Association of ambient non-methane hydrocarbons exposure with respiratory hospitalizations: A time series study in Taipei, Taiwan.
Ambient hydrocarbons are important precursors of ground-level ozone and secondary organic aerosol formation. However, few studies have assessed the health impact of airborne hydrocarbons. We conducted this time series ecological study to evaluate the association of short-term airborne hydrocarbons exposure with hospital admissions for respiratory diseases, while controlling for co-exposure to criteria pollutants. Taipei air pollution and weather data for the period spanning from January 2010 to December 2017 were obtained from Taiwan Air Quality Monitoring Network. Subsequently, daily pollutant concentrations were linked with daily hospital admission counts for respiratory diseases into a time series data frame. The standard generalized additive Poisson model adjusted for temporal trends, seasonal variations, weather conditions, and calendar effects, was applied to examine the short-term associations of acute airborne hydrocarbon exposure with respiratory hospital admissions. Next, the robustness of the associations was tested using two-pollutant models with further adjustment for fine particulate matter (PM2.5) and gaseous pollutants. The results demonstrated that an interquartile range increase in non-methane hydrocarbon (NMHC) exposure on lag0 day (0.15 ppm) was associated with a 0.86% (95% confidence interval: 0.37%-1.36%), 2.06% (0.77%-3.38%), and 1.25% (0.31%-2.20%) increment in all-respiratory-disease-, asthma-, and chronic-obstructive-pulmonary-disease-linked hospital admissions, respectively. The associations were robust with further adjustment for co-exposure to PM2.5 and ozone. The acute effect estimate of methane on each respiratory category was sensitive to the co-pollutant adjustment and lost statistical significance in the two-pollutant models. In conclusion, we confirmed that airborne NMHC exposure increased the risk of respiratory-disease-related hospital admissions in Taipei; this information may aid in the regulation of hydrocarbon pollution.


Minimally Invasive Mechanical Circulatory Support Through the Perioperative Pulmonary Thromboendarterectomy Period: A Case Report.
A 64-year-old man being evaluated for pulmonary thromboendarterectomy (PTE) preoperatively experienced pulseless electrical activity secondary to right ventricular failure while undergoing bronchoscopy. After return of spontaneous circulation, a percutaneous right ventricular assist device (RVAD) was placed through the right internal jugular vein. He continued on right ventricular support with demonstration of right ventricular recovery over the following 8 days, and subsequently underwent PTE for treatment of his primary condition. He recovered and was weaned from his RVAD support uneventfully. The need for RVAD support has traditionally been a contraindication for PTE; however, circulatory assist devices have been used as a salvage procedure for right-heart failure after PTE. This case highlights the potential for percutaneous mechanical circulatory support in treating severe perioperative right ventricular dysfunction, and to facilitate successful recovery in patients undergoing PTE.


RETRODISPLACEMENT OF THE ORAL AND ANAL OPENINGS IN DENDRASTERID SAND DOLLARS.
In regular echinoids, the mouth opening (or peristome) and the anal opening (or periproct) are located centrally. In irregular echinoids, the peristome tends to shift toward the anterior end of the test, whereas the periproct typically shifts toward the posterior end. This produces an anatomically polarized morphology, which is consistent with functional expectations. In the dendrasterid sand dollars, however, the peristome and periproct have been displaced in the "wrong" directions; the peristome has shifted posteriorly, whereas the periproct has shifted anteriorly. These movements, which run counter to functional expectations, may be termed "retrodisplacements." This study presents a new model for the development of the oral surface in dendrasterids. The model assumes that the "Dendraster pattern" of development (which occurs in dendrasterids) was derived from the older "Echinarachnius pattern" (which occurs in other northern Pacific sand dollars). The Echinarachnius pattern includes two successive phases of asymmetric growth: the first phase favors anterior growth, whereas the second phase favors posterior growth. These two phases are normally balanced, and at maturity, the test appears to be symmetrical. But if the second phase of unequal growth were suppressed through a heterochronic change in development, the effects on test development would be profound. On the aboral surface, the predicted effects include posterior displacement of the apical system. On the oral surface, the predicted effects include retrodisplacement of the peristome and periproct, as well as conspicuous changes in ambulacral and interambulacral development. In fact, all of the predicted effects are characteristic features of dendrasterids. The model assumes that the oral and aboral surfaces could be simultaneously affected by the same developmental processes. This assumption is supported by empirical evidence: in dendrasterids, there is a strong correlation between the displacement of the apical system (on the aboral surface) and the displacement of the peristome (on the oral surface). The displacement of the apical system (known as "apical eccentricity") is regarded as a valuable adaptation, because it facilitates suspension feeding. But if oral and aboral development are linked, then selective pressure for apical eccentricity would simultaneously produce new oral characters as well. Thus, the retrodisplacement of the peristome and periproct in dendrasterids may be related to developmental constraints. These unusual characters may have little or no functional significance.


Decreased Glycocalyx Shedding on Presentation in Hemorrhaging Geriatric Trauma Patients.
Plasma levels of syndecan-1 (Sdc-1), a biomarker of endothelial glycocalyx (EG) damage, correlate with worse outcomes in trauma patients. However, EG injury is not well characterized in injured older adults (OA). The aims of this study were to characterize Sdc-1 shedding in OA trauma patients relative to younger adults (YA) and determine associations with putative regulators of EG sheddases. We performed a secondary analysis of data from the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios (PROPPR) trial, stratifying bluntly injured subjects into OA and YA groups based on upper age quartile (57 y). Plasma Sdc-1 levels were compared in OA and YA at hospital arrival through postinjury day 3, and the independent association between age and Sdc-1 level at arrival was determined after adjusting for differences in gender, shock index (SI), and pre-existing comorbidities. In a follow-up analysis, case-control matching was used to create populations of OA and YA with equivalent SI and injury severity score. Levels of Sdc-1 were compared between these matched groups, and the relationships with candidate regulators of EG shedding were assessed. Of 680 subjects in the Pragmatic, Randomized Optimal Platelet, and Plasma Ratios trial, 350 (51%) had blunt injuries, and 92 (26.3%) of these were OA. Plasma Sdc-1 levels at arrival, 2 h, and 6 h were significantly lower in OA compared to YA (all P < 0.05). After adjusting for sex, pre-existing morbidities and SI, age was associated with decreased Sdc-1 levels at arrival. In the matched analyses, Sdc-1, high-mobility group box 1 and tissue inhibitor of metalloproteinase-2 levels were lower in OA compared to YA. Both high-mobility group box-1 and tissue inhibitor of metalloproteinase-2 significantly correlated with arrival Sdc-1 and were inversely associated with age. This study indicates that increased age is independently associated with decreased Sdc-1 levels among patients with blunt injuries. Suppressed plasma levels of sheddases in relation to diminished Sdc-1 shedding suggest that mechanisms regulating EG cleavage may be impaired in injured older adults. These findings provide novel insight into the age-dependent impact of injury on the vascular endothelium, which could have important implications for the clinical management of older adults following trauma.


The methymycin/pikromycin pathway: a model for metabolic diversity in natural product biosynthesis.
The methymycin/pikromycin (Pik) macrolide pathway represents a robust metabolic system for analysis of modular polyketide biosynthesis. The enzymes that comprise this biosynthetic pathway display unprecedented substrate flexibility, combining to produce six structurally diverse macrolide antibiotics in Streptomyces venezuelae. Thus, it is appealing to consider that the pikromycin biosynthetic enzymes could be leveraged for high-throughput production of novel macrolide antibiotics. Accordingly, efforts over the past decade have focused on the detailed investigation of the six-module polyketide synthase, desosamine sugar assembly and glycosyl transfer, and the cytochrome P450 monooxygenase that is responsible for hydroxylation. This review summarizes the advances in understanding of pikromycin biosynthesis that have been gained during the course of these investigations.


Tuberculous otitis media: a resurgence?
Tuberculosis is a global health problem that is especially prevalent in developing countries such as India. Recently, atypical presentation has become more common and a high index of suspicion is essential. This study analysed the various presenting symptoms and signs of tuberculous otitis media and the role of diagnostic tests, with the aim of formulating criteria for the diagnosis. A total of 502 patients underwent tympanomastoidectomy over a two-year period. Microbiological and histopathological examinations and polymerase chain reaction analysis of tissue taken during tympanomastoidectomy were performed. A total of 25 patients (5 per cent) were diagnosed with tuberculous otitis media. Severe mixed hearing loss, facial palsy, labyrinthine fistula, post-aural fistula, perichondritis and extradural abscess were noted. There seems to be a resurgence in tuberculous otitis media in India. Microbiological, histopathological and polymerase chain reaction tests for tuberculosis are helpful for its diagnosis.


Morphological and molecular comparisons between tibialis anterior muscle and levator veli palatini muscle: A preliminary study on their augmentation potential.
Tibialis anterior (TA) muscle and other somite-derived limb muscles remain the prototype in skeletal muscle study. The majority of head muscles, however, develop from branchial arches and maintain a number of heterogeneities in comparison with their limb counterparts. Levator veli palatini (LVP) muscle is a deep-located head muscle responsible for breathing, swallowing and speech, and is central to cleft palate surgery, yet lacks morphological and molecular investigation. In the present study, multiscale in vivo analyses were performed to compare TA and LVP muscle in terms of their myofiber composition, in-situ stem cell population and augmentation potential. TA muscle was identified to be primarily composed of type 2B myofibers while LVP muscle primarily consisted of type 2A and 2X myofibers. In addition, LVP muscle maintained a higher percentage of centrally-nucleated myofibers and a greater population of satellite cells. Notably, TA and LVP muscle responded to exogenous Wnt7a stimulus in different ways. Three weeks after Wnt7a administration, TA muscle exhibited an increase in myofiber number and a decrease in myofiber size, while LVP muscle demonstrated no significant changes in myofiber number or myofiber size. These results suggested that LVP muscle exhibits obvious differences in comparison with TA muscle. Therefore, knowledge acquired from TA muscle studies requires further testing before being applied to LVP muscle.


ESTIMATION OF SINGLE GENERATION MIGRATION DISTANCES FROM GEOGRAPHIC VARIATION IN ANIMAL MITOCHONDRIAL DNA.
A new approach is introduced for the analysis of dispersal from the geographic distributions of mtDNA lineages. The method is based on the expected spatial distributions of lineages arising under a multigeneration random walk process. Unlike previous methods based on the predicted equilibria between genetic drift and gene flow, this approach is appropriate for non-equilibrium conditions, and yields an estimate of dispersal distance rather than dispersal rate. The theoretical basis for this method is examined, and an analysis of mtDNA restriction site data for Peromyscus maniculatus is presented as an example of how this approach can be applied to empirical data.


[Ovarian tissue cryopreservation in girls].
Girls who undergo treatment for cancer are at risk of ovarian hormonal dysfunction and subfertility due to the detrimental effects of some chemotherapeutic agents and/or radiotherapy on the gonads. Consequently, fertility-preserving techniques shouldbe discussed before starting gonadotoxic therapy. Ovarian tissue cryopreservation is currently the only option to preserve fertility in prepubertal girls and should be considered if the risk of premature ovarian failure is high. This promising approach involves the storage of a large number of follicles, which may subsequently be transplanted or cultured to obtain mature ovocytes. The results of ovarian tissue cryopreservation in adults are encouraging: at least twenty children have been born after orthotopic autografting of frozen-thawed ovarian cortex. It has been shown twice that transplantedprepubertal ovarian tissue can induce puberty, confirming the functional capacity of frozen-thawed prepubertal ovarian tissue.


circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis.
Background and aim: As non-coding RNAs, circular RNAs (circRNAs) contribute to the progression of malignancies by regulating various biological processes. In prostate cancer, however, there is still a lack of understanding regarding the potential molecular pathways and roles of circRNAs. Methods: Loss-off function experiments were performed to investigate the potential biological function of circRNA in the progression of prostate cancer. Western blot, qRT-PCR, and IHC assay were used to examine the expression level of different genes or circRNAs. Further molecular biology experiments were conducted to uncover the molecular mechanism underlying circRNA in prostate cancer using dual luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: A novel circRNA (hsa_circ_0124696, named circROBO1) was identified as a significantly upregulated circRNA in both prostate cancer cells and tissues. Suppression of circROBO1 significantly attenuated the proliferation of prostate cancer cells. In addition, we found that the knockdown of circROBO1 remarkably increased the sensitivity of prostate cancer to enzalutamide treatment. A deceleration in glycolysis rate was observed after inhibition of circROBO1, which could suppress prostate cancer growth and overcome resistance to enzalutamide. Our results revealed that circROBO1 promotes prostate cancer growth and enzalutamide resistance via accelerating glycolysis. Conclusion: Our study identified the biological role of the circROBO1-miR-556-5p-PGK1 axis in the growth and enzalutamide resistance of prostate cancer, which is the potential therapeutic target of prostate cancer.


Transdiagnostic and sex differences in cognitive profiles of autism spectrum disorder and attention-deficit/hyperactivity disorder.
An increasing number of studies have shown that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share symptoms and aetiologies. However, transdiagnostic comparisons between ASD and ADHD is complicated due to the sex differences within each condition. To clarify the similarities and differences in the cognitive functioning between ASD and ADHD, while considering potential sex differences, this study compared cognitive profiles assessed by the WAIS-III between the four groups created by orthogonally combining diagnosis and sex based on the data from 277 ASD males, 86 ASD females, 99 ADHD males and 64 ADHD females. The analysis revealed three major findings. First, performance IQ and perceptual organization index were higher in ADHD males than in ASD males and ADHD females. Second, Gaussian mixture model fitting revealed two clusters underlying the distribution of subindex scores. The percentage of being classified into the cluster that scored lower in all the subindices was higher in females than in males irrespective of diagnosis. Third, feature importance for classification of ASD and ADHD yielded by random forest classifier, a supervised machine learning algorithm, revealed that autism quotient was most informative feature in classifying ASD and ADHD in males, while the discrepancy between verbal and performance intelligence quotient was in females, indicating that the set of behavioral features contributing to classification differs between males and females. Thus, these findings indicate that sex as well as diagnosis is critical in determining the cognitive profiles of people with ASD and ADHD. LAY SUMMARY: The present study compared profiles of cognitive functions measured by Wechsler Adult Intelligence Scale between males and females with ASD and ADHD. The analyses revealed clear sex differences in cognitive functions in both ASD and ADHD and that the set of cognitive functions useful in classifying ASD and ADHD differed between males and females. Thus, biological sex seems to be a critical factor in determining the cognitive profiles of people with ASD and ADHD.


Association of AKI-D with Urinary Findings and Baseline eGFR in Hospitalized COVID-19 Patients.
AKI is common in patients hospitalized with coronavirus disease 2019 (COVID-19). Risk factors for AKI requiring dialysis (AKI-D) are not fully understood. We aimed to identify risk factors associated with AKI-D and AKI not requiring dialysis (AKI-ND). We reviewed electronic health records of 3186 patients aged ≥18 years old who were hospitalized with COVID-19 across six hospitals. Patient characteristics, urinalysis findings, and inflammatory markers were analyzed for association with in-hospital AKI status (AKI-D, AKI-ND, or no AKI), and we subsequently evaluated mortality. After adjustment for multiple covariates, higher baseline eGFR was associated with 30% lower odds of AKI-D and 11% lower odds of AKI-ND (for AKI-D, OR, 0.70; 95% CI, 0.64 to 0.77; for AKI-ND, OR, 0.89; 95% CI, 0.85 to 0.92). Patients with obesity and those who were Latino had increased odds of AKI-D, whereas patients with congestive heart failure or diabetes with complications had increased odds of AKI-ND. Females had lower odds of in-hospital AKI (for AKI-D, OR, 0.28; 95% CI, 0.17 to 0.46; for AKI-ND, OR, 0.83; 95% CI, 0.70 to 0.99). After adjustment for covariates and baseline eGFR, 1-4+ protein on initial urinalysis was associated with a nine-fold increase in odds of AKI-D (OR, 9.00; 95% CI, 2.16 to 37.38) and more than two-fold higher odds of AKI-ND (OR, 2.28; 95% CI, 1.66 to 3.13). Findings of 1-3+ blood and trace glucose on initial urinalysis were also associated with increased odds of both AKI-D and AKI-ND. AKI-D and AKI-ND were associated with in-hospital death (for AKI-D, OR, 2.64; 95% CI, 1.13 to 6.17; for AKI-ND, OR, 2.44; 95% CI, 1.77 to 3.35). Active urine sediments, even after adjustment for baseline kidney function, and reduced baseline eGFR are significantly associated with increased odds of AKI-D and AKI-ND. In-hospital AKI was associated with in-hospital death. These findings may help prognosticate patients hospitalized with COVID-19.


Happiness in texting times.
Assessing national levels of happiness has become an important research and policy issue in recent years. We examined happiness and satisfaction in Ireland using phone text messaging to collect large-scale longitudinal data from 3,093 members of the general Irish population. For six consecutive weeks, participants' happiness and satisfaction levels were assessed. For four consecutive weeks (weeks 2-5) a different random third of the sample got feedback on the previous week's mean happiness and satisfaction ratings. Text messaging proved a feasible means of assessing happiness and satisfaction, with almost three quarters (73%) of participants completing all assessments. Those who received feedback on the previous week's mean ratings were eight times more likely to complete the subsequent assessments than those not receiving feedback. Providing such feedback data on mean levels of happiness and satisfaction did not systematically bias subsequent ratings either toward or away from these normative anchors. Texting is a simple and effective means to collect population level happiness and satisfaction data.


Predicting resistance to endocrine therapy in breast cancer: It's time for epigenetic biomarkers (Review).
Notwithstanding the marked progress in breast cancer (BC) management, it still constitutes the most common malignancy in women and a major cause of morbidity and mortality, thus remaining a major health issue worldwide. Most BC cases are hormone receptor (HR) positive (luminal A or B molecular subtypes) and endocrine treatment (ET) is an important therapeutic modality at all disease stages. Nevertheless, despite substantial improvements in BC patient outcome, effectiveness of ET is limited, as up to 40% of patients eventually relapse or progress and endocrine resistant BC has a less favorable prognosis and constitutes a therapeutic challenge. The biological mechanisms underlying endocrine resistance are, however, still poorly understood. In this review, we focused on data regarding the main epigenetic mechanisms associated with the development of endocrine treated‑resistant BC described so far, including alterations in DNA methylation, non‑coding RNAs, chromatin remodeling, post‑translational histone modifications and histone variants. Notably, specific epigenetic alterations have been characterized in this subset of breast tumors and may be of clinical value for individualized patient management in the future.


Is VEGF a Key Target of Cotinine and Other Potential Therapies Against Alzheimer Disease?
The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.


Kala-azar (visceral Leishmaniasis) from Khotang.
Kala-azar is a chronic infection of reticuloendothelial system caused by flagellated protozoan, leishmania donovani injected into human host by the bite of the sand fly (phlebotomous) previously infected by biting and sucking the blood of a patient of leishmaniasis. It is characterized by irregular fever of long duration, large spleen and liver, anaemia, leucopenia and progressive emaciation. This article reports a case of a 10 year old girl from Khotang, a nonendemic zone for Kala-azar, who presented with long history of abdominal distension for 11 months, fever for 9 months, cough for a week and weight loss. Clinical examination revealed pallor, enlarged liver and huge splenomegaly. Investigations confirmed the diagnosis of kala-azar by the presence of L.D bodies in bone marrow smear. The patient is being treated with i.v Amphotericin B in Infectious Disease Hospital, Teku.


[Specific antibodies to herpes simplex virus, cytomegalovirus and rubella virus: distribution in amniotic fluid and blood].
Fifty-nine unselected pregnant women were included in the study at the time of delivery. Immediately post partum maternal blood was obtained by venous puncture, and fetal blood from the umbilical cord. Amniotic fluid was obtained by amniocentesis during labor prior to rupture of the amniotic sac. Virus-specific rubella, herpes simplex and cytomegalo virus antibodies were determined with a commercial enzyme immune test. The virus-specific antibody titers are higher by a factor of 1.3 to 1.5 in the fetal than in the maternal serum. In contrast, the concentration of the corresponding antibodies in the amniotic fluid is approximately 5 titer levels (log 2) lower than in the maternal serum - regardless of the maternal antibody titer level. In view of its low concentration of antibodies the amniotic fluid can hardly be regarded as an "immunological barrier" if it serves as a "transport or distribution medium" in some virus infections. However, passive intra-amniotic immunization could be useful for combating certain virus infections during pregnancy, especially just before term.


Clean unzipping by steam etching to synthesize graphene nanoribbons.
A simple, clean method of steam etching carbon nanotubes is reported for the synthesis of graphene nanoribbons. The chemical mechanism of carbon nanotube unzipping is also discussed. As an anode catalyst, as-prepared graphene nanoribbons combined with Pt exhibit quite a high catalytic activity for ethanol electro-oxidation in fuel cells.


The Effect of Emotional Intelligence and Academic Social Networking Sites on Academic Performance During the COVID-19 Pandemic.
During the COVID-19 pandemic, there has been an increase in the use of digital platforms for educational purposes, and increased use of smartphones and social media has affected the academic performance of students. In this study, we explored how emotional intelligence can, directly and indirectly, influence academic performance, with academic social networking sites (ASNS) as a mediator. A survey questionnaire comprising 42 items was used to collect data on emotional intelligence, ASNS, and academic performance. In total, 305 undergraduate university students participated in the study. Partial least squares structural equation modeling (SmartPLS-SEM 3.2.2) was used to measure the effects of emotional intelligence and ASNS. Two dimensions of emotional intelligence, namely, self-regulation and self-awareness, showed significant positive effects on academic performance. Similarly, emotional intelligence and subscales of self-regulation, self-awareness and social skills showed a positive effect on ASNS. Likewise, ASNS showed a significant positive effect on academic performance. Looking at indirect influence, three dimensions of emotional intelligence, including self-regulation, self-awareness, and social skills, exerted a significant positive indirect influence on academic performance. Thus, outcomes of this study indicate that ASNS worked as a mediator between emotional intelligence and academic performance. Emotional intelligence contributes directly and indirectly to increased academic performance. Together with emotional intelligence, ASNS played a positive and significant role in nurturing academic performance during the COVID-19 pandemic.


Boundary effects of molecular diffusion in nanoporous materials: a pulsed field gradient nuclear magnetic resonance study.
The boundary conditions of intraparticle diffusion in nanoporous materials may be chosen to approach the limiting cases of either absorbing or reflecting boundaries, depending on the host-guest system under study and the temperature of measurement. Pulsed field gradient nuclear magnetic resonance is applied to monitor molecular diffusion of n-hexane and of an n-hexane-tetrafluoromethane mixture adsorbed in zeolite crystallites of type NaX under either of these limiting conditions. Taking advantage of the thus-established peculiarities of mass transfer at the interface between the zeolite bulk phase and the surrounding atmosphere, three independent routes for probing the crystal size are compared. These techniques are based on (i) the measurement of the effective diffusivity under complete confinement, (ii) the application of the so-called NMR tracer desorption technique, and (iii) an analysis of the time dependence of the effective diffusivity in the short-time limit where, by an appropriate variation of the adsorbate and the measuring conditions, the limiting cases of reflecting and adsorbing boundaries could be considered. All these techniques are found to yield coinciding results, which are in excellent agreement with the crystal sizes determined by microscopy.


A multicenter study of treatment of primary CNS lymphoma.
To characterize the therapeutic variables correlated to outcome in 370 patients with primary CNS lymphoma. Planned treatment was radiotherapy (RT) in 98 patients, chemotherapy (CHT) in 32, RT followed by CHT in 36, and CHT followed by RT in 197 patients. High-dose methotrexate (HD-MTX; 1 to 8 g/m2) was used in 169 patients and intrathecal CHT in 109. One hundred sixteen patients are alive (median follow-up 24 months), with a 2-year overall survival of 37%. Patients treated with CHT followed by RT had improved survival with respect to patients treated with RT alone. Patients receiving HD-MTX-based primary CHT survived longer than those treated with other drugs. HD-MTX associated with other cytostatics, in particular HD-cytarabine, produced better results than HD-MTX alone. No correlation between MTX dose and survival was found. In patients receiving HD-MTX, consolidation RT or intrathecal CHT did not improve survival. Age, performance status, lactate dehydrogenase serum level, CSF protein level, site of disease, and use of HD-MTX were all predictors of survival. Combination CHT-RT is superior to RT alone. Patients treated with primary CHT containing HD-MTX exhibited improved survival. In these patients, the addition of HD-cytarabine was associated with a better survival, whereas intrathecal CHT was not correlated to outcome. RT may be unnecessary in patients achieving complete remission after receiving HD-MTX-based primary CHT.


Hyperglycemia Suppresses RANKL-Induced Osteoclast Differentiation through LXRβ Expression in RAW264.7 Cells.
There have been reports that hyperglycemia suppresses osteoclast (OCL) differentiation, although the underlying mechanism is poorly understood. Here we demonstrated that high glucose suppresses OCL differentiation through activation of liver X receptor (LXR) β, a recently reported glucose-sensing nuclear receptor. The effect of hyperglycemia on osteoclastogenesis was tested in RAW264.7 cells, a murine macrophage cell line. Cells were treated with receptor activator of NF-κB ligand (RANKL) under normoglycemic (5.5 mM glucose), normoglycemic with high osmotic pressure (5.5 mM glucose + 10.0 mM mannitol), and hyperglycemic (15.5 mM glucose) conditions. RANKL-induced osteoclastogenesis was significantly suppressed by high-glucose treatment. Mannitol treatment also significantly suppressed osteoclastogenesis, but the inhibitory effect was lower than for high-glucose treatment. The suppression of mRNA expression of Lxrβ by RANKL was significantly restored by high glucose, but not mannitol. Additionally, the deactivation of Lxrβ by siRNA attenuated high-glucose-induced suppression of osteoclastogenesis. Although further validation of the underlying pathway is necessary, targeting LXRβ is a potential therapeutic approach to treating osteoporosis.


Preferential transduction of human hepatocytes with lentiviral vectors pseudotyped by Sendai virus F protein.
One of the major challenges facing gene therapy is the development of vectors targeting specific cell types. Restricting gene delivery to the relevant cell type leads to reduced T-cell responses to transgene products and prolonged gene expression. In this study, we demonstrate that vectors derived from human immunodeficiency virus (HIV) can be pseudotyped with Sendai virus fusion protein F. Such vectors transduced human hepatoma cells and primary human hepatocytes efficiently, but not non-liver cells. Several different approaches were also taken to significantly increase the titer of the pseudotyped vector. These studies may facilitate HIV vector-mediated gene delivery into liver in vivo.


Adaptive tests of temporal resolution: comparison with the gaps-in-noise test in normal-hearing young adults.
Auditory processing disorder patients may have deficits in auditory temporal resolution. This study explored: (1) the ear specific norms for young adults using the adaptive tests of temporal resolution (ATTR); (2) the reliability of ATTR using two different modes of stimuli presentation; and (3) the concurrent validity of ATTR with reference to the gaps-in-noise (GIN) test. GIN and ATTR were administered through a standard audiometer and headphones. As ATTR can also be completed using a computer with commercially available headphones, thresholds from these two variants were compared. Thirty normal-hearing young adults were recruited. The mean ATTR gap detection thresholds (GDTs) derived under audiometer administration were 4.60 ms (SD 1.49) and 4.97 ms (SD 1.98) for the left and right ear, respectively. The approximated threshold (A. th.), an equivalent measure to the GDT in the GIN, mean values were 5.37 ms (SD 0.98) and 5.33 ms (SD 1.07) for left and right ears, respectively. No significant threshold difference was found between the ATTR variants. A positive, moderate correlation was found, and Bland-Altman plot analysis revealed good agreement, between GDT and A.th. ATTR and GIN results were moderately associated. Moreover, the ATTR was found to have high test-retest reliability and high specificity for the current participants.


Pan-Cancer Analyses Identify the CTC1-STN1-TEN1 Complex as a Protective Factor and Predictive Biomarker for Immune Checkpoint Blockade in Cancer.
The CTC1-STN1-TEN1 (CST) complex plays a crucial role in telomere replication and genome stability. However, the detailed mechanisms of CST regulation in cancer remain largely unknown. Here, we perform a comprehensive analysis of CST across 33 cancer types using multi-omic data from The Cancer Genome Atlas. In the genomic landscape, we identify CTC1/STN1 deletion and mutation and TEN1 amplification as the dominant alteration events. Expressions of CTC1 and STN1 are decreased in tumors compared to those in adjacent normal tissues. Clustering analysis based on CST expression reveals three cancer clusters displaying differences in survival, telomerase activity, cell proliferation, and genome stability. Interestingly, we find that CTC1 and STN1, but not TEN1, are co-expressed and associated with better survival. CTC1-STN1 is positively correlated with CD8 T cells and B cells and predicts a better response to immune checkpoint blockade in external datasets of cancer immunotherapy. Pathway analysis shows that MYC targets are negatively correlated with CTC1-STN1. We experimentally validated that knockout of CTC1 increased the mRNA level of c-MYC. Furthermore, CTC1 and STN1 are repressed by miRNAs and lncRNAs. Finally, by mining the connective map database, we discover a number of potential drugs that may target CST. In sum, this study illustrates CTC1-STN1 as a protective factor and provides broad molecular signatures for further functional and therapeutic studies of CST in cancer.


Ventilatory and analgesic effects of dezocine in humans.
The respiratory depressant and analgesic effects of intravenous dezocine were evaluated in six healthy volunteers. Single 0.15 mg/kg doses were compared with identical amounts of morphine, and the two drugs were given in combination. Five successive 0.15 mg/kg doses of dezocine also were given to identify dose-effect relationships. Respiratory center sensitivity was monitored by carbon dioxide (CO2) rebreathing and mouth occlusion pressure (P0.1) measurement, while analgesia to experimental pain was tested with submaximal tourniquet ischemia. Single 0.15 mg/kg doses of dezocine produced significantly more tolerance to experimental pain and greater respiratory depression than a comparable dose of morphine in the first hour, but effects of both drugs were similar thereafter. Multiple doses of dezocine progressively increased pain tolerance from 46 +/- 14% above control with the first dose to 70 +/- 18% above control with the second dose (cumulative total 0.30 mg/kg). Additional dezocine doses did not result in significantly more analgesia. Depression of CO2 sensitivity followed a similar pattern. Morphine 0.15 mg/kg, when given to subjects who had received a prior dose of dezocine, produced no additional effect beyond that observed with dezocine. With the reverse sequence, dezocine increased the respiratory depression of morphine but also produced a dramatic increment in analgesia, which suggested an additive action. Dezocine is therefore an effective analgesic with morphine-like effects. In human subjects it appears to be a slightly more potent analgesic than morphine in identical clinical doses (0.15 mg/kg). Dezocine is similar to other agonist-antagonist analgesics in that it exhibits a ceiling effect for respiratory depression that parallels its analgesic activity.


Linkage studies of cholestasis familiaris groenlandica/Byler-like disease with polymorphic protein and blood group markers.
In Greenland, and especially East Greenland (Tasiilaq), a common recessive disease, cholestasis familiaris groenlandica (CFG)/Byler-like disease, occurs in Eskimo children [1]. In a period from 1964-1991, at least 22 children out of about 2,121 newborns were born with this disease (gene frequency q = 0.102). Samples from 126 persons, from a large pedigree in East Greenland including 7 affected and from two families in West Greenland with a total of 3 affected children, have been collected for studying 45 polymorphic markers and for mapping the CFG disease. Polymorphisms and exclusion data were found for the following markers: A1BG, ABO, ACP1, AHSG, C1R, C6, FY, GC, GLO1, GPT, HP, ITIH1, JK, GYPA, GYPB, ORM, P1, PGM1, PI, PON, RH and TCN2. Small positive lod scores (Z < 1.5) were found to the following markers: ITIH1, JK and TCN2. The following markers were nonpolymorphic in this material: ADA, AK1, ALAD, APOA4, APOH, BF, C3, BCHE, CHE2, CO, ESD, FUCA2, F13A1, F13B, KEL, LE, FUT1, LU, PEPD, PGD, PGP, PLG, FUT2, SOD1 and TF.


Morphing for faster computations in transformation optics.
We propose to use morphing algorithms to deduce some approximate wave pictures of scattering by cylindrical invisibility cloaks of various shapes deduced from the exact computation (e.g. using a finite element method) of scattering by cloaks of two given shapes, say circular and elliptic ones, thereafter called the source and destination images. The error in L(2) norm between the exact and approximate solutions deduced via morphing from the source and destination images is typically less than 2 percent if control points are judiciously chosen. Our approach works equally well for rotators and concentrators, and also unveils some device which we call rotacon since it both rotates and concentrates electromagnetic fields. However, it breaks down for superscatterers (deduced from non-monotonic transforms): the error in L(2) norm is about 25 percent. We stress that our approach might greatly accelerate numerical studies of 2D and 3D cloaks.


Assessment of antiproliferative activity of pectic substances obtained by different extraction methods from rapeseed cake on cancer cell lines.
In this work the antiproliferative activity of pectic substances obtained by different extraction methods from defatted rapeseed cake was assessed on cancer cell lines. The process consisted of sequential treatment with alkalized water (pH∼8), EDTA (0.01 M), alkaline protease (Alkalase 2.4L) and a commercial pectinase preparation (Viscozyme L or Pectinex Ultra SP-L). Pectic extracts identification was performed using spectroscopy and chromatography techniques. FT-IR and HPLC-IR results suggest that the neutral pectic extracts produced would be arabinogalactans and β-galactans. All the pectic substances extracted (acid and neutral) from RSC exhibited antiproliferative activity, being more effective on MCF-7 cells than Caco-2. The most effective pectic extract was obtained by Alkalase 2.4 L which killed over 80% of MCF-7 cells and 60% of Caco-2 cells. At less than 10 mg/mL pectic extracts enriched in neutral sugars also exhibited antiproliferative activity (50 and 40%, respectively), which was superior to the modified citric pectins activity at the same concentration for the breast cancer cell line (61.6% for MCF-7 and 49.9% for Caco-2 cells). These results show that the antiproliferative activity depends on both the type of pectin (acid or neutral) and the extraction procedure.


Microvascular free bone transfer: experimental technique on rat's femur.
A technique of microsurgical femur transplantation on rats is presented. This experimental model is used for better understanding of the bone physiology in autotransplantation and in homotransplantation.


Structural neuroimaging in neuropsychology: History and contemporary applications.
Neuropsychology's origins began long before there were any in vivo methods to image the brain. That changed with the advent of computed tomography in the 1970s and magnetic resonance imaging in the early 1980s. Now computed tomography and magnetic resonance imaging are routinely a part of neuropsychological investigations with an increasing number of sophisticated methods for image analysis. This review examines the history of neuroimaging utilization in neuropsychological investigations, highlighting the basic methods that go into image quantification and the various metrics that can be derived. Neuroimaging methods and limitations for identify what constitutes a lesion are discussed. Likewise, the influence of various demographic and developmental factors that influence quantification of brain structure are reviewed. Neuroimaging is an integral part of 21st Century neuropsychology. The importance of neuroimaging to advancing neuropsychology is emphasized. (PsycINFO Database Record


Trypanosomiasis control, Democratic Republic of Congo, 1993-2003.
In the Democratic Republic of Congo (DRC), human African trypanosomiasis (HAT) reached unprecedented levels in the 1990s. To assess recent trends and evaluate control efforts, we analyzed epidemiologic and financial data collected by all agencies involved in HAT control in DRC from 1993 to 2003. Funds allocated to control populations, as well as to the population screened, doubled from 1993 to 1997 and from 1998 to 2003. The number of cases detected decreased from 26,000 new cases per year in 1998 to 11,000 in 2003. Our analysis shows that HAT control in DRC is almost completely dependent on international aid and that sudden withdrawal of such aid in 1990 had a long-lasting effect. Since 1998, control efforts intensified because of renewed donor interest, including a public-private partnership, and this effort led to a major reduction in HAT incidence. To avoid reemergence of this disease, such efforts should be sustained.


Complementation of a Chlamydomonas reinhardtii mutant defective in the nuclear gene encoding the chloroplast coupling factor 1 (CF1) gamma-subunit (atpC).
Chlamydomonas reinhardtii strain atpC1 is a mutant defective in the nuclear gene that encodes the CF1 ATP synthase gamma-subunit polypeptide. Photoautotrophic growth was restored to atpC1 after it was transformed with wild-type DNA. Transformed strains were acetate-independent and arsenate-sensitive, similar in phenotype to the progenitor wild-type strain from which atpC1 was generated. Three transformed strains were examined in detail. Southern blot analyses demonstrated that the transformants were complements and not revertants. The transforming DNA integrated into the nuclear genome in a nonhomologous manner and at a low copy number. Northern blot analyses showed that the gamma-subunit mRNA in the complemented strains was expressed at the same relative level as that of wild-type. Western blots of total protein showed that whereas atpC1 was unable to synthesize any CF1 gamma-subunit, all three complemented strains could. Furthermore, the Western blot analyses demonstrated that the mutation in atpC1 had a pleiotropic effect on the accumulation of the CF1 beta-subunit which was relieved upon complementation. Cell extracts from atpC1 did not have any CF1-dependent catalytic activity, whereas extracts from all of the complemented strains and the wild-type strain had identical activities.


Crystal structures of the glycopeptide sulfotransferase Teg12 in a complex with the teicoplanin aglycone.
The TEG gene cluster, a glycopeptide biosynthetic gene cluster that is predicted to encode the biosynthesis of a polysulfated glycopeptide congener, was recently cloned from DNA extracted directly from desert soil. This predicted glycopeptide gene cluster contains three closely related sulfotransferases (Teg12, -13, and -14) that sulfate teicoplanin-like glycopeptides at three unique sites. Here we report a series of structures: an apo structure of Teg12, Teg12 bound to the desulfated cosubstrate 3'-phosphoadenosine 5'-phosphate, and Teg12 bound to the teicoplanin aglycone. Teg12 appears to undergo a series of significant conformational rearrangements during glycopeptide recruitment, binding, and catalysis. Loop regions that exhibit the most conformational flexibility show the least sequence conservation between TEG sulfotransferases. Site-directed mutagenesis guided by our structural studies confirmed the importance of key catalytic residues as well as the importance of residues found throughout the conformationally flexible loop regions.


Does the Acute Care Spinal Cord Injury Setting Predict the Occurrence of Pressure Ulcers at Arrival to Intensive Rehabilitation Centers?
The objective of this study was to evaluate the impact of acute care in specialized spinal cord injury (SCI) trauma centers on the prevalence of pressure ulcers (PU) upon arrival at a functional rehabilitation center after a traumatic SCI. This is a retrospective cohort study among 123 patients with traumatic SCI referred to intensive functional rehabilitation between January 1, 2009, and December 31, 2011. Group 1 (n = 90) was referred from a level 1 specialized SCI trauma center and group 2 (n = 33) was referred from seven trauma centers not specialized in SCI. The total prevalence of patients with PU at admission to functional rehabilitation was 33.3% (26.7% in group 1 and 51.5% in group 2, P = 0.017). There were also more patients with multiple PU in group 2 (24.2% vs. 2.2%, P = 0.0001). A binary logistic regression showed a significant relationship between the occurrence of PU and the type of acute care facility as well as the ASIA (American Spinal Injury Association) Impairment Scale grade. Receiving acute care at the specialized SCI trauma center was associated with a decrease in the number of patients developing one and multiple PU. These results highlight the importance of specialized SCI trauma centers in acute care of patients with traumatic SCI in reducing PU at their admission to functional rehabilitation settings.


Does formyl-methionyl-leucyl-phenylalanine exert a physiological role in labor in women?
The classical chemotactic receptor for N-formyl peptides has traditionally been associated with polymorphonuclear and mononuclear phagocytes; however, several recent reports indicate that this receptor is also expressed in non-myeloid cells. In this study we have investigated the presence of binding sites for formyl-methionyl-leucyl-phenylalanine (fMLP) in human amniotic membranes of laboring and nonlaboring women; we have also evaluated the effect of the peptide on prostaglandin E (PGE) release from the same tissue. Our results demonstrate the presence of specific, saturable binding sites for 3H-fMLP; Scatchard plot analysis suggests the presence of both high- and low-affinity binding sites in laboring amnion, while only the low-affinity receptors were evident in nonlaboring tissue. N-t-butoxycarbonyl-methionyl-leucyl-phenylalanine (Boc-MLP), a formyl peptide receptor antagonist, inhibited 3H-fMLP binding in both preparations. In addition, fMLP was able to significantly increase PGE synthesis in perifused amnion fragments from laboring and nonlaboring women. This effect was counteracted by Boc-MLP treatment. The presence of specific binding sites for fMLP in amniotic tissue and their differing expression in laboring versus nonlaboring membranes, together with the action of the peptide on PGE synthesis, all suggest a physiological role for fMLP in labor.


Temporal analysis of pathogenic events in virulent and avirulent Brucella melitensis infections.
Despite progress in mouse models of brucellosis, much remains unknown regarding Brucella dissemination and tissue localization. Here, we report the dynamics of Brucella infection in individual mice using bioluminescent Brucella melitensis. Bioluminescent imaging of infected interferon regulatory factor-1 knockout (IRF-1(-/-)) mice identified acute infection in many tissues. Brucella was found to replicate in the salivary glands of IRF-1(-/-) and wild-type C57BL/6 mice suggesting a previously unknown tissue preference. Establishing a niche in this region may have relevance in humans where infection can result from ingestion of few bacteria. Sublethal infection of IRF-1(-/-) mice resulted in chronic Brucella localization in tail joints, an infection parallel to osteoarticular brucellosis in humans. Importantly, bioluminescent imaging rapidly identified attenuated EZ::TN/lux mutants in infected mice and revealed differences in dissemination, thereby defining the contribution of Brucella genes to virulence and tissue localization. Surprisingly, a virB mutant, though defective in persistence, disseminated similarly to virulent Brucella, suggesting bacterial spread is independent of VirB proteins that are important for intracellular survival. Together, our results reveal kinetics of acute and chronic Brucella infection in individual mice that parallels human infection as well as readily identified attenuated bacteria. Our approach facilitates identifying virulence determinants that may control tissue specific replication and may help develop therapeutics to overcome Brucella-induced chronic debilitating conditions.


Petrous apex cholesterol granuloma: pictorial review of radiological considerations in diagnosis and surgical histopathology.
Petrous apex cholesterol granulomas are expansile, cystic lesions containing cholesterol crystals surrounded by foreign body giant cells, fibrous tissue reaction and chronic inflammation. Appropriate treatment relies on an accurate radiological diagnosis and an understanding of the distinguishing radiological features of relevant entities in the differential diagnosis of this condition. Firstly, this paper presents a pictorial review of the relevant radiological features of petrous apex cholesterol granuloma, and highlights unique features relevant to the differential diagnosis. Secondly, it reviews the histopathological and radiological findings associated with surgical drainage of these lesions. Radiological features relevant to the differential diagnosis of petrous apex cholesterol granuloma are reviewed, together with radiological and histopathological features relevant to surgical management. Following surgical management, histopathological and radiological evidence demonstrates that the patency of the surgical drainage pathway is maintained. Accurate diagnosis of petrous apex cholesterol granuloma is essential in order to instigate appropriate treatment. Placement of a stent in the drainage pathway may help to maintain patency and decrease the likelihood of symptomatic recurrence.


Frequency of Food Insecurity and Associated Health Outcomes in Pediatric Patients at a Federally Qualified Health Center.
Food insecurity (FI) has been recognized as a public challenge not only for developing countries but also for the U.S. The present study was designed to identify the prevalence of FI and the association of household FI with the health status of pediatric patients seen at a Federally Qualified Health Center in New Jersey which provides health care mainly for Latino patients. Patients were included if they were screened for FI at their well visits during a 4-month period following implementation of the 2-item screening tool recommended by American Academy of Pediatrics. We compared demographic and morbidity data of children with FI to those living in food-secure households. The results are presented as the distribution of frequency (%) and odds ratios (OR) with 95% confidence interval (95% CI). FI was detected in 15.8% (95% CI 14.2-17.5%) of 486 studied children. We recorded higher rates of anemia (10.4 vs. 3.2%, p < 0.005), hypercholesterolemia (10.4 vs. 3.4%, p < 0.01), and any morbidity (24.7 vs. 9.3%, p < 0.02) in children living in FI households. Multivariate logistic regression analysis revealed an association of household FI with at least one recorded morbidity independent of the patient's age, gender, and body mass index (OR 1.79, 95% CI 1.31-2.43). No one was diagnosed with diabetes, and only a few with asthma and hypertension. We have concluded that living in households with FI increased the risk for unfavorable health outcomes in a predominantly economically disadvantage community of children within the U.S.


Real-time on-line blend uniformity monitoring using near-infrared reflectance spectrometry: a noninvasive off-line calibration approach.
A robust, noninvasive, real-time, on-line near-infrared (NIR) quantitative method is described for blend uniformity monitoring of a pharmaceutical solid dosage form containing 29.4% (w/w) drug load with three major excipients (crospovidone, lactose, and microcrystalline cellulose). A set of 21 off-line, static calibration samples were used to develop a multivariate partial least-squares (PLS) calibration model for on-line prediction of the API content during the blending process. The concentrations of the API and the three major excipients were varied randomly to minimize correlations between the components. A micro electrical-mechanical system (MEMS) based portable, battery operated NIR spectrometer was used for this study. To minimize spectral differences between the static and dynamic measurement modes, the acquired NIR spectra were preprocessed using standard normal variate (SNV) followed by second derivative Savitzky-Golay using 21 points. The performance of the off-line PLS calibration model were evaluated in real-time on 16 laboratory scale (30 L bin size) blend experiments conducted over 3 months. To challenge the robustness of the off-line calibration model, several blend experiments were conducted using a different bin size, faster revolution speed and variations in the potency of the API. Employing the PLS calibration model developed using the off-line calibration approach, the real-time API NIR (%) predictions for all experiments were all within 90-110%. These results were confirmed using the conventional thief sampling of the final blend followed by high performance liquid chromatography (HPLC) analysis. Further confirmation was established through content uniformity by HPLC of manufactured tablets. Finally, the optimized off-line PLS method was successfully transferred to a production site which involved using a secondary NIR instrument with a 15-fold scale-up in bin size from development.


Prolonged regional nerve blockade by controlled release of local anesthetic from a biodegradable polymer matrix.
Prolonged nerve blockade is potentially useful in the management of many acute and chronic pain problems. Aside from infusions via an indwelling catheter, most currently available nondestructive techniques for prolonging local anesthetic action cannot provide more than 1-2 days of blockade. Bioerodible polymer matrixes have been used to deliver a variety of drugs in patients and animals for periods lasting weeks to years. Previously, dibucaine and bupivacaine were incorporated into copolymers of 1,3 bis(p-carboxyphenoxy) propane-sebacic acid anhydride (1:4), and demonstrated sustained release in vitro following incubation of the drug-polymer matrixes in phosphate-buffered solution (pH 7.4, 37 degrees C). In the present study, cylindrical pellets made from polymer matrixes incorporated with bupivacaine-HCl were implanted surgically along the sciatic nerves of rats. Neural block was assessed by direct observation of motor skills and by leg-withdrawal latency to a hot surface. Biochemical and histologic examinations were performed 2 weeks after implantation. Sensory and motor blockade was produced for periods ranging from 2 to 6 days. Contralateral control legs receiving polymer implants without drug showed no block. Blockade was reversible, and animals appeared to recover sensory and motor function normally. Biochemical indexes of nerve and muscle function were indistinguishable from contralateral controls. This biodegradable polymer system provides a promising new alternative for the delivery of local anesthetics to peripheral nerves to produce prolonged blockade for the management of acute and chronic pain.


Mutational dynamics of early and late relapsed childhood ALL: rapid clonal expansion and long-term dormancy.
Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Refractory/relapsed cALL presents a survival rate of ∼45% and is still one of the leading causes of death by disease among children. Mechanisms, such as clonal competition and evolutionary adaptation, govern treatment resistance. However, the underlying clonal dynamics leading to multiple relapses and differentiating early (<36 months postdiagnosis) from late relapse events remain elusive. Here, we use an integrative genome-based analysis combined with serial sampling of relapsed tumors (from primary tumor to ≤4 relapse events) from 19 pre-B-cell cALL patients (8 early and 11 late relapses) to assess the fitness of somatic mutations and infer their ancestral relationships. By quantifying both general clonal dynamics and newly acquired subclonal diversity, we show that 2 distinct evolutionary patterns govern early and late relapse: on one hand, a highly dynamic pattern, sustained by a putative defect of DNA repair processes, illustrating the quick emergence of fitter clones, and on the other hand, a quasi-inert evolution pattern, suggesting the escape from dormancy of leukemia stem cells likely spared from initial cytoreductive therapy. These results offer new insights into cALL relapse mechanisms and highlight the pressing need for adapted treatment strategies to circumvent resistance mechanisms.


Hemodynamic Significance of Middle Cerebral Artery Stenosis Associated With the Severity of Ipsilateral White Matter Changes.
Background: Previous studies conflicted in the association between intracranial atherosclerotic stenosis (ICAS) and the severity of white matter changes (WMC). Aims: We aimed to investigate the relationships between the severity of luminal stenosis and the hemodynamic significance of middle cerebral artery (MCA) stenosis, and the severity of ipsilateral WMC. Methods: In this cross-sectional study, patients with a recent ischemic stroke or transient ischemic attack and a 50-99% MCA-M1 stenosis in the Chinese Intracranial Atherosclerosis study cohort were analyzed. The post- to pre-stenotic signal intensity ratio (SIR) was obtained in time-of-flight MR angiography (MRA) to represent the hemodynamic significance of MCA-M1 stenosis, with a lower SIR indicating a hemodynamically more severe lesion. The severity of ipsilesional WMC was assessed by an age-related WMC (ARWMC) scale in T2-weighted fluid attenuated inversion recovery MR imaging. The relationships between the degree of MCA-M1 stenosis, SIR, and ipsilesional ARWMC scale were analyzed. The MCA-M1 lesion with a higher percentage of stenosis was chosen for analyses in patients with bilateral MCA-M1 stenoses. Results: Among 180 subjects (mean age, 64 years), a lower SIR of MCA-M1 stenosis (Spearman correlation coefficient, -0.543; p < 0.001), but not the degree of stenosis (p = 0.93), was significantly linearly correlated with a higher ipsilateral ARWMC. Multivariate ordinal logistic regression identified older age (OR = 1.037; 95% CI, 1.008-1.066; p = 0.011) and lower SIR (OR = 0.010; 95% CI, 0.002-0.058; p < 0.001) as independent predictors for more severe ipsilateral WMC. Conclusion: Patients with hemodynamically more severe ICAS are more likely to have more severe ipsilateral WMC. Longitudinal studies with sequential imaging exams may further reveal the impact of hemodynamic significance of ICAS on the development and progression of WMC.


Identifying metabolomic profiles of inflammatory diets in postmenopausal women.
We previously showed that a food-based empirical dietary inflammatory pattern (EDIP) score is associated with circulating inflammatory biomarkers. Metabolomic profiling of inflammatory diets may therefore provide insights on mechanisms contributing to disease etiology and prognosis. We aimed to elucidate metabolites associated with inflammatory diets among postmenopausal women, utilizing a robust study design that incorporates independent discovery and validation datasets. This baseline cross-sectional investigation evaluated associations between continuous EDIP scores calculated from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable-adjusted linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women's Health Initiative (WHI) Hormone Therapy trial participants and results were replicated in an independent dataset of 810 WHI Observational Study participants. Secondary analyses were stratified by standard body mass index (BMI, kg/m2) categories. In discovery and replication datasets statistical significance was based on false-discovery rate adjusted P < 0.05. After adjusting for energy intake, BMI, physical activity, and other confounding variables, 23 metabolites were significantly associated with EDIP score in the discovery dataset. Of these, the following ten were replicated: trigonelline, caffeine, acethylamino-6-amino-3-methyluracil, 7-methylxanthine, 1,7-dimethyluric acid, 3-methylxanthine, C18:3CE, glycine, associated with lower dietary inflammatory potential; whereas C52:3 triacylglycerol and linoleate associated with higher dietary inflammatory potential. Four of the ten were associated [glycine (inversely), caffeine, 1,7-dimethyluric acid, C52:3 triacylglycerol, (positively)], with C-reactive protein levels. In secondary analyses, associations showed differences by BMI category. Four metabolites, related to coffee/caffeine metabolism were inversely associated among normal weight women, and 83 metabolites associated with EDIP among overweight/obese women, including 40 (48%) that were also associated with C-reactive protein. Metabolites associated with coffee/caffeine and lipid metabolism may reflect the inflammatory potential of diet. Potential differences by BMI and the linkage to disease outcomes, require further study.


Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer.
Lung cancer is the leading cause of cancer death in the world, and greater than 90% of lung cancers are cigarette smoke-related. Current treatment options are inadequate, because the molecular basis of cigarette-induced lung cancer is poorly understood. Here, we show that human primary or immortalized bronchial epithelial cells exposed to cigarette smoke for eight days in culture rapidly proliferate, show anchorage-independent growth, and form tumors in nude mice. Using this model of the early stages of smoke-induced tumorigenesis, we examined the molecular changes leading to lung cancer. We observed that the embryonic signaling pathways mediated by Hedgehog and Wnt are activated by smoke. Pharmacological inhibition of these pathways blocked the transformed phenotype. These experiments provide a model in which the early stages of smoke-induced tumorigenesis can be elicited, and should permit us to identify molecular changes driving this process. Results obtained so far indicate that smoke-induced lung tumors are driven by activation of two embryonic regulatory pathways, Hedgehog (Hh) and Wnt. Based on the current and emerging availability of drugs to inhibit Hh and Wnt signaling, it is possible that an understanding of the role of Hh and Wnt in lung cancer pathogenesis will lead to the development of new therapies.


New methods for predicting visual acuity after cataract surgery.
Recent advances in technology have contributed to better evaluation of potential visual acuity in patients with cataracts. The blue field entoptic test, the clinical interferometers, and the Potential Acuity Meter are discussed with respect to their basic principles, clinical uses, advantages, and limitations. There are problems in evaluating these instruments, but their findings can play an important role in clinical decision making.


Primary pulmonary neoplasia in cats: assessment of computed tomography findings and survival.
To identify variables with a preoperative computed tomography scan that influence survival of cats undergoing surgical removal of a primary lung tumour. A secondary objective was to determine whether histologic type and or grade of feline pulmonary tumours affects long term survival. Medical records were retrospectively reviewed for cats with preoperative computed tomography scans and surgical resection of primary lung tumours. Pulmonary carcinomas were reviewed for histologic diagnosis using two different approaches, histologic grade as well as major histologic pattern. Median survival time of all (n = 28) cats was 156 days. Median survival time for cats with lymph node enlargement was 65 days versus 498 days for cats without lymph node enlargement on preoperative computed tomography scan. Median survival time for cats with preoperative pleural effusion was 2 · 5 days versus 467 days for cats without pleural effusion. Cats with low or intermediate grade tumours had a median survival time of 730 days versus 105 days for cats with high grade tumours. Cats with preoperative lymph node enlargement and pleural effusion have shorter survival times than cats without.


Clinical Experience of Treatment of Facial Malformations in Oto-Palato-Digital Syndrome: A Familial Patient.
Oto-palato-digital syndrome type 1 (OPD1) is an X-linked recessive disorder comprising characteristic facial appearances and skeletal alterations. The authors report OPD1 in a mother and her 2 sons who had multiple common congenital anomalies. Both of the brothers were born with mild hearing impairment, frontal bossing with prominent supraorbital ridges, downslanting palpebral fissures, dental malocclusion, and palatal clefts. They underwent a series of aesthetic surgeries for their facial malformations with good cosmetic results. The mother had a milder phenotype with less prominent craniofacial defects that did not require surgical correction. The older brother required a 2-jaw surgery whereas the younger brother required a surgically assisted rapid palatal expansion. In the second series of operations, both brothers underwent scraping of their prominent supraorbital ridge. They have been free of complications throughout their 16-year follow-up. The authors also screened the family for possible genetic etiologies and identified mutations in the causative gene of OPD1 on Xq28 in all 3 patients. In conclusion, the authors have identified 3 patients with OPD1, performed surgical treatments on the affected brothers and have obtained good reconstructive results. There are no reports involving OPD1 patients who have received good surgical treatment. With careful examination and identification of patients with characteristic facies and skeletal abnormalities, it is our opinion that the authors can help more patients with this disease through surgical management.


HSPRO acts via SnRK1-mediated signaling in the regulation of Nicotiana attenuata seedling growth promoted by Piriformospora indica.
Nicotiana attenuata HSPRO (NaHSPRO) is a negative regulator of seedling growth promoted by the fungus Piriformospora indica. Homologs of NaHSPRO in Arabidopsis thaliana (i.e., AtHSPRO1 and AtHSPRO2) are known to physically interact with the AKINβγ subunit of the SnRK1 complex. To investigate whether NaHSPRO is associated with SnRK1 function during the stimulation of seedling growth by P. indica, we studied N. attenuata plants silenced in the expression of NaGAL83 (as-gal83 plants)--a gene that encodes for the regulatory β-subunit of SnRK1--and plants silenced in the expression of both NaHSPRO and NaGAL83 (ir-hspro/as-gal83 plants). The results showed that P. indica differentially stimulated the growth of both as-gal83 and ir-hspro/as-gal83 seedlings compared with control seedlings, with a magnitude similar to that observed in ir-hspro seedlings. Thus, we showed that, similar to NaHSPRO, NaGAL83 is a negative regulator of seedling growth stimulated by P. indica. We propose that the effect of NaHSPRO on seedling growth is associated with SnRK1 signaling.


Molecular mechanism that induces activation of Spätzle, the ligand for the Drosophila Toll receptor.
The Drosophila Toll receptor is activated by an endogenous cytokine ligand Spätzle. Active ligand is generated in response to positional cues in embryonic dorso-ventral patterning and microbial pathogens in the insect immune response. Spätzle is secreted as a pro-protein and is processed into an active form by the serine endoproteases Easter and Spätzle-processing enzyme during dorso-ventral patterning and infection, respectively. Here, we provide evidence for the molecular mechanism of this activation process. We show that the Spätzle prodomain masks a predominantly hydrophobic region of Spätzle and that proteolysis causes a conformational change that exposes determinants that are critical for binding to the Toll receptor. We also gather that a conserved sequence motif in the prodomain presents features of an amphipathic helix likely to bind a hydrophobic cleft in Spätzle thereby occluding the putative Toll binding region. This mechanism of activation has a striking similarity to that of coagulogen, a clotting factor of the horseshoe crab, an invertebrate that has changed little in 400 million years. Taken together, our findings demonstrate that an ancient passive defense system has been adapted during evolution and converted for use in a critical pathway of innate immune signaling and embryonic morphogenesis.


The dispersion of defective endogenous murine retroviral elements suggests retrotransposition-mediated amplification.
The dispersion of four replication-defective endogenous proviruses, originally detected in 129 strain mice and shown to have extensive deletions of gag, pol, and env gene regions, was investigated in 13 inbred strains and substrains of mice. Using probes to sequences flanking the integration sites in 129 mice, unique genomic Eco RI fragments were assigned to each of the four endogenous proviral elements. Analyses revealed that certain of these proviral elements are present both in strains closely related to strain 129 (i.e., strains 101 and LP/J) and in more distantly related strains (i.e., strains BALB/cJ, A/J, and C3H/HeJ). In mouse strains lacking proviral integration at a particular locus, the size of the corresponding Eco RI genomic fragment and absence of a characteristic Kpn I site indicated the lack of a residual solitary long terminal repeat. Hybridization of oligonucleotide probes that distinguish the specific deletions present within these elements identified additional analogous proviral integrations at many different sites in all strains investigated. These data indicate that the diversification of these proviral elements found in inbred strains is generated by integration of new copies, rather than excision through homologous recombination. Moreover, the results are consistent with other endogenous retroviruses providing the trans-acting proteins necessary to package the defective viral RNA.


Administration of the antimycotic agents fluconazole and itraconazole to leukaemia patients: a comparative pharmacokinetic study.
This report presents the results of a randomized parallel design comparative study of the serum concentrations of fluconazole and itraconazole after administration of 100 mg orally to patients with leukaemia. Each group consisted of ten patients. The antimycotic drugs were administered with a standard breakfast immediately before the start of chemotherapy (day one) and on days eight and fifteen. No significant differences (p > 0.05; ANOVA) in the pharmacokinetic parameters of fluconazole (AUC, Cmax, Tmax) were found during the three days of the trial. It is concluded that there is no clinically important pharmacokinetic interaction between fluconazole and the chemotherapeutic agents given to this group of patients. A pharmacokinetic interaction between fluconazole and the fever suffered by some of the patients also seems unlikely. No significant differences (p < 0.05; ANOVA) in the pharmacokinetic parameters of itraconazole (AUC, Cmax, Tmax) were found during the three days of the trial, although the statistical power of the data was low. The significantly greater variability of all pharmacokinetic parameters for itraconazole than for fluconazole and the sharp increases and decreases in AUC during the course of the trial found for some patients in the itraconazole group suggest the need for caution in this group of patients.


Rooster semen cryopreservation: effect of pedigree line and male age on postthaw sperm function.
The fertility rates of cryopreserved poultry semen are highly variable and not reliable for use in preservation of commercial genetic stocks. Our objective was to evaluate the cryosurvival of semen from 8 pedigreed layer lines at 2 different ages: the onset and end of commercial production. Semen from 160 roosters (20/line) was frozen individually with 11% glycerol at 6 and 12 mo of age. Glycerol was removed from thawed semen by Accudenz gradient centrifugation. The viability of thawed sperm from each male was determined using fluorescent live-dead staining and flow cytometry; sperm velocity parameters were measured using computerized motion analysis. The fertilizing ability of thawed sperm was evaluated in vitro by assessing hydrolysis of the inner perivitelline membrane. The postthaw function of sperm from the elite lines varied widely, despite the fact that fresh semen from all of these lines typically yielded high fertility rates. The percentage of thawed sperm with intact plasma membranes ranged from 27.8 + or - 2.1 to 49.6 + or - 1.9 and varied among lines and between age groups. Thawed sperm from 2 lines consistently demonstrated the highest and lowest motility parameters, whereas the velocity parameters of the remaining 6 lines varied widely. The mean number of hydrolysis points per square millimeter of inner perivitelline membrane ranged from 12.5 + or - 4.1 (line 2) to 103.3 + or - 30.2 (line 6). Age effects were observed for 4 out of 8 lines; however, improved postthaw sperm function at 12 mo of age was not consistent for all 3 assays. These results demonstrate variability among pedigreed lines in withstanding glycerol-based semen cryopreservation and provide a model for delineating genotypic and phenotypic factors affecting sperm cryosurvival.


Reproducibility and repeatability of peripheral microvascular assessment using iontophoresis in conjunction with laser Doppler imaging.
Interrogation of peripheral vascular function is increasingly recognized as a noninvasive surrogate marker for coronary vascular function and carries with it important prognostic information regarding future cardiovascular risk. Laser Doppler imaging (LDI) is a completely noninvasive method for looking at peripheral microvascular function. We sought to look at reproducibility and repeatability of LDI-derived assessment of peripheral microvascular function between arms and 8 weeks apart. We used LDI in conjunction with iontophoretic application of ACh and SNP to look at endothelium-dependent and -independent microvascular function, respectively, in a mixture of women with cardiac syndrome X and healthy volunteers. We looked at variation between arms (n = 40) and variation at 8 weeks apart (n = 22). When measurements were corrected for skin resistance, there was nonsignificant variation between arms for ACh (2.7%) and SNP (3.8%) and nonsignificant temporal variation for ACh (3.5%) and SNP (4.7%). Construction of Bland-Altman plots reinforce that measurements have good repeatability. Elimination of the baseline perfusion response had deleterious effects on repeatability. LDI can be used to assess peripheral vascular response with good repeatability as long as measurements are corrected for skin resistance, which affects drug delivery. This has important implications for the future use of LDI.


ADEQUATE SHELTERS AND QUICK REACTIONS TO WARNING: A KEY TO CIVIL DEFENSE.
Case histories collected by investigators in Japan during 1945 illustrate both the effectiveness of shelters and the dangers inherent in apathy of the population, which suffered needless casualties by ignoring air raid warnintgs. Adequate shelters and immediate response to warnings are essential to survival in nuclear attack.


Evaluation by CBCT of Root and Canal Morphology in Mandibular Premolars in an Iranian Population.
To compare the root canal morphology in the left and right mandibular premolars on cone beam computed tomography (CBCT) images. In this analytical cross-sectional study, 457 CBCT images, including human left and right mandibular premolars were evaluated. CBCT scans were investigated in the three spatial planes and differences in the number of roots and canals were recorded. Data were analysed using chi-square test. The significance level was set at P < 0.05. From 914 mandibular first premolars, in the left side, 85.6% had one root and 14.4% had two roots; 69.6% had one canal and 30.4% had two canals. In the right side 87.3% had one root and 12.7% had two roots; 66.5% had one canal and 33.5% had two canals. There was no statistically significant difference in the number of roots (P = 0.440) and canals (P = 0.321) between left and right mandibular first premolars. From 914 mandibular second premolars, in the left side, 94.3% had one root and 5.7% had two roots; 77.9% had one canal and 22.1% had two canals. In the right side, 95.6% had one root and 4.4% had two roots; 83.4% had one canal and 16.6% had two canals. There was a significant difference in the number of canals between the left and right mandibular second premolars (P = 0.036). The root canal morphology in the mandibular left and right premolars was different, but there was a significant difference only in the number of canals in the mandibular second premolars.


The challenge and importance of defining critical limb ischemia.
Patients with critical limb ischemia are at risk of limb loss and have very high cardiovascular and total mortality rates, which are greater than can be accounted for by the usual risk factors for atherosclerosis. A definition of critical ischemia is necessary to determine the natural history of the disease and to assess and compare the efficacy of various forms of therapy. The definition needs to be based on hemodynamic criteria because clinical manifestations and outcomes are not reliable. The reasons for the difficulties in arriving at a generally acceptable definition are explored. Building on the previous work of others, modified hemodynamic definitions for critical and subcritical ischemia, which include measurements of pressures and of indices of microcirculation, are proposed.


Accounting for quality in the measurement of hospital performance: evidence from Costa Rica.
This paper provides insights into how Costa Rican public hospitals responded to the pressure for increased efficiency and quality introduced by the reforms carried out over the period 1997-2001. To that purpose we compute a generalized output distance function by means of non-parametric mathematical programming to construct a productivity index, which accounts for productivity changes while controlling for quality of care. Our results show an improvement in hospital performance mainly driven by quality increases. The adoption of management contracts seems to have contributed to such enhancement, more notably for small hospitals. Further, productivity growth is primarily due to technical and scale efficiency change rather than technological change. A number of policy implications are drawn from these results.


A comparison study: applying segmentation to array CGH data for downstream analyses.
Array comparative genomic hybridization (CGH) allows detection and mapping of copy number of DNA segments. A challenge is to make inferences about the copy number structure of the genome. Several statistical methods have been proposed to determine genomic segments with different copy number levels. However, to date, no comprehensive comparison of various characteristics of these methods exists. Moreover, the segmentation results have not been utilized in downstream analyses. We describe a comparison of three popular and publicly available methods for the analysis of array CGH data and we demonstrate how segmentation results may be utilized in the downstream analyses such as testing and classification, yielding higher power and prediction accuracy. Since the methods operate on individual chromosomes, we also propose a novel procedure for merging segments across the genome, which results in an interpretable set of copy number levels, and thus facilitate identification of copy number alterations in each genome. http://www.bioconductor.org


Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster.
Departures from Hardy-Weinberg (HW) equilibria and pairwise disequilibria were estimated in a sample of unrelated healthy individuals typed for six RFLPs in the apo AI-CIII-AIV gene region. The sample was composed of males and females, selected for health, from two populations, those of exclusively French-Canadian (FC) and those of some non-French-Canadian (NFC) ancestry. An approach suggested by Weir and Cockerham, which includes estimates of nonrandom association (disequilibria) between three and four alleles at two loci as well as the traditional associations between two alleles, at two loci was used. The pattern of departures from HW equilibria suggested that the genetic structures of the FC and NFC are different. Departure from HW equilibrium at an RFLP locus could not be predicted from information about other loci in the same gene region. Nonrandom associations were also evident from the pairwise analyses. Two pairs of loci had significant diallelic disequilibria, while two other pairs had significant triallelic disequilibria. All of the RFLP pairs had at least one measure of disequilibrium at its maximum value determined by allele frequencies. Inferences about pairwise disequilibria depended on the statistical approach used. Sizes of the pairwise disequilibria were not correlated with the physical distance between loci. The impact of these disequilibria on RFLP-phenotype association studies is discussed.


Sensitivity of monthly heart rate and psychometric measures for monitoring physical performance in highly trained young handball players.
The aim of the present study was to examine whether monthly resting heart rate (HR), HR variability (HRV) and psychometric measures can be used to monitor changes in physical performance in highly-trained adolescent handball players. Data were collected in 37 adolescent players (training 10±2.1 h.wk(-1)) on 11 occasions from September to May during the in-season period, and included an estimation of training status (resting HR and HRV, the profile of mood state (POMS) questionnaire), and 3 physical performance tests (a 10-m sprint, a counter movement jump and a graded aerobic intermittent test, 30-15 Intermittent Fitness Test). The sensitivity of HR and psychometric measures to changes in physical performance was poor (< 20%), irrespective of the training status markers and the performance measures. The specificity was however strong (> 75%), irrespective of the markers and the performance measures. Finally, the difference in physical performance between players with better vs. worse estimated training status were all almost certainly trivial. The present results highlight the limitation of monthly measures of resting HR, HRV and perceived mood and fatigue for predicting in-season changes in physical performance in highly-trained adolescent handball players. This suggests that more frequent monitoring might be required, and/or that other markers might need to be considered.


Molecular cloning of DNA complementary to a mouse alpha-fetoprotein mRNA sequence.
DNA complementary to mouse yolk sac messenger RNA has been inserted at the PstI site of the plasmid pBR322 by annealing of the oligo(dG)-tailed plasmid DNA with the oligo(dC)-tailed mouse DNA. Transformation of Escherichia coli strain RRI with this annealed DNA yielded clones bearing recombinant plasmids. The clones were screened for DNA complementary to mouse alpha-fetoprotein (AFP) messenger RNA sequences by hybridization with a cDNA probe transcribed from an AFP mRNA of over 90% purity. Out of nine plasmids that were isolated and analyzed by restiction mapping, all had homologous insert DNA of various lengths. The plasmid with the longest insert, pAF6, contained 1.65 kb of added DNA, which is about 70% of the AFP mRNA. This clone was positively identified by a hybridization-translation procedure to contain a cDNA sequence for AFP. A restriction map of this clone and the orientation of the message are presented.


Smoking and Lung Cancer Mortality in the United States From 2015 to 2065: A Comparative Modeling Approach.
Tobacco control efforts implemented in the United States since the 1960s have led to considerable reductions in smoking and smoking-related diseases, including lung cancer. To project reductions in tobacco use and lung cancer mortality from 2015 to 2065 due to existing tobacco control efforts. Comparative modeling approach using 4 simulation models of the natural history of lung cancer that explicitly relate temporal smoking patterns to lung cancer rates. U.S. population, 1964 to 2065. Adults aged 30 to 84 years. Models were developed using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010). Each model projected lung cancer mortality by smoking status under the assumption that current decreases in smoking would continue into the future (status quo trends). Sensitivity analyses examined optimistic and pessimistic scenarios. Under the assumption of continued decreases in smoking, age-adjusted lung cancer mortality was projected to decrease by 79% between 2015 and 2065. Concomitantly, and despite the expected growth, aging, and longer life expectancy of the U.S. population, the annual number of lung cancer deaths was projected to decrease from 135 000 to 50 000 (63% reduction). However, 4.4 million deaths from lung cancer are still projected to occur in the United States from 2015 to 2065, with about 20 million adults aged 30 to 84 years continuing to smoke in 2065. Projections assumed no changes to tobacco control efforts in the future and did not explicitly consider the potential effect of lung cancer screening. Tobacco control efforts implemented since the 1960s will continue to reduce lung cancer rates well into the next half-century. Additional prevention and cessation efforts will be required to sustain and expand these gains to further reduce the lung cancer burden in the United States. National Cancer Institute.


Implantation of the C-loop Simcoe posterior chamber lens.
A simple, one-handed technique of insertion of the popular C-loop Simcoe posterior chamber lens can be achieved without the use of special instrumentation. While a large pupil is preferable, this technique is readily useful for cases where the pupil has constricted. The inferior loop and the lens are placed into the posterior chamber and the capsular bag together. The superior loop is directly placed into the superior capsular fornix. Lens positioning is completed with a modified Sinskey hook.


Toxicity, immunogenicity, and tumor radioimmunodetecting ability of two human monoclonal antibodies in patients with metastatic colorectal carcinoma.
Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.


Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models.
Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.


The psychometric properties of the Portuguese version of the Stroke Quality of Life Scale.
Quality of life (QoL) is currently of particular importance to health services and is regarded a key dimension for the assessment of stroke outcomes. However there are few instruments available for the Portuguese population. The aim of the present work is to determine the psychometric properties of the Portuguese version of the Stroke Quality of Life Scale (ECVI-38), including acceptability, construct and criterion validity. The sample comprised 51 patients with a clinical history of stroke (2 to 24 months prior) from the outpatient clinic of two Portuguese hospitals.. Patients with neuropsychiatric pathologies or other health conditions that might affect QoL were excluded. Parallel to the application of the ECVI-38, several other tests were used in order to determine the discriminative and concurrent validity of the scale. The ECVI-38 showed good acceptability, with missing data below 10%, and ceiling and floor effects below 80%. Cronbach's alpha for the total scale was 0.94 and ranged between 0.7 and 0.9 in each domain. ECVI-38 results were able to differentiate patients according to the severity of neurological impairment. Every domain of the scale correlated significantly with instruments of similar content. The Portuguese version of the ECVI-38 showed good psychometric characteristics.


A pilot study of dose intense doxorubicin and cyclophosphamide followed by infusional paclitaxel in high-risk primary breast cancer.
We conducted a pilot study of dose dense doxorubicin and cyclophosphamide (AC) combination chemotherapy followed by infusional paclitaxel (T) in primary breast cancer to determine its safety and feasibility. Twenty-two subjects (10 with stage II and > or = 4 positive lymph nodes, and 12 with stage III disease) were treated with AC (A 60 mg/m2 and C 2000 mg/m2) with filgrastim every 14 days for three cycles followed by infusional paclitaxel (140 mg/m2 over 96 h) every 14 days for three cycles. Mean overall cycle length was 15.3 days and mean duration of therapy was 92 days. Dose reductions of C or T were required in 7/132 (5.3%) cycles for mucositis, diarrhea, or failure to recover platelets by day 15. Ninety-five percent of subjects had grade 4 neutropenia and 1 subject had a platelet nadir of < 20,000. Actual delivered dose intensity (DI) over six cycles was: A 27 mg/m2 per week; C 892 mg/m2 per week; T 64 mg/m2 per week (90.6, 89.2, and 91.4% of planned DI, respectively). Average total dose administered was: A 180 mg/m2; C 5880 mg/m2; T 403 mg/m2 (100, 98, and 96% of planned total doses, respectively). Clinical response rate in 10 subjects receiving neoadjuvant therapy was 100% (4 complete response, 6 partial response). Four subjects had a pathologic complete response (three subjects without evidence of malignancy and one subject with ductal carcinoma in situ.) Administration of dose dense AC followed by infusional paclitaxel in 14-day cycles is feasible and this regimen is active in breast cancer.


Hand-arm vibration and the risk of vascular and neurological diseases-A systematic review and meta-analysis.
Increased occurrence of Raynaud's phenomenon, neurosensory injury and carpal tunnel syndrome has been reported for more than 100 years in association with work with vibrating machines. The current risk prediction modelling (ISO-5349) for "Raynaud's phenomenon" is based on a few studies published 70 to 40 years ago. There are no corresponding risk prediction models for neurosensory injury or carpal tunnel syndrome, nor any systematic reviews comprising a statistical synthesis (meta-analysis) of the evidence. Our aim was to provide a systematic review of the literature on the association between Raynaud's phenomenon, neurosensory injuries and carpal tunnel syndrome and hand-arm vibration (HAV) exposure. Moreover the aim was to estimate the magnitude of such an association using meta-analysis. This systematic review covers the scientific literature up to January 2016. The databases used for the literature search were PubMed and Science Direct. We found a total of 4,335 abstracts, which were read and whose validity was assessed according to pre-established criteria. 294 articles were examined in their entirety to determine whether each article met the inclusion criteria. The possible risk of bias was assessed for each article. 52 articles finally met the pre-established criteria for inclusion in the systematic review. The results show that workers who are exposed to HAV have an increased risk of vascular and neurological diseases compared to non-vibration exposed groups. The crude estimate of the risk increase is approximately 4-5 fold. The estimated effect size (odds ratio) is 6.9 for the studies of Raynaud's phenomenon when including only the studies judged to have a low risk of bias. The corresponding risk of neurosensory injury is 7.4 and the equivalent of carpal tunnel syndrome is 2.9. At equal exposures, neurosensory injury occurs with a 3-time factor shorter latency than Raynaud's phenomenon. Which is why preventive measures should address this vibration health hazard with greater attention.


A pilot study of the Functional Living Index-Cancer (FLIC) Scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study.
Quality of life is an important factor in the assessment of cancer therapy, but it is difficult to define and measure. The Functional Living Index-Cancer (FLIC) was designed specifically for cancer patients under treatment. The Eastern Cooperative Oncology Group (ECOG) mounted a pilot study to assess the feasibility and sensitivity of the patient-oriented FLIC scale for assessment of quality of life. The results of this study show that the FLIC scores correlate with the functional status of patients on treatment: high scores on the FLIC prior to therapy were found to correlate with good performance status (p = 0.0001), and decreases in the FLIC score during therapy correlated with a decline in performance status (p = 0.0001), with poor performance status (p = 0.0002), and greater than 5% recent weight loss (p = 0.004). However, there was poor compliance to completion of the instrument, indicating a need for future research into this aspect of assessing quality of life in the cooperative group setting.