A new perspective on blame culture: an experimental study.
Recently, a range of different institutions worldwide has identified the 'culture of blame' and the fear of being punished as the principal reasons for the lack of medical error reporting and, consequently, of their reiteration and of the poor quality of patient care. Despite much theoretical debate, there currently exist no experimental studies that directly investigate the presence and pervasiveness of the blame and punishment culture in health care contexts. In order to document empirical evidence for this culture in medicine and nursing, we conducted an experimental study asking physicians and nurses to express their fear of blame or punishment in the context of having made an error that would cause: (i) no; (ii) mild; (iii) severe consequences; or (iv) the death of the patient. Two hundred and forty-nine health care providers (38 physicians, 11 medical students, 127 nurses and 73 nursing students) were included in the study. Two main data emerged: first, in general, the fear of being blamed is higher than the fear of being punished. Second, while the fear of being blamed is equally distributed among all participants, the fear of being punished varies according to the experience of subjects (it is higher in nursing students than in seniors nurses) and to their professional role (student and senior nurses are more susceptible to it than medical students and senior physicians). Given the relevance of these factors in medical error reporting and the evidence that they are so deep-seated not only in senior professionals, but also in students, we argue that an educational approach, together with an organization-based intervention, is desirable to shape cultural attitudes of health care providers in the direction of a 'safety culture'.


The law, adolescents, and the APOE epsilon 4 genotype: a view from Canada.
The presence of an apolipoprotein E (APOE) epsilon 4 allele may be a risk factor for the severity of the consequences of head trauma, both short-term and long-term. If this proves to be true, genetic testing for APOE status might be encouraged, or required, to minimize the costs of participation in high-contact sports, such as ice hockey, soccer, rugby, and boxing, where head injury is likely to occur. Under some circumstances, testing minors for this purpose might be justifiable. This would raise complex ethical and legal questions about respective powers and rights of adolescents and parents. The wishes of the "nearly competent" adolescent not to be tested should override parental desires for testing, although such a conclusion has only limited warrant in Canadian law. If a mature adolescent wishes testing, but the parents do not, testing may be permissible--although Canadian law is again unclear. The physician should not be able to inform the parents of the test results without the adolescent's consent, nor should the adolescent be forced to disclose those results.


Shortcuts to adiabaticity by counterdiabatic driving.
The evolution of a system induced by counterdiabatic driving mimics the adiabatic dynamics without the requirement of slow driving. Engineering it involves diagonalizing the instantaneous Hamiltonian of the system and results in the need of auxiliary nonlocal interactions for matter waves. Here, experimentally realizable driving protocols are found for a large class of single-particle, many-body, and nonlinear systems without demanding the spectral properties as an input. The method is applied to the fast decompression of Bose-Einstein condensates in different trapping potentials.


Intracardiac thrombosis and aortic dissecting aneurysms in mustached tamarins (Saguinus mystax) with cardiomyopathy.
Spontaneous intracardiac thrombosis is rarely reported in animals, particularly nonhuman primates. The finding of 2 cases of intracardiac thrombi in mustached tamarins (Saguinus mystax) that died as a consequence of congestive heart failure prompted us to do a retrospective study to determine the frequency of this condition. Clinical records, necropsy reports, and tissues from 60 mustached tamarins that died or were euthanized between 1996 and 2009 were reviewed. Of the 60 monkeys whose cases were reviewed, 10 (16.6%) had intracardiac thrombi, and 4 (6.6%) had dissecting aortic aneurysms. Of the 10 animals with intracardiac thrombosis, 3 had left ventricular involvement alone; 4 monkeys had thrombi only in the right ventricle, and the remaining 3 animals exhibited thrombi in both ventricles. Myocardial fibrosis and chronic renal disease were common findings in affected animals. The causes of the intracardiac thrombosis in the tamarins in the present study are not known, but the clinical signs and gross and microscopic lesions suggest that congestive heart failure secondary to cardiomyopathy is the primary contributor. In addition, the cause of the aortic dissecting aneurysms in the tamarins in this study is not known. Further studies are required to determine whether factors including aortic curvature, genetic background, or hypertension-alone or in combination-play a role. To our knowledge, the current retrospective study is the first report of intracardiac thrombosis and aortic aneurysms in mustached tamarins.


Electron-transfer mechanism in the N-demethylation of N,N-dimethylanilines by the phthalimide-N-oxyl radical.
The reactivity of the phthalimide N-oxyl radical (PINO) toward the N-methyl C-H bond of a number of 4-X-substituted N,N-dimethylanilines (X = OMe, OPh, CF(3), CO(2)Et, CN) has been investigated by product and kinetic analysis. PINO was generated in CH(3)CN by reaction of N-hydroxyphthalimide (NHPI) with Pb(OAc)(4) or, for the kinetic study of the most reactive substrates (X = OMe, OPh), with tert-butoxyl radical produced by 266 nm laser flash photolysis of di-tert-butyl peroxide. The reaction was found to lead to the N-demethylation of the N,N-dimethylaniline with a rate very sensitive to the electron donating power of the substituent (rho(+) = -2.5) as well as to the oxidation potential of the substrates. With appropriately deuterated N,N-dimethylanilines the intermolecular and intramolecular deuterium kinetic isotope effects (DKIEs) were measured for some substrates (X = OMe, CO(2)Et, CN) with the following results. First, intramolecular DKIE [(k(H)/k(D))(intra)] was found to be always different and higher than intermolecular DKIE [(k(H)/k(D))(inter)]; second, no intermolecular DKIE [(k(H)/k(D))(inter) = 1] was observed for X = OMe, whereas substantial values of (k(H)/k(D))(inter) were exhibited by X = CO(2)Et (4.8) and X = CN (5.8). These results, while are incompatible with a single step hydrogen atom transfer from the N-C-H bond to the N-oxyl radical, as proposed for the reaction of PINO with benzylic C-H bonds, can be nicely interpreted on the basis of a two-step mechanism involving a reversible electron transfer from the aniline to PINO leading to an anilinium radical cation, followed by a proton-transfer step that produces an alpha-amino carbon radical. In line with this conclusion the reactivity data exhibited a good fit with the Marcus equation and a lambda value of 37.6 kcal mol(-1) was calculated for the reorganization energy required in this electron-transfer process. From this value, a quite high reorganization energy (>60 kcal mol(-1)) is estimated for the PINO/NHPI(-H)(-) self-exchange reaction. It is suggested that the N-demethylated product derives from the reaction of the alpha-amino carbon radical with PINO to form either a cross-coupling product or an alpha-amino carbocation. Both species may react with the small amounts of H(2)O present in the medium to form a carbinolamine that, again by hydrolysis, can be eventually converted into the N-demethylated product.


Rescue of Citrus sudden death-associated virus in Nicotiana benthamiana plants from cloned cDNA: insights into mechanisms of expression of the three capsid proteins.
Citrus sudden death-associated virus (CSDaV) is a member of the genus Marafivirus in the family Tymoviridae, and has been associated with citrus sudden death (CSD) disease in Brazil. Difficulties in the purification of CSDaV from infected citrus plants have prevented progress in the investigation of the role of this virus in CSD and an understanding of its molecular biology. In this work, we have constructed a full-length cDNA clone of CSDaV driven by the 35S promoter (35SRbz-CSDaV). Agrobacterium tumefaciens-mediated inoculation of 35SRbz-CSDaV in Nicotiana benthamiana plants enabled a fast recovery of large amounts of virions from the agroinfiltrated leaves, which allowed a better molecular characterization of CSDaV. In vivo analyses of mutant versions of 35SRbz-CSDaV revealed the expression strategies used by CSDaV for production of the capsid proteins (CPs). We showed that CSDaV virions contain three forms of CP, each of which is generated from the same coding sequence, but by different mechanisms. The major CPp21 is a product of direct translation by leaky scanning from the second start codon in the subgenomic RNA (sgRNA), whereas the minor CPs, p25 and p23, are produced by direct translation from the first start codon in the sgRNA and by trans-proteolytic cleavage processing derived from the p25 precursor, respectively. Together, these findings contribute to advance our understanding of CSDaV genome expression strategies. In addition, the construction and characterization of the CSDaV infectious clone represent important steps towards the investigation of the role of this virus in CSD and of its use as a tool for citrus biotechnology.


Hypothetical blood-pressure-lowering interventions and risk of stroke and dementia.
We aimed to study the effects of hypothetical interventions on systolic blood pressure (SBP) and smoking on risk of stroke and dementia using data from 15 years of follow-up in the Rotterdam Study. We used data from 4930 individuals, aged 55-80 years, with no prior history of stroke, dementia or cognitive impairment, followed for 15 years within the Rotterdam Study, a population-based cohort. We defined the following sustained interventions on SBP: (1) maintaining SBP below 120 mmHg, (2) maintaining SBP below 140 mmHg, (3) reducing SBP by 10% if above 140 mmHg, (4) reducing SBP by 20% if above 140 mmHg, and a combined intervention of quitting smoking with each of these SBP-lowering strategies. We considered incident stroke and incident dementia diagnoses as outcomes. We applied the parametric g-formula to adjust for baseline and time-varying confounding. The observed 15-year risk for stroke was 10.7%. Compared to no specified intervention (i.e., the "natural course"), all interventions that involved reducing SBP were associated with a stroke risk reduction of about 10% (e.g., reducing SBP by 20% if above 140 mmHg risk ratio: 0.89; 95% CI 0.76, 1). Jointly intervening on SBP and smoking status further decreased the risk of stroke (e.g., risk ratio: 0.83; 95% CI 0.71, 0.94). None of the specified interventions were associated with a substantive change in dementia risk. Our study suggests that a joint intervention on SBP and smoking cessation during later life may reduce stroke risk, while the potential for reducing dementia risk were not observed.


Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficile.
BACKGROUNDFecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection (rCDI) in adults and children, but donor stool samples are currently screened for only a limited number of potential pathogens. We sought to determine whether putative procarcinogenic bacteria (enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and Escherichia coli harboring the colibactin toxin) could be durably transmitted from donors to patients during FMT.METHODSStool samples were collected from 11 pediatric rCDI patients and their respective FMT donors prior to FMT as well as from the patients at 2-10 weeks, 10-20 weeks, and 6 months after FMT. Bacterial virulence factors in stool DNA extracts and stool cultures were measured by quantitative PCR: Bacteroides fragilis toxin (bft), Fusobacterium adhesin A (fadA), and Escherichia coli colibactin (clbB).RESULTSFour of 11 patients demonstrated sustained acquisition of a procarcinogenic bacteria. Whole genome sequencing was performed on colony isolates from one of these donor/recipient pairs and demonstrated that clbB+ E. coli strains present in the recipient after FMT were identical to a strain present in the donor, confirming strain transmission. Conversely, 2 patients exhibited clearance of procarcinogenic bacteria following FMT from a negative donor.CONCLUSIONBoth durable transmission and clearance of procarcinogenic bacteria occurred following FMT, suggesting that additional studies on appropriate screening measures for FMT donors and the long-term consequences and/or benefits of FMT are warranted.FUNDINGCrohn's & Colitis Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine, the National Cancer Institute, and the Canadian Institutes of Health Research.


Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis.
Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence regarding the association between pioglitazone and bladder cancer risk is confusing. A systematic search of databases was carried out, and other relevant papers were also identified. Then, the analyses were conducted according to the PRISMA and MOOSE guidelines. After quality assessment, nine datasets from 10 available studies were included on the basis of inclusion criteria. The incidence of bladder cancer among pioglitazone ever users and never users, pooled from four cohort and one randomized studies, were 84.51 and 66.68 per 100,000 person-years, respectively. Nine studies representing 2,596,856 diabetic patients were recognized as eligible for overall study; the result suggested an increased risk of bladder cancer in patients exposed to pioglitazone. A persistent significance was detected after being adjusted by age, gender, and use of other diabetes medications. Subgroup analyses indicated that the significantly increased incidence of bladder cancer was found in men, but not in women. Additionally, the analyses addressing increasing exposure to pioglitazone observed a dose-response relation between exclusive ever use of pioglitazone and bladder cancer in terms of cumulative duration of use and cumulative dosage. With some limitations, our results suggest an increased risk of bladder cancer in diabetic patients using pioglitazone, especially for men with long-term and high-dose exposure. Additional studies are needed to provide more precise evidences to support our results.


[Case report: seventeen year old primipara with placenta increta, treated with methotrexate].
A seventeen year old girl in her first pregnancy had a normal vaginal delivery of a healthy male infant. Afterwards, the placenta was retained and subsequent MRI and ultrasound confirmed placenta increta. There was no history of prior uterine surgery. Conservative treatment with methotrexate was chosen in order to conserve the uterus. During the following nine weeks after birth remnants of the placenta were gradually expelled from the uterus. Subsequently MRI and ultrasound confirmed an empty uterus. When the diagnosis of placenta increta is confirmed the current recommendation is hysterectomy to prevent life threatening bleeding or infection. Conservative treatments have been described to avoid hysterectomy with methotrexate as being one of the options.


Subspeciality Interests Among the Ophthalmology Residents: A Mixed-Methods Study.
To determine the popular subspeciality choices among ophthalmology residents, to explore the factors affecting that choice, and to identify the obstacles that they face while selecting a subspeciality fellowship. Mixed-methods study. Place and Duration of the Study: Department of Ophthalmology of Hayatabad Medical Complex and Lady Reading Hospital, Peshawar, from 1st September to 30th November, 2021. The qualitative (1st) phase comprised of focussed group discussion (FGD) followed by an online in-depth interview (IDI). Quantitative (2nd) phase was conducted as online survey and consisted of currently enrolled FCPS-ophthalmology residents. Themes were generated and used to modify the pre-designed questionnaire. Questionnaire was piloted and necessary adjustments were made. In the 2nd phase, the online link of the questionnaire was shared with the eligible participants all over the country. For the association between categorical variables, the Pearson Chi-square test was used with significance at p-value <0.05. Results: Nine participants were recruited in the first phase and three themes were generated. In the second phase, a total of 138 responses were received, among which mean age was 29.37 + 3.9 years, and 74 (53.6%) participants were males. The top three subspeciality choices were cataract and refractive surgery (n = 31, 22.5%), vitreoretinal surgery (n = 30, 21.7%) and orbit and oculoplasty (n = 13, 9.4%). Sixty-two (48.8%) participants stated interest in the career to be the main reason to choose a particular fellowship, and 54 (42.5%) participants identified challenging subspeciality as the main obstacle. An association between gender and the intended subspeciality showed significant results (p = 0.029). Ophthalmology residents of Pakistan have different approaches and motivations for selecting a fellowship programme. Professional needs and scientific reasons are their main motivations. Ophthalmology, Fellowship, Motivations, Career choices, Mentor, Pakistan.


Successful treatment of bleeding due to ileal varices in a patient with hepatocellular carcinoma.
This case report concerns a 62-year-old female who was known to have cirrhosis. An endoscopic examination showed no evidence of haemorrhaging due to either oesophageal or gastric varices. Angiographic studies demonstrated extravasation from the ileal varices. There was a prominent arterio-portal shunt in the liver, and the shunt was considered to be a contributing factor to induce portal hypertension and variceal bleeding in the ileum. Therefore, transcatheter arterial embolization was performed, but was unsuccessful. As a result, the patient underwent a laparotomy, and a dilatating ileocaecal vein and a communicating ovarian vein were selectively ligated. Following the procedure, the haemorrhaging stopped and she then recovered. The patient is doing well 21 months after surgery at the time of writing.


Direct MS-MS identification of isoxsuprine-glucuronide in post-administration equine urine.
Isoxsuprine is routinely recovered from enzymatically-hydrolyzed, post-administration urine samples as parent isoxsuprine in equine forensic science. However, the specific identity of the material in horse urine from which isoxsuprine is recovered has never been established, although it has long been assumed to be a glucuronide conjugate (or conjugates) of isoxsuprine. Using ESI/MS/MS positive mode as an analytical tool, urine samples collected 4-8 h after isoxsuprine administration yielded a major peak at m/z 554 that was absent from control samples and resisted fragmentation to daughter ions. Titration of this material with increasing concentrations of sodium acetate yielded m/z peaks consistent with the presence of monosodium and disodium isoxsuprine-glucuronide complexes, suggesting that the starting material was a dipotassium-isoxsuprine-glucuronide complex. Electrospray ionization mass spectrometry negative mode disclosed the presence of a m/z 476 peak that declined following enzymatic hydrolysis and resulted in the concomitant appearance of peaks at m/z 300 and 175. The resulting peaks were consistent with the presence of isoxsuprine (m/z 300) and a glucuronic acid residue (m/z 175). Examination of the daughter ion spectrum of this putative isoxsuprine-glucuronide m/z 476 peak showed overlap of many peaks with those of similar spectra of authentic morphine-3- and morphine-6-glucuronides, suggesting they were derived from glucuronic acid conjugation. These data suggest that isoxsuprine occurs in post-administration urine samples as an isoxsuprine-glucuronide conjugate and also, under some circumstances, as an isoxsuprine-glucuronide-dipotassium complex.


The use and impact of rapid health technology assessments.
To consider the impact of rapid health technology assessments undertaken as part of a program in a provincial healthcare system in response to urgent requests for advice. Review of the development and preparation of 20 rapid assessment reports, communication with decision makers within the healthcare system, and appraisal of data subsequent to preparation of the reports. Fourteen of the assessments were judged to have had an influence on policy and other decisions, as judged by responses from those who had requested advice. Another four were considered to have provided guidance, while having less immediate influence on decisions, and two others had no apparent impact. Quality of the assessments was considered acceptable, on the basis of literature that subsequently became available and from comments received. These brief reports are considered to be a useful component of a health technology assessment program. However, they should be regarded as provisional appraisals and followed up with more detailed evaluation where possible.


Double-blind placebo-controlled randomized clinical trial of ginger (Zingiber officinale Rosc.) in the prophylactic treatment of migraine.
Previous studies have shown an analgesic effect of ginger in the acute treatment of migraine, and there is anecdotal evidence of its efficacy in migraine prophylaxis. This study aimed to evaluate the potential of ginger to prevent migraine attacks. This double-blind, placebo-controlled randomized clinical trial took place at the Headache Clinic, Universidade Federal de Minas Gerais (Belo Horizonte, Minas Gerais, Brazil), involving 107 patients. Only subjects diagnosed with episodic migraine, aged between 18 and 60 years old, and who were not taking any prophylactic medication, were enrolled in the study. After one month of observation, subjects selected for the study were randomized 1:1 into placebo and treatment groups. Patients received capsules three times per day of 200 mg of dry extract of ginger (5% active ingredient) or placebo (cellulose) for three months. Visits were performed monthly and the patients were asked to fill in a migraine diary. The adherence to treatment was evaluated by counting capsules. The percentage of patients who responded to treatment (i.e. a reduction of 50% in the number of migraine attacks at the end of treatment) did not differ between the groups. There was a decrease in the number of days with severe pain, analgesic use for acute migraine and duration of migraine attacks in both groups, without significant difference between ginger and placebo groups. Ginger provides no greater benefit in the prophylactic treatment of migraine when compared to placebo. This trial is registered at ClinicalTrials.gov (NCT02570633).


Assessing instrument handling and operative consequences simultaneously: a simple method for creating synced multicamera videos for endosurgical or microsurgical skills assessments.
There has been an increasing interest in assessment of technical skills in most medical and surgical disciplines. Many of these assessments involve microscopy or endoscopy and are thus amenable to video recording for post hoc review. An ideal skills assessment video would provide the reviewer with a simultaneous view of the examinee's instrument handling and the operative field. Ideally, a reviewer should be blinded to the identity of the examinee and whether the assessment was performed as a pretest or posttest examination, when given in conjunction with an educational intervention. We describe a simple method for reliably creating deidentified, multicamera, time-synced videos, which may be used in technical skills assessments. We pilot tested this method in a pediatric airway endoscopy Objective Assessment of Technical Skills (OSATS). Total video length was compared with the OSATS administration time. Thirty-nine OSATS were administered. There were no errors encountered in time-syncing the videos using this method. Mean duration of OSATS videos was 11 minutes and 20 seconds, which was significantly less than the time needed for an expert to be present at the administration of each 30-minute OSATS (P < 0.001). The described method for creating time-synced, multicamera skills assessment videos is reliable and may be used in endosurgical or microsurgical skills assessments. Compared with live review, post hoc video review using this method can save valuable expert reviewer time. Most importantly, this method allows a reviewer to simultaneously evaluate an examinee's instrument handling and the operative field while being blinded to the examinee's identity and timing of examination administration.


Distribution, prevalence, and genetic characterization of Baylisascaris procyonis in selected areas of Georgia.
Baylisascaris procyonis is an intestinal nematode of raccoons (Procyon lotor) that can cause fatal larval migrans in numerous species of birds and mammals, including humans. Although this parasite has historically been absent in the southeastern United States, it has been found in isolated regions in the Appalachian Mountains and was recently documented in DeKalb County, Georgia. The first objective of the current study was to investigate the distribution and prevalence of B. procyonis in selected populations of raccoons in Georgia. Intestinal tracts of 312 raccoons from 25 Georgia counties were examined for B. procyonis. The only county where B. procyonis was detected was Clarke County, where 12 of 116 (10.3%) raccoons were infected. In Clarke County, significantly more juveniles (P = 0.049) were infected compared with adults, and no differences in prevalence were noted by sex, season of capture, or land use (rural vs. urban); however, significantly (P = 0.0370) higher worm burdens were found in infected raccoons from urban/suburban locations compared with rural areas. In addition, Toxascaris leonina , a morphologically similar ascarid, was found in 3 raccoons from Clarke County (n = 2) and Morgan County (n = 1). A second objective was to determine if sequence polymorphisms were associated with B. procyonis from different geographic regions. Because sequences from a single worm from Japan had been entered into GenBank, we obtained nematodes from Kentucky and Texas for comparison with our samples from Georgia. Sequence analysis of the 18S and 5.8S rRNA genes and the internal transcribed spacer (ITS) -1 and ITS-2 regions confirmed Georgia samples were B. procyonis. Although several polymorphic bases were observed within both ITS regions, none was associated with a particular geographic location. These data indicate that the distribution of B. procyonis within Georgia is increasing and only limited genetic variation is present in the rRNA and ITS gene regions among B. procyonis from the southern United States and introduced populations in Japan.


Conventional medical management of inflammatory bowel disease.
Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti-tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively.


[Radiotherapy of bone tumors. Analysis of a historic series and review of the literature].
The authors report a series of patients with osteosarcoma or Ewing's sarcoma irradiated 1968-1988 at the Institute of Radiology of "La Sapienza" University, Rome. Twelve of 17 osteosarcoma patients (71%) died and 5 are alive, with a median survival of 13 months. Seven of 12 Ewing's sarcoma patients (58%) died and 5 are alive (42%), with a median survival of 67 months. These results are similar to those of most contemporary series in the literature; the long follow-up of our series allowed us to calculate actuarial survival rates at 5, 10 and 15 years of 41%, 34% and 17%, respectively, in osteosarcoma patients and 75%, 45% and 34% for those with Ewing's sarcoma. The review of the literature on the management of bone tumors high-lights the importance of new developments and technologies to improve the life expectancy of these patients. The authors discuss the role of modern imaging techniques in defining tumor margins and predicting treatment-induced tumor regression and the research into new therapeutic approaches. Multimodality combinations and new schedules appear promising tools to improve prognosis and to reduce side-effects, thus stressing the need of combined efforts of surgeons, radiotherapists and chemotherapists. State-of-the-art radiotherapy can further increase local control with higher total doses to the lesion and selectively sparing adjacent normal tissues, thanks to 3D treatment planning of hadron beam equipment.


Alpha 1-adrenoceptor subtype mediates norepinephrine-induced contraction of the rabbit isolated ovarian artery.
The interactions between selective alpha-adrenoceptor agonists and antagonists were studied in the rabbit isolated ovarian artery in an attempt to characterize the alpha-adrenoceptor subtype present in the smooth muscle of this vessel. Norepinephrine, epinephrine, and phenylephrine, but not clonidine or BHT-920, contracted the ovarian artery in a concentration dependent manner. The rank order of potency was epinephrine greater than norepinephrine greater than phenylephrine. The contractions were competitively antagonized by prazosin, phentolamine, and yohimbine. However, prazosin and phentolamine were approximately 100-500 times more potent than yohimbine against norepinephrine and phenylephrine. Observations were unchanged when arterial segments were used after endothelial removal. Norepinephrine-induced contractions of the ovarian artery were relatively resistant to blockade by diltiazem. The results suggest that exclusively alpha 1-adrenoceptors are present in vascular smooth muscle cells of the ovarian artery, whose activation operates through a mechanism relatively independent of Ca2+ influx into the smooth muscle cells.


Third molar development by measurements of open apices in an Italian sample of living subjects.
The aim of this study is to analyse the age-predicting performance of third molar index (I3M) in dental age estimation. A multiple regression analysis was developed with chronological age as the independent variable. In order to investigate the relationship between the I3M and chronological age, the standard deviation and relative error were examined. Digitalized orthopantomographs (OPTs) of 975 Italian healthy subjects (531 female and 444 male), aged between 9 and 22 years, were studied. Third molar development was determined according to Cameriere et al. (2008). Analysis of covariance (ANCOVA) was applied to study the interaction between I3M and the gender. The difference between age and third molar index (I3M) was tested with Pearson's correlation coefficient. The I3M, the age and the gender of the subjects were used as predictive variable for age estimation. The small F-value for the gender (F = 0.042, p = 0.837) reveals that this factor does not affect the growth of the third molar. Adjusted R(2) (AdjR(2)) was used as parameter to define the best fitting function. All the regression models (linear, exponential, and polynomial) showed a similar AdjR(2). The polynomial (2nd order) fitting explains about the 78% of the total variance and do not add any relevant clinical information to the age estimation process from the third molar. The standard deviation and relative error increase with the age. The I3M has its minimum in the younger group of studied individuals and its maximum in the oldest ones, indicating that its precision and reliability decrease with the age.


Surgical Management of Airway Stenosis During Pregnancy: A Scoping Review.
There are several options for surgical management of subglottic stenosis, including endoscopic and open procedures. However, treatment algorithms, outcomes, and anesthetic management of subglottic stenosis during pregnancy are not well described. MEDLINE, EMBASE, and the Cochrane databases. A scoping review of management of subglottic stenosis during pregnancy was performed, and then reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria consisted of those with subglottic or tracheal stenosis aged greater than 18 years, those in whom management was performed during pregnancy, and those who reported delivery related outcomes. After systematic review and detailed search of 330 identified articles, 15 articles met inclusion criteria and were included in the final analysis. All studies were case reports or case series (level 4 evidence). This study identified 27 patients. The median age was 29 and the median gestational age at intervention was 28 weeks. Left lateral positioning and fetal heart rate monitoring were used in nearly every case. The most common intervention performed was endoscopic balloon dilation. In many cases, jet ventilation or transnasal humidified rapid insufflation ventilatory exchange was satisfactory for maintenance of the airway. Three women ultimately required tracheostomy prior to labor and delivery. There was no fetal death or complications reported in these studies, and all but one woman proceeded to deliver at term. Endoscopic balloon dilation during pregnancy is safe and effective, resulting in optimized respiratory outcomes for the mother and safe delivery of the fetus. The third trimester appears to be safe for airway intervention. Laryngoscope, 2023.


Coracoid impingement: diagnosis and treatment.
Coracoid impingement is a controversial, well-known diagnosis that results in anterior shoulder pain. Idiopathic, traumatic, and iatrogenic etiologies have been identified. Proper diagnosis requires a focused clinical examination of the anterior shoulder and adjacent structures. MRI and CT are helpful in evaluating coracoid morphology as well as the integrity of the rotator cuff and long head of the biceps. Imaging is an essential diagnostic tool. Initial management consists of physical therapy and injection therapies. Surgery may be required when nonsurgical methods are unsuccessful. Successful functional and subjective outcomes have been reported with both open and arthroscopic techniques.


Determinants of Infection Outcome in HCV-Genotype 4.
Hepatitis C virus (HCV) infection represents a worldwide health problem and has been for long an attractive point of research due to diversity among different genotypes regarding unique geographical distribution and diverse treatment outcome. HCV is considered a major cause of chronic liver disease and cirrhosis, which leads to liver failure and hepatocellular carcinoma requiring liver transplantation. Of the HCV genotypes identified, HCV genotype 4 (HCV-4) is the least studied. HCV-4 is responsible for ∼10% of HCV infections and is common in the Middle East and Africa; recently it is increasingly prevalent in European Countries. HCV-4 is a continuing epidemic in Egypt, having the highest prevalence of HCV worldwide. "Know your epidemic, know your response" concept necessitates better understanding of HCV-4 characteristics to control disease dissemination and progression, which compromises the life quality of chronic HCV-infected patients. In this review, we discuss the epidemiology, natural history, and treatment options for patients with HCV-4 infection.


Perceived need and barriers to adolescent mental health care: agreement between adolescents and their parents.
Mental disorders cause high burden in adolescents, but adolescents often underutilise potentially beneficial treatments. Perceived need for and barriers to care may influence whether adolescents utilise services and which treatments they receive. Adolescents and parents are stakeholders in adolescent mental health care, but their perceptions regarding need for and barriers to care might differ. Understanding patterns of adolescent-parent agreement might help identify gaps in adolescent mental health care. A nationally representative sample of Australian adolescents aged 13-17 and their parents (N = 2310), recruited between 2013-2014, were asked about perceived need for four types of adolescent mental health care (counselling, medication, information and skill training) and barriers to care. Perceived need was categorised as fully met, partially met, unmet, or no need. Cohen's kappa was used to assess adolescent-parent agreement. Multinomial logistic regressions were used to model variables associated with patterns of agreement. Almost half (46.5% (s.e. = 1.21)) of either adolescents or parents reported a perceived need for any type of care. For both groups, perceived need was greatest for counselling and lowest for medication. Identified needs were fully met for a third of adolescents. Adolescent-parent agreement on perceived need was fair (kappa = 0.25 (s.e. = 0.01)), but poor regarding the extent to which needs were met (kappa = -0.10 (s.e. = 0.02)). The lack of parental knowledge about adolescents' feelings was positively associated with adolescent-parent agreement that needs were partially met or unmet and disagreement about perceived need, compared to agreement that needs were fully met (relative risk ratio (RRR) = 1.91 (95% CI = 1.19-3.04) to RRR = 4.69 (95% CI = 2.38-9.28)). Having a probable disorder was positively associated with adolescent-parent agreement that needs were partially met or unmet (RRR = 2.86 (95% CI = 1.46-5.61)), and negatively with adolescent-parent disagreement on perceived need (RRR = 0.50 (95% CI = 0.30-0.82)). Adolescents reported most frequently attitudinal barriers to care (e.g. self-reliance: 55.1% (s.e. = 2.39)); parents most frequently reported that their child refused help (38.7% (s.e. = 2.69)). Adolescent-parent agreement was poor for attitudinal (kappa = -0.03 (s.e. = 0.06)) and slight for structural barriers (kappa = 0.02 (s.e. = 0.09)). There are gaps in the extent to which adolescent mental health care is meeting the needs of adolescents and their parents. It seems important to align adolescents' and parents' needs at the beginning and throughout treatment and to improve communication between adolescents and their parents. Both might provide opportunities to increase the likelihood that needs will be fully met. Campaigns directed towards adolescents and parents need to address different barriers to care. For adolescents, attitudinal barriers such as stigma and mental health literacy require attention.


Coronary artery calcification and epicardial adipose tissue as independent predictors of mortality in COVID-19.
Recent epidemiological studies have demonstrated that common cardiovascular risk factors are strongly associated with adverse outcomes in COVID-19. Coronary artery calcium (CAC) and epicardial fat (EAT) have shown to outperform traditional risk factors in predicting cardiovascular events in the general population. We aim to determine if CAC and EAT determined by Computed Tomographic (CT) scanning can predict all-cause mortality in patients admitted with COVID-19 disease. We performed a retrospective, post-hoc analysis of all patients admitted to Montefiore Medical Center with a confirmed COVID-19 diagnosis from March 1st, 2020 to May 2nd, 2020 who had a non-contrast CT of the chest within 5 years prior to admission. We determined ordinal CAC scores and quantified the epicardial (EAT) and thoracic (TAT) fat volume and examined their relationship with inpatient mortality. A total of 493 patients were analyzed. There were 197 deaths (39.95%). Patients who died during the index admission had higher age (72, [64-80] vs 68, [57-76]; p < 0.001), CAC score (3, [0-6] vs 1, [0-4]; p < 0.001) and EAT (107, [70-152] vs 94, [64-129]; p = 0.023). On a competing risk analysis regression model, CAC ≥ 4 and EAT ≥ median (98 ml) were independent predictors of mortality with increased mortality of 63% (p = 0.003) and 43% (p = 0.032), respectively. As a composite, the group with a combination of CAC ≥ 4 and EAT ≥ 98 ml had the highest mortality. CAC and EAT measured from chest CT are strong independent predictors of inpatient mortality from COVID-19 in this high-risk cohort.


Solution-phase and solid-phase sequential, selective modification of side chains in KDYWEC and KDYWE as models for usage in single-molecule protein sequencing.
Single-molecule protein sequencing is regarded as a promising new method in the field of proteomics. It potentially offers orders of magnitude improvements in sensitivitiy and throughput for protein detection when compared to mass spectrometry. However, the development of such a technology faces significant barriers, especially in the need to chemically derivatize specific amino-acid types with unique labels. For example, fluorescent dyes would be suitable for single-molecule microscopy or nanopore-based sequencing. These emerging single-molecule protein-sequencing technologies suggests a need to develop an amino acid side chain-selective modification scheme that could target several side chains of interest. Current work for modifying residues focuses mainly on one or two side chains. The need to label many side chains, as recent computational modeling suggests, is required for high protein, sequencing coverage of the human proteome. Herein, we report our stragety for modifying two model peptides KYDWEC and KDYWE containing the most reactive residues, using highly opitmized mass labels in a sequential and selective fashion both using solution-phase and solid-phase chemistries, respectively. This will serve as a step towards a modification scheme appropriate for single-molecule studies.


Increased skin temperature in Alzheimer's disease is associated with sleepiness.
The 24-h rhythms in sleep and temperature both change in Alzheimer's disease (AD). Characteristic changes consist of a more fragmented diurnal sleep profile with frequent nocturnal awakenings and daytime sleepiness, as well as a reduction in the amplitude of the 24-h rhythm in core body temperature (CBT). Although the 24-h rhythm in CBT is to a large extent the result of a 24-h rhythm in heat loss from the skin caused by pronounced changes in skin blood flow and consequently skin temperature (Ts), changes in the diurnal skin temperature profile in AD as compared to normal aging have remained unexplored. Because recent work indicates a causal contribution of fluctuations in skin temperature to daytime sleepiness and nocturnal sleep depth, the present study aimed to investigate the skin temperature rhythm in AD and its association with daytime sleepiness and nocturnal sleep. Ambulatory recorders were used to estimate sleep and 24-h rhythms in skin temperature in 55 AD patients and 26 matched non-demented elderly controls. Subjective sleep and daytime sleepiness were obtained using questionnaires. The results indicate that AD patients had a significantly higher daytime proximal skin temperature (PST) than elderly controls. In both AD patients and elderly controls, an elevated daytime PST was associated with more daytime sleepiness. The findings suggest a deficient downregulation of daytime proximal skin blood flow that might contribute to daytime sleepiness. Because daytime sleepiness contributes to cognitive dysfunction in AD, further research into the underlying mechanisms and possible reversibility is warranted.


Genetic isolation of fragmented populations is exacerbated by drift and selection.
Reduced genetic variation at marker loci in small populations has been well documented, whereas the relationship between quantitative genetic variation and population size has attracted little empirical investigation. Here we demonstrate that both neutral and quantitative genetic variation are reduced in small populations of a fragmented plant metapopulation, and that both drift and selective change are enhanced in small populations. Measures of neutral genetic differentiation (F(ST)) and quantitative genetic differentiation (Q(ST)) in two traits were higher among small demes, and Q(ST) between small populations exceeded that expected from drift alone. This suggests that fragmented populations experience both enhanced genetic drift and divergent selection on phenotypic traits, and that drift affects variation in both neutral markers and quantitative traits. These results highlight the need to integrate natural selection into conservation genetic theory, and suggests that small populations may represent reservoirs of genetic variation adaptive within a wide range of environments.


Jasmonic Acid Methyl Ester Induces Xylogenesis and Modulates Auxin-Induced Xylary Cell Identity with NO Involvement.
In Arabidopsis basal hypocotyls of dark-grown seedlings, xylary cells may form from the pericycle as an alternative to adventitious roots. Several hormones may induce xylogenesis, as Jasmonic acid (JA), as well as indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) auxins, which also affect xylary identity. Studies with the ethylene (ET)-perception mutant ein3eil1 and the ET-precursor 1-aminocyclopropane-1-carboxylic acid (ACC), also demonstrate ET involvement in IBA-induced ectopic metaxylem. Moreover, nitric oxide (NO), produced after IBA/IAA-treatments, may affect JA signalling and interact positively/negatively with ET. To date, NO-involvement in ET/JA-mediated xylogenesis has never been investigated. To study this, and unravel JA-effects on xylary identity, xylogenesis was investigated in hypocotyls of seedlings treated with JA methyl-ester (JAMe) with/without ACC, IBA, IAA. Wild-type (wt) and ein3eil1 responses to hormonal treatments were compared, and the NO signal was quantified and its role evaluated by using NO-donors/scavengers. Ectopic-protoxylem increased in the wt only after treatment with JAMe(10 μM), whereas in ein3eil1 with any JAMe concentration. NO was detected in cells leading to either xylogenesis or adventitious rooting, and increased after treatment with JAMe(10 μM) combined or not with IBA(10 μM). Xylary identity changed when JAMe was applied with each auxin. Altogether, the results show that xylogenesis is induced by JA and NO positively regulates this process. In addition, NO also negatively interacts with ET-signalling and modulates auxin-induced xylary identity.


Model of the rotational Raman gain coefficients for N(2) in the atmosphere.
A model for stimulated Raman scattering in the atmosphere is described for the pure rotational transitions in N(2). This model accounts for the wavelength dependence of the N(2) polarizability anisotropy, altitude and seasonal temperature variations in the atmosphere, and the O(2). foreign-gas density broadening. This information is used to calculate the steady-state plane-wave Raman gain profile over the lower 100 km of the atmosphere. Over altitudes of 0-40 km, temperature variations produce 30% changes in the gain coefficients of 1 km(-1) cm(2) MW(-1) for the strongest lines at Stokes wavelengths of 350 nm.


The influence of model order reduction on the computed fractional flow reserve using parameterized coronary geometries.
Computational fluid dynamics (CFD) models combined with patient-specific imaging data are used to non-invasively predict functional significance of coronary lesions. This approach to predict the fractional flow reserve (FFR) is shown to have a high diagnostic accuracy when comparing against invasively measured FFR. However, one of the main drawbacks is the high computational effort needed for preprocessing and computations. Hence, uncertainty quantification may become unfeasible. Reduction of complexity is desirable, computationally inexpensive models with high diagnostic accuracy are preferred. We present a parametric comparison study for three types of CFD models (2D axisymmetric, Semi-3D and 3D) in which we study the impact of model reduction on three models on the predicted FFR. In total 200 coronary geometries were generated for seven geometrical characteristics e.g. stenosis severity, stenosis length and vessel curvature. The effect of time-averaged flow was investigated using unsteady, mean steady and a root mean square (RMS) steady flow. The 3D unsteady model was regarded as reference model. Results show that when using an unsteady or RMS flow, predicted FFR hardly varies between models contrary to using average flows. The 2D model with RMS flow has a high diagnostic accuracy (0.99), reduces computational time by a factor 162,000 and the introduced model error is well below the clinical relevant differences. Stenosis severity, length, curvature and tapering cause most discrepancies when using a lower order model. An uncertainty analysis showed that this can be explained by the low variability that is caused by variations in stenosis asymmetry.


Combined Use of Emodin and Ginsenoside Rb1 Exerts Synergistic Neuroprotection in Cerebral Ischemia/Reperfusion Rats.
Acute ischemic stroke (AIS) generally causes neurological dysfunction and poses a serious threat to public health. Here, we aimed to assess the independent and combined effects of ginsenoside Rb1 (GRb1) and Emodin on neuroprotection through regulating Connexin 43 (Cx43) and Aquaporin 4 (AQP4) expression in cerebral ischemia/reperfusion (I/R) model rats. Adult male Sprague-Dawley (SD) rats were randomly divided into five groups: sham group, I/R group, Emodin group, GRb1 group and Emodin+GRb1 group. They were further allocated to four subgroups according to the 6h, 1d, 3d, and 7d time points except the sham group. Based on the modified Longa suture method, the focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). The neurological deficit scores (NDS), blood brain barrier (BBB) permeability and cerebral infarction area were assessed at each corresponding time point. Cx43 and AQP4 levels were assessed by Real-time PCR and Immunofluorescence. Compared with I/R group, both the independent and combined use of GRb1 and Emodin could alleviate NDS, reduce the BBB permeability, reduce the infarction area and down-regulate Cx43 and AQP4 expression at 6h, 1d, 3d, and 7d after I/R (P < 0.05). The Emodin+GRb1 group had more significant effects than Emodin group and GRb1 group (P < 0.05). In conclusion, the combination of Emodin and GRb1 exerts synergistically neuroprotective functions through regulating AQP4 and Cx43 after I/R.


The impact of diagnostic testing on therapeutic interventions.
To gain insight into the usefulness of managing the earlier phase of decision making, we examined the relationship between selected diagnostic tests and the therapeutic interventions they might trigger. Medicare's National Claims History and Part B files were used to obtain summary information on 100% of all physician claims submitted from 1987 through 1993. We regressed the annual rates of selected therapeutic interventions on selected diagnostic tests, which had been previously paired based on the clinical expectation that the test might drive subsequent intervention. These data represent the physician services received by approximately 30 million elderly Americans in each of 7 years. Coefficient of determination (R2). The annual rate for the diagnostic tests increased rapidly during the period (range, 1.4- to 3.0-fold increase) and accounted for the bulk of the variance in therapeutic intervention rates (R2>0.80, P<.01) for five diagnostic-therapeutic pairs: cardiac catheterization with cardiac revascularization procedures, imaging of the spine with back surgery, swallowing studies with percutaneous gastrostomy, mammography with breast biopsy and excision, and prostate biopsy with prostatectomy. Although the rate of abdominal ultrasound increased during the period, it was not related with either cholecystectomy or abdominal aortic aneurysm repair. There has been a substantial increase in diagnostic testing in the United States that closely tracked the increase of clinically relevant downstream procedures. Managing diagnostic testing could be an important strategy for controlling the increase of therapeutic interventions.


Re-fixation and perseveration patterns in neglect patients during free visual exploration.
The literature suggests that neglect patients not only show impairments in directing attention toward the left, contralesional space, but also present with perseverative behavior. Moreover, previous studies described re-fixations during visual search tasks, and interpreted this finding as an impairment of spatial working memory. The aim of the present study was to study re-fixations and perseverations (i.e., recurrent re-fixations to same locations) during free visual exploration, a task with high ecological validity. We hypothesized that: (1) neglect patient would perform re-fixations more frequently than healthy controls within the right hemispace; and, (2) the re-fixation behavior of neglect patients would be characterized by perseverative fixations. To test these hypotheses, we assessed 22 neglect patients and 23 healthy controls, measuring their eye movements during free exploration of naturalistic pictures. The results showed that neglect patients tend to re-fixate locations within the ipsilesional hemispace when they freely explore naturalistic pictures. Importantly, the saliency of discrete locations within the pictures has a stronger influence on fixation behavior within the contralesional than within the ipsilesional hemispace in neglect patients. Finally, the results indicated that, for re-fixations, saliency plays a more important role within the contralesional than the ipsilesional hemispace. Moreover, we found evidence that re-fixation behavior of neglect patients is characterized by frequent recurrent re-fixations back to the same spatial locations which may be interpreted as perseverations. Hence, with the present study, we could better elucidate the mechanism leading to re-fixations and perseverative behavior during free visual exploration in neglect patients.


[Role of catecholamines and serotonin in regulating cyclic and tonic secretion of gonadotropic hormones].
In female rats with normal estrous cycle, in the proestrus phase, a significant decrease of the serotonine level was revealed in the anterior and medio-basal parts of the hypothalamus which coincided with ascent of the releasing factor for gonadotropic hormones in the hypothalamus and for gonadotropins in the hypophysis. The dophamine level in the hypothalamic anterior and medio-basal parts changed in different ways attaining during oestrus its maximal values in the anterior and medio-basal parts of the hypothalamus. No regular changes were revealed in noradrenaline content in the course of estrous cycle in any hypothalamic area. For purposes of studying the mechanisms of regulation of the gonadotropins tonic secretion, the same parameters were recorded in androgensterile and ovariectomized rats. Levels of serotonine and noradrenaline revealed no regular connection with changes in the gonadotropins production, while the anterior part of hypothalamis dophamine concentration in the was in reverse proportion to the extent of gonadotropic secretion. Serotonine seemed to participate in regulation of the cyclic but not the tonic secretion of gonadotropins, while dophamine seemed to exert an inhibitory effect on regulation of tonic secretion of gonadotropins.


Naturally occurring enzyme activity variation in Drosophila melanogaster. II. Relationships among enzymes.
This report describes an investigation of the specificities of the genetic effects, caused by whole chromosome substitution, on the activities of 23 enzymes in Drosophila melanogaster. Two types of correlation estimates are examined, the product-moment correlation over the chromosome substitution line means and the corresponding correlation of line effects, which is a standardized covariance component estimate. The two types of correlations give very similar results. Although there is ample evidence for specific line effects on individual enzyme activities, there are extensive intercorrelations among many of the enzymes for both second- and third-chromosome substitution lines. The pattern of correlations with respect to the metabolic functions or other properties of the enzymes is difficult to visualize by inspection of the correlation matrix, so a multivariate graphical technique, the biplot (GABRIEL 1971), was employed to obtain a two-dimensional view of relationships among the enzyme activities. The second and third chromosome lines show similar patterns. Four of the five mitochondrial enzymes form one highly intercorrelated group whereas another highly intercorrelated group contains several cytosolic enzymes. Within the cytosolic group, particularly high correlations are observed between enzymes that have glucose 6-phosphate as a substrate or product and between enzymes that are NADP-dependent. Although the pattern of intercorrelations is not clearly explicable in terms of metabolic relationships among the enzymes, there is some tendency for enzymes that catalyze sequential reactions or share a substrate or product to have correlated activity levels.


Genetic variation in myosin 1H contributes to mandibular prognathism.
Several candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2-q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set. Thirty-three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2°, a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05. An association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport. More strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism.


The KxGxYR and DxE motifs in the C-tail of the Middle East respiratory syndrome coronavirus membrane protein are crucial for infectious virus assembly.
The coronavirus' (CoV) membrane (M) protein is the driving force during assembly, but this process remains poorly characterized. Previously, we described two motifs in the C-tail of the Middle East respiratory syndrome CoV (MERS-CoV) M protein involved in its endoplasmic reticulum (ER) exit (211DxE213) and trans-Golgi network (TGN) retention (199KxGxYR204). Here, their function in virus assembly was investigated by two different virus-like particle (VLP) assays and by mutating both motifs in an infectious MERS-CoV cDNA clone. It was shown that the 199KxGxYR204 motif was essential for VLP and infectious virus assembly. Moreover, the mislocalization of the M protein induced by mutation of this motif prevented M-E interaction. Hampering the ER export of M by mutating its 211DxE213 motif still allowed the formation of nucleocapsid-empty VLPs, but prevented the formation of fully assembled VLPs and infectious particles. Taken together, these data show that the MERS-CoV assembly process highly depends on the correct intracellular trafficking of its M protein, and hence that not only specific protein-protein interacting motifs but also correct subcellular localization of the M protein in infected cells is essential for virus formation and should be taken into consideration when studying the assembly process.


Do anthropometrics, biomechanics, and laterality explain V1 side preference in skiers?
In cross-country (XC) skiing, the V1 and V2 alternate skate techniques are asymmetric, and skiers can choose either the right or left side for pole support. The overall purpose of this study was to investigate V1 side preference in elite XC skiers, notably by documenting V1 skate side preference, dominant and nondominant V1 peak speeds, left- to right-side differences (Δ L-R) in laboratory-based measurements, and relationships between side preference data. Sixteen male elite XC skiers completed one incremental speed test using V1 on their dominant side and another incremental speed test using V1 on their nondominant side while roller-skiing on a treadmill. During these tests, V1 peak speed, pole forces, and plantar forces were measured. A whole-body dual-energy x-ray absortiometry (DXA) scan measured anthropometric parameters and questionnaires established side preference for V2 alternate, overall laterality in XC skiing, handedness, footedness, and injury prevalence. Left-to-right V1 side preference was equally distributed among skiers. V1 peak speed was approximately 4.5% greater on the dominant versus nondominant sides. V1 peak Δ L-R were positively related to Δ L-R in V1-dominant peak pole forces only. Questionnaire data indicated that more skiers preferred V2 alternate right, with moderate correlations between preferred V1 and V2 alternate sides. The expression of a dominant side in V1 and V2 alternate increased as skiing speed increased from moderate to 15-km endurance-race to sprint-race speeds. However, no relationships were established between V1 or V2 side preference and handedness, footedness, or number of one-sided injuries. Δ L-R in measurements provide limited explanations for V1 side preferences in elite XC skiers. In fact, no systematic relations exist between V1 side preferences and anthropometric, biomechanical, or questionnaire data.


[Research in the pharmaceutical industry cannot be objective].
In the face of tight public budgets more and more studies are being funded by the pharmaceutical industry. At the same time responsibility for conducting company-funded trials is increasingly being shifted to contract research organisations. Pharmaceutical manufacturers sponsor trials that primarily pursue company interests. The dominance of company-funded research does not only have a bearing on the choice of study priorities, though. Company sponsorship also has an influence on the results of trials. Company-funded trials are four times more likely to find evidence in favour of the trial drug than studies funded by other sponsors. There are several contributory factors, from study design (design bias) to data manipulation. And non-publication (publication bias) can distort knowledge. As a result, it is largely impossible to reliably assess the benefit and harm of medical drugs on the basis of published trials. This will have repercussions for the reliability of meta-analyses, guidelines and patient information leaflets. One consequence may be treatment errors.


Comparative in-vitro activity of cefoperazone-tazobactam and cefoperazone-sulbactam combinations against ESBL pathogens in respiratory and urinary infections.
The emergence and subsequent widespread dissemination of bacterial resistance to a variety of beta-lactam antibiotics by the elaboration of ESBL (Extended Spectrum Beta Lactamase) poses a serious threat to the effective use of beta lactam antibiotics and cephalosporins. Cefoperazone combination with the beta lactamase inhibitor tazobactam would be a strong basis for rational therapeutics when dealing with ESBL producing pathogen mediated infections. The objective of the study was to investigate the in vitro efficacy of cefoperazone-tazobactam and cefoperazone-sulbactam against ESBL producing respiratory and urinary pathogens. 54 samples (34 samples of urine and 20 samples of sputum) were collected from 9 hospitals in Mumbai. The pathogens isolated from urine included E. coli (n = 27), K. pneumoniae (n = 6), and Serratia marcescens (n = 1). The pathogens isolated from sputum included Pseudomonas aeruginosa (n = 5), Streptococcus pneumoniae (n = 1) and Klebsiella pneumoniae (n = 14). The Kirby Bauer disc diffusion method was used to evaluate the susceptibility of the isolated pathogens to cefoperazone-tazobactam and cefoperazone-sulbactam. In sputum samples, all the isolates of Pseudomonas aeruginosa were susceptible to cefoperazone-tazobactam while one isolate was resistant to cefoperazone-sulbactam. Streptococcus pneumoniae and Klebsiella pneumoniae were sensitive to both the antibiotic formulations. In uropathogens, higher susceptibility rates to cefoperazone-tazobactam (96% vs. 89%) were observed for Escherichia coli. Similarly higher rates of susceptibility to cefoperazone-tazobactam were observed for Klebsiella as compared to cefoperazone-sulbactam (83% vs. 67%). Serratia marcescens was sensitive to cefoperazone-tazobactam but was intermediate resistant to cefoperazone-sulbactam. The isolates of Klebsiella pneumoniae that were resistant to cefoperazone-sulbactam were susceptible to cefoperazone-tazobactam. The results of the current in vitro study corroborate the efficacy of the beta lactamase inhibitor tazobactam in improving the spectrum of activity and efficacy of cefoperazone.


Factors Influencing Head and Neck Surgical Oncologists' Transition from Curative to Palliative Treatment Goals.
Objective The factors influencing head and neck surgical oncologists' goals of care and decisions to initiate conversations about transitioning to palliative-intent treatment for patients with limited curative treatment options are incompletely understood. Lack of guidance for physicians on this topic can lead to inconsistent utilization of palliative services, as well as confusing, upsetting experiences for patients and families. We review the literature investigating the clinical factors, inter- and intrapersonal factors, and financial and health care system considerations that head and neck cancer physicians weigh during this decision-making process. Data Sources PubMed. Review Methods Selected literature on head and neck surgical oncologists' decision making in end-of-life care and palliative therapy was reviewed and analyzed thematically. Conclusions Physicians taking into account patients' clinical trajectories often overestimate the negative impact of head and neck cancer symptoms on their quality of life, suggesting that patients' expectations of quality of life should be discussed early, before communication barriers arise. How head and neck clinicians perceive and are influenced by patients' desired degree of autonomy, which varies greatly depending on the severity of illness, is still unclear. Patients' financial and insurance status affects decision making about hospice care. Finally, physician demographics (eg, age, subspecialization, practice setting), emotions, and philosophical background may exert unconscious biases that have not been fully determined for head and neck surgical oncologists. Implications for Practice A more comprehensive understanding of the head and neck surgical oncologist's approach toward considering a transition to therapy with palliative intent may help guide advancements in this complex counseling process, leading to improvements in patient care, quality of life, and outcomes.


Rates of problematic gambling in a British homeless sample: a preliminary study.
Homelessness and problem gambling are two public health concerns in the UK that are rarely considered concurrently, and little is known about the extent of gambling involvement and problematic gambling in the homeless. We recruited 456 individuals attending homelessness services in London, U.K. All participants completed a screen for gambling involvement, and where gambling involvement was endorsed, the Problem Gambling Severity Index (PGSI) was administered. The PGSI risk categories were compared against data from the 2010 British Gambling Prevalence Survey (BGPS). PGSI problem gambling was indicated in 11.6% of the homeless population, compared to 0.7% in the BGPS. Of participants endorsing any PGSI symptoms, a higher proportion of homeless participants were problem gamblers relative to the low and moderate risk groups, compared to the BGPS data. These results confirm that the homeless constitute a vulnerable population for problem gambling, and that diagnostic tools for gambling involvement should be integrated into homelessness services in the U.K.


Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse.
Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.


Nucleic acid amplification technology for the diagnosis of genital herpes infection.
Nucleic acid amplification technologies are well-characterized methods for the rapid and sensitive diagnosis of a wide variety of infectious diseases. Herpes simplex virus amplification is no exception, demonstrating as much as a ninefold enhancement in sensitivity over viral culture in some settings. Currently, there are no US Food and Drug Administration-approved systems for herpes simplex virus amplification; hence, most laboratories utilize in-house-developed PCR-based systems. Unfortunately, the utilization of herpes simplex virus amplification has been confined to the investigations of suspected herpes simplex virus encephalitis, largely due to cost and the need for appropriately trained technical staff. Recent methodological advances will help to render herpes simplex virus nucleic acid amplification technologies more applicable to routine practice. However, the use of nucleic acid amplification technologies for the diagnosis of genital herpes infection remains highly controversial.


Common dependence on stress for the two fundamental laws of statistical seismology.
Two of the long-standing relationships of statistical seismology are power laws: the Gutenberg-Richter relation describing the earthquake frequency-magnitude distribution, and the Omori-Utsu law characterizing the temporal decay of aftershock rate following a main shock. Recently, the effect of stress on the slope (the b value) of the earthquake frequency-magnitude distribution was determined by investigations of the faulting-style dependence of the b value. In a similar manner, we study here aftershock sequences according to the faulting style of their main shocks. We show that the time delay before the onset of the power-law aftershock decay rate (the c value) is on average shorter for thrust main shocks than for normal fault earthquakes, taking intermediate values for strike-slip events. These similar dependences on the faulting style indicate that both of the fundamental power laws are governed by the state of stress. Focal mechanisms are known for only 2 per cent of aftershocks. Therefore, c and b values are independent estimates and can be used as new tools to infer the stress field, which remains difficult to measure directly.


[13 years old scenarios for this year].
This article examines two scenarios, published in 1987, for the future development of Norwegian health care towards the year 2000. The scenarios emphasize different external forces and priorities. The 1987 scenarios are then assessed in the light of actual developments during the period. Scenario I describes a picture characterised by reduced economic growth 1987-2000 compared to previous decades, resulting in a year 2000 health care system with limited resources and hard priorities, focus on cost containment, increased efficiency, and search for alternative solutions. In Scenario II, the year 2000 health care system had more resources; however, the demand for services was as high or higher than in the 1980s. Instead of improvements in efficiency, alternative modes of financing health care and social security had evolved. Increasing knowledge among consumers, dissatisfaction and new technology had driven up costs, and health care professions tried to take advantage of the situation. This scenario is characterized by people wanting more, and getting more.


Transmission of the haplosporidian parasite MSX Haplosporidium nelsoni to the eastern oyster Crassostrea virginica in an upweller system.
The haplosporidian oyster parasite MSX (Multinucleated Sphere X) Haplosporidium nelsoni was transmitted to eastern oysters Crassostrea virginica. Hatchery-raised, MSX-free juvenile oysters were placed in upweller tanks. Water to the tanks was filtered through a screen with 1 mm2 openings and originated from the water column overlaying naturally infected oysters beds (MSX prevalence 17 to 57%). MSX was diagnosed by histopathological analysis. MSX-disease (57% prevalence) with increased mortality (19%) was observed 11 wk after the beginning of the exposure and mortality of 80% after 16 wk. The study demonstrates transmission of MSX via water-borne infectious agents capable of passing through a 1 mm filter.


AtNUDX6, an ADP-ribose/NADH pyrophosphohydrolase in Arabidopsis, positively regulates NPR1-dependent salicylic acid signaling.
Here, we investigated the physiological role of Arabidopsis (Arabidopsis thaliana) AtNUDX6, the gene encoding ADP-ribose (Rib)/NADH pyrophosphohydrolase, using its overexpressor (Pro35S:AtNUDX6) or disruptant (KO-nudx6). The level of NADH in Pro35S:AtNUDX6 and KO-nudx6 plants was decreased and increased, respectively, compared with that of the control plants, while the level of ADP-Rib was not changed in either plant. The activity of pyrophosphohydrolase toward NADH was enhanced and reduced in the Pro35S:AtNUDX6 and KO-nudx6 plants, respectively. The decrease in the activity of NADH pyrophosphohydrolase and the increase in the level of NADH were observed in the rosette and cauline leaves, but not in the roots, of the KO-nudx6 plants. Notably, the expression level of AtNUDX6 and the activity of NADH pyrophosphohydrolase in the control plants, but not in the KO-nudx6 plants, were increased by the treatment with salicylic acid (SA). The expression of SA-induced genes (PR1, WRKY70, NIMIN1, and NIMIN2) depending on NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1), a key component required for pathogen resistance, was significantly suppressed and enhanced in the KO-nudx6 and Pro35S:AtNUDX6 plants, respectively, under the treatment with SA. Induction of thioredoxin h5 (TRX-h5) expression, which catalyzes a SA-induced NPR1 activation, was suppressed and accelerated in the KO-nudx6 and Pro35S:AtNUDX6 plants, respectively. The expression of isochorismate synthase1, required for the regulation of SA synthesis through the NPR1-mediated feedback loop, was decreased and increased in the KO-nudx6 and Pro35S:AtNUDX6 plants, respectively. Judging from seed germination rates, the KO-nudx6 plants had enhanced sensitivity to the toxicity of high-level SA. These results indicated that AtNUDX6 is a modulator of NADH rather than ADP-Rib metabolism and that, through induction of TRX-h5 expression, AtNUDX6 significantly impacts the plant immune response as a positive regulator of NPR1-dependent SA signaling pathways.


Imaging markers for Alzheimer disease: which vs how.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.


[Can serum protein S100beta predict neurological deterioration after moderate or minor traumatic brain injury?].
Patients with moderate traumatic brain injury (TBI) (Glasgow Coma Scale, GCS, 9-13) or minor TBI (GCS 14-15) are at risk for subsequent neurological deterioration. Serum protein S-100 is believed to reflect brain damage following TBI. In patients with normal or minor CT scan abnormalities on admission, we tested whether the determination of serum protein S-100 beta could predict secondary neurological deterioration. Sixty-seven patients with moderate or minor TBI were prospectively studied. Serum samples were collected on admission within 12 hours postinjury to measure serum protein S-100 levels. Neurological outcome was assessed up to seven days after trauma. Secondary neurological deterioration was defined as two points or more decrease from the initial GCS, or any treatment for neurological deterioration. Nine patients had a secondary neurological deterioration after trauma. No differences in serum levels of protein S-100 were found between these patients and those without neurological aggravation (n=58 patients): 0.93 microg/l (0.14-4.85) vs 0.39 microg/l (0.04-6.40), respectively. The proportion of patients with abnormal levels of serum protein S-100 at admission according to two admitted cut-off levels (>0.1 and >0.5 microg/l) was comparable between the two groups of patients. Elevated serum levels of protein S-100 were found in patients with Injury Severity Score (ISS) of more than 16 (n=23 patients): 1.26 microg/l (0.14-6.40) vs 0.22 microg/l (0.04-6.20) in patients with ISS less than 16 (n=44 patients). The dosage of serum protein S-100 on admission failed to predict patients at risk for neurological deterioration after minor or moderate TBI. Extracranial injuries can increase serum protein S-100 levels, then limiting the usefulness of this dosage in this clinical setting.


Complementary and Alternative Medicine Approaches for Pediatric Pain: A Review of the State-of-the-science.
In recent years, the use of complementary and alternative medicine (CAM) in pediatric populations has increased considerably, especially for chronic conditions such as cancer, rheumatoid arthritis and cystic fibrosis in which pain may be a significant problem. Despite the growing popularity of CAM approaches for pediatric pain, questions regarding the efficacy of these interventions remain. This review critically evaluates the existing empirical evidence for the efficacy of CAM interventions for pain symptoms in children. CAM modalities that possess a published literature, including controlled trials and/or multiple baseline studies, that focused on either chronic or acute, procedural pain were included in this review. The efficacy of the CAM interventions was evaluated according to the framework developed by the American Psychological Association (APA) Division 12 Task Force on Promotion and Dissemination of Psychological Procedures. According to these criteria, only one CAM approach reviewed herein (self-hypnosis/guided imagery/relaxation for recurrent pediatric headache) qualified as an empirically supported therapy (EST), although many may be considered possibly efficacious or promising treatments for pediatric pain. Several methodological limitations of the existing literature on CAM interventions for pain problems in children are highlighted and future avenues for research are outlined.


Hyaluronidase activity of human Hyal1 requires active site acidic and tyrosine residues.
Hyaluronidases are a family of endolytic glycoside hydrolases that cleave the beta1-4 linkage between N-acetylglucosamine and glucuronic acid in hyaluronan polymers via a substrate-assisted mechanism. In humans, turnover of hyaluronan by this enzyme family is critical for normal extracellular matrix remodeling. However, elevated expression of the Hyal1 isozyme accelerates tumor growth and metastatic progression. In this study, we used structural information, site-directed mutagenesis, and steady state enzyme kinetics to probe molecular determinants of human Hyal1 function. Mutagenesis of active site residues Glu(131) and Tyr(247) to Gln and Phe, respectively, eliminated activity at all hyaluronan concentrations (to 125 microm or 2.5 mg/ml). Conservative mutagenesis of Asp(129) and Tyr(202) significantly impaired catalysis by increases of 5- and 10-fold in apparent K(m) and reductions in V(max) of 95 and 50%, respectively. Tyr(247) and Asp(129) are required for stabilization of the catalytic nucleophile, which arises as a resonance intermediate of N-acetylglucosamine on the substrate. Glu(131) is a likely proton donor for the hydroxyl leaving group. Tyr(202) is a substrate binding determinant. General disulfide reduction had no effect on activity in solution, but enzymatic deglycosylation reduced Hyal1 activity in a time-dependent fashion. Mutagenesis identified Asn(350) glycosylation as the requisite modification. Deletion of the C-terminal epidermal growth factor-like domain, in which Asn(350) is located, also eliminated activity, irrespective of glycosylation. Collectively, these studies define key components of Hyal1 active site catalysis, and structural factors critical for stability. Such detailed understanding will allow rational design of enzyme modulators.


Molecular approaches toward a therapy for multiple sclerosis.
Treatment of experimental allergic encephalomyelitis with monoclonal antibodies to products of immune response genes and to surface markers on T cells was reviewed. Both anti Ia therapy and anti T4 therapy can reverse ongoing paralysis, and block subsequent relapses. The appearance of T4 cells and Ia antigens in relapse was demonstrated. The prospects for human therapy with chimeric human-mouse immunoglobulins and isotypic variants was discussed, with particular attention to the immunotherapy of multiple sclerosis.


Irradiation compared with chlorination for elimination of Escherichia coli O157:H7 internalized in lettuce leaves: influence of lettuce variety.
Pathogenic bacteria internalized in leaf tissues are not effectively removed by surface treatments. Irradiation has been shown to inactivate leaf-internalized bacteria, but many aspects of targeting these protected pathogens remain unknown. Bacterial cells of a cocktail mixture of 3 isolates of Escherichia coli O157:H7 were drawn into the leaves of iceberg, Boston, green leaf, and red leaf lettuce using vacuum perfusion. The inoculated leaves were treated with a 3-min wash with sodium hypochlorite solution (0, 300, or 600 ppm) or various doses of ionizing radiation (0.25 to 1.5 kGy). Leaves were stomached to recover the internalized cells and survivors enumerated. Washes with 0 ppm (water), 300 ppm, and 600 ppm chlorine solutions each gave reductions of less than 1 log. These reductions were statistically significant only in the case of green leaf lettuce. In contrast, irradiation effectively reduced E. coli O157:H7 on all varieties examined, with all doses tested being significantly reduced from the untreated control. The specific variety influenced the efficacy of irradiation. The greatest reduction obtained was 5 logs on iceberg lettuce treated with 1.5 kGy. The D(10) values (the dose necessary to achieve a 1 log reduction) were significantly (P < 0.05) different among the varieties of lettuce tested, and ranged from 0.30 kGy (iceberg) to 0.45 kGy (Boston). These values were observed to be notably higher than previous irradiation D(10) values for E. coli O157:H7 surface inoculated onto these 4 lettuce varieties. This study has shown that irradiation is able to effectively reduce viable E. coli O157:H7 cells internalized in lettuce, and that the variety of lettuce influences the specific response.


Evaluation of Functional Connectivity in the Brain Using Positron Emission Tomography: A Mini-Review.
Resting-state networks (RSNs) exhibit spontaneous functional connectivity in the resting state. Previous studies have evaluated RSNs mainly based on spontaneous fluctuations in blood oxygenation level-dependent (BOLD) signals during functional magnetic resonance imaging (fMRI). However, separation between regional increases in cerebral blood flow (CBF) and oxygen consumption is theoretically difficult using BOLD-fMRI. Such separation can be achieved using quantitative 15O-gas and water positron emission tomography (PET). In addition, 18F-FDG PET can be used to investigate functional connectivity based on changes in glucose metabolism, which reflects local brain activity. Previous studies have highlighted the feasibility and clinical usefulness of 18F-FDG-PET for the analysis of RSNs, and recent studies have utilized simultaneous PET/fMRI for such analyses. While PET provides seed information regarding the focus of the abnormalities (e.g., hypometabolism and reduced target binding), fMRI is used for the analysis of functional connectivity. Thus, as PET and fMRI provide different types of information, integrating these modalities may aid in elucidating the pathological mechanisms underlying certain diseases, and in characterizing individual patients.


Possible species differences between Sarcocystis from mule deer and cattle.
In preliminary studies with Sarcocystis from bovine (Bos taurus) and mule deer (Odocoileus hemionus hemionus), a coccidia-free laboratory dog (Canis familiaris) and captive coyote (Canis latrans) were fed flesh from a local Sarcocystis-infected bovine and later flesh from an infected mule deer from Eastern Oregon. Sporocysts were passed in the feces of both canine hosts 10-15 days after ingestion of infected meat. There was a statistical difference in the size of sporocysts derived from bovine and deer. It was concluded that the Sarcocystis from bovine and mule deer probably constitute distinct species with a life cycle dependent on the respective ruminant host and a canine host.


Structure, function, and dynamics of the dimerization and DNA-binding domain of oncogenic transcription factor v-Myc.
The protein product (c-Myc) of the protooncogene c-myc is a transcriptional regulator playing a key role in cellular growth, differentiation, and apoptosis. Deregulated myc genes, like the transduced retroviral v-myc allele, are oncogenic and cause cell transformation. The C-terminal bHLHZip domain of v-Myc, encompassing protein dimerization (helix-loop-helix, leucine zipper) and DNA contact (basic region) surfaces, was expressed in bacteria as a highly soluble p15(v-myc )recombinant protein. Dissociation constants (K(d)) for the heterodimer formed with the recombinant bHLHZip domain of the Myc binding partner Max (p14(max)) and for the Myc-Max-DNA complex were estimated using circular dichroism (CD) spectroscopy and quantitative electrophoretic mobility shift assay (EMSA). Multi-dimensional NMR spectroscopy was used to characterize the solution structural and dynamic properties of the v-Myc bHLHZip domain. Significant secondary chemical shifts indicate the presence of two separated alpha-helical regions. The C-terminal leucine zipper region forms a compact alpha-helix, while the N-terminal basic region exhibits conformational averaging with substantial alpha-helical content. Both helices lack stabilizing tertiary side-chain interactions and represent exceptional examples for loosely coupled secondary structural segments in a native protein. These results and CD thermal denaturation data indicate a monomeric state of the v-Myc bHLHZip domain. The (15)N relaxation data revealed backbone mobilities which corroborate the existence of a partially folded state, and suggest a "beads-on-a-string" motional behaviour of the v-Myc bHLHZip domain in solution. The preformation of alpha-helical regions was confirmed by CD thermal denaturation studies, and quantification of the entropy changes caused by the hydrophobic effect and the reduction of conformational entropy upon protein dimerization. The restricted conformational space of the v-Myc bHLHZip domain reduces the entropy penalty associated with heterodimerization and allows rapid and accurate recognition by the authentic Myc binding partner Max.


Disseminated intravascular coagulation in rabbits: synergistic activity of meningococcal endotoxin and materials egested from leucocytes containing meningococci.
Leucocyte-egested material was harvested after the quantitative in-vitro phagocytosis of Neisseria meningitidis by rabbit or mouse polymorphonuclear leucocytes. The egested material was injected subcutaneously into rabbits and followed 24 h later with an intravenous injection of what would by itself have been a non-lethal quantity of meningococcal endotoxin, or with an equivalent dose of endotoxin in the form of meningococcal cell-wall blebs. Of 32 rabbits treated in this manner, 12 developed disseminated intravascular coagulation and six of these 12 had renal cortical necrosis. The remainder exhibited less severe lesions resembling those of endotoxaemia. Rabbits were not sensitised to meningococcal endotoxin when materials egested from leucocytes containing Staphylococcus epidermidis were used. A description of the pathological findings in the rabbits is presented.


[Morphological studies in the late period after autotransplantation of the left lung and removal of the right (intact) lung].
Morphological examinations were carried out in 3 animals, in which during the late period after left-side pulmonary autotransplantation the right lung was removed. The results during long-term survival of these animals showed the cardinal importance for success lying in anatomical sufficiency of vascular and bronchial anastomoses, fair compensatory capacity of external breathing, absence of severe structural changes in the autografted lung, ventilation of physiologic atelectases, and development of compensatory hypertrophy after resection of the intact lung. Examinations of nerval structures of the main bronchus of the autografted lung showed recovery of nerve fibers. The pulmonary autograft guaranteed normal function of organism after resection of the intact lung. This confirms the functional and structural restitution of the organism.


The effects of neutrophil to lymphocyte and platelet to lymphocyte ratios on prognosis in patients undergoing mechanical thrombectomy for acute ischemic stroke.
The aim of the study was to investigate the effect of neutrophil lymphocyte (NLR) and platelet lymphocyte ratio (PLR) on prognosis in acute ischemic stroke (AIS) patients undergoing mechanical thrombectomy. A retrospective study was made of the data of 56 patients aged 20-80 years who were diagnosed with AIS and underwent mechanical thrombectomy. Thrombolysis in Brain Ischemia (TIBI) status was evaluated with transcranial Doppler after treatment. The National Institutes of Health Stroke Scale (NIHHS) and modified Rankin scale (mRS) were used to indicate neurological and functional deficits. No difference was determined in the NLR and PLR between patients with or without middle cerebral artery (MCA) occlusion, T and basilar occlusion. These ratios were also no different between the groups with different degrees of recanalization. Platelet lymphocyte ratio was lower in patients with a dramatic improvement at the 24th hour (p=0.046). Neutrophil lymphocyte ratio was higher in patients with symptomatic hemorrhage (p=0.046). Although no relationship with outcome has yet been shown, the association with hemorrhagic change and the recovery parameters at the 24th hour may enable NLR and PLR to be used as significant prognostic factors in patients with acute ischemic stroke undergoing mechanical thrombectomy. Further studies are needed. Ischemia, Mechanical thrombectomy, Neutrophil lymphocyte ratio, Platelet lymphocyte ratio, Stroke.


Combining voxel intensity and cluster extent with permutation test framework.
In a massively univariate analysis of brain image data, statistical inference is typically based on intensity or spatial extent of signals. Voxel intensity-based tests provide great sensitivity for high intensity signals, whereas cluster extent-based tests are sensitive to spatially extended signals. To benefit from the strength of both, the intensity and extent information needs to be combined. Various ways of combining voxel intensity and cluster extent are possible, and a few such combining methods have been proposed. Poline et al.'s [NeuroImage 16 (1997) 83] minimum P value approach is sensitive to signals whose either intensity or extent is significant. Bullmore et al.'s [IEEE Trans. Med. Imag. 18 (1999) 32] cluster mass method can detect signals whose intensity and extent are sufficiently large, even when they are not significant by intensity or extent alone. In this work, we study such combined inference methods using combining functions (Pesarin, F., 2001. Multivariate Permutation Tests. Wiley, New York) and permutation framework [Holmes et al., J. Cereb. Blood Flow Metab. 16 (1996) 7], which allow us to examine different ways of combining voxel intensity and cluster extent information without knowing their distribution. We also attempt to calibrate combined inference by using weighted combining functions, which adjust the test according to signals of interest. Furthermore, we propose meta-combining, a combining function of combining functions, which integrates strengths of multiple combining functions into a single statistic. We found that combined tests are able to detect signals that are not detected by voxel or cluster size test alone. We also found that the weighted combining functions can calibrate the combined test according to the signals of interest, emphasizing either intensity or extent as appropriate. Though not necessarily more sensitive than individual combining functions, the meta-combining function is sensitive to all types of signals and thus can be used as a single test summarizing all the combining functions.