The different outcomes in the elderly with subclinical hypothyroidism diagnosed by age-specific and non-age-specific TSH reference intervals: a prospectively observational study protocol.
Subclinical hypothyroidism (SCH) is a common endocrine disorder characterized by elevated thyroid-stimulating hormone (TSH) levels and normal free thyroxine (FT4) levels. The overdiagnosis and overtreatment of SCH in elderly patients have become concerns as TSH levels naturally increase with age. Studies have shown that many elderly patients with SCH can recover without treatment, and the administration of levothyroxine (L-T4) does not improve their prognosis. Therefore, It is necessary to establish age-specific reference ranges for TSH in elderly individuals to aid in clinical decision-making and prevent overdiagnosis. This is a multicenter prospective study that focuses on Chinese elderly patients with SCH who have TSH levels below 10 mU/L. After obtaining the informed consent of the patients, their initial diagnosis information will be registered, and they will be asked to fill out questionnaires such as the Montreal Cognitive Assessment-Basic (MoCA-B), Hamilton Depression Scale (HAMD), Hypothyroidism Symptom Questionnaire (SRQ), frail scale(FRAIL), fatigue scale, and EQ-5D. In addition, thyroid function tests, blood lipid analysis, carotid artery ultrasound, and thyroid ultrasound examinations will be conducted. Patients will also be grouped according to FT4 levels, the changes in FT4 and its relationship with TSH can also be described. For patients over 80 years old, a decrease in FT4 will be used as an endpoint event, while for patients between 60-80 years old, TSH levels greater than or equal to 10mIU/L or a decline in FT4 will be used as the endpoint event. The TSH reference intervals of the general and elderly populations will be used to calculate medical costs associated with multiple follow-ups of patients, and a social-economic analysis will also be conducted. This study will prospectively observe elderly patients with SCH who are screened using both age-specific and non-age-specific TSH reference ranges for the elderly population. We will compare the results of elderly patients diagnosed with SCH using different reference ranges and analyze their association with FT4 to identify meaningful SCH patients and reduce over diagnosis and over treatment of elderly SCH. The Medical Science Research Ethics Committee of the First Affiliated Hospital of China Medical University approved this study (ID: AF-SOP-07-1.1-01). The results will be published in an open-access journal. https://www.chictr.org.cn/, identifier ChiCTR2300070831.


Humic acid formation in artificial soils amended with compost at different stages of organic matter evolution.
A composting process was conducted under optimal conditions for 150 d, obtaining three biomasses at different levels of maturity: raw material (RM), fresh compost obtained after 11 d of composting (FC), and evolved compost (EC) obtained after 150 d of composting. During the composting process, HAs were extracted and fully characterized by mass balance, DRIFT, and 1H and 13C-nuclear magnetic resonance spectroscopy. Each compost sample was incubated for 180 d in an artificial soil, after which HA extraction was repeated and characterized. To compare composts containing different amounts of labile organic matter (OM), an equal amount of unhydrolyzable OM was added to the soils. Our results indicated that compost HAs consist of a biologically and chemically stable fraction (i.e., the unhydrolyzable HA [U-HA]) and a labile fraction, whose relative contents depended on the composting duration. Humic acid from more EC contained a higher amount of recalcitrant fraction (aromatic carbon) and a lesser amount of labile fraction (aliphatic carbon) than HA from RM and FC. These results suggest that the humification process during composting preserves the more recalcitrant fraction of the compost-alkali soluble/acid insoluble fraction (HA-fraction). Incubation of composts in soil showed that due to the higher labile fraction content, HAs from raw material were more degraded than those from EC. The abundance of labile carbon of soil amended with less-evolved compost (RM and FC) allowed the more recalcitrant fractions of U-HA to be more preserved than in EC. These results suggest that less-evolved compost could contribute more than well evolved compost to the stable soil OM.


Facing off with unfair others: introducing proxemic imaging as an implicit measure of approach and avoidance during social interaction.
Nonverbal behavior expresses many of the dynamics underlying face-to-face social interactions, implicitly revealing one's attitudes, emotions, and social motives. Although research has often described nonverbal behavior as approach versus avoidant (i.e., through the study of proxemics), psychological responses to many social contexts are a mix of these two. Fairness violations are an ideal example, eliciting strong avoidance-related responses such as negative attitudes, as well as strong approach-related responses such as anger and retaliation. As such, nonverbal behavior toward unfair others is difficult to predict in discrete approach versus avoidance terms. Here we address this problem using proxemic imaging, a new method which creates frequency images of dyadic space by combining motion capture data of interpersonal distance and gaze to provide an objective but nuanced analysis of social interactions. Participants first played an economic game with fair and unfair players and then encountered them in an unrelated task in a virtual environment. Afterwards, they could monetarily punish the other players. Proxemic images of the interactions demonstrate that, overall, participants kept the fair player closer. However, participants who actively punished the unfair players were more likely to stand directly in front of those players and even to turn their backs on them. Together these patterns illustrate that fairness violations influence nonverbal behavior in ways that further predict differences in more overt behavior (i.e., financial punishment). Moreover, they demonstrate that proxemic imaging can detect subtle combinations of approach and avoidance behavior during face-to-face social interactions.


Autoradiographic localization of nicotinic receptor binding in rat brain using [3H]methylcarbamylcholine, a novel radioligand.
Light microscopic autoradiography was used to visualize the neuroanatomical distribution of nicotinic receptors in rat brain using a novel radioligand, [3H]methylcarbamylcholine (MCC). Specific [3H]MCC binding to slide-mounted tissue sections of rat brain was saturable, reversible and of high affinity. Data analysis revealed a single population of [3H]MCC binding sites with a Kd value of 1.8 nM and Bmax of 20.1 fmol/mg protein. Nicotinic agonists and antagonists competed for [3H]MCC binding sites in slide-mounted brain sections with much greater potency than muscarinic drugs. The rat brain areas containing the highest densities of [3H]MCC binding were in thalamic regions, the medial habenular nucleus and the superior colliculus. Moderate densities of [3H]MCC binding were seen over the anterior cingulate cortex, the nucleus accumbens, the zona compacta of substantia nigra and ventral tegmental area. Low densities of [3H]MCC binding were found in most other brain regions. These data suggest that [3H]MCC selectively labels central nicotinic receptors and that these receptors are concentrated in the thalamus, the medial habenular nucleus and the superior colliculus of the rat brain.


Salicylic acid and the hypersensitive response initiate distinct signal transduction pathways in tobacco that converge on the as-1-like element of the PR-1a promoter.
Tobacco pathogenesis-related protein 1a (PR-1a) is induced in plants during the hypersensitive response (HR) after exposure of plants to salicylic acid (SA) and by developmental cues. Gene activation by these diverse stimuli is mediated via an as-1-like element in the PR-1a upstream region. To further analyze the significance of this cis-acting sequence, an authentic as-1 element from the cauliflower mosaic virus 35S RNA promoter was inserted into the PR-1a promoter in place of the as-1-like motif. Reporter gene analysis in transgenic tobacco plants demonstrated that as-1 can functionally replace the as-1-like element in the PR-1a promoter in response to all stimuli. However, reporter gene induction from the as-1 carrying promoter was enhanced in response to SA compared to the wild-type promoter, and the ratio of reporter gene activities in SA treated leaf tissue to tissue exhibiting the HR increased with the as-1 promoter construct. Our findings support a model where PR-1a gene expression relies on at least two distinct signal transduction pathways initiated by SA and by a yet unknown signal produced during the HR, that promote different, albeit related, transcription complexes on the PR-1a as-1-like element. Analysis of PR-1 proteins in plants expressing salicylate hydroxylase yielded additional evidence that an HR dependent pathway leads to high level PR-1 gene induction in tobacco.


Evaluation of laboratory markers for the detection of infections in open-heart surgery patients.
This study compared the efficiency of interleukin-6 (IL-6), human neutrophil lipocalin (HNL), C-reactive protein (CRP) and white blood cell (WBC) count for the early detection of postoperative bacterial infections after open-heart surgery. These laboratory markers were determined preoperatively and monitored daily during the first 6 postoperative days. Postoperative bacterial infections were diagnosed in 17 of 54 studied patients needing at least 3 d of intensive care. Patients with less than 3 d of intensive care were not studied. HNL and WBC count showed no significant differences between infected and non-infected groups, whereas both IL-6 and CRP were significantly higher in the infected group. IL-6 levels were higher (p < 0.01) in the infected patients on the first postsurgical day, although with considerable interindividual variation. CRP levels rose on the second postsurgical day and showed less variation (p < 0.01). Calculation of the differences between preoperative and postoperative levels of IL-6 and CRP was not helpful for early detection of postoperative infections. Although IL-6 showed an earlier mean rise than CRP in patients developing postoperative infection, its substantial interindividual variation limits its clinical usefulness. HNL and WBC counts were ineffectual as indicators of postoperative infections in this study.


Post traumatic stress disorder in African American men exposed to violent trauma.
Research has shown strong association between exposures to violence resulting in post traumatic stress symptoms. Despite the high lifetime prevalence of post traumatic stress disorder (PTSD) and exposure to violence among African American men, research outcomes are limited and inconsistent. African American youth who live in low-income urban areas routinely face various contextual specific risks factors that leave them susceptible to loss and trauma in their lifetime resulting in persistent PTSD over time. Personas of resilience found in African American men exposed to chronic violence often mask trauma symptoms raising concerns on the evaluation of PTSD symptomology among African American men as well as the process of resilience and coping methods within this population. Limitations to research include convenience sampling limited to specific cities and exclusion of incarcerated African American men. In addition, there is a lack of longitudinal studies detailing the physiological and psychological course of PTSD and rates of recovery in African Americans. Health care systems and providers must be equipped, informed, and prepared to responding to mental health needs of African American men. The understanding of the expression and presence of PTSD among African American men will result in improvements of healthcare professionals' ability to evaluate, diagnose, and provide treatment for PTSD among this group whose symptoms of trauma may be misinterpreted or overlooked.


Sutureless Deep Sclerectomy: A Preliminary Report.
This study describes a modification of deep sclerectomy, making it completely sutureless, with a 6-month follow-up period. This was a prospective pilot phase that included 24 eyes of 16 patients, 13 male individuals and 3 female individuals, with medically uncontrolled open-angle glaucomas despite maximally tolerated medical therapy. After excising the deep flap, no sutures are added to the superficial scleral flap or to the conjunctiva. A statistically significant reduction of the intraocular pressure was reported during all the follow-up visits without serious complications.


Effects of temperature, salt, and deuterium oxide on the self-aggregation of alkylglycosides in dilute solution. 2. n-Tetradecyl-beta-D-maltoside.
The effects of salt, temperature, and deuterium oxide on the self-aggregation of n-tetradecyl-beta-d-maltoside (C(14)G(2)) in dilute solution have been investigated by static light scattering, dynamic light scattering (DLS), small-angle neutron scattering (SANS), tensiometry, and capillary viscometry. SANS data show that the micelles can be described as relatively flexible polymer-like micelles with an elliptical cross section, at least at temperatures between 35 and 50 degrees C. The micelles grow in one dimension with increasing temperature and concentration. DLS and viscometry data suggest that the micelle size reaches a maximum at 60-70 degrees C. Comparison of DLS data in D(2)O and H(2)O shows that the micelles are larger in the former case. The effect of salt on the micelle size was found to follow the Hofmeister series. Thus, at constant salt concentration, the micelle size decreases according to the sequence SO(4)(2)(-) > Cl(-) > NO(3)(-) > I(-) > SCN(-), where I(-) and SCN(-) act as salting-in anions. From tensiometric data, it can be concluded that the temperature effects on micelle morphology do not correlate directly with those on unimer solubility. Rather, the temperature effect on the hydrocarbon chain conformation seems to be decisive for the micelle morphology. At constant temperature, on the other hand, the effect of salt and deuterium isotope is attributable to changes in effective headgroup area, including intermolecular interactions and water of hydration.


A simple biological index for detection of alcoholic liver disease in drinkers.
To make liver biopsy unnecessary in certain cases, PGA (P, prothrombin time; G, gamma-glutamyl transpeptidase; A, apoliprotein AI), a simple biological index combining a specific test for severe liver disease (prothrombin time), a sensitive test of alcoholic liver disease (serum gamma-glutamyl transpeptidase), and a test for liver fibrosis (serum apolipoprotein AI), was evaluated in a training sample of 333 drinkers and validated in 291 other drinkers. All patients underwent an intercostal liver biopsy, and the specimen was independently read by two pathologists. The PGA index varied from 0 to 12. When PGA was less than or equal to 2, the probability of cirrhosis was 0% and the probability of normal liver or minimal changes 83%. Conversely, when PGA was greater than or equal to 9, the probability of normal liver or minimal changes was 0% and the probability of cirrhosis 86%. These values did not vary between training and validation periods, between asymptomatic vs. symptomatic subjects or between PGA at admission vs. PGA 1 week later. This index could be useful for general practitioners in identifying subjects at high risk for severe alcoholic liver disease.


L-arginine does not improve biochemical and hormonal response in trained runners after 4 weeks of supplementation.
It has been hypothesized that L-arginine improves exercise performance by increasing nitric oxide synthesis and levels of insulin and growth hormone (GH). Metabolic and hormonal responses to chronic L-arginine supplementation may clarify the mechanisms underlying its putative physiologic effects on physical performance. Therefore, the aim of this study was to investigate the effects that 4 weeks of supplementation with L-arginine would have on metabolic and hormonal parameters at rest and in response to exercise. Fifteen healthy runners were divided into treatment (ARG; 6 g L-arginine) and placebo (PLA; 6 g cornstarch) groups. On the first visit, blood samples were collected for baseline, and the supplement or placebo was provided. After 4 weeks of supplementation (second visit), blood samples were collected at the following intervals: at rest, immediately after the first 5-km time-trial running test (5km-TT), immediately after the second 5km-TT, and after 20 minutes of recovery (+20). In addition to exercise performance (total running time), plasma nitrate, nitrite, nitrate plus nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum insulin, GH, insulin-like growth factor 1, and cortisol concentrations were evaluated. There were significant increases in plasma nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum GH, and cortisol at the first 5km-TT, immediately after the second 5km-TT, and +20 in both ARG and PLA. Nitrate plus nitrite and nitrate increased only at +20. No significant change was observed in serum insulin and insulin-like growth factor 1 in any sample period. Total running time did not differ significantly between the 2 tests, in either ARG or PLA. Thus, according to our results, 4 weeks of L-arginine supplementation did not cause beneficial changes in metabolic and hormonal parameters, beyond those achieved with exercise alone.


The human salivary RNA transcriptome revealed by massively parallel sequencing.
Evaluation of the salivary transcriptome is an emerging diagnostic technology with discriminatory power for disease detection. This study explored massively parallel sequencing for providing nucleotide-level sequence information for each RNA in saliva. Transcriptome profiling with the SOLiD™ system was applied to RNA isolated from unstimulated cell-free saliva (CFS) and whole saliva (WS) from healthy human volunteers. Sequenced reads were aligned to human genome build 18 and the Human Oral Microbiome Database (HOMD). Massively parallel sequencing enabled the acquisition of complete sequence information for each nucleotide position of the human salivary transcriptome through alignment to multiple sequence databases. Approximately 20%-25% of the sequenced reads from CFS aligned to the human genome, and approximately 30% of the sequenced reads aligned to the HOMD. We detected the expression of >4000 coding and noncoding genes in CFS and WS. Gene expression at different genome loci showed that the structural integrity of the transcripts for the annotated genes was preserved in saliva. A single measurement provided RNA sequence information of gene transcript abundance for both coding and noncoding RNAs and identified sequences from >400 different microbial species within a single sample. Contrary to previous data suggesting that salivary RNA is highly fragmented, in our study the structural integrity of RNA was preserved. The high degree of sequence alignment to annotated exons and introns for each of the respective reference genomes, with sequence coverage spanning the full length of the genes, provides strong evidence that the salivary transcriptome is a complex RNA network.


Apparent size and morphology of bacterial microcompartments varies with technique.
Bacterial microcompartments (MCPs) are protein-based organelles that encapsulate metabolic pathways. Metabolic engineers have recently sought to repurpose MCPs to encapsulate heterologous pathways to increase flux through pathways of interest. As MCP engineering becomes more common, standardized methods for analyzing changes to MCPs and interpreting results across studies will become increasingly important. In this study, we demonstrate that different imaging techniques yield variations in the apparent size of purified MCPs from Salmonella enterica serovar Typhimurium LT2, likely due to variations in sample preparation methods. We provide guidelines for preparing samples for MCP imaging and outline expected variations in apparent size and morphology between methods. With this report we aim to establish an aid for comparing results across studies.


Physical mapping of genes on yeast mitochondrial DNA: localization of antibiotic resistance loci, and rRNA and tRNA genes.
We have physically mapped the loci conferring resistance to antibiotics that inhibit mitochondrial protein synthesis (erythromycin, chloramphenicol and paromomycin) or respiration (oligomycin I and II), as well as the 21s and 14s rRNA and tRNA genes on the restriction map of the mitochondrial genome of the yeast Saccharomyces cerevisiae. The mitochondrial genes were localized by hybridization of labeled RNA probes to restriction fragments of grande (strain MH41-7B) mitochondrial DNA (mtDNA) generated by endonucleases EcoRI, HpaI, BamHI, HindIII, SalI, PstI and HhaI. We have derived the HhaI restriction fragment map of MH41-7B mit DNA, to be added to our previously reported maps for the six other endonucleases. The antibiotic resistance loci (antR) were mapped by hybridization of 3H-cRNA transcribed from single marker petite mtDNA's of low kinetic complexity to grande restriction fragments. We have chosen the single Sal I site as the origin of the circular physical map and have positioned the antibiotic loci as follows: C (99.5-1.Ou)--P (27-36.Ou)--OII (58.3-62u--OI (80-84u)--E (94.4-98.4u). The 21s rRNA is localized at 94.4-99.2u, and the 14s rRNA is positioned between 36.2-39.8u. The two rRNA species are separated by 36% of the genome. Total mitochondrial tRNA labeled with 125I hybridized primarily to two regions of the genome, at 99.5-11.5u and 34-44u. A third region of hybridization was occasionally detected at 70--76u, which probably corresponds to seryl and glutamyl tRNA genes, previously located to this region by petite deletion mapping.


Mediums and messages: an argument against biotechnical enhancement of soldiers in the armies of liberal democracies.
Assuming that one believes that individuals and states can morally defend values, beliefs, and institutions with force (in short, that just wars are morally possible), one logically wants just combatants to possess the physical, mental, and spiritual capacities that will enable them to win the war. On the other hand, being a just combatant in a just war does not morally entitle that combatant to do anything to win that war. The moral requirement for just combatants to fight justly is codified in international law of war and in state-specific legal documents such as the United States Uniform Code of Military Justice. While it is almost unequivocally clear to soldiers and civilians who soldiers cannot harm in the performance of their duties, and why these people are exempt from harm, it is less clear what the state itself (assuming throughout the discussion that the state is a just combatant in a just war) can morally do to its own soldiers to enhance their chances of victory: can the state do anything to soldiers to give them an advantage on the field of battle? For United States soldiers and their counterparts in most Western liberal democracies, the answer is obviously no. Deeply embedded social and cultural norms in Western democracies mandate that the state set and enforce rigid lines which drill sergeants and earnest commanders cannot cross, even in the name of combat readiness, grounding these norms in notion of basic rights appealed to in the U.S. Constitution. In this essay, I argue against some types of drug-induced internal biotechnical enhancement of soldiers on the grounds that, in the present state of technology, it is not reasonable to suppose that the military can perform such enhancement operations on soldiers without causing irrevocable psychological damage that would certainly and unjustifiably alienate the soldiers from the very society they serve.


Potassium channels contribute to activity-dependent regulation of dendritic inhibition.
GABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent regulation of GABAergic inhibition.


Changes in cervical range of motion and sagittal alignment in early and late phases after total disc replacement: radiographic follow-up exceeding 2 years.
This was a retrospective clinical study in which the follow-up period exceeded 2 years. The authors investigated the time course of radiographic changes in the cervical range of motion (ROM) and sagittal alignment after cervical total disc replacement involving the ProDisc-C artificial disc. Eighteen patients who underwent C5-6 total disc replacement were followed for an average of 27 months. Cervical neutral and flexion-extension lateral radiographs were obtained before and at 1 and 3 months after surgery for early-phase observations and at the last follow-up for late-phase observation. Segmental ROM values in the treated, superior, and inferior adjacent segments were measured. For whole-neck motion, C2-7 ROM was also measured. The percentage contributions of ROM at functional and adjacent segments to whole-neck motion were calculated. For evaluating sagittal alignment, C2-7 and C5-6 Cobb angles were measured. All data from ProDisc-C arthroplasty were compared with the results obtained in 22 patients who underwent C5-6 interbody fusion in which a Solis cage was used and who were followed for an average of 25 months. In the ProDisc-C group, C2-7 and C5-6 ROM significantly decreased in the early phase after surgery and returned to preoperative levels in the late phase. Both superior and inferior adjacent segments showed significantly decreased ROM in the acute phase after surgery and returned to the preoperative values in the late phase. In terms of contributions to whole-neck motion, the ROM of the functional and adjacent segments did not change significantly compared with the preoperative ROM. In the cage group, C2-7 ROM was also significantly decreased in the early phase after surgery and returned to preoperative levels at the late phase. Both superior and inferior adjacent segments exhibited significantly increased ROM and percentage contributions to whole-neck motion in the early and late phases. Sagittal alignment of the whole cervical spine became significantly more lordotic in the late phase in the ProDisc-C group. The C5-6 Cobb angle became significantly lordotic in the ProDisc-C group, whereas there was no significant change in C5-6 Cobb angle in the cage group. In the early phase after ProDisc-C replacement, the ROM of the entire neck as well as functional and adjacent segments decreased but, at the late phase, they returned to the preoperative state. Contributions of functional and adjacent segments to whole-neck motion were not changed after ProDisc-C replacement. Adjacent-segmental motion could be saved by ProDisc-C replacement instead of interbody cage fusion. Segmental degenerative kyphosis was significantly corrected in patients who underwent ProDisc-C replacement.


Creating an integrated health care system as a basis for managed care excellence: a health plan's perspective.
Environmental factors and sentiments of leaders within health care organizations are stimulating the rapid evolution toward integrated health care systems. This article outlines the strategic considerations that led to the development of an organization spanning health care delivery, financing, and administration. The perspective is that of Medica, a successful health maintenance organization (HMO) operating in the mature and very competitive Minneapolis/St. Paul marketplace. Traditional approaches to managing care as a third-party intermediary were deemed unlikely to support future success and the next level of performance in meeting community needs. Key considerations, critical success factors, and a variety of unanswered questions are discussed.


Hearing loss mediates executive function impairment in sleep-disordered breathing.
Sleep-disordered breathing (SDB) is often co-morbid with conductive hearing loss in early childhood due to a shared aetiology of adenotonsillar hypertrophy. Hearing loss is independently associated with impairment of executive function and behavioural difficulties. We hypothesised that these impairments in children with SDB may be mediated through hearing loss. Fifty-eight children including 37 snorers awaiting adenotonsillectomy and 21 healthy non-snoring controls, aged 3-5 years, were assessed with pure tone audiometry, Strengths and Difficulties (SDQ), Behaviour Rating of Executive Function (BRIEF-P), and Childhood Middle Ear Disease and Hearing questionnaires. Polysomnography in snoring children generated an obstructive apnoea/hypopnea index (OAHI). Two regression models examined the effect of SDB and the mediating impact of hearing loss on BRIEF and SDQ. Snoring children had significantly poorer hearing, greater past exposure to hearing loss, and higher total SDQ and BRIEF-P scores than non-snoring controls. The first regression model, including all children, demonstrated that the impact of snoring on BRIEF_P, but not SDQ, was entirely mediated by a history of hearing loss exposure but not same-day audiometry. The second model examined snoring children only, categorising the group into 12 with obstructive sleep apnoea (OSA) (OAHI ≥ 5) and 25 without OSA. OSA had a direct effect on SDQ scores, but this was not mediated by a history of hearing loss. In early childhood, conductive hearing loss mediates the relationship between SDB, irrespective of severity, and parent report of executive function but not behaviour. Treatment of hearing loss in pre-school SDB might improve executive function.


Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in "real-world" treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.


[Cytochrome bd as Antioxidant Redox Enzyme].
One of the main functions of enzyme complexes that constitute electron transport (respiratory) chains of organisms is to maintain cellular redox homeostasis by oxidizing reducing equivalents, NADH and quinol. Cytochrome bd is a unique terminal oxidase of the chains of many bacteria including pathogenic species. This redox enzyme couples the oxidation of ubiquinol or menaquinol by molecular oxygen to the generation of proton motive force, a universal energy currency. The latter is used by the organism to produce ATP, another cellular energy currency, via oxidative phosphorylation. Escherichia coli contains two bd-type oxidases, bd-I and bd-II, encoded by the cydAB and appCB operons, respectively. Surprisingly, both bd enzymes make a further contribution to molecular mechanisms of maintaining the appropriate redox balance in the bacterial cell by means of elimination of reactive oxygen species, such as hydrogen peroxide. This review summarizes recent data on the redox-modulated H2O2-scavenging activities of cytochromes bd-I and bd-II from E. coli. The possibility of such antioxidant properties in cytochromes bd from other bacteria is also discussed.


[Cardiotoxicity of mianserin, an antidepressant (author's transl)].
The effect of mianserin on cardiac function was investigated on 60 adults with known heart disease, the drug previously having been shown not to influence the action of phenprocoumon. After satisfactory anticoagulation had been established, all patients were given additionally two different dosage regimens of mianserin or a placebo in a double-blind trial lasting three weeks. The dose was gradually increased to a maximal daily level of 30 mg or 60 mg, respectively, on the sixth day. Heart rate, blood pressure and electrocardiogram were obtained before and after mianserin had been added. There was no statistically significant difference between the three trial groups with respect to the three measured variables.


Transcriptional response of P. pastoris in fed-batch cultivations to Rhizopus oryzae lipase production reveals UPR induction.
The analysis of transcriptional levels of the genes involved in protein synthesis and secretion is a key factor to understand the host organism's responses to recombinant protein production, as well as their interaction with the cultivation conditions. Novel techniques such as the sandwich hybridization allow monitoring quantitatively the dynamic changes of specific RNAs. In this study, the transcriptional levels of some genes related to the unfolded protein response (UPR) and central metabolism of Pichia pastoris were analysed during batch and fed-batch cultivations using an X-33-derived strain expressing a Rhizopus oryzae lipase under control of the formaldehyde dehydrogenase promoter (FLD1), namely the alcohol oxidase gene AOX1, the formaldehyde dehydrogenase FLD1, the protein disulfide isomerase PDI, the KAR2 gene coding for the BiP chaperone, the 26S rRNA and the R. oryzae lipase gene ROL. The transcriptional levels of the selected set of genes were first analysed in P. pastoris cells growing in shake flask cultures containing different carbon and nitrogen sources combinations, glycerol + ammonium, methanol + methylamine and sorbitol + methylamine. The transcriptional levels of the AOX1 and FLD1 genes were coherent with the known regulatory mechanism of C1 substrates in P. pastoris, whereas ROL induction lead to the up-regulation of KAR2 and PDI transcriptional levels, thus suggesting that ROL overexpression triggers the UPR. This was further confirmed in fed-batch cultivations performed at different growth rates. Transcriptional levels of the analysed set of genes were generally higher at higher growth rates. Nevertheless, when ROL was overexpressed in a strain having the UPR constitutively activated, significantly lower relative induction levels of these marker genes were detected. The bead-based sandwich hybridization assay has shown its potential as a reliable instrument for quantification of specific mRNA species in P. pastoris cells grown in fed-batch cultures. As a proof-of-principle, the influence of the carbon and nitrogen sources, the specific growth rate, as well as the ROL overexpression on the transcriptional levels of a reduced set of bioprocess-relevant genes has been quantitatively studied, revealing that ROL overexpression and secretion seems to trigger the UPR in P. pastoris, resulting in a physiological bottleneck for the production process.


Obesity in adults is associated with reduced lung function in metabolic syndrome and diabetes: the Strong Heart Study.
The purposes of this study were to investigate whether reduced lung function is associated with metabolic syndrome (MS) and diabetes (DM) in American Indians (AIs) and to determine whether lower pulmonary function presents before the development of DM or MS. The Strong Heart Study (SHS) is a multicenter, prospective study of cardiovascular disease (CVD) and its risk factors among AI adults. The present analysis used lung function assessment by standard spirometry at the SHS second examination (1993-1995) in 2,396 adults free of overt lung disease or CVD, with or without DM or MS. Among MS-free/DM-free participants, the development of MS/DM at the SHS third examination (1996-1999) was investigated. Significantly lower pulmonary function was observed for AIs with MS or DM. Impaired pulmonary function was associated with MS and DM after adjustment for age, sex, abdominal obesity, current smoking status, physical activity index, hypertension, and SHS field center. Both forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were negatively associated with insulin resistance or DM severity and with serum markers of inflammation (P < 0.05). FVC and FEV1-to-FVC ratio both predicted DM in unadjusted analyses but not when adjusted for covariates, including waist circumference. In the adjusted model, abdominal obesity predicted both MS and DM. Reduced lung function is independently associated with MS and with DM, and impaired lung function presents before the development of MS or DM; these associations may result from the effects of obesity and inflammation.


Pisa syndrome (pleurothotonus) in a polytoxicomanic patient.
We describe the case of a 33-year-old drug addict who developed Pisa syndrome (pleurothotonus) following an intoxication with tramadol, alprazolam, diazepam, bromazepam, alcohol and dothiepin. Pisa syndrome abated as the patient recovered from his intoxication. We discuss the possible causes of Pisa syndrome and suggest that high doses of the tricyclic antidepressant dothiepin might be the most appropriate explanation for the appearance of Pisa syndrome in this patient.


Genome sequences and evolutionary biology, a two-way interaction.
Complete genome sequences are accumulating rapidly, culminating with the announcement of the human genome sequence in February 2001. In addition to cataloguing the diversity of genes and other sequences, genome sequences will provide the first detailed and complete data on gene families and genome organization, including data on evolutionary changes. Reciprocally, evolutionary biology will make important contributions to the efforts to understand functions of genes and other sequences in genomes. Large-scale, detailed and unbiased comparisons between species will illuminate the evolution of genes and genomes, and population genetics methods will enable detection of functionally important genes or sequences, including sequences that have been involved in adaptive changes.


Prevention of E.N.T. diseases.
World Health Organization has announced 'HEALTH FOR ALL BY YEAR 2000'. Unfortunately the emphasis at present is only on early diagnosis of a disease and its treatment. The modern investigations and treatment has become very costly which a poor man cannot afford. Preventive medicine is less costly. The developing countries have many socio-economic problems of population explosion, poverty, ignorance, illiteracy, shifting of population from rural to urban areas for employment and traffic jams in cities. Rapid industrialization has resulted in indiscriminate cutting of trees and forests and increasing pollution. Under the present circumstances one wonders whether it would be possible to achieve the WHO's object of health for all or will it remain a dream! The role of 'Yoga and Meditation' and vegetarian diet has been recognised world over for maintenance of normal physical and mental health; these help to lessen mental tension in the present competitive world full of stress and strain for all of us. 3-4% of people in the world avail the beneficial effects of alternative system of medicine is complete as each has its own merits and limitations. Hence our aim should be to choose an integrated system of medicine which would help in preventing diseases and treat them early by a safe and effective procedure. In the present political situation in our country none of the parties have announced any definite programme for population control, through it is a grave problem. We will not be able to fulfil our object of reaching our target of Health for all without strict population control major. Unless this programme is undertaken seriously as a priority in a co-ordinated disciplined manner by all of us and completed in a given period of time, the younger generation will not forgive us. We hope that as true citizens of India we will not spare any efforts on our part in attaining this objective for a bright future.


A Case of Eccrine Syringofibroadenoma Related to Senile Gluteal Dermatosis.
Eccrine syringofibroadenoma (ESFA) is a tumor of eccrine ductal differentiation. ESFA is a rare disease, with only approximately 80 cases reported worldwide. ESFA can be classified into five subtypes. Senile gluteal dermatosis (SGD) was first reported in Japan in 1979. It is a relatively common geriatric dermatosis in East Asia, and characterized by hyperkeratotic lichenified skin lesions in the gluteal region. An 86-year-old woman presented with a solitary recurrent dark brown plaque in the sacral area. There was a hyperkeratotic lichenified brownish patch around the plaque, which was clinically considered SGD. Histopathological examination of biopsy specimen revealed thin anastomosing reticulated strands of basaloid cuboidal cells. The tumor extends from the basal layer of the epidermis to the dermis. These findings are consistent with those of ESFA. The patient was treated with total excision of the skin lesion. Reactive ESFA is related to tissue regeneration and remodeling after damage, such as trauma and burns. There is no literature reporting ESFA related to SGD so far, but there have been few reports of cases occurring in soles or buttocks, which are constantly under pressure. This is the first report on reactive ESFA related to SGD, and further research is needed to reveal the pathogenic mechanism.


Antimetastatic drugs in prostate cancer.
Despite the benefits of local therapy with radical prostatectomy and radiation, many patients with prostate cancer require hormonal ablation. While chemotherapy has proven efficacy when the disease progresses to androgen-independent prostate cancer, patients ultimately succumb to the disease, thus the identification of other active therapies is needed. Future treatment modalities include molecular targeted therapies. Prostate cancer has been an ideal model to study the multiple steps required in the metastatic cascade. These steps have been utilized in the development of metastasis inhibitors. This review will present promising agents that have been tested preclinically or are undergoing clinical investigation for their abilities in preventing prostate cancer metastasis. Because prostate cancer metastasizes preferentially to the bone, special attention will be given to agents that interfere with this pattern of metastasis. Specifically, the efficacy of angiogenesis inhibitors, metalloproteinase inhibitors, inhibitors of prostate cancer cell- endothelial cell interactions, and bisphosphonates will be reported. In addition, the introduction of these novel agents has raised many questions as to the relevance and optimal utilization of current clinical trial designs. Issues regarding combination therapy with chemotherapy, optimal timing of treatment with metastatic inhibitors, and the need for surrogate endpoints for molecular targeted therapies will be discussed.


Vocal communication is tied to interpersonal arousal coupling in caregiver-infant dyads.
It has been argued that a necessary condition for the emergence of speech in humans is the ability to vocalise irrespective of underlying affective states, but when and how this happens during development remains unclear. To examine this, we used wearable microphones and autonomic sensors to collect multimodal naturalistic datasets from 12-month-olds and their caregivers. We observed that, across the day, clusters of vocalisations occur during elevated infant and caregiver arousal. This relationship is stronger in infants than caregivers: caregivers vocalisations show greater decoupling with their own states of arousal, and their vocal production is more influenced by the infant's arousal than their own. Different types of vocalisation elicit different patterns of change across the dyad. Cries occur following reduced infant arousal stability and lead to increased child-caregiver arousal coupling, and decreased infant arousal. Speech-like vocalisations also occur at elevated arousal, but lead to longer-lasting increases in arousal, and elicit more parental verbal responses. Our results suggest that: 12-month-old infants' vocalisations are strongly contingent on their arousal state (for both cries and speech-like vocalisations), whereas adults' vocalisations are more flexibly tied to their own arousal; that cries and speech-like vocalisations alter the intra-dyadic dynamics of arousal in different ways, which may be an important factor driving speech development; and that this selection mechanism which drives vocal development is anchored in our stress physiology.


Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties.
Siglecs are transmembrane sialoglycan binding proteins, most of which are expressed on leukocyte subsets and have inhibitory motifs that translate cell surface ligation into immune suppression. In humans, Siglec-8 on eosinophils, mast cells and basophils and Siglec-9 on neutrophils, monocytes and some T-cells, mediate immune cell death, inhibition of immune mediator release and/or enhancement of anti-inflammatory mediator release. Endogenous sialoglycan ligands in tissues, mostly uncharacterized, engage siglecs on leukocytes to inhibit inflammation. Glycan array analyses demonstrated that Siglec-8, Siglec-9 and their mouse counterparts Siglec-F and Siglec-E (respectively) have distinct glycan binding specificities, with Siglec-8 more structurally restricted. Since siglecs are involved in lung inflammation, we studied Siglec-8 and Siglec-9 ligands in human lungs and airways. Siglec-8 ligands are in tracheal submucosal glands and cartilage but not airway epithelium or connective tissues, whereas Siglec-9 ligands are broadly distributed. Mouse airways do not have Siglec-8 ligands, whereas Siglec-9 ligands are on airways of both species. Extraction of human airways and lung followed by electrophoretic resolution and siglec blotting revealed Siglec-8 ligands in extracts of human trachea and cultured tracheal gland cells, but not parenchyma or cultured airway epithelial cells whereas Siglec-9 ligands were extracted from all airway and lung tissues and cells tested. Siglec-8 and Siglec-9 ligands in airways appear to be high molecular weight O-linked sialoglycoproteins. These data reveal differential glycan specificities of Siglec-8, Siglec-9 and their mouse counterparts Siglec-F and Siglec-E, and the tissue distributions and molecular characteristics of Siglec-8 and Siglec-9 sialoglycan ligands on human airways and lungs.


Adherence to a Traditional Mexican Diet Is Associated with Lower Hepatic Steatosis in US-Born Hispanics of Mexican Descent with Overweight or Obesity.
Hispanics of Mexican descent have disproportionate rates of non-alcoholic fatty liver disease (NAFLD). The purpose of this work is to investigate the association between the traditional Mexican diet score (tMexS) and hepatic steatosis and fibrosis, two NAFLD-related clinical endpoints, in Hispanic adults of Mexican descent. Data from 280 Hispanic adults of Mexican descent (n = 102 men, 178 women) with overweight or obesity enrolled in a cross-sectional observational study were analyzed. The tMexS was calculated from 24 h dietary recalls. Hepatic steatosis and fibrosis measurements were assessed using transient elastography (Fibroscan®). Linear regression models testing the association between tMexS and hepatic steatosis and fibrosis were run individually and through the stratification of significant modifiers. Mean tMexS were 5.9 ± 2.1, hepatic steatosis scores were 288.9 ± 48.9 dB/m, and fibrosis scores were 5.6 ± 2.2 kPa. Among the US-born group, with every point increase in the tMexS, there was a statistically significant 5.7 lower hepatic steatosis point (95% CI: -10.9, -0.6, p-value = 0.07). Higher adherence to a traditional Mexican diet was associated with lower hepatic steatosis in US-born Hispanics of Mexican descent. Findings from the current work may serve to inform future culturally relevant interventions for NAFLD prevention and management in individuals of Mexican descent.


Investigation of fatty aldehyde and alcohol synthesis from fatty acids by αDox- or CAR-expressing Escherichia coli.
Fatty aldehydes are among the most important flavor and fragrance compounds. Most biotechnological production approaches make use of the one step conversion of fatty acids from renewable sources by the enzymes α-dioxygenase (αDox) or carboxylic acid reductase (CAR). Their reaction mechanisms and cofactor dependencies are very different. In contrast to heme-containing αDox which requires only oxygen as cosubstrate, CAR needs NADPH and ATP, which is a clear argument for the application of a whole cell catalyst. Therefore we compared fatty acid biotransformations with growing Escherichia coli cells expressing αDox or CAR to investigate their suitability for fatty aldehyde and also fatty alcohol production. Our results show the main product of fatty acid conversions with αDox-expressing cells to be the expected Cn-1 aldehyde. However, 14% of the products consist of the corresponding alcohol, but in addition, 17% of the products consist of further shortened aldehydes, alcohols and acids that result from the consecutive activity of αDox and a putative endogenous fatty aldehyde dehydrogenase activity in E. coli. Conversely, CAR-expressing cells produced only the unshortened fatty aldehyde and alcohol, whereby the latter surprisingly accounts for at least 80% of the products. The considerably higher extend of aldehyde reduction of CAR-expressing cells was shown to be causally connected to the CAR-mediated fatty acid conversion. Our study provides an overview about the applicability of αDox- or CAR-based whole cell catalysts and gives a detailed description of side products as well as suggestions for tailored strain engineering.


Diagnostic Accuracy of a Novel Mobile Phone Application for the Detection and Monitoring of Atrial Fibrillation.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults, associated with significant morbidity, increased mortality, and rising health-care costs. Simple and available tools for the accurate detection of arrhythmia recurrence in patients after electrical cardioversion (CV) or ablation procedures for AF can help to guide therapeutic decisions. We conducted a prospective, single-center study to evaluate the accuracy of Cardiio Rhythm Mobile Application (CRMA) for AF detection. Patients >18 years of age who were scheduled for elective CV for AF were enrolled in the study. CRMA finger pulse recordings, utilizing an iPhone camera, were obtained before (pre-CV) and after (post-CV) the CV. The findings were validated against surface electrocardiograms. Ninety-eight patients (75.5% men), mean age of 67.7 ± 10.5 years, were enrolled. No electrocardiogram for validation was available in 1 case. Pre-CV CRMA readings were analyzed in 97 of the 98 patients. Post-CV CRMA readings were analyzed for 92 of 93 patients who underwent CV. One patient left before the recording was obtained. The Cardiio Rhythm Mobile Application correctly identified 94 of 101 AF recordings (93.1%) as AF and 80 of 88 non-AF recordings (90.1%) as non-AF. The sensitivity was 93.1% (95% confidence interval [CI] = 86.9% to 97.2%) and the specificity was 90.9% (95% CI = 82.9% to 96.0%). The positive predictive value was 92.2% (95% CI = 85.8% to 95.8%) and the negative predictive value was 92.0% (95% CI = 94.8% to 95.9%). In conclusion, the CRMA demonstrates promising potential in accurate detection and discrimination of AF from normal sinus rhythm in patients with a history of AF.


The apoptosis mediator mDAP-3 is a novel member of a conserved family of mitochondrial proteins.
Programmed cell death is essential for organ development and regeneration. To identify molecules relevant for this process, full length cDNA cloning of a short, developmentally regulated murine cDNA fragment, MERM-3, was performed and showed a 1.7 kb mRNA encoding a 45 kDa protein with an ATP/GTP binding motive (P-loop). Sequence analysis revealed an 82% amino acid identity to the human death associated protein 3 (hDAP-3), a positive mediator of apoptosis. The full length sequence being the murine orthologue of hDAP-3 is therefore referred to as mDAP-3. In situ hybridization and northern blot analysis showed an abundant mRNA expression with a pronounced expression in highly proliferative epithelial compartments. For mDAP-3, cytochrome c release and induction of cell death could be demonstrated by overexpression of a mDAP-3/EGFP fusion protein. DAP-3 mediated apoptosis was shown to depend on a functional P-loop. Intracellular localization studies using the mDAP-3/EGFP fusion protein, cell fractionation and protease protection experiments localized mDAP-3 to the mitochondrial matrix. DAP-3, in contrast to cytochrome c, retained its mitochondrial localization during apoptosis induction. A mutant of a putative yeast orthologue of mDAP-3, YGL129c, here referred to as yDAP-3, has been shown to exhibit disrupted mitochondrial function. yDAP-3 deficient mutants could be shown to progressively loose mitochondrial DNA. Loss of mitochondrial DNA in yDAP-3 was partially prevented by transfection of the yDAP-3 deficient mutant with mDAP-3, indicating functional complementation by murine DAP-3 in the yeast system. These data identify mDAP-3 as one of the first proapoptotic factors in the mitochondrial matrix and provide evidence for a critical, evolutionary conserved role of members of the DAP-3 protein family for mitochondrial biogenesis.


Risk Prediction of Pancreatic Cancer in Patients With Recent-onset Hyperglycemia: A Machine-learning Approach.
New-onset diabetes (NOD) has been suggested as an early indicator of pancreatic cancer. However, the definition of NOD by the American Diabetes Association requires 2 simultaneous or consecutive elevated glycemic measures. We aimed to apply a machine-learning approach using electronic health records to predict the risk in patients with recent-onset hyperglycemia. In this retrospective cohort study, health plan enrollees 50 to 84 years of age who had an elevated (6.5%+) glycated hemoglobin (HbA1c) tested in January 2010 to September 2018 with recent-onset hyperglycemia were identified. A total of 102 potential predictors were extracted. Ten imputation datasets were generated to handle missing data. The random survival forests approach was used to develop and validate risk models. Performance was evaluated by c -index, calibration plot, sensitivity, specificity, and positive predictive value. The cohort consisted of 109,266 patients (mean age: 63.6 y). The 3-year incidence rate was 1.4 (95% confidence interval: 1.3-1.6)/1000 person-years of follow-up. The 3 models containing age, weight change in 1 year, HbA1c, and 1 of the 3 variables (HbA1c change in 1 y, HbA1c in the prior 6 mo, or HbA1c in the prior 18 mo) appeared most often out of the 50 training samples. The c -indexes were in the range of 0.81 to 0.82. The sensitivity, specificity, and positive predictive value in patients who had the top 20% of the predicted risks were 56% to 60%, 80%, and 2.5% to 2.6%, respectively. Targeting evaluation at the point of recent hyperglycemia based on elevated HbA1c could offer an opportunity to identify pancreatic cancer early and possibly impact survival in cancer patients.


Transversely isotropic elastic properties of multi-walled boron nitride nanotubes under a thermal environment.
The temperature-dependent transversely isotropic elastic properties of multi-walled boron nitride nanotubes (MWBNNTs) were determined using molecular dynamics simulations with a three-body Tersoff potential force field. These elastic properties were calculated by applying the four different loading conditions on MWBNNTs: uniaxial tension, torsional moment, in-plane biaxial tension and in-plane shear. The effect of chirality, number of layers and aspect ratio (AR) were taken into consideration. The results reveal that the elastic constants of MWBNNTs decrease as their number of layers increase. The elastic moduli of MWBNNTs do not depend on the AR, but are a function of chirality. Furthermore, the effect of temperature on the transversely isotropic elastic constants of MWBNNTs was studied. Higher temperature considerably affects the mechanical properties of MWBNNTs. For instance, the reduction in the values of axial Young's, longitudinal shear, plane-strain bulk and in-plane shear moduli of MWBNNTs was found to be by approximately 10% due to the increase in temperature. The results reveal that the mechanical properties and failure behavior of MWBNNTs significantly depend on the number of layers, chirality and temperature. The finding of this work can be utilized for engineering MWBNNT-based advanced nanocomposite structures for specific application under thermal environment.


Pharmacokinetics of Human Red Blood Cell Microparticles Prepared Using High-Pressure Extrusion Method.
Red blood cell microparticles (RMPs) is a high potency hemostatic agent, which may serve as a viable therapeutic approach. They generate thrombin in vitro and effective in arresting bleeding in animal bleeding models. However, prior to ascertaining the clinical efficacy of RMPs, detailed preclinical evaluation is necessary. Therefore, we aimed to characterize RMPs, ascertain their stability, and determine their pharmacokinetics in rats. RMPs were prepared from human RBCs by a high-pressure extrusion method. Pharmacokinetic parameters were computed from groups receiving various RMPs dosing regimens. Volume of distribution, elimination rate constant, and clearance for RMPs were also assessed. Major portion of prepared microparticles were RMPs and a very small portion of particles were from platelets and leukocytes. RMPs were stable when stored at 5 and -20°C for at least 12 months. In vivo half-life was found to vary for each paradigm, but in general, was less than 2 min for most of the paradigms evaluated. Our results demonstrate that RMPs are stable during prolonged storage and have a short half-life. Therefore, the clinical use of RMPs as a hemostatic agent, within a tailored treatment paradigm, may be advantageous in achieving prolonged systemic therapeutic benefit without provoking any thrombotic complications.


Evaluation of a parent-designed programme to support tooth brushing of infants and young children.
This study developed and tested an intervention to help parents establish a routine of brushing their young children's teeth twice a day. Community-based participatory research methods were used to engage parents in the design of the intervention to maximize its relevance and acceptability to others. Input was obtained by interviews and focus groups. The resulting intervention was four 90-min small-group sessions that provided educational information, direct instruction, practice and peer-to-peer problem-solving. A pre- to post-non-randomized design was used to evaluate the intervention's effect to increase or maintain parents' twice daily brushing. Intervention participants were 67 primary caregivers of children under six years of age. Of the 67 initial participants, 50 completed a post-intervention questionnaire administered 4 to 8 weeks following the intervention. The proportion of parents who reported brushing their young children's teeth twice a day increased significantly from 59 per cent prior to the intervention to 89 per cent post-intervention (McNemar's X(2) = 10.71, P = 0.002). There were concomitant and statistically significant increases over the study period in parents' confidence for brushing twice a day, attitudes about the importance of brushing and their self-efficacy for tooth brushing. Parents' knowledge of children's oral health, assessed by a 15-item scale developed for this study ('Things to Know About Baby Teeth'), also increased significantly. Twice daily tooth brushing is a low-cost, effective strategy to reduce the risk of childhood caries. As demonstrated here, community-based efforts can help parents achieve this important health behaviour.


The effect of mutations in the uvrD cistron of Escherichia coli on repair resynthesis.
The resynthesis step of the excision repair pathway has been examined in Escherichia coli K12 strains isogenic except for mutations in the uvrD cistron. Strains mutant at the uvrD3, uvrD101, uvrE156, and recL152 loci exhibited slight but distinct differences in their response to ultraviolet radiation. The repair capacity of the uvrD101 mutant was given special attention. Repair resynthesis in this mutant was saturated at fluences greater than about 20 J/m2. Isopycnic analysis of repaired deoxyribonucleic acid from this strain revealed a two-fold increase over its wild-type counterpart in the amount of repair replication performed after a dose of 15 J/m2. Sedimentation velocity analysis of DNA after selective photolysis of bromouracil-containing repaired regions showed that the uvrD101 mutation exerted its primary effect on the long-patch component of excision repair. The uvrD101 mutant performed long-patch repair at a larger number of sites than the number repaired by this mode in the wild-type strain; these patches were more extensive in length than the long-patch component in wild-type.


Enhancing diagnostic accuracy in common human poxvirus infections during mpox outbreak: A dermoscopy review.
Poxviruses belong to the Poxviridae family, a group of pathogens known for their high infectivity in humans, posing significant health threats. One of the most well-known representatives of poxvirus infections is smallpox, which has been successfully eradicated. However, in recent years, there has been a resurgence in cases of mpox, another member of the Poxviridae family, raising concerns about the potential for a global pandemic or a worldwide health crisis. While the typical clinical presentation of mpox and other poxvirus infections often involves cutaneous lesions, there have been reports of various atypical and non-classic clinical manifestations. Dermoscopy has emerged as a crucial diagnostic tool, aiding dermatologists in clinical practice to make informed decisions. In this summary, we provide an overview of the clinical and dermoscopic features of representative cutaneous lesions associated with human poxvirus infections, including mpox, orf, milker's nodule, and molluscum contagiosum.


Transfer of regulatory properties from tolerogenic to proinflammatory dendritic cells via induced autoreactive regulatory T cells.
Infectious tolerance is a term generally assigned to the process through which regulatory T cells (Tregs) transfer immunoregulatory properties to other T cells. In this study, we demonstrated that a similar process applies to human dendritic cells (DCs), albeit through a different mechanism. We induced and cloned proinsulin-specific Tregs using tolerogenic DCs and investigated mechanisms by which induced Ag-specific regulatory T cells (iaTregs) endorse the suppressive effects. iaTregs expressed FOXP3, programmed death-1, and membrane-bound TGF-β and upregulated IL-10 and CTLA-4 after stimulation with the cognate Ag. The iaTregs suppressed effector T cells only when both encountered the cognate Ags on the same APCs (linked suppression). This occurred independently of IL-10, TGF-β, programmed death-1, or CTLA-4. Instead, iaTregs used a granzyme B-mediated mechanism to kill B cells and monocytes, whereas proinflammatory DCs that resisted being killed were induced to upregulate the inhibitory receptors B7 (family) homolog 3 and ICOS ligand. These re-educated mature monocyte-derived dendritic cells (mDCs) suppressed effector T cells and induced IL-10-producing cells from the naive T cell pool. Our data indicated that human tolerogenic DCs confer infectious tolerance by inducing Ag-specific Tregs, which, in turn, re-educate proinflammatory mature DCs into DCs with regulatory properties.


Profiling Living Bacteria Informs Preparation of Fecal Microbiota Transplantations.
Fecal microbiota transplantation is a compelling treatment for recurrent Clostridium difficile infections, with potential applications against other diseases associated with changes in gut microbiota. But variability in fecal bacterial communities-believed to be the therapeutic agent-can complicate or undermine treatment efficacy. To understand the effects of transplant preparation methods on living fecal microbial communities, we applied a DNA-sequencing method (PMA-seq) that uses propidium monoazide (PMA) to differentiate between living and dead fecal microbes, and we created an analysis pipeline to identify individual bacteria that change in abundance between samples. We found that oxygen exposure degraded fecal bacterial communities, whereas freeze-thaw cycles and lag time between donor defecation and transplant preparation had much smaller effects. Notably, the abundance of Faecalibacterium prausnitzii-an anti-inflammatory commensal bacterium whose absence is linked to inflammatory bowel disease-decreased with oxygen exposure. Our results indicate that some current practices for preparing microbiota transplant material adversely affect living fecal microbial content and highlight PMA-seq as a valuable tool to inform best practices and evaluate the suitability of clinical fecal material.


Impact of TBI on caregivers of veterans with TBI: Burden and interventions.
Describe State-of-the-Art in practice and research in caregiving with individuals, specifically, Veterans with traumatic brain injury (TBI) and the implications for current practice and future research. Professional literature and personal experience of review panel. Unpaid caregiving for individuals with TBI is most often provided by a spouse, parent or other blood relative; the majority of caregivers are women. Although caregiving can be rewarding, it also may create financial burden and psychological stress. Depression among family caregivers occurs four times more frequently than in the general population. Positive coping can help reduce the impact of stress, and Department of Veterans Affairs (VA) programmes are available to ease financial burden. Group interventions show promise in reinforcing and improving positive coping for both family caregivers and Veterans with TBI. Identifying the specific needs of caregivers and families of Veterans with TBI and other traumatic injuries, including post-traumatic stress syndrome (PTSD), will require further longitudinal research. Currently available group interventions and programmes appear to benefit injured Veterans and their family caregivers financially and psychologically. Increased understanding of characteristics of quality family caregiving and its long term costs and benefits is likely to lead to additional improvements in these interventions and programmes.


Differentiation of Dictyostelium discoideum cells in suspension culture.
Differentiation of Dictyostelium discoideum cells in suspension culture is reported, using a medium containing glucose, albumin, cyclic AMP, EDTA and streptomycin in a phosphate buffer. Production of UDPgalactose:polysaccharide transferase, an enzyme specifically present in prespore cells, and the formation of prespore-specific antigens in more than 60% of the cells, are demonstrated. Differentiation in this medium differs from that previously reported with other suspension systems in that (a) cells form only small, amorphous agglomerates, (b) there is an absolute requirement for cyclic AMP and (c) prior formation of loose cell mounds on a solid substratum is essential for subsequent differentiation in this medium. This last requirement indicates that the differentiation process, giving rise to the prespore-specific enzyme and antigen, can be resolved into two distinct stages, one requiring cell contact on a solid substratum and the other proceeding in small agglomerates incubated in the medium. This medium may be useful for elucidating the role of cyclic AMP and cell contact in slime mould development.


Variability in women's desire for information about mammography screening: implications for informed consent.
This study aimed to explore women's desire for information about mammography screening in a population where overly optimistic perceptions of mammography screening were common. A self-administered questionnaire was completed by 2305 women aged 50-69 years, residents of Geneva, Switzerland. The questionnaire assessed the respondents' wish to receive information (detailed, general or none) about seven aspects of mammography screening: personal risk of breast cancer, prevention of breast cancer, benefits of mammography screening, limitations, minor inconveniences, more important problems, why some people oppose screening. The seven items formed a unidimensional scale (Cronbach's alpha=0.91). Women differed considerably in their stated desire for detailed or general information. For instance, whereas 14% wanted detailed information on all items and 36% general information on all items, 39% were not interested in detailed information on the limits and adverse consequences of screening. In multivariate analysis, some women's characteristics were associated with higher scores of desire for information, but little variance was explained (adjusted R=0.05). In conclusion, many women currently decline information about mammography screening that is deemed relevant by public health authorities. This may lead to poorly informed choices in an important area of prevention.


'The Problem of the Color Line': Faculty approaches to teaching Social Justice in Baccalaureate Nursing Programs.
Social justice is put forth as a core professional nursing value, although conceptualizations within foundational documents and among nurse educators remain inconsistent and contradictory. The purpose of this study was to explore how faculty teach social justice in theory courses in Baccalaureate programs. This qualitative study utilized constructivist grounded theory methods to examine processes informing participants' teaching. Participants utilize four overarching approaches: fostering engaging classroom climates, utilizing various naming strategies, framing diversity and culture as social justice, and role modeling a critical stance. They deploy specific strategies, varying largely by race, educational background, and nursing specialty. A background in social sciences supports pedagogy that interrogates health inequities rather than merely raising awareness about disparities. Findings also reveal that faculty of color navigate institutional structures predicated upon colorblind racism and problematic views of culture, which many white faculty teaching non-Community Health Nursing courses described doing. To enact social justice and be answerable to our communities, concerted anti-oppression efforts are needed across education, research, practice, and policy. This includes sustained commitment to address colonialism and whiteness in every institution that defines, promotes, and claims to advance nursing so that we can fulfill our responsibility to address unjust systems and structures to serve our communities.


The oral case presentation: toward a performance-based rhetorical model for teaching and learning.
The oral case presentation is an important communicative activity in the teaching and assessment of students. Despite its importance, not much attention has been paid to providing support for teachers to teach this difficult task to medical students who are novices to this form of communication. As a formalized piece of talk that takes a regularized form and used for a specific communicative goal, the case presentation is regarded as a rhetorical activity and awareness of its rhetorical and linguistic characteristics should be given due consideration in teaching. This paper reviews practitioners' and the limited research literature that relates to expectations of medical educators about what makes a good case presentation, and explains the rhetorical aspect of the activity. It is found there is currently a lack of a comprehensive model of the case presentation that projects the rhetorical and linguistic skills needed to produce and deliver a good presentation. Attempts to describe the structure of the case presentation have used predominantly opinion-based methodologies. In this paper, I argue for a performance-based model that would not only allow a description of the rhetorical structure of the oral case presentation, but also enable a systematic examination of the tacit genre knowledge that differentiates the expert from the novice. Such a model will be a useful resource for medical educators to provide more structured feedback and teaching support to medical students in learning this important genre.


Development of a half-cell for x-ray structural analysis of liquid electrolytes in rechargeable batteries.
A half-cell of the rechargeable Li-ion battery was developed to characterize an electrolyte structure using high energy x-ray total scattering measurements in combination with a two-dimensional x-ray detector. The scattering pattern consisted of strong Bragg peaks from electrodes and diffuse scatterings from sapphire windows, in addition to a weak halo pattern from the electrolyte. By selectively removing the signals of the electrodes and windows using specific numerical procedures, we could successfully extract the structural information of the electrolyte, which was in reasonable agreement with the reference data obtained from the electrolyte in a glass capillary. The present demonstration with a half-cell is expected to shed new light on operand characterization of the electrolyte structure during charging and discharging.


Chronic Chagas disease with advanced cardiac complications in Japan: Case report and literature review.
Due to the unprecedented recent increases in global migration, Chagas disease has become a global health threat and its epidemiology has drastically changed. Here we describe the first case in Japan of benznidazole treatment for chronic Chagas disease characterized by advanced cardiac complications. A 55-year-old Japanese-Brazilian woman who had previously presented with chronic heart failure was diagnosed as having Chagas disease and treated with benznidazole to prevent aggravation of her cardiac complications. However, benznidazole administration was stopped on day 56 due to severe drug-induced peripheral neuritis. Sixteen months later, her serologic test for Trypanosoma cruzi is still positive and she is being followed regularly by cardiology. Despite an estimated prevalence of over 4000 cases in Japan, only a few cases of Chagas disease have been reported. A Medline search revealed only 7 cases identified between 1995 and 2014 in Japan: in 6 cases, complications of chronic Chagas disease were apparent at the time of presentation, and sudden death occurred in 2 of these cases due to cardiac complications. This clinical case and literature review re-emphasize the urgent need to establish a surveillance network and improve the diagnostic methods and treatment framework for Chagas disease in Japan.


Evaluation of powdery mildew-resistance of grape germplasm and rapid amplified polymorphic DNA markers associated with the resistant trait in Chinese wild Vitis.
The resistance of wild Vitis germplasm, including Chinese and American wild Vitis and Vitis vinifera cultivars, to powdery mildew (Uncinula necator Burr.) was evaluated for two consecutive years under natural conditions. Most of the Chinese and North American species displayed a resistant phenotype, whereas all of the European species were highly susceptible. The Alachua and Conquistador accessions of Vitis rotundifolia species, which originated in North America, were immune to the disease, while Baihe-35-1, one of the accessions of Vitis pseudoreticulata, showed the strongest resistance among all Chinese accessions evaluated. Three rapid amplified polymorphic DNA (RAPD) markers, OPW02-1756, OPO11-964, and OPY13-661, were obtained after screening 520 random primers among various germplasm, and these markers were found to be associated with powdery mildew resistance in Baihe-35-1 and in some Chinese species, but not in any European species. Analysis of F₁ and F₂ progenies of a cross between resistant Baihe-35-1 and susceptible Carignane (V. vinifera) revealed that the three RAPD markers were linked to the powdery resistant trait in Baihe-35-1 plants. Potential applications of the identified RAPD markers for gene mapping, marker-assisted selection, and breeding were investigated in 168 F₂ progenies of the same cross. Characterization of the resistant phenotype of the selected F₂ seedlings for breeding a new disease-resistant grape cultivar is in progress.


Effects of Stochastic Single-Molecule Reactions on Coherent Ensemble Oscillations in the KaiABC Circadian Clock.
How do many constituent molecules in a biochemical system synchronize, giving rise to coherent system-level oscillations? One system that is particularly suitable for use in studying this problem is a mixture solution of three cyanobacterial proteins, KaiA, KaiB, and KaiC: the phosphorylation level of KaiC shows stable oscillations with a period of approximately 24 h when these three Kai proteins are incubated with ATP in vitro. Here, we analyze the mechanism behind synchronization in the KaiABC system theoretically by enhancing a model previously developed by the present author. Our simulation results suggest that positive feedback between stochastic ATP hydrolysis and the allosteric structural transitions in KaiC molecules drives oscillations of individual molecules and promotes synchronization of oscillations of many KaiC molecules. Our simulations also show that the ATPase activity of KaiC is correlated with the oscillation frequency of an ensemble of KaiC molecules. These results suggest that stochastic ATP hydrolysis in each KaiC molecule plays an important role in regulating the coherent system-level oscillations. This property is robust against changes in the binding and unbinding rate constants for KaiA to/from KaiC or KaiB, but the oscillations are sensitive to the rate constants of the KaiC phosphorylation and dephosphorylation reactions.


Effects of human lymphocytes on cultured normal and malignant cells.
With a modified microcytotoxicity assay, the effects of lymphocytes from normal volunteers and from patients with a variety of solid malignant tumors were tested in vitro against both normal and neoplastic target cells. The study was divided into three sequential time phases in each of which a different method of lymphocyte separation was used. Lymphocytes were separated by a Ludox-polyvinyl-pyrrolidone technique in the first phase, by nylon wool filtration in the second phase, and by a Ficoll-Hypaque technique in the third phase of the study. In the first two phases of the study, lymphocytes from both normal volunteers and cancer patients were frequently toxic on both tumor cells and fibroblasts. In the last phase of the study types of target cells. Cancer patient lymphocytes were more frequently toxic on tumor cells but no more frequently toxic on fibroblasts than were normal lymphocytes. The different results obtained in the last phase of the study cannot be attributed solely to the different method of lymphocyte separation, since other factors, such as better growth status of the target cells and greater facility in performing the assays, might also be responsible. Results of the last phase of the study raise the possibility that both specific and nospecific reactions may contribute to the toxicity observed in this laboratory with cancer patient lymphocytes tested against tumor cells. It has not yet been possible to reduce the level or frequency of the nonspecific reactions to such a degree that the microcytotoxicity assay can be used clinically to document clearly or to follow the putative tumor-specific immunity of individual cancer patients.


Coarse graining of force fields for metal-organic frameworks.
We have adapted our genetic algorithm based optimization approach, originally developed to generate force field parameters from quantum mechanic reference data, to derive a first coarse grained force field for a MOF, taking the atomistic MOF-FF as a reference. On the example of the copper paddle-wheel based HKUST-1, a maximally coarse grained model, using a single bead for each three and four coordinated vertex, was developed as a proof of concept. By adding non-bonded interactions with a modified Buckingham potential, the resulting MOF-FF-CGNB is able to predict local deformation energies of the building blocks as well as bulk properties like the tbovs.pto energy difference or elastic constants in a semi-quantitative way. As expected, the negative thermal expansion of HKUST-1 is not reproduced by the maximally coarse grained model. At the expense of atomic resolution, substantially larger systems (up to tens of nanometers in size) can be simulated with respect to structural and mechanical properties, bridging the gap to the mesoscale. As an example the deformation of the [111] surface of HKUST-1 by a "tip" could be computed without artifacts from periodic images.


Telangiectatic osteogenic sarcoma of the extremities. Results in 17 patients treated with neoadjuvant chemotherapy.
Seventeen patients with telangiectatic osteogenic sarcoma (TOS) of the extremities were treated with neoadjuvant chemotherapy, according to two different protocols. Preoperatively, the patients received high-dose methotrexate (HD-MTX) and cisplatinum (CPD) (HD-MTX/CPD) and doxorubicin. CPD was delivered intraarterially, the other drugs intravenously. Limb-salvage surgery was performed in 12 instances, and five patients were treated with amputation. Postoperative chemotherapy was tailored according to the grade of chemotherapy-induced necrosis. In 13 cases (86%), the resultant grade of necrosis was greater than 90% (good responders). The mean follow-up interval was 3.5 years with a range of 18 to 78 months. Fourteen patients (82%) remained continuously disease-free, while three patients developed lung metastases. Two of these died because of uncontrolled disease, whereas the third patient is alive and disease-free after metastasectomy. No local recurrences were observed. These results are better than those observed in 215 contemporary cases of conventional osteosarcoma treated with the same protocols. This study confirms that TOS is not a uniformly lethal tumor as suggested by prior reports. By employing neoadjuvant chemotherapy, a high percentage of patients with TOS can be cured, and in most of them, a limb-sparing surgery is possible and safe.


Extending the p-plot: heuristics for multiple testing. HNRC group.
In the problem of large-scale multiple testing the p-plot is a graphically based competitor to the notoriously weak Bonferroni method. The p-plot is less stringent and more revealing in that it gives a gauge of how many hypotheses are decidedly false. The method is elucidated and extended here: the bootstrap reveals bias and sampling error in the usual point estimates, a bootstrap-based confidence interval for the gauge is given, as well as two acceptably powerful blanket tests of significance. Guidelines for use are given, and interpretational pitfalls pointed out, in the discussion of a case study linking premortem neuropsychological and postmortem neuropathologic data in an HIV cohort study.


C. elegans RNA-dependent RNA polymerases rrf-1 and ego-1 silence Drosophila transgenes by differing mechanisms.
Drosophila possesses the core gene silencing machinery but, like all insects, lacks the canonical RNA-dependent RNA polymerases (RdRps) that in C. elegans either trigger or enhance two major small RNA-dependent gene silencing pathways. Introduction of two different nematode RdRps into Drosophila showed them to be functional, resulting in differing silencing activities. While RRF-1 enhanced transitive dsRNA-dependent silencing, EGO-1 triggered dsRNA-independent silencing, specifically of transgenes. The strain w; da-Gal4; UAST-ego-1, constitutively expressing ego-1, is capable of silencing transgene including dsRNA hairpin upon a single cross, which created a powerful tool for research in Drosophila. In C. elegans, EGO-1 is involved in transcriptional gene silencing (TGS) of chromosome regions that are unpaired during meiosis. There was no opportunity for meiotic interactions involving EGO-1 in Drosophila that would explain the observed transgene silencing. Transgene DNA is, however, unpaired during the pairing of chromosomes in embryonic mitosis that is an unusual characteristic of Diptera, suggesting that in Drosophila, EGO-1 triggers transcriptional silencing of unpaired DNA during embryonic mitosis.


Early ontogeny of face grooming in mice.
A U-shaped function of behavioral growth characterizes the early ontogeny of face grooming in mice. In the first few postnatal days (0-100 hr), mice groom their face by using temporally isolated strokes, or bouts of strokes, which vary in amplitude and symmetry. Later on (100-200 hr), bouts disappear, asymmetry is eliminated, and the amplitude of strokes is gradually restricted; the infants engage in stereotyped, double-handed, temporally isolated strokes. Finally (200-300 hr), bouts reappear, including both short and long, symmetrical and asymmetrical, strokes. These changes, are accompanied by unidirectional changes such as an increasing participation of the trunk, the neck, and the head in grooming, which lead to the flexible organization of face grooming seen in adults. Instead of describing development in terms of emerging unitary "acts," we have recorded from high-speed films three simultaneous aspects of movement: the movements of the separate limb and body segments, the resultant paths which are traced by the forepaws, and the paths of contact which are traced on the face. This method of description discloses (a) reversible changes, and (b) a change in the relative stability of each of these aspects of face grooming, in the course of early ontogeny.


Long-term effect of glimepiride and rosiglitazone on non-conventional cardiovascular risk factors in metformin-treated patients affected by metabolic syndrome: a randomized, double-blind clinical trial.
We evaluated the effect of glimepiride plus metformin and rosiglitazone plus metformin on glucose, and on cardiovascular risk parameters such as lipoprotein(a) (Lp[a]) and homocysteine (HCT) in patients with type 2 diabetes and metabolic syndrome. Ninety-nine patients in the multicentre, randomized, double-blind study took metformin (1500 mg/day) plus glimepiride (2 mg/day) or rosiglitazone (4 mg/day) for 12 months. Changes in body mass index, glycosylated haemoglobin (HbA1c), Lp(a) and HCT were primary efficacy variables. Fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) and homeostasis model assessment index were also used to assess efficacy. On average, HbA1c decreased by 9.1% and 8.1%, FPG decreased by 7.3% and 10.9%, and PPG decreased by 7.6% and 10.5%, respectively, in the glimepiride and rosiglitazone groups after 12 months. Patients receiving rosiglitazone experienced more rapid improvement in glycaemic control than those on glimepiride, and showed a significant improvement in insulin resistance-related parameters. There was a statistically significant decrease in basal homocysteinaemia in glimepiride-treated patients (-27.3%), but not in rosiglitazone-treated patients. Rosiglitazone plus metformin significantly improved long-term control of insulin resistance-related parameters compared with glimepiride plus metformin, although glimepiride treatment was associated with a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients, and with significant improvements in non-traditional risk factors for cardiovascular disease, such as basal homocysteinaemia and plasma Lp(a) levels.


A methodology to estimate the kinematics of pediatric occupants in frontal impacts.
The goal of this article is to propose a new methodology to estimate the sagittal plane displacement of the head, spine, and pelvis of a 6-year-old (6YO) occupant during a high-speed frontal impact. Research has shown major discrepancies between the spinal kinematics of current pediatric anthropomorphic test devices and humans during frontal impacts. This article provides an estimation of the kinematics of a pediatric subject that may assist in the development of physical and computational models of a 6YO occupant in high-speed frontal impacts. This article presents data on 4 different experimental data sets corresponding to noninjurious low-speed (nominally 9 km/h) frontal impacts involving pediatric and adult volunteers and to low-speed (9 km/h) and high-speed (40 km/h) frontal impacts with postmortem human subjects (PMHS). Kinematic data from each subject were first normalized to the size of a 50th percentile within its age group. Two already published and commonly used scaling methods (mass scaling and the Society of Automotive Engineers [SAE] scaling methods) were assessed using volunteer data. A new scaling method based on energy considerations was developed. Both the mass scaling and the SAE scaling methods failed to predict the actual pediatric displacement at 9 km/h. The newly proposed method substantially improved the prediction of the pediatric kinematics at low speed and it was applied to the high-speed PMHS data to provide an approximation of the displacements of the head, thoracic spine, and pelvis of a 6YO occupant in a 40 km/h frontal impact. A new scaling method based on energy conservation improved the prediction of the displacement of the pediatric head, thoracic spine, and pelvis at 9 km/h. This method was then applied to the response of the PMHS in a high-speed impact to provide an approximation of the 6YO kinematics in a 40 km/h frontal impact. The article also discusses the limitations of the method, which failed to completely describe the kinematics of pediatric occupants.


A case of colloid milium in patient with beta thalassaemia major.
Colloid milium (CM) is a rare cutaneous condition characterized by translucent papules occurring on sun-exposed regions including the face, neck and dorsal aspects of the hands and back. Clinically, there are two variants of CM: an adult-onset type and a juvenile form. The juvenile form is inherited and presents before puberty. Probably this variant is because of an inherited susceptibility to ultraviolet (UV) light and can be transmitted as both autosomal recessive and autosomal dominant character. In this paper, we report an interesting case of adult CM in a transfused patient affected by beta thalassaemia major. The association of CM with beta thalassaemia, to our knowledge, has not been reported previously, in literature. Thus, this case represents the first case of CM associated with beta thalassaemia major. In our view, the lesion could be related to excess iron, similar to pseudoxanthoma elastic-like lesions, another cutaneous disorder which is present in beta thalassaemia. As our patient is a farmer and was exposed to sun during his work, UV light damage could have have a role in promoting the development of the disease. Other cases of CM associated with beta thalassaemia should be reported to confirm these hypotheses.


Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group.
Cancer patients requiring strong opioid analgesia (n = 202; mean age, 61.5 years; range, 18-89 years; 55% men) were recruited from 38 United Kingdom palliative care centers into a randomized, open, two-period, crossover study comparing transdermal fentanyl with sustained-release oral morphine. Patients received one treatment for 15 days followed immediately by the other for 15 days. Daily diaries were completed. Both treatments appeared equally effective in terms of pain control, as assessed by the Memorial Pain Assessment Card and European Organization for Research and Treatment of Cancer (EORTC) pain scores. Fentanyl was associated with significantly less constipation (p < 0.001) and less daytime drowsiness (p = 0.015) but greater sleep disturbance (p = 0.004) and shorter sleep duration (p = 0.008) than morphine. The World Health Organization (WHO) performance status and EORTC global quality of life scores showed no significant difference between treatment groups. Of those patients who were able to express a preference (n = 136), significantly more preferred the fentanyl patches (p = 0.037). We conclude that, in this study, transdermal fentanyl provided pain relief that was acceptable to cancer patients and was associated with less constipation and sedation than morphine. These reduced side effects may contribute to patients preference for the patches.


Reflections on the culture of veterans.
Veterans, as a cultural group, present unique challenges to health care providers. Veteran culture includes health inequalities and health disparities related to posttraumatic stress disorder, depression, and substance abuse that must be understood in context to provide the best care possible to this population. Veterans are not, however, frequently viewed in terms of culturally competent nursing care. Changes in the approach to this population are necessary to provide effective, comprehensive, and compassionate care.


Integration of steroid hormone initiated membrane action to genomic function in the brain.
Estrogen is a ligand for the estrogen receptor (ER), which on binding 17beta-estradiol, functions as a ligand-activated transcription factor and regulates the transcription of target genes. This is the slow genomic mode of action. However, rapid non-genomic actions of estrogen also exist at the cell membrane. Using a novel two-pulse paradigm in which the first pulse rapidly initiates non-genomic actions using a membrane-limited estrogen conjugate (E-BSA), while the second pulse promotes genomic transcription from a consensus estrogen response element (ERE), we have demonstrated that rapid actions of estrogen potentiate the slower transcriptional response from an ERE-reporter in neuroblastoma cells. Since rapid actions of estrogen activate kinases, we used selective inhibitors in the two-pulse paradigm to determine the intracellular signaling cascades important in such potentiation. Inhibition of protein kinase A (PKA), PKC, mitogen activated protein kinase (MAPK) or phosphatidylinositol 3-OH kinase (PI-3K) in the first pulse decreases potentiation of transcription. Also, our data with both dominant negative and constitutive mutants of Galpha subunits show that Galpha(q) initiates the rapid signaling cascade at the membrane in SK-N-BE(2)C neuroblastoma cells. We discuss two models of multiple kinase activation at the membrane Pulses of estrogen induce lordosis behavior in female rats. Infusion of E-BSA into the ventromedial hypothalamus followed by 17beta-estradiol in the second pulse could induce lordosis behavior, demonstrating the applicability of this paradigm in vivo. A model where non-genomic actions of estrogen couple to genomic actions unites both aspects of hormone action.


Intrapleural Anticancer Therapy for Malignant Pleural Diseases: Facts or Fiction?
Malignant pleural diseases involves both primary pleural malignancies (e.g., mesothelioma) as well as metastatic disease involving the pleura. The management of primary pleural malignancies remains a challenge, given their limited response to conventional treatments such as surgery, systemic chemotherapy, and immunotherapy. In this article, we aimed to review the management of primary pleural malignancy as well as malignant pleural effusion and assess the current state of intrapleural anticancer therapies. We review the role intrapleural chemotherapy, immunotherapy, and immunogene therapy, as well as oncolytic viral, therapy and intrapleural drug device combination. We further discuss that while the pleural space offers a unique opportunity for local therapy as an adjuvant option to systemic therapy and may help decrease some of the systemic side effects, further patient outcome-oriented research is needed to determine the exact role of these treatments within the armamentarium of currently available options.