In vivo evaluation of intramedullary interlocking nail fixation of transverse femoral osteotomies in foals.
To evaluate an intramedullary interlocking nail for stabilization of transverse femoral osteotomies in foals. A transverse osteotomy and restabilization with an intramedullary interlocking nail was performed on the right femur in three foals and the left femur in three foals. Six foals weighing 149 to 207 kg. The femur was destabilized with a transverse middiaphyseal osteotomy and repaired with a 0.5-in (12.7 mm) interlocking nail. The implanted femurs were radiographed monthly until completion of the study 6 months after surgery. At the completion of the study, all foals were observed for evidence of lameness, gluteal thickness was determined by ultrasonographic measurement, and a necropsy was performed. Healing was satisfactory in all foals. Five of the six had osseous bridging of the osteotomy apparent radiographically by 3 to 4 months. The sixth foal had postoperative infection but was healed radiographically in 5 months. There was a mean decrease in gluteal muscle thickness of 6.6 mm (P = .04) in the operated limb of the five foals that healed without complication. Two foals were lame at the completion of the project; one foal with varus deformities of the contralateral limb was mechanically lame, and another was grade 2/5 lame on the operated limb. On necropsy, there was circumferential enlargement of the diaphysis of all operated limbs with the majority of the callus at the cranial and medial aspects of the cortex. All nails were solid within the medullary cavity. The intramedullary interlocking nail provided adequate stabilization for repair of the transverse osteotomy. Further investigation is warranted before use for stabilization of spontaneously occurring fracture configurations.


A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition.
T cells generally recognize peptide antigens bound to MHC proteins through contacts with residues found within or immediately flanking the seven- to nine-residue sequence accommodated in the MHC peptide-binding groove. However, some T cells require peptide residues outside this region for activation, the structural basis for which is unknown. Here, we have investigated a HIV Gag-specific T cell clone that requires an unusually long peptide antigen for activation. The crystal structure of a minimally antigenic 16-mer bound to HLA-DR1 shows that the peptide C-terminal region bends sharply into a hairpin turn as it exits the binding site, orienting peptide residues outside the MHC-binding region in position to interact with a T cell receptor. Peptide truncation and substitution studies show that both the hairpin turn and the extreme C-terminal residues are required for T cell activation. These results demonstrate a previously unrecognized mode of MHC-peptide-T cell receptor interaction.


Effects of S-adenosyl-1,8-diamino-3-thiooctane on polyamine metabolism.
Exposure of mammalian cells (transformed mouse fibroblasts or rat hepatoma cells) to S-adenosyl-1,8-diamino-3-thiooctane produced profound changes in the intracellular polyamine content. Putrescine was increased and spermidine was decreased, consistent with the inhibition of spermidine synthase by this compound, which is a potent and specific "transition-state analogue inhibitor" of the isolated enzyme in vitro. The spermine content of the cells was increased by exposure to this drug presumably since spermine synthase was able to use a greater proportion of the available decarboxylated S-adenosylmethionine when spermidine synthase was inhibited. The decarboxylated S-adenosylmethionine content rose substantially because the activity of S-adenosylmethionine decarboxylase was increased in response to the decline in spermidine. These results indicate that S-adenosyl-1,8-diamino-3-thiooctane is taken up by mammalian cells and is an effective inhibitor of spermidine synthase in vivo and that S-adenosylmethionine decarboxylase is regulated by the content of spermidine, but not of spermine. The growth of SV-3T3 cells was substantially reduced in the presence of S-adenosyl-1,8-diamino-3-thiooctane at concentrations of 50 microM or greater. Such inhibition was reversed by the addition of spermidine but not by putrescine. When SV-3T3 cells were exposed to 5 mM alpha-(difluoromethyl)ornithine and 50 microM S-adenosyl-1,8-diamino-3-thiooctane, the content of all polyamines was reduced. Putrescine and spermidine declined by more than 90% and spermine by 80%. Such cells grew very slowly unless spermidine was added.


Mortality in COPD: inevitable or preventable? Insights from the cardiovascular arena.
Mortality due to chronic obstructive pulmonary disease continues to rise, whereas mortality rates related to cardiovascular disease appear to be slowing, or even declining. This is due at least in part to more widespread use of preventative therapies that have been shown to reduce cardiovascular mortality, raising the question of whether appropriate use of therapies for chronic obstructive pulmonary disease which potentially reduce mortality could have a similar impact. This article discusses approaches used successfully in managing heart disease and considers whether these can be applied to chronic obstructive pulmonary disease and whether a better understanding of the strongest predictors of mortality in chronic obstructive pulmonary disease is needed. It reviews the role of inhaled corticosteroids, both alone and in combination with long-acting beta(2)-agonists, in individuals with chronic obstructive pulmonary disease, including the role of combination therapy with inhaled corticosteroids/long-acting beta(2)-agonists (budesonide/formoterol or salmeterol/fluticasone propionate) in decreasing exacerbations and improving health status, potentially providing survival benefits in chronic obstructive pulmonary disease. This review also discusses the potential impact of treatments indicated for cardiovascular disease on chronic obstructive pulmonary disease and possible links between the two diseases.


Environmental influences on inflammatory bowel disease manifestations. Lessons from epidemiology.
Environmental factors play an important role in the disease manifestation, course and prognosis of inflammatory bowel disease. Observations on temporal trends and geographical distribution point at risk factors associated with a Western lifestyle. A large number of studies have been performed on various factors such as diet, smoking, and several infectious agents. Childhood exposures modifying immune responses in later life form a particularly interesting field. However, so far, only smoking in Crohn's disease, and smoking cessation in ulcerative colitis can be considered established as risk factors for the manifestation of the disease. Smoking is also associated with a poor prognosis in Crohn's disease. A strong negative association of appendectomy with ulcerative colitis has been very consistent across many studies; however, the implications of this finding are still obscure.


The glycine transporter type 1 inhibitor N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine potentiates NMDA receptor-mediated responses in vivo and produces an antipsychotic profile in rodent behavior.
Glycine acts as a necessary coagonist for glutamate at the NMDA receptor (NMDAR) complex by binding to the strychnine-insensitive glycine-B binding site on the NR1 subunit. The fact that glycine is normally found in the brain and spinal cord at concentrations that exceed those required to saturate this site has led to the speculation that glycine normally saturates NMDAR-containing synapses in vivo. However, additional lines of evidence suggest that synaptic glycine may be efficiently regulated in synaptic areas by the glycine transporter type 1 (GlyT1). The recent description of a potent and selective GlyT1 inhibitor (N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine [NFPS]) provides a tool for evaluation of the hypothesis that inhibition of GlyT1 may increase synaptic glycine and thereby potentiate NMDAR function in vivo. In the present study, we found that (+)-NFPS demonstrated >10-fold greater activity in an in vitro functional glycine reuptake assay relative to the racemic compound. In vivo, (+/-)-NFPS significantly enhanced long-term potentiation in the hippocampal dentate gyrus induced by high-frequency electrical stimulation of the afferent perforant pathway. Furthermore, (+)-NFPS induced a pattern of c-Fos immunoreactivity comparable with the atypical antipsychotic clozapine and enhanced prepulse inhibition of the acoustic startle response in DBA/2J mice, a strain with low basal levels of prepulse inhibition. Collectively, these data suggest that selective inhibition of GlyT1 can enhance NMDAR-sensitive activity in vivo and also support the idea that GlyT1 may represent a novel target for developing therapeutics to treat disorders associated with NMDAR hypofunction.


Contrasting Cases of HIV Vasculopathy Associated Fusiform Aneurysms.
Human Immunodeficiency Virus (HIV) vasculopathy encompasses the development of aneurysms, stenosis and vessel occlusions. Intracranial fusiform aneurysms in Human Immunodeficiency Virus (HIV) were originally described in children; however, HIV-associated aneurysms are increasingly recognized in adults. Purpose: We present two cases to highlight the spectrum of severity and outline instructive clinical courses. Case one is a 52-year-old woman with HIV, Acquired Immunodeficiency Syndrome (AIDS)-defining progressive multifocal leukoencephalopathy (PML) and an 18 years course of cerebral aneurysms, aneurysm thrombosis and the development of right middle cerebral artery (MCA) moyamoya pattern collaterals. Case two is a 55-year-old man with AIDS-defining cerebral toxoplasmosis, complicated by IRIS and anterior and posterior circulation fusiform aneurysm formation. Conclusions: The combination of both fusiform abnormalities and Moyamoya, discussed in our first case has not been previously described. In comparison, our second case actually demonstrated improvement in vasculopathy after nine-months of antiretroviral therapy (ART) adherence.


Implications of epidemic-pandemic convergence for routine care adoption of contingency management: A case study.
The significant increase in opioid-related drug overdoses during the coronavirus disease (COVID-19) pandemic has put an unprecedented burden on hospital emergency departments, who saw as high as an approximate 150% increase in emergency department (ED) admission rates in the initial months of the pandemic. Although overdose is a clear sign of problem drug use, only a small proportion of nonfatal overdose patients enroll in treatment within 30 days of their overdose. To bridge the gap between opioid overdoses and treatment entry, a smartphone-smart debit card contingency management program was developed to promote entry into medication-assisted treatment by out-of-treatment opioid users who have recently received care in a hospital emergency department. The case study described in this article highlights a successful implementation of this intervention despite numerous disruptions related to COVID-19 that would have made engagement difficult without the remote access to contingency management provided by this technology. Patient status over time is presented in conjunction with contingency management earnings. Technology-based contingency management may provide improved scalability, rigorous outcomes metrics, and lower costs than prior onsite, manual contingency management (CM) approaches. The COVID-19 pandemic, in combination with the opioid epidemic has created a context in which historical obstacles to the adoption of contingency management may be overcome. This case study demonstrates the potential utility of smartphone-based contingency management when in-person care is difficult to access or disrupted. The requirement for further research demonstrating the efficacy of these approaches is discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


New replacement name for Chrysotus infirmus Wei, Zhang & Zhou, 2014 (Diptera, Dolichopodidae, Diaphorinae).
Chrysotus weii Zhou, nom. n., the new replacement name is proposed for the species Chrysotus infirmus Wei, Zhang & Zhou, 2014 (Diptera: Brachycera: Dolichopodidae: Diaphorinae), which was preoccupied by Chrysotus infirmus Parent, 1933.


[Automated external defibrillators, life vest defibrillator, or both?].
As most understand, survival of cardiac arrest victims falls significantly if cardioversion is not performed promptly. The standard of practice for out-of-hospital defibrillation is the implantable cardiac defibrillator; however, much has been written and discussed about the use of automated external defibrillators. Not as much has been written about life vest wearable defibrillators. How to use these devices will be reviewed in this article.


Hypoxic sensitizer and cytotoxin for head and neck cancer.
Tumour hypoxia is well recognised as a major factor contributing to radioresistance. This article examines the role of hypoxia in influencing the treatment outcome following radiotherapy (RT), and reviews the rationale and results of clinical trials that utilise hypoxic sensitizers or cytotoxins in the treatment of head and neck carcinoma. Histologic evidence for tumour hypoxia in human neoplasms was first reported in 1955. Since then, direct measurement by microelectrodes has revealed heterogeneity in intratumoural oxygen concentrations, and low oxygen concentrations are associated with poor local-regional control by RT. These findings coupled with the result of nuclear imaging studies employing radiolabelled imidazoles, provide strong evidence for the existence of tumour hypoxia which influences RT treatment outcome. Hyperbaric oxygen (HBO) trials for head and neck cancer, conducted in the early 1970s, demonstrated that HBO improved local control and survival rates in patients with head and neck cancer receiving radiotherapy (RT). Since the mid-1970s, clinical research in overcoming tumour hypoxia was mainly centred on the use of nitro-imidazoles as hypoxic cell sensitizers. However, the results from several major clinical trials remain inconclusive. Specifically, the Radiation Therapy Oncology Group (RTOG) misonidazole head and neck trial (298 patients) showed no benefit. The Danish misonidazole trial (626 patients) showed no overall benefit, however positive results were observed in a subgroup (304 pharyngeal cancer patients). Although the European Organisation for Research and Teaching of Cancer (EORTC) misonidazole trial with hyperfractionated RT showed no benefit, the Danish nimorazole trial demonstrated an overall benefit in survival as well as local control. The European etanidazole (ETA) trial (374 patients) showed no advantage of adding the drug to RT. The RTOG ETA trial (504 patients) showed no global benefit. However, positive results were observed in a subset of patients with early nodal disease (197 patients). In addition, a recent meta-analysis by Overgaard, utilising pooled results in the literature demonstrated that modification of tumour hypoxia significantly improved local-regional control in head and neck cancers with an odds ratio of 1.23 (95% confidence limits 1.09 to 1.37). Hypoxic cytotoxins, such as tirapazamine, represent a novel approach in overcoming radioresistant hypoxic cells. Tirapazamine is a bioreductive agent which, by undergoing one electron reduction in hypoxic conditions, forms cytotoxic free radicals that produce DNA strand breaks causing cell death. In vitro and in vivo laboratory studies demonstrate that tirapazamine is 40 to 150 times more toxic to cells under hypoxic conditions as compared to oxygenated conditions and that tirapazamine is superior to ETA in enhancing fractionated irradiation in mouse SCCVII and other tumour types with an enhancement ratio of 1.5 to 3.0. Phase I studies demonstrated that therapeutic doses of tirapazamine can be given safely. A multi-institutional phase II trial using tirapazamine with concurrent RT for head and neck cancer is now in progress.


Use of a Modified Frazier Water Protocol in Critical Illness Survivors With Pulmonary Compromise and Dysphagia: A Pilot Study.
Limited information is available regarding use of the Frazier free water protocol (FWP) with hospitalized patients who have dysphagia and have survived a critical illness with compromised pulmonary status. This pilot study used a two-group nonequivalent comparison group design to evaluate the FWP in 15 adults admitted to a respiratory care unit (RCU) with dysphagia concerns. Inclusion criteria included recommendation for a modified diet with thickened liquids by a dysphagia therapist and ability to follow the specific free water guidelines. The 15 control participants were chosen from a retrospective chart review of consecutive RCU admissions that met the same inclusion criteria. The intervention group for whom the free water guidelines were implemented did not differ significantly from the control group in rate of development of aspiration pneumonia, χ²(30) = .01, p = 1.00.


Non-word repetition in children with language impairment--pitfalls and possibilities.
Specific language impairment has, although not without controversy, been considered as a consequence of a phonological memory deficit. Non-word repetition has been proposed as a reliable index of phonological memory and also as predictive of lexical and grammatical development in normally developing and language-impaired children. The main aim was to study the relationship between repetition of words and non-words and expressive language skills (phonology and grammar) in 27 5-year-old children with language impairment. The authors also wanted to explore the influence of lexical stress on repetition skills. The results showed that words were significantly easier to repeat than non-words and that non-word repetition skills were significantly correlated to phonological and grammatical development. The most important predictor of non-word repetition skills was output phonology. The conclusion is that non-word repetition is not a single, reliable index of phonological memory in preschool children with language impairment. Also, the influence of prosodic variables on segmental aspects of speech production should not be overlooked in non-word construction, since it was found that unstressed syllables were omitted six times more often in prestressed than in post-stressed positions of the words and non-words.


Spatial Clustering of Tobacco Retailers Near U.S. Public Schools.
Previous studies have found that tobacco retailers cluster near schools. However, all retail outlets may locate near each other and near schools due to existing infrastructure and zoning policies. We assessed whether tobacco retailers cluster near schools in the United States more than expected when accounting for existing retail locations. We identified 322,056 probable tobacco retailers, 95,110 public schools, and >3.8 million businesses comparable to tobacco retailers in land use and business type. We created 500 simulated tobacco retailer datasets by randomly selecting from the larger list of businesses. For each simulated dataset, we calculated distance from schools to the nearest tobacco retailer (proximity) and count of tobacco retailers within 800 meters of schools (density). Observed proximity and density values were compared to 95% coverage intervals from the 500 simulations. We stratified analyses by urbanicity, percentage of students in the free and reduced-priced lunch program (FRLP), and percentage of Hispanic/Latino, non-Hispanic Black, and non-Hispanic white students. Tobacco retailers were closer to schools in rural areas, cities, and towns and more dense around schools in rural areas, cities, and suburbs compared to random locations in potential retail space. Schools with more students receiving FRLP had higher density than expected while schools with fewer students receiving FRLP had lower density than expected. Within rural areas, clustering did not vary across sociodemographic group. Within non-rural areas, there were inequities in clustering by racial, ethnic, and socioeconomic school composition. Tobacco retailers cluster near schools after accounting for existing business patterns. There are inequities in clustering by sociodemographic school composition. This study provides compelling evidence that tobacco retailers cluster near U.S. public schools and there are racial, ethnic, and socioeconomic inequities in clustering, even when accounting for overall retail location patterns. Given that public schools tend to reflect neighborhood demographics, policies to limit tobacco retailers near schools may reduce both school-based and neighborhood-based inequities.


Improved method to track chlorophyll degradation.
An analytical method capable of identifying >30 chlorophyll-related compounds in plant extracts has been developed. The method employs liquid chromatography coupled to UV-vis, MS, and MS/MS detection. It can be applied without modification to analyze natural chlorophyll degradation products and other metalloporphyrines. It was successfully applied to identify chlorophyll derivatives found in rehydrated spinach powder and conventionally canned and Veri-Green-processed beans. In the Veri-Green-processed beans several degradation products were identified that are zinc-containing analogues to the chlorophyll derivatives found in vegetables after conventional canning. They have been characterized by liquid chromatography and mass spectrometry.


Lack of an association between the ASN-108 mutation in the dihydrofolate reductase gene and in vivo resistance to sulfadoxine/pyrimethamine in Plasmodium falciparum.
Sulfadoxine/pyrimethamine (SP) is considered an alternative treatment for acute uncomplicated malaria caused by Plasmodium falciparum resistant to chloroquine. However, the appearance of resistance to this drug has been reported since its initial use in Colombia. Molecular analysis of the dihydrofolate reductase gene indicates a correlation between in vitro resistance to SP and the Asn-108 point mutation. Little is known about the association of this point mutation and in vivo resistance to SP. We used a mutation-specific polymerase chain reaction strategy to analyze the presence of the Asn-108 point mutation in 48 clinical samples with adequate clinical response (ACR), 2 early treatment failures (ETF), and 1 late treatment failure (LTF). The Asn-108 mutation was detected in 36 of the ACR samples and in all of the ETF and LTF samples. Eleven ACR samples amplified with the wild-type-specific primer and one amplified with the primer for the Thr-108 mutation described for resistance to cycloguanil. These results suggest that the Asn-108 marker may not be useful in predicting SP treatment failure.


The role of mitochondria in cellular iron-sulfur protein biogenesis: mechanisms, connected processes, and diseases.
Iron-sulfur (Fe/S) clusters belong to the most ancient protein cofactors in life, and fulfill functions in electron transport, enzyme catalysis, homeostatic regulation, and sulfur activation. The synthesis of Fe/S clusters and their insertion into apoproteins requires almost 30 proteins in the mitochondria and cytosol of eukaryotic cells. This review summarizes our current biochemical knowledge of mitochondrial Fe/S protein maturation. Because this pathway is essential for various extramitochondrial processes, we then explain how mitochondria contribute to the mechanism of cytosolic and nuclear Fe/S protein biogenesis, and to other connected processes including nuclear DNA replication and repair, telomere maintenance, and transcription. We next describe how the efficiency of mitochondria to assemble Fe/S proteins is used to regulate cellular iron homeostasis. Finally, we briefly summarize a number of mitochondrial "Fe/S diseases" in which various biogenesis components are functionally impaired owing to genetic mutations. The thorough understanding of the diverse biochemical disease phenotypes helps with testing the current working model for the molecular mechanism of Fe/S protein biogenesis and its connected processes.


Circadian variation in heart-rate variability in localization-related epilepsy.
Case-control studies of sudden unexpected death in epilepsy (SUDEP) have reported that SUDEP is more likely to occur during sleep and thus presumably during night hours. The circadian variation of heart-rate variability (HRV) might be of relevance to this risk. We examined night versus daytime HRV in patients with newly diagnosed and refractory localization-related epilepsy, assessing the effects of drug treatment and epilepsy surgery on the night/daytime HRV ratio. We used spectral analysis to assess HRV and calculated the night-time (00.00-05.00)/daytime (07.30-21.30) ratio of HRV in 14 patients with newly diagnosed localization-related epilepsy before and during carbamazepine (CBZ) treatment and in 21 patients with temporal lobe epilepsy before and after epilepsy surgery. Both groups were compared with age- and sex-matched controls. No significant differences were found from controls in the night/daytime ratios of HRV whether compared before or after initiation of treatment with CBZ in newly diagnosed epilepsy patients. When patients were used as their own controls, night/daytime ratios of standard deviation of RR intervals (p = 0.04) and total power (p = 0.04) were significantly lower during treatment than before. Compared with those of controls, the night/daytime ratios were lower in epilepsy surgery patients before surgery [low-frequency power (p = 0.04); high-frequency power (p = 0.04)]. Night/daytime ratios did not change significantly after surgery. The HRV of the patients was more affected during night-time when the risk of SUDEP seems to be highest in such patients.


Extremely high avidity association of Fe(III) with the sickle red cell membrane.
Red blood cells (RBCs) from patients with sickle cell anemia and thalassemia carry abnormal accumulations of molecular Fe(III) at the cytosol/membrane interface. The avidity of the red cell membrane for this iron has not been defined. Using open ghost membranes prepared from sickle RBC, we examined the ability of membrane-associated Fe(III) to resist removal by 15 chelators representing a 40-log range of affinities for Fe(III). Efficacy of chelators was compared with literature values for their idealized affinity for iron as represented by the cummulative stability constant (beta n), their effective stability constant reflecting affinity under biologic conditions (Keff), and an indicator of their ability to chelate Fe(III) in the presence of an insoluble phase of iron (Ksol). Deferoxamine, a very high affinity chelator having log beta n = 30.6, was found to be the lowest affinity chelator able to remove RBC membrane Fe(III). Regardless of chelator beta n, only those agents able to preserve log Keff > or = 12 were able to do so, indicating that the membrane's effective avidity for Fe(III) is on the order of 10(12). Additional confirmation that membrane avidity for Fe(III) is extremely high is found in the observation that only chelators having log Ksol > 0 were effective. Potential physiologic iron chelators in cytoplasm of pathologic red cells are unable to prevent or reverse iron accumulation on the membrane because they do not have sufficiently high affinity for iron. These data argue that RBC membrane Fe(III) is truly pathologic.


Using evidence to enhance the recovery of patients undergoing colorectal surgery: part 2.
This is the second part of a three-part series describing how an enhanced recovery clinical pathway uses a multidisciplinary team to reduce postoperative stress and complications, improve recovery, and decrease hospital length of stay without affecting patient safety for patients undergoing colorectal surgery. Last month, patient education and discharge planning were discussed. This part discusses multimodal analgesia and standardized postoperative nausea and vomiting prophylaxis. Next month, fluids, diet, tubes and drains, and early mobilization will be discussed.


Outcomes with different administration schedules of bortezomib in bortezomib, lenalidomide and dexamethasone (VRd) as first-line therapy in multiple myeloma.
Induction therapy for multiple myeloma with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (d) (VRd) was traditionally administered as bortezomib given twice weekly on a 3 week cycle. A modified schedule of weekly bortezomib has been adopted over time to decrease treatment burden for patients and reduce treatment-emergent neuropathy. This study evaluates the response rates and outcomes with different schedules of bortezomib in VRd administered for first-line treatment for patients with newly diagnosed MM (NDMM). We retrospectively analyzed patients treated with upfront VRd from June 30th 2008 to December 31st 2018, for variations of bortezomib administration. Five hundred and fifty-five (555) NDMM patients met inclusion criteria; median age 63 years and 61% men. Bortezomib was administered twice weekly every 21 days in 43%, once weekly every 21 days in 41% and once weekly every 28 days in 16%. Though peripheral sensory neuropathy was more frequent with twice weekly dosing (P = .002), this group achieved shorter time to best response (P = .01). Weekly every 21-day treatment saw higher VGPR or better rates (P = .02). However, with median follow up time of 37 months (IQR 22-56), we found no difference in PFS or OS among the groups. While small differences in response rates were found among the varying administration schedules of bortezomib administration, there was no significant effect on PFS or OS. Given that VRd remains a first line standard of care option for newly diagnosed MM, in the absence of a large trial comparing bortezomib dosing schedule modifications, these results are helpful in supporting current practices of once weekly administration.


Serum 25-hydroxyvitamin D is associated with incident peripheral artery disease among white and black adults in the ARIC study cohort.
Low 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with peripheral artery disease (PAD). Prevalence of low 25(OH)D and PAD differ between whites and blacks. However, these associations have not been studied prospectively or in a population based cohort. We tested the hypothesis that low 25(OH)D is associated with greater risk of incident PAD in white and black adults. 25(OH)D was measured in serum collected at ARIC visit 2 (1990-1992). We followed 11,789 ARIC participants free of PAD at visit 2 through 2011 for incident PAD events. 25(OH)D (ng/mL) was categorized as deficient (<20), insufficient (20 to <30) or sufficient (≥30). PAD was defined by an ankle brachial index (ABI) of <0.9 at ARIC visits 3 or 4 or a hospital diagnosis with an ICD-9 code indicating PAD during follow-up. Analysis used multivariable-adjusted Cox proportional hazards regressions. Over a mean follow-up of 17.1 years, 1250 incident PAD events were identified. 22% of whites and 61% of blacks were 25(OH)D deficient. After adjustment for demographic characteristics, the hazard ratio (95% CI) of PAD in participants with deficient versus sufficient 25(OH)D was 1.49 (1.26, 1.76). Inclusion of BMI, physical activity, and smoking status attenuated the association [1.25 (1.06, 1.48)]. The association between 25(OH)D and PAD was qualitatively stronger in blacks (p for interaction = 0.20). Deficient 25(OH)D was associated with increased risk of PAD in black and white participants. Whether treatment of low vitamin D through supplementation or modest sunlight exposure prevents PAD is unknown.


STUDY OF THE MENTAL STATE OF STUDENTS IN THE PROCESS OF ONLINE EDUCATION DURING THE CORONAVIRUS PANDEMIC.
The aim: Exploring the specifics of the underlying mental states of university students in the context of online learning during the COVID-19 pandemic and identifying their relationship to mental health. Materials and methods: The study of mental states was carried out using three valid methods, namely: a clinical questionnaire for the detection and evaluation of neurotic states (K. Yakhin, D. Mendelevich), a questionnaire for diagnosing the level of social frustration (L. Wasserman, adaptation of V. Bojko), State-Trait Anxiety Inventory (STAI) (Ch. Spielberger, adaptation by Yu. Khanin). The author's questionnaire (L. Borysenko) was used to study the connection between the factors of online learning and emotional states of students. The obtained empirical data were subjected to qualitative and quantitative processing. Results: The analysis of the obtained data allows to state the fact of predominance of high and increased level of situational and personal anxiety in the subjects in the conditions of online learning. In the process of psychodiagnosis of neurotic states, it was found that most students have a level of painful or borderline mental conditions such as anxiety, neurotic depression, asthenia and autonomic disorders. It was found that students have an elevated level and high level of social frustration. The main factors of online learning, which, according to students, cause them to deteriorate mental health are: forced to stay in a confined space, lack of direct social contacts, prolonged stay in a static position, increased study load and volume of tasks, anxiety for academic success and quality professional training, concern for their health and the health of their loved ones. Conclusions: The forced transition to online learning due to the COVID-19 pandemic has negatively affected the mental state of many students. In most respondents, this manifested itself in increased anxiety, depression, autonomic reactions due to limited opportunities to communicate with teachers and classmates, new learning conditions and increased workload.


[Dr. Moritz Wallach--a century of medicine and tradition in Shaare Zedek].
Dr. Wallach, who founded the Shaare Zedek Hospital and managed the institution for forty-five years, was instrumental in providing modern medical care to Jerusalem residents since his arrival in the city in 1891. He dedicated his life to medicine, to the Jerusalem Jewish community, and to improving the quality of service provided by the existing medical establishment. He was one of the outstanding personalities in a city and community struggling for existence. The Jewish religious character that marks today's Shaare Zedek hospital was determined 100 years ago by Dr. Wallach, who integrated the ancient Jewish moral spirit into a modern medical service tradition. While fulfilling his daily tasks, both as a practicing physician and as the hospital-director, Dr. Wallach became a role model to those who followed him. He mixed freely with the "elite" and his personal relations with local dignitaries, political figures, influential westerners, intellectuals, and important foreign diplomats contributed significantly to the growth, success, and reputation the hospital enjoyed during the last century. On the other hand, he was also personally involved with destitute new immigrants to Eretz Israel and actively engaged in finding jobs, housing, and employment for them. Dr. Wallach became a legend in his own time, both locally and internationally. Due to his professional status and personality, Dr. Wallach became a representative of the Jewish community. He had the ability to speak for the Jews with the Ottoman authorities, and afterwards with the British Mandate authorities. He played a significant role in educating the population in public responsibility, while concurrently leaving his mark on generations of physicians who learned from him the value of precision, loyalty, professional secrecy, and medical responsibility. He was one of the "Giants" of the land (Yishuv) in its critical formative years.


Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain.
The contribution of metabolomic factors to the association of healthy lifestyle with type 2 diabetes risk is unknown. We assessed the association of a composite measure of lifestyle with plasma metabolite profiles and incident type 2 diabetes, and whether relevant metabolites can explain the prospective association between healthy lifestyle and incident type 2 diabetes. A Healthy Lifestyle Score (HLS) (5-point scale including diet, physical activity, smoking status, alcohol consumption and BMI) was estimated in 1016 Hortega Study participants, who had targeted plasma metabolomic determinations at baseline examination in 2001-2003, and were followed-up to 2015 to ascertain incident type 2 diabetes. The HLS was cross-sectionally associated with 32 (out of 49) plasma metabolites (2.5% false discovery rate). In the subset of 830 participants without prevalent type 2 diabetes, the rate ratio (RR) and rate difference (RD) of incident type 2 diabetes (n cases = 51) per one-point increase in HLS was, respectively, 0.69 (95% CI, 0.51, 0.93), and - 8.23 (95% CI, - 16.34, - 0.13)/10,000 person-years. In single-metabolite models, most of the HLS-related metabolites were prospectively associated with incident type 2 diabetes. In probit Bayesian Kernel Machine Regression, these prospective associations were mostly driven by medium HDL particle concentration and phenylpropionate, followed by small LDL particle concentration, which jointly accounted for ~ 50% of the HLS-related decrease in incident type 2 diabetes. The HLS showed a strong inverse association with incident type 2 diabetes, which was largely explained by plasma metabolites measured years before the clinical diagnosis.


Total arterial myocardial revascularization using new composite graft techniques for internal mammary and/or radial arteries conduits.
Total arterial myocardial revascularization (TAMR) is feasible because of the excellent long-term patency of the arterial conduits. We present five new surgical configurations for TAMR. Between December 1998 and July 1999, 34 patients with triple vessel disease underwent TAMR. All patients were in CCS III or IV. Sketelonized internal mammary arteries (IMAs) were used. The surgical techniques for TAMR consisted of Y or T composite grafts constructed between the in situ RIMA and free LIMA graft or radial artery (RA) conduit in three different configurations. Other techniques uses included a T graft constructed between the RA conduit and free LIMA graft in two configurations. Twenty-six (76%) patients underwent contrast-enhanced TTE color Doppler before and after adenosine provocative test, and seven (20%) patients had postoperative coronary angiography. Overall, 144 anastomoses (average number per patient, 4.2) were completed. One (2.9%) patient undergoing an inverted T graft technique died on postoperative day 2. Another patient (2.9%) undergoing the right Y graft technique using IMAs and RA suffered perioperative AMI due to RA conduit vasospasm. Contrast-enhanced TTE color Doppler before and after the adenosine provocative test and at 1 week postoperation revealed a coronary flow reserve (CFR) of 2.1 +/- 0.2 in the LIMA stem, and in the RIMA stem, a CFR of 2.3 +/- 0.3 (P < 0.007). In one patient undergoing the right Y graft technique using IMAs, we found only anomalous flow dynamic parameters of RIMA, suggesting a partial graft closure. The angiographic examination revealed a free LIMA graft closure. At 6 +/- 2.4 months after operation 33 patients were alive and free of angina. The IMAs stem evaluation by TTE color Doppler at follow-up revealed a 2.45 +/- 0.1 mm LIMA diameter and 2.6 +/- 0.2 mm RIMA diameter, which was more than early postoperative data of P < 0.001 and P < 0.007, respectively. These data indicate that TAMR in young patients perhaps offers a better postoperative outcome and perhaps should be part of the surgical armamentarium. These techniques apply the "nontouch" principle and should be taken into consideration in patients with a heavily calcified aorta. Contrast-enhanced TTE color Doppler is a safe, accurate, and noninvasive test, which allows assessment of IMA patency and CFR evaluation. The flow reserve of the IMAs seems to be adequate for multiple coronary anastomoses.


Central ossifying fibroma, periapical cemento-osseous dysplasia and complex odon-toma occurring in the same jaw.
Central ossifying fibroma is a rare, benign fibro-osseous lesion that arises from the periodontal ligament. Periapical cemento-osseous dysplasia is another variant of fibro-osseous lesion which occurs in the anterior region of the mandible of females. Odontoma is a benign odontogenic tumor that contains enamel, dentine cement and pulp tissue. A 46-year-old woman was referred to the Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, with two non-painful swellings on both sides of the mandible, which had been slowly growing over a period of one year. Our differential diagnosis was florid cemento-osseous dysplasia, focal cemento-osseous dysplasia for the right side, complex odontoma for the left side and periapical cement-osseous dysplasia for the anterior side. The historical feature revealed ossifying fibroma, complex odontoma and periapical cemento-osseous dysplasia. The occurrence of these three lesions in the same jaw has been rarely reported in the literature. The relationship between the occurrence of these three lesions is not obvious it could be coincidental. It seems that more case reports are needed to establish the relationship between them.


Identification of genetic variants and individual genes associated with postpartum hypocalcemia in Holstein cows.
Periparturient hypocalcemia is a complex metabolic disorder that occurs at the onset of lactation because of a sudden irreversible loss of Ca incorporated into colostrum and milk. Some cows are unable to quickly adapt to this demand and succumb to clinical hypocalcemia, commonly known as milk fever, whereas a larger proportion of cows develop subclinical hypocalcemia. The main goal of this study was to identify causative mutations and candidate genes affecting postpartum blood calcium concentration in Holstein cows. Data consisted of blood calcium concentration measured in 2513 Holstein cows on the first three days after parturition. All cows had genotypic information for 79 k SNP markers. Two consecutive rounds of imputation were performed: first, the 2513 Holstein cows were imputed from 79 k to 312 k SNP markers. This imputation was performed using a reference set of 17,131 proven Holstein bulls with 312 k SNP markers. Then, the 2513 Holstein cows were imputed from 312 k markers to whole-genome sequence data. This second round of imputation used 179 Holstein animals from the 1000 Bulls Genome Project as a reference set. Three alternative phenotypes were evaluated: (1) total calcium concentration in the first 24 h postpartum, (2) total calcium concentration in the first 72 h postpartum calculated as the area under the curve; and (3) the recovery of total calcium concentration calculated as the difference in total calcium concentration between 72 and 24 h. The identification of genetic variants associated with these traits was performed using a two-step mixed model-based approach implemented in the R package MixABEL. The most significant variants were located within or near genes involved in calcium homeostasis and vitamin D transport (GC), calcium and potassium channels (JPH3 and KCNK13), energy and lipid metabolism (CA5A, PRORP, and SREBP1), and immune response (IL12RB2 and CXCL8), among other functions. This work provides the foundation for the development of novel breeding and management tools for reducing the incidence of periparturient hypocalcemia in dairy cattle.


[Significance and management of testicular microlithiasis].
Testicular microlithiasis is an infrequent urologic diagnosis of non well-known etiology; it has been observed in patients with infertility, testicular atrophy, chromosomopathies, etc., and it had been considered as a benign non progressive disease for a long time. Recent reports have shown its occasional association with malignant tumors. We look for evidences about the significance of testicular microlithiasis and its relationship with gonadal pathologies. We perform an electronic bibliographic search in both The Cochrane library and MEDLINE. We performed a manual search in the AUA Update Series, Current Opinion Urology, and bibliographic citations from selected studies. We report one case of bilateral testicular microlithiasis studied at our center which is illustrative. Most published articles are case reports with bibliographic review. The real incidence is unknown, although depending on the series varies from 0.04% in autopsies to 18.1% in testicular ultrasound series. It is more frequent in chryptorchidism, infertility, varicocele, testicular torsion, brain and sympathetic nervous system calcifications, pseudohermaphroditism, Down's syndrome, Klinefelter and Carney, cystic fibrosis, germ cell tumors and carcinoma in situ. There are series which report testicular tumor up to 46% of patients with testicular microlithiasis. It has been described tumor development during follow-up of testicular microlithiasis between 15 months and 11 years, so that it is believed to be a predisposing factor, a possible indirect indicator of premalignant disease, or a tumor marker. It has been also described in normal testicles. The presence of testicular microlithiasis and its association to both benign diseases and malignant tumors makes a careful evaluation and follow-up necessary, mainly in patients with chryptorchidism, infertility, testicular atrophy, and contralateral testicular tumor; it is recommended testicular ultrasound each semester/year, physical examination, and testicular markers determination; to proceed with testicular biopsy is reasonable in patients of high risk (focal unilateral microlithiasis without mass, or the aforementioned chryptorchidism, infertility, testicular atrophy, and testicular tumor).


Tolosa-Hunt syndrome as initial presentation of Systemic Lupus Erythematosus.
Case presentation of newly diagnosed systemic lupus erythematosus (SLE) presenting initially as Tolosa-Hunt syndrome (THS). Retrospective clinical case. Case report. A healthy young man developed acute binocular diplopia within 2 days without other neurological deficits. Bilateral 6th cranial nerve palsy was observed with general reduction in the visual field test. Emergent brain magnetic resonance image (MRI) was performed, which revealed severe inflammation in the cavernous sinus, superior orbital fissure, and apex of the orbit. No cavernous thrombosis or intracranial lesion was shown in the MRI. THS was diagnosed and the patient's CN 6 palsy recovered quickly after corticosteroid treatment. However, severe anaemia was discovered during admission (Hb=6.0), so the patient was evaluated by profound laboratory tests, which revealed SLE. With painful ophthalmoplegia, cavernous sinus syndrome is highly suspected. THS is one of the differential diagnoses for cavernous sinus syndrome. THS is a rare disease, recognized by the National Organization for Rare Disorders, and characterized by inflammatory changes in the cavernous sinus, superior orbital fissure and/or orbital apex under image study. The inflammatory changes are mostly idiopathic, but secondary causes such as sarcoidosis or other autoimmune diseases need to be ruled out. Physicians should be aware of possible underlying conditions, such as immunosuppressed status as in SLE, as the true cause of THS.


Pulmonary vascular air embolism in hyaline membrane disease.
Pulmonary vascular air embolism is a rare, fatal complication of positive-pressure ventilation in hyaline membrane disease. Sudden deterioration of an infant on respiratory therapy should alert the clinician and radiologist to the possibility of this entity. A case history with typical radiographic findings is presented.


A self-aligning upper-limb exoskeleton preserving natural shoulder movements: kinematic compatibility analysis.
NESM-γ is an upper-limb exoskeleton to train motor functions of post-stroke patients. Based on the kinesiology of the upper limb, the NESM-γ includes a four degrees-of-freedom (DOF) active kinematic chain for the shoulder and elbow, along with a passive chain for self-aligning robotic joint axes with the glenohumeral (GH) joint's center of rotation. The passive chain accounts for scapulohumeral rhythm and trunk rotations. To assess self-aligning performance, we analyzed the kinematic and electromyographic data of the shoulder in eight healthy subjects performing reaching tasks under three experimental conditions: moving without the exoskeleton (baseline), moving while wearing the exoskeleton with the passive DOFs properly functioning, i.e., unlocked (human-in-the-loop(HIL)-unlocked), and with the passive DOFs locked (HIL-locked). Comparison of baseline and HIL-unlocked conditions showed nearly unchanged anatomical movement patterns, with a root-mean-square error of shoulder angle lower than 5 deg and median deviations of the GH center of rotation below 20 mm. Peak muscle activations showed no significant differences. In contrast, the HIL-locked condition deviated significantly from the baseline, as observed by the trunk and GH trajectory deviations up to 50 mm, accompanied by increased peak muscle activations in the Deltoid and Upper Trapezius muscles. These findings highlight the need for kinematic solutions in shoulder exoskeletons that can accommodate the movements of the entire shoulder complex and trunk to achieve kinematic compatibility.


[Effect of forskolin and quinacrine on leukocyte functions under the effect of low-dose radiation].
The adenylate cyclase and phospholipase A2 incorporation in the functional responses as well as lipid peroxidation processes and glutathione system homeostasis of animal leukocytes to small doses of ionizing radiation (1-100 mGy) have been estimated. The cells were irradiated by introduction of radioactive isotope 14C-leucine into the incubation medium. It is established that the ionizing radiation has different effects on the modification of cellular functions by the agents, which change adenylate cyclase and phospholipase A2 activity. Neutralization of stimulative irradiation effect on chemokinesis of polymorphonuclear leukocytes by quinacrine (the inhibitor of phospholipase A2) indicates for certain, that metabolism of eicosanoids takes immediate part in the cell response to ionizing radiation. Apparently, adenylate cyclase has no influence on this process, where at indicates the lack of influence of forskolin (the stimulator of adenylate cyclase) on the spontaneous motility, and on the radiation action on this leukocyte function. Rosette forming ability of lymphocytes is regulated by both enzymes because it is modified both by the inhibitor of phospholipase A2, and by the adenylate cyclase stimulant. In this case it is impossible to exclude the action of ionizing radiation both through the adenylate cyclase cascade, and through the eicosanoid metabolism. In all the concentration range the radionuclides do not affect the studied biochemical indexes of the cell, but change the action of the modifiers.


Role of the US President's Emergency Plan for AIDS Relief in responding to tuberculosis and HIV coinfection.
The intersection of tuberculosis (TB) and human immunodeficiency virus (HIV) infection has eroded gains made in TB control, because previously well-functioning national TB programs have been overwhelmed by the dual challenges posed by TB and HIV coinfection. The US President's Emergency Plan for AIDS Relief (PEPFAR), through its direct support of >2.4 million persons receiving HIV treatment and, in 2009, support of >308,000 HIV-infected persons receiving TB treatment, works closely with national governments and other partners to strengthen the response to TB and HIV coinfection. PEPFAR-supported activities fall within the World Health Organization's 2004 framework for collaborative TB and HIV activities, including critical interventions to (1) develop organizational methods of collaboration across the 2 programs, (2) reduce the burden of HIV infection among patients with TB, and (3) reduce the burden of TB among persons with HIV infection or AIDS. To date, PEPFAR and partners have made important gains in coverage and scope of HIV testing, referral, and antiretroviral therapy for patients with TB. TB screening of HIV-infected patients is also beginning to increase, although greater progress needs to be made in increasing access to isoniazid preventive therapy and strengthening TB infection control. Continued strategic integration of TB and HIV interventions into PEPFAR-supported programs is essential to easing the patient burden of dual infection, improving patient outcomes, and, ultimately, decreasing rates of TB in areas with a high prevalence of TB.


The electrophysiological correlates of developmental dyslexia: New insights from lexical decision and reading aloud in adults.
Many studies have described the electrophysiological specificities of print processing in dyslexic readers, mostly using lexical decision tasks. The aim of the present study was twofold: a) to assess for the first time the electrophysiological correlates of print processing in dyslexic adults in the under-investigated context of reading aloud tasks, acknowledged to be especially relevant to investigate phonological processes relatively to lexical decision; and b) to assess whether the electrophysiological specificities described in dyslexic readers in lexical decision correspond to a different neuronal network engaged in print processing. 21 dyslexic university students and matched controls performed a lexical decision task and a reading aloud task on words and pseudowords under EEG recording. In lexical decision, the pattern of results indicates the engagement of similar brain processes between the groups, but with a sub-efficient visual word form processing in dyslexia. In reading aloud, between group differences revealed completely different distributions of the electric field at scalp between the two groups after the N2 time window, suggesting alternative processing strategies in dyslexic readers. Those specificities seem to be related to their core phonological deficits. Crucially, the present results suggest that the nature of electrophysiological divergences in print processing in dyslexic readers vary according to the task: while lexical decision task appears to be well suited to assess divergences in lexical access, reading aloud tasks should also be used in ERP investigation as it allows a better insight into phonological processes and thus be better suited in the framework of the phonological deficit theory of dyslexia.


Targeting lipid rafts inhibits protein kinase B by disrupting calcium homeostasis and attenuates malignant properties of melanoma cells.
Failure of current therapeutic modalities to treat melanoma remains a challenge for clinical and experimental oncology. The aggressive growth and apoptotic resistance of this tumor are mediated, in part, by aberrantly activated protein kinase B/Akt (PKB). In many cells, PKB signaling depends on integrity of cholesterol-enriched membrane microdomains (rafts). However, it is still unclear if rafts support deregulated PKB activity in melanoma. In this study, ablation of rafts in murine (B16BL6-8, JB/RH1) and human (GA) melanoma lines by cholesterol-chelating methyl-beta-cyclodextrin (MbetaCD) reduced levels of constitutively active PKB in a dose- and time-dependent manner, while reconstitution of microdomains restored PKB activity. PKB was sensitive to the membrane-permeable Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid tetra (acetocymethyl) ester and to the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) implying the contribution of Ca2+ signaling to PKB deregulation. Indeed, malignant and apoptosis-resistant clone of B16BL6 melanoma (B16BL6-8) displayed significantly higher [Ca2+](i) and store-operated Ca2+ influx (SOC) relative to non-malignant apoptosis-sensitive B16BL6 clone (Kb30) expressing barely detectable basal levels of active PKB. Raft ablation in B16BL6-8 cells robustly inhibited SOC and decreased [Ca2+](i) to levels comparable with those detected in Kb30 cells. Treating cells by PKB-inhibiting doses of M beta CD dramatically impaired their apoptotic resistance and capacity to generate tumors. Furthermore, weekly intraperitoneal injections of M beta CD to mice grafted with melanoma cells at doses of 300 and 800 mg/kg significantly attenuated tumor development. Our data implicate membrane rafts in enhancing the resistance of melanoma to apoptosis and indicate that targeting raft microdomains is a potentially effective strategy to cure this frequently fatal form of cancer.


Sensitivity to DNA damage induced by benzo(a)pyrene diol epoxide and risk of lung cancer: a case-control analysis.
Levels of DNA adducts vary greatly in vivo, attributable to individual differences in enzymatic bioactivation of benzo(a)pyrene. We developed an assay to measure the levels of DNA adducts induced in vitro by benzo(a)pyrene diol epoxide (BPDE), a bioactivated form of benzo(a)pyrene. In this large molecular epidemiological study of lung cancer, we tested the hypothesis that the level of in vitro BPDE-induced adducts is associated with risk of lung cancer. This hospital-based case-control study included 221 newly diagnosed lung cancer cases and 229 healthy controls frequency matched on age, sex, ethnicity, and smoking status. Short-term cultured peripheral blood lymphocytes from each subject were exposed in vitro to BPDE (4 microm) for 5 h, and the 32P-postlabeling method was then used to measure BPDE-induced DNA adducts in the host cells. Overall, the patients had significantly higher levels of BPDE-DNA adducts than did the controls (mean +/- SD per 107 nucleotides, 93.2+/-89.3 for cases versus 63.7+/-61.1 for controls; P = 0.001). Univariate and multivariate logistic regression analyses were performed to calculate the crude and adjusted odds ratios and their 95% confidence intervals. When the median adduct level of controls (46/10(7) nucleotides) was used as the cutoff point, 64% of cases had higher levels (odds ratio, 2.15; 95% confidence interval, 1.39-3.33, adjusted for age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24 h, and family history of cancer). Stratified analyses showed consistently higher levels of BPDE-induced adducts in cases than in controls, regardless of subgroup of age, sex, ethnicity, body mass index, recent weight loss, pack-years smoked, smoking in the last 24 h, and family history of cancer. A significant dose-response relationship between the quartile levels of BPDE-induced DNA adducts and the risk of lung cancer was observed (trend test, P < 0.001). The significant association between the level of in vitro BPDE-induced DNA adducts and risk for lung cancer suggests that subjects very sensitive to BPDE-induced DNA damage may have a suboptimal ability to remove the BPDE-DNA adducts and so are susceptible to tobacco carcinogen exposure and, therefore, may be at increased risk of lung cancer.


Dual functional monoclonal antibody PF-04605412 targets integrin alpha5beta1 and elicits potent antibody-dependent cellular cytotoxicity.
Integrin α5β1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies.


Low-frequency acoustic sweep monitoring of bone integrity and osteoporosis.
We developed a noninvasive method to evaluate bone structural integrity. It is based on the measurement of the dynamic characteristics of the bone using sweeping sound excitation in the range of acoustic frequencies. The Quality Factor (a measure of material damping) has been used as an indicator of the tendency of the bone to fracture. Results of animal studies have supported this hypothesis since linear correlations were observed between bone density, quality factor, and impact strength. A vibration excitation in the form of an acoustic sweep signal is applied to a bone to measure the quality factor. Rat bones were tested, obtained from animals with osteoporosis age-dependent (tested in vitro) or ovariectomy-induced (tested in vivo), and compared with bones of healthy (control) rats. The change in damping was, on average, equal or greater to the change in density. Moreover, excellent correlation of the quality factor was obtained with bone fracture energy measured with an impact test. During a vibration cycle, the changing strain results in temperature changes due to the reciprocity of temperature and strain. Nonreversible conduction of heat due to the unequal temperature change results in entropy production that is enhanced due to the stress concentration about the voids associated with bone porosity. Damping is a measure of the production of entropy. Its measure, the quality factor, represents a potentially useful tool for monitoring bone integrity, which is deteriorating in diseases characterized by disruption of the trabecular architecture, such as osteoporosis. A computational model yielded results that are in good correlation with the experimental results.


Solid-solid phase equilibria in the NaCl-KCl system.
Solid solutions, structurally ordered but compositionally disordered mixtures, can form for salts, metals, and even organic compounds. The NaCl-KCl system forms a solid solution at all compositions between 657 °C and 505 °C. Below a critical temperature of 505 °C, the system exhibits a miscibility gap with coexisting Na-rich and K-rich rocksalt phases. We calculate the phase diagram in this region using the semi-grand canonical Widom method, which averages over virtual particle transmutations. We verify our results by comparison with free energies calculated from thermodynamic integration and extrapolate the location of the critical point. Our calculations reproduce the experimental phase diagram remarkably well and illustrate how solid-solid equilibria and chemical potentials, including those at metastable conditions, can be computed for materials that form solid solutions.


Identification of TRIML2, a novel p53 target, that enhances p53 SUMOylation and regulates the transactivation of proapoptotic genes.
The tumor-suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell-cycle arrest, senescence, and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell-cycle arrest, whereas the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences, a gene-expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite-motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of proapoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3), and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress. The defined actions of TRIML2, in part, explain the underlying molecular basis for increased apoptotic potential of the R72 variant of p53.


Mind-Body Interventions for Pediatric Inflammatory Bowel Disease.
Pediatric inflammatory bowel disease is an autoimmune disease that causes chronic inflammation of the gastrointestinal mucosa. There is emerging evidence that the brain-gut connection affects inflammatory bowel disease (IBD) patients more than previously thought. This is evidenced by comorbid mood disorders, irritable bowel symptoms concurrent with quiescent IBD, and the potential of psychosocial stressors to trigger IBD flares. Mind-body interventions such as psychotherapy, relaxation, mindfulness, biofeedback, yoga, and clinical hypnosis offer an adjunct to standard medical treatment for IBD. We will review the current evidence base for these mind- body interventions in the treatment of pediatric IBD, illustrate a case study, and offer suggestions for future research for this promising field.


Mitochondrial reactive oxygen species generation in blood cells is associated with disease severity and exercise intolerance in heart failure patients.
Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as New York Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.


Effect of low-frequency repetitive transcranial magnetic stimulation on interhemispheric inhibition.
We studied the effects of 1-Hz repetitive transcranial magnetic stimulation (rTMS) on the excitability of interhemispheric connections in 13 right-handed healthy volunteers. TMS was performed using figure-eight coils, and surface electromyography (EMG) was recorded from both first dorsal interosseous (FDI) muscles. A paired-pulse method with a conditioning stimulus (CS) to the motor cortex (M1) followed by a test stimulus to the opposite M1 was used to study the interhemispheric inhibition (ppIHI). Both CS and TS were adjusted to produce motor-evoked potentials of approximately 1 mV in the contralateral FDI muscles. After baseline measurement of right-to-left IHI (pre-RIHI) and left-to-right IHI (pre-LIHI), rTMS was applied over left M1 at 1 Hz with 900 stimuli at 115% of resting motor threshold. After rTMS, ppIHI was studied using both the pre-rTMS CS (post-RIHI and post-LIHI) and an adjusted post-rTMS CS set to produce 1-mV motor evoked potentials (MEPs; post-RIHI(adj) and post-LIHI(adj)). The TS was set to produce 1-mV MEPs. There was a significant reduction in post-LIHI (P = 0.0049) and post-LIHI(adj) (P = 0.0169) compared with pre-LIHI at both interstimulus intervals of 10 and 40 ms. Post-RIHI was significantly reduced compared with pre-RIHI (P = 0.0015) but pre-RIHI and post-RIHI(adj) were not significantly different. We conclude that 1-Hz rTMS reduces IHI in both directions but is predominantly from the stimulated to the unstimulated hemisphere. Low-frequency rTMS may be used to modulate the excitability of IHI circuits. Treatment protocols using low-frequency rTMS to reduce cortical excitability in neurological and psychiatric conditions need to take into account their effects on IHI.


Toxicological Assessment of the Role of Alcohol and Drugs in Drug-Facilitated Sexual Assault Cases in New Zealand.
This report details the toxicology profile of victims of drug-facilitated sexual assault (DFSA) in New Zealand from 2015 to 2018. This study represents all of the toxicology results for DFSA cases in New Zealand during this time period, of which there were 161 cases. Blood and urine samples were screened for legal and illicit drugs in addition to testing for alcohol and correlating alcohol concentration with sampling delay. Our results indicate that increased delay in sampling time resulted in a corresponding decrease in alcohol concentration. In victims who had declared alcohol use but of which none was detected, the average sampling time was 14 hours for blood and 17 hours for urine, which is in excess of the average sampling delay for even the lowest alcohol-positive samples. The most frequently detected alcohol concentration was in the range of 51-80 mg/100 mL for blood and 121-200 mg/100 mL for urine with an average sampling time of 8.5 and 6.5 hours, respectively. We also examined acetone concentrations in alcohol-positive samples, and our results indicate that 82% of blood alcohol-positive samples contained acetone at concentrations between 5 and 10 mg/L and 68% of alcohol-positive urine samples contained acetone at a concentration >20 mg/L. It may be that the nature of sexual assault affects an individual's metabolism of alcohol and results in increased acetone production. Cannabis was the most commonly detected illicit drug, followed by methamphetamine. In relation to medicinal drugs, there was a high usage of antidepressants and antipsychotics, suggesting the victims may have been people of vulnerable personality. Based on case information, it does not appear there are many cases where stupefaction by unknown administration of a drug has occurred, instead loss of consent through voluntary alcohol and drug consumption is more common and poses a greater risk than surreptitious drug administration.


EEG EPs analysis of magnetic stimulation on acupoint of Shenmen(HT7).
Acupuncture is a useful irritation therapy clinically. Acupuncture at acupoints is proved to have specific function on human body. Magnetic stimulation is a new kind of stimulating technique of non-invasive, painless and effective. The effect of magnetic stimulation on acupoint is a new subject in recent years. In this paper, the electroencephalogram (EEG) evoked potentials (EPs) of magnetic stimulation by stimulating the acupoint of Shenmen(HT7) are studied. The experiments are divided into four groups: quiet, acupoint stimulation, mock stimulation and mock point stimulation. The EEG EPs are collected and an obvious P150 component is obtained. The amplitudes of P150s are analyzed and compared. The P150s are localized in brain by dipole model and the coronal, sagittal and axial plans are painted and observed. The results show that acupoint stimulation on acupoint of Shenmen(HT7) can evoke stronger nerve activity of somatosensory than stimulation on common surface. The dipole source of acupoint stimulation and common surface stimulation are both focused on the cingulated gyrus which related to somatosensory.


CSCD: a database for cancer-specific circular RNAs.
Circular RNA (circRNA) is a large group of RNA family extensively existed in cells and tissues. High-throughput sequencing provides a way to view circRNAs across different samples, especially in various diseases. However, there is still no comprehensive database for exploring the cancer-specific circRNAs. We collected 228 total RNA or polyA(-) RNA-seq samples from both cancer and normal cell lines, and identified 272 152 cancer-specific circRNAs. A total of 950 962 circRNAs were identified in normal samples only, and 170 909 circRNAs were identified in both tumor and normal samples, which could be further used as non-tumor background. We constructed a cancer-specific circRNA database (CSCD, http://gb.whu.edu.cn/CSCD). To understand the functional effects of circRNAs, we predicted the microRNA response element sites and RNA binding protein sites for each circRNA. We further predicted potential open reading frames to highlight translatable circRNAs. To understand the association between the linear splicing and the back-splicing, we also predicted the splicing events in linear transcripts of each circRNA. As the first comprehensive cancer-specific circRNA database, we believe CSCD could significantly contribute to the research for the function and regulation of cancer-associated circRNAs.


The shorter the person, the higher the blood pressure: a birth cohort study.
Short adult stature is known to be associated with increased cardiovascular morbidity and mortality, but the underlying explanatory mechanisms remain largely unknown. The purpose of the current study was to evaluate the relationship between height and blood pressure (BP), a major determinant of cardiovascular disease (CVD). We performed BP measurements including 24-h ambulatory BP measurements in 534 participants (mean age 61 ± 3 years, 51.3% women) from the Helsinki Birth Cohort Study. None of the study participants had medication affecting vasculature or BP. We assessed the influence of height on CVD risk factors with a standardized z-score representing the difference from the mean value for the whole study cohort. Daytime SBP, pulse pressure, and mean arterial pressure showed significant inverse associations with height (adjusted for age, leisure-time physical activity, body fat percentage, and smoking). Height was by itself a strong determinant of pulse pressure independently of BMI. In addition, total cholesterol, triglycerides, and apolipoprotein B concentrations decreased with increasing height. Shorter individuals have higher BP levels than taller individuals. This may at least partly explain the inverse association between height and CVD. In normal weight and slightly overweight individuals, the relationship between BP and height is independent of BMI and adiposity.


Functional and pharmacological characterization of an S5 domain hERG mutation associated with short QT syndrome.
Congenital short QT syndrome (SQTS) is a repolarization disorder characterized by abbreviated QT intervals, atrial and ventricular arrhythmias and a risk of sudden death. This study characterized a missense mutation (I560T) in the S5 domain of the hERG K+ channel that has been associated with variant 1 of the SQTS. Whole cell patch clamp recordings of wild-type (WT) and I560T hERG current (IhERG) were made at 37 °C from hERG expressing HEK 293 cells, and the structural context of the mutation was investigated using a recently reported cryo-EM structure of hERG. Under conventional voltage clamp, the I560T mutation increased IhERG amplitude without altering the voltage-dependence of activation, although it accelerated activation time-course and also slowed deactivation time-course at some voltages. The voltage dependence of IhERG inactivation was positively shifted (by ∼24 mV) and the time-course of inactivation was slowed by the I560T mutation. There was also a modest decrease in K+ over Na+ ion selectivity with the I560T mutation. Under action potential (AP) voltage clamp, the net charge carried by hERG was significantly increased during ventricular, Purkinje fibre and atrial APs, with maximal IhERG also occurring earlier during the plateau phase of ventricular and Purkinje fibre APs. The I560T mutation exerted only a modest effect on quinidine sensitivity of IhERG: the IC50 for mutant IhERG was 2.3 fold that for WT IhERG under conventional voltage clamp. Under AP voltage clamp the inhibitory effect of 1 μM quinidine was largely retained for I560T hERG and the timing of peak I560T IhERG was altered towards that of the WT channel. In both the open channel structure and a closed hERG channel model based on the closely-related EAG structure, I560T side-chains were oriented towards membrane lipid and away from adjacent domains of the channel, contrasting with previous predictions based on homology modelling. In summary, the I560T mutation produces multiple effects on hERG channel operation that result in a gain-of-function that is expected to abbreviate ventricular, atrial and Purkinje fibre repolarization. Quinidine is likely to be of value in offsetting the increase in IhERG and altered IhERG timing during ventricular APs in SQTS with this mutation.


A geometric confidence ellipse approach to the estimation of the ratio of two variables.
One is often interested in the ratio of two variables, for example in genetics, assessing drug effectiveness, and in health economics. In this paper, we derive an explicit geometric solution to the general problem of identifying the two tangents from an arbitrary external point to an ellipse. This solution permits numerical integration of a bivariate normal distribution over a wedge-shaped region bounded by the tangents, which yields an evaluation of the tangent slopes as confidence limits on the ratio of the component variables. After suitable adjustment of the confidence coverage of the ellipse, these confidence limits are shown to be equivalent to those from Fieller's method. However, the geometric approach allows additional interpretation of the data through identification of the points of tangency, the ellipse itself, and expressions for the coverage probability of the confidence interval. Numerical evaluations using the theoretical expressions for the geometric confidence intervals (but ignoring sample variation in the underlying parameters) suggested that they perform well overall and are slightly conservative. Simulations that do take account of sample variation in the underlying parameters again suggested that the intervals perform well overall, although here they are slightly anti-conservative. Coverage probabilities for the confidence intervals were only weakly dependent on the distance and correlation of the ellipse, but there were asymmetries in the failure rates of the upper and lower confidence limits in some configurations. The probability of no real solution existing was also evaluated. These ideas are illustrated by a practical example.


Do cutaneous receptors contribute to the changes in the amplitude of the H-reflex during massage?
Massage is known to produce a reduction in spinal reflex excitability. However, the mechanisms subserving this phenomenon have yet to be elucidated. This study was undertaken to determine the role of superficial cutaneoreceptors overlying the triceps surae during the application of a massage. Twelve neurologically healthy volunteers were subjected to an interrupted repeated measures design consisting of eight conditions. Each condition was comprised of eleven H-reflex recordings obtained from the right soleus muscle. Six conditions served to establish baseline control levels, while the remaining two conditions consisted of reflex recordings obtained simultaneous to the application of the massage. During the first massage condition, subjects were at rest while a three minute petrissage was applied to the right triceps surae muscle group. The second massage condition was always preceded by the application of a topical anaesthetic to abolish the sensation to touch and pin-prick to the skin area that was to be massaged. It was expected that the cutaneous afferents would not play any major role in the changes associated with the application of the massage. H-reflex amplitudes recorded during each massage condition (1.20 mV +/- 0.30 SEM, 1.05 mV +/- 0.23 SEM, respectively) were significantly reduced (F7.77 = 26.048, p < 0.01) in contrast to all control conditions (range: 2.21 to 2.63 mV). However, no difference was observed between the two massage conditions. The inhibitory effects of massage on the soleus H-reflex do not appear to originate from mechanical stimulation of cutaneous mechanoreceptors. It seems more likely that deep mechanoreceptors are involved.


A glycoside of Nicotina tabacum affects mouse dopaminergic behavior.
Climbing in the forced swimming test is considered a dopaminergic-specific behavior. A substance of Nicotina tabacum affecting dopamine neuronal activity was investigated using the mouse behavioral system. The substance was found to be a glycoside with the peripheral sugar chain structures Fuc alpha 1-2Gal, Gal beta 1-4GlcNAc and GalNAc alpha 1-3GalNAc and with basic polymannoses. The glycoside dose-dependently increased behavior via D2 neuronal activity, but not D1 activity. This suggests that smoking can affect human brain function not only via the nicotinic cholinergic neuron, but also via the D2 neuron.


Transglutaminase 2 is involved in autophagosome maturation.
Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but it is enhanced in response to stress, e.g. nutrient deprivation, hypoxia, mitochondrial dysfunction and infection. "Tissue" transglutaminase (TG2) accumulates, both in vivo and in vitro, to high levels in cells under stressful conditions. Therefore, in this study, we investigated whether TG2 could also play a role in the autophagic process. To this end, we used TG2 knockout mice and cell lines in which the enzyme was either absent or overexpressed. The ablation of TG2 protein both in vivo and in vitro, resulted in an evident accumulation of microtubule-associated protein 1 light chain 3 cleaved isoform II (LC3 II) on pre-autophagic vesicles, suggesting a marked induction of autophagy. By contrast, the formation of the acidic vesicular organelles in the same cells was very limited, indicating an impairment of the final maturation of autophagolysosomes. In fact, the treatment of TG2 proficient cells with NH4Cl, to inhibit lysosomal activity, led to a marked accumulation of LC3 II and damaged mitochondria similar to what we observed in TG2-deficient cells. These data indicate a role for TG2-mediated post-translational modifications of proteins in the maturation of autophagosomes accompanied by the accumulation of many damaged mitochondria.


Characteristically distinct isolates of the nuclear polyhedrosis virus from Spodoptera litura.
More than 100 isolates were plaque-purified to examine the genetic variations in four wild stocks of Spodoptera litura nuclear polyhedrosis virus (NPV) collected in Japan. These isolates were characterized by their in vitro host range in three established insect cell lines, growth characteristics, polyhedral protein, DNA restriction endonuclease pattern and DNA hybridization. The isolates were separated into four distinct groups: (I) isolates corresponding to Autographa californica NPV, (II and IV) two different groups of isolates of S. littoralis NPV which had been previously characterized and (III) isolates with no correspondence to any reported virus group. Of the S. litura NPV wild stocks, two were mixtures of more than two different groups of NPVs. We have discussed the advantage of having a mixture of different NPV groups in the same wild virus stocks.


Effects of heparin on lipolytic enzyme activities in vivo and in vitro.
The in vivo and in vitro effects of heparin on the lipolytic enzyme activities of normal rabbit serum and tissues were investigated. An acute intravenous injection of heparin produced the following changes in enzyme activities: in serum, phospholipase and lipase were increased, cholesterol esterase unchanged; in tissues phospholipase was increased, lipase was increased in heart and liver but decreased in aorta, cholesterol esterase was increased in heart but decreased in liver and aorta. In vitro phospholipase and lipase were increased by low concentrations of heparin, but decreased by high concentrations. Cholesterol esterase was decreased irrespective of heparin concentration. It is suggested that heparin may affect lipolytic enzyme activities by influencing the ionic state of the enzyme and substrate.


Static and dynamic assessment of myocardial perfusion by computed tomography.
Recent developments in computed tomography (CT) technology have fulfilled the prerequisites for the clinical application of myocardial CT perfusion (CTP) imaging. The evaluation of myocardial perfusion by CT can be achieved by static or dynamic scan acquisitions. Although both approaches have proved clinically feasible, substantial barriers need to be overcome before its routine clinical application. The current review provides an outline of the current status of CTP imaging and also focuses on disparities between static and dynamic CTPs for the evaluation of myocardial blood flow.


A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.
Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low-dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high-risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment-related grade 3-4 non-haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18-50%] and 6.8 months overall and 38% [95% CI, 19-57%] and 7.2 months at the MTD. The median disease-free survival was 7.4 months. Fifty-two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.


Use of human papillomavirus DNA, E6/E7 mRNA, and p16 immunocytochemistry to detect and predict anal high-grade squamous intraepithelial lesions in HIV-positive and HIV-negative men who have sex with men.
Men who have sex with men (MSM) are at high risk of having anal cancer. Anal high-grade squamous intraepithelial lesion (HSIL) is the precursor of anal cancer. We explored the use of different biomarkers associated with human papillomavirus (HPV) infection and HPV-mediated cell transformation to detect and predict HSIL among HIV-positive and HIV-negative MSM. A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled and followed for 12 months. High-resolution anoscopy (HRA) with biopsies were performed at every visit along with anal sample collection for cytology, high-risk HPV DNA genotyping, HPV E6/E7 mRNA, and p16 immunocytochemistry. Performance characteristics and area under the receiver operator characteristics curve were calculated for these biomarkers at baseline, and Cox regression compared the usefulness of these biomarkers in predicting incident HSIL. High-risk HPV DNA, E6/E7 mRNA, and p16 immunocytochemistry each identified 43-46% of MSM whose baseline test positivity would trigger HRA referral. E6/E7 mRNA had the highest sensitivity (64.7%) and correctly classified the highest number of prevalent HSIL cases. With the exception of p16 immunochemistry, most tests showed significant increases in sensitivity but decreases specificity versus anal cytology, while the overall number of correctly classified cases was not significantly different. Baseline or persistent type 16 and/or 18 HPV DNA was the only test significantly predicting incident histologic HSIL within 12 months in models adjusted for HIV status and low-grade squamous intraepithelial lesions at baseline. Countries with a high HIV prevalence among MSM and limited HRA resources may consider using biomarkers to identify individuals at high risk of HSIL. E6/E7 mRNA had the highest sensitivity for prevalent HSIL detection regardless of HIV status, whereas type 16 and/or 18 HPV DNA performed best in predicting development of incident HSIL within 12 months.


antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline.
Secondary metabolites produced by bacteria and fungi are an important source of antimicrobials and other bioactive compounds. In recent years, genome mining has seen broad applications in identifying and characterizing new compounds as well as in metabolic engineering. Since 2011, the 'antibiotics and secondary metabolite analysis shell-antiSMASH' (https://antismash.secondarymetabolites.org) has assisted researchers in this, both as a web server and a standalone tool. It has established itself as the most widely used tool for identifying and analysing biosynthetic gene clusters (BGCs) in bacterial and fungal genome sequences. Here, we present an entirely redesigned and extended version 5 of antiSMASH. antiSMASH 5 adds detection rules for clusters encoding the biosynthesis of acyl-amino acids, β-lactones, fungal RiPPs, RaS-RiPPs, polybrominated diphenyl ethers, C-nucleosides, PPY-like ketones and lipolanthines. For type II polyketide synthase-encoding gene clusters, antiSMASH 5 now offers more detailed predictions. The HTML output visualization has been redesigned to improve the navigation and visual representation of annotations. We have again improved the runtime of analysis steps, making it possible to deliver comprehensive annotations for bacterial genomes within a few minutes. A new output file in the standard JavaScript object notation (JSON) format is aimed at downstream tools that process antiSMASH results programmatically.


Myeloperoxidase G-463A polymorphism and risk of lung and prostate cancer in a Turkish population.
Myeloperoxidase (MPO) is a phase I enzyme that can bioactivate many specific procarcinogens, including polycyclic aromatic hydrocarbons and aromatic amines. The MPO gene contains a common single nucleotide polymorphism, for which the -463G>A substitution within the promoter region has been shown to reduce MPO expression and activity. We investigated the association between the MPO -463G>A polymorphism and lung and prostate cancer in a Turkish population. MPO genotypes in the study populations were determined using polymerase chain reaction-based restriction fragment length polymorphism assay. The allelic frequency was significantly different between the cases and controls for lung cancer (p=0.02), but not prostate cancer (p=0.30). No significant difference was noted between the lung and prostate cancer cases and control populations in terms of genotype distribution (p=0.07, p=0.53, respectively). Control groups of lung and prostate cancer were in Hardy-Weinberg equilibrium (p=0.87 and p=0.41, respectively). To determine the protective effect against lung cancer among individuals with the -463A allele, G/A and A/A genotypes were combined. Comparison of the G/G and G/A + A/A genotypes between the lung cancer cases and control groups showed a statistically significant relationship (p=0.032, OR=0.60, 95% CI 0.38-0.95). No gender-specific difference was found in terms of genotype distribution between the lung cancer patients and the controls (female, p=0.20; male, p=0.34). In the case of smokers, a difference in genotype distribution between the lung cancer patients and the controls was statistically significant (p=0.02), although this difference was not statistically significant for non-smokers (p=0.90). Overall, no statistically significant difference was found between the prostate cancer cases and the controls in terms of genotype combination (p=0.46, OR=0.83, 95% CI 0.51-1.36). Additionally, in smokers and non-smokers, no significant relationship was determined between the prostate cancer patients and the control population (p=0.21, p=0.91, respectively). These results suggest that the MPO -463A allele significantly contributes to a protective effect overall and in smokers against lung cancer.


Anterior capsulotomy for obsessive-compulsive disorder: a review of old and new literature.
Over the last two decades, deep brain stimulation (DBS) has gained popularity as a treatment of severe and medically refractory obsessive-compulsive disorder (OCD), often using brain targets informed by historical lesional neurosurgical procedures. Paradoxically, the use of DBS in OCD has led some multidisciplinary teams to revisit the use of lesional procedures, especially anterior capsulotomy (AC), although significant aversion still exists toward the use of lesional neurosurgery for psychiatric disorders. This paper aims to review all literature on the use of AC for OCD to examine its effectiveness and safety profile.All publications on AC for OCD were searched. In total 512 patients were identified in 25 publications spanning 1961-2018. In papers where a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was available, 73% of patients had a clinical response (i.e., > 35% improvement in Y-BOCS score) and 24% patients went into remission (Y-BOCS score < 8). In the older publications, published when the Y-BOCS was not yet available, 90% of patients were deemed to have had a significant clinical response and 39% of patients were considered symptom free. The rate of serious complications was low.In summary, AC is a safe, well-tolerated, and efficacious therapy. Its underuse is likely a result of historical prejudice rather than lack of clinical effectiveness.


Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis.
Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.


A family study of dermatoglyphic traits in India: resolution of genetic and uterine environmental effects for palmar pattern ridge counts.
The inheritance of palmar pattern ridge counts for individual palmar areas, combined distal areas, and all ten areas combined was investigated in families belonging to two strictly endogamous Brahmin castes of peninsular India. Ridge count phenotypes were obtained by the method proposed by Malhotra et al. (1981a), however, zero observations (indicating patterns not circumscribed by triradii) were excluded from analysis. Path analytic methods were applied in order to determine the relative influences of polygenes, intrauterine environment, and residual environment. The proportion of genetic variation was, in general, consistently greater in one population than the other, and significant intrauterine environmental effects were detected for the population with lower heritabilities. The results of this investigation suggest that a simple polygenic model may not be sufficient to explain the inheritance of ridge counts in the interdigital IV configurational area. Distal pattern ridge counts do not appear to be influenced by more or less uterine environmental effects than all areas considered together. The proportion of genetic variation for the total palmar pattern ridge count was 52% in both populations.