An immersive environment for the direct visualization and segmentation of volumetric data sets.
This paper describes a software environment for visualizing and segmenting volumetric data sets such as CT, MRI and the Visible Human data set. The goal is to produce an intuitive environment where the expert knowledge of the end user can be employed to directly guide visualization and segmentation of the data. The environment is built around the Fakespace Immersive Workbench (TM), which provides the user with the illusion that the data set volume resides in the space directly above the workbench surface. Using a position/orientation-tracked probe the user is able to interact with the visualization algorithm and segment the data set to expose features of interest. Segmentation can be performed in either the ray space of the volume rendering algorithm or the coordinate space of the data volume itself. The segmentation results can be saved and used for other purposes including the construction of polygonal models.


Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: a 24-month study.
The aim was to assess the long-term effect of trimetazidine on myocardial perfusion, using gated single photon emission computerized tomography (SPECT). 200 patients (aged 54.7 +/- 12 years) with ischemic left ventricular dysfunction (LVD) and multivessel coronary artery disease were randomized to receive trimetazidine 20mg three times daily or a placebo for 24 months. At baseline and after 24 months of treatment, all patients underwent a symptom-limited cardiopulmonary exercise test concluded by the injection of (99m)Tc-MIBI (technetium-99m methoxy-isobutyl-isonitrile). Imaging of post-stress gated SPECT and resting gated SPECT were performed. Standard antianginal therapy was interrupted for 48 hours (nitrates for 6 hours) before the exercise tests and resumed immediately after testing. On initial evaluation, summed stress and rest scores (SSS and SRS, respectively), systolic wall thickness (SWT), and wall motion score index (WMI), heart rate, SBP, and rate pressure product were similar at rest and peak exercise in both groups. After 24 months, 91% of patients in the trimetazidine group versus 22% in the placebo group showed a significant decrease of the frequency of anginal episodes per week (3.9 vs 5.7, p < 0.01). Weekly nitroglycerin (glyceryl trinitrate) tablet consumption was significantly lower with trimetazidine than with placebo at endpoint (2.3 +/- 0.8 vs 6.1 +/- 1.6, p < 0.01). This was supported by perfusion SPECT data. Compared with baseline values, SSS and SRS were significantly reduced with trimetazidine (from 19.8 +/- 7.7 to 11.2 +/- 6.1, p < 0.00001 and from 12.4 +/- 8.7 to 5.8 +/- 3.3, p < 0.00001, respectively). There was a nonsignificant decrease from baseline values in both SRS and SSS with placebo group (from 11.9 +/- 8.3 to 11.2 +/- 7.4 and 18.1 +/- 6.3 to 17.9 +/- 9.2, respectively). Duration of peak exercise increased significantly from baseline values with trimetazidine (from 4.6 to 5.8 minutes, p < 0.01) but not with placebo (from 5.4 to 5.8 minutes). Accordingly, mean maximum work at peak exercise improved by 1.2 metabolic equivalents with trimetazidine. This was proved by gated SPECT with an increase in SWT score of 89.5% (p < 0.00001) and in ejection fraction of 23% with trimetazidine (p < 0.001) without significant changes in hemodynamic parameters. Trimetazidine improves ischemic attacks in patients with ischemic cardiomyopathy, clinically and objectively as seen in gated SPECT myocardial perfusion. The improvement in myocardial function with trimetazidine was not accompanied by hemodynamic changes.


"While you're up, get me a grant": a guide to grant writing.
Over the past few years, the number of well-trained researchers has increased, but the amount of money available for research has remained the same or even decreased. Consequently, competition for support is keener than it ever was. How a grant is written may tip the balance between getting funded or not. This article provides some guidelines for writing better proposals, touching on the various parts of the protocol and how it should be packaged. It addresses both the overt purpose of the proposal, which is telling the reviewers what you want to do, why, and how; and the covert message, which is convincing them that you have the ability to do what you propose. The article also discusses the review mechanism, who it is who reads the grant, and why this matters.


Variation in absorption of NPH insulin due to intramuscular injection.
To evaluate the importance of accidental intramuscular injection of NPH insulin, we measured disappearance rates of 125I-labeled NPH insulin (Protaphane) from subcutaneous and intramuscular injection sites in the thighs of 11 insulin-dependent diabetes mellitus patients. Both subcutaneous and intramuscular absorption rates were measured four times in each patient. NPH insulin was absorbed much faster when given intramuscularly than when given subcutaneously (T50% = 5.3 vs. 10.3 h, P less than 0.0001). The intrapatient (day-to-day) coefficient of variation (C.V.) of T50% values (C.V. T50%) for subcutaneously injected NPH insulin in this study, where all injections were guided by ultrasound determination of the subcutaneous fat layer, was 18.4%. Intrapatient variation of absorption was significantly lower for subcutaneously than intramuscularly injected NPH insulin (C.V. T50% = 18.4 vs. 29.8%, P less than 0.01) and was also lower than interpatient variation for subcutaneously injected insulin (C.V. T50% = 18.4 vs. 50%, P less than 0.0001). The faster absorption rate and shorter duration of action, together with the higher day-to-day variation in absorption, led us to conclude that intramuscular injection of NPH insulin should be avoided.


Erinaceolactones A to C, from the culture broth of Hericium erinaceus.
Three novel compounds, erinaceolactones A to C (1-3), and a known compound (4) were isolated from the culture broth of Hericium erinaceus. The planar structures of 1-3 were determined by the interpretation of spectroscopic data. The absolute configuration of 3 was determined by X-ray crystallography. Although compound 4 had been synthesized, it was isolated from a natural source for the first time. In the bioassay examining plant-growth regulatory activity of these compounds (1-4) and other components of the fungus (5-8), compounds 1, 2, and 4-8 suppressed the growth of lettuce.


Neuromuscular and metabolic responses to high-intensity intermittent cycling protocols with different work-to-rest ratios.
To investigate the effects of work-to-rest-ratio manipulation on neuromuscular and metabolic responses during 2 high-intensity intermittent training (HIT) protocols to exhaustion. Since different exercise durations were expected, the authors hypothesized that the protocol registering a longer duration would have a more pronounced effect on neuromuscular responses, while the other would challenge the cardiopulmonary system more. Thirteen competitive cyclists (age 19 ± 2 y) performed a preliminary incremental test to identify their maximal power output and 2 intermittent protocols to exhaustion (40:20s and 30:30s) at a fixed work rate of 135%Pmax interspersed by passive recovery. Surface electromyographic (sEMG) parameters (including muscle-fiber conduction velocity), cardiopulmonary parameters, and blood lactate concentration [La-] were recorded. Time to exhaustion and total work were significantly higher for the 30:30s (38 ± 13 min, 495 ± 161 kJ) than for the 40:20s (10 ± 3 min, 180 ± 51 kJ). No differences were found in sEMG parameters for the 2 protocols. Mean and peak values of VO2, heart rate, ventilatory parameters (except for the peak value of respiratory frequency), and [La-] were significantly higher in the 40:20s than in the 30:30s. These results do not support the hypothesis that a longer time spent at high intensity has a more pronounced effect on neuromuscular responses, as no differences in EMG parameters were found in the 2 HIT protocols. Regarding metabolic responses, while the 40:20s led to maximal values of VO2, [La-], and ventilatory parameters within a few minutes, the 30:30s allowed maintenance of moderately high values for a considerably longer period, especially for [La-] and ventilatory parameters.


Strengthening midwifery in the South-East Asian region: A scoping review of midwifery-related research.
Improving sexual, reproductive, maternal, newborn, and adolescent health outcomes necessitates greater commitment to, and investments in, midwifery. To identify future research priorities to advance and strengthen midwifery, we conducted a scoping review to synthesise and report areas of midwifery that have been explored in the previous 10 years in the 11 countries of the World Health Organization's South-East Asia region. Electronic peer-reviewed databases were searched for primary peer-reviewed research published in any language, published between January 2012 and December 2022 inclusive. A total of 7086 citations were screened against the review inclusion criteria. After screening and full text review, 195 sources were included. There were 94 quantitative (48.2%), 67 qualitative (34.4%) and 31 mixed methods (15.9%) studies. The majority were from Indonesia (n = 93, 47.7%), India (n = 41, 21.0%) and Bangladesh (n = 26, 13.3%). There were no sources identified from the Democratic People's Republic of Korea or the Maldives. We mapped the findings against six priority areas adapted from the 2021 State of the World's Midwifery Report and Regional Strategic Directions for Strengthening Midwifery in the South-East Asia region (2020-2024): practice or service delivery (n = 73, 37.4%), pre-service education (n = 60, 30.8%), in-service education or continuing professional development (n = 51, 26.2%), workforce management (n = 46, 23.6%), governance and regulation (n = 21, 10.8%) and leadership (n = 12, 6.2%). Most were published by authors with affiliations from the country where the research was conducted. The volume of published midwifery research reflects country-specific investment in developing a midwifery workforce, and the transition to midwifery-led care. There was variation between countries in how midwife was defined, education pathways, professional regulation, education accreditation, governance models and scope of practice. Further evaluation of the return on investment in midwifery education, regulation, deployment and retention to support strategic decision-making is recommended. Key elements of leadership requiring further exploration included career pathways, education and development needs and regulatory frameworks to support and embed effective midwifery leadership at all levels of health service governance.


[Trial of the culture media Microcult GC for detection of gonococci].
A trial of the culture medium 'Microcult GC' for the detection of gonorrhea in 246 patients confirms its utility. The direct smear of the exudate is still indispensable. The best culture medium is the Thayer-Martin plate. The main advantage of the new medium tested is its simple utilization technique which makes it suitable for the practitioner.


Axial Chlorine Induced Electron Delocalization in Atomically Dispersed FeN4 Electrocatalyst for Oxygen Reduction Reaction with Improved Hydrogen Peroxide Tolerance.
Atomically dispersed iron sites on nitrogen-doped carbon (Fe-NC) are the most active Pt-group-metal-free catalysts for oxygen reduction reaction (ORR). However, due to oxidative corrosion and the Fenton reaction, Fe-NC catalysts are insufficiently active and stable. Herein, w e demonstrated that the axial Cl-modified Fe-NC (Cl-Fe-NC) electrocatalyst is active and stable for the ORR in acidic conditions with high H2 O2 tolerance. The Cl-Fe-NC exhibits excellent ORR activity, with a high half-wave potential (E1/2 ) of 0.82 V versus a reversible hydrogen electrode (RHE), comparable to Pt/C (E1/2 = 0.85 V versus RHE) and better than Fe-NC (E1/2 = 0.79 V versus RHE). X-ray absorption spectroscopy analysis confirms that chlorine is axially integrated into the FeN4. More interestingly, compared to Fe-NC, the Fenton reaction is markedly suppressed in Cl-Fe-NC. In situ electrochemical impedance spectroscopy reveals that Cl-Fe-NC provides efficient electron transfer and faster reaction kinetics than Fe-NC. Density functional theory calculations reveal that incorporating Cl into FeN4 can drive the electron density delocalization of the FeN4 site, leading to a moderate adsorption free energy of OH* (∆GOH* ), d-band center, and a high onset potential, and promotes the direct four-electron-transfer ORR with weak H2 O2 binding ability compared to Cl-free FeN4, indicating superior intrinsic ORR activity.


Intestinal epithelial CD23 mediates enhanced antigen transport in allergy: evidence for novel splice forms.
We previously demonstrated enhanced transepithelial antigen transport in the intestine of allergic rodents associated with elevated expression of the low-affinity IgE receptor CD23 on enterocytes. Here, we examined the role of CD23 in the transport phenomenon using CD23-/- mice and characterized the isoform of intestinal epithelial CD23. Jejunal segments of sensitized mice were challenged with antigen. Enhanced transepithelial antigen transport and transmucosal antigen flux were found in the intestine of sensitized CD23+/+ but not CD23-/- mice. RT-PCR showed that enterocytes expressed only the isoform b of CD23. Sequencing revealed classic and alternative CD23b transcripts lacking exon 5 (bDelta5) or 6, all of which were translated into functional IgE receptors. The protein encoded by bDelta5 but not the classic b transcript was able to mediate the uptake of anti-CD23 or IgE, whereas both CD23 proteins were internalized after binding to IgE/antigen complexes. Our results suggest that the classic and alternative forms of CD23b display distinct endocytic properties, suggesting that they are likely to play different roles in transepithelial transport of IgE and allergens.


Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, barcelona, Spain, from 2002 to 2003.
We conducted population-based surveillance for Candida bloodstream infections in Spain to determine its incidence, the extent of antifungal resistance, and risk factors for mortality. A case was defined as the first positive blood culture for any Candida spp. in a resident of Barcelona, from 1 January 2002 to 31 December 2003. We defined early mortality as occurring between days 3 to 7 after candidemia and late mortality as occurring between days 8 to 30. We detected 345 cases of candidemia, for an average annual incidence of 4.3 cases/100,000 population, 0.53 cases/1,000 hospital discharges, and 0.73 cases/10,000 patient-days. Outpatients comprised 11% of the cases, and 89% had a central venous catheter (CVC) at diagnosis. Overall mortality was 44%. Candida albicans was the most frequent species (51% of cases), followed by Candida parapsilosis (23%), Candida tropicalis (10%), Candida glabrata (8%), Candida krusei (4%), and other species (3%). Twenty-four isolates (7%) had decreased susceptibility to fluconazole (MIC > or = 16 microg/ml). On multivariable analysis, early death was independently associated with hematological malignancy (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.1 to 10.4). Treatment with antifungals (OR, 0.05; 95% CI, 0.01 to 0.2) and removal of CVCs (OR, 0.3; 95% CI, 0.1 to 0.9) were protective factors for early death. Receiving adequate treatment, defined as having CVCs removed and administration of an antifungal medication (OR, 0.2; 95% CI, 0.08 to 0.8), was associated with lower odds of late mortality; intubation (OR, 7.5; 95% CI, 2.6 to 21.1) was associated with higher odds. The incidence of candidemia and prevalence of fluconazole resistance are similar to other European countries, indicating that routine antifungal susceptibility testing is not warranted. Antifungal medication and catheter removal are critical in preventing mortality.


Desipramine and 2-hydroxydesipramine in human breast milk and the nursing infant's serum.
Desipramine and its metabolite 2-hydroxydesipramine were measured in the milk of a nursing mother and in the plasma of the mother and infant during administration of 300 mg/day of desipramine to the mother. Similar concentrations of both compounds were found in maternal plasma and milk. A pharmacokinetic plot of the milk over 24 hours showed the expected rise and fall of the substances following a single nighttime dose. Neither parent compound nor metabolite could be detected in the infant's serum even though the measurements were made shortly after peak ingestion by the infant. Furthermore, no clinical signs of toxicity were observed in the infant after 3 weeks of treating the mother with desipramine.


The barley lectin carboxyl-terminal propeptide is a vacuolar protein sorting determinant in plants.
We have previously shown that the 15-amino acid carboxyl-terminal propeptide of probarley lectin is necessary for the proper sorting of this protein to the plant vacuole. A mutant form of the protein lacking the carboxyl-terminal propeptide is secreted. To test whether the carboxyl-terminal propeptide is the vacuole sorting determinant of probarley lectin, we examined in transgenic tobacco the processing and sorting of a series of fusion proteins containing the secreted protein, cucumber chitinase, and regions of probarley lectin. Pulse-labeling experiments demonstrated that the fusion proteins were properly translocated through the tobacco secretory system and that cucumber chitinase and cucumber chitinase fusion proteins lacking the carboxyl-terminal propeptide were secreted. The cucumber chitinase fusion protein containing the carboxyl-terminal propeptide was properly processed and sorted to the vacuole in transgenic tobacco as confirmed by organelle fractionation and electron microscopy immunocytochemistry. Therefore, the barley lectin carboxyl-terminal propeptide is both necessary and sufficient for protein sorting to the plant vacuole.


The tumoricidal properties of inflammatory tissue macrophages and multinucleate giant cells.
Peritoneal exudate cells from C3H/HeN mice infected with bacille Calmette Guérin (BCG) and subcutaneous inflammatory macrophages from uninfected mice exhibit spontaneous cytotoxicity for tumor cells in vitro, but their tumoricidal activity can be increased by incubation in vitro with lymphokines released by mitogen- or antigen-stimulated lymphocytes. Inflammatory macrophages from these sites are only susceptible to activation in vitro by lymphokines for a short period (less than 4 days) following their initial emigration from the circulation to the site of inflammation. The expression of tumoricidal activity by activated macrophages is similarly short-lived (less than 4 days). Once the tumoricidal state is lost it cannot be restored by further incubation with lymphokines in vitro. Fusion of macrophages to form multinucleate giant cells (MGCs) accompanies the loss of tumoricidal activity and the onset of resistance to activation by lymphokines, but the fusion process is not responsible for these changes, since unfused macrophages are similarly affected. Activation and acquisition of tumoricidal properties is confined to young macrophages recruited from the circulation during acute inflammation. Older macrophages and MGCs in chronic inflammatory lesions in which recruitment of new macrophages has ceased are nontumoricidal and are refractory to activation by lymphokines in vitro. These findings are discussed in relation to the efficiency of macrophage-mediated destruction of tumors in vivo and the amplification of macrophage antitumor activity by immunotherapeutic agents.


Non-traumatic Tension Gastrothorax: A Potential Mimicker of Tension Pneumothorax.
Tension gastrothorax is a rare, life-threatening clinical condition caused by intrathoracic herniation of the stomach through a diaphragmatic defect which becomes increasingly distended over time. If not recognized promptly, this can rapidly progress to respiratory distress, mediastinal shift, and hemodynamic compromise. Initial clinical presentation and imaging findings closely mirror those of tension pneumothorax, confounding diagnosis and potentially leading to unnecessary interventions with increased risk of morbidity and mortality. Here, we present a case of an elderly female who presented with a non-traumatic tension gastrothorax and a review of key imaging features and strategies to aid in recognition and accurate diagnosis of this emergent clinical entity.


Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement.
To determine whether there are factors, such as the diffusing capacity for carbon monoxide (DLCO) or pulmonary artery pressure (PAP) on echocardiogram, that can predict the development of pulmonary hypertension (PHT) in patients with limited scleroderma. Using the large Pittsburgh Scleroderma Databank, 106 patients who had the diagnosis of PHT after January 1, 1982, were matched with 106 controls by scleroderma subtype, age, sex, race, disease duration, and the mean time to the diagnosis of PHT after the initial Pittsburgh visit. Autoantibodies, vascular features, use of calcium channel blockers, extent of pulmonary function, and echocardiogram findings were determined at any time prior to the diagnosis of PHT (or prior to the matched time in controls). Patients with PHT had a mean DLCO of 52% of predicted at an average of 4.5 years prior to the diagnosis of PHT. This was markedly decreased compared with the values in controls, whose mean DLCO was 81% of predicted (P < 0.0001). The estimated mean PAP on echocardiogram was only slightly higher in the PHT patients compared with controls (34 mm Hg versus 29 mm Hg; P not significant). Nineteen PHT patients had 4 serial measurements of the DLCO during the 15 years prior to the diagnosis of PHT. The initial mean DLCO was 80% of predicted, which decreased in a linear manner to a mean of 35% of predicted at the time of diagnosis of PHT, whereas the value in controls remained at approximately 80% of predicted (P < 0.0001). PHT patients had more severe Raynaud's phenomenon and more severe digital tip ulcers, but they used calcium channel blockers significantly less frequently (37% versus 61% of controls; P < 0.01). The predominance of nucleolar autoantibodies and the absence of anti-Scl 70 antibody were associated with PHT. A decreasing DLCO is an excellent predictor of the subsequent development of isolated PHT in limited scleroderma. The DLCO may be significantly decreased for many years prior to the diagnosis of PHT. The presence of autoantibodies and the PAP may also be helpful predictors. The long-term use of calcium channel blockers may be protective, but newer agents that are more effective in treating PHT may also be helpful in altering the natural history of this serious complication in limited scleroderma.


Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates.
Paraoxonase (PON1) is an HDL-associated enzyme capable of hydrolyzing multiple substrates, including several organophosphorous insecticides and nerve agents, oxidized lipids, and a number of drugs or pro-drugs. Several polymorphisms in the paraoxonase (PON1) gene have been described, which have been shown to affect either the catalytic efficiency of hydrolysis or the expression level of PON1. This review discusses the relevance of these polymorphisms for modulating sensitivity to organophosphorous compounds. Animal studies characterizing the PON1 polymorphisms have demonstrated the relevance of PON1 in modulating OP toxicity and have indicated the importance of an individual's PON1 status (i.e., genotype and phenotype taken together) rather than genotyping alone. Nevertheless, direct confirmation in humans of the relevance of PON1 status in conferring susceptibility to OP toxicity is still elusive. Recent studies examining the involvement of PON1 status in determining OP susceptibility of Gulf War veterans, sheep dippers, and individuals poisoned with chemical warfare agents represent a step in the right direction, but more studies are needed, with better documentation of both the level of exposure and the consequences of exposure.


Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer.
To evaluate the effect of discontinuation of the antiandrogen, flutamide, in patients with metastatic prostate cancer who are progressing on hormonal therapy. Thirty-six patients with progressive disease on hormonal treatment that included flutamide had discontinuation of the antiandrogen. Thirty-five (95%) had progressive increases in prostate-specific antigen (PSA) levels, despite castrate levels of testosterone. Twenty-five patients (69%) were treated with combined androgen blockade (orchiectomy or gonadotropin-releasing hormone [GnRH] analog plus flutamide) as initial therapy and 11 (31%) were started on monotherapy alone. Patients who had not undergone a previous orchiectomy were continued on the GnRH analog. Patients were monitored clinically and with serial PSA measurements, radionuclide scans, and radiographs as indicated to assess response. Considering the 35 patients with increasing PSA values, 10 (29%) showed a significant decline (> or = 80% in seven, and > or = 50% in three) in PSA from baseline. All 10 had received combined androgen blockade as initial therapy. The duration of decline was short (median, 5+ months; range, 2 to 10+), but was associated with improvement in clinical symptoms, while one patient had a partial response in an epidural mass with parallel decline in PSA. None of the patients started on single hormone therapies responded. Discontinuation of flutamide was associated with a significant decrease in PSA values in 10 of 25 patients (40%; 95% confidence interval, 21% to 59%) and clinical improvement in a subset of patients who had an initial response, but later progressive disease on combined androgen blockade. A trial of flutamide withdrawal should be considered in patients progressing on total androgen blockade before the initiation of more toxic therapies. It is likely that flutamide withdrawal has contributed to the observed responses in phase II trials of both second-line hormonal therapies and new cytotoxic agents. Future phase II trials in hormone-refractory prostatic cancer must control for this observation, and insure that progression off flutamide is documented before initiation of alternative treatment.


Damage control surgery for abdominal trauma.
Trauma is one of the leading causes of death in any age group. The 'lethal triad' of acidosis, hypothermia, and coagulopathy has been recognized as a significant cause of death in patients with traumatic injuries. In order to prevent the lethal triad two factors are essential, early control of bleeding and prevention of further heat loss. In patients with major abdominal trauma, damage control surgery (DCS) avoids extensive procedures on unstable patients, stabilizes potentially fatal problems at initial operation, and applies staged surgery after successful initial resuscitation. It is not currently known whether DCS is superior to immediate surgery for patients with major abdominal trauma. To assess the effectiveness of DCS compared to traditional immediate definitive surgical treatment for patients with major abdominal trauma. We searched the Cochrane Injuries Group Specialised Register, CENTRAL (The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, Web of Science: Science Citation Index & ISI Proceedings, Current Controlled Trials MetaRegister, Clinicaltrials.gov, Zetoc, and CINAHL for all published and unpublished randomised controlled trials. We did not restrict the searches by language, date, or publication status. Searches were conducted in August 2008. Randomised controlled trials of DCS versus immediate traditional surgical repair were included in this review. We included patients with major abdominal trauma (Abbreviated Injury Scale > 3) who were undergoing surgery. Patient selection was crucial as patients with relatively simple abdominal injuries should not undergo unnecessary procedures. Two authors independently evaluated the search results. A total of 1523 studies were identified by our search. No randomised controlled trials comparing DCS with immediate and definitive repair in patients with major abdominal trauma were found. A total of 1521 studies were excluded because they were not relevant to the review topic and two studies were excluded because they were case-control studies. Evidence that supports the efficacy of DCS with respect to traditional laparotomy in patients with major abdominal trauma is limited.


A diabetes control program in a public health care setting.
The Houston Diabetes Control Program is part of an effort by the State of Texas and approximately 30 other programs throughout the United States to ensure that persons with diabetes-related complications receive ongoing state-of-the-art preventive care and treatment. For the past 5 years, this program has served an urban, high-risk patient population with special cultural, ethnic, and economic challenges. The intervention has included the development and implementation of protocols for the prevention and care of diabetes-related complications of the eyes, lower extremities, and cardiovascular system, as well as general management of diabetes and patient and professional education. The program is ongoing in nine community health centers located in low-income neighborhoods of a large metropolitan area. The results thus far indicate an increase in sensitive eye examinations from 8 percent to 26 percent of the patient population, a reduction in incidence of legal blindness from 9.5 to 2.7 per 1,000 during a 4-year period, an increase in foot examinations from 18 percent to 44 percent of the patient population, and 77 percent of hypertensive patients in good control of blood pressure at less than 160 over 95 mmHg (millimeters of mercury). On the average, there have not been significant long-term improvements in weight reduction or blood glucose control. The major challenges for this program are (a) improvement in control of glycemia, hypertension, and cholesterol; (b) more effective diet and physical activity interventions; and (c) more effective education approaches that help patients to understand metabolic and cardiovascular functions. These challenges will require collaboration of health care professionals in constructive and imaginative ways through their unselfish commitment toward common goals.


Evaluation of the diagnostic work-up in children with myocarditis and idiopathic dilated cardiomyopathy.
The underlying etiology of dilated cardiomyopathy (DCM) in children varies, 14-22% is secondary to myocarditis, and the majority remains idiopathic. Etiology has prognostic value; however, 'a clinical diagnosis of myocarditis' has been frequently used because the gold standard [endomyocardial biopsy (EMB)] is often not performed. Therefore, a consistent diagnostic approach and interpretation is needed. In this multicenter study, we evaluated the diagnostic approach and interpretation of the viral results in children with myocarditis and idiopathic DCM. We included 150 children with DCM, of whom 103 were assigned the diagnosis myocarditis (n = 21) or idiopathic DCM (n = 82) by the attending physician. Viral tests were performed in 97/103 patients, in only 34% (n = 35) some of the tests were positive. Of those patients, we evaluated the probability of the assigned diagnosis using the viral test results. We classified viral test results as reflecting definite or probable myocarditis in 14 children and possible or unlikely myocarditis in 21 children. Based on this classification, 23% of patients were misclassified. We found that in children with DCM, the diagnostic approach varied and the interpretation was mainly based on viral results. Since a 'clinical diagnosis of myocarditis' has been frequently used in daily practice because of the lack of EMB results, a uniform protocol is needed. We propose to use viral test results in several steps (blood PCR, serology, PCR and/or cultures of the gastro-intestinal and respiratory tract, and EMB results) to estimate the probability of myocarditis.


Conserved structure, regulatory elements, and transcriptional regulation from the GATA-1 gene testis promoter.
Transcription factor GATA-1 was first identified in erythroid cells, but was later shown to also be expressed in Sertoli cells of the mouse testis. GATA-1 transcription in testis initiates from a different first exon (exon IT) than the erythroid mRNA (transcribed from exon IE). To begin to address the question of how expression of GATA-1 might be differentially regulated in Sertoli and erythroid cells, we have cloned and determined the structure of the IT promoters of both the rat and mouse GATA-1 genes. The transcription regulatory mechanism(s) controlling the synthesis of exon IT-derived mRNA was investigated by transfection of wild-type and mutant reporter genes, with and without co-transfected GATA factor expression plasmids, into either fibroblasts or Sertoli cell lines. Two GATA binding sites in the IT promoter were found to be required for GATA factor-mediated activation in fibroblasts: GATA-IT-directed reporter gene expression was activated only after co-transfection with GATA-1, implying that transcriptional activation of GATA-1 in the testis might be at least partially mediated through these GATA regulatory elements. We also found that the endogenous GATA-1 gene was silent in primary culture and two different Sertoli cell lines, and that the repression of co-transfected GATA-1 reporter genes could not be relieved by forced expression of GATA-1 in Sertoli cells. Thus the GATA-IT promoter may be under the control of a regulatory network in Sertoli cells which involves both positive and negative regulation of transcription, and conserved GATA motifs found in the IT promoter may be required for transducing these effects.


Current concepts on osteonecrosis of the femoral head.
It is estimated that 20000 to 30000 new patients are diagnosed with osteonecrosis annually accounting for approximately 10% of the 250000 total hip arthroplasties done annually in the United States. The lack of level 1 evidence in the literature makes it difficult to identify optimal treatment protocols to manage patients with pre-collapse avascular necrosis of the femoral head, and early intervention prior to collapse is critical to successful outcomes in joint preserving procedures. There have been a variety of traumatic and atraumatic factors that have been identified as risk factors for osteonecrosis, but the etiology and pathogenesis still remains unclear. Current osteonecrosis diagnosis is dependent upon plain anteroposterior and frog-leg lateral radiographs of the hip, followed by magnetic resonance imaging (MRI). Generally, the first radiographic changes seen by radiograph will be cystic and sclerotic changes in the femoral head. Although the diagnosis may be made by radiograph, plain radiographs are generally insufficient for early diagnosis, therefore MRI is considered the most accurate benchmark. Treatment options include pharmacologic agents such as bisphosphonates and statins, biophysical treatments, as well as joint-preserving and joint-replacing surgeries. the surgical treatment of osteonecrosis of the femoral head can be divided into two major branches: femoral head sparing procedures (FHSP) and femoral head replacement procedures (FHRP). In general, FHSP are indicated at pre-collapse stages with minimal symptoms whereas FHRP are preferred at post-collapse symptomatic stages. It is difficult to know whether any treatment modality changes the natural history of core decompression since the true natural history of core decompression has not been delineated.


A quantitative study on the mental health of Turkish seafarers.
Physically and mentally healthy seafarers with professional knowledge and skills are needed for maritime transportation to be safe and sustainable. Mental problems experienced by seafarers can lead to negative consequences, such as bullying, substance dependency, assault, murder and suicide. Accordingly, this study examined the effects of differences between the socio-demographic characteristics of Turkish seafarers on their depression, which is an important criterion for determining mental disorders. Data collected from 403 participants through quantitative research methods were analyzed using SPSS version 25.0 and AMOS version 23.0. Although periodic physical and mental health checks are performed on seafarers, it was found from the analysis results that 33.2% of Turkish seafarers experience mental issues. Moreover, the study determined that the socio-demographic characteristics of seafarers made some differences in their depression levels.


The Impact of Docosahexaenoic Acid on Alzheimer's Disease: Is There a Role of the Blood-Brain Barrier?
There currently is no cure or established preventative treatment for Alzheimer's disease (AD). Considering the increasing aging population and the subsequent high prevalence of AD worldwide, identifying a cost-effective way to prevent AD is an essential unmet medical need. Relative to healthy human brain samples, postmortem AD brain samples have been shown to exhibit lower docosahexaenoic acid (DHA) levels, an essential polyunsaturated fatty acid required for normal neuronal function. However, findings from different studies are controversial and it is not clear whether this alteration in DHA brain levels is a cause or consequence of AD. Animal studies have also demonstrated that administration of DHA can alleviate the underlying pathophysiology of AD, including but not limited to amyloid pathology, tau pathology, and neuroinflammation. Moreover, DHA has been suggested to exert cognitive-enhancing effects and epidemiological studies have suggested that regular consumption of fish or omega-3 fatty acid enriched diets can attenuate the cognitive decline in AD and/or lower the risk of developing AD. However, the beneficial effects of DHA in AD have not been clearly demonstrated by current human randomised-control trials. In addition, the underlying reasons for the lower brain levels of DHA in AD remain to be fully characterised. However, given that the brain has limited capacity to produce DHA de novo and obtains DHA from the plasma, one plausible explanation for the lower brain levels of DHA in AD is reduced bloodbrain barrier (BBB) transport of this fatty acid in AD, as has been reported in one mouse model of AD. Unfortunately, the actual mechanisms governing the BBB transport of DHA in healthy conditions are not clearly understood, complicating the relationship between reduced BBB transport of DHA, attenuated DHA brain levels and AD pathology. The purpose of this review, therefore, is to summarise the findings of the biochemical, functional and epidemiological studies assessing the impact of DHA on the progression of AD, with a focus on how brain DHA levels alter in AD, the mechanisms thought to be held responsible for the apparent protective effects of DHA in AD, and the factors governing BBB transport of DHA in AD.


Molecular cloning of cDNAs and genes coding for beta-methylcrotonyl-CoA carboxylase of tomato.
Tomato cDNA and genomic clones were isolated by using as a probe a cDNA clone that had originally been identified by its ability to direct the synthesis of a biotin-containing polypeptide in Escherichia coli. The nucleotide sequences of the newly isolated cDNAs indicate that they are clones of a single mRNA molecule. However, one of the cDNA clones contains an insertion of a sequence which we identified as an unspliced intron. The amino acid sequence deduced from the nucleotide sequence of the cDNAs showed similarity to regions of previously sequenced biotin enzymes, indicating that the isolated cDNAs code for a biotin-containing protein. Portions of the cDNAs were expressed in E. coli as glutathione S-transferase or beta-galactosidase fusion proteins. Each fusion protein was purified and used to immunize rabbits. The resulting antisera recognized a 78-kDa biotin-containing polypeptide in tomato leaf extracts. In addition, both antisera specifically inhibited beta-methylcrotonyl-CoA carboxylase activity in extracts from tomato leaves. These characterizations have identified the isolated tomato cDNAs and genes as coding for the 78-kDa biotin subunit of beta-methylcrotonyl-CoA carboxylase. Comparison of the deduced amino acid sequence of the biotin subunit of beta-methylcrotonyl-CoA carboxylase with other biotin enzymes suggest that this subunit contains the biotin carboxylase and biotin carboxyl-carrier domains.


Differential binding of chemokines to macrophages and neutrophils in the human inflamed synovium.
In chronic inflammatory foci, such as the rheumatoid joint, there is enhanced recruitment of phagocytes from the blood into the tissues. Chemokines are strongly implicated in directing the migration of these cells, although little is known regarding the chemokine receptors that could mediate their chemotaxis into the joint tissue. Therefore the objective of the study was to identify chemokine binding sites on macrophages and neutrophils within the rheumatoid synovium using radiolabeled ligand binding and in situ autoradiography. Specific binding sites for CCL3 (macrophage inflammatory protein-1alpha), CCL5 (RANTES), CCL2 (monocyte chemoattractant protein-1) and CXCL8 (IL-8) were demonstrated on CD68+ macrophages in the subintimal and intimal layers. The number and percentage of intimal cells that bound chemokines were greater in inflamed regions compared to noninflamed regions. The intensity of intimal binding varied between chemokines with the rank order, CCL3 > CCL5 > CCL2 > CXCL8. Neutrophils throughout the synovium bound CXCL8 but did not show any signal for binding CCL2, CCL3 or CCL5. Immunohistochemistry showed that both CXCR1 and CXCR2 are expressed by macrophages and neutrophils in the rheumatoid and nonrheumatoid synovia, suggesting that both of these receptors are responsible for the CXCL8 binding. The chemokine binding sites described on phagocytes may be involved in the migration of these cells into the inflamed joint.


Calcium ion binding properties of Medicago truncatula calcium/calmodulin-dependent protein kinase.
A calcium/calmodulin-dependent protein kinase (CCaMK) is essential in the interpretation of calcium oscillations in plant root cells for the establishment of symbiotic relationships with rhizobia and mycorrhizal fungi. Some of its properties have been studied in detail, but its calcium ion binding properties and subsequent conformational change have not. A biophysical approach was taken with constructs comprising either the visinin-like domain of Medicago truncatula CCaMK, which contains EF-hand motifs, or this domain together with the autoinhibitory domain. The visinin-like domain binds three calcium ions, leading to a conformational change involving the exposure of hydrophobic surfaces and a change in tertiary but not net secondary or quaternary structure. The affinity for calcium ions of visinin-like domain EF-hands 1 and 2 (K(d) = 200 ± 50 nM) was appropriate for the interpretation of calcium oscillations (~125-850 nM), while that of EF-hand 3 (K(d) ≤ 20 nM) implied occupancy at basal calcium ion levels. Calcium dissociation rate constants were determined for the visinin-like domain of CCaMK, M. truncatula calmodulin 1, and the complex between these two proteins (the slowest of which was 0.123 ± 0.002 s(-1)), suggesting the corresponding calcium association rate constants were at or near the diffusion-limited rate. In addition, the dissociation of calmodulin from the protein complex was shown to be on the same time scale as the dissociation of calcium ions. These observations suggest that the formation and dissociation of the complex between calmodulin and CCaMK would substantially mirror calcium oscillations, which typically have a 90 s periodicity.


Development and evaluation of a novel Vital Signs Alert device for use in pregnancy in low-resource settings.
Haemorrhage, hypertension, sepsis and abortion complications (often from haemorrhage or sepsis) contribute to 60% of all maternal deaths. Each is associated with vital signs (blood pressure (BP) and pulse) abnormalities, and the majority of deaths are preventable through simple and timely intervention. This paper presents the development and evaluation of the CRADLE Vital Signs Alert (VSA), an accurate, low-cost and easy-to-use device measuring BP and pulse with an integrated traffic light early warning system. The VSA was designed to be used by all cadres of healthcare providers for pregnant women in low-resource settings with the aim to prevent avoidable maternal mortality and morbidity. The development and the mixed-methods clinical evaluation of the VSA are described. Preliminary fieldwork identified that introduction of BP devices to rural clinics improved antenatal surveillance of BP in pregnant women. The aesthetics of the integrated traffic light system were developed through iterative qualitative evaluation. The traffic lights trigger according to evidence-based vital sign thresholds in hypertension and haemodynamic compromise from haemorrhage and sepsis. The VSA can be reliably used as an auscultatory device, as well as its primary semiautomated function, and is suitable as a self-monitor used by pregnant women. The VSA is an accurate device incorporating an evidence-based traffic light early warning system. It is designed to ensure suitability for healthcare providers with limited training and may improve care for women in pregnancy, childbirth and in the postnatal period.


Eribulin in advanced liposarcoma and leiomyosarcoma.
The heterogeneity of soft tissue sarcomas (STS) presents a formidable management challenge. Consequently, one of the main research goals is to define specific tailored therapy for each histological subtype and to develop a more personalised approach to treatment. The standard first line chemotherapy for advanced STS is doxorubicin, with or without ifosfamide, however, a number of different drugs are emerging as active therapies beyond first-line. Areas covered: Eribulin has recently been approved for advanced liposarcoma, after an anthracycline-containing regimen, demonstrating an overall survival (OS) advantage in liposarcoma and leiomyosarcoma in a randomised Phase III clinical trial. In this manuscript, an overview of the efficacy and safety of eribulin in STS is presented, highlighting different clinical outcomes between histological subtypes and comparing data with other effective drugs used in the treatment of sarcomas. The potential mechanisms of action of eribulin are also described, including its activity as potent microtubule-destabilizing anticancer agent, which has other antitumor biological effects. Expert commentary: Eribulin is highly effective in some STS populations and also has an acceptable toxicity profile. Further studies are required to better understand the precise mechanism of action of this agent and potential role in combination schedules.


Owning solutions: a collaborative model to improve quality in hospital care for Aboriginal Australians.
Well-documented health disparities between Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) and non-Aboriginal Australians are underpinned by complex historical and social factors. The effects of colonisation including racism continue to impact negatively on Aboriginal health outcomes, despite being under-recognised and under-reported. Many Aboriginal people find hospitals unwelcoming and are reluctant to attend for diagnosis and treatment, particularly with few Aboriginal health professionals employed on these facilities. In this paper, scientific literature and reports on Aboriginal health-care, methodology and cross-cultural education are reviewed to inform a collaborative model of hospital-based organisational change. The paper proposes a collaborative model of care to improve health service delivery by building capacity in Aboriginal and non-Aboriginal personnel by recruiting more Aboriginal health professionals, increasing knowledge and skills to establish good relationships between non-Aboriginal care providers and Aboriginal patients and their families, delivering quality care that is respectful of culture and improving Aboriginal health outcomes. A key element of model design, implementation and evaluation is critical reflection on barriers and facilitators to providing respectful and culturally safe quality care at systemic, interpersonal and patient/family-centred levels. Nurses are central to addressing the current state of inequity and are pivotal change agents within the proposed model.


Are dietary antioxidant intake indices correlated to oxidative stress and inflammatory marker levels?
Epidemiologic and experimental studies have shown that a high intake of individual dietary antioxidants is associated with a reduced risk of cancers. Few studies, however, have investigated the influences of a combination of dietary antioxidants. We evaluated the association of two dietary antioxidant indices, the Dietary Antioxidant Quality Score (DAQS) and the Composite Dietary Antioxidant Index (CDAI), with 10 oxidative stress or inflammation biomarkers (urinary F2-isoprostanes [15-F2t-IsoP]; urinary F2-isoprostane metabolites [15-F2t-IsoPM]; urinary prostaglandin E2 metabolite [PGEM]; C-reactive protein [CRP]; interleukin-1beta [IL-1β]; interleukin-6 [IL-6]; tumor necrosis factor-alpha [TNF-α]; soluble TNF-receptor 1 [sTNF-R1]; soluble TNF-receptor 2 [sTNF-R2]; and soluble GP130 [sGP130]) in 3853 participants of the Shanghai Women's Health Study (SWHS). We found the DAQS and CDAI to be highly correlated (r=0.72), and both were inversely associated with levels of IL-1β (ptrend=0.02 and 0.03, respectively) and TNF-α (ptrend=0.005 and 0.003, respectively). In addition, IL-6 and sTNF-R2 levels were inversely associated with the DAQS score; β-coefficient(±SE) for average-quality and high-quality group versus low-quality group were -0.22(±0.13) and -0.30(±0.13) (ptrend=0.06) for IL-6; -0.06(±0.04) and -0.10(±0.04) (ptrend=0.01) for sTNF-R2. Neither the DAQS nor CDAI score was significantly associated with oxidative stress or other inflammatory biomarkers. Our observations lead us to hypothesize that these two indices offer a potential aggregate method of measuring dietary anti-inflammation, but not anti-oxidation properties.


Glutamine metabolism in chick enterocytes: absence of pyrroline-5-carboxylase synthase and citrulline synthesis.
This study was designed to determine whether pyrroline-5-carboxylate (P-5-C) synthase is deficient in chick enterocytes therefore resulting in the lack of synthesis of ornithine and citrulline from glutamine. Post-weaning pig enterocytes, which are known to contain P-5-C synthase and to synthesize both ornithine and citrulline from glutamine, were used as positive controls. Enterocytes were incubated at 37 degrees C for 0-30 min in the presence of 2 mM [U-14C]glutamine or 2 mM ornithine plus 2 mM NH4Cl. In chick enterocytes, glutamine was metabolized to NH3, CO2, glutamate, alanine and aspartate, but not to ornithine, citrulline, arginine or proline. Likewise, there was no formation of citrulline, arginine, alanine or aspartate from ornithine in chick enterocytes. Furthermore, the rate of conversion of ornithine into proline in chick enterocytes was only about 4% of that in cells from pigs. To elucidate the reason for the inability of chick enterocytes to synthesize ornithine and citrulline from glutamine, the activities of the enzymes involved were measured. No activity of P-5-C synthase or ornithine carbamoyltransferase was found in chick enterocytes, in contrast with cells from post-weaning pigs. It was also demonstrated that the activity of ornithine aminotransferase in chick enterocytes was only 3% of that in cells from pigs. Thus the present findings elucidate the biochemical reason for the lack of endogenous synthesis of ornithine and citrulline in chicks. Our results also explain previous observations that ornithine cannot replace arginine or proline in the diet of chicks. We suggest that the absence of P-5-C synthase and ornithine carbamoyltransferase in enterocytes is the metabolic basis for the nutritional requirement of arginine in the chick.


Wearable Photoplethysmography for Cardiovascular Monitoring.
Smart wearables provide an opportunity to monitor health in daily life and are emerging as potential tools for detecting cardiovascular disease (CVD). Wearables such as fitness bands and smartwatches routinely monitor the photoplethysmogram signal, an optical measure of the arterial pulse wave that is strongly influenced by the heart and blood vessels. In this survey, we summarize the fundamentals of wearable photoplethysmography and its analysis, identify its potential clinical applications, and outline pressing directions for future research in order to realize its full potential for tackling CVD.


[Antitumor resistance in depositing Mycobacterium tuberculosis in the lungs of rats].
In the experiments on rats of "Wistar" line and non-inbred rats the author has demonstrated that the inflammatory process in the lungs induced by non-virulent mycobacteria of BCG strain is able to decrease the organism resistance to the occurrence of chemically induced tumors. Desensibilization with PPD prior to the appearance of tumors would contribute to restoration of their antitumor resistance.


Torsion of the greater omentum or appendices epiploicae.
The authors conducted a 20-year review of the records of patients with torsion of greater omentum or appendices epiploicae admitted to the Vancouver General Hospital. Presenting signs and symptoms, operative findings and some recent reports are examined and conclusions are given. Diagnosis of the condition is rarely made preoperatively owing to the lack of specific symptoms. When a straightforward diagnosis of appendicitis has been made, yet a normal appendix is found, torsion of omentum should be considered and excluded.


The effect of rotator cuff tear size on shoulder strength and range of motion.
Prospective cohort study. To determine the effect of rotator cuff tear size on shoulder strength and range of motion. Patients with rotator cuff pathology typically present with weakness and motion loss in various motions. The extent to which the presence of a rotator cuff tear and the size of the tear affect strength and range of motion is not well understood. Sixty-one patients scheduled for surgery, with a diagnosis of a rotator cuff tear and/or subacromial impingement, underwent examination for shoulder pain, function, range of motion, and strength. The extent of rotator cuff pathology was documented during subsequent surgery (presence of tear, tear size, tear thickness). There were 10 massive tears, 15 large tears, 13 medium tears, 12 small tears, and 11 rotator cuffs without a tear. Patients had marked weakness in abduction strength at 90 degrees and 10 degrees of abduction, in external rotation strength at 90 degrees, and in the "full can test" (all, P<.0001). Marked range of motion losses in shoulder flexion and external rotation at 0 degrees and 90 degrees abduction (all, P<.001) were also observed. Abduction strength deficit at 10 degrees was affected by rotator cuff tear size (P<.0001). Twenty of 25 patients with large or massive tears had deficits greater than 50%, compared with only 1 of 11 patients with no tear, 2 of 12 patients with a small tear, and 5 of 13 patients with a medium tear (P<.0001). Other strength and range of motion deficits or indices of pain and function were unaffected by tear size. Weakness of greater than 50% relative to the contralateral side in shoulder abduction at 10 degrees of abduction was indicative of a large or massive rotator cuff tear.


Influence of reconstruction algorithms on image quality in SPECT myocardial perfusion imaging.
We investigated if image- and diagnostic quality in SPECT MPI could be maintained despite a reduced acquisition time adding Depth Dependent Resolution Recovery (DDRR) for image reconstruction. Images were compared with filtered back projection (FBP) and iterative reconstruction using Ordered Subsets Expectation Maximization with (IRAC) and without (IRNC) attenuation correction (AC). Stress- and rest imaging for 15 min was performed on 21 subjects with a dual head gamma camera (Infinia Hawkeye; GE Healthcare), ECG-gating with 8 frames/cardiac cycle and a low-dose CT-scan. A 9 min acquisition was generated using five instead of eight gated frames and was reconstructed with DDRR, with (IRACRR) and without AC (IRNCRR) as well as with FBP. Three experienced nuclear medicine specialists visually assessed anonymized images according to eight criteria on a four point scale, three related to image quality and five to diagnostic confidence. Statistical analysis was performed using Visual Grading Regression (VGR). Observer confidence in statements on image quality was highest for the images that were reconstructed using DDRR (P<0·01 compared to FBP). Iterative reconstruction without DDRR was not superior to FBP. Interobserver variability was significant for statements on image quality (P<0·05) but lower in the diagnostic statements on ischemia and scar. The confidence in assessing ischemia and scar was not different between the reconstruction techniques (P = n.s.). SPECT MPI collected in 9 min, reconstructed with DDRR and AC, produced better image quality than the standard procedure. The observers expressed the highest diagnostic confidence in the DDRR reconstruction.


Projected health-care resource needs for an effective response to COVID-19 in 73 low-income and middle-income countries: a modelling study.
Since WHO declared the COVID-19 pandemic a Public Health Emergency of International Concern, more than 20 million cases have been reported, as of Aug 24, 2020. This study aimed to identify what the additional health-care costs of a strategic preparedness and response plan (SPRP) would be if current transmission levels are maintained in a status quo scenario, or under scenarios where transmission is increased or decreased by 50%. The number of COVID-19 cases was projected for 73 low-income and middle-income countries for each of the three scenarios for both 4-week and 12-week timeframes, starting from June 26, 2020. An input-based approach was used to estimate the additional health-care costs associated with human resources, commodities, and capital inputs that would be accrued in implementing the SPRP. The total cost estimate for the COVID-19 response in the status quo scenario was US$52·45 billion over 4 weeks, at $8·60 per capita. For the decreased or increased transmission scenarios, the totals were $33·08 billion and $61·92 billion, respectively. Costs would triple under the status quo and increased transmission scenarios at 12 weeks. The costs of the decreased transmission scenario over 12 weeks was equivalent to the cost of the status quo scenario at 4 weeks. By percentage of the overall cost, case management (54%), maintaining essential services (21%), rapid response and case investigation (14%), and infection prevention and control (9%) were the main cost drivers. The sizeable costs of a COVID-19 response in the health sector will escalate, particularly if transmission increases. Instituting early and comprehensive measures to limit the further spread of the virus will conserve resources and sustain the response. WHO, and UK Foreign Commonwealth and Development Office.


Prediction model for adult height of small for gestational age children at the start of growth hormone treatment.
GH treatment is approved for short children born small for gestational age (SGA). The optimal dose is not yet established. Our objective was to develop a model for prediction of height at the onset of puberty and of adult height (AH). Two GH studies were performed in short SGA children. A total of 150 SGA children with height sd scores (SDS) less than -2, age 3 yr or older, no signs of catch-up growth, available height at the onset of puberty, and at least 1 yr of GH treatment before the onset of puberty were studied. In one study, patients were randomly assigned to either 0.033 or 0.067 mg/kg x d; in the other study all received 0.033 mg/kg x d. In 71 children, AH was reached. Height SDS at the onset of puberty and AH SDS were calculated. Determinants positively related to height SDS at the onset of puberty were: height SDS at the start; target height SDS; and GH dose, whereas age at the start and female gender were negatively related. Positively related to AH SDS were: height SDS and chronological age--bone age at the start; target height SDS; and GH dose, whereas serum IGF binding protein (IGFBP)-3 SDS at the start was negatively related. There was a significant interaction between GH dose and IGFBP-3 SDS, indicating a smaller GH dose effect for higher levels of IGFBP-3. The final model explained 57% of the variance in height SDS at the onset of puberty and 41% of AH SDS. The prediction model for height SDS at the onset of puberty and AH SDS of short SGA children treated with GH provides useful information about the expected long-term growth. Because GH dosage is one of the determinants, the model aids in determining the optimal GH dose for each child.


Catabolite inactivation of the yeast maltose transporter occurs in the vacuole after internalization by endocytosis.
The maltose transporter of Saccharomyces cerevisiae is rapidly degraded during fermentation in the absence of a nitrogen source. The location and mechanism of degradation of the transporter have been investigated. Using mutants defective in endocytosis, we have shown that degradation of this transporter requires internalization by endocytosis. In addition, studies of mutants defective in proteasome or vacuolar proteolysis revealed that degradation occurs in the vacuole and is independent of proteasome function. The results also revealed that degradation of the maltose transporter requires Sec18p and raised the question of whether in the absence of Sec18p activity the internalized maltose transporter is recycled back to the plasma membrane.


Potential for Front of Pack Labeling Exposure to Impact US Dietary Choices: A Population-Based Cross-Sectional Study Using NHANES 2017-2018.
In recent years, front-of-pack nutrition labeling (FOPL) schemes have proliferated, but the components of the diet subject to FOPL have not been described. This study quantified the proportion and elements of the diet that would be subject to FOPL in the US. The 2017-2018 National Health and Nutrition Examination Survey (n = 7121; age ≥2 year) 24-h dietary recalls were used to identify foods/beverages subject to FOPL. The proportion of dietary energy and additional dietary constituents subject to FOPL was estimated. Overall, 57% of dietary energy would be subject to FOPL. Individuals consuming more away-from-home meals had lower exposure to FOPL. Adults with a healthy-weight and those consuming a more healthful diet had more exposure to FOPL. Protein, sodium, potassium, whole fruit, vegetables, and unprocessed meats were less subject to FOPL as compared to total sugars, added sugars, calcium, fruit juice, milk, yogurt, nuts/seeds and whole grains. Because less than 60% of the diet would be impacted by FOPL, implementation of such a policy may have limited reach for the US diet and demonstrates some inconsistencies with current dietary guidance regarding the under- and over-representation of key food groups and nutrients.


Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects.
The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed. Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing. Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD(20), geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p=0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p=0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens. Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.


Medulloblastoma: freedom from relapse longer than 8 years--a therapeutic cure?
Seventy-seven patients presenting with medulloblastoma between 1958 and 1986 were treated at Stanford University Medical Center and studied retrospectively. Multimodality therapy utilized surgical extirpation followed by megavoltage irradiation. In 15 cases chemotherapy was used as adjunctive treatment. The 10- and 15-year actuarial survival rates were both 41% with an 18-year maximum follow-up period (median 4.75 years). There were no treatment failures after 8 years of tumor-free survival. Gross total removal of tumor was achieved in 22 patients (32%); the surgical mortality rate was 3.9%. No significant difference was noted in the incidence of metastatic disease between shunted and nonshunted patients. The classical form of medulloblastoma was present in 67% of cases while the desmoplastic subtype was found in 16%. Survival rates were best for patients presenting after 1970, for those with desmoplastic tumors, and for patients receiving high-dose irradiation (greater than or equal to 5000 cGy) to the posterior fossa. Although early data on freedom from relapse suggested a possible beneficial effect from chemotherapy, long-term follow-up results showed no advantage from this modality of treatment. The patterns of relapse and survival were examined; 64% of relapses occurred within the central nervous system, and Collins' rule was applicable in 83% of cases beyond the period of risk. Although patients treated for recurrent disease could be palliated, none were long-term survivors. The study data indicate that freedom from relapse beyond 8 years from diagnosis can be considered as a cure in this disease. Long-term follow-up monitoring is essential to determine efficacy of treatment and to assess survival patterns accurately.


Acute Responses of Youth Elite Players to a Football Match in Terms of Blood Markers.
The current study verified the acute responses of participants to a football match in terms of blood markers. Sixteen elite U-18 male football players were divided into two groups: experimental (EG, n = 10), who played a friendly football match; and control (CG), who were not exposed to any physical exertion. Intravenous blood samples were collected from both groups at baseline, pre-match, half-time, and post-match. The blood analysis consisted of four groups: immunological (leukocytes, platelets, and cortisol), muscle damage (creatine kinase and lactate dehydrogenase), metabolic (lactate, glucose, erythrocytes, hematocrit, hemoglobin, and urea), and electrolytic (sodium, calcium, and potassium). Edwards' training impulse demonstrated that the first half was more demanding than the second half (p = 0.020). Significant changes between time points and groups were observed for leukocytes (pre-match: 6920 ± 1949; post-match: 13,890 ± 3292; p ≤ 0.05) and cortisol (pre-match: 10.78 ± 3.63; post-match: 19.15 ± 7.40; p ≤ 0.05). CK (pre-match: 516.50 ± 248.38; post-match: 713.70 ± 308.20; p ≤ 0.05) and LDH (pre-match: 348.80 ± 36.49; post-match: 414.80 ± 26.55; p ≤ 0.05) increased significantly across the time points for the EG, with no difference between the groups, however. Raised lactate (pre-match: 1.05 ± 0.32; post-match: 3.24 ± 1.60; p ≤ 0.05) and glucose (pre-match: 72.54 ± 9.76; post-match: 101.42 ± 19.87; p ≤ 0.05) differences between the groups at half-time were also observed. These current findings provide helpful information to better understand football match demands regarding physiological effects.


Stapedial synkinesis causing change in hearing threshold with facial motion.
Synkinetic facial movement after facial nerve regeneration is a well-documented phenomenon. Rarely, patients recovering from facial nerve injury report feelings of auditory ringing, fullness, and a sensation of ear tightness as a result of stapedial muscle involvement. It is exceedingly rare for such synkinesis to produce perceivable changes in hearing threshold. We report a unique case of stapedial synkinesis causing pure-tone changes in hearing threshold with activation of the facial musculature. A single patient is presented who developed stapedial synkinesis after suboccipital resection of a unilateral acoustic neuroma. Despite facial nerve sparing, surgery resulted in House-Brackmann grade V/VI right facial nerve paralysis that improved to Grade III/VI after 7 months. Synkinesis developed that caused eye closure with puckering of the lips. Puckering of the lips likewise caused decreased hearing in the right ear, corresponding to a measured decrease of 10 dB in the PTA. Over the next several months, facial motion continued to improve, and hearing changes became less bothersome, so no intervention was undertaken. The changes presented in the hearing threshold fit within the classically described 15-dB attenuation provided by the stapedial reflex. Although no intervention was undertaken in this particular case, some patients with unremitting stapedial synkinesis might benefit from sectioning of the stapedial muscle. Thus, consideration should be made for audiometric evaluation with and without facial muscle contraction in the evaluation of individuals with synkinetic facial movement.


Effectiveness of sildenafil citrate (Viagra) and tadalafil (Cialis) on sexual responses in Saudi men with erectile dysfunction in routine clinical practice.
Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction, yet enhanced satisfaction has been infrequently assessed in the sexual trials. We evaluated the efficacy of sildenafil vs. tadalafil, in Saudi men with erectile dysfunction and determined the self-based rating of medicinal preference. Sildenafil citrate (Viagra) is a potent inhibitor of the electrolytic enzyme type V phosphodiesterase (PDE5), in the corpus cavernosum and therefore increases the penile response to sexual stimulation. Tadalafil (Cialis) is also a PDE5 inhibitor that increases the level of cyclic guanosine monophosphate (cGMP) in cavernous smooth muscle cells. Whereas cGMP is a second messenger for the vasodilator effects of nitric oxide causing smooth muscle relaxation, which in turn leads to penile erection; however the mechanism by which cGMP stimulates relaxation of the smooth muscles remains to be elucidated. Both sildenafil and tadalafil have a rapid onset with the effectiveness up to 4 hours and 36 hours respectively. In this study subjects treated with 100 mg oral dose of sildenafil / 20 mg tadalafil were found to be associated with higher mean scores for the questions of the International Index of Erectile Function (IIEF). Frequency of penetration and maintenance of erection after sexual penetration and/or during masturbation were found to be enhanced significantly (p<0.001) in both sildenafil/tadalafil treated men. Similarly mean domain of erectile function, orgasmic function, and intercourse satisfaction also showed a significantly positive improvement (p/0.001) in both the treated groups in comparison with their age matched untreated controls. Interestingly in all the cases, tadalafil group showed considerably greater positive responses than the sildenafil group but within the same significant levels. Strikingly the sexual-desire domain in sildenafil treated men with respect to their aged matched controls showed a non-significant difference, where as this difference was found to be highly significant in tadalafil treated group. Similarly mean scores for the overall satisfaction domains of the IIEF in comparison with the untreated subjects showed a significant positive response in the sildenafil treated group (p<0.001), where as tadalafil treated group showed a highly significant positive response (p<0.005). These findings suggest that both sildenafil and tadalafil may assist an individual in extending/enhancing the excitement phase or prolonging the sexual interaction. These studies further conclude that there is a major point of difference between the short-acting agent sildenafil and the longer acting tadalafil. This probably allows more choice about the onset of sexual responses with tadalafil than with sildenafil.


Characterization of a K562 multidrug-resistant cell line.
A daunorubicin-resistant variant of the K562 human leukemia cell line (K562-R), which demonstrates cross-resistance to other anthracycline antibiotics and Vinca alkaloids, has been developed in vitro by continuous exposure to daunorubicin. Cross-resistance to anthracyclines and Vinca alkaloids is reversed when cells are exposed to drugs in the presence of verapamil, a calcium channel blocker. The K562-R cell line overexpresses a 4.5-kilobase mRNA, which is thought to code for the Mr 170,000 membrane glycoprotein associated with multidrug resistance. Transport studies indicate reduced intracellular accumulation and retention of daunorubicin in the K562-R cells as compared to the parent cell line. These studies further suggest the presence of distinct cellular pools composed of both rapidly and slowly exchanging drug, with the rapidly exchanging pool being more pronounced in the resistant line. The development of multidrug resistance in the K562-R cell line is also associated with the overexpression of five different cell surface membrane proteins ranging in molecular weight between 50,000 and 210,000, whose function remains to be defined.


Should obese patients be counselled to follow a low-glycaemic index diet? Yes.
A reduction in dietary fat has been widely advocated for the prevention and treatment of obesity and related complications. However, the efficacy of low-fat diets has been questioned in recent years. One potential adverse effect of reduced dietary fat is a compensatory increase in the consumption of high glycaemic index (GI) carbohydrate, principally refined starchy foods and concentrated sugar. Such foods can be rapidly digested or transformed into glucose, causing a large increase in post-prandial blood glucose and insulin. Short-term feeding studies have generally found an inverse association between GI and satiety. Medium-term clinical trials have found less weight loss on high GI or high glycaemic load diets compared to low GI or low glycaemic load diets. Epidemiological analyses link GI to multiple cardiovascular disease risk factors and to the development of cardiovascular disease and type 2 diabetes. Physiologically orientated studies in humans and animal models provide support for a role of GI in disease prevention and treatment. This review examines the mechanisms underlying the potential benefits of a low GI diet, and whether such diets should be recommended in the clinical setting.


Connecting local active forces to macroscopic stress in elastic media.
In contrast with ordinary materials, living matter drives its own motion by generating active, out-of-equilibrium internal stresses. These stresses typically originate from localized active elements embedded in an elastic medium, such as molecular motors inside the cell or contractile cells in a tissue. While many large-scale phenomenological theories of such active media have been developed, a systematic understanding of the emergence of stress from the local force-generating elements is lacking. In this paper, we present a rigorous theoretical framework to study this relationship. We show that the medium's macroscopic active stress tensor is equal to the active elements' force dipole tensor per unit volume in both continuum and discrete linear homogeneous media of arbitrary geometries. This relationship is conserved on average in the presence of disorder, but can be violated in nonlinear elastic media. Such effects can lead to either a reinforcement or an attenuation of the active stresses, giving us a glimpse of the ways in which nature might harness microscopic forces to create active materials.


Nitrogen K-Edge X-ray Absorption Spectra of Ammonium and Ammonia in Water Solution: Assessing the Performance of Polarizable Embedding Coupled Cluster Methods.
The recent development of liquid jet and liquid leaf sample delivery systems allows for accurate measurements of soft X-ray absorption spectra in transmission mode of solutes in a liquid environment. As this type of measurement becomes increasingly accessible, there is a strong need for reliable theoretical methods for assisting in the interpretation of the experimental data. Coupled cluster methods have been extensively developed over the past decade to simulate X-ray absorption in the gas phase. Their performance for solvated species, on the contrary, remains largely unexplored. Here, we investigate the current state of the art of coupled cluster modeling of nitrogen K-edge X-ray absorption of aqueous ammonia and ammonium based on quantum mechanics/molecular mechanics, where both the level of coupled cluster calculations and polarizable embedding are scrutinized. The results are compared to existing experimental data as well as simulations based on transition potential density functional theory.


A business approach to dental practice.
While the approach to dental practice has changed through the decades, the characteristics of a successful practice remain constant. This article presents some of those characteristics, as well as means of achieving them.


Selective staining of pancreatic beta-cell granules. Evolution and present status.
Presented herein are the rationale, evolution, and present status of the alcian blue (AB)-aldehyde pararosaniline (AP) method for the selective staining of pancreatic beta-cell granules in paraffin sections of fixed tissues. Acidic mucins of pancreatic ductal and ductular cells and granules of mast cells and basophils normally stain strongly with AP; prestaining them with AB prevents their staining with AP. After AB staining, only certain islet cells, assumed to be beta, and cells of insulinomas bind AP strongly. Detailed working procedures are provided for the primary method (A) and two variants (B and C). The stainability of beta-cell granules in paraffin sections depends on the adequacy of primary fixation.


Production and beta decay of rp-process nuclei 96Cd, 98In, and 100Sn.
The beta-decay properties of the N=Z nuclei 96Cd, 98In, and 100Sn have been studied. These nuclei were produced at the National Superconducting Cyclotron Laboratory by fragmenting a 120 MeV/nucleon 112Sn primary beam on a Be target. The resulting radioactive beam was filtered in the A1900 and the newly commissioned Radio Frequency Fragment Separator to achieve a purity level suitable for decay studies. The observed production cross sections of these nuclei are lower than predicted by factors of 10-30. The half-life of 96Cd, which was the last experimentally unknown waiting point half-life of the astrophysical rp process, is 1.03_{-0.21};{+0.24} s. The implications of the experimental T_{1/2} value of 96Cd on the abundances predicted by rp process calculations and the origin of A=96 isobars such as 96Ru are explored.


Erlotinib: preclinical investigations.
Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.


Event-related potential correlates of paranormal ideation and unusual experiences.
Separate dimensions of schizotypy have been differentially associated with electrophysiological measures of brain function, and further shown to be modified by sex/gender. We investigated event-related potential (ERP) correlates of two subdimensions of positive schizotypy, paranormal ideation (PI) and unusual experiences (UEs). Seventy-two individuals with no psychiatric diagnosis (men=36) completed self-report measures of UE and PI and performed an auditory oddball task. Average scores for N100, N200 and P300 amplitudes were calculated for left and right anterior, central and posterior electrode sites. Multiple linear regression was used to examine the relationships between the measures of schizotypy and ERPs across the entire sample, as well as separately according to sex. PI was inversely associated with P300 amplitude at left-central sites across the entire sample, and at right-anterior electrodes in women only. Right-anterior P300 and right-posterior N100 amplitudes were negatively associated with UE in women only. Across the entire sample, UE was negatively associated with left-central N100 amplitude, and positively associated with left-anterior N200 amplitude. These results provide support from electrophysiological measures for the fractionation of the positive dimension of schizotypy into subdimensions of PI and UE, and lend indirect support to dimensional or quasidimensional conceptions of psychosis. More specifically, they suggest that PI may be associated with alteration in contextual updating processes, and that UE may reflect altered sensory/early-attention (N100) mechanisms. The sex differences observed are consistent with those previously observed in individuals with schizophrenia.


Selective Uropathogenic E. coli Detection Using Crossed Surface-Relief Gratings.
Urinary tract infections (UTIs) are one of the major burdens on public healthcare worldwide. One of the primary causes of UTIs is the invasion of the urinary tract by uropathogenic Escherichia coli (UPEC). Improper treatment of bacterial infections like UTIs with broad-spectrum antibiotics has contributed to the rise of antimicrobial resistance, necessitating the development of an inexpensive, rapid and accurate detection of UPEC. Here, we present real-time, selective and label-free detection of UPEC using crossed surface-relief gratings (CSRGs) as nanometallic sensors incorporated into an optical sensing platform. CSRGs enable real-time sensing due to their unique surface plasmon resonance (SPR)-based light energy exchange, resulting in detection of a very-narrow-bandwidth SPR signal after the elimination of residual incident light. The platform's sensing ability is experimentally demonstrated by the detection of bulk refractive index (RI) changes, with a bulk sensitivity of 382.2 nm/RIU and a resolution in the order of 10-6 RIU. We also demonstrate, for the first time, CSRG-based real-time selective capture and detection of UPEC in phosphate-buffered saline (PBS) solution, in clinically relevant concentrations, as opposed to other UTI-causing Gram-negative bacteria. The platform's detection limit is calculated to be 10⁵ CFU/mL (concentration on par with the clinical threshold for UTI diagnosis), with a dynamic range spanning four orders of magnitude. This work paves the way for the development of inexpensive point-of-care diagnosis devices focusing on effective treatment of UTIs, which are a burden on public healthcare due to the rise in the number of cases and their recurrences in the recent past.


nMETR: technique for facile recovery of hypomethylation genomic tags.
Genome-wide methylation studies frequently lack adequate controls to estimate proportions of background reads in the resulting datasets. To generate appropriate control pools, we developed technique termed nMETR (non-methylated tag recovery) based on digestion of genomic DNA with methylation-sensitive restriction enzyme, ligation of adapter oligonucleotide and PCR amplification of non-methylated sites associated with genomic repetitive elements. The protocol takes only two working days to generate amplicons for deep sequencing. We applied nMETR for human DNA using BspFNI enzyme and retrotransposon Alu-specific primers. 454-sequencing enabled identification of 1113 nMETR tag sites, of them ~65% were parts of CpG islands. Representation of reads inversely correlated with methylation levels, thus confirming nMETR fidelity. We created software that eliminates background reads and enables to map and annotate individual tags on human genome. nMETR tags may serve as the controls for large-scale epigenetic studies and for identifying unmethylated transposable elements located close to genomic CpG islands.


The Interplay between Phase Separation and Gene-Enhancer Communication: A Theoretical Study.
The phase separation occurring in a system of mutually interacting proteins that can bind on specific sites of a chromatin fiber is investigated here. This is achieved by means of extensive molecular dynamics simulations of a simple polymer model that includes regulatory proteins as interacting spherical particles. Our interest is particularly focused on the role played by phase separation in the formation of molecule aggregates that can join distant regulatory elements, such as gene promoters and enhancers, along the DNA. We find that the overall equilibrium state of the system resulting from the mutual interplay between binding molecules and chromatin can lead, under suitable conditions that depend on molecules concentration, molecule-molecule, and molecule-DNA interactions, to the formation of phase-separated molecular clusters, allowing robust contacts between regulatory sites. Vice versa, the presence of regulatory sites can promote the phase-separation process. Different dynamical regimes can generate the enhancer-promoter contact, either by cluster nucleation at binding sites or by bulk spontaneous formation of the mediating cluster to which binding sites are successively attracted. The possibility that such processes can explain experimental live-cell imaging data measuring distances between regulatory sites during time is also discussed.


HPA-10w(b) (La(a)): genetic determination of a new platelet-specific alloantigen on glycoprotein IIIa and its expression in COS-7 cells.
The heterodimeric complex glycoprotein (GP)IIb-IIIa, the fibrinogen receptor of platelets, carries numerous alloantigen systems. These polymorphisms are responsible for the immune response after transfusion or during pregnancy. In the latter case, the mother develops an antibody against an epitope present on fetal platelets, and this results in platelet destruction in the fetus. In this report, we describe the molecular characterization of a new alloantigen (La(a)) on GPIIIa responsible for neonatal alloimmune thrombocytopenia (NAIT). Using polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) and DNA sequencing, we found a point mutation (G to A) in a heterozygous state on the GPIIIa gene leading to amino acid substitution Arg to Gln at position 62 of the mature protein. Transient expression of GPIIb-IIIa complexes in Cos-7 cells using wild-type or mutated GPIIIa cDNA allowed us to demonstrate that this mutation was responsible for expression of the La(a) epitope.


Development of megestrol acetate solid dispersion nanoparticles for enhanced oral delivery by using a supercritical antisolvent process.
In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS) process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was <500 nm. Powder X-ray diffraction and differential scanning calorimetry measurements showed that megestrol acetate was present in an amorphous or molecular dispersion state within the solid dispersion nanoparticles. Hydroxypropylmethyl cellulose (HPMC) solid dispersion nanoparticles significantly increased the maximum dissolution when compared with polyvinylpyrrolidone K30 solid dispersion nanoparticles. The extent and rate of dissolution of megestrol acetate increased after the addition of a surfactant into the HPMC solid dispersion nanoparticles. The most effective surfactant was Ryoto sugar ester L1695, followed by D-α-tocopheryl polyethylene glycol 1000 succinate. In this study, the solid dispersion nanoparticles with a drug:HPMC:Ryoto sugar ester L1695 ratio of 1:2:1 showed >95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0-24 hours) and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol acetate solid dispersion nanoparticles using the supercritical antisolvent process is a promising approach to improve the dissolution and absorption properties of megestrol acetate.


A cost comparison of laboratory charges in treating childhood leukemia. A children's cancer group analysis.
A comparative cost analysis of the front-line acute lymphoblastic leukemia studies of two collaborative pediatric oncology groups was performed to document the charges incurred by the patients for only mandatory laboratory and radiographic data on each protocol. The required laboratory and radiographic data on each protocol were tabulated to derive the charges at Phoenix Children's Hospital in July 1992. A comparison between the two pediatric oncology groups was made for each risk category of patients with acute lymphoblastic leukemia. A consistent cost difference between the two groups was attributed to the relatively expensive laboratory support required on group Y protocols. The changing reimbursement environment is affecting the practice patterns of pediatric oncologists, who must be cognizant of the charges for performing scientific clinical trials. Pediatric oncologists must continue to provide quality care without jeopardizing progress.


Matrix stiffness triggers chemoresistance through elevated autophagy in pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) has a signature of extremely high matrix stiffness caused by a special desmoplastic reaction, which dynamically stiffens along with the pathological process. The poor prognosis and low five-year survival rate of PDAC are partly owing to chemoresistance triggered by substrate stiffness. Understanding the potential mechanisms of matrix stiffness causing PDAC chemoresistance is of great significance. In this study, methacrylated gelatin hydrogel was used as platform for PANC-1 and MIA-PaCa2 cell culture. The results indicated that compared to soft substrate, stiff substrate distinctively reduced the gemcitabine sensitivity of pancreatic cancer. Intriguingly, transmission electron microscopy, immunofluorescence staining, western blot and qRT-PCR assay showcased that the number of autophagosomes and the expression of LC3 were elevated. The observations indicate that matrix stiffness may regulate the autophagy level, which plays a vital role during chemoresistance. In brief, soft substrate exhibited low autophagy level, while the counterpart displayed elevated autophagy level. In order to elucidate the underlying interaction between matrix stiffness-mediated cell autophagy and chemoresistance, rescue experiments with rapamycin and chloroquine were conducted. We found that inhibiting cell autophagy dramatically increased the sensitivity of pancreatic cancer cells to gemcitabine in the stiff group, while promoting autophagy-driven chemoresistance in the soft group, demonstrating that matrix stiffness modulated chemoresistance via autophagy. Furthermore, RNA-seq results showed that miR-1972 may regulate autophagy level in response to matrix stiffness. Overall, our research shed light on the synergistic therapy of PDAC combined with gemcitabine and chloroquine, which is conducive to promoting a therapeutic effect.


Adverse events, compliance, and changes in therapy.
Compliance with medical therapy represents a multifactorial problem with marked consequences for individual and public health. Among the many contributing factors, the choice of drug may also determine the degree of compliance. Various studies investigating either compliance or persistence with antihypertensive therapy using a variety of methods have suggested that adherence to therapy may show the following pattern: diuretics < beta-blockers < calcium channel blockers < ACE inhibitors. Furthermore, two recent studies have shown that therapy with angiotensin II receptor blockers may be associated with better long-term adherence than other antihypertensive monotherapies including angiotensin converting enzyme inhibitors. Since medication compliance with antihypertensive therapy, among other factors, closely correlates with the experience of side effects, it may be speculated that the different classes of antihypertensives may induce varying degrees of compliance and persistence due to their different tolerability profiles. Side effects may induce variable compliance and nonpersistence by yet another mechanism. Therapy turbulence, ie, any change in medication, is also associated with nonpersistence. Therefore, side effects may directly or indirectly (via inducing therapy turbulence) underly variable compliance and nonpersistence.


The cost-effectiveness of early cabergoline treatment compared to levodopa in Sweden.
The cost of Parkinson's disease (PD) is associated with the progression of the disease. Levodopa is a potent treatment for this disease, but long-term treatment results in motor complications that are associated with both costs and considerable patient discomfort. The introduction of dopamine agonists early in the treatment of PD leads to a delay in these complications, but the treatment as such is associated with higher costs. We compared the cost-effectiveness of the dopamine agonist cabergoline (with the possibility of adding levodopa later) with that of levodopa alone. A Markov model with states of the disease without motor complications defined by Hoehn and Yahr stages, and a specific state for patients with motor complications was constructed. Transition probabilities between Hoehn and Yahr states were calculated from a previously published clinical trial using an ordered probit regression model. The risk of suffering from motor complications was estimated using a Weibull model. Mortality was assumed to be the same as in the general population. Costs were estimated based on a cross-sectional study performed in southern Sweden, and only direct costs were included. In the base case the model was run for 5 years (10 cycles) and extended to 10 years in a sensitivity analysis, and costs and effects were discounted at a rate of 3%. In the base case it was predicted that the cost in the levodopa arm was 7,453 euros (67,754 Swedish crowns) compared to 11,777 euros (107,065 crowns) in the cabergoline arm. However, patients treated with cabergoline gained 0.31 years without motor complications, giving an incremental cost-effectiveness ratio for cabergoline of 13,863 euros (126,023 crowns) per year of motor complications avoided (YMA). Running the model for 10 years resulted in a more favorable cost-effectiveness ratio: 6,122 euros/YMA (55,659 crowns). The model was robust to variations in discounting rates and to variations in the estimation of costs. Although no benchmark figure pertaining specifically to Parkinson's disease has been reported to suggest the economic value of a year without motor complications (gained as a result of treatment for Parkinson's disease), US$ 60,000 per QALY gained is a figure that is often used to assess cost-effectiveness in the literature. Using this criterion, cabergoline is cost-effective if the treatment saves 0.065 QALYs. Cabergoline is even more likely to be cost-effective when also considering indirect and informal costs. More research on the relationship between motor complications and quality of life is needed.