A systematic review of the limitations and approaches to improve detection and management of peripheral arterial disease in Hispanics.
Peripheral arterial disease (PAD) is a highly prevalent public health problem associated with major detrimental effects on quality of life and functional status, and it is also the main cause of limb amputation. More importantly, PAD has been classified as a coronary artery disease equivalent, meaning that patients with a diagnosis of PAD carry a risk for major coronary events equal to that of established coronary artery disease. PAD is also a potent predictor of stroke and death. Despite its frequent occurrence (8 to 10 million Americans are affected), little is known about the natural history of PAD in racial/ethnic minorities, particularly in Hispanics, who represent 12.5% of the United States population. Furthermore, the disease is commonly underdiagnosed and undertreated in this minority group, and outcomes are poorer in Hispanics as compared with whites. Limited access to health care, difficulties for recruitment in population-based studies, and limitations of the noninvasive screening tests are well-established barriers to determine the prevalence and natural history of PAD in Hispanics. Although the most widely used test for assessment of patients at risk for PAD is the ankle-brachial index (ABI), the test has substantial limitations in individuals with diabetes and arterial calcification, which are highly prevalent in Hispanics. The ABI should, therefore, be supplemented by the use of other noninvasive tests, such as the pulse volume recordings (PVR) and toe-brachial index. Besides the use of a combination of diagnostic techniques, the implementation of a research methodology that improves recruitment of Hispanics in population-based studies is necessary to obtain better knowledge of the epidemiology of the disease in this group. Community-based participatory research may be the most appropriate approach to study this ethnic minority because it overcomes barriers for limited access to health care and increases the possibility of overcoming distrust of research on the part of communities. Understanding the epidemiology of PAD to improve its detection and treatment among Hispanics is relevant to reduce disparities in the health status of this group, the most rapidly growing ethnic minority in the United States.


Mutans streptococcal infection induces salivary antibody to virulence proteins and associated functional domains.
The interplay between mucosal immune responses to natural exposure to mutans streptococci and the incorporation and accumulation of these cariogenic microorganisms in oral biofilms is unclear. An initial approach to explore this question would be to assess the native secretory immunity emerging as a consequence of Streptococcus mutans infection. To this end, we analyzed salivary immunoglobulin A (IgA) antibody to mutans streptococcal glucosyltransferase (Gtf) and glucan binding protein B (GbpB) and to domains associated with enzyme function and major histocompatibility complex (MHC) class II binding in two experiments. Salivas were collected from approximately 45-day-old Sprague-Dawley rats, which were then infected with S. mutans SJ32. Infection was verified and allowed to continue for 2 to 2.5 months. Salivas were again collected following the infection period. Pre- and postinfection salivas were then analyzed for IgA antibody activity using peptide- or protein-coated microsphere Luminex technology. S. mutans infection induced significant levels of salivary IgA antibody to Gtf (P < 0.002) and GbpB (P < 0.001) in both experiments, although the levels were usually far lower than the levels achieved when mucosal immunization is used. Significantly (P < 0.035 to P < 0.001) elevated levels of postinfection salivary IgA antibody to 6/10 Gtf peptides associated with either enzyme function or MHC binding were detected. The postinfection levels of antibody to two GbpB peptides in the N-terminal region of the six GbpB peptides assayed were also elevated (P < 0.031 and P < 0.001). Interestingly, the patterns of the rodent response to GbpB peptides were similar to the patterns seen in salivas from young children during their initial exposure to S. mutans. Thus, the presence of a detectable postinfection salivary IgA response to mutans streptococcal virulence-associated components, coupled with the correspondence between rat and human mucosal immune responsiveness to naturally presented Gtf and GbpB epitopes, suggests that the rat may be a useful model for defining mucosal responses that could be expected in humans. Under controlled infection conditions, such a model could prove to be helpful for unraveling relationships between the host response and oral biofilm development.


Candidate locus approach for studying the genetics of asthma and atopy.
Insights into the complex genetic factors underlying asthma and atopy have arisen from investigating genes whose functions are likely to be involved in the pathogenesis of these disorders. Candidate genes have now been studied on 13 human autosomes, and genetic linkage analysis and association studies have identified potentially important genes on chromosomes 5, 6, 11 and 14. However, these four regions do not account for all the heritability of these disorders, and additional regions are now being identified by systematic searches of the whole genome.


Radio-Guided Occult Lesion Localization With 99m Tc for the Localization of Nonpalpable Melanoma and Soft Tissue Sarcoma Lesions: A Feasibility Study.
Localization techniques are needed to facilitate resection of nonpalpable lesions. In this study, the feasibility of radio-guided occult lesion localization (ROLL) with 99m Tc is investigated for the localization of nonpalpable, small, suspicious, or proven melanoma or soft tissue sarcoma lesions at various locations throughout the body. Patients with nonpalpable, suspicious, or proven melanoma or soft tissue sarcoma lesions were selected for this study. Within 24 hours before surgery, a median dose of 33.92 MBq 99m Tc-labeled human albumin particles ( 99m Tc-NA or 99m Tc-MAA) was injected in the lesion under ultrasound guidance. A hand-held gamma probe was used to detect the radioactive signal and guidance during surgery. In this study, 20 patients with a total of 25 lesions were included and analyzed. The median size of the lesions was 1.8 cm (interquartile range [IQR], 1.8-4.0 cm), of which 44% were intramuscular located and 36% were subcutaneous, and 20% consisted of suspicious lymph nodes, mostly in the lower extremity. At median 4 hours (IQR, 3-6 hours) postinjection, 99m Tc ROLL showed a 100% intraoperative identification rate with proper signal identification with the gamma probe in all patients. With a median surgery time of 76 minutes (IQR, 45-157 minutes), all targeted lesions could be resected without 99m Tc-related complications, resulting in 88% microscopically margin-negative resection. No reoperations were needed for the same lesion. The 99m Tc ROLL procedure is feasible for the localization and excision of small, nonpalpable melanoma and soft tissue sarcoma lesions at various locations in the body.


Glutamate controls vessel-associated migration of GABA interneurons from the pial migratory route via NMDA receptors and endothelial protease activation.
During cortex development, fine interactions between pyramidal cells and migrating GABA neurons are required to orchestrate correct positioning of interneurons, but cellular and molecular mechanisms are not yet clearly understood. Functional and age-specific expression of NMDA receptors by neonate endothelial cells suggests a vascular contribution to the trophic role of glutamate during cortical development. Associating functional and loss-of-function approaches, we found that glutamate stimulates activity of the endothelial proteases MMP-9 and t-PA along the pial migratory route (PMR) and radial cortical microvessels. Activation of MMP-9 was NMDAR-dependent and abrogated in t-PA-/- mice. Time-lapse recordings revealed that glutamate stimulated migration of GABA interneurons along vessels through an NMDAR-dependent mechanism. In Gad67-GFP mice, t-PA invalidation and in vivo administration of an MMP inhibitor impaired positioning of GABA interneurons in superficial cortical layers, whereas Grin1 endothelial invalidation resulted in a strong reduction of the thickness of the pial migratory route, a marked decrease of the glutamate-induced MMP-9-like activity along the PMR and a depopulation of interneurons in superficial cortical layers. This study supports that glutamate controls the vessel-associated migration of GABA interneurons by regulating the activity of endothelial proteases. This effect requires endothelial NMDAR and is t-PA-dependent. These neurodevelopmental data reinforce the debate regarding safety of molecules with NMDA-antagonist properties administered to preterm and term neonates.


Improved metathesis lifetime: chelating pyridinyl-alcoholato ligands in the second generation Grubbs precatalyst.
Hemilabile ligands can release a free coordination site "on demand" of an incoming nucleophilic substrate while occupying it otherwise. This is believed to increase the thermal stability and activity of catalytic systems and therefore prevent decomposition via free coordination sites. In this investigation chelating pyridinyl-alcoholato ligands were identified as possible hemilabile ligands for incorporation into the second generation Grubbs precatalyst. The O,N-alcoholato ligands with different steric bulk could be successfully incorporated into the precatalysts. The incorporation of the sterically hindered, hemilabile O,N-ligands improved the thermal stability, activity, selectivity and lifetime of these complexes towards the metathesis of 1-octene. A decrease in the activity of the second generation Grubbs precatalyst was additionally observed after incorporating a hemilabile O,N-ligand with two phenyl groups into the system, while increasing their lifetime.


PVDF Nanofiber Modified with ZnO Nanowires/Polydopamine for the Treatment of Sewage Containing Heavy Metals, Organic Dyes, and Bacteria.
In various countries worldwide, the issue of wastewater contamination poses a significant threat due to its intricate composition of heavy metals, organic dyes, and microorganisms, thereby complicating the purification process. Consequently, researchers have expressed considerable interest in materials capable of eliminating organic, heavy metal, and microbial pollutants. This study focuses on the fabrication of a water purification membrane (PDA/ZnO-NWs/PVDF) with a hierarchical structure and the ability to remove multiple pollutants. The membrane was created by modifying poly(vinylidene fluoride) (PVDF) nanofiber with zinc oxide nanowires (ZnO-NWs) and reinforcing it with polydopamine (PDA). The experimental results demonstrate that the PDA/ZnO-NWs/PVDF membrane exhibits a range of functionalities, including long-lasting superhydrophilicity, Cu(II) adsorption, photocatalytic degradation, and antibacterial ability. The manipulation of the DA synthesis procedure allows for the adjustment of the wettability, adsorption, and photocatalytic and antibacterial activities of the PDA/ZnO-NWs/PVDF composite. According to the Langmuir isotherm, the maximum Cu(II) adsorption capacity of the PDA/ZnO-NWs/PVDF membrane is determined to be 65.75 mg/g, which is significantly higher (27.26 mg/g) than that of the ZnO-NWs/PVDF membrane (38.49 mg/g). The PDA/ZnO-NWs/PVDF composite exhibited a notable degradation capacity toward rhodamine B under natural sunlight, reaching a maximum of 5.97 mg/g. Additionally, the degradation rate achieved during daylight hours was as high as 90.42%. Furthermore, the antibacterial efficacy of the PDA/ZnO-NWs/PVDF composite against both Gram-positive and Gram-negative bacteria approached 100%. This work presents a promising approach for the treatment of wastewater containing various coexisting contaminants.


Variations of total vertical maxillary excess.
The long-face syndrome is a well-recognized entity, yet the pathogenesis of this malformation remains obscure and variations are generally not recognized. Fifty lateral cephalometric radiographs of patients who underwent vertical maxillary reductions were studied using the architectural and structural analysis of Delaire. Several subgroups of vertical maxillary excess that had not been recognized previously were identified. The most common dysmorphic type was the classically described long-face syndrome; the next most common consisted of patients who had short upper lips, normal maxillas, and long faces secondary to vertical chin excess. In all, six different variations of vertical maxillary excess were identified. Concomitantly, in the majority of cases there was associated vertical mandibular chin excess. It is suggested that these variations may have differing pathogeneses.


Eph-Pak2a signaling regulates branching of the pharyngeal endoderm by inhibiting late-stage epithelial dynamics.
Branching morphogenesis depends on the precise temporal and spatial control of epithelial dynamics. In the vertebrate head, endodermal branches, called pharyngeal pouches, form through the transient stratification, collective migration and reorganization of epithelial cells into bilayers. Here, we report novel requirements for the EphrinB ligands B2a and B3b, the Ephb4a receptor and the Pak2a kinase in the development of pouches and the posterior facial skeleton that depends on pouches for its segmentation. Time-lapse imaging in zebrafish shows that EphB-Pak2a signaling is required to stabilize pouch epithelial cells at the end of branching morphogenesis. Transgenic rescue experiments further demonstrate that endodermal Eph-ephrin signaling promotes pouch integrity by targeting Pak2a to the plasma membrane, where subsequent activation by Wnt4a-Cdc42 signaling increases junctional E-cadherin in maturing pouches. Integration of Eph-ephrin and Wnt4a signaling through Pak2a thus signals the end of branching morphogenesis by increasing intercellular adhesion that blocks further epithelial rearrangements.


Inhibition of VEGF and Angiopoietin-2 to Reduce Brain Metastases of Breast Cancer Burden.
For metastases in the central nervous system, angiogenesis enhances metastatic potential and promotes progression. Primary factors which drive vessel growth are vascular endothelial growth factor (VEGF) and angiopoietin-2. Preclinical models show inhibition of either factor reduces metastases spread and inhibits growth. This work sets out to answer two questions in a preclinical mouse model. First, whether the combined inhibition of VEGF and angiopoietin-2, reduces passive permeability and limits drug uptake into brain metastases; and second, whether this inhibition reduces metastases burden in brain. We observed combinatorial inhibition of VEGF and angiopoietin-2, decreased (p < 0.05) angiogenesis and vascular branching in an aortic ring assay and decreased (p < 0.05) endothelial wound closure times. Using a brain metastases of breast cancer model (induced by intracardiac injections of brain seeking MDA-MB-231Br cells or 4T1Br cells), we observed, similar to VEGF, angiopoetin-2 expression correlates to increased angiogenesis (p < 0.05) and increased lesion permeability. To determine efficacy, animals were administered bevacizumab plus L1-10 (angiopoietin inhibitor) twice per week until neurological symptoms developed. Lesion permeability significantly decreased by ∼50% (p < 0.05) compared to untreated lesions, but remained ∼25% greater (p < 0.0%) than brain. In subsequent experiments, animals were administered similar regimens but sacrificed on day 32. The number of metastatic lesions developed was significantly (p < 0.001) reduced in the bevacizumab group (56%) and combination group (86%). Lesions' size was reduced in bevacizumab treated lesions (∼67%) and bevacizumab and L1-10 treated lesions (∼78%) developing area < 0.5 mm2. In summary, combinatorial inhibition of VEGF and angiopoietin reduces lesion permeability and brain metastatic burden.


Effect of protein intake on plasma and erythrocyte free amino acids and serum IGF-I and IGFBP-1 levels in rats.
Amino acid (AA) levels in plasma and erythrocytes (RBC) were determined in rats (n = 29) fed diets with 6, 21, and 35% protein, and their association with insulin-like growth factor I (IGF-I), insulin, or IGF-binding protein (IGFBP)-1 levels was studied. Free AA in plasma and RBC were determined by reversed-phase high-pressure liquid chromotography, and IGF-I, IGFBP-1, and insulin plasma levels were determined by RIA. Rats fed the low-protein (6%) diet were growth-retarded and had lower serum IGF-I levels and higher serum IGFBP-1 levels than the other two groups (P < 0.0001). In rats fed the low-protein diet, most of the nonessential AA (NEAA) in both plasma and RBC increased, whereas the essential AA (EAA), with the exception of threonine, decreased. When the groups were combined, both RBC and plasma EAA-to-NEAA ratios were positively correlated to IGF-I (r = 0.76 and 0.80, respectively; P < 0.0001) and inversely correlated to IGFBP-1 levels (r = -0.67, P < 0.001 and r = -0.78, P < 0.0001, respectively). A significant inverse correlation was found between RBC glutamate and IGF-I (r = -0.85, P < 0.0001, n = 25) and insulin (r = -0.72, P < 0.001, n = 21), and a positive correlation was found for IGFBP-1 (r = 0.78, P < 0.0001, n = 24). In multiple regression analysis, only IGF-I remained as an independent variable. Threonine was the only EAA with a significant inverse correlation to insulin (r = -0.66, P < 0.001). We hypothesize that AA metabolism is associated to changes in IGF-I, insulin, and IGFBP-1 levels in rats on different protein intakes.


Clostridium botulinum type A haemagglutinin-positive progenitor toxin (HA(+)-PTX) binds to oligosaccharides containing Gal beta1-4GlcNAc through one subcomponent of haemagglutinin (HA1).
Haemagglutinin (HA) activity of Clostridium botulinum type A 19S and 16S toxins (HA-positive progenitor toxin; HA(+)-PTX) was characterized. HA titres against human erythrocytes of HA(+)-PTX were inhibited by the addition of lactose, D-galactose, N-acetyl-D-galactosamine and D-fucose to the reaction mixtures. A direct glycolipid binding test demonstrated that type A HA(+)-PTX strongly bound to paragloboside and some neutral glycolipids, but did not bind to gangliosides. Type A HA(+)-PTX also bound to asialoglycoproteins (asialofetuin, neuraminidase-treated transferrin), but not to sialoglycoproteins (fetuin, transferrin). Although glycopeptidase F treatment of asialofetuin abolished the binding of HA(+)-PTX, endo-alpha-N-acetylgalactosaminidase treatment did not. Thus these results can be interpreted as indicating that type A HA(+)-PTX detects and binds to Gal beta 1-4GlcNAc in paragloboside and the N-linked oligosaccharides of glycoproteins. Regardless of neuraminidase treatment, type A HA(+)-PTX bound to glycophorin A which is a major sialoglycoprotein on the surface of erythrocytes. Both native glycophorin A and neuraminidase-treated glycophorin A inhibited the binding of erythrocytes to type A HA(+)-PTX. Since the N:-linked oligosaccharide of glycophorin A is di-branched and more than 50% of this sugar chain is monosialylated, type A HA(+)-PTX probably bound to the unsialylated branch of the N-linked oligosaccharide of glycophorin A and agglutinated erythrocytes. One subcomponent of HA, designated HA1, did not agglutinate native erythrocytes, although it did bind to erythrocytes, paragloboside and asialoglycoproteins in a manner quite similar to that of HA(+)-PTX. These results indicate that type A HA(+)-PTX binds to oligosaccharides through HA1.


Neuromuscular exercise for chronic musculoskeletal pain in older people: a randomised controlled trial in primary care in Hong Kong.
Exercise therapy is commonly prescribed by primary care physicians (PCPs) in the management of chronic musculoskeletal (MSK) pain. To evaluate the clinical effectiveness of a supervised neuromuscular (NM) exercise programme in older people with chronic MSK pain. This was a 12-week, two-arm, randomised controlled trial comparing 6 weeks of supervised NM exercise versus waiting list controls. The authors enrolled 72 participants with chronic MSK pain at seven public primary care clinics. Participants were randomly allocated in block sizes of 12 to the NM (n = 36) and control groups (n = 36) in a 1:1 ratio. Data were collected at baseline, 6, and 12 weeks. The primary outcome was the Brief Pain Inventory (BPI) pain severity score at 6 weeks post-intervention. Secondary outcomes included the BPI interference score; Pain Self-Efficacy Questionnaire (PSEQ), Short Form Health Survey (SF-12), 7-item Generalised Anxiety Disorder (GAD-7), and 9-item Patient Health Questionnaire (PHQ-9) scores; and functional measurements using the Timed-Up- and-Go test and handgrip strength. At 6 weeks, the NM group demonstrated a significantly greater improvement in the BPI pain severity score (between-group difference = -1.27; 95% confidence interval [CI] = -2.08 to -0.45; P<0.01), PSEQ (between-group difference = 6.5; 95% CI = 2.22 to 10.77; P<0.01), and SF-12 physical scores (between-group difference = 3.4; 95% CI = 0.05 to 6.75; P<0.05) compared with the control group. Statistically significant overall trends of improvement were also observed for the BPI interference and PHQ-9 scores. NM exercise has the potential to reduce pain and improve self-efficacy and physical function in older people with chronic MSK pain. It can be an option for PCPs in exercise prescriptions.


Patient and provider predictors of telemental health use prior to and during the COVID-19 pandemic within the Department of Veterans Affairs.
The current study examined patient and provider differences in use of phone, video, and in-person mental health (MH) services. Participants included patients who completed ≥ 1 MH appointment within the Department of Veterans Affairs (VA) from 10/1/17-7/10/20 and providers who completed ≥ 100 VA MH appointments from 10/1/17-7/10/20. Adjusted odds ratios (aORs) are reported of patients and providers: (a) completing ≥1 video MH appointment in the pre-COVID (10/1/17-3/10/20) and COVID (3/11/20-7/10/20) periods; and (b) completing the majority of MH visits via phone, video, or in-person during COVID. The sample included 2,480,119 patients/31,971 providers in the pre-COVID period, and 1,054,670 patients/23,712 providers in the COVID period. During the pre-COVID and COVID periods, older patients had lower odds of completing ≥ 1 video visit (aORs < .65). During the COVID period, older age and low socioeconomic status predicted lower odds of having ≥ 50% of visits via video versus in-person or phone (aORs < .68); schizophrenia and MH hospitalization history predicted lower odds of having ≥ 50% of visits via video or phone versus in-person (aORs < . 64). During the pre-COVID and COVID periods, nonpsychologists (e.g., psychiatrists) had lower odds of completing video visits (aORs < . 44). Older providers had lower odds of completing ≥ 50% of visits via video during COVID (aORs <. 69). Findings demonstrate a digital divide, such that older and lower income patients, and older providers, engaged in less video care. Nonpsychologists also had lower video use. Barriers to use must be identified and strategies must be implemented to ensure equitable access to video MH services. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone: adverse effects at 12-month follow-up. ACTOBAT Study Group.
The Australian Collaborative Trial of Antenatal Thyrotropin-Releasing Hormone (ACTOBAT) assessed the efficacy of 200 microg of thyrotropin-releasing hormone (TRH) in combination with glucocorticoids in the prevention of neonatal lung disease. This paper reports the 12-month follow-up of the infants from the trial completed in 1994. This was a double-blinded randomized controlled trial. Women were recruited from level 3 perinatal centers throughout Australia. Mothers who had not withdrawn from treatment and whose infants were discharged alive (1262 infants). Extensive efforts were made to trace this entire cohort. A questionnaire was mailed to parents for self-completion immediately before their baby's/babies' first birthday. The questionnaire included a checklist to assess sensory, motor, language, and social development, and use of health services. Milestone scores were developed from items on the follow-up form. Treatment with TRH was associated with an increased risk of motor delay, social delay, fine motor delay, sensory impairment, and early language impairment. No differences were seen between treatment and placebo groups for motor impairment. Multivariate analyses were performed, adjusting for chronological age, duration of gestation at randomization, time from randomization to delivery, parity, history of perinatal death, history of preterm rupture of the membranes, infant sex, singleton or twin status, maternal age, and maternal blood pressure (systolic and diastolic) at randomization. For the total cohort (N = 1022), treatment with TRH was associated with motor delay (odds ratio [OR], 1.51; 95% confidence interval [CI] 1.11 to 2.05); social delay (OR 1.40; 95% CI 1.01 to 1.95); sensory impairment (OR, 2.00; 95% CI 1.06 to 3.74); severe impairment (OR, 1.75; 95% CI 1.07 to 2.87); and a trend toward motor impairment (OR, 1.50; 95% CI .97 to 2.33), early language impairment (OR, 1.27, 95% CI .90 to 1.79), and fine motor delay (OR, 1.15; 95% CI .83 to 1.60). There were no differences between the treatment groups in hospital admissions (OR, 1.08; 95% CI .83 to 1.42), doctors' visits (general practitioner OR adj, 1.09; 95% CI .79 to 1.50 or specialist OR adj 1.15; 95% CI .87 to 1.49), respiratory symptoms (OR adj, 1.16; 95% CI .88 to 1.53), or behavioral disturbances (OR adj, .93; 95% CI .71 to 1.21). Because antenatal administration of TRH is associated with small, consistent deficits in major milestone achievements at 12 months of age, it is essential that additional planned trials make provision for long-term follow-up. Antenatal TRH should only be used in the context of a clinical trial.


Enhanced selectivity of hyperthermic purging of human progenitor cells using Goralatide, an inhibitor of cell cycle progression.
Recurrence of leukemia is a major problem after autologous stem cell transplantation. One potential means of reducing this risk is to purge the autologous transplant in vitro by hyperthermia. We have demonstrated that after a hyperthermic treatment of 120 min at 43 degrees C, the leukemic progenitor cells (CFU-AML) are decreased by 5-log but the normal hematopoietic committed progenitor cells (CFU-GM, BFU-E and CFU-E) are reduced by only 1-log. Moreover, the hyperthermic sensitivity coincides with the stem cell hierarchy, ie CFU-GM are less heat sensitive than BFU-E, while CFU-E are the most sensitive. The impact of pretreatment with the tetrapeptide AcSDKP (Goralatide) on the proliferative activity and heat sensitivity of the normal and leukemic progenitor cells was determined. An incubation of 21 h at 37 degrees C with 10(-9) M Goralatide reduces the number of normal hematopoietic progenitor cells in S-phase and concomitantly decreases their hyperthermic sensitivity. This effect implies that the proliferative activity is the major determinant for the detected differences in hyperthermic sensitivity of the subsets in the normal hematopoietic stem cell compartment. In contrast, the cell cycle progression of leukemic progenitor cells is not affected and hence these cells are not protected from hyperthermia-induced cell killing after preincubation with Goralatide. Thus, the treatment with Goralatide increases the therapeutic window of hyperthermia and increases the potential value of this physical purging technique.


Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study.
Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.


Physical Chemistry of Bile: Detailed Pathogenesis of Cholelithiasis.
Despite the overwhelming prevalence of cholelithiasis, many health care professionals are not familiar with the basic pathophysiology of gallstone formation. This article provides an overview of the biochemical pathways related to bile, with a focus on the physical chemistry of bile. We describe the important factors in bile synthesis and secretion that affect the composition of bile and consequently its liquid state. Within this biochemical background lies the foundation for understanding the clinical and sonographic manifestation of cholelithiasis, including the pathophysiology of cholesterol crystallization, gallbladder sludge, and gallstones. There is a brief discussion of the clinical manifestations of inflammatory and obstructive cholestasis and the impact on bile metabolism and subsequently on liver function tests. Despite being the key modality in diagnosing cholelithiasis, ultrasound has a limited role in the characterization of stone composition.


Model-Informed Precision Dosing of Antibiotics in Pediatric Patients: A Narrative Review.
Optimal pharmacotherapy in pediatric patients with suspected infections requires understanding and integration of relevant data on the antibiotic, bacterial pathogen, and patient characteristics. Because of age-related physiological maturation and non-maturational covariates (e.g., disease state, inflammation, organ failure, co-morbidity, co-medication and extracorporeal systems), antibiotic pharmacokinetics is highly variable in pediatric patients and difficult to predict without using population pharmacokinetics models. The intra- and inter-individual variability can result in under- or overexposure in a significant proportion of patients. Therapeutic drug monitoring typically covers assessment of pharmacokinetics and pharmacodynamics, and concurrent dose adaptation after initial standard dosing and drug concentration analysis. Model-informed precision dosing (MIPD) captures drug, disease, and patient characteristics in modeling approaches and can be used to perform Bayesian forecasting and dose optimization. Incorporating MIPD in the electronic patient record system brings pharmacometrics to the bedside of the patient, with the aim of a consisted and optimal drug exposure. In this narrative review, we evaluated studies assessing optimization of antibiotic pharmacotherapy using MIPD in pediatric populations. Four eligible studies involving amikacin and vancomycin were identified from 418 records. Key articles, independent of year of publication, were also selected to highlight important attributes of MIPD. Although very little research has been conducted until this moment, the available data on vancomycin indicate that MIPD is superior compared to conventional dosing strategies with respect to target attainment. The utility of MIPD in pediatrics needs to be further confirmed in frequently used antibiotic classes, particularly aminoglycosides and beta-lactams.


Exome-Wide Meta-Analysis Identifies Rare 3'-UTR Variant in ERCC1/CD3EAP Associated with Symptoms of Sleep Apnea.
Obstructive sleep apnea (OSA) is a common sleep breathing disorder associated with an increased risk of cardiovascular and cerebrovascular diseases and mortality. Although OSA is fairly heritable (~40%), there have been only few studies looking into the genetics of OSA. In the present study, we aimed to identify genetic variants associated with symptoms of sleep apnea by performing a whole-exome sequence meta-analysis of symptoms of sleep apnea in 1,475 individuals of European descent. We identified 17 rare genetic variants with at least suggestive evidence of significance. Replication in an independent dataset confirmed the association of a rare genetic variant (rs2229918; minor allele frequency = 0.3%) with symptoms of sleep apnea (p-valuemeta = 6.98 × 10-9, βmeta = 0.99). Rs2229918 overlaps with the 3' untranslated regions of ERCC1 and CD3EAP genes on chromosome 19q13. Both genes are expressed in tissues in the neck area, such as the tongue, muscles, cartilage and the trachea. Further, CD3EAP is localized in the nucleus and mitochondria and involved in the tumor necrosis factor-alpha/nuclear factor kappa B signaling pathway. Our results and biological functions of CD3EAP/ERCC1 genes suggest that the 19q13 locus is interesting for further OSA research.


Association between adequacy of antenatal care and neonatal outcomes in Rwanda: a cross-sectional study design using the Rwanda demographic and health surveys.
Maternal and neonatal health services are life-saving interventions for neonatal health outcomes. As Rwanda endeavors to accomplish sustainable development goals, adequate ANC is essential to lessen of neonatal mortality. The utilization of ANC continues to be inadequate and high neonatal mortality rate persevere in Rwanda. Understanding the direct and indirect factors that affect newborn health outcomes is necessary for well-targeted interventions. However, few studies had been conducted in Rwanda to evaluate the importance of ANC in improving neonatal health. This study therefore assessed the association between ANC and neonatal outcomes. The Demographic and Health Surveys (DHS) are household surveys that are cross-sectional, nationally representative, and used to collect data on population, health, and nutrition. Data from the 2010,2015 and 2020 Rwanda Demographic and Health Surveys (RDHS) were used. The study involved 17,747 women between the ages of 15 and 49 who had a single live birth and at least one ANC visit in five years prior to each survey. Bivariate and multivariable logistic regression, a survey adjusted for clusters at multiple level, and the estimation of adjusted odds ratios (aOR) and 95% confidence intervals were used to evaluate the relationship between the outcome and independent variables. Out of 17,747 women ;7638(42.91%) of the mothers had adequate ANC visits and low birth weight (LBW) was found among 833(4.63%) neonates. The birth of a LBW baby (aOR:4.64;95%CI:3.19,6.74) was directly related to increased odds of neonatal death. Mothers aged 20-34 years (aOR:0.40; 95%CI:0.20,0.81), a preceding birth interval of 24months or greater (aOR:0.41:95%CI:0.28,0.60), baby being female (aOR:0.72; 95%CI:0.54,0.96), having adequate ANC visits (aOR:0.64;95% CI:0.46,0.89) and the birth order of the newborn being ranked second or third (aOR:0.60; 95%CI:0.38,0.95) were negatively associated with neonatal death. Health education programs targeting teen and primigravida mothers should be encouraged. Among the newborn survival interventions, addressing short birth intervals and the effective management of LBW cases should be explored. The findings confirm the fundamental importance of adequate ANC in the neonatal survival.


Recent Advances in Bioinspired Hydrogels: Materials, Devices, and Biosignal Computing.
The remarkable ability of biological systems to sense and adapt to complex environmental conditions has inspired new materials and novel designs for next-generation wearable devices. Hydrogels are being intensively investigated for their versatile functions in wearable devices due to their superior softness, biocompatibility, and rapid stimulus response. This review focuses on recent strategies for developing bioinspired hydrogel wearable devices that can accommodate mechanical strain and integrate seamlessly with biological systems. We will provide an overview of different types of bioinspired hydrogels tailored for wearable devices. Next, we will discuss the recent progress of bioinspired hydrogel wearable devices such as electronic skin and smart contact lenses. Also, we will comprehensively summarize biosignal readout methods for hydrogel wearable devices as well as advances in powering and wireless data transmission technologies. Finally, current challenges facing these wearable devices are discussed, and future directions are proposed.


Monitoring hyperhydration during high-dose chemotherapy: body weight or fluid balance?
Body weight and fluid input/output are usually monitored for checking fluid balance in case of intravenous hyperhydration during nephrotoxic chemotherapy. The reliability of measuring fluid input/output is uncertain. Moreover, this measurement is redundant, complex, labour-intensive and represents an occupational hazard for nurses and other health-care workers handling fluids or body excreta. In a prospective cohort study, we determined the concordance between body weight and fluid intake/output. We also examined the clinical consequences with respect to the safety of selecting only body weight measurement as a parameter for fluid overload. A total of 591 combined observations of fluid balances and body weights were collected. We observed a higher increase in body weight than in fluid balance. The Pearson correlation between fluid balance and body weight was relatively low (r = 0.28). With regard to the safety of measuring body weight only, we found 4 cases (0.6%) who might not have received furosemide if the fluid input/output had not been measured, without clinical consequences, however. After standardization, body weight can safely be used as the only parameter for monitoring fluid retention in case of hyperhydration during chemotherapy.


Extracapsular invasion as a risk factor for disease recurrence in colorectal cancer.
To evaluate the presence of extracapsular invasion (ECI) in positive nodes as a predictor of disease recurrence disease in colorectal cancer. Two hundred and twenty-eight consecutive patients who underwent colorectal resection were identified for inclusion in this study, of which 46 had positive lymph nodes. Among 46 cases with stage IIIcolorectal cancer, 16 had ECI at positive nodes and 8 had disease recurrence. The clinical and pathological features of these cases were reviewed. In the univariate analysis, the number of positive lymph nodes and depth of tumor invasion were significantly associated with the presence of ECI at positive nodes. Multivariate analysis demonstrated that only ECI was a predictor of recurrence. The recurrence-free interval differed significantly among patients with ECI at positive nodes. Our results suggest that ECI at metastatic nodes can identify which cases are at high risk of short-term disease recurrence in colorectal cancer.


Polycyclic pyrroloindoline-containing natural products with a unique 3-heptyl-2a,4a-diazapentaleno[1,6-ab]indene core isolated from Alstonia scholaris.
Alscholarine C (1), featuring an unprecedented pyrroloindoline-containing natural product (PiNP) with a 6/5/5/5 tetracyclic carbon skeleton, and four known PiNPs (2-5), namely demethylalstoscholarinine E (2), Nb-demethylechitamine (3), winphylline A (4), and echitamine (5), were isolated from Alstonia scholaris. Compound 1 was characterized by a hexahydropyrrolo[2,3-b] indole (HPI) core fused to a unique 4-heptylimidazolidine motif, forming an unparalleled 3-heptyl-2a,4a-diazapentaleno[1,6-ab]indene ring system. Their structures were established by spectroscopic analysis, quantum-chemical calculated 13C NMR data with DP4+ probability analyses, and ECD calculations and comparison. A plausible biosynthetic pathway of 1 was proposed. Compound 1 exhibited potential anti-inflammatory activity against LPS-stimulated NO production in RAW264.7 cells.


Biochemical study of cellular antigen-antibody reaction in tissue culture. I. Activation and release of a protease.
The correlation between morphological and biochemical changes produced by the antigen-antibody reaction was studied in cultures of tissue monocytes taken from sensitized animals. The cells were grown under conditions which allowed collection of samples from the culture fluid as well as microscopic observation. Introduction of the antigen into the culture medium causes rapid release of a protease characterized by its susceptibility to sulfhydryl block and its optimum pH in the neutral range. Protease activation occurs simultaneously with morphological changes in the cytoplasm of the cultured cells. Delayed changes affecting the mitochondria and Golgi bodies appear after the peak of the proteolytic reaction and may be secondary to it. The gradual inactivation of the protease observed in the course of the antigen-antibody reaction will be discussed in a separate paper.


The utility of neuroimaging studies for informing educational practice and policy in reading disorders.
Educational neuroscience is an emerging scientific field that brings together researchers from neuroscience, psychology, and education to explore the neurocognitive processes underlying educational practice and theory. In this brief article, we take reading disorder (RD, also known as developmental dyslexia) as an example, and explore trends in neuroimaging research, which may have future implications for educational practice and policy. Specifically, we present two examples that have been central to research efforts in our laboratory: (a) utilizing multimodal neuroimaging to optimize criteria to diagnose RD, and (b) identifying neuroimaging markers that predict future academic outcomes. Such research is faced with important challenges, and rigorous validation is necessary before any claims of the widespread practical utility of neuroimaging can be made. Nevertheless, we contend that neuroimaging studies offer opportunities for providing critical information that could lead to advancing theory of reading and RD. This could in turn lead to better diagnostic criteria and more accurate and earlier identification of RD.


Doppler echocardiographic evaluation of patients with porcine mitral valves.
The application of Doppler echocardiography to the study of valvular function has recently been extended to include prosthetic valves. We have used Doppler echocardiography to evaluate 40 patients with porcine mitral valves (PMV) implanted 0.5 to 99 months prior to examination. Three parameters of PMV flow were assessed: maximum diastolic left ventricular inflow velocity (Vmax), pressure half-time (P1/2t), and presence or absence of mitral regurgitation (MR). Normally functioning PMV (n = 29) were characterized by Vmax less than or equal to 180 cm/sec and P1/2t less than or equal to 160 msec. Within this group, P1/2t was not correlated significantly with the age of the patient nor with prosthesis size. Doppler correctly identified all 10 patients with MR. Among these 10 patients, Vmax was 206 +/- 53 cm/sec, significantly higher than the mean observed in normally functioning prostheses (136 +/- 24 cm/sec, p less than 0.001). In eight patients with stenosis of the PMV, mean P1/2t was 220 +/- 63 msec, and in seven of eight, it was greater than or equal to 180 msec (p less than 0.001 compared to normals). We conclude that: (1) Vmax less than or equal to 180 cm/sec, P1/2t less than or equal to 160 msec, and absence of systolic turbulence in the left atrium characterize normally functioning PMV; (2) P1/2t greater than or equal to 180 msec identifies patients with stenosis of the PMV; and (3) Doppler echocardiography can detect MR and separate mitral from tricuspid regurgitation.


Identifying non-traditional electronic datasets for population-level surveillance and prevention of cardiometabolic diseases: a scoping review protocol.
Cardiometabolic diseases, including cardiovascular disease, obesity and diabetes, are leading causes of death and disability worldwide. Modern advances in population-level disease surveillance are necessary and may inform novel opportunities for precision public health approaches to disease prevention. Electronic data sources, such as social media and consumer rewards points systems, have expanded dramatically in recent decades. These non-traditional datasets may enhance traditional clinical and public health datasets and inform cardiometabolic disease surveillance and population health interventions. However, the scope of non-traditional electronic datasets and their use for cardiometabolic disease surveillance and population health interventions has not been previously reviewed. The primary objective of this review is to describe the scope of non-traditional electronic datasets, and how they are being used for cardiometabolic disease surveillance and to inform interventions. The secondary objective is to describe the methods, such as machine learning and natural language processing, that have been applied to leverage these datasets. We will conduct a scoping review following recommended methodology. Search terms will be based on the three central concepts of non-traditional electronic datasets, cardiometabolic diseases and population health. We will search EMBASE, MEDLINE, CINAHL, Scopus, Web of Science and Cochrane Library peer-reviewed databases and will also conduct a grey literature search. Articles published from 2000 to present will be independently screened by two reviewers for inclusion at abstract and full-text stages, and conflicts will be resolved by a separate reviewer. We will report this data as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. No ethics approval is required for this protocol and scoping review, as data will be used only from published studies with appropriate ethics approval. Results will be disseminated in a peer-reviewed publication.


[Standards, Options and Recommendations (SOR) for endocrine therapy in patients with non metastatic breast cancer. FNCLCC].
The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for endocrine therapy in patients with non metastatic breast cancer. Data have been identified by literature search using Medline, Embase, Cancerlit and Cochrane databases - until july 1999 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to 125 independent reviewers. The main recommendations for the endocrine therapy of patients with non metastatic breast cancer are: 1) Endocrine therapy modalities depend on menopausal status or age of women: ovarian suppression for premenopausal women, antiestrogen drug therapy for postmenopausal women (standard). 2) Tamoxifen (20 mg/d - 5 years) is beneficial to women with positive estrogen receptor tumor (standard, level of evidence A). There is no indication of tamoxifen treatment for women with negative estrogen receptor tumor (standard, level of evidence A). 3) For postmenopausal women with positive estrogen receptor tumor, tamoxifen is the standard adjuvant treatment (level of evidence A). For postmenopausal women with negative estrogen receptor, adjuvant chemotherapy has to be considered (option, level of evidence A). No adjuvant treatment has to be considered for women with poor health condition (option). 4) For premenopausal women with estrogen receptor tumor, results of clinical trials of chemotherapy versus endocrine therapy, suggest a benefit for endocrine therapy. However, there is no sufficient evidence to consider endocrine therapy alone as a standard adjuvant treatment. 5) For premenopausal women, chemotherapy + ovarian suppression or chemotherapy + tamoxifen are not better than chemotherapy alone (level of evidence A). 6) For postmenopausal women, administration of chemotherapy plus adjuvant tamoxifen versus the same tamoxifen alone, is of additional benefit in reducing recurrences but not in prolonging overall survival (standard, level of evidence A). 7) Balance of known benefits (delay to recurrence and death) and risks (side-effects of therapy) for adjuvant chemoendocrine therapy has to be taken into consideration before decision making. Chemoendocrine therapy can be indicated for women at high risk of developing metastatic disease (recommendation, experts agreement).


Effect of vigabatrin (gamma-vinyl GABA) on amino acid levels in CSF of epileptic patients.
Vigabatrin (gamma-vinyl GABA) is a new anticonvulsive drug that irreversibly inhibits the activity of GABA transaminase. The effect of vigabatrin on neurotransmission-related amino acids in CSF of 28 epileptic patients was studied and the relationship between the amino acid pattern and clinical response during 7 months of administration of vigabatrin. Of this study population, 46% had more than 50% decrease in seizure frequency (responders). In 54% the seizures decreased less than 50% (nonresponders). In the whole study group, the levels of total GABA during vigabatrin treatment were 283%, free GABA 197%, homocarnosine 310% and glycine 128% that of the levels at baseline in the same patients. Glutamate, glutamine, aspartate, asparagine, and taurine concentrations did not change. The amino acid pattern in CSF during administration of vigabatrin did not differ significantly in responders and nonresponders. The study suggests that both GABAergic and glycinergic neurotransmission are affected by vigabatrin. The changes in CSF levels of neurotransmitter amino acids are, however, not necessarily related to the clinical response.


Externalizing problems, attention regulation, and household chaos: a longitudinal behavioral genetic study.
Previous research documented a robust link between difficulties in self-regulation and development of externalizing problems (i.e., aggression and delinquency). In this study, we examined the longitudinal additive and interactive genetic and environmental covariation underlying this well-established link using a twin design. The sample included 131 pairs of monozygotic twins and 173 pairs of same-sex dizygotic twins who participated in three waves of annual assessment. Mothers and fathers provided reports of externalizing problems. Teacher report and observer rating were used to assess twin's attention regulation. The etiology underlying the link between externalizing problems and attention regulation shifted from a common genetic mechanism to a common environmental mechanism in the transition across middle childhood. Household chaos moderated the genetic variance of and covariance between externalizing problems and attention regulation. The genetic influence on individual differences in both externalizing problems and attention regulation was stronger in more chaotic households. However, higher levels of household chaos attenuated the genetic link between externalizing problems and attention regulation.


Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses.
Different modes of cell death regulate immunity. Whereas necrotic (necroptotic, pyroptotic) cell death triggers inflammation, apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction. A number of IL-1 family cytokines are produced by necrotic cells to induce sterile inflammation. However, release of IL-1 family proteins from apoptotic cells to regulate inflammation was not described. Here we show that IL-38, a poorly characterized IL-1 family cytokine, is produced selectively by human apoptotic cells to limit inflammation. Depletion of IL-38 in apoptotic cells provoked enhanced IL-6 and IL-8 levels and AP1 activation in co-cultured human primary macrophages, subsequently inducing Th17 cell expansion at the expense of IL-10-producing T cells. IL-38 was N-terminally processed in apoptotic cells to generate a mature cytokine with distinct properties. Both full-length and truncated IL-38 bound to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1). However, whereas the IL-38 precursor induced an increase in IL-6 production by human macrophages, truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. In conclusion, we identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion, which might be relevant in resolution of inflammation, autoimmunity, and cancer.


Horizontal gradient in ventilation distribution due to a localized chest wall abnormality.
Horizontal gradients in the distribution of ventilation and of regional vital capacities, as well as a reversed vertical, esophageal pressure gradient, were observed in a patient with a unilateral painful chest wall lesion. The distribution abnormalities disappeared after surgical treatment. These findings suggest that the interdependency between chest wall and lungs, and within the latter, between lobes, is an important factor determining the regional distribution of ventilation and the pleural pressure gradient in man.


MosChito rafts as a promising biocontrol tool against larvae of the common house mosquito, Culex pipiens.
Mosquito control is of paramount importance, in particular, in light of the major environmental alterations associated with human activities, from climate change to the altered distribution of pathogens, including those transmitted by Arthropods. Here, we used the common house mosquito, Culex pipiens to test the efficacy of MosChito raft, a novel tool for mosquito larval control. MosChito raft is a floating hydrogel matrix, composed of chitosan, genipin and yeast cells, as bio-attractants, developed for the delivery of a Bacillus thuringiensis israeliensis (Bti)-based bioinsecticide to mosquito larvae. To this aim, larvae of Cx. pipiens were collected in field in Northern Italy and a novel colony of mosquito species (hereafter: Trescore strain) was established. MosChito rafts, containing the Bti-based formulation, were tested on Cx. pipiens larvae from the Trescore strain to determine the doses to be used in successive experiments. Thus, bioassays with MosChito rafts were carried out under semi-field conditions, both on larvae from the Trescore strain and on pools of larvae collected from the field, at different developmental stages. Our results showed that MosChito raft is effective against Cx. pipiens. In particular, the observed mortality was over 50% after two days exposure of the larvae to MosChito rafts, and over 70-80% at days three to four, in both laboratory and wild larvae. In conclusion, our results point to the MosChito raft as a promising tool for the eco-friendly control of a mosquito species that is not only a nuisance insect but is also an important vector of diseases affecting humans and animals.


Transcatheter "edge-to-edge" mitral valve repair: influence of bias in randomized trials.
Functional mitral regurgitation (FMR) is the result of three-dimensional structural disruption of the mitral valve due to left ventricular dysfunction. The "edge-to-edge" surgical technique has given rise to the percutaneous transcatheter edge-to-edge repair (TEER) technique to treat FMR; however, the lack of a mitral annuloplasty ring makes TEER only partially effective, with uncertain long-term results. The MITRA-FR and COAPT trials, on which current TEER recommendations are based, show conflicting results. COAPT results possible bias has influenced current recommendations issued by clinical practice guidelines in favor of TEER in FMR.


Dynamics of beating cardiac tissue under slow periodic drives.
Effects of mechanical coupling on cardiac dynamics are studied by monitoring the beating dynamics of a cardiac tissue which is being pulled periodically at a pace slower than its intrinsic beating rate. The tissue is taken from the heart of a bullfrog that includes pacemaker cells. The cardiac tissue beats spontaneously with an almost constant interbeat interval (IBI) when there is no external forcing. On the other hand, the IBI is observed to vary significantly under an external periodic drive. Interestingly, when the period of the external drive is about two times the intrinsic IBI of the tissue without pulling, the IBI as a function of time exhibits a wave packet structure. Our experimental results can be understood theoretically by a phase-coupled model under external driving. In particular, the theoretical prediction of the wave-packet period as a function of the normalized driving period agrees excellently with the observations. Furthermore, the cardiac mechanical coupling constant can be extracted from the experimental data from our model and is found to be insensitive to the external driving period. Implications of our results on cardiac physiology are also discussed.


Chemical, morphological and microhardness analysis of coronary dentin submitted to internal bleaching with hydrogen peroxide and violet LED.
Violet LED has been used for internal bleaching, however its implications on coronary dentin composition are unclear. The present study aims to evaluate the effect of bleaching with violet LED, either associated with 35 % hydrogen peroxide or not, on microhardness, chemical composition, and morphological characteristics of coronal dentin. Thirty maxillary canines were selected to obtain 30 blocks of coronal dentin, distributed in 3 groups (n = 10): 35 % hydrogen peroxide (HP); violet LED (LED); HP 35 % + LED, (HP+LED). The chemical analysis was performed by FTIR and the morphological evaluation of the dentin structure by confocal laser scanning microscopy before (T0) and after treatment (T1). The microhardness analysis was performed by microdurometer after bleaching. The data were submitted to repeated measures ANOVA test (P> 0.05). The intensity of the inorganic peaks decreased after bleaching for all groups (P = 0.003). There was an increase in the organic peak intensity after bleaching with HP, a decrease for LED, while HP+LED did not change the intensity (P = 0.044). Moreover, the inorganic/organic ratio decreased for HP (P = 0.022), while for LED and HP+LED there was no significant changes (P>0.05). HP and HP+LED showed lower microhardness values compared to LED (P< 0.05). Regarding morphological changes, an increase in the perimeter of the dentinal tubules was found for all groups, with the smallest increase being observed for LED. HP bleaching decreased the chemical stability and microhardness of the coronal dentin, while the violet LED treatments had no significant impact on dentin stability. In all groups, there was an increase in exposure of the dentinal tubules after bleaching, which was less pronounced with the violet LED bleaching.


Texture-induced vibrations in the forearm during tactile exploration.
Humans can detect and discriminate between fine variations of surface roughness using active touch. It is hitherto believed that roughness perception is mediated mostly by cutaneous and subcutaneous afferents located in the fingertips. However, recent findings have shown that following abolishment of cutaneous afferences resulting from trauma or pharmacological intervention, the ability of subjects to discriminate between textures roughness was not significantly altered. These findings suggest that the somatosensory system is able to collect textural information from other sources than fingertip afference. It follows that signals resulting of the interaction of a finger with a rough surface must be transmitted to stimulate receptor populations in regions far away from the contact. This transmission was characterized by measuring in the wrist vibrations originating at the fingertip and thus propagating through the finger, the hand and the wrist during active exploration of textured surfaces. The spectral analysis of the vibrations taking place in the forearm tissues revealed regularities that were correlated with the scanned surface and the speed of exploration. In the case of periodic textures, the vibration signal contained a fundamental frequency component corresponding to the finger velocity divided by the spatial period of the stimulus. This regularity was found for a wide range of textural length scales and scanning velocities. For non-periodic textures, the spectrum of the vibration did not contain obvious features that would enable discrimination between the different stimuli. However, for both periodic and non-periodic stimuli, the intensity of the vibrations could be related to the microgeometry of the scanned surfaces.


Ontogenesis of somatomedin and insulin receptors in the human fetus.
This study examines the ontogenesis of somatomedin and insulin receptors in man. Particulate plasma membranes were prepared by ultracentrifugation from various tissues removed from fetuses after abortion and classified as less than 17, 17-25, and greater than 25 cm in length. The binding of iodinated insulinlike growth factors 1 (IGF-1) and 2 (IGF-2), somatomedin A (SMA), multiplication-stimulating activity (MSA), and insulin was examined at the different ages. In the liver, cross-reaction studies revealed separate insulin and IGF-2 receptors. The Scatchard plots of insulin binding to liver membranes were curvilinear and showed an increase in the concentration of insulin receptors with advancing age. A single IGF-2 receptor was found on liver and no alteration was observed during development. The brain contained a lower concentration of insulin receptors. A change in the brain receptors for somatomedins occurred during development. Early in gestation, a high concentration of a low-affinity IGF-1 receptor was found. After approximately the 17th wk of gestation a higher affinity IGF-1 receptor appeared, which then increased in concentration. Cross-reaction studies also revealed changes in the specificity of these receptors during development. In the youngest fetal group IGF-2 was preferentially bound. Around midgestation a separate IGF-1 receptor, indicated by the preferential displacement of iodinated IGF-1 by IGF-1, appeared. In contrast, iodinated IGF-2 bound to a receptor where IGF-1 and IGF-2 were equipotent.


Comparison of scoring systems in predicting the severity of acute pancreatitis.
To investigate the prognostic usefulness of several existing scoring systems in predicting the severity of acute pancreatitis (AP). We retrospectively analyzed the prospectively collected clinical database from consecutive patients with AP in our institution between January 2011 and December 2012. Ranson, Acute Physiology and Chronic Health Evaluation (APACHE)-II, and bedside index for severity in acute pancreatitis (BISAP) scores, and computed tomography severity index (CTSI) of all patients were calculated. Serum C-reactive protein (CRP) levels were measured at admission (CRPi) and after 24 h (CRP24). Severe AP was defined as persistent organ failure for more than 48 h. The predictive accuracy of each scoring system was measured by the area under the receiver-operating curve (AUC). Of 161 patients, 21 (13%) were classified as severe AP, and 3 (1.9%) died. Statistically significant cutoff values for prediction of severe AP were Ranson≥3, BISAP≥2, APACHE-II≥8, CTSI≥3, and CRP24≥21.4. AUCs for Ranson, BISAP, APACHE-II, CTSI, and CRP24 in predicting severe AP were 0.69 (95%CI: 0.62-0.76), 0.74 (95%CI: 0.66-0.80), 0.78 (95%CI: 0.70-0.84), 0.69 (95%CI: 0.61-0.76), and 0.68 (95%CI: 0.57-0.78), respectively. APACHE-II demonstrated the highest accuracy for prediction of severe AP, however, no statistically significant pairwise differences were observed between APACHE-II and the other scoring systems, including CRP24. Various scoring systems showed similar predictive accuracy for severity of AP. Unique models are needed in order to achieve further improvement of prognostic accuracy.


MRI acquisition and analysis protocol for in vivo intraorbital optic nerve segmentation at 3T.
To present a new acquisition and analysis protocol for reliable and reproducible segmentation of the entire intraorbital optic nerve (ION) mean cross-sectional area by means of magnetic resonance imaging (MRI) at 3 tesla (T). Eight healthy volunteers (mean age 31, five were male) gave written informed consent and both of their IONs were imaged individually using a coronal-oblique T2-weighted fast multidynamic image acquisition scheme; the proposed acquisition scheme has its rationale in combining separately acquired volumes and registering them to account for motion-related artifacts commonly associated with longer acquisitions. Mean cross-sectional area of each ION was measured using a semiautomated image analysis protocol that was based on an active surface model previously described and used for spinal cord imaging. Reproducibility was assessed for repeated scans (scan-rescan) and repeated image analysis performance (intraobserver). Mean and SD values of the left ION cross-sectional area for the eight healthy volunteers were 5.0 (±0.7) mm² and for the right ION were 5.3 (±0.8) mm². Mean scan-rescan coefficient of variation (COV) for the left ION was 4.3% and for the right was 4.4%. Mean intraobserver COV for the left ION was 2.1% and for the right was 1.8%. This study presents a new MRI acquisition and analysis protocol for reliable and reproducible in vivo measurement of the entire ION mean cross-sectional area as demonstrated in a pilot study of healthy subjects. The protocol presented here can be used in future studies of the ION in disease state.


[Determination of the beta-lactamase-inhibiting capacity of different compounds by using a penicillinase-forming strain of Staphylococcus aureus 5A].
A diffusion method with the use of a penicillinase-forming strain of Staph. aureus 5A was applied to determination of the beta-lactamase inhibitory activity of various compounds. The method is based on measuring the difference in the size of the growth inhibition zones of the staphylococci on trays with and without benzylpenicillin. The method is rather informative. However, a nonspecific secondary beta-lactamase inhibitory effect of high doses of the antibiotic inhibitors of the protein synthesis is possible. Two diffusion methods for determination of the beta-lactamase inhibitory activity of various compounds, i.e. the indicator method based on the direct contact of crystalline penicillinase with the experimental substrate and the method using a penicillinase-producing strain of Staph. aureus 5A and various beta-lactamase-producing strains of bacteria without preliminary obtaining of beta-lactamase preparations were compared. It was shown that the indicator method was more rapid, simple and accurate. Still, it did not provide determination of the antibacterial activity of the compounds. It is advised to use both methods for screening various compounds and studying their beta-lactamase inhibitory activity.


Machine smoking results compared to human uptake of cigarette smoke.
Studies of plasma concentrations and the application of pharmacokinetic parameters in human smoking published during recent years are reviewed. It is clear that this approach contributes to better understanding and to the quantitative evaluation of many problems related to human smoking, such as: first, smoking behavior, second, self-regulation and compensation when switching between different brands and third, relationships between in vitro machine smoking yields and actual human uptake. The reviewed articles show that the widely believed opinion that cigarettes with low yields, when in vitro tested, are less hazardous, must be questioned. For the majority of cigarette brands there is no defensible correlation between in vitro analytical machine yields and actual uptake and bioavailability. Based on these findings suggestions are given to modify the use of tar and nicotine yields obtained by in vitro machine testing methods for classification purpose.


Newly detected abnormal glucose regulation and long-term prognosis after acute myocardial infarction: Comparison of an oral glucose tolerance test and glycosylated haemoglobin A1c.
An oral glucose tolerance test (OGTT) and/or glycosylated haemoglobin A1c (HbA1c) in patients with acute myocardial infarction (AMI) identify patients with increased mortality risk, but no comparison of the long-term prognostic values has yet been investigated. This study was a prospective cohort enrolling patients with AMI between 2002 until 2008 and follow-up until 1st October, 2012. Patients without known diabetes mellitus (DM) underwent an OGTT. Seventy-nine patients with known DM did not have an OGTT performed. Primary endpoint was all-cause mortality. We included 548 patients with AMI, of whom 469 underwent a standardized OGTT and were stratified according to OGTT and HbA1c. During 9.8years of follow-up, 179 (33%) patients died. In patients having increased HbA1c ≥6.5%, a significantly increased mortality was observed (Hazard Ratio (HR) 1.60 [1.09-2.34]). However, when adjusting for known DM, no significance was detected. An OGTT did not show a significantly increased mortality, if used separately. A combined estimate showed a significantly increased mortality in patients categorized as newly diagnosed DM by OGTT and HbA1c<6.5% (HR 1.56 [95% CI 1.07-2.30]) compared to patients categorized as normal/impaired fasting glycaemia/impaired glucose tolerance by OGTT and HbA1c <6.5%. Approximately 50% of the patients with newly diagnosed DM by OGTT were only detected due to 2-hour post-load glucose values. An OGTT is recommended in AMI patients without known DM and HbA1c<6.5%. Patients categorized as newly diagnosed DM by OGTT although HbA1c <6.5% share the same high risk of mortality as patients with HbA1c≥6.5%.


Bilateral Anterior Knee Pain in a High School Cross-Country Runner: An Atypical Etiology.
Anterior knee pain is a common complaint found in distance runners, and can be the end result of a variety of benign processes. A 17-year-old female cross-country runner presented to a sports medicine clinic with insidious onset of bilateral patellofemoral pain (PFP). In the workup of the significant quadriceps weakness discovered on her initial examination, a principal contributing cause of her PFP, she was found to have a form of spinal muscular atrophy, an uncommon neurodegenerative disease that typically requires multidisciplinary medical care. Her case provides a good example for clinicians to consider, at times, an in-depth assessment of the root causes of benign conditions.


Morphologic conversion of a neuroblastoma-derived cell line by E6-mediated p53 degradation.
Neuroblastoma-derived tumor cells, unlike cells from other tumor types, characteristically express a wildtype but cytoplasmically sequestered p53 protein. To ascertain whether the p53 in these cells retained any physiological activity, we inactivated it in SK-N-SH cells, a neuroblastoma-derived cell line, by introducing the human papilloma virus type 16 E6 expression plasmid. Parent SK-N-SH cell cultures are composed of two cell types exhibiting characteristic morphologies designated neuroblastic (N-type) or substrate-adherent fibroblastic (S-type) cells, both of which have been shown to spontaneously transdifferentiate or interconvert. We report here that down-regulation of p53 resulted in conversion of SK-N-SH cells to the substrate-adherent fibroblast-like S-type cells. The morphologic conversion was accompanied by a loss of neurofilament expression, a marker for the neuronal N-type cells, an increase in the expression of vimentin, and a lack of responsiveness to retinoic acid-induced neuronal differentiation. Importantly, we did not observe N-type cells in the E6-transfected cell population, suggesting that they were incapable of transdifferentiating to the N-type morphology. We also tested the ability of these E6-transfected S-type cells to form colonies in soft agar and observed a markedly reduced capacity of these cells to do so when compared with the parent and mutant E6-transfected cells. These results suggest that p53 is required for the maintenance of the neuroblastic tumorigenic phenotype.


Overcrowding in medium-volume emergency departments: effects of aged patients in emergency departments on wait times for non-emergent triage-level patients.
This study aims to examine patient wait times from triaging to physician assessment in the emergency department (ED) for non-emergent patients, and to see whether patient flow and process (triage) are impacted by aged patients. A retrospective study method was used to analyse 185 patients in three age groups. Key data recorded were triage level, wait time to physician assessment and ED census. Multiple linear regression analysis was used to determine the strength of association with increased wait time. A longer average wait time for all patients occurred when there was an increase in the number of patients aged > or = 65 years in the ED. Further analysis showed 12.1% of the variation extending ED wait time associated with the triage process was explained by the number of patients aged > or = 65 years. In addition, extended wait time, overcrowding and numbers of those who left without being seen were strongly associated (P < 0.05) with the number of aged patients in the ED. The effects of aged patients on ED structure and process have significant implications for nursing. Nursing process and practice sets clear responsibilities for nursing to ensure patient safety. However, the impact of factors associated with aged patients in ED, nursing's role and ED process can negatively impact performance expectations and requires further investigation.


Phosphoinositides and the Fate of Legionella in Phagocytes.
Legionella pneumophila is the causative agent of a severe pneumonia called Legionnaires' disease. The environmental bacterium replicates in free-living amoebae as well as in lung macrophages in a distinct compartment, the Legionella-containing vacuole (LCV). The LCV communicates with a number of cellular vesicle trafficking pathways and is formed by a plethora of secreted bacterial effector proteins, which target host cell proteins and lipids. Phosphoinositide (PI) lipids are pivotal determinants of organelle identity, membrane dynamics and vesicle trafficking. Accordingly, eukaryotic cells tightly regulate the production, turnover, interconversion, and localization of PI lipids. L. pneumophila modulates the PI pattern in infected cells for its own benefit by (i) recruiting PI-decorated vesicles, (ii) producing effectors acting as PI interactors, phosphatases, kinases or phospholipases, and (iii) subverting host PI metabolizing enzymes. The PI conversion from PtdIns(3)P to PtdIns(4)P represents a decisive step during LCV maturation. In this review, we summarize recent progress on elucidating the strategies, by which L. pneumophila subverts host PI lipids to promote LCV formation and intracellular replication.


Ecological study of Vibrio cholerae in Vellore.
Vellore is endemic for cholera due to Vibrio cholerae O1 and O139. In a previous study the prevalence of Vibrio cholerae in drinking water, lakes and sewage outfalls in a single 2-months period in Vellore, India was determined. In addition water samples from three sites were also tested for the presence of V. cholerae O1 and O139 by fluorescent antibody staining. This follow on study has examined how the environmental distribution of V. cholerae at the same sites alters over a 12-month period and the relationship to the clinical pattern of cholera in Vellore. Samples of water were collected from fixed sites at three water bodies each month between April 1997 and March 1998. Bacteria isolated from samples were identified by standard biochemical tests and isolated strains of V. cholerae tested for their ability to agglutinate O1 and O139 antisera. Samples were also tested for the presence of V. cholerae O1 and O139 by fluorescent antibody staining. The clinical isolation rate of V. cholerae in Vellore, maximum temperature and rainfall were also studied. The results demonstrate the presence in the environment of viable but non-cultivable (VNC) V. cholerae in 10 of 12 months of the study year as well as their viability. Their prevalence in the environment also correlated with the isolation of these pathogens from clinical samples over the same study period.


A Systematic Analysis of Errors in Target Localization and Treatment Delivery for Stereotactic Radiosurgery Using 2D/3D Image Registration.
To determine the localization uncertainties associated with 2-dimensional/3-dimensional image registration in comparison to 3-dimensional/3-dimensional image registration in 6 dimensions on a Varian Edge Linac under various imaging conditions. The systematic errors in 6 dimensions were assessed by comparing automatic 2-dimensional/3-dimensional (kV/MV vs computed tomography) with 3-dimensional/3-dimensional (cone beam computed tomography vs computed tomography) image registrations under various conditions encountered in clinical applications. The 2-dimensional/3-dimensional image registration uncertainties for 88 patients with different treatment sites including intracranial and extracranial were evaluated by statistically analyzing 2-dimensional/3-dimensional pretreatment verification shifts of 192 fractions in stereotactic radiosurgery and stereotactic body radiotherapy. The systematic errors of 2-dimensional/3-dimensional image registration using kV-kV, MV-kV, and MV-MV image pairs were within 0.3 mm and 0.3° for the translational and rotational directions within a 95% confidence interval. No significant difference ( P > .05) in target localization was observed with various computed tomography slice thicknesses (0.8, 1, 2, and 3 mm). Two-dimensional/3-dimensional registration had the best accuracy when pattern intensity and content filter were used. For intracranial sites, means ± standard deviations of translational errors were -0.20 ± 0.70 mm, 0.04 ± 0.50 mm, and 0.10 ± 0.40 mm for the longitudinal, lateral, and vertical directions, respectively. For extracranial sites, means ± standard deviations of translational errors were -0.04 ± 1.00 mm, 0.2 ± 1.0 mm, and 0.1 ± 1.0 mm for the longitudinal, lateral, and vertical directions, respectively. Two-dimensional/3-dimensional image registration for intracranial and extracranial sites had comparable systematic errors that were approximately 0.2 mm in the translational direction and 0.08° in the rotational direction. The standard 2-dimensional/3-dimensional image registration tool available on the Varian Edge radiosurgery device, a state-of-the-art system, is helpful for robust and accurate target positioning for image-guided stereotactic radiosurgery.


Polyoma mutants that productively infect F9 embryonal carcinoma cells do not rescue wild-type polyoma in F9 cells.
Mouse embryonal carcinoma cells are refractory to infection by wild-type polyoma virus, the infection process apparently being blocked at a stage after adsorption and penetration but before early protein synthesis. Polyoma virus mutants capable of productive infection of mouse embryonal carcinoma cells have been isolated and these mutants all have DNA sequence alterations in a noncoding region near the origin of replication of the viral genome. PyF101 and PyF441 are two mutants selected for their ability to infect the embryonal carcinoma cell line F9. Here we show that these PyF mutants do not rescue replication of wild-type polyoma during a mixed infection of F9 cells. The mutant and wild-type DNAs were distinguished on the basis of restriction fragments obtained by digestion with Msp I or BstNI, and no wild-type DNA was detected in F9 cells coinfected with wild-type polyoma and with either PyF101 or PyF441. The mutant viruses do not appear to inhibit wild-type replication during a mixed infection because both mutant and wild-type DNAs can replicate efficiently in coinfected 3T6 cells which are permissive for both mutant and wild-type viruses. A double mutant having the PyF101 mutation and the ts-25E temperature-sensitive mutation in polyoma large tumor antigen was constructed and found to be temperature-sensitive for replication in F9 cells. This double mutant, designated PyFts-1, can be rescued in F9 cells at the restrictive temperature by coinfection with PyF441. These results suggest that the PyF mutations affect two processes in F9 cells, one involving expression of polyoma early genes and a second involving viral DNA replication.


A Fuzzy Logic Prompting Mechanism Based on Pattern Recognition and Accumulated Activity Effective Index Using a Smartphone Embedded Sensor.
Sufficient physical activity can reduce many adverse conditions and contribute to a healthy life. Nevertheless, inactivity is prevalent on an international scale. Improving physical activity is an essential concern for public health. Reminders that help people change their health behaviors are widely applied in health care services. However, timed-based reminders deliver periodic prompts suffer from flexibility and dependency issues which may decrease prompt effectiveness. We propose a fuzzy logic prompting mechanism, Accumulated Activity Effective Index Reminder (AAEIReminder), based on pattern recognition and activity effective analysis to manage physical activity. AAEIReminder recognizes activity levels using a smartphone-embedded sensor for pattern recognition and analyzing the amount of physical activity in activity effective analysis. AAEIReminder can infer activity situations such as the amount of physical activity and days spent exercising through fuzzy logic, and decides whether a prompt should be delivered to a user. This prompting system was implemented in smartphones and was used in a short-term real-world trial by seventeenth participants for validation. The results demonstrated that the AAEIReminder is feasible. The fuzzy logic prompting mechanism can deliver prompts automatically based on pattern recognition and activity effective analysis. AAEIReminder provides flexibility which may increase the prompts' efficiency.


ATR signalling: more than meeting at the fork.
Preservation of genome integrity via the DNA-damage response is critical to prevent disease. ATR (ataxia telangiectasia mutated- and Rad3-related) is essential for life and functions as a master regulator of the DNA-damage response, especially during DNA replication. ATR controls and co-ordinates DNA replication origin firing, replication fork stability, cell cycle checkpoints and DNA repair. Since its identification 15 years ago, a model of ATR activation and signalling has emerged that involves localization to sites of DNA damage and activation through protein-protein interactions. Recent research has added an increasingly detailed understanding of the canonical ATR pathway, and an appreciation that the canonical model does not fully capture the complexity of ATR regulation. In the present article, we review the ATR signalling process, focusing on mechanistic findings garnered from the identification of new ATR-interacting proteins and substrates. We discuss how to incorporate these new insights into a model of ATR regulation and point out the significant gaps in our understanding of this essential genome-maintenance pathway.


[Chromatin remodeling in estrogen-dependent and independent human breast cancer cell lines].
Chromatin restricts the accessibility of DNA to regulatory factors; its remodeling over the regulatory regions contributes to the control of gene expression. An increasing number of evidence links defects in chromatin remodeling machinery and cancer. Our aim is to elucidate the role of chromatin structure in the control of the expression of hormone-induced genes in breast cell lines estrogen-dependent or -independent for growth. Mammary tumor growth is controlled by steroid hormones via their nuclear receptor and by growth factors via tyrosine kinase receptors. 50 % of these tumors elude to hormonal control. This limits the anti-estrogen therapy. As a model, we have analyzed in several cell lines the chromatin organization of the regulatory regions of two genes, pS2 that is associated with a good prognostic, and cathepsin D (catD) that is a bad prognostic marker. The expression of the two genes is estrogen-regulated in estrogen-dependent cell line MCF7. In contrast in the hormone-independent cell line MDA MB 231, pS2 is not expressed and catD is constitutively expressed. Within the regulatory regions of pS2 gene, we have localized two regions that undergo a hormone-dependent change in chromatin structure in MCF7 cells but not in MDA MB 231. The lack of chromatin remodeling in MDA MB 231 cells is not due to the absence of expression of the estrogen receptor in the cell line. The expression of pS2 gene can be correlated with chromatin remodeling over the regulatory regions of pS2 gene. In contrast catD regulatory regions did not display hormone-dependent changes in chromatin structure, suggesting that hormone regulation takes place within regions with a constitutively open chromatin structure.


Mossy fiber-granule cell synapses in the normal and epileptic rat dentate gyrus studied with minimal laser photostimulation.
Dentate granule cells become synaptically interconnected in the hippocampus of persons with temporal lobe epilepsy, forming a recurrent mossy fiber pathway. This pathway may contribute to the development and propagation of seizures. The physiology of mossy fiber-granule cell synapses is difficult to characterize unambiguously, because electrical stimulation may activate other pathways and because there is a low probability of granule cell interconnection. These problems were addressed by the use of scanning laser photostimulation in slices of the caudal hippocampal formation. Glutamate was released from a caged precursor with highly focused ultraviolet light to evoke action potentials in a small population of granule cells. Excitatory synaptic currents were recorded in the presence of bicuculline. Minimal laser photostimulation evoked an apparently unitary excitatory postsynaptic current (EPSC) in 61% of granule cells from rats that had experienced pilocarpine-induced status epilepticus followed by recurrent mossy fiber growth. An EPSC was also evoked in 13-16% of granule cells from the control groups. EPSCs from status epilepticus and control groups had similar peak amplitudes ( approximately 30 pA), 20-80% rise times (approximately 1.2 ms), decay time constants ( approximately 10 ms), and half-widths (approximately 8 ms). The mean failure rate was high (approximately 70%) in both groups, and in both groups activation of N-methyl-D-aspartate receptors contributed a small component to the EPSC. The strong similarity between responses from the status epilepticus and control groups suggests that they resulted from activation of a similar synaptic population. No EPSC was recorded when the laser beam was focused in the dentate hilus, suggesting that indirect activation of hilar mossy cells contributed little, if at all, to these results. Recurrent mossy fiber growth increases the density of mossy fiber-granule cell synapses in the caudal dentate gyrus by perhaps sixfold, but the new synapses appear to operate very similarly to preexisting mossy fiber-granule cell synapses.


Helping patients with diabetes: resources from the National Diabetes Education Program.
To familiarize pharmacists with the National Diabetes Education Program (NDEP) and to demonstrate the value of NDEP materials in the care of patients with diabetes. The NDEP website (www.ndep.nih.gov) and PubMed (www.ncbi.nlm.nih.gov/pubmed). NDEP is a collaboration between the National Institutes of Health, Centers for Disease Control and Prevention, and many organization partners. Since 1997, a large number of materials have been created by NDEP using an evidence-based, expert- and patient-reviewed approach to development. Materials are nonbranded and reflect current medical knowledge and practice. Educational materials are available for persons at risk for diabetes, those with diabetes, family members of persons with diabetes, employers, and professionals. The Pharmacy, Podiatry, Optometry, and Dentistry (PPOD) workgroup of NDEP promotes the value of pharmacists and other professionals in diabetes education and management. Resources are available to educate about the value of the PPOD professionals. NDEP provides evidence-based, high-quality educational materials that pharmacists will find useful in the counseling of persons with diabetes.


Vitamin C consumption does not impair training-induced improvements in exercise performance.
To test the hypothesis that antioxidants can attenuate high-intensity interval training-induced improvements in exercise performance. Two groups of recreationally active males performed a high-intensity interval running protocol, four times per week for 4 wk. Group 1 (n = 8) consumed 1 g of vitamin C daily throughout the training period, whereas Group 2 (n = 7) consumed a visually identical placebo. Pre- and posttraining, subjects were assessed for VO2max, 10 km time trial, running economy at 12 km/h and distance run on the YoYo intermittent recovery tests level 1 and 2 (YoYoIRT1/2). Subjects also performed a 60 min run before and after training at a running velocity of 65% of pretraining VO2max so as to assess training-induced changes in substrate oxidation rates. Training improved (P < .0005) VO2max, 10 km time trial, running economy, YoYoIRT1 and YoYoIRT2 in both groups, although there was no difference (P = .31, 0.29, 0.24, 0.76 and 0.59) between groups in the magnitude of training-induced improvements in any of the aforementioned parameters. Similarly, training also decreased (P < .0005) mean carbohydrate and increased mean fat oxidation rates during submaximal exercise in both groups, although no differences (P = .98 and 0.94) existed between training conditions. Daily oral consumption of 1 g of vitamin C during a 4 wk high-intensity interval training period does not impair training-induced improvements in the exercise performance of recreationally active males.


CEC separation of ofloxacin enantiomers using imprinted microparticles prepared in molecular crowding conditions.
Molecular crowding is a new concept to obtain molecularly imprinted polymers (MIPs) with greater capacity and selectivity, which could shift the equilibrium of a print molecule reacting with functional monomers in the direction of complex formation side. In this work, molecular crowding agent was first applied to the preparation of MIPs microparticles by precipitation polymerization. A new system of molecular crowding surrounding was developed, composed of polystyrene and tetrahydrofuran, in the presence of the template (S)-ofloxacin. Partial filling capillary electrochromatography (CEC) was utilized to evaluate imprinting effect of the resulting microparticles by chiral separations of ofloxacin. Some important parameters in the preparation, i.e. template to monomer ratio, influence of cross-linking monomers and functional monomer composition on the CEC separation of MIP microparticles were investigated. Baseline separation of ofloxacin (R(s) =1.53) was obtained under optimized conditions and the highest theory plate of the later eluent (S)-ofloxacin was 5400. The textural and morphological parameters for imprinted particles, such as Brunauer-Emmett-Teller surface areas, pore volumes and pore size distributions have also been determined. Compared to the MIP microparticle prepared by conventional precipitation polymerization, the (S)-ofloxacin-imprinted particles formed under molecular crowding conditions showed higher selectivity (α=1.09) and separation efficiency (<25 min) in the CEC mode.


Structure-based design of SARS-CoV-2 papain-like protease inhibitors.
The COVID-19 pandemic is caused by SARS-CoV-2, an RNA virus with high transmissibility and mutation rate. Given the paucity of orally bioavailable antiviral drugs to combat SARS-CoV-2 infection, there is a critical need for additional antivirals with alternative mechanisms of action. Papain-like protease (PLpro) is one of the two SARS-CoV-2 encoded viral cysteine proteases essential for viral replication. PLpro cleaves at three sites of the viral polyproteins. In addition, PLpro antagonizes the host immune response upon viral infection by cleaving ISG15 and ubiquitin from host proteins. Therefore, PLpro is a validated antiviral drug target. In this study, we report the X-ray crystal structures of papain-like protease (PLpro) with two potent inhibitors, Jun9722 and Jun9843. Subsequently, we designed and synthesized several series of analogs to explore the structure-activity relationship, which led to the discovery of PLpro inhibitors with potent enzymatic inhibitory activity and antiviral activity against SARS-CoV-2. Together, the lead compounds are promising drug candidates for further development.


Marker genotypes and population admixture and their association with body weight, height and relative body mass in United States federal bison herds.
Elucidating genetic influences on bison growth and body composition is of interest, not only because bison are important for historical, cultural, and agricultural reasons, but also because their unusual population history makes them valuable models for finding influential loci in both domestic cattle and humans. We tested for trait loci associated with body weight, height, and bison mass index (BMI) while controlling for estimated ancestry to reduce potential confounding effects due to population admixture in 1316 bison sampled from four U.S. herds. We used 60 microsatellite markers to model each phenotype as a function of herd, sex, age, marker genotypes, and individual ancestry estimates. Statistical significance for genotype and its interaction with ancestry was evaluated using the adaptive false discovery rate. Of the four herds, two appeared to be admixed and two were nonadmixed. Although none of the main effects of the loci were significant, estimated ancestry and its interaction with marker loci were significantly associated with the phenotypes, illustrating the importance of including ancestry in the models and the dependence of genotype-phenotype associations on background ancestry. Individual loci contributed approximately 2.0% of variation in weight, height, and BMI, which confirms the utility and potential importance of adjusting for population stratification.


The Serological Evidence of Cytomegalovirus Infection as a Potent Aetiological Factor for Cleft Lip/Palate, Mental Retardation and Deafness.
Congenital Cytomegalovirus (CCMV) infection is estimated to occur in 0.5% to 2% of all deliveries across the world. According to the available literature about Human Cytomegalovirus (HCMV) infected children, 0.5% to 1% acquire Cytomegalovirus (CMV) in utero, 40% acquire the infection within the first decade of life, between 15% to 70% acquire CMV infection in group day care settings and continue to shed the virus for 6 to 48 months after primary infection. Although, 90% of the infected infants are clinically asymptomatic at birth, shreds of evidence show that these infants are at risk for audiological, neurological, and developmental sequelae. Despite this, HCMV still remains undetected due to silent or asymptomatic nature of the virus. The present study was aimed to test the hypothesis that HCMV can be a potential aetiologic factor in the development of cleft lip/palate, mental retardation and deafness. The study was carried out in a controlled setting under strict aseptic conditions. Blood samples were collected from 80 children, who were selected strictly adhering to the inclusion criteria and were divided into four groups containing 20 children each. Group 1: 20 children with cleft lip/palate, Group 2: 20 mentally retarded children, Group 3: 20 completely deaf children and Group 4: 20 normal Children (control). The samples were tested for HCMV-specific Immunoglobulin G (IgG) and Immunoglobulin M (IgM) antibodies by using solid phase enzyme-linked immunosorbent assay and the obtained data were analysed statistically using ANOVA and Post-Hoc Tukey's tests. In the study group (Group1, 2 and 3) children, the overall positivity for HCMV- specific IgG was 100% and 5% borderline to IgM antibodies whereas in the control group (Group 4) it was 80% negative to HCMV- specific IgG and 100% negative to IgM antibodies. From the observations noted in the present study, HCMV could be suggested as the potent aetiologic factor in the development of cleft lip/palate, mental retardation and deafness.