Synergism between rocuronium and cisatracurium: comparison of the Minto and Greco interaction models.
This study was conducted to investigate the pharmacodynamic interaction between rocuronium and cisatracurium using the response surface model, which is not subject to the limitations of traditional isobolographic analysis. One hundred and twenty patients were randomly allocated to receive one of the fifteen predefined combinations of rocuronium and cisatracurium. To study single drugs, cisatracurium 0.2, 0.15, or 0.1 mg/kg or rocuronium 0.8, 0.6 or 0.4 mg/kg doses were administered alone. To study the pharmacodynamic interaction, drugs were applied in three types of combination ratio, i.e., half dose of each drug alone, 75% of each single dose of rocuronium and 25% of each single dose of cisatracurium, and vice versa. Train-of-four (TOF) ratio and T1% (first twitch of the TOF presented as percentage compared to the initial T1) were used as pharmacodynamic endpoints, and the Greco and Minto models were used as surface interaction models. The interaction term α of the Greco model for TOF ratio and T1% measurements showed synergism with values of 0.977 and 1.12, respectively. Application of the Minto model resulted in U50 (θ) values (normalized unit of concentration that produces 50% of the maximal effect in the 0 < θ < 1 region) less than 1 for both TOF ratio and T1% measurements, indicating that rocuronium and cisatracurium exhibit synergism. Response surface modeling of the interaction between rocuronium and cisatracurium, based on considerations of their effects on muscle relaxation as measured by TOF ratio and T1%, indicated that the two drugs show considerable synergism.


GM crops: science, politics and communication.
As the public debate in Europe about genetically modified (GM) crops heats up and the trade row between the United States and the European Union over GM food escalates, what better time to examine the issues with an international group of experts (Box 1). Their views are diverse, but they all agree that we need more impartial communication, less propaganda and an effective regulatory regime that is based on a careful case-by-case consideration of GM technology. It seems that GM crops are here to stay, so let us hope that these requirements are met and that the developing nations that perhaps have the most to gain from this technology can start to reap its benefits.


Variation and treatment of vessels in laparoscopic right hemicolectomy.
With the introduction of complete mesocolic excision (CME) and the application of laparoscopic technique, surgery for colon cancer has become more standardized and the curative effect has improved [1]. The key points in laparoscopic right hemicolectomy are high ligation of main vessels and root dissection of lymph nodes. The wide range of variations in vascular architecture and intraoperative bleeding are common causes of prolonged surgical time, wound hemorrhage, and even transfer to the opening operation. The superior mesenteric vein (SMV) is the most important anatomical landmark in CME for the right colon, and guides all the steps of lymph node dissection. The SMV appears as a pale blue bulge on laparoscopy, which enables accurate positioning. The ileocolic vessel pedicle is relatively constant and facilitates accurate positioning. The intersection of the ileocolic vessel pedicle and the SMV is the optimal starting point in laparoscopic right hemicolectomy using a medial-to-lateral approach. A sheath with an avascular plane can be reached after opening the SMV vascular sheath, which results in less bleeding and enables vascular root and thorough lymph node dissection. The first step is to manage the ileocolic vessels. The ileocolic artery (ICA) is located anterior to the ileocolic vein (ICV) for about one-third of the incidence. The ileocolic vessels are relatively long and are easy to work with. In the vast majority of cases, the ICV drains into the SMV, and into the gastrocolic trunk (GCT) in about 2.5% of cases. The reported incidence of a right colic artery (RCA) is controversial; the RCA is absent in about 50% of cases and often crosses the SMV. The right colic vein (RCV) usually drains into the GCT, but sometimes drains directly into the SMV. The middle colic vessels have great variability and a close anatomical relationship with the pancreas, duodenum, and GCT. Moreover, the transverse colon and mesentery are long, and root positioning and processing of the middle colic vein (MCV) are relatively difficult. With the SMV and pancreas as anatomic landmarks, it is more feasible to locate the blood vessels in the neck of the pancreas. The middle colic artery (MCA) originates from the superior mesenteric artery (SMA), and the distance from the inferior border of the pancreas differs slightly in the literature, but is at the most 5 cm. Identification of the MCA trunk and branches, as well as the common origin of the MCA and RCA, is of great importance for the maintaining the blood supply during surgery for primary colon cancer. The MCV mainly drains into the SMV and GCT; however, if branching variation drains into the jejunal vein, inferior mesenteric vein, or splenic vein, the effect is serious when a vessel is torn. Isolation of the GCT is the step at which bleeding will likely occur in standard right resection and is a difficult stage of the surgery. The GCT has five origins including the right gastroepiploic vein (RGV), right colic vein (RCV), accessory right colic vein (ARCV), pancreaticduodenal vein (PDV), and MCV, which can have 2, 3, or 4 branches; therefore, familiarity with variants may be helpful to avoid bleeding. Approximately 5-10% of colon cancers at the hepatic flexure have No. 6 group lymph node metastasis, and laparoscopic radical extended right hemicolectomy requires thorough dissection of No. 6 group lymph nodes and the omental arcade 10 cm from the pylorus. The inferior arteriovenous vessels are a common source of bleeding, and the RGV can serve as a clue to finding the artery. The core area of laparoscopic radical extended right hemicolectomy includes the pancreatic neck, duodenum, and right gastroepiploic vessels. The difficulty lies with the standard treatment of the GCT. A medial-to-lateral approach is more in line with the principle of no-touch in tumor surgery and is applied from lower to upper, inside to outside, and left to right, for both the vessels and plane of dissection. Familiarity with vascular variation and the management of vessels in key areas are essential for successful surgery.


Nurses' perceptions of multidisciplinary team work in acute health-care.
Multidisciplinary teamwork is viewed as one of the key processes through which care is managed in the British National Health Service, and yet is often viewed as one of the most problematic. Working in a multidisciplinary team requires many skills, which involves understanding not only one's own role but also the role of other professionals. The aim of this study was to explore nurses' perceptions of multidisciplinary teamwork in acute health-care. Nineteen nurses were interviewed using the critical incident approach to obtain their perceptions of multidisciplinary teamwork. Direct observation was conducted to record interactions between nurses and health-care professionals in multidisciplinary teams. In total, 14 meetings were attended in elder care and orthopaedics and seven in acute medicine. The findings of this study identified three barriers that hindered teamwork: (i) differing perceptions of teamwork; (ii) different levels of skills acquisitions to function as a team member; and (iii) the dominance of medical power that influenced interaction in teams. Thus, education establishments and nursing managers need to ensure that the acquisition of team-playing skills is an integral part of continued professional development.


Simple renal cyst: an observation.
In the present study 1500 patients having abdominal ultrasonography were included. Unsuspected renal cysts were detected in 76 patients (5.06%). The age range was between 8 and 86 years with a maximum incidence being at 41-60 years age group. These asymptomatic cysts were observed commonly in the upper pole of right kidney. Incidence as well as size increased with age. Usually these cysts do not require any surgical intervention unless complicated.


The efficiency of ozonated water from a water treatment plant to inactivate Cryptosporidium oocysts during two seasonal temperatures.
We investigated the efficiency of residual ozone from an advanced water treatment plant with an applied dose of 2.5 mg l(-1) to inactivate viable Cryptosporidium oocysts during summer (i.e. 24 degrees C) and winter (i.e. 18.9 degrees C) in Queensland, Australia. Containers for sample collection were inoculated with 1,000 oocysts l(-1) and filled with ozonated water. Ozone residual concentrations were measured at 0, 5 and 10 min intervals. Viability was determined by excystation. Non-ozonated water from the plant, trip and laboratory controls were also analysed. The applied ozone dose of 2.5 mg l(-1) produced an immediate residual concentration of 1.25 mg 1(-1) at 24 degrees C and 1.34 mg 1(-1) at 18.9 degrees C in unseeded samples. The initial ozone residual in seeded containers was 1.22+/-0.03 mg 1(-1) at 24 degrees C and 1.37+/-0.04 mg 1(-1) at 18.9 degrees C. There was a gradual increase in inactivation of oocysts, with 49% of oocysts inactivated at 0 min to 92% after 10 min at 24 degrees C and 57% at 0 min to 92.8% at 10 min at 18.9 degrees C.


The effects of rational stage directed imagery on self-concept and reduction of psychological stress in adolescent delinquent females.
This study examined the effect of four treatment conditions on self-concept and reduction of psychological stress in adolescent delinquent females. The treatments were Rational State Directed Imagery, a cognitive behavioral approach that utilized intensive muscle relaxation and vivid-emotive-imagery, a rational (cognitive) restructuring treatment, a placebo condition, and a no treatment control. Ss were assigned randomly to one of these treatment groups, which met 1 hour per week for 6 consecutive weeks, with in-vivo homework assignments also utilized. Statistically scale were noted for the RSDI group at the posttest and at a 2-month follow-up, which supports the therapeutic efficacy of this treatment. Support was found for the effectiveness of the rational (cognitive) restructuring approach immediately posttreatment; however these effects disappeared at the 2-month follow-up. The placebo and control groups showed no significant effects at either posttreatment or the follow-up. These results suggest that RSDI has potential for use as a short-term psychotherapeutic approach when self-concept modification is a primary goal.


Evaluation of a Cryptococcus capsular polysaccharide detection FungiXpert LFA (lateral flow assay) for the rapid diagnosis of Cryptococcosis.
Cryptococcus is an opportunistic pathogenic fungus and is the major cause of fungal meningitis. The cryptococcal antigen (CrAg) lateral flow assay (LFA) is an immunochromatographic test system that has simplified diagnosis as a point-of-care test. In this study, we evaluated the diagnostic performance of Cryptococcal capsular polysaccharide detection FungiXpert (Genobio Pharmaceutical, Tianjin, China) using serum and cerebrospinal fluid (CSF) samples for the diagnosis of cryptococcosis and investigated the cross-reaction of the assays to pathogenic fungi and bacterium by comparing it to the U.S. Food and Drug Administration (US FDA)-approved IMMY CrAg LFA. Eighty CSF and 119 serum/plasma samples from 158 patients were retrospectively collected to test for qualitative or semi-quantitative detection of CrAg. Cross-reaction of the assays was tested using 28 fungi and 1 bacterium. Compared to IMMY CrAg LFA, the FungiXpert LFA demonstrated 99.1% sensitivity and 98.9% specificity in the qualitative test. In the 96 semi-quantitative CrAg assay results, 39 (40.6%) test titers of FungiXpert LFA were 1-2 dilutions higher than those of IMMY CrAg LFA. The Intraclass Correlation Coefficient of the Semi-quantitative results of CrAg titer tests via the two assays was 0.976. Similar to IMMY CrAg LFA, FungiXpert LFA showed cross-reactivity with Trichosporon asahii. Compared with the IMMY CrAg LFA, the FungiXpert LFA showed an equal, yet, excellent performance. However, it is important to note that these two assays have potential cross-reactivity to T. asahii when diagnosing patients. FungiXpert LFA is a rapid screening method for the effective and practical diagnosis and treatment of cryptococcosis. The FungiXpert LFA was developed to diagnose fungal meningitis caused by Cryptococcus yeasts, by using serum or cerebrospinal fluid. It was compared to an existing lateral flow assay (LFA). The FungiXpert LFA performed well in qualitative and semi-quantitative tests.


In search of neural mechanisms of mirror neuron dysfunction in schizophrenia: resting state functional connectivity approach.
It has been repeatedly shown that schizophrenia patients have immense alterations in goal-directed behaviour, social cognition, and social interactions, cognitive abilities that are presumably driven by the mirror neurons system (MNS). However, the neural bases of these deficits still remain unclear. Along with the task-related fMRI and EEG research tapping into the mirror neuron system, the characteristics of the resting state activity in the particular areas that encompass mirror neurons might be of interest as they obviously determine the baseline of the neuronal activity. Using resting state fMRI, we investigated resting state functional connectivity (FC) in four predefined brain structures, ROIs (inferior frontal gyrus, superior parietal lobule, premotor cortex and superior temporal gyrus), known for their mirror neurons activity, in 12 patients with first psychotic episode and 12 matched healthy individuals. As a specific hypothesis, based on the knowledge of the anatomical inputs of thalamus to all preselected ROIs, we have investigated the FC between thalamus and the ROIs. Of all ROIs included, seed-to-voxel connectivity analysis revealed significantly decreased FC only in left posterior superior temporal gyrus (STG) and the areas in visual cortex and cerebellum in patients as compared to controls. Using ROI-to-ROI analysis (thalamus and selected ROIs), we have found an increased FC of STG and bilateral thalamus whereas the FC of these areas was decreased in controls. Our results suggest that: (1) schizophrenia patients exhibit FC of STG which corresponds to the previously reported changes of superior temporal gyrus in schizophrenia and might contribute to the disturbances of specific functions, such as emotional processing or spatial awareness; (2) as the thalamus plays a pivotal role in the sensory gating, providing the filtering of the redundant stimulation, the observed hyperconnectivity between the thalami and the STGs in patients with schizophrenia might explain the sequential overload with sensory inputs that leads to the abnormal cognitive processing.


Determination of serum calcium levels by 42Ca isotope dilution inductively coupled plasma mass spectrometry.
Serum calcium level is an important clinical index that reflects pathophysiological states. However, detection accuracy in laboratory tests is not ideal; as such, a high accuracy method is needed. We developed a reference method for measuring serum calcium levels by isotope dilution inductively coupled plasma mass spectrometry (ID ICP-MS), using 42Ca as the enriched isotope. Serum was digested with 69% ultrapure nitric acid and diluted to a suitable concentration. The 44Ca/42Ca ratio was detected in H2 mode; spike concentration was calibrated by reverse IDMS using standard reference material (SRM) 3109a, and sample concentration was measured by a bracketing procedure. We compared the performance of ID ICP-MS with those of three other reference methods in China using the same serum and aqueous samples. The relative expanded uncertainty of the sample concentration was 0.414% (k=2). The range of repeatability (within-run imprecision), intermediate imprecision (between-run imprecision), and intra-laboratory imprecision were 0.12%-0.19%, 0.07%-0.09%, and 0.16%-0.17%, respectively, for two of the serum samples. SRM909bI, SRM909bII, SRM909c, and GBW09152 were found to be within the certified value interval, with mean relative bias values of 0.29%, -0.02%, 0.10%, and -0.19%, respectively. The range of recovery was 99.87%-100.37%. Results obtained by ID ICP-MS showed a better accuracy than and were highly correlated with those of other reference methods. ID ICP-MS is a simple and accurate candidate reference method for serum calcium measurement and can be used to establish and improve serum calcium reference system in China.


Trachelectomy during pregnancy: what has experience taught us?
The treatment of early stage cervical malignancy in a pregnant patient remains a challenge. We report the successful application of a vaginal radical trachelectomy (VRT) during pregnancy to treat a patient diagnosed with early stage cervical cancer and subsequently review the published work. A 22-year-old female diagnosed at the gestational age of 17 weeks with International Federation of Gynecology and Obstetrics stage IB1 squamous cell cervical carcinoma was treated with VRT at 19(+5) weeks. At 36 weeks, the patient underwent a scheduled cesarean section. A healthy male infant was delivered with a weight of 2795 g. After 13 months of follow-up, the patient is doing well with no evidence of recurrent disease.


Hydrogen peroxide biosensor with a supramolecular layer-by-layer design.
A new sensor design is reported for the construction of an amperometric enzyme biosensor toward H (2)O(2). It was based in the supramolecular immobilization of alternating layers of horseradish peroxidase (either modified with 1-adamantane or beta-cyclodextrin-branched carboxymethylcellulose residues) on Au electrodes coated with polythiolated beta-cyclodextrin polymer. The analytical response of the electrodes, using 1 mM hydroquinone as an electrochemical mediator, increases when the number of enzyme layers increases. The biosensor having three enzyme layers showed a sensitivity of 720 microA/M cm (2) and a detection limit of 2 microM and retained 96% of its initial activity after 30 days of storage. The host-guest supramolecular nature of the immobilization method was confirmed by cyclic voltammetry.


How to carry out a health-orientated marathon training programme for running and inline skating.
More and more people want to do something for their health. Nevertheless, certain reluctance exists when it comes to committing oneself to higher sporting aims, as well as some uncertainty concerning proper training. Two model projects have been developed, aimed at motivating larger parts of the population towards a health-orientated training programme. Both projects serve as a basis for further, similarly designed large-scale projects. In the running project a health-focused run training programme was set up aimed at preparing people, previously inexperienced in running, for a marathon. In the inline project an inline training programme was developed which comprised both the training of essential techniques as well as individualized endurance training, the aim being the participation in an inline marathon. A total of more than 1000 people participated in both projects. The health check performed before the beginning of the project revealed some pathological findings, demonstrating the necessity of a medical examination before taking up regular training. Both projects led to an improvement in endurance performance. In addition, the blood-chemical metabolic parameters showed clear optimization, in particular the lipid profile. The inline technique training resulted in an improvement of the braking skills, which is accompanied by a reduction in the risk of injuries. Both model projects have shown that large-scale sports programmes that focus primarily on the prevention of injuries and disease (under sport-medical guidance) with a performance incentive are accepted by the population, provided they offer a high fun factor.


[Immunohistochemical study of the apoptotic and proliferative mechanisms in the intestinal mucosa during coeliac disease].
Mechanisms leading to morphological changes of the small intestine during coeliac disease are not yet completely recognized, however, two main processes have been suggested recently: remodelling of mucosa by matrix metalloproteinases, and mucosal atrophy by apoptosis. The aim of this study was to analyze the expression of proteins regulating apoptosis and some markers of proliferation in the mucosa of the small intestine of children with active (ACD) and latent form (LCD) of coeliac disease (CD). Intestinal biopsies of 43 children with ACD and LCD were analyzed by standard indirect immunohistochemical technique for Fas, Fas ligand (Fas-L), tissue transglutaminase (tTG), Bcl-2, Bid, glutathione S-transferase (GST), CAS 3, CAS 8, PARP, Ki-67, Topoisomerase IIa, PCNA expression. We found significantly lower numbers of Fas-expressing enterocytes in ACD patients than in LCD patients and controls. The number of Fas-positive mucosal lymphocytes was decreased in ACD when compared with LCD. Fas-L expression in enterocytes and mucosal lymphocytes was higher in ACD and LCD compared to controls. We found significantly more Bcl-2 negative lymphocytes in ACD than in LCD and controls. Bid expression in enterocytes was higher in LCD compared to ACD and controls. In intraepithelial lymphocytes, there was higher Bid expression in LCD than in ACD and controls compared to expression in mucosal lymphocytes, where was found higher number of positive cells in controls than in ACD and LCD. Expression of CAS 8 in mucosal lymphocytes was significantly higher in ACD compared to LCD. The expression of tTG in extracellular matrix and basal lamina was significantly higher in LCD and ACD when compared to controls. Expression of tTG was higher in the group of ACD and LCD in the enterocytes and in the lymphocytes. Our findings showed that Fas/Fas-L, Bcl-2, and CAS 8 may be involved in modulation of apoptosis during CD. Increased apoptotic elimination of IEL in LCD can partially explain preservation of the normal villous architecture. Increased tTG expression may be an early sign of increased apoptosis or may be related to its role in CD pathogenesis.


Immunohistochemical study of sex steroid hormones in primary liver cancer.
Paraffin-embedded tissue sections from 29 patients with primary liver carcinomas were retrospectively studied for the presence of estradiol and testosterone using the peroxidase-antiperoxidase (PAP) technique. Twenty-seven hepatomas and two cholangiomas were treated with antiestradiol and antitestosterone primary serum. Estradiol was detected in 17 cases and testosterone in 11 cases of hepatomas. The two cases of cholangiocarcinoma were positive for estradiol and negative for testosterone. The immunohistochemical reaction in the tumor cells was mainly cytoplasmic and in a few cases both cytoplasmic and intranuclear. The positivity of the reaction in the tumour cells was compared with that of the adjacent non-neoplastic liver tissue and bile duct cells. Our findings were also analyzed in relation to tumor differentiation and the age and sex of the patients.


Reversal and Indel Distance With Intergenic Region Information.
Recent works on genome rearrangements have shown that incorporating intergenic region information along with gene order in models provides better estimations for the rearrangement distance than using gene order alone. The reversal distance is one of the main problems in genome rearrangements. It has a polynomial time algorithm when only gene order is used to model genomes, assuming that repeated genes do not exist and that gene orientation is known, even when the genomes have distinct gene sets. The reversal distance is NP-hard and has a 2-approximation algorithm when incorporating intergenic regions. However, the problem has only been studied assuming genomes with the same set of genes. In this work, we consider the variation that incorporates intergenic regions and that allows genomes to have distinct sets of genes, a scenario that leads us to include indels operations (insertions and deletions). We present a 2.5-approximation algorithm using the labeled intergenic breakpoint graph, which is based on the well-known breakpoint graph structure. We also present an experimental analysis of the proposed algorithm using simulated data, which showed that the practical approximation factor is considerably less than 2.5. Furthermore, we used the algorithm in real genomes to construct a phylogenetic tree.


Impact of mandatory motorcycle helmet wearing legislation on head injuries in Viet Nam: results of a preliminary analysis.
To compare estimated prevalence of head injuries among road traffic injury patients admitted to hospitals, before and after the introduction of a mandatory helmet law in the Socialist Republic of Viet Nam. Before and after study of all road traffic injury patients with head injuries admitted to 20 provincial and central hospitals 3 months before and after the new law came into effect on 15 December 2007. Relative risk was computed and comparison made for the periods of 3 months before and after the new law. The study found a 16 percent reduction in the risk of road traffic head injuries (4683 to 3522; relative risk [RR] 0.84; 95% confidence interval [CI] 0.81-0.87) and an 18 percent reduction in the risk of road traffic death (deaths in hospital plus injured patients discharged to die at home; 566 to 417; RR 0.82; 95% CI 0.73-0.93). Over the first 3 months of the comprehensive mandatory helmet legislation there has been a significant reduction in the risk of road traffic head injuries among patients admitted to 20 hospitals. The Viet Nam Government's decision to require all motorcycle riders and passengers to wear helmets is suspected of leading to positive road safety benefits and should be seen as a policy example for other low- and middle-income countries with a high utilization of motorcycles for transport.


Interferon-tau and pregnancy.
A type I interferon known as IFN-tau is expressed massively by the outer epithelium (trophectoderm) of the preimplantation trophoblast of ruminant ungulate species, such as cattle and sheep, for a few days during early pregnancy. They signal to the mother that she is pregnant and indirectly prevent regression of the corpus luteum so that progesterone production is maintained and normal ovarian cyclicity avoided. Despite their clear roles as reproductive hormones, the IFN-tau have the typical antiviral, antiproliferative, and immunomodulatory activities of other type I IFN. They are most closely related to the 172 amino acid IFN-omega. Unlike other type I IFN, they are not virally inducible and appear to be produced constitutively as the trophectoderm first forms during the development of the blastocyst. The discovery of the IFN-tau illustrates the diverse activities of interferons and their likely involvement in the normal embryonic development of mammals. The diversity of mechanisms different groups of mammals use to prolong the functional life span of the corpus luteum in early pregnancy is probably the consequence of genetic conflict between the genes of the mother and her offspring, which has led to remarkably high rates of change in placental structure and trophoblast signaling mechanisms.


[Ocular hemodynamics following local administration of clonidine].
The influence of topically applied clonidine 0.125% on ocular hemodynamics was investigated in ten patients with open-angle glaucoma and ten healthy volunteers, using a new, differentiated method. Ocular perfusion pressures were determined by Ulrich's method of oculo-oscillodynamography. Following monocular application of clonidine 0.125% eye drops a clear decrease in systemic blood pressure and a somewhat less pronounced reduction of ocular perfusion pressure was observed in both groups of patients. The reduction in ocular perfusion pressures was higher in the eye after drop application than in the untreated control eye. It must therefore be assumed that clonidine 0.125% eye drops have a local perfusion pressure-reducing effect in addition to their systemic effect.


Dengue fever risk and prevention for short-term group travelers to tropical regions.
The purpose of this study is to describe dengue fever infections in a group traveling from northern Louisiana to Mexico. Of 50 travelers in the group, three adolescents aged 15-16 developed febrile symptoms a few days after returning. Clinical diagnosis suggested dengue fever. Serum samples were obtained from the three adolescents and from 19 of the adults (age 18 and older) who were in the group. The samples were analyzed by the Centers for Disease Control using dengue IgM capture enzyme linked immunosorbant assay. Results confirmed the three symptomatic adolescents and five asymptomatic adults had been infected with the Flaviviridae virus that causes dengue. We conclude that since there is no vaccine to prevent dengue infections, travelers to high-risk areas should take steps to prevent infection and that clinicians encountering patients with febrile illnesses after travel to such regions should consider a diagnosis of dengue fever.


The practice of pre-marketing safety assessment in drug development.
The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years.


Genotype (cystatin C) and EEG phenotype in Alzheimer disease and mild cognitive impairment: a multicentric study.
Previous findings demonstrated that haplotype B of CST3, the gene coding for cystatin C, is a recessive risk factor for late-onset Alzheimer's disease (AD; Finckh, U., von der Kammer, H., Velden, J., Michel, T., Andresen, B., Deng, A., Zhang, J., Muller-Thomsen, T., Zuchowski, K., Menzer, G., Mann, U., Papassotiropoulos, A., Heun, R., Zurdel, J., Holst, F., Benussi, L., Stoppe, G., Reiss, J., Miserez, A.R., Staehelin, H.B., Rebeck, G.W., Hyman, B.T., Binetti, G., Hock, C., Growdon, J.H., Nitsch, R.M., 2000. Genetic association of the cystatin C gene with late-onset Alzheimer disease. Arch. Neurol. 57, 1579-1583). In the present multicentric electroencephalographic (EEG) study, we analyzed the effects of CST3 haplotypes on resting cortical rhythmicity in subjects with AD and mild cognitive impairment (MCI) with the hypothesis that sources of resting EEG rhythms are more impaired in carriers of the CST3 B haplotype than non-carriers. We enrolled a population of 84 MCI subjects (42% with the B haplotype) and 65 AD patients (40% with the B haplotype). Resting eyes-closed EEG data were recorded in all subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that the amplitude of alpha 1 (parietal, occipital, temporal areas) and alpha 2 (occipital area) was statistically lower in CST3 B carriers than non-carriers (P < 0.01). Whereas there was a trend towards statistical significance that amplitude of occipital delta sources was stronger in CST3 B carriers than in non-carriers. This was true for both MCI and AD subjects. The present findings represent the first demonstration of relationships between the AD genetic risk factor CST3 B and global neurophysiological phenotype (i.e., cortical delta and alpha rhythmicity) in MCI and AD subjects, prompting future genotype-EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects.


Quantum phases of a vortex string.
We argue that the world sheet dynamics of magnetic k strings in the Higgs phase of the mass-deformed N = 4 theory is controlled by a bosonic O(3) sigma model with anisotropy and a topological theta term. The theory interpolates between a massless O(2) symmetric regime, a massive O(3) symmetric phase, and another massive phase with a spontaneously broken Z(2) symmetry. The first two phases are separated by a Kosterlitz-Thouless transition. When theta = pi, the O(3) symmetric phase flows to an interacting fixed point; sigma model kinks and their dyonic partners become degenerate, mirroring the behavior of monopoles in the parent gauge theory. This leads to the identification of the kinks with monopoles confined on the string.


Detecting the mass and position of an adsorbate on a drum resonator.
The resonant frequency shifts of a circular membrane caused by an adsorbate are the sensing mechanism for a drum resonator. The adsorbate mass and position are the two major (unknown) parameters determining the resonant frequency shifts. There are infinite combinations of mass and position which can cause the same shift of one resonant frequency. Finding the mass and position of an adsorbate from the experimentally measured resonant frequencies forms an inverse problem. This study presents a straightforward method to determine the adsorbate mass and position by using the changes of two resonant frequencies. Because detecting the position of an adsorbate can be extremely difficult, especially when the adsorbate is as small as an atom or a molecule, this new inverse problem-solving method should be of some help to the mass resonator sensor application of detecting a single adsorbate. How to apply this method to the case of multiple adsorbates is also discussed.


[Toxic effect of formaldehyde on mouse different brain regions].
The aim of this study was to explore the mechanism of the nervous system lesions induced by formaldehyde (FA). Male Balb/c mice were exposed to gaseous formaldehyde for 7 days (8 h/d) with three different concentrations (0, 0.5 and 3.0 mg/m(3)). A group of animals injected with the nitric oxide synthase inhibitor L-NMMA (0.01 mL/g) was also set and exposed to 3.0 mg/m(3) FA. The concentrations of cAMP, cGMP, NO and the activity of NOS in cerebral cortex, hippocampus and brain stem were determined by corresponding assay kits. The results showed that, compared with the control (0 mg/m(3) FA) group, the cAMP contents in cerebral cortex and brain stem were significantly increased in 0.5 mg/m(3) FA group (P < 0.05), but decreased in 3.0 mg/m(3) FA group (P < 0.05); The concentration of cAMP in hippocampus was significantly decreased in 3.0 mg/m(3) FA group (P < 0.05). In comparison with the control group, L-NMMA group showed unchanged cAMP contents and NOS activities in different brain regions, but showed increased cGMP contents in hippocampus and NO contents in cerebral cortex (P < 0.05). In addition, compared with 3.0 mg/m(3) FA group, L-NMMA group showed increased contents of cAMP and reduced NOS activities in different brain regions, as well as significantly decreased cGMP contents in cerebral cortex and brain stem and NO content in brain stem. These results suggest that the toxicity of FA on mouse nervous system is related to NO/cGMP and cAMP signaling pathways.


Total Synthesis of Cinnamodial-Based Dimer (-)-Capsicodendrin.
We describe the first total synthesis of cinnamodial-based dimer (-)-capsicodendrin. First, we developed a 12-step synthetic route to access (-)-cinnamodial from 1-vinyl-2,6,6-trimethylcyclohexene. We then showed that (-)-cinnamodial can selectively dimerize to (-)-capsicodendrin under kinetically controlled basic conditions. Our observations regarding a facile conversion of (-)-capsicodendrin back to (-)-cinnamodial hint at the possibility that (-)-capsicodendrin is a chemical reservoir of insecticidal (-)-cinnamodial and Cinnamosma genus plants release it upon environmental stresses.


Early childhood head injury attenuates declines in impulsivity and aggression across adolescent development in twins.
Head injury during development has been associated with behavioral changes such as impulsivity and antisocial behavior. This study investigates the extent to which behavioral changes associated with childhood head injury are sustained through adolescence and emerging adulthood. Survey data was collected at 5 waves spanning 12 years (ages 9-20) from the University of Southern California Risk Factors for Antisocial Behavior twin study. Impulsivity was measured by errors of commission in a Go/NoGo behavioral task, and aggression was measured through youth self-report using the Reactive-Proactive Aggression Questionnaire. Head injury was assessed retrospectively using caregiver questionnaires at twin ages 14-15 years and self-reported at ages 19-20 years. Participants with a head injury in early childhood showed significant delay in the normative developmental decline of impulsivity relative to the noninjured by mid-adolescence (ages 14-15.) Moreover, earlier age at injury was related to a slower decrease in impulsivity and greater increase in reactive aggression scores. Finally, among discordant monozygotic twin pairs, the twin with a head injury experienced significantly less decline in impulsivity by ages 19-20 than the noninjured co-twin. These findings indicate early childhood head injury may play a significant role in blunting the decline in impulsivity across development, exposing an additional risk factor for antisocial behavior. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Deletion of Yersinia pestis ail Causes Temperature-Sensitive Pleiotropic Effects, Including Cell Lysis, That Are Suppressed by Carbon Source, Cations, or Loss of Phospholipase A Activity.
Maintenance of phospholipid (PL) and lipopoly- or lipooligosaccharide (LPS or LOS) asymmetry in the outer membrane (OM) of Gram-negative bacteria is essential but poorly understood. The Yersinia pestis OM Ail protein was required to maintain lipid homeostasis and cell integrity at elevated temperature (37°C). Loss of this protein had pleiotropic effects. A Y. pestis Δail mutant and KIM6+ wild type were systematically compared for (i) growth requirements at 37°C, (ii) cell structure, (iii) antibiotic and detergent sensitivity, (iv) proteins released into supernatants, (v) induction of the heat shock response, and (vi) physiological and genetic suppressors that restored the wild-type phenotype. The Δail mutant grew normally at 28°C but lysed at 37°C when it entered stationary phase, as shown by cell count, SDS-PAGE of cell supernatants, and electron microscopy. Immunofluorescence microscopy showed that the Δail mutant did not assemble Caf1 capsule. Expression of heat shock promoter rpoE or rpoH fused to a lux operon reporter were not induced when the Δail mutant was shifted from 28°C to 37°C (P < 0.001 and P < 0.01, respectively). Mutant lysis was suppressed by addition of 11 mM glucose, 22 or 44 mM glycerol, 2.5 mM Ca2+, or 2.5 mM Mg2+ to the growth medium or by a mutation in the phospholipase A gene (pldA::miniTn5, ΔpldA, or PldAS164A). A model accounting for the temperature-sensitive lysis of the Δail mutant and the Ail-dependent stabilization of the OM tetraacylated LOS at 37°C is presented. IMPORTANCE The Gram-negative pathogen Yersinia pestis transitions between a flea vector (ambient temperature) and a mammalian host (37°C). In response to 37°C, Y. pestis modifies its outer membrane (OM) by reducing the fatty acid content in lipid A, changing the outer leaflet from being predominantly hexaacylated to being predominantly tetraacylated. It also increases the Ail concentration, so it becomes the most prominent OM protein. Both measures are needed for Y. pestis to evade the host innate immune response. Deletion of ail destabilizes the OM at 37°C, causing the cells to lyse. These results show that a protein is essential for maintaining lipid asymmetry and lipid homeostasis in the bacterial OM.


Exosomes: a new horizon in lung cancer.
Circulating exosomes are the major mediators of cell-cell communication. They have been found in various body fluids of healthy individuals and patients with malignancies as cargos of several molecules including miRNAs. Several studies have underlined the role of exosome miRNAs in different tumor types, including lung cancer, suggesting their potential use as biomarkers and therapeutic agents. An overview of the biology and function of exosomes and exosome miRNAs as indicators of diagnosis and treatment response in lung cancer is presented. In addition, preliminary data on exosomes as potential therapeutic agents are reported.


Silencing FAT10 inhibits metastasis of osteosarcoma.
Metastasis is the main challenge of osteosarcoma treatment. Herein, we first reveal the oncogenic role of FAT10 in metastasis of osteosarcoma. FAT10 was upregulated in osteosarcoma, especially in metastatic osteosarcoma. High level of FAT10 was associated with poorer prognosis of osteosarcoma patients. Moreover, Transwell and Matrigel assays revealed that silencing FAT10 significantly inhibited the invasive and migratory abilities of osteosarcoma cells. Metastasis assay in vivo showed that silencing FAT10 decreased the number of mice with distant metastasis. We also found that FAT10 may act its oncogenic functions through regulating HOXB9. Collectively, the results suggested that FAT10 may be a novel therapeutic target for osteosarcoma patients.


Reduction of low density and high density lipoprotein cholesterol by fat-modified diets. A survey of recent findings.
The aim of this review is to summarize recent findings concerning the effects of fat-modified diets on serum lipoproteins, especially on high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol concentrations. Generally, both HDL and LD cholesterol are reduced in subjects on diets enriched in polyunsaturated fatty acids (PUFA diets). The only exceptions to this rule are hypertriglyceridaemic patients with low HDL or LDL concentrations. The changes in HDL and LDL cholesterol are inversely related to the respective HDL and LDL concentrations before dietary treatment. Increasing HDL cholesterol concentrations are seen only during simultaneous body weight reduction. Low HDL cholesterol concentrations are not normalized on PUFA diets. The ratio of LDL cholesterol to HDL cholesterol shows only marginal changes during treatment with a PUFA diet. Thus we cannot clearly state how a lipid-lowering diet might contribute to the anti-atherogenic effect which seems to be characteristic of this type of diet, on the basis not of the change in fasting serum lipoprotein concentrations, but of epidemiological and experimental data.


Sequential actin-based pushing forces drive meiosis I chromosome migration and symmetry breaking in oocytes.
Polar body extrusion during oocyte maturation is critically dependent on asymmetric positioning of the meiotic spindle, which is established through migration of the meiosis I (MI) spindle/chromosomes from the oocyte interior to a subcortical location. In this study, we show that MI chromosome migration is biphasic and driven by consecutive actin-based pushing forces regulated by two actin nucleators, Fmn2, a formin family protein, and the Arp2/3 complex. Fmn2 was recruited to endoplasmic reticulum structures surrounding the MI spindle, where it nucleated actin filaments to initiate an initially slow and poorly directed motion of the spindle away from the cell center. A fast and highly directed second migration phase was driven by actin-mediated cytoplasmic streaming and occurred as the chromosomes reach a sufficient proximity to the cortex to activate the Arp2/3 complex. We propose that decisive symmetry breaking in mouse oocytes results from Fmn2-mediated perturbation of spindle position and the positive feedback loop between chromosome signal-induced Arp2/3 activation and Arp2/3-orchestrated cytoplasmic streaming that transports the chromosomes.


Functional Recovery, Symptoms, and Quality of Life 1 to 5 Years After Traumatic Brain Injury.
Many level I trauma center patients experience clinical sequelae at 1 year following traumatic brain injury (TBI). Longer-term outcome data are needed to develop better monitoring and rehabilitation services. To examine functional recovery, TBI-related symptoms, and quality of life from 1 to 5 years postinjury. This cohort study enrolled trauma patients across 18 US level I trauma centers between 2014 and 2018. Eligible participants were enrolled within 24 hours of injury and followed up to 5 years postinjury. Data were analyzed January 2023. Mild TBI (mTBI), moderate-severe TBI (msTBI), or orthopedic traumatic controls (OTC). Functional independence (Glasgow Outcome Scale-Extended [GOSE] score 5 or higher), complete functional recovery (GOSE score, 8), better (ie, lower) TBI-related symptom burden (Rivermead Post Concussion Symptoms Questionnaire score of 15 or lower), and better (ie, higher) health-related quality of life (Quality of Life After Brain Injury Scale-Overall Scale score 52 or higher); mortality was analyzed as a secondary outcome. A total 1196 patients were included in analysis (mean [SD] age, 40.8 [16.9] years; 781 [65%] male; 158 [13%] Black, 965 [81%] White). mTBI and OTC groups demonstrated stable, high rates of functional independence (98% to 100% across time). While odds of independence were lower among msTBI survivors, the majority were independent at 1 year (72%), and this proportion increased over time (80% at 5 years; group × year, P = .005; independence per year: odds ratio [OR] for msTBI, 1.28; 95% CI, 1.03-1.58; OR for mTBI, 0.81; 95% CI, 0.64-1.03). For other outcomes, group differences at 1 year remained stable over time (group × year, P ≥ .44). Odds of complete functional recovery remained lower for persons with mTBI vs OTC (OR, 0.39; 95% CI, 0.28-0.56) and lower for msTBI vs mTBI (OR, 0.34; 95% CI, 0.24-0.48). Odds of better TBI-related symptom burden and quality of life were similar for both TBI subgroups and lower than OTCs. Mortality between 1 and 5 years was higher for msTBI (5.5%) than mTBI (1.5%) and OTC (0.7%; P = .02). In this cohort study, patients with previous msTBI displayed increased independence over 5 years; msTBI was also associated with increased mortality. These findings, in combination with the persistently elevated rates of unfavorable outcomes in mTBI vs controls imply that more monitoring and rehabilitation are needed for TBI.


Neural correlates of IgE-mediated allergy.
Although many authors have considered a direct interaction between allergic reactions and behavioral changes, supporting evidence has been elusive. In this series of studies we show that after oral or nasal ovalbumin (OVA) challenge, allergic mice present increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (CeA). Mice with food allergy display higher levels of anxiety and increased serum corticosterone levels, and allergy-activated neurons express corticotropin-releasing factor (CRF) in the PVN and CeA. OVA-allergic mice develop aversion to an antigen-containing solution, and also avoid a dark compartment previously associated with nebulized OVA. Results on brain Fos expression and behavioral data seem compatible with adaptive responses. Removal of IgE by either antibody depletion or the development of oral tolerance precluded all responses analyzed here. C-sensitive fiber destruction by neonatal capsaicin inhibited the activation in the PVN, but not in the CeA, and decreased the magnitude of food aversion. Cromolyn, a mast cell stabilizer, completely blocked Fos expression in the PVN and CeA, and precluded the development of aversion to the dark compartment associated with nebulized OVA. Employing mice that do not develop an important inflammatory infiltrate following nasal OVA challenge, we found that inflammatory cells are not required at the site of challenge in order to trigger neural or behavioral correlates of murine experimental asthma. Altogether, we have built a solid foundation for understanding neuroimmune interactions during allergic responses that may contribute to the comprehension of psychological disorders associated with allergy.


Clinical Outcomes and Economic Impact of Oritavancin for Gram-Positive Infections: A Single Academic Medical Center Health System Experience.
Vancomycin treatment of complicated Gram-positive infections is associated with laboratory monitoring, nephrotoxicity, and multiple daily dosing. Oritavancin, a lipoglycopeptide antibiotic with a once-weekly dosing strategy and similar but slightly broader spectrum of activity, presents several opportunities over vancomycin to improve compliance and convenience for the patient. Minimal real-world clinical and acquisition cost data in the inpatient setting and clinical data surrounding multiple dosing in the outpatient setting have limited oritavancin use despite its potential logistic advantages. We describe inpatient and outpatient oritavancin administration, clinical outcomes, and economic impact. This was a single-center, retrospective case series of patients treated with at least one dose of oritavancin between May 2015 and September 2017 at an academic medical center in the USA. A simplified cost-avoidance analysis was conducted assuming the patient had a national health insurance plan and focused on hospital days prevented. Seventy-five patients received oritavancin during the study period. The most common use of oritavancin was in patients with acute bacterial skin and skin structure infections (ABSSSI), defined as cellulitis, abscess or non-surgical wounds (n = 25, 33%), followed by surgical wound infections (n = 12, 16%) and osteomyelitis or septic arthritis (n = 10, 13%). Clinical cure or improvement was achieved in 68 patients (93.2%), while five patients (6.8%) failed treatment; adverse reactions were reported in nine patients (12%). Thirty-five patients received oritavancin as inpatients; 20 patients (57%) had at least one hospital day avoided due to inpatient oritavancin administration resulting in a total cost avoidance of US$343,654. In this series of 75 patients with Gram-positive infections, oritavancin treatment resulted in clinical cure or improvement in most patients, and was generally well tolerated. Inpatient administration may avoid costs and outpatient administration is a reasonable consideration for patients in which prolonged antibiotic therapy is necessary.


CT and MRI of the ear and temporal bone: current state of the art and future prospects.
Computed tomography (CT) and magnetic resonance imaging (MRI) have become the radiographic investigations of choice for the vast majority of ear and temporal bone disorders. CT provides excellent images of bone and is indicated where osseous changes are of greatest diagnostic importance. MRI is superior in the evaluation of the eighth nerve complex and the central nervous system. Anticipated future advances include the production of three-dimensional images, more rapid scan times permitting dynamic (cine) studies, and the imaging of labeled chemical markers with insights into physiologic derangements.


The mid-forearm arteriovenous fistula as vascular access for haemodialysis.
Successful chronic haemodialysis requires permanent vascular access. The Scribner procedure which utilizes an external arteriovenous shunt, the internal synthetic arteriovenous shunt and the direct arteriovenous fistula as described by Cimino and Brescia have all been used for haemodialysis. Of the three methods, the arteriovenous fistula is the most trouble-free and durable. However, as originally described and constructed in the distal forearm, the morbidity associated with this method is significant. The cubital fossa fistula has even more problems. The mid-forearm fistula was designed by the authors and has been used for chronic haemodialysis over the past eighteen years. This article compares the various methods of access used in the haemodialysis units of the University Hospital of the West Indies and the Kingston Regional Hospital. The mid-forearm fistula was found to have the lowest initial failure rate and was associated with fewer complications than any of the other methods used for access.


Parenting Mediates Symptoms and Impairment in Children With ADHD-Inattentive Type.
The current study investigates potential pathways between inattentive symptom severity, positive and negative parenting practices, and functional impairment (i.e., academic, social, and home impairment) in a sample of children diagnosed with attention-deficit/hyperactivity disorder, Predominantly Inattentive Type (ADHD-I). Participants included 199 children and their parents and teachers enrolled in a randomized clinical trial investigating the efficacy of an integrated psychosocial intervention for children with ADHD-I. Boys constituted slightly more than half the sample; children averaged 8.6 years of age (range = 7-11) and were from varied ethnic/racial backgrounds. As part of the initial screening and assessment procedures, parents and teachers completed questionnaires assessing child behavior and parent/family functioning. Results supported both main effects of symptoms and parenting on impairment, as well as a mediational path between symptoms and impairment via parenting, as observed by parents in the home setting. Specifically, higher severity of inattention was associated with higher rates of homework, social, and home impairment. Negative parenting contributed to homework and home impairment, and positive and negative parenting contributed to social impairment, incrementally above and beyond the impact of inattention symptom severity alone. Negative parenting partially mediated the relationship between inattentive symptom severity and impairment, such that higher rates of inattention were associated with higher rates of negative parenting, which in turn was associated with higher rates of homework, social, and home impairment. Results provide support for underlying mechanisms for associations between symptoms and impairment in children with ADHD-I and identify potential intervention targets to improve impairment experienced by these children.


Application of Ovarian Cancer Organoids in Precision Medicine: Key Challenges and Current Opportunities.
Ovarian cancer (OC) is the leading cause of death among gynecologic malignances. Over the past decades, human-derived models have advanced from monolayer cell cultures to three-dimensional (3D) organoids that could faithfully recapitulate biological characteristics and tumor heterogeneity of primary tissues. As a complement of previous studies based on cell lines or xenografts, organoids provide a 3D platform for mutation-carcinogenesis modeling, high-throughput drug screening, genetic engineering, and biobanking, which might fulfill the gap between basic research and clinical practice. Stepwise, cutting-edge bioengineering techniques of organoid-on-a-chip and 3D bioprinting might converge current challenges and contribute to personalized therapy. We comprehensively reviewed the advantages, challenges, and translational potential of OC organoids. Undeniably, organoids represent an excellent near-physiological platform for OC, paving the way for precision medicine implementation. Future efforts will doubtlessly bring this innovative technique from bench to bedside.


C1 esterase inhibitor gene expression in rat Kupffer cells, peritoneal macrophages and blood monocytes: modulation by interferon gamma.
Kupffer cells (KC) represent the main part of the tissue macrophages. Beside phagocytosis of particulate material, involvement of KC in immunological and inflammatory reactions has been supposed. As C1 esterase inhibitor (C1-INH) is a serine protease inhibitor involved in such processes, the aim of this work was to study C1-INH synthesis in KC and, by comparison, in peritoneal macrophages (PM) and blood monocytes (MC) of the rat. C1-INH synthesis was studied on the protein level by biosynthetic labeling, immunoprecipitation, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and on the RNA level by Northern blotting of total RNA or by in situ hybridization. KC were found to express C1-INH gene spontaneously. C1-INH synthesis represents 1.3 +/- 0.2% of total protein synthesis at day 1 of culture and the absolute amount each cell synthesis remains constant during the whole time in culture. Transcripts of C1-INH were detected both in freshly isolated and in cultured KC. In contrast, spontaneous C1-INH gene expression was not detectable in freshly isolated PM, but only in cultured PM. In MC, C1-INH was not detectable at any time, whatever. Treatment of the cells with interferon gamma increased C1-INH synthesis in KC and in PM and caused an induction of C1-INH synthesis in MC. The results suggest that constitutive C1-INH synthesis is a functional marker for mature tissue macrophages.


IgE cross-reactivity of phospholipase A2 and hyaluronidase of Apis dorsata (Giant Asian Honeybee) and Apis mellifera (Western Honeybee) venom: Possible use of A. mellifera venom for diagnosis of patients allergic to A. dorsata venom.
Diagnostic and therapeutic reagents are unavailable for anaphylaxis arising from stings by Apis dorsata. Venom profiles and cross-reactivity of A. dorsata and Apis mellifera were compared, to ascertain whether venom of A. mellifera can be used for diagnosis in A. dorsata allergy. Both venom profiles were similar by High Performance Liquid Chromatography and SDS-PAGE. Sera of 29 of 30 (96.7%) patients with anaphylaxis to A. dorsata stings had IgE to the phospholipase-2 (PLA2) doublet (15 and 16 kDa) of A. dorsata venom by immunoblot, compared to 26 of 30 (86.7%) with the PLA2 of A. mellifera and a purified preparation of PLA2. Twelve patients (40%) with severe anaphylaxis had IgE reactivity to a 39 kDa protein band of venom of both species, a third band, identified in immunoblot as hyaluronidase. The cross-reactivity of PLA2 and hyaluronidase of A. dorsata and A. mellifera were further confirmed by immunoblot inhibition results. Twenty five of 30 (83.3%) of our patients had positive venom specific IgE (>0.35 KUA/L) reactivity to Phadia ImmunoCAPs of A. mellifera venom. The observed IgE cross reactivity suggests the possibility of using A. mellifera venom as a diagnostic test for A. dorsata venom allergy.


Psychological impact of screening for familial ovarian cancer: reactions to initial assessment.
To assess the psychological impact on women attending a familial ovarian cancer screening clinic. 157 women referred for screening completed an investigator designed questionnaire, the Spielberger State Trait Anxiety Scale and the Centre for Epidemiological Studies Depression Scale prior to the screening interview and an eight-item questionnaire post-assessment. 95.4% saw the screening as valuable. Thirty-one point four percent of all patients scored about the cutoff point for depression. Sixteen percent exhibited high levels of anxiety. Fifty-six point four percent of patients accurately perceived their risk. Twenty-one point five percent of those who accurately perceived themselves as being at high risk had high anxiety and 40.6% reported significant depressive symptoms. Of the 26.5% of patients who overestimated their risks, 40.0% reported significant depressive symptoms and 22.6% were anxious. Of the 17.1% who minimized their risk, none were anxious (0.0%), and only 15.8% were depressed. Attendees at a familial ovarian cancer screening clinic may have high levels of depression and anxiety.


Co-operative function and mutual stabilization of the half ATP-binding cassette transporters HAF-4 and HAF-9 in Caenorhabditis elegans.
Caenorhabditis elegans HAF-4 and HAF-9 are half ABC (ATP-binding-cassette) transporters that are highly homologous to the human lysosomal peptide transporter TAPL [TAP (transporter associated with antigen processing)-like; ABCB9]. We reported previously that both HAF-4 and HAF-9 localize to the membrane of a subset of intestinal organelles, and are required for the formation of these organelles and other physiological aspects. In the present paper, we report the genetic and physical interactions between HAF-4 and HAF-9. Overexpression of HAF-4 and HAF-9 did not rescue the intestinal organelle defect of the haf-9 and haf-4 deletion mutants respectively, indicating that they cannot substitute for each other. Double haf-4 and haf-9 mutants do not exhibit more severe phenotypes than the single mutants, suggesting their co-operative function. Immunoprecipitation experiments demonstrated their physical interaction. The results of the present study suggest that HAF-4 and HAF-9 form a heterodimer. Furthermore, Western blot analysis of the deletion mutants and RNAi (RNA interference) knockdown experiments in GFP (green fluorescent protein)-tagged HAF-4 or HAF-9 transgenic worms suggest that HAF-4-HAF-9 heterodimer formation is required for their stabilization. The findings provide a clue as to how ABC transporters adopt a stable functional form.


Ultrasensitive and selective detection of dopamine using cobalt-phthalocyanine nanopillar-based surface acoustic wave sensor.
A highly selective and sensitive surface acoustic wave (SAW) sensor of dopamine (DA) was developed by depositing cobalt phthalocyanine (CoPc) nanopillars on gold-coated sensing platform of SAW sensor. The developed biosensor presents a sensitivity of 1.6°/nM, has a low limit of detection (LOD) on the order of 0.1 nM, and imparts more selectivity toward DA, since the detection limit of the interfering ascorbic acid (AA) is as high as 1 mM. To understand the selectivity mechanisms of this sensor toward DA, density functional theory-based chemical calculations were carried out. Calculations suggest two different types of interactions: dative bond with a very strong character for DA-CoPc complexes, and significant ionic character in the case of AA-CoPc ones. The interaction energies, in liquid phase, were estimated to be equal to -81 kJ mol(-1) and -38 kJ mol(-1) for DA-CoPc and AA-CoPc complexes, respectively, therefore accounting for the selective detection of DA over AA using tandem CoPc nanopillar-based SAW sensor device. This work demonstrates a simple and efficient design of SAW sensors employing thin nanostructured CoPc biomolecular recognition layers for DA detection.


Correlation of Medical College Admission Test Scores and Self-assessment Materials with the United States Medical Licensing Examination Step 1 Performance.
Purpose Candidates' performance on the United States Medical Licensing Examination (USMLE) Step 1 examination had been correlated with the Medical College Admission Test (MCAT). However, in 2015, a new MCAT format was released and its correlation with Step 1 remains to be fully analyzed. Preparation for Step 1 typically involves purchasing and perusing practice tests from the National Board of Medical Examiners (NBME) and UWorld; however, their predictive value to performance on Step 1 remains to be ascertained, especially with the release of five new NBME practice tests. Additionally, there is a need for accurately predicting Step 1 scores to self-evaluate study progress and reduce student anxiety. Rationale Program directors rank USMLE Step 1 scores as the number one criterion in selecting interviewees for residency. Step 1 scores are more important than Step 2 scores, Dean's letter, or other letters of recommendation in determining the overall ranking of a candidate after interviews. Hypotheses The authors hypothesized that the new MCAT scores correlated positively with Step 1 scores and that the new NBME practice tests were more predictive of performance on Step 1 as compared to old NBME tests. Methods Linear regression analysis followed by either analysis of variance (ANOVA) or Student's t-tests were used to analyze 399 responses. Data obtained was used to update an existing Step 1 score predictor, which was then validated. Results A positive correlation between the MCAT (average score: 510.1 ± 6.3) and Step 1 scores (average score: 246.1 ± 14.2) was observed. While new NBME practice tests were more predictive of Step 1 scores than old NBME tests, UWorld test scores were the most predictive. Students who practiced with the new NBME practice tests scored significantly higher than students who did not use them. However, students using any of the UWorld practice tests did significantly better than students who practiced using only NBME practice tests but not UWorld practice tests. Ironically, NBME16,the second-most correlativetest to Step 1 performance, is no longer available for purchase. Overall, taking six or more practice tests significantly enhanced Step 1 scores; the optimal number of tests was found to be between six and nine. The predicted score by an updated Step 1 score predictor was within 3.8 points or 1.6% of the actual Step 1 score. Conclusions We believe this study will aid in the selection and purchase of appropriate self-assessment tests as preparatory material for the USMLE Step 1 examination. It will also introduce them to an existing Step 1 score predictor that will help determine their readiness for Step 1.


Induction by chloroquine of differentiation of cultured mouse myeloid leukemia cells.
The effect of chloroquine on differentiation of cultured mouse myeloid leukemia Ml cells was examined. On treatment with 5 approximately 25 microgram/ml of chloroquine diphosphate for 1 approximately 4 days, the cells were induced to phagocytize latex beads, to form Fc rosettes, to form dispersed colonies in soft agar, and to synthesize lysozyme, unlike untreated cells. The morphology of about 40% of the cells changed during treatment with 20 microgram/ml of chloroquine diphosphate for 4 days; some cells developed small eccentrically located nuclei, and others ring-shaped or segmented nuclei. These results show that Ml cells differentiate into cells resembling macrophages or granulocytes on treatment with chloroquine.


A molecular-structure hypothesis.
The self-similar symmetry that occurs between atomic nuclei, biological growth structures, the solar system, globular clusters and spiral galaxies suggests that a similar pattern should characterize atomic and molecular structures. This possibility is explored in terms of the current molecular structure-hypothesis and its extension into four-dimensional space-time. It is concluded that a quantum molecule only has structure in four dimensions and that classical (Newtonian) structure, which occurs in three dimensions, cannot be simulated by quantum-chemical computation.


[Effects of a basic metabolic diet rich in polyene fatty acids on the pattern of glycerophospholipid fatty acids in patients with hyperlipoproteinemia].
In 77 patients with primary hyperlipoproteinaemia of the types IIa, IIb and IV who for 8 months had been treated with a metabolic basic diet enriched by polyene fatty acid gas-chromatographic analyses of the fatty acid compound of the glycerophospholipids were carried out in four-month intervals. In all three types of hyperlipoproteinaemia in a different size and increase of poly-unsaturated and a decrease of saturated and mono-unsaturated fatty acid could be observed. A metabolic basic diet rich in polyene fatty acid has a favourable influence on atherogenic constellations of the fatty acids of the glycerophospholipids.


Manufacturing of Corrosion Inhibitors and Flow Improvers from Recycling of Waste at Hail City, Saudi Arabia: Physicochemical and Electrochemical Studies on Steel in Petroleum Industries.
The aim of the present research paper is to convert daily waste materials generated by human activity at Hail city into useful petroleum additives. In this respect, novel multifunctional corrosion inhibitors working as inhibitors and flow improvers for crude oil were prepared. Polyethylene terephthalate (PET) plastic waste is used in the production of corrosion inhibitors and flow improvers for petroleum crude oil. A multifunctional corrosion inhibitor for the SABIC carbon steel in corrosive seawater for application in the petroleum industry was manufactured using PET waste that was gathered, cleaned, and used as starting materials. The PET green recycling method takes place via the Abdel-Hameed green recycling reported method. In the first step, PET waste was reacted without a solvent with a diamine to form the diamino derivative of phthalic acid amide (PETAA), which was characterized by FT-IR, 1HNMR, and elemental analysis. In the presence of a catalyst, the used recycling method is a solvent-free green recycling process that is environmentally friendly. Chemical and electrochemical measurements were performed, and the effects of concentration and temperature were studied. The inhibition efficiency was found to increase with concentration. A maximum inhibition of 97% was obtained using 4000 ppm from the prepared PETAA inhibitor, while the efficiency decreased with temperature. Potentiodynamic polarization (PDP) data indicates the mixed-type nature of the used inhibitor. According to potentiodynamic polarization data, the inhibitor boosts polarization resistance and inhibition performance by adsorbing on the metal/electrolyte interface. The data from electrochemical impedance spectroscopy (EIS) show that the charge-transfer mechanism is the primary governing factor in the steel dissolution process. The size of the semicircle grows in direct proportion to the concentration of the inhibitor. The prepared additive acts as a flow improver (viscosity improvers and pour point depressants) for waxy crude oil, indicating that it can be used in the manufacturing of multifunctional inhibitors in the petroleum industry. The depression in the pour point temperatures depended on the concentration and composition of the additive prepared from the plastic waste collected from Hail city.


Massive Bleeding and Massive Transfusion.
Massive bleeding in trauma patients is a serious challenge for all clinicians, and an interdisciplinary diagnostic and therapeutic approach is warranted within a limited time frame. Massive transfusion usually is defined as the transfusion of more than 10 units of packed red blood cells (RBCs) within 24 h or a corresponding blood loss of more than 1- to 1.5-fold of the body's entire blood volume. Especially male trauma patients experience this life-threatening condition within their productive years of life. An important parameter for clinical outcome is to succeed in stopping the bleeding preferentially within the first 12 h of hospital admission. Additional coagulopathy in the initial phase is induced by trauma itself and aggravated by consumption and dilution of clotting factors. Although different aspects have to be taken into consideration when viewing at bleedings induced by trauma compared to those caused by major surgery, the basic strategy is similar. Here, we will focus on trauma-induced massive hemorrhage. Currently there are no definite, worldwide accepted algorithms for blood transfusion and strategies for optimal coagulation management. There is increasing evidence that a higher ratio of plasma and RBCs (e.g. 1:1) endorsed by platelet transfusion might result in a superior survival of patients at risk for trauma-induced coagulopathy. Several strategies have been evolved in the military environment, although not all strategies should be transferred unproven to civilian practice, e.g. the transfusion of whole blood. Several agents have been proposed to support the restoration of coagulation. Some have been used for years without any doubt on their benefit-to-risk profile, whereas great enthusiasm of other products has been discouraged by inefficacy in terms of blood transfusion requirements and mortality or significant severe side effects. This review surveys current literature on fluid resuscitation, blood transfusion, and hemostatic agents currently used during massive hemorrhage in order to optimize patients' blood and coagulation management in emergency medical aid.


Subretinal fibrovascular proliferation in retinal arteritis with multiple aneurysmal dilatations: a case report.
A 14-year-old boy with bilateral retinal arteritis with multiple aneurysmal dilatations complicated by secondary macular subretinal fibrovascular proliferation and epimacular membrane formation is described. This complication has not been previously reported in this rare disorder. Systemic steroid and immunosuppressive therapy did not change the course of the disease. Improvement of macular edema and subretinal exudation was achieved following pars plana vitrectomy, posterior hyaloid dissection and epiretinal membrane removal.


Escape from host-antitumor immunity.
Cancer cells may express proteins recognizable by the individual's immune system as foreign because they are either tumor-specific or not expressed at high levels in normal tissues to which the host is tolerant. There is now much evidence that tumors can be immunogenic, that is, that they frequently express antigens in a form recognizable by the host immune system. This has been shown not only in experimental animals but also for spontaneously occurring human tumors. Tumors therefore may progress by evolving variants that can evade immune responses or by developing other strategies to "escape" the immune response. The purpose of this review is to consider the current status of knowledge concerning these different tumor escape strategies.


Label-free optical metabolic imaging of adipose tissues for prediabetes diagnosis.
Rationale: Prediabetes can be reversed through lifestyle intervention, but its main pathologic hallmark, insulin resistance (IR), cannot be detected as conveniently as blood glucose testing. In consequence, the diagnosis of prediabetes is often delayed until patients have hyperglycemia. Therefore, developing a less invasive diagnostic method for rapid IR evaluation will contribute to the prognosis of prediabetes. Adipose tissue is an endocrine organ that plays a crucial role in the development and progression of prediabetes. Label-free visualizing the prediabetic microenvironment of adipose tissues provides a less invasive alternative for the characterization of IR and inflammatory pathology. Methods: Here, we successfully identified the differentiable features of prediabetic adipose tissues by employing the metabolic imaging of three endogenous fluorophores NAD(P)H, FAD, and lipofuscin-like pigments. Results: We discovered that 1040-nm excited lipofuscin-like autofluorescence could mark the location of macrophages. This unique feature helps separate the metabolic fluorescence signals of macrophages from those of adipocytes. In prediabetes fat tissues with IR, we found only adipocytes exhibited a low redox ratio of metabolic fluorescence and high free NAD(P)H fraction a1. This differential signature disappears for mice who quit the high-fat diet or high-fat-high-sucrose diet and recover from IR. When mice have diabetic hyperglycemia and inflamed fat tissues, both adipocytes and macrophages possess this kind of metabolic change. As confirmed with RNA-seq analysis and histopathology evidence, the change in adipocyte's metabolic fluorescence could be an indicator or risk factor of prediabetic IR. Conclusion: Our study provides an innovative approach to diagnosing prediabetes, which sheds light on the strategy for diabetes prevention.


Mechanistic and kinetic study on the reaction of methylperoxy radical with atomic iodine.
Singlet and triplet potential energy surfaces for the CH3O2 with I reaction have been investigated computationally to propose the reaction mechanisms and possible products. Multichannel RRKM theory and transition-state theory have been used to compute the overall and individual rate constants at 200-3000K and 10-14-1014Torr. On the singlet PES, addition-elimination, substitution and H-abstraction mechanisms are located, and the addition-elimination mechanism is dominant. At 70Torr with N2 as bath gas, IM1(CH3OOI) formed by collisional stabilization is dominated at 200-300K, whereas CH2O and HIO are the major products at the temperatures between 350 and 3000K; The title reaction exhibits the typical falloff behavior. The results show that temperature and pressure affect the yield of products. Furthermore, the predicted rate constants at 298K 70Torr of N2 agree well with the available experimental values. On the triplet PES, the most favorable product should be CH3I+O2(3Σ) at atmospheric condition. Other two pathways on the triplet PES will not compete with the pathways on the singlet PES in kinetically and thermodynamically.


LncRNA PTCSC3 Alleviates the Postoperative Distant Recurrence of Gastric Cancer by Suppression of lncRNA HOXA11-AS.
It is worldwide accepted that lncRNA PTCSC3 is a tumor suppressor in glioma and thyroid cancer, whereas its role in the recurrence of gastric cancer is unknown. We recruited 80 GC patients (46 males and 34 females, 44 to 68 years, 56.3±6.7 years) in our study. Two human GC cell lines AGS and SNU-1 were transfected with PTCSC3 and HOXA11-AS expression vectors. Then, qPCR was used to detect the level of relative mRNA. Both invasion and migration assays were performed to detect the effect of the lncRNA on gastric cancer cell motility. In the present study, we showed that PTCSC3 was downregulated in plasma of gastric cancer patients than in plasma of healthy controls. Follow-up study indicated that PTCSC3 was further downregulated in patients with distant-recurrence but not in patients with local recurrence only or non-recurrence. LncRNA HOXA11-AS was upregulated in plasma of gastric cancer cells than in plasma of healthy controls and was inversely correlated with PTCSC3 in plasma of gastric cancer patients. PTCSC3 overexpression mediated the downregulation of HOXA11-AS in gastric cancer cells, while HOXA11-AS overexpression failed to significantly affect PTCSC3. PTCSC3 overexpression led to inhibited, while HOXA11-AS overexpression led to promoted migration and invasion of gastric cancer cells. In addition, HOXA11-AS overexpression reduced the effects of PTCSC3 overexpression. Therefore, lncRNA PTCSC3 alleviates in the postoperative distant recurrence of gastric cancer possible by suppression of HOXA11-AS.


Prognostic significance of tumor-infiltrating lymphocytes in oropharyngeal cancer.
The presence of tumor-infiltrating lymphocytes has been shown to significantly improve clinical outcomes in many types of cancer. However; their effects on outcomes in patients with oropharyngeal cancer specifically have yet to be elucidated. We conducted a retrospective study in an effort to shed light on this issue. We reviewed the records of 48 consecutively presenting patients with oropharyngeal cancer; and we performed immunohistochemistry to analyze their archived paraffin-embedded tissue samples for the presence of CD3-positive tumor-infiltrating lymphocytes. We also used real-time polymerase chain reaction testing to look for human papillomavirus type 16 (HPV-16) in the tumors. We found that patients with large numbers of tumor-infiltrating lymphocytes (CD3high) had a significantly lower incidence of metastasis at presentation than did those with low numbers of tumor-infiltrating lymphocytes (CD31low) (40.0 vs. 88.5%; p = 0.001), regardless of HPV status. When HPV status was taken into account, the correlation between a high CD3 count and a lower rate of metastasis was maintained in the HPV-positive patients but not in the HPV-negative patients. We also found that the CD3high patients had higher rates of overall survival and disease-free survival at 3 and 5 years than did the CD3low patients; however; these differences only approached but did not reach statistical significance.


Influence of the emollient on emulsions containing lamellar liquid crystals: from molecular organization towards applicative properties.
The sensory perception of cosmetic emulsions is complex as it is governed by an important number of parameters like the choice of raw materials, their interactions, the structural organisation of the system, etc. The aim of the present work was to go further in the interpretation of the emollient-surfactant interactions, towards the emulsions applicative properties. For this purpose, two systems containing liquid crystals of the lamellar type were formulated, differing only in the selected emollient. First, the liquid crystals types were checked using different tools like the optical microscopy under the bright and polarized light, the wide-angle X rays diffraction and, finally, thermogravimetric analysis. Next, two sensory attributes, namely compression force and difficulty of spreading, were evaluated by a sensory panel. In addition to that, complementary instrumental characterizations (flow tests, textural analysis and contact angle measurements) were performed in order to understand how the panel could discriminate the products. The results showed that isohexadecane emollient induces the α-gel structures, while caprylic capric triglycerides favour the formation of the lamellar liquid crystals near to α-gel. For the compression force, the results point out that there is no direct interaction between the oil phase and the skin. For this attribute, depending on its chemical structure, emollient impacts the human perception only by changing the lamellar phase type. Concerning the difficulty of spreading, both the emulsion structure and the emollient properties should be considered. Immediate perception is impacted by the emulsions destruction, making the droplet roll one on each other. Then, once the droplets monolayer is disrupted, the emollient comes into direct contact with the skin. In this case, the perception is governed by the direct affinity of the emollient with the skin, nonpolar emollients being easier to spread if compared to polar ones. The sensory perception is guided not only by the choice of the raw materials but also by their interactions. It was shown that the chemical structure of the emollients affected the molecular organization of liquid crystals present in the emulsion and, consequently, directly or indirectly its sensory perception.


Electrochemistry in microscopic domains. 1. The electrochemical cell and its voltammetric and amperometric response.
Microscopic aqueous sample droplets of nano- and picoliter volumes were formed on the bottom of a polystyrene dish under water-saturated heptane. The electrochemical cell consisted of a beveled carbon fiber microdisk working electrode and a reference electrode with a miniature junction, both inserted into the studied droplet. Both electrodes had a nominal tip diameter of 7.5 microns. Cyclic voltammetry and chronoamperometry in droplets of 3.3 mM ruthenium hexaammine trichloride in 0.1 M KCl solution were performed with this system. The experiments revealed for the first time major deviations in both voltammetric and amperometric microelectrode behavior in picoliter domains as compared to nanoliter volume and bulk solution. The concept and criteria of electrochemical microscopicity of volume is discussed. This work also provides a simple and robust experimental model system to verify electrochemical experiments in restricted domains such as in or near single biological cells or in microscopic tissue cavities. The methodology developed has, however, more general analytical and physicochemical applications as well.


Materialism moderates the impact of mortality salience on impulsive tendencies toward luxury brands.
Luxury goods have been shown to help individuals coping with death-related anxiety. However, the extent to which the symbolic value allocated to possessions (i.e., materialism) moderates this effect is still unclear. Here, we investigated the impact of materialism on impulsive approach tendencies toward luxury clothing brands in a context of mortality salience. Results showed that the impact of mortality salience was moderated by materialism with lower impulsive approach tendencies toward luxury clothing brands observed in non-materialistic participants. These findings highlight how materialism values may impact luxury consumption through impulsive pathways in a situation of death-related anxiety.


In-vitro study of the synergy between beta-lactam antibiotics and glycopeptides against enterococci.
The synergy between glycopeptides and beta-lactams was studied using different techniques such as broth macrodilution, killing curves and agar dilution combined with agar diffusion. Two glycopeptide-resistant enterococci isolated from different clinical samples were used. Results showed different effects with significant changes in MICs. Antibacterial activity was related to the concentration of glycopeptide and beta-lactam for Enterococcus faecalis 8253, while for Enterococcus faecium 8072 a paradoxical effect was observed. With this strain, the best synergic effect was detected at teicoplanin concentrations of 1-4 mg/L, but antibacterial activity was reduced at concentrations of 8, 16 and 32 mg/L. No synergic effect was observed with vancomycin. The combination of agar dilution with agar diffusion techniques may constitute a simple method for routine detection of synergic effects between glycopeptides and beta-lactams.


Protective effect of Smilax excelsa L. pretreatment via antioxidant, anti-inflammatory effects, and activation of Nrf-2/HO-1 pathway in testicular torsion model.
The protective effects of the ethanol extract of Smilax excelsa L. (SE) leaves were investigated on testicular tissue of rats with a torsion model in this study. The chemical composition of the extract was detected by means of liquid chromatography with tandem mass spectrometry (LC-MS/MS). SE extract was given for 21 days before torsion was created in the treatment group. The sperm parameters of the torsion group were impaired, and there was an increase in MDA level as well as a decrease in GSH level and GPx activity compared to the control group. TNF-α and NF-κB levels in the torsion group increased as compared to those in the control group. The expression levels of Nrf-2 and HO-1 were lower in the torsion group than those in the control group. The SE pretreatment group has improved sperm, oxidative stress, and inflammatory markers when compared to the torsion group, and the Nrf-2/HO-1 pathway was activated. PRACTICAL APPLICATIONS: Smilax excelsa L. is a plant with economic value used in traditional medicine in the treatment of stomachache, bloating, and breast cancer in Northwest Anatolia. It has an antioxidant effect due to the flavonoids and anthocyanins it contains. The protective effect against ischemia-reperfusion-induced tissue and reproductive damage in testicular tissue were demonstrated with the study. When the histological examinations of the tissues were evaluated, it was found that morphological structure of the tissues was retained in the treatment group. The findings indicate that SE prevents tissue damage in the torsion model by antioxidant and anti-inflammatory effects and activating Nrf-2/HO-1 pathway.


Expression of positional candidates for shell thickness in the chicken.
Expression of 12 positional candidates for QTL affecting shell thickness at 53 wk of lay age (ST53) was investigated by real-time PCR in the distal part of chicken oviducts (uterus) with a forming eggshell. In the local chicken breed Green-legged Partridgenous, the complete cDNA CR523443 (ChEST985k21) was downregulated with ratio of means 0.49 (P < or = 0.01) in the group with low ST53 (248.6 +/- 16.62 microm) relative to the group with the highest ST53 (372.4 +/- 2.07 microm). Expression of this gene was highly correlated (0.85, P < or = 0.01) with shell thickness. No significant difference in expression between the 2 groups with thick (378.4 +/- 3.65 microm) and thin (227.8 +/- 8.99 microm) shell and no significant correlation of expression level with ST53 were detected in Rhode Island Red, which could be explained by strict selection to egg quality traits, including optimal shell thickness in this commercial layer breed. These data suggested that CR523443 was a candidate gene for QTL ST53 in the chicken.


Rapid analysis of colipase gene variants by multicapillary electrophoresis.
Despite of the fact that the Human Genome Project was completed more than a decade ago, identification of the genetic background of polygenic diseases is still challenging. Several somewhat different approaches are available to investigate inheritable factors of complex phenotypes, all require, however efficient, high-throughput techniques for SNP genotyping. In this paper, we report a robust and reliable multiplex PCR-RFLP for genotype and haplotype analysis of six SNPs (rs41270082, rs3748051, rs142027015, rs3748048, rs73404011, and rs72925892) of the colipase (CLPS) gene. A multicapillary (12 capillaries) electrophoresis unit was used for high throughput and sensitive analysis of the digestion fragments. A Microsoft Excel-based spreadsheet was designed for the flexible visualization and evaluation of the electrophoretic separations, which is readily adaptable for any kind of electrophoresis application. Haplotype analysis of the two loci localized in close proximity of each other was carried out by molecular method, extended haplotypes including all five SNPs in the 5' upstream region were calculated. The techniques were applied in a case-control association study of type 2 diabetes mellitus. Although, single marker analysis did not reveal any significant association, it was observed that the rare GGCCG haplotype of the five 5' upstream region SNPs was about three times more frequent among patients compared to healthy control population. Our results demonstrated the applicability of multicapillary CGE in large-scale, high-throughput SNP analysis, and suggested that the CLPS gene polymorphisms might be considered as genetic risk factor for type 2 diabetes mellitus.


Survival of block and fascial-wrapped diced cartilage grafts: an experimental study in rabbits.
Cartilage grafts have become an integral part in plastic surgery. Classic autogenous cartilage harvesting techniques are associated with significant donor- and recipient-site morbidity. The use of cartilage micrografts wrapped in a sleeve was first developed to decrease the complication rates of block cartilage grafts. The aim of this study was to compare the resorption rate of solid block cartilage graft and diced cartilage wrapped in fascia graft in rabbits. In 12 rabbits, 1 solid block cartilage and 1 diced graft wrapped in fascia were implanted in subcutaneous pockets. By the end of the fourth month, the cartilage implants were dissected free and photographed and weighed exactly. Then specimens were stained with hematoxylin and eosin to determine their architectural characteristics. In the solid block cartilage graft group, the means ± standard deviation preimplant weight values were 5.34 ± 1.68. The weight was changed to 7.74 ± 3.26. The change was not statistically significant. In diced cartilage grafts wrapped in fascia, the means ± standard deviation preimplanted weight values were 8.13 ± 1.83. These values were changed to 2.79 ± 1.97, meaning statistically significant resorption of diced cartilage grafts wrapped in fascia (P < 0.001). In histologic examination, block cartilage grafts showed viable cartilage but diced cartilage grafts wrapped in fascia yielded fibrosis and inflammatory cell infiltration. The amplitude of resorption of the diced cartilage wrapped in fascia is considerable compared with one-piece block grafts. It may be anticipated that the enthusiasm for this technique will decline once the long-term results of pertaining clinical studies are available.


Therapeutic Role of Zinc Supplementation in Children Hospitalized with Pneumonia.
Introduction Pneumonia is one of the major causes of death in children younger than age five, especially in developing countries. The World Health Organization recommends children from a developing country take zinc supplements. We conducted this study to explore the efficacy of zinc supplementation in alleviating symptoms and shortening of hospital stay in children with pneumonia. Materials and methods We conducted this prospective, randomized controlled trial in the Department of Pediatrics, Civil Hospital, Jamshoro. We included 100 children of both genders randomized into two equal groups of zinc-supplemented and non-zinc-supplemented study groups after informed consent was obtained from the parents and legal guardians. The participants were aged 28 days to five years and admitted in the hospital with pneumonia. We monitored for hypoxia, tachypnea, chest indrawing, and cyanosis, and we recorded the total length of hospital stay for each group. Results We found no significant difference in symptom changes (i.e., hypoxia, tachypnea, chest indrawing, and cyanosis) between the zinc and non-zinc groups. However, hospital length of stay was significantly shorter for patients in the zinc-supplemented group compared to the non-zinc-supplemented group. Conclusion Zinc supplementation did not yield a statistically significant reduction in symptoms in children with severe pneumonia. Zinc supplements given during an acute episode are not beneficial in short-term clinical recovery from severe pneumonia in hospitalized children.


[Multifactor predictive model in patients with myocardial infarction based on modern biomarkers].
Objective To study the prognostic role of current serum biomarkers in patients with myocardial infarction (MI) by constructing a multifactorial model for prediction of cardiovascular complications (CVC) in remote MI. Acute coronary syndrome is a major cause of death and disability in the Russian Federation. Introduction of current biomarkers, such as N-terminal pro-brain natriuretic peptide, stimulating growth factor (ST2), and centraxin-2 (Pentraxin, Ptx-3), provides more possibilities for diagnostics and calculation of risk for CVC.Materials and Methods Concentrations of biomarkers were measured in 180 patients with MI (mean age, 61.4±1.7) upon admission. At one year, specific and composite endpoints were determined (MI, acute cerebrovascular disease, admission for CVD, and cardiovascular death). Based on this information, a prognostic model for subsequent events was developed.Results A mathematical model was created for computing the development of a composite endpoint. In this model, the biomarkers NT-proBNP, Ptx-3 and, to a lesser extent, ST2 demonstrated their prognostic significance in diagnosis of CVC with a sensitivity of 78.79 % and specificity of 86.67 % (area under the curve, AUC 0.73).Conclusion In patients with remote MI, the biomarkers NT-proBNP, ST2, and Ptx-3 improve prediction of CVC.


Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics.
Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68+ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.


[Association of single nucleotide polymorphism of vitamin D receptor gene start codon and the susceptibility to prostate cancer in the Han nationality in Hubei area].
To investigate single nucleotide polymorphism of vitamin D receptor (VDR) gene start codon in the Han nationality in Hubei area and its relationship to the susceptibility to prostate cancer (PCa), and to study the possible mechanism for PCa. The VDR genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 80 patients with PCa and 96 normal male controls from the Han nationality in Hubei area, using endonuclease Fok I. Direct sequencing was done in part of the PCR products. The frequency distribution of Fok I alleles in this cohort all followed the Hardy-Weinberg equilibrium. The distribution of genotypes and alleles had no significant difference between PCa patients and normal male controls( P > 0.05). The results indicated no significant relationship between Fok I polymorphism of VDR gene start codon and PCa in the Han nationality in Hubei area.