Confidence intervals for the mean of sound exposure levels.
This text transposes standard statistical estimators of the mean and its confidence intervals to the field of occupational noise exposure, assuming that the samples are independent and lognormally distributed. The hypothesis of lognormality is applied to the values of A-weighted sound exposure as defined in ISO 1999 and expressed in Pa(2).h, which is equivalent to the currently accepted hypothesis of normality applied to the values of equivalent continuous A-weighted sound pressure level L(Aeq,T) expressed in dB(A). By expressing the initial data and results in dB(A), the text provides an unbiased estimator of the mean sound exposure level and tables of confidence intervals according to the sample size n and the standard deviation S(L) of the L(Aeq,T) measured values. The values of the following confidence intervals are given: exact one-sided upper and lower 95 and 97.5% confidence intervals and exact two-sided symmetrical 95% confidence interval. These results are compared with the approximate two-sided symmetrical 95% confidence interval proposed in standard, ISO 9612. This comparison demonstrates that the use of the approximate confidence interval can markedly underestimate the upper limit of the confidence interval when n is small and if S(L) is above 3 dB(A).


Cutaneous T cell lymphoma: characterization by monoclonal antibodies.
Monoclonal antibodies to human T cells permit the characterization of the surface phenotype of cutaneous T cell lymphoma (CTCL). The majority of CTCL cells are reactive with OKT1 and OKT3 monoclonals, which identify peripheral T cells and mature thymocytes. The neoplastic cells also react with OKT4, which recognizes the inducer T cell subset; they are, however, unreactive with OKT5 monoclonal, which identifies cytotoxic/suppressor T cell subsets. These data are in agreement with previous functional studies demonstrating that CTCL is a neoplasm of inducer (helper) T cells.


Influence of Acute Antipsychotic Treatment on Cardiorespiratory Coupling and Heart Rate Variability.
A major contributing factor associated with increased cardiac mortality in patients with schizophrenia (SCZ) seems to be a dysfunction of the autonomic nervous system (ANS). The link between ANS dysfunction and SCZ is multifactorial, but some reports suggest that the use of antipsychotics could be implicated. This case illustrates the time course of autonomic improvement in response to antipsychotic treatment in an inpatient with SCZ in acute psychosis. To this end, we documented markers of autonomic function during hospitalization. Heart rate variability (HRV; cardiac autonomic modulation) analysis showed an increased variability over time (from Day 1 to Day 3), with strongest reaction at Day 3. The respiration analysis showed an increased respiratory variability over time (from Day 1 to Day 3) suggesting improved autonomic modulation in response to the pharmacotherapy. Cardiorespiratory coupling (CRC; surrogate of cardiorespiratory synchrony and cardiovagal modulation) showed an increasing influence of heart rate on respiration and increased from Day 1 to Day 3. The concurrent improvement of psychosis and autonomic function in response to antipsychotic treatment in this patient suggest a potential cardio protective role of antipsychotics in the acute setting. Prospective trials aimed at examining the cardiovascular implications of acute psychosis treatment in patients with schizophrenia are warranted.


Recent perspectives of management of breast cancer metastasis - an update.
Breast cancer is the leading cause of cancer related deaths in women and one of the most common cancers globally. The major obstacle in the management of breast cancer, especially at advanced stages, is metastasis. Metastasis in the advanced stages of breast cancer could decrease survival to approximately 5 years. The reasons could include lack of targeted receptors or chemotherapeutic agents for the management of advanced-stage breast cancer metastasis. The new emerging avenues for the management of this deadly pathological state include local manipulations like radiofrequency ablation (RFA), microwave thermotherapy, cryosurgery (cryotherapy), chemoembolization, radioembolization, breast surgery, or metastasectomy. Few single-institution reports showed improved survival in selected patients like those with oligometastatic stage IV breast cancer. The present review article focused on these emerging new multimodality treatment approaches for a possible efficient management.


Oral contraceptives as substrates and inhibitors for human cytosolic SULTs.
Cytosolic sulfotransferases (SULTs) in mammals are involved in the biotransformation and homeostasis of various endogenous and xenobiotic compounds. The current study aimed to examine the sulfation of contraceptive compounds by various human cytosolic SULTs and to investigate the inhibitory effects and mode of action of these compounds on the sulfation of 17beta-estradiol, a major endogenous estrogen. A systematic study using all eleven known human cytosolic SULTs revealed the differential substrate specificity of these enzymes for the eight representative contraceptive compounds and two endogenous estrogens (estrone and 17beta-estradiol) tested as substrates. Activity data showed that SULT1A1 displayed the strongest activity toward 17alpha-ethynylestradiol. Kinetic studies revealed that the V (max) value of the sulfation of 17alpha-ethynylestradiol by SULT1A1 was 1.64 times that of the sulfation of 17beta-estradiol, while the K (m) values were almost equal for the two compounds. The inhibitory effects of three contraceptive compounds on the sulfation of 17beta-estradiol by SULT1A1 were examined. IC(50) values determined were 0.193, 1.84, and 2.98 mM, respectively, for 19-norethindrone acetate, ethynodiol diacetate and mifepristone. Kinetic analyses indicated that the mechanism underlying the inhibition by these contraceptives is of a mixed noncompetitive type. Metabolic labeling experiments confirmed the sulfation of contraceptive compounds and the release of their sulfated derivatives by HepG2 human hepatoma cells. Collectively, the results obtained suggest a role of sulfation in the metabolism of contraceptive compounds in vivo. Moreover, in view of their inhibitory effects on the sulfation of 17beta-estradiol, these compounds may potentially act to disrupt the homeostasis of endogenous estrogens.


Metabolic Profiling of Water-Soluble Compounds from the Extracts of Dark Septate Endophytic Fungi (DSE) Isolated from Scots Pine (Pinus sylvestris L.) Seedlings Using UPLC-Orbitrap-MS.
Endophytes are microorganisms living inside plant hosts and are known to be beneficial for the host plant vitality. In this study, we isolated three endophytic fungus species from the roots of Scots pine seedlings growing on Finnish drained peatland setting. The isolated fungi belonged to dark septate endophytes (DSE). The metabolic profiles of the hot water extracts of the fungi were investigated using Ultrahigh Performance Liquid Chromatography with Diode Array Detection and Electron Spray Ionization source Mass Spectrometry with Orbitrap analyzer (UPLC-DAD-ESI-MS-Orbitrap). Out of 318 metabolites, we were able to identify 220, of which a majority was amino acids and peptides. Additionally, opine amino acids, amino acid quinones, Amadori compounds, cholines, nucleobases, nucleosides, nucleotides, siderophores, sugars, sugar alcohols and disaccharides were found, as well as other previously reported metabolites from plants or endophytes. Some differences of the metabolic profiles, regarding the amount and identity of the found metabolites, were observed even though the fungi were isolated from the same host. Many of the discovered metabolites have been described possessing biological activities and properties, which may make a favorable contribution to the host plant nutrient availability or abiotic and biotic stress tolerance.


Production by Aeromonas of common enterobacterial antigen and its possible taxonomic significance.
In a study of production of the common enterobacterial antigen (CA) by members of the Aeromonas group, ten strains of A. shigelloides, nine strains of A. hydrophila, and nine strains of A. salmonicida were used. Passive hemagglutination and hemolysis tests as well as the hemagglutination-inhibition procedure revealed that all strains of A. shigelloides, in contrast to the strains of the other two species, produce this antigenic determinant. The antigen of A. shigelloides was demonstrated even when the supernatant fluids of agar-grown cultures were used in a dilution of 1:1,000, whereas 10-times concentrated supernatant fluids obtained from the other two species were negative. Supernatant liquids of cultures of A. shigelloides failed to induce a significant CA immune response in rabbits; nonetheless, the animals were primed immunologically and responded with prompt production of CA antibodies in significant titers to a booster injection of a subeffective dose of CA obtained from Salmonella typhimurium. Strains of A. hydrophila and A. salmonicida neither induced CA antibody formation nor primed the animals. It is concluded that of the three species of the Aeromonas group only A. shigelloides, which may produce O antigen cross-reacting with Shigella sonnei and which has been isolated from patients with dysentery or gastroenteritis, produces CA. Production of this antigen, therefore, may help to characterize microorganisms belonging or related to the family Enterobacteriaceae.


In vitro pharmacological inhibition of human vascular smooth muscle cell proliferation for the prevention of hemodialysis vascular access stenosis.
Vascular access for chronic hemodialysis often fails as a result of stenosis caused primarily by the proliferation of vascular smooth muscle cells (VSMC). Various drugs have been shown to inhibit the proliferation of VSMC under different conditions. In this study, we compared the inhibitory effect of ten drugs on the proliferation of human aortic smooth muscle cells (SMC) in culture. Quiescent cells were cultured in the presence of growth factors, fetal bovine serum and incremental concentrations of the test drug. Cell proliferation was assessed by the MTT reduction assay. Aspirin, enalaprilat, heparin, hydroxyurea, indomethacin and tirofiban were ineffective. While dipyridamole, paclitaxel, tranilast and verapamil inhibited cell proliferation, the concentrations required were significantly higher than the clinical plasma levels achieved after systemic administration. Local delivery of these drugs to the target site may therefore be a more effective and appropriate strategy for the prevention of hemodialysis vascular access stenosis.


Recovery of a bundle of bones leading to unveiling of a murder mystery.
A bundle of bones, packed in a gunny bag, was detected by the villagers in a jungle situated in Bankura, West Bengal. After thorough autopsy, it revealed that the bones belonged to a male person aged 25 +/- 2 years of stature 167.5 +/- 5 cm. It also revealed that the person was a chronic smoker and his cause of death was head injury, probably homicidal in nature. Subsequent investigation by police unveiled a gruesome incidence of killing a man by his wife and her paramour.


Food sensitivity in the dog: a quantitative study.
Over a period of one year, 251 dogs were presented to a UK-based dermatology referral clinic. Eighty-five of these were either diagnosed as having symptoms compatible with atopy (58 dogs), or suffered from chronic otitis or recurrent pyoderma. All 85 were placed on a carefully restricted diet for eight to nine weeks in an attempt to establish whether the symptoms were due to food sensitivity. In total, 19 were shown to have food sensitivity, representing 7.6 per cent of all dogs presented to the clinic, and one-third (32.7 per cent) of those dogs with signs compatible with a diagnosis of atopy. In five dogs with proven food sensitivity, otitis was the principal clinical sign and, in two others, recurrent pyoderma. In the population studied, labradors appeared to be predisposed to the condition. Improvement was monitored by asking owners to assess their dog's symptoms on an ordinal scale of pruritus. In those cases in which food sensitivity was confirmed, significant reduction in pruritus occurred. Most of these could be maintained long term on a commercial restricted-component diet. Particular effort was made to ensure owner compliance with the diet trials, using an explanation and model based upon a Venn diagram showing assumed links between atopy and several 'flare factors'. It was found that this approach significantly enhanced client understanding and cooperation. It is concluded that a careful approach, monitored by active clinical audit, will help to establish the true incidence of food sensitivity.


Interpretation of sex hormone-binding globulin levels in thyroid disorders.
Sex hormone-binding globulin (SHBG) levels were followed in three groups of female subjects to evaluate interrelationships between its levels and parameters characterizing thyroid function. In the first part of the study the data from 201 patients with thyroid and other endocrine dysfunctions were grouped according to SHBG or basic laboratory parameters of thyroid function (thyrotropin, free thyroxine). Particular attention was paid to the presence of antithyroid antibodies (against thyroglobulin or thyroid peroxidase). Analysis of covariance revealed that SHBG changes were significant only in hyperthyroidism, and were not influenced by the presence of antibodies. Age was a minor factor influencing SHBG levels, in contrast to thyroid status. In a well-defined group of 16 females with severe hypothyroidism after total thyroidectomy because of thyroid cancer the low SHBG levels increased significantly to physiologic values after reaching normal thyroid function, irrespective of contraceptive use. In the final part of the study SHBG levels were correlated with the basic laboratory data, reflecting thyroid function in a sample of normal female population (129 subjects) screened for iodine deficiency in one region of the Czech Republic. After adjustment for age, the only significant positive correlation was between SHBG and free triiodothyronine.


Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells.
Angiotensin-II (AT-II), which is produced mainly by the renin-angiotensin system (RAS), has been shown to stimulate neovascularization. AT-II induces vascular endothelial growth factor (VEGF), which plays a pivotal role in tumor angiogenesis. The role of AT-II, however, in VEGF-mediated tumor development has not yet been elucidated. We examined the effect of RAS inhibition by angiotensin-I converting enzyme (ACE) inhibitor on VEGF-mediated tumor development and angiogenesis in a murine experimental model using a retroviral tetracycline-regulated (Retro-Tet) gene expression system. This system allows VEGF gene expression to be manipulated in vivo by providing tetracycline in the drinking water. In an allograft study, the ACE inhibitor, perindopril (PE) significantly attenuated VEGF-mediated tumor development accompanying the suppression of neovascularization in the tumor at a clinically comparable low dose. In vitro study showed that perindoprilat, which is an active form of PE, inhibited VEGF-induced endothelial cell migration. These results suggested that RAS played an important role in VEGF-mediated tumor development and angiogenesis.


Isolated Neutropenia Due to Immune Checkpoint Inhibitors.
In this article, we explore the correlation between immune checkpoint inhibitors (ICIs) and neutropenia. Immune checkpoint inhibitors have revolutionized cancer treatment and management by maximizing the innate abilities of the immune system. However, this therapeutic potential is accompanied by a range of immune-related adverse effects (irAEs), including neutropenia, which is a rare but potentially life-threatening side effect of this mode of cancer treatment. Through an in-depth analysis of various case reports, we have compiled a detailed table summarizing the occurrences of neutropenia associated with different ICIs, the grades of neutropenia, treatments used, and patient outcomes. Management of neutropenia must include an approach based on early diagnosis of the condition and a treatment based on its severity. This review discusses different therapeutic interventions, ranging from the administration of corticosteroids and intravenous immunoglobulin (IVIG) to the use of granulocyte colony-stimulating factor (filgrastim) and, in very severe cases, a stem cell transplant. We have also enlisted salient side effects caused by these interventions. Our findings emphasize that while neutropenia is a relatively rare adverse effect of ICIs, its severity necessitates increased awareness among healthcare professionals. As ICIs continue to be seen as an integral component of cancer therapy, a comprehensive understanding of neutropenia as a side effect and its management is critical for optimizing patient outcomes. A crucial purpose of this review is to highlight the need to achieve a balance between acquiring the therapeutic benefits of various treatment strategies for irAEs and considering their potential side effects, especially with the use of steroids. Achieving this equilibrium is very important in optimizing patient care during immunotherapy, as these irAE management options can both mitigate the neutropenia triggered by ICIs and potentially give rise to secondary complications. Therefore, a careful assessment of the risks and benefits associated with each treatment approach is essential in tailoring irAE management.


[Health status of delinquent male youths].
Objective. To assess the health status of delinquent male youths at the time of their admission to a juvenile correctional center.Design. Cross-sectional descriptive study over a 6-year period (1995-2000). Setting. Health primary care. Juvenile correctional center in Zaragoza, Spain. Participants. Two hundred forty male adolescents were admitted during the study period. Mean age was 15 years (SD, 1.3) (range, 13-17 years). Measurements and main results. Health status via medical history and physical examination was assessed according to standard protocols and individualized complementary laboratory examinations were performed. Most frequent health problems were smoking habit (97.1%), drug/alcohol abuse (54.1%), odontologic (40%), psychopathologic disorders (17.1%), incomplete immunization status (16.6%), growth and nutritional disorders (14.5%) growth delay (5.8%), malnutrition (3.3%), overweight (2.1%), obesity (3.3%) , infectious diseases associated with intravenous drug use and/or risk sexual behaviors (10.4%) hepatitis C (4.6%), hepatitis B (2.9%), AIDS (2.1%), syphilis (0.8%) , dermatological (10%), opthalmological (7.5%), and respiratory (5%). Less prevalent health problems were orthopedic (3.3%), anemia (3.3%), otic (2.5%), cardiovascular (2.5%), and intestinal parasitism (1.6%). Conclusions. Early intervention during the stay into juvenile correctional center regarding their physical health and especially their mental health, from the sanitary and educative viewpoint, presents a unique opportunity to solve the basic health needs of these high-risk adolescents.


Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats.
We aimed to compare the effects of chronic and acute administration of structurally different antihypertensives, diuretics - indapamide and hydrochlorothiazide, ACE inhibitor - captopril and indapamide+captopril combination on endothelium-dependent relaxation of femoral artery isolated from nitric oxide (NO)-deficient rats. In the chronic experiment, femoral artery was isolated from Wistar rats receiving L-NAME (40 mg/kg/day) solely or with indapamide (1 mg/kg/day), hydrochlorothiazide (10 mg/kg/day), captopril (10 mg/kg/day), and indapamide+captopril combination for seven weeks. In the acute in vitro experiment, the incubation medium with femoral artery isolated from L-NAME-hypertensive rats was supplemented with investigated antihypertensives in the same concentration 10(-4) mol/l. Interestingly, chronic L-NAME treatment did not cause a reduction of vasorelaxation. Indapamide+captopril elevated relaxation above the control level and completely prevented blood pressure increase induced by L-NAME. Acute incubation with captopril only or indapamide+captopril improved relaxation of femoral artery isolated from L-NAME-hypertensive rats, while the incubation with all antihypertensives increased vasorelaxation of femoral artery isolated from control Wistar rats. In conclusion, NO might be involved in the indapamide- and hydrochlorothiazide-induced improvement of vasorelaxation, while different vasorelaxing factors (prostacyclin, EDHF) contribute to the captopril-induced improvement of vasorelaxation. During the chronic treatment additive and synergic effects of indapamide and captopril may contribute to the prevention of hypertension and increase of vasorelaxation.


Beta blocker therapy, decompensated heart failure, and inotropic interactions: current perspectives.
Beta blockers are a fundamental treatment in chronic heart failure (HF), yet concern and disagreement regarding their role in the treatment of decompensated HF and during hospitalization are common in clinical practice. This review summarizes the literature on various aspects of beta blocker treatment during acute and chronic decompensated HF. In recent years evidence has accumulated concerning the efficacy and tolerability of beta blockers in decompensated HF. Clinical analyses show that withdrawal of chronic beta blockade should be avoided when possible during hospitalization and that beta blockertherapy be initiated as soon as hemodynamic stability and a euvolemic state are achieved. This strategy may increase adherence to beta blockers after discharge and lower rehospitalization and mortality rates. We also discuss the various positive inotrope regimens (phosphodiesterase inhibitors, levosimendan, dobutamine) and their interactions with beta blockers in decompensated HF.


The blink reflex test does not show abnormalities in a large group of patients with chronic migraine.
The blink reflex - a simple, non-invasive and inexpensive test - may be indicative of lesions or dysfunctions of the brainstem, and particularly assesses the trigeminal-facial arch. Results from alterations of the blink reflex in patients with headaches have provided controversial data. Registration of the waves R1 and R2 (ipsilateral to the stimulus) and R2c (contralateral to the stimulus) by electroneuromyography. A large number of controls (n=160) and patients with chronic migraine (n=160) were studied. No significant differences were observed between the two groups. It is possible that this relatively simple and primitive reflex is not affected unless there is significant damage to the brainstem.


A comparison of neon versus helium ion beam induced deposition via Monte Carlo simulations.
The ion beam induced nanoscale synthesis of PtCx (where x ∼ 5) using the trimethyl (methylcyclopentadienyl)platinum(IV) (MeCpPt(IV)Me3) precursor is investigated by performing Monte Carlo simulations of helium and neon ions. The helium beam leads to more lateral growth relative to the neon beam because of its larger interaction volume. The lateral growth of the nanopillars is dominated by molecules deposited via secondary electrons in both the simulations. Notably, the helium pillars are dominated by SE-I electrons whereas the neon pillars are dominated by SE-II electrons. Using a low precursor residence time of 70 μs, resulting in an equilibrium coverage of ∼4%, the neon simulation has a lower deposition efficiency (3.5%) compared to that of the helium simulation (6.5%). At larger residence time (10 ms) and consequently larger equilibrium coverage (85%) the deposition efficiencies of helium and neon increased to 49% and 21%, respectively; which is dominated by increased lateral growth rates leading to broader pillars. The nanoscale growth is further studied by varying the ion beam diameter at 10 ms precursor residence time. The study shows that total SE yield decreases with increasing beam diameters for both the ion types. However, helium has the larger SE yield as compared to that of neon in both the low and high precursor residence time, and thus pillars are wider in all the simulations studied.


Late relapse of Hodgkin's lymphoma - is it different in clinical characteristics and outcome?
The purpose of this study was to evaluate the clinical characteristics, prognostic factors, therapy and outcomes of patients with very late relapse (>5 years) of Hodgkin's lymphoma (HL). We retrospectively reviewed the database of all relapsed patients with HL treated between 1999 and 2009 and compared the clinical characteristics and survival of patients who relapsed before and after 5 years of follow up. Among the group of 102 patients with relapsed HL 16 (15.68%) patients had very late relapse of disease. Median time to very late relapse was 86 months (range 61- 199). On relapse most of these patients (11; 68.5%) were in advanced clinical stage. Eleven (68.75%) patients with very late relapse were treated with high dose chemotherapy and autologous stem cell transplantation (ASCT). Second complete response was achieved in 13 (81.25%) patients. At a median follow up of 4.5 years after therapy, 13 (81.25%) patients are still alive (10 without disease and 3 with disease), while 3 patients died (2 from HL, and 1 from brain tumor). There was no significant difference between patients with very late relapse and patients who relapse earlier in terms of initial clinical parameters. Median overall survival of patients with very late relapse was significantly longer than in patients with earlier relapse (p=0.001), but survival calculated from the time оf relapse was not significantly different between these two groups of patients (p=0.83). An open question that remains is whether high dose therapy and ASCT is necessary in most patients with very late relapse of disease. Individualization of therapy in patients with very late relapse of HL is mandatory, tailored on risk factors and comorbidities.


Targeting cancer stem cells by using the nanoparticles.
Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-β, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs.


Muscle activation during cycling at different cadences: effect of maximal strength capacity.
The purpose of this study was to examine the influence of maximal strength capacity on muscle activation, during cycling, at three selected cadences: a low cadence (50 rpm), a high cadence (110 rpm) and the freely chosen cadence (FCC). Two groups of trained cyclists were selected on the basis of the different maximal isokinetic voluntary contraction values (MVCi) of their lower extremity muscles as follow: F(min) (lower MVCi group) and F(max) (higher MVCi group). All subjects performed three 4-min cycling exercises at a power output corresponding to 80% of the ventilatory threshold under the three cadences. Neuromuscular activity of vastus lateralis (VL), rectus femoris (RF) and biceps femoris (BF) was studied quantitatively (integrated electromyography, IEMG) and qualitatively (timing of muscle bursts during crank cycle). Cadence effects were observed on the EMG activity of VL muscle and on the burst onset of the BF, VL and RF muscles. A greater normalized EMG activity of VL muscle was observed for the F(min) group than the F(max) group at all cadences (respectively F(min) vs. F(max) at 50 rpm: 17+/-5% vs. 38+/-6%, FCC: 22+/-7% vs. 44+/-5% and 110 rpm: 21+/-6% vs. 45+/-6%). At FCC and 110 rpm, the burst onset of BF and RF muscles of the F(max) group started earlier in the crank cycle than the F(min) group These results indicate that in addition to the cadence, the maximal strength capacity influences the lower extremity muscular activity during cycling.


Cervical cancer risk factors and predictors of cervical dysplasia among women in south-west Nigeria.
This study identified predictors of cervical dysplasia and assessed the prevalence of risk factors for cervical cancer among women of different socioeconomic classes in Ogun State, Nigeria. In a two-phase study, self-reported information on cervical cancer awareness, risk factors and cervical cancer screening practices was obtained from 278 randomly selected working women. A random subset was screened for dysplasia using visual inspection with acetic acid (VIA). Of the 278 women, 126 (45.3%) were semi-skilled while 152 (54.7%) were skilled and professional workers. Median age at first sexual intercourse was 19 years (range 13-29) and lower than the median age at first marriage (25 years). Gonorrhoea and genital warts were the commonest reported sexually transmitted infections. Only 12.2% of the women used male condoms as their primary method of birth control and 4.7% of the women had ever had a Papanicolaou smear, a practice that was significantly higher among the professional/skilled compared with semi-skilled workers (P = 0.031). Of the 125 screened, 20 (16%) had positive VIA. Young age at first sex (< or = 17 years) (OR = 3.7 (95% CI, 1.07-12.8)) and early first marriage (< 25 years) (3.3 (1.00-10.9)) were associated with a positive VIA. Women with lower parity (0-3) had borderline significantly increased risk of having a positive VIA (3.1 (0.9-10.6)). Women currently over 34 years and those without a history of sexually transmitted infections had lower risk of positive VIA (P > 0.05). Acceptable screening services and cervical cancer awareness campaigns that address modifiable risk factors are urgently needed in this community.


Urban biosphere and society: partnership of cities--introduction.
This paper reports on issues of conservation, equitable use of resources, and the improvement of quality of life for all persons living in densely populated cites. Case studies are presented that examine UNESCO's concept of biosphere reserve, demonstrating the elasticity and usefulness of the concept as a way to promote global sustainability and governance on local, regional and global levels.


Frequency dependence of power and its implications for contractile function of muscle fibers from the digital flexors of horses.
The digital flexors of horses must produce high force to support the body weight during running, and a need for these muscles to generate power is likely limited during locomotion over level ground. Measurements of power output from horse muscle fibers close to physiological temperatures, and when cyclic strain is imposed, will help to better understand the in vivo performance of the muscles as power absorbers and generators. Skinned fibers from the deep (DDF) and superficial (SDF) digital flexors, and the soleus (SOL) underwent sinusoidal oscillations in length over a range of frequencies (0.5-16 Hz) and strain amplitudes (0.01-0.06) under maximum activation (pCa 5) at 30°C. Results were analyzed using both workloop and Nyquist plot analyses to determine the ability of the fibers to absorb or generate power and the frequency dependence of those abilities. Power absorption was dominant at most cycling frequencies and strain amplitudes in fibers from all three muscles. However, small amounts of power were generated (0.002-0.05 Wkg(-1)) at 0.01 strain by all three muscles at relatively slow cycling frequencies: DDF (4-7 Hz), SDF (4-5 Hz) and SOL (0.5-1 Hz). Nyquist analysis, reflecting the influence of cross-bridge kinetics on power generation, corroborated these results. The similar capacity for power generation by DDF and SDF versus lower for SOL, and the faster frequency at which this power was realized in DDF and SDF fibers, are largely explained by the fast myosin heavy chain isoform content in each muscle. Contractile function of DDF and SDF as power absorbers and generators, respectively, during locomotion may therefore be more dependent on their fiber architectural arrangement than on the physiological properties of their muscle fibers.


U.S. clinical studies of the treatment of anemia with fluosol-DA 20%.
This article describes the progress of clinical studies of the perfluorochemical (PFC) emulsion Fluosol-DA 20% in the United States. To date, two studies have been completed and one is in progress. All three studies have been restricted to the treatment of acute anemia in patients who refused blood transfusions on religious grounds, i.e., Jehovah's Witnesses. The first protocol, referred to as the "Humanitarian Protocol" (no. 79006), was initiated in November 1979. Jehovah's Witness patients who were considered to have a lethal degree of anemia were treated with Fluosol to supplement oxygen transport. Collection of specific data was not mandated in this protocol. Six patients were treated under this protocol until it was replaced by the "Medical Use Protocol" (no. 79007). In this second study, hemodynamic and oxygen transport data were collected while patients breathed room air and 100% inspired oxygen before and after a Fluosol infusion. Seven patients were treated under this protocol and it was concluded that the PFC was transporting the expected amount of oxygen based on its known oxygen solubility. This increased oxygen transport by the PFC resulted in increased oxygen consumption and arterial and mixed venous blood oxygenation. Two of the seven patients had adverse reactions to a 0.5-ml test dose of Fluosol, manifested by an increase in pulmonary artery systolic pressure. The third and current anemia protocol as of this writing is a randomized controlled study with data collection similar to the Medical Use Protocol.(ABSTRACT TRUNCATED AT 250 WORDS)


Cost-effectiveness of expanded hepatitis A vaccination among adults with diagnosed HIV, United States.
Hepatitis A virus can cause severe and prolonged illness in persons with HIV (PWH). In July 2020, the Advisory Committee on Immunization Practices (ACIP) expanded its recommendation for hepatitis A vaccination to include all PWH aged ≥1 year. We used a decision analytic model to estimate the value of vaccinating a cohort of adult PWH aged ≥20 years with diagnosed HIV in the United States using a limited societal perspective. The model compared 3 scenarios over an analytic horizon of 1 year: no vaccination, current vaccine coverage, and full vaccination. We incorporated the direct medical costs and nonmedical costs (i.e., public health costs and productivity loss). We estimated the total number of infections averted, cost to vaccinate, and incremental cost per case averted. Full implementation of the ACIP recommendation resulted in 775 to 812 fewer adult cases of hepatitis A in 1 year compared with the observed vaccination coverage. The incremental cost-effectiveness ratio for the full vaccination scenario was $48,000 for the 2-dose single-antigen hepatitis A vaccine and $130,000 for the 3-dose combination hepatitis A and hepatitis B vaccine per case averted, compared with the observed vaccination scenario. Depending on type of vaccine, full hepatitis A vaccination of PWH could lead to ≥80% reduction in the number of cases and $48,000 to $130,000 in additional cost per case averted. Data on hepatitis A health outcomes and costs specific to PWH are needed to better understand the longer-term costs and benefits of the 2020 ACIP recommendation.


Inducers and inhibitors of biomineralization: lessons from pathological calcification.
Ectopic calcification is a common response to soft tissue injury and systemic mineral imbalance and can lead to devastating clinical consequences when present in joints, heart valves and blood vessels. We have hypothesized that mineralization of matrices in any tissue is normally controlled by a balance between procalcific and anticalcific regulatory proteins such that abnormal deposition of apatite is avoided. Alterations in this balance induced by injury, disease or genetic deficiency are postulated to induce ectopic mineral deposition. Over the past several years, we have developed in vitro and in vivo models of ectopic calcification to investigate potential inducers and inhibitors of this process. Osteopontin, a secreted phosphoprotein, has emerged as a major inhibitor of ectopic mineralization. Osteopontin is a potent inhibitor of vascular cell calcification in vitro and mice lacking osteopontin are highly susceptible to ectopic calcification. Furthermore, osteopontin treatment of biomaterials protected against ectopic mineralization. Our studies indicate that in addition to inhibiting apatite crystal initiation and growth, osteopontin stimulates resorption of ectopic calcification via peripheral macrophages and giant cells. In contrast, inorganic phosphate has emerged as a major inducer of mineralization in these systems. Elevated inorganic phosphate (Pi) was shown to induce smooth muscle cell matrix calcification with morphological properties similar to those observed in calcified human valves and atherosclerotic plaques. Furthermore, mineralization induced by inorganic phosphate was dependent on the activity of the sodium-dependent phosphate cotransporter, Pit-1. These studies implicate controlled, transcellular transport of Pi as a major requirement for matrix calcification.


Noncovalent Liquid Phase Functionalization of 2H-WS2 with PDI: An Energy Conversion Platform with Long-Lived Charge Separation.
Transition metal dichalcogenides are attractive 2D materials in the context of solar energy conversion. Previous investigations have focused predominantly on the properties of these systems. The realization of noncovalent hybrids with, for example, complementary electroactive materials remains underexplored to this date for exfoliated WS2. In this contribution, we explore WS2 by means of exfoliation and integration together with visible light-absorbing and electron-accepting perylene diimides into versatile electron-donor acceptor hybrids. Important is the distinct electron-donating feature of WS2. Detailed spectroscopic investigations of WS2-PDI confirm the electron donor/acceptor nature of the hybrid and indicate that green light photoexcitation leads to the formation of long-lived WS2•+-PDI•- charge-separated states.


Hepatotoxicity and nephrotoxicity in rats induced by carbon tetrachloride and the protective effects of Teucrium polium and vitamin C.
This work investigated the protective effects of Teucrium polium (T. polium) and vitamin C (Vit C) against carbon tetrachloride (CCl4) induced hepatotoxicity and nephrotoxicity in rats. T. polium reduced the Fer reduced antioxidant power (FRAP) (IC50 = 0.89 mg/ml) and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 0.049 µg/ml) than Vit C, FRAP (IC50 = 0.71 mg/ml) and DPPH (IC50 = 0.029 µg/ml). Male albino Wistar rats were divided into six groups: Group I was used as controls, Group II received CCl4 in olive oil (0.5 ml/kg) by gavage, Group III received CCl4 in olive oil (0.5 ml/kg) by gavage after 3 d of receiving T. polium (5 g/l), orally, Group IV received T. polium (5 g/l) alone, by gavage, for 7 d, Group V received CCl4 in olive oil (0.5 ml/kg) by gavage after 3 d of receiving Vit C (250 mg/kg) by gavage and Group VI received Vit C (250 mg/kg) alone by gavage. CCl4 showed an increase of serum hepatic and renal markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine. Moreover, we noted an increase of lipid peroxidations and a decrease in antioxidants enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) of CCl4 rats compared to controls. The pretreatment with (200 mg/kg) of T. polium and with Vit C (250 mg/kg) by gavage, for 7 d, displayed their ability to protect against oxidative damage and biochemical changes induced by CCl4. Our results were in accordance with histopathological observations.


Reversibly controlling preferential protein adsorption on bone implants by using an applied weak potential as a switch.
A facile method is needed to control the protein adsorption onto biomaterials, such as, bone implants. Herein we doped taurocholic acid (TCA), an amphiphilic biomolecule, into an array of 1D nano-architectured polypyrrole (NAPPy) on the implants. Doping TCA enabled the implant surface to show reversible wettability between 152° (superhydrophobic, switch-on state) and 55° (hydrophilic, switch-off state) in response to periodically switching two weak electrical potentials (+0.50 and -0.80 V as a switch-on and switch-off potential, respectively). The potential-switchable reversible wettability, arising from the potential-tunable orientation of the hydrophobic and hydrophilic face of TCA, led to potential-switchable preferential adsorption of proteins as well as cell adhesion and spreading. This potential-switchable strategy may open up a new avenue to control the biological activities on the implant surface.


Treatment of idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in most cases, and effective treatment is still lacking. This review examines the current status of treatment options and complexities in the management of patients with IPF. Although optimal therapy for IPF has not been identified, ongoing research efforts warrant reason for optimism. Current management of IPF includes not only judicious use of available pharmacological agents tailored to individual circumstances but also patient education through realistic assessment of prognosis, discussion of pros and cons of pharmacotherapy, early consideration of lung transplantation when applicable, treatment of complications, supportive care, and encouragement to participate in clinical trials.


Prenatal Diagnosis and Management of a Fetal Goiter Hypothyroidism due to Dyshormonogenesis.
Fetal goiter is a rare disorder not expected to be found during a healthy woman's pregnancy. It can be a prenatal manifestation of congenital hypothyroidism due to thyroid dyshormonogenesis and it can lead to serious perinatal complications. A vascularized fetal neck mass was detected at 29 weeks' gestation of a healthy primigravida. Magnetic resonance was suggestive of goiter causing airway deviation without polyhydramnios. Maternal thyroid function was normal and thyroid antibodies were negative. Two intra-amniotic levothyroxine infusions were performed at 32 and 33 weeks. Serial imaging control showed no progression of the mass. Elective caesarean section was performed at 38 weeks. The male newborn was admitted to the intensive care unit due to cardiorespiratory insufficiency with pulmonary hypertension. Hormonal assays revealed primary congenital hypothyroidism and ultrasonography confirmed diffuse goiter. Levothyroxine was started. Currently, he is 6 years old with adequate growth and normal psychomotor development. Genetic study found a heterozygous mutation in the TPO gene.


Adolescents with co-occurring substance use and mental conditions in a private managed care health plan: prevalence, patient characteristics, and treatment initiation and engagement.
This study examined the prevalence, patient characteristics, and treatment initiation and engagement of adolescents with co-occurring substance use (SU) and serious mental health (MH) diagnoses in a private, managed care health plan. We identified 2,005 adolescents aged 12-17, who received both SU and MH diagnoses within a 1-year window between 1/1/2000 and 12/31/2002; 57% were girls. Gender variations were found in diagnoses received and point of identification. Being dually diagnosed in specialty departments (rather than Primary Care and Emergency) and receiving both diagnoses within a shorter time period were associated with treatment initiation and engagement.


Dental plaque, gingival inflammation and tooth -discolouration with different commercial -formulations of 0.2% chlorhexidine rinse: a double-blind randomised controlled clinical trial.
To investigate the efficacy of various formulations of chlorhexidine 0.2% (CHX) in terms of plaque and gingival bleeding control compared to each other and to saline rinse (CTRL) over a 35-day rinsing period. Seventy subjects were randomly allocated to one of 4 groups rinsing twice daily for 35 days. The different groups used CHX 0.2% rinse with alcohol (CHX1) and without alcohol (CHX2), with an antidiscolouration system (CHX3) or saline rinse (CTRL). Clinical examinations to evaluate full-mouth plaque scores (FMPS) and periodontal parameters were performed at baseline, 7, 21 and 35 days. Tooth discolouration (TD) was measured at each time point using digital photographs and spectrophotometric analysis. At 35 days, CTRL showed the highest levels of plaque. The mean changes in FMPS from baseline were 69.8% ± 6.8 for CHX1, 57.5% ± 9.8 for CHX2, 43.7% ± 9.8 for CHX3 and 25.8% ± 7.7 for CTRL. Statistically significant differences were demonstrated between CHX1 and CHX3 (p = 0.02), CHX2 vs CHX3 (p ≤ 0.05) and CHX1/CHX2 vs CHX3 (p < 0.05). In contrast, CHX3 appeared more effective in reducing inflammatory indexes. TD increased over time in 60% to 70% of participants, although lighter staining was found in the CHX3 group. Greater FMPS reduction was observed in participants with staining vs without staining (26.0% ± 12.3, p = 0.04). Conventional CHX appeared more effective in terms of plaque reduction. Interestingly, the newest formulation showed a higher control of gingival inflammation. Staining was associated with lower plaque levels.


Expression of macrophage functions in hybrids of a myeloma cell line with inflammatory macrophages: evidence for negative control mechanisms in the expression of macrophage functions.
Mouse inflammatory macrophages from C57BL/6N mice were fused with BALB/c mouse-derived myeloma cells (the CANS series). The hybrids in the early period after cell fusion (8 weeks) showed no macrophage functions (chemotaxis, EA and EAC rosette-forming abilities, phagocytosis or lysozyme production). EA rosette-forming ability was observed when these hybrids were treated with trypsin, whereas other macrophage functions were not. After prolonged culture, the hybrids (12 clones of 13 randomly selected) showed all the macrophage functions along with chromosome loss. Myeloma cell functions (kappa light chain production) were found in the young hybrids soon after cell fusion but were absent in the aged hybrids. These results indicated that reexpression of macrophage properties, except for EA rosette-forming abilities, takes place after the loss of chromosomes or genes repressing the expression of macrophage functions.


Seasonal shifts in isoprenoid emission composition from three hyperdominant tree species in central Amazonia.
Volatile isoprenoids regulate plant performance and atmospheric processes, and Amazon forests comprise the dominant source to the global atmosphere. Still, there is a poor understanding of how isoprenoid emission capacities vary in response to ecophysiological and environmental controls in Amazonian ecosystems. We measured isoprenoid emission capacities of three Amazonian hyperdominant tree species - Protium hebetatum, Eschweilera grandiflora, Eschweilera coriacea - across seasons and along a topographic and edaphic environmental gradient in the central Amazon. From wet to dry season, both photosynthesis and isoprene emission capacities strongly declined, while emissions increased among the heavier isoprenoids: monoterpenes and sesquiterpenes. Plasticity across habitats was most evident in P. hebetatum, which emitted sesquiterpenes only in the dry season, at rates that significantly increased along the hydro-topographic gradient from white sands (shallow root water access) to uplands (deep water table). We suggest that emission composition shifts are part of a plastic response to increasing abiotic stress (e.g. heat and drought) and reduced photosynthetic supply of substrates for isoprenoid synthesis. Our comprehensive measurements suggest that more emphasis should be placed on other isoprenoids, besides isoprene, in the context of abiotic stress responses. Shifting emission compositions have implications for atmospheric responses because of the strong variation in reactivity among isoprenoid compounds.


Sustained decreased in coronary blood flow and excitation of cardiac sensory fibers following sympathetic stimulation.
The effect of electrical stimulation of the efferent cardiac sympathetic nerves on activity of afferent cardiac fibers in the sympathetic nerves and coronary hemodynamics of anesthetized dogs has been examined. During partial constriction of the coronary artery, a brief stimulation of the efferent cardiac sympathetic nerves resulted in sustained excitation of the afferent fibers and a sustained decrease in blood flow of the constricted artery which were associated with systolic bulge of the left ventricle and elevation of the ST segment of electrocardiogram. These changes were not produced without constriction. Pretreatment with phentolamine suppressed excitation of the afferent fibers, development of systolic bulge and elevation of the ST segment. Also, the decrease in coronary blood flow induced by stimulation was replaced by an increase after the administration of the agent. Propranolol suppressed excitation of the fibers, systolic bulge and elevation of the ST segment, but could not eliminate the decrease in blood flow. The results indicate that sympathetic stimulation caused a decrease in coronary blood flow through excitation of the alpha-adrenergic receptors while increasing cardiac work load and energy requirements through excitation of the beta-adrenergic receptors, leading to more severe myocardial ischemia and excitation of the afferent fibers.


Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis.
Excessive adrenergic signaling may be harmful in sepsis. Using β-blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting β-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome. After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables. Esmolol was infused for 11 (9-14) hours; the target heart rate (80-100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8-12] vs 14 [11-20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups. In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival.


Morphological studies of effector cell-microvessel interactions in adoptive immunotherapy in tumor-bearing animals.
Murine lymphokine-activated natural killer (A-NK) cells are able to migrate to and accumulate in tumor metastases. However, the exact migratory pattern is as yet unknown. In the present study, we have investigated the migration from the vasculature towards malignant tissues of various effector cells. Our results indicate that murine A-NK cells seem to be arrested for an extended period of time in the microvasculature and also, although infrequently, to adhere to the endothelial lining of larger vessels close to tumor tissues before extravasation. While murine T lymphokine-activated killer and rat A-NK cells accumulate significantly in the subendothelial areas of larger venules in normal tissues, no such accumulation is observed with respect to murine A-NK cells. Electron microscopy reveals that the murine A-NK cells undergo an extreme deformation during extravasation and tumor infiltration. Furthermore, the cells are shown to be in an activated stage probably facilitating their migration, and hence, the elimination of tumor cells.


Antibody Derived Peptides for Detection of Ebola Virus Glycoprotein.
Current Ebola virus (EBOV) detection methods are costly and impractical for epidemic scenarios. Different immune-based assays have been reported for the detection and quantification of Ebola virus (EBOV) proteins. In particular, several monoclonal antibodies (mAbs) have been described that bind the capsid glycoprotein (GP) of EBOV GP. However, the currently available platforms for the design and production of full-length mAbs are cumbersome and costly. The use of antibody fragments, rather than full-length antibodies, might represent a cost-effective alternative for the development of diagnostic and possibly even therapeutic alternatives for EBOV. We report the design and expression of three recombinant anti-GP mAb fragments in Escherichia coli cultures. These fragments contained the heavy and light variable portions of the three well-studied anti-GP full-length mAbs 13C6, 13F6, and KZ52, and are consequently named scFv-13C6, scFv-13F6, and Fab-KZ52, respectively. All three fragments exhibited specific anti-GP binding activity in ELISA experiments comparable to that of full-length anti-GP antibodies (i.e., the same order of magnitude) and they are easily and economically produced in bacterial cultures. Antibody fragments might represent a useful, effective, and low cost alternative to full-length antibodies in Ebola related capture and diagnostics applications.


Some effects of removal of external calcium on pig striated muscle.
Bundles of about 800 cells from the m. thyreopharyngicus of pigs were used to measure activation and inactivation during contracture by K+ depolarization. When [Ca2+] in the medium was lowered to less than 5 X 10(-10) M for 3 min (replacing Ca2+ by Mg2+) the activation occurred at the same [K+] in the medium as in normal solution (3 mM-Ca2+) but inactivation was shifted to lower external [K+]. The absolute value of this shift in terms of membrane potential is uncertain, because [K+] at the cell surface is unknown. Exposure for 4 min to Ca2+-free medium (Ca2+ being replaced by Mg2+) had no effect on contractility tested after a subsequent rest of 22-25 min in normal solution ( [Ca2+] = 2 mM). However, if the muscle underwent one maximal K+ contracture in Ca2+-free medium the response (tetanus or K+ contracture) after the same interval in normal solution was strongly reduced, although the membrane potential recovered fully. K+ contractures in normal solution could be repeated without loss of contractile force. A K+ contracture in Ca2+-free medium had very little effect on the response to caffeine, tested after 25 min in normal solution. It seems that Ca2+ is lost into Ca2+-free medium only during depolarization, from a site which is not accessible to Ca2+ from outside at the resting membrane potential, or from inside at any membrane potential. This site might be located inside the transverse-tubular membrane and, when loaded with Ca2+, might represent the positive group of the model of Chandler, Rakowski & Schneider ( 1976b ), the movement of which during depolarization activates and inactivates the Ca2+ release from the sarcoplasmic reticulum.


Placental nutrient transporters adapt during persistent maternal hypoglycaemia in rats.
Maternal malnutrition is associated with decreased nutrient transfer to the foetus, which may lead to foetal growth restriction, predisposing children to a variety of diseases. However, regulation of placental nutrient transfer during decreased nutrient availability is not fully understood. In the present study, the aim was to investigate changes in levels of placental nutrient transporters accompanying maternal hypoglycaemia following different durations and stages of gestation in rats. Maternal hypoglycaemia was induced by insulin-infusion throughout gestation until gestation day (GD)20 or until end of organogenesis (GD17), with sacrifice on GD17 or GD20. Protein levels of placental glucose transporters GLUT1 (45/55 kDa isotypes) and GLUT3, amino acid transporters SNAT1 and SNAT2, and insulin receptor (InsR) were assessed. On GD17, GLUT1-45, GLUT3, and SNAT1 levels were increased and InsR levels decreased versus controls. On GD20, following hypoglycaemia throughout gestation, GLUT3 levels were increased, GLUT1-55 showed the same trend. After cessation of hypoglycaemia at end of organogenesis, GLUT1-55, GLUT3, and InsR levels were increased versus controls, whereas SNAT1 levels were decreased. The increases in levels of placental nutrient transporters seen during maternal hypoglycaemia and hyperinsulinemia likely reflect an adaptive response to optimise foetal nutrient supply and development during limited availability of glucose.


Electronic spectroscopy of the Au(6p)-Kr complex.
We report electronic absorption spectra, recorded using one- and two-color resonance-enhanced multiphoton ionization spectroscopy, of the Au-Kr complex. The transition is localized on the gold atom, and corresponds to a 6p<--6s atomic excitation; we observe transitions to the D (2)Pi(1/2) and D (2)Pi(3/2) spin-orbit states. In addition, we report the results of ab initio calculations, which consider electronic states arising from the 6 (2)S, 5 (2)D, and 6 (2)P atomic energy levels of Au. Further, we also report an accurate value for the dissociation energy of the ground state of Au-Kr, based on basis set extrapolated RCCSD(T) calculations. The experimental results are discussed in the light of the theoretical ones.


Effect of bone-soft tissue friction on ultrasound axial shear strain elastography.
Bone-soft tissue friction is an important factor affecting several musculoskeletal disorders, frictional syndromes and the ability of a bone fracture to heal. However, this parameter is difficult to determine using non-invasive imaging modalities, especially in clinical settings. Ultrasound axial shear strain elastography is a non-invasive imaging modality that has been used in the recent past to estimate the bonding between different tissue layers. As most elastography methods, axial shear strain elastography is primarily used in soft tissues. More recently, this technique has been proposed to assess the bone-soft tissue interface. In this paper, we investigate the effect of a variation in bone-soft tissue friction coefficient in the resulting axial shear strain elastograms. Finite element poroelastic models of bone specimens exhibiting different bone-soft tissue friction coefficients were created and mechanically analyzed. These models were then imported to an ultrasound elastography simulation module to assess the presence of axial shear strain patterns. In vitro experiments were performed to corroborate selected simulation results. The results of this study show that the normalized axial shear strain estimated at the bone-soft tissue interface is statistically correlated to the bone-soft tissue coefficient of friction. This information may prove useful to better interpret ultrasound elastography results obtained in bone-related applications and, possibly, monitor bone healing.


Immature T lymphocytes in the peripheral blood of bone marrow transplant recipients.
Recipients of allogeneic bone marrow transplants are characterized by an immunodeficiency of varying intensity and duration. We have previously demonstrated the presence of in vivo activated suppressor T lymphocytes in immunodeficient patients with chronic graft-versus-host disease. To determine the basis of the immunodeficiency of transplant recipients early after transplantation, the lymphocytes of transplant recipients were analyzed phenotypically by E-rosette formation and staining with monoclonal antibodies (OKT-3, -6, and -8) and functionally by their blastogenic response to mitogens. Only 15% of transplant recipients' assays 0-3 months and 16% of assays 3-12 months following transplant were in the normal range. Transplant recipients during the first year after transplantation were characterized by an increased percentage (57%) of patients with a normal percentage of E-rosette-forming cells but reduced PHA responsiveness. In vitro coculture experiments demonstrated that their lack of PHA responsiveness was not due to the presence of in vivo activated suppressor cells or a decrease in mitogen-presenting cells. Staining with monoclonal antibodies revealed that the T lymphocytes from the majority of recipients at 0-3 months following transplantation contained a percentage of OKT8-positive cells greater than or equal to the percentage of OKT3-positive cells. This pattern (OKT8 greater than or equal to OKT3) was not found in the peripheral blood T lymphocytes of normal people but was found in 13 of 15 thymuses. Monoclonal staining with OKT6, a thymocyte-specific antibody, revealed positive staining of more than 10% of the peripheral blood leukocytes in the majority of recipients 0-3 months following transplantation, compared with only a few normals. We concluded that the circulating T lymphocytes of transplant recipients are phenotypically and functionally immature, and that their relative immaturity contributes to the transplant recipients' immunodeficiency.


Control of swelling of responsive nanogels by nanoconfinement.
The volume phase transition (VPT) behavior and the swelling properties of individual thermoresponsive poly(N-isopropylacrylamide) (PNIPAM)-based nanogels are investigated by in situ atomic force microscopy (AFM). Using a template-based synthesis method, cylindrical nanogels are synthesized for different polymerization times within nanopores (80 nm) of poly(ethylene terephthalate) (PET) track-etched membranes. The confinement conditions, characterized by the ratio Φ between the average chain length and the pore diameter, are varied between 0.35 and 0.8. After dissolving the membranes, the volume of individual nanogels composed of PNIPAM-g-PET diblock copolymers is numerically extracted from AFM images while varying the water temperature from 28 to 44 °C. From the measured volumes, the swelling of nanogels is investigated as a function of both the water temperature and the confinement conditions imposed during the synthesis. Contrary to the VPT, the maximum swelling of the nanogels is strongly affected by these confinement conditions. The volume of nanogels in the swollen state can reach 1.1 to 2.1 times their volume in the collapsed state for a ratio Φ of 0.8 and 0.5, respectively. These results open a new way to tune the swelling of nanogels, simply by adjusting the degree of confinement imposed during their synthesis within nanopores, which is particularly interesting for biomedical applications requiring a high degree of control over swelling properties, such as drug-delivery nanotools.


Theoretical perspectives on non-Born-Oppenheimer effects in chemistry.
The Born-Oppenheimer approximation, which assumes that the electrons respond instantaneously to the motion of the nuclei, breaks down for a wide range of chemical and biological processes. The rate constants of such nonadiabatic processes can be calculated using analytical theories, and the real-time nonequilibrium dynamics can be described using numerical atomistic simulations. The selection of an approach depends on the desired balance between accuracy and efficiency. The computational expense of generating potential energy surfaces on-the-fly often favours the use of approximate, robust and efficient methods such as trajectory surface hopping for large, complex systems. The development of formally exact non-Born-Oppenheimer methods and the exploration of well-defined approximations to such methods are critical for providing benchmarks and preparing for the next generation of faster computers. Thus, the parallel development of rigorous but computationally expensive methods and more approximate but computationally efficient methods is optimal. This Perspective briefly summarizes the available theoretical and computational non-Born-Oppenheimer methods and presents examples illustrating how analytical theories and nonadiabatic dynamics simulations can elucidate the fundamental principles of chemical and biological processes. These examples also highlight how theoretical calculations are able to guide the interpretation of experimental data and provide experimentally testable predictions for nonadiabatic processes. This article is part of the theme issue 'Chemistry without the Born-Oppenheimer approximation'.


Exercise is Medicine for Concussion.
Sport-related concussion (SRC) is a physiological brain injury that produces cerebral and systemic effects, including exercise intolerance. Exercise intolerance after concussion is believed to be the result of autonomic nervous system (ANS) dysfunction. Ventilation is inappropriately low for the level of exercise intensity, raising arterial carbon dioxide (PaCO2) levels. Elevated PaCO2 increases cerebral blood flow (CBF) out of proportion to exercise intensity, which is associated with symptoms that limit exercise performance. Thus, elevated exercise PaCO2 may signal incomplete recovery from SRC. This article reviews recent observational and experimental data and presents the evidence that subthreshold aerobic exercise normalizes the cerebrovascular physiological dysfunction and is "medicine" for patients with concussion and persistent postconcussive symptoms (PPCS). It discusses the systematic evaluation of exercise tolerance after concussion using the Buffalo Concussion Treadmill Test (BCTT) and reviews the utility of the Buffalo Concussion Bike Test (BCBT), the data from which are used to establish an individualized heart rate "dose" of subthreshold exercise to safely speed recovery, which also may work in the acute recovery phase after SRC with the potential to reduce the incidence of PPCS. Evaluation and treatment approaches based on the physiology of concussion suggest that exercise is medicine for concussion, potentially adding a new dimension to concussion care to help safely speed recovery and prevent PPCS in some patients.


68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105.
The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.


Expression of major histocompatibility complex class II but not of CD8 molecules by lectin-stimulated peripheral CD4+ T cells in LEC mutant rats.
LEC rats show a congenital maturational arrest from CD4+8+ to CD4+8- but not to CD4-8+ cells in the thymus. However, some CD4+ cells exist in peripheral lymph nodes. In normal F344 rats, a part of CD4+ T cells expressed CD8 molecules upon concanavaline A (Con A) stimulation. The percentage of CD4+8+ cells and the level of CD8 expression in F344 rat CD4+ cells were enhanced by the glucocorticoid hormone dexamethasone. In contrast, although LEC rat CD4+ cells induced DNA synthesis normally upon Con A stimulation, expression of CD8 was significantly reduced. Furthermore, addition of dexamethasone did not restore the inhibition of CD8 expression. However, LEC rat CD4+ cells could induce CD8 expression, when stimulated by T cell receptor (TCR) cross-linking with anti-TCR monoclonal antibody, suggesting that the TCR-mediated signal is normally transduced in LEC rat CD4+ cells. On the other hand, LEC rat CD4+ cells showed normal expression of major histocompatibility complex (MHC) class II antigens, when stimulated by either Con A or TCR cross-linking, indicating that signals for the induction of MHC class II expression are normal in LEC rat CD4+ cells. Activation of peripheral CD4+ cells has been reported to induce simultaneous expression of CD8 and MHC class II molecules in rats. However, our results using LEC rat CD4+ cells suggest that Con A-induced signaling pathways for CD8 and MHC class II expression can be separable.


Bilateral occipital calcification, epilepsy and coeliac disease: clinical and neuroimaging features of a new syndrome.
Twenty patients affected by bilateral occipital cortical-subcortical calcification (BOC) are described, 19 (95%) had epilepsy. In 8 of 16 cases studied, intestinal biopsy revealed coeliac disease. Fourteen patients had occipital partial epilepsy with a relatively benign outcome, while 4 patients were affected by a severe form of epilepsy, with very frequent, drug-resistant, generalised and partial seizures with mental deterioration. One patient had a single episode of convulsive status epilepticus at four months of age. The neurological examination was normal in all patients. CT showed flocculo-nodular, cortico-subcortical BOC, without enhancement and without lobar or hemispheric atrophy. MRI was normal. The clinical and neuroimaging features of these patients are different therefore from those with the Sturge-Weber Syndrome. The study confirms a high prevalence of coliac disease in patients with BOC, but the relationship between these two pathologies still needs to be clarified.


Impact of deeper groundwater depth on vegetation and soil in semi-arid region of eastern China.
Understanding the impact of deep groundwater depth on vegetation communities and soil in sand dunes with different underground water tables is essential for ecological restoration and the conservation of groundwater. Furthermore, this understanding is critical for determining the threshold value of groundwater depth that ensures the survival of vegetation. This paper was conducted in a semi-arid region in eastern China, and the effects of deep groundwater depth (6.25 m, 10.61 m, and 15.26 m) on vegetation communities and soil properties (0-200 cm) across three dune types (mobile, semi-fixed, and fixed dunes) were evaluated in a sand ecosystem in the Horqin Sandy Land. For vegetation community, variations in the same species are more significant at different groundwater depths. For soil properties, groundwater depth negatively influences soil moisture, total carbon, total nitrogen, available nitrogen, available phosphorus concentrations, and soil pH. Besides, groundwater depth also significantly affected organic carbon and available potassium concentrations. In addition, herb species were mainly distributed in areas with lower groundwater depth, yet arbor and shrub species were sparsely distributed in places with deeper groundwater depth. As arbor and shrub species are key drivers of ecosystem sustainability, the adaptation of these dominant species to increasing groundwater depth may alleviate the negative effects of increasing groundwater depth; however, restrictions on this adaptation were exceeded at deeper groundwater depth.


Temporal Reinforcement of Naloxone Training Results in Significant Retention of Anti-bias and Overdose-Response Knowledge.
The opioid epidemic is an increasingly severe problem affecting public health and leading to significant economic burdens on healthcare systems. Overdose reversal training and de-stigmatization efforts are common strategies used to combat this epidemic. Nevertheless, healthcare professionals report a lack of confidence in administering naloxone and high stigmatization levels toward people with opioid use disorder (OUD). While one-time educational training reduces stigma and improves naloxone administration confidence, we previously demonstrated that knowledge retention at a three-month follow-up is reduced among a cohort of medical students. This study aimed to improve the effectiveness of opioid overdose awareness and reversal training (OOART) with a three-month follow-up abbreviated OOART (aOOART) booster video. Voluntary OOART was offered to first-year medical students (M1) at the Drexel University College of Medicine in 2022. At this training, 82 students completed a pre-training survey to establish a baseline knowledge and attitude toward people with OUD and their familiarity with the steps to reverse an opioid overdose. Following the hour-long training, 64 of 82 (79%) participants completed the post-training survey to measure the immediate retention of training information. After 2.5 months, students were randomly selected to receive a 6.5-minute aOOART booster video or serve as an unboosted control. Students in the booster and non-booster cohorts then completed a three-month follow-up survey. Students who received the aOOART booster had significantly increased opioid reversal knowledge scores compared to non-boosted control students at the three-month follow-up. The aOOART booster resulted in a retention of the lowered stigma, and participants expressed a higher willingness to respond to an opioid overdose compared to participants who did not receive the booster video at the three-month follow-up. This study shows that an aOOART booster method improves knowledge retention following initial OOART. Further, the aOOART booster video served to maintain participants' reduced stigma toward people with OUD and maintained participants' willingness to respond to an opioid overdose. These results support the incorporation of an abbreviated, periodic OOART reinforcement video into opioid overdose response training nationwide. We believe this "booster video" approach is a novel and effective method to improve healthcare professionals' and medical student preparedness to render appropriate care to people with OUD.


My Lifelong Passion for Biochemistry and Anaerobic Microorganisms.
Early parental influence led me first to medical school, but after developing a passion for biochemistry and sensing the need for a deeper foundation, I changed to chemistry. During breaks between semesters, I worked in various biochemistry labs to acquire a feeling for the different areas of investigation. The scientific puzzle that fascinated me most was the metabolism of the anaerobic bacterium Clostridium kluyveri, which I took on in 1965 in Karl Decker's lab in Freiburg, Germany. I quickly realized that little was known about the biochemistry of strict anaerobes such as clostridia, methanogens, acetogens, and sulfate-reducing bacteria and that these were ideal model organisms to study fundamental questions of energy conservation, CO2 fixation, and the evolution of metabolic pathways. My passion for anaerobes was born then and is unabated even after 50 years of study.


Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.
Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment. In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data. Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions. Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.


US Trends in Prevalence of Sleep Problems and Associations with Chronic Kidney Disease and Mortality.
To better understand the relation between sleep problems and CKD, we examined temporal trends in the prevalence of self-reported sleep problems in adults in the United States and their associations with CKD and all-cause mortality. Using data from 27,365 adult participants in five biannual National Health and Examination Surveys (2005-2006 through 2013-2014), we studied five self-reported sleep problems-trouble sleeping, sleep disorder, nocturia (urinating ≥2 times/night), inadequate sleep (<7 hours/night), and excessive sleep (>9 hours/night)-plus a composite index. We conducted three types of analysis: temporal trends in the prevalence of each sleep measure by CKD status, using model-based standardization; cross-sectional analysis of associations between four CKD measures and each sleep measure, using logistic regression; and survival analysis of the association between each sleep measure and mortality, using Cox regression. The prevalence of trouble sleeping and sleep disorder increased over the five surveys by 4% and 3%, respectively, whereas the other sleep problems remained relatively stable. All sleep problems, except inadequate sleep, were more common during the study period among adults with CKD than without CKD (40% versus 21% for nocturia; 5% versus 2% for excessive sleep; 30% versus 25% for trouble sleeping; 12% versus 8% for sleep disorder). Both eGFR <30 ml/min per 1.73 m2 and albuminuria were positively associated with nocturia and excessive sleep. Excessive sleep and nocturia were also associated with higher mortality (adjusted hazard ratio for >9 versus 7-9 hours/night=1.7; 95% CI, 1.3 to 2.1; and for nocturia=1.2; 95% CI, 1.1 to 1.4). The high prevalence of sleep problems among persons with CKD and their associations with mortality suggest their potential importance to clinical practice. Future work could examine the health effects of identifying and treating sleep problems in patients with CKD.


Regulation of angiotensin type 2 receptor in bovine granulosa cells.
Angiotensin II (AngII) is best known for its role in blood pressure regulation, but it also has documented actions in the reproductive system. There are two AngII receptors, type 1 (AGTR1) and type 2 (AGTR2). AGTR2 mediates the noncardiovascular effects of AngII and is expressed in the granulosa cell layer in rodents and is associated with follicle atresia. In contrast, expression of AGTR2 is reported to occur only in theca cells in cattle. The objective of the present study was to determine whether AngII also plays a role in follicle atresia in cattle. RT-PCR demonstrated AGTR2 mRNA in both granulosa and theca cells of bovine follicles. The presence of AGTR2 protein was confirmed by immunofluorescence. Abundance of AGTR2 mRNA in granulosa cells was higher in healthy compared with atretic follicles, whereas in theca cells, it did not change. Granulosa cells were cultured in serum-free medium, and treatment with hormones that increase estradiol secretion (FSH, IGF-I, and bone morphogenetic protein-7) increased AGTR2 mRNA and protein levels, whereas fibroblast growth factors inhibited estradiol secretion and AGTR2 protein levels. The addition of AngII or an AGTR2-specific agonist to granulosa cells in culture did not affect estradiol secretion or cell proliferation but inhibited abundance of mRNA encoding serine protease inhibitor E2, a protein involved in tissue remodeling. Because estradiol secretion is a major marker of nonatretic granulosa cells, these data suggest that AngII is not associated with follicle atresia in cattle but may have other specific roles during follicle growth.


Prediction and identification of novel sRNAs involved in Agrobacterium strains by integrated genome-wide and transcriptome-based methods.
Small RNAs (sRNAs) are a class of gene regulators in bacteria, playing a central role in their response to environmental changes. Bioinformatic prediction facilitates the identification of sRNAs expressed under different conditions. We propose a novel method of prediction of sRNAs from the genome of Agrobacterium based on a positional weight matrix of conditional sigma factors. sRNAs predicted from the genome are integrated with the virulence-specific transcriptome data to identify putative sRNAs that are overexpressed during Agrobacterial virulence induction. A total of 384 sRNAs are predicted from transcriptome data analysis of Agrobacterium fabrum and 100-500 sRNAs from the genome of different Agrobacterial strains. In order to refine our study, a final set of 10 novel sRNAs with best features across different replicons targeting virulence genes were experimentally identified using semi-quantitative polymerase chain reaction. Since Ti plasmid plays a major role in virulence, out of 10 sRNAs across the replicons, 4 novel sRNAs differentially expressed under virulence induced and non-induced conditions are predicted to be present in the Ti plasmid T-DNA region flanking virulence-related genes like agrocinopine synthase, indole 3-lactate synthase, mannopine synthase and tryptophan monooxygenase. Further validation of the function of these sRNAs in conferring virulence would be relevant to explore their role in Agrobacterium-mediated plant transformation.


Pulmonary infection control window in treatment of severe respiratory failure of chronic obstructive pulmonary diseases: a prospective, randomized controlled, multi-centred study.
Early withdraw from invasive mechanical ventilation (MV) followed by noninvasive MV is a new strategy for changing modes of treatment. This study was conducted to estimate the feasibility and the efficacy of early extubation and sequential noninvasive MV commenced at beginning of pulmonary infection control window in patients with exacerbated hypercapnic respiratory failure caused by chronic obstructive pulmonary diseases (COPD). A prospective, randomized controlled study was conducted in eleven teaching hospitals; respiratory or medical intensive care units in China. Ninety intubated COPD patients with severe hypercapnic respiratory failure triggered by pulmonary infection (pneumonia or purulent bronchitis) were involved in the study. When the pulmonary infection had been controlled by antibiotics and comprehensive therapy, the "pulmonary infection control window (PIC window)" has been reached. Each case was randomly assigned to study group (extubation and noninvasive MV via facial mask immediately) or control group (invasive MV was received continuously after PIC window by using conventional weaning technique). Study group (n = 47) and control group (n = 43) had similar clinical characteristics initially and at the time of PIC window. Compared with control group, study group had shorter duration of invasive MV [(6.4 +/- 4.4) days vs (11.3 +/- 6.2) days, P = 0.000], lower rate of ventilator associated pneumonia (VAP) (3/47 vs 12/43, P = 0.014), fewer days in ICU [(12 +/- 8) days vs (16 +/- 11) days, P = 0.047] and lower hospital mortality (1/47 vs 7/43, P = 0.025). In COPD patients requiring intubation and invasive MV for hypercapnic respiratory failure, which is exacerbated by pulmonary infection, early extubation followed by noninvasive MV initiated at the start of PIC window may decrease significantly the duration of invasive MV, the risk of VAP and hospital mortality.


Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity.
Expression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics. In the present work, we report the in vitro screening of a library of 150 small molecules with the scaffold bearing quinolones, oxazines, benzoxazines, isoxazoli(di)nes, pyrimidinones, quinolines, benzoxazines, and 4-thiazolidinones, thiadiazolo[3,2-a]pyrimidin-5-one, 1,2,4-triazolo-1,3,4-thiadiazoles, and azaspiranes against the enzymatic activity of human heparanase. The identified lead compounds were evaluated for their heparanase-inhibiting activity using sulfate [35S] labeled extracellular matrix (ECM) deposited by cultured endothelial cells. Further, anti-invasive efficacy of lead compound was evaluated against hepatocellular carcinoma (HepG2) and Lewis lung carcinoma (LLC) cells. Among the 150 compounds screened, we identified 1,2,4-triazolo-1,3,4-thiadiazoles bearing compounds to possess human heparanase inhibitory activity. Further analysis revealed 2,4-Diiodo-6-(3-phenyl-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)phenol (DTP) as the most potent inhibitor of heparanase enzymatic activity among the tested compounds. The inhibitory efficacy was demonstrated by a colorimetric assay and further validated by measuring the release of radioactive heparan sulfate degradation fragments from [35S] labeled extracellular matrix. Additionally, lead compound significantly suppressed migration and invasion of LLC and HepG2 cells with IC50 value of ~5 μM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme. Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer.


Early mutation bursts in colorectal tumors.
Tumor growth is an evolutionary process involving accumulation of mutations, copy number alterations, and cancer stem cell (CSC) division and differentiation. As direct observation of this process is impossible, inference regarding when mutations occur and how stem cells divide is difficult. However, this ancestral information is encoded within the tumor itself, in the form of intratumoral heterogeneity of the tumor cell genomes. Here we present a framework that allows simulation of these processes and estimation of mutation rates at the various stages of tumor development and CSC division patterns for single-gland sequencing data from colorectal tumors. We parameterize the mutation rate and the CSC division pattern, and successfully retrieve their posterior distributions based on DNA sequence level data. Our approach exploits Approximate Bayesian Computation (ABC), a method that is becoming widely-used for problems of ancestral inference.


Stroop performance, dissociation, and trauma exposure in a community sample of children.
Extending previous research with adults, the current study examined Stroop task performance under selective and divided attention demands in a community sample of school-age children (N = 97). Stroop interference scores in both attention conditions were calculated. Higher levels of child-reported dissociation were associated with better interference control under divided attention conditions and worse control under selective attention conditions; lower levels of dissociation were associated with the opposite pattern. Both family violence exposure and Stroop interaction scores explained unique variance in dissociation scores. Although research with adults has generally assumed or implied that cognitive correlates of dissociation are a consequence of dissociation, the current findings with school-age children suggest that future research should evaluate executive function performance (in this case, interference control) as a possible risk factor for dissociation.


[Enhanced inhibitory effect of MUC1 gene vaccine on breast cancer growth by GM-CSF].
To investigate if GM-CSF adjuvant could enhance the inhibitory effect of the MUC1 gene vaccine on EMT6 breast cancer growth. Female BALB/c mice were immunized intramuscularly with 100 microgram MUC1 gene vaccine 3 times at 3 week intervals. On 1, 3 and 5 days after intramuscular immunization, GM-CSF 100 microL(1 microg/100 microL) was given s.c. respectively. Three weeks after the last immunization, tumor challenge experiments were performed by using MUC1 expressing tumor cell line EMT6. Tumor growth inhibition was observed two weeks later. After 43 d of challenge experiments, all mice were killed and tumors were weighted. CTL-specific cytotoxicity was detected by (51)Cr release assay. After 43 d of challenge experiments, the size of EMT6 tumor in MUC1 DNA+GM-CSF, MUC1 DNA, pcDNA3.1(+)+GM-CSF and pcDNA3.1(+) group were (135+/-33.8) mm(3), (250+/-34.3) mm(3), (568+/-43.6) mm(3) and (596+/-48.2) mm(3), respectively. The average weight (g) of EMT6 tumors in those four groups were 0.81+/-0.42, 1.23+/-0.41, 2.30+/-0.48 and 2.28+/-0.58, respectively. EMT6 breast cancer growth in mice of MUC1 gene vaccine group was suppressed significantly(P<0.05), compared with that in pcDNA3.1(+) control group. Co-delivery of GM-CSF adjuvant and MUC1 DNA immunization enhanced the antitumour effects(P<0.05). The cytotoxicity of MUC1-specific CTLs to EMT6 target cells was different at various ratios of effector cells to target cells. At ratios of 100:1, 50:1, 25:1 and 12.5:1, the specific lysis for MUC1 DNA+GM-CSF group reached 68.5%, 53.4%, 35.9% and 28.5%, MUC1 cDNA group 54.1%, 39.8%, 26.4% and 20.1%, while for control groups 13.2%, 10%, 8.2%, 7.2% and 11.7%, 9.8%, 7.7%, 7.0%, respectively. GM-CSF enhanced the cytotoxicity of CTL induced by MUC1 DNA immunization(P<0.05). GM-CSF adjuvant significantly enhanced the inhibitory effect of the MUC1 gene vaccine on EMT6 breast cancer growth.


THE EVOLUTION OF SOCIAL SIGNALS: MORPHOLOGICAL, FUNCTIONAL, AND GENETIC INTEGRATION OF THE SEX PHEROMONE IN NAUPHOETA CINEREA.
Social signals that mediate intraspecific interactions can be complex, conveying considerable information concerning the probable behavior of individuals and minimizing overt aggression and wasted energy. In the cockroach Nauphoeta cinerea, male-male competition and female mate choice are mediated by a multicomponent male-produced sex pheromone. In this study, I examine variation in this pheromone. First I measure differences among males in both individual pheromone compounds and the overall composition of the pheromone. Principal component analysis is used to quantify and describe pheromone composition. Next, I explore some of the causes and consequences of this variation by examining the pheromone of males with different social experiences. Compared to subordinate males, dominant males have significantly less variable quantities of the individual pheromone compounds and are significantly less variable in the composition of their pheromone. Because of an association between status and mating success, male-male competition can result in stabilizing sexual selection on the sex pheromone. Finally, I test the hypothesis that the pheromone compounds evolve in a manner consistent with their function. As predicted for morphologically integrated characters, the patterns of phenotypic, genetic, and environmental correlations among my measures of pheromone compounds and composition match functional patterns suggested by this study and the developmental patterns demonstrated in my previous studies. Based on these studies of the N. cinerea sex pheromone, I argue that stabilizing sexual selection shapes the evolution of pheromonal communication involved in social interactions among male N. cinerea. Further, I argue that coordinated evolution of social signals may be possible due to the morphological integration of their multiple compounds.


Development and evaluation of reverse transcription-loop-mediated isothermal amplification assay for rapid and real-time detection of Japanese encephalitis virus.
The standardization and validation of a one-step, single-tube accelerated quantitative reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay is reported for rapid and real-time detection of Japanese encephalitis virus (JEV). The RT-LAMP assay reported in this study is very simple and rapid; the amplification can be obtained in 30 min under isothermal conditions at 63 degrees C by employing a set of six primers targeting the E gene of JEV. The RT-LAMP assay demonstrated exceptionally higher sensitivity compared to that of RT-PCR, with a detection limit of 0.1 PFU. The specificities of the selected primer sets were established by cross-reactivity studies with other closely related members of the JEV serocomplex as well as by evaluation of healthy human volunteers. The comparative evaluation of the RT-LAMP assay for clinical diagnosis with a limited number of patient cerebrospinal fluid samples revealed 85% concordance with conventional RT-PCR, with a sensitivity and a specificity of 100% and 86%, respectively. The concentration of virus in most of the clinical samples was 10(2) to 10(5) PFU/ml, as determined from the standard curve based on the time of positivity in the samples. In addition, the monitoring of gene amplification can also be visualized with the naked eye by using SYBR green I fluorescent dye. Thus, due to easy operation without a requirement of sophisticated equipment and skilled personnel, the RT-LAMP assay reported here is a valuable tool for the rapid and real-time detection of JEV not only by well-equipped laboratories but also by peripheral diagnostic laboratories with limited financial resources in developing countries.


Co3O4 nanoparticles decorated carbon nanofiber mat as binder-free air-cathode for high performance rechargeable zinc-air batteries.
An efficient, durable and low cost air-cathode is essential for a high performance metal-air battery for practical applications. Herein, we report a composite bifunctional catalyst, Co3O4 nanoparticles-decorated carbon nanofibers (CNFs), working as an efficient air-cathode in high performance rechargeable Zn-air batteries (ZnABs). The particles-on-fibers nanohybrid materials were derived from electrospun metal-ion containing polymer fibers followed by thermal carbonization and a post annealing process in air at a moderate temperature. Electrochemical studies suggest that the nanohybrid material effectively catalyzes oxygen reduction reaction via an ideal 4-electron transfer process and outperforms Pt/C in catalyzing oxygen evolution reactions. Accordingly, the prototype ZnABs exhibit a low discharge-charge voltage gap (e.g. 0.7 V, discharge-charge at 2 mA cm(-2)) with higher stability and longer cycle life compared to their counterparts constructed using Pt/C in air-cathode. Importantly, the hybrid nanofiber mat readily serves as an integrated air-cathode without the need of any further modification. Benefitting from its efficient catalytic activities and structural advantages, particularly the 3D architecture of highly conductive CNFs and the high loading density of strongly attached Co3O4 NPs on their surfaces, the resultant ZnABs show significantly improved performance with respect to the rate capability, cycling stability and current density, promising good potential in practical applications.