Posterior interosseous nerve palsy caused by a ganglion: Conservative treatment with ultrasound-guided needle aspiration.
Posterior interosseous nerve palsy caused by a ganglion is not common and most previous patients were treated with excisional surgery. We treated a case conservatively with needle aspiration using ultrasonography, after a nerve conduction study. A 77-year-old man presented with impaired active finger extension of the left metacarpophalangeal joints. The nerve conduction study revealed conduction block of the left radial nerve near the elbow. Ultrasonography demonstrated a hypoechoic mass anterior to the radial neck compressing the posterior interosseous nerve. Then, needle aspiration of the mass was conducted under ultrasonography. Two months later, active finger extension recovered to normal. A ganglion can be diagnosed with ultrasonography and needle aspiration can be carried out safely under ultrasonography. A nerve conduction study can assess the degree of nerve damage. The combination of ultrasonography and a nerve conduction study can facilitate conservative treatment of needle aspiration for posterior interosseous nerve palsy caused by a ganglion.


In vivo stimulation of the insulin receptor kinase in human skeletal muscle. Correlation with insulin-stimulated glucose disposal during euglycemic clamp studies.
To assess the relationship between insulin receptor (IR) kinase activity and insulin action in vivo in humans, we measured glucose disposal rates (GDR) during a series of euglycemic clamp studies. Simultaneously, we measured IR kinase activity in IRs extracted from skeletal muscle obtained by needle biopsy at the end of each clamp. By preserving the phosphorylation state of the receptors as it existed in vivo at the time of biopsy, we could correlate GDR and IR kinase in skeletal muscle. Eight nondiabetic, nonobese male subjects underwent studies at insulin infusion rates of 0, 40, 120, and 1,200 mU/m2 per min. Kinase activity, determined with receptors immobilized on insulin agarose beads, was measured at 0.5 microM ATP, with 1 mg/ml histone, followed by SDS-PAGE. Insulin increased GDR approximately sevenfold with a half-maximal effect at approximately 100 microU/ml insulin and a maximal effect by approximately 400 microU/ml. Insulin also increased IR kinase activity; the half-maximal effect occurred at approximately 500-600 microU/ml insulin with a maximal 10-fold stimulation over basal. Within the physiologic range of insulin concentrations, GDR increased linearly with kinase activation (P less than 0.0006); at supraphysiologic insulin levels, this relationship became curvilinear. Half-maximal and maximal insulin-stimulated GDR occurred at approximately 20 and approximately 50% maximal kinase activation, respectively. These results are consistent with a role of the kinase in insulin action in vivo. Furthermore, they demonstrate the presence of a large amount of "spare kinase" for glucose disposal.


A Novel Method Using Quantum Dots for Testing the Barrier Function of Cultured Epithelial Cell Sheets.
The corneal epithelium provides a barrier to protect the deeper structures of the eye from any particles or pathogens. Cultured epithelial cell sheets are used in transplantation surgery for corneal repair or regeneration. The purpose of this study was to develop a novel method using fluorescent quantum dot nanoparticles for validating the quality and barrier function of cultured epithelial cell sheets. Human function epithelial cell sheets, cultured from oral mucosal or corneal limbal cells, were incubated in either normal calcium-containing medium or medium containing no calcium with a calcium chelator. Also contained in the media were suspensions of two different sizes of quantum dots. Following incubation, analysis of quantum dot penetration was carried out using confocal microscopy. In contrast to the cell sheets incubated in calcium-containing medium, removal of extracellular calcium resulted in the disruption of tight junctions, compromising the cell sheet's barrier function. This caused a reduction in transepithelial electrical resistance and deeper, more ubiquitous penetration of the quantum dots into the paracellular space and interior of the cell sheet. This method provides easy to interpret qualitative and quantitative data on the functionality of a cell sheet's tight junctions, as well as nanoscale and microscale structural information on its surface and interior morphology, and any localized areas of damage or abnormality. This novel technique could be used as part of the validation system for cultured epithelial cell sheets for use in transplantation.


Dead fish swimming: a review of research on the early migration and high premature mortality in adult Fraser River sockeye salmon Oncorhynchus nerka.
Adult sockeye salmon Oncorhynchus nerka destined for the Fraser River, British Columbia are some of the most economically important populations but changes in the timing of their homeward migration have led to management challenges and conservation concerns. After a directed migration from the open ocean to the coast, this group historically would mill just off shore for 3-6 weeks prior to migrating up the Fraser River. This milling behaviour changed abruptly in 1995 and thereafter, decreasing to only a few days in some years (termed early migration), with dramatic consequences that have necessitated risk-averse management strategies. Early migrating fish consistently suffer extremely high mortality (exceeding 90% in some years) during freshwater migration and on spawning grounds prior to spawning. This synthesis examines multidisciplinary, collaborative research aimed at understanding what triggers early migration, why it results in high mortality, and how fisheries managers can utilize these scientific results. Tissue analyses from thousands of O. nerka captured along their migration trajectory from ocean to spawning grounds, including hundreds that were tracked with biotelemetry, have revealed that early migrants are more reproductively advanced and ill-prepared for osmoregulatory transition upon their entry into fresh water. Gene array profiles indicate that many early migrants are also immunocompromised and stressed, carrying a genomic profile consistent with a viral infection. The causes of these physiological changes are still under investigation. Early migration brings O. nerka into the river when it is 3-6° C warmer than historical norms, which for some late-run populations approaches or exceeds their critical maxima leading to the collapse of metabolic and cardiac scope, and mortality. As peak spawning dates have not changed, the surviving early migrants tend to mill in warm lakes near to spawning areas. These results in the accumulation of many more thermal units and longer exposures to freshwater diseases and parasites compared to fish that delay freshwater entry by milling in the cool ocean environment. Experiments have confirmed that thermally driven processes are a primary cause of mortality for early-entry migrants. The Fraser River late-run O. nerka early migration phenomenon illustrates the complex links that exist between salmonid physiology, behaviour and environment and the pivotal role that water temperature can have on population-specific migration survival.


Health-related quality of life as an independent predictor of long-term disability for patients with relapsing-remitting multiple sclerosis.
Predictive factors of long-term disability in patients with relapsing-remitting multiple sclerosis (RR-MS) are well known, but the weight of these factors does not explain the entire change of disability. Few studies have examined the predictive value of quality of life (QoL). To determine the value of the initial level of QoL to predict changes in the disability status of patients with MS and to determine if specific-MS questionnaires predict more accuracy in these changes than generic questionnaires. multicenter, multi-regional, and longitudinal study. Main inclusion criteria: patients with RR-MS subtype and an Expanded Disability Status Scale (EDSS) score lower than 7.0. Sociodemographic and clinical data were recorded at baseline. Every 6 months up to month 24, QoL (MusiQoL and SF-36) was recorded. At 24 months, individuals were defined into two 'disability change' groups: the worsened and not worsened patients. Five-hundred and twenty-six patients were enrolled: 386 (83.7%) not worsened and 75 (16.3%) worsened patients at 24 months. The activity of daily living and the relationship with healthcare workers dimensions of MusiQoL questionnaire were independent predictors of change in the EDSS score after 24 months. The physical-functioning dimension of the SF-36 questionnaire predicted independently disability change after 24 months. Patient-reported baseline QoL levels provide additional prognostic information on MS disability beyond traditional clinical or sociodemographic factors. These findings reinforce the importance of incorporating a patient's evaluation of their own QoL level during patient monitoring and the assessment of treatment effects.


A subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma.
Adenoid cystic carcinoma (ACC) is a basaloid tumor consisting of myoepithelial and ductal cells typically arranged in a cribriform pattern. Adenoid cystic carcinoma is generally regarded as a form of salivary gland carcinoma, but it can arise from sites unassociated with salivary tissue. A rare form of prostate carcinoma exhibits ACC-like features; it is no longer regarded as a true ACC but rather as prostatic basal cell carcinoma (PBCC) and within the spectrum of basaloid prostatic proliferations. True ACCs often harbor MYB translocations resulting in the MYB-NFIB fusion protein. MYB analysis could clarify the true nature of prostatic carcinomas that exhibit ACC features and thus help refine the classification of prostatic basaloid proliferations. Twelve PBCCs were identified from the pathology consultation files of Johns Hopkins Hospital. The histopathologic features were reviewed, and break-apart fluorescence in situ hybridization for MYB was performed. All 12 cases exhibited prominent basaloid histology. Four were purely solid, 7 exhibited a cribriform pattern reminiscent of salivary ACC, and 1 had a mixed pattern. The MYB rearrangement was detected in 2 (29%) of 7 ACC-like carcinomas but in none (0%) of the 5 PBCCs with a prominent solid pattern. True ACCs can arise in the prostate as is evidenced by the presence of the characteristic MYB rearrangement. When dealing with malignant basaloid proliferations in the prostate, recommendations to consolidate ACCs with other tumor types may need to be reassessed, particularly in light of the rapidly advancing field of biologic therapy where the identification of tumor-specific genetic alterations presents novel therapeutic targets.


A primary cilia-dependent etiology for midline facial disorders.
Human faces exhibit enormous variation. When pathological conditions are superimposed on normal variation, a nearly unbroken series of facial morphologies is produced. When viewed in full, this spectrum ranges from cyclopia and hypotelorism to hypertelorism and facial duplications. Decreased Hedgehog pathway activity causes holoprosencephaly and hypotelorism. Here, we show that excessive Hedgehog activity, caused by truncating the primary cilia on cranial neural crest cells, causes hypertelorism and frontonasal dysplasia (FND). Elimination of the intraflagellar transport protein Kif3a leads to excessive Hedgehog responsiveness in facial mesenchyme, which is accompanied by broader expression domains of Gli1, Ptc and Shh, and reduced expression domains of Gli3. Furthermore, broader domains of Gli1 expression correspond to areas of enhanced neural crest cell proliferation in the facial prominences of Kif3a conditional knockouts. Avian Talpid embryos that lack primary cilia exhibit similar molecular changes and similar facial phenotypes. Collectively, these data support our hypothesis that a severe narrowing of the facial midline and excessive expansion of the facial midline are both attributable to disruptions in Hedgehog pathway activity. These data also raise the possibility that genes encoding ciliary proteins are candidates for human conditions of hypertelorism and FNDs.


Scanning Tunneling Microscopy and Nanolithography on a Conducting Oxide, Rb0.3MoO3.
The scanning tunneling microscope has been used to image and modify the surface of a conducting oxide (Rb(0.3)MoO(3))in ambient atmosphere. Individual octahedral MoO(6) units of the oxide can be imaged, and under certain conditions defects can be created in the surface that are stable in air. The ability to produce nanometer-sized structures on the surface of an oxide is demonstrated and discussed with reference to nanolithographic applications.


Reciprocal Inhibitory Glomerular Circuits Contribute to Excitation-Inhibition Balance in the Mouse Olfactory Bulb.
The major inhibitory interneurons in olfactory bulb (OB) glomeruli are periglomerular cells (PGCs) and short axon cells (SACs). PGCs and SACs provide feedforward inhibition to all classes of projection neurons, but inhibition between PGCs and SACs is not well understood. We crossed Cre and GFP transgenic mice and used virally-delivered optogenetic constructs to selectively activate either SACs or GAD65cre-ChR2-positive PGCs while recording from identified GAD65cre-ChR2-positive PGCs or SACs, respectively, to investigate inhibitory interactions between these two interneuron types. We show that GAD65cre-ChR2-positive PGCs robustly inhibit SACs and SACs strongly inhibit PGCs. SACs form the interglomerular circuit, which inhibits PGCs in distant glomeruli. Activation of GAD65cre-ChR2-positive PGCs monosynaptically inhibit mitral cells (MCs), which complements recent findings that SACs directly inhibit MCs. Thus, both classes of glomerular inhibitory neurons inhibit each other, as well as OB output neurons. We further show that olfactory nerve input to one glomerulus engages the interglomerular circuit and inhibits PGCs in distant glomeruli. Sensory activation of the interglomerular circuit directly inhibits output neurons in other glomeruli and by inhibiting intraglomerular PGCs, may potentially disinhibit output neurons in other glomeruli. The nature and context of odorant stimuli may determine whether inhibition or excitation prevails so that odors are represented in part by patterns of active and inactive glomeruli.


TNF and bone.
Bone is subject to permanent remodeling during development and through life. This activity is essential for (a) proper shaping and growth of each bone during development; (b) maintenance of bone mass as well as structural integrity of the micro architecture of bone through adult life, and (c) tissue repair needed for healing of fracture as well as of micro-damage. In addition to genetically linked rare developmental diseases, disturbances in bone remodeling are causing common bone pathologies, which severely impair the quality of life of patients. Among them are postmenopausal osteoporosis and local as well as systemic bone loss observed in chronic inflammatory diseases such as rheumatoid arthritis. The role of TNF-alpha in mediating bone remodeling will be presented and discussed in this chapter.


The effects of Carthamus tinctorius L. on placental histomorphology and survival of the neonates in mice.
Carthamus tinctorius L. (Safflower) is a member of the asteraceae family which is used as a food additive but also has medicinal applications. This study investigated its effects on placental histomorphology and survival of mice neonates. Eighty Balb/C pregnant mice were randomly distributed into one control and three experimental groups (n=20). The control group received only distilled water, whereas experimental groups were administered intraperitoneally C. tinctorius extract at doses of 0.7, 1.4, and 2.8 mg/kg during the organogenesis period (6(th) to 16(th) day of gestation). On the 17(th) day of gestation, half of the animals were euthanized; their fetuses and placentas were removed and histomorphological study was performed. In the rest of the animals after parturition, the number of neonates was counted. Survival rates were periodically calculated for neonates within days 5, 15, 25, and 42 after birth. The results were evaluated by one-way ANOVA. The results showed that treatment with 1.4 and 2.8 mg/kg C. tinctorius extract caused reduction in the trophoblastic giant cells ratio and increasing in the proportion of labyrinthine interhemal membrane (LIM). Moreover, the size of the labyrinthine zone per whole placenta, weight, diameter, and thickness of the placenta in the mice administered with 1.4 and 2.8 mg/kg C. tinctorius extract became lower than those of controls (p<0.05). In addition, in the treated mice with 1.4 and 2.8 mg/kg C. tinctorius extract, the number of neonate was drastically decreased on days 5, 15, 25, and 42 after birth. It is concluded that treatment with C. tinctorius extract in doses of 1.4 and 2.8 mg/kg induces toxic changes in the placental structure so caution should be paid to popular consumption of this plant both as an alternative medicine and as a food additive.


[Clinical analysis of patients referred for lung transplantation in eastern Japan].
We investigated the indications for lung transplantation (LTx) in Japan and discussed questions regarding the current Japanese criteria of LTx. This study examined 37 patients referred to our institute for LTx. Among these patients, there were 11 cases of primary pulmonary hypertension (PPH), 6 of lymphoangiomyomatosis (LAM), 4 of Eisenmenger's syndrome, 3 of bronchiolitis obliterans, 2 each of bronchiectasis, idiopathic pulmonary fibrosis (IPF), and pneumoconiosis, and 7 of other diseases. The most frequent age group was 30-39 years (12 cases, 32.4%), and more than half of the patients were female (22 cases, 59.5%). The regions of residence of the patients were Tohoku (19 patients), Kanto (16), and Chubu (2). Patients were referred from all over eastern Japan. On evaluation, LTx was contraindicated in 5 cases, in 4 of which mechanical ventilation had been installed before consultation with us. Six patients died before registration on the Japan Organ Transplant Network (JOT). 6 transplant candidates were registered with JOT, but one (PPH) died after 6 months of waiting, and one (LAM) received a lung transplant from a brain dead cadaver donor. We propose to reform and clarify the Japanese criteria for LTx-both indications and contraindications, to include such indications as a survival probability of less than two years, and such contraindications as mechanical ventilation. Early consultation at LTx centers was hoped for, in accordance with the International Guidelines and a transplant window.


1,25-dihydroxyvitamin D3, transforming growth factor beta1, calcium, and ultraviolet B radiation induce apoptosis in cultured human keratinocytes.
Apoptosis is a cellular process of self-directed suicide that plays a key role during morphogenesis and in the maintenance of homeostasis in continuously renewing tissues. Currently, apoptosis is detected mainly by gel electrophoresis of fragmented DNA and by typical ultrastructural features such as cell shrinkage and chromatin condensation. Recently, an in situ technique was developed that allows the detection of the apoptotic process in cells and the quantitation of apoptosis in cell populations. We applied this technique to evaluate the apoptotic process in cultured normal human keratinocytes under basic conditions and after stimulation with factors and agents that are presumed but have never been proved to induce apoptosis in these cells. Apoptosis was analyzed after stimulation with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], transforming growth factor beta1 (TGFbeta1), calcium, UVB, or tumor necrosis factor alpha (TNFalpha). All these factors except TNFalpha induced apoptosis in human keratinocytes. Whereas UVB and calcium were good apoptogenic stimuli at 6 and 24 h, respectively, the vitamin D derivative and TGFbeta1 induced apoptosis after 5 and 6 d in culture. Apoptosis was also established by DNA fragmentation and electron microscopy. Finally, TUNEL technique showed that the number of apoptotic cells increases slightly (5-10%) from 24 to 144 h even in untreated keratinocytes. Our studies indicate that factors normally involved in the regulation of cell growth and differentiation can also control apoptosis.


Modulating Complex Sentence Processing in Aphasia Through Attention and Semantic Networks.
Lexical processing impairments such as delayed and reduced activation of lexical-semantic information have been linked to syntactic processing disruptions and sentence comprehension deficits in individuals with aphasia (IWAs). Lexical-level deficits can also preclude successful lexical encoding during sentence processing and amplify the processing costs of similarity-based interference during syntactic retrieval. We investigate whether two manipulations to engage attention and pre-activate semantic features of a target (to-be-retrieved) noun will (a) boost lexical activation during initial lexical encoding and (b) facilitate syntactic dependency linking through improved resolution of interference in IWAs and neurologically unimpaired age-matched controls (AMCs). Eye-tracking-while-listening with a visual world paradigm was used to investigate whether semantic and attentional manipulations modulated initial lexical processing and downstream syntactic retrieval of the direct-object noun in object-relative sentences. In the attention and semantic manipulations, the AMC group showed no changes in initial lexical access levels; however, gaze patterns revealed clear facilitations in dependency linking and interference resolution. In the IWA group, the attentional cue increased and maintained activation of N1 with modest facilitations in dependency linking. In the semantic condition, IWA results showed a greater degree of facilitation during dependency linking. The results suggest that attention and semantic activation are parameters that may be manipulated to strengthen encoding of lexical representations to facilitate retrieval (i.e., dependency linking) and mitigate similarity-based interference. In IWAs, these manipulations may help to reduce lexical processing deficits that can preclude successful encoding.


The expression of gastrointestinal differentiation markers in extrahepatic cholangiocarcinoma: clinicopathological significance based on tumor location.
The expression of gastrointestinal differentiation markers is associated with the tumorigenesis and prognosis of digestive cancers. However, little is known about the significance of gastrointestinal differentiation marker profiles in patients with extrahepatic cholangiocarcinoma (CCA), which is classified as perihilar and distal CCA. The purpose of this study was to clarify the role of gastrointestinal differentiation marker expression in extrahepatic CCA based on tumor location. We examined the expression of gastrointestinal differentiation markers in resected perihilar (n = 30) and distal (n = 54) CCAs based on the immunohistochemical expression of the following markers: MUC2, MUC5AC, MUC6, CD10, CDX-2, and cytokeratin 20. Expression scores were determined semiquantitatively based on the rate of positively stained cells. Furthermore, we performed hierarchical clustering of the CCAs based on the immunohistochemical expression scores to evaluate differences in the expression patterns of the 6 gastrointestinal differentiation markers. Consequently, perihilar and distal CCAs were stratified into 2 subgroups each. Among the perihilar CCAs, subgroup 1 was characterized by lower expression of MUC5AC and MUC6, a larger median tumor size, and a significantly worse prognosis compared with subgroup 2. Furthermore, the immunohistological subgroup (subgroup 1 versus 2) and TNM stage (stage III versus II) were independent predictors of patient survival. Among the distal CCAs, subgroup 1 was characterized by lower expression of MUC5AC compared with subgroup 2. We suggest that gastrointestinal differentiation marker profiles are useful for stratifying perihilar and distal CCAs. In addition, gastrointestinal differentiation markers play a crucial role in tumor development, particularly in perihilar CCA.


Description of the vasospasm phenomena following perimesencephalic nonaneurysmal subarachnoid hemorrhage.
Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PM-NASAH) is characterized by a benign course compared with aneurysmal SAH. While vasospasm (VS) after aneurysmal SAH is considered responsible for serious complications, VS post-PM-NASAH is not well documented. Our purpose was to characterize the incidence and course of VS among 63 patients--one of the largest databases of PM-NASAH patients with documented blood flow velocities in the literature. Data from 63 patients that were admitted with PM-NASAH from 2000 to 2012 and underwent transcranial Doppler tests to assess cranial vessel flow velocity was analyzed. On average, the maximal flow velocity was measured on the 7th day after hemorrhage. Higher risk for VS was associated with younger age, female sex, and higher Hunt and Hess scores, a lower risk for patients treated with statins (P < 0.05). Using velocity thresholds for diagnosis of VS, 49.2% showed evidence of VS. This is the first description of blood flow velocities in PM-NASAH. VS average onset was on the 4th day, average cessation on day 15 after hemorrhage. No patients showed clinical manifestation of VS. VS post-PM-NASAH is not as rare as previously believed. However, its lack of clinical significance raises questions regarding the need for diagnosis and may suggest a less intensive treatment protocol.


Reduced expression of catenin subtypes is a potential indicator of unfavorable prognosis in esophageal squamous cell carcinoma.
Catenins are cytoplasmic proteins that play a pivotal role in cell adhesion. Conflicting results regarding the significance of their expression in esophageal squamous cell carcinoma (ESCC) have been reported. The expression of α-, β- and γ-catenin was examined using immunohistochemical methods in 69 samples collected from patients with ESCC who were surgically treated without any preoperative induction therapy. Reduced α-, β- and γ-catenin expression was observed in 48 (69.7%), 36 (52.2%) and 44 (63.8%) ESCC samples, respectively. According to univariate analysis, ESCC patients exhibiting the reduced expression of β-catenin (P=0.028), γ-catenin (P=0.010), α- and γ-catenin combined (P=0.047) or β- and γ-catenin combined (P=0.046) had a significantly more unfavorable rate of survival. Multivariate analysis demonstrated that the reduced expression of γ-catenin (P=0.015) as well as lymph node metastasis (P=0.015) could serve as independent prognostic indicators of unfavorable prognosis in ESCC patients. Reduced immunohistochemical expression of γ-catenin may thus prove to be a powerfull and useful predictor of prognosis in patients with ESCC.


From the Cover: Comparative Proteomics Reveals Silver Nanoparticles Alter Fatty Acid Metabolism and Amyloid Beta Clearance for Neuronal Apoptosis in a Triple Cell Coculture Model of the Blood-Brain Barrier.
Silver nanoparticles (AgNPs) enter the central nervous system through the blood-brain barrier (BBB). AgNP exposure can increase amyloid beta (Aβ) deposition in neuronal cells to potentially induce Alzheimer's disease (AD) progression. However, the mechanism through which AgNPs alter BBB permeability in endothelial cells and subsequently lead to AD progression remains unclear. This study investigated whether AgNPs disrupt the tight junction proteins of brain endothelial cells, and alter the proteomic metabolism of neuronal cells underlying AD progression in a triple cell coculture model constructed using mouse brain endothelial (bEnd.3) cells, mouse brain astrocytes (ALT), and mouse neuroblastoma neuro-2a (N2a) cells. The results showed that AgNPs accumulated in ALT and N2a cells because of the disruption of tight junction proteins, claudin-5 and ZO-1, in bEnd.3 cells. The proteomic profiling of N2a cells after AgNP exposure identified 298 differentially expressed proteins related to fatty acid metabolism. Particularly, AgNP-induced palmitic acid production was observed in N2a cells, which might promote Aβ generation. Moreover, AgNP exposure increased the protein expression of amyloid precursor protein (APP) and Aβ generation-related secretases, PSEN1, PSEN2, and β-site APP cleaving enzyme for APP cleavage in ALT and N2a cells, stimulated Aβ40 and Aβ42 secretion in the culture medium, and attenuated the gene expression of Aβ clearance-related receptors, P-gp and LRP-1, in bEnd.3 cells. Increased Aβ might further aggregate on the neuronal cell surface to enhance the secretion of inflammatory cytokines, MCP-1 and IL-6, thus inducing apoptosis in N2a cells. This study suggested that AgNP exposure might cause Aβ deposition and inflammation for subsequent neuronal cell apoptosis to potentially induce AD progression.


[Tolerance of physical exercise in angina pectoris].
Bicycle tests were used in 250 patients suffering from angina pectoris. The exercise was practised until the prodromal signs of an anginal seizure appeared. The mean values of exercise causing an anginal seizure appeared to be equal to 5.1 plus or minus 0.26 kgm/kg in angina decubitus and angina of effort; 11.9 plus or minus 0.67 kgm/kg is cases of daily seizures of angina of effort; 20.8 plus or minus 0.85 kg/kg in cases of several seizures a week after increased physical exercises, and 29.0 plus or minus 2.21 kgm/kg in cases of rare seizures (once a week or less frequently). This permits to believe that in cases of angina pectoris difficult of diagnosis its severity can be made precise by means of bicycle tests. The physician's assessment of the severity of angina is influenced by the physical activity of the patient in everyday life.


Association of age with health-related quality of life in a cohort of patients with systemic lupus erythematosus: the Georgians Organized Against Lupus study.
To examine whether older age was associated with lower health-related quality of life (HRQOL) among patients with systemic lupus erythematosus (SLE) and whether differential disease-related damage and activity explained these associations. We used cross-sectional data on 684 patients with SLE aged ≥20 years from the Georgians Organized Against Lupus cohort to estimate the associations between age (categorised as 20-39, 40-59 and ≥60 years) and HRQOL (Short Form-12 norm-based domain and physical component summary (PCS) and mental component summary (MCS) scores), using multivariable linear regression. We then examined the effect of disease-related damage and activity on these associations. The mean age of the cohort was 48.2±13.1 years (range, 20-88 years), with 28.0%, 52.9% and 19.1% of participants being aged 20-39, 40-59 and ≥60 years, respectively; 79.0% were African-American and 93.7% were female. The mean PCS score was 39.3 (41.8, 38.7 and 37.4 among those aged 20-39, 40-59 and ≥60 years, respectively), while the mean MCS score was 44.3 (44.2, 43.8 and 46.1, respectively). In general, lower physical but not mental HRQOL scores were associated with older age. With adjustment, older ages (40-59 and ≥60, respectively, vs 20-39) remained associated (β (95% CI)) with lower PCS (-2.53 (-4.58 to -0.67) and -3.57 (-6.19 to -0.96)) but not MCS (0.47 (-1.46 to 2.41) and 1.20 (-1.52 to 3.92)) scores. Associations of age with HRQOL domain and summary scores were not substantially changed by further adjustment for disease-related damage and/or activity. Nearly one in five participants in this large, predominantly African-American cohort of patients with SLE was at least 60 years old. The associations of older age with lower physical, but not mental, HRQOL were independent of accumulated SLE damage and current SLE activity. The results suggest that studies of important geriatric outcomes in the setting of SLE are needed to inform patient-centred clinical care of the ageing SLE population.


Association between life-span extension by caloric restriction and thiol redox state in two different strains of mice.
The hypothesis that the life-extending effect of caloric restriction (CR) is associated with an attenuation of the age-related pro-oxidant shift in the thiol redox state was tested employing a novel experimental design. Amounts of GSH, GSSG, and protein mixed disulfides (Pr-SSG) in the skeletal muscle and liver were compared between two strains of mice that have similar life spans when fed ad libitum (AL), but different life spans under the standard CR regimen. The life span of one strain, C57BL/6, is extended under CR, whereas it remains unaffected in the other strain, DBA/2. Mice were fed AL or 40% less food starting at 4 months and compared at 6 and 24 months of age. The amounts of GSSG and Pr-SSG increased and the GSH:GSSG ratios decreased with age in both strains of AL-fed mice. CR prevented these age-related changes in the C57BL/6, whose life span is extended by CR, but not in the DBA/2 mice, in which it remains unaffected. CR enhanced the activity of glutamate-cysteine ligase in the C57BL/6, but not in the DBA/2 mice. The results suggest that longevity extension by CR may be associated with the attenuation of age-related pro-oxidizing shifts in the thiol redox state.


Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia.
Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.


Antiphospholipid antibodies as cause of pregnancy loss.
Antiphospholipid antibodies detected by lupus anticoagulant, anticardiolipin or anti-beta2 glycoprotein I assays were associated with fetal loss. Rather than being diagnostic tools only, antiphospholipid antibodies are thought to be pathogenic. The strongest demonstration of their pathogenic role lies in the ability to induce fetal resorptions--the experimental equivalents of the human fetal losses--when passively infused in pregnant naive animals. However, still debated is how the antibodies might induce the obstetrical manifestations. Thrombotic events at the placental levels might be related to endothelial cell activation, inhibition of protein C/S system and fibrinolysis as well as to Annexin V displacement. However, the thrombophilic state apparently cannot explain all the miscarriages and a direct antibody-mediated damage on the trophoblast has been suggested. During differentiation to syncytium, trophoblasts express cell membrane anionic phospholipids that can bind beta2 glycoprotein I, the main cationic phospholipid binding protein recognized by the antiphospholipid antibodies. Adhered beta2-glycoprotein I might be recognized by the antibodies that, once bound, strongly interfere with in vitro trophoblast cell maturation so resulting in a defective placentation. These mechanisms have been suggested to play a role in early fetal loss, while thrombotic events would be responsible for miscarriages late in the pregnancy.


Survival and DNA degradation in anhydrobiotic tardigrades.
Anhydrobiosis is a highly stable state of suspended animation in an organism due to its desiccation, which is followed by recovery after rehydration. Changes occurring during drying could damage molecules, including DNA. Using the anhydrobiotic tardigrade Paramacrobiotus richtersi as a model organism, we have evaluated the effects of environmental factors, such as temperature and air humidity level (RH), on the survival of desiccated animals and on the degradation of their DNA. Tardigrades naturally desiccated in leaf litter and tardigrades experimentally desiccated on blotting paper were considered. Replicates were kept at 37 degrees C and at different levels of RH for 21 days. RH values and temperature, as well as time of exposure to these environmental factors, have a negative effect on tardigrade survival and on the time required by animals to recover active life after desiccation. DNA damages (revealed as single strand breaks) occurred only in desiccated tardigrades kept for a long time at high RH values. These results indicate that during the anhydrobiotic state, damages take place and accumulate with time. Two hypotheses can be formulated to explain the results: (i) oxidative damages occur in desiccated specimens of P. richtersi, and (ii) high temperatures and high RH values change the state of the disaccharide trehalose, reducing its protective role.


Deacetylase inhibitors for the treatment of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a diverse group of myeloid disorders, with patients being at risk for cytopenias or progression to acute myeloid leukemia. Several classification and prognostic scoring systems have been developed. High-intensity treatments are not appropriate for all patients. Two demethylating agents, azacitidine and decitabine, are approved for the treatment of MDS, although many patients do not derive long-term benefit and eventually progress. Deacetylase inhibitors have emerged as novel treatment candidates based on mechanistic rationale and preliminary data. This article reviews existing data on MDS treatment and discusses the rationale and potential for combination with deacetylase inhibitors.


Association Between Mobility Measured During Hospitalization and Functional Outcomes in Older Adults With Acute Myocardial Infarction in the SILVER-AMI Study.
Many older survivors of acute myocardial infarction (AMI) experience functional decline, an outcome of primary importance to older adults. Mobility impairment has been proposed as a risk factor for functional decline but has not been evaluated to date in older patients hospitalized for AMI. To examine the association of mobility impairment, measured during hospitalization, as a risk marker for functional decline among older patients with AMI. Prospective cohort study among 94 academic and community hospitals in the United States. Participants were 2587 hospitalized patients with AMI who were 75 years or older. The study dates were January 2013 to June 2017. Mobility was evaluated during AMI hospitalization using the Timed "Up and Go," with scores categorized as preserved mobility (≤15 seconds to complete), mild impairment (>15 to ≤25 seconds to complete), moderate impairment (>25 seconds to complete), and severe impairment (unable to complete). Self-reported function in activities of daily living (ADLs) (bathing, dressing, transferring, and walking around the home) and walking 0.4 km (one-quarter mile) was assessed at baseline and 6 months after discharge. The primary outcomes were worsening of 1 or more ADLs and loss of ability to walk 0.4 km from baseline to 6 months after discharge. The association between mobility impairment and risk of functional decline was evaluated with multivariable-adjusted logistic regression. Among 2587 hospitalized patients with AMI, the mean (SD) age was 81.4 (4.8) years, and 1462 (56.5%) were male. More than half of the cohort exhibited mobility impairment during AMI hospitalization (21.8% [564 of 2587] had mild impairment, 16.0% [414 of 2587] had moderate impairment, and 15.2% [391 of 2587] had severe impairment); 12.8% (332 of 2587) reported ADL decline, and 16.7% (431 of 2587) reported decline in 0.4-km mobility. Only 3.8% (30 of 800) of participants with preserved mobility experienced any ADL decline compared with 6.9% (39 of 564) of participants with mild impairment (adjusted odds ratio [aOR], 1.24; 95% CI, 0.74-2.09), 18.6% (77 of 414) of participants with moderate impairment (aOR, 2.67; 95% CI, 1.67-4.27), and 34.7% (136 of 391) of participants with severe impairment (aOR, 5.45; 95% CI, 3.29-9.01). Eleven percent (90 of 800) of participants with preserved mobility declined in ability to walk 0.4 km compared with 15.2% (85 of 558) of participants with mild impairment (aOR, 1.51; 95% CI, 1.04-2.20), 19.0% (78 of 411) of participants with moderate impairment (aOR, 2.03; 95% CI, 1.37-3.02), and 24.6% (95 of 386) of participants with severe impairment (aOR, 3.25; 95% CI, 2.02-5.23). This study's findings suggest that mobility impairment assessed during hospitalization may be a potent risk marker for functional decline in older survivors of AMI. These findings also suggest that brief, validated assessments of mobility should be part of the care of older hospitalized patients with AMI to identify those at risk for this important patient-centered outcome.


Effects of gastric loading on the sucking response and voluntary milk intake in neonatal piglets.
The effects of loading the stomach of piglets with 100 ml of milk after 6 hr of fasting and immediately before allowing them access to the dam were studied. Piglets gained less weight and rested more often on preloaded days. This suggests that gastric receptors exist and signal distension of the stomach. Monitoring sucking responses to a rubber teat revealed that although preloading the stomach substantially reduced voluntary milk intake during the initial 10-min. period of the test, the vigorous oral activity continued largely unabated. Isotonic saline suppressed the voluntary milk intake of the piglets for a shorter period than milk or isotonic glucose solution.


Apomorphine responses in Parkinson's disease and the pathogenesis of motor complications.
We studied the contribution of basal ganglia circuitry downstream from the nigrostriatal dopaminergic system to the pathogenesis of levodopa associated motor complications by means of an apomorphine dose-response paradigm in 28 parkinsonian patients grouped according to their clinical response to levodopa therapy. With progression from the dopa-naive to the severely fluctuating dyskinetic state, apomorphine response duration shortened, the dose-response slope steepened, and the therapeutic window narrowed. Because apomorphine acts independently of the integrity of presynaptic dopaminergic neurons, our results suggest that postsynaptic alterations account mainly for the appearance of response complications. The present findings support the possibility, raised by animal model studies, that motor response complications arise as a consequence of altered signal transduction mechanisms in striatal medium-sized neurons.


[Cholestasis and listeriosis in the third trimester of pregnancy].
Listeriosis is an infection produced by Listeria monocytogenes. It is infrequent and affects people at extreme ages, pregnant women, immunocompromised people and, occasionally, healthy people. Its incidence has increased in recent years and shows a certain tendency to seasonality, increasing in summer. It can appear sporadically or as outbreaks. In pregnant women the infection is most frequently produced in the third trimester and the symptoms are usually light. Nonetheless, the infection of the fetus is severe, and can produce miscarriages, fetal deaths, corioamnionitis and premature births with the newborn infected, manifested in the form of granulomatosis infantiseptica with abscesses and scattered granulomas or at a later stage , as meningitis or sepsis. Intrahepatic cholestasis is a reversible form of cholestasis, its cause is unknown, it is specific to pregnancy and is more frequent in multiparous women, in the third trimester and rarely before the 26th week. It disappears following childbirth and is the second cause of jaundice in pregnancy, after hepatitis. The diagnosis of cholestasis is basically clinical. It appears as palmoplantar pruritus but can also produce nausea, vomiting and abdominal discomfort localized in the right hypochondrium. Given that listeriosis and cholestasis can have a shared symptomology, the possibility of listeriosis must be borne in mind in order for early implementation of the mechanisms of diagnostic confirmation (cultivation of sterile fluids or tissues: blood, neonatal CSF, amniotic liquid or placenta) and specific treatment. We present a case of cholestasis and listeriosis in the third trimester with a good maternofetal result.


Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators.
Recent studies suggest that class III antiarrhythmic agents may have enhanced efficacy in the treatment of ventricular tachycardia. This study describes the first clinical assessment of the new class III agent ibutilide to suppress inducible monomorphic ventricular tachycardia (VT) in human beings. Fifty-five patients with coronary artery disease and inducible sustained monomorphic VT at baseline received either low (0.005 mg/kg + 0.001 mg/kg, load and maintenance infusion, respectively), middle (0.01 mg/kg + 0.002 mg/kg), or high dose (0.02 mg/kg + 0.004 mg/kg) infusions of ibutilide followed by repeat programmed ventricular stimulation. The mean age of the study group was 65.5 +/- 9.5 years and mean left ventricular ejection fraction was 36% +/- 11%. Of 48 evaluable patients, 21 (44%) were rendered noninducible after ibutilide, with no difference in efficacy among the three dosing groups (p = 0.83). Ventricular effective refractory periods, QTc interval, and ventricular monophasic action potential duration were prolonged over baseline at all tested cycle lengths. The QTc and action potential prolongation were dose related. Serious drug-related adverse reactions included sustained polymorphic VT in two patients (3.6%), spontaneous monomorphic VT in one patient (1.8%), heart block in one patient (1.8%), and hypotension in one patient (1.8%). Ibutilide prolongs ventricular repolarization in human beings and demonstrates efficacy in suppressing inducible monomorphic VT. Significant cardiovascular side effects occurred in 12.7% of patients.


Searching for the mark of Cain.
MEDFORD, MASSACHUSETTS--Hampered by political, ethical, and methodological problems, a small group of researchers is trying to understand the biological roots of violence. The field has generated some interesting findings and hypotheses about how hormones, genes, and the brain control aggressive behavior. But although the goal is to ultimately find a treatment for violent behavior, researchers emphasize that they are not advocating drugging everybody who has ever committed a crime--or is deemed prone to do so.


Introspection during visual search.
Recent advances in the field of metacognition have shown that human participants are introspectively aware of many different cognitive states, such as confidence in a decision. Here we set out to expand the range of experimental introspection by asking whether participants could access, through pure mental monitoring, the nature of the cognitive processes that underlie two visual search tasks: an effortless "pop-out" search, and a difficult, effortful, conjunction search. To this aim, in addition to traditional first order performance measures, we instructed participants to give, on a trial-by-trial basis, an estimate of the number of items scanned before a decision was reached. By controlling response times and eye movements, we assessed the contribution of self-observation of behavior in these subjective estimates. Results showed that introspection is a flexible mechanism and that pure mental monitoring of cognitive processes is possible in elementary tasks.


Activation of particulate guanylate cyclase by Escherichia coli heat-stable enterotoxin is regulated by adenine nucleotides.
Guanylate cyclase is regulated by adenine nucleotides in membranes of intestinal mucosal cells. Basal guanylate cyclase was activated about twofold by adenine nucleotides. Activation was specific for adenine, as compared with the pyrimidine nucleotides UTP and CTP. In addition, enzyme activation was obtained in the presence of saturating concentrations of GTP, the substrate for guanylate cyclase. The most potent adenine nucleotide was the nonhydrolyzable analog of ATP, adenosine 5'-O-(3-thiotriphosphate). Adenine nucleotide activation was specific for the particulate form of guanylate cyclase, as compared with the soluble form. Also, adenine nucleotides potentiated the activation of guanylate cyclase by the heat-stable enterotoxin produced by Escherichia coli. Indeed, enzyme activation by adenine nucleotides and toxin was greater than the sum of individual activations by these agents. Adenine nucleotides regulate guanylate cyclase by increasing the maximum velocity of the enzyme without altering its affinity for substrate or its cooperativity. In addition to stimulating guanylate cyclase, adenine nucleotides decreased the specific binding of the heat-stable enterotoxin to receptors in intestinal membranes. The coordinated regulation of the toxin-receptor interaction and guanylate cyclase activity by a process utilizing nonhydrolyzable analogs of a purine nucleotide is similar to the mechanisms involved in the hormone regulation of adenylate cyclase by guanine nucleotide-binding proteins. These data suggest that an adenine nucleotide-dependent protein may couple the toxin-receptor interaction to the regulation of particulate guanylate cyclase in intestinal membranes.


Soluble Heparin Binding Epidermal Growth Factor-Like Growth Factor Is a Regulator of GALGT2 Expression and GALGT2-Dependent Muscle and Neuromuscular Phenotypes.
GALGT2 (also B4GALNT2) encodes a glycosyltransferase that is normally confined to the neuromuscular and myotendinous junction in adult skeletal muscle. GALGT2 overexpression in muscle can inhibit muscular dystrophy in mouse models of the disease by inducing the overexpression of surrogate muscle proteins, including utrophin, agrin, laminins, and integrins. Despite its well-documented biological properties, little is known about the endogenous regulation of muscle GALGT2 expression. Here, we demonstrate that epidermal growth factor receptor (EGFR) ligands can activate the human GALGT2 promoter. Overexpression of one such ligand, soluble heparin-binding EGF-like growth factor (sHB-EGF), also stimulated mouse muscle Galgt2 gene expression and expression of GALGT2-inducible surrogate muscle genes. Deletion analysis of the GALGT2 promoter identified a 45-bp region containing a TFAP4-binding site that was required for sHB-EGF activation. sHB-EGF increased TFAP4 binding to this site in muscle cells and increased endogenous Tfap4 gene expression. sHB-EGF also increased muscle EGFR protein expression and activated EGFR-Akt signaling. sHB-EGF expression was concentrated at the neuromuscular junction, and Hbegf deletion reduced Galgt2-dependent synaptic glycosylation. Hbegf deletion also mimicked Galgt2-dependent neuromuscular and muscular dystrophy phenotypes. These data demonstrate that sHB-EGF is an endogenous regulator of muscle Galgt2 gene expression and can mimic Galgt2-dependent muscle phenotypes.


Identification of a dehydrogenase required for lactose metabolism in Caulobacter crescentus.
Caulobacter crescentus, which thrives in freshwater environments with low nutrient levels, serves as a model system for studying bacterial cell cycle regulation and organelle development. We examined its ability to utilize lactose (i) to gain insight into the metabolic capacities of oligotrophic bacteria and (ii) to obtain an additional genetic tool for studying this model organism, aiming to eliminate the basal enzymatic activity that hydrolyzes the chromogenic substrate 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside (X-gal). Using a previously isolated transposon mutant, we identified a gene, lacA, that is required for growth on lactose as the sole carbon source and for turning colonies blue in the presence of X-gal. LacA, which contains a glucose-methanol-choline (GMC) oxidoreductase domain, has homology to the flavin subunit of Pectobacterium cypripedii's gluconate dehydrogenase. Sequence comparisons indicated that two genes near lacA, lacB and lacC, encode the other subunits of the membrane-bound dehydrogenase. In addition to lactose, all three lac genes are involved in the catabolism of three other beta-galactosides (lactulose, lactitol, and methyl-beta-d-galactoside) and two glucosides (salicin and trehalose). Dehydrogenase assays confirmed that the lac gene products oxidize lactose, salicin, and trehalose. This enzymatic activity is inducible, and increased lac expression in the presence of lactose and salicin likely contributes to the induction. Expression of lacA also depends on the presence of the lac genes, implying that the dehydrogenase participates in induction. The involvement of a dehydrogenase suggests that degradation of lactose and other sugars in C. crescentus may resemble a proposed pathway in Agrobacterium tumefaciens.


Nanobody-mediated control of gene expression and epigenetic memory.
Targeting chromatin regulators to specific genomic locations for gene control is emerging as a powerful method in basic research and synthetic biology. However, many chromatin regulators are large, making them difficult to deliver and combine in mammalian cells. Here, we develop a strategy for gene control using small nanobodies that bind and recruit endogenous chromatin regulators to a gene. We show that an antiGFP nanobody can be used to simultaneously visualize GFP-tagged chromatin regulators and control gene expression, and that nanobodies against HP1 and DNMT1 can silence a reporter gene. Moreover, combining nanobodies together or with other regulators, such as DNMT3A or KRAB, can enhance silencing speed and epigenetic memory. Finally, we use the slow silencing speed and high memory of antiDNMT1 to build a signal duration timer and recorder. These results set the basis for using nanobodies against chromatin regulators for controlling gene expression and epigenetic memory.


Peripheral transmission in primary sensory nerves.
Primary sensory nerves do not only transfer messages to the central nervous system but also transmit messages to the periphery. The peripheral response is one of defense, including neurogenic inflammation such as miosis and a breakdown of the blood aqueous barrier in the eye or vasodilatation and plasma extravasation in the skin. Recent pharmacological, biochemical and immunohistochemical studies have revealed that tachykinins are the most likely transmitters at peripheral as well as central endings of primary sensory nerves. Furthermore, studies with trigeminal nerve-innervated and isolated rabbit iris sphincter muscle have clearly shown that the peripheral neurotransmission is affected by many neuromodulators and irritants. It is not unlikely that the neurotransmission mechanisms at peripheral endings are analogous to those at central endings in the primary sensory nerves.


Salt loading in canola oil fed SHRSP rats induces endothelial dysfunction.
This study aimed to determine if 50 days of canola oil intake in the absence or presence of salt loading affects: (1) antioxidant and oxidative stress markers, (2) aortic mRNA of NADPH oxidase (NOX) subunits and superoxide dismutase (SOD) isoforms and (3) endothelial function in SHRSP rats. SHRSP rats were fed a diet containing 10 wt/wt% soybean oil or 10 wt/wt% canola oil, and given tap water or water containing 1% NaCl for 50 days. Without salt, canola oil significantly increased RBC SOD, plasma cholesterol and triglycerides, aortic p22 (phox) , NOX2 and CuZn-SOD mRNA, and decreased RBC glutathione peroxidase activity. With salt, canola oil reduced RBC SOD and catalase activity, LDL-C, and p22 (phox) mRNA compared with canola oil alone, whereas plasma malondialdehyde (MDA) was reduced and RBC MDA and LDL-C were higher. With salt, the canola oil group had significantly reduced endothelium-dependent vasodilating responses to ACh and contractile responses to norepinephrine compared with the canola oil group without salt and to the WKY rats. These results indicate that ingestion of canola oil increases O2 (-) generation, and that canola oil ingestion in combination with salt leads to endothelial dysfunction in the SHRSP model.


Removal of endocrine disrupting chemicals in a large scale membrane bioreactor plant combined with anaerobic-anoxic-oxic process for municipal wastewater reclamation.
The removal of eight typical endocrine disrupting compounds (EDCs) in a full scale membrane bioreactor combined with anaerobic-anoxic-oxic process (A(2)/O-MBR) for municipal wastewater reclamation located in Beijing was investigated. These EDCs, including 4-octylphenol (4-OP), 4-n-nonylphenol (4-n-NP), bisphenol A (BPA), estrone (E1), 17α-estradiol (17α-E2), 17β-estradiol (17β-E2), estriol (E3) and 17α-ethinylestradiol (EE2), were simultaneously analyzed by gas chromatography/mass spectrometry after derivatization. The concentrations of eight EDCs were also measured in sludge of anaerobic, anoxic, oxic and membrane tanks to measure sludge-water distribution coefficients (K(d) values) as the indicator of adsorption propensity of target compound to sludge. The removal efficiencies of EDCs reached above 97%, except for 4-n-NP removal efficiency of 72%, 4-OP removal efficiency of 75% and EE2 removal efficiency of 87% in the A(2)/O-MBR process. The high K(d) values indicated that the sludge had a large adsorption capacity for these EDCs, and significantly contributed to removal of EDCs. Yeast estrogen screen assay was performed on samples to assess the total estrogenic activity by measuring the 17β-E2 equivalent quantity (EEQ), expressed in ng-EEQ/L. The measured EEQ value was markedly reduced from 72.1 ng-EEQ/L in the influent to 4.9 ng-EEQ/L in the effluent. Anoxic tank and anaerobic tank contributed to 80% and 37% in total EEQ removal, respectively.


Factors associated with multidrug-resistant bacteria in healthcare-associated infections: a pediatric intensive care unit case-control study.
To investigate the prevalence of factors related to healthcare-associated infections, caused by multidrug-resistant bacteria, in a pediatric intensive care unit. A retrospective case-control study conducted from January 1, 2007 to December 31, 2018, in São Paulo (SP), Brazil. The study was carried out at the pediatric intensive care unit of a high-complexity, tertiary care general hospital. The study included patients aged 1 month to 19 years, admitted to the pediatric intensive care unit, diagnosed as healthcare-associated infections. There was significant evidence of infection by multidrug-resistant bacteria associated with immunosuppressed patients (p<0.001), in whom the likelihood of multidrug-resistant bacteria infection was estimated to be nine-fold higher than among non-immunosuppressed patients (OR 8.97; 95%CI 2.69-29.94). In the analysis of multiple logistic regression model, we observed that immunosuppressed patients had an 8.5-fold higher chance of multidrug-resistant bacteria infection when compared to non-immunosuppressed patients (OR 8.48; 95%CI 2.54-28.35; p=0.001). There is evidence of association between the Case Group and presence of Gram-positive (p=0.007), coagulase-negative Staphylococcus (p<0.001), and Gram-negative (p=0.041) microorganisms. The immunocompromised-state variable is a factor related to healthcare-associated infections caused by multidrug-resistant bacteria, and the Case Group presented higher proportions of Gram-positive microorganisms and coagulase-negative Staphylococcus.


Effects of different kinds of fluorides on enolase and ATPase activity of a fluoride-sensitive and fluoride-resistant Streptococcus mutans strain.
Enolase and ATPase are sensitive to fluoride. It is unclear whether this sensitivity differs for F-sensitive and F-resistant cells or for different types of fluoride. Permeabilized cells of the fluoride-sensitive strain Streptococcus mutans C180-2 and its fluoride-resistant mutant strain C180-2 FR were preincubated at pH 7 or 4 with NaF, the amine fluorides Olaflur and Dectaflur and amine chloride controls. After preincubations, enolase and ATPase activities of the cells were assessed. Enolase activity was more inhibited after preincubation at pH 7 with NaF than with Olaflur. Amine chloride stimulated, although not with statistical significance, the enolase activity of both strains. After preincubation at pH 4 the enolases were strongly inactivated, but the fluoride-resistant strain's enolase to a lesser extent. The results suggested that amine acts to protect enolase activity against the detrimental low pH effect. Gene sequencing showed that the enolase genes of the fluoride-resistant and fluoride-sensitive strain were identical. ATPase activity was not reduced after NaF preincubation at either pH 7 or pH 4. The amine fluorides and their chloride controls in the preincubation mixture reduced the ATPase activity significantly at both pH values. In conclusion, our results showed that preincubation with amine fluoride did not inhibit enolase activity more effectively than NaF. The amine part of the molecule may protect enolase activity against preincubations at low pH. ATPase activity was not inhibited by NaF preincubation but was significantly inhibited after preincubation with amine fluorides and amine chlorides.


Analysis of neurogranin (NRGN) in schizophrenia.
A recent study reported a genome-wide significant association between schizophrenia and rs12807809-a SNP located approximately 3 kbp upstream of the neurogranin gene (NRGN). We sought to determine if (a) NRGN contains common exonic variants or variants affecting expression (eQTLs) that could account for the association with rs12807809 and (b) there exist rare non-synonymous highly penetrant variants that could potentially confer high risk of schizophrenia. We sequenced all four exons of NRGN in a screening set of 14 individuals but found no novel common polymorphisms. We additionally sequenced the coding exons in up to 1,113 individuals (699 cases) but this revealed only a singleton-coding variant in exon 2 (G246T leading to Gly-55 → Val amino acid change) in which prediction of function analysis suggested is likely to be benign. Finally, analysis of a brain expression dataset of at least 130 individuals did not identify any eQTLs that were correlated with associated SNP rs12807809 following correction for multiple testing.


Self-assembling Peptides with Internal Ionizable Unnatural Amino Acids: A General Approach to pH-responsive Peptide Materials.
Self-assembled peptides are an emerging family of biomaterials that show great promise for a range of biomedical and biotechnological applications. Introducing and tuning the pH-responsiveness of the assembly is highly desirable for improving their biological activities. Inspired by proteins with internal ionizable residues, we report a simple but effective approach to constructing pH-responsive peptide assembly containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. Through a combined experimental and computational investigation, we demonstrate that these residues can be accommodated and stabilized within the internal hydrophobic compartment of the peptide assembly. The hydrophobic microenvironment shifts their pKa significantly from a basic pH typically found for free amines to a more biologically relevant pH in the weakly acidic range. The pH-induced ionization and ionization-dependent self-assembly and disassembly are thoroughly investigated and correlated with the biological activity of the assembly. This new approach has unique advantages in tuning the pH-responsiveness of self-assembled peptides across a large pH range in a complex biological environment. We anticipate the ionizable amino acids developed here can be widely applicable to the synthesis and self-assembly of many amphiphilic peptides with endowed pH-responsive properties to enhance their biological activities toward applications ranging from targeted therapeutic delivery to proton transport.


Alterations in the cellular envelope of spontaneous IIIManL-defective mutants of Streptococcus salivarius.
In Streptococcus salivarius, the phosphoenolpyruvate: mannose phosphotransferase system (PTSMan) transports and concomitantly phosphorylates mannose, glucose, fructose and 2-deoxyglucose. PTSMan consists of a membrane Enzyme II and two forms of Enzyme III (IIIMan) having molecular masses of 38.9 kDa (IIIManH) and 35.2 kDa (IIIManL) respectively. We have previously reported the isolation of spontaneous mutants lacking IIIManL, and showed that they exhibited abnormal growth when cultured in mixtures of sugars containing glucose. The mutants also synthesize several cytoplasmic glucose-repressible proteins during growth on glucose and some of them constitutively express a fructose PTS which is induced by fructose in the parental strain. We have now investigated the properties and composition of the cellular envelope of three S. salivarius IIIManL-defective mutants (strains A37, B31 and G29) after growth on glucose. The mutants have altered sensitivity to various toxic compounds that interfere with cell-envelope functions. The mutants also exhibited altered membrane-protein profiles when analysed by two-dimensional PAGE and modified total lipid and phosphorus contents and lipid/protein ratio. In one mutant (strain G29), the proportion of the phospholipids separated by TLC was different from the parental strain. Electron microscopy indicated that one mutant (strain A37) possessed more fimbriae than the parental strain. The results suggested that these IIIManL-defective mutants were affected in a global regulatory gene controlling several cellular or physiological functions, many of these being related to the cellular envelope.


Cells segmentation from 3-D confocal images of early zebrafish embryogenesis.
We designed a strategy for extracting the shapes of cell membranes and nuclei from time lapse confocal images taken throughout early zebrafish embryogenesis using a partial-differential-equation-based segmentation. This segmentation step is a prerequisite for an accurate quantitative analysis of cell morphodynamics during embryogenesis and it is the basis for an integrated understanding of biological processes. The segmentation of embryonic cells requires live zebrafish embryos fluorescently labeled to highlight sub-cellular structures and designing specific algorithms by adapting classical methods to image features. Our strategy includes the following steps: the signal-to-noise ratio is first improved by an edge-preserving filtering, then the cell shape is reconstructed applying a fully automated algorithm based on a generalized version of the Subjective Surfaces technique. Finally we present a procedure for the algorithm validation either from the accuracy and the robustness perspective.


[Analysis of a economic model of a populational influenza immunization strategy in healthy employees].
A debate exists as to whether it is advisable to extend the influenza immunization programs to the entire population, possibly due to the economic impact of this measure. This study is aimed at analyzing the cost-benefit ratio of an influenza immunization strategy among our country's working population. Economic study from a social standpoint, including the direct and indirect costs (lost productive time, adverse effects) of the immunization. The costs avoided include the loss of productivity (from the human capital standpoint) and the health costs avoided when the infection is prevented. A costs avoided/costs incurred ratio, known as the Return Rate (RR) is constructed. The costs are converted into constant 2003 Euros. The data was compiled from published sources and a sensitivity analysis presented. The average cost of each immunization is 13.58 (95% CI 13.54-13.62) Euros. Each case of influenza avoided saves an average expense of 374.71 (95% CI 372.59-376.83) Euros. Every 1000 immunizations would avoid an average of 29.3 influenza cases (95% CI 29.0-29.5). The net cost of immunization is 2.60 (95% CI 2.51-2.70) euros. The RR has an average value of 0.80 (95% CI 0.79-0.81), median 0.74, interquartile range (0.53-1.02) Euros. In the case of avoiding more than 36 cases of influenza per 1000 immunizations, the RR takes on values >1. The influenza immunization strategy for the working population is solely cost-effective for situations of high influence incidence and high vaccine effectiveness.


Aqueous self-assembly of arginine and K8SiW11O39: fine-tuning the formation of a coacervate intended for sprayable anticorrosive coatings.
Coacervates are commonly thought to be formed from the liquid-liquid phase separation of macromolecules, such as oppositely charged polyelectrolytes, proteins or peptides. Unlike conventional systems, we here show an entirely novel coacervate obtained from the self-assembly of arginine (Arg) and K8[α-SiW11O39] (SiW11) in water. The formation of the coacervate Arg/SiW11 is confirmed by combined techniques, including turbidity, rheology, optical microscopy, and scanning and transmission electron microscopy. Assessment of the rheological response reveals that the complex coacervate exhibits shear thinning behaviour. X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) spectroscopy, elemental analysis and thermogravimetric analysis are used to characterize the coacervate. The thermodynamic parameters of the coacervation are monitored by isothermal titration calorimetry (ITC), which identifies that the formation of the coacervate by mixing of Arg and SiW11 is driven by a combination of entropic and enthalpic effects. The resultant coacervate shows a typical upper critical solution temperature (UCST) phenomenon, which is strongly dependent on the concentration of the species. Furthermore, we demonstrate that the coacervation could be tuned by stoichiometry and pH. A phase diagram for the complexation of Arg and SiW11 thus has been constructed using turbidity measurements. Such a phase diagram is a very useful tool for the preparation of coacervates from a specific combination of Arg and SiW11. Finally, the acid induced gelation of the coacervate has been explored to fabricate an anticorrosive coating to protect a copper plate from exposure to acid vapour.


[The age-related factor in the pathology of consciousness in craniocerebral trauma].
In children (n = 103), elderly and old persons (n = 42), abnormal consciousness was comparatively studied in the acute period of brain injury. The revealed clinical features were compared with the previously described syndromes of consciousness disorders in young and middle-aged patients. The authors consider it appropriate to identify quantitative (deafening, sopor, coma) and qualitative (obscure consciousness, confusion, and mixed types differing in the ratio of productive to deficiency symptoms). Depressed consciousness was found to be prevalent in children, obscure consciousness was most typical in adults, confusion was common in elderly and old patients. The low presentation of productive disorders and their low association mainly with brain injury in patients who are on the different poles of ontogenesis are explained in the context of the teaching of cerebral functional asymmetry.


Social adjustment of chronic dialysis patients.
The author gathered information by questionnaire about the leisure activities of 102 patients receiving chronic hemodialysis. The patients reported a severe decrease in interest, especially in family and social leisure activities, and an even greater decrease in actual participation in leisure activities. The results indicate that hemodialysis patients do not suppress or deny the many problems they experience. The author hypothesizes that the paucity of information in this area is probably linked to the denial of the staff who treat these patients. The sharp decline in the leisure activities to the group studied suggests the need to devise methods of intervention to improve the quality of life of chronic dialysis patients.


Anxiety sensitivity and posttrauma stress symptoms in female undergraduates following a campus shooting.
Participants were recruited from female undergraduate students participating in an ongoing longitudinal study at the time of a campus shooting. Eighty-five percent (N = 691) of the 812 students who were invited to participate in the current study completed questionnaires an average of 27 days following a campus shooting. In a mixed cross-sectional and longitudinal design, the cognitive and the physical concerns dimensions of postshooting anxiety sensitivity accounted for unique variance in posttrauma stress symptom severity (cross-sectional), after controlling for preshooting psychological symptoms (longitudinal). The cognitive concerns dimension showed the strongest relationship. Anxiety sensitivity also appeared to moderate the relationships of hyperarousal symptoms with reexperiencing and numbing symptoms.


Comparison of the carbon footprint of different patient diets in a Spanish hospital.
Mitigating climate change requires management strategies to reduce greenhouse gas emissions in any sector, including the health system. Carbon footprint calculations should play a key role in quantifying and communicating these emissions. Food is among the categories with low accuracy because the carbon footprint for food is still under development. We aimed to quantify the carbon footprint of different diets. Average carbon footprint for a normal diet was based on detailed composition data in Juan Ramón Jiménez Hospital (Huelva, Spain). In addition, the carbon footprints of 17 other therapeutic diets were estimated using a streamlined variation of each diet published by Benidorm Clinical Hospital (Spain). The carbon footprint was calculated for 18 hospital diets for a variety of patients. The reference menu corresponds to the normal diet provided to patients who do not have special dietary requirements. This menu has a low carbon footprint of 5.083 CO₂ eq/day. Hospital diets contribute to the carbon footprint of a hospital. The type of diet has a significant impact on the greenhouse gas emissions. A Mediterranean diet is associated with lower environmental impact than diets with more meat, in particular red meat.


Fc receptor mediated immune regulation and gene expression.
Exogenous Fc receptors (FcR) have been demonstrated to either augment or inhibit endogenous FcR mediated immunity, immune regulation and gene expression. Other immune regulatory or modulator molecules, such as the H2 histocompatibility antigens, interferon, transfer factor and leukocyte chalones might involve association with or alter the synthesis or status of FcR, thus effecting regulation of immunity and/or gene expression. FcR provide a unique opportunity for eliciting the mechanisms and perhaps altering the immunity and/or gene expression which influence immune regulation, cellular differentiation, viral replication and malignant transformation.


Spatial and Temporal Patterns of Neurogenesis in the Chick Retina.
Chick embryo retinas were labelled in ovo by single injections of [3H]thymidine at selected times between days 2 and 12 of incubation. Embryos were later removed, at different stages of development, and the retinas processed for autoradiography of either serial sections or dissociated cell preparations. Analysis of unlabelled cells shows that neurogenesis starts, on day 2 of incubation, in a dorsotemporal area of the central retina, close to the posterior pole and to the optic nerve head. A gradient of neurogenesis spreads from this central area to the periphery, where neurogenesis ends, shortly after day 12, when the last few bipolar cells withdraw from the cell cycle. Additional dorsal-to-ventral and temporal-to-nasal gradients can be discerned in our autoradiographs. In all retinal sectors, ganglion cells start first to withdraw from the cell cycle, followed, with substantial overlapping, by amacrine, horizontal, photoreceptor plus Müller, and bipolar neuroblasts. Ganglion cells are also the first to reach the 50% level of unlabelled cells, followed this time by horizontal, photoreceptor, amacrine, Müller and bipolar cells. Finally, 100% levels of unlabelled cell populations are attained simultaneously by ganglion, horizontal and photoreceptor cells, followed by amacrine, then by Müller, and last by bipolar cells. Although all classes of neurons, in varying proportions, are being produced most of the time, our results also demonstrate that, in any given retinal area, the first cells leaving the cycle are determined to become ganglion cells, and the last ones bipolar cells, and not other types.


Blocking the B7-H4 pathway with novel recombinant antibodies enhances T cell-mediated antitumor responses.
B7-H4 inhibits T-cell activation and is widely expressed by solid neoplasms. We have recently demonstrated that the expression of B7-H4 on the surface of malignant cells in vivo is inducible, and that novel anti-B7-H4 recombinant antibodies can reverse the inhibition of tumor-specific T cells. Thus, antibodies targeting the B7-H4 pathways may extend the survival of cancer patients by restoring T cell-mediated antitumor responses.


Endoscopic laser therapy for oesophageal cancer.
Most oesophageal cancers are incurable by the time the diagnosis is made. Treatment is therefore often palliative, and endoscopic modalities cause considerably less general upset to the patient than surgery, radiotherapy or chemotherapy. Nd:YAG laser recanalisation of advanced obstructing cancers is safe and effective for exophytic tumours that are endoscopically accessible in over 80% of cases. The risk of perforation is less than half that associated with insertion of a perforation is less than half that associated with insertion of a prosthesis, although it is higher in patients who have previously been treated by radiotherapy. After laser treatment, half the patients are able to maintain adequate nutrition until the time of their death from disseminated disease. The other half get further dysphagia due to recurrent exophytic tumour or compression from extrinsic tumour. A few develop fibrous stricturing in the laser treated area. However, many of these recurrences can be treated again with the laser or by dilation with or without a prosthesis. The quality of swallowing is better after laser treatment, as any residual oesophageal muscle function in that area can be used (not possible with a prosthesis), although several treatment sessions are usually required. In the future, the precision of laser effects may make it possible to safely ablate early tumours in their entirety.


Genetic diversity, demographic history and neo-sex chromosomes in the Critically Endangered Raso lark.
Small effective population sizes could expose island species to inbreeding and loss of genetic variation. Here, we investigate factors shaping genetic diversity in the Raso lark, which has been restricted to a single islet for approximately 500 years, with a population size of a few hundred. We assembled a reference genome for the related Eurasian skylark and then assessed diversity and demographic history using RAD-seq data (75 samples from Raso larks and two related mainland species). We first identify broad tracts of suppressed recombination in females, indicating enlarged neo-sex chromosomes. We then show that genetic diversity across autosomes in the Raso lark is lower than in its mainland relatives, but inconsistent with long-term persistence at its current population size. Finally, we find that genetic signatures of the recent population contraction are overshadowed by an ancient expansion and persistence of a very large population until the human settlement of Cape Verde. Our findings show how genome-wide approaches to study endangered species can help avoid confounding effects of genome architecture on diversity estimates, and how present-day diversity can be shaped by ancient demographic events.


Ultra-Fast Degradation of Chemical Warfare Agents Using MOF-Nanofiber Kebabs.
The threat associated with chemical warfare agents (CWAs) motivates the development of new materials to provide enhanced protection with a reduced burden. Metal-organic frame-works (MOFs) have recently been shown as highly effective catalysts for detoxifying CWAs, but challenges still remain for integrating MOFs into functional filter media and/or protective garments. Herein, we report a series of MOF-nanofiber kebab structures for fast degradation of CWAs. We found TiO2 coatings deposited via atomic layer deposition (ALD) onto polyamide-6 nanofibers enable the formation of conformal Zr-based MOF thin films including UiO-66, UiO-66-NH2 , and UiO-67. Cross-sectional TEM images show that these MOF crystals nucleate and grow directly on and around the nanofibers, with strong attachment to the substrates. These MOF-functionalized nanofibers exhibit excellent reactivity for detoxifying CWAs. The half-lives of a CWA simulant compound and nerve agent soman (GD) are as short as 7.3 min and 2.3 min, respectively. These results therefore provide the earliest report of MOF-nanofiber textile composites capable of ultra-fast degradation of CWAs.


Chain-end functionalized nanopatterned polymer brushes grown via in situ nitroxide free radical exchange.
The patterning of biologically active materials has been accomplished by the use of imprint lithography of functional photopolymer resins to create controlled nanoscale patterns of a cross-linked photopolymer containing embedded initiator groups. Functionalized polymer brushes consisting of polystyrene and poly(N,N-dimethylacrylamide) were grown from these patterned layers by nitroxide-mediated polymerization. Chain-end functionalization of the brush layer was accomplished by nitroxide radical exchange during the polymerization. Accordingly, brush layers terminated by pyrene and biotin functional groups were obtained by exchange with the appropriate alkoxyamines. The presence of pyrene functionality at the chain ends of the brushes was confirmed by fluorescent emission measurements. Fluorescently labeled streptavidin protein was selectively attached with high selectivity to the patterned biotinylated brush layer through biotin-streptavidin interactions. The functionalized polymer grafted surfaces and nanopatterns have been successfully characterized using a fluorescence spectrophotometer, AFM, SEM, confocal microscopy, and water contact angle measurements.


Probing the membrane targeting C1 subdomains of PKC with bivalent ligands.
Protein kinase C is a family of ubiquitously expressed signal transducing proteins. The hallmark for PKC activation is its translocation to membranes following generation of lipid second messengers. This process is mediated by C1 and C2 membrane-targeting modules, whose engagement on membranes provides energy for a conformational change crucial to PKC activity. Novel and conventional subfamilies of PKC have two C1 domains, namely C1A and C1B, each of which contain a binding pocket for a messenger. Several studies addressed the issue of simultaneous activation of both C1 domains by specifically designed bivalent activators based on phorbol esters, benzolactam and other PKC ligands. Many bivalent ligands displayed 1-2 orders of magnitude higher potency then their monovalent congeners. Most effective were the "dimeric" ligands linked with 10-14 carbon spacers. Lower than predicted potency and lack of marked isoform selectivity indicate that those compounds do not activate both C1 domains at the same time, or that process is unfavored due to steric or conformational reasons. However, high binding affinity for some of them provides hope that related PKC activators that are isoform selective can be developed. As to the nature of the linkers: flexible and lipophilic oligomethylene chains proved superior over flexible and hydrophilic oligoethylene glycol or rigid and lipophilic benzene in recruiting PKC to the membranes.


Acoustic Propulsion of Vitamin C Loaded Teabots for Targeted Oxidative Stress and Amyloid Therapeutics.
We report the fabrication of ascorbic acid (AA) template nanomotors using buds of Camelia sinensis, undergoing fuel-free propulsion. The motors, namely, Teabots, display propulsion by converting the sound energy from the acoustic field into a mechanical one. The mesh-like structures of the anionic Teabots facilitate superior adsorption of ascorbic acid (AA-Teabots) undergoing a controlled release. The motors show antioxidant properties at the physiological pH range by scavenging intracellular reactive oxygen species. Interestingly, the percentage release of ascorbic acid is significantly higher under the influence of ultrasound exposure, as compared to the normal pH-dependent release. The motors were also efficient in the degradation of artificially synthesized toxic amyloid fibrils. The acoustic delivery of AA-Teabots could protect HEK-293 cells from oxidative injuries alongside preventing protein-aggregation derived diseases. Soon, such acoustic powered biocompatible AA-Teabots are envisioned to provide an attractive approach in proficient delivery and controlled release of therapeutic payloads at targeted zones.


Hormonal adaptation to the stresses imposed upon sodium balance by pregnancy and lactation in the Yanomama Indians, a culture without salt.
The Yanomama Indians of northern Brazil and southern Venezuela have been identified as a "no-salt" culture. In this study, data were obtained to determine in this population the adjustments of sodium-related hormones to the stresses imposed upon sodium balance by pregnancy and prolonged lactation. Controls against the possibility that findings in the Yanomama were ethnic rather than dietary were provided by similar observations in the Guaymi Indians of Panama, who have free access to salt. Urinary concentrations of sodium were approximately 1 mEq/l in male and female Yanomama, with 24-hour excretion rates in the males averaging 1 mEq, similar to our prior observation. The pregnant Yanomama had exceeding high urinary concentrations of aldosterone. These were associated with higher plasma renin activities and serum aldosterone concentrations than in all other subjects. Although pregnant Guaymi had elevations of serum and urinary aldosterone, these were significantly lower (p < 0.001) than those of the Yanomama. Prolonged lactation in the Yanomama was associated with elevation of plasma renin activity and serum and urinary aldosterone concentration compared with the Guaymi, but were not higher than those in nonlactating Yanomama females. The findings suggest that pregnancy in a salt-poor environment is associated with an exaggerated augmentation of hormonal responses that enhance positive sodium balance.


Differential pathophysiology of bacterial translocation after thermal injury and sepsis.
Bacterial translocation (BT) occurs transiently after thermal injury and may result from an ischemic intestinal insult. To evaluate continued intestinal ischemia in the ongoing BT associated with sepsis after injury, rats were randomized to (1) 30% burn injury with Pseudomonas wound infection (BI), (2) BI + fluid resuscitation (BI + Fluid), (3) BI after allopurinol pretreatment to inhibit xanthine oxidase (BI + Allo), or (4) BI after azapropazone pretreatment to inhibit neutrophil degranulation (BI + Aza). On postburn days (PBD) 1, 4, and 7, animals were studied for evidence of BT and intestinal lipid peroxidation. BI + Fluid, BI + Allo, and BI + Aza significantly (p less than 0.05) reduced rates of BT and ileal lipid peroxidation acutely after thermal injury (PBD 1) compared to BI. All four groups had equally high rates of BT associated with the onset of sepsis (PBDs 4 and 7), without evidence of further intestinal lipid peroxidation. These data indicate that the chronic gut barrier failure associated with sepsis after injury occurs independently of continued intestinal ischemia.


Auditory and Visual External Cues Have Different Effects on Spatial but Similar Effects on Temporal Measures of Gait Variability.
Walking synchronized to external cues is a common practice in clinical settings. Several research studies showed that this popular gait rehabilitation tool alters gait variability. There is also recent evidence which suggests that alterations in the temporal structure of the external cues could restore gait variability at healthy levels. It is unknown, however, if such alterations produce similar effects if the cueing modalities used are different; visual or auditory. The modality could affect gait variability differentially, since there is evidence that auditory cues mostly act in the temporal domain of gait, while visual cues act in the spatial domain of gait. This study investigated how synchronizing steps with visual and auditory cues that are presented with different temporal structures could affect gait variability during treadmill walking. Three different temporal structured stimuli were used, invariant, fractal and random, in both modalities. Stride times, length and speed were determined, and their fractal scaling (an indicator of complexity) and coefficient of variation (CV) were calculated. No differences were observed in the CV, regardless of the cueing modality and the temporal structure of the stimuli. In terms of the stride time's fractal scaling, we observed that the fractal stimulus induced higher values compared to random and invariant stimuli. The same was also observed in stride length, but only for the visual cueing modality. No differences were observed for stride speed. The selection of the cueing modality seems to be an important feature of gait rehabilitation. Visual cues are possibly a better choice due to the dependency on vision during walking. This is particularly evident during treadmill walking, a common practice in a clinical setting. Because of the treadmill effect on the temporal domain of gait, the use of auditory cues can be minimal, compared to visual cues.


The Detrimental Effect of Type II Diabetes Mellitus on Infected Patients with COVID-19.
COVID-19 is no longer a global public health emergency, but it still affects numerous diseases and needs further research. Diabetic COVID-19 patients with major complications or intensive care had high mortality rates. This review provides pathophysiological descriptive data on diabetes mellitus type 2 and shows how COVID-19 infection in Saudi Arabia predicts disease severity and prognosis. This review was conducted through online research on MEDLINE/PubMed databases, Scopus, and Web of Science based on links between COVID-19 and diabetes mellitus type 2 patients. By using the keywords 'COVID-19', 'diabetes', ' correlation', and impact on 'population' from December 2022 to February 2023. The full texts of the articles that were retrieved were accessed. The COVID-19 epidemic has affected the community, especially diabetics, and their daily life. According to our research on prior studies, most COVID-19 patients in Saudi Arabia had diabetes as a comorbidity. We underline the necessity of thorough study to better understand COVID-19 and its association with diabetes to design and implement evidence-based initiatives and policies in Saudi Arabia, where diabetes is a major health issue.


Androgen ablation therapy does not increase the risk of late morbidity following 3D-conformal radiotherapy of organ-confined prostate cancer: the experience of the European Institute of Oncology.
Androgen ablation therapy in conjunction with radiotherapy--neoadjuvant and adjuvant--has consistently been shown to be associated with improved biochemical and local control, whereas controversy still remains as regards its benefit in terms of overall survival. The objective of this study is to determine the impact of androgen ablation in combination to 3D-conformal radiotherapy on late treatment-related toxicity. 236 patients were treated with 3D-conformal radiotherapy to a total dose ranging from 70 and 78.6 Gy. Fifty-six patients did not receive any form of androgen ablation whereas 176 were given at least 3 months of neoadjuvant androgen ablation. Of these, 64 stayed on androgen ablation for a median time of 6 months post-radiotherapy. Acute toxicity was evaluated weekly during the course of treatment. Late toxicity was assessed at 3-months intervals during the follow-up. Toxicity was scored according to the RTOG criteria. The median follow-up was 24.6 months (range, 12-62). The incidence of late genitourinary toxicity was: 3% G2, 3.5% G3, 0.5% G4. The incidence of late gastrointestinal toxicity was: 12% G2, 2% G3, 1% G4. No association was observed between the use of androgen ablation and late treatment-related toxicity. High-risk patients who continued on androgen ablation long-term were not found to have an increased risk of developing late toxicity with respect to those who never had any form of androgen ablation or those only treated neoadjuvantly. In our experience, the use of androgen ablation does not impact on late toxicity following high dose 3D-conformal radiotherapy for prostate cancer.


Federal Funding For Research On The Leading Causes Of Death Among Children And Adolescents.
Firearm injuries are the second-leading cause of death for US children and adolescents (ages 1-18). This analysis quantified the federal dollars granted to research for the leading US causes of death for this age group in 2008-17. Several federal data sources were queried. On average, in the study period, $88 million per year was granted to research motor vehicle crashes, the leading cause of death in this age group. Cancer, the third-leading cause of mortality, received $335 million per year. In contrast, $12 million-only thirty-two grants, averaging $597 in research dollars per death-went to firearm injury prevention research among children and adolescents. According to a regression analysis, funding for pediatric firearm injury prevention was only 3.3 percent of what would be predicted by mortality burden, and that level of funding resulted in fewer scientific articles than predicted. A thirtyfold increase in firearm injury research funding focused on this age group, or at least $37 million per year, is needed for research funding to be commensurate with the mortality burden.


Elucidating the Structure, Dynamics, and Interaction of a Choline Chloride and Citric Acid Based Eutectic System by Spectroscopic and Molecular Modeling Investigations.
Eutectic solvent systems are versatile solvents that have found widespread use in numerous applications. Traditional solvents are homogeneous, having only one component, and their chemistry is relatively simple, with some exceptions. On the other hand, deep eutectic solvents (DESs) comprise binary components, generally a donor and an acceptor in hydrogen bonding with varying ratios. The interaction chemistry among the donor and acceptor involved in hydrogen bonding in DESs is complicated. Although numerous research is focused on the synthesis and application of DESs, few studies are reported to elucidate the complex structure and dynamic and interaction behavior of DESs. In this study, we employed calorimetry, vibrational spectroscopy techniques including FTIR and Raman, and nuclear magnetic resonance to derive insight into the structural feature and noncovalent contact of choline chloride (ChCl) and citric acid (CA) while they formed DESs. The 1:1 ChCl/CA eutectic system showed phase transitions and melting peaks with the most pronounced peak at 156.22 °C, suggesting the DESs melting at a lower temperature than the melting temperatures of ChCl and CA. In addition to IR and Raman findings, 1H NMR investigations demonstrate hydrogen bonding intermolecular interactions between ChCl and CA, supporting the formation of 1:1 ChCl/CA DESs based on the deshielded chemical shifts of the proton for Ch. The interaction of the chloride anion with the methyl protons (H4) and methylene protons (H3) of ChCl as well as the strong hydrogen bonding interactions between the hydroxyl hydrogen (H1) of ChCl with one of CA's carbonyl oxygens both supported the formation of conformer E. In addition, molecular dynamics followed by the density functional theory (DFT) was employed to visualize the structure and interaction of DESs using the ωB97XD theory and 6-311++G (d,p) basis set. Both experimental and theoretical IR, Raman, and structural analyses provided evidence of the formation of DESs by possessing hydrogen bonds. These multifaceted experimental and computational investigations provide details of structural and intermolecular interactions of ChCl/CA DESs.


Modulation of human dendritic cell maturation and function by natural IgG antibodies.
Dendritic cells (DCs) are professional antigen-presenting cells, which have a central role in the initiation of primary immune responses and in maintaining immune tolerance. The functions of DCs can be regulated both by environmental signals as well as signals delivered by endogenous molecules. Recently we have examined regulation of human DCs by B cells via natural IgG antibodies. Natural antibodies (NAbs) are defined as antibodies that circulate in normal individuals in the absence of deliberate immunization or microbial aggression. We demonstrate that the differentiation of DCs is severely impaired in primary immunodeficient patients such as X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID) at least in part due to the deficiency of circulating NAbs. Further, we show that NAbs are able to restore normal phenotypes of DCs from patients with XLA and CVID. Our results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.