Enhanced myocardial depression in diabetic rats during E. coli sepsis.
The aim of this study was to determine whether diabetes enhanced the sensitivity of the myocardium to the deleterious effects of in vivo-administered Escherichia coli. Diabetes was induced in two groups of animals. One group received 70 mg/kg streptozotocin (iv) and exhibited a severe diabetes with elevated fasting and fed blood glucose concentrations and a markedly abnormal response to an oral glucose load. The second group received 45 mg/kg streptozotocin, was mildly diabetic (termed "latent" diabetes), and was characterized by normal fasting blood glucose but slightly elevated fed blood glucose and an abnormal response to a glucose load. A third group of rats received vehicle and served as time-matched control animals. Four weeks after induction of diabetes, all animals were catheterized under ether anesthesia and some received intraperitoneal injections of live E. coli. In vitro myocardial performance was assessed using the isolated, perfused working heart preparation. Ventricular function curves were generated by changing left atrial filling pressure and measuring changes in heart rate, cardiac output, and aortic peak systolic pressure. Cardiac performance in the severe diabetic group was depressed at the highest preload but was unchanged at lower preloads. Function in the latent diabetic group was not different from control. Sepsis induced a slight decrease in cardiac performance in the control group and resulted in larger reductions in the latent and severe diabetic groups. A depression in aortic flow was the major consequence of sepsis in the latent diabetic group, whereas decreased coronary flow was the primary change in the severe diabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)


Communication between Human Dendritic Cell Subsets in Tuberculosis: Requirements for Naive CD4(+) T Cell Stimulation.
Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c(+) cells and pDCs (C-type lectin 4C(+) cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141(hi) DCs (C-type lectin 9A(+) cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c(+) DCs compared to CD141(hi) DCs and pDCs. CD1c(+) DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c(+) DCs were able to activate autologous naïve CD4(+) T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4(+) T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c(+) cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c(+) DCs and pDCs favors stimulation of CD4(+) T cells.


Immunoactivative role of indoleamine 2,3‑dioxygenase in gastric cancer cells in vitro.
To study the role of indoleamine 2,3-dioxygenase (IDO) in immune response and immune escape in gastric cancer, the human IDO gene was cloned by reverse transcription-polymerase chain reaction (RT-PCR) and inserted into the pIRES2-EGFP vector to construct the IDO expression vector (pIRES2-EGFP-IDO). BGC-823 cells were transfected with the vector by electroporation and selected stable expression with G418. IDO expression was determined by RT-PCR and Western blot analysis. The enzymatic activity of IDO was estimated by determining tryptophan and kynurenine concentrations in the cell culture medium by an amino acid analyzer. To assess the effect of IDO on T cell-mediated cytotoxicity and proliferation, T cells from patients with gastric cancer were co-cultured with the IDO-transfected BGC-823 cells in the presence or absence of 1-MT, a competitive inhibitor of IDO. Cells transfected with the vector expressed high levels of IDO mRNA and protein, and a significantly higher level of kynurenic acid was detected in the culture medium of the transfected cells compared to the non-transfected cells (P<0.001). T cells co-cultured with the IDO-transfected cells exhibited significantly lower cytotoxicity compared to the control group (P<0.05). Additionally, IDO-transfected cells treated with 1-MT exhibited higher toxicity compared to the untreated IDO-transfected cells (P<0.01). We conclude that IDO plays a key role in gastric cancer immune suppression, possibly by inhibiting T cell-mediated cytotoxicity and proliferation in vitro.


Nebulization versus metered-dose inhaler and spacer in bronchodilator responsiveness testing: a retrospective study.
The recommended delivery mode for bronchodilators in bronchodilator responsiveness (BDR) testing remains controversial. To compare the efficacy of salbutamol administration using a nebulizer versus a metered-dose inhaler (MDI) with spacer in BDR testing. A retrospective study. This study examined the data of patients with chronic obstructive pulmonary disease who completed BDR testing between 1 December 2021 and 30 June 2022, at Xiangya Hospital, Central South University. After administering 400 μg of salbutamol through an MDI with spacer or 2.5 mg using a nebulizer, the changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were analyzed in patients with moderate-to-very severe spirometric abnormalities [pre-bronchodilator FEV1 percentage predicted values (FEV1%pred) ⩽59%]. Significant responsiveness was assessed as >12% and >200 mL improvement in FEV1 and/or FVC or >10% increase in FEV1%pred or FVC percentage predicted values (FVC%pred) from pre- to post-bronchodilator administration. Of the enrolled 894 patients, 83.2% were male (median age, 63 years). After propensity score matching, 240 pairs of patients were selected. The increment in FEV1 and increased FEV1 relative to the predicted value (ΔFEV1%pred) were significantly higher in patients <65 years and those with severe spirometric abnormalities in the nebulization group than patients in the MDI group (all p < 0.05). Compared with MDI with spacer, patients who used nebulization had a 30 mL greater increase in ΔFEV1 (95% CI: 0.01-0.05, p = 0.004) and a 1.09% greater increase in ΔFEV1%pred (95% CI: 0.303-1.896, p = 0.007) from baseline. According to the > 12% and >200 mL increase criterion, the significant BDR rate with nebulization was 1.67 times higher than that with an MDI with spacer (OR = 1.67, 95% CI: 1.13-2.47, p = 0.009). Salbutamol delivered using a nebulizer may be preferable to an MDI with spacer in certain circumstances. Nebulization has the potential to increase responsiveness to salbutamol in BDR testing.


The protective effects of pirfenidone in preventing abdominal aortic aneurysm formation.
Vascular endothelial growth factor (VEGF)-mediated angiogenesis participates in the initiation and progression of abdominal aortic aneurysm (AAA). Pirfenidone is a compound that has anti-inflammatory and antioxidant properties and suppresses angiogenesis. Pirfenidone targets the extracellular matrix (ECM) and has therapeutic effects on fibrotic diseases. Therefore, we speculated that pirfenidone might have meaningful therapeutic effects in AAA, and the current study was designed to investigate this capacity. An AAA model was constructed in mice using a long-term injection of angiotensin II (Ang II), followed by a 28-day administration of 200 mg/kg/day pirfenidone. Increased maximal external diameter of the abdominal artery, promoted levels of VEGF-A and its receptor VEGF-R2, upregulated matrix metallopeptidases (MMP)-2 and MMP-9, and elevated release of pro-inflammatory cytokines were observed in AAA mice, which were extremely repressed by 200 mg/kg pirfenidone. Human aortic endothelial cells (HAECs) were stimulated with Ang II for 1 day, in the presence or absence of pirfenidone (100 nM). Elevated expression of VEGF-A and VEGF-R2, facilitated proliferation, increased tube formation ability, and upregulated MMP-2 and MMP-9 were observed in Ang II-stimulated HAECs, all of which were significantly rescued by 100 nM pirfenidone. Finally, the elevated levels of myeloid differentiation primary response 88 and phosphorylated nuclear factor-kappa-B subunit p65 observed in Ang II-stimulated HAECs were repressed by pirfenidone. Collectively, pirfenidone alleviated AAA by inhibiting ECM degradation and ameliorating endothelial dysfunction.


Effects of pulmonary and intercostal denervation on the response of breathing frequency to varying inspiratory flow.
In mechanically ventilated awake and sleeping humans, it has been shown that increasing inspiratory flow rate (V'I) exerted a reflex excitatory effect on respiratory output. Mechanoreceptors located in intercostal muscles or within the lung have been suggested as possible pathways that may mediate the excitatory effect of V'I. To test this, five patients with bilateral lung transplantation (LTP) and eight quadriplegics with spinal cord transection at the level of C6-C7 (QP) were studied. Patients were connected to a volume cycle ventilator in the assist volume-control mode and V'I was randomly changed. V'I pattern was square and all breaths were patient-triggered. V'I values of 30, 60 and 90 L x min(-1) were studied. Each level of V'I was sustained for 15 breaths. Airway pressures, end-tidal partial pressure of carbon dioxide (PCO2), airflows and volumes were measured breath by breath. Thirty seven trials in LTP and sixty in QP, where V'I was randomly changed between 30 and 90 L x min(-1), were analysed. In both groups of patients, minute ventilation increased and total breath duration decreased significantly as V'I increased. These changes were complete in the first breath after V'I transition, without evidence of adaptation of the response. The magnitude of the response did not differ between the two groups of patients and was comparable to that observed previously in conscious normal subjects. We conclude that the excitatory effect of inspiratory flow rate on breathing frequency persists in patients who have pulmonary or intercostal denervation. These results do not favour receptors located within the lung (below the resection lines) or in the intercostal muscles to mediate the response of breathing frequency to flow rate.


SCORE2 Report 13: Intraretinal Hemorrhage Changes in Eyes With Central or Hemiretinal Vein Occlusion Managed With Aflibercept, Bevacizumab or Observation. Secondary Analysis of the SCORE and SCORE2 Clinical Trials.
To investigate the relationship between intraretinal macular hemorrhage and visual acuity outcomes in eyes with central retinal vein occlusion or hemiretinal vein occlusion managed with aflibercept, bevacizumab, or observation. Retrospective analysis of data from 2 randomized clinical trials. A total of 362 participants were randomized in the Study of Comparative Treatments for Retinal Vein Occlusion 2, and 88 participants randomized to observation in the Standard Care vs Corticosteroid in Retinal Vein Occlusion Study. Participants received monthly intravitreal aflibercept or bevacizumab through month 6 or observation through month 8. The main outcome was visual acuity letter score (VALS). Reduced area of hemorrhage by month 6 was observed in 70.7% (116 of 164) of aflibercept-treated eyes, 63.8% (104 of 163) of bevacizumab-treated eyes, and 42.2% (27 of 64) of observation eyes by month 8 (P < .01). Relative to eyes with hemorrhage during follow-up, aflibercept-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 8.0 (99% confidence interval [CI]: 1.9, 14.2); bevacizumab-treated eyes without hemorrhage at month 6 had a mean VALS improvement of 3.2 (99% CI: -4.6, 11.0); and observation eyes without hemorrhage at month 8 had a mean VALS improvement of 13.5 (99% CI: 0.4, 26.5). At month 6, the presence of hemorrhage and the change in central subfield thickness (CST) were significantly associated with the change in VALS; however, CST was a more important predictor. Improvement in hemorrhage during follow-up was associated with visual acuity improvements and predicted visual acuity changes beyond what was explained by CST. These findings suggest that intraretinal macular hemorrhage is an important indicator of disease severity in retinal vein occlusion.


The prevalence of tardive dyskinesia in neuroleptic-treated diabetics. A controlled study.
In a controlled study, we compared the prevalence of tardive dyskinesia in 38 neuroleptic-treated diabetics with the prevalence of tardive dyskinesia in a group of 38 nondiabetic neuroleptic-treated controls, matched for age, sex, psychiatric diagnosis, and dose and duration of neuroleptic treatment. Members of each group were evaluated for movement disorders by a rater who used standard rating scales and was "blind" to all diagnoses and treatments. Neuroleptic-treated diabetics had a significantly higher prevalence and severity of tardive dyskinesia. There were no differences between groups on other possible risk factors for tardive dyskinesia, including parkinsonism, anticholinergic drug treatment, or cognitive function. These data suggest that diabetes mellitus should be examined further as a risk factor for tardive dyskinesia.


Tungiasis in a free-ranging jaguar (Panthera onca) population in Brazil.
Tungiasis is an ectoparasitic disease caused by fleas of the genus Tunga. The disease is reported to occur mostly in human populations. In wildlife, however, the occurrence and impact of this disease remains uncertain. We captured and examined 12 free-ranging jaguars for the presence of Tunga penetrans in the Pantanal region of Mato Grosso do Sul state, Brazil. Tungiasis prevalence was 100% in the population; lesions were confined to the jaguar's paws. T. penetrans was identified based on the characteristics of the embedded fleas and the morphological identification of a collected free-living flea. The intensity and stage of infestation varied between individual animals. However, in general, all captured jaguars were in good health. The 100% prevalence of tungiasis may be related to the fact that all captures were performed during the dry season. Their high ecological requirements for space make jaguars potential disseminators of T. penetrans in the Pantanal region. Because cattle ranching and ecotourism are the main economic activities in the Pantanal, further studies should evaluate the risks of tungiasis to human and animal health. To the best of our knowledge, this is the first report of tungiasis in jaguars.


Development of molecularly imprinted poly(methacrylic acid)/silica for clean-up and selective extraction of cholesterol in milk prior to analysis by HPLC-UV.
In the present paper the assessment of a novel molecularly imprinted polymer, poly(methacrylic acid)/silica, for clean-up and selective extraction of cholesterol in milk samples is described. The relative selectivity coefficient (k) values for cholesterol/5-α-cholestane and cholesterol/7-dehydrocholesterol systems were found to be 5.08 and 6.08, respectively, thus attesting the selectivity of the MIP for cholesterol under competitive adsorption with structurally analogous steroid compounds. The milk analysis was initially based on saponification followed by liquid-liquid extraction with n-hexane. Then, the protocol of molecularly imprinted solid phase extraction (MISPE) was carried out by loading the milk hexanic extract through 200 mg of MIP or NIP (non-imprinted polymer) packed into SPE cartridges at a flow rate of 0.6 mL min(-1). The washing step was performed by using n-hexane followed by further elution with ethanol and HPLC-UV analysis at 208 nm. From the breakthrough curve the maximum adsorption capacity of the MIP towards cholesterol was found to be 29.51 mg g(-1). The precision of the MISPE protocol was assessed as intra- and inter-days yielding RSD (relative standard deviations) lower than 4.10%. Cleaner HPLC chromatograms were obtained for milk samples submitted to the MISPE protocol in comparison to the solid phase extraction using the NIP or modified octadecyl silica (C18). Recoveries varying from 96.6 up to 102.2% for milk samples spiked with cholesterol were achieved, thus ensuring the accuracy of the proposed method.


A framework for integrating information resources for chemical emergency management and response.
Effective emergency management and response require appropriate utilization of various resources as an incident evolves. This manuscript describes the information resources used in chemical emergency management and operations and how their utility evolves from the initial response phase to recovery to event close out. The authors address chemical hazard guidance in the context of four different phases of emergency response: preparedness, emergency response (both initial and ongoing), recovery, and mitigation. Immediately following a chemical incident, during the initial response, responders often use readily available, broad-spectrum guidance to make rapid decisions in the face of uncertainties regarding potential exposure to physical and health hazards. Physical hazards are described as the hazards caused by chemicals that can cause harm with or without direct contact. Examples of physical hazards include explosives, flammables, and gases under pressure. This first line of resources may not be chemical-specific in nature, but it can provide guidance related to isolation distances, protective actions, and the most important physical and health threats. During the ongoing response phase, an array of resources can provide detailed information on physical and health hazards related to specific chemicals of concern. Consequently, risk management and mitigation actions evolve as well. When the incident stabilizes to a recovery phase, the types of information resources that facilitate safe and effective incident management evolve. Health and physical concerns transition from acute toxicity and immediate hazards to both immediate and latent health effects. Finally, the information inputs utilized during the preparedness phase include response evaluations of past events, emergency preparedness planning, and chemical-specific guidance about chemicals present. This manuscript details a framework for identifying the effective use of information resources at each phase and provides case study examples from chemical hazard emergencies.


An analysis of and intervention in the sexual transmission of disease.
Sexually transmitted diseases are a serious threat to the public health. Indeed, when an individual seeks medical treatment for a sexually transmitted disease, health authorities frequently attempt to identify, procure, and treat that individual's sexual contact(s). We conducted a comparative analysis of three alternative approaches to tracing the sexual partners of individuals diagnosed as having a sexually transmitted disease. The first approach involved counseling individuals (n = 27) infected with either gonorrhea or nongonococcal urethritis and exhorting them to procure their sexual partners for treatment. In addition to counseling, the second and third approaches involved distributing "occasion cards" for patients to use when informing sexual contacts of the need for treatment. Moreover, in the second approach, the counselor (a nurse or physician) informed infected patients (n = 19) that they and their partners could waive the $3 clinic fee contingent upon the partners seeking treatment within 1 week. In the third approach, the counselor asked infected persons (n = 19) to accept a follow-up telephone contact if their sexual partners failed to seek treatment within 1 week. The third approach was most effective. Ninety percent of the partners identified through this approach sought treatment, versus only about 60% of the partners in the other two conditions. The third approach was also the least expensive, costing about $2.95 to procure each partner for treatment.


Granule cell raphes in the developing mouse cerebellum.
The cerebellar cortex of many vertebrates shows a striking parasagittal compartmentation that is thought to play a role in the establishment and maintenance of functional cerebellar connectivity. Here, we demonstrate the existence of multiple parasagittal raphes of cells in the molecular layer of the developing cerebellar cortex of postnatal mouse. The histological appearance and immunostaining profile of the raphe cells suggest that they are migrating granule cells. We therefore conclude that the granule cell raphes previously described in birds also exist in a mammalian species. The raphes in mouse are visible on nuclear stains from around birth to postnatal day 6 and are frequently found at the boundaries of Purkinje cell segments that differentially express cadherins ("early-onset" parasagittal banding pattern). A similar relation between the raphe pattern and various markers for the early-onset banding pattern has been found in the chicken cerebellum. One of the cadherins mapped in the present study (OL-protocadherin) continues to be expressed in specific Purkinje cell segments until at least postnatal day 14. At this stage of development, the borders of the OL-protocadherin-positive Purkinje cell segments coincide with the borders of Purkinje cell segments that express zebrin II, a marker for the "late-onset" parasagittal banding pattern which persists in the adult cerebellum. These findings demonstrate that the early-onset banding pattern, as reflected in the complementary arrangement of raphes/Purkinje cell segments, and the late-onset pattern of zebrin II expression share at least some positional cues during development.


A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells.
SALL4 is a member of the SALL gene family that encodes a group of putative developmental transcription factors. Murine Sall4 plays a critical role in maintaining embryonic stem cell (ES cell) pluripotency and self-renewal. We have shown that Sall4 activates Oct4 and is a master regulator in murine ES cells. Other SALL gene members, especially Sall1 and Sall3 are expressed in both murine and human ES cells, and deletions of these two genes in mice lead to perinatal death due to developmental defects. To date, little is known about the molecular mechanisms controlling the regulation of expressions of SALL4 or other SALL gene family members. This report describes a novel SALL4/OCT4 regulator feedback loop in ES cells in balancing the proper expression dosage of SALL4 and OCT4 for the maintenance of ESC stem cell properties. While we have observed that a positive feedback relationship is present between SALL4 and OCT4, the strong self-repression of SALL4 seems to be the "break" for this loop. In addition, we have shown that SALL4 can repress the promoters of other SALL family members, such as SALL1 and SALL3, which competes with the activation of these two genes by OCT4. Our findings, when taken together, indicate that SALL4 is a master regulator that controls its own expression and the expression of OCT4. SALL4 and OCT4 work antagonistically to balance the expressions of other SALL gene family members. This novel SALL4/OCT4 transcription regulation feedback loop should provide more insight into the mechanism of governing the "stemness" of ES cells.


Control of RFM strain endogenous retrovirus in RFM mouse cells.
RFM/Un mice express an endogenous type C retrovirus throughout their life span in many tissues; primary or established embryo fibroblast cell cultures do not express a virus but can be induced by exposure to 5-iodo-2'-deoxyuridine. All of our sources yielded a single ecotropic virus (RFV) which appeared to be related more closely to the endogenous N-tropic virus (WN1802N) of BALB/c mice than to Gross leukemia virus on the basis of two-dimensional gel electropherograms of virion proteins. No xenotropic or recombinant viruses were isolated by cocultivation techniques. RFV is N-tropic, and RFM/Un cells possess the Fv-1n allele, as indicated by restriction of B-tropic virus and susceptibility to Gross strain N-tropic virus. However, RFM cells are highly resistant to RFV and other endogenous N-tropic viruses. This resistance is expressed by two-hit titration kinetics and by inhibition of viral linear duplex DNA formation. This is similar to the effects of the Fv-1 locus, but preliminary work has shown no apparent genetic linkage between the two restrictions. The relative strength of the restriction, the presence of a single class of ecotropic virus, and the absence of recombinant viruses suggest that in RFM mice virus is expressed only in cells in which it is induced and not by cell-to-cell transmission.


Bacteriophage lambda receptor site on the Escherichia coli K-12 LamB protein.
We have analyzed eight new phage-resistant missense mutations in lamB. These mutations identify five new amino acid residues essential for phage lambda adsorption. Two mutations at positions 245 and 382 affect residues which were previously identified, but lead to different amino acid changes. Three mutations at residues 163, 164, and 250 enlarge and confirm previously proposed phage receptor sites. Two different mutations at residue 259 and one at 18 alter residues previously suggested as facing the periplasmic face. The mutation at residue 18 implicates for the first time the amino-terminal region of the LamB protein in phage adsorption. The results are discussed in terms of the topology of the LamB protein.


Sorafenib for advanced hepatocellular carcinoma: a systematic review.
To evaluate the effectiveness and toxicity of sorafenib for advanced hepatocellular carcinoma. According to the Cochrane handbook for systematic review, two reviewers independently completed the whole process of literature search, study selection, data collection, and quality assessment. Seven electric databases(PubMed, Cochrane Library, Embase, Chinese Journal Full-text Database, Chinese Biomedical Literature Database, Chinese Scientific and Technical Journal Database, Chinese Medical Association Digital Periodicals Database) were searched and randomized controlled trials (RCT) of sorafenib in the treatment of advanced hepatocellular carcinoma were collected and analyzed. Two RCT involving 828 patients were finally included. Compared with placebo, sorafenib significantly extended the overall survival and time to radiologic progression and improved the disease control rate. The main adverse effects were systemic, gastrointestinal, and dermatologic symptoms (grade 1 or 2 in severity), although the incidences were significantly higher in sorafenib groups than in control groups. Sorafenib is effective and safe for the treatment of advanced hepatocellular carcinoma.


Seoul virus enhances regulatory and reduces proinflammatory responses in male Norway rats.
Zoonotic pathogens, including hantaviruses, are maintained in the environment by causing persistent infection in the absence of disease in their reservoir hosts. Spillover of hantaviruses to humans can cause severe disease that is mediated by excessive proinflammatory responses. The mechanisms mediating hantaviral persistence in rodent reservoirs remain largely unknown. Male Norway rats were inoculated with their species-specific hantavirus, Seoul virus (SEOV), and viral RNA, cytokine, and chemokine responses were evaluated in spleen and lung tissue. More viral RNA was detectable in the lungs than spleen, with copies of SEOV peaking 15-30 days post-inoculation (p.i.) and persisting for 60 days p.i. In the lungs, the expression and production of proinflammatory mediators (i.e., IL-1beta, IL-6, TNF-alpha, IFN-gamma, CCL5, CCL2, CX3CL1, CXCL10, VCAM, VEGF, and NOS2) remained at or below baseline throughout SEOV infection; whereas, regulatory factors, including TGF-beta and FoxP3 were elevated. Conversely, in the spleen, proinflammatory responses were induced while regulatory responses remained unchanged during infection. To determine whether reduced proinflammatory responses mediate hantavirus persistence in the lungs, male rats were administered rIL-1beta or vehicle for 30 days during SEOV infection. SEOV persistence and shedding were not affected by IL-1beta treatment. Proinflammatory responses were elevated in rIL-1beta-treated rats, but remained within physiological levels, suggesting that supra-physiological concentrations may be necessary for viral clearance at the cost of causing disease. Elevated regulatory responses may suppress excessively high proinflammatory responses at a site of elevated SEOV replication to contribute to viral persistence and prevent proinflammatory-mediated disease in reservoir hosts.


Effect of the nitrogen source on phycobiliprotein synthesis and cell reserves in a chromatically adapting filamentous cyanobacterium.
Cyanobacteria can utilize nitrate or ammonium as a source of fixed nitrogen for cell growth. In the filamentous Calothrix sp. strain PCC 7601, these two sources of nitrogen differently influenced the phycobiliprotein composition of the phycobilisomes, the major light-harvesting antennae. When compared to nitrate, growth in the presence of ammonium resulted in intracellular steady-state levels 35% lower for phycoerythrin and 46% higher for phycocyanin. Besides these differences in cell pigmentation, a rapid but transient accumulation of cyanophycin granule polypeptide occurred in ammonium-grown cells, while these macromolecules were not detected in cells grown with nitrate. In contrast, glycogen reserves displayed a dynamic pattern of accumulation and disappearance during cell growth which varied only slightly with the nitrogen source. The observed changes in cell pigmentation are reminiscent of the phenomenon of complementary chromatic adaptation, in which green and red wavelengths promote the syntheses of phycoerythrin and phycocyanin-2, respectively. As in complementary chromatic adaptation, the regulation of synthesis of phycoerythrin and phycocyanin-2 by the nitrogen source occurred mainly at the mRNA level. Moreover, the transcriptional start sites for the expression of the cpeBA and the cpc2 operons, which respectively encode the two subunits of phycoerythrin and phycocyanin-2, were the same in cells grown in nitrate or ammonium, and identical to those in green- and red-light-grown cells. The results of this study suggest that acclimation to the spectral light quality and to the nitrogen source share some common regulatory elements.


Effects of Platelet-Rich Fibrin on Hard Tissue Healing: A Histomorphometric Crossover Trial in Sheep.
Bone defects lead to aesthetic and functional losses, causing dental rehabilitation to be more difficult. The objective of this work is to histologically assess the hard tissue healing of bone defects filled with platelet-rich fibrin (PRF) alone or as an adjuvant for mixing with and covering anorganic bovine bone (ABB), compared to ABB covered with a resorbable collagen membrane (CM). This study was designed as a crossover animal study. Four 5-mm tibia defects, 5 mm apart from each other, were surgically created on the tibias of 6 sheep. The defects were randomly filled with ABB + CM; PRF alone; ABB+PRF; or were left empty. The animals were euthanized on days 10, 20, and 40 post-operatively. No group showed any signs of bone necrosis. Inflammation was observed in 2 control and 3 test defects with no statistically significant difference between groups at each time point. The ABB + CM and ABB + PRF groups experienced the highest bone regeneration ratios. No differences between the empty-defect and PRF groups were observed in regard to bone regeneration. No statistical difference was observed between the ABB+PRF and ABB + CM groups in regard to bone regeneration and the amount of residual graft material at each time point. The use of PRF should be preferred due to its autogenous origin, low cost, and ease of use.


Musical hallucinations, acquired deafness, and depression.
Musical hallucinations associated with acquired deafness are rarely reported in the psychiatric literature. In the few cases studied no evidence of psychiatric disturbance is noted. The authors describe two patients with musical hallucinations while in a state of nonpsychotic depression. One of these suffered from acquired deafness and no organic pathology was demonstrable in the other. Cessation of musical hallucinations occurred concomitantly in both patients with improvement of the affective state. Depression might have a contributory role in the occurrence of such hallucinations.


Impact of food and nutrition interventions on poverty in an informal settlement in the Vaal Region of South Africa.
UNICEF has stated that urban poverty is primarily found in squatter settlements. At present 13.5% of all South African households live in informal settlements. The major research question is to what extent does poverty influence the food, nutrition and health of informal-settlement dwellers. The purpose of the present study was to determine the depth of poverty in this community and to measure the possible effect that planned food and nutrition interventions may have on eliminating poverty in this area. Pre-tested questionnaires were administered to 340 randomly-selected caregivers. A validated quantified FFQ was administered by trained enumerators as the test measurement for dietary intake and food consumption patterns and 24 h recall was used as the reference measurement, and the data were analysed. A poverty model was used to measure the impact of extra income on the poverty levels of 190 households. Of the respondents 89% lived in Zn shacks and the average household size was 4.9 individuals. The unemployment rate was 94.2% for respondents and 64.9% for their partners. The majority of households (68.8%) had an income of <R 500 ( pound35) per month and 58.3% spent <R 100 ( pound6.90) per week on food. The average poverty gap was R 1342.21 ( pound93) and the poverty gap ratio was 56%. The poverty model showed that an increase of R 500 ( pound35) in monthly household income results in a poverty gap ratio of 35%. The poverty model confirmed that the impact of food and nutrition interventions on poverty can be measured and that when planning these interventions the model could be used to measure their feasibility. The results indicate that this community is poverty-stricken and has chronic food insecurity, and they will be used to facilitate planning and implementation of sustainable income-generating community-based interventions to promote urban food security and alleviate poverty in this community.


Coherent properties of super-continuum containing clearly defined solitons.
With the use of numerical simulations based on generalized nonlinear Schrödinger equation, we study for the first time the coherence of super-continuum (SC), generated in tapered and cobweb fibers in the regime with clearly defined solitions in spectrum. We suggest a simple model, which explains the influence of pump pulses power and duration on SC coherence. A possibility of concerned SC generation regime application in optical frequencies metrology is discussed.


Transmembrane protein 14A protects glomerular filtration barrier integrity.
Transmembrane protein 14A (TMEM14A) is a relatively unknown protein that is now identified to be required for maintaining the integrity of the glomerular filtration barrier. It is an integral transmembrane protein of 99 amino acids with three transmembrane domains. TMEM14A has been implied to suppress Bax-mediated apoptosis in other studies. Other than that, little is currently known of its function. Here, we show that its expression is diminished before onset of proteinuria in a spontaneously proteinuric rat model. Knocking down tmem14a mRNA translation results in proteinuria in zebrafish embryos without affecting tubular reabsorption. Also, it is primarily expressed by podocytes. Lastly, an increase in glomerular TMEM14A expression is exhibited in various proteinuric renal diseases. Overall, these results suggest that TMEM14A is a novel factor in the protective mechanisms of the nephron to maintain glomerular filtration barrier integrity.


Knowledge and awareness of risk factors for cardiovascular disease among Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992.
Cardiovascular disease is the leading cause of death and disability in older people, who account for an increasing proportion of Canada's population. Knowledge and awareness of risk factors is essential for changes in behaviour, yet little is known about these issues in older people. The Canadian Heart Health Surveys database provides a unique resource to examine knowledge and awareness of cardiovascular risk factors in older Canadians. This descriptive cross-sectional study used data from the Canadian provinces' Heart Health Surveys, for the years 1986 to 1992. Sampling within each province consisted of stratified, 2-stage, replicated probability samples; 4976 people 55 to 74 years of age were included in the present analysis. Knowledge and awareness of cardiovascular risk factors was determined from the survey question "Can you tell me what are the major causes of heart disease or heart problems?" Blood pressure was measured during a home visit; anthropometric and blood measurements were obtained during a clinic visit. Cardiovascular health status was determined by self-reporting. Smoking and stress or worry were mentioned as major causes of heart disease by the greatest proportion of participants (41% and 44% respectively); hypertension was mentioned by only 16%. Men and women did not differ in their awareness of high blood cholesterol (cited by 23% of participants), smoking (41%), excess weight (30%) or lack of exercise (28%) as causes of heart disease. A greater proportion of women than men were aware of hypertension (19% v. 12%) and heredity (31% v. 17%) as major causes of heart disease. Awareness of risk factors was consistently lower in the older age group (65-74 v. 55-64 years). Among women, there was greater awareness of the respective risk factors as causes of heart disease among those who were smokers (60% v. 35% of nonsmokers), those who had a body mass index (BMI) of 25 or greater (38% v. 24% of those with a BMI less than 25) and those who were hypertensive (22% v. 17% of those without hypertension). Those who had experienced a heart attack had greater awareness of the major causes of heart disease than those who had not; this pattern was stronger among women than among men. Of those in whom elevated cholesterol level was identified during the course of the study, 62% of men and 67% of women were unaware of their cholesterol status. Of those in whom high blood pressure was diagnosed, 43% of men and 33% of women were unaware of their hypertensive status. Awareness of the major causes of cardiovascular disease is low among older Canadians, especially among men and in those 65 to 74 years of age.


Early Management of Cervical Spine Trauma: WFNS Spine Committee Recommendations.
Epidemiology, prevention, early management of cervical spine trauma and it's reduction are the objectives of this review paper. A PubMed and MEDLINE search between 2009 and 2019 were conducted using keywords. Case reports, experimental studies, papers other than English language and and unrelated studies were excluded. Up-to-date information on epidemiology of spine trauma, prevention, early emergency management, transportation, and closed reduction were reviewed and statements were produced to reach a consensus in 2 separate consensus meeting of World Federation of Neurosurgical Societies (WFNS) Spine Committee. The statements were voted and reached a positive or negative consensus using Delphi method. Global incidence of traumatic spinal injury is higher in low- and middle-income countries. The most frequent reasons are road traffic accidents and falls. The incidence from low falls in the elderly are increasing in high-income countries due to ageing populations. Prevention needs legislative, engineering, educational, and social efforts that need common efforts of all society. Emergency care of the trauma patient, transportation, and in-hospital acute management should be planned by implementing detailed protocols to prevent further damage to the spinal cord. This review summarizes the WFNS Spine Committee recommendations on epidemiology, prevention, and early management of cervical spine injuries.


[Surgical approaches for limbal stem cell deficiency].
Stem cells are the ultimate source of the rapidly self-renewing corneal epithelium and are located in the basal layer of the limbal epithelium. A variety of diseases can compromise the stem cell pool, causing an entity called limbal stem cell deficiency. Several therapeutic strategies should be taken into account. Ocular surface defence should be restored prior to any kind of stem cell transplantation to assure a sufficient and stable tearfilm. Surgical strategies comprise superficial keratectomy with or without amniotic membrane transplantation, conjunctival-limbal autograft and keratolimbal allograft transplantation. A damaged limbal and corneal stroma can be reconstructed by amniotic membrane as a biological substrate. First encouraging results have been reported using tissue bio-engineered limbal epithelium on amniotic membrane for corneal surface reconstruction. The correct diagnosis and a restored ocular surface defence are a prerequisite for subsequent transplantation of limbal stem cells. Optimal patient selection for the respective surgical approach and systemic immunosuppression protocols to improve allograft survival need to be further investigated.


Homoarginine and Clinical Outcomes in Renal Transplant Recipients: Results From the Assessment of Lescol in Renal Transplantation Study.
Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study. Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107). Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 μmol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 μmol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 μmol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13-5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36-4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63-10.69) and 2.50 (95% CI, 1.38-4.55), respectively. Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.


The nuclear rDNA region of Gyrodactylus arcuatus and G. branchicus (Monogenea: Gyrodactylidae).
The primary structure of the ribosomal DNA internal transcribed spacers (ITS-1 and ITS-2) and 5.8S rRNA gene were used to characterize and identify 2 monogenean species of Gyrodacrylus living externally on the threespine stickleback (Gasterosteus aculeatus). The ITS region was amplified by PCR from freshwater, brackish, and marine isolates of Gyrodactylus arcuatus and G. branchicus, and the ends of the coding regions were identified by comparative alignment. No intraspecific and very low interspecific variation were observed in the 5.8S rRNA gene; high inter- and low intraspecific variation were revealed in the ITS-1 and ITS-2 regions. The morphological species identification was in all cases confirmed by the molecular identification. Intraspecifically, samples from 2 locations in the North Sea could be differentiated, but the Baltic sample resembled North Sea genotypes. Our approach offers perspectives for a multimetric genetical, morphometrical, and ecological taxonomy of the genus Gyrodactylus.


Assisted assembly of bacteriophage T7 core components for genome translocation across the bacterial envelope.
In most bacteriophages, genome transport across bacterial envelopes is carried out by the tail machinery. In viruses of the Podoviridae family, in which the tail is not long enough to traverse the bacterial wall, it has been postulated that viral core proteins assembled inside the viral head are translocated and reassembled into a tube within the periplasm that extends the tail channel. Bacteriophage T7 infects Escherichia coli, and despite extensive studies, the precise mechanism by which its genome is translocated remains unknown. Using cryo-electron microscopy, we have resolved the structure of two different assemblies of the T7 DNA translocation complex composed of the core proteins gp15 and gp16. Gp15 alone forms a partially folded hexamer, which is further assembled upon interaction with gp16 into a tubular structure, forming a channel that could allow DNA passage. The structure of the gp15-gp16 complex also shows the location within gp16 of a canonical transglycosylase motif involved in the degradation of the bacterial peptidoglycan layer. This complex docks well in the tail extension structure found in the periplasm of T7-infected bacteria and matches the sixfold symmetry of the phage tail. In such cases, gp15 and gp16 that are initially present in the T7 capsid eightfold-symmetric core would change their oligomeric state upon reassembly in the periplasm. Altogether, these results allow us to propose a model for the assembly of the core translocation complex in the periplasm, which furthers understanding of the molecular mechanism involved in the release of T7 viral DNA into the bacterial cytoplasm.


Social issues of the Alzheimer's patient and family.
Families caring for a person with Alzheimer's disease (AD) soon discover that it is unlike any other illness. Coping with a degenerative brain disease is much different than dealing with a physical disability. AD is more disruptive to, and has greater impact on, the family than other chronic diseases. AD caregiving carries with it a high financial, social, and emotional price. Families must work toward effectively coping with the disease, decreasing the harmful effects on the family, and keeping family conflicts to a minimum. Support groups can provide families with much-needed information on the disease, emotional and practical support, and an expressive or advocacy outlet. Formal services can help relieve some of the burden of caring for an AD patient. Family members must remember that there is no "right" way to care for a person with AD, and each family must determine, with the help of the appropriate professionals and services, how to best meet its own needs. Given the burdens of care, however, even small interventions may translate into improvements in the quality of life or confidence of the caregiver.


Detection and identification of Mycobacterium species by polymerase chain reaction (PCR) from paraffin-embedded tissue compare to AFB staining in pathological sections.
Polymerase chain reaction (PCR) is a recent, rapid and reliable method in the detection of causative organism. The authors tried to determine the possibility of using PCR technique as an alternative way to detect mycobacterial DNA from paraffin-embedded tissue to avoid repeated biopsy from the patient. Paraffin-embedded tissue blocks, the corresponding histopathologic slides, and cultural results were retrospectively searched for according to the patient's records, the granuloma clinic, Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand from 1994-2000. One hundred and thirty-one tissue blocks and slides were found but only 120 cultural results were retrieved Histologic sections were reviewed for AFB findings and PCR was done using 16S rRNA sequences to detect M. tuberculosis by one-tube nested technique and multiplex PCR for M. marinum and M. fortuitum complex. The causative organisms were identified by AFB staining in pathologic sections 31.29%, by PCR 35.87%, and by culture 30.00% of tested samples. The sensitivity of PCR when compared to AFB result was 29.26%, specificity 61.11% but when compared to cultural results, the sensitivity of PCR was 66.67% and AFB sensitivity was 41.66% with specificity 76.19% and 72.61% respectively. The low sensitivity of the PCR method may be due to formalin fixation, deparaffinization process, DNA extraction method, the use of 16S rRNA-based primers and the length of the expected product, and the tissue type that may have Taq polymerase inhibitor. Therefore, PCR should be used to augment the information of the conventional method in the diagnosis of mycobacterial infection.


The behavioral effects of cooperative and competitive board games in preschoolers.
Traditional board games are a common social activity for many children, but little is known about the behavioral effects of this type of game. The current study aims to explore the behavioral effects of cooperative and competitive board games in four-to-six-year-old children (N = 65). Repeatedly during 6 weeks, children in groups of four played either cooperative or competitive board games in a between-subject design, and shortly after each game conducted a task in which children's cooperative, prosocial, competitive, and antisocial behavior were observed. The type of board game did not have an effect on cooperative, prosocial or antisocial behavior. Cooperative and competitive board games elicited equal amounts of cooperative and prosocial behavior, which suggest that board games, regardless of type, could have positive effects on preschoolers' social behavior. Our results suggest that children may compete more after playing competitive board games; but the measure of competitive behavior in particular was unreliable. Preschoolers enjoyed playing cooperative board games more than competitive board games, which may be one reason to prefer their use.


Pegylated Metal-Phenolic Networks for Antimicrobial and Antifouling Properties.
Metal-phenolic networks (MPNs) have recently attracted great interest in material chemistry and biomaterials because of their biocompatible, versatile, and multifunctional properties. In this paper, we describe a facile method for preparation of a designable antifouling, antimicrobial, and substrate-independent coating assembled from the coordination of metal ions and catecholic groups. Hydrophilic and catecholic polymers were synthesized by copolymerization of dopamine methacrylamide (DMA) and poly(ethylene glycol)methyl methacrylate (PEGMA) to afford p(PEGMA- co-DMA). To investigate the assembly and formation of MPN films, two different metal ions, that is, ferrous (FeII) and ferric (FeIII) ions, to react with p(PEGMA- co-DMA) were compared. The binding constants between iron ions and p(PEGMA- co-DMA) have been investigated by ultraviolet-visible spectroscopy (UV-vis). Measurements with atomic force microscopy, contact angle goniometer, and X-ray photoelectron spectroscopy (XPS) were carried out to quantitatively analyze the surface morphology, wettability, and interfacial elemental compositions of coatings, respectively. Moreover, ellipsometric measurements were performed to obtain the film thickness and grafting density. In addition, the pH-responsive property of the MPN films was investigated at different pH values, showing fast disassembly of the networks at low pH. The antifouling properties of the obtained coatings were analyzed by exposing them to bacteria of Escherichia coli and Staphylococcus epidermidis and NIH-3T3 fibroblasts under observation of fluorescence microscopy and cell imaging analysis. The findings suggest that the MPN from complexation of p(PEGMA- co-DMA) and metal ions provides excellent antifouling, pH-responsive, and biocompatible properties on a wide range of substrates. Furthermore, the released iron ions can effectively suppress the growth of bacteria. Accordingly, the new coating architecture offers a universal feature to control surface properties and functionalization for various applications.


microRNA Expression Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients and Differences from Patients Treated with Anti-VEGF Therapy.
microRNAs (miRNAs) mediate the pathological mechanisms of diabetic retinopathy. In this study, we compared miRNA expression profiles in the vitreous between patients with proliferative diabetic retinopathy (PDR) and patients with a macular hole as non-diabetic controls, and between PDR patients treated with anti-vascular endothelial growth factor (VEGF) therapy and untreated PDR patients. Vitreous samples of non-diabetic and PDR patients were screened for miRNAs with quantitative polymerase chain reaction (qPCR) panels. miRNA candidates were validated in vitreous samples of a second, independent cohort. In addition, the effect of anti-VEGF therapy was investigated in the vitreous of a third study population consisting of PDR patients who had not received anti-VEGF therapy and PDR patients who had received preoperative anti-VEGF therapy. During screening, seven miRNAs were found to be significantly higher in the vitreous of PDR patients, whereas two miRNAs were found to be significantly lower compared with non-diabetic controls. Validating the expression of these miRNAs in a second cohort resulted in the identification of six miRNAs that were expressed at significantly higher rates in the vitreous of PDR patients: hsa-miR-20a-5p, hsa-miR-23b-3p, hsa-miR-142-3p, hsa-miR-185-5p, hsa-miR-326, and hsa-miR-362-5p. Among these six miRNAs, hsa-miR-23b-3p levels were lower in the anti-VEGF-treated group of PDR patients compared with untreated PDR patients. In this study, we identified six miRNAs that are expressed more highly in PDR patients and one miRNA that is expressed at a lower levels in anti-VEGF-treated PDR patients. miRNAs identified in the vitreous of PDR patients may improve our understanding of the mechanisms leading to PDR.


Dose escalation study of carboplatin and cyclophosphamide with filgrastim support: a phase I study.
This clinical trial was designed to explore dose escalation of carboplatin and cyclophosphamide when supported with filgrastim. Twenty-seven patients who had advanced solid tumors received up to six cycles of treatment; a total of 92 cycles of chemotherapy were delivered. Two control groups received standard-dose carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2), with and without filgrastim. Subsequently, the doses of both carboplatin and cyclophosphamide were increased simultaneously by 50% of the standard dose in sequential cohorts. Doses of up to 2.5 times the standard dose were explored. A final dose of carboplatin, 600 mg/m2, and cyclophosphamide, 1,500 mg/m2, was tested in 4 patients. The duration of neutropenia was brief, even at the highest dose levels. The mean duration of grade 3 or 4 neutropenia was 5.8 days at standard dose without filgrastim and 5.4 days at 2.5 times standard dose with filgrastim. More severe neutropenia was more prolonged at higher doses but remained brief in duration. The mean duration of neutropenia of less than 100 x 10(6)/l was 0.4 days at standard dose without filgrastim and 1.3 days at 2.5 times standard dose. There was no evidence of cumulative neutropenia over repeated cycles of treatment. In contrast, thrombocytopenia was both dose limiting and cumulative. The mean duration of grade 3 or 4 thrombocytopenia was 1.6 days at standard dose and 9.6 days at 2.5 times standard dose. An average of 2.3 platelet transfusions per cycle of treatment was required at the highest dose. Thrombocytopenia was worse with repetitive cycles of therapy. The mean duration of grade 3 or 4 thrombocytopenia was 2.2 days after the first cycle of chemotherapy and 7.8 days after cycle four. The maximum tolerated dose, as defined prospectively, was not reached but further dose escalation was not thought to be warranted because of the severity of thrombocytopenia. When supported with filgrastim, carboplatin and cyclophosphamide can be administered safely with substantially increased dose and acceptable toxicity.


Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate.
Jaundice is a common cause for diagnostic works-up and therapeutic intervention in neonates. This is motivated by the risk for severe neurological sequelae (kernicterus). The mainstays of treatment for the past decades have been exchange transfusion and phototherapy. Exchange transfusion is now becoming rare due to immune prophylaxis in Rhesus-negative women, and treatment of sensitised infants with intravenous immunoglobulin. Several different pharmacological approaches have been studied as far as the treatment of neonatal jaundice. Of these, the focus of attention in recent years has been on the haem oxygenase inhibitors (metal meso- and protoporphyrins). These are effective inhibitors of bilirubin production and have been shown to significantly reduce peak serum bilirubin levels in several clinical trials, both when used prophylactically and therapeutically. However, questions remain regarding long-term safety, as well as the advisability of whole-scale inhibition of bilirubin production. Nevertheless, in selected infants with a high risk of severe jaundice, the use of haem oxygenase inhibitors may be acceptable. Pharmacotherapy in jaundiced infants is fraught with risks, as many drugs may increase the entry of bilirubin into the brain and presumably, the risk for neurotoxicity. Both the displacement of bilirubin from its albumin binding and interference with the function of phosphoglycoprotein in the blood-brain barrier are documented mechanisms in this respect.


Gender-related dimorphism in aortic insufficiency in murine mucopolysaccharidosis type I.
Hurler syndrome (mucopolysaccharidosis type I/H; MPS I/H) is a lethal heritable enzymopathy that leads to an accumulation of glycosaminoglycans (GAGs) and dysfunction of multiple organs of the body, including the heart. As gender-related differences are common in heart disease and a murine model for mucopolysaccharidosis type I (MPSI) has been used for the preclinical evaluation of strategies to correct heart valve disease in Hurler syndrome, the study aim was to determine the impact of gender on heart disease in the murine MPSI model. Murine hearts were examined by high-resolution ultrasound biomicroscopy, the tissue and urinary contents of GAGs were measured, and the quantitative reverse transcribed ribonucleic acid polymerase chain reaction for metalloproteinase (MMP) -9 and -12 determined. In MPSI mice, aortic insufficiency (AI) in conjunction with depressed myocardial function was observed significantly more often in males than females. Neither the total body GAG burden nor myocardial GAG content was responsible for this difference. In contrast, in the aorta the expression of extracellular matrix tissue MMP-12, but not MMP-9, was significantly elevated in males with AI when compared to females with AI. Gender-related dimorphism occurs in cardiac valvular disease in MPSI mice. Male MPSI mice showed an increased incidence of AI associated with an increase in the MMP-12 content of the aortic arch. The evaluation of findings in relation to gender is important in the experimental treatment of murine models of disease, so that gender-related variations in genetic penetrance are not mistaken for disease correction.


Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures.
Protoplasmic astrocytes in mammalian CNS tissues in vivo have a highly complex 3D morphology, but in dissociated cell cultures they often assume a flattened, fibroblast-like morphology bearing only a few, simple processes. By fluorescent labeling and confocal reconstruction we show that many astrocytes in organotypic hippocampal slice cultures exhibit a more native complex cytoarchitecture. Although astrocytes at the surface of slice cultures show a reactive form with several thick glial fibrillary acidic protein (GFAP)-positive processes, astrocytes situated in deeper portions of tissue slices retain a highly complex 3D morphology with many fine spine- or veil-like protrusions. Dozens of astrocytes can be labeled in single slice cultures by gene gun-mediated ballistic delivery of gold or tungsten particles carrying cDNAs (Biolistics), lipophilic dyes (DiOlistics), or fluorescent intracellular calcium indicators (Calistics). Expression of a membrane-targeted form of eGFP (Lck-GFP) is superior to soluble eGFP for resolving fine astrocytic processes. Time-lapse confocal imaging of Lck-GFP transfected astrocytes or "calistically" labeled astrocytes show structural remodeling and calcium transients, respectively. This approach provides an in vitro system for investigating the functional architecture, development and dynamic remodeling of astrocytes and their relationships to neurons and glia in live mammalian brain tissues.


Whole mitochondria genome mutational spectrum in occupationally exposed lead subjects.
Lead is a public health hazard substance affecting millions of people worldwide especially those who are occupationally exposed. Our study aimed to investigate the effect of occupational lead exposure on mitochondria DNA (mtDNA). By sequencing the whole mitochondria genome, we identified 25 unique variants in lead exposed subjects affecting 10 protein coding genes in the order of MT-ND1, MT-ND2, MT-CO2, MT-ATP8, MT-ATP6, MT-CO3, MT-ND3, MT-ND4, MT-ND5, and MT-CYB. Mitochondria functional analysis revealed that exposure to lead can reduce reactive oxygen species (ROS) levels, alter mitochondria membrane potential (MMP) and increase mitochondrial mass (MM). This was further supported by mtDNA copy number analysis which was increased in lead exposed individuals compared to unexposed control group indicating the compensatory mechanism that lead has in stabilizing the mitochondria. This is the first report of mtDNA mutation and copy number analysis in occupationally lead exposed subjects where we identified mtDNA mutation signature associated with lead exposure thus providing evidence for altered molecular mechanism to compensate mitochondrial oxidative stress.


Prevalence of Attention Deficit Hyperactivity Disorder in Detention Settings: A Systematic Review and Meta-Analysis.
Background: Previous studies have reported a high prevalence of attention deficit hyperactivity disorder (ADHD) among people living in detention (PLD) corresponding to a five- to ten-fold increase compared to the general population. Our main study objective was to provide an updated ADHD prevalence rate for PLD, including PLD in psychiatric units. Sub-objectives included (i) comparing different ways of assessing ADHD, including DSM-5 criteria and (ii) identifying which types of PLD are more likely to have ADHD. Methods: We conducted a systematic review and meta-analysis following the PRISMA guidelines and the MOOSE checklist. PubMed/Medline, PsycINFO, and Web of Sciences were searched combining "ADHD" and "prison" keywords and synonyms for articles published between January 1, 1966 and January 2, 2018. Potential sources of variation to the meta-analytic ADHD prevalence rate were investigated using meta-regressions and subgroups analyses. Results: The meta-analysis pooled 102 original studies including 69,997 participants. The adult ADHD prevalence rate was 26.2% (95% confidence interval: 22.7-29.6). Retrospective assessments of ADHD in childhood were associated with an increased prevalence estimate (41.1, 95% confidence interval: 34.9-47.2, p < 0.001). There was no significant difference in the prevalence estimate between screenings and clinical interviews in adulthood. Only three studies used the DSM-5 definition of ADHD and results were non-significantly different with other DSM versions. We found no difference according to participants' characteristics. Conclusion: Our results confirmed the high prevalence rate of ADHD among PLD, corresponding to a five-fold increase compared to the general population. In light of such high ADHD prevalence, our results reinforce the importance of addressing this critical public health issue by (i) systematically offering ADHD screening and diagnosis to all individuals entering detention, and (ii) delivering treatment, monitoring, and care for ADHD during and after detention. These strategies may help reduce recidivism and reincarceration, as well as violence in detention settings, in addition to improving the health and wellbeing of people living in detention. Additionally, our study suggests that using screening scales may be a reliable way of assessing ADHD, although caution is needed because a complete evaluation by an experienced clinician is required to provide a formal diagnosis.


Antioxidative efficiency of Triticum aestivum L. exposed to chromium stress.
Wheat (Triticum aestivum L. cv Sonalika) seedlings were grown in presence of K2Cr2O7 (10, 50 and 100 ppm) for 7 days and growth, total chlorophyll, activities of antioxidative enzymes like superoxide dismutase (SOD; EC 184.108.40.206), catalase (CAT; EC 188.8.131.52) and guaiacol peroxidase (POX; EC 188.8.131.52) and lipid peroxidation were determined in root and shoot tissues. Growth of the seedlings was significantly (p < or = 0.05) depressed and at 100 ppm, root length was reduced by 63% and shoot length by 44% in comparison to the respective controls. Total chlorophyll loss in shoots was about 46% at 10 ppm of K2Cr2O7 which further increased to 80% at 100 ppm. Both in root and shoot tissues, activities of SOD and CAT declined with increase of metal in growth medium and it was significant (p < or = 0.05) even at lowest concentration of the metal tested. But POX activity showed a different trend. In root tissues it was decreased whereas in shoots, there was many fold increase in the activity (about 370% over control at 100 ppm). Malondialdehyde (MDA) content increased both in root and shoot tissues, but it reached significant (p < 0.05) level at 50 ppm in roots and at 100 ppm in shoot tissues. Even though antioxidative enzyme activities were not assayed in germinating embryos, inhibition in germination percentage (by 40% at 100 ppm) and increase in lipid peroxidation level (by 71% over control at 100 ppm) were observed in 2-day-old embryos, germinated in presence of K2Cr2O7 (10, 50 and 100 ppm). The results indicated the imposition of oxidative stress situations both during germination and early stages of seedling growth by Cr6 stress, which might be one of the probable reasons behind Cr toxicity in plants.


Development of pneumococcal vaccines over the last 10 years.
Although significant improvements in the prevention of pneumococcal infections have been achieved in recent years, Streptococcus pneumoniae remains a leading cause of morbidity and mortality. To prevent S. pneumoniae infections, vaccines have been developed for several years. In this review, the most important emerging problems regarding pneumococcal conjugate vaccines (PCVs) are discussed in addition to the status of new vaccine design and development. Given the medical, social and economic relevance of pneumococcal diseases, the availability of effective and safe vaccines against S. pneumoniae is a key objective of public health. Protein vaccines using agents different from capsular polysaccharides (CPs) or whole-cell vaccines seem to induce a broader immune response than PCVs and theoretically offer definitive solutions, as they can stimulate both humoral and cellular immunity. Moreover, these vaccines, particularly the whole-cell vaccine, are simpler to produce and significantly less expensive. However, the development of these preparations is very far from completion. It is highly likely that for a long time, no new safe and effective pneumococcal vaccines will be available. The best formulation of new pneumococcal vaccines has not been established. Consequently, an effort towards the expanded use of the available vaccines has to be made.


Genetic, metabolic and clinical delineation of an MRPS23-associated mitochondrial disorder.
MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed. Their available family members were also studied. Eight members homozygous for the MRPS23 p.P40L were identified. All were from Hmong hilltribe. Seven presented with alteration of consciousness and recurrent vomiting, while the eighth who was a younger brother of a proband was found pre-symptomatically. Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV. PCR-Sanger-sequencing confirmed the variant, which was estimated to have occurred 1550 years ago. These results establish the MRPS23-associated mitochondrial disorder inherited in an autosomal recessive pattern and provide insight into its clinical and metabolic features.


Tipping in complex systems under fast variations of parameters.
Abrupt changes in the state of a system are often undesirable in natural and human-made systems. Such transitions occurring due to fast variations of system parameters are called rate-induced tipping (R-tipping). While a quasi-steady or sufficiently slow variation of a parameter does not result in tipping, a continuous variation of the parameter at a rate greater than a critical rate results in tipping. Such R-tipping would be catastrophic in real-world systems. We experimentally demonstrate R-tipping in a real-world complex system and decipher its mechanism. There is a critical rate of change of parameter above which the system undergoes tipping. We discover that there is another system variable varying simultaneously at a timescale different from that of the driver (control parameter). The competition between the effects of processes at these two timescales determines if and when tipping occurs. Motivated by the experiments, we use a nonlinear oscillator model, exhibiting Hopf bifurcation, to generalize such type of tipping to complex systems where multiple comparable timescales compete to determine the dynamics. We also explain the advanced onset of tipping, which reveals that the safe operating space of the system reduces with the increase in the rate of variations of parameters.


Hepatitis Transmission Risk in Kidney Transplantation (the HINT study): A Cross-Sectional Survey of Transplant Clinicians in Australia and New Zealand.
Interpreting hepatitis serology and virus transmission risk in transplantation can be challenging. Decisions must balance opportunity to transplant against potential infection transmission. We aimed to survey understanding among the Australian and New Zealand medical transplant workforce of hepatitis risk in kidney donors and recipients. An anonymous, self-completed, cross-sectional survey was distributed via electronic mailing lists to Australian and New Zealand clinicians involved in kidney transplantation (2014-2015). We compared interpretation of clinical scenarios with paired donor and recipient hepatitis B virus and hepatitis C virus serology to recommendations in clinical practice guidelines. We used logistic regression modeling to investigate characteristics associated with decisions on transplant suitability in scenarios with poor (<50%) guideline concordance (odds ratios [OR]). One hundred ten respondents had representative workforce demographics: most were male (63%) nephrologists (74%) aged 40 to 49 years. Although donor and recipient hepatitis status was largely well understood, transplant suitability responses varied among respondents. For a hepatitis B virus surface antigen-positive donor and vaccinated recipient, 44% suggested this was unsuitable for transplant (guideline concordant) but 35% suggested this was suitable with prophylaxis (guideline divergent). In 4 scenarios with transplant suitability guideline concordance less than 50%, acute transplant care involvement predicted guideline concordant responses (OR, 1.69; P = 0.04). Guideline concordant responses were chosen less by hepatologists, intensive care doctors (OR, 0.23, 0.35, respectively; P = 0.01), and New Zealanders (guideline concordant responses OR, 0.17; P < 0.01; alternative responses OR, 4.31; P < 0.01). Despite broadly consistent interpretations of hepatitis serology, transplant suitability decisions varied and often diverged from guidelines. Improved decision support may reduce clinician variability.


Hierarchical Mo-doped CoP3 interconnected nanosheet arrays on carbon cloth as an efficient bifunctional electrocatalyst for water splitting in an alkaline electrolyte.
Design and fabrication of highly efficient and robust noble-metal-free bifunctional electrocatalysts for overall water splitting in alkaline media is challenging. Herein, we report a unique bifunctional electrocatalyst consisting of three-dimensional (3D) hierarchical Mo-doped CoP3 nanosheet arrays on carbon cloth (Mo-CoP3 NAs@CC) fabricated by a facile electrodeposition process and the subsequent PH3 plasma-assisted phosphorization. Benefiting from the hierarchical nanostructure and doping effect of Mo, the optimal Mo-CoP3-2@CC electrode demonstrates excellent HER and OER catalytic activity with an overpotential of 62 and 300 mV at 10 mA cm-2, respectively, and reasonable stability up to 20 h in 1.0 M KOH. Impressively, when Mo-CoP3-2@CC is used as both HER and OER electrodes in an alkaline electrolyzer, a current density of 10 mA cm-2 is achieved at a cell voltage of only 1.65 V, and the stable water-splitting current is maintained for 25 h, showing great promise for practical applications.


Effects of the Informed Health Choices primary school intervention on the ability of children in Uganda to assess the reliability of claims about treatment effects: a cluster-randomised controlled trial.
Claims about what improves or harms our health are ubiquitous. People need to be able to assess the reliability of these claims. We aimed to evaluate an intervention designed to teach primary school children to assess claims about the effects of treatments (ie, any action intended to maintain or improve health). In this cluster-randomised controlled trial, we included primary schools in the central region of Uganda that taught year-5 children (aged 10-12 years). We excluded international schools, special needs schools for children with auditory and visual impairments, schools that had participated in user-testing and piloting of the resources, infant and nursery schools, adult education schools, and schools that were difficult for us to access in terms of travel time. We randomly allocated a representative sample of eligible schools to either an intervention or control group. Intervention schools received the Informed Health Choices primary school resources (textbooks, exercise books, and a teachers' guide). Teachers attended a 2 day introductory workshop and gave nine 80 min lessons during one school term. The lessons addressed 12 concepts essential to assessing claims about treatment effects and making informed health choices. We did not intervene in the control schools. The primary outcome, measured at the end of the school term, was the mean score on a test with two multiple-choice questions for each of the 12 concepts and the proportion of children with passing scores on the same test. This trial is registered with the Pan African Clinical Trial Registry, number PACTR201606001679337. Between April 11, 2016, and June 8, 2016, 2960 schools were assessed for eligibility; 2029 were eligible, and a random sample of 170 were invited to recruitment meetings. After recruitment meetings, 120 eligible schools consented and were randomly assigned to either the intervention group (n=60, 76 teachers and 6383 children) or control group (n=60, 67 teachers and 4430 children). The mean score in the multiple-choice test for the intervention schools was 62·4% (SD 18·8) compared with 43·1% (15·2) for the control schools (adjusted mean difference 20·0%, 95% CI 17·3-22·7; p<0·00001). In the intervention schools, 3967 (69%) of 5753 children achieved a predetermined passing score (≥13 of 24 correct answers) compared with 1186 (27%) of 4430 children in the control schools (adjusted difference 50%, 95% CI 44-55). The intervention was effective for children with different levels of reading skills, but was more effective for children with better reading skills. The use of the Informed Health Choices primary school learning resources, after an introductory workshop for the teachers, led to a large improvement in the ability of children to assess claims about the effects of treatments. The results show that it is possible to teach primary school children to think critically in schools with large student to teacher ratios and few resources. Future studies should address how to scale up use of the resources, long-term effects, including effects on actual health choices, transferability to other countries, and how to build on this programme with additional primary and secondary school learning resources. Research Council of Norway.


Longitudinal follow-up of patients with traumatic brain injury: outcome at two, five, and ten years post-injury.
The deleterious consequences of traumatic brain injury (TBI) impair capacity to return to many avenues of pre-morbid life. However, there has been limited longitudinal research examining outcome beyond five years post-injury. The aim of this study was to examine aspects of function, previously shown to be affected following TBI, over a span of 10 years. One hundred and forty one patients with TBI were assessed at two, five, and 10 years post-injury using the Structured Outcome Questionnaire. Fatigue and balance problems were the most common neurological symptoms, with reported rates decreasing only slightly during the 10-year period. Mobility outcomes were good in more than 75% of patients, with few participants requiring aids for mobility. Changes in cognitive, communication, behavioral, and emotional functions were reported by approximately 60% of the sample at all time points. Levels of independence in activities of daily living were high during the 10-year period, and as many as 70% of subjects returned to driving. Nevertheless, approximately 40% of patients required more support than before their injury. Only half the sample returned to previous leisure activities and fewer than half were employed at each assessment time post-injury. Although marital status remained stable over time, approximately 30% of participants reported difficulties in personal relationships. Older age at injury did not substantially alter the pattern of changes over time, except in employment. Overall, problems that were evident at two years post-injury persisted until 10 years post-injury. The importance of these findings is discussed with reference to rehabilitation programs.


Ventricular septal rupture and cardiogenic shock complicating STEMI during COVID-19 pandemic: An old foe re-emerges.
The COVID 19 pandemic resulted in a total reduction in the number of hospitalizations for acute coronary syndromes. A consequence of the delay in coronary revascularization has been the resurgence of structural complications of myocardial infarctions. Ventricular septal rupture (VSR) complicating late presenting acute myocardial infarction (AMI) is associated with high mortality despite advances in both surgical repair and perioperative management. Current data suggests a declining mortality with delay in VSR repair; however, these patients may develop cardiogenic shock while waiting for surgery. Available options are limited for patients with VSR who develop right ventricular failure and cardiogenic shock. The survival rate is very low in patients with cardiogenic shock undergoing surgical or percutaneous VSR repair. In this study we present two late presenting ST elevation MI patients who were complicated by rapidly declining hemodynamics and impending organ failure. Both patients were bridged with venoarterial extracorporeal membrane oxygenation (ECMO) to cardiac transplant.


[Significance of preoperative urodynamics for clinical diagnosis of female patients with stress urinary incontinence].
To investigate the impact of preoperative urodynamic study on the diagnosis and treatment for female patients with clinical diagnosis of stress urinary incontinence by studying their diagnosis and treatment database, and to assess its clinical significance of urodynamic study. From April 2011 to December 2015, 196 female patients diagnosed clinically with stress urinary incontinence underwent preoperative urodynamics study, after excluding pelvic organ prolapse. The preoperative urodynamic data of these 196 cases were analyzed and the clinical significance of urodynamics on differential diagnosis and treatment for the female patients with stress urinary incontinence was evaluated. In this study, 23 cases (11.73%) changed or amended their diagnoses by the urodynamic study, which were inconsistent with the previous clinical diagnoses concluded by the symptoms, physical examinations, and lab tests. A total of 10 cases underwent a different surgery or conservative treatment instead of the original treatment according to urodynamic study. Of them, 3 were diagnosed as detrusor overactive and undertook conservative treatment; 3 were diagnosed as bladder outlet obstruction plus stress urinary incontinence and were undertaken the transurethral resection of the bladder neck (TURBN) plus tension free vaginal tape (TVT); 2 were diagnosed as bladder outlet obstruction plus stress urinary incontinence and were undertaken TURBN alone; 1 was diagnosed as bladder outlet obstruction plus stress urinary incontinence and was undertaken TURBN plus tension free vaginal tape obturator (TOT); 1 was found no abnormal bladder function turned out to be interstitial cystitis and went for a bladder instillation of drug. The changed treatments avoided the risk of dysuria or residual urine increased after operation due to inappropriate surgical methods. In order to make a correct diagnosis and suitable treatment for female patients with stress urinary incontinences, the preoperative urodynamic study is necessary besides detailed medical history, physical examination, and laboratory tests. With the help of the urodynamic study, the concomitant diseases of patients with stress urinary incontinence may be detected, the individualized treatment regimen can be developed, and more importantly, the inappropriate surgical decision can be avoided.


Properties of a DNA ligase mutant of Escherichia coli: introduction of strand breaks in DNA.
Strand breaks accumulated in the DNA of a temperature-sensitive DNA ligase mutant of Escherichia coli growing at the restrictive temperature, as detected by zone sedimentation through alkaline sucrose density gradients. The rate of strand breakage was increased by concomitant thymine starvation. Rifampicin and chloramphenicol inhibited the accumulation of strand breaks in the DNA. There was a correlation between the accumulation of strand breaks in the DNA and lethality, suggesting that such breaks are the basis for lethality at the restrictive temperature.


Serum autoantibodies for the diagnosis and management of autoimmune liver diseases.
The spectrum of autoimmune liver diseases (AILD) includes primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. The immunological mechanisms triggering the initiation and perpetuation of AILD remains unknown, while autoantigens are now recognized in most cases, and are generally nontraditional in their widespread distribution. Sensitive and specific methods for the detection of serum autoantibodies in patients affected by AILD represent a challenge for researchers and clinicians who desire to obtain an early and certain diagnosis as well as markers of disease control. To this regard, the use and interpretation of serum autoantibodies in AILD may be seen as paradigmatic for the large gaps in our knowledge based on the lack of true population-based studies. The present review article will critically discuss the available evidence on the use of autoantibody findings in the diagnosis or management of autoimmune liver disease.


Contributions of LFA-1 and Mac-1 to brain injury and microvascular dysfunction induced by transient middle cerebral artery occlusion.
Although the beta2-integrins have been implicated in the pathogenesis of cerebral ischemia-reperfusion (I/R) injury, the relative contributions of the alpha-subunits to the pathogenesis of ischemic stroke remains unclear. The objective of this study was to determine whether and how genetic deficiency of either lymphocyte function-associated antigen-1 (LFA-1) or macrophage-1 (Mac-1) alters the blood cell-endothelial cell interactions, tissue injury, and organ dysfunction in the mouse brain exposed to focal I/R. Middle cerebral artery occlusion was induced for 1 h (followed by either 4 or 24 h of reperfusion) in wild-type mice and in mice with null mutations for either LFA-1 or Mac-1. Neurological deficit and infarct volume were monitored for 24 h after reperfusion. Platelet- and leukocyte-vessel wall adhesive interactions were monitored in cortical venules by intravital microscopy. Mice with null mutations for LFA-1 or Mac-1 exhibited significant reductions in infarct volume. This was associated with a significant improvement in the I/R-induced neurological deficit. Leukocyte adhesion in cerebral venules did not differ between wild-type and mutant mice at 4 h after reperfusion. However, after 24 h of reperfusion, leukocyte adhesion was reduced in both LFA-1- and Mac-1-deficient mice compared with their wild-type counterparts. Platelet adhesion was also reduced at both 4 and 24 h after reperfusion in the LFA-1- and Mac-1-deficient mice. These findings indicate that both alpha-subunits of the beta2-integrins contribute to the brain injury and blood cell-vessel wall interactions that are associated with transient focal cerebral ischemia.


Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease.
Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.


Cost-Effectiveness of a Statewide Campaign to Promote Aspirin Use for Primary Prevention of Cardiovascular Disease.
The U.S. Preventive Services Task Force in 2009 recommended increased aspirin use for primary prevention of cardiovascular disease (CVD) in men ages 45 to 79 years and women ages 55 to 79 years for whom benefit outweighs risk. This study estimated the clinical efficacy and cost-effectiveness of a statewide public and health professional awareness campaign to increase regular aspirin use among the target population in Minnesota to reduce first CVD events. A state-transition Markov model was developed, adopting a payer perspective and lifetime time horizon. The main outcomes of interest were quality-adjusted life years, costs, and the number of CVD events averted among those without a prior CVD history. The model was based on real-world data about campaign effectiveness from representative state-specific aspirin use and event rates, and estimates from the scholarly literature. Implementation of a campaign was predicted to avert 9874 primary myocardial infarctions in men and 1223 primary ischemic strokes in women in the target population. Increased aspirin use was associated with as many as 7222 more major gastrointestinal bleeding episodes. The cost-effectiveness analysis indicated cost-saving results for both the male and female target populations. Using current U.S. Preventive Services Task Force recommendations, a state public and health professional awareness campaign would likely provide clinical benefit and be economically attractive. With clinician adjudication of individual benefit and risk, mechanisms can be made available that would facilitate achievement of aspirin's beneficial impact on lowering risk of primary CVD events, with minimization of adverse outcomes.


Effect of fluoxetine on menstrual cycle length in women with premenstrual dysphoria.
To examine whether changes in menstrual cycle length occurred in women who received 20 mg of fluoxetine per day and women who received 60 mg of fluoxetine per day as compared with women who received placebo. A two-cycle, single-blind placebo phase was followed by a six-cycle double-blind phase. Only placebo nonresponders were randomized to one of three treatment arms: placebo, fluoxetine 20 mg/day, or fluoxetine 60 mg/day. Cycle length was established using a prospective daily calendar. Cycle-length data from women who completed at least three treatment cycles were used in this analysis. Cycle-length change was defined a priori as cycle lengthening or shortening of 4 days or more (1 or more standard deviations from the mean change between baseline cycles). Eleven of the 62 women receiving 60 mg of fluoxetine per day and seven of the 70 women receiving 20 mg of fluoxetine per day but only one of the 61 women in the placebo group demonstrated cycle-length change at the end of the first treatment cycle (P = .011). In total, 15% of the women in the fluoxetine 60 mg/day group demonstrated a cycle-length change during two of the three observed cycles compared with 6% of the women in the fluoxetine 20 mg/day group and 3% of the women in the placebo group (P = .048). Women with cycle-length changes demonstrated either shortening or lengthening only. There were no differences between the number of women with changes in either direction. Cycle-length change occurred more frequently in the fluoxetine 60 mg/day group than in the fluoxetine 20 mg/day or placebo groups. The effects of selective serotonin reuptake inhibitors on menstrual cycle length are mostly unknown and warrant careful monitoring in women of reproductive age, who are the prime consumers of these medications.


Parylene-C coated microporous PDMS structure protecting from functional deconditioning of platelets exposed to cardiostimulants.
Most elderly patients after orthopedic and dental implant surgeries are exposed to cardiostimulants to reduce potential blood pressure-related risks of cardiovascular diseases. Such treatments lead to deconditioning of platelet function, which is an important factor in wound healing treatments. We introduced an innovative parylene-C coated microporous PDMS structure that can prevent the functional deconditioning of platelets caused by certain cardiostimulants. At different concentrations of cardiostimulants (IPR; isoprenaline and DA; dopamine), pre-activation, activation, and post-activation of platelets were intensively examined under mechanical and chemical stimulation mimicking the physiological environment on four different surfaces (glass, flat parylene-C coated glass (F-PPXC), microporous PDMS structure (P-PDMS), and parylene-C-coated microporous PDMS structure (S-PPXC)). The 3D microporous structure with parylene-C (S-PPXC) surface could attenuate the deconditioning of platelet function caused by IPR. Moreover, the S-PPXC surface further enhanced the DA-dependent stimulation of platelet function. The reason for this is that the 3D microporous structure with parylene-C S-PPXC induced stable and fast adhesion of platelets through increased surface roughness and softness, resulting in a significant enhancement of platelet activity. Therefore, we propose the use of functional S-PPXC surfaces as a novel strategy in the development of biomedical products.


Different Signal Enhancement Pathways of Attention and Consciousness Underlie Perception in Humans.
It is not yet known whether attention and consciousness operate through similar or largely different mechanisms. Visual processing mechanisms are routinely characterized by measuring contrast response functions (CRFs). In this report, behavioral CRFs were obtained in humans (both males and females) by measuring afterimage durations over the entire range of inducer stimulus contrasts to reveal visual mechanisms behind attention and consciousness. Deviations relative to the standard CRF, i.e., gain functions, describe the strength of signal enhancement, which were assessed for both changes due to attentional task and conscious perception. It was found that attention displayed a response-gain function, whereas consciousness displayed a contrast-gain function. Through model comparisons, which only included contrast-gain modulations, both contrast-gain and response-gain effects can be explained with a two-level normalization model, in which consciousness affects only the first level and attention affects only the second level. These results demonstrate that attention and consciousness can effectively show different gain functions because they operate through different signal enhancement mechanisms.SIGNIFICANCE STATEMENT The relationship between attention and consciousness is still debated. Mapping contrast response functions (CRFs) has allowed (neuro)scientists to gain important insights into the mechanistic underpinnings of visual processing. Here, the influence of both attention and consciousness on these functions were measured and they displayed a strong dissociation. First, attention lowered CRFs, whereas consciousness raised them. Second, attention manifests itself as a response-gain function, whereas consciousness manifests itself as a contrast-gain function. Extensive model comparisons show that these results are best explained in a two-level normalization model in which consciousness affects only the first level, whereas attention affects only the second level. These findings show dissociations between both the computational mechanisms behind attention and consciousness and the perceptual consequences that they induce.


Interrogation of Carboxy-Terminus Localized GJA1 Variants Associated with Erythrokeratodermia Variabilis et Progressiva.
Although inherited GJA1 (encoding Cx43) gene mutations most often lead to oculodentodigital dysplasia and related disorders, four variants have been linked to erythrokeratodermia variabilis et progressiva (EKVP), a skin disorder characterized by erythematous and hyperkeratotic lesions. While two autosomal-dominant EKVP-linked GJA1 mutations have been shown to lead to augmented hemichannels, the consequence(s) of keratinocytes harboring a de novo P283L variant alone or in combination with a de novo T290N variant remain unknown. Interestingly, these variants reside within or adjacent to a carboxy terminus polypeptide motif that has been shown to be important in regulating the internalization and degradation of Cx43. Cx43-rich rat epidermal keratinocytes (REKs) or Cx43-ablated REKs engineered to express fluorescent protein-tagged P283L and/or T290N variants formed prototypical gap junctions at cell-cell interfaces similar to wildtype Cx43. Dye coupling and dye uptake studies further revealed that each variant or a combination of both variants formed functional gap junction channels, with no evidence of augmented hemichannel function or induction of cell death. Tracking the fate of EKVP-associated variants in the presence of the protein secretion blocker brefeldin A, or an inhibitor of protein synthesis cycloheximide, revealed that P283L or the combination of P283L and T290N variants either significantly extended Cx43 residency on the cell surface of keratinocytes or delayed its degradation. However, caution is needed in concluding that this modest change in the Cx43 life cycle is sufficient to cause EKVP, or whether an additional underlying mechanism or another unidentified gene mutation is contributing to the pathogenesis found in patients. This question will be resolved if further patients are identified where whole exome sequencing reveals a Cx43 P283L variant alone or, in combination with a T290N variant, co-segregates with EKVP across several family generations.