Comparison of upfront versus deferred cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving systemic therapy: a systematic review and meta-analysis.
This study aimed to conduct a pooled analysis to compare the outcomes of patients with metastatic renal cell carcinoma who received presurgical systemic therapy [(ST); including immunotherapy and/or targeted therapy] followed by cytoreductive nephrectomy (CN) [(deferred CN; (dCN)] with those who underwent upfront CN (uCN) followed by ST. The present study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search was conducted in PubMed, Embase, Web of Science, Scopus, and the Cochrane Library database to identify eligible comparative studies up to April 2023. To evaluate their relevance, pooled hazard ratio with 95% CIs were calculated. A total of 3157 patients were included in nine studies. The dCN group was observed to be correlated with superior overall survival (OS) compared to the uCN group (hazard ratio =0.71, 95% CI 0.57-0.89, P =0.003). Moreover, the authors conducted subgroup analyses according to the type of ST, sample size, sex, age, and risk score, and observed similar outcomes for OS across most subgroups. The results of this study demonstrated that dCN may be associated with improved OS compared to uCN in patients with metastatic renal cell carcinoma receiving ST. However, no significant differences were found between the uCN and dCN groups in the immunotherapy-based combinations subgroup. Further research is needed to confirm these results.


Bronchoalveolar lavage in systemic sclerosis with lung involvement: role and correlations with functional, radiological and scintigraphic parameters.
To evaluate the role and the prognostic value of bronchoalveolar lavage (BAL) in scleroderma patients with interstitial lung disease. We reviewed the records of 79 patients with systemic sclerosis (SSc) who had dyspnea and pulmonary involvement and underwent BAL study. Sixty-two patients were prospectively followed up for 12-36 months and re-evaluated by pulmonary function tests (PFTs). Seventy-nine SSc patients were enrolled (71 F and 8 M), 55 with limited and 24 with a diffuse form; mean age 55 ± 13 years; mean disease duration 55.2 ± 59 months. All patients were ANA positive, of these 30 were anti-topoisomerase-1 positive (anti-Topo1) and 22 were anti-centromere positive (ACA). Thirty-one patients had alveolitis (39.2%) that was neutrophilic in 12 patients, eosinophilic in 3 and mixed (neutrophilic and eosinophilic) in 16 patients. Compared to patients without alveolitis, those with alveolitis had a significant reduction of carbon monoxide diffusing capacity (DLCO), forced vital capacity (FVC) and more elevated lung high-resolution computed tomography (HRCT) scores. Furthermore, alveolar clearance was significantly accelerated. No differences were found between patients with and without alveolitis regarding disease subsets (diffuse vs limited-SSc); a significant predominance of anti-Topo1 antibodies was found in the alveolitis group and of ACA antibodies in the non-alveolitis cohort. During the follow-up, (range: 12-36 months) 62 patients, 26 with and 36 without alveolitis were re-evaluated with PFTs. In the alveolitis group, 12 patients (46.1%) showed stable lung function parameters and 14 had worsened (53.8%). In this group, 20 patients (77%) received cyclophosphamide (CYC): 11 (55%) worsened (5 of them died of cardio-pulmonary complications) and 9 (45%) remained stable. Six patients could not be treated; of these 3 remained stable and 3 worsened. Among 36 patients with normal BAL, 11 (30.5%) showed stable lung function parameters, 13 improved (36.1%) and 12 worsened (33.3%); in this last group, 2 patients died of extra-pulmonary complications. Six patients, with progression of lung fibrosis, were treated with CYC: 3 of them improved and 3 remained stable. Our study revealed a trend toward a more severe course in the SSc patients with BAL alveolitis; probably the non-significant result is related to the low number of the examined subjects and to the selection criteria. However, BAL remains the only tool to exclude lung infections and, in our experience, a useful instrument to evaluate interstitial lung disease in SSc patients.


High prevalence of cognitive impairment after intracerebral hemorrhage.
Cognitive impairment seems to be frequent in intracerebral hemorrhage (ICH) survivors, but remains widely understudied. In this study, we investigated the frequency and patterns of vascular cognitive disorders (VCDs) in patients with cerebral amyloid angiopathy (CAA)-related and deep ICH compared to patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) and healthy controls. We prospectively recruited 20 patients with CAA-related lobar ICH, 20 with deep ICH, 20 with MCI-AD and 17 healthy controls. Patients with cognitive decline pre-ICH were excluded from the analysis. Each participant underwent a comprehensive neuropsychological assessment and a structural brain MRI. Cognitive assessment was performed at a median delay of 4 months after the acute phase in ICH patients, and more than 6 months after the first complaint in MCI-AD patients. Cognitive profiles were compared between groups. The prevalence of VCDs in the ICH groups was estimated using the recent VASCOG criteria. "Mild" and "major VCDs" were respectively observed in 87.5% and 2.5% of all ICH patients. Every patient in the CAA group had mild VCDs. No significant difference was observed in cognitive functioning between CAA-related and deep ICH patients. The most impaired process in the CAA group was naming, with a mean (±standard deviation) z-score of -5.2 ±5.5, followed by processing speed (-4.1±3.3), executive functioning (-2.6 ±2.5), memory (-2.4 ±3.5) and attention (-0.9 ±1.3). This cognitive pattern was different from the MCI-AD patients, but the groups were only different in gestural praxis, and by construction, in memory processes. VCDs are frequent after ICH. Cognitive patterns of patients with deep or CAA-related ICH did not differ, but there was impaired performance in specific domains distinct from the effects of Alzheimer's disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01619709.


Stress-induced birefringence in the isotropic phases of lyotropic mixtures.
In this work, the frequency dependence of the known mechano-optical effect which occurs in the micellar isotropic phases (I) of mixtures of potassium laurate (KL), decanol (DeOH), and water is investigated in the range from 200mHz to 200Hz. In order to fit the experimental data, a model of superimposed damped harmonic oscillators is proposed. In this phenomenological approach, the micelles (microscopic oscillators) interact very weakly with their neighbors. Due to shape anisotropy of the basic structures, each oscillator i (i=1,2,3,...,N) remains in its natural oscillatory rotational movement around its axes of symmetry with a frequency ω_{0i}. The system will be in the resonance state when the frequency of the driving force ω reaches a value near ω_{0i}. This phenomenological approach shows excellent agreement with the experimental data. One can find f∼2.5, 9.0, and 4.0Hz as fundamental frequencies of the micellar isotropic phases I, I_{1}, and I_{2}, respectively. The different micellar isotropic phases I, I_{1}, and I_{2} that we find in the phase diagram of the KL-DeOH-water mixture are a consequence of possible differences in the intermicellar correlation lengths. This work reinforces the possibilities of technological applications of these phases in devices such as mechanical vibration sensors.


Treatment of foregut fistula with biologic plugs.
Enteric fistulas are a recognised complication of various diseases and surgical interventions. Non-operative medical management will result in closure of 60-70% of all fistulas over a six- to eight-week period, those that fail non-operative management will require operative intervention if they are to close. We present a series of upper gastrointestinal fistula managed with endoscopic intervention and insertion of biological fistula plug over a 3-year period across three Hospitals, both public and private, in Western Australia. Over a three-year period, 14 patients were referred for treatment of acute or persistent foregut fistulas. All fistulas were managed with endoscopic intervention and insertion of a porcine small intestine sub-mucosa plug (Biodesign (®) Cook medical Inc., Bloomington, IN, USA). No patients with fistula were excluded. Data were collected on patient demographics and underlying diagnosis. The biological plugs were deployed using three different endoscopic techniques (direct deployment via the endoscope, catheter-assisted endoscopic deployment, or a pull through via a guide wire using a rendezvous technique). Fourteen patients with foregut fistula were treated using biological plugs. The age of the fistulas treated ranged from 14 days to 3 years. The fistulas were predominantly gastric in origin (eight cases). Three oesophageal, one gastro-pleural-bronchial, and two jejunal fistulas were also managed using this technique. Of the 14 fistulas treated using this method, 13 resolved following the treatment. Median time to closure of the fistula was 2 days (range 1-120 days). Three patients required more than one intervention to complete closure. Biological plugs offer a further option for management of the traditionally difficult foregut fistula, without major morbidity associated with other treatment modalities. It is limited to the ability to deploy the plug endoscopically.


Induced pluripotent stem cell (iPSC) lines from two individuals carrying a homozygous (BGUi007-A) and a heterozygous (BGUi006-A) mutation in ELP1 for in vitro modeling of familial dysautonomia.
Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy affecting the development and function of the peripheral nervous system. FD causing gene is IKBKAP, encoding IkappaB kinase complex-associated protein also named elongator complex like protein 1 (IKAP/ELP1). The most common mutation (IVS20 + 6 T > C) causes an exon 20 skipping, leading to a truncated protein. We report the generation of two induced pluripotent stem cell lines from an FD patient with a homozygous mutation in ELP1 and his heterozygous healthy family relative. Both lines highly express pluripotency markers, can differentiate into the three germ layers, retain the disease-causing mutation and display normal karyotypes.


B cells assume the command.
A proinflammatory B cell cytokine activates autoimmunity, and B cell depletion treats multiple sclerosis (Li et al., this issue).


Surgical Resection of Retroperitoneal Sarcomas: Analysis of Factors Determining Outcome.
Retroperitoneal sarcomas (RS) are rare malignant tumors characterized by high local recurrence rates and poor survival, Aggressive surgical resection may improve local recurrence rates and disease-specific survival (DSS), The aim of our study was to determine predictors of survival and local recurrence in primary RS. We performed a retrospective analysis and identified 68 patients who underwent surgical resection of a primary RS between 1985 and 2010, Clinical and pathologic variables were used to create univariate and multivariate models for both survival and recurrence. 68 patients (37% male) with mean age 59 (range 25-84) underwent surgical resection for RS. Median tumor size was 12.0 cm (range 7.0-18.0 cm). 75% of tumors were intermediate/high grade, Incontinuity organ resection was performed in 29 (43%) patients. Seven patients (10%) underwent vascular resection with graft placement. Overall survival at 5, 10 and 15 years was 55%, 42%, and 33%, respectively. Grade (p<0.007), tumor size (p=0.048) and margin status (p<0.05) were found to significantly affect local recurrence. In a multivariate analysis, recurrent disease (p<0.001), age (p<0.003) and high/intermediate grade (p<0.001) significantly affected DSS. Incontinuity organ resection did not significantly affect recurrence (HR = 1.1, CI 0.63 - 1.85) or survival (HR = 1.4, CI 0.8 - 2.9). Surgical resection of RS affords the best chance of survival. Incontinuity organ resection did not affect outcome on multivariate analysis; however, margin status did significantly affect recurrence and could not be achieved without aggressive resection of incontinuity organs.


RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.


The 3'-terminal sequence of mitochondrial 13S ribosomal RNA.
We have examined the 3'-terminal sequence of the "small" structural ribosomal RNA ("13S") of hamster cell mitochondria, using a procedure involving [3H]isoniazide labeling of samples subjected to sequential periodate oxidation and beta-elimination. The terminus was found to be PyUAUUAOH, which is similar, but not identical, to the corresponding terminus of eukaryotic cytoplasmic 18S rRNA.


Cardiorespiratory, hematological and physical performance responses of anemic subjects to iron treatment.
Twenty-nine adult iron-deficient anemis subjects (13 men and 16 women) with hemoglobin levels of 4.0 to 12.0 g/100 ml blood were divided into either an iron treatment or placebo group. Hematological, cardiorespiratory and performance data were collected before, during, and after treatment and compared with data from a control group of subjects (4 men and 6 women) from the same socioeconomic population. Hemoglobin levels for the iron treatment group improved from 7.7 to 12.4 g for the women and from 7.1 to 14.0 g for the men. Values for the control group were 13.9 g and 14.3 g for the women and men, respectively. The placebo group showed virtually no change over the 80-day period (8.1-8.4 g for women and 7.7-7.4 g for men). Peak exercise heart rates (5 min, 40-cm step test) were significantly reduced after treatment from 155 to 113 for the iron treatment men and 152 to 123 for the women compared with the placebo group which showed no changes. Values for the control group were 119 and 142 for the men and women, respectively. In response to the exercise test, no difference in oxygen consumption was found between the iron treatment and placebo group although 15% more O2 was delivered per pulse in the iron treatment group. Blood lactates were significantly highein the placebo than iron treatment group both at rest, 1.18 versus 0.64 mmole/liter, and 1 min after exercise, 5.30 versus 2.68 mmoles/liter. No changes in handgrip or shoulder adductor strength were observed following treatment. These results clearly support the concept that performance requiring high oxygen delivery is significantly affected by hemoglobin levels.


The role of oxygen vacancies and their location in the magnetic properties of Ce(1-x)Cu(x)O(2-δ) nanorods.
Ceria (CeO2) is a promising dilute magnetic semiconductor. Several studies report that the intrinsic and extrinsic structural defects are responsible for room temperature ferromagnetism in undoped and transition metal doped CeO2 nanostructures; however, the nature of the kind of defect necessary to promote and stabilize the ferromagnetism in such a system is still a matter of debate. In the work presented here, nanorods from the system Ce1-xCuxO2-δ with x = 0, 0.01, 0.03, 0.05 and 0.10, with the more stable {111} surface exposed were synthesized by a microwave-assisted hydrothermal method. A very careful structure characterization confirms that the Cu in the samples assumes a majority 2+ oxidation state, occupying the Ce (Ce(4+) and Ce(3+)) sites with no secondary phases up to x = 0.05. The inclusion of the Cu(2+) in the CeO2 structure leads to the introduction of oxygen vacancies in a density proportional to the Cu(2+) content. It is supposed that the spatial distribution of the oxygen vacancies follows the Cu(2+) distribution by means of the formation of a defect complex consisting of Cu(2+) ion and an oxygen vacancy. Superconducting quantum interference device magnetometry demonstrated a diamagnetic behavior for the undoped sample and a typical paramagnetic Curie-Weiss behavior with antiferromagnetic interactions between the Cu(2+) ions for the single phase doped samples. We suggest that the presence of oxygen vacancies is not a sufficient condition to mediate ferromagnetism in the CeO2 system, and only oxygen vacancies in the surface of nanostructures would lead to such a long range magnetic order.


The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging.
Mammalian target of rapamycin complex 2 (mTORC2), one of two different enzymatic complexes of mTOR, regulates a diverse set of substrates including Akt. mTOR pathway is one of well-known mediators of aging process, however, its role in skin aging has not been determined. Skin aging can be induced by physical age and ultraviolet (UV) irradiation which are intrinsic and extrinsic factors, respectively. Here, we report increased mTORC2 pathway in intrinsic and photo-induced skin aging, which is implicated in the activation of nuclear factor-κB (NF-κB). UVB-irradiated or aged mice skin revealed that mTORC2 activity and its component, rictor were significantly upregulated which in turn increased Akt activation and Akt-dependent IκB kinase α (IKKα) phosphorylation at Thr23 in vivo. We also confirmed that UVB induced the mTORC2/Akt/IKKα signaling pathway with HaCaT human normal keratinocytes. The increased mTORC2 signaling pathway during skin aging were associated to NF-κB activation. Suppression of mTORC2 activity by the treatment of a mTOR small inhibitor or knockdown of RICTOR partially rescued UVB-induced NF-κB activation through the downregulation of Akt/IKKα activity. Our data demonstrated the upregulation of mTORC2 pathway in intrinsic and photo-induced skin aging and its role in IKKα/NF-κB activation. These data not only expanded the functions of mTOR to skin aging but also revealed the therapeutic potential of inhibiting mTORC2 in ameliorating both intrinsic skin aging and photoaging.


Diffusing an HIV prevention intervention for African American Women: integrating afrocentric components into the SISTA Diffusion Strategy.
Although race and gender are not indicators for HIV/AIDS, both have disproportionately impacted African American women. African American women represent 13% of the U.S. female population and 67% of the AIDS cases among women (Fitzpatrick, The U.S. HIV/AIDS Epidemic in Women and Adolescent Females, HIV Prevention Conference, Atlanta, GA, 2005). The statistics underscore the need for targeted interventions that employ culturally relevant activities to enhance self-esteem and communication skills while encouraging positive behavior change. Factors facilitating intervention effectiveness include culturally relevant components such as cultural practices, beliefs, values, norms, and ideologies (Janz et al., "Evaluation of 37 AIDS Projects," Health Education Quarterly, 23(1), 80-97, 1996). HIV prevention programs targeting African American women should incorporate an approach that includes ethnic heritage as ameans to instill pride, therebymotivating positive behavior change and empowering women. Afrocentric approaches incorporate philosophies relevant to people of African descent and may be spiritually based. Coupling culturally relevant HIV prevention interventions with a culturally relevant diffusion strategy may enhance community receptiveness. The SISTA intervention (DiClemente & Wingood, "A Randomized Controlled Trial of an HIV Sexual Risk Reduction Intervention for Young African-American Women," Journal of the American Medical Association, 274(16), 1271-1276, 1995) incorporates both culturally and gender-relevant activities to empower African American women to make healthy life choices. The article presents the strategy used to nationally diffuse SISTA, which incorporated Afrocentric components within implementation delivery. Lessons learned demonstrate the significance of integrating additional Afrocentric and gender-relevant material to an existing intervention for African American women.


Nitrite adulteration of workplace urine drug-testing specimens. I. Sources and associated concentrations of nitrite in urine and distinction between natural sources and adulteration.
The active ingredient in the commercial workplace urine drug-testing adulterant, Klear, was previously determined to be nitrite ion. Nitrite adulteration compromises the confirmation of some drugs, notably the marijuana metabolite. A previously reported bisulfite step overcomes some nitrite adulteration, but it cannot do so in every case, which leaves the laboratory to report the specimen as not suitable for testing. Unlike many other adulterants, nitrite is found in normal urine at low concentrations. In order to defend a report of nitrite adulteration, it is necessary to provide evidence that the amount of nitrite in a workplace urine specimen could not arise by normal means. The objectives of this study were to identify all sources of nitrite in urine and the range of concentrations associated with these sources and to determine if nitrite adulteration can be supported based upon a quantitative result. The scientific literature was reviewed for internal and external sources of nitrite and their concentration ranges and are reported. The following specimens were obtained and nitrite concentrations measured by a spectrophotometric method: clinical specimens nitrite positive by test strip (< 15 micrograms/mL); specimens culture positive for nitrate-reducing microorganisms (< 36 micrograms/mL); specimens from patients on medications that may metabolize to nitrite (< 6 micrograms/mL); and drug-test specimens, both negative (< 130 micrograms/mL) and others that appeared to be adulterated with nitrite (range 1910-12,200 micrograms/mL, mean 5910). The literature and the nitrite measurements of this study indicate a substantial difference between concentrations from natural sources compared with adulteration. A quantitative measurement of nitrite by a well-structured assay can provide scientifically valid and forensically defensible proof of adulteration with a nitrite-containing substance.


Understanding the influence of alendronate on the morphology and phase transformation of apatitic precursor nanocrystals.
Bisphosphonates (BPs) are a class of synthetic pyrophosphate analogs that can prevent the loss of bone mass, given orally to treat postmenopuasal osteoporosis. It is not clear yet if the benefits of BPs include the possibility of affecting bone apatitic precursors transition for bone consolidation except for encouraging osteoclasts to undergo apoptosis. Furthermore, the complexity of the in vivo system makes it difficult to isolate and study such extracellular topographical cues that trigger bone turnover response. Herein, we proposed a wet-chemical approach employing alendronate sodium (AS) as a guide of hydroxyapatite (HA) precursor growth and conversion which was initiated from the nucleantion of octacalcium phosphate (OCP) in a cell membrane-mimicking surfactant micelle aqueous system. The nanocrystal clusters of dicalcium phosphate dihydrate (DCPD) and OCP nanocryatals were readily precipitated within a relatively narrow AS concentration range (2-8 μM). However, such low concentrations of AS seemed to stabilize the more acidic phases, and to delay the transformation into HA, to an extent which increased on increasing AS concentration. In contrast, at a slight higher concentrations (16-32 μM), AS promoted HA precipitation after ageing for 1h. It was found that the effect of AS on the phase selectivity of apatitic precursors was concentration-dependent within a prolonged ageing time stage (0.5-168 h). The AS-assisted reactions in vitro offer an expedient way to understand the underlying implementarity between bone and BPs for bone consolidation, and to improve our understanding of benefit of BP dosages on bone turnover and trauma healing.


Long-term liquid storage and reproductive evaluation of an innovative boar semen extender (Formula12®) containing a non-reducing disaccharide and an enzymatic agent.
There are no reports of saccharolytic enzymes being used in the preparation of formulations for animal semen extenders. In the present study, the use of an innovative semen extender (Formula12®) in the long-term liquid storage of boar semen at 17°C was evaluated. The formulation included use of a disaccharide (sucrose) as the energy source precursor coupled to an enzymatic agent (invertase). The innovative extender was evaluated and compared in vitro to a commercial extender (Vitasem LD®) for the following variables: Total Motility (TM), Forward Progressive Motility (FPM), sperm morphology, membrane integrity, acrosome integrity, and chromatin instability. Boar sperm diluted in Formula12® and stored for 12 days at 17°C maintained a commercially acceptable FPM (>70%). Using the results from the in vitro study, an AI field trial was performed. A total of 170 females were inseminated (135 with Formula12® and 35 with Vitasem LD®). The pregnancy rates were 97.8% compared with 91.4%, and the farrowing rates were 96.3% compared with 88.6% when Formula12® and Vitasem LD® were used, respectively. The mean number of piglets born/sow were 14.92±0.46 compared with 13.83±0.70, and the number of piglets born alive/sow were 14.07±0.46 compared with 12.12±0.70 (P<0.05). The results obtained in this study demonstrated that use of the innovative concept to provide a precursor of glucose and fructose as energy sources for an enzymatic agent in an extender allowed for meeting the metabolic requirements of boar sperm during storage at 17°C. It is suggested that there was a beneficial effect on fertilizing capacity of boar sperm in the female reproductive tract with use of these technologies.


Variables associated with change in quality of life among persons with dementia in nursing homes: a 10 months follow-up study.
To investigate variables associated with change in quality of life (QOL), measured by QUALID scale and three subscales; tension, sadness and wellbeing, among dementia patients in nursing homes. A 10 months follow-up study including 198 (female 156, 79%) nursing home patients, mean age 87 (s.d 7.7) years. Scales applied; quality of life in late stage dementia (QUALID) scale and three subscales (wellbeing, sadness and tension), neuropsychiatric inventory questionnaire 10 items (NPI-10-Q), clinical dementia rating (CDR) scale, physical self-maintenance (PSMS) scale and a scale of general medical health. Use of psychotropic medication, gender and age was collected from the patient's records. Mean baseline QUALID score: 20.6 (s.d.7.0), follow-up score: 22.9 (s.d.7.4), mean change 2.8 (s.d.7.4). QOL improved in 30.8%, were unchanged in 14.7%, deteriorated in 54.6% of patients. A regression analysis revealed that change in QUALID score was significantly associated with: QUALID baseline score (beta -.381, p-value.000), change in NPI score (beta.421, p-value.000), explained variance 38.1%. Change in score on wellbeing subscale associated with: change in PSMS score (beta.185, p-value.019), wellbeing baseline score (beta -.370, p-value.000), change in NPI score (beta.186, p-value.017), explained variance 25.3%. Change in score on tension subscale associated with: change in CDR sum-of-boxes (beta.214, p-value.003), change in NPI score (beta.270, p-value.000), tension baseline score (beta -.423, p-value.000), explained variance 34.6%. Change in score on sadness subscale associated with: change in NPI score (beta.404, p-value.000), sadness baseline score (beta -.438, p-value.000), explained variance 38.8%. The results imply that a lower baseline score (better QOL) results in a larger change in QOL (towards worse QOL). Change in QOL is mostly associated with change in neuropsychiatric symptoms. In almost 50% of patients QOL did not deteriorate.


Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice.
Early growth response (Egr)-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation, and wound healing; however, little is known about the role of Egr-1 in acute liver injury. We tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure biphasically increased hepatic egr-1 mRNA accumulation at 1 h and again at 4-5.5 h after treatment in wild-type mice. Within 4-5.5 h after GalN/LPS exposure, wild-type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma alanine aminotransferase activities. In contrast, these parameters were largely attenuated in egr-1(-/-) mice. The initial expression of tumor necrosis factor-alpha, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 mRNA or protein was equivalent between genotypes at 1 h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1(-/-) compared with wild-type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1(-/-) compared with wild-type mice 4 h after GalN/LPS. Whereas caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were detected in wild-type mice at 4 and 5.5 h after GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1(-/-) mice. Delayed development of apoptosis was associated with an extension of survival by 1 h in egr-1(-/-) compared with wild-type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis, and subsequent mortality in GalN/LPS-induced acute liver injury.


Vascular anatomy of the fetus.
Real-time ultrasonography is utilized in this study to demonstrate most of the large vessels in fetuses from 22 weeks on. Images of the aorta, the coronary ostium, the vessels of the aortic arch, the carotids, the ductus arteriosus, the superior mesenteric artery, the celiac axis, the common iliac artery, the external iliac artery, and the femoral artery are demonstrated. Additionally, images of the subclavian vein, the superior mesenteric veins, the splenic vein, the portal vein, the hepatic veins, the ductus venosus, the renal veins, the iliac veins, and the inferior vena cava, as well as the pulmonary artery and veins and the azygos vein, are presented.


The maximin principle of pi-radical packings.
A two-term model is proposed for hydrocarbon and N-containing pi-radicals which are in close contact with one another. The first term is attractive (due to partially occupied frontier pi-orbitals), and the second, repulsive (due to hard-core repulsion between close-lying atoms). This model is applied to dimers where intermolecular contacts are closer than <0.95 x the sum of the atomic van der Waals radii. The maximin principle is proposed. The maximin principle states that the lowest energy conformation maximizes overlap of the frontier orbitals while simultaneously minimizing intermolecular contacts. A Hückel Hamiltonian, the mu(2)-Hamiltonian, which contains the above attractive and repulsive terms, is applied. The interaction surfaces of two pi-hydrocarbon radical cations were calculated for the three systems known crystallographically to contain cations in close contact: naphthalene, fluoranthene, and pyrene. The global minima of these surfaces correspond to the experimentally determined structures. The mu(2)-Hamiltonian energy surfaces of the naphthalene cation dimer are qualitatively similar to those calculated at the RHF/6-311G(d,p) and MP2/6-311G(d,p) levels. The maximin principle is applied to N-containing pi-radicals. Except in the case of tetracyanoethene, the maximin principle correctly predicts the most common dimer crystal packing. (MgPc)(NO(3)).0.5THF and (MgPc)(ReO(4)).1.5THF (Pc = phthalocyanine) were prepared: both new crystal structures follow the maximin principle. The maximin principle is used to suggest the dimer cation ground state of oligoacenes, cations important as organic hole-based semiconductors.


[Evaluation of an outpatient multidisciplinary Neuro-HIV clinic by the patients and referring doctors].
The neurocognitive complaints among HIV infected patients remain frequent, and to establish their etiology can be challenging. We created in 2011 an outpatient Neuro-HIV clinical platform that takes advantage of a multidisciplinary approach with 5 specialists (neuropsychologist, neurologist, psychiatrist, infectiologist and neuroradiologist). In order to estimate its utility, we conducted two questionnaire-based interviews by phone calls with the patients and their referring physicians. Three quarters of both the patients and the physicians interviewed consider the platform useful or essential. Even though there is often no immediate treatment for cognitive disorders, the patients receive from this multidisciplinary approach a better understanding of their disease, which may help them to better cope with their anxieties in daily life.


Natural occurrence of lymphocytes showing cytotoxic activity to BALB/c radiation-induced leukemia RL male 1 cells.
Spleen cells from untreated young male and female C57BL/6 and C58 mice and of male C3H/He mice showed cytotoxic activity in vitro against BALB/c X-radiation-induced leukemia RL male 1 cells by 51Cr-releasing lymphocyte-mediated cytoxicity (LMC) tests, but old mice of these strains lacked LMC activity. In contrast, spleen cells from male and female AKR, BALB/c, and DBA/2 mice, and from female C3H/He mice had no appreciable LMC activity. The proportion of active cells in spleens from young (C57BL/6 times BALB/c)F1 or reciprocal hybrid mice was higher in females than in males. The specificity of the LMC reaction of RL male 1 cells, determined by LMC inhibition assays, was somewhat different from that of previously reported serologic X.1 tests. Thus the antigen detected by LMC has been tentatively designated X.1'. The main effector cells in this system were uncharacterized cells not adherent to glass surfaces or nylon-wool columns. These findings in RL male 1 leukemia extend the evidence for the presence of naturally occurring LMC. With the single unexplained exception of strain C3H/He, the LMC activity against RL male 1 cells, exhibited by untreated mice of various strains, corresponded with a previous classification of mouse strains immunologically as X.1 responders or as X.1 nonresponders according to their ability to reject X.1-positive leukemia cells.


The use of combination drug therapy in the treatment of hypertension.
Data from the National Health and Nutritional Examination Survey and from the World Health Organization have clearly demonstrated that, worldwide, less than one quarter of hypertensive patients are adequately controlled by our currently accepted blood pressure (BP) goals. These patients remain at significant risk for the development of cardiovascular disease. Although, there are multiple reasons contributing to inadequate blood pressure control, the most important include: 1) patient compliance; 2) acceptance of inadequate BP control by clinicians; 3) lower BP goals; and 4) the fact that it is very difficult or impossible to achieve adequate BP control with monotherapy in the majority of patients. The use of combination therapy, either as first-line treatment or much earlier in the course of treating hypertensive patients, may provide the solution to many of these management problems. Low-dose combination therapy provides several advantages in that: 1) it will be more effective than monotherapy due to the additive effect on BP of complementary drugs; 2) it will provide 24-hour efficacy with once-a-day dosing since most of the low-dose combination drugs include long-acting components; 3) it will have a higher response rate than monotherapy and will be effective in most subgroups of hypertensive patients due to the complementary nature of combination therapy; 4) it may have fewer metabolic side effects than higher dose monotherapy since metabolic side effects also tend to be dose dependent; 5) it may have fewer dose-dependent side effects than monotherapy, as BP control is obtained at lower doses of each of the component drugs; 6) it is more convenient than monotherapy; 7) it may cost less, since low-dose combination therapy tends to be a little more expensive than each of the components but cheaper than if each of the components were used separately. For these reasons, the use of low-dose combination therapy as first-line treatment or much earlier in the stepped-care approach may play a major role in improving the dismal control rates in hypertensive patients, which may ultimately have a positive impact on the rate of development of cardiovascular disease.


Factors influencing quality of life for disabled and nondisabled elderly population: the results of a multiple correspondence analysis.
Objectives. The aim of our study is to examine the role of some factors (sociodemographic patterns, social relationship support, and trust in healthcare actors) on structure of quality of life among the Italian elderly population, by stratifying according to presence or absence of disability. Methods. Using data of the Italian National Institute of Statistics (ISTAT) survey, we obtained a sample of 25,183 Italian people aged 65+ years. Multiple Correspondence Analysis (MCA) was used to test such a relationship. Results. By applying the MCA between disabled and nondisabled elderly population, we identified three dimensions: "demographic structure and social contacts," "social relationships," "trust in the Italian National Health Services (INHS)." Furthermore, the difference in trust on the INHS and its actors was seen among disabled and non-disabled elderly population. Conclusions. Knowledge on the concept of quality of life and its application to the elderly population either with or without disability should make a difference in both people's life and policies and practices affecting life. New domains, such as information and trusting relationships both within and towards the care network's nodes, are likely to play an important role in this relationship.


Simulations of the protein folding process using topology-based models depend on the experimental structure.
Topology-based potentials (also known as Go-type models) have been widely used in the study of the protein folding problem. When a topology-based potential is applied, the structure of the native state of the protein considered has to be known in advance. This fact gives to these models a semiempirical character, and therefore the quality of the simulation results obtained for the folding transition relies, among other factors, on the accuracy of the experimental structural data employed. In this work, we use a topology-based potential to carry out folding simulations of a protein whose structure has been determined both with NMR spectroscopy and x-ray crystallography. This way, we have been able to establish to which extent the differences in the topologies of the two experimental structures, easily ignored in a standard structural analysis for this protein, affect the thermodynamic characteristics of the folding transition defined in the simulations.


A new look at male sterilisation (no-scalpel vasectomy) in Orissa.
The author looks into the comparatively newly introduced procedure of 'no-scalpal vasectomy' as it is practiced in Orissa, compares it with the conventional vasectomy and other methods of sterilisation in terms of advantages and gives the outline of the NSV procedure along with postoperative advice in a brief manner.


[A new, sensitive haemagglutination inhibition test for the specific detection of human choriongonadotropine (HCG) in urine].
The reliability and clinical usefulness of a new pregnancy tube test with a sensitivity of 125 IU HCG/l was tested on 1142 urine samples. No false-negative results and 0.6% false-positive results were observed; a crossreaction with LH was seen above 1400 IU LH/l. In all cases of ectopic pregnancies (n = 49) the test yielded a positive result. In daily urine samples, collected during the luteal phase of the cycle, of 10 women who became pregnant, the test gave a positive result 13.6 days (on the average) after the rise of the basal body temperature. Especially in acute gynaecological emergencies the test is of value, because of its sensitivity and practicability.


An evaluation of neuropeptide Y status in subacute sclerosing panencephalitis patients.
This study aimed to evaluate the neuropeptide Y values of patients with subacute sclerosing panencephalitis. The study comprised 38 patients diagnosed with subacute sclerosing panencephalitis at our clinic, who were being routinely followed-up, together with a control group of 36. Using the Risk and Haddad classification for clinical staging, 16 patients were determined as Stage II and 22 patients as Stage III. Neuropeptide Y values were measured by Enzyme Immunoassay methods. The neuropeptide Y values of the all patients with subacute sclerosing panencephalitis were found to be significantly high compared to the control group (p<0.01). The neuropeptide Y values of the Stage III group were found to be significantly high compared to the Stage II and control groups (p<0.05). The neuropeptide Y values of the Stage II group were not determined to be significant compared to the control group (p≤0.05). Neuropeptide Y can be considered a useful parameter to confirm diagnosis at advanced stages and to establish differences between stages in patients with subacute sclerosing panencephalitis.


Small-size LD-based automobile headlamp design with long illumination distance and wide illumination range.
Due to the large size of an automobile headlamp that has a laser as the light source, it is difficult to reflect the advantages of high laser brightness into the effect of automobile illumination, so it has not been promoted. We propose a laser headlamp system that integrates low-beam and high-beam structures with superior illumination effects (longer illumination distance and wider illumination range) by designing freeform optical components and optical structure. The small-volume headlamp can meet the requirements of the Economic Commission for Europe regulation (ECE) R112. The structure volume of the headlamp proposed in this study is only 100∗70∗70m m 3, and the maximum luminance is 120 lx (simulation result) and 78.5 lx (test result). The view angle of the low beam is 13.6°, and the high beam is 15.6°, indicating that the solution is suitable for automotive illumination.


Prognostic features of thyroid cancer. A long-term followup of 68 cases.
Sixty-eight cases of thyroid cancer were followed for 10 to 38 years after diagnosis. A minimum followup period of 10 years was necessary because of the long natural history of low-grade thyroid carcinoma. The prognosis of the disease was evaluated with regard to several parameters: age, sex, histologic appearance of the tumor, extent of disease, and treatment. The best prognosis was found in women less than 40 years of age with papillary carcinoma in whom there was neither extrathyroid extension nor metastasis and who were treated by surgery alone. Extrathyroidal cancer in the neck treated by radical neck dissection had a 100% survival rate at 15 years postdiagnosis. The poorest prognosis was in male patients over 60 years of age with metastatic undifferentiated carcinoma.


[Nocturnal frontal lobe epilepsy is often misdiagnosed as sleep disorders in children: a case series].
INTRODUCTION. We present a series of children who underwent a video-polysomnographic recording at our Sleep and Epilepsy Unit, who received a diagnosis of nocturnal frontal lobe epilepsy (NFLE). AIMS. To describe electroclinical and video polygraphic features of paediatric NFLE that differentiate this condition from other sleep disorders that overlap and mimic the sleep motor and autonomic events of NFLE. PATIENTS AND METHODS. The inclusion criterion was that the patients have their first video-EEG-PSG recording in our laboratory. RESULTS. Twenty-four out of 190 children were diagnosed with NFLE (group 1); while 166 had other sleep disorders (group 2). Among children diagnosed with NFLE, seven were referred for sleep-disordered breathing, seven for parasomnias, two for insomnia, two for hypersomnia, and one for periodic limb movements, while five were referred for epilepsy. In group 1, perinatal history was normal in most cases (21 out of 24) and a familiar history of epilepsy was found in four cases. Sleep-disordered breathing was diagnosed as a comorbid condition in four children. Standard EEG was normal in 21 cases. Interictal EEG showed epileptic discharges in four cases, while ictal EEG was expressed by a rhythmic theta activity preceded by an arousal and/or a short background desynchronization, movement artifacts, and autonomic changes. All seizures, repeated highly stereotyped motor events, were followed by stage shifts and/or a postural change and, by short awakenings. CONCLUSIONS. We found a high percentage of children with NFLE, often misdiagnosed or associated with other sleep disorders, which may be a trigger for nocturnal seizures.


Smells like a heart attack, but is it?
Methaemoglobinaemia is rare. Acute myocardial infarction (AMI) is common. The authors present a unique case of methaemaglobinaemia masquerading as an AMI. A middle-aged male was urgently referred to a tertiary cardiac centre for primary percutaneous coronary intervention with acute chest pain, cyanosis and tachycardia. However, on arrival, his ECG was felt to be within normal limits. Similarly unremarkable, were his echocardiogram and routine blood tests. Arterial blood gas analysis revealed a methaemaglobinaemia of 28.5% which normalised spontaneously. This was thought to be secondary to the use of smelling salts, inhaled earlier that day in the gymnasium. This is the first reported case of smelling salts inducing methaemaglobinaemia and of methaemaglobinaemia mimicking an AMI.


Feminist Approaches to Gender Equity in Perú: The Roles of Conflict, Militancy, and Pluralism in Feminist Activism.
For the past several decades, coordinated efforts from within the women's social movement in Perú have led to groundbreaking legislation surrounding gender equity - for example, the National Gender Equality Policy of 2019 and the Gender Parity Law of 2020. These institutionalized policy changes mark milestones on the path to gender equity, certainly in Perú, but activist efforts that targeted these outcomes can inform women globally. The current study investigated key components of feminist activism by social movement actors themselves through the use of testimonio with nine key leaders in the movement. Using a liberation psychology approach and thematic narrative analysis, the findings suggested three key components of feminist activism: conflict, militant identity, and pluralism that were critical in processes of change. Centering majority world women's voices contributes to the production of knowledge regarding approaches to gender equity, in particular because much that has been written about feminist action in psychology has been produced among samples of white women in the United States. Implications for understanding how the findings have the potential for global change are discussed.


[Endocrine and metabolic disorders in anorexia nervosa. Their meaning].
The authors distinguish among the hormonal and metabolic disturbances found in Anorexia nervosa those, numerous, which are the results of emaciation only, and others which could be signs of central neuro-chemical dysregulation. The disturbances of the gonadotropic function and of the control of the "hunger-fattening" phenomena are probably of the latter type; however the nature of those dysfunctions and of their corresponding neuro-mediators remain so far hypothetical.


Resveratrol has dose-dependent effects on DNA fragmentation and mitochondrial activity of ovine secondary follicles cultured in vitro.
The worldwide consumption of red wine, nuts and grapes has resulted in increased human exposure to resveratrol, which could affect reproductive function. However, the effect of resveratrol on in vitro culture of early-stage ovarian follicles has never been investigated. The aims of the present study were to evaluate the effect of resveratrol on sheep secondary follicle morphology, growth, DNA fragmentation, intracellular levels of glutathione (GSH) and active mitochondria. Secondary follicles were isolated from the ovaries and cultured for 18 days in supplemented α-MEM+ (control medium) or in control medium containing resveratrol (2, 10 or 30 µM). The parameters analyzed were morphology, antrum formation, follicle diameter, DNA fragmentation, GSH levels and mitochondrial activity. After 18 days, all resveratrol groups significantly decreased the percentages of morphologically normal follicles compared with the control group (α-MEM+). Antrum formation was higher in both α-MEM+ and 2 µM resveratrol groups than in the 10 µM resveratrol group. In addition, 30 µM resveratrol increased the percentage of oocytes with DNA damage compared with the control. Oocytes from follicles treated with 10 or 30 µM resveratrol significantly decreased intracellular GSH levels compared with the 2 µM resveratrol group. Moreover, follicles in α-MEM+ (control) showed more active mitochondria than those in 10 or 30 µM resveratrol. In conclusion, ovine isolated secondary follicles are able to grow to the antral stage after in vitro culture in medium containing 2 µM resveratrol, maintaining the same rates of DNA damage, GSH levels and mitochondrial function as the control medium. However, the addition of 30 µM resveratrol increased DNA fragmentation and oxidative stress through decreasing mitochondrial activity.


Normal hematocrits in preadolescent children.
Hematocrits were studied in 471 children aged 11, 12, or 13 years who resided in an affluent suburb of Pittsburgh. It was found that different microhematocrit machines gave slightly different results, so all values were corrected to a reading that would have been obtained using a Wintrobe hematocrit tube. A true Gaussian curve was obtained, suggesting that these children are a valid source of "normal" values. Mean hematocrit was 43%, with 95% confidence limits of 39 to 47%, and was the same for boys and girls. These are slightly higher values than usually are accepted as normal for this age group, and for the girls, values are comparable to those of women. A group of 220 black children of the same age who participated in a sickle-cell screening program had comparable mean hematocrits, but the distribution curve was skewed, suggesting that a small but significant number were anemic.


Early Versus Late Conversion From Immediate to Prolonged-Release Tacrolimus After Renal Transplantation: Clinical Effects and Treatment Costs.
Prolonged-release tacrolimus (PR-TAC) was associated with improved renal function after transplantation when compared to immediate-release tacrolimus (IR-TAC) although evidence is still scarce. This study aimed to compare clinical outcomes and treatment costs in patients who converted from IR-TAC to PR-TAC during the first year after renal transplantation (RT) (early converters [EC]) or after that period (late converters [LC]). We performed a retrospective study including 79 patients (EC, 39; LC, 41) which were followed up over 60 months. A mixed-effects approach was used to investigate the differences between both groups regarding renal and metabolic outcomes as well as treatment costs. The median time from RT to conversion was 3 months for EC and 25 months for LC. For both EC and LC, a significant increase in estimated glomerular filtration rate was observed after conversion (5.2 and 4.9 mL/min per 1.73 m2, respectively). During the first year after RT, EC presented a higher estimated glomerular filtration rate and inferior tacrolimus trough levels when compared to LC, with higher mean treatment costs associated. However, thereafter, these outcomes were similar between groups over the remaining time. At the end of follow-up, no significant differences were found regarding allograft acute rejection (2.6% and 2.4%), new-onset diabetes (15.7% vs 12.2%) or cardiovascular events (5.2% vs 7.3%). There was a significant benefit on renal function after conversion from IR-TAC to PR-TAC. During the first year after RT, EC presented improved renal function, but higher treatment costs. None of these differences persisted at the end of follow-up.


Unique pattern of ORC2 and MCM7 localization during DNA replication licensing in the mouse zygote.
In eukaryotes, DNA synthesis is preceded by licensing of replication origins. We examined the subcellular localization of two licensing proteins, ORC2 and MCM7, in the mouse zygotes and two-cell embryos. In somatic cells ORC2 remains bound to DNA replication origins throughout the cell cycle, while MCM7 is one of the last proteins to bind to the licensing complex. We found that MCM7 but not ORC2 was bound to DNA in metaphase II oocytes and remained associated with the DNA until S-phase. Shortly after fertilization, ORC2 was detectable at the metaphase II spindle poles and then between the separating chromosomes. Neither protein was present in the sperm cell at fertilization. As the sperm head decondensed, MCM7 was bound to DNA, but no ORC2 was seen. By 4 h after fertilization, both pronuclei contained DNA bound ORC2 and MCM7. As expected, during S-phase of the first zygotic cell cycle, MCM7 was released from the DNA, but ORC2 remained bound. During zygotic mitosis, ORC2 again localized first to the spindle poles, then to the area between the separating chromosomes. ORC2 then formed a ring around the developing two-cell nuclei before entering the nucleus. Only soluble MCM7 was present in the G2 pronuclei, but by zygotic metaphase it was bound to DNA, again apparently before ORC2. In G1 of the two-cell stage, both nuclei had salt-resistant ORC2 and MCM7. These data suggest that licensing follows a unique pattern in the early zygote that differs from what has been described for other mammalian cells that have been studied.


Hot Water Generates Crystalline Organic Materials.
In hot water: Hydrothermal crystallization was recently used to transform amporphous polymer networks into amide-linked, stable covalent-organic frameworks. This work is highlighted in the context of the synthesis and especially crystallization of organic materials by using high-temperature water.


Surface Ligand Modification on Ultrathin Ni(OH)2 Nanosheets Enabling Enhanced Alkaline Ethanol Oxidation Kinetics.
The ethanol oxidation reaction (EOR) is an economical pathway in many electrochemical systems for clean energy, such as ethanol fuel cells and the anodic reaction in hydrogen generation. Noble metals, such as platinum, are benchmark catalysts for EOR owing to their superb electrochemical capability. To improve sustainability and product selectivity, nickel (Ni)-based electrocatalysts are considered promising alternatives to noble-metal EOR. Although Ni-based electrocatalysts are relieved from intermediate poisoning, their performances are largely limited by their relatively high onset potential. Therefore, the EOR usually competes with the oxygen evolution reaction (OER) at working potentials, resulting in a low EOR efficiency. Here, we demonstrate a strategy to modify the surface ligands on ultrathin Ni(OH)2 nanosheets, which substantially improved their catalytic properties for the alkaline EOR. Chemisorbed octadecylamine ligands could create an alcoholophilic layer at the nanosheet surface to promote alcohol diffusion and adsorption, resulting in outstanding EOR activity and selectivity over the OER at higher potential. These non-noble-metal-based 2D electrocatalysts and surface ligand engineering showcase a promising strategy for achieving high-efficiency electrocatalysis of EOR in many practical electrochemical processes.


Targeted combined aerosol chemotherapy in dogs and radiologic toxicity grading.
We investigated whether combination chemotherapy, targeted with the AeroProbe® Intracorporeal Nebulizing Catheter (INC), could be safely administered, and developed a radiologic grading scheme to monitor subclinical effects on the lungs. In anesthetized and mechanically ventilated healthy dogs (n = 3), we introduced the INC via a flexible bronchoscope into the right caudal lung lobe and administered escalating dosages of gemcitabine (1, 2, 3, or 6 mg/kg) followed by cisplatin (10 mg/m(2)). Treatments were performed every 2 weeks for 4 treatments and dogs were monitored weekly with physical examination, biochemical tests, and thoracic radiographs. Dogs were sacrificed 2 weeks after the final treatment and tissues examined histologically. A radiologic grading scheme was developed to monitor subclinical pulmonary toxicity. No significant side effects occurred in any dog. All dogs developed focal pneumonitis radiographically, and chronic, severe pneumonia with fibrosis histologically limited to the treated portion of the lung. Radiologic scores increased over time following increasing doses of chemotherapy. Targeted aerosol delivery of gemcitabine and cisplatin by INC was clinically well tolerated. This minimally invasive method is promising for lung cancer treatment, especially given the lack of clinical toxicity. The proposed radiologic grading scheme provides a method to monitor subclinical local drug toxicity.


RefRGim: an intelligent reference panel reconstruction method for genotype imputation with convolutional neural networks.
Genotype imputation is a statistical method for estimating missing genotypes from a denser haplotype reference panel. Existing methods usually performed well on common variants, but they may not be ideal for low-frequency and rare variants. Previous studies showed that the population similarity between study and reference panels is one of the key factors influencing the imputation accuracy. Here, we developed an imputation reference panel reconstruction method (RefRGim) using convolutional neural networks (CNNs), which can generate a study-specified reference panel for each input data based on the genetic similarity of individuals from current study and references. The CNNs were pretrained with single nucleotide polymorphism data from the 1000 Genomes Project. Our evaluations showed that genotype imputation with RefRGim can achieve higher accuracies than original reference panel, especially for low-frequency and rare variants. RefRGim will serve as an efficient reference panel reconstruction method for genotype imputation. RefRGim is freely available via GitHub: https://github.com/shishuo16/RefRGim.


Location, location, location. Salmonella senses ethanolamine to gauge distinct host environments and coordinate gene expression.
Chemical and nutrient signaling mediate all cellular processes, ensuring survival in response to changing environmental conditions. Ethanolamine is a component of phosphatidylethanolamine, a major phospholipid of mammalian and bacterial cell membranes. Ethanolamine is abundant in the gastrointestinal (GI) tract from dietary sources as well as from the normal turnover of intestinal epithelial and bacterial cells in the gut. Additionally, mammalian cells maintain intracellular ethanolamine concentrations through low and high-affinity uptake systems and the internal recycling of phosphatidylethanolamine; therefore, ethanolamine is ubiquitous throughout the mammalian host. Although ethanolamine has profound signaling activity within mammalian cells by modulating inflammatory responses and intestinal physiology, ethanolamine is best appreciated as a nutrient for bacteria that supports growth. In our recent work (Anderson, et al. PLoS Pathog (2015), 11: e1005278), we demonstrated that Salmonella enterica serovar Typhimurium (Salmonella) exploits ethanolamine signaling to adapt to distinct host environments to precisely coordinate expression of genes encoding metabolism and virulence, which ultimately enhances disease progression.


Resilience Among Language Learners: The Roles of Support, Self-Efficacy, and Buoyancy.
The growth of positive psychology has generated different perceptions and concepts on the authorization of learners, such as the construct of resilience and buoyancy. It has been argued that buoyancy has a central function in the educational process as buoyant pupils are more about to participate in activities presented in the classroom and also they are interested to cope with stress in challenging situations especially in English as a foreign language (EFL) learning context. Moreover, to protect against these adversities in reactions to unexpected situations, a related concept exists in positive psychology, labeled resilience that designates persistence and underlines people's capabilities in face of adversities. The expansion of factors such as self-efficacy and social support seem to have great impacts on different aspects of learners. To this end, the present review attempts to highlight these two noteworthy elements in managing learners' resilience and buoyancy. Consistent with this review, some recommendations for future inquiries are presented and instructional implications are offered.


The need for dental health screening and referral programs.
School-based dental health screening and referral programs can have a tremendous impact on a community. They provide examinations to children, some of whom have never seen a dentist, and refer those in need of treatment. When coordinated with other dental health activities, these programs can also raise the overall consciousness about oral health and need for health care in children and parents alike. By their concern for dental health and encouragement to the children to participate in the screening programs and follow through on referrals, school officials can serve as role models to the children and further reinforce the importance of dental health. By conducting the screenings on a local level, the problem is seen as a community one, and is more likely to be meaningfully addressed. School officials, health personnel and teachers are instrumental in initiating and conducting these programs and are thus responsible for the benefits the children derive from the screenings.


Coexistence of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Sjogren Syndrome, Antiphospholipid Syndrome, and Ankylosing Spondylitis.
A 37-year-old Bangladeshi woman presented with low back and several joints pain and swelling for months together; there was significant morning stiffness for more than two hours. Repeated abortions, dry eye, hair fall, photosensitivity, and oral ulcer were the additional complaints. Clinical examination unveiled asymmetrical peripheral and both sacroiliac joint tenderness, positive modified Schober's test, and limited chest expansion. Schirmer's test was positive. The history of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) among 1st-degree relatives was also significant. Biochemical analysis revealed pancytopenia, raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and mild microscopic proteinuria. The patient was seropositive for rheumatoid factor (RF), antibodies against cyclic citrullinated peptides (anti-CCP), antinuclear antibody (ANA), anti-Sm antibody, anti-Sjögren's-syndrome-related antigen A and B (anti-SSA/SSB), antiphospholipid (aPL-IgG/IgM), and HLA B27; however, serum complement (C3 and C4) levels were normal. Basal cortisol level measured elevated. Besides, X-ray and MRI of lumbosacral spines demonstrated sacroiliitis. There was radiological cardiomegaly, echocardiography unveiled atrial regurgitation, and ascending aorta aneurysm. Based on the abovementioned information, RA, AS, and systemic lupus erythematosus (SLE) have been diagnosed. Moreover, the patient developed Sjogren's syndrome (SS), antiphospholipid lipid syndrome (APS), Cushing syndrome, ascending aorta aneurysm, and atrial regurgitation. Her disease activity score for RA (DAS28), DAS for AS (ASDAS), SLE disease activity index (SLEDAI), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) scores were 3.46, 2.36, 23, and 5, respectively. The patient received hydroxychloroquine (200 mg daily), pulsed cyclophosphamide, prednisolone (20 mg in the morning), and naproxen 500 mg (twice daily). To our best knowledge, this is the first report documenting RA, AS, and SLE with secondary SS and APS.


Measurements validating the confocal scanning laser holography microscope.
A confocal scanning laser holography (CSLH) microscope that uniquely combines the concepts of confocal microscopy with holography has been validated for making nonintrusive, full three-dimensional (3D) intensity and phase measurements of objects from a single viewpoint of observation without loss of object information. The phase measurements have been used to determine the 3D refractive indices of a point source heated silicone oil. The refractive indices are converted to 3D temperature measurements, which are useful for heat transfer studies. An important feature of CSLH is its nonintrusive 3D scanning method, which enables its application to the study of Marangoni convection in microgravity with minimal operational vibrations affecting the motion of fluid in the specimen.


Acute effects and mechanism of action of ketanserin in patients with primary Raynaud's phenomenon.
This study evaluates the vasoactive effects and mode of action of ketanserin, a selective 5HT2 receptor antagonist, on digital circulation in 11 patients with primary Raynaud's phenomenon. Reflex digital vasoconstriction was induced by moderate body cooling. We found that ketanserin given intravenously in a dose of 10 mg, normalized digital skin temperature and digital blood flow as estimated by venous occlusion plethysmography and laser-Doppler flowmetry. However, effects of ketanserin on transcutaneously measured oxygen pressure were modest. This could imply a preferential effect of ketanserin on arteriovenous shunt flow. Pretreatment with high doses of the selective and nonselective alpha-adrenoreceptor antagonists prazosin and phentolamine did not abolish the effects of ketanserin on digital blood flow. However, under alpha-adrenoceptor blockade the small effects of ketanserin on normal blood pressure disappeared. Thus, in contrast to the effects in the systemic circulation, the principal mechanism underlying digital vasodilation after ketanserin is unlikely to involve alpha-adrenoceptor antagonism. We conclude that 5HT2 receptors are present in the digital vasculature. In patients with primary Raynaud's phenomenon, their activation plays an important role in cold-induced digital vasoconstriction.


Evaluation and treatment of the unilateral paralyzed vocal fold.
The evaluation and treatment of patients with unilateral vocal fold paralysis have evolved as improvements in objective measurements of phonatory function and new modalities for treatment have developed. A thorough history, physical examination, subjective voice evaluation, objective voice analysis, and electromyography are used to make a diagnosis, determine the cause, and plan treatment. The goal of treatment of the patient with a unilateral vocal fold paralysis is to restore normal phonatory function without aspiration. Multiple modalities have developed to allow for restoration of nearly normal phonatory function, and these include voice therapy alone or in combination with injection medialization, laryngoplastic phonosurgery, or laryngeal reinnervation. Otolaryngologists should be familiar with the incidence, cause, evaluation, and state-of-the-art treatment of unilateral vocal fold paralysis of optimize patient care and avoid suboptimal results often seen with antiquated or inappropriate treatment.


Evaluation of a cultural competence course.
This study addressed the perceived lack of an integrated course with theoretical and experiential knowledge related to cultural competence for public health nurses (PHNs) and the importance of providing culturally competent services to clients. Mixed methods were used to examine the effectiveness of a course to increase 76 PHNs' level of cultural competence. A one-group repeated measures design was used to ascertain the pattern of change in participants over time. The qualitative results complemented the quantitative findings, which were significant in relating to the five dimensions of Campinha-Bacote's model of cultural competence.


The differential diagnosis of congenital analgesia and other diseases with diminished pain perception in childhood. Case report and review.
This paper reports the case of a boy aged 10 months who suffers from congenital analgesia in its pure form. All clinical, biochemical, neuro=physiological and histological data considered to be significant in the differential diagnosis are presented. The findings in all diseases in which impairment of pain sensation occurs are tabulated. 38 patients meet the diagnostic criteria for pure congenital analgesia. The diagnostic criteria are generalized indifference to pain dating from birth; no impairment of other sensory modalities; normal intelligence; normal deep tendon reflexes; no visceral pain perception; normal skin biopsy; no diminution of myelinated or un-myelinated nerve fibres in sural nerve biopsy; normal motor and sensory nerve conduction velocities and normal karyotype. The mode of inheritance remains unclear, but it is assumed, that congenital analgesia might be an autosomal-recessively inherited disease.


Real-time 31P NMR reveals different gradient strengths in polyphosphoester copolymers as potential MRI-traceable nanomaterials.
Polyphosphoesters (PPEs) are used in tissue engineering and drug delivery, as polyelectrolytes, and flame-retardants. Mostly polyphosphates have been investigated but copolymers involving different PPE subclasses have been rarely explored and the reactivity ratios of different cyclic phospholanes have not been reported. We synthesized binary and ternary PPE copolymers using cyclic comonomers, including side-chain phosphonates, phosphates, thiophosphate, and in-chain phosphonates, through organocatalyzed ring-opening copolymerization. Reactivity ratios were determined for all cases, including ternary PPE copolymers, using different nonterminal models. By combining different comonomers and organocatalysts, we created gradient copolymers with adjustable amphiphilicity and microstructure. Reactivity ratios ranging from 0.02 to 44 were observed for different comonomer sets. Statistical ring-opening copolymerization enabled the synthesis of amphiphilic gradient copolymers in a one-pot procedure, exhibiting tunable interfacial and magnetic resonance imaging (MRI) properties. These copolymers self-assembled in aqueous solutions, 31 P MRI imaging confirmed their potential as MRI-traceable nanostructures. This systematic study expands the possibilities of PPE-copolymers for drug delivery and theranostics.


Effects of Desiccation Practices of Cultured Atlantic Oysters (Crassostrea virginica) on Vibrio spp. in Portersville Bay, Alabama, USA.
The expansion of off-bottom aquaculture to the Gulf of Mexico has raised public health concerns for human health officials. High temperatures in the Gulf of Mexico are associated with high levels of Vibrio parahaemolyticus and Vibrio vulnificus. Routine desiccation practices associated with off-bottom aquaculture expose oysters to ambient air, allowing Vibrio spp. to proliferate in the closed oyster. Currently, there is limited research on the length of time needed for Vibrio spp. levels in desiccated oysters to return to background levels, defined as the levels found in oysters that remain continually submersed and not exposed to ambient air. This study determined the time needed to return V. parahaemolyticus, V. vulnificus, and Vibrio cholerae levels to background levels in oysters exposed to the following desiccation practices: 3-h freshwater dip followed by 24-h ambient air exposure, 27-h ambient air exposure, and control. All oysters were submerged at least 2 weeks prior to the beginning of each trial, with the control samples remaining submerged for the duration of each trial. Vibrio spp. levels were enumerated from samples collected on days 0, 1, 2, 3, 7, 10, and 14 after resubmersion using a three-tube most-probable-number enrichment followed by BAX PCR. V. cholerae levels were frequently (92%) below the limit of detection at all times, so they were not statistically analyzed. V. parahaemolyticus and V. vulnificus levels in the 27-h ambient air exposure and the 3-h freshwater dip followed by 24-h ambient air exposure samples were significantly elevated compared with background samples. In most cases, the Vibrio spp. levels in oysters in both desiccation treatments remained elevated compared with background levels until 2 or 3 days post-resubmersion. However, there was one trial in which the Vibrio spp. levels did not return to background levels until day 7. The results of this study provide scientific support that oyster farmers should be required to implement a minimum 7-day resubmersion regimen. This length of time allowed the Vibrio spp. levels to become not significantly different across all treatments.


Decomposing Chemical Space: Applications to the Machine Learning of Atomic Energies.
We apply a number of atomic decomposition schemes across the standard QM7 data set─a small model set of organic molecules at equilibrium geometry─to inspect the possible emergence of trends among contributions to atomization energies from distinct elements embedded within molecules. Specifically, a recent decomposition scheme of ours based on spatially localized molecular orbitals is compared to alternatives that instead partition molecular energies on account of which nuclei individual atomic orbitals are centered on. We find these partitioning schemes to expose the composition of chemical compound space in very dissimilar ways in terms of the grouping, binning, and heterogeneity of discrete atomic contributions, e.g., those associated with hydrogens bonded to different heavy atoms. Furthermore, unphysical dependencies on the one-electron basis set are found for some, but not all of these schemes. The relevance and importance of these compositional factors for training tailored neural network models based on atomic energies are next assessed. We identify both limitations and possible advantages with respect to contemporary machine learning models and discuss the design of potential counterparts based on atoms and the intrinsic energies of these as the principal decomposition units.


Multicolor Luminescent Patterning via Photoregulation of Electron and Energy Transfer Processes in Quantum Dots.
Ability to create high-contrast multicolor luminescent patterns is essential to realize the full potential of quantum dots (QDs) in display technologies. The idea of using a nonemissive state is adopted in the present work to enhance the color-contrast of QD-based photopatterns. This is achieved at a multicolor level by the photoregulation of electron and energy transfer processes in a single QD nanohybrid film, composed of one QD donor and two dye acceptors. The dominance of photoinduced electron transfer over the energy transfer process generates a nonluminescent QD nanohybrid film, which provides the black background for multicolor patterning. The superior photostability of QDs over dyes is used for the photoregulation of electron and energy transfer processes. Selective photodegradation of electron acceptor dye triggered the onset of the energy transfer process, thereby imparting a luminescent color to the QD nanohybrid film. Further, a controlled photoregulation of energy transfer process paved the way for multicolor patterning.


Anaesthesia and tuberous sclerosis.
The anaesthetic management of a patient with tuberous sclerosis undergoing two-stage scoliosis surgery is described. The patient suffered from severe mental retardation, seizures and facial angiofibromas. General anaesthesia using isoflurane and nitrous oxide in oxygen, supplemented with opioid analgesia and hydralazine, and labetalol to induce hypotension, appeared to be satisfactory. Postoperative recovery was delayed and complicated by pleural effusion, sputum retention and mild seizures. Tuberous sclerosis is an autosomal dominant disease well known for its neurocutaneous manifestations. Other organs such as the heart, lungs and kidneys may be involved. The potential problems in the anaesthetic management of a patient with tuberous sclerosis are discussed.


[Alpha 2-antiplasmin in childhood].
In 119 children, predominantly newborns and babies with sepsis, alpha 2-Antiplasmin was determined by the use of the chromogenic substrate S-2251. In healthy newborns, the inhibitor level averaged 65 per cent of the adult level. Already in the initial phase of sepsis, enhanced alpha 2-antiplasmin values were observed. During the further course, they increased markedly. Thus, alpha 2-antiplasmin proved to be an acute phase reactant together with fibrinogen, factors II and X, and alpha 1-antitrypsin measured as trypsin inhibitor capacity. The correlation analysis in all subgroups showed moderately tight binding to fibrin. In patients with shock or in those who decreased, lower levels were measured. The overproduction is assumed to be caused by disseminated intravascular coagulation processes. In other diseases such as respiratory distress, alpha 2-antiplasmin was reduced. In case of disseminated intravascular coagulation that was not caused by sepsis consumption of components dominated. In the probability paper, distribution of the values of the subgroups was found to differ markedly. Thus, the inhibitor proved to be of diagnostic value.


Alpha 1 blockers. Safe, effective treatment for hypertension.
Alpha 1-adrenergic blocking agents, used alone or in combination with other medications, are efficacious in the management of hypertension. They are safe and well tolerated, and they offer unique advantages. Their mechanism of action in lowering blood pressure targets elevated peripheral vascular resistance, which is the principal hemodynamic abnormality of essential hypertension. The alpha 1 blockers maintain cardiac output and blood flow to vital organs, and they do not affect renin release. These agents have beneficial lipid and metabolic effects and can improve left ventricular hypertrophy, theoretically having a positive impact on cardiovascular morbidity and mortality. The only drug interaction identified with the alpha 1 blockers is an increased hypotensive effect when they are combined with other antihypertensive agents. A further advantage of the alpha 1 blockers is that, because of the widespread location of alpha 1 receptors, the agents offer potential benefit for a number of disease states, including benign prostatic hyperplasia. They also provide an especially useful antihypertensive choice for middle-aged and elderly patients.


Intermittent Theta Burst Stimulation Improves the Spatial Cognitive Function of Rats with Chronic Hypertension-induced Cerebral Small Vessel Disease.
We investigated whether intermittent theta burst stimulation (iTBS) can improve the spatial cognitive function of rats with hypertension-induced cerebral small vessel disease. To prove our hypothesis, stroke-prone renovascular hypertensive rats (RHRSPs) were treated with iTBS beginning at postoperative week 22. The Morris water maze was performed to assess spatial cognitive function. The expression of the N-methyl-d-aspartate receptor (NMDAR) subunits NR1, NR2A and NR2B, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), p-CaMKIIα and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) in the hippocampus were evaluated by western blot analysis. The distribution of GluR1, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBa-1) in the CA1 and CA3 regions and dentate gyrus (DG) of the hippocampus were evaluated by immunofluorescence analysis. Treatment with iTBS significantly improved the spatial cognitive function of RHRSPs, increased the expression of NR2B, p-CaMKIIα and GluR1 in the hippocampus, and decreased the proliferation of astrocytes and microglia. Our results showed that iTBS treatment had a beneficial effect on the cognitive impairments induced by cerebral small vessel disease, potentially through the activation of the NR2B-CaMKII pathway, an increase in GluR1 expression and the suppression of astrocyte and microglial activation.


[Expressions and time-dependent changes of FAK and phospho-FAK during skin incised wound healing in mouse].
To study the expressions of focal adhesion kinase (FAK) and phospho-FAK( p-FAK) during skin incised wound healing and the applicability of time-dependent expressions of FAK and p-FAK. The expression of FAK and p-FAK in cutaneous incised wound in mouse were investigated by immunohistochmeistry and Western blotting. FAK and p-FAK expression were detected in polymorphonuclear cells (PMNs) in the wound and adjacent regions 3 hours post-injury. The expressions of FAK and p-FAK were detected in a large number of infiltrating PMNs and some of mononuclear cells (MNCs) from 6 to 24 hours after injury. The MNCs and fibroblastic cells (FBCs) accounted for most part of the FAK and p-FAK positive cells from 3 to 14 days after injury. The numbers of FAK-positive cells increased continuously, reaching a peak at post-injury day 3, and then started to decrease from post-injury day 5 to 14. The changes of p-FAK-positive cells were similar to that of the FAKs, and reached a peak at 12 hours after injury. Both FAK and p-FAK displayed a time-dependent expression during skin incised wound healing in mouse, with p-FAK being superior to FAK. Both FAK and p-FAK may potentially be used as new markers for determination of the wound interval.


Taxonomical study into two new species of Philometra (Nematoda: Philometridae) previously identified as Philometra lateolabracis (Yamaguti, 1935).
Males of the nematode Philometra lateolabracis (Yamaguti, 1935), the type species of the genus Philometra Costa, 1845, were discovered for the first time in gonads of its type host, the Japanese seaperch, Lateolabraxjaponicus (Cuvier). Morphological comparisons carried out between the collected male and female P. lateolabracis with the male and female philometrid nematodes previously reported as P. lateolabracis infecting chicken grunt, Parapristipoma trilineatum (Thunberg), and red sea bream, Pagrus major (Temminck et Schlegel), revealed that the latter represent two new species, Philometra isaki sp. n. and Philometra madai sp. n., respectively. Molecular comparison of ITS2 rDNA between P. lateolabracis and P. madai supported the morphological conclusion that the two nematodes obtained from different fish species should be assigned to different species.


[The Saint Eligius, his life and work and his traces in numismatics].
The goldsmith Eligius lived probably from 589 to 660 A. D. and was mint master of the Merovingian royal court in Paris. Some rare gold coins from his workshop have survived. Later Eligius became a priest and died as the Bishop of Noyon. His life was marked by charity, the reason he was canonized and became patron of many artisanal and artistic professions, including the veterinarians and farriers. As a patron of the mint masters his image appears on little medals to control the weight of coins. On modern coins his name can only be found once on a shilling dated 1623 from the Maccagno mint near the Lake Maggiore; however his picture is on numerous medals and pilgrims' plaques as well as on the merit medal from the veterinarians of Quebec.


Theoretical derivation of heuristic molecular lipophilicity potential: a quantum chemical description for molecular solvation.
We present the theoretical derivation of a heuristic molecular lipophilicity potential (HMLP), which gives a structure-based and quantum chemical description of an important aspect of molecular solvation. The quantum mechanical electrostatic potential (ESP) V(r) on a formal molecular surface is calculated, and then the molecular lipophilicity potential L(r) is constructed by comparing the local electron density with the ESP on the surrounding atoms using a screening function. The screening function is derived from statistical mechanical theory treating the polar solvent molecules as dipoles. HMLP is able to describe the main interactions of solute molecules with polar and nonpolar solvent molecules. HMLP is a unified lipophilicity and hydrophilicity potential: its positive values represent lipophilicity, and its negative values represent hydrophilicity. In this paper, several examples show that HMLP gives more reliable descriptions for the molecular solvation than some other methods, such as atomic partial charges and the empirical lipophilicity potential.


Intrinsic worker mortality depends on behavioral caste and the queens' presence in a social insect.
According to the classic life history theory, selection for longevity depends on age-dependant extrinsic mortality and fecundity. In social insects, the common life history trade-off between fecundity and longevity appears to be reversed, as the most fecund individual, the queen, often exceeds workers in lifespan several fold. But does fecundity directly affect intrinsic mortality also in social insect workers? And what is the effect of task on worker mortality? Here, we studied how social environment and behavioral caste affect intrinsic mortality of ant workers. We compared worker survival between queenless and queenright Temnothorax longispinosus nests and demonstrate that workers survive longer under the queens' absence. Temnothorax ant workers fight over reproduction when the queen is absent and dominant workers lay eggs. Worker fertility might therefore increase lifespan, possibly due to a positive physiological link between fecundity and longevity, or better care for fertile workers. In social insects, division of labor among workers is age-dependant with young workers caring for the brood and old ones going out to forage. We therefore expected nurses to survive longer than foragers, which is what we found. Surprisingly, inactive inside workers showed a lower survival than nurses but comparable to that of foragers. The reduced longevity of inactive workers could be due to them being older than the nurses, or due to a positive effect of activity on lifespan. Overall, our study points to behavioral caste-dependent intrinsic mortality rates and a positive association between fertility and longevity not only in queens but also in ant workers.


Biophysical and formulation studies of the Schistosoma mansoni TSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis.
A candidate vaccine to prevent human schistosomiasis is under development. The vaccine is comprised of a recombinant 9 kDa antigen protein corresponding to the large extracellular domain of a tetraspanin surface antigen protein of Schistosoma mansoni, Sm-TSP-2. Here, we describe the biophysical profile of the purified, recombinant Sm-TSP-2 produced in the yeast PichiaPink, which in preclinical studies in mice was shown to be an effective vaccine against intestinal schistosomiasis. Biophysical techniques including circular dichroism, intrinsic and extrinsic fluorescence and light scattering were employed to generate an empirical phase diagram, a color based map of the physical stability of the vaccine antigen over a wide range of temperatures and pH. From these studies a pH range of 6.0-8.0 was determined to be optimal for maintaining the stability and conformation of the protein at temperatures up to 25 °C. Sorbitol, sucrose and trehalose were selected as excipients that prevented physical degradation during storage. The studies described here provide guidance for maximizing the stability of soluble recombinant Sm-TSP-2 in preparation of its further development as a vaccine.


Inhibition of TACC3 by a small molecule inhibitor in breast cancer.
Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.


Actinomycosis and tonsillar disease.
A 10-year-old female presented with complaints of submandibular swelling, sore throat, painful deglutition, difficulty in speech and fever. The patient gave history of recurrent tonsillitis associated with snoring and breathing difficulty during sleep. Oral examination revealed inflamed, hypertrophied tonsils and dental caries. Throat swab culture was positive for β-haemolytic streptococci. The patient underwent elective tonsillectomy and histopathological examination revealed characteristic colonies of actinomycetes. The patient was put on intravenous penicillin and after 6 months of follow-up is disease free. The report recommends that histopathological examination must be performed in cases of recurrent tonsillitis with tonsillar hypertrophy. Microscopic examination may reveal actinomycetes which may not be evident on culture; treatment requires a longer course of high-dose penicillins. This further supports the view that actinomycetes have a causal association with recurrent tonsillitis and tonsillar hypertrophy.


In vitro transformation of fetal brain cells from CDF rats exposed in utero to N-ethyl-N-nitrosourea: morphologic and immunologic studies.
Inbred CDF rats received 250 mg N-ethyl-N-nitrosourea (ENU)/kg body weight in monosodium phosphate buffer (pH 5.5) during late pregnancy (18-21 days). Control rats received only buffer. One hour after ENU or buffer administration, the fetuses were delivered and fetal brain cells (FBC) were put in long-term tissue culture. Cell growth consisted of monolayers of glial, fibroblastic, and epithelial-like cells. FBC from buffer-treated rats could not be subcultured for more than 13-15 passages; only one culture was maintained up to the 26th passage. FBC from ENU-treated rats showed in vitro malignant transformation beginning at the 8th passage (100 days). Injection of these cells sc into irradiated or neonatally thymectomized syngeneic rats induced small palpable tumors that regressed completely by 15-28 days. Small nonprogressively growing subcutaneous tumors in normal rats, however, were obtained only after the 19th in vitro passage (200 days). These transformed FBC appeared highly antigenic. Tumor-associated antibody was demonmmune adherence assays. Rats immunized with irradiated malignant FBC showed rising tumor antibody titers. The antibody was absorbed by ENU-exposed FBC but not by normal fetal or adult syngeneic brain cells. We concluded that ENU-exposed cells become malignant when grown in vitro for at least 8 passages (100 days) but grow in vivo in X-irradiated or neonatally thymectomized rats only. These antigenic and tumorigenic clones may be selected in vitro, where they grow readily in the absence of immune resistance.


Interactions of the acid and base catalysts on staphylococcal nuclease as studied in a double mutant.
The mechanism of the phosphodiesterase reaction catalyzed by staphylococcal nuclease is believed to involve concerted general acid-base catalysis by Arg-87 and Glu-43. The mutual interactions of Arg-87 and Glu-43 were investigated by comparing kinetic and thermodynamic properties of the single mutant enzymes E43S (Glu-43 to Ser) and R87G (Arg-87 to Gly) with those of the double mutant, E43S + R87G, in which both the basic and acidic functions have been inactivated. Denaturation studies with guanidinium chloride, CD, and 600-MHz 1D and 2D proton NMR spectra, indicate all enzyme forms to be predominantly folded in absence of the denaturant and reveal small antagonistic effects of the E43S and R87G mutations on the stability and structure of the wild-type enzyme. The free energies of binding of the divalent cation activator Ca2+, the inhibitor Mn2+, and the substrate analogue 3',5'-pdTp show simple additive effects of the two mutations in the double mutant, indicating that Arg-87 and Glu-43 act independently to facilitate the binding of divalent cations and of 3',5'-pdTP by the wild-type enzyme. The free energies of binding of the substrate, 5'-pdTdA, both in binary E-S and in active ternary E-Ca(2+)-S complexes, show synergistic effects of the two mutations, suggesting that Arg-87 and Glu-43 interact anticooperatively in binding the substrate, possibly straining the substrate by 1.6 kcal/mol in the wild-type enzyme. The large free energy barriers to Vmax introduced by the R87G mutation (delta G1 = 6.5 kcal/mol) and by the E43S mutation (delta G2 = 5.0 kcal/mol) are partially additive in the double mutant (delta G1+2 = 8.1 kcal/mol). These partially additive effects on Vmax are most simply explained by a cooperative component to transition state binding by Arg-87 and Glu-43 of -3.4 kcal/mol. The combination of anticooperative, cooperative, and noncooperative effects of Arg-87 and Glu-43 together lower the kinetic barrier to catalysis by 8.1 kcal/mol.


High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer.
Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.


Relationship of maternal grain intake and serum triglyceride levels with infant birth weight: Mothers and Children's Environmental Health (MOCEH) study.
Maternal serum triglyceride (TG) level is known to be associated with neonatal birth weight. Although Koreans traditionally consume relatively high amounts of grain and grain products, mainly in the form of white rice, and the consumption is positively associated with serum TG levels, no study has investigated the relationship between dietary grain intake, serum TG levels and neonatal birth weight in pregnant women. This study was conducted to identify the association between infant birth weight and maternal intake of grain, as well as serum TG levels. Subjects were 1011 pregnant women at 12-28 weeks' gestational age and their offspring. Maternal serum TG levels, dietary intake and infant birth weight were measured. Serum TG levels were positively related to neonatal birth weight both at mid-pregnancy (P=0.0015) and at late pregnancy (P<0.0001). Such an association only existed in subjects with the highest tertile of grain intake at mid-pregnancy (P=0.0055) but was observed in all tertiles at late pregnancy (1st P=0.0186, 2nd P=0.0146, 3rd P=0.0099). The relationship between maternal TG levels and infant birth weight may depend on dietary grain intake and stages of pregnancy in Korean pregnant women.