunologic Response of HIV-Infected Children to Different Regimens of Antiretroviral Therapy: A Retrospective Observational Study.
Both abacavir- (ABC-) based and zidovudine- (AZT-) based regimens are widely utilized for managing HIV infection in children. Unfortunately, there is a lack of data regarding their immunological response and associated risk factors in Ethiopia. A retrospective hospital-based cohort study was conducted on HIV-infected children in Jimma Medical Center (JMC). A total of 179 records were reviewed by including data from November 2015 to April 2017. Data were collected on sociodemographic, clinical characteristics of patients and drug-related variables. Data analysis was done using STATA 13.1. Mixed-effect linear regression was performed to assess the difference in CD4+ changes between groups adjusting for baseline characteristics. The change in predicted CD4 count attributed to each regimen was also assessed by marginal analysis. P < 0.05 for slope of the random-effect linear regression was used as an indicator for the presence of association. Of 179 patients, 98 (54.7%) were females. The mean (±SD) duration of follow-up was 939.8 ± 478.3 and 984.92 ± 453.1 days for ABC and AZT groups, respectively. AZT group had a significant CD4+ count gain per visit compared with their ABC counterparts ((β = 20.51, 95% CI [6.37-34.65]), P = 0.004) over time. The regimen AZT + 3TC + LPV/r tended to have an excellent predicted CD4+ lymphocyte count change relative to all other regimens, while ABC + 3TC + LPV/r had the least immunologic recovery (margins 338.0 cells/mm3 versus 249.13 cells/mm3 (P < 0.001)). Baseline CD4+ lymphocyte count, ART group, WHO clinical stages, and viral load were independent predictors for CD4+ change overtime. AZT-based regimens seem to have better immunological response compared to ABC-based regimens. Immunologic response was described worse in patients with a viral load of >1000copies/ml, low baseline CD4+ count, advanced WHO clinical stages, and ABC-containing regimens. Further study is needed to clarify these aspects.


Detection of EML4-ALK fusion gene and features associated with EGFR mutations in Chinese patients with non-small-cell lung cancer.
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and epidermal growth factor receptor (EGFR) define specific molecular subsets of lung cancer with distinct clinical features. We aimed at revealing the clinical features of EML4-ALK fusion gene and EGFR mutation in non-small-cell lung cancer (NSCLC). We enrolled 694 Chinese patients with NSCLC for analysis. EML4-ALK fusion gene was analyzed by real-time polymerase chain reaction, and EGFR mutations were analyzed by amplified refractory mutation system. Among the 694 patients, 60 (8.65%) patients had EML4-ALK fusions. In continuity correction χ (2) test analysis, EML4-ALK fusion gene was correlated with sex, age, smoking status, and histology, but no significant association was observed between EML4-ALK fusion gene and clinical stage. A total of 147 (21.18%) patients had EGFR mutations. In concordance with previous reports, EGFR mutation was correlated with age, smoking status, histology, and clinical stage, whereas patient age was not significantly associated with EGFR mutation. Meanwhile, to our surprise, six (0.86%) patients had coexisting EML4-ALK fusions and EGFR mutations. EML4-ALK fusion gene defines a new molecular subset in patients with NSCLC. Six patients who harbored both EML4-ALK fusion genes and EGFR mutations were identified in our study. The EGFR mutations and the EML4-ALK fusion genes are coexistent.


Localization of the gamma-subunit of the skeletal muscle L-type voltage-dependent calcium channel gene (CACNLG) to human chromosome band 17q24 by in situ hybridization and identification of a polymorphic repetitive DNA sequence at the gene locus.
The skeletal muscle dihydropyridine receptor consists of five subunits and fulfils an essential role in excitation-contraction coupling. A genomic clone for the human gamma subunit was used to map the gene (CACNLG) to chromosome band 17q24 by in situ hybridization. Contained within the gene is a 416-bp polymorphic repetitive DNA element that is potentially useful as a genetic marker.


Impairment of Tonoplast H-ATPase as an Initial Physiological Response of Cells to Chilling in Mung Bean (Vigna radiata [L.] Wilczek).
Biochemical alterations of cellular membranes in chilling-sensitive mung bean (Vigna radiata [L.] Wilczek) hypocotyls were investigated with reference to chilling injury. Reversible decreases in activities of tonoplast H(+)-ATPase and in vivo respiration became manifest within 24 hours of chilling when tissues suffered no permanent injury as assessed by electrolyte leakage and regrowth capacity. These changes were found to be the earliest cellular responses to chilling. A density-shift on a sucrose density gradient was observed in Golgi membranes early in the chilling treatment, suggesting that Golgi function and/or membrane biogenesis via the Golgi may have been altered upon chilling. After chilling more than 2 days, irreversible changes were generally produced in cellular membranes including the plasma membrane, endoplasmic reticulum, and mitochondria. Respiratory functions remained intact in mitochondria isolated from tissues prechilled for 24 hours, but were impaired after prechilling for 3 days. Given the important role of the tonoplast H(+)-ATPase in the active transport of ions and metabolites, the early decline in the tonoplast H(+)-ATPase activity may give rise to an alteration of the cytoplasmic environment and, consequently, trigger a series of degenerative reactions in the cells.


R-Axion at Colliders.
We study the effective theory of a generic class of hidden sectors where supersymmetry is broken together with an approximate R-symmetry at low energy. The light spectrum contains the gravitino and the pseudo-Nambu-Goldstone boson of the R-symmetry, the R-axion. We derive new model-independent constraints on the R-axion decay constant for R-axion masses ranging from GeV to TeV, which are of relevance for hadron colliders, lepton colliders, and B factories. The current bounds allow for the exciting possibility that the first sign of supersymmetry will be the R-axion. We point out its most distinctive signals, providing a new experimental handle on the properties of the hidden sector and a solid motivation for searches of axionlike particles.


Amesergide and structurally related nor-D-ergolines: 5HT2 receptor interactions in the rat.
A series of tricyclic (nor-D) partial ergolines were synthesized via a highly convergent enantiospecific strategy, ultimately arising from a racemic tricyclic ketone. Michael addition to an acrylamide, followed by reductive methylation, afforded the key intermediate. Selective deprotection and oxidation provided the tricyclic ergoline. Vascular 5HT2 receptor interactions for the partial ergolines were dramatically reduced compared to the parent ergoline, amesergide, as determined in vivo by activation of a pressor response or blockade of 5HT-induced pressor responses in pithed rats. The desisopropyl tricyclic ergolines possessed some modest pressor activity that was unlikely to be related to 5HT2 receptor activation since these compounds did not inhibit the pressor response to serotonin. In contrast, the isopropyl tricyclic ergolines exhibited no agonist activity, but inhibited the pressor response to serotonin at 1 mg/kg i.v. The ergoline amesergide inhibited the pressor response to serotonin in doses of 0.01-0.1 mg/kg i.v. The homochiral isopropyl tricyclic ergoline was more potent as a 5HT2 receptor antagonist than the epimeric (unnatural stereochemistry) analogue. Thus, the isopropyl moiety on the indole nitrogen is important for vascular 5HT2 receptor affinity in the rat. Most importantly, these data suggest that conformational rigidity of the ergoline D-ring is required for optimal 5HT2 receptor interactions in the rat.


An analytical model for surface EMG generation in volume conductors with smooth conductivity variations.
A nonspace invariant model of volume conductor for surface electromyography (EMG) signal generation is analytically investigated. The volume conductor comprises planar layers representing the muscle and subcutaneous tissues. The muscle tissue is homogeneous and anisotropic while the subcutaneous layer is inhomogeneous and isotropic. The inhomogeneity is modeled as a smooth variation in conductivity along the muscle fiber direction. This may reflect a practical situation of tissues with different conductivity properties in different locations or of transitions between tissues with different properties. The problem is studied with the regular perturbation theory, through a series expansion of the electric potential. This leads to a set of Poisson's problems, for which the source term in an equation and the boundary conditions are determined by the solution of the previous equations. This set of problems can be solved iteratively. The solution is obtained in the two-dimensional Fourier domain, with spatial angular frequencies corresponding to the longitudinal and perpendicular direction with respect to the muscle fibers, in planes parallel to the detection surface. The series expansion is truncated for the practical implementation. Representative simulations are presented. The proposed model constitutes a new approach for surface EMG signal simulation with applications related to the validation of methods for information extraction from this signal.


Seasonal changes in testicular structure and localization of a sperm surface glycoprotein during spermatogenesis in sea urchins.
Testes of the sea urchin, Strongylocentrotus purpuratus, undergo morphological changes consistent with a reproductive season that includes the winter months in the northern hemisphere (c. November to March). These changes can be observed in the basal germinal epithelia (BGE) of testicular acini as alterations in the gradients of meiosis and spermatogenesis from the peripheral (basal) to the inner (luminal) regions. Early in the season, large numbers of spermatogonia and primary spermatocytes along with large, spherical nutritive phagocytes (NPs) occupy most of the BGE. Relatively few secondary spermatocytes, spermatids, and spermatozoa are present. In the middle of the season more spermatocytes, spermatids, and spermatozoa are observed within well-defined spermatogenic columns that run between elongated NPs. Late in the season the BGE diminishes as the number of spermatogenic cells within it decreases dramatically and the lumen becomes distended with mature spermatozoa. To trace the origin and location of a 210 KD sperm surface antigen during spermatogenesis, a monoclonal antibody that recognizes this antigen, MAb J18/2, was used to probe testis sections. Indirect immunofluorescence microscopy detected the antigen throughout the BGE. Immunogold electron microscopy further localized it to the intracellular vesicles within spermatogenic cells of all stages. In mature spermatozoa the 210 KD surface antigen was detected not only on the sperm surfaces overlying the acrosomes and tails but also within the acrosome, suggesting the presence of an intracellular store of this antigen. Other than the occasional detection of antigen within the residual bodies of NPs, which contain phagocytosed spermatozoa, no antigen was detected in somatic cells of the testis, indicating that it is generated within the spermatogenic cells themselves.