T-helper-2 cytokine responses to Sj97 predict resistance to reinfection with Schistosoma japonicum.
Although schistosomiasis is effectively treated with Praziquantel, rapid reinfection with rebound morbidity precludes effective control based on chemotherapy alone and justifies current efforts to develop vaccines for these parasites. Using a longitudinal treatment-reinfection study design with 616 participants 7 to 30 years of age, we evaluated the relationship between cytokine responses to Schistosoma japonicum soluble adult worm extract (SWAP), Sj97, Sj22.6, and Sj67, measured 4 weeks after treatment with Praziquantel, and resistance to reinfection in a population from Leyte, The Philippines, where S. japonicum is endemic. S. japonicum transmission was high: 54.8% and 91.1% were reinfected within 6 and 18 months, respectively. A Th2 bias in the following cytokine ratios, interleukin-4 (IL-4)/IL-12, IL-5/IL-12, IL-13/IL-12, IL-4/gamma-IFN (IFN-gamma), IL-5/IFN-gamma, and IL-13/IFN-gamma, in response to SWAP predicted a 1.4- to 2.9-month longer time to reinfection (P < 0.05) and a 27 to 55% lower intensity of reinfection (P < 0.05). Similarly, a Th2 bias in response to Sj97 predicted a 1.6- to 2.2-month longer time to reinfection (P < 0.05) and a 30 to 41% lower intensity of reinfection (P < 0.05). Only a high IL-5/IL-10 ratio in response to Sj22.6 predicted a 3.0-month-longer time to reinfection (P = 0.03). Cytokine responses to Sj67 were not associated with protection. In a large population-based treatment-reinfection study we found that Th2 responses to SWAP and Sj97 consistently predicted resistance to reinfection. These findings underscore Th2-type immune responses as central in human resistance to S. japonicum and support Sj97 as a leading vaccine candidate for this parasite.


The role of catalase in pulmonary fibrosis.
Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12) compared to control lungs (n = 10). Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-β expression and total collagen content following bleomycin treatment compared to wild-type mice. Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.


Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death.
Protein kinase C (PKC) modulates growth, differentiation and apoptosis in a cell-specific fashion. Overexpression of PKC-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-alpha cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G1 arrest that was accompanied by Cip1 expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-alpha cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-alpha cells that waned at higher concentrations. TPA-treated MCF-7-PKC-alpha cells accumulated in G2/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-alpha cells expressed gadd-45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression of gadd45 in a p53-independent fashion.


Enhanced infarct border zone function and altered mechanical activation predict inducibility of monomorphic ventricular tachycardia in patients with ischemic cardiomyopathy.
To prospectively determine whether mechanical behavior of left ventricular wall segments that contain different degrees of scar tissue and are located at different distances from the interface between infarcted and noninfarcted myocardial tissue can help predict inducibility of monomorphic ventricular tachycardia (VT) in patients with ischemic cardiomyopathy. This HIPAA-compliant study was institutional review board approved; written informed consent was obtained from all patients. Forty-six patients (36 men, 10 women; mean age +/- standard deviation, 61.6 years +/- 11.9) with prior myocardial infarction (MI) and left ventricular dysfunction were referred for defibrillator implantation and underwent an electrophysiologic examination and tagged contrast-enhanced magnetic resonance (MR) imaging. Peak circumferential shortening strain (Ecc) and time to peak Ecc were measured in 12 segments from short-axis sections. Remote, adjacent, and border zones were defined according to increasing proximity to the MI. Patients in whom monomorphic VT could be induced (ie, inducible patients) were considered positive for inducibility. Relationships between inducibility of monomorphic VT, peak Ecc, and time to peak Ecc were analyzed with one-way analysis of variance and Bonferroni test. Inducible patients had more infarcted and border zone sectors and a shorter time to peak Ecc than did noninducible patients in the border zone and adjacent and infarcted regions (P < .001). Peak Ecc in the border zone of inducible patients (-11.42% +/- 0.46 [standard error]) was greater than that in noninducible patients (-10.18% +/- 0.38; P < .05). Ratio of Ecc in border zone and in remote regions was greater (P < .05) in inducible patients than in noninducible patients (1.31 +/- 0.27 vs 0.64 +/- 0.13, respectively). Enhanced border zone function defined as greater Ecc and earlier time to peak Ecc showed positive correlation to VT inducibility in patients with prior MI and left ventricular dysfunction.


Outcome in patients who require renal support after surgery for ruptured abdominal aortic aneurysm.
Over a 3-year period haemofiltration and dialysis was provided for 18 patients who developed renal failure after operation for ruptured abdominal aortic aneurysm (AAA). Four of the patients underwent operation elsewhere and were transferred when renal failure was diagnosed. The median duration of renal support in the 11 survivors was 24 days, while the seven patients who died received support for a median of 11 days. By 3 months after operation eight of the 11 survivors were independent of dialysis. Renal support was life saving in eight of 91 patients operated on in Oxford for ruptured AAA and reduced the 30-day operative mortality rate from a potential 47 per cent to an actual 38 per cent. Haemofiltration and haemodialysis for acute renal failure after surgery for ruptured aortic aneurysm is clinically justified and results in the long-term survival of most patients.


Comparison of Two Major Perioperative Bleeding Scores for Cardiac Surgery Trials: Universal Definition of Perioperative Bleeding in Cardiac Surgery and European Coronary Artery Bypass Grafting Bleeding Severity Grade.
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Research into major bleeding during cardiac surgery is challenging due to variability in how it is scored. Two consensus-based clinical scores for major bleeding: the Universal definition of perioperative bleeding and the European Coronary Artery Bypass Graft (E-CABG) bleeding severity grade, were compared in this substudy of the Transfusion Avoidance in Cardiac Surgery (TACS) trial. As part of TACS, 7,402 patients underwent cardiac surgery at 12 hospitals from 2014 to 2015. We examined content validity by comparing scored items, construct validity by examining associations with redo and complex procedures, and criterion validity by examining 28-day in-hospital mortality risk across bleeding severity categories. Hierarchical logistic regression models were constructed that incorporated important predictors and categories of bleeding. E-CABG and Universal scores were correlated (Spearman ρ = 0.78, P < 0.0001), but E-CABG classified 910 (12.4%) patients as having more severe bleeding, whereas the Universal score classified 1,729 (23.8%) as more severe. Higher E-CABG and Universal scores were observed in redo and complex procedures. Increasing E-CABG and Universal scores were associated with increased mortality in unadjusted and adjusted analyses. Regression model discrimination based on predictors of perioperative mortality increased with additional inclusion of the Universal score (c-statistic increase from 0.83 to 0.91) or E-CABG (c-statistic increase from 0.83 to 0.92). When other major postoperative complications were added to these models, the association between Universal or E-CABG bleeding with mortality remained. Although each offers different advantages, both the Universal score and E-CABG performed well in the validity assessments, supporting their use as outcome measures in clinical trials.


Anatomy of soft tissues of the spinal canal.
Important issues regarding the spread of solutions in the epidural space and the anatomy of the site of action of spinal and epidural injections are unresolved. However, the detailed anatomy of the spinal canal has been incompletely determined. We therefore examined the microscopic anatomy of the spinal canal soft tissues, including relationships to the canal walls. Whole mounts were prepared of decalcified vertebral columns with undisturbed contents from three adult humans. Similar material was prepared from a macaque and baboon immediately on death to control for artifact of tissue change after death. Other tissues examined included nerve root and proximal spinal nerve complex and dorsal epidural fat obtained during surgery. Slides were examined by light microscopy at magnifications of 10-40x. There is no fibrous tissue in the epidural space. The epidural fat is composed of uniform cells enclosed in a fine membrane. The dorsal fat is only attached to the canal wall in the dorsal midline and is often tenuously attached to the dura. The dura is joined to the canal wall only ventrally at the discs. Veins are evident predominantly in the ventral epidural space. Nerve roots are composed of multiple fascicles which disperse as they approach the dorsal root ganglion. An envelope of arachnoid encloses the roots near the site of exit from the dura. These features of the fat explain its semifluid consistency. Lack of substantial attachments to the dura facilitate movement of the dura relative to the canal wall and allow distribution of injected solution. Fibrous barriers are an unlikely explanation for asymmetric epidural anesthesia, but the midline fat could impede solution spread. Details of nerve-root structure and their envelope of pia-arachnoid membrane may be relevant to anesthetic action.


Mesothelioma Cells Depend on the Antiapoptotic Protein Bcl-xL for Survival and Are Sensitized to Ionizing Radiation by BH3-Mimetics.
The incidence of mesothelioma continues to rise and prognosis remains dismal owing to resistance to conventional therapies and few novel treatment options. Failure to activate apoptotic cell death is a resistance mechanism that may be overcome by inhibition of antiapoptotic Bcl-2 proteins using BH3-mimetic drugs. We investigated the role of antiapoptotic proteins in the radioresistance of mesothelioma, identifying clinically relevant targets for radiosensitization and evaluating the activity of BH3-mimetics alone and in combination with radiation therapy in preclinical models. Mesothelioma cell lines 211H, H2052, and H226 exposed to BH3-mimetics demonstrated Bcl-xL dependence that correlated with protein expression and was confirmed by genetic knockdown. The Bcl-xL inhibitor A1331852 exhibited cytotoxic (EC50, 0.13-1.42 μmol/L) and radiosensitizing activities (sensitizer enhancement ratios, 1.3-1.8). Cytotoxicity was associated with induction of mitochondrial outer membrane permeabilization and caspase-3/7 activation. Efficacy was maintained in a 3-dimensional model in which combination therapy completely eradicated mesothelioma spheroids. Clinical applicability was confirmed by immunohistochemical analysis of Bcl-2 proteins in patient samples and radiosensitizing activity of A1331852 in primary patient-derived mesothelioma cells. Mesothelioma cells exhibit addiction to the antiapoptotic protein Bcl-xL, and their intrinsic radioresistance can be overcome by small molecule inhibition of this novel therapeutic target.


Does the extension of primary care practice opening hours reduce the use of emergency services?
Overcrowding in emergency departments generates potential inefficiencies. Using regional administrative data, we investigate the impact that an increase in the accessibility of primary care has on emergency visits in Italy. We consider two measures of avoidable emergency visits recorded at list level for each General Practitioner. We test whether extending practices' opening hours to up to 12 hours/day reduces the inappropriate utilization of emergency services. Since subscribing to the extension program is voluntary, we account for the potential endogeneity of participation in a count model for emergency admissions in two ways: first, we use a two-stage residual inclusion approach. Then we exploit panel methods on data covering a three-year period, thus accounting directly for individual heterogeneity. Our results show that increasing primary care accessibility acts as a restraint on the inappropriate use of emergency departments. The estimated effect is in the range of a 10-15% reduction in inappropriate admissions.


Effects of low and hyper Dk rigid gas permeable contact lenses on Bcl-2 expression and apoptosis in the rabbit corneal epithelium.
To study Bcl-2 expression and apoptotic cell shedding of the rabbit corneal epithelium during extended wear of low and hyper Dk rigid gas permeable (RGP) contact lenses. Rabbits were fit with either a low or a hyper Dk RGP lens (Dk/Ltotal= 10 and 97). The rabbits wore the lenses for either 24 hours, 3 days, or 1 week at which point they were humanely sacrificed. Immunocytochemistry and western blot analyses were performed to detect Bcl-2 in the corneal epithelium; TUNEL assay (TdT-mediated dUTP nick-end labeling) was used to identify apoptotic epithelial cells. 1) Immunocytochemistry: In the normal cornea, antibodies to Bcl-2 uniformly stained nuclei of all epithelial cell layers. Occasional surface epithelial cells, however, showed no anti-Bcl-2 nuclear staining; concomitant TUNEL assay revealed that all TUNEL-labeled-surface cells were Bcl-2 negative. By contrast, RGP contact lens wear, regardless of test lens oxygen transmissibility or lens wearing interval, significantly decreased both the total number of Bcl-2 negative and TUNEL-labeled cells on the epithelial surface (P < 0.05). In addition, contact lens wear was associated with labeling of keratocytes with TUNEL assay in the anterior stroma. 2) Western blot analysis: Total epithelial layer Bcl-2 expression was markedly decreased in the low Dk lens test group but was similar to control values in the hyper Dk lens test group. Bcl-2 protein seems to play an important role in the regulation of apoptotic cell shedding in the normal rabbit corneal epithelium. The identical staining pattern was seen in previous studies of the normal human cornea. RGP contact lens wear, however, appears to block the changes in Bcl-2 protein prior to apoptotic surface cell shedding, suggesting a lens-related anti-apoptotic effect. Taken together, these findings may explain why contact lens wear reduces surface cell exfoliation as previously reported in human studies.


Action mechanism and signal pathways of Psidium guajava L. aqueous extract in killing prostate cancer LNCaP cells.
Aqueous extract of Psidium guajava L. budding leaves (PE) has been shown to possess anti-prostate cancer activity in a cell line model. We examined whether its bioactivity could be conserved either in the presence or the absence of synthetic androgen R1881. In both cases, PE was shown to inhibit LNCaP cell proliferation and down-regulate expressions of androgen receptor (AR) and prostate specific antigen (PSA). The cytotoxicity of PE was shown by enhanced LDH release in LNCaP cells. The flow cytometry analysis revealed cell cycle arrests at G(0)/G(1) phase with huge amount of apoptotic LNCaP cells after treatment with PE for 48 h in a dose-responsive manner, which was also confirmed by TUNEL assay. From the results of decreased Bcl-2/Bax ratio, inactivation of phosphor-Akt, activation of phosphor-p38, phospho-Erk1/phospho-Erk2, the molecular action mechanism of PE to induce apoptosis in LNCaP cells was elucidated. Compatible with the in vitro study findings, treatment with PE (1.5 mg/mouse/day) significantly diminished both the PSA serum levels and tumor size in a xenograft mouse tumor model. Conclusively, PE is a promising anti-androgen-sensative prostate cancer agent.


Metabolic and endocrine response to exercise: sympathoadrenal integration with skeletal muscle.
Skeletal muscle has the capacity to increase energy turnover by ∼1000 times its resting rate when contracting at the maximum force/power output. Since ATP is not stored in any appreciable quantity, the muscle requires a coordinated metabolic response to maintain an adequate supply of ATP to sustain contractile activity. The integration of intracellular metabolic pathways is dependent upon the cross-bridge cycling rate of myosin and actin, substrate availability and the accumulation of metabolic byproducts, all of which can influence the maintenance of contractile activity or result in the onset of fatigue. In addition, the mobilisation of extracellular substrates is dependent upon the integration of both the autonomic nervous system and endocrine systems to coordinate an increase in both carbohydrate and fat availability. The current review examines the evidence for skeletal muscle to generate power over short and long durations and discusses the metabolic response to sustain these processes. The review also considers the endocrine response from the perspective of the sympathoadrenal system to integrate extracellular substrate availability with the increased energy demands made by contracting skeletal muscle. Finally, the review briefly discusses the evidence that muscle acts in an endocrine manner during exercise and what role this might play in mobilising extracellular substrates to augment the effects of the sympathoadrenal system.


The Care Span: Growth of racial and ethnic minorities in US nursing homes driven by demographics and possible disparities in options.
Between 1999 and 2008, the number of elderly Hispanics and Asians living in US nursing homes grew by 54.9 percent and 54.1 percent, respectively, while the number of elderly black residents increased 10.8 percent. During the same period, the number of white nursing home residents declined 10.2 percent. These shifts have been driven in part by changing demographics, especially the fast growth of older minority populations. However, the numbers of minority residents in nursing homes increased more rapidly than the minority population overall, even in areas with high concentrations of minority populations. Thus, these results may indicate unequal minority access to home and community-based alternatives, which are generally preferred for long-term care. When designing initiatives to balance institutional and noninstitutional long-term care, policy makers should take steps to reduce racial and ethnic disparities.


The intracellular loops of the GB2 subunit are crucial for G-protein coupling of the heteromeric gamma-aminobutyrate B receptor.
The gamma-aminobutyrate B (GABA(B)) receptor is the first discovered G-protein-coupled receptor (GPCR) that needs two subunits, GB1 and GB2, to form a functional receptor. The GB1 extracellular domain (ECD) binds GABA, and GB2 contains enough molecular determinants for G-protein activation. The precise role of the two subunits in G-protein coupling is investigated. GB1 and GB2 are structurally related to the metabotropic glutamate, Ca(2+)-sensing and other family 3 GPCRs in which the second (i2) as well as the third (i3) intracellular loop play important roles in G-protein coupling. Here, the role of the i2 loops of GB1 and GB2 in the GABA(B) receptor ability to activate G(alpha)-proteins is investigated. To that aim, the i2 loops were swapped between GB1 and GB2 heptahelical domains (HDs), either in the wild-type subunits or in the chimeric subunits GB1/2 that contain the ECD of GB1 and the HD of GB2. The effect of an additional mutation within the i3 loop of GB2 that prevents coupling of the heteromeric receptor was also examined. Combinations of interest were found to be correctly addressed at the cell surface and to assemble into heteromers. Taken together our data revealed the following new information on the G-protein coupling of the heteromeric GABA(B) receptor: 1) the i2 loop of GB2 within the GB2 HD is required for the heteromeric GABA(B) receptor to couple to G-proteins, whereas the i2 loop of GB1 is not; 2) the presence of the i2 loop of GB2 within the GB1 HD is not sufficient to allow coupling of GB1; 3) the GB2 HD activates the Gqi9 protein whether it is associated with the GB2 or GB1 ECD; 4) in the combination with two GB2 HDs, each is able to couple to G-proteins; and finally, 5) the use of mutations in i2, i3, or both within the GB2 HD brings evidence for the absence of domain swapping enabling the exchange of region including i2 and i3 between the subunits.


Retrosigmoid approach for resection of cerebellopontine angle meningioma and decompression of the trigeminal nerve.
Cerebellopontine angle (CPA) lesions account for up to 10% of all intracranial tumors. The most common CPA lesions are vestibular schwannomas (70-80%), meningiomas (10-15%) and epidermoid cysts (5%). CPA tumors are estimated to be the secondary cause for up to 9.9% patients with trigeminal neuralgia. We demonstrate a case of medically refractory trigeminal neuralgia caused by a CPA meningioma that was successfully treated via retrosigmoid approach. The patient had immediate and dramatic symptomatic improvement after surgery. Detailed surgical techniques of retrosigmoid craniotomy and tumor dissection are presented in high definition video with narration. The video can be found here: http://youtu.be/55j9QCQEsH8 .


Sequential steps for developmental arrest in Arabidopsis seeds.
The continuous growth of the plant embryo is interrupted during the seed maturation processes which results in a dormant seed. The embryo continues development after germination when it grows into a seedling. The embryo growth phase starts after morphogenesis and ends when the embryo fills the seed sac. Very little is known about the processes regulating this phase. We describe mutants that affect embryo growth in two sequential developmental stages. Firstly, embryo growth arrest is regulated by the FUS3/LEC type genes, as mutations in these genes cause a continuation of growth in immature embryos. Secondly, a later stage of embryo dormancy is regulated by ABI3 and abscisic acid; abi3 and aba1 mutants exhibit premature germination only after embryos mature. Mutations affecting both developmental stages result in an additive phenotype and double mutants are highly viviparous. Embryo growth arrest is regulated by cell division activities in both the embryo and the endosperm, which are gradually switched off at the mature embryo stage. In the fus3/lec mutants, however, cell division in both the embryo and endosperm is not arrested, but rather is prolonged throughout seed maturation. Furthermore ectopic cell division occurs in seedlings. Our results indicate that seed dormancy is secured via at least two sequential developmental processes: embryo growth arrest, which is regulated by cell division and embryo dormancy.


Pooled DNA sequencing to identify SNPs associated with a major QTL for bacterial wilt resistance in Italian ryegrass (Lolium multiflorum Lam.).
SNPs and candidate genes associated with bacterial wilt resistance in Italian ryegrass were identified by sequencing the parental plants and pooled F1 progeny of a segregating population. Italian ryegrass (Lolium multiflorum Lam.) is one of the most important forage grass species in temperate regions. Its yield, quality and persistency can significantly be reduced by bacterial wilt, a serious disease caused by Xanthomonas translucens pv. graminis. Although a major QTL for bacterial wilt resistance has previously been reported, detailed knowledge on underlying genes and DNA markers to allow for efficient resistance breeding strategies is currently not available. We used pooled DNA sequencing to characterize a major QTL for bacterial wilt resistance of Italian ryegrass and to develop inexpensive sequence-based markers to efficiently target resistance alleles for marker-assisted recurrent selection. From the mapping population segregating for the QTL, DNA of 44 of the most resistant and 44 of the most susceptible F1 individuals was pooled and sequenced using the Illumina HiSeq 2000 platform. Allele frequencies of 18 × 106 single nucleotide polymorphisms (SNP) were determined in the resistant and susceptible pool. A total of 271 SNPs on 140 scaffold sequences of the reference parental genome showed significantly different allele frequencies in both pools. We converted 44 selected SNPs to KASP™ markers, genetically mapped these proximal to the major QTL and thus validated their association with bacterial wilt resistance. This study highlights the power of pooled DNA sequencing to efficiently target binary traits in biparental mapping populations. It delivers genome sequence data, SNP markers and potential candidate genes which will allow to implement marker-assisted strategies to fix bacterial wilt resistance in outcrossing breeding populations of Italian ryegrass.


Gas Chromatography-Mass Spectrometry (GC-MS) and Gas Chromatography-Infrared (GC-IR) Analyses of the Chloro-1- n-pentyl-3-(1-naphthoyl)-Indoles: Regioisomeric Cannabinoids.
The analytical differentiation of the indole ring regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles is described in this report. The regioisomeric chloroindole precursor compounds, N- n-pentyl chloroindole synthetic intermediates, and the target chloro-substituted naphthoylindoles showed the equivalent gas chromatographic elution order based on the position of chlorine substitution on the indole ring. The regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles yield electron ionization mass spectra having equivalent major fragments resulting from cleavage of the groups attached to the central indole nucleus. Fragment ions occur at m/z 127 and 155 for the naphthyl and naphthoyl cations common to all indoles having the naphthoyl group substituted at the indole-3 position. Fragments resulting from the loss of the naphthoyl and/or n-pentyl groups from the molecular radical cation yield the cations at m/z 318, 304, 248, and 178. The characteristic (M-17)+ fragment ion at m/z 358 resulting from the loss of OH radical is significant in the mass spectra of all these compounds with 1-naphthoyl groups substituted at the indole-3 position. The vapor phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers.


Features of medical records in community practices and their association with preventive service delivery.
Medical records are important for facilitating the process and quality of care. However, little is known about their current state in primary care practices. This article describes features of medical record systems in diverse practices and examines their association with preventive service delivery rates. Medical records were reviewed from a consecutive sample of outpatients seen by 198 family physicians in 79 community-based practices in Northeast Ohio. The physicians were participants in a clinical trial designed to increase preventive service delivery. Research nurses performed baseline medical record reviews and used ethnographic field notes and a practice environment checklist to provide global assessments of features of medical records. In 79 practices, 3462 medical records were reviewed. Medical records were rated as highly easy to use in 52% of practices; outpatient visit notes were dictated in 54%. Nine percent of practices grouped individual charts by family. Patient notes were computerized in 1% of practices, although several practices had previously tried and abandoned computerized systems. Flow sheets for immunization, screening, and counseling were present on 71%, 63%, and 16% of charts and were used on 34%, 33%, and 3% of charts, respectively. The presence and use of flow sheets were associated with higher preventive service delivery rates. Medical record organization, completeness, and use vary widely, and computerized records remain rare. The association of flow sheet presence and use with preventive service delivery rates shows the potential importance of medical records for enhancing the process and outcome of patient care.


Spotlight on daytime napping during early childhood.
Daytime napping undergoes a remarkable change in early childhood, and research regarding its relationship to cognitive development has recently accelerated. In this review, we summarize our current understanding of this relationship focusing on children aged <5 years. First, we evaluate different studies on the basis of the experimental design used and the specific cognitive processes they investigate. Second, we analyze how the napping status of children may modulate the relationship between learning and napping. Third, the possible role of sleep spindles, ie, specific electroencephalographic components during sleep, in cognitive development is explored. We conclude that daytime napping is crucial in early memory development.


Preparedness for caregiving: A phenomenological study of the experiences of rural Australian family palliative carers.
The care of people with life-limiting illnesses is increasingly moving away from an acute setting into the community. Thus, the caregiver role is growing in significance and complexity. The importance of preparing and supporting family caregivers is well established; however, less is known about the impact of rurality on preparedness and how preparedness shapes the caregiving continuum including bereavement. The aim of this study, conducted in 2017, was to explore how bereaved rural family palliative carers described their preparedness for caregiving. Interpretative phenomenological analysis was employed following semi-structured interviews with four women and six men (N = 10, aged 55-87 years). Participants were recruited voluntarily through past engagement with a Regional Specialist Palliative Care Consultancy Service in Australia. The experiences of caregivers illustrated a lack of preparedness for the role and were characterised by four major themes: Into the unknown, Into the battle, Into the void and Into the good. The unknown was associated with a lack of knowledge and skills, fear, prognostic communication, exclusion, emotional distress and grief experience. Battles were experienced in a number of ways: intrapsychically (existing within the mind), through role conflict and identity; interpersonally with the patient, clinician and family; and systematically (against health, financial and legal systems). The void was felt during isolation in caregiving, in relinquishing the role, in bereavement and in feeling abandoned by service providers. Positive experiences, such as being valued, included and connected to supports, and the fostering of closer relationships and deeper meaning, occurred less frequently but temporarily buffered against negative aspects. Implications from this study for policy and practice centre on the frequent, purposeful and genuine engagement of caregivers. Services and clinicians are encouraged to enhance communication practices, promote meaningful inclusion, address access issues and enhance support at role relinquishment.


Examining the Neighborhood Attributes of Recently Housed Partner Violence Survivors in Rapid Rehousing.
Survivors' considerations for re-housing following intimate partner violence (IPV) are understudied despite likely neighborhood-level influences on women's safety. We assess housing priorities and predictors of re-housing location among recent IPV survivors (n = 54) in Rapid Re-housing (RRH) in the Baltimore-Washington Metropolitan Area. Choropleth maps depict residential location relative to census tract characteristics (neighborhood deprivation index (NDI) and residential segregation) derived from American Community Survey data (2013-2017). Linear regression measured associations between women's individual, economic, and social factors and NDI and segregation. In-depth interviews (n = 16) contextualize quantitative findings. Overall, survivors re-housed in significantly more deprived and racially segregated census tracts within their respective regions. In adjusted models, trouble securing housing (B = 0.74, 95% CI: 0.13, 1.34), comfortability with proximity to loved ones (B = 0.75, 95% CI: 0.02, 1.48), and being unsure (vs unlikely) about IPV risk (B = -0.76, 95% CI: -1.39, -0.14) were significantly associated with NDI. Economic dependence on an abusive partner (B = -0.31, 95% CI: -0.56, -0.06) predicted re-housing in segregated census tracts; occasional stress about housing affordability (B = 0.39, 95% CI: 0.04, 0.75) predicted re-housing in less segregated census tracts. Qualitative results contextualize economic (affordability), safety, and social (familiarity) re-housing considerations and process impacts (inspection delays). Structural racism, including discriminatory housing practices, intersect with gender, exacerbating challenges among survivors of severe IPV. This mixed-methods study further highlights the significant economic tradeoffs for safety and stability, where the prioritization of safety may exacerbate economic devastation for IPV survivors. Findings will inform programmatic policies for RRH practices among survivors.


Gravity field of the Moon from the Gravity Recovery and Interior Laboratory (GRAIL) mission.
Spacecraft-to-spacecraft tracking observations from the Gravity Recovery and Interior Laboratory (GRAIL) have been used to construct a gravitational field of the Moon to spherical harmonic degree and order 420. The GRAIL field reveals features not previously resolved, including tectonic structures, volcanic landforms, basin rings, crater central peaks, and numerous simple craters. From degrees 80 through 300, over 98% of the gravitational signature is associated with topography, a result that reflects the preservation of crater relief in highly fractured crust. The remaining 2% represents fine details of subsurface structure not previously resolved. GRAIL elucidates the role of impact bombardment in homogenizing the distribution of shallow density anomalies on terrestrial planetary bodies.


Liver transplantation for neurologic Wilson's disease: reflections on two cases within a mexican cohort.
Liver transplantation (LT) in Wilson s disease (WD) is mostly indicated when progressing liver disease or acute liver failure occurs. In patients with neurological manifestations, this procedure has not gained wide acceptance based on previous reports of dismal prognosis. To describe a Mexican cohort of pa- tients with WD with special focus on LT in patients with deteriorating neurological manifestations. Patients with confirmed WD and their first-degree relatives were evaluated at the hepatology clinic of a tertiary referral hospital. Attention was placed on therapy and outcome. Eleven patients were followed for a period of up to 80 months (7 probands and 4 affected family members), 10 patients having hepatic manifestations and 4 having neuro psychia- tric phenomena. Pharmacologic treatment was uniform in most patients, and LT was indicated in 2 cases because of deteriorating neurological status. These patients had total remission of their neurological manifestations with marked improvement on imaging studies. Follow-up and pharmacologic treatment was flawed by several adverse conditions present in our population. Patients with progressing neurological disease had a favorable outcome after LT, a similar response to the one reported by several authors. In conclusion, LT should be strongly considered for the treatment of these patients.


Current View of Risk Factors for Periodontal Diseases.
Periodontal diseases are infections, and many forms of the disease are associated with specific pathogenic bacteria which colonize the subgingival area. At least two of these microorganisms, Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, also invade the periodontal tissue and are virulent organisms. Initiation and progression of periodontal infections are clearly modified by local and systemic conditions called risk factors. The local factors include pre-existing disease as evidenced by deep probing depths and plaque retention areas associated with defective restorations. Systemic risk factors recently have been identified by large epidemiologic studies using multifactorial statistical analyses to correct for confounding or associated co-risk factors. Risk factors which we know today as important include diabetes mellitus, especially in individuals in whom metabolic control is poor, and cigarette smoking. These two risk factors markedly affect the initiation and progression of periodontitis, and attempts to manage these factors are now an important component of prevention and treatment of adult periodontitis. Systemic conditions associated with reduced neutrophil numbers or function are also important risk factors in children, juveniles, and young adults. Diseases in which neutrophil dysfunction occurs include the lazy leukocyte syndrome associated with localized juvenile periodontitis, cyclic neutropenia, and congenital neutropenia. Recent studies also point to several potentially important periodontal risk indicators. These include stress and coping behaviors, and osteopenia associated with estrogen deficiency. There are also background determinants associated with periodontal disease including gender (with males having more disease), age (with more disease seen in the elderly), and hereditary factors. The study of risk in periodontal disease is a rapidly emerging field and much is yet to be learned. However, there are at least two significant risk factors-smoking and diabetes-which demand attention in current management of periodontal disease. J Periodontol 1996;67:1041-1049.


Surface Acoustic Wave Resonators for Wireless Sensor Network Applications in the 433.92 MHz ISM Band.
Surface acoustic wave (SAW) resonators are low cost devices that can operate wirelessly on a received radio frequency (RF) signal with no requirement for an additional power source. Multiple SAW resonators operating as transponders that form a wireless sensor network (WSN), often need to operate at tightly spaced, different frequencies inside the industrial, scientific and medical (ISM) bands. This requires nanometer precision in the design and fabrication processes. Here, we present results demonstrating a reliable and repeatable fabrication process that yields at least four arrays on a single 4-inch wafer. Each array consists of four single-port resonators with center frequencies allocated inside four different sub-bands that have less than 50 kHz bandwidth and quality factors exceeding 8000. We see promise of standard, low-cost photolithography techniques being used to fabricate multiple SAW resonators with different center resonances all inside the 433.05 MHz-434.79 MHz ISM band and a mere 100 kHz spacing. We achieved that by leveraging the intrinsic process variation of photolithography and the impact of the metallization ratio and metal thickness in rendering distinct resonant frequencies.


Circadian dysfunction causes aberrant hypocotyl elongation patterns in Arabidopsis.
Many endogenous and environmental signals control seedling growth, including several phototransduction pathways. We demonstrate that the circadian clock controls the elongation of the Arabidopsis hypocotyl immediately upon germination. The pattern of hypocotyl elongation in constant light includes a daily growth arrest spanning subjective dawn and an interval of rapid growth at subjective dusk. Maximal hypocotyl growth coincides with the phase during which the cotyledons are raised, in the previously described rhythm of cotyledon movement. The rhythm of hypocotyl elongation was entrained by light-dark cycles applied to the imbibed seed and its period was shortened in the toc1-1 mutant, indicating that it is controlled by a similar circadian system to other rhythmic markers. The daily groth arrest is abolished by the early flowering 3 (elf3) mutation, suggesting that this defect may cause its long-hypocotyl phenotype. Mutations that affect the circadian system can therefore cause gross morphological phenotypes, not because the wild-type gene functions pleiotropically in several signalling pathways, but rather because the circadian clock exerts wide-spread control over plant physiology.


Impact on clinical outcome of secondary brain insults during the neurointensive care of patients with subarachnoid haemorrhage: a pilot study.
To analyse the occurrence and influence on outcome of secondary brain insults during neurointensive care of patients with subarachnoid haemorrhage. Sixty one seriously ill patients with subarachnoid haemorrhage with a poor neurological grade, acute hydrocephalus, or intraventricular and/or intracerebral haemorrhages, who were referred as emergency cases to the neurosurgical intensive care unit during 1990 and 1991, comprised the study patients. The follow up performed according to the Glasgow outcome scale 14 months (median) later showed 23 patients with good recovery (38%), 11 with moderate disability (18%), seven with severe disability (11%), and two in a vegetative state (3%); 18 patients had died (30%). Clinical outcome was significantly related to the CT modified Hunt and Hess grade (P = 0.006). In total, 164 secondary brain insults (potentially avoidable factors) of various types were seen at the unit during the first seven days after the haemorrhage. Patients with a favourable outcome had significantly fewer secondary insults than patients with an unfavourable outcome (P = 0.0008). The occurrence of insults in each patient was related to the neurological grade (CT modified Hunt and Hess grade, P = 0.05). Multivariate analysis with the CT modified Hunt and Hess grade and the number of secondary brain insults during the first week as explanatory variables and favourable outcome as the dependent variable, showed that the number of complications was a significant independent predictor of favourable outcome (beta = -0.38, SE(beta) = 0.17, P = 0.03), whereas the CT modified Hunt and Hess grade did not reach significance (beta = -1.2, SE(beta) = 0.81, P = 0.14). The clinical outcome after subarachnoid haemorrhage is at least partly determined by the number of secondary insults. Therefore, vigorous attempts should be made to avoid all events that may potentially increase the risk of secondary cerebral ischaemia. Prospective studies must be initiated to define the role of "priming" of the brain and the impact of specific individual secondary insults in patients with subarachnoid haemorrhage.


Congenital malformations of the central nervous system: clinical approach.
Central nervous system (CNS) malformations represent important factor of morbidity and mortality in children. The aim of the study was to determine the incidence, type and clinical features of CNS malformations in children who were admitted at the Neonatal and Child Neurology Department, Neonatal Intensive Care Unit and Paediatric Intensive Care Unit of Paediatric Clinic, University of Sarajevo Clinics Centre, from January 1st, 2002 to December 31st, 2006. There were total of 16520 admissions at the Paediatric Clinic over the studied period. CNS malformations, solitary or multiple, have been diagnosed in 100 patients (0,61%). The total number of various CNS malformations was 127. Lethal outcome was established in 9/100 cases (9%). The most frequent CNS malformations were neural tube defects 49/127 (38,6%). Hydrocephalus was seen in 34/127 (26,8%), microcephaly in 24/127 (18,9%), agenesis of corpus callosum in 10/127 (7,9%), Dandy Walker malformation in 6/127 (4,7%) and other CNS malformations in 4/127 (3,1%). In 20/100 of patients neural tube defect was associated with hydrocephalus (20%). CNS malformations were prenatally diagnosed in 13/100 of patients (13%). Primary prevention of CNS malformations can be improved in our country by better implementation of preconceptional folic acid therapy for all women of childbearing age. Secondary prevention by prenatal diagnosis requires advanced technical equipment and adequate education of physicians in the field of foetal ultrasonography. In our circumstances, prenatal diagnostics of CNS malformations is still not developed enough.


Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation.
Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.


Discovery of a pupping site and nursery for critically endangered green sawfish Pristis zijsron.
A pilot study targeting sawfishes in the southern Pilbara region of Western Australia, which is undergoing a major expansion in human activity, was conducted using gillnets during April and October 2011 in the Ashburton Estuary and adjacent mangrove creeks. Catch per unit effort was greatest in the Ashburton Estuary in October, due to an influx of green sawfish Pristis zijsron pups, and was orders of magnitude higher than previously reported for any Pristidae; the study sites contained P. zijsron up to almost 3 m total length. This study identified the first pupping site for P. zijsron in Western Australia, and the most southerly known nursery area for the species in Australian waters, and is potentially the most important globally.


Molecular characterization of prothoracicotropic hormone (PTTH) from the giant silkmoth Antheraea pernyi: developmental appearance of PTTH-expressing cells and relationship to circadian clock cells in central brain.
Using a PCR strategy, we have cloned the cDNA for prothoracicotropic hormone (PTTH) from the giant silkmoth, Antheraea pernyi. The A. pernyi PTTH cDNA encodes a preprohormone of 221 amino acids that is 51 and 71% identical at the amino acid level with Bombyx mori and Samia cynthia ricini PTTHs, respectively. Bacterially expressed, recombinant A. pernyi PTTH stimulates adult development when injected into debrained pupae. PTTH protein (ca. 30 kDa by Western blot) and mRNA (ca. 0.9 kb by Northern blot) are expressed in brain. Immunocytochemistry and in situ hybridization show that PTTH protein and mRNA are colocalized in L-NSC III from Day 4 of embryogenesis through adult life, with little variation in either protein or mRNA levels at the various ecdyses. A pair of cells expressing immunoreactivity for the circadian clock protein PER is located in the same region as PTTH-expressing L-NSC III in A. pernyi brain. However, double-label immunocytochemical studies show that PTTH and PER are located in different cells. The close anatomical location between PTTH- and PER-expressing cells suggests routes of communication between these two cell populations that may be important for the circadian control of PTTH release.


Identification of pigments in paint cross sections by reflection visible light imaging microspectroscopy.
A setup for reflection visible light imaging microspectroscopy (VIS-imaging) as well as its evaluation and application is described and tested. The spatial resolution of the system is approximately 1 microm at a spectral resolution of 4 nm. The optical contrast between different colored particles in the surface of a sample is optimized with a new image processing method for mapping of the distribution of the identified pigment particles. The potential of VIS-imaging in the study of paint cross sections obtained from paintings is explored. Spectra obtained from pigment particles in these cross sections result in classification or identification of several pigments. The investigated paint samples are challenging test cases, as they contain several colored materials with a very fine distribution. VIS-imaging can identify and map the most common traditional blue pigments, i.e., smalt, azurite, ultramarine, and indigo in 17th century oil paintings. Smalt can be identified even after complete discoloration. VIS-imaging analysis assisted in the identification and mapping of modern synthetic red and yellow pigments in a 20th century painting.


Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression.
Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations within the sialidase gene NEU1. Five novel mutations were identified. Four are missense and one is nonsense: c.674G>C (p.R225P), c.893C>T (p.A298V), c.3G>A (p.M1?), c.941C>G (p.R341G), and c.69G>A (p.W23X). We have used our findings and diagnostic tools to confirm the presence of a homozygous null allele in a neonate sibling. Recombinant adenoviruses expressing the mutant sialidase alleles in primary cell cultures were utilized to assess the impact of each mutation on enzyme activity and intracellular localization. None of the mutant alleles expressed significant enzymatic activity. The p.R341G mutation exerts its pathological effect by perturbing substrate binding, while the p.A298V and p.R225P mutations appear to impair the folding of the sialidase enzyme. Our findings point to mutation-sensitive amino acids involved in catalytic function or structural stability and indicate the potential utility of these mutations for molecular diagnosis of this rare disease.


Survival of Mycobacterium avium subspecies paratuberculosis in retail pasteurised milk.
A survey of retail purchased semi-skimmed pasteurised milk (n = 368) for Mycobacterium avium subspecies paratuberculosis (MAP) was conducted between May 2014 and June 2015 across the midlands of England using the Phage-PCR assay. Overall, 10.3% of the total samples collected contained viable MAP cells, confirming that pasteurisation is not capable of fully eliminating human exposure to viable MAP through milk. Comparison of the results gained using the Phage-PCR assay with the results of surveys using either culture or direct PCR suggest that the phage-PCR assay is able to detect lower numbers of cells, resulting in an increase in the number of MAP-positive samples detected. Comparison of viable count and levels of MAP detected in bulk milk samples suggest that MAP is not primarily introduced into the milk by faecal contamination but rather are shed directly into the milk within the udder. In addition results detected an asymmetric distribution of MAP exists in the milk matrix prior to somatic cell lysis, indicating that the bacterial cells in naturally contaminated milk are clustered together and may primarily be located within somatic cells. These latter two results lead to the hypothesis that intracellular MAP within the somatic cells may be protected against heat inactivation during pasteurisation, accounting for the presence of low levels of MAP detected in retail milk.


Root bark extracts of Juncus effusus and Paeonia suffruticosa protect salivary gland acinar cells from apoptotic cell death induced by cis-platinum (II) diammine dichloride.
Cis-platinum (II) diammine dichloride (CDDP) is a platinum-based anticancer agent, and is often used for chemotherapy for malignant tumors, albeit CDDP has serious side-effects, including xerostomia (dry mouth). Since patients with xerostomia have reduced quality of life, it is urgent and important to identify nontoxic and natural agents capable of reducing the adverse effect of chemotherapy on salivary gland function. Therefore, we commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only on xerostomia, but also on oral diseases. In the present study, we report on two Chinese medical herbal extracts from the root barks of Juncus effusus and Paeonia suffruticosa. The two extracts showed a protective effect in NS-SV-Ac cells from the cytotoxicity and apoptosis caused by CDDP. The effect was dependent on the p53 pathway, protein kinase B/Akt 1 and mitochondrial apoptosis-related proteins (i.e. Bcl-2 and Bax), but was not dependent on nuclear factor κB. Notably, the apoptosis-protective effect of the extracts was not observed in adenocystic carcinoma cell lines. Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects on xerostomia. Thus, in the present study, we elucidated the potency of these herbal extracts as novel candidates for xerostomia to improve the quality of life of patients undergoing chemotherapy.


Food security for infants and young children: an opportunity for breastfeeding policy?
Increased global demand for imported breast milk substitutes (infant formula, follow-on formula and toddler milks) in Asia, particularly China, and food safety recalls have led to shortages of these products in high income countries. At the same time, commodification and trade of expressed breast milk have fuelled debate about its regulation, cost and distribution. In many economies suboptimal rates of breastfeeding continue to be perpetuated, at least partially, because of a failure to recognise the time, labour and opportunity costs of breast milk production. To date, these issues have not figured prominently in discussions of food security. Policy responses have been piecemeal and reveal conflicts between promotion and protection of breastfeeding and a deregulated trade environment that facilitates the marketing and consumption of breast milk substitutes. The elements of food security are the availability, accessibility, utilization and stability of supply of nutritionally appropriate and acceptable quantities of food. These concepts have been applied to food sources for infants and young children: breastfeeding, shared breast milk and breast milk substitutes, in accordance with World Health Organization (WHO)/United Nations Children's Fund (UNICEF) guidelines on infant feeding. A preliminary analysis indicates that a food security framework may be used to respond appropriately to the human rights, ethical, economic and environmental sustainability issues that affect the supply and affordability of different infant foods. Food security for infants and young children is not possible without high rates of breastfeeding. Existing international and national instruments to protect, promote and support breastfeeding have not been implemented on a wide scale globally. These instruments need review to take into account the emerging trade environment that includes use of the internet, breast milk markets and globalised supply chains for breast milk substitutes. New approaches are required to handle the long-standing policy conflicts that surround infant and young child feeding. Placing breastfeeding in a food security framework may achieve the political attention and policy co-ordination required to accelerate breastfeeding rates in a range of economies.


Assessment of the Therapeutic Potential of Metallothionein-II Application in Focal Cerebral Ischemia In Vitro and In Vivo.
Metallothionein-II (MT-II) is an ubiquitously expressed small-molecular-weight protein and highly induced in various species and tissues upon stress, inflammation, and ischemia. MT-deficiency exacerbates ischemic injury in rodent stroke models in vitro and in vivo. However, there is conflicting data on the potential neuroprotective effect of exogenously applied metallothionein. Thus, we applied MT-II in an in vitro stroke model and intraperitoneally (i.p.) in two in vivo standard models of transient middle cerebral artery occlusion (MCAO) (a 'stringent' one [60 min MCAO/48 h reperfusion] and a 'mild' one [30 min MCAO/72 h reperfusion]), as well as i.v. together with recombinant tissue plasminogen activator (rtPA) to evaluate if exogenous MT-II-application protects against ischemic stroke. Whereas MT-II did not protect against 60 min MCAO, there was a significant reduction of direct and indirect infarct volumes and neurological deficit in the MT-II (i.p.) treated animals in the 'mild' model at 3d after MCAO. Furthermore, MT-II also improved survival of the mice after MCAO, suppressed TNF-α mRNA induction in ischemic brain tissue, and protected primary neuronal cells against oxygen-glucose-deprivation in vitro. Thus, exogenous application of MT-II protects against ischemic injury in vitro and in vivo. However, long-term studies with different species and larger sampling sizes are required before a clinical use can be envisaged.


Clinical characteristics of synthetic cannabinoid-induced psychotic disorders: a single-center analysis of hospitalized patients.
This study was designed to evaluate synthetic cannabinoid (SC)-induced psychotic disorders in terms of their structure and clinical characteristics among hospitalized patients in Russia. It was a longitudinal, observational cohort study which included a total of 46 male patients who underwent the inpatient treatment in the intensive care unit or emergency department due to the SC-induced psychoses. Data on sociodemographic and disease-related characteristics, psychometric assessment scales obtained in face-to-face interviews, were recorded in all patients. The duration of catamnestic follow-up period was 2 years, with the major focus on manifestation of the schizophrenic process. Mean (SD) age of the patients with psychotic disorders induced by the SC use was 23.2 (3.5) years. Among 46 patients, 29 (63%) were SC-dependent and 17 (37%) were diagnosed with SC abuse. Average age at onset was 16.4 for psychoactive substances and 19.7 years for SC use. Marijuana was the most common first used substance. Based on our observations, we identified four clinical variants of the SC-induced psychoses. Our findings revealed that psychotic disorders are typical for the SC intoxication and most commonly influence young adults. Based on our observations, we identified four clinical variants of the SC-induced psychoses and revealed the signs which may indicate them. This study emphasizes the role of appropriate psychiatric management of SC-induced psychoses, since often only catamnestic long-term follow-up enables clinicians to determine the correct diagnosis and reveal the manifestation of the schizophrenic process.


Porphyrins for dye-sensitised solar cells: new insights into efficiency-determining electron transfer steps.
Porphyrin molecules offer immense potential as the light harvesting component of dye-sensitised nanocrystalline TiO(2) solar cells. Synthetic porphyrin dyes were amongst the first dyes trialled for sensitisation of inorganic semiconducting oxides. Today, they exhibit the best performance reported for dye-sensitised solar cells. Accompanying the significant performance improvement over the last two decades is a much improved understanding of efficiency-determining fundamental electron transfer steps, from charge photogeneration to recombination. In this feature article we highlight our recent discoveries of the influence of porphyrin molecule structure on efficiency determining electron transfer kinetics and device performance by systematically changing the molecular structure and observing electron injection and recombination kinetics using time-resolved optical and electrical probes. Despite our observation of ultrafast charge injection for all porphyrin dyes studied by transient absorption spectroscopy, the injection yield estimated using an internal standard remains below 100% and depends strongly on the molecular structure. The observed discrepancy between kinetic competition and the injection yield is attributed to non-injecting dyes, probably arising due to inhomogeneity. A very interesting sub-ns (0.5 ns to 100 ns) charge recombination channel between photo-injected electrons and porphyrin cations is observed, which is found to be more prominent in free-base porphyrin dyes with a conjugated linker. Charge recombination between the acceptor species in the redox containing electrolyte and injected electrons is shown to be an important limitation of most porphyrin-sensitised solar cells, accelerated by the presence of porphyrin molecules at the TiO(2)-electrolyte interface. This recombination reaction is strongly dependent on the porphyrin molecular structure. Bulky substituents, using a porphyrin dimer instead of a porphyrin monomer, a light soaking treatment of freshly prepared films and co-sensitization of TiO(2) with multiple dyes are shown to be successful strategies to improve electron lifetime. Finally, new developments unique to porphyrin dye-sensitised solar cells, including performance enhancements from a light exposure treatment of a zinc porphyrin dye, a significant performance improvement observed after co-sensitisation of TiO(2) with free-base and zinc porphyrin dyes and the use of porphyrin dimers with increased light harvesting in thin-film TiO(2) solar cells are described.


Continuous wave laser absorption techniques for gasdynamic measurements in supersonic flows.
Line-of-sight measurements of velocity, temperature, pressure, density, and mass flux were performed in a transient shock tube flow using three laser absorption schemes. All methods employed an intracavity-doubled ring dye laser tuned to an OH transition in the A(2) summation operator(+) ? X(2)II (0,0) band at 306 nm. In the first scheme, the gas was labeled by 193.3-nm excimer photolysis of H(2)O, and the passage of the generated OH was detected downstream. In the second method, the laser was tuned at a rate of 3 kH(z) over the R(1)(7) and R(1)(11) line pair, and absorption was simultaneously monitored at 90 and 60 degrees with respect to the flow. Velocity was determined from the Doppler shift of the profiles and the temperature from the intensity ratio of the lines. Pressure was determined from both the magnitude of absorption and the collisional broadening. In the third method, the laser wavelength was fixed at a single frequency, and a continuous measurement of velocity and pressure was obtained using the signals from the two beam paths. All methods gave results which compare favorably to calculated values.


Certain beta-blockers can decrease beta-adrenergic receptor number: I. Acute reduction in receptor number by tertatolol and bopindolol.
We have previously reported that a potent new beta-blocker, tertatolol, when given at therapeutic doses to healthy volunteers, rapidly reduced the number of human mononuclear leukocyte beta-receptors. In the present study, the mechanism of receptor regulation by beta-antagonists incubated with target cells in vitro was investigated. Two different cell types (human mononuclear leukocytes and S49 murine lymphoma cells) were used, and beta-adrenergic receptors were measured using either the hydrophilic ligand 3H-CGP 12177 (specific for surface receptors) or lipophilic 125I-pindolol (which measures total receptors). In a comparison between beta-blockers, tertatolol and bopindolol, but not propranolol and pindolol, were found to rapidly (1 hour at 37 degrees C) reduce the number of beta-adrenergic receptors. This was paralleled by a reduction in isoproterenol-stimulated cyclic AMP accumulation. The reduction in receptors was the same whether surface or total receptors were measured; thus, it was not due to receptor sequestration. This effect was not caused by partial agonist activity (bopindolol is a weak partial agonist); in parallel experiments, tertatolol and bopindolol, but not pindolol (potent partial agonist) and isoproterenol (full agonist), reduced beta-adrenergic receptors. Finally, this effect was not due to irreversible binding: the receptor reduction induced by the irreversible blocker bromo-acetyl-alprenolol-methane (BAAM) was stable for several hours, while the effect of tertatolol and bopindolol was slowly reversed over the same time course. We suggest that tertatolol and bopindolol have two effects on beta-adrenergic receptors: they bind competitively, and then they modify the receptors so that they are no longer available for binding by ligands or catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)


Cellular applications of 31P and 13C nuclear magnetic resonance.
High-resolution nuclear magnetic resonance (NMR) studies of cells and purified mitochondria are discussed to show the kind of information that can be obtained in vivo. In suspensions of Escherichia coli both phosphorus-31 and carbon-13 NMR studies of glycolysis and bioenergetics are presented. In rat liver cells the pathways of gluconeogenesis from carbon-13-labeled glycerol are followed by carbon-13 NMR. In the intact liver cells cytosolic and mitochondrial pH's were separately measured by phosphorus-31 NMR. In purified mitochondria the internal and external concentrations of inorganic phosphate, adenosine diphosphate, and adenosine triphosphate were determined by phosphorus-31 NMR while the pH difference across the membrane was measured simultaneously.


Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors.
The Pim family of proto-oncogenes encodes a distinct class of serine/threonine kinases consisting of PIM1, PIM2, and PIM3. Although the Pim genes are evolutionarily highly conserved, the contribution of PIM proteins to mammalian development is unclear. PIM1-deficient mice were previously described but showed only minor phenotypic aberrations. To assess the role of PIM proteins in mammalian physiology, compound Pim knockout mice were generated. Mice lacking expression of Pim1, Pim2, and Pim3 are viable and fertile. However, PIM-deficient mice show a profound reduction in body size at birth and throughout postnatal life. In addition, the in vitro response of distinct hematopoietic cell populations to growth factors is severely impaired. In particular, PIM proteins are required for the efficient proliferation of peripheral T lymphocytes mediated by synergistic T-cell receptor and interleukin-2 signaling. These results indicate that members of the PIM family of proteins are important but dispensable factors for growth factor signaling.


In-house preparation of hydrogels for batch affinity purification of glutathione S-transferase tagged recombinant proteins.
Many branches of biomedical research find use for pure recombinant proteins for direct application or to study other molecules and pathways. Glutathione affinity purification is commonly used to isolate and purify glutathione S-transferase (GST)-tagged fusion proteins from total cellular proteins in lysates. Although GST affinity materials are commercially available as glutathione immobilized on beaded agarose resins, few simple options for in-house production of those systems exist. Herein, we describe a novel method for the purification of GST-tagged recombinant proteins. Glutathione was conjugated to low molecular weight poly(ethylene glycol) diacrylate (PEGDA) via thiol-ene "click" chemistry. With our in-house prepared PEGDA:glutathione (PEGDA:GSH) homogenates, we were able to purify a glutathione S-transferase (GST) green fluorescent protein (GFP) fusion protein (GST-GFP) from the soluble fraction of E. coli lysate. Further, microspheres were formed from the PEGDA:GSH hydrogels and improved protein binding to a level comparable to purchased GSH-agarose beads. GSH containing polymers might find use as in-house methods of protein purification. They exhibited similar ability to purify GST tagged proteins as purchased GSH agarose beads.


Development of a statistical model for discrimination of rupture status in posterior communicating artery aneurysms.
Intracranial aneurysms at the posterior communicating artery (PCOM) are known to have high rupture rates compared to other locations. We developed and internally validated a statistical model discriminating between ruptured and unruptured PCOM aneurysms based on hemodynamic and geometric parameters, angio-architectures, and patient age with the objective of its future use for aneurysm risk assessment. A total of 289 PCOM aneurysms in 272 patients modeled with image-based computational fluid dynamics (CFD) were used to construct statistical models using logistic group lasso regression. These models were evaluated with respect to discrimination power and goodness of fit using tenfold nested cross-validation and a split-sample approach to mimic external validation. The final model retained maximum and minimum wall shear stress (WSS), mean parent artery WSS, maximum and minimum oscillatory shear index, shear concentration index, and aneurysm peak flow velocity, along with aneurysm height and width, bulge location, non-sphericity index, mean Gaussian curvature, angio-architecture type, and patient age. The corresponding area under the curve (AUC) was 0.8359. When omitting data from each of the three largest contributing hospitals in turn, and applying the corresponding model on the left-out data, the AUCs were 0.7507, 0.7081, and 0.5842, respectively. Statistical models based on a combination of patient age, angio-architecture, hemodynamics, and geometric characteristics can discriminate between ruptured and unruptured PCOM aneurysms with an AUC of 84%. It is important to include data from different hospitals to create models of aneurysm rupture that are valid across hospital populations.


Pancreatic secretion by nonparallel exocytosis: potential resolution of a long controversy.
The idea that pancreatic digestive enzyme secretion can occur in a nonparallel manner has been controversial because of its presumed incompatibility with the exocytosis secretory mechanism. Correlation and regression analysis of enzyme output by the rabbit pancreas after it is stimulated with cholecystokinin and chymodenin revealed that digestive enzymes are secreted in a highly linked fashion, compatible with exocytosis and with nonparallel secretion. Thus, exocytosis and nonparallel secretion are not contradictory processes, but rather nonparallel secretion is due to exocytosis from heterogeneous sources within the pancreas.


PsPMEP, a pollen-specific pectin methylesterase of pea (Pisum sativum L.).
Pectin methylesterases (PMEs) are a family of enzymes involved in plant reproductive processes such as pollen development and pollen tube growth. We have isolated and characterized PsPMEP, a pea (Pisum sativum L.) pollen-specific gene that encodes a protein with homology to PMEs. Sequence analysis showed that PsPMEP belongs to group 2 PMEs, which are characterized by the presence of a processable amino-terminal PME inhibitor domain followed by the catalytic PME domain. Moreover, PsPMEP contains several motifs highly conserved among PMEs with the essential amino acid residues involved in enzyme substrate binding and catalysis. Northern blot and in situ hybridization analyses showed that PsPMEP is expressed in pollen grains from 4 days before anthesis till anther dehiscence and in pollinated carpels. In the PsPMEP promoter region, we have identified several conserved cis-regulatory elements that have been associated with gene pollen-specific expression. Expression analysis of PsPMEP promoter fused to the uidA reporter gene in Arabidopsis thaliana plants showed a similar expression pattern when compared with pea, indicating that this promoter is also functional in a non-leguminous plant. GUS expression was detected in mature pollen grains, during pollen germination, during pollen tube elongation along the transmitting tract, and when the pollen tube reaches the embryo sac in the ovule.


The use of pyloric exclusion for treating duodenal trauma: case series.
Significant controversy exists regarding the best surgical treatment for complex duodenal injuries. The aims of this study were to report on a series of eight cases of duodenal repairs using pyloric exclusion and to describe reported complications or improvements in clinical outcomes among patients with complex duodenal trauma. Cross-sectional study followed by a case series in a university hospital. Data on eight patients with duodenal trauma who underwent pyloric exclusion over a 17.5 year period were collected and analyzed. The causes of the injuries included penetrating gunshot wounds (GSW) in five patients and motor vehicle accidents (blunt trauma) in three patients. The time elapsed until surgery was longer in the blunt trauma group, while in one patient, the gunshot injury was initially missed and thus the procedure was carried out 36 hours after the original injury. The injuries were grade III (50%) or IV (50%) and the morbidity rate was 87.5%. Four patients (50%) died during the postoperative period from complications, including hypovolemic shock (one patient), sepsis (peritonitis following the missed injury) and pancreatitis with an anastomotic fistula (two patients). Pyloric exclusion was associated with multiple complications and a high mortality rate. This surgical technique is indicated for rare cases of complex injury to the duodenum and the surgeon should be aware that treatment with a minimalistic approach, with only primary repair, may be ideal.


National Influenza Surveillance in the Philippines from 2006 to 2012: seasonality and circulating strains.
The results of routine influenza surveillance in 13 regions in the Philippines from 2006 to 2012 are presented, describing the annual seasonal epidemics of confirmed influenza virus infection, seasonal and alert thresholds, epidemic curve, and circulating influenza strains. Retrospective analysis of Philippine influenza surveillance data from 2006 to 2012 was conducted to determine seasonality with the use of weekly influenza positivity rates and calculating epidemic curves and seasonal and alert thresholds using the World Health Organization (WHO) global epidemiological surveillance standards for influenza. Increased weekly influenza positive rates were observed from June to November, coinciding with the rainy season and school opening. Two or more peaks of influenza activity were observed with different dominant influenza types associated with each peak. A-H1N1, A-H3N2, and two types of B viruses circulated during the influenza season in varying proportions every year. Increased influenza activity for 2012 occurred 8 weeks late in week 29, rather than the expected week of rise of cases in week 21 as depicted in the established average epidemic curve and seasonal threshold. The intensity was severe going above the alert threshold but of short duration. Southern Hemisphere vaccine strains matched circulating influenza virus for more surveillance years than Northern Hemisphere vaccine strains. Influenza seasonality in the Philippines is from June to November. The ideal time to administer Southern Hemisphere influenza vaccine should be from April to May. With two lineages of influenza B circulating annually, quadrivalent vaccine might have more impact on influenza control than trivalent vaccine. Establishment of thresholds and average epidemic curve provide a tool for policy-makers to assess the intensity or severity of the current influenza epidemic even early in its course, to help plan more precisely resources necessary to control the outbreak. Influenza surveillance activities should be continued in the Philippines and funding for such activities should already be incorporated into the Philippine health budget.


Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content.
Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determineD the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.


Improving the efficacy of Chloroquine and Hydroxychloroquine against SARS-CoV-2 may require Zinc additives - A better synergy for future COVID-19 clinical trials.
The recent outbreak of coronavirus disease 2019 (COVID-19), is now officially declared as a pandemic by the World Health Organization. As of now, there is no known effective pharmaceutical agent against the SARS-CoV-2 virus. However, several precautionary measures have been prescribed to prevent further spread of the virus, which include avoidance of social gatherings, proper handwashing, frequently disinfecting of used items and surfaces and so on. More recent studies have highlighted the possibility of treating patients infected with the novel SARS-CoV-2 virus with chloroquine and hydroxychloroquine, of which mechanism of action is not completely understood. We seek to draw the attention of the scientific community to the possibility of drastically reducing the effects of the virus on the affected patients and improving clinical trials outcome through the synergistic action of zinc and chloroquine in patients suffering from the coronavirus disease.


Leptin gene (TTTC)(n) microsatellite polymorphism in pre-eclampsia and HELLP syndrome.
Leptin plays an important role in energy homeostasis. There is polymorphism on the leptin (LEP) gene. Our aim was to compare the tetranucleotide repeat (TTTC)(n) polymorphism in the 3'-flanking region in the LEP gene on DNA samples from patients with pre-eclampsia (PE), hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome and healthy pregnant controls. Blood samples were collected from healthy pregnant women (n=88), patients with PE (n=79) and HELLP (n=77) syndrome. Fluorescent PCR and DNA fragment analysis was performed from the isolated DNA for the detection of (TTTC) repeats. The electrophoretograms were evaluated and patients were assigned to two groups; class I low (<190 bp) or class II high (> or =190 bp) PCR fragments. We observed similar distributions of the class I and class II (TTTC) alleles in the groups studied (class I allele: healthy pregnant 58.5%; severe pre-eclamptic 58.3%; HELLP syndrome 52.6%). We detected a higher frequency of the II/II genotype in HELLP syndrome patients (32.4%) compared to healthy controls (22.7%). However, the difference was not statistically significant. In an ethnically homogenous population, the LEP gene (TTTC) microsatellite polymorphism in the 3'-flanking region does not show a significant difference in the allele and genotype distribution in healthy pregnant, pre-eclamptic and HELLP syndrome patients. Furthermore, we recommend a new classification of the class I and class II alleles based on the distribution of the (TTTC) microsatellites.


The transition from differentiation to growth during dermomyotome-derived myogenesis depends on temporally restricted hedgehog signaling.
The development of a functional tissue requires coordination of the amplification of progenitors and their differentiation into specific cell types. The molecular basis for this coordination during myotome ontogeny is not well understood. Dermomytome progenitors that colonize the myotome first acquire myocyte identity and subsequently proliferate as Pax7-expressing progenitors before undergoing terminal differentiation. We show that the dynamics of sonic hedgehog (Shh) signaling is crucial for this transition in both avian and mouse embryos. Initially, Shh ligand emanating from notochord/floor plate reaches the dermomyotome, where it both maintains the proliferation of dermomyotome cells and promotes myogenic differentiation of progenitors that colonized the myotome. Interfering with Shh signaling at this stage produces small myotomes and accumulation of Pax7-expressing progenitors. An in vivo reporter of Shh activity combined with mouse genetics revealed the existence of both activator and repressor Shh activities operating on distinct subsets of cells during the epaxial myotomal maturation. In contrast to observations in mice, in avians Shh promotes the differentiation of both epaxial and hypaxial myotome domains. Subsequently, myogenic progenitors become refractory to Shh; this is likely to occur at the level of, or upstream of, smoothened signaling. The end of responsiveness to Shh coincides with, and is thus likely to enable, the transition into the growth phase of the myotome.


Exploring MEDLINE abstracts with XplorMed.
XplorMed is a publicly available web tool conceived to make life easier for MEDLINE(c) users looking for scientific information. Searching scientific literature is an information retrieval problem. Abstracts that are of possible interest to the user are usually selected by a keyword search followed by manual screening, which often results in the retrieval of a large number of abstracts. Interesting references can be buried among irrelevant ones because of nonspecific queries. XplorMed is intended to extract dependency relations between the words of the abstracts. These relations can be filtered and arranged to deduce different subjects in the query and offer a condensed view of the abstract, allowing users to select texts of interest without having to read them all. XplorMed is available http://www.bork. embl-heidelberg.de/xplormed.


Image-guided tumor surgery: The emerging role of nanotechnology.
Surgical resection is a mainstay treatment for solid tumors. Yet, methods to distinguish malignant from healthy tissue are primarily limited to tactile and visual cues as well as the surgeon's experience. As a result, there is a possibility that a positive surgical margin (PSM) or the presence of residual tumor left behind after resection may occur. It is well-documented that PSMs can negatively impact treatment outcomes and survival, as well as pose an economic burden. Therefore, surgical tumor imaging techniques have emerged as a promising method to decrease PSM rates. Nanoparticles (NPs) have unique characteristics to serve as optical contrast agents during image-guided surgery (IGS). Recently, there has been tremendous growth in the volume and types of NPs used for IGS, including clinical trials. Herein, we describe the most recent contributions of nanotechnology for surgical tumor identification. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery Diagnostic Tools > in vivo Nanodiagnostics and Imaging.


Comparison of 0.625-mm source computed tomographic images versus 5-mm thick reconstructed images in the evaluation for renal calculi in at-risk patients.
CT has become a well-established modality in the evaluation of urinary calculi. The advent of multidetector CT (MDCT) scanners and submillimeter thick slice acquisitions has yielded CT images with even greater resolution. MDCT scanners allow for source data slice acquisition with submillimeter slice thickness. These source images can then be reconstructed to thicker slices for more convenient interpretation of the CT scan. Previous authors have looked at the effect of slice thickness on detection of urinary calculi. We investigated whether the thin slice source images yielded detection of additional stones and the potential significance of detecting these additional stones. Ninety-five consecutive patients who were referred to our outpatient imaging center for CT, with a clinical history placing them at risk for urinary calculi, were included in the study. In 49 (52%) of the 95 patients, more calculi were visualized using the 0.625-mm thick images than with the 5-mm thick images. In 34 (69%) of these 49 patients, the additional findings were thought to be "clinically significant," while in the remaining 15 (31%) patients, the additional findings were not thought to be clinically significant. In 46 (48%) of the 95 patients, there were no additional urinary calculi identified on the 0.625-mm thick images compared with that observed on 5-mm thick images. The results from this study encourage reviewing the thin slice source images of MDCTs in patients at risk for urinary calculi, because important clinical decisions may hinge on the additional findings made on these images.


A computer assisted follow up system for spinal cord injury patients.
The comprehensive care of patients with traumatic spinal cord injuries (SCI) necessitates, among other things, a structured, life-long follow up. The high consumption of medical care in chronic SCI patients, often a result of diseases affecting many different organ systems, soon causes the cumulated medical documentation to be extensive and therefore hard to survey. The possibilities for rational patient management, adequate quality assurance, and clinical research may improve considerably by computerisation of medical records. A computerised medical records system for SCI has recently been developed, using a semistructured medical record format for data input and a medical entity dictionary for facilitated data storage and retrieval. The principles for developing this computer-assisted follow up system are described.


Exercise-induced subendocardial dysfunction in dogs with left ventricular hypertrophy.
The effects of treadmill exercise on regional myocardial blood flow and function were examined in 10 adult, conscious dogs with left ventricular hypertrophy (LVH) induced by aortic banding in puppies, which resulted in a left ventricular (LV) weight/body weight ratio of 8.5 +/- 0.3. Data were compared with results from eight control dogs with an LV weight/body weight ratio of 4.9 +/- 0.2. At rest, LV systolic and end-diastolic pressures were significantly greater (p less than 0.01), and mean arterial pressure was significantly less (p less than 0.05) in LVH dogs. Mean myocardial blood flow (control dogs, 0.98 +/- 0.11 ml/min/g; LVH dogs, 1.16 +/- 0.06 ml/min/g) and the transmural blood flow distribution at baseline, as assessed by endocardial/epicardial blood flow ratio (control, 1.35 +/- 0.12; LVH, 1.21 +/- 0.09), were similar in the two groups. During exercise to a target heart rate (240 beats/min), LVH dogs demonstrated greater (p less than 0.01) increases in LV systolic and end-diastolic pressures. In control dogs, as expected, exercise augmented velocity of circumferential fiber shortening (16 +/- 9%) and shortening fraction (15 +/- 5%), but in LVH dogs, exercise reduced the velocity of circumferential fiber shortening (-14 +/- 6%) and shortening fraction (-17 +/- 5%). Exercise also increased full wall thickening (35 +/- 5%), subendocardial wall thickening (66 +/- 10%), and subepicardial wall thickening (44 +/- 9%) in control dogs. In LVH dogs, exercise increased subepicardial wall thickening (31 +/- 9%) and reduced subendocardial wall thickening (-40 +/- 7%); full wall thickening did not change (-11 +/- 9%). This was associated with a fall in endocardial/epicardial flow ratio to 0.72 +/- 0.05 (p less than 0.01) in LVH dogs. The subendocardial dysfunction persisted late into recovery, at a time when the transmural blood flow distribution had returned to baseline; this occurrence suggested myocardial stunning. Thus, in dogs with LVH, selective subendocardial hypoperfusion and profound selective depression in subendocardial wall thickening are observed during exercise. The subendocardial dysfunction persisted into recovery despite resolution of the perfusion abnormality.


Role of tongue pressure production in oropharyngeal swallow biomechanics.
The tongue is important for orofacial movements, including swallowing. Although numerous studies have focused on tongue pressure against the palate, its physiological role has not been fully evaluated. The tongue pressure generation may have the temporal coordination with the swallowing relational organs. The aim of this study was to clarify the physiological mechanisms of tongue pressure and to investigate the temporal relationship among tongue pressure, supra-hyoid muscle activity, and videofluorographic (VF) images during swallowing. Fifteen healthy young subjects participated. Tongue pressure measured using a sensor sheet with five channels, electromyographic EMG, and VF was recorded synchronously during 4-ml barium swallowing. Swallowing behavior in VF images with and without the sensor sheet was compared. Furthermore, the temporal relationship between events measured from tongue pressure, EMG, and VF was evaluated. Swallowing behavior on VF images was not affected by placement of the sensor sheet. Tongue pressure at the posterio-lateral point of the hard palate tended to have biphasic peaks. Tongue pressure production with a monophasic pattern appeared during the same period as the second peak in the biphasic pattern. The onset of tongue pressure was later than the start of hyoid movement and onset of EMG, and offset was observed between the hyoid at the up-forward position and reposition. Onset of tongue pressure at the anterior area was correlated with the start of slight hyoid elevation. Offset of tongue pressure at the posterio-lateral points was strongly time locked with the hyoid at the up-forward position. The present results suggested the temporal coordination of tongue pressure generation with the swallowing-related organs. That is, the tongue pressure was produced for bolus propulsion, and was closely related to hyoid movement temporally during swallowing. These results may contribute to clarify the clinical state with the disorder of tongue kinetics.


The mechanism of corticosteroids in treating asthma.
It would be difficult for physicians or allergists to imagine doing without corticosteroids in managing difficult cases of bronchial asthma. It is beyond any doubt that CS act on many sites to help reverse the pathologic process of bronchial asthma. Corticosteroids enhance the beta-adrenergic response to relieve the muscle spasm. They also act by reversing the mucosal edema, decreasing vascular permeability by vasoconstriction, and inhibiting the release of LTC4 and LTD4. Corticosteroids reduce the mucus secretion by inhibiting the release of secretagogue from macrophages. Corticosteroids inhibit the late phase reaction by inhibiting the inflammatory response and interfering with chemotaxis. This action may be due to the inhibition of LTB4 release. The eosinopenic effect of corticosteroids may help to prevent the cytotoxic effect of the major basic protein and other inflammatory mediators released from eosinophils. Corticosteroids have no effect on the immediate hypersensitivity reaction and have no direct role in bronchial reactivity. By blocking the late reaction, they prevent the increased airway reactivity observed with late bronchial reactions. The limitation of using corticosteroids are their side effects. They vary from tolerable to life threatening side effects. Each tissue in the body is a target for corticosteroids. The mechanism of adverse effects have been studied in extensive detail but many questions are yet to be answered. Alternate-day therapy and inhalation therapy are meant to minimize these side effects. The expansion of using inhaled steroid therapy and finding some inhaled preparations that have even less systemic side effects seems a reasonable approach to deal with severe asthma.


Risk of early surgery for Crohn's disease: implications for early treatment strategies.
In this study we aimed to define the rate of early surgery for Crohn's disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohn's disease. We assembled a retrospective cohort of patients with Crohn's disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohn's disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors. Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery. The rate of surgery is high in the first 3 yr after diagnosis of Crohn's disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohn's disease.