Saturable first-pass kinetics of propranolol.
Reduced bioavailability (F) due to hepatic first-pass extraction of an oral dose (D) is a well-known pharmacokinetic phenomenon. An integrated solution for Michaelis-Menten kinetics of the first-pass effect is derived from the maximal metabolic rate (Vm), volume of distribution (Vd), first order absorption rate constant (ka), Michaelis constant (Km), and liver blood flow (Q). F = 1 - VmVd/kaD ln (1 + kaD/QKm) This equation for single dosage can also be extended to steady state kinetics after multiple dosing in which the amount of a drug present in the hepatic circulation is considered. According to the literature, the bioavailability of a single 80 mg oral dose of propranolol (F = 0.22) increases after multiple doses Fss = 0.36). Based on the first pass equations for single dosage and multiple dosing, the maximal metabolic rate (Vm = 0.043 mg l-1 h-1) corresponding to 310 mg per day and the Michaelis constant (Km = 0.10 mg/l) were calculated for propranolol. Incorporation of nonlinear plasma protein binding in this concept may explain the lack of threshold phenomenon for a single dose of less than 40 mg propranolol. Zero order absorption kinetics could explain why cumulation kinetics seem linear even at an excessive dosage of 960 mg propranolol per day. From these derivations it may be concluded that multiple dosing, increase in plasma protein binding, high absorption rate, and increased portal venous blood flow will increase bioavailability, whereas slow release formulations, fractional drug dosage, and saturable absorption kinetics will decrease bioavailability of first-pass drugs like propranolol.


A sensitive electrochemical immunosensing interface for label-free detection of aflatoxin B1 by attachment of nanobody to MWCNTs-COOH@black phosphorene.
A label-free electrochemical immunosensor has advantages of real-time and rapid detection, but it is weak in detection of small molecular toxins such as aflatoxin B1 (AFB1). The greatest obstacle to achieving this is that small molecules bound to a common immunosensing interface cannot interfere with electron transfer effectively and the detection signal is so weak. Therefore, a sensitive electrochemical immunosensing interface for small molecules is urgently needed. Here, we employed functionalized black phosphorene (BP) as electrode modification materials and anti-AFB1 nanobody (Nb) as a biorecognition element to construct a very sensitive immunosensing interface towards small molecular AFB1. The BP functionalized by carboxylic multi-walled carbon nanotubes (MWCNTs-COOH) via P-C bonding behaved with a satisfactory stability and good catalytic performance for the ferricyanide/ferrocyanide probe, while the small-sized Nb showed good compatibility with the functionalized BP and also had less influence on electron transfer than monoclonal antibody (mAb). Expectedly, the as-prepared immunosensing interface was very sensitive to AFB1 detection by differential pulse voltammetry (DPV) in a redox probe system. Under optimized conditions, a linear range from 1.0 pM to 5.0 nM and an ultralow detection limit of 0.27 pM were obtained. Additionally, the fabricated immunosensor exhibited satisfactory stability, specificity, and reproducibility. The strategy proposed here provides a more reliable reference for label-free sensing of small molecules in food samples.


Cardiac stress biomarkers after red blood cell transfusion in patients at risk for transfusion-associated circulatory overload: a prospective observational study.
Transfusion-associated circulatory overload (TACO) is a leading cause of serious reactions. In regard to TACO, little is known regarding biomarkers as a predictor, their most informative timing, or thresholds of significance or differentiation from other reactions. In this study of inpatients at risk for TACO (age ≥ 50 years) receiving 1 red blood cell unit, cardiac biomarkers, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and high-sensitivity troponin were measured at baseline, 6 to 12 hours (except troponin) posttransfusion, and 18 to 24 hours posttransfusion. Primary outcome was a critical increase in biomarkers (>1.5-fold increase and supranormal) at 18 to 24 hours. Fifty-one patients were analyzed; 29% had cardiovascular disease, 73% had one or more cardiac risk factors, and 50% took cardiac or antihypertensive therapies. Although eight (16%) developed an increase in systolic pressure of at least 30 mmHg and four (8%) reported dyspnea and/or cough, none had TACO. At baseline, BNP level was more than 100 ng/L in 59% and NT-proBNP was more than 300 pg/mL in 83%. A total of 25% had a BNP critical increase, 33% had a NT-proBNP critical increase, and 2% had a troponin critical increase at 18 to 24 hours. Overall, 38% had at least one biomarker critical increase and NT-proBNP/BNP concordance was 84%. An increase in the NT-proBNP (>1.5-fold increase and >300 pg/mL) at 18 to 24 hours was the commonest biomarker change. An increase of the NT-proBNP at 18 to 24 hours may be the preferred surrogate marker for identifying a patient experiencing physiologic difficulty in handling the volume challenge. Larger studies are needed to clarify the risk of TACO for a given pretransfusion biomarker profile and the correlation between TACO and increase in biomarkers after transfusion.


Epidemiological, clinical and serological studies on trichinellosis in Henan Province, China.
The epidemiological, clinical and serological studies on human trichinellosis in Henan Province were carried out from January 1992 to December 1996. The results showed that 467 patients attending our department came from 12 administrative areas and cities of the Province and they acquired the infection mainly by eating undercooked dumplings, tasting the raw pork filling for dumplings, ingesting scalded pork or mutton. There was the high incidence season of trichinellosis during the winter. Most of the patients were workers, officers and merchants aged 20-49 years, and the incidence was higher in males than in females. The main clinical manifestations of trichinellosis were fever, general myalgia, muscle tiredness and eosinophilia. Most of the patients had not any gastrointestinal symptoms and rash. Eyelid edema was only seen in the early courses of the disease. Eosinophil count increased with time, reached to the peak 3 weeks and decreased markedly 6 weeks after the onset of the disease. Eosinophil levels elevated obviously 1 week after therapy, began to drop rapidly 2 weeks after therapy, and decreased to a near normal levels 4 weeks after therapy. Anti-Trichinella antibodies were detected by IFAT using the frozen sections of the purified T. spiralis larvae as antigen. The specific antibodies were observed in only 70.2% of patients one week after onset of disease, and increased to 91, 94.3, and 100%; 2, 3, and 4 weeks, respectively after the onset. The antibody positive rate was evidently increased to 100% 1 week after therapy with abendazole, then decreased to 25% 4 months after therapy.


Clinical significance of circulating tumor cells detected by an invasion assay in peripheral blood of patients with ovarian cancer.
The invasive growth of circulating tumor cells (CTCs) propagates cancer metastasis. The aims of this study were to evaluate the association of invasive CTCs, detected by a novel cell invasion assay, with disease stage, CA-125 level and patient survival. Peripheral blood samples from 71 patients undergoing evaluation for ovarian malignancy were assessed for the presence of invasive CTCs using a cell invasion assay that enriches and identifies tumor cells with a cell adhesion matrix (CAM). Invasive CTCs were identified as cells exhibiting CAM invasion (CAM+) and expressing standard epithelial markers (Epi+). 43 (60.6%) patients had detectable CTCs: 0/5 benign patients, 1/10 (10%) early stage, 39/52 (73.1%) late stage and 3/4 (75%) unstaged patients (p-value <0.001). CTC counts ranged from 0-149 CTCs/ml with stage III/IV patients exhibiting significantly higher mean counts (41.3 CTCs/ml) than stage I/II patients (6.0 CTCs/ml) and benign patients (0 CTCs/ml, p-value=0.001). A positive correlation between CTC count and CA-125 level was observed (Spearman correlation coefficient r=0.309, p-value=0.035). Kaplan-Meier curves revealed a significant decrease in disease-free survival in patients with detectable CTCs (median survival 15.0 months vs. 35.0 months, log-rank p-value=0.042). Tumor grade and tumor histology did not influence CTC detection. Invasive CTCs can be detected in a majority of epithelial ovarian cancer patients and may predict shorter disease-free survival. Furthermore, higher CTC counts may reflect later stage disease and higher CA-125 levels.


System-Centered Care: How Bureaucracy and Racialization Decenter Attempts at Person-Centered Mental Health Care.
This article presents a study exploring structural biases within mental health organizations, in the context of person-centered care-an emerging framework for health systems globally. Findings revealed how surrounding institutional structures conditioned a powerful influence on clinical operations, in which there is a risk for clients to be systemically seen as a non-person, that is, as a racialized or bureaucratic object. Specifically, the article elucidates how racial profiles could become determinants of care within institutions; and how another, covert form of institutional objectification could emerge, in which clients became reduced to unseen bureaucratic objects. Findings illuminated a basic psychosocial process through which staff could become unwitting carriers of systemic agenda and intentionality-a type of "bureaucra-think"-and also how some providers pushed against this climate. These findings, and emergent novel concepts, add to the severely limited research on institutional bias and racism within psychological science.


Introduction of freedom of choice for hospital outpatient care in Portugal: Implications and results of the 2016 reform.
In Portugal, the National Health Service (NHS) assures universal access to medical treatment and care that is free at the point of delivery - except for relatively small user charges. Freedom of choice is limited and competition between the public and the private sectors is almost non-existent. In May 2016, the Ministry of Health introduced a new law that facilitates the referral of NHS users from primary healthcare units to outpatient consultations in NHS hospitals outside of the referral area. However, for inpatient care, patients are still bound to receive treatment within their referral area, which is determined by place of residence. The aim of the reform was to provide a timelier response to citizens' health needs and to increase efficiency. According to preliminary data from June 2016 to May 2017, 10.6% of all outpatient referrals from NHS primary health care units were made to an NHS hospital out of the referral area, with the highest proportion in the Lisbon (15.8%) region. In general, median waiting time for first outpatient consultation increased after the introduction of choice in the five specialties with the highest proportions of out-of-area referrals - but it reduced in two departments with the longest waiting times prior to the reform. The reform constitutes a major change to the relationship between NHS hospitals, with foreseeable consequences in hospital funding and the patients' perception of hospital quality.


Resource allocation of beech seedlings (Fagus sylvatica L.) -relationship to earthworm activity and soil conditions.
The physiological activity and C and N allocation of beech seedlings planted in two different beech forest soils (acid brown earth, rendzina) were studied over 80 days. One adult earthworm Octolasion lacteum (Örley) was placed in half of the containers. Transpiration, CO2, assimilation, chlorophyll synthesis and N incorporation were higher in the acid brown earth than in the rendzina. Fine root production was also higher in the acid brown earth. Production of stems and total N incorporation were higher in the O. lacteum treatments than in the controls. Burrowing activity of O. lacteum did not affect total root production but stimulated the transfer of C and N towards aboveground parts of the plants and shifted the large root to fine root ratio towards large roots. O. lacteum effects were similar in both soils. It is concluded that endogeic earthworms significantly affect resource allocation patterns of beech seedlings over a wide range of soils. This effect can be partly explained by an increased availability of N in soils worked by earth-worms.


Organizational characteristics and restraint use for hospitalized nursing home residents.
To examine the effect of organizational characteristics on physical restraint use for hospitalized nursing home residents. Secondary analysis of data obtained between 1994 to 1997 in a prospective phase lag design experiment using an advanced practice nurse (APN) intervention aimed at reducing physical restraint for a group of hospitalized nursing home residents. Eleven medical and surgical units in one 600-bed teaching hospital. One hundred seventy-four nursing home residents aged 61 to 100, hospitalized for a total of 1,085 days. Physical restraint use, APN intervention, age, perceived fall risk, behavioral phenomena, perceived treatment interference, mental state, severity of illness, day of week, patient-registered nurse (RN) ratio, patient-total nursing staff ratio, and skill mix. Controlling for the APN intervention, age, and patient behavioral characteristics (all of which increased the likelihood of restraint use), weekend days as an organizational characteristic significantly increased the odds of restraint (weekend day and patient-RN ratio on physical restraint use: odds ratio (OR) = 1.92, 95% confidence interval (CI) = 1.38-2.68, P <.001; weekend day and patient-total staff ratio on physical restraint use: OR = 1.91, 95% CI = 1.37-2.66, P <.001; weekend day and skill mix on physical restraint use: OR = 1.91, 95% CI = 1.37-2.67, P <.001). Key findings suggest that organization of hospital care on weekends and patient characteristics that affect communication ability, such as severely impaired mental state, English as a second language, sedation, and sensory-perceptual losses, may be overlooked variables in restraint use.


New clerodane diterpenoids from Croton crassifolius.
Two new clerodane diterpenoids (1-2), one new clerodane diterpenoid alkaloid (3), as well as thirteen known compounds were isolated from Croton crassifolius. The structures of new compounds were established by a combination of spectroscopic methods, including HRMS, (1)H NMR, (13)C NMR, (1)H (1)H COSY, HSQC, HMBC, NOESY and X-ray crystallographic analysis. Compound 3 is firstly reported as the clerodane-type diterpenoid alkaloid in natural products. All of the compounds were evaluated for in vitro cytotoxic activities against CT26.WT cell using the MTT method.


Acute bursitis calcarea trochanterica in an infant, with perforation into the hip joint demonstrated by arthrogram.
A case of bursitis calcarea trochanterica acuta is reported in a boy aged four months. The calcification was amorphous, and arthrography revealed extension into the hip joint. The lesion was treated surgically.


Effects of melatonin on aluminium-induced neurobehavioral and neurochemical changes in aging rats.
This study aimed to investigate the potential protective effects of melatonin (Mel) against aluminium-induced neurodegenerative changes in aging Wistar rats (24-28months old). Herein, aluminium chloride (AlCl3) (50mg/kg BW/day) was administered by gavage, and melatonin (Mel) was co-administered to a group of Al-treated rats by an intra-peritoneal injection at a daily dose of 10mg/kg BW for four months. The findings revealed that aluminium administration induced a significant decrease in body weight associated with marked mortality for the old group of rats, which was more pronounced in old Al-treated rats. Behavioural alterations were assessed by 'open fields', 'elevated plus maze' and 'Radial 8-arms maze' tests. The results demonstrated that Mel co-administration alleviated neurobehavioral changes in both old and old Al-treated rats. Melatonin was noted to play a good neuroprotective role, reducing lipid peroxidation (TBARs), and enhancing enzymatic (SOD, CAT and GPx) activities in the brain organs of old control and old Al-treated rats. Mel treatment also reversed the decrease of AChE activity in the brain tissues, which was confirmed by histological sections. Overall, the results showed that Mel administration can induce beneficial effects for the treatment of Al-induced neurobehavioral and neurochemical changes in the central nervous system (CNS).


Comparison between two different concentrations of a fixed dose of ropivacaine in interscalene brachial plexus block for pain management after arthroscopic shoulder surgery: a randomized clinical trial.
Only a few studies have evaluated the differences between varying concentrations of a fixed dose of local anesthetics. This study was conducted to compare the effects of two different concentrations of a fixed dose of ropivacaine used in ultrasound-guided interscalene brachial plexus block. This prospective, randomized, double-blind study included 62 patients who underwent arthroscopic surgery under general anesthesia. The patients were randomly assigned to receive ultrasound-guided interscalene block with 75 mg of ropivacaine at one of two concentrations: 0.75% (10 ml; group C) or 0.375% (20 ml; group V). Time to onset of sensory blockade, degree of blockade, pulmonary function changes, analgesic duration of the interscalene block, postoperative opioid requirement within 24 h, postoperative pain scores, satisfaction, and incidence of complications were recorded. Although the time to onset of sensory blockade was shorter for group C (P = 0.015), successful blockade was achieved at 30 min after the interscalene block in both groups. The analgesic duration of the interscalene block was not significantly different between the groups. The amount of opioid used within 24 h after surgery was significantly reduced for group V compared with group C (P = 0.016). The rest of the parameters did not show any significant differences between the two groups. Compared with 10 ml of 0.75% ropivacaine, interscalene block with 20 ml of 0.375% ropivacaine could be effective for the reduction of postoperative opioid requirement within 24 h after surgery despite it might not prolong the analgesic duration.


Fluorescence ratiometric DNA detection by peptide nucleic acid-pyrene binary probes.
We developed a method for detecting DNA by excimer fluorescence from two peptide nucleic acids (PNAs) modified with a pyrene (Pyr). The two PNA-Pyr probes were prepared by solid-phase peptide synthesis, and we assessed fluorescence from the mixture of probes with DNA. From the results, excimer fluorescence derived from the two PNA-Pyr probes forming hybrids with the complementary DNA was observed, and the two probes showed the maximum excimer/monomer ratio when the probes and DNA were hybridized at a 1:1:1 ratio, indicating that the PNA-Pyr probes can detect target DNA. Furthermore, we adjusted the spatial arrangement between the two PNA-Pyr hybrids formed on the DNA to promote optimal excimer formation. As a result, optimal excimer formation was achieved by spacing the two nucleobases between the formed two hybrids and further inserting a hexamethylene linker (C6) between the PNA and Pyr of the PNA-Pyr probe on one side.


Effects of a diet plus exercise program on thyroid function in patients with obesity.
Studies of thyroid function after diet-induced weight loss in patients with obesity have yielded conflicting results. It is not known whether adding exercise to diet affects thyroid function in this patient population. The aim of the study was to prospectively evaluate the effects of a rehabilitation program on weight, body composition and thyroid function in euthyroid patients with obesity. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) in euthyroid patients with severe obesity were analyzed before and at the end of a 3-month rehabilitation program. Relationships between body weight or composition and changes in thyroid function were also investigated. Each study participant acted as his/her own control. The study population consisted of 34 euthyroid patients with obesity (18 men and 16 women; mean ± SD age: 51 ± 12). The mean BMI was 49.3 ± 12.4 kg/m2 before the program and 46 ± 10.8 (p < 0.005) at the end, with a mean body weight loss of 11 kg (p < 0.05) and a mean fat mass loss of 6.8 kg (p < 0.05). The weight and fat mass losses were not significantly correlated with the serum concentrations of TSH, FT3 and FT4 measured at the end of the program. A 3-month rehabilitation program combining diet and exercise produced weight and fat mass losses without inducing thyroid dysfunction in patients with obesity.


Utility of initial EEG in first complex febrile seizure.
The risk of developing epilepsy following febrile seizures (FS) varies between 2% and 10%, with complex febrile seizures (CFS) having a higher risk. We examined the utility of detected epileptiform abnormalities on the initial EEG following a first CFS in predicting subsequent epilepsy. This was a retrospective study of consecutive patients (ages 6-60 months) who were neurologically healthy or mildly delayed, seen in the ED following a first CFS and had both an EEG and minimum of 2-year follow-up. Data regarding clinical characteristics, EEG report, development of subsequent epilepsy, and type of epilepsy were collected. Established clinical predictors for subsequent epilepsy in children with FS and EEG status were evaluated for potential correlation with the development of subsequent epilepsy. Sensitivity, specificity, and positive and negative predictive values of an abnormal EEG (epileptiform EEG) were calculated. A group of 154 children met our inclusion criteria. Overall, 20 (13%) children developed epilepsy. The prevalence of epilepsy was 13% (CI 8.3-19.6%). Epileptiform abnormalities were noted in 21 patients (13.6%), EEG slowing in 23 patients (14.9%), and focal asymmetry in six (3.8%). Epileptiform EEGs were noted in 20% (4/20) of patients with epilepsy and 13% (17/134) of patients without epilepsy (p=0.48). At an estimated risk of subsequent epilepsy of 10% (from population-based studies of children with FS), we determined that the PPV of an epileptiform EEG for subsequent epilepsy was 15%. None of the clinical variables (presence of more than 1 complex feature, family history of epilepsy, or status epilepticus) predicted epilepsy. An epileptiform EEG was not a sensitive measure and had a poor positive predictive value for the development of epilepsy among neurologically healthy or mildly delayed children with a first complex febrile seizure. The practice of obtaining routine EEG for predicting epilepsy after the first CFS needs clarification by well-defined prospective studies.


Engineering pulmonary vasculature in decellularized rat and human lungs.
Bioengineered lungs produced from patient-derived cells may one day provide an alternative to donor lungs for transplantation therapy. Here we report the regeneration of functional pulmonary vasculature by repopulating the vascular compartment of decellularized rat and human lung scaffolds with human cells, including endothelial and perivascular cells derived from induced pluripotent stem cells. We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol. Using these methods we achieved ∼75% endothelial coverage in the rat lung scaffold relative to that of native lung. The regenerated endothelium showed reduced vascular resistance and improved barrier function over the course of in vitro culture and remained patent for 3 days after orthotopic transplantation in rats. Finally, we scaled our approach to the human lung lobe and achieved efficient cell delivery, maintenance of cell viability and establishment of perfusable vascular lumens.


Nucleosome destabilization by polyamines.
The roles and molecular interactions of polyamines (PAs) in the nucleus are not fully understood. Here their effect on nucleosome stability, a key regulatory factor in eukaryotic gene control, is reported, as measured in agarose embedded nuclei of H2B-GFP expressor HeLa cells. Nucleosome stability was assessed by quantitative microscopy [1,2] in situ, in close to native state of chromatin, preserving the nucleosome constrained topology of the genomic DNA. A robust destabilizing effect was observed in the millimolar concentration range in the case of spermine, spermidine as well as putrescine, which was strongly pH and salt concentration-dependent, and remained significant also at neutral pH. The integrity of genomic DNA was not affected by PA treatment, excluding DNA break-elicited topological relaxation as a factor in destabilization. The binding of PAs to DNA was demonstrated by the displacement of ethidium bromide, both from deproteinized nuclear halos and from plasmid DNA. The possibility that DNA methylation patterns may be influenced by PA levels is contemplated in the context of gene expression and DNA methylation correlations identified in the NCI-60 panel-based CellMiner database: methylated loci in subsets of high-ODC1 cell lines and the dependence of PER3 DNA methylation on PA metabolism.


Prefrontal and striatal dopamine metabolism during enhanced rebound hyperphagia induced by space restriction--a rat model of binge eating.
Several lines of evidence indicate that abnormalities in brain dopamine and serotonin metabolism may play an important role in bulimia nervosa. However, the regional neurochemical mechanism of the binge eating is poorly understood. Our purpose was to elucidate brain neurochemical mechanisms of binge eating using a rat model. The dopamine release and metabolism in the prefrontal cortex (PFC) and in the ventrolateral striatum (VLS) of rats were studied using microdialysis during enhanced rebound hyperphagia induced by space restriction (an animal model of binge eating). The rats showed rebound hyperphagic state when they were released from scheduled feeding (2 hours/day feeding for 7 days). The hyperphagia was further enhanced when they were put in a space-restricted cage where their mobility was restricted. Dopamine release and metabolism were increased both in the PFC and in the VLS during the enhanced rebound hyperphagia. These results tentatively suggest that increased dopamine release and metabolism in the PFC and in the VLS may be related to space restriction and to activation of motor function involved in feeding behavior, respectively. The enhanced rebound hyperphagia induced by space restriction may be useful as an animal model of binge eating.


Comparison of Difference in Hematologic and Hemodynamic Outcomes between Primary Total Knee Arthroplasty and Revision of Infected Total Knee Arthroplasty.
This study is to identify preoperative cautions for revision of infected total knee arthroplasty (TKA) by understanding the differences in hematologic and hemodynamic changes between primary TKA and revision of infected TKA. The study included 40 patients in each of the two groups: one group with patients who underwent TKA and the other group with patients who underwent revision of infected TKA. All patients matched for age and body mass index. The following data were compared between the groups: changes in blood pressure, variations in hemoglobin level, amount of postoperative blood loss and transfused blood, incidence of blood transfusion, white blood cell (WBC) count, albumin level, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and liver enzyme level. The hemoglobin levels, transfusion rate, and the amount of blood loss were significantly higher in the revision group (p=0.012). In both groups, CRP reached the highest level on the 3rd postoperative day but it was normalized 2 weeks postoperatively; however, the revision TKA group showed a greater tendency to normalization (p=0.029). There were significant differences between the groups in ESR, WBC, blood pressure, and changes in liver enzyme levels. Revision of infected TKA results in greater hemodynamic variations than primary TKA. Therefore, more efforts should be made to identify pre- and postoperative hemodynamic changes and hematologic status.


Factors Associated with Asthma Severity in Children: Data from the French COBRAPed Cohort.
Severe asthma (SA) in children is a complex, heterogeneous disease, associated with a considerable burden. However, factors influencing asthma severity are poorly described and may differ according to age. To determine whether factors associated with asthma severity differ between preschoolers with severe recurrent wheeze (SRW) and school-age children with SA. Data from the French multicenter prospective observational cohort of preschool (3-6 years) children with SRW and nonsevere recurrent wheeze (NSRW) and school-age (7-11 years) children with SA and nonsevere asthma (NSA) (Pediatric Cohort of Bronchial Obstruction and Asthma) were analyzed. A total of 131 preschool children (92 SRW and 49 NSRW) and 207 school-age children (92 SA and 115 NSA) were included. In both univariable and multivariable analysis, SRW was associated with second-hand smoke exposure (multivariable analysis: odds ratio [95% CI], 29.8 [3.57-3910]) and exposure to mold/dampness at home (multivariable analysis: odds ratio [95% CI], 4.22 [1.25-18.2]) compared with NSRW. At school-age, history of atopic dermatitis and food allergy was more frequent in children with SA than in those with NSA. Multivariable analysis confirmed that SA was associated with a history of food allergy (odds ratio [95% CI], 5.01 [2.23-11.9]). Our data suggest that factors influencing asthma severity may differ according to age. In preschool children with SRW, second-hand smoke and exposure to mold are predominant, whereas associated allergic disorders are mainly involved in SA at school-age.


Immunomodulatory activity of polysaccharide isolated from Angelica sinensis.
The immunomodulatory activities of an Angelica sinensis polysaccharide (AP), purified from the fresh root of A. sinensis Diels, were investigated in vitro in relation to the specificity to immune cells. AP consisted of rhamnose, arabinose, mannose, glucose, galactose with the molar ratio of 1.00:4.54:2.98:11.09:7.45. Cell proliferation results showed that proliferation of total spleen cells, macrophages and T cells were promoted by the action of AP. The treatment of AP increased the production of IL-2 and IFN-gamma, while that of IL-4 was decreased. RT-PCR analysis displayed that the IL-2 and IFN-gamma gene expression were enhanced but the IL-4 gene expression was decreased. Some differences in cytokines secretion pattern were also detected, the expression of IFN-gamma was rapidly augmented while that of IL-2 responded later. The flow cytometry results showed that the percentage of CD4(+)T cell in total spleen cells was remarkably increased by AP, while that of CD8(+)T cell was slightly decreased. In conclusion, AP has immunomodulatory activity by regulating expression of Th1 and Th2 related cytokines. The time-effect relation of cytokines response also suggests that macrophages and natural killer cells involved in nonspecific immunity were primary activated, and helper T cell were secondarily affected by AP.


Betulonic acid regulates oviduct epithelial cell inflammation through the TLR4, MAPK, and JAK/STAT signalling pathways.
Infertility is a common disease among women of childbearing age and seriously endangers the reproductive health of human beings. We aimed to study the active effect and mechanism of betulonic acid (BTA) on tubal inflammatory infertility. An inflammatory model was established in isolated rat oviduct epithelial cells. Immunofluorescence of cytokeratin 18 was performed in cells. The therapeutic effect of BTA on cells was observed. Subsequently, we added JAK/STAT inhibitor AG490 and MAPK inhibitor U0126 and measured the levels of inflammatory factors via enzyme-linked immunosorbent assay and qRT-PCR. CCK-8 assay was applied to test cell proliferation, whereas flow cytometry was used to measure apoptosis. The levels of TLR4, IκBα, JAK1, JAK2, JAK3, Tyk2, STAT3, p38, ERK and the phosphorylation of p65 were determined by Western blotting. Betulonic acid inhibited the activation of TLR4 and NF-κB signalling pathways, and significantly downregulated IL-1β, IL-6, and TNF-α, with high doses being the most effective. Furthermore, high-dose BTA promoted the proliferation of oviduct epithelial cells and inhibited apoptosis. In addition, BTA inhibited the activation of JAK/STAT signalling pathway to perform effectively in oviduct epithelial cells inflammation. The addition of AG490 led to the inhibition of the JAK/STAT signalling pathway. BTA also inhibited the activation of MAPK signalling pathway in oviduct epithelial cells inflammation. Under U0126 treatment, the inhibition of proteins in MAPK pathway by BTA was weakened. Therefore, BTA inhibited the TLR, JAK/STAT and MAPK signalling pathways. Our study provided a new therapeutic strategy for infertility caused by oviduct inflammation.


Control of water balance in infants with bronchopulmonary dysplasia: role of endogenous vasopressin.
Babies with chronic bronchopulmonary dysplasia (BPD) can sometimes develop pallor, systemic and pulmonary edema, oliguria, and hyponatremia not attributable to cardiopulmonary or renal impairment. These signs and symptoms might, however, be explained by inappropriate control of vasopressin secretion. To test this hypothesis, we measured plasma vasopressin and osmolality, serum sodium and potassium concentrations, urine output and osmolality, and free water clearance in 26 normoxic infants with BPD aged 1-4 months. All of these infants required supplemental oxygen (FiO2 0.41 +/- 0.03, mean +/- 1 SE) to maintain O2 saturation of greater than 88%, and six infants also required mechanical ventilation. As controls, 10 infants of similar age but without BPD were also studied. None of the infants had been discharged from the nursery and was receiving any medications, and all were clinically stable when studied. Compared to control infants, infants with BPD had significantly elevated plasma vasopressin concentrations (control 5.2 +/- 0.9 pg/ml; BPD 42.4 +/- 5.1; mean +/- SE, p less than 0.05). Moreover, infants with BPD had hyponatremia and hypotonic plasma, and both urine output and free water clearance were significantly reduced. These data suggest that some infants with chronic BPD have elevated vasopressin levels that are functionally significant. We speculate that excessive stimulation of vasopressin secretion may explain some of the pulmonary and nonpulmonary signs and symptoms in infants with chronic BPD.


Current Options for the Treatment of Food Allergy.
Food allergy is increasing in prevalence; as a result, there is intense focus on developing safe and effective therapies. Current methods of specific immunotherapy include oral, sublingual, and epicutaneous, while nonspecific methods that have been investigated include: Chinese herbal medicine, probiotics, and anti-IgE antibodies. Although some studies have demonstrated efficacy in inducing desensitization, questions regarding safety and the potential for achieving immune tolerance remain. Although some of these therapies demonstrate promise, further investigation is required before their incorporation into routine clinical practice.


A kinetic analysis of kappa-opioid agonist binding using the selective radioligand [3H]U69593.
The interaction of the nonselective opioid ligand [3H]bremazocine and of the kappa-opioid [3H]U69593 with the kappa-receptor was investigated in guinea-pig cortical membranes. Each radioligand bound to a single population of high-affinity sites, although [3H]U69593 apparently recognised only 70% of those sites labelled by [3H]bremazocine. Naloxone and the kappa-selective ligands U69593 and PD117302 exhibited full inhibition of the binding of both radioligands. Kinetic analysis demonstrated biphasic rates of association and dissociation for both [3H]bremazocine and [3H]U69593. Detailed analysis of the binding of [3H]U69593 revealed that the fast rate of association was dependent on radioligand concentration, in contrast to the slow rate, which was independent of ligand concentration. Guanylyl-5'-imidodiphosphate (GppNHp) inhibited binding of [3H]U69593; saturation analysis demonstrated that the inhibitory effects of GppNHp resulted in a decrease in affinity without any significant change in binding capacity. GppNHp attenuated the formation of the slow component of [3H]U69593 binding, while accelerating the fast component. The data are consistent with the formation of a high-affinity complex between the kappa-receptor and a guanine nucleotide binding protein. Guanine nucleotides promote the dissociation of this ternary complex and the stabilisation of a lower-affinity state of the receptor.


Prebiotic triose glycolysis promoted by co-catalytic proline and phosphate in neutral water.
Proline and phosphate promote a near-quantitative aldol reaction between glycolaldehyde phosphate and formaldehyde at neutral pH in water. Our results demonstrate the important role of general acid-base catalysis in water and underscore the essential role that amino acid catalysis may have played in early evolution of life's core metabolic pathways.


First data from the German Lipoprotein Apheresis Registry (GLAR).
In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft für Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases. In 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers. There has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings.


Molecular aspects of disaccharidase deficiencies.
We have described the methods used for studying the biosynthesis and the post-translational processing of sucrase-isomaltase (SI), lactase-phlorizin hydrolase (LPH) and maltase-glucoamylase (MGA) in human small intestinal mucosa. Our results are discussed in the context of findings by other researchers. A surprising finding coming out of all these studies is that SI, LPH and MGA are structurally quite different. SI and LPH are both synthesized as large molecular weight precursors which are proteolytically processed to the mature enzymes. In the case of SI, this processing occurs after insertion of the precursor into the brush border membrane and is catalysed by pancreatic proteases; the mature form consists of the two subunits sucrase and isomaltase, the latter containing an N-terminal peptide anchor. Proteolytic processing of the LPH-precursor occurs intracellularly, yielding a mature enzyme in the form of a two active site polypeptide which is anchored via a C-terminal peptide. The role of the large cleaved propolypeptide of LPH is not yet known. MGA is the largest of the three disaccharidases, having a molecular weight of greater than 300 kDa. No proteolytic processing seems to be taking place during biogenesis of MGA in human mucosa, and the mode of attachment to the membrane is unknown at present. The application of the methods described to the investigation of congenital sucrase-isomaltase deficiency (CSID) and lactase restriction in adults is presented and differences between CSID and LPH restriction are discussed.


Studies on the filtration properties of isolated renal basement membranes.
1. The filtration properties of films of renal basement membrane were studied in vitro using pressure filtration chambers. 2. Retention of cytochrome c by the films was found to be dependent upon the filtration pressure indicating that it was transferred across the films by convective as well as diffusive flow. In contrast, serum albumin was transferred by diffusive movement only. 3. When solutions containing both cytochrome c and IgG were filtered it was found that increasing the filtration pressure reduced the flux of cytochrome c across the films. A similar phenomenon occurred when serum was filtered, less protein passed through the films at high filtration pressures. These phenomena are explained by concentration-polarisation effects. 4. The flux of cytochrome c through the films was found to decrease in a non-linear manner as the films thickness was increased. With thin films, the flux of cytochrome c increased in a non-linear manner as the concentration of the protein in the overstanding solution was increased. With thicker films the flux was linearly dependent on concentration. These findings are interpreted as supporting the view that movement of cytochrome c occurs, at least in part, by convective flow.


Post-transfusion purpura secondary to passive transfer of anti-P1A1 by blood transfusion.
A patient developed severe post-transfusion purpura (PTP) following transfusion of two units of packed red blood cells. The timing of the patient's thrombocytopenia suggested passive immunization rather than the typical anamnestic response associated with classical PTP. Investigation of the blood donors revealed one with evidence of a platelet specific antibody of high titre. This donor was typed as P1A1 negative and the antibody was shown to have anti-P1A1 specificity.


Evaluation of zinc effect on cadmium action in lipid peroxidation and metallothionein levels in the brain.
Cadmium (Cd) is a known hepato- and nephrotoxic pollutant and zinc (Zn) metalloproteins are important targets of Cd. Hence, the administration of Zn may mitigate Cd toxic effects. However, the interaction of Cd and Zn has been little investigated in the brain. Previously, we reported a protective effect of Zn on mortality caused by Cd in rats. Here, we tested whether the protective effect of Zn could be related to changes in brain Zn-proteins, metallothionein (MT) and δ-aminolevulinate dehydratse (δ-ALA-D). Male adult rats were daily administered for 10 days with Zn (2 mg kg-1), Cd (0.25 and 1 mg kg-1) and 0.25 mg kg-1 of Cd plus Zn and 1 mg kg-1 of Cd plus Zn. The body weight loss, food intake deprivation, and mortality occurred in 1 mg kg-1 of Cd, but Zn co-administration did mitigate these effects. The brain Zn content was not modified by treatment with Cd, whereas cerebral Cd levels increased in animals exposed to Cd. The administration of 0.25 mg kg-1 of Cd (with or without Zn) induced lipid peroxidation and decreased MT concentration, but 2 mg kg-1 of Zn and 1 mg kg-1 of Cd did not change these parameters. Brain δ-ALA-D was not modified by Cd and/or Zn treatments. Since the co-administration of Zn did not attenuate the changes induced by Cd in the brain, our results suggest that the protective effect of Zn on impairments caused by Cd in animal status is weakly related to a cerebral interaction of these metals.


Being and doing in the outdoors brings something extra! Evaluating the Danish Healthy in Nature Project.
Little is known of the potential of using nature and outdoor activities in relation to community-based health promotion programmes. This study seeks a better understanding of how people with mental or chronic physical health problems experience a local outdoor health promotion or rehabilitation programmes and a better understanding of how these programs contribute to the participant's health and well-being. The study is based on data from the Healthy in Nature project targeting adults with chronic physical health problems and adults with mental health problems. Data was collected using a qualitative multiple case study design involving five selected cases with both qualitative interviews and observation. Data was analysed using Braun et al.'s 6-phase guide to qualitative reflexive thematic analysis, employing Self-Determination Theory as a theoretical framework. Results: Overall, the participants in the two groups experienced increased competence, autonomy, and relatedness, and the participants expressed the importance of both being in a natural environment and doing outdoor activities (friluftsliv). The study makes a valuable contribution to the field of health promotion and rehabilitation pointing to nature and friluftsliv as important elements that offer great potential to community-based health promotion.


Intramuscular injection of tetracycline decreased gut microbial diversity in mouse.
Antibiotics contribute a lot to human beings and can kill bacteria effectively. However, more and more studies show that antibiotics can disturb the intestinal microbial community. It has been widely reported that oral antibiotics can reduce the diversity of intestinal microflora, but the effect of intramuscular injection on intestinal microflora is less studied. In this study, we sequenced the intestinal microflora of mice treated with tetracycline by 16SrRNA method, and found that intramuscular injection of tetracycline (TET) can also reduce the intestinal microbial richness of mice. In addition, the results showed that within a certain range (3 mg), with the increase of TET injection concentration, the wind of intestinal microflora in mice decreased significantly. When the injection concentration reached saturation, although the amount of TET injection was increased, the degree of intestinal flora affected was not increased. The results showed that the degree of diversity decrease was in direct proportion to the amount of tetracycline injection in the saturated concentration, but not positively related to the high amount of TET injection after exceeding the saturated concentration.


Man and his parasites: integration of biomedical and social approaches to transmission and control.
The significance of sociocultural and behavioural factors in the transmission and control of parasitic infections has been underestimated. Explanations for this neglect include the failure of communication between biomedics and social scientists and reliance on control measures such as mass chemotherapeutic and anti-vector programmes which do not involve the participation of the community at risk. The need for an integrated approach to both the impact of parasitic infections and their control is now being recognised. Given their very high prevalence and the background socio-economic and other factors which exacerbate the problem, parasites of the subtropical and tropical countries will be the main emphasis of this discussion. The paper will illustrate a number of methodologies employed to look at the relationship between sociocultural and parasitic infections rather than provide a catalogue of interesting and yet isolated examples of human risk behaviours. These methodologies will include assessments of both individual risk factors and a broader framework to include larger social groupings including 'outsiders' involved in control programmes. Finally, the importance of this type of emphasis within control strategies will be discussed and a concluding section on research priorities and recommendations will be presented.


The δ18O-inferred thermal reconstruction for the Pleistocene based on the modification of existing glacial and interglacial paleoclimatic models.
The determination of the climatic factors related to the Paleolithic archaeological, or fossils sites of the late Neogene and Quaternary periods would require the knowledge of all the fossil specimen's age-site-related paleoclimatic factors. Because the necessary high-temporal resolution georeferenced, paleoclimatic models do not exist for most of the periods of the Pliocene and Pleistocene epoch, at the first step, the former climatic conditions should be reconstructed according to the age-site pair data. The idea of the developed method is, that using the foraminiferal oxygen isotope (δ18O) ratio values, the available Pleistocene glacial and interglacial paleoclimatic model pairs can provide the bases for the reconstruction of the former thermal conditions for any period during the Pleistocene epoch. In a technical sense, the approach is based on the observation that the changes in the Cenozoic δ18O record can correspond with the global mean temperature alterations. Determining the cold and warm periods-related δ18O ratio values, new, georeferenced paleoclimatic models can be produced. The main steps of the developed method are as follows:•Determination of the oxygen isotope ratio (δ18O) which corresponds to the former thermal conditions of a site.•Using a scaling technique to create new, approximate climate maps by changing glacial and interglacial maps.•Reconstruction of the monthly mean temperature values based on the thermal conditions of the warmest and the coldest quarters.


ACE gene polymorphism and cardiac structure in patients with insulin resistance.
Angiotensin-converting enzyme (ACE) is a key enzyme in the production of angiotensin II, thus may participate in the modulation of cardiac growth. The aim of our study is to analyze the ACE gene I/D polymorphisms in patients with insulin resistance (IR) and to evaluate its relationship to left ventricular mass and functions. Eighteen subjects (13 female and 5 male, mean age 39.8 +/- 14) with IR were enrolled in the present study. Twenty-three healthy people without IR were recruited as the control group. ACE amplification of DNA was performed by polymerase chain reaction methodology. Fasting glucose and insulin, postprandial glucose, homeostasis model assessment (HOMA-IR) and HOMA-beta, lipid profile, anthropometric measurements were assessed. Left ventricular structure and functions were measured by echocardiography. Distribution of I/D polymorphism of the ACE gene in the study group was as follows: genotype II-0%, ID-38.9%, DD-61.1% of patients. Distribution of individual genotypes was similar in patients with and without IR. No significant difference was found between genotype groups in terms of anthropometric measurements and metabolic parameters and blood pressure. Echocardiography showed no significant changes in left ventricular structure and functions in patients with IR. We considered that in patients with IR, there is no relationship between I/D polymorphism of the ACE gene and LVH.


Endoscope-assisted, minimally invasive evacuation of sub-acute/chronic epidural hematoma: Novelty or paradox of Theseus?
Sub-acute/chronic epidural hematoma (EDH) may present with nagging symptoms of headache, nausea, vomiting, lethargy, etc. We attempted to offer a minimally invasive, single burr hole, endoscope-assisted evacuation of EDHs instead of a conventional craniotomy. Seven patients with sub-acute/chronic EDH (six supratentorial and one infratentorial) presented to us 3 to 7 days after low-velocity road traffic accidents with complaints of headache and lethargy. The EDH volumes measured between 20 to 50 ml, and the patients were operated on using a single burr hole made through a small incision. We used 0-, 30- and 70-degree, angulated, rigid, high-definition endoscopes to identify and evacuate the organized clots in the extradural space. Flexible catheters were used for suction and irrigation. After achieving hemostasis, the dura was hitched back to the burr hole site. The wound was closed over a negative suction drain. All patients had prompt recovery from symptoms. Postoperative CT scans showed complete or near complete evacuation of the hematomas. The hospital stay and analgesic requirements were minimal. There was no infective complication or conversion to conventional open surgery. The average time for surgery was 77.8 min, and average blood loss was 328.5 ml. Endoscope-assisted evacuation of sub-acute/chronic EDH is a novel concept, which offers quick relief from symptoms in a minimally invasive fashion and a cosmetically acceptable way. None of the standard principles of surgery are hampered. It avoids extensive dissection of the temporalis or sub-occipital muscles. However, achieving hemostasis can be difficult. Further study and better equipment will validate the procedure.


Intermediate tidal volume is an acceptable option for ventilated patients with acute respiratory distress syndrome.
Evidence only proves low surpasses high tidal volume (VT) for acute respiratory distress syndrome (ARDS). Intermediate VT is a common setting for ARDS patients and has been demonstrated as effective as low VT in non-ARDS patients. The effectiveness of intermediate VT in ARDS has not been studied and is the objective of this study. A retrospective cohort study. Five ICUs with their totally 130 beds in Taiwan. ARDS patients under invasive ventilation. No. 28-D mortality. Totally 382 patients, with 6958 ventilator settings eligible for lung protection, were classified into low (mean VT=6.7ml/kg), intermediate (mean VT=8.9ml/kg) and high (mean VT=11.2ml/kg) VT groups. With similar baseline ARDS and ICU severities, intermediate and low VT groups did not differ in 28-D mortality (47% vs. 63%, P=0.06) or other outcomes such as 90-D mortality, ventilator-free days, ventilator-dependence rate. Multivariate analysis revealed high VT was independently associated with 28-D and 90-D mortality, but intermediate VT was not significantly associated with 28-D mortality (HR 1.34, CI 0.92-1.97, P=0.13) or 90-D mortality. When the intermediate and low VT groups were matched in propensity scores (n=66 for each group), their outcomes were also not significantly different. Intermediate VT, with its outcomes similar to small VT, is an acceptable option for ventilated ARDS patients. This conclusion needs verification through clinical trials.


Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes.
Accumulating evidences demonstrated that statins impaired glucose utilization. This study was aimed to investigate whether PXR was involved in the atorvastatin-impaired glucose utilization. Rifampicin/PCN served as PXR activator control. Glucose utilization, glucose uptake, protein levels of GLUT2, GCK, PDK2, PEPCK1 and G6Pase in HepG2 cells were measured. PXR inhibitors, PXR overexpression and PXR siRNA were applied to verify the role of PXR in atorvastatin-impaired glucose utilization in cells. Hypercholesterolemia rats induced by high fat diet feeding, orally received atorvastatin (5 and 10 mg/kg), pravastatin (10 mg/kg) for 14 days, or intraperitoneally received PCN (35 mg/kg) for 4 days. Results showed that glucose utilization was markedly inhibited by atorvastatin, simvastatin, pitavastatin, lovastatin and rifampicin. Neither rosuvastatin nor pravastatin showed the similar effect. Atorvastatin and pravastatin were selected for the following study. Atorvastatin and rifampicin significantly inhibited glucose uptake and down-regulated GLUT2 and GCK expressions. Similarly, overexpressed PXR significantly down-regulated GLUT2 and GCK expressions and impaired glucose utilization. Ketoconazole and resveratrol attenuated the impaired glucose utilization by atorvastatin and rifampicin in both parental and overexpressed PXR cells. PXR knockdown significantly up-regulated GLUT2 and GCK proteins and abolished the decreased glucose consumption and uptake by atorvastatin and rifampicin. Animal experiments showed that atorvastatin and PCN significantly elicited postprandial hyperglycemia, leading to increase in glucose AUC. Expressions of GLUT2 and GCK in rat livers were markedly down-regulated by atorvastatin and PCN. In conclusion, atorvastatin impaired glucose utilization in hepatocytes via repressing GLUT2 and GCK expressions, which may be partly due to PXR activation.


Impact of alkaline electro-activation treatment on physicochemical and functional properties of sweet whey.
The impact of alkaline electro-activation (EA) on the protein solubility, foaming, and emulsifying characteristics of whey was investigated. EA caused protein aggregation and conjugation. At low electric current and holding time, proteins aggregation through disulfide bonds was observed, whereas increasing currents and holding times caused proteins to conjugate with sugars such as lactose, lactulose and galactose. The EA process improved the protein solubility at the pH range of 4.0-7.0. Compared to untreated whey, which produced micron-sized and unstable emulsions at pH 3, whey samples treated under 750 mA and 24-48 h holding time formed nano-sized and stable emulsions at this pH. Furthermore, although both untreated and EA-whey produced stable emulsions at pH 7, those emulsions prepared with EA-whey had smaller particle size and were more stable against droplet flocculation. EA-treated whey tended to generate foams with significantly higher overrun and stability. The present study demonstrated that EA can enhance the functionality of whey.


Ultrastructural data, with special reference to bouton/glial relationships, from the hypoglossal nucleus after a second axotomy of the hypoglossal nerve.
The left hypoglossal nerve of adult male albino rats was prevented from regenerating to the tongue after a distal axotomy by implanting the proximal stump into normally innervated left sternomasoid muscle. Eighty-four days after implantation, the hypoglossal nerve was transected again and its regeneration to the tongue unimpeded. From 8 to 70 days after this second axotomy the left hypoglossal nuclei were processed for quantitative ultrastructural analysis. The first aim of this study was to compare regeneration success in the hypoglossal nucleus after second axotomy with that accompanying outgrowth of the hypoglossal nerve into denervated sternomastoid muscle. During quantitative analysis a second aim developed, of elucidating bouton/glial relationships. The second axotomy induced loss and return of subsurface cisterns, dispersal and reassembly of Nissl substance, increase and decrease of microglial numbers, slight further loss and partial return of boutons with clear spherical vesicles and symmetrical synapses, slight increase and decrease of boutons with clear flat vesicles and symmetrical synapses, regrowth of retracted dendrites and restoration of their synapses, and gradual diminution of numbers of electron-dense neurones and dendrites. Astrocytes remained hypertrophied throughout. When compared with events in the hypoglossal nucleus accompanying innervation of denervated sternomastoid muscle by the hypoglossal nerve, the results suggest (1) that regeneration of the hypoglossal nerve to its own tongue muscle instead of to a foreign muscle caused no acceleration of recovery in the hypoglossal nucleus, and (2) that the microglial response is dependent on nerve integrity and not on bouton behaviour.


Hypercholesterolemic effect of indomethacin in the rat.
The effect of indomethacin on serum lipid constituents of the albino rat was investigated. Indomethacin 1 mg/kg, but not 10 mg/kg body weight, orally administered daily for 3 days, significantly raised total serum cholesterol level from a control value of 58.17 +/- 3.40 to 108.50 +/- 15.3 (N = 10; P less than 0.05) and free cholesterol level from 52.96 +/- 2.21 to 101.17 +/- 9.52 (N = 10; P less than 0.05). Indomethacin, 1 mg/kg p.o. daily for 3 days, also raised serum triglycerides from 45.0 +/- 7.33 to 118.30 +/- 9.05 (N = 10; P less than 0.001), while it reduced phospholipid content from 189.57 +/- 58.04 to 98.75 +/- 25.85 (N = 10; P less than 0.05). The higher dose of indomethacin 10 mg/kg p.o. daily for three days resulted in a significant increase in non-esterified fatty acids, triglycerides and total calcium, while it reduced total bilirubin, phosphorous and total lipid content of rat serum. The results indicate that according to the dose administered, indomethacin could lead to serious derangements in lipid profiles.


Encircling overlapping multipulse shock waveforms for transthoracic defibrillation.
This study was performed to determine the efficacy of new encircling overlapping multipulse, multipathway waveforms for transthoracic defibrillation. Alternative waveforms for transthoracic defibrillation may improve shock success. First, we determined the shock success achieved by three different waveforms at varying energies (18-150 J) in 21 mongrel dogs after short-duration ventricular fibrillation. The waveforms tested included the traditional damped sinusoidal waveform, a single pathway biphasic waveform, and a new encircling overlapping multipulse waveform delivered from six electrode pads oriented circumferentially. Second, in 11 swine we compared the efficacy of encircling overlapping multipulse shocks given from six electrode pads and three capacitors versus encircling overlapping shocks given from a device utilizing three electrodes and one capacitor. In the first experiment, the encircling overlapping waveform performed significantly better than biphasic and damped sinusoidal waveforms at lower energies. The shock success rate of the overlapping waveform (six pads) ranged from 67+/-4% (at 18-49 J energy) to 99+/-3% at > or = 150 J; at comparable energies biphasic waveform shock success ranged from 26+/-5% (p < 0.01 vs. encircling overlapping waveforms) to 99+/-5% (p = NS). Damped sinusoidal waveform shock success ranged from 4+/-1% (p < 0.01 vs. encircling overlapping waveform) to 73+/-9% (p = NS). In the second experiment the three electrode pads, one capacitor encircling waveform achieved shock success rates comparable with the six-pad, three-capacitor waveform; at 18-49 J, success rates were 45+/-15% versus 57+/-12%, respectively (p = NS). At 100 J, success rates for both were 100%. We conclude that encircling overlapping multipulse multipathway waveforms facilitate transthoracic defibrillation at low energies. These waveforms can be generated from a device that requires only three electrodes and one capacitor.


Effect of autophagy gene DRAM on proliferation, cell cycle, apoptosis, and autophagy of osteoblast in osteoporosis rats.
The research aimed at detecting the autophagy level of osteoblast in osteoporosis rat, and investigating the effect of autophagy gene damage-regulated autophagy modulator (DRAM) on osteoblast proliferation, cell cycle, apoptosis, and autophagy. The level of osteocalcin (OCN) and C-telopeptide (CTX) in serum of ovariectomized (OVX) rats was detected by enzyme-linked immunosorbent assay (ELISA). The Oil Red-O staining was used to observing bone histological changes. The messenger RNA level and protein expression level of Runt-related transcription factor 2 (Runx2; osteoblast markers) and other autophagy-related genes were revealed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The changes of autophagy in osteoblasts were detected by immunofluorescence staining. The following experiments were performed in osteoblasts of OVX rats through transfected with silencing DRAM to detecting cell proliferation, cell cycle, and apoptosis by Cell Counting Kit-8 assays and flow cytometry. The result of ELISA showed a significantly elevated of OCN and CTX in OVX rats as well a high fat content compared with sham-operated rats. The expression of Runx2 in bone of proximal tibia was higher by qRT-PCR and western blot analysis. The immunofluorescence staining and transmission electron microscope observe revealed that pcDNA3-DRAM could promote the autophagy in OVX rats. Besides that, overexpression of DRAM inhibited cell proliferation, promoted apoptosis, and enhanced autophagy in osteoblasts. The results of Oil Red-O staining indicated that overexpression of DRAM enhanced lipid accumulation in osteoporosis rats. The autophagy level of OVX rats was weakened, but overexpressed DRAM could increase the autophagy level of osteoblast, suppress proliferation, and induce apoptosis of osteoblast.


Erectile dysfunction in hypertensive males in Kenya: a tertiary referral hospital experience.
Erectile dysfunction (ED) in males can be organic or/and psychological. To determine the burden of ED among adult hypertensive men attending ambulatory clinic at Kenyatta National Hospital, Nairobi, Kenya. Descriptive cross-sectional study on patients on antihypertensive medications, followed for ≥ one month. The tools used were five-item International Index of Erectile Function (IIEF-5) for ED and Alcohol Use Disorders Identification Test for alcohol use. Among 385 patients, the mean age was 56.2 ±11.3 years, median follow up in medical clinic was 5 years. The mean body mass index was 26.3 ± 4.6 kg/m2, 209(54.3%) were pre-obese/obese. Current smokers were 76(19.7%) while 133(34.5%) were former smokers. Alcohol use in the past year was reported by 256(68.5%), while hazardous alcohol intake was in 54(14%). Prescribed antihypertensives in various combinations included angiotensin converting enzyme inhibitors/angiotensin receptor blockers to 292(75.8%), calcium channel blockers to 238(61.8%), beta blockerso 129(33.5%) and thiazide diuretics on 77(20%). Using IIEF-5 tool, the prevalence of ED was 364(94.5%) (95%CI 92.2-96.6) distributed as mild in 255(70%), moderate 76(21.9%) and 33(9.1%) severe. The burden of ED is high among hypertensive males. Precipitants of ED like cigarette smoking and alcohol use and use of antihypertensives which can cause ED are prevalent too.


A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.
This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). This phase II multiinstitutional study enrolled patients with recurrent/metastatic SCCHN into two cohorts: those without (arm A) and those with (arm B) before exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1,500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (PFS; arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy. Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, and 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34-159) and 17% of arm B subjects (median, 163 days, range, 135-195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62-374) and 155 (95% CI, 75-242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue. Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects.


Opportunistic electronic reminders. Improving performance of preventive care in general practice.
Preventive care is an important role for general practitioners, yet opportunities for prevention are often missed. We provided an automatic electronic record preventive care reminder system for 12 preventive care activities for one 10 doctor practice. All patients who attended were randomised by the terminal digit of their record number. The control uptake of opportunistic prevention was low; ranging from 1.5% (tetanus immunisation) to 27% (influenza immunisation). The reminders increased this by significant but small amounts for four out of 12 activities (immunisation for tetanus and pneumococcus and recording of allergies and weight), insignificant increases for four (mumps, measles and rubella immunisation, recording of smoking, and taking of cervical smears and of blood pressure), and insignificantly decreased influenza immunisation, and screening for diabetes and hyperlipidaemia. Opportunistic electronic reminders have the potential to increase preventive care in general practice.


Fractures of the Humeral Ulnar Condyle in Children - a Rare but Complicated Injury.
Ulnar humeral condyle fractures are rare paediatric elbow fractures, classified as Salter-Harris IV paediatric elbow injuries. Due to constant radiological changes in the elbow with varying manifestation of ossification centres as well as late ossification of the trochlea, diagnosis of these injuries is challenging. To avoid long-term complications, the treating surgeon should be familiar with the rare injury picture, diagnostics and adequate therapeutic measures. The present retrospective study includes data on all paediatric cases from 2002 to 2019 with primary or secondary treatment at a paediatric traumatology centre for ulnar condyle fracture with a minimum follow-up of 12 months. Range of motion, joint stability under valgus and varus stress as well as axial ratios of the injured and uninjured side were evaluated in a clinical follow-up examination. The Mayo Elbow Performance Score was used to objectify functional results. 20 children, average age 8.6 years (4 - 13) and average follow-up time 25 months, were included. Radiological evaluation based on Jakob and Fowles classification revealed a type I fracture in three cases, a type II fracture in one case and a type III fracture in 16 cases. Three cases were treated nonoperatively with an upper arm cast. 17 children were treated with open reduction and internal fixation. Diagnosis of three fractures was delayed. No postoperative complications such as infections, nerve damage or nonunions. 15 children showed free elbow function. Three children showed slightly restricted elbow extension by less than 10° and two by 10°-20°. All children showed free pro/supination. 18 children showed a physiological and bilaterally identical arm axis compared to the uninjured side. Two children showed a slightly increased cubitus valgus with a 5 - 10° difference between sides. Radiologically, two children with delayed fracture treatment showed partial necrosis of the trochlea. The Mayo Elbow Score showed good (2) to excellent results in all children (18). Very good clinical and functional results can be expected if the injury is diagnosed without delay followed by adequate therapy. Misdiagnosis of ulnar condyle fractures can be associated with the development of nonunions and functional restrictions as well as, after operative therapy, trochlear necrosis. Children up to the age of 6 in particular are at risk of misdiagnosis due to faulty assessment of the cartilaginous trochlea.


Cefuroxime, rifampicin and pulse lavage in decontamination of allograft bone.
The risk of bacterial infection through allogenic bone transplantation is one of the major problems facing tissue banks. Different screening methods and decontamination procedures are being used to achieve a safe surgical result. The purpose of this study was to investigate the contamination rate in fresh frozen bone allografts after treating them with different decontamination methods. The allografts were contaminated by rubbing on the operating theatre floor for 60 min, after which they were rinsed either with sterile physiological saline, cefuroxime or rifampicin solution or they were washed with low-pressure pulse lavage of sterile physiological saline. Our findings show that low-pressure pulse lavage with sterile saline solution is very effective in removing bacteria from bone allograft, when compared with the antibiotic solutions tested.


Adenosine receptors linked to adenylate cyclase activity in human neuroblastoma cells: modulation during cell differentiation.
In IMR32 neuroblastoma cells, the two adenosine receptor agonists N6-R-phenylisopropyladenosine and 5'-N-ethylcarboxamidoadenosine dose-dependently stimulated membrane adenylate cyclase activity with potencies consistent with the presence of adenosine receptors of the A2-subtype. The S enantiomer of N6-R-phenylisopropyladenosine induced a significantly lower stimulation of adenylate cyclase, accordingly to its lower ability to activate adenosine receptors. These effects were selectively counteracted by the adenosine receptor antagonist theophylline and, conversely, were not affected by the A1-adenosine receptor selective blocker 8-cyclopentyl-1,3-dipropylxanthine. No adenosine receptors belonging to the A1-subtype seem, therefore, to be present in this cell line, as also shown by the lack of inhibitory activity of N6-R-phenylisopropyladenosine on both basal and forskolin-stimulated adenylate cyclase activity. Activation of A2-receptors did not modify intracellular basal calcium levels, did not influence calcium influx through voltage-dependent calcium channels and did not modify calcium influx and redistribution induced by muscarinic receptor activation. Prolonged exposure of cells to either N6-R-phenylisopropyladenosine or 5'-N-ethylcarboxamidoadenosine was associated with a small but significant degree of morphological differentiation, comparable to that induced by dibutyryl cAMP, and therefore presumably related to the prolonged increase of intracellular cAMP levels elicited by the two adenosine agonists. After cellular differentiation induced with either dibutyryl cAMP or 5-bromodeoxyuridine, a selective desensitization of A2-receptor stimulated adenylate cyclase activity was found.(ABSTRACT TRUNCATED AT 250 WORDS)


Potential prescribing omissions may have no influence on cause of death in care-dependent older adults with percutaneous endoscopic gastrostomy tube.
Studies of medication use in patients with a percutaneous endoscopic gastrostomy (PEG) tube have not been conducted adequately. The aim of this study was to describe medication use of care-dependent older adults with PEG and evaluate whether potential prescribing omissions (PPO) would affect the cause of death or acute illness. In a geriatric long-term care hospital, 116 inpatients aged ≥65 years with insertion of a PEG tube because of dysphagia were enrolled and followed for 2 years: 2016-2018. The patients were divided into two groups, i.e., group A (who died between 2016 and 2018) and group B (who continued to be hospitalized in 2018). Clinical data and prescribed medications were recorded. Logistic regression models were conducted to assess the associations between survival and variables: age, gender, serum albumin level, serum creatinine level, body mass index (BMI), number of drugs and PPO. The patients' mean age was 85.3 ± 10.2 years, 57.8% were women and the mean number of drugs was 6.8 ± 3.5. Medications for managing symptoms, such as constipation and gastrointestinal symptoms, were commonly prescribed. The most common PPO medications were antiplatelet agents and anticoagulants. On logistic regression analysis, PPO had no influence on the cause of death or acute illness. Lower age, higher serum albumin level and body mass index were associated with survival in both univariate and multivariate models. Polypharmacy was prevalent in patients with PEG. Given the finding that PPO had no influence on health outcome, rational deprescribing could be warranted. Geriatr Gerontol Int 2020; 20: 961-966.


Specific detection of tau seeding activity in Alzheimer's disease using rationally designed biosensor cells.
The prion-like propagation of tau in neurodegenerative disorders implies that misfolded pathological tau can recruit the normal protein and template its aggregation. Here, we report the methods for the development of sensitive biosensor cell lines for the detection of tau seeding activity. We performed the rational design of novel tau probes based on the current structural knowledge of pathological tau aggregates in Alzheimer's disease. We generated Förster resonance energy transfer (FRET)-based biosensor stable cell lines and characterized their sensitivity, specificity, and overall ability to detect bioactive tau in human samples. As compared to the reference biosensor line, the optimized probe design resulted in an increased efficiency in the detection of tau seeding. The increased sensitivity allowed for the detection of lower amount of tau seeding competency in human brain samples, while preserving specificity for tau seeds found in Alzheimer's disease. This next generation of FRET-based biosensor cells is a novel tool to study tau seeding activity in Alzheimer's disease human samples, especially in samples with low levels of seeding activity, which may help studying early tau-related pathological events.


Inhibition of 1,25(OH)2D production by hypercalcemia in osteitis fibrosa cystica: influence on parathyroid hormone secretion and hungry bone disease.
Primary hyperparathyroidism is usually associated with normal or elevated serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. We report a 63-year-old patient with extreme hypercalcemia (ionized serum calcium, 2.51 mmol/l; normal range, 1.19-1.36), very high serum concentrations of intact immunoreactive parathyroid hormone (iPTH) (145 pmol/l; normal range, 1-6.8), radiological lesions of osteitis fibrosa cystica, only mildly impaired renal function (creatinine clearance, 69 ml/min/m2) and very low serum levels of 1,25(OH)2D (28.8 pmol/l; normal range, 72-120). Presurgery normalization of the calcemia with normal saline, salmon calcitonin and pamidronate caused an increase in 1,25(OH)2D serum concentration to 228.3 pmol/l. A negative correlation could be established between ionized calcium and 1,25(OH)2D levels during that period (r2 = 0.80, P < 0.04). While serum calcium decreased with treatment, serum iPTH also decreased to 48.6 pmol/l, suggesting some 1,25(OH)2D inhibition of parathyroid adenoma function. Serum alkaline phosphatase also rose from 309 to 390 units/l (normal range, 25-97), suggesting the beginning of resolution of her osteitis fibrosa cystica prior to surgery. Surgical removal of a parathyroid adenoma was associated with a decrease in serum calcium and iPTH levels. To our surprise, the hypocalcemia could be managed easily with 1500 mg of oral calcium carbonate daily, even if the hungry bone disease became more active with an increase in alkaline phosphatase to 486 units/l. This was explained by the very high levels of serum 1,25(OH)2D (> 200 pmol/l) which prevailed in the postsurgery period and were probably related to decreased bone resorption and increased bone formation. This case illustrates that normalizing serum calcium prior to surgery in patients with primary hyperparathyroidism and osteitis fibrosa cystica can be highly beneficial.


[Effect of light deprivation on GABA metabolism in subcellular fractions of the rabbit visual system].
Specific activity of glutamate decarboxylase was decreased in subfractions of light and heavy synaptosomes, and gamma-aminobutyric acid (GABA) transaminase activity--also in subfractions of free mitochondria, isolated from visual zone of brain cortex and of anterior mesencephalon but not from locomotive region of brain cortex of the light-deprived rabbits. Decrease in the ratio GABA transaminase/glutamate decarboxylase indicated distinct inhibition of GABA degradation as compared with its synthesis due to absence of sensory impulsation within the early periods of postnatal ontogenesis of the animals.


Fiber bragg grating sensor based device for simultaneous measurement of respiratory and cardiac activities.
This paper reports a novel optical ballistocardiography technique, which is non-invasive, for the simultaneous measurement of cardiac and respiratory activities using a Fiber Bragg Grating Heart Beat Device (FBGHBD). The unique design of FBGHBD offers additional capabilities such as monitoring nascent morphology of cardiac and breathing activity, heart rate variability, heart beat rhythm, etc., which can assist in early clinical diagnosis of many conditions associated with heart and lung malfunctioning. The results obtained from the FBGHBD positioned around the pulmonic area on the chest have been evaluated against an electronic stethoscope which detects and records sound pulses originated from the cardiac activity. In order to evaluate the performance of the FBGHBD, quantitative and qualitative studies have been carried out and the results are found to be reliable and accurate, validating its potential as a standalone medical diagnostic device. The developed FBGHBD is simple in design, robust, portable, EMI proof, shock proof and non-electric in its operation which are desired features for any clinical diagnostic tool used in hospital environment.


Single-cell omics traces the heterogeneity of prostate cancer cells and the tumor microenvironment.
Prostate cancer is one of the more heterogeneous tumour types. In recent years, with the rapid development of single-cell sequencing and spatial transcriptome technologies, researchers have gained a more intuitive and comprehensive understanding of the heterogeneity of prostate cancer. Tumour-associated epithelial cells; cancer-associated fibroblasts; the complexity of the immune microenvironment, and the heterogeneity of the spatial distribution of tumour cells and other cancer-promoting molecules play a crucial role in the growth, invasion, and metastasis of prostate cancer. Single-cell multi-omics biotechnology, especially single-cell transcriptome sequencing, reveals the expression level of single cells with higher resolution and finely dissects the molecular characteristics of different tumour cells. We reviewed the recent literature on prostate cancer cells, focusing on single-cell RNA sequencing. And we analysed the heterogeneity and spatial distribution differences of different tumour cell types. We discussed the impact of novel single-cell omics technologies, such as rich omics exploration strategies, multi-omics joint analysis modes, and deep learning models, on future prostate cancer research. In this review, we have constructed a comprehensive catalogue of single-cell omics studies in prostate cancer. This article aimed to provide a more thorough understanding of the diagnosis and treatment of prostate cancer. We summarised and proposed several key issues and directions on applying single-cell multi-omics and spatial transcriptomics to understand the heterogeneity of prostate cancer. Finally, we discussed single-cell omics trends and future directions in prostate cancer.


Oxidative stress: Roles in skeletal muscle atrophy.
Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.


Clinical classification of tissue perfusion based on the central venous oxygen saturation and the peripheral perfusion index.
We investigated whether combining the peripheral perfusion index (PI) and central venous oxygen saturation(ScvO2) would identify subsets of patients for assessing the tissue perfusion and predicting outcome during the resuscitation in critically ill patients. A total of 202 patients with central venous catheters for resuscitation were enrolled in this prospective observational study. The arterial, central venous blood gas and the PI were measured simultaneously at the enrollment (T0) and 8 h (T8) after early resuscitation. Based on the distribution of the PI in healthy population, a cutoff of PI ≥ 1.4 was defined as a normal PI. Moreover, the critical value of PI was defined as the best cutoff value related to the mortality in the study population. The PI impairment stratification is defined as follows: a normal PI(≥ 1.4), mild PI impairment (critical value < PI < 1.4) and critical PI impairment (PI ≤ critical value). The PI at T8 was with the greatest AUC for prediction the 30-day mortality and PI is an independent risk factor for 30-day mortality. Moreover, a cutoff of PI < 0.6 is related to poor outcomes following resuscitation. So, based on cutoffs of ScvO2 (70%) and critical PI (0.6) at T8, we assigned the patients to four categories: group 1 (PI ≤ 0.6 on ScvO2 < 70%), group 2 (PI ≤ 0.6 on ScvO2 ≥ 70%), group 3 (PI > 0.6 on ScvO2 < 70%), and group 4 (PI > 0.6 on ScvO2 ≥ 70%). The combination of low ScvO2(<70%) and PI(≤ 0.6) was associated with the lowest survival rates at 30 days [log rank (Mantel-Cox) = 87.518, p < 0.0001]. The sub-group patients who had high ScvO2(>80%) at T8 were with low mortality and high PI. Moreover, the normal PI (≥ 1.4) did not show a better outcome than mild impaired PI (0.6-1.4) patients who had a normalized ScvO2(>70%) after resuscitation. The PI was correlated with the lactate, P(v-a)CO2, and ScvO2 in all the measurements (n = 404). These relationships are strengthened with abnormal PI (PI < 1.4) but not with normal PI (PI ≥ 1.4). Complementing ScvO2 assessment with PI can better identify endpoints of resuscitation and adverse outcomes. Pursuing a normalized PI (≥ 1.4) may not result in better outcomes for a mild impaired PI after ScvO2 is normalized.


Prevention of Wrong-level Surgery in the Thoracic Spine: Preoperative Computer Tomography Fluoroscopy-guided Percutaneous Gold Fiducial Marker Placement in 57 Patients.
Retrospective review. The aim of this study was to evaluate the feasibility, safety,s and complications of computer tomography (CT) fluoroscopy-guided percutaneous transpedicular gold fiducial marker insertion to reduce incidence of wrong-level surgery in the thoracic spine. Intraoperative localization of the correct thoracic level can be challenging and time-consuming, especially in obese patients and patients with anatomical variations. In the literature there are very few studies containing low numbers of patients which assessed CT or CT fluoroscopy-guided fiducial marker placement of the thoracic spine. Description of this technique has been similarly scarce. All patients who underwent percutaneous CT fluoroscopy-guided gold fiducial marker placement of the thoracic spine were retrospectively reviewed. Indications for surgery included degenerative disc disease, infection, spinal metastasis, and intra- and extradural tumors. Gold fiducial markers were placed using a percutaneous CT fluoroscopy-guided transpedicular approach with local anesthesia. In addition, sex, age, body mass index (BMI), thoracic level, related pathology, and procedure-related complications were also recorded. A total of 57 patients (24 females, 33 males) were included. Mean age was 58.6 ± 15.5 years. No complications during CT fluoroscopy-guided gold fiducial marker placement were recorded. Intraoperative localization was successful in all patients. Mean BMI was 32.98 kg/m (range, 18.63-56.03 kg/m), and 63% of patients were obese (>30 kg/m). T7 (n = 11) was the most often marked vertebral body, followed by T10 (n = 10) and T6 (n = 7). The most cranial and most caudal levels marked were T2 and T12, respectively. Preoperative CT fluoroscopy-guided percutaneous gold fiducial marker placement is safe, feasible, and accurate. The resulting facilitated localization of the intended thoracic level of surgery can reduce the length of surgery and prevent wrong-level surgery. Further studies are needed to evaluate in the effect on exposure to radiation and quantify the difference in operating room time. 4.


Long-acting beta-agonists and the risk of intensive care unit admission in children.
A possible association between long-acting beta-agonists (LABA) and severe asthma exacerbations including death remains controversial. We examined whether LABA in the setting of combination therapy with inhaled corticosteroids (ICS) increase the risk of near-fatal asthma in children using a case-control study design. Medical records from admissions for asthma exacerbations in children 4-18 years of age during the 2005 calendar year at Children's Hospital of Pittsburgh of UPMC were reviewed. Cases and controls were determined by pediatric intensive care unit (PICU) and floor admission, respectively. Exposure was defined by LABA use in combination with ICS versus ICS alone. Records from 85 PICU and 96 pediatric floor admissions were reviewed. LABA use in combination with ICS did not increase the risk of PICU admission (odds ratio 1.07, 95% CI 0.46-2.52) compared to ICS only without LABA. After adjusting for demographics, asthma severity, history of PICU admissions, and concurrent infection, LABA/ICS use still did not increase the risk of PICU admission (adjusted odds ratio 0.84, 95% CI 0.26-2.76) compared to ICS alone. There were no deaths and five intubations within the study period. The combination of LABA and ICS did not appear to increase the risk of near-fatal asthma in children.


Linking primatology and archaeology: The transversality of stone percussive behaviors.
Since the launch of the Journal of Human Evolution fifty years ago, the archaeology of human origins and the evolution of culture have witnessed major breakthroughs with the identification of several new archaeological sites whose chronology has been slowly pushed back until the discovery of the earliest evidence of stone tool making at Lomekwi 3 (West Turkana, Kenya), at 3.3 Ma. Parallel to these discoveries, the study of wild primates, especially chimpanzees (Pan troglodytes), allowed the development of models to understand key aspects of the behavior of extinct hominin species. Indeed, chimpanzees possess an impressive diversity of tool-aided foraging behaviors, demonstrating that technology (and culture) is not exclusive to humans. Additionally, current research has also shown that wild capuchin monkeys (Sapajus libidinosus) and long-tailed macaques (Macaca fascicularis) also rely on stone percussive foraging behaviors. The investigation of these primates is boosting new interpretative models to understand the origins of stone flaking and the archaeological signature left by these primates. This review aims to present an examination of the state-of-the-art and the current advances made in the study of the earliest hominin technology and primate percussive behaviors. Overall, we argue that while it has been shown that extant primates can generate unintentional flakes, early hominins exhibited skills in the production and use of flakes not identified in primates. Nonetheless, we stand up to continue developing interdisciplinary approaches (i.e., primate archaeology) to study extant primates, as these endeavors are essential to move forward toward a detailed understanding of the technological foraging behaviors beyond the genus Homo. Finally, we discuss future challenges for the study of the emergence of stone technology.


From site data to safety assessment: analysis of present and future hydrological conditions at a coastal site in Sweden.
This paper presents an analysis of present and future hydrological conditions at the Forsmark site in Sweden, which has been proposed as the site for a geological repository for spent nuclear fuel. Forsmark is a coastal site that changes in response to shoreline displacement. In the considered time frame (until year 10 000 AD), the hydrological system will be affected by landscape succession associated with shoreline displacement and changes in vegetation, regolith stratigraphy, and climate. Based on extensive site investigations and modeling of present hydrological conditions, the effects of different processes on future site hydrology are quantified. As expected, shoreline displacement has a strong effect on local hydrology (e.g., groundwater flow) in areas that change from sea to land. The comparison between present and future land areas emphasizes the importance of climate variables relative to other factors for main hydrological features such as water balances.


Identification of the reactive sulfhydryl groups of S-adenosylmethionine synthetase.
S-Adenosylmethionine synthetase from Escherichia coli is rapidly inactivated by N-ethylmaleimide. In the presence of excess N-ethylmaleimide inactivation follows pseudo first-order kinetics, and loss of enzyme activity correlates with the incorporation of 2 eq of N-[ethyl-2-3H]maleimide/subunit. Preincubation of the enzyme with methionine and the ATP analog adenylylimidodiphosphate reduced the rate of N-ethylmaleimide incorporation more than 30-fold. Two N-[ethyl-2-3H]maleimide-labeled tryptic peptides were purified from the modified enzyme by reverse phase high performance liquid chromatography. The modified residues were identified as cysteine 90 and cysteine 240 by comparison of the amino acid compositions of these peptides with the protein sequence. These are the first residues to be implicated in the activity and/or structure of the enzyme. N-Ethylmaleimide-modified S-adenosylmethionine synthetase exists mainly as a dimer in conditions where the native enzyme is a tetramer. Accumulation of the dimer parallels the loss of the enzyme activity. When an enzyme sample was partially inactivated, separation of tetrameric and dimeric enzyme forms by gel filtration revealed that the residual enzyme activity was solely present in the tetramer and N-[ethyl-2-3H] maleimide was present predominantly in the dimer. Gel filtration studies of the tetramer-dimer equilibrium for the native enzyme indicated that the dissociation constant between the tetramer and dimers is less than 6 x 10(-11) M. Similar studies for the N-ethylmaleimide-modified protein indicated that the dissociation constant of the tetramer is approximately 4 x 10(-4) M. Upon modification the strength of dimer-dimer interactions is diminished by at least 9 kcal/mol.


Conformational changes at the carboxyl terminus of Galpha occur during G protein activation.
To understand the dynamics of conformational changes during G protein activation, surface exposed cysteine residues on Galpha were fluorescently labeled. Limited trypsinolysis and mutational analysis of recombinant Galphat/Galphai1 determined that two cysteines are the major fluorescent labeling sites, Cys210, located in the switch II region, and Cys347 at the C terminus. Mutants with serines replacing Cys210 (Chi6a) and Cys347 (Chi6b) were single fluorescently labeled with lucifer yellow (LY), while a double mutant (Chi6ab) was no longer labeled. When Chi6b was labeled with LY on Cys210, AlF4- caused a 220% increase in LY fluorescence, indicating that the fluorescent group at Cys210 is a reporter of conformational change in the switch II region. Chi6a labeled at Cys347 also showed an AlF4--dependent increase in LY fluorescence (91%), indicating that Galpha activation leads to a conformational change at the COOH terminus. Preactivation of the protein with AlF4- before labeling led to a decreased incorporation of LY into Cys347 suggesting that Galpha activation buries Cys347. This COOH-terminal conformational change may provide the structural basis for communication between the GDP-binding site on Galpha and activated receptors, and may contribute to dissociation of activated Galpha subunit from activated receptor.


Management of gunshot-related forearm bone defect by sequential internal fixation and deferred bone grafting: experience from a tertiary hospital in Mogadishu.
Gunshot-related forearm fractures are rare injuries, usually incurring bone defect. The aim of the study was to report clinical and radiological results for sequential internal fixation and bone grafting in acute civilian forearm gunshot fractures with bone defect. The procedure involves staged techniques consisting of bone debridement, soft-tissue closure and temporary intramedullary Kirschner wire fixation, followed by deferred bone grafting. To our knowledge, the present study is the first to investigate this surgical sequence in such injuries. Between June 2018 and September 2019, 6 civilian cases (5 male, 1 female) with a mean age of 26 years (range, 19-36 years) were operated on by sequential internal fixation and bone grafting for acute forearm gunshot fractures with segmental bone defect. Demographics, injury characteristics and surgical features were recorded. The Tang classification system was used to evaluate clinical and radiological results at final follow-up. Mean follow-up was 27 months (range: 21-32 months). Defect location was in the radius in 4 patients and in the ulna in 2, with a mean defect size of 3.75 cm (range, 2-8 cm). Union was achieved in 5 patients, at a mean 7 months (range, 4-10 months). Functional outcome was excellent in 4 patients, good in 1 and fair in 1. Sequential internal fixation and bone grafting seems a reliable option in the treatment of acute forearm gunshot fractures with bone defect. LEVEL OF EVIDENCE: Level IV - Retrospective study.