The risks and benefits of providing HIV services during the COVID-19 pandemic.
The COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services. We used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics. Maintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19-146 discounted deaths per 10,000 clients. While there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.


TCR transfer induces TCR-mediated tonic inhibition of RAG genes in human T cells.
Induction of the TCR signaling pathway terminates the expression of RAG genes, and a link between this pathway and their transcriptional control is evident from the recent demonstration of their re-expression if the TCR is subsequently lost or down-regulated. Since unstimulated T cells display a steady-state level of "tonic" TCR signaling, i.e. in the absence of any antigenic stimulus, it was uncertain whether this control was exerted through ligand-dependent or ligand-independent TCR signaling. Here we demonstrate for the first time that exogenous TCR α and β chains transferred into the human immature RAG(+) T cell line Sup-T1 by lentiviral transduction inhibit RAG expression through tonic signaling, and that this inhibition could itself be reverted by pharmacological tonic pathway inhibitors. We also suggest that mature T cells already expressing an endogenous TCR on their surface maintain some levels of plasticity at the RAG locus when their basal TCR signaling is interfered with. Lastly, we show that the TCR constructs employed in TCR gene therapy do not possess the same basal signaling transduction capability, a feature that may have therapeutic implications.


Bacterial population in traditional sourdough evaluated by molecular methods.
To study the microbial communities in artisanal sourdoughs, manufactured by traditional procedure in different areas of Sicily, and to evaluate the lactic acid bacteria (LAB) population by classical and culture-independent approaches. Forty-five LAB isolates were identified both by phenotypic and molecular methods. The restriction fragment length polymorphism and 16S ribosomal DNA gene sequencing gave evidence of a variety of species with the dominance of Lactobacillus sanfranciscensis and Lactobacillus pentosus, in all sourdoughs tested. Culture-independent method, such as denaturing gradient gel electrophoresis (DGGE) of the V6-V8 regions of the 16S rDNA, was applied for microbial community fingerprint. The DGGE profiles revealed the dominance of L. sanfranciscensis species. In addition, Lactobacillus-specific primers were used to amplify the V1-V3 regions of the 16S rDNA. DGGE profiles flourished the dominance of L. sanfranciscensis and Lactobacillus fermentum in the traditional sourdoughs, and revealed that the closely related species Lactobacillus kimchii and Lactobacillus alimentarius were not discriminated. Lactobacillus-specific PCR-DGGE analysis is a rapid tool for rapid detection of Lactobacillus species in artisanal sourdough. This study reports a characterization of Lactobacillus isolates from artisanal sourdoughs and highlights the value of DGGE approach to detect uncultivable Lactobacillus species.


Functional heterogeneity in the early distal tubule of the Amphiuma kidney: evidence for two modes of Cl- and K+ transport across the basolateral cell membrane.
Measurements of cell volume and basolateral cell membrane potential difference (Vbl) were made simultaneously and on the same cell to study chloride and potassium transport across the basolateral cell membrane of individual cells from the Amphiuma early distal tubule or diluting segment. Two distinct types of responses of Vbl are evident when either chloride is lowered or potassium is raised in the basolateral solution. In one cell type (high basolateral conductance, HBC), these maneuvers cause large depolarizations in Vbl, suggesting that the basolateral cell membrane has significant partial conductances to both chloride and to potassium. In contrast, Vbl of another group (low basolateral conductance, LBC) is much less sensitive to the same maneuvers, indicating that the partial conductance of the basolateral cell membrane is quite low. Consistent with the difference in partial conductance is the ratio of resistances, which is immeasurably high in HBC cells and averages 1.2 +/- 0.4 in LBC cells. Increasing basolateral potassium to 98 mM causes both types to swell, with HBC cells swelling approximately two times faster than LBC cells. In both cell types, potassium-induced cell swelling is inhibited by removing chloride from the perfusion solutions. In animals kept in a low-potassium environment, the number of HBC cells is approximately equal to the number of LBC cells. The proportion of LBC cells increases following potassium adaptation. This data suggests that there are at least two types of cells present in Amphiuma early distal tubule, one cell type in which both chloride and potassium move across the basolateral cell membrane primarily via a conductive pathway and another in which the movements are mostly electroneutral, probably involving a K-Cl cotransport system, and that this heterogeneity may change in response to the metabolic state of the animal.


Evaluation of 2 breast cancer risk models in a benign breast disease cohort.
More than 1.5 million women per year have a benign breast biopsy resulting in concern about their future breast cancer (BC) risk. This study examined the performance of 2 BC risk models that integrate clinical and histologic findings in this population. The BC risk at 5 and 10 years was estimated with the Breast Cancer Surveillance Consortium (BCSC) and Benign Breast Disease to Breast Cancer (BBD-BC) models for women diagnosed with benign breast disease (BBD) at the Mayo Clinic from 1997 to 2001. Women with BBD were eligible for the BBD-BC model, but the BCSC model also required a screening mammogram. Calibration and discrimination were assessed. Fifty-six cases of BC were diagnosed among the 2142 women with BBD (median age, 50 years) within 5 years (118 were diagnosed within 10 years). The BBD-BC model had slightly better calibration at 5 years (0.89; 95% confidence interval [CI], 0.71-1.21) versus 10 years (0.81; 95% CI, 0.70-1.00) but similar discrimination in the 2 time periods: 0.68 (95% CI, 0.60-0.75) and 0.66 (95% CI, 0.60-0.71), respectively. In contrast, among the 1089 women with screening mammograms (98 cases of BC within 10 years), the BCSC model had better calibration (0.94; 95% CI, 0.85-1.43) and discrimination (0.63; 95% CI, 0.56-0.71) at 10 years versus 5 years (calibration, 1.31; 95% CI, 0.94-2.25; discrimination, 0.59; 95% CI, 0.46-0.71) where discrimination was not different from chance. The BCSC and BBD-BC models were validated in the Mayo BBD cohort, although their performance differed by 5-year risk versus 10-year risk. Further enhancement of these models is needed to provide accurate BC risk estimates for women with BBD.


Implementation of active support in Victoria, Australia: an exploratory study.
Active support is an effective intervention to support engagement of residents with intellectual disability in group homes. This survey explored resident characteristics of the people supported by organisations implementing active support, the provision of active support, its procedures and systems, and resident engagement in meaningful activity and relationships. Information was collected through questionnaires and direct observation of 33 group homes from 6 organisations in Victoria, Australia, with a 5-10-year history of implementing active support. Residents with lower support needs were engaged with little staff contact or assistance. Use of active support systems and structures was mixed. Only one organisation consistently provided good active support. Administrative systems and structures are not sufficient to change staff interaction and thus resident experience. Shared supported accommodation services may represent an inefficient use of resources for more able residents, as staff resources are not maximised to support for resident engagement.


Conditions for successful implementation of couple-based collaborative management model of diabetes among community-dwelling older Chinese: a qualitative comparative analysis.
Diabetes mellitus is a prevalent and potentially devastating chronic illness affecting many older adults. Given spousal involvement in many aspects of diabetes management, coping with their partners is increasingly seen as a potential solution to make up for limited resources. This study aimed to identify the key conditions for optimal implementation of couple-based collaborative management model (CCMM) among Chinese older couples with type 2 diabetes mellitus. Older couples and community healthcare practitioners were selected according to couples' joint intervention attendance rate and community's average attendance rate. This mixed methods research consisted of a qualitative phase and a quantitative phase. In the qualitative phase, in-depth interviews were conducted among 12 pairs of couples in the intervention group and 4 corresponding practitioners, in the follow-up period of the multicentered RCT from January to April 2022. Qualitative comparative analysis (QCA) in the quantitative phase to identify conditions influencing CCMM's implementation and to explore necessary and sufficient combinations of conditions (i.e., solutions) for improving patients' glycated hemoglobin (HbA1c) control (outcome). Key conditions included implementation process, couple's role in diabetes management, their belief and perception of CCMM, as well as objective obstacles and subjective initiative for behavior change. Accordingly, major barriers in CCMM's implementation were patients' strong autonomy (particularly among husbands), misbelief and misperception about diabetes management as a result of low literacy, and mistrust of the practitioners. QCA further revealed that no single condition was necessary for effective HbA1c control, while three types of their combinations would be sufficient. Solution 1 and 2 both comprised the presence of spousal willingness to help, plus correct belief and perception of diabetes management, well embodying the utility of couple collaborative management in supporting patients' HbA1c control. On the other hand, solution 3 indicated that high-quality implementation even without spousal support, can promote the patient's subjective initiative to overcome objective obstacles, suggesting enhanced self-management for HbA1c control. Tailored CCMM should be implemented in reference to older couple's preferences and literacy levels, to ensure intervention fidelity, and establish correct understanding of collaborative management among them.


Identiy of brain alcohol dehydrogenase with liver alcohol dehydrogenase.
A method for obtaining electrophoretically homogeneous rat liver alcohol dehydrogenase (EC 220.127.116.11) at a specific activity of 2-2.5 mumol/min per mg of protein is presented. Anti-sera prepared against the purified enzyme inhibit alcohol dehydrogenase by up to 75% and cause precipitation of virtually all the enzyme. The antisera were shown by immunoelectrophoresis of a partially purified liver homogenate to be specifically directed against alcohol dehydrogenase and were used to demonstrate that the alcohol dehydrogenases of rat brain and liver share common antigens. The total activity of alcohol dehydrogenase in rat brain homogenates is normally quite low, with as much as 10% of the total activity attributable to the activity in the blood contained within the brain; in cases of severe liver damage (induced experimentally with carbon tetrachloride) this contribution may rise to as much as 60%.


Bivalirudin anticoagulation for cardiopulmonary bypass during cardiac surgery.
Heparin is the primary anticoagulant for cardiopulmonary bypass (CPB) support during cardiac surgery. While widely used, ∼2% of cardiac surgery patients develop heparin-induced thrombocytopenia (HIT) and 4-26% develop heparin resistance. Bivalirudin is an alternative anticoagulant mainly used for percutaneous coronary interventions. Given the challenges associated with heparin anticoagulation, we conducted a review to explore the use of bivalirudin for CPB surgery. PubMed and Embase scoping review included 2 randomized controlled trials, a retrospective comparison study, 3 pilot studies, and 30 case reports. To provide a contemporary series, we searched for articles published from 2010 to 2023. Our review included studies from both adult and pediatric populations. While data is limited, bivalirudin seems to supply similar effectiveness and safety as heparin for CPB anticoagulation. Across the three comparative studies, the heparin cohorts had a 0-9% mortality rate and 0-27% rate of major bleeding/reoperation compared to a 0-3% mortality and 0-6% major bleeding/reoperation rate for the bivalirudin cohorts. Bivalirudin was successfully used as an anticoagulant in a wide range of CPB surgeries (e.g., heart transplants, ventricular assisted device placements, and valve repairs). Successful patient outcomes were reported with bivalirudin infusion of ∼2 mg/kg/hour, activated clotting time monitoring (target >400 s or 2.5× baseline), use of cardiotomy suctions, minimization of stagnant blood, and post-bypass modified ultrafiltration. Bivalirudin is a safe and effective anticoagulant for CPB, especially for patients with HIT or heparin resistance. Further comparative research is called for to optimize bivalirudin utilization for CPB during cardiac surgery.


Impaired immune responses toward alloantigens and tumor cells but normal thymic selection in mice deficient in the beta2 integrin leukocyte function-associated antigen-1.
We have generated mice deficient in the beta2 integrin LFA-1 by targeted disruption of the CD11a gene in embryonic stem cells. In vitro LFA-1 -/- cells exhibit a delayed proliferative response toward alloantigens in the MLR. In vivo the host-vs-graft reaction toward injected allogeneic cells is also reduced. Alloantigen-specific CTLs generated from LFA-1 -/- mice are impaired in their cytotoxic activity toward allogeneic spleen cells as well as cell line targets. The proliferative response of LFA-1 -/- splenocytes following stimulation by LPS, PMA plus ionomycin, or immobilized anti-CD3epsilon mAb is normal, but Con A-stimulated proliferation is greatly diminished. We observe typical edema formation in a delayed type hypersensitivity reaction to SRBC with normal extravasation of leukocytes and demonstrate recruitment of neutrophils to an LPS-induced inflammatory site in these mice, suggesting that LFA-1 does not play an essential role in lymphocyte homing and leukocyte extravasation. We further show that LFA-1 -/- mice are susceptible to metastasis of B16 melanoma tumors, although their in vitro NK cell activity appears normal. A study of LFA-1 -/- mice expressing transgenic TCRs indicates that thymic maturation and selection of T cells are unaffected by the loss of LFA-1. Our results indicate that LFA-1 is important for alloantigen-triggered T cell proliferation and cytotoxicity, for Con A stimulation of T cells, and in tumor rejection. It does not appear to play an essential role in lymphocyte homing and leukocyte extravasation or in T cell maturation and selection in the thymus.


Inflammation-responsive transcription factor SAF-1 activity is linked to the development of amyloid A amyloidosis.
Abundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman's disease. An inflammation-responsive transcription factor, SAF (for SAA activating factor), has been implicated in the sustained expression of amyloidogenic SAA under chronic inflammatory conditions. However, its role in the pathogenesis of AA amyloidosis has thus far remained obscure. In this paper we have shown that SAF-1, a major member of the SAF family, is abundantly present in human AA amyloidosis patients. To assess whether SAF-1 is directly linked to the pathogenesis of AA amyloidosis, we have developed a SAF-1 transgenic mouse model. SAF-1-overexpressing mice spontaneously developed AA amyloidosis at the age of 14 mo or older. Immunohistochemical analysis confirmed the nature of the amyloid deposits as an AA type derived from amyloidogenic SAA1. Furthermore, SAF-1 transgenic mice rapidly developed severe AA amyloidosis in response to azocasein injection, indicating increased susceptibility to inflammation. Also, during inflammation SAF-1 transgenic mice exhibited a prolonged acute phase response, leading to an extended period of SAA synthesis. Together, these results provide direct evidence that SAF-1 plays a key role in the development of AA amyloidosis, a consequence of chronic inflammation.


Posthearing developmental refinement of temporal processing in principal neurons of the medial superior olive.
In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect sound localization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14-P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 +/- 3 to 17 +/- 2 mV; tau = 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.


Muscarinic toxin selective for m4 receptors impairs memory in the rat.
The selectivity of the muscarinic toxin MT3 from green mamba snake venom was corroborated by inhibition of the binding of [3H]NMS, a classical muscarinic radioligand, to native and cloned muscarinic receptors, showing 214-fold higher affinity for m4 than for m1 subtype, without significant binding to the others. The highest concentrations of MT3 sites (putative m4 receptors) in the rat brain were found in striatum and olfactory tubercle, intermediate concentration in dentate gyrus and CA1, and lower but still conspicuous levels in CA3 and frontal cortex. MT3 caused retrograde amnesia of an inhibitory avoidance task, when injected into the dorsal hippocampus of rats after training, suggesting a positive role of these MT3 sensitive sites, which are probably m4 muscarinic receptors, in memory consolidation of this task.


Estrogens, breast cancer, and intestinal flora.
Epidemiologic evidence has linked diet to breast cancer, with the highest cancer rates observed in women who eat a high fat-low fiber diet. There is also substantial information, both clinical and experimental, that implicates estrogens in the etiology of breast cancer. A recent study from our laboratory has shown that diet influences levels of estrogens, and the main mechanism is metabolism of estrogens in the intestine. The intestinal microflora plays a key role in the enterohepatic circulation of estrogens by deconjugating bound estrogens that appear in the bile, thereby permitting the free hormones to be reabsorbed. By suppressing the microflora with antibiotic therapy, fecal estrogens increase and urinary estrogens decrease, changes indicating diminished intestinal reabsorption. A low fat-high fiber diet is associated with similar findings-high fecal estrogens and low urinary estrogens. It appears that the microflora plays a key role in the metabolism of female sex hormones.


Effect of proliferating cell nuclear antigen ubiquitination and chromatin structure on the dynamic properties of the Y-family DNA polymerases.
Y-family DNA polymerases carry out translesion synthesis past damaged DNA. DNA polymerases (pol) eta and iota are usually uniformly distributed through the nucleus but accumulate in replication foci during S phase. DNA-damaging treatments result in an increase in S phase cells containing polymerase foci. Using photobleaching techniques, we show that poleta is highly mobile in human fibroblasts. Even when localized in replication foci, it is only transiently immobilized. Although ubiquitination of proliferating cell nuclear antigen (PCNA) is not required for the localization of poleta in foci, it results in an increased residence time in foci. poliota is even more mobile than poleta, both when uniformly distributed and when localized in foci. Kinetic modeling suggests that both poleta and poliota diffuse through the cell but that they are transiently immobilized for approximately 150 ms, with a larger proportion of poleta than poliota immobilized at any time. Treatment of cells with DRAQ5, which results in temporary opening of the chromatin structure, causes a dramatic immobilization of poleta but not poliota. Our data are consistent with a model in which the polymerases are transiently probing the DNA/chromatin. When DNA is exposed at replication forks, the polymerase residence times increase, and this is further facilitated by the ubiquitination of PCNA.


Dynamic freedom: substrate stress relaxation stimulates cell responses.
Tissue engineers have explored a set of materials cues that can allow control of cell viability and guide cell fate and functions. Although the effect of substrate stiffness on cell fate has been extensively studied and established, the role of substrate stress relaxation, the ability of a substrate to dissipate cell-induced forces, is only emerging. Recently, several studies have demonstrated that substrate stress relaxation is an important mechanical cue for cell spreading, proliferation and differentiation in vitro. In this mini-review, we highlight the influence of substrate stress relaxation on cell behavior and function as well as provide future perspectives. Firstly, we describe the methods used for characterizing the stress relaxation/creep responses of hydrogels along with the molecular origin of viscoelastic properties. Then, we highlight the most recent studies elucidating the stress relaxation effect on cellular behavior using physically cross-linked hydrogels. Finally, we report on an emerging alternative design of tunable viscoelastic hydrogels: chemically cross-linked (reversible linkages) adaptable hydrogels that have been used as stable 3D cell culture platforms for a few years in the era of hydrogel systems.


Primary primitive peripheral neuroectodermal tumor of the prostate. Immunophenotypic and molecular study of a case.
A case of primitive peripheral neuroectodermal tumor arising in the prostate gland of a 31-year-old man and first diagnosed through a biopsy is reported. Microscopically, the tumor was made up of solid nests and sheets of small round cells, and it was difficult to distinguish the neoplasm from other small round cell tumors, such as small cell carcinoma, rhabdomyosarcoma, or malignant lymphoma. Immunohistochemically, the tumor cells showed immunoreactivity for CD99, vimentin, neuron-specific enolase, and synaptophysin. The neoplasm was excised by a radical surgical procedure preceded by chemotherapy and radiation therapy. The morphologic diagnosis of the prostatectomy specimen was complemented by molecular analysis performed on viable microdissected tissue obtained from formalin-fixed, paraffin-embedded tumor sections. Polymerase chain reaction and sequencing assessment showed the presence of EWS/FLI1 type 2 chimeric transcript, confirming the diagnosis of peripheral primitive neuroectodermal tumor. To our knowledge, this is the first description of a primary peripheral primitive neuroectodermal tumor in the prostate gland.


Use of foscarnet for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation from a related donor.
Foscarnet is an active agent against cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT), as well as ganciclovir. We investigated the usefulness of foscarnet in patients who underwent related allogeneic HSCT. Foscarnet was used in 320 patients with a median age of 45 years (range 15-72). The purpose of administration was CMV disease in 65, preemptive use in 248 and prophylaxis in 7. Totally, 194 patients had a history of prior ganciclovir treatment. The reason for foscarnet use was insufficient therapeutic effect of prior ganciclovir in 99, and adverse event including myelosuppression in 95. The response rate in symptom was 52% for the CMV disease patients. Antigenemia disappeared in 77% of the preemptive treatment and improved in 13% of the patients. No outbreak of CMV disease was recognized. The total effectiveness of therapeutic and preemptive use was significantly higher for patients without prior ganciclovir (91 vs. 76%, P = 0.001). Adverse events of grade 3 or higher were recognized in 24%, including electrolyte abnormalities in 11%, neutropenia in 8%, and thrombocytopenia in 8%. Renal damage was only observed in 3% of patients. Foscarnet was concluded to be a safe and effective anti-CMV agent and to be a suitable alternative to ganciclovir.


Impact of a teacher-led school handwashing program on children's handwashing with soap at school and home in Bihar, India.
Handwashing with soap is an important preventive health behavior, and yet promoting this behavior has proven challenging. We report the results of a program that trained teachers to deliver a handwashing with soap behavior change program to children in primary schools in Bihar, India. Ten intervention schools selected along with ten nearby control schools, and intervention schools received the "School of Five" program promoting handwashing with soap using interactive stories, games, and songs, behavioral diaries to encourage habit formation, and public commitment. Households with children aged 8-13 attending the nearby school were enrolled in the study. Handwashing with soap was measured using sticker diaries before eating and after defecation 4 weeks after the intervention was completed. Children in the treatment reported 15.1% more handwashing with soap on key occasions (35.2%) than those in the control group (20.1%) (RR: 1.77, CI: (1.22, 2.58), p = .003). There was no evidence that handwashing with soap after defecation was higher in the treatment group than the control group (RR: 1.18, CI: (0.88, 1.57), p = .265), but there was strong evidence that handwashing with soap was greater in the treatment than in the control before eating (RR: 2.68, 95% CI: (1.43, 5.03), p = .002). Rates of handwashing increased both at home (RR: 1.63, CI: 1.14, 2.32), p = .007) and at school (RR: 4.76, 95% CI: (1.65, 17.9), p = .004), though the impact on handwashing with soap at key occasions in schools was much higher than at home. Promoting handwashing with soap through teachers in schools may be an effective way to achieve behavior change at scale.


Cardiac Dysfunction in Severely Burned Patients: Current Understanding of Etiology, Pathophysiology, and Treatment.
Patients who experience severe burn injuries face a massive inflammatory response resulting in hemodynamic and cardiovascular complications. Even after immediate and appropriate resuscitation, removal of burn eschar and covering of open areas, burn patients remain at high risk for serious morbidity and mortality. As a result of the massive fluid shifts following the initial injury, along with large volume fluid resuscitation, the cardiovascular system is critically affected. Further, increased inflammation, catecholamine surge, and hypermetabolic syndrome impact cardiac dysfunction, which worsens outcomes of burn patients. This review aimed to summarize the current knowledge about the effect of burns on the cardiovascular system.A comprehensive search of the PubMed and Embase databases and manual review of articles involving effects of burns on the cardiovascular system was conducted.Many burn units use multimodal monitors (e.g., transpulmonary thermodilution) to assess hemodynamics and optimize cardiovascular function. Echocardiography is often used for additional evaluations of hemodynamically unstable patients to assess systolic and diastolic function. Due to its noninvasive character, echocardiography can be repeated easily, which allows us to follow patients longitudinally.The use of anabolic and anticatabolic agents has been shown to be beneficial for short- and long-term outcomes of burn survivors. Administration of propranolol (non-selective β-receptor antagonist) or oxandrolone (synthetic testosterone) for up to 12 months post-burn counteracts hypermetabolism during hospital stay and improves cardiac function.A comprehensive understanding of how burns lead to cardiac dysfunction and new therapeutic options could contribute to better outcomes in this patient population.


Treatment satisfaction and glycemic control in young Type 1 diabetic patients in transition from pediatric health care: CSII versus MDI.
To evaluate whether continuous subcutaneous insulin infusion (CSII) may have any advantage over multiple daily injections (MDI) on glycemic control and treatment satisfaction in young patients with Type 1 diabetes in transition to an adult diabetes center. The study population consisted of 125 patients on MDI; 38 out of the 43 patients considered eligible for CSII completed the study and the 82 remaining on MDI served as control group. Glycemic control and treatment satisfaction [diabetes treatment satisfaction questionnaire (DTSQ)] were evaluated in all patients at baseline and after 12 weeks. At baseline, the two groups were well matched for demographic characteristics and glycemic control. DTSQ score was lower in CSII group (21.1 ± 8.8 vs. 25.1 ± 7.1, P = 0.011). After 12 weeks, a similar decrease in HbA1C was observed in both groups [difference -0.3 % (95 % CI-0.6 to 0.1, P = 0.847)]. Mean amplitude glucose excursions,blood glucose standard deviation, and overall hypoglycemia were significantly reduced in CSII group. DTSQ overall score increased in CSII and decreased in MDI (difference between groups = 9.9, 95 % CI 8.0-12.0, P<0.001), while perceived hyperglycemia and hypoglycemia decreased in CSII compared with MDI (difference:-2.5 and -2.0, respectively, P<0.001 for both). Among young Type 1 diabetic patients in transition from Pediatrics,CSII showed a similar efficacy in reducing HbA1c compared with MDI, with less hypoglycemia and glycemic excursions, and was better in improving overall treatment satisfaction and the rate of perceived hyperglycemia and hypoglycemia.


Synergism of Electrospun Nanofibers and Pulsed Electromagnetic Field on Osteogenic Differentiation of Induced Pluripotent Stem Cells.
According to the current therapies failure for bone fractures and lesions, tissue engineering showed a great potential to help solve these challenges. Because the use of growth factors is very limited in the clinic, it could be very useful that could be introducing an alternative to it. Extremely low frequency pulsed electromagnetic fields (PEMF, 1 mT, 50 Hz) were used for achieving this aim. The PEMF potential in combination with electrospun polycaprolactone (PCL) nanofibers was used to investigate the osteogenic potential of human induced pluripotent stem cells (iPSCs). Several relevant osteogenic markers, such as Alizarin red staining, alkaline phosphatase activity, calcium content, gene expression, and immunocytochemistry, were used to evaluate osteoinductivity of PEMF. Results were shown that PEMF alone can induce osteogenic differentiation, but this capability increased when used in combination with PCL nanofibers significantly. In addition, simultaneous use of osteogenic medium, PEMF and PCL surprisingly increased osteogenic differentiation potential of iPSCs. According to the results, PEMF alone, iPSCs-seeded PCL, and both of them could be considered as a promising candidate for use in bone tissue engineering applications.


Changes in haem synthesis associated with occupational exposure to organic and inorganic sulphides.
1. Analysis of reticulocytes for delta-amino-laevulinic acid synthase (AmLev synthase, EC 22.214.171.124) and haem synthase (EC 126.96.36.199) activity in 17 workers in pulp production with low-level hydrogen sulphide and methylmercaptan exposure showed decreased activities in eight and six cases respectively. 2. Erythrocyte protoporphyrin concentration was below the control range in seven cases. 3. Low AmLev synthase and haem synthase activities were found in one patient with hydrogen sulphide intoxication 1 week after the event. The activities had returned to the control levels 2 months later, though erythrocyte protoporphyrin remained abnormally low. 4. In vitro, hydrogen sulphide inhibited haem synthase with an apparent Ki of 3.4 mmol/l. Sulphide anion, on the other hand, inhibited AmLev synthase activity 85% at 10 mmol/l concentration. Thiosulphate anion inhibited AmLev synthase activity 18% (Ki 27 mmol/l) and haem synthase activity 43% at 10 mmol/l concentration. Selenite inhibited AmLev synthase (Ki 5.1 mmol/l) and haem synthase (Ki 9.0 mmol/l). 5. The assay of AmLev synthase and haem synthase could be a valuable addition to the assessment of workers' health in industries generating hydrogen sulphide or/and methylmercaptan, although the mechanism of the toxic effect remains speculative.


Heterostructure design of one-dimensional ZnO@CoNi/C multilayered nanorods for high-efficiency microwave absorption.
Dimensional design and heterogeneous interface engineering are promising approaches for the fabrication of superior absorbers with high loss performance and a wide effective bandwidth. Therein, ZnO nanorods were successfully synthesized and combined with CoNi nanosheets by hydrothermal method, and PDA was then encapsulated on the surface of the material to form a unique one dimensional (1D) core-sheath structure. The extensive defects and residual functional groups are present in the calcined material, as well as the multiple heterogeneous interfaces enhance the dielectric loss induced by polarization. Simultaneously, the 1D structure wrapped with PDA offers an efficient pathway for electron transfer, hence facilitating the enhancement of conductive loss. In addition, the CoNi-LDHs sheet layer stacked on the surface not only causes multiple scattering and reflections of electromagnetic waves, but also provides magnetic losses to optimize the impedance matching. Finally, radar cross section (RCS) simulations further reveal that the composite can dissipate electromagnetic energy in practical applications. Consequently, the 1D multilayer ZnO@CoNi/C composite exhibits an optimal reflection loss of -55 dB with a thickness of 2.3 mm and an effective absorption bandwidth (EAB) value of 6.8 GHz when the filling ratio is only 20 wt%. In summary, this paper provides a new direction for the fabrication of 1D multilayer nonhomogeneous interfacial absorbers with excellent performance.


Cold spell en route delays spring arrival and decreases apparent survival in a long-distance migratory songbird.
Adjusting the timing of annual events to gradual changes in environmental conditions is necessary for population viability. However, adaptations to weather extremes are poorly documented in migratory species. Due to their vast seasonal movements, long-distance migrants face unique challenges in responding to changes as they rely on an endogenous circannual rhythm to cue the timing of their migration. Furthermore, the exact mechanisms that explain how environmental factors shape the migration schedules of long-distance migrants are often unknown. Here we show that long-distance migrating semi-collared flycatchers Ficedula semitorquata delayed the last phase of their spring migration and the population suffered low return rates to breeding sites while enduring a severe cold spell en route. We found that the onset of spring migration in Africa and the timing of Sahara crossing were consistent between early and late springs while the arrival at the breeding site depended on spring phenology at stopover areas in each particular year. Understanding how environmental stimuli and endogenous circannual rhythms interact can improve predictions of the consequences of climate changes on migratory animals.


Combined promoter methylation analysis of CADM1 and MAL: an objective triage tool for high-risk human papillomavirus DNA-positive women.
Screening women for high-grade cervical intraepithelial neoplasia or cervical cancer (CIN3(+)) by high-risk human papillomavirus (hrHPV) testing has as side-effect the detection of hrHPV-positive women without clinically relevant lesions. Here, we developed an objective assay assessing the methylation status of the promoter regions of CADM1 and MAL to triage hrHPV-positive women for CIN3(+). In a training set (51 women with CIN3(+) and 224 without CIN2(+)), panels consisting of one to four quantitative methylation-specific PCR (qMSP) assays (CADM1-m12,CADM1-m18,MAL-m1,MAL-m2) were analyzed. Cross-validated receiver-operating characteristics (ROC) curves were constructed and the panel with highest partial cross-validated area under the curve (AUC) was used for validation in an independent set of 236 consecutive hrHPV-positive women from a screening cohort. In the validation set, the ROC curve of the panel was compared with CIN3(+) sensitivity and specificity of cytology and of cytology combined with HPV16/18 genotyping. In the training set, CADM1-m18 combined with MAL-m1 was the best panel (cross-validated partial AUC = 0.719). In the validation set, this panel revealed CIN3(+) sensitivities ranging from 100% (95% CI: 92.4-100) to 60.5% (95% CI: 47.1-74.6), with corresponding specificities ranging from 22.7% (95% CI: 20.2-25.2) to 83.3% (95% CI: 78.4-87.4). For cytology these were 65.8% (95% CI: 52.3-79.0) and 78.8% (95% CI: 73.7-83.1) and for cytology/HPV16/18, these were 84.2% (95% CI: 72.0-92.7) and 54.0% (95% CI: 49.2-58.7), respectively. The point estimates of both cytology and cytology/HPV16/18 were equal to the values of the ROC curve of CADM1-m18/MAL-m1. We developed an objective methylation marker panel that was equally discriminatory for CIN3(+) as cytology or cytology with HPV16/18 genotyping in hrHPV-positive women. This opens the possibility for complete cervical screening by objective, nonmorphological molecular methods.


Zeolites as Adsorbents and Photocatalysts for Removal of Dyes from the Aqueous Environment.
This study investigated the potential of zeolites (NH4BETA, NH4ZSM-5, and NaY) to remove two frequently used dyes, methylene blue (MB) and rhodamine B (RB), from an aqueous environment. The removal of dyes with zeolites was performed via two mechanisms: adsorption and photocatalysis. Removal of dyes through adsorption was achieved by studying the Freundlich adsorption isotherms, while photocatalytic removal of dyes was performed under UV irradiation. In both cases, the removal experiments were conducted for 180 min at two temperatures (283 K and 293 K), and dye concentrations were determined spectrophotometrically. Additionally, after photodegradation, mineralization was analyzed as chemical oxygen demand. A computational analysis of the structures of MB and RB was performed to gain a deeper understanding of the obtained results. The computational analysis encompassed density functional theory (DFT) calculations and analysis of two quantum-molecular descriptors addressing the local reactivity of molecules. Experimental results have indicated that the considered zeolites effectively remove both dyes through both mechanisms, especially NH4BETA and NH4ZSM-5, due to the presence of active acidic centers on the outer and inner surfaces of the zeolite. The lowest efficiency of dye removal was achieved in the presence of NaY zeolite, which has a lower SiO2/Al2O3 ratio. A more efficient reduction was completed for RB dye, which agrees with the computationally obtained information about reactivity.


Triosephosphate isomerase is dispensable in vitro yet essential for Mycobacterium tuberculosis to establish infection.
ABSTRACT Triosephosphate isomerase (TPI) catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). This reaction is required for glycolysis and gluconeogenesis, and tpi has been predicted to be essential for growth of Mycobacterium tuberculosis. However, when studying a conditionally regulated tpi knockdown mutant, we noticed that depletion of TPI reduced growth of M. tuberculosis in media containing a single carbon source but not in media that contained both a glycolytic and a gluconeogenic carbon source. We used such two-carbon-source media to isolate a tpi deletion (Δtpi) mutant. The Δtpi mutant did not survive with single carbon substrates but grew like wild-type (WT) M. tuberculosis in the presence of both a glycolytic and a gluconeogenic carbon source. (13)C metabolite tracing revealed the accumulation of TPI substrates in Δtpi and the absence of alternative triosephosphate isomerases and metabolic bypass reactions, which confirmed the requirement of TPI for glycolysis and gluconeogenesis in M. tuberculosis. The Δtpi strain was furthermore severely attenuated in the mouse model of tuberculosis, suggesting that M. tuberculosis cannot simultaneously access sufficient quantities of glycolytic and gluconeogenic carbon substrates to establish infection in mice. IMPORTANCE The importance of central carbon metabolism for the pathogenesis of M. tuberculosis has recently been recognized, but the consequences of depleting specific metabolic enzymes remain to be identified for many enzymes. We investigated triosephosphate isomerase (TPI) because it is central to both glycolysis and gluconeogenesis and had been predicted to be essential for growth of M. tuberculosis. This work identified metabolic conditions that make TPI dispensable for M. tuberculosis growth in culture and proved that M. tuberculosis relies on a single TPI enzyme and has no metabolic bypass for the TPI-dependent interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate in glycolysis and gluconeogenesis. Finally, we demonstrate that TPI is essential for growth of the pathogen in mouse lungs.


Post-uptake metabolism affects quantification of amino acid uptake.
• The quantitative significance of amino acids to plant nutrition remains controversial. This experiment determined whether post-uptake metabolism and root to shoot export differ between glycine and glutamine, and examined implications for estimation of amino acid uptake. • Field soil containing a Eucalyptus pauciflora seedling was injected with uniformly (13)C- and (15)N-labelled glycine or glutamine. I quantified (15)N and (13)C excess in leaves and roots and intact labelled amino acids in leaves, roots and stem xylem sap. A tunable diode laser quantified fluxes of (12)CO(2) and (13)CO(2) from leaves and soil. • 60-360 min after addition of amino acid, intact molecules of U-(13)C,(15)N glutamine were < 5% of (15)N excess in roots, whereas U-(13)C,(15)N glycine was 30-100% of (15)N excess in roots. Intact molecules of glutamine, but not glycine, were exported from roots to shoots. • Post-uptake metabolism and transport complicate interpretation of isotope labelling such that root and shoot contents of intact amino acid, (13)C and (15)N may not reflect rates of uptake. Future experiments should focus on reconciling discrepancies between intact amino acid, (13)C and (15)N by determining the turnover of amino acids within roots. Alternatively, post-uptake metabolism and transport could be minimized by harvesting plants within minutes of isotope addition.


Intimate partner violence screening intention instrument for Thai nursing students: A principal component analysis.
Identifying factors related to intimate partner violence (IPV) screening intentions of future nurses is critical, but no studies specific to this research area exist in Thailand; nor does any validated instrument currently exist to systematically evaluate Thai nursing students' IPV training or measure their readiness to address IPV. The purpose of this study was to develop the Intimate Partner Violence Screening Intention, Nursing Students (IPVSI-NS) for Thai nursing students and identify components explaining their intentions to screen for intimate partner violence (IPV). We designed a Thai-language, culturally appropriate 36-item instrument based on the theory of planned behavior (TPB), which describes intentions as the precursors of actual behaviour. We then conducted an anonymous cross-sectional online survey of female senior Thai nursing students (N = 594). Principal component analysis with varimax methods was used to examine the component structure of the instrument. The internal consistency reliability and convergent construct validity were evaluated. See Supporting File S1. A six-component structure was evident which explained 59.56% of variance and identified: attitudes (advantages and disadvantages of screening), subjective norms (support from important people, and opinions of important people and policy) and perceived behavioural control (training experience, teamwork, facility resources and screening barriers). The IPVSI-NS, based on the TPB, provides a psychometrically sound, reliable and valid tool for Thai nursing educators and researchers to advance nursing education, practice and research regarding IPV. Provides support for the components of the TPB (attitude, subjective norm and perceived behavioural control) as an excellent fit to predict intention of IPV screening for future clinical nurses. Implications for future research and educational practice are discussed.


[Mechanism of the intensification of the immune response to Staphylococcus in mice after the transplantation of primed donor splenocytes].
Experiments on CBA, C57Bl/6 mice and (CBA X X C57Bl/6)F1 hybrids were made to study the mechanism of stimulation of the immune response to staphylococci after injection of primed splenocytes. The stimulating action of immune splenocytes was reversed after their in-vitro treatment with anti-immunoglobulin serum and complement. The stimulant effect was also seen in a semi-allogeneic system (adoptive transfer of CBA mice immune cells to (CBA X C57Bl/6)F1 recipients). Preincubation of splenocytes with CBA-anti-C57Bl/6-serum and complement prior to demonstration of antibody-forming cells did not influence their number in the spleen of hybrid recipients injected with immune cells carrying parent genotype but decreased this indicator of the immune response in control mice. It is concluded that stimulation of the immune response to staphylococci after transplantation of primed splenocytes is due to the anamnestic response of donor's cells repeatedly stimulated by antigen in the recipient's host.


The basis of antimalarial action: non-weak base effects of chloroquine on acid vesicle pH.
Biologically active concentrations of chloroquine increase the pH of the parasite's acid vesicles within 3-5 min. This increase in pH results from two mechanisms, one of which is markedly reduced in chloroquine-resistant parasites. Because chloroquine is a weak base, it increases vesicle pH by that mechanism in chloroquine-susceptible and resistant parasites and mammalian cells (based on its two pKs and on the delta pH between the acid vesicle and the extracellular environment). In chloroquine-susceptible parasites, but not resistant parasites or mammalian cells, chloroquine increases the pH of acid vesicles 700- to 800-fold more than can be accounted for by its properties as a weak base. The increase in acid vesicle pH caused by these non-weak base effects of nanomolar chloroquine in susceptible parasites suggests that chloroquine acts by interfering with acid vesicle functions in the parasite such as the endocytosis and proteolysis of hemoglobin, and the intracellular targeting of lysosomal enzymes. The non-weak base effects of nanomolar chloroquine on parasite vesicle pH are also responsible for its safety because these chloroquine concentrations do not affect mammalian cells.


Cleverballoon: An integrated approach for developing a drug-coated balloon with everolimus.
Coronary artery disease (CAD) is a chronic disease associated with high mortality and morbidity. Although treatment with drug-eluting stents is the most frequent interventional approach for coronary artery disease, drug-coated balloons (DCBs) constitute an innovative alternative, especially in the presence of certain anatomical conditions in the local coronary vasculature. DCBs allow the fast and homogenous transfer of drugs into the arterial wall, during the balloon inflation. Their use has been established for treating in-stent restenosis caused by stent implantation, while recent clinical trials have shown a satisfactory efficacy in de novo small-vessel disease. Several factors affect DCBs performance including the catheter design, the drug dose and formulation. Cleverballoon focuses on the design and development of an innovative DCB with everolimus. For the realization of the development of this new DCB, an integrated approach, including in- vivo, in-vitro studies and in-silico modelling towards the DCB optimization, is presented.Clinical Relevance-The proposed study introduces the integration of in- vivo, in-vitro and in silico approaches in the design and development process of a new DCB, following the principles of 3R's for the replacement, reduction, and refinement of animal and clinical studies.


Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia.
To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions. Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD. Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD.


A study of the transferability of influenza case detection systems between two large healthcare systems.
This study evaluates the accuracy and transferability of Bayesian case detection systems (BCD) that use clinical notes from emergency department (ED) to detect influenza cases. A BCD uses natural language processing (NLP) to infer the presence or absence of clinical findings from ED notes, which are fed into a Bayesain network classifier (BN) to infer patients' diagnoses. We developed BCDs at the University of Pittsburgh Medical Center (BCDUPMC) and Intermountain Healthcare in Utah (BCDIH). At each site, we manually built a rule-based NLP and trained a Bayesain network classifier from over 40,000 ED encounters between Jan. 2008 and May. 2010 using feature selection, machine learning, and expert debiasing approach. Transferability of a BCD in this study may be impacted by seven factors: development (source) institution, development parser, application (target) institution, application parser, NLP transfer, BN transfer, and classification task. We employed an ANOVA analysis to study their impacts on BCD performance. Both BCDs discriminated well between influenza and non-influenza on local test cases (AUCs > 0.92). When tested for transferability using the other institution's cases, BCDUPMC discriminations declined minimally (AUC decreased from 0.95 to 0.94, p<0.01), and BCDIH discriminations declined more (from 0.93 to 0.87, p<0.0001). We attributed the BCDIH decline to the lower recall of the IH parser on UPMC notes. The ANOVA analysis showed five significant factors: development parser, application institution, application parser, BN transfer, and classification task. We demonstrated high influenza case detection performance in two large healthcare systems in two geographically separated regions, providing evidentiary support for the use of automated case detection from routinely collected electronic clinical notes in national influenza surveillance. The transferability could be improved by training Bayesian network classifier locally and increasing the accuracy of the NLP parser.


Zingiber officinale Roscoe (ginger) as an adjuvant in cancer treatment: a review.
Despite acquiring a strong understanding of the molecular basis and advances in treatment, cancer is the second major cause of death in the world. In clinics, the stagedependent treatment strategies may include surgery, radiotherapy and systemic treatments like hormonotherapy and chemotherapy, which are associated with side effects. The use of traditional herbal medicine in cancer patients is on a rise, as it is believed that these medications are non toxic and alleviate the symptoms of cancer, boost the immune system, or may tackle the cancer itself. Since antiquity the rhizome of Zingiber officinale Roscoe commonly known as ginger (family Zingiberaceae) have widely been used as a spice and condiment in different societies. Additionally, ginger also has a long history of medicinal use in various cultures for treating common colds, fever, to aid digestion, treat stomach upset, diarrhoea, nausea, rheumatic disorders, gastrointestinal complications and dizziness. Preclinical studies have also shown that ginger possesses chemopreventive and antineoplastic properties. It is also reported to be effective in ameliorating the side effects of γ-radiation and of doxorubicin and cisplatin; to inhibit the efflux of anticancer drugs by P-glycoprotein (P-gp) and to possess chemosensitizing effects in certain neoplastic cells in vitro and in vivo. The objective of this review is to address observations on the role of ginger as adjuvant to treatment modalities of cancer. Emphasis is also placed on the drawbacks and on future directions for research that will have a consequential effect on cancer treatment and cure.


Donor Indocyanine Green Clearance Test Predicts Graft Quality and Early Graft Prognosis After Liver Transplantation.
Transplantation centers have given much attention to donor availability. However, no reliable quantitative methods have been employed to accurately assess graft quality before transplantation. Here, we report that the indocyanine green (ICG) clearance test is a valuable index for liver grafts. We performed the ICG clearance test on 90 brain-dead donors within 6 h before organ procurement between March 2015 and November 2016. We also analyzed the relationship between graft liver function and early graft survival after liver transplantation (LT). Our results suggest that the ICG retention rate at 15 min (ICGR15) of donors before procurement was independently associated with 3-month graft survival after LT. The best donor ICGR15 cutoff value was 11.0%/min, and we observed a significant increase in 3-month graft failure among patients with a donor ICGR15 above this value. On the other hand, a donor ICGR15 value of ≤ 11.0%/min could be used as an early assessment index of graft quality because it provides additional information to the transplant surgeon or organ procurement organization members who must maintain or improve organ function to adapt the LT. An ICG clearance test before liver procurement might be an effective quantitative method to predict graft availability and improve early graft prognosis after LT.


SynCardia Portable Freedom Driver: A Single-Center Experience With 11 Patients.
The portable Freedom Drive (SynCardia Inc, Tucson, AZ USA) for total artificial heart (TAH-t) support was approved for an investigational device exemption study in March 2010. We review our center's experience with the portable driver. A retrospective review was conducted of patients who underwent TAH-t implantation and transfer to portable driver from September 2008 to June 2012, with follow-up through December 2012. A total of 30 patients underwent TAH-t implantation during this time period, with 11 patients successfully transferred to the Freedom Driver. Transfer to Freedom Driver after TAH-t implant was a median of 46 days (range, 225-86 days). Ninety-one percent (10) of 11 patients transferred to Freedom Driver were bridged to transplantation. One patient died on support. Five (45.5%) of 11 patients were discharged home and 5 (45.5%) remained in-patient on the portable driver before transplantation. Four patients (80%) successfully discharged home required at least 1 hospital readmission (range, 1-5 admissions per patient). Six patients (55%) transferred to the portable driver required a return to a main driver console. Two patients were temporarily maintained on the main driver then returned to the Freedom Driver for bridge to transplantation. Patients with TAH-t can be considered for transfer to the portable Freedom Driver while awaiting transplantation. Issues that complicated this patient population included inadequate social support, hemodynamic instability, and concurrent morbidities. The potential benefits of the portable driver are currently undergoing assessment. These may include increased mobility and improved quality of life, opportunity for discharge home, and decreased overall medical costs.


A radiation hybrid map of the cat genome: implications for comparative mapping.
Ordered gene maps of mammalian species are becoming increasingly valued in assigning gene variants to function in human and animal models, as well as recapitulating the natural history of genome organization. To extend this power to the domestic cat, a radiation hybrid (RH) map of the cat was constructed integrating 424 Type I-coding genes with 176 microsatellite markers, providing coverage over all 20 feline chromosomes. Alignment of parallel RH maps of human and cat reveal 100 conserved segments ordered (CSOs) between the species, nearly three times the number observed with reciprocal chromosome painting analyses. The observed number is equivalent to theoretical predictions of the number of conserved segments to be found between cat and human, implying that 300-400 Type I gene markers is sufficient to reveal nearly all conserved segments for species that exhibit the most frequently observed "slow" rate of genome reorganization. The cat-human RH map comparisons provide a new genomic tool for comparative gene mapping in the cat and related Felidae, and provide confirmation that the cat genome organization is remarkably conserved compared with human. These data demonstrate that ordered RH-based gene maps provide the most precise assessment of comparing genomes, short of contig construction or full-sequence determination.


Risk factors associated with early smoking onset in two large birth cohorts.
We use prospective data from the ongoing British Cohort Study (BCS) and Millennium Cohort Study (MCS) to: 1) document changes in the prevalence of childhood smoking onset; 2) assess whether broad historic shifts in key risk factors, such as maternal education, parental smoking, and peer childhood smoking, explain observed cohort changes in childhood smoking; and 3) evaluate whether inequalities in onset have narrowed or widened during this period. The children in these two studies were born 31 years apart (i.e., BCS in 1970; MCS in 2001), and were followed from infancy through early adolescence (n = 23,506 children). Our outcome variable is child self-reports of smoking (ages 10, 11). Early life risk factors were assessed via parent reports in infancy and age 5. Findings reveal that the odds of childhood smoking were over 12 times greater among children born in 1970 versus 2001. The decline in childhood smoking by cohort was partly explained by increases in maternal education, decreases in mothers' and fathers' smoking, and declines in the number of children whose friends smoked. Results also show that childhood smoking is now more linked to early life disadvantages, as MCS children were especially likely to smoke if their mother had low education or used cigarettes, or if the child had a friend who smoked. Although the prevalence of child and adult smoking has dropped dramatically in the past three decades, policy efforts should focus on the increased social inequality resulting from the concentration of early life cigarette use among disadvantaged children.


Surface antigens of BK virus-induced tumor cells.
The presence and nature of surface antigens in BKV-induce tumor cells was studied by transplantation rejection experiments, immunofluorescent staining and by complement-mediated cytotoxicity assay. Immunization with an irradiated BKV-induced hamster tumor cell line protective syngeneic hamsters not only against a challenge of the same tumor cells but also against a SV40-induced hamster tumor cell line. A control hamster cell line (HDC-22) was also able to protect the hamsters against the later challenge with a BKV-transformed hamster cell line. In addition to species-specific reactions, cross-reactions between BKV-transformed hamster and rat tumor cells were detected by immunofluorescent staining of surface antigens. This reactivity was not due to the Forssman antigen, because the rat cell lines studied were negative by the same method using Forssman antiserum. By the complement-mediated cytolytic antibody assay using [51]Cr-labelled tumor cells as targets a "public" antigen was found again in BKV-, SV40- and non-virally transformed hamster and BKV-transformed rat cell lines.


VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes.
Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic alleles are implicated, either in homozygosis or compound heterozygosis. In this report, to identify the common underlying pathogenic mechanism of VRK1 polymorphisms, we have studied all human VRK1 variants identified in these neurological phenotypes from a biochemical point of view by molecular modeling, protein stability and kinase activity assays. Molecular modelling predicted that VRK1 variant proteins are either unstable or have an altered kinase activity. The stability and kinase activity of VRK1 pathogenic variants detected two groups. One composed by variants with a reduced protein stability: R133C, R358X, L195V, G135R and R321C. The other group includes VRK1variants with a reduced kinase activity tested on several substrates: histones H3 and H2AX, p53, c-Jun, coilin and 53BP1, a DNA repair protein. VRK1 variants with reduced kinase activity are H119R, R133C, G135R, V236M, R321C and R358X. The common underlying effect of VRK1 pathogenic variants with reduced protein stability or kinase activity is a functional insufficiency of VRK1 in patients with neuromotor developmental syndromes. The G135 variant cause a defective formation of 53BP1 foci in response to DNA damage, and loss Cajal bodies assembled on coilin.


Receptor-targeting fluorescence imaging and theranostics using a graphene oxide based supramolecular glycocomposite.
Intercellular glycoligand-receptor interactions are implicated in a number of disease-related processes. Effective tools that target these receptors may facilitate disease theranostics. However, owing to their low binding affinity, multivalent presentation of glycoligands is needed to increase the avidity with transmembrane receptors. While previous strategies focus on the covalent coupling of glycoligands to a synthetic backbone, we show here that the use of graphene oxide (GO) greatly enhances the cellular and tissue imaging ability of a small-molecule fluorescence glycoprobe. We determine that GO with an optimum size may serve as a clustering platform to reinforce the interaction of the glycoprobe with its selective receptor on a cancer cell. This phenomenon has been consistently observed with the xenograft tissue of a tumor-bearing mouse. Using this principle we have further constructed a supramolecular glycocomposite by co-assembling the glycoprobe and an anticancer drug onto a single GO surface. In addition to imaging ability, this material displays improved toxicity for liver cancer cells that over express the glycoprotein receptor, when compared to the control cells.


Long-term evaluation of air sensor technology under ambient conditions in Denver, Colorado.
Air pollution sensors are quickly proliferating for use in a wide variety of applications, with a low price point that supports use in high-density networks, citizen science, and individual consumer use. This emerging technology motivates the assessment under real-world conditions, including varying pollution levels and environmental conditions. A seven-month, systematic field evaluation of low-cost air pollution sensors was performed in Denver, Colorado, over 2015-2016; the location was chosen to evaluate the sensors in a high-altitude, cool, and dry climate. A suite of particulate matter (PM), ozone (O3), and nitrogen dioxide (NO2) sensors were deployed in triplicate and were collocated with federal equivalent method (FEM) monitors at an urban regulatory site. Sensors were evaluated for their data completeness, correlation with reference monitors, and ability to reproduce trends in pollution data, such as daily concentration values and wind-direction patterns. Most sensors showed high data completeness when data loggers were functioning properly. The sensors displayed a range of correlations with reference instruments, from poor to very high (e.g., hourly-average PM Pearson correlations with reference measurements varied from 0.01 to 0.86). Some sensors showed a change in response to laboratory audits/testing from before the sampling campaign to afterwards, such as Aeroqual, where the O3 response slope changed from about 1.2 to 0.6. Some PM sensors measured wind-direction and time-of-day trends similar to those measured by reference monitors, while others did not. This study showed different results for sensor performance than previous studies performed by the U.S. EPA and others, which could be due to different geographic location, meteorology, and aerosol properties. These results imply that continued field testing is necessary to understand emerging air sensing technology.


A New Theoretical Approach of Wall Transpiration in the Cavity Flow of the Ferrofluids.
An idea of permeable (suction/injection) chamber is proposed in the current work to control the secondary vortices appearing in the well-known lid-driven cavity flow by means of the water based ferrofluids. The Rosensweig model is conveniently adopted for the mathematical analysis of the physical problem. The governing equation of model is first transformed into the vorticity transport equation. A special finite difference method in association with the successive over-relaxation method (SOR) is then employed to numerically simulate the flow behavior. The effects of intensity of magnetic source (controlled by the Stuart number), aspect ratio of the cavity, rate of permeability (i.e., α p = V 0 U ), ratio of speed of suction/injection V 0 to the sliding-speed U of the upper wall of a cavity, and Reynolds number on the ferrofluid in the cavity are fully examined. It is found that the secondary vortices residing on the lower wall of the cavity are dissolved by the implementation of the suction/injection chamber. Their character is dependent on the rate of permeability. The intensity of magnetic source affects the system in such a way to alter the flow and to transport the fluid away from the magnetic source location. It also reduces the loading effects on the walls of the cavity. If the depth of cavity (or the aspect ratio) is increased, the secondary vortices join together to form a single secondary vortex. The number of secondary vortices is shown to increase if the Reynolds number is increased for both the clear fluid as well as the ferrofluids. The suction and injection create resistance in settlement of solid ferroparticles on the bottom. The results obtained are validated with the existing data in the literature and satisfactory agreement is observed. The presented problem may find applications in biomedical, pharmaceutical, and engineering industries.


Mechanisms underlying blockade of allograft acceptance by TLR ligands.
Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4(+)Foxp3(+) T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that although Th17 cells differentiate from naive alloreactive T cells, these cells do not arise from natural Tregs in either CpG-treated or untreated graft recipients. Finally, we show that CpG impairs natural Treg suppressor capability and prevents Treg-dependent allograft acceptance in an IL-6-independent fashion. Our data therefore suggest that TLR signals do not prevent prolonged graft acceptance by directing natural Tregs into the Th17 lineage or by using other IL-6-dependent mechanisms. Instead, graft destruction results from the ability of CpG to drive Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4(+)Foxp3(+) Tregs.


Calcium participates in feedback regulation of the oscillating ROP1 Rho GTPase in pollen tubes.
Biological oscillation occurs at various levels, from cellular signaling to organismal behaviors. Mathematical modeling has allowed a quantitative understanding of slow oscillators requiring changes in gene expression (e.g., circadian rhythms), but few theoretical studies have focused on the rapid oscillation of cellular signaling. The tobacco pollen tube, which exhibits growth bursts every 80 s or so, is an excellent system for investigating signaling oscillation. Pollen tube growth is controlled by a tip-localized ROP1 GTPase, whose activity oscillates in a phase about 90 degrees ahead of growth. We constructed a mathematical model of ROP1 activity oscillation consisting of interlinking positive and negative feedback loops involving F-actin and calcium, ROP1-signaling targets that oscillate in a phase about 20 degrees and 110 degrees behind ROP1 activity, respectively. The model simulates the observed changes in ROP1 activity caused by F-actin disruption and predicts a role for calcium in the negative feedback regulation of the ROP1 activity. Our experimental data strongly support this role of calcium in tip growth. Thus, our findings provide insight into the mechanism of pollen tube growth and the oscillation of cellular signaling.


Elimination diets in the management of eosinophilic esophagitis.
Eosinophilic esophagitis, an increasingly recognized chronic inflammatory disorder isolated to the esophagus, is triggered by an abnormal allergic response to dietary antigens. Current treatment includes swallowed topical steroids and dietary modification, which aim to resolve symptoms and prevent long-term complications such as formation of strictures. The dietary approach has become more widely accepted because long-term steroid therapy is associated with potential risks. Dietary treatment includes elemental and elimination diets. An exclusive elemental diet, which requires replacement of all intact protein with amino acid-based formula, offers the best response of all available therapies, with remission in up to 96% of subjects proving it to be superior to all other available therapies including topical steroids. However, compliance with this approach is challenging because of poor taste and monotony. The high cost of formula and the associated psychosocial problems are additional drawbacks of this approach. Empiric and allergy test-directed elimination diets have gained popularity given that elimination of a limited number of foods is much easier and as such is more readily acceptable. There is a growing body of literature supporting this type of therapy in both children and adults. This paper reviews the evidence for all types of dietary therapy in eosinophilic esophagitis.


Comparative QSAR studies on peptide deformylase inhibitors.
Comparative quantitative structure-activity relationship (QSAR) analyses of peptide deformylase (PDF) inhibitors were performed with a series of previously published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives having antibacterial activity against Escherichia coli PDF, using 2D and 3D QSAR methods, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR). Statistically reliable models with good predictive power were generated from all three methods (CoMFA r (2) = 0.957, q (2) = 0.569; CoMSIA r (2) = 0.924, q (2) = 0.520; HQSAR r (2) = 0.860, q (2) = 0.578). The predictive capability of these models was validated by a set of compounds that were not included in the training set. The models based on CoMFA and CoMSIA gave satisfactory predictive r (2) values of 0.687 and 0.505, respectively. The model derived from the HQSAR method showed a low predictability of 0.178 for the test set. In this study, 3D prediction models showed better predictive power than 2D models for the test set. This might be because 3D information is more important in the case of datasets containing compounds with similar skeletons. Superimposition of CoMFA contour maps in the active site of the PDF crystal structure showed a meaningful correlation between receptor-ligand binding and biological activity. The final QSAR models, along with information gathered from 3D contour and 2D contribution maps, could be useful for the design of novel active inhibitors of PDF.


A Comparison of Behavioral Methods for Indexing the Auditory Processing of Temporal Fine Structure Cues.
Purpose Growing evidence supports the inclusion of perceptual tests that quantify the processing of temporal fine structure (TFS) in clinical hearing assessment. Many tasks have been used to evaluate TFS in the laboratory that vary greatly in the stimuli used and whether the judgments require monaural or binaural comparisons of TFS. The purpose of this study was to compare laboratory measures of TFS for inclusion in a battery of suprathreshold auditory tests. A subset of available TFS tasks were selected on the basis of potential clinical utility and were evaluated using metrics that focus on characteristics important for clinical use. Method TFS measures were implemented in replication of studies that demonstrated clinical utility. Monaural, diotic, and dichotic measures were evaluated in 11 young listeners with normal hearing. Measures included frequency modulation (FM) tasks, harmonic frequency shift detection, interaural phase difference (TFS-low frequency), interaural time difference (ITD), monaural gap duration discrimination, and tone detection in noise with and without a difference in interaural phase (N0S0, N0Sπ). Data were compared with published results and evaluated with metrics of consistency and efficiency. Results Thresholds obtained were consistent with published data. There was no evidence of predictive relationships among the measures consistent with a homogenous group. The most stable tasks across repeated testing were TFS-low frequency, diotic and dichotic FM, and N0Sπ. Monaural and diotic FM had the lowest normalized variance and were the most efficient accounting for differences in total test duration, followed by ITD. Conclusions Despite a long stimulus duration, FM tasks dominated comparisons of consistency and efficiency. Small differences separated the dichotic tasks FM, ITD, and N0Sπ. Future comparisons following procedural optimization of the tasks will evaluate clinical efficiency in populations with impairment.


A new approach to detect early or hidden fungal development in indoor environments.
In addition to the biodegradation problems encountered in buildings, exposure of their occupants to mold is responsible for numerous diseases such as respiratory infections, immediate or delayed allergies and different types of irritations. However, current techniques are unable to detect mold at an early stage of development or hidden contaminants. Moularat et al., in 2008 has established chemical fingerprints of moldy growth from Volatile Organic Compounds (VOCs) arising specifically from fungal metabolism and developed the Fungal Contamination Index (FCI) (Moularat et al., 2008a,b). This index has the advantage of detecting fungal development both reliably and rapidly before any visible signs of contamination could be detected. However, even though the FCI has been widely tested, VOCs' analysis by GC/MS, which is required for index calculation, is incompatible with real-time monitoring strategy for indoor environments. In this context, researches around FCI exploitation have been followed up in order to provide a monitoring device widely deployable which is the result of the miniaturization of an analytical chain for portable, reliable and low-cost applications. This device is based on one hand the selection and concentration of chemical compounds from the sample of interest and on the other hand the development of an array of different conducting polymer based sensors in order to obtain a specific footprint. This fungal contamination detection device was the subject of patent applications by the CSTB. The modularity of the system (ability to vary both the elements of detection polymers and retention time of interest) allows for expansion of its use to other pollutants.


Sulfadoxine-pyrimethamine embryopathy in Wistar rats.
Pregnant Wistar rats received a therapeutic dose (0.72 mg/kg body weight) of intramuscular sulfadoxine-pyrimethamine on days 5, 12, and 19 of gestation. The treated animals showed elevated neutrophilic lobe average and increased urinary excretion of formiminoglutamic acid (FIGLU) as compared with controls (p < 0.001), confirming folic acid deficiency due to sulfadoxine-pyrimethamine treatment. Complete embryo resorption occurred in the treatment group, while the control animals littered normally. These findings imply that sulfadoxine-pyrimethamine should be used with utmost caution in early pregnancy as this regimen can lead to folic acid deficiency and consequent pregnancy wastage.


PMLPR: A novel method for predicting subcellular localization based on recommender systems.
The importance of protein subcellular localization problem is due to the importance of protein's functions in different cell parts. Moreover, prediction of subcellular locations helps to identify the potential molecular targets for drugs and has an important role in genome annotation. Most of the existing prediction methods assign only one location for each protein. But, since some proteins move between different subcellular locations, they can have multiple locations. In recent years, some multiple location predictors have been introduced. However, their performances are not accurate enough and there is much room for improvement. In this paper, we introduced a method, PMLPR, to predict locations for a protein. PMLPR predicts a list of locations for each protein based on recommender systems and it can properly overcome the multiple location prediction problem. For evaluating the performance of PMLPR, we considered six datasets RAT, FLY, HUMAN, Du et al., DBMLoc and Höglund. The performance of this algorithm is compared with six state-of-the-art algorithms, YLoc, WOLF-PSORT, prediction channel, MDLoc, Du et al. and MultiLoc2-HighRes. The results indicate that our proposed method is significantly superior on RAT and Fly proteins, and decent on HUMAN proteins. Moreover, on the datasets introduced by Du et al., DBMLoc and Höglund, PMLPR has comparable results. For the case study, we applied the algorithms on 8 proteins which are important in cancer research. The results of comparison with other methods indicate the efficiency of PMLPR.


Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway.
Palmitoylation is postulated to regulate Ras signaling by modulating its intracellular trafficking and membrane microenvironment. The mechanisms by which palmitoylation contributes to these events are poorly understood. Here, we show that dynamic turnover of palmitate regulates the intracellular trafficking of HRas and NRas to and from the Golgi complex by shifting the protein between vesicular and nonvesicular modes of transport. A combination of time-lapse microscopy and photobleaching techniques reveal that in the absence of palmitoylation, GFP-tagged HRas and NRas undergo rapid exchange between the cytosol and ER/Golgi membranes, and that wild-type GFP-HRas and GFP-NRas are recycled to the Golgi complex by a nonvesicular mechanism. Our findings support a model where palmitoylation kinetically traps Ras on membranes, enabling the protein to undergo vesicular transport. We propose that a cycle of depalmitoylation and repalmitoylation regulates the time course and sites of Ras signaling by allowing the protein to be released from the cell surface and rapidly redistributed to intracellular membranes.


Immunologically induced generation of tetraene and pentaene leukotrienes in the peritoneal cavities of menhaden-fed rats.
The generation of sulfidopeptide leukotrienes and leukotriene B (LTB) in response to an IgG-mediated immune complex reaction in the peritoneal cavities of rats fed either a menhaden oil-supplemented diet or a beef tallow-supplemented diet for 9 to 10 wk was determined with the combined techniques of radioimmunoassay (RIA) and reverse-phase high performance liquid chromatography. Rats on the fish fat diet (FFD) incorporated eicosapentaenoic acid (EPA) into pulmonary and splenic tissues with an EPA:arachidonic acid ratio of approximately 2:1, whereas rats on the beef fat diet (BFD) showed no detectable EPA. The estimated total quantities of immunoreactive sulfidopeptide leukotrienes generated by each group of rats were similar, ranging from 70 to 99 ng/ rat in the FFD groups and 65 to 109 ng/rat in the BFD groups; for rats on the FFD this total included the pentaene products LTC5, LTD5, and LTE5 in quantities ranging from 24 to 39 ng/rat. The total quantities of immunoreactive LTB generated in the two groups of rats were similar, being 6 to 29 ng LTB4/rat for the BFD groups and the sum of LTB4 and LTB5 of 8 to 36 ng/rat for the FFD groups. There was a two- to seven-fold preferential generation of immunoreactive LTB5 over LTB4 in the FFD rats. LTC5 was equipotent with LTC4 in contracting guinea pig pulmonary parenchymal strips and ileal tissues. In contrast, LTB5 was 1/30 to 1/60 as potent and did not reach the same maximum as LTB4 in eliciting neutrophil chemotaxis. The finding that FFD favors the immunologic generation of LTB5, which has attenuated biologic activity when compared to LTB4, suggests that EPA-enriched tissues may produce less pro-inflammatory activity than tissues that are EPA-poor.


Photosynthetic utilization of internal carbon dioxide by hollow-stemmed plants.
The hollow stems of wet-meadow and bog plants often contain relatively large amounts of carbon dioxide. The internal carbon dioxide apparently originates from respiration of root and stem cells. Some of this carbon dioxide is fixed photosynthetically by stem tissues and is thus recycled within the plant. Such internal stem photosynthesis would be advantageous, particularly in the early stages of growth in cold, wet, high-altitude environments.


Diet-induced obesity has a differential effect on adipose tissue and macrophage inflammatory responses of young and old mice.
Obesity and aging are both associated with increased inflammation in adipose tissue. In this study, we investigated effect of diet-induced obesity on inflammatory status in young and old mice. Young (2 months) and old (19 months) C57BL/6 mice were fed a low-fat (10%, LF) or high-fat (60%, HF) diet for 4.5 months. Adipose tissue from old/LF mice expressed higher levels of IL-1β, IL-6, TNFα, and cyclooxygenase-2 mRNA compared with young/LF mice. HF diet upregulated expression of all these inflammatory markers in young mice to the levels seen in the aged. Adipocytes, but not stromal vascular cells, from old/LF mice produced more IL-6, TNFα, and prostaglandin (PG)E2 than those from young/LF mice. HF diet resulted in an increase of all these markers produced by adipocytes in young, but only TNFα in old mice. PGE2 produced by peritoneal macrophages (Mϕ's) was upregulated with aging, and HF diet induced more IL-6, TNFα, and PGE2 production in young but not in old mice. Thus, HF diet/obesity induces an inflammatory state in both visceral fat cells and peritoneal Mϕ's of young mice, but not so in old mice. Together, these results suggest that HF diet-induced obesity may speed up the aging process as characterized by inflammatory status. This study also indicates that animals have a differential response, depending on their ages, to HF diet-induced obesity and inflammation. This age-related difference in response to HF diet should be considered when using inflammation status as a marker in investigating adverse health impacts of HF diet and obesity.


Effects of retinoic acid, triiodothyronine and hydrocortisone on mucin and lysozyme expression in cultured human middle ear epithelial cells.
Mucous hypersecretion is a major complication of otitis media and can prolong the disease course and increase morbidity. Mucin, a major component of mucus, is a macromolecular complex of glycoprotein and makes mucus viscous. Lysozyme is a secretory element of the middle ear mucosa. which has a non-specific and innate antibacterial function. We attempted to identify factors that regulate these secretory products and their morphological phenotype using cultured human middle ear epithelial cells. Cellular differentiation was induced by creating an air liquid interface on culture day 9 in serum-free conditioned media. Omission of retinoic acid (RA) caused decrease in the secretion of mucin and lysozyme, and in the cellular expression of MUC 2, MUC 5AC and MUC 5B mRNA. In contrast, removal of triiodothyronine (T3) caused an increase in the secretion of mucin and the level of MUC5AC mRNA. When hydrocortisone (HC) was removed from the media, the secretion of mucin was decreased with out an apparent change of message level. The expression of MUC 1 mRNA was not changed by the respective deficiency of RA. T3 or HC. The effect of T3 or HC on lysozyme was not significant. This study shows that RA, T3 and HC influence the morphological phenotype and the secretory function of mucin and lysozyme in cultured human middle ear epithelial cells. This culture system can serve as an in vitro model for study of the regulation of various cellular secretions in human middle ear epithelium.


The effect of halide salts on the production of Gymnoascus reessii polyenylpyrroles.
Addition of NaCl to the solid-phase fermentation of an Australian isolate of Gymnoascus reessii resulted in enhanced production of chloropolyenylpyrroles, while the addition of NaBr suppressed chloropolyenylpyrrole production in favor of bromo and dechloro analogues. Access to a wider selection of polyenylpyrroles provided scope for SAR comparisons on this rare class of cytotoxic natural products, with the bromo- and dechloropolyenylpyrroles displaying significantly reduced cytotoxicity. These results suggest that the chloro substituent is a critical element in the pharmacophore for this rare class of natural product.


Prospective study of dietary fat and risk of cataract extraction among US women.
The authors examined prospectively the association between dietary fat intake and cataract extraction in adult women from the Nurses' Health Study. A total of 71,083 women were followed prospectively for up to 16 years between 1984 and 2000. Dietary fat was assessed by repeated food frequency questionnaires. Incident cases of cataract extraction were determined by a biennial questionnaire. The multivariate-adjusted relative risk for the highest compared with the lowest quintile of total fat intake was 1.10 (95% confidence interval (CI): 0.99, 1.22; p(trend) = 0.01). Women in the highest quintile of long-chain omega-3 fatty acid had a 12% lower risk of cataract extraction compared with those in the lowest quintile (relative risk = 0.88, 95% CI: 0.79, 0.98; p(trend) = 0.02). Total fish intake was inversely associated with cataract (for intake of > or = 3/week vs. <1/month: relative risk = 0.89, 95% CI: 0.81, 0.98; p(trend) = 0.01). The authors' findings suggest that higher intake of long-chain omega-3 fatty acid (eicosapentaenoic acid and docosahexaenoic acid) and consumption of fish may modestly reduce the risk of cataract.


[The influence of 6-months treatment with exenatide on type 2 diabetes mellitus compensation, anthropometric and biochemical parameters].
Exenatide, a synthetic GLP-1 analogue, is a new antidiabetic agent from the group ofincretine mimetics coming into the daily clinical practice. In our study we evaluated the effect of 6-months treatment with exenatide on diabetes compensation, anthropometric and biochemical parameters in the patients with poorly controlled type 2 diabetes mellitus and obesity. We included 18 patients with poorly controlled diabetes (mean HbA1c 8.5 +/- 0.3%) treated with diet and peroral antidiabetic agents (4 patients were treated with insulin in the past). Exenatide was administered via subcutaneous injection twice daily for 6 months. Patients were examined after 1 month, when the dose ofexenatide was increased from 5 microg twice daily to 10 microg twice daily and after 3 and 6 months. We evaluated the diabetes compensation, biochemical parameters, body weight changes and side effects ofexenatide. 6-months exenatide treatment significant decreased body weight (baseline vs 6 month treatment 107.3 +/- 4.4 kg vs 103.7 +/- 4.6 kg, p = 0.02), BMI (36.7 +/- 1.2 kg/m2 vs 35.3 +/- 1.3 kg/m2, p = 0.01) a HbA1c (8.5 +/- 0.3% vs 7.4 +/- 0.4%, p = 0.04) and increased HDL-cholesterol (0.92 +/- 0.1 mmol/l vs 0.98 +/- 0.1 mmol/l, p = 0.02). Fasting glycemia tended to decline at the end of the study, but the difference did not reach the statistical significance. The area under the curve of glycemia levels after the standardized breakfast in the subgroup of 8 patients after the 6-months exenatide treatment was significantly lower when compared to baseline values (2,908 +/- 148 vs 2,093 +/- 194, p = 0.03). Concentrations of total and LDL-cholesterol and triglycerides did not change significantly. The most frequent side effects of exenatide treatments were transient anorexia and nausea (38.5%), dyspepsia and functional gastrointestinal discomfort (38.5%) and various neuropsychical symptoms (nervosity and insomnia - 30.8%). Most of the side effects disappeared during the treatment, none of these side effects was a reason for discontinuation of a treatment. 3 minor hypoglycemic episodes occured in patients simultaneously treated with derivates of sulfonylurea, but no serious hypoglycemia occured during the entire study. Exenatide treatment in obese patients with poor diabetes control was accompanied by statistically significant decrease of body weight, improvement of diabetes control and increase in HDL-cholesterol.


Background rates of x-ray transition-edge sensor micro-calorimeters under a frequency domain multiplexing readout for solar axion-like particles' detection.
We report on the x-ray background rate measured with transition-edge sensors (TES) micro-calorimeters under frequency-domain multiplexing (FDM) readout as a possible technology for future experiments aiming at a direct detection of axion-like particles. Future axion helioscopes will make use of large magnets to convert axions into photons in the keV range and x-ray detectors to observe them. To achieve this, a detector array with high spectral performance and extremely low background is necessary. TES are single-photon, non-dispersive, high-resolution micro-calorimeters and represent a possible candidate for this application. We have been developing x-ray TES micro-calorimeters and an FDM readout technology in the framework of the space-borne x-ray astronomical observatories. We show that the current generation of our detectors is already a promising technology for a possible axion search experiment, having measured an x-ray background rate of 2.2(2) × 10-4 cm-2 s-1 keV-1 with a cryogenic demonstrator not optimized for this specific application. We then make a prospect to further improve the background rate down to the required value (<10-7 cm-2 s-1 keV-1) for an axion-search experiment, identifying no fundamental limits to reach such a level.


Atropine does not attenuate cerebral vasodilatation during hypercapnia.
To study the contribution of cholinergic nerves to cerebral vasodilation during hypercapnia, we blocked muscarinic cholinergic receptors with atropine. We used two new approaches. First, total and regional cerebral blood flow (CBF) were measured with microspheres. Second, efficacy and specificity of muscarinic blockade by atropine were examined using the cranial window method. In anesthetized cats we measured CBF with 15-micrometers microspheres six times during each experiment: during normocapnia (PCO2 = 32-34 Torr), moderate hypercapnia (PCO2 = 48-50 Torr), and severe hypercapnia (PCO2 = 61-64 Torr), before and after intravenous administration of vehicle or atropine (0.5 mg/kg). Hypercapnia produced graded increases in blood flow in all areas of the brain. Atropine did not attenuate increases in CBF during hypercapnia. We examined efficacy and specificity of muscarinic blockade by atropine using the cranial window method. Acetylcholine (10(-7) and 10(-6) M) and adenosine (10(-7) and 10(-5) M), dissolved in artificial cerebrospinal fluid, dilated pial arteries in a dose-dependent fashion. Intravenous administration of atropine attenuated vasodilation produced by acetylcholine but did not affect the response to adenosine. Thus atropine, at a dose that effectively blocked muscarinic receptors, did not attenuate the increase in CBF during hypercapnia. The study suggests that cholinergic nerves are not involved in steady-state cerebral vasodilatation during hypercapnia.