Intrinsic material property differences in bone tissue from patients suffering low-trauma osteoporotic fractures, compared to matched non-fracturing women.
Osteoporotic (low-trauma) fractures are a significant public health problem. Over 50% of women over 50yrs. of age will suffer an osteoporotic fracture in their remaining lifetimes. While current therapies reduce skeletal fracture risk by maintaining or increasing bone density, additional information is needed that includes the intrinsic material strength properties of bone tissue to help develop better treatments, since measurements of bone density account for no more than ~50% of fracture risk. The hypothesis tested here is that postmenopausal women who have sustained osteoporotic fractures have reduced bone quality, as indicated with measures of intrinsic material properties compared to those who have not fractured. Transiliac biopsies (N=120) were collected from fracturing (N=60, Cases) and non-fracturing postmenopausal women (N=60, age- and BMD-matched Controls) to measure intrinsic material properties using the nano-indentation technique. Each biopsy specimen was embedded in epoxy resin and then ground, polished and used for the nano-indentation testing. After calibration, multiple indentations were made using quasi-static (hardness, modulus) and dynamic (storage and loss moduli) testing protocols. Multiple indentations allowed the median and variance to be computed for each type of measurement for each specimen. Cases were found to have significantly lower median values for cortical hardness and indentation modulus. In addition, cases showed significantly less within-specimen variability in cortical modulus, cortical hardness, cortical storage modulus and trabecular hardness, and more within-specimen variability in trabecular loss modulus. Multivariate modeling indicated the presence of significant independent mechanical effects of cortical loss modulus, along with variability of cortical storage modulus, cortical loss modulus, and trabecular hardness. These results suggest mechanical heterogeneity of bone tissue may contribute to fracture resistance. Although the magnitudes of differences in the intrinsic properties were not overwhelming, this is the first comprehensive study to investigate, and compare the intrinsic properties of bone tissue in fracturing and non-fracturing postmenopausal women.


Population movements and problems of malaria eradication in Africa.
Population movements of various kinds are among the outstanding demographic features of the African continent and entail serious difficulties for malaria eradication. The majority of these movements are free and uncontrolled and are frequently inter-territorial in nature, hampering nation-wide or more limited malaria eradication projects and resulting in much reinfection.The author examines in some detail the types of population movements and their relationship to malaria problems in the Republic of Sudan, Ethiopia, Somalia, East Africa, Zanzibar, the Federation of Rhodesia and Nyasaland, Nigeria and Ghana. He concludes that these movements cannot be stopped and must be taken into account in planning malaria eradication programmes. More information on them and on the complex relationships between parasites, vectors and human beings is required, and inter-territorial co-operation is essential in obtaining this information and in planning.


Laparoscopic live donor nephrectomy: the University of Maryland 3-year experience.
We determined whether laparoscopic living donor nephrectomy decreases the morbidity of renal donation for the donor, while providing a renal allograft of a quality comparable to that of open donor nephrectomy. In a 3-year period laparoscopic donor nephrectomy was performed via the transperitoneal approach. We evaluated donor and recipient medical records for preoperative donor characteristics, intraoperative parameters and complications, and postoperative recovery and complications. Of the 320 laparoscopic donor nephrectomies performed the left kidney was removed in 97.5%. Intraoperative complications, which developed in 10.4% of cases, tended to occur early in the experience and required conversion to open nephrectomy in 5. Average operative time was 31/2 hours and warm ischemia time was 21/2 minutes. As the series progressed, blood loss as well as laparoscopic port size and number decreased but extraction site size remained constant at 7 cm. Urinary retention, prolonged ileus, thigh numbness and incisional hernia were the most common postoperative complications. Postoperative analgesic requirements were low and average hospitalization was 66 hours. Laparoscopic donor nephrectomy appears to be safe and decreases morbidity in the renal donor. Allograft function is comparable to that in open nephrectomy series. The availability of laparoscopic harvesting may be increasing the living donor volunteer pool.


Bring Out Your (Sort-of, Mostly, All) Dead: Should Those Dead by Neurological Criteria Be Research Subjects?
In the fall of 2021 a news story reported of a successful experimental xenotransplant of a genetically engineered pig kidney in to the circulatory system of a research subject who was dead by neurological criteria. Although not a first of its kind, this case raises the issue of the ethics of research on those declared brain dead. Such possibilities have been discussed in the published literature since 1974, when Willard Gaylin expressed concern over human dignity when he imagined hospital wards filled with "neomorts" used for education, teaching, research, and manufacturing. In this essay, the author explores the nuances of whether such subjects are considered alive, dead, or something in between. Notions of consent/permission and risk/benefit are determined by this categorization. After discussing the 2005 Consensus Panel Guidelines on Research with the Recently Dead, the essay concludes with the need for a liminal state between living and dead that respects human dignity but also recognizes the utilitarian value of such experiments to protect fully alive humans. Having not just guidelines but oversight structures such as the University of Pittsburgh's Committee for Oversight of Research Involving the Dead (CORID) and regulations are necessary if such work is to become more common.


Intrinsic brain connectivity predicts impulse control disorders in patients with Parkinson's disease.
Impulse control disorders can be triggered by dopamine replacement therapies in patients with PD. Using resting-state functional MRI, we investigated the intrinsic brain network connectivity at baseline in a cohort of drug-naive PD patients who successively developed impulse control disorders over a 36-month follow-up period compared with patients who did not. Baseline 3-Tesla MRI images of 30 drug-naive PD patients and 20 matched healthy controls were analyzed. The impulse control disorders' presence and severity at follow-up were assessed by the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale. Single-subject and group-level independent component analysis was used to investigate functional connectivity differences within the major resting-state networks. We also compared internetwork connectivity between patients. Finally, a multivariate Cox regression model was used to investigate baseline predictors of impulse control disorder development. At baseline, decreased connectivity in the default-mode and right central executive networks and increased connectivity in the salience network were detected in PD patients with impulse control disorders at follow-up compared with those without. Increased default-mode/central executive internetwork connectivity was significantly associated with impulse control disorders development (P < 0.05). Our findings demonstrated that abnormal brain connectivity in the three large-scale networks characterizes drug-naive PD patients who will eventually develop impulse control disorders while on dopaminergic treatment. We hypothesize that these divergent cognitive and limbic network connectivity changes could represent a potential biomarker and an additional risk factor for the emergence of impulse control disorders. © 2017 International Parkinson and Movement Disorder Society.


Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure.
Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. We found that in melanocytes, CPDs are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These "dark CPDs" constitute the majority of CPDs and include the cytosine-containing CPDs that initiate UV-signature C→T mutations. Dark CPDs arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but induces CPDs by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically generated excited electronic states are relevant to mammalian biology.


Doppler optical coherence tomography monitoring of microvascular tissue response during photodynamic therapy in an animal model of Barrett's esophagus.
Doppler optical coherence tomography (DOCT) is an imaging modality that allows assessment of the microvascular response during photodynamic therapy (PDT) and may be a powerful tool for treatment monitoring/optimization in conditions such as Barrett's esophagus (BE). To assess the technical feasibility of catheter-based intraluminal DOCT for monitoring the microvascular response during endoluminal PDT in an animal model of BE. Thirteen female Sprague-Dawley rats underwent esophagojejunostomy to induce enteroesophageal reflux for 35 to 42 weeks and the formation of Barrett's mucosa. Of these, 9 received PDT by using the photosensitizer Photofrin (12.5 mg/kg intravenous), followed by 635-nm intraluminal light irradiation 24 hours after drug administration. The remaining 4 surgical rats underwent light irradiation without Photofrin (controls). Another group of 5 normal rats, without esophagojejunostomy, also received PDT. DOCT imaging of the esophagus by using a catheter-based probe (1.3-mm diameter) was performed before, during, and after light irradiation in all rats. Distinct microstructural differences between normal squamous esophagus, BE, and the transition zone between the 2 tissues were observed on DOCT images. Similar submucosal microcirculatory effects (47%-73% vascular shutdown) were observed during PDT of normal esophagus and surgically induced BE. Controls displayed no significant microvascular changes. No apparent difference was observed in the PDT-induced vascular response between normal rat esophagus and the BE rat model. Real-time monitoring of PDT-induced vascular changes by DOCT may be beneficial in optimizing PDT dosimetry in patients undergoing this therapy for BE and other conditions.


Synthesis of novel folic acid-functionalized biocompatible block copolymers by atom transfer radical polymerization for gene delivery and encapsulation of hydrophobic drugs.
Two synthetic routes to folic acid (FA)-functionalized diblock copolymers based on 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] and either 2-(dimethylamino)ethyl methacrylate [DMA] or 2-(diisopropylamino)ethyl methacrylate [DPA] were explored. The most successful route involved atom transfer radical polymerization (ATRP) of MPC followed by the tertiary amine methacrylate using a 9-fluorenylmethyl chloroformate (Fmoc)-protected ATRP initiator. Deprotection of the Fmoc groups produced terminal primary amine groups, which were conjugated with FA to produce two series of novel FA-functionalized biocompatible block copolymers. Nonfunctionalized MPC-DMA diblock copolymers have been previously shown to be effective synthetic vectors for DNA condensation; thus, these FA-functionalized MPC-DMA diblock copolymers appear to be well suited to gene therapy applications based on cell targeting strategies. In contrast, the FA-MPC-DPA copolymers are currently being evaluated as pH-responsive micellar vehicles for the delivery of highly hydrophobic anticancer drugs.


Comparison of Levofloxacin-Based, 10-day Sequential Therapy with 14-day Quadruple Therapy for Helicobacter Pylori Eradication: A Randomized Clinical Trial.
BACKGROUND Considering the importance of Helicobacter pylori (H. pylori) eradication, this clinical trial was designed to prospectively evaluate the efficacy of levofloxacin-based, sequential therapy in comparison with quadruple therapy for eradicating H. pylori. METHODS Overall 156 patients with dyspepsia and H. pylori infection were included in this study and were randomly allocated to either 10-day sequential therapy group (group A) to receive pantoprazole (40 mg twice daily), amoxicillin (1 gr twice daily), levofloxacin (500 mg twice daily), and tinidazole (500 mg twice daily) (PALT) or 14-day quadruple therapy group (group B) to receive pantoprazole, clarithromycin, bismuth subcitrate, and amoxicillin (PABC). At the end of the study the eradication rate in each group was assessed by urea breath test (UBT). RESULTS Age range of the participants was 18-65 years (average 36.9 years) and 50% of them (78 patients) were men. 78 patients were allocated to group A and 78 patients to groupe B. After antibiotic therapy, all the patients received acid suppression therapy with Proton Pump Inhibitor (PPI) for 4 weeks and then the eradication rate was confirmed by UBT (Heli FAN plus 13C, Germany). Before performing UBT, all the participants were requested to halt consumption of PPI for at least 1 week. During the treatment there was not any major complication but in group A (sequential therapy), two patients complained of minor complications including musculoskeletal pain. None of the patients in group B had any complaint or side effect. The rate of H. pylori eradication in group A was 78.2% (61 patients) while this rate in group B was 83.3% (65 patients) with no significant difference between the two groups (p = 0.42). In subgroup analysis, the rate of eradication among men in group A and B were 76.9% and 89.7%, respectively (p = 0.22) while the eradication rate among women were 79.4% and 76.9%, respectively (p = 1.00). CONCLUSION It seems that levofloxacin base sequential therapy does not have any advantage in comparison with quadruple regimen and until finding any more effective short course therapy for H. Pylori eradication; we encourage quadruple regimen to be used as the first line therapy.


Salivary concentration of progesterone and cortisol significantly differs across individuals after correcting for blood hormone values.
Between-individual variation of salivary progesterone (P4) and cortisol levels does not always closely reflect blood hormone concentrations. This may be partly a function of individual differences in salivary hormone excretion. We tested whether time of day at sampling and ethnicity contributed to individual variation in salivary hormones after adjusting for blood hormone levels. Forty-three Caucasian and 15 Japanese women (18-34 years) collected four sets of matched dried blood spot (DBS) and saliva specimens across a menstrual cycle (N = 232 specimen sets). Linear fixed-effects (LFE) models were used to estimate the effects of diurnal variation and ethnicity on salivary P4 and cortisol while adjusting for DBS levels. For each hormone, women with exclusively positive or negative residuals (unexplained variance) from the LFE models were categorized as high- or low-saliva-to-DBS hormone ratio (SDR; high or low salivary secretors), respectively. We found that salivary P4 (P < 0.05) was significantly higher in early morning compared to the afternoon, after controlling for DBS levels, ethnicity, and BMI. After further adjusting for this diurnal effect, significant individual variation in salivary P4 and cortisol remained: sixteen and nine women, respectively were categorized as low or high salivary secretors for both hormones (P < 0.001), suggesting systematic individual-specific variation of salivary hormonal concentration. We conclude that when saliva is used to quantify P4 or cortisol levels, time of day at sampling should be controlled. Even with this adjustment, salivary P4 and cortisol do not closely mirror between- individual variation of serum P4 and cortisol in a substantial proportion of individuals.


Gynecologic ultrasound in emergency medicine.
The true value of ultrasound in acute abdominal pain lies in its ability to detect gynecologic disorders and effectively rule out other causes of acute abdominal pain that require surgical repair. Although the emergent gynecologic indications discussed in this article are few in number, this does not suggest that the nonpregnant patient presenting to the ED with abdominal pain should not receive an ultrasound examination. On the contrary, the author believes that in a "perfect world," ultrasound should be the initial imaging study in most of these patients. The reality is that it is difficult to convince radiology colleagues to call in a sonologist in the middle of the night for any indication other than ovarian torsion when CT scans can diagnose ovarian cysts and tubo-ovarian abscess. As was pointed out in the section on ovarian torsion, even adequate ovarian blood flow does not rule out this diagnosis.Ideally, an ultrasound of the pelvis could be undertaken at the time of the pelvic examination, adding as little as 5 to 10 minutes. If a gynecologic disorder could be confirmed, other imaging studies might be unnecessary,thereby reducing cost (potential savings on laboratory tests, cervical cultures, or CT scans), length of stay, and adverse complications of CT(contrast material reactions, and radiation exposure).Emergency medicine ultrasound continues to grow at a rapid pace. We are working toward a time when most EPs will be competent and comfortable performing bedside ultrasound examinations in a limited number of applications. The gynecologic application of ultrasound,however, requires skill beyond the level of the primary applications of emergency medicine ultrasound-specifically, mastering Doppler ultra-sound. Although ultrasound has proved to be a valuable imaging modality in the nonpregnant patient with acute abdominal pain when performed by a seasoned sonographer, the role of ED ultrasound has been limited to those EPs with significantly more training. The author believes that even limited expertise in gynecologic ultrasound is valuable in helping direct the management of these patients. Further research by skilled EP sonographers eventually will help define the role of EPs in this particular application of ultrasound. EPs should not be discouraged from developing expertise in this examination when a confirmatory study in radiology will be performed. Miles on the "ultrasound odometer" will not only sharpen sonographic skills but also will help the EP to better communicate with nonpregnant patients presenting with abdominal pain. There is a fairly specific barometer already in place to gauge one's gynecologic ultrasound skills: a seasoned EP sonographer never skips over the chart of a young woman with right lower quadrant pain.


Protocol to Create Chronic Wounds in Diabetic Mice.
Chronic wounds develop as a result of defective regulation in one or more complex cellular and molecular processes involved in proper healing. They impact ~6.5M people and cost ~$40B/year in the US alone. Although a significant effort has been invested in understanding how chronic wounds develop in humans, fundamental questions remain unanswered. Recently, we developed a novel mouse model for diabetic chronic wounds that have many characteristics of human chronic wounds. Using db/db-/- mice, we can generate chronic wounds by inducing high levels of oxidative stress (OS) in the wound tissue immediately after wounding, using a one-time treatment with inhibitors specific to the antioxidant enzymes catalase and glutathione peroxidase. These wounds have high levels of OS, develop biofilm naturally, become fully chronic within 20 days after treatment and can remain open more for more than 60 days. This novel model has many features of diabetic chronic wounds in humans and therefore can contribute significantly to advancing fundamental understanding of how wounds become chronic. This is a major breakthrough because chronic wounds in humans cause significant pain and distress to patients and result in amputation if unresolved. Moreover, these wounds are very expensive and time-consuming to treat, and lead to significant loss of personal income to patients. Advancements in this field of study through the use of our chronic wound model can significantly improve health care for millions who suffer under this debilitating condition. In this protocol, we describe in great detail the procedure to cause acute wounds to become chronic, which has not been done before.


Register of oncological diseases in canton sarajevo.
NONE DECLARED. The register of oncological diseases in Canton Sarajevo is important as it can be used to track and improve healthcare, especially in older age groups. The oncological registers are a way of recording data, suitable as a source of indicators. In the analyzed register, 1124 new cases of malignancy were recorded. There are slightly more malignant diseases in male (53%). The incidence of cancer varies depending of the age of patients. This analysis gives us important estimation in the relation of cancer morbidity, cancer types, age distribution, demographic factors, cancer stages and important cancer risks. The register and the analysis give us a chance for correlating and comparing the state of oncological diseases with other countries.


Targeting astrocytes in bipolar disorder.
Astrocytes are homeostatic cells of the central nervous system, which are critical for development and maintenance of synaptic transmission and hence of synaptically connected neuronal ensembles. Astrocytic densities are reduced in bipolar disorder, and therefore deficient astroglial function may contribute to overall disbalance in neurotransmission and to pathological evolution. Classical anti-bipolar drugs (lithium salts, valproic acid and carbamazepine) affect expression of astroglial genes and modify astroglial signalling and homeostatic cascades. Many effects of both antidepressant and anti-bipolar drugs are exerted through regulation of glutamate homeostasis and glutamatergic transmission, through K(+) buffering, through regulation of calcium-dependent phospholipase A2 (that controls metabolism of arachidonic acid) or through Ca(2+) homeostatic and signalling pathways. Sometimes anti-depressant and anti-bipolar drugs exert opposite effects, and some effects on gene expression in drug treated animals are opposite in neurones vs. astrocytes. Changes in the intracellular pH induced by anti-bipolar drugs affect uptake of myo-inositol and thereby signalling via inositoltrisphosphate (InsP3), this being in accord with one of the main theories of mechanism of action for these drugs.


COMT Val158Met polymorphism and executive functions in obsessive-compulsive disorder.
This study investigated the association between the catechol-O-methyl transferase (COMT) Val158Met polymorphism and executive functions in 101 patients with obsessive-compulsive disorder (OCD) and 100 healthy-control subjects (HS). Results showed that there was no significant difference for the genotype distributions between the OCD and HS groups. OCD-Met carrier subgroup's TMT B-A difference and lexical fluency scores were found to be significantly poorer than both HS subgroups. These findings suggest that lower activity of COMT associated with the Met allele, leading to higher levels of dopamine in the prefrontal cortex, lead to poorer executive function in OCD.


Contrast-enhanced MRI findings of the knee in healthy children; establishing normal values.
To define normative standards for the knee in healthy children using contrast-enhanced MRI, focusing on normal synovial membrane thickness. Secondly, presence of joint fluid and bone marrow oedema was evaluated. For this study, children without disorders potentially resulting in (accompanying) arthritis were included. Patients underwent clinical assessments, followed by contrast-enhanced MRI. MRI features were evaluated in consensus using the Juvenile Arthritis MRI Scoring (JAMRIS) system. Additionally, the presence of joint fluid was evaluated. No cartilage lesions or bone abnormalities were observed. We included 57 healthy children. The overall mean thickness of the normal synovial membrane was 0.4 mm (min-max; 0.0-1.8mm). The synovium was thickest around the cruciate ligaments and retropatellar and suprapatellar regions. The mean overall diameter of the largest pocket of joint fluid was 2.8 mm (min-max; 0.9-8.0mm). Bone marrow changes were observed in three children (all in the apex patellae). The normal synovial membrane was maximally 1.8 mm thick, indicating that the JAMRIS cut-off value of 2 mm can be considered a valid measure for evaluating synovial hypertrophy. Some joint fluid and bone marrow changes suggestive of bone marrow oedema in the apex patellae can be seen in healthy children. • Knowledge on the normal synovial appearance using contrast-enhanced MR is lacking. • In healthy children, normal synovial membrane is maximally 1.8 mm thick. • Normal synovium is thickest around the cruciate ligaments, retropatellar and suprapatellar. • Bone marrow oedema in the apex patellae is seen in healthy children.


Adenovirus type 12 early region 1A proteins repress class I HLA expression in transformed human cells.
The adenovirus type 12 (Ad12) early region 1A (E1A) gene is thought to play a major role in repressing class I major histocompatibility complex expression in transformed rodent cells. However, since transformation by adenovirus requires both E1A and E1B genes, it has not been demonstrated whether the Ad12 E1A gene acts alone or synergistically with the E1B gene to accomplish this effect. Moreover, it is not known whether the repression of class I antigen synthesis by Ad12-transforming gene products occurs only in rodent cells. We show that the Ad12 E1A gene, in the absence of the E1B gene, is capable of greatly reducing the levels of class I HLA antigens and mRNAs in primary human cells transformed by the E1A gene of Ad12 and the large tumor antigen (T-antigen) gene of BK virus; control cells transformed by BK virus T-antigen gene alone or the highly related simian virus 40 T-antigen gene showed no apparent alteration in class I HLA expression. Human recombinant interferon gamma was able to restore synthesis of class I HLA antigens in transformed cells that produced Ad12 E1A proteins, indicating that these cells were not deficient for class I genes. These results strongly indicate that the Ad12 E1A proteins modulate class I gene expression by similar mechanisms in both transformed rodent and human cells.


Thermal inactivation of staphylococcal enterotoxins B and C.
Thermal inactivation profiles of staphylococcal enterotoxins B (SEB) and C (SEC) at 80, 100, and 121 C showed that SEC is more resistant than SEB to heat. After 24 h of incubation at 25 C, some reactivation (recovery of serological reactivity) occurred in toxins that had been inactivated by heat. If the toxin was stirred during heating, reactivation did not occur. An examination of the reactivation kinetics of heat-treated SEC showed that reactivation was temperature dependent. At 25 C, the incubation temperature of heat-treated crude SEC (80 C for 10 min), 100% reactivation occurred after 24 h, whereas at 4 C only slight reactivation was observed. We and others observed that heat-treated toxins initially lost more serological activity when heated at a low temperature (80 C) than at a higher temperature (100 C); in the present study we demonstrate that this is a reversible phenomenon.


Rational Design, Synthesis, and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella typhimurium O-Acetylserine Sulfhydrylase.
Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS), a highly conserved pyridoxal 5'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design, synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.


The effect of indirect calorimetry measurement on claudication pain in patients with peripheral arterial occlusive disease.
The effect of indirect calorimetry measurement on the duration to onset and maximal claudication pain and hemodynamic measures was evaluated. Fifteen male patients with peripheral arterial occlusive disease (PAOD) performed two graded exercise tests (GXTs) in random order, one with and the other without the use of indirect calorimetry measurement. During the tests the time to onset and maximal claudication pain was recorded. Before and after the tests, ankle/brachial systolic pressure index (ABI) was determined. The time to onset of claudication pain was shorter for the test with indirect calorimetry (4:49+/-3:50 vs 5:44+/-4:39 min:sec, p < 0.005). Time to maximal claudication pain was not significantly different between the two conditions (8:58+/-3:01 min:sec with indirect calorimetry, 9:39+/-3:36 min:sec, without). There were no significant differences in ABI between the two testing sessions at any time point. Results of this study suggest that indirect calorimetry measurement can be utilized without compromising maximal claudication pain time or hemodynamic measurements but that time to onset of claudication pain is hastened with indirect calorimetry measurement in patients with PAOD.


Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study.
Coronavirus disease-2019 (COVID-19) is a life-threatening infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Diabetes has rapidly emerged as a major comorbidity for COVID-19 severity. However, the phenotypic characteristics of diabetes in COVID-19 patients are unknown. We conducted a nationwide multicentre observational study in people with diabetes hospitalised for COVID-19 in 53 French centres in the period 10-31 March 2020. The primary outcome combined tracheal intubation for mechanical ventilation and/or death within 7 days of admission. Age- and sex-adjusted multivariable logistic regressions were performed to assess the prognostic value of clinical and biological features with the endpoint. ORs are reported for a 1 SD increase after standardisation. The current analysis focused on 1317 participants: 64.9% men, mean age 69.8 ± 13.0 years, median BMI 28.4 (25th-75th percentile: 25.0-32.7) kg/m2; with a predominance of type 2 diabetes (88.5%). Microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively. The primary outcome was encountered in 29.0% (95% CI 26.6, 31.5) of participants, while 10.6% (9.0, 12.4) died and 18.0% (16.0, 20.2) were discharged on day 7. In univariate analysis, characteristics prior to admission significantly associated with the primary outcome were sex, BMI and previous treatment with renin-angiotensin-aldosterone system (RAAS) blockers, but not age, type of diabetes, HbA1c, diabetic complications or glucose-lowering therapies. In multivariable analyses with covariates prior to admission, only BMI remained positively associated with the primary outcome (OR 1.28 [1.10, 1.47]). On admission, dyspnoea (OR 2.10 [1.31, 3.35]), as well as lymphocyte count (OR 0.67 [0.50, 0.88]), C-reactive protein (OR 1.93 [1.43, 2.59]) and AST (OR 2.23 [1.70, 2.93]) levels were independent predictors of the primary outcome. Finally, age (OR 2.48 [1.74, 3.53]), treated obstructive sleep apnoea (OR 2.80 [1.46, 5.38]), and microvascular (OR 2.14 [1.16, 3.94]) and macrovascular complications (OR 2.54 [1.44, 4.50]) were independently associated with the risk of death on day 7. In people with diabetes hospitalised for COVID-19, BMI, but not long-term glucose control, was positively and independently associated with tracheal intubation and/or death within 7 days. clinicaltrials.gov NCT04324736.


Housing First and harm reduction: a rapid review and document analysis of the US and Canadian open-access literature.
Housing First is an evidence-based practice intended to serve chronically homeless individuals with co-occurring serious mental illness and substance use disorders. Despite housing active substance users, harm reduction is an often-overlooked element during the Housing First implementation process in real-world settings. In this paper, we explore the representation of the Housing First model within the open-access scholarly literature as a potential contributing factor for this oversight. We conducted a rapid review of the US and Canadian open-access Housing First literature. We followed a document analysis approach, to form an interpretation of the articles' content related to our primary research questions. A total of 55 articles on Housing First were included in the final analysis. Only 21 of these articles (38.1%) included explicit mention of harm reduction. Of the 34 articles that did not discuss harm reduction, 22 provided a description of the Housing First model indicating it does not require abstinence from substance use; however, descriptions did not all clearly indicate abstinence was not required beyond program entry. Additional Housing First descriptions focused on the low-barrier entry criteria and/or the intervention's client-centeredness. Our review demonstrated a lack of both explicit mention and informed discussion of harm reduction in the Housing First literature, which is likely contributing to the Housing First research-practice gap to some degree. Future Housing First literature should accurately explain the role of harm reduction when discussing it in the context of Housing First programming, and public agencies promoting Housing First uptake should provide resources for proper implementation and monitor program fidelity to prevent model drift.


Molecular evolution of vertebrate neurotrophins: co-option of the highly conserved nerve growth factor gene into the advanced snake venom arsenalf.
Neurotrophins are a diverse class of structurally related proteins, essential for neuronal development, survival, plasticity and regeneration. They are characterized by major family members, such as the nerve growth factors (NGF), brain-derived neurotrophic factors (BDNF) and neurotrophin-3 (NT-3), which have been demonstrated here to lack coding sequence variations and follow the regime of negative selection, highlighting their extremely important conserved role in vertebrate homeostasis. However, in stark contrast, venom NGF secreted as part of the chemical arsenal of the venomous advanced snake family Elapidae (and to a lesser extent Viperidae) have characteristics consistent with the typical accelerated molecular evolution of venom components. This includes a rapid rate of diversification under the significant influence of positive-selection, with the majority of positively-selected sites found in the secreted β-polypeptide chain (74%) and on the molecular surface of the protein (92%), while the core structural and functional residues remain highly constrained. Such focal mutagenesis generates active residues on the toxin molecular surface, which are capable of interacting with novel biological targets in prey to induce a myriad of pharmacological effects. We propose that caenophidian NGFs could participate in prey-envenoming by causing a massive release of chemical mediators from mast cells to mount inflammatory reactions and increase vascular permeability, thereby aiding the spread of other toxins and/or by acting as proapoptotic factors. Despite their presence in reptilian venom having been known for over 60 years, this is the first evidence that venom-secreted NGF follows the molecular evolutionary pattern of other venom components, and thus likely participates in prey-envenomation.


Motivational readiness for physical activity and quality of life in long-term lung cancer survivors.
Little is known about the relationship between motivational readiness for physical activity and quality of life (QOL) in long-term lung cancer survivors. Long-term survivors are considered those who are living 5 years or more following a cancer diagnosis. This project examined the relationship between a self-report measure of motivational readiness for physical activity and QOL in a sample of 272 long-term lung cancer survivors. Participants (54% male, average age 70 years old) completed the mailed survey an average of 6 years after being diagnosed with lung cancer. Survey measures included the stage of change for physical activity and a set of single item QOL and symptom scales. Thirty-seven percent of respondents reported they currently engaged in regular physical activity (a total of 30 min or more per day, at least 5 days per week). Kruskal-Wallis tests revealed that those who reported engaging in regular physical activity reported a better overall QOL, better QOL on all five domains of QOL functioning (mental, physical, social, emotional, and spiritual), and fewer symptoms compared to those with a sedentary lifestyle. Physical activity level may have important QOL and symptom management benefits for long-term lung cancer survivors.


The microbial flora of clinically infected cutaneous metastases: a retrospective study.
Symptomatic cutaneous metastases are associated with discharge, malodour, pruritus and pain, all of which may negatively impact quality of life and cutaneous health. We conducted a retrospective chart review of patients referred to the Dermatology Service at Memorial Sloan Kettering Cancer Center between August 2006 and June 2015, and characterized the microbial flora and antimicrobial management of cutaneous metastases in 64 patients. We detected pathogenic and/or opportunistic bacteria in 50% of skin lesions. The most commonly isolated organisms were Staphylococcus aureus and Pseudomonas aeruginosa. Patients treated with oral antibiotics, alone or in combination with topical agents, had a statistically significant better improvement in infectious symptoms than those treated without oral antibiotics. Our findings suggest that the normal skin microbial flora is disrupted in patients with symptomatic skin metastases. Oral antibiotics may provide benefit when used as first-line therapy for infected skin lesions in patients with symptomatic cutaneous metastases.


Total parenteral nutrition alters NPY/PYY receptor levels in the rat brain.
The regulation of appetite and satiety is complex and may involve peptide mediators such as cholecystokinin (CCK) and neuropeptide Y (NPY). Studies have indicated that calories administered enterally and parenterally impact on feeding, and possibly via the release of such mediators. Recent data from our laboratory have shown that total parenteral nutrition (TPN) reduces sham feeding in dogs by 50%. We hypothesized that TPN may alter feeding via an NPY-mediated mechanism. To test our hypothesis, we examined the effect of continuous administration of TPN on NPY receptor levels in the rat brain. Rats were surgically prepared with intravenous catheters. After 72 h of TPN infusion, the rats were anesthesized with sodium pentobarbital and their brains were removed. Neuropeptide Y receptor density was assessed by autoradiography in the paraventricular nucleus, olfactory cortex, dentate gyrus, and thalamus. These results were compared to the control group receiving intravenous saline. A third group receiving enteral nutrition was examined as well. Neuropeptide Y receptor numbers were significantly increased in the paraventricular nucleus of rats receiving TPN compared to the groups receiving intravenous saline or enteral nutrition. We conclude that continuous parenteral nutrition significantly increases NPY receptor density in the rat brain suggesting that TPN may impact feeding via the regulation of NPY receptor-mediated effects.


Trauma-informed medical care: CME communication training for primary care providers.
Trauma exposure predicts mental disorders, medical morbidity, and health care costs. Yet trauma-related impacts have not received sufficient attention in primary care provider (PCP) training programs. This study adapted a theory-based approach to working with trauma survivors, Risking Connection, into a 6-hour CME course, Trauma-Informed Medical Care (TI-Med), and evaluated its efficacy. We randomized PCPs to training or wait-list (delay) conditions; wait-list groups were trained after reassessment. The primary outcome assessing newly acquired skills was a patient-centeredness score derived from Roter Interactional Analysis System ratings of 90 taped visits between PCPs and standardized patients (SPs). PCPs were family medicine residents (n=17) and community physicians (n=13, 83% family medicine specialty), from four sites in the Washington, DC metropolitan area. Immediately trained PCPs trended toward a larger increase in patient centeredness than did the delayed PCPs, with a moderate effect size (.66). The combined trained PCP groups showed a significant increase in patient centeredness from before to after training. This is a promising approach to supporting relationship-based trauma-informed care among PCPs to help promote better patient health and higher compliance with medical treatment plans.


Evaluation of the Frequency of "Not Relevant" Responses on the Dermatology Life Quality Index by Sociodemographic Characteristics of Patients With Psoriasis.
"Not relevant" responses (NRRs) on the Dermatology Life Quality Index (DLQI) are common among patients with psoriasis and may be associated with an underestimation of disease severity. To evaluate the associations between (1) patient sociodemographic characteristics and the frequency of NRRs on the DLQI and (2) NRR frequency and treatment satisfaction. This cross-sectional study using data from the Dermatology Clinical Effectiveness Research Network from February 2010 to June 2011 assessed the responses on the DLQI of 1733 patients with psoriasis. Differences in the frequency of NRRs by sex, race/ethnicity, insurance type, income, educational attainment, marital status, and employment status were evaluated using the 2-tailed χ2 test. Multivariable logistic regression analysis was used to evaluate the associations between sociodemographic characteristics and having at least 1 NRR. Multivariable linear regression analysis was used to evaluate the association between having a DLQI score reclassified from 10 or less to more than 10 using the DLQI-Relevant scoring modification and the scores on the Treatment Satisfaction Questionnaire for Medication. Data were analyzed between July 2019 and November 2019. Of 1733 patients with psoriasis, 879 (50.7%) were female, and 1470 (84.8%) were non-Hispanic white individuals. The DLQI items 6 (sport, 223 patients [12.9%]), 9 (sexual difficulties, 214 patients [12.3%]), and 7 (work or study, 126 patients [7.3%]) had the greatest frequency of NRRs. In multivariable logistic regression analysis, male sex (odds ratio [OR], 0.63; 95% CI, 0.48-0.82) and income of more than $100 000 (OR, 0.45; 95% CI, 0.26-0.79) were associated with decreased odds of NRRs. By contrast, single (OR, 1.85; 95% CI, 1.31-2.61) or widowed or divorced (OR, 2.60; 95% CI, 1.80-3.74) marital status and unemployed or disabled employment status (OR, 1.98; 95% CI, 1.35-2.89) were associated with increased odds of NRRs. Having a DLQI score that would be reclassified from 10 or less to more than 10 using the DLQI-Relevant scoring modification was associated with lower global satisfaction scores on the Treatment Satisfaction Questionnaire for Medication (coefficient, -9.8; 95% CI, -16.3 to -3.4). There were sociodemographic differences in the frequency of NRRs on the DLQI among this cohort of patients with psoriasis. These differences may be associated with an underestimation of disease burden and treatment disparities owing to subsequent undertreatment among certain sociodemographic groups. Further study is needed to optimize the quality-of-life assessment among patients with psoriasis or other inflammatory skin diseases in diverse settings.


Loss of cortical function in mice after decapitation, cervical dislocation, potassium chloride injection, and CO2 inhalation.
Electroencephalograms (EEG) and visual evoked potentials (VEP) in mice were recorded to evaluate loss of cortical function during the first 30 s after euthanasia by various methods. Tracheal cannulae (for positive-pressure ventilation, PPV) and cortical surface electrodes were placed in mice anesthetized with inhaled halothane. Succinylcholine was used to block spontaneous breathing in the mice, which then underwent continuous EEG recording. Photic stimuli (1 Hz) were presented to produce VEPs superimposed on the EEG. Anesthesia was discontinued immediately before euthanasia. Compared with that obtained before euthanasia, EEG activity during the 30-s study period immediately after euthanasia was significantly decreased after cervical dislocation (at 5 to 10 s), 100% PPV-CO2 (at 10 to 15 s), decapitation (at 15 to 20 s), and cardiac arrest due to KCl injection (at 20 to 25 s) but not after administration of 70% PPV-CO2. Similarly, these euthanasia methods also reduced VEP amplitude, although 100% PPV-CO2 treatment affected VEP amplitude more than it did EEG activity. Thus, 100% PPV-CO2 treatment significantly decreased VEP beginning 5 to 10 s after administration, with near abolition of VEP by 30 s. VEP amplitude was significantly reduced at 5 to 10 s after cervical dislocation and at 10 to 15 s after decapitation but not after either KCl or 70% PPV-CO2 administration. The data demonstrate that 100% PPV-CO2, decapitation, and cervical dislocation lead to rapid disruption of cortical function as measured by 2 different methods. In comparison, 70% PPV-CO2 and cardiac arrest due to intracardiac KCl injection had less rapid effects on cortical function.


Focal Hemodynamic Responses in the Stimulated Hemisphere During High-Definition Transcranial Direct Current Stimulation.
High-definition transcranial direct current stimulation (HD-tDCS) using a 4 × 1 electrode montage has been previously shown using modeling and physiological studies to constrain the electric field within the spatial extent of the electrodes. The aim of this proof-of-concept study was to determine if functional near-infrared spectroscopy (fNIRS) neuroimaging can be used to determine a hemodynamic correlate of this 4 × 1 HD-tDCS electric field on the brain. In a three session cross-over study design, 13 healthy males received one sham (2 mA, 30 sec) and two real (HD-tDCS-1 and HD-tDCS-2, 2 mA, 10 min) anodal HD-tDCS targeting the left M1 via a 4 × 1 electrode montage (anode on C3 and 4 return electrodes 3.5 cm from anode). The two real HD-tDCS sessions afforded a within-subject replication of the findings. fNIRS was used to measure changes in brain hemodynamics (oxygenated hemoglobin integral-O2 Hbint ) during each 10 min session from two regions of interest (ROIs) in the stimulated left hemisphere that corresponded to "within" (Lin ) and "outside" (Lout ) the spatial extent of the 4 × 1 electrode montage, and two corresponding ROIs (Rin and Rout ) in the right hemisphere. The ANOVA showed that both real anodal HD-tDCS compared to sham induced a significantly greater O2 Hbint in the Lin than Lout ROIs of the stimulated left hemisphere; while there were no significant differences between the real and sham sessions for the right hemisphere ROIs. Intra-class correlation coefficients showed "fair-to-good" reproducibility for the left stimulated hemisphere ROIs. The greater O2 Hbint "within" than "outside" the spatial extent of the 4 × 1 electrode montage represents a hemodynamic correlate of the electrical field distribution, and thus provides a prospective reliable method to determine the dose of stimulation that is necessary to optimize HD-tDCS parameters in various applications.


Outward currents in developing Drosophila flight muscle.
The development of two different voltage-sensitive potassium channels was studied in Drosophila flight muscle by voltage clamp techniques. Early in development active channels are not present in the membrane. The first channels to appear are the A current channels, which carry a fast, rapidly inactivating potassium current. The channels for delayed rectification appear later. Channels carrying inward current also appear only after the A current channels. During development, the A current may be easily studied in isolation from other currents and thus provides a desirable system for studying the genetic determinants of this current.


Non-specific binding of IgG1 to Heligmosomoides polygyrus: adult worm homogenate superantigen is a target for immunoglobulin-induced inhibition.
Previous evidence had indicated that selected antigens contained in H. polygyrus adult worm homogenate (AWH) could bind non-specifically to mouse IgG1. To determine whether H. polygyrus superantigen was one of these binding molecules, an inhibition assay was carried out using monoclonal antibodies (MoAb) to block the in vitro superantigen response. The results indicated that non-specific IgG1 binding could inhibit the cellular response to the superantigen. This assumption was tested using affinity chromatography to extract those antigens which bound non-specifically to mouse IgG1. Both the protein fraction which bound to the column and the unfractionated AWH demonstrated superantigen activity, as described previously. In contrast, the unbound fraction contained no superantigen activity. None of the tested fractions exhibited non-specific mitogen activity. These results indicate that the superantigen produced by H. polygyrus binds to host IgG1 of any specificity and this binding can inhibit further host recognition of this molecule. Additionally, it was demonstrated that an apparently similar superantigen is also contained in L4 homogenate, and is strongly represented in the excretory/secretory (E/S) proteins produced by both adult and L4 parasitic stages. Therefore, it is probable that H. polygyrus superantigen influences the host during both the L4 and adult stages of the life-cycle.


Influence of Time-Pickoff Circuit Parameters on LiDAR Range Precision.
A pulsed time-of-flight (TOF) measurement-based Light Detection and Ranging (LiDAR) system is more effective for medium-long range distances. As a key ranging unit, a time-pickoff circuit based on automatic gain control (AGC) and constant fraction discriminator (CFD) is designed to reduce the walk error and the timing jitter for obtaining the accurate time interval. Compared with Cramer-Rao lower bound (CRLB) and the estimation of the timing jitter, four parameters-based Monte Carlo simulations are established to show how the range precision is influenced by the parameters, including pulse amplitude, pulse width, attenuation fraction and delay time of the CFD. Experiments were carried out to verify the relationship between the range precision and three of the parameters, exclusing pulse width. It can be concluded that two parameters of the ranging circuit (attenuation fraction and delay time) were selected according to the ranging performance of the minimum pulse amplitude. The attenuation fraction should be selected in the range from 0.2 to 0.6 to achieve high range precision. The selection criterion of the time-pickoff circuit parameters is helpful for the ranging circuit design of TOF LiDAR system.


An epidemic of respiratory complaints exacerbated by mass psychogenic illness in a military recruit population.
The authors report an episode of mass psychogenic illness exacerbating respiratory symptoms in military recruits. The epidemic occurred over a 10- to 12-hour period in September 1988, in a group initially complaining of cough and pleuritic chest pain. More than 1,800 men were evacuated from their barracks because of a suspected toxic gaseous exposure. Approximately 1,000 recruits developed at least one new symptom, 375 were evacuated by ambulance to receive further medical evaluation, and at least eight were hospitalized. Air sample testing from the area was unremarkable, and there were few abnormal physical examination or laboratory findings. The epidemiologic investigation included a questionnaire administered 2 weeks after the epidemic to 1,000 of the recruits involved. A total of 55% of those who completed the questionnaire reported the onset of at least one new symptom after supper, with at least 25% reporting the new onset of cough, light-headedness, chest pain, shortness of breath, headache, sore throat, or dizziness. A total of 18% received further medical evaluation. The development of new symptoms and the receipt of further medical evaluation were associated with evidence of physical stress, mental stress, and awareness of rumors of odors, gases, and/or smoke. This epidemic was unique because of its size and its occurrence in an all-male population.


Diagnosis as a social determinant: the development of prosocial behaviour before and after an autism spectrum diagnosis.
Jutel and Nettleton (2011) discuss diagnosis as not only a major classification tool for medicine but also an interactive social process that itself may have ramifications for health. Consideration of diagnosis as a social determinant of health outcomes led to the formulation of our research question: Can we detect a change in the development of prosocial symptoms before and after an Autism Spectrum Disorder (ASD) diagnosis? We examined the developmental trajectory of prosocial skills of children, as impairment in social skills is given as a core symptom for children with ASD. We used a validated scale measuring prosocial behaviour for a sample of 57 children where the measure was repeatedly recorded over ten years. We plotted the developmental trajectory of the prosocial trait in this sample who were enrolled in a longitudinal birth cohort study based in South West England. Multi-factorial fixed effect modelling suggests that the developmental trajectory of this measure of behaviour was not significantly altered by ASD diagnosis, or the consequences of diagnosis, either for better or worse. Further analysis was conducted on a subset of 33 of the children who had both pre-diagnosis and post-diagnosis information, and the same result obtained. The results indicate that prosocial behaviours may be resistant to typical 'treatments': provision of educational and specialist health services triggered by a clinical ASD diagnosis. The implications of this for considering diagnosis as a social determinant are discussed.


Some observations on the fine structure of the giant nerve fibers of the earthworm, Eisenia foetida.
Sectioned dorsal giant fibers of the earthworm Eisenia foetida have been studied with the electron microscope. The giant axon is surrounded by a Schwannian sheath in which the lamellae are arranged spirally. They can be traced from the outer surface of the Schwann cell to the axon-Schwann membranes. Irregularities in the spiral arrangement are frequently observed. Desmosome-like attachment areas occur on the giant fiber nerve sheath. These structures appear to be arranged bilaterally in columns which are oriented slightly obliquely to the long axis of the giant fiber and aligned linearly from the axon to the periphery of the sheath. At these sites they bind together apposing portions of Schwann cell membrane comprising the sheath. Longitudinal or oblique sections of the nerve sheath attachment areas are reminiscent of the Schmidt-Lantermann clefts of vertebrate peripheral nerve. Septa of the giant fibers have been examined. They are symmetrical or non-polarized and consist of the two plasma membranes of adjacent nerve units. Characteristic vesicular and tubular structures are associated with both cytoplasmic surfaces of these septa.


Evaluation of net protein contribution, methane production, and net returns from beef production as duration of confinement increases in the cow-calf sector1.
Intensification of cow-calf production may provide a sustainable solution for meeting increasing beef demand in the face of diminishing resources. However, intensification with its greater reliance on cereal grains potentially decreases the upcycling of human-inedible protein into beef. A previously described model was used to evaluate cow-calf intensification on beef's ability to meet human protein requirements. Four scenarios were compared, based on a 1,000 cow herd: 1) Conventional cow-calf production system (0CON), 2) cows limit-fed in confinement for 4 mo after weaning (4CON), 3) cows limit-fed in confinement for 8 mo after breeding (8CON), or 4) cows limit-fed in confinement year-round (12CON). Changes were not made to either the stocker or feedlot segments of the beef value chain. Net protein contribution (NPC) was calculated by multiplying the ratio of human-edible protein (HeP) in beef produced to HeP in feed by the protein quality ratio. A NPC >1 indicates that the production system is positively contributing to meeting human requirements, whereas a NPC <1 indicates the sector or value chain is competing with humans for HeP. Methane was estimated based on proportion of forage in diet and total methane production was reported per kg HeP. In the cow-calf sector, HeP conversion efficiency (HePCE) decreased from 2,640.83 to 0.37 while methane production decreased from 4.53 to 1.82 kg/kg HeP produced as the length of intensification increased from 0CON to 12CON. Decreased HePCE resulted in NPC values for cow-calf sector of 8,036.80, 4.93, 2.19, and 1.28 for 0CON, 4CON, 8CON, and 12CON, respectively. Protein quality ratio of the entire beef value chain increased from 3.15 to 3.33, while HePCE decreased from 0.99 to 0.39 as length of intensification increased from 0CON to 12CON. For the beef value chain, NPC was 3.11, 2.30, 1.73, and 1.31 for 0CON, 4CON, 8CON, and 12CON, respectively. Across the value chain, confinement of cows for 12 mo decreased enteric methane from 3.05 to 1.53 kg/kg HeP (0CON and 12CON, respectfully). Additionally, profitability of the cow-calf operation decreased from $249.34 to $102.16 per cow as intensification increased. Of confinement scenarios, probability of loss to an operation was least (4%) for 4CON. Feed costs increased by $260.79 per cow for 0CON when drought conditions existed (0COND). Total methane production was reduced by intensification and none of the scenarios evaluated competed with humans for HeP.


Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism.
The primary roles attributed to the human immunodeficiency virus type 1 (HIV-1) Vpu protein are the degradation of the viral receptor CD4 and the enhancement of virion release. With regard to CD4 downregulation, Vpu has been shown to act as an adapter linking CD4 with the ubiquitin-proteasome machinery via interaction with the F-box protein betaTrCP. To identify additional cellular betaTrCP-dependent Vpu targets, we performed quantitative proteomics analyses using the plasma membrane fraction of HeLa cells expressing either wild-type Vpu or a Vpu mutant (S52N/S56N) that does not bind betaTrCP. One cellular protein, BST-2 (CD317), was consistently underrepresented in the membrane proteome of cells expressing wild-type Vpu compared to the proteome of cells expressing the Vpu mutant. To verify the biological relevance of this phenotype for HIV pathogenesis, we showed that in T cells infected with HIV-1, BST-2 downregulation occurred in a Vpu-dependent manner. Recently, BST-2 has been identified as the interferon-inducible cellular factor Tetherin, which restricts HIV virion release in the absence of Vpu. We address here the unresolved mechanism of Vpu-mediated BST-2 downregulation. Our data show that the presence of wild-type Vpu reduced cell surface and total steady-state BST-2 levels, whereas that of the mutant Vpu had no effect. In addition, treatment of cells with the lysosome acidification inhibitor concanamycin A, but not treatment with the proteasome inhibitor MG132, reduced BST-2 downregulation by wild-type Vpu, thereby suggesting that the presence of Vpu leads to the degradation of BST-2 via an endosome-lysosome degradation pathway. The importance of betaTrCP in this process was confirmed by demonstrating that in the absence of betaTrCP, BST-2 levels were restored despite the presence of Vpu. Taken together, these data support the hypothesis that, in similarity to its role in CD4 degradation, Vpu acts as an adapter molecule linking BST-2 to the cellular ubiquitination machinery via betaTrCP. However, in contrast to the proteasome-dependent degradation of CD4, which occurs in the endoplasmic reticulum, Vpu appears to interact with BST-2 in the trans-Golgi network or in early endosomes, leading to lysosomal degradation of BST-2. Via this action, Vpu could counter the tethering function of BST-2, resulting in enhanced HIV-1 virion release. Interestingly, although HIV-2 does not express Vpu, an isolate known to exhibit enhanced viral egress can downregulate surface BST-2 by an as-yet-unknown mechanism that does not appear to involve degradation. Understanding the molecular mechanisms of both Vpu-dependent and -independent mediated antagonism of BST-2 will be critical for therapeutic strategies that exploit this novel viral function.


Disruption of insulin signaling in Myf5-expressing progenitors leads to marked paucity of brown fat but normal muscle development.
Insulin exerts pleiotropic effects on cell growth, survival, and metabolism, and its role in multiple tissues has been dissected using conditional knockout mice; however, its role in development has not been studied. Lineage tracing experiments have demonstrated that interscapular brown adipose tissue (BAT) arises from a Myf5-positive lineage shared with skeletal muscle and distinct from the majority of white adipose tissue (WAT) precursors. In this study, we sought to investigate the effects of impaired insulin signaling in the Myf5-expressing precursor cells by deleting the insulin receptor gene. Mice lacking insulin receptor in the Myf5 lineage (Myf5IRKO) have a decrease of interscapular BAT mass; however, muscle development appeared normal. Histologically, the residual BAT had decreased cell size but appeared mature and potentially functional. Expression of adipogenic inhibitors preadipocyte factor-1, Necdin, and wingless-type MMTV integration site member 10a in the residual BAT tissue was nonetheless increased compared with controls, and there was an enrichment of progenitor cells with impaired adipogenic differentiation capacity, suggesting a suppression of adipogenesis in BAT. Surprisingly, when cold challenged, Myf5IRKO mice did not show impaired thermogenesis. This resistance to cold could be attributed to an increased presence of uncoupling protein 1-positive brown adipocytes in sc WAT as well as increased expression of lipolytic activity in BAT. These data suggest a critical role of insulin signaling in the development of interscapular BAT from Myf5-positive progenitor cells, but it appears to be dispensable for muscle development. They also underscore the importance of compensatory browning of sc WAT in the absence of BAT for thermoregulation.


Aging increases neuronal nitric oxide release and superoxide anion generation in mesenteric arteries from spontaneously hypertensive rats.
We hypothesized that neuronal NO release as well as its bioavailability and vasomotor response could be affected when aging and hypertension are present simultaneously. The neuronal nitric oxide (NO) release, its metabolism and vasomotor response induced by electrical field stimulation was analyzed in isolated segments of endothelium-denuded mesenteric arteries from young and old spontaneously hypertensive rats (SHR). The nitric oxide synthase (NOS) inhibitor N(G)-nitro-arginine-methyl ester (L-NAME) and NOS inhibitor 7-nitroindazole both strengthened electrical field stimulation-elicited contractions more in arteries from young than aged SHR rats. Superoxide dismutase (SOD) potentiated the L-NAME effect in segments from old rats, whereas catalase decreased the contractions induced by electrical field stimulation and noradrenaline but did not modify the L-NAME effect. In noradrenaline-precontracted segments, sodium nitroprusside induced a similar relaxation in arteries from both experimental groups. This relaxation was increased by SOD in old SHR. 8Br cGMP induced greater relaxation in segments from old than from young SHR. Electrical field stimulation induced a tritium release in arteries preincubated with [(3)H]-noradrenaline, that was similar in both young and old SHR rats. Electrical field stimulation induced NO(2)(-) formation, which was greater in segments from old than young SHR rats. Basal cGMP levels and those stimulated with sodium nitroprusside were similar in segments from both groups. Superoxide anion production was greater from old than young SHR rats. Peroxynitrite production induced by electrical field stimulation was only detected in segments from old SHR. The results obtained in mesenteric arteries from old SHR showed increased neuronal NO release and superoxide anion production with respect to those observed in arteries from young SHR rats. This induced decreased NO bioavailability through peroxynitrite formation. The final effect is to decrease the involvement of neuronal NO in electrical field stimulation-induced vasomotor response in arteries from old SHR rats.


Effect of an anabolic steroid (metandienon) on plasma LH-FSH, and testosterone and on the response to intravenous administration of LRH.
Plasma levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as the response of LH and FSH to the intravenous administration of 100 mug of luteinizing hormone releasing hormone (LRH) were measured in 16 well-trained athletes (mean age 30 years) before and after 2 months of daily oral intake of 15 mg of metandienon, and anabolic steroid (Anabolin, 17 alpha-methyl-17beta-hydroxy-1,4-androstadien-3-one, Medica, Finland). All athletes continued to train regularly, just as they had done for several years. During administration of metandienon the mean plasma testosterone level fell 69%, from 29.4 +/- 11.6 nmol/1 to 9.1 +/- 7.5 nmol/1. The mean plasma levels of LH and FSH also fell significantly (P less than 0.001 and P less than 0.01, respectively), both about 50%. Because LH and FSH levels were low after administration of the steroid the maximum stimulation values after LRH administration were also lower than pre-treatment values although the mean increments did not differ significantly before and after administration of the anabolic steroid. However, after treatment, the FSH response curve had a biphasic pattern in most subjects, with peaks at 10 to 20 and 50 to 60 min after the iv injection of LRH. Administration of LRH after the treatment period had no effect on FSH secretion in two subjects and no effect on LH secretion in one. Our results show that administration of an anabolic steroid causes a pronounced lowering of plasma levels of testosterone, LH and FSH but causes no gross alteration in the response of LH secretion to stimulation by LRH. The reason for the biphasic response pattern of FSH to LRH administration in most subjects is not known.


Cell surface hydrophobicity-associated adherence of Candida dubliniensis to human buccal epithelial cells.
Microbial adherence to mucosal surfaces is an important first step in the initiation of the pathogenic process in the oral cavity. Candida albicans, the most adherent and pathogenic Candida species, utilizes a variety of mechanisms to adhere to human tissues. Although the strongest mechanism of adherence involves mannoprotein adhesins on C. albicans, cell surface hydrophobicity (CSH) plays an important role in the adherence process by providing hydrophobic interactions that turn the initial attachment between the yeast and a surface into a strong bond. Recent cell wall analytical and comparative studies showed that, Candida dubliniensis, unlike C. albicans, possesses cell surface variations that allow it to be constantly hydrophobic, regardless of growth temperature. Based on these observations, the present study was designed to compare the adherence abilities of C. dubliniensis and C. albicans to pooled human buccal epithelial cells (BEC), in regards to their cell surface hydrophobicity. Ten C. albicans and nine C. dubliniensis isolates, as well as the C. albicans hydrophobic variant A9V10 were evaluated for adherence with BEC using visual aggregation in the wells of a microtiter plate and microscopic examination. All 11 C. albicans isolates failed to show adherence to BEC, visually or microscopically, when grown at 37 degrees C. The same isolates, however, showed significant increase in aggregation and microscopic adherence to BEC when grown at 25 degrees C. All C. dubliniensis isolates tested and the A9V10 C. albicans hydrophobic variant resulted in visual aggregation and adhered to BEC when grown at either temperature. The findings from this study show that, based on comparative adherence results and growth temperature changes, C. dubliniensis seems to have greater adherence to BEC than do typical C. albicans strains and that hydrophobic interactions seem to be the mechanism of adherence involved. Although many questions remain to be answered regarding the clinical implications of this observed in vitro enhanced adherence of C. dubliniensis to human BEC, these findings support the establishment of this novel species as a clinically significant yeast.


Prognostic variables in nearly drowned, comatose children.
Prognostic variables were evaluated in 51 nearly drowned, comatose children, and they included values for age, estimated submersion time, initial arterial pH and core temperature, mean intracranial pressure (ICP), and mean cerebral perfusion pressure (CPP); the latter two values were obtained during the first 24 hours. There were 33 survivors (19 with intact neurologic survival and 14 with brain damage) and 18 deaths. Estimated submersion time and mean ICP and mean CPP determined survival but could not predict the neurologic outcome (intact survival or brain damage). Age, arterial pH, and core temperature were not useful variables in predicting outcome. This study discourages the use of these unreliable variables in predicting survival in nearly drowned, comatose victims and, in addition, cautions against the use of mean ICP, mean CPP, and submersion time as predictors of neurologic outcome. Since mean ICP and mean CPP measurements are reliable in predicting survival but not neurologic outcome, major efforts should be undertaken to explore neurophysiologic and metabolic prognostic factors that may either discourage or mandate early institution of aggressive cerebral resuscitative measures in nearly drowned victims.


[Molecular biological approach to screening essential genes as potential targets for antifungal targets in pathogenic yeast Candida].
We established a system, named ETS system, for screening and identification of essential genes from the pathogenic haploid yeast Candida glabrata by using temperature-sensitive (ts) mutants. Based on the general concepts that ts mutations are generated within essential genes in the genome by virtue of point mutation, the ETS system enabled us to screen and identify a variety of essential genes from the C. glabrata genomic DNA library as the genes that complement ts mutations. The ETS system established in the present study may provide novel potential antifungal targets.


Effects of stimulus rate and gender on the auditory middle latency response.
The effects of stimulus rate and gender on the auditory middle latency response (AMLR) waveforms were examined in 20 young adult male and female subjects. Four different repetition rates were presented to subjects (1.1/sec, 4.1/sec, 7.7/ sec, and 11.3/sec). Stimulus repetition rate had a significant effect on Pa latency, Pa amplitude, and Pb amplitude. Pa and Pb amplitudes decreased with increasing the stimulus rate, and Pa latency significantly increased with increasing the stimulus rate. No significant differences were seen on Pb latency or site of recording. Gender had a significant effect on Pa latency and Pa amplitude. Pa latencies were longer in male subjects, and Pa amplitudes were larger in female subjects. Gender did not have a significant effect on the Pb waveform.


Spondyloepiphyseal dysplasia with nephrotic syndrome (Schimke immunoosseous dysplasia).
We report a 3-year-old girl with the association of spondyloepiphyseal dysplasia, nephrotic syndrome, and signs of defective cellular immunity. The findings are similar to those reported by Spranger et al., which have become known as Schimke immunoosseous dysplasia.


Animal and vegetal poles of the mouse egg predict the polarity of the embryonic axis, yet are nonessential for development.
Recent studies suggest early (preimplantation) events might be important in the development of polarity in mammalian embryos. We report here lineage tracing experiments with green fluorescent protein showing that cells located either near to or opposite the polar body at the 8-cell stage of the mouse embryo retain their same relative positions in the blastocyst. Thus they come to lie on either end of an axis of symmetry of the blastocyst that has recently been shown to correlate with the anterior-posterior axis of the postimplantation embryo (see R. J. Weber, R. A. Pedersen, F. Wianny, M. J. Evans and M. Zernicka-Goetz (1999). Development 126, 5591-5598). The embryonic axes of the mouse can therefore be related to the position of the polar body at the 8-cell stage, and by implication, to the animal-vegetal axis of the zygote. However, we also show that chimeric embryos constructed from 2-cell stage blastomeres from which the animal or the vegetal poles have been removed can develop into normal blastocysts and become fertile adult mice. This is also true of chimeras composed of animal or vegetal pole cells derived through normal cleavage to the 8-cell stage. We discuss that although polarity of the postimplantation embryo can be traced back to the 8-cell stage and in turn to the organisation of the egg, it is not absolutely fixed by this time.


Proximity of the popliteal artery to the PCL during simulated knee arthroscopy: implications for establishing the posterior trans-septal portal.
This study defines the sagittal distance from the posterior cruciate ligament (PCL) to the popliteal artery under simulated arthroscopic conditions. This information is relevant for posterior knee arthroscopy, particularly for the safe establishment of the posterior trans-septal portal. Measurements from the PCL to the popliteal artery were made on sagittal magnetic resonance images obtained in a previous study of 10 fresh-frozen cadaveric knees. The mean sagittal distance from the mid-PCL to the popliteal artery was 29.1 +/- 11 mm (range: 18-55 mm). The mean sagittal distance from the proximal PCL fovea to the popliteal artery was 9.7 +/- 5 mm (range: 3-16 mm). The results of this study provide the arthroscopist working in the posterior compartments of the knee with a more detailed knowledge of the anatomic relationship between the PCL and popliteal artery. This knowledge will help minimize the risk of iatrogenic vascular injury during arthroscopic knee surgery.


[Treatment for advanced Parkinson's disease with intestinal levodopa/carbidopa gel: review of efficacy and safety].
Late stages of Parkinson's disease (PD) are characterized by the development of motor fluctuations and dyskinesia which inevitably emerge during the disease due to long-term use of levodopa and hinder treatment. The use of intestinal levodopa/carbidopa gel stabilizes the drug blood concentration and reduces the severity of motor parkinsonian symptoms. The literature of the last two decades on the efficacy and safety of intrarenal introduction of intestinal levodopa/carbidopa gel in PD patients is reviewed.A data analysis of intestinal levodopa/carbidopa gel revealed the efficacy of this method in the late stages of PD. The drug reduced motor symptoms, severity of motor fluctuations and dyskinesia and improved quality of life. Some studies demonstrated the decrease in PD stage, as evaluated by Hoehn and Yahr, during treatment with intestinal levodopa/carbidopa gel. The good tolerability profile allows for possibility of using this method for multiyear treatment. Side-effects were mostly related to drug delivery. All of them may be overcome in future in the process of technical improvement.


Generation of Potent Anti-HER1/2 Immunotoxins by Protein Ligation Using Split Inteins.
Cell targeting protein toxins have gained increasing interest for cancer therapy aimed at increasing the therapeutic window and reducing systemic toxicity. Because recombinant expression of immunotoxins consisting of a receptor-binding and a cell-killing moiety is hampered by their high toxicity in a eukaryotic production host, most applications rely on recombinant production of fusion proteins consisting of an antibody fragment and a protein toxin in bacterial hosts such as Escherichia coli ( E. coli). These fusions often lack beneficial properties of whole antibodies like extended serum half-life or efficient endocytic uptake via receptor clustering. Here, we describe the production of full-length antibody immunotoxins using self-splicing split inteins. To this end, the short (11 amino acids) N-terminal intein part of the artificially designed split intein M86, a derivative of the Ssp DnaB intein, was recombinantly fused to the heavy chain of trastuzumab, a human epidermal growth factor receptor 2 (HER2) receptor targeting antibody and to a nanobody-Fc fusion targeting the HER1 receptor, respectively. Both antibodies were produced in Expi293F cells. The longer C-terminal counterpart of the intein was genetically fused to the protein toxins gelonin or Pseudomonas Exotoxin A, respectively, and expressed in E. coli via fusion to maltose binding protein. Using optimized in vitro splicing conditions, we were able to generate a set of specific and potent immunotoxins with IC50 values in the mid- to subpicomolar range.


N-methylnicotinamide failed to induce endothelial prostacyclin release in perfused rat hindquarters.
N-methylnicotinamide, a nicotinamide derivative, possesses anti-thrombotic activity, although the mechanism of its action is unclear. Using a rat model of isolated perfused hindlimb, we tested whether this metabolite of nicotinamide is able to inhibit the vasoconstrictive effects of epinephrine, norepinephrine, and angiotensin II, thereby releasing prostacyclin from the endothelium. We found that N-methylnicotinamide administration by infusion or bolus injection did not change the course of perfusion pressure and did not inhibit the vasoconstrictive action of epinephrine, norepinephrine, or angiotensin II. In contrast, prazosin was able to completely abolish the constriction induced by epinephrine. Moreover, we did not find any changes in the level of a stable prostacyclin analog measured in the collected perfusate samples. Thus, we did not observe any endothelial prostacyclin-releasing properties of N-methylnicotinamide in the perfused rat hindquarters model.


Cerulenin is a potent inhibitor of antigen processing by antigen-presenting cells.
Cerulenin is an antibiotic that inhibits eukaryotic lipid and sterol synthesis and blocks lipid modification of proteins. The effect of cerulenin on the ability of accessory cells to present antigen to T cells was investigated. This antibiotic strongly inhibits the ability of accessory cells to present antigen to murine T-T hybrids. This effect is observed for multiple distinct antigens including L-glutamic acid60-L-alanine30-L-tyrosine10, bovine insulin, L-glutamic acid56-L-lysine35-L-phenylalanine9, and ovalbumen. Presentation by both macrophage and B lymphoblastoid cell lines is inhibited. The ability to effectively pulse these cells with antigen is inhibited but not the ability of these same cells to present antigen that they have previously processed. Furthermore, this inhibition is selective as it can occur without significant inhibition of the antigen-presenting cell protein or DNA synthesis. Cerulenin does not inhibit antigen uptake or catabolism as assessed with labeled antigen. By these criteria this drug is shown to interfere with an antigen-processing step. The ability of cerulenin to block processing was compared with other known inhibitors. Although cerulenin was effective with all antigens tested, at least one inhibitor was not. Taken together, these results suggest that the effect of cerulenin may define a distinct step in antigen processing and provides evidence that some other processing events are not universally required. The ability of cerulenin to interfere with antigen processing is discussed in the context of the known actions of this antibiotic and events of antigen processing and presentation.


[The Integral-2MT television analyzer of the morphological characteristics of tumor cells].
Integral-2MT is designed for differential diagnosis of tumor-like neoplasms. It also provides for automatized morphological parameter examination of cells which are either deposited on the slides or photographed in the form of a positive or negative picture. The analyser design and its operation principle are described. The analyser structural diagram is based on the modular main principle using the Electronika-60M microcomputer. The analyser software permits to determine 8 morphological cell parameters, to calculate statistical cell population features, to draw automatically histograms in various scales according to the operator's choice. The possible application spheres are described.


Dual Biocontrol Potential of the Entomopathogenic Fungus, Isaria javanica, for Both Aphids and Plant Fungal Pathogens.
Dual biocontrol of both insects and plant pathogens has been reported for certain fungal entomopathogens, including Beauveria bassiana and Lecanicillum spp. In this study, we demonstrate, for the first time, the dual biocontrol potential of two fungal isolates identified by morphological and phylogenetic analyses as Isaria javanica. Both these isolates caused mortality in the greater wax moth, and hence can be considered entomopathogens. Spores of the isolates were also pathogenic to nymphs of the green peach aphid (Myzus persicae), with an LC50 value of 107 spores/mL 4 days after inoculation and an LT50 of 4.2 days with a dose of 108 spores/mL. In vitro antifungal assays also demonstrated a strong inhibitory effect on the growth of two fungi that are pathogenic to peppers, Colletotrichum gloeosporioides and Phytophthora capsici. These results indicate that I. javanica isolates could be used as novel biocontrol agents for the simultaneous control of aphids and fungal diseases, such as anthracnose and Phytophthora blight, in an integrated pest management framework for red pepper.


Front-line treatment of advanced non-small-cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial.
To evaluate the tolerance and efficacy of the combination of docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC). Fifty-one chemotherapy-naive patients with NSCLC were treated with gemcitabine 900 mg/m2 intravenously on days 1 and 8 and docetaxel 100 mg/m2 intravenously on day 8 with granulocyte colony-stimulating factor (150 microg/m2, subcutaneously) support from day 9 to day 15. Treatment was repeated every 3 weeks. The patients' median age was 64 years. The World Health Organization performance status was 0 to 1 in 39 patients and 2 in 12 patients. Fifteen patients (29%) had stage IIIB disease, and 36 (71%) had stage IV; histology was mainly squamous cell carcinoma (59%). A partial response was achieved in 19 patients (37.5%; 95% confidence interval, 24% to 50%); stable disease and progressive disease were each observed in 16 patients (31.4%). The median duration of response and the time to tumor progression were 5 and 6 months, respectively. The median survival was 13 months, and the actuarial 1-year survival was 50.7%. Grade 4 anemia and thrombocytopenia were rare (2%). Four patients (8%) developed grade 3 or 4 neutropenia, and all were complicated with fever; there was no treatment-related death. Grade 3 or 4 diarrhea occurred in three patients (6%), grade 2 or 3 neurotoxicity in four patients (8%), grade 2 or 3 asthenia in 10 patients (20%), and grade 2 or 3 edema in 10 patients (20%). The combination of docetaxel/gemcitabine is well tolerated, can be used for outpatients, and is active for the treatment of advanced NSCLC. This treatment merits further comparison with other cisplatin- or carboplatin-based combinations.


WO3/W:BiVO4/BiVO4 graded photoabsorber electrode for enhanced photoelectrocatalytic solar light driven water oxidation.
We demonstrate the dual advantages of graded photoabsorbers in mesoporous metal oxide-based hetero interfacial photoanodes in improving photogenerated charge carrier (e-/h+) separation for the solar light-driven water-oxidation process. The pre-deposition of sol-gel-derived, tungsten-doped bismuth vanadate (W:BiVO4) onto a primary BiVO4 water oxidation layer forms graded interfaces, which facilitate charge transfer from the primary photoabsorber to the charge transport layer, thereby superseding the thickness-controlled charge recombination at the BiVO4 water oxidation catalyst. As a result, the WO3/BiVO4 hetero photoanode containing the photoactive W:BiVO4 interfacial layer showed 130% higher photocurrent than that of the interfacial layer-free hetero photoelectrode owing to the enhanced charge separation led water oxidation process.


[Caregivers of elderly with advanced cancer: vulnerable actors].
Cancer presents high prevalence and mortality rates among elderly Brazilians, and family members provide meaningful care, especially during terminal illness. A literature review focused on the impact for families and the physical, psychological, social, and economic burden for family caregivers of seniors with advanced cancer, as well as related interventions. More studies are needed on family caregivers of elderly with advanced cancer in Brazil in order to develop programs to protect these important social actors.


Adolescents' understanding and use of nicotine in e-cigarettes.
Nicotine harms adolescent brain development and contributes to addiction. Some adolescents report using nicotine-free e-cigarettes, but the accuracy of their reporting is unclear. We explored adolescents' use of nicotine-free e-cigarettes and understanding of chemicals in e-cigarettes, including nicotine. Using social media, we recruited 1589 US adolescents (aged 15-17) who reported past 30-day use of e-cigarettes in 2016. We assessed perceptions of the nicotine source in e-liquid and whether e-cigarette aerosol is just "water vapor." We explored differences among adolescents who usually used e-cigarettes with nicotine (n = 473) and without nicotine (n = 452). We used weights to calibrate our sample to the Youth Risk Behavior Survey. Twenty-nine percent usually used e-cigarettes without nicotine, 28% with nicotine, 39% with "both," and 5% were "not sure." Few participants (17% of non-nicotine users vs. 34% of nicotine users, p < .001) understood the nicotine was derived from tobacco. Youth who thought e-cigarette aerosol was just water vapor were more likely to usually use without nicotine. Older adolescents and current tobacco users were less likely to usually use without nicotine. The adolescents who reported usually using e-cigarettes without nicotine had poorer knowledge of e-cigarettes. This lack of understanding could contribute to inaccurate reporting of nicotine use. Most youth thought the nicotine in e-cigarettes was artificial, potentially indicating a belief that this nicotine is "safer." The US Food & Drug Administration will require nicotine warnings on e-cigarettes in 2018; a complementary educational campaign could address youths' misperceptions about nicotine and other chemicals in e-cigarette aerosol.


Enhancement of Contralesional Motor Control Promotes Locomotor Recovery after Unilateral Brain Lesion.
There have been controversies on the contribution of contralesional hemispheric compensation to functional recovery of the upper extremity after a unilateral brain lesion. Some studies have demonstrated that contralesional hemispheric compensation may be an important recovery mechanism. However, in many cases where the hemispheric lesion is large, this form of compensation is relatively limited, potentially due to insufficient connections from the contralesional hemisphere to the paralyzed side. Here, we used a new procedure to increase the effect of contralesional hemispheric compensation by surgically crossing a peripheral nerve at the neck in rats, which may provide a substantial increase in connections between the contralesional hemisphere and the paralyzed limb. This surgical procedure, named cross-neck C7-C7 nerve transfer, involves cutting the C7 nerve on the healthy side and transferring it to the C7 nerve on the paretic side. Intracortical microstimulation, Micro-PET and histological analysis were employed to explore the cortical changes in contralesional hemisphere and to reveal its correlation with behavioral recovery. These results showed that the contralesional hemispheric compensation was markedly strengthened and significantly related to behavioral improvements. The findings also revealed a feasible and effective way to maximize the potential of one hemisphere in controlling both limbs.


Antimicrobial stewardship: philosophy versus practice.
To promote the judicious use of antimicrobials and preserve their usefulness in the setting of growing resistance, a number of policy-making bodies and professional societies have advocated the development of antimicrobial stewardship programs. Although these programs have been implemented at many institutions in the United States, their impact has been difficult to measure. Current recommendations advocate the use of both outcome and process measures as metrics for antimicrobial stewardship. Although patient outcome metrics have the greatest impact on the quality of care, the literature shows that antimicrobial use and costs are the indicators measured most frequently by institutions to justify the effectiveness of antimicrobial stewardship programs. The measurement of more meaningful outcomes has been constrained by difficulties inherent to these measures, lack of funding and resources, and inadequate study designs. Antimicrobial stewardship can be made more credible by refocusing the antimicrobial review process to target specific disease states, reassessing the usefulness of current metrics, and integrating antimicrobial stewardship program initiatives into institutional quality and safety efforts.


Per-period co-payments and the demand for health care: evidence from survey and claims data.
When health insurance reforms involve non-linear price schedules tied to payment periods (for example, fees levied by quarter or year), the empirical analysis of its effects has to take the within-period time structure of incentives into account. The analysis is further complicated when demand data are obtained from a survey in which the reporting period does not coincide with the payment period. We illustrate these issues using as an example a health care reform in Germany that imposed a per-quarter fee of €10 for doctor visits and additionally set an out-of-pocket maximum. This co-payment structure results in an effective 'spot' price for a doctor visit that decreases over time within each payment period. Taking this variation into account, we find a substantial reform effect-especially so for young adults. Overall, the number of doctor visits decreased by around 9% in the young population. The probability of visiting a physician in any given quarter decreased by around 4 to 8 percentage points.


A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo.
Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug-drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.


Location Modification Factors for Potential Dose Estimation.
A U.S. Department of Energy facility must comply with the National Emission Standard for Hazardous Air Pollutants for radioactive air emissions. The standard is an effective dose of less than 0.1 mSv y to the maximum public receptor. Additionally, a lower dose level may be assigned to a specific emission point in a State issued permit. A method to efficiently estimate the expected dose for future emissions is described. This method is most appropriately applied to a research facility with several emission points with generally low emission levels of numerous isotopes.


Benzo(a)pyrene metabolism in primary cultures of mouse epidermal cells and untransformed and transformed epidermal cell lines.
The metabolism of [3H]benzo(a)pyrene [B(a)P] by cultures of primary mouse epidermal cells and untransformed and transformed epidermal cell lines was investigated. All three cell types effectively metabolized [3H]B(a)P. The major organic solvent-extractable metabolites found intracellularly in primary cultures were trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene and 3-hydroxybenzo(a)pyrene, although quantities of 9-hydroxybenzo(a)pyrene, trans-9,10-dihydro-9,10-dihydroxybenzo(a)pyrene, and quinones also were present. The major organic solvent-soluble metabolites found in the extracellular medium were trans-9,10-dihydro-9,10-dihydroxybenzo(a)pyrene and trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, with smaller quantities of unconjugated phenols and quinones. The major water-soluble metabolites found in the extracellular medium were conjugated with glucuronic acid [primarily 3-hydroxybenzo(a)pyrene and several quinones]. No sulfate conjugates of [3H]B(a)P metabolites were detected. [3H]B(a)P metabolism was similar in cultures of untransformed and transformed epidermal cell lines but differed from the primary cultures. The major intracellular and extracellular organic solvent-soluble metabolites were diols. Little or no unconjugated phenols were detected. Both the untransformed and transformed epidermal cell lines converted [3H]B(a)P to water-soluble metabolites, primarily glucuronide conjugates. In contrast to the primary cells, a major pathway of trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene metabolism in the untransformed and transformed cell lines was a glucuronide conjugate. Primary mouse epidermal cells provide an important model system for studying factors affecting the activation and detoxification of hydrocarbon carcinogens.