Quality-Control Analytical Methods: Pharmaceutical and Analytical Considerations of the Significance of pH.
Most drugs are weak acids or weak bases. The solubility, stability, activity, absorption, and bioavailability of these drug molecules are highly pH dependent. This article discusses the importance of pH in pharmacuetical preparation and analysis.


Effects of topical antiinflammatory agents on Freund's adjuvant-induced skin lesions in rats.
Freund's adjuvant, when administered intradermally to rats, causes polyarthritis as well as inflammation of the skin, eye, gastrointestinal and genitourinary tracts. We assessed the effects of antiinflammatory drugs on ear skin lesions to determine if this might be a useful skin inflammation model. The hind paw of male Lewis rats was injected with Mycobacterium butyricum in paraffin oil. Lesions appeared between days 13 and 15 after adjuvant injection. Each ear exhibited on average 1 to 3 highly erythematous, elevated lesions, 2 to 3 mm in diameter. By histology, the lesions consisted of epidermal hyperplasia, with a prominent accumulation of inflammatory cells in the dermis. Ears were treated topically with glucocorticoids, cyclosporine and indomethacin on days 15 through 21 after adjuvant injection. By day 22, dexamethasone, fluocinolone acetonide, and cyclosporine caused near-complete clearing of lesions whereas indomethacin exacerbated the inflammation by causing increased numbers of skin lesions. These results show the potential usefulness of adjuvant-induced skin lesions in rats as a novel subchronic inflammation model.


LncRNA NEAT1 sponges miR-214 to regulate M2 macrophage polarization by regulation of B7-H3 in multiple myeloma.
LncRNA NEAT1 was associated with the tumorigenesis of multiple myeloma (MM). However, the mechanisms of M2 macrophage polarization involved with NEAT1 in MM are still unknown. Bone marrow samples, multiple myeloma cells RPMI 8226 and monocyte cell line THP-1 were used in this study. The expression of NEAT1 and miR-214 was modified by transfection with the shNEAT1 or miR-214 inhibitor. The expression of NEAT1, miR-214 and B7-H3 in MM patient tissues and cells was analyzed by RT-qPCR. ELISA assay was used to determine the release of B7-H3 in the supernatant of cell culture. The patient survival curve was analyzed using Kaplan-Meier method. The macrophage polarization markers were examined by RT-qPCR and western blotting. The interaction between NEAT1, miR-214 and B7-H3 was analyzed by Dual-Luciferase reporter and RIP assays. AG490 was used to block the JAK2/STAT3 signaling. Co-culture of THP-1 and RPMI 8226 cells was used for macrophage polarization. NEAT1 and B7-H3 were up-regulated, but miR-214 was obviously down-regulated in MM patients. B7-H3, NEAT1 and miR-214 were associated with overall survival time of MM patients. NEAT1 silencing induced miR-214 and inhibited the expression and release of B7-H3 and then suppressed M2 macrophage polarization via inhibiting the JAK2/STAT3 signaling. NEAT1 directly targeted miR-214, and miR-214 directly bound to B7-H3. MiR-214 inhibitor reversed the down-regulation and release of B7-H3 and M2 macrophage polarization caused by shNEAT1. The specific JAK2/STAT3 signaling inhibitor AG490 abrogated M2 macrophage polarization. NEAT1 promoted M2 macrophage polarization by sponging miR-214 and then regulating B7-H3, thus accelerating MM progression via the JAK2/STAT3 signaling pathway. Our study revealed novel mechanisms of M2 macrophage polarization and provided new potential clinical therapeutic targets for MM.


Negative wealth shocks in later life and subsequent cognitive function in older adults in China, England, Mexico, and the USA, 2012-18: a population-based, cross-nationally harmonised, longitudinal study.
Household wealth is positively related to cognitive health outcomes in later life. However, the association between negative wealth shocks and cognitive function in later life, and whether this association might differ across countries at different levels of economic development, is unclear. We aimed to investigate whether negative wealth shocks in later life are associated with cognitive function in older adults in China, England, Mexico, and the USA, and whether this association is modified by country income level. For this population-based, cross-nationally harmonised, longitudinal study, data were analysed from core interviews of the population-based US Health and Retirement Study (2012 and 2016) and its partner studies in China (the China Health and Retirement Longitudinal Study; 2015 and 2018), England (the English Longitudinal Study of Ageing; 2012 and 2016), and Mexico (Mexican Health and Aging Study; 2012 and 2015-16), and their respective Harmonized Cognitive Assessment Protocols (HCAPs). Negative wealth shocks over the follow-up periods of the respective cohorts were defined in two ways: an extreme loss of 75% or greater from the baseline amount of wealth, and a decline in within-population wealth quintile rank. The primary outcome was the harmonised general cognitive function (GCF) factor score, which was constructed with factor analysis on the HCAP neuropsychological assessments of memory, orientation, attention, executive function, and verbal fluency performance (mean 0; SD 1). We used sampling-weighted, multivariable-adjusted linear models to examine associations. Data from 9465 participants were included in this analysis: 3796 from China, 1184 from England, 1193 from Mexico, and 3292 from the USA. The mean baseline age of participants was 68·5 (SD 5·4) years in China (49·8% women), 72·0 (7·0) years in England (54·6% women), 70·6 (6·8) years in Mexico (55·1% women), and 72·7 (7·5) years in the USA (60·4% women). A wealth loss of 75% or greater was negatively associated with subsequent cognitive function in the USA (β -0·16 SD units; 95% CI -0·29 to -0·04) and China (-0·14; -0·21 to -0·07), but not in England (-0·01; -0·24 to 0·22) or Mexico (-0·11; -0·24 to 0·03). Similarly, within-population wealth quintile rank declines were negatively associated with subsequent cognitive function in the USA (β -0·07 per quintile rank decline; 95% CI -0·11 to -0·03) and China (β -0·07; -0·09 to -0·04), but not in England (-0·05; -0·11 to 0·01) or Mexico (-0·03; -0·07 to 0·01). The impact of wealth shocks in later life on subsequent lower level of cognitive function of older adults in China, England, Mexico, and the USA differed across macro-level socioeconomic structures. These findings suggest that government policies and social safety nets in countries with different levels of economic development might have a role in protecting older adults from adverse health effects of wealth losses in later life. US National Institute on Aging, US National Institutes of Health.


Diffusion MR imaging in glioma: does it have any role in the pre-operation determination of grading of glioma?
To investigate the role of the diffusion MR weighted sequence in the pre-operative grading of gliomas, and its application in defining the different components of these tumours. Seventeen patients with gliomas (eight high grade, nine low grade) had diffusion weighted imaging. Apparent diffusion coefficients (ADCs) of different components of tumours were measured. ADC of the cystic portion of the tumour was significantly higher than ADCs of the enhanced tumour, non-enhanced tumour and perifocal oedema (P < 0.01). No significant difference in ADC values between low grade and high grade glioma (P > 0.7) was found nor was there any difference between oligoglioma and non-oligoglioma (P > 0.29). ADC value was useful to differentiate the cystic from the solid components of the tumours. However, it was not useful in pre-operative grading of glioma.


The Influence of Prior Functional Status on Self-Care Improvement During a Skilled Nursing Facility Stay.
Older adults' prior health status can influence their recovery after a major illness. We investigated the association between older adults' independence in self-care tasks prior to a skilled nursing facility (SNF) stay and their self-care function at SNF admission, discharge, and the change in self-care function during an SNF stay. Retrospective study of 100% national CMS data files from October 1, 2018, to December 31, 2019. The sample included 616,073 Medicare fee-for-service beneficiaries who were discharged from an SNF between October 1, 2018, and December 31, 2019. The admission Minimum Data Set (MDS) was used to determine residents' prior ability (independent, some help, dependent) to complete self-care tasks before the current illness, exacerbation, or injury. Seven self-care tasks from MDS Section GG were used to calculate total scores (range 7-42 points) for self-care at admission, discharge, and the change in self-care between admission and discharge. Most residents (62.0%) were independent, 35.3% needed some help, and 2.64% were dependent in self-care prior to SNF admission. Nearly 25% of residents with urinary incontinence, 28.8% with bowel incontinence, and 31.7% with moderate-severe cognitive impairment were independent in self-care prior to SNF admission compared with approximately 70% of residents without these conditions. Compared with residents who were dependent in self-care prior to SNF admission, those who were independent or needed some help had significantly higher self-care total scores at admission (5.67 vs 4.21 points, respectively) and discharge (6.44 vs 3.82 points, respectively) and exhibited greater improvement in self-care (3.48 vs 1.62 points, respectively). Our findings are evidence that the new MDS item for a resident's independence in self-care tasks before SNF admission is a valid measure of their prior self-care function. This is clinically useful information and should be considered when developing rehabilitation goals.


"Cut and combine": an easy membrane-supported combinatorial synthesis technique.
A combinatorial synthesis process involving sequential cycles of cutting a membrane support into pieces and combining these into groups and subjecting the groups to simultaneous solid-phase chemical reactions is demonstrated by the rapid assembly of four hundred N-terminally biotinylated, soluble, octameric peptide pools. Index patterns printed onto the synthesis membrane allowed a direct identification of the compounds. These were used to study protein kinase substrate selection in a parallel microplate adapted 32P-phosphorylation assay with subsequent spotting on a biotin-capture membrane.


Punctal occlusion in keratoconjunctivitis sicca.
Occlusion of the lacrimal puncta is a useful and underutilized procedure in the treatment of keratoconjunctivitis sicca. When artificial tears no longer ameliorate symptoms and the Schirmer tests are 2 mm/5 min or less (repeatedly), combined with positive rose bengal staining, punctal occlusion is indicated. Diathermy is the most practical technique for permanent closure, whereas various punctum plugs can be applied for a temporary effect.


Neutralizing Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Patients With Central Nervous System and Localized Cryptococcosis: Longitudinal Follow-up and Literature Review.
Neutralizing anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (AAbs) have been increasingly recognized to predispose healthy individuals to disseminated cryptococcosis. However, studies have only considered patients with central nervous system (CNS) infection. No longitudinal study has captured the disease spectrum and clinical course. We prospectively enrolled adults without human immunodeficiency virus infection who had disseminated or unusual cryptococcosis. We compared the demographics, clinical features, kinetics of serum cryptococcal antigen (CrAg) titers, anti-GM-CSF AAb concentrations, and treatment outcomes between patients with (case patients) and without (control patients) anti-GM-CSF AAbs. Additional reports from the literature were also reviewed. Twenty-three patients were enrolled, of whom 6 tested positive for anti-GM-CSF AAbs. All case patients with positive fungal cultures (5/5 [100%]) were infected with Cryptococcus gattii VGII. Among them, 3 had exclusively pulmonary involvement, and 1 had only musculoskeletal lesions. Patients with CNS cryptococcosis exhibited a higher serum concentration of anti-GM-CSF AAbs than those with extraneural cryptococcosis. Case patients had higher initial and peak levels of serum CrAg and longer duration of antigenemia compared with the control patients. All case patients who had completed antifungal therapy had favorable outcomes without recurrence. Testing for anti-GM-CSF AAbs should be considered for not only previously healthy patients with disseminated cryptococcosis but also those with unexplained, localized cryptococcosis. Recurrence after completion of antifungal therapy was rare despite the persistence of anti-GM-CSF AAbs.


Renal adenocarcinoma: prognostics and treatment reflected by survival.
A retrospective study of 164 patients with renal adenocarcinoma has reconfirmed the highly malignant potential of this neoplasm. Stage and size of the tumor appear to be the best prognostic parameters. Radical surgery appears to have improved survival statistics. Follow-up must be indefinite since late metastases are not uncommon.


Thick Graft Versus Double-Bundle Technique on Posterior Cruciate Ligament Reconstruction: Experimental Biomechanical Study with Cadavers.
Objective To evaluate the biomechanical effect of graft thickness compared with the double-bundle technique on posterior cruciate ligament (PCL) reconstruction in human cadaveric knees. Methods A total of 9 human cadaveric knees were tested in 5 conditions: intact knee (INT); single-bundle reconstruction with a 10-mm quadriceps tendon (SB); double-bundle reconstruction with a 10 mm-quadriceps tendon for the anterolateral bundle and a 7-mm doubled semitendinosus tendon for the posteromedial bundle (DB); single-bundle reconstruction with a 10-mm quadriceps tendon plus a 7-mm doubled semitendinosus tendon (SBT); and PCL-deficient (NoPCL). The posterior tibial translation (PTT) was measured in response to a 134-N posterior tibial load at 0 ∘ , 30 ∘ , 60 ∘ e 90 ∘ of knee flexion. Results The PTT values of the DB and SBT techniques were always significantly lower (better stability) than those of the SB technique. The PTT values of the SBT technique were significantly lower than those of the DB technique at 60 ∘ ( p = 0.005) and 90 ∘ ( p = 0.001). Conclusions Graft enlargement improves knee stability in isolated PCL reconstructions, whereas the graft division in the two-bundle technique worsens this stability at 60 ∘ and 90 ∘ of knee flexion. The findings of the present study suggest that knee stability in PCL reconstructions may be improved with the use of thicker grafts in the SB technique rather than performing the DB technique.


Randomized controlled trial of stress reduction with meditation and health education in black men and women with high normal and normal blood pressure.
Black men and women suffer from disparities in morbidity and mortality from hypertension, cardiovascular disease, and currently, COVID-19. These conditions are associated with social determinants of health and psychosocial stress. While previous trials demonstrated that stress reduction with meditation lowered BP in the grade I range in Black adults, there is a paucity of evidence for high normal and normal BP. This randomized controlled trial was conducted to evaluate the effect of stress reduction with the Transcendental Meditation (TM) technique in Black adults with high normal BP and normal BP using international classifications. A total of 304 Black men and women with high normal (130-139/85-89 mm Hg) and normal BP (120-129/80-84 mm Hg) were randomized to either TM or health education (HE) groups. BP was recorded at 3, 6, 9, 12, 24, 30 and 36 months after baseline. Linear mixed model analysis was conducted to compare the BP change between TM and HE participants in the high-normal BP and normal-BP groups. Survival analysis for hypertensive events was conducted. After an average of 19.9 ± 11.1 months follow-up, TM participants in the high-normal BP group showed significantly lower posttest SBP (-3.33 mm Hg, p = 0.045). There was no difference in DBP (-0.785 mm Hg, p = 0.367) compared to HE participants. In the normal BP group, the SBP and DBP were not different between the TM and HE participants. The hazard ratio for hypertensive events was 0.52 (p = 0.15) in the high normal BP group (7 TM vs 13 HE) with no difference in the normal BP group. This RCT found that meditation lowered systolic BP in Black men and women with high normal BP but not in normal BP participants. These results may be relevant to reducing health disparities in CVD and related co-morbidities.


Tissue-specific Fc gamma and complement receptor expression by alveolar macrophages determines relative importance of IgG and complement in promoting phagocytosis of Pseudomonas aeruginosa.
Because the expression of IgG Fc receptors and complement receptors on macrophages may vary in a tissue-specific manner, we used monoclonal antibodies and flow cytometry to define the expression and function of opsonin receptors on fresh normal and cystic fibrosis (CF) bronchoalveolar lavage (BAL) macrophages. Using flow cytometry to separately analyze individual types of cells, we then determined the relative contributions of IgG and complement to phagocytosis of Pseudomonas aeruginosa by fresh BAL cells, avoiding alterations in receptor expression due to in vitro purification or culturing techniques. Neither normal nor CF BAL macrophages express appreciable amounts of the complement receptors CR1, CR2, or CR3. These results were confirmed by immunohistochemical staining of fixed lung sections. BAL macrophages express a high-affinity IgG receptor, Fc gamma RI, that is not found on neutrophils (PMN). In contrast, chemoattractant-stimulated blood PMN express large amounts of CR1 and CR3 but do not express Fc gamma RI. These results correlate with phagocytosis assays, which show that phagocytosis by macrophages is enhanced by relatively low concentrations of IgG but that the addition of complement does not further increase their phagocytosis. In contrast, low concentrations of IgG alone do not promote phagocytosis by PMN, whereas addition of complement markedly enhances phagocytosis by PMN. These results may explain the previously reported sensitivity of macrophages rather than PMN to the "blocking" effects of anti-Pseudomonas antibodies from CF patients, and emphasize the pathologic significance of interference with IgG and complement mediated opsonization in the lung in CF.


Endogenous bioactive gibberellin/abscisic acids and enzyme activity synergistically promote the phytoremediation of alkaline soil by broomcorn millet (Panicum miliaceum L.).
Broomcorn millet (Panicum miliaceum L.), an important food crop, grows in arid and semi-arid areas that face soil saline-alkalization. To date, no studies have investigated the mechanisms by which broomcorn millet seeds respond to and tolerate alkali stress. In this study, six broomcorn millet genotypes (B102, B220, B269, B279, B289, and B297) were selected to explore the physiological and molecular mechanisms of alkali stress at the germination stage. The results showed that alkali stress delayed the germination of broomcorn millet, and α-amylase activity was positively correlated with the germination rate. After alkali stress, the genotypes with lower alkali damage rates exhibited stronger antioxidant defenses. Real-time polymerase chain reaction analysis showed that alkali stress downregulated gibberellic acid (GA) synthesis genes but upregulated GA inactivation and abscisic acid (ABA) synthesis genes. Similarly, seeds displayed lower GA concentrations and higher ABA concentrations after alkali stress. Therefore, the ratios of various GAs/ABA decreased within the range of 35.77% to approximately 96.45%. Additionally, genotypes associated with lower alkali damage rates had higher GA/ABA ratios. These findings indicate that the alkali tolerance of broomcorn millet at the germination stage may be attributed to higher GA/ABA ratios, higher α-amylase activity, and stronger antioxidant defense, which synergistically resist alkali stress. This study will contribute to molecular breeding aiming to enhance alkali-tolerance and restoration of alkaline soils.


Surface ultrastructure of human arteries with special reference to the effects of smoking.
The surface ultrastructure of uterine arteries from 20 women was studied with scanning electron microscopy. Specimens were excised and fixed under pressure shortely after removal of the uterus during hysterectomy. Two groups of patients were selected: non-smokers and women who smoked more than 15 cigarettes a day. The prevalence of seven different morphological criteria was evaluated without knowledge of the smoking habits of the patients. Endothelial cells were usually well demarcated and distributed with their length axis paralledl to that of the artery. The cell nucleus was revealed by a gentle bulging into the lumen, and cell borders by the presence of rows of microvilli. Inter- and intracellular holes alon the cell borders were more common in arteries from smokers, whereas microvillie were more common on the cell surfaces of arteries from non-smokers. These differences might be related to cell injury. Previous studies indicate that holes are more frequent in injured than in non-injured cells, whereas the surface of injured cells is often smoother than that of non-injured cells. Therefore, these data may be taken to suggest that smoking can lead to endothelial injury in man.


Lung deposition, lung clearance and renal accumulation of inhaled cadmium chloride and cadmium sulphide in rats.
Rats were exposed 6 h/day over 10 days to 0.3 mg/m3 of water soluble cadmium chloride and 0.2, 1.0 and 8.0 mg/m3 of insoluble cadmium sulphide, then killed at intervals over a 3-month period for serial measurements of lung, renal and faecal cadmium. CdCl2 and high-dose CdS animals showed a transient increase in lung weight. Clearance of both compounds was biphasic. Approximately 40% of deposited material was cleared during the 10-day exposure period. For CdCl2, only 9% of the lung burden was cleared rapidly after the last exposure (half-life 1.0 days) and 47% slowly (half-life 87 days), leaving a residual lung burden of 44%. For CdS, 41% of the lung burden was cleared rapidly (half-life 1.4 days) and 40% slowly (half-life 42 days), leaving a final residue 19%. In the CdS high-dose group, the retention of CdS in the lung was greater than that in the CdS low-dose groups, indicating that clearance mechanisms may possibly have been impaired in the high-dose group by too great a lung burden. For both compounds, faecal cadmium was initially high. Renal accumulation of cadmium was substantial for CdCl2 during the exposure period and continued over the following months until it represented approximately 35% of the total cadmium cleared from the lung. For CdS, renal accumulation was only 1% of the amount cleared from the lung. The bioavailability of Cd from CdS is thus poor, the majority being cleared from the lungs and excreted in the faeces. However, the bioavailability of inhaled CdS measured as cadmium in the kidney is greater than the bioavailability of orally ingested CdS.


How do in vitro reconstituted actin-based motility assays provide insight into in vivo behavior?
Recent live cell image analysis of actin dynamics in lamellipodia of motile cells has shown that regulated treadmilling, which supports actin-based propulsion of functionalized particles in biomimetic reconstituted motility assays, is also responsible for lamellipodia extension. In both cases, filaments are created by branching with Arp2/3 complex only at the membrane or particle surface, grow transiently and are capped; ADF/cofilin enhances the treadmilling but does not sever filaments in the body of the meshwork. Differences between the cellular and biomimetic systems suggest that additional regulatory mechanisms take place in lamellipodia.


Direct Observation of Halide Migration and its Effect on the Photoluminescence of Methylammonium Lead Bromide Perovskite Single Crystals.
Optoelectronic devices based on hybrid perovskites have demonstrated outstanding performance within a few years of intense study. However, commercialization of these devices requires barriers to their development to be overcome, such as their chemical instability under operating conditions. To investigate this instability and its consequences, the electric field applied to single crystals of methylammonium lead bromide (CH3 NH3 PbBr3 ) is varied, and changes are mapped in both their elemental composition and photoluminescence. Synchrotron-based nanoprobe X-ray fluorescence (nano-XRF) with 250 nm resolution reveals quasi-reversible field-assisted halide migration, with corresponding changes in photoluminescence. It is observed that higher local bromide concentration is correlated to superior optoelectronic performance in CH3 NH3 PbBr3 . A lower limit on the electromigration rate is calculated from these experiments and the motion is interpreted as vacancy-mediated migration based on nudged elastic band density functional theory (DFT) simulations. The XRF mapping data provide direct evidence of field-assisted ionic migration in a model hybrid-perovskite thin single crystal, while the link with photoluminescence proves that the halide stoichiometry plays a key role in the optoelectronic properties of the perovskite.


Primary trochlear headache and other trochlear painful disorders.
The trochlear region is a source of distinct pain that may give rise to specific primary pain disorders (primary trochlear headache), but also modulate other pre-existing headache disorders such as migraine. The sensory innervation of this region, by a branch of the ophthalmic division of the trigeminal nerve, may explain the modulatory influence of the nociceptive afferents of this region over migraine headache. We propose the term "trochlear migraine" to refer to the coexistence of strictly unilateral migraine and ipsilateral trochleodynia, with the improvement of migraine being dependent on the resolution of the trochleodynia. Trochleitis is an inflammatory trochleodynia, being frequently idiopathic and rarely secondary to usually immunologic and rheumatologic disorders. We postulate that nociceptive afferents from the inner part of the orbit may sustain the activation of trigeminal neurons, thus sensitizing or exacerbating migraine. Decreasing the possible wind-up induced from this nociceptive afferent stimulation may be effective in controlling headache.


Ashkenazi Anxieties: A Transnational Social History of Jewish Genetic Admixture Modeling, 1971-1986.
During the late 1970s and early 1980s, population geneticists sought computational solutions to integrate greater numbers of genetic traits into their debates about the ancestral relationships of human groups. At the same time, geneticists' longstanding assumptions about Jewish communities, especially Ashkenazim, were challenged by a series of social, political, and intellectual developments. In Israel, the entrenched cultural and political dominance of Ashkenazi Jews faced major social upheaval. Meanwhile, to counteract lingering anti-Semitism in Europe and the United States, Arthur Koestler's The Thirteenth Tribe and Raphael Patai and Jennifer Patai Wing's The Myth of the Jewish Race argued that Jewish identity was not connected to biological ancestry from the ancient Israelites. Drawing on scientific publications and archived correspondence, this article reconstructs a transnational social history showing how geneticists responded to these shifting claims about Ashkenazi identity and ancestry. Many argued that these claims could be tested using new statistical models, which provided allegedly more "objective" estimates of ancestral gene frequencies and histories of population admixture. However, they simultaneously engaged in heated debates over the relative superiority of competing statistical approaches. These debates reveal how the transnational reverberations of Israeli ethnic politics and Euro-American anti-Semitism affected the development of new calculations for genetic admixture, permanently shifting the assumptions of population genetic research on Jewish populations as well as other human groups.


Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors.
Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.


Obstructed calycocystostomy site in association with a transplanted kidney: percutaneous management.
We have used advanced endourologic techniques in the treatment of an obstructed lower-pole calycocystostomy site. The unusual clinical course that led to this problem and the interventional treatment used are discussed.


Pharmacokinetics and biotransformation investigation in beagle dog of active compounds from naoxintong capsule.
Naoxintong Capsule (NXTC), a standardized herbal medicine, has been widely applied in treating cardiovascular and cerebrovascular diseases with remarkable efficacy. However, the efficacy contributing components of NXTC are unclear, and the in vivo absorption and metabolism processes of NXTC remain largely obscured. In this study, using beagle dog as model species, we have identified and tentatively characterized 25 prototype and 15 catabolites of NXTC in beagle dog plasma by ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS). We have proposed the in vivo bio-transformation pathways of these absorbed constituents. In addition, for six crucial components, we have developed a quantitative method and conducted plasma pharmacokinetic study of these six components by rapid resolution liquid chromatography tandem triple quadrupole mass spectrometry (RRLC-QQQ-MS/MS). In conclude, our study provided comprehensive insights into the understanding of the plasma absorbed components profiling of NXTC as well as their in vivo transformation behaviors, which would be of great value for identifying efficacy contributing critical components as well as mechanism related investigations of NXTC in the future.


The mirror-neuron system and handedness: a "right" world?
To assess the relationship between the mirror-neuron system (MNS), an observation-execution matching system, and handedness, we acquired functional magnetic resonance imaging from 11 right-handed (RH) and eight left-handed (LH) subjects to identify regions involved in processing action (execution and observation) of the right and left upper limbs. During the execution tasks, LH subjects had a more bilateral pattern of activation than RH. An interaction between handedness and hand observed during the observation conditions was detected in several areas of the MNS and the motor system. The within- and between-groups analyses confirmed different lateralizations of the MNS and motor system activations in RH and LH subjects during the observation tasks of the dominant and nondominant limbs. The comparison of the execution vs. observation task demonstrated that during the execution task with their dominant limbs, RH subjects activated areas of the motor system in the left hemisphere, whereas LH subjects also activated areas of the MNS. During the execution task with the nondominant limbs, both groups activated regions of the MNS and motor system. Albeit this study is based on a small sample, the patterns of MNS activations observed in RH and LH subjects support the theory that suggests that this system is involved in brain functions lateralization. In LH people, this system might contribute to their adaptation to a world essentially built for right-handers through a mechanism of mirroring and imitation.


[Acute multifocal placoid pigment epitheliopathy with inflammatory CSF findings. A special form of borreliosis?].
A 24-year-old woman with acute multifocal placoid pigment epitheliopathy in both eyes had no signs or symptoms other than the impaired vision. Visual evoked potentials demonstrated prolonged latency. Lumbar CSF showed inflammatory changes. Serum antibody titres against Borrelia burgdorferi were markedly elevated. Cortisone treatment was without success, but intravenous penicillin quickly brought about improvement in vision. Borrelia infection may thus have been the cause of the multifocal placoid pigment epitheliopathy.


An ultrastructural study of the human micropolycystic ovary.
The basement membrane of follicles in the micropolycystic ovaries of infertile women was thickened compared to that in the ovaries of normal women or those with typical polycystic ovaries.


Dilemmas in decision-making about resuscitation--a focus group study of older people.
Cardiopulmonary resuscitation (CPR) may be used by default on patients suffering a cardiac arrest in hospital in the UK unless there is an order that specifies otherwise in the patient's notes. Guidelines recommend that the decision involves competent and willing patients or, in the case of incapacitation, their families. In practice, patient autonomy is often compromised. Ideally, discussion of preferences for end-of-life care should take place prior to hospitalisation. The majority of research on this topic has been conducted on hospitalised patients, so little is known about the views of older, but healthy, people about resuscitation decision-making. The present study was designed to address this gap. A series of eight focus groups involving a total of 48 participants over the age of 65 was conducted to explore people's views about the factors guiding resuscitation decision-making. A qualitative analysis, which emphasised the dilemmatic nature of resuscitation decision-making, identified two broad thematic dilemmas that subsumed six specific themes which contribute to resolving the dilemmas: quality of life (medical condition, mental versus physical incapacity, age and ageing, and burden), and the involvement of others (doctors and families) versus loss of autonomy. The dilemma underlying quality of life is that an acceptable quality of life after CPR cannot be assured. The dilemma underlying the involvement of others is that individual autonomy may be lost. The themes and subthemes provide the basis for guiding these difficult discussions in advance of serious illness.


The routine cutoff displacement of 2 mm may not reliably reflect the stability of paediatric lateral humeral condyle fractures.
Lateral humeral condyle fracture is one of the most common fractures in children. However, the prediction of the stability of the fracture with a cutoff displacement of 2 mm remains controversial. The aim of this study was to evaluate the reliability of the routine cutoff displacement of 2 mm in predicting the stability of paediatric lateral humeral condyle fractures. A cohort of 79 children with imaging results for lateral humeral condyle fractures from 2013 to 2019 was evaluated. The displacement on the radiographs was measured by three surgeons at different levels, and ultrasound images were obtained by two senior surgeons. The interobserver and intraobserver reliability was assessed by the intraclass correlation coefficient (ICC). A binary logistic regression model and receiver operating characteristic (ROC) curves were used to evaluate the association between the measurement and the integrity of cartilage hinges. The ICC for the interobserver reliability was 0.85, and the intraobserver reliability was 0.93. For each additional millimetre of displacement, the odds of cartilage hinge disruption increased by 70%. The ROC curve determined that the Youden index was only 0.07 (sensitivity, 97.8%; specificity, 8.8%) with a cutoff displacement of 2 mm. The routine cutoff displacement of 2 mm may not reliably reflect the stability of paediatric lateral humeral condyle fractures. The cutoff value is sensitive but not specific for predicting whether the cartilage hinge is intact.


Procalcitonin for the diagnosis of invasive candidiasis: what is the evidence?
Procalcitonin is a widely used marker for the evaluation of infection and sepsis and to guide antibiotic therapy. During the last decade, several studies evaluated its role and diagnostic performance as a surrogate marker for the identification of Candida spp. in suspected invasive candidiasis. A low serum level and a favorable negative predictive value are the main findings for procalcitonin in this setting. The aim of this report is to provide an updated brief summary of the evidence supporting the use of PCT for the management of invasive candidiasis.


A novel isocoumarin derivative induces mitotic phase arrest and apoptosis of human multiple myeloma cells.
The isocoumarin NM-3 reverses resistance of human multiple myeloma (MM) cells to dexamethasone and is in clinical trials. In the present work, the NM-3 analog, 185322, has been studied for activity against MM cells. Human U266, RPMI8226 and primary MM cells were analyzed for the effects of 185322 on cell cycle distribution, tubulin polymerization and induction of apoptosis. We show that, in contrast to NM-3, treatment with 185322 is associated with a marked arrest of MM cells in M phase. The results also demonstrate that treatment with 185322 is associated with a rapid decrease in tubulin assembly and an increase in Bcl-2 phosphorylation, consistent with disruption of mitosis. Our results further demonstrate that mitotic failure induced by 185322 results in activation of an apoptotic response in MM cell lines and primary MM cells. By contrast, 185322 had little if any effect on growth and survival of human carcinoma cells. These findings identify a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of MM cells.


Alteration of the major phosphorylation site of eukaryotic protein synthesis initiation factor 4E prevents its association with the 48 S initiation complex.
Site-directed mutagenesis was used to replace the serine residue at the primary phosphorylation site of human eukaryotic initiation factor (eIF) 4E with an alanine residue. The mutated cDNA was transcribed in vitro, and the transcript was used to direct protein synthesis in a reticulocyte lysate system. The variant protein (eIF-4EAla) was retained on a 7-methylguanosine 5'-triphosphate (m7GTP)-Sepharose affinity column and was specifically eluted by m7GTP. Examination of eIF-4EAla by isoelectric focusing revealed two species which had the same pI values as the phosphorylated and nonphosphorylated forms of unaltered eIF-4E (here designated eIF-4ESer). However, conversion of unphosphorylated eIF-4EAla to the putative phosphorylated eIF-4EAla in the reticulocyte lysate system was slower than the corresponding conversion of eIF-4ESer. The possibility that the more acidic form of eIF-4EAla was due to NH2-terminal acetylation was ruled out by an experiment in which the acetyl-CoA pool of the reticulocyte lysate system was depleted with oxaloacetate and citrate synthase. The more acidic form of eIF-4EAla was, however, eliminated by treatment with calf intestine alkaline phosphatase, suggesting that it results from a second-site phosphorylation. When translation reaction mixtures were resolved on sucrose density gradients, the 35S-labeled eIF-4ESer was found on the 48 S initiation complex in the presence of guanylyl imidodiphosphate, as reported earlier (Hiremath, L.S., Hiremath, S.T., Rychlik, W., Joshi, S., Domier, L.L., and Rhoads, R.E. (1989) J. Biol. Chem. 264, 1132-1138). eIF-4EAla, by contrast, was not found on the 48 S complex, suggesting that phosphorylation of eIF-4E is necessary for it to carry out its role of transferring mRNA to the 48 S complex. Supporting this interpretation was the finding that eIF-4ESer isolated from 48 S initiation complexes consisted predominantly of the phosphorylated form.


Influence of Pt Alloying on the Fluorescence of Fully Inorganic, Colloidal Gold Nanoclusters.
Noble metal alloy nanoclusters (NCs) are interesting systems as the properties of two or more elements can be combined in one particle, leading to interesting fluorescence phenomena. However, previous studies have been exclusively performed on ligand-capped NCs from wet chemical synthesis. This makes it difficult to differentiate to which extent the fluorescence is affected by ligand-induced effects or the elemental composition of the metal core. In this work, we used laser fragmentation in liquids (LFL) to fabricate colloidal gold-rich bi-metallic AuPt NCs in the absence of organic ligands and demonstrate the suitability of this technique to produce molar fraction series of 1nm alloy NC. We found that photoluminescence of ligand-free NCs is not a phenomenon limited to Au. However, even minute amounts of Pt atoms in the AuPt NCs lead to quenching and red-shift of the fluorescence, which may be attributed to the altered surface charge density.


Projections of the insular cortex to orbitofrontal and medial prefrontal cortex: A tracing study in the rat.
The dense fiber pathways that connect the insular cortex with frontal cortices are thought to provide these frontal areas with interoceptive information, crucial for their involvement in executive functions. Using anterograde neuroanatomical tracing, we mapped the detailed organization of the projections from the rat insular cortex to its targets in orbitofrontal (OFC) and medial prefrontal (mPFC) cortex. In OFC, main insular projections distribute to lateral and medial parts, avoiding ventral parts. Whereas projections from the primary gustatory cortex densely innervate dorsolateral OFC, likely corresponding to what in primates is known as the secondary gustatory cortex, these projections avoid mPFC. Instead, mPFC is targeted almost exclusively by projections from agranular fields of the insular cortex. Finally, "parietal" domains of the insular cortex project specifically to the dorsolateral OFC, and strongly innervate ventral portions of mPFC, i.e., the dorsal peduncular cortex.


Reactivity of peroxidase-labeled lectins in rabbit submandibular and sublingual glands.
The carbohydrate histochemistry of rabbit submandibular and sublingual glands has been examined by the use of 4 peroxidase-labeled lectins at the light microscopic level. In the submandibular gland, the striated ducts appeared to be the formations which were more reactive to all lectins. In the sublingual gland, the terminal tracts were the most reactive secreting portions, because they bound all the lectins used. The material contained in the lumen of the ducts of submandibular and sublingual glands always reacted fairly intensely. The binding of lectins to salivary glands indicated the possibility to use lectins for the explanation of the transport properties both of the striated ducts and of the terminal tracts.


Comparative in vitro activity of ceftriaxone against clinical bacterial isolates in Nigeria.
The in vitro activity of ceftriaxone, a cephalosporin derivative, recently introduced in Nigeria was compared with the activities of other related beta-lactam antibiotics such as cefotaxime, cefuroxime, cephaloridine, cloxacillin/ampicillin and ampicillin against 530 local clinical isolates of gram-negative and gram-positive bacteria. The spectra of activity and potency of ceftriaxone and cefotaxime were generally similar against the Enterobacteriaceae, Pseudomonas aeruginosa, Serratia spp., Streptococcus spp. and Neisseria gonorrhoeae, but less active against Staphylococcus aureus and Staphylococcus epidermidis when compared to cefotaxime. All the other beta-lactam antibiotics tested were less active than ceftriaxone. The action of ceftriaxone was bactericidal and the minimum inhibitory concentration values observed with R-plasmid beta-lactamase mediated resistant Escherichia coli, Klebsiella spp., Proteus spp. and N. gonorrhoeae strains did not exceed the maximum value obtained with the beta-lactamase-negative strains.


Posterior reversible encephalopathy syndrome after intravenous caffeine for post-lumbar puncture headaches.
A 33-year-old woman developed severe post-lumbar puncture headaches in the course of work-up for multiple sclerosis. Immediately after receiving treatment with intravenous caffeine, she became blind and experienced a generalized tonic-clonic seizure. Brain MR imaging then showed vasogenic parieto-occipital edema. She recovered clinically and radiologically within 72 hours. After 1 year of follow-up, there was no recurrence of symptoms or radiologic changes.


Does nasogastric tube decompression get used less often with laparoscopic and hand-assisted compared with open colectomy?
Laparoscopic surgery is associated with well-known benefits, one of which is earlier return of bowel function. Since the laparoscopic approach to colon resections was introduced in the early 1990s, it has become the standard of care. Hand-assisted laparoscopic surgery (HALS) is a surgical approach in which dissection is facilitated by the surgeon's hand within the abdominal cavity during laparoscopy. The purpose of this study was to compare the incidence of postoperative ileus and the need for nasogastric tube (NGT) decompression in patients undergoing elective colon resections. Following institutional review board approval, we performed a retrospective review of a prospectively collected database. Included were patients who underwent elective left-sided large bowel resections between 2009 and 2012. Exclusion criteria were urgent operation, stoma creation, ASA IV classification, NGT left in place at the end of surgery, and postoperative anastomotic leakage. Patients were divided into three groups: laparoscopic surgery, HALS, and open surgery. We evaluated the incidence of postoperative ileus and the use of nasogastric decompression in each group. A total of 243 patients were included in this study; 73 patients underwent open surgery, 89 patients underwent HALS, and 81 patients underwent laparoscopic surgery. The proportion of patients who needed postoperative nasogastric decompression was significantly reduced in patients undergoing laparoscopic surgery (3.7%) or HALS (4.5%) compared with those who underwent open resection (17.8%). The time from surgery to first flatus and first bowel movement, the time to tolerate solid diet, and the total length of postoperative hospital stay also were all significantly reduced in the laparoscopic and HALS groups compared with the open surgery group. There were no significant differences in any of these measures between the laparoscopic group and the hand-assisted group. Like laparoscopy, HALS is associated with less postoperative ileus and necessitates less NGT decompression than does open surgery.


Homologous recombination: how RecA finds the perfect partner.
How do two identical DNA sequences find each other during homologous recombination, amidst a 'sea' of unrelated DNA? New studies reveal how RecA promotes the search for homology by sampling DNA in three dimensions.


Fish melanin-concentrating hormone disperses melanin in amphibian melanophores.
Melanin-concentrating hormone (MCH), which was isolated from salmon pituitary and caused melanin concentration in fish scale melanophores, has been tested on cultured chromatophores of an amphibian, the bullfrog tadpole. MCH induced dispersion of melanin in cultured melanophores of the tadpole. The duration of the dispersing effect of MCH was relatively short compared with that of alpha-melanocyte-stimulating hormone (alpha-MSH). MCH also induced the concentration of cultured iridophores of bullfrog tadpole.


Staged repair of supravalvular aortic stenosis associated with severe multiple peripheral pulmonary stenoses: report of extended peripheral pulmonary arterioplasty.
This paper describes surgical experience in supravalvular aortic stenosis associated with severe multiple peripheral pulmonary stenoses treated by a staged approach: initial staged repair of the bilateral pulmonary stenoses by arterioplasty through a thoracotomy and later definitive intracardiac repair of supra-valvular aortic stenosis. Our experience in two cases proved that the peripheral pulmonary arteries could be exposed up to the segmental branches by dissection from the pulmonary hilum through a lateral thoracotomy without damaging the lung parenchyma. The stenotic areas could then be repaired with either a bifurcated or trifurcated pericardial patch.


New Insights Into the Mechanism of COP9 Signalosome-Cullin-RING Ubiquitin-Ligase Pathway Deregulation in Urological Cancers.
Urological cancers are a very common type of cancer worldwide and have alarming high incidence and mortality rates, especially in kidney cancers, illustrate the urgent need for new therapeutic targets. Recent publications point to a deregulated COP9 signalosome (CSN)-cullin-RING ubiquitin-ligase (CRL) pathway which is here considered and investigated as potential target in urological cancers with strong focus on renal cell carcinomas (RCC). The CSN forms supercomplexes with CRLs in order to preserve protein homeostasis and was found deregulated in several cancer types. Examination of selected CSN-CRL pathway components in RCC patient samples and four RCC cell lines revealed an interesting deregulated p27(Kip1)-Skp2-CAND1 axis and two p27(Kip1) point mutations in 786-O cells; p27(Kip1)V109G and p27(Kip1)I119T. The p27(Kip1) mutants were detected in patients with RCC and appear to be responsible for an accelerated growth rate in 786-O cells. The occurrence of p27(Kip1)V109G and p27(Kip1)I119T in RCC makes the CSN-CRL pathway an attractive therapeutic target.


A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals.
Differential speeds in biochemical reactions have been proposed to be responsible for the differences in developmental tempo between mice and humans. However, the underlying mechanism controlling the species-specific kinetics remains to be determined. Using in vitro differentiation of pluripotent stem cells, we recapitulated the segmentation clocks of diverse mammalian species varying in body weight and taxa: marmoset, rabbit, cattle, and rhinoceros. Together with mouse and human, the segmentation clock periods of the six species did not scale with the animal body weight, but with the embryogenesis length. The biochemical kinetics of the core clock gene HES7 displayed clear scaling with the species-specific segmentation clock period. However, the cellular metabolic rates did not show an evident correlation. Instead, genes involving biochemical reactions showed an expression pattern that scales with the segmentation clock period. Altogether, our stem cell zoo uncovered general scaling laws governing species-specific developmental tempo.


Training the cervical muscles with prescribed motor tasks does not change muscle activation during a functional activity.
Both low-load and high-load training of the cervical muscles have been shown to reduce neck pain and change parameters of muscle function directly related to the exercise performed. The purpose of this study was to investigate whether either training regime changes muscle activation during a functional task which is known to be affected in people with neck pain and is not directly related to either exercise protocol. Fifty-eight female patients with chronic neck pain were randomised into one of two 6-week exercise intervention groups: an endurance-strength training regime for the cervical flexor muscles or low-load training of the cranio-cervical flexor muscles. The primary outcome was a change in electromyographic (EMG) amplitude of the sternocleidomastoid (SCM) muscle during a functional, repetitive upper limb task. At the 7th week follow-up assessment both intervention groups demonstrated a reduction in their average intensity of pain (P<0.05). However, neither training group demonstrated a change in SCM EMG amplitude during the functional task (P>0.05). The results demonstrate that training the cervical muscles with a prescribed motor task may not automatically result in improved muscle activation during a functional activity, despite a reduction in neck pain.


Antigenic and genomic homogeneity of successive Mycoplasma hominis isolates.
Sixty Mycoplasma hominis isolates were obtained from the cervices of pregnant women and from the ears or pharynges of their newborn babies. The isolates were examined by SDS-PAGE and pulsed-field gel electrophoresis. Antigenic and genomic profiles were obtained for 16 series with two or more successive isolates. Both analyses led to the conclusion that isolates from the same woman were identical or nearly identical, while isolates from different women exhibited a high degree of variation with respect to both genomic and antigenic profiles.


Affinity and inhibitory capacity of T-cell proliferation of monoclonal anti-Ia antibodies.
The rates of dissociation from the surface of Ia-positive spleen cells of three different anti-Ia monoclonal antibodies were evaluated and compared with their inhibitory effects on T-lymphocyte proliferative responses involving the same spleen cell population, either as a source of accessory cells (responses to soluble antigens) or as allogeneic stimulating cells. In general, a direct relationship was observed between the affinity with which these monoclonal antibodies interact with Ia-positive cells and the magnitude of their inhibitory effects, whether soluble antigen- or alloantigen-induced responses were tested. These results indicate that the affinity of monoclonal antibodies is a factor that has to be considered to the same extent as their fine specificity when interpreting the results of inhibitory studies of T-cell responses by anti-Ia monoclonal antibodies.


Punctuality, pain and time-orientation among Sicilian-Canadians.
Southern Italians, including immigrants residing in North America, are often labeled as having a present time-orientation. This notion, in turn, has been used as an explanation for diverse phenomena commonly attributed to southern Italians--such as 'arriving late for appointments'; 'seeking immediate relief from the sensation of pain'; and, generally displaying 'a high degree of emotion and expression in their illness behavior'. Labeling an entire group of people as having a particular time-orientation, however, may generate stereotypes that affect negatively the type of medical treatment patients receive. In this paper, I challenge the unsubstantiated notion that southern Italians are present time-oriented. The data I have collected among Sicilian-Canadians indicates that there are alternative explanations for the phenomena people commonly attribute to southern Italians. I will support my contention by examining: (1) Sicilian-Canadian conceptions of punctuality; and, (2) the communicative dimension of the pain experience.


Concomitant Heterotopic Pancreas and Endometriosis as a Rare Cause of Ileo-Ileal Intussusception in a Young Woman with Spina Bifida: Case Report and Literature Review.
Isolated heterotopic pancreas (HP) as the primary cause of bowel intussusception is extremely rare. We report a case of a 33-year-old female patient with spina bifida admitted to the Emergency Surgical Department for ileal intussusception due to the presence of heterotopic pancreas associated with endometriosis. Symptomatic ileal intussusception for ectopic pancreas is usually associated with overt gastrointestinal blood loss (predominantly melena), abdominal pain, vomiting, and weight loss. Treatment is universally surgical. Isolated heterotopic pancreas is a rare condition; it should be considered in the differential diagnosis of bowel intussusception.


Rapid assessment of total and polycyclic aromatic contents in heavy oils.
The monitoring of the content of polycyclic aromatic hydrocarbons (PAHs) is important for evaluating heavy oil products, especially those most likely to cause environmental impacts. In this study, a comparison between samples of heavy petroleum fractions, using different methods, was carried out. The calculation of carbon distribution and polycyclic aromatic contents was compared with other methods using Fourier transform infrared spectroscopy (FTIR). Therefore, it was possible to quickly estimate the aromatic content by the FTIR method, and the results showed consistency with those obtained through traditional methods. A rapid method, using extraction with dimethyl sulfoxide followed by FTIR measurements, was proposed and shown as particularly useful and reliable for a quick quantification of the PAH content, when compared to the traditional IP 346 method. Furthermore, the difference in total aromatic and PAH concentrations may be more clearly established. This rapid method may be used for the evaluation of PAH content in samples obtained from studies for their removal from complex heavy oil fractions.


Specific and non-specific nasal provocation tests in children with perennial allergic rhinitis.
nasal provocation tests (NPT) have been extensively used in clinical practice to evaluate chronic rhinopathies, mainly allergic rhinitis (AR). we submitted 10 perennial AR children (aged from six to 15 years) to histamine (H), Dermatophagoides pteronyssinus (Dp) and Blomia tropicalis (Bt) NPT. All children were sensitized (positive skin prick test, mean wheal > 3 mm) to both mites. Dp and Bt specific NPT were realized in two occasions, apart one week, always preceeded 24 hours by H challenge. Increased concentrations were applied to the nasal mucosa during each NPT: H (0,03 to 16 mg/ml), Dp (1/100,000 to 1 /2.5) and Bt (1/125,000 to 1/10). NPT were evaluated by clinical and rhinomanometric parameters (total score, TS), and by lung function tests. NPT was considered positive, when total nasal resistance (TNR) doubled in relation to basal value. H NPT was positive twice in 8/10 patients. Concordance between H concentration that induces a positive NPT measured by TNR or TS was observed. Regarding to specific NPT, 90 % of patients were positive to Dp and 60 % to Bt. There was no concordance between the allergen concentration that induces a positive SPT and a positive NPT, considering the different concentrations. There were no modification in lung function tests during both specific and non-specific provocation tests. NPT with H is an objective and reproducible method which allow evaluate nasal reactivity. Specific NPT have restricted indications, mainly when there where doubts about AR's etiology.


Spectrophotometric determination of adrenaline with an oxidative column in a FIA assembly.
A single channel FIA assembly is proposed for the spectrophotometric determination of adrenaline, the aqueous sample solution is directly injected into the carrier stream leading the sample through a manganese dioxide column at 80 degrees C, and on to the spectrophotometer flow-cell. The calibration graph is linear up to 17 ppm of adrenaline. The influence of other substances has been studied and the method has been applied to the determination of adrenaline in a pharmaceutical formulation.


Peroxide-induced cell death and lipid peroxidation in C6 glioma cells.
Peroxides are often used as models to induce oxidative damage in cells in vitro. The aim of the present study was to elucidate the role of lipid peroxidation in peroxide-induced cell death. To this end (i) the ability to induce lipid peroxidation in C6 rat astroglioma cells of hydrogen peroxide (H2O2), cumene hydroperoxide (CHP) and t-butyl hydroperoxide (t-BuOOH) (ii) the relation between peroxide-induced lipid peroxidation and cell death in terms of time and concentration dependency and (iii) the capability of the lipid peroxidation chain breaking alpha-tocopherol to prevent peroxide-induced lipid peroxidation and/or cell death were investigated. Lipid peroxidation was characterised by measuring thiobarbituric acid reactive substances (TBARS) and, by HPLC, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and hexanal. Within 2 h CHP, t-BuOOH and H2O2 induced cell death with EC50 values of 59+/-9 microM, 290+/-30 microM and 12+/-1.1 mM, respectively. CHP and t-BuOOH, but not H2O2 induced lipid peroxidation in C6 cells with EC50 values of 15+/-14 microM and 130+/-33 microM, respectively. The TBARS measured almost exclusively consisted of MDA. 4-HNE was mostly not detectable. The concentration of hexanal slightly increased with increasing concentrations of organic peroxides. Regarding time and concentration dependency lipid peroxidation preceded cell death. Pretreatment with alpha-tocopherol (10 microM, 24 h) prevented both, peroxide-induced lipid peroxidation and cell death. The results strongly indicate a major role of lipid peroxidation in the killing of C6 cells by organic peroxides but also that lipid peroxidation is not involved in H2O2 induced cell death.


Spectroscopic investigation on assisted sonocatalytic damage of bovine serum albumin (BSA) by metronidazole (MTZ) under ultrasonic irradiation combined with nano-sized ZnO.
The previous work proved that the bovine serum albumin (BSA) could be damaged under the combined action of ultrasonic irradiation and ZnO. In this work, the assisted sonocatalytic damage of BSA using metronidazole (MTZ) as a sensitizer was further investigated by means of UV-vis and fluorescence spectra. The results indicated that the adding of MTZ could obviously promote the sonocatalytic damage of BSA under ultrasonic irradiation in the presence of nano-sized ZnO powder. Furthermore, it was found that the damage degree of BSA was aggravated by some influencing factors except ionic kind and strength. In addition, the damage site of BSA was also studied with synchronous fluorescence technology. It was found that the damage site was mainly at tryptophan (Trp) residue.


Improving Copy Number Variant Detection from Sequencing Data with a Combination of Programs and a Predictive Model.
Bioinformatics tools for analyzing copy number variants (CNVs) from massively parallel sequencing (MPS) data are less well developed compared with other variant types. We present an efficient bioinformatics pipeline for CNV detection from gene panel MPS data in neuromuscular disorders. CNVs were generated in silico into samples sequenced with a previously published MPS gene panel. The in silico CNVs from these samples were analyzed with four programs having complementary CNV detection ranges: CoNIFER, XHMM, ExomeDepth, and CODEX. A logistic regression model was trained with the obtained set of in silico CNV detections to predict true-positive CNV detections among all CNV detections from samples. This model was validated using 66 control samples with a verified true-positive (n = 58) or false-positive (n = 8) CNV detection. Applying all four programs together provided more sensitive detection results with in silico CNVs than other program combinations or any program alone. Furthermore, a model with CNV detection-specific scores from all four programs as variables performed overall best in the validation. No single program could detect all CNV sizes and types equally or with enough accuracy. Therefore, a combination of carefully selected programs should be used to maximize detection accuracy. In addition, the detected CNVs should be reviewed with a statistical model to streamline and standardize the filtering of the detections for annotation.


Functional promoter polymorphisms of the receptor for advanced glycation end products in children and adolescents with type 1 diabetes.
RAGE promoter polymorphisms are associated with increases in RAGE expression. A case-control association study was conducted involving a Euro-Brazilian population of children and adolescents with type 1 diabetes (n = 90) and healthy controls (n = 105), which were matched by sex and age. Genotyping by PCR-RFLP the -429T>C (rs1800625), -374T>A (rs1800624), and 63 bp deletion/insertion (-407 to -345 bp) showed no significant differences (P > 0.05) between the groups.


Comparison of clinical outcome between histidine-triptophan-ketoglutalate solution and cold blood cardioplegic solution in mitral valve replacement.
This study was conducted to compare the effect of histidine-triptophan-ketoglutalate solution (HTK) with that of cold blood cardioplegic solution (CBC) in mitral valve surgery. Forty-six patients who underwent mitral valve replacement between January 1994 and December 1996 were enrolled in this study. Twenty patients received HTK (HTK group), while 27 patients had CBC (CBC group) as myocardial protection. HTK was given as a single high dose, whereas CBC was used in the usual multidose format. The doses of inotropic agent at the end of extracorporeal circulation did not differ between the HTK group and the CBC group. Creatine kinase values (units) on day 1 and day 2 were 1140+/-412, 921+/-436 for the HTK group and 904+/-335, 816+/-420 for the CBC group, respectively (p = NS). Spontaneous defibrillation occurred in 26% of the CBC group and 90% of the HTK group (p < 0.05). Pacing was temporarily used in 20% of the HTK group and 44% of the CBC group after extracorporeal circulation (p < 0.05). These results suggest that HTK provided more adequate myocardial protection in mitral valve surgery.


The Associations of Habitual Intake of Sulfur Amino Acids, Proteins and Diet Quality with Plasma Sulfur Amino Acid Concentrations: The Maastricht Study.
Plasma sulfur amino acids (SAAs), i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH), and taurine, are potential risk factors for obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies plasma SAA concentrations. To investigate whether the intake of SAAs and proteins or diet quality is associated with plasma SAAs. Data from a cross-sectional subset of The Maastricht Study (n = 1145, 50.5% men, 61 interquartile range: [55, 66] y, 22.5% with prediabetes and 34.3% with type 2 diabetes) were investigated. Dietary intake was assessed using a validated food frequency questionnaire. The intake of SAAs (total, methionine, and cysteine) and proteins (total, animal, and plant) was estimated from the Dutch and Danish food composition tables. Diet quality was assessed using the Dutch Healthy Diet Index, the Mediterranean Diet Score, and the Dietary Approaches to Stop Hypertension score. Fasting plasma SAAs were measured by liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS-MS). Associations were investigated with multiple linear regressions with tertiles of dietary intake measures (main exposures) and z-standardized plasma SAAs (outcomes). Intake of total SAAs and total proteins was positively associated with plasma tCys and cystathionine. Associations were stronger in women and in those with normal body weight. Higher intake of cysteine and plant proteins was associated with lower plasma tHcy and higher cystathionine. Higher methionine intake was associated with lower plasma tGSH, whereas cysteine intake was positively associated with tGSH. Higher intake of methionine and animal proteins was associated with higher plasma taurine. Better diet quality was consistently related to lower plasma tHcy concentrations, but it was not associated with the other SAAs. Targeted dietary modifications might be effective in modifying plasma concentrations of tCys, tHcy, and cystathionine, which have been associated with obesity and cardiometabolic disorders.


Striatal delivery of rAAV-hAADC to rats with preexisting immunity to AAV.
We tested the hypotheses that initial immunization of rats with rAAV might limit subsequent transduction by rAAV-hAADC when stereotaxically infused into the striatum and that the level of inhibition would correlate with AAV neutralizing antibody titers. Immunohistochemical detection of AADC and analysis by stereology revealed that the control group (no immunization) had the greatest volume of distribution of AADC (20.32 +/- 2.03 mm3) (+/-SD). There was a 58% decrease in spread (8.46 +/- 3.67 mm3, P < 0.008) in the high-dose immunization group (5 x 10(10) vg rAAV-null). Transduction weakly correlated with preexisting titer levels of neutralizing antibody at the time of intrastriatal rAAV-hAADC infusion. Only rats with neutralizing antibody titers of 1:1208 +/- 332 had significantly decreased AADC transgene expression compared to the unimmunized control group. Immunohistochemistry on serial sections for inflammatory markers including GFAP, CD11b, CD4, and CD8a revealed normal morphology and no cellular infiltration, suggesting little immune reaction in the CNS. We conclude that rAAV vectors can transduce brain tissue in the context of preexisting immunity, but that efficiency of transduction declines significantly in the presence of very high titers of neutralizing antibodies. These results have important implications for gene therapy for CNS disorders.


Outcomes of hospitalized patients with myocardial infarction and immune thrombocytopenic purpura: a cross sectional study over 15 years.
Immune Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by low platelet counts and mucocutaneous bleeding. The outcomes of hospitalized patients with ITP and myocardial infarction (MI) have not been extensively studied and may help identify risk factors associated with adverse outcomes in this unique patient population. Patients with ITP who were admitted with MI using the National Inpatient Database for the years 2000 to 2014. Patient demographics, hospital characteristics and medical comorbidities were studied. Chi square test was used to determine associations with statistical significance and logistic regression was used to determine independent predictors of mortality. A total of 753732 hospitalized patients with ITP were identified over the time period of 2000 to 2014, of which 37695 patients had both ITP and acute MI. There were more females with ITP in general (60% females vs. 40 males), but more males with ITP and acute MI (55.8% males vs. 44.2% females; P=0.0000). Caucasians were affected the most (5.5%) amongst all races and the age group of 65-79 years had the highest percentage of patients with ITP and MI (7.3%). The classical risk factors of hypertension, hyperlipidemia, and diabetes were also noted to be highly prevalent in patients with ITP and MI. 10.05% of patients with ITP and acute MI died during hospitalization, while 4% of all patients with ITP died during hospitalization (P<0.05). Multiple regression showed that stent placement, female gender, blood transfusions, platelet transfusion, 80+ age group and higher Charlson's score were independent predictors of mortality in patients with ITP which have MI. MI is associated with an increased rate of in-hospital death in patients with ITP. Both blood transfusions and platelet transfusions adversely affect outcomes in the management of AMI in ITP patients.


Development of a geometry-based respiratory motion-simulating patient model for radiation treatment dosimetry.
Temporal and spatial anatomical changes caused by respiration during radiation treatment delivery can lead to discrepancies between the prescribed and actually received radiation doses. This paper presents a study to construct a respiratory-motion-simulating, four-dimensional (4D) patient anatomical and dosimetry model for the study of dosimetric effects of organ motion on various radiation treatment plans and delivery strategies. A 3D VIP-Man (VIsible Photographic Man) model has been reconstructed using the Non-Uniform Rational B-Splines (NURBS) method to reflect the deformation of organs during respiration by manipulating surface control points as time-dependent equations. The 4D model is applied to dose simulation using the Monte Carlo code EGS4 (Electron Gamma Shower, version 4). Two delivery scenarios in radiation therapy were simulated: "gating" treatment and 4D "image-guided" treatment. For each delivery scenario, one conformal plan and one Intensity Modulated Radiation Therapy (IMRT) plan were developed. A lesion in the left lung was modeled to investigate the impact of respiratory motion on radiation dose distributions. Based on target dose volume histograms (DVHs), it is demonstrated that it is important to use accurate "gating" to improve the dose distribution. The results also suggest that, during a 4D "image-guided" treatment delivery, monitoring of patient breathing pattern is critical. This study demonstrates the potential of using "standard" motion-simulating patient model for 4D treatment planning and motion management.


Chemotaxis or adhesion gradient? Pronephric duct elongation does not depend on distant sources of guidance information.
Previously published experimental studies have led to conflicting interpretations concerning the mechanism guiding pronephric duct elongation in the urodele embryo. Although most studies have led to the conclusion that duct migration is directed by an adhesion gradient (haptotaxis), one set of experiments has been interpreted as supporting chemotactic guidance. We have resolved this conflict by conducting grafting experiments in Ambystoma embryos which distinguish between these two possible mechanisms of cell guidance. Our results provide an alternative explanation for the observations originally interpreted as supporting chemotaxis and add further evidence for adhesive guidance.


Improved survival after an educational project on colon cancer management in the county of Stockholm--a population based cohort study.
Outcomes in rectal cancer have improved dramatically after the introduction of total mesorectal excision (TME). Recently, the TME concept has been transformed into that of complete mesocolic excision (CME) in an attempt to improve prognosis for patients with colon cancer. Multidisciplinary team (MDT) workshops including the CME concept were held annually between 2004 and 2008 at the Karolinska University Hospital. The workshops focused on preoperative staging, surgery and histopathology and included lectures and live surgery sessions. To compare survival before and after the "Stockholm Colon Cancer Project" all patients diagnosed with a right sided colon cancer between January 1, 2001 and December 31, 2003 (Group 1) and from January 1, 2006 until December 31, 2008 (Group 2) in Stockholm were identified from the Swedish ColoRectal Cancer Registry (SCRCR). The proportion of patients having a tumour resection and the proportion having emergency surgery was higher in Group 1. There were more early tumours and more R0 resections in Group 2. Overall survival in all diagnosed patients and disease free survival after tumour resection was improved in the second time period. Surgical teaching programmes may have an impact on the management and outcome in colon cancer. The exact impact from the "Stockholm Colon Cancer Project" cannot be established, however it is likely that it contributed to the improved survival.


Pretreatment Body Mass Index (BMI) as an Independent Prognostic Factor in Nasopharyngeal Carcinoma Survival: A Systematic Review and Meta-Analysis.
We performed a meta-analysis to investigate the association between pretreatment body mass index (BMI) and prognosis of nasopharyngeal carcinoma (NPC). Case-control and cohort studies were searched from PubMed, Web of Science, EMBASE, and CNKI databases. Pooled hazard ratios (HR) with 95% confidence intervals (CI) for overall survival (OS) or distant metastasis-free survival (DMSF) were used to estimate the prognostic value. Bias in the included studies was evaluated using funnel plots. The results showed that compared with normal weight patients, the estimated HR of OS was 1.54 (95% CI: 1.25-1.90; P < 0.05) for underweight, 0.63 (95% CI: 0.48-0.83; P < 0.05) for overweight, and 0.67 (95% CI: 0.41-1.08; P = 0.102) obese patients. We also found that compared with normal-weight patients, the estimated HR of DMFS was 1.63 (95% CI: 1.38-1.92; P < 0.05) for underweight, 0.83 (95% CI: 0.61-1.13; P = 0.244) for overweight, and 0.60 (95% CI: 0.39-0.92; P < 0.05) for patients with obesity. BMI is an independent prognostic factor for NPC survival. Being underweight before treatment was associated with poorer OS and DMFS in patients with NPC. Neither overweight nor obesity before treatment has an unfavorable effect on NPC survival.


Quantification of spindles in comatose patients.
Quantification of spindles in comatose patients is easily possible by measurement of ERD (event-related desynchronization). ERD can either be positive (e.g., alpha blocking or alpha attenuation) or negative (spindle activity within the alpha band) or can be missing. Follow-up measurements in a comatose patient demonstrate the different time courses of VEP (visual evoked potential) and ERD during clinical recovery. That means that VEP and ERD are generated by different neuronal systems as reactions to the same external stimulus.


Emerging trends in candidemia: a higher incidence but a similar outcome.
The clinical presentation and outcome of candidemia has changed in recent years. We compared two 5-year periods (2000-2004 and 2005-2009) in a single institution. We recorded 419 candidemia episodes during the study period (124 in the first period and 295 in the second period). We observed a significant increase in the number of cases per 1000 admissions per year, from 0.57 in 2000 to 1.52 in 2009 (χ(2) LT <0.001). Candida albicans was the most frequently isolated species (42.2%), followed by Candida parapsilosis (34.4%) and Candida glabrata (12.9%). In the second period, episodes were associated with higher comorbidity and were more commonly nosocomial, with a more frequent catheter-related source and an increased rate of C. glabrata infection. No significant differences were observed in susceptibility by species during the study period. According to multivariate analysis, the independent factors associated with higher mortality were shock, age >50 years, elevated comorbidity score (Charlson index >6), and source of candidemia other than catheter. In contrast to the increase in comorbid conditions observed in recent years, mortality remained similar during both periods (~37% during the first month). This finding could be attributed to a significant increase in catheter-related candidemia and better outcome, as well as to a potential improvement in the management of antifungal therapy in recent years.


The usefulness of CEA as an indicator for early detection and a guide to the treatment of recurrent gastric cancer.
The usefulness of carcinoembryonic antigen (CEA) as an indicator for recurrence and a guide to the treatment was evaluated from a retrospective analysis of 88 patients with recurrent gastric cancer. Sixty-two of these patients (70.5 per cent), 25 of whom had a preoperative positive assay, and 37 a negative assay, had elevated levels of CEA after disease progression. Averaged CEA level in patients with liver metastasis was significantly higher (872 ng/ml) than in those with peritoneal metastasis (68 ng/ml), with lymph node metastasis (103 ng/ml) or with local metastasis (93 ng/ml) (p less than 0.01). An elevation of CEA was found prior to the clinical manifestation of recurrence, and the average lead time was 4 months. In 25 patients with a lead time of more than 4 months, survival time after CEA elevation was 13.3 months, which was longer than the 6.5 months of 28 patients with less than 4 months. Thirty-seven of the 88 patients were treated after recurrence. The average survival period after the detection of recurrence was 9.4 months in patients with surgical treatments followed by chemotherapy, 5.9 months in those with chemotherapy alone and 3.8 months in those with surgery alone. The average survival period of 26 patients with positive CEA assays in recurrence was 5.1 months longer than of patients with negative assays. This fact suggested that early detection of recurrence followed by various treatments, in the elevated CEA group, contributes to favorable results.


Conversion of albumin into a transmitter of the ultra long-range interaction of human erythrocytes.
Previous experiments in our laboratory and elsewhere have shown that extended macromolecules of high molecular weight are needed in the suspending medium to transmit the quantum-mechanical coherent interaction of human erythrocytes. Albumin, a globular protein, does not transmit the interaction at physiological concentrations. Albumin can be converted into a transmitter by preheating a solution of albumin to 62 degrees C for 20 min. Such treatment unravels the tertiary structure of albumin and allows it to polymerize.


Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson's disease.
Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson's disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson's disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson's disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson's disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson's disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson's disease are caused by intestinal dysbiosis needs to be considered.


Deletion of Mocos Induces Xanthinuria with Obstructive Nephropathy and Major Metabolic Disorders in Mice.
Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an under-recognized disorder. Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiologic functions of this gene which is found in a large number of pathways and is known to be associated with autism. Mocos-deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilation, Tamm-Horsfall (uromodulin) protein (THP) deposits, tubular cell necrosis with neutrophils, and occasionally hydronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems, and important alterations of the metabolism of purines, amino acids, and phospholipids. Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology. Mocos-deficient mice develop a lethal obstructive nephropathy associated with profound metabolic changes. Studying MOCOS functions may provide important clues about the underlying pathogenesis of xanthinuria and other diseases requiring early diagnosis.


Differential Insurance Plan Coverage and Surgeon Reimbursement of Pediatric Circumcision at an Urban, Midwestern Hospital.
To explore private vs public pediatric circumcision insurance coverage and surgeon reimbursement. A telephone survey about circumcision coverage (Current Procedural Terminology codes: 54150, 54161) was conducted in October 2021 with insurance plan representatives from the 12 plans that comprised ≥1% of institutional pediatric urology visits to compare plan characteristics and coverage details. Circumcision billing data were collected at one pediatric hospital to assess surgeon reimbursement (insurance+patient payment) by plan type using bivariate statistics. Ten plans (5 private and 5 public) responded (83.3% response rate). All except one public plan covered newborn circumcision. For non-newborn circumcisions, most public plans (80%) had unrestricted coverage, whereas all private plans required medical necessity. Median reimbursement for newborn circumcision (CPT: 54150) was $484 for private and $78 for public plans, P < .001 while median reimbursement for non-newborn circumcision (CPT: 54161) was $314 for private and $147 for public plans, P < .001. Private insurance plans reimburse significantly more than public plans for newborn circumcision. For non-newborn circumcision, private plans reimburse more than public but the coverage is more restricted, with a smaller differential between newborn and non-newborn circumcision. This coverage and reimbursement structure may indirectly encourage newborn circumcision for privately insured boys and non-newborn circumcision for publicly insured boys.


Bacterial Vaginosis and Spontaneous Clearance of Chlamydia trachomatis in the Longitudinal Study of Vaginal Flora.
Up to 26% of urogenital Chlamydia trachomatis infections spontaneously resolve between detection and treatment. Mechanisms governing natural resolution are unknown. We examined whether bacterial vaginosis (BV) was associated with greater chlamydia persistence versus spontaneous clearance in a large, longitudinal study. Between 1999 and 2003, the Longitudinal Study of Vaginal Flora followed reproductive-age women quarterly for 1 year. Baseline chlamydia screening and treatment were initiated after ligase chain reaction testing became available midstudy, and unscreened endocervical samples were tested after study completion. Chlamydia clearance and persistence were defined between consecutive visits without chlamydia-active antibiotics (n = 320 persistence/n = 310 clearance). Associations between Nugent score (0-3, no BV; 4-10, intermediate/BV), Amsel-BV, and chlamydia persistence versus clearance were modeled with alternating and conditional logistic regression. Of chlamydia cases, 48% spontaneously cleared by the next visit (310/630). Nugent-intermediate/BV was associated with higher odds of chlamydia persistence (adjusted odds ratio [aOR] = 1.89; 95% confidence interval [CI], 1.30-2.74), and the findings were similar for Amsel-BV (aOR 1.39; 95% CI, .99-1.96). The association between Nugent-intermediate/BV and chlamydia persistence was stronger in a within-participant analysis of 67 participants with both clearance/persistence intervals (aOR = 4.77; 95% CI, 1.39-16.35). BV symptoms did not affect any results. BV is associated with greater chlamydia persistence. Optimizing the vaginal microbiome may promote chlamydia clearance.


Structural determinant for cold inactivation of rodent L-xylulose reductase.
L-Xylulose reductase (XR) is a homotetramer belonging to the short-chain dehydrogenase/reductase family. Human XR is stable at low temperature, whereas the enzymes of mouse, rat, guinea pig, and hamster are rapidly dissociated into their inactive dimeric forms. In order to identify amino acid residues that cause cold inactivation of the rodent XRs, we have here selected Asp238, Leu242, and Thr244 in the C-terminal regions of rodent XRs and performed site-directed mutagenesis of the residues of mouse XR to the corresponding residues (Glu, Trp, and Cys) of the human enzyme. Cold inactivation was prevented partially by the single mutation of L242W and the double mutation of L242W/T244C, and completely by the double mutation of D238E/L242W. The L242W and L242W/T244C mutants existed in both tetrameric and dimeric forms at low temperature and the D238E/L242W mutant retained its tetrameric structure. No preventive effect was exerted by the mutations of D238E and T244C, which were dissociated into their dimeric forms upon cooling. Crystallographic analysis of human XR revealed that Glu238 and Trp242 contribute to proper orientation of the guanidino group of Arg203 of the same subunit to the C-terminal carboxylate group of Cys244 of another subunit through the neighboring residues, Gln137 and Phe241. Thus, the determinants for cold inactivation of rodent XRs are Asp238 and Leu242 with small side chains, which weaken the salt bridges between Arg203 and the C-terminal carboxylate group, and lead to cold inactivation.


[Is there a shift in the epidemiology of hepatitis A in Mexican children?].
Twenty years ago, prevalence of Hepatitis A in Mexican children was 90%. To describe a shift in the prevalence of Hepatitis A virus (HAV) infection and to demonstrate an increment in the age at the first contact with HAV, in a sample of Mexican children. Reports of antiviral serologic studies collected from 1991 to 2005 from patients attending a pediatric hospital, were reviewed, and those with IgM anti-HAV positive in serum were selected. Age at the moment of acute infection was analyzed. Additionally, a serological survey searching IgG anti-HAV was made in a group of HAV unvaccinated children. From 1708 determinations of IgM, 221 were positive (13%). According to the year of report, five groups were constituted. Mean age by group was: 1991-1993 of 6.4 years, 1994-1996 of 8.0, 1997-1999 of 8.4, 2000-2002 of 8.0 and from 2003-2005 of 10.1 years. In a cohort of 259 unvaccinated children (mean of age 8.59 years), IgG antibodies were detected in 51%. In the infantile population studied a Hepatitis A epidemiology shift is suggested.


The role of potassium channels in the vasodilatory effect of levosimendan in human internal thoracic arteries.
We investigated the role of potassium channels in vasodilatory effect of levosimendan in human internal thoracic arteries. Samples of redundant internal thoracic arteries obtained from patients undergoing a coronary artery bypass graft surgery were cut into 3 mm wide rings and suspended in 20 ml organ baths. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. Levosimendan (10(-8)-10(-5) M) or cromakalim (10(-8)-10(-5) M) produced concentration-dependent relaxation responses in human internal thoracic arteries precontracted by 10(-6) M phenylephrine. The relaxant responses to levosimendan did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of human internal thoracic artery rings with adenosine 3',5'-triphosphate (ATP)-dependent potassium channel blocker glibenclamide (10(-6) M) for 30 min significantly inhibited the relaxant responses to both levosimendan and cromakalim. The Ca2+-activated potassium channel blocker iberiotoxin (10(-7) M) also caused a significant but smaller inhibition on relaxant responses to levosimendan. Incubation of the rings with the voltage-dependent potassium channel blocker 4-aminopyridine (5 mM) for 10 min did not cause significant alterations in relaxant responses to levosimendan. The findings of this study suggested that levosimendan-induced relaxation responses in human internal thoracic arteries were depended on the activation of ATP-dependent and Ca2+-activated potassium channels.


Detection of Vulnerable Plaque in Patients with Cryptogenic Stroke.
In up to 40% of ischemic stroke cases the etiology remains unknown. A substantial proportion of these patients has non- or only mildly stenosing carotid artery plaques not fulfilling common criteria for large artery stroke, but beeing suspicious for arterio-arteriell embolism. Several imaging techniques allow the non-invasive analysis of plaque features. Nevertheless, carotid MRI might be best suited to assess the key features of vulnerable plaques. This review article discusses potential causes of cryptogenic stroke, the role of plaque imaging in non-stenosing plaques and the association of vulnerable plaques and specific plaque features with stroke risk and stroke recurrence.


Experimental verification of rapid, sporadic particle motions by direct imaging of glassy colloidal systems.
We analyze data from confocal microscopy experiments of a colloidal suspension to validate predictions of rapid sporadic events responsible for structural relaxation in a glassy sample. The trajectories of several thousand colloidal particles are analyzed, confirming the existence of such rapid events responsible for the structural relaxation of significant regions of the sample, and complementing prior observations of dynamical heterogeneity. Thus, our results provide the first direct experimental verification of the emergence of relatively compact clusters of mobility which allow the dynamics to transition between the large periods of local confinement within its potential energy surface, in good agreement with the picture envisioned long ago by Adam and Gibbs and Goldstein.


Mycoplasmal panencephalitis: a neuropathologic documentation.
Mycoplasmas, particularly Mycoplasma pneumoniae, have been implicated as causative agents in a large variety of central nervous system diseases, especially acute childhood encephalitis. Postulated pathomechanisms for mycoplasma-mediated neurological disease have included: direct infection, autoimmunity, and vascular occlusion. Neuropathologic data are meager and are reviewed. We report a 3-year-old boy, who developed signs and symptoms of encephalitis 7 days after the onset of fever with cough and death 5 days later. At autopsy, he displayed diffuse vasogenic edema and perivascular to infiltrative inflammatory cells, the latter most prominent in gray matter of brainstem and amygdala. The predominant cell was the CD68-positive macrophage, followed by the T-lymphocyte. Cells immunolabeled with a polyclonal antibody to M. pneumoniae included perivascular to parenchymal macrophages/microglia, occasional oligodendrocytes, and neurons, particularly in brainstem. Affected neurons varied from morphologically normal to profoundly degenerate and necrotic. Ultrastructural study of the inferior olive confirmed the presence of 260-600 nm cell-wall-free microorganisms, consistent with mycoplasma, in perivascular cells and neurons. Foci of acute disseminated encephalomyelitis also were rarely identified. This case report confirms the postulated role of direct infection of brain by mycoplasma in acute childhood encephalitis, but also reveals a virus-like infection of central neurons. The pathogenesis of acute childhood encephalitis due to mycoplasma seems to be multifactorial.


[Etiopathogenic heterogeneity of mitral and aortic valve diseases. Clinico-pathological study].
This study comprises the evaluation of 120 surgically excised mitral and aortic valves, in an attempt to clearly define the nature of the underlying process. To this effect histopathological and clinical criteria were established and categorized in 4 levels of diagnostic accuracy for rheumatic fever. Ninety three percent of the mitral valves were recognized as probably or certainly rheumatic in origin, whereas only 38.4% of the aortic cases were classified in this category. Included is a discussion of the various etiopathogenic possibilities, other than rheumatic, regarding chronic valve deformities of the heart.


Detection of artificial occlusal caries in a phosphor imaging plate system with two types of LCD monitors versus three different films.
The aim of this study was to determine diagnostic performance of a storage phosphor plate system Digora Optime (Soredex, Helsinki, Finland) with two types of LCD monitor in the detection of artificial caries when compared to Ultraspeed (D), Ektaspeed Plus (E), and Insight (F) radiographic films. Seventy extracted human molars-with artificial caries-were radiographed under identical standardized conditions using (1) a storage phosphor plate system Digora (Soredex, Helsinki, Finland), (2) Insight, (3) Ektaspeed Plus, and (4) Ultraspeed (Carestream Health Inc, Rochester, NY). All digital images and radiographs were examined by three observers for the presence or absence of artificial caries using a five-point confidence scale. Digital images were evaluated both on a LCD computer monitor (Philips 170S, Holland) and medical monitor-3 megapixel monochrome display (Me355i2, Totoku, Tokyo)-with brightness and contrast enhancement. Observer responses were evaluated using ROC analysis and other measurements for diagnostic accuracy. Storage phosphor images with medical monitor demonstrated higher mean A (z) values (0.70 +/- 0.08) than digital images with computer monitor and conventional films. Storage phosphor images with medical monitor presented the highest score, 0.97, 0.90, 0.94, for each observer, respectively. Also, true positive observations (0.82) and positive likelihood ratios (2.71) were higher in enhanced storage phosphor images with medical monitor. Caries detection of mechanically created lesions by experienced radiologists is roughly comparable when examining D-speed film images and Digora images on both the computer and medical LCD monitors, and appears to be poorer on E- and F-speed film images.