Effects of angle Class II, division 1 treatment with jumping-the-bite appliances. A longitudinal study.
The present study investigated treatment effects in patients with Angle Class II, Division 1 malocclusions treated with jumping-the-bite appliances on the basis of cast evaluation and lateral cephalometrics. A significant reduction in overjet (p < 0.001) and overbite (p < 0.01) occurred during the course of treatment. A significant reduction in the SNA-angle (p < 0.001) and increase in the SNB-angle (p < 0.001) led to a reduced ANB-angle (p < 0.001). The treatment effect on the maxilla was greater than on the mandible. A slight posterior rotation of the maxilla (p < 0.05) occurred whereas the other vertical relations did not change significantly. The upper incisors were significantly retruded (p < 0.001) while the lower incisors were increasingly protruded (p < 0.001). The interincisal angle was not markedly altered.


A Review of Clostridium difficile Infection at the University Hospital of the West Indies, Jamaica.
This study examined the frequency of Clostridium difficile infection (CDI) among hospital admission and diarrhoeal stool samples over a six-year period. A review of all suspected cases of C difficile positive patients from 2007 to 2012 at the University Hospital of the West Indies (UHWI), Jamaica, was performed. Clostridium difficile infection was confirmed by clinical features and a positive enzyme-linked immunosorbent assay (ELISA) stool test for Clostridium Toxins A and B. The demographics, clinical features, risk factors, treatment and outcomes were also examined. There were 56 patients reviewed. The most commonly affected age group was 40-59 years of age. The proportion of CDI cases per total stool samples increased from 0.5% in 2007 to 5.9% in 2010 then fell to 2.2% in 2011 but increased again to 4.3% in 2012. The proportion of cases per total UHWI admissions also increased from 0.12 cases per 1000 admissions in 2007 to 1.16 in 2010 and 1.36 in 2012 (p < 0.001). Most CDI cases were nosocomial (76% males, 48.6% females). Co-morbidities included hypertension and end-stage renal disease. Ceftazidime was the most common antibiotic associated with the development of CDI. Resolution occurred in 62.5% of patients. Duration of hospital stay was longer in males than females (≥ 21 versus < 7 days) and males had more adverse outcomes, with death in 23.8% versus 11.4%. There has been an increase in the frequency of CDI at UHWI with a greater than expected frequency of community acquired CDI. Increased awareness is needed of the increasing risk for CDI and measures must be taken to prevent the disease, especially in hospitalized patients.


The Impact of Administrative Academic Units (AAU) Grants on the Family Medicine Research Enterprise in the United States.
The Health Resources and Services Administration (HRSA) awards funding to primary care departments-or "Academic Administrative Units" (AAUs) at US medical schools-to strengthen or grow these departments and ultimately increase the output of primary care physicians into the US workforce. One aspect of these AAU grants that is often overlooked is the fact that they support research infrastructure for these departments. This study used multiple methods, including content analysis of current AAU grant abstracts (n=23), publications resulting from AAU funding (n=79), and survey responses from AAU project directors (n=19) to explore and describe the impact of current AAU grants on family medicine research in the United States. Federal support for family medicine departments remains very low compared to other disciplines. Several AAU grants have provided direct support for research activities as stipulated in the grant abstracts (6/23). However, most grants appear to have facilitated scholarly activity of some sort, including evaluation and quality improvement activities. Two practice-based research networks are supported with AAU funds, and at least 79 publications over the past 10 years, representing a wide variety of methodological approaches and topics, have been produced and indexed in PubMed with explicit acknowledgment of AAU funding. In the absence of substantial NIH support for family medicine departments, the AAU funding mechanism remains a crucial, but often overlooked, factor in facilitating scholarly activity in departments of family medicine.


Herd-level ELISA seroprevalence of bovine viral diarrhea antibodies in bulk-tank milk in Chilean dairy herds.
Our objective in this cross-sectional study was to determine the seroprevalence in 1996 of commercial dairy herds in central Chile positive to bovine viral diarrhea (BVD) virus, by the detection of antibodies in bulk-tank milk samples. Samples were obtained from 501 dairy farms ( approximately 50,000 cows) from the Metropolitan, VI, VII and VIII regions of Chile. An indirect ELISA was used to detect BVD antibodies. An absorbance (A450) > or = 0.55 was considered positive. The apparent proportion of positive herds ranged from 71.2 to 83% by region and did not differ by region. We concluded that exposure to BVD was widely distributed in the central area of Chile in 1996.


Editorial: Testing the Validity of the Limited Prosocial Emotions Specifier.
Colins et al.1 address a timely and important topic. Specifically, both the DSM-5 and the International Classification of Diseases, 11th edition (ICD-11) for the first time introduced a specifier (ie, with limited prosocial emotions) for the diagnosis of conduct disorder (DSM-5) or for the diagnoses of conduct-dissocial and oppositional defiant disorders (ICD-11) to designate those persons with these disorders who also show elevated levels of callous-unemotional (CU) traits. This change was based on research showing that children and adolescents with significant conduct problems who also show elevated levels of CU traits seem to be an etiologically and clinically important subgroup of persons with these disorders.2,3 The DSM-5 chose not to conduct field trials to test the validity of new diagnoses (only reliability) and, instead, considers research on new diagnoses as the field trials for future revisions of the manual.4 Thus, the work by Colins et al.1 is critical for this validation process. The study by Colins et al. has a number of methodological features that make their results particularly informative.1 The most notable feature was the use of a large nonreferred sample that was followed from 3 to 5 years of age to 11 to 13 years of age with a high retention rate. The authors also provide a nice summary of past attempts to validate the LPE specifier, which has provided mixed support at best. However, they also note that most of these studies did not use the full criteria for the LPE specifier and that this is an important limitation that Colins et al. overcome, especially given that the criteria include only 4 symptoms. Thus, the authors' findings that children with the LPE specifier and serious conduct problems exhibited more conduct disorder (CD) symptoms and comorbid problems (ie, fearlessness, symptoms of oppositional defiant disorder, and attention-deficit/hyperactivity disorder [ADHD]) and were at higher risk for future CD symptoms 3 years later are critical advances.


Neural substrates on the judgment of sequential benefits and losses.
People need to adapt to situations where they experience sequential benefits (or losses) to ensure survival. This study investigated the neural substrates involved in judgments of sequential benefits and losses. A total of 29 healthy volunteers participated in this study, in which they were asked to participate in a game of purchasing stocks while a magnetic resonance imaging scan was performed. This game had two main types of trials: (1) participants received four sequential financial benefits (or losses), and (2) participants received an equal amount of benefits (or losses) immediately. The results showed greater activation of the orbitofrontal cortex (OFC) when four benefits were received sequentially than when an equal amount of benefits was received immediately. This indicates that the OFC plays a crucial role in the process of mental integration of sequential benefits and interpretation of their valuations. It also showed greater activation of the dorsal striatum when four sequental losses were received than when an equal amount of losses was received immediately. However, it cannot be concluded that activation of the dorsal striatum reflects the differences between sequential and immediate losses, because previous studies have not confirmed this perspective. Therefore, it is necessary to clarify the function of the striatum in processing these losses.


Lack of herbal supplement characterization in published randomized controlled trials.
Herbal supplements in the United States and abroad have poor quality control and high content variability. We assessed the extent to which recently published randomized controlled trials of herbal supplements characterized and verified the content of the supplement under study. We identified all MEDLINE-indexed English language randomized controlled trials evaluating single-herb preparations of echinacea, garlic, ginkgo, saw palmetto, or St. John's wort that were published between January 1, 2000, and February 9, 2004. From each article we extracted information characterizing the herbal supplement studied. Of 81 randomized controlled trials meeting inclusion criteria, 12 (15%) reported performing tests to quantify actual contents, and 3 (4%) provided adequate data to compare actual with expected content values of at least one chemical constituent. In those 3 studies, actual content varied between 80% and 113% of expected values. Studies of higher overall quality (Jadad score > or =3) performed testing somewhat less frequently (5/54; 9%) than those with lower Jadad scores (7/27; 26%) (P = .09). Documented characterization of herbal supplements in published randomized controlled trials is inadequate. Investigators may be unaware of the extent to which herbal quality-control issues may detract from the value of otherwise well-designed clinical trials. The scientific and clinical utility of future herbal randomized controlled trials would be enhanced if authors provided evidence that the herbal products studied were of high quality.


Conservation biological control in strawberry: effect of different pollen on development, survival, and reproduction of Neoseiulus californicus (Acari: Phytoseiidae).
Wild vegetation surrounding crops may provide temporary habitat and potential food sources for phytoseiids in different seasons. Monthly vegetation samples of wild plants adjacent to strawberry plants and wild plants in a vegetation strip close to the crop were taken. The frequency of Neoseiulus californicus, Tetranychus urticae and other mites and insects was recorded. In addition, in a laboratory assay, the survival, developmental time and fecundity of females fed on pollen of strawberry and pollen of wild plants where N. californicus was recorded during their flowering, were estimated. Pollen from Urtica urens, Lamium amplexicaule, Convolvulus arvensis, Sonchus oleraceous, Galega officinalis, and Fragaria x ananassa (strawberry) allowed development of N. californicus to adult, but not reproduction. Survival was 70-80 % when fed on pollen from S. oleraceus, G. officinalis and C. arvensis, 80-90 % when fed on pollen from U. urens and F. x ananassa, and more than 90 % when fed on T. urticae and on pollen from L. amplexicaule. In autumn and winter, U. urens, L. amplexicaule and S. oleraceous could promote the persistence of N. californicus when prey density in strawberry is low, offering T. urticae, thrips and pollen. In summer, pollen of C. arvensis and G. officinalis would contribute to the persistence of N. californicus when the strawberry crop is ending and offers scarce food resources. Although the pollen of these plants would not enable the predator population to increase, the presence of these plants in the vicinity of strawberry could contribute to the persistence of N. californicus population and help to limit T. urticae growth when this pest begins to colonize the crop.


Anthropometric approach to lumbar vertebral body volumes.
To assess the relationship between the maximum volume of lumbar vertebral bodies and patient morphological features. Knowledge of the volume of the vertebral body is useful when performing vertebroplasty and kyphoplasty. 129 patients (18-85 years) were included consecutively over an 8-month period. All had been subject to abdominopelvic CT scans. The weight, height and body mass index (BMI) were known. The volume of each vertebral body was calculated using the formula V = π R (2). H (V = volume, R = radius, H = height). A statistical analysis of the data divided into three groups, men/women, men only and women only, was conducted by calculating the Pearson correlation coefficient. The volume of the vertebral body increased from L1 to L4, but the volume of the L5 vertebral body was lower than that of L3 and L4 in all three groups. The volumes of the vertebral bodies were greater in men than in women. Calculating the correlation coefficient showed that the variable most correlated with volume was patient's height in both the men/women and women-only groups, while the most correlated variable in the male-only group was weight. Vertebral height was the variable most correlated with overall height in all three groups. There is a wide variability in the volume of lumbar vertebrae. The volume of the vertebral body appears to vary not only with a person's height but also their weight. The vertebral body seems to expand with weight in men.


Genetic parameters and genetic trend of some yield traits of Holstein Friesian cattle population in Tropical Region (Teke).
This study was conducted to determine the milk yield and reproduction characteristics, genetic trend, and breeding values of Holstein cattle reared in Teke region (Antalya, Burdur, Denizli, and Isparta provinces) of Turkey. In this study, 9844 lactation and reproductive records of Holstein Friesian dairy cattle for the period of 2010 to 2017 were used. For this purpose, variance components and the heritability were calculated based on calving interval (CI) and number of inseminations per conception (NIC) from fertility characteristics and lactation length (LL), 305-day milk yield (305 DMY), and dry period (DP). It was determined that CI, NIC, LL, 305 DMY, and DP were 0.11, 0.10, 0.11, 0.33, and 0.01, respectively. The genetic trend of 305 DMY was 111.5 kg/year. The average breeding value was negative between 2005 and 2009 and positive between 2010 and 2015. In conclusion, the fact that especially 305 DMY heritability was generally higher in this study than the values reported by other studies conducted in Turkey and the genetic trend for 305 DMY was positive and high indicates that breeding value of Holstein cattle in the Teke region is high. Therefore, it can be recommended to continue the pedigree breeding of Holstein cattle in this region, keep pedigree and yield records meticulously, estimate breeding values for selecting animals with superior yield characteristics and using them in future generations, and include current biotechnological methods in breeding program to increase the efficiency in selection.


Live Cell Adhesion, Migration, and Invasion Assays.
Cell migration is a fundamental procedure involved in many physiological processes such as embryological development, tissue formation, immune defense or inflammation, and cancer progression. Here, we provide four in vitro assays that describe step-by-step cell adhesion, migration and invasion strategies, and their corresponding image data quantification. These methods include the following: two-dimensional wound healing assays, two-dimensional individual cell-tracking experiments by live cell imaging, and three-dimensional spreading and transwell assays. These optimized assays will facilitate physiological and cellular characterization of cell adhesion and motility, which may be used for fast screening of specific therapeutic drugs for adhesion function, novel strategies in pathophysiological diagnosis, and assaying new molecules involved in migration and invasion metastatic properties of cancer cells.


Caring for the injured: Exploring the immediate and long-term consequences of injury in medieval Cambridge, England.
To combine paleopathological and biomechanical analysis to reconstruct the impact that a severe skeletal injury had on an individual's ability to function and participate in medieval society. Three medieval individuals from Cambridge, England with ante-mortem fractures to the lower limb were analyzed. Plain X-rays were used to determine the degree of malunion, rotation and overlap of each fracture. Cortical bone architecture of the injured individuals and 28 uninjured controls were analyzed using micro-computed tomography (µCT). Clinical and functional consequences were examined using the Bioarcheology of Care framework. The mechanism of injury, the secondary complications, and the extent of the care received was reconstructed for each individual. Bilateral asymmetry in the cortical bone architecture revealed the long-term alterations to each individual's gait. Each of these individuals survived a severe injury resulting in chronic physical impairment, though not all would have been considered 'disabled'. This research contributes to the discussion about medieval care provision and social constructions of disability by illustrating how an interdisciplinary approach provides insight into the experiences of those with physical impairments. The integration of µCT imaging within the Bioarcheology of Care model is a novel approach with great potential for application across the field. Biomechanical analysis was restricted to cortical geometry. Further study of bilateral asymmetry in trabecular architecture could complement our understanding of altered loading modalities in past societies.


Lazy Sundays: role of day of the week and reactivity on objectively measured physical activity in older people.
The aim of this study was to assess the effect of day of the week and wearing a device (reactivity) on objectively measured physical activity (PA) in older people. Walking duration as a measure for PA was recorded from 1333 German community-dwelling older people (≥65 years, 43.8% women) over 5 days using accelerometers (activPAL). Least-square means of PA with 95%-confidence intervals (95%-CI) from multi-level analysis were calculated for each day of the week and each measurement day (days after sensor attachment). Walking duration on Sundays was significantly lower compared to working days (Sunday vs. Monday-Friday: - 12.8 min (95%-CI: - 14.7; - 10.9)). No statistically significant difference compared to working days was present for Saturdays. The linear slope for measurement day and walking duration was marginal and not statistically significant. Studies using PA sensors in older people should assess Sundays and working days to adequately determine the activity level of the participants.


Injury-induced rapid activation of MAPK signaling in dechorionated eggs and larvae of the silkworm Bombyx mori.
Previous study showed that diapause in Bombyx mori eggs can be terminated by dechorionation and that activation in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) in dechorionated cultured eggs is involved in diapause termination. In the present study, the possible mechanism underlying activation of ERK upon dechorionation was further investigated. Results showed that mechanical injury of diapause eggs without medium incubation also resulted in rapid increase in the phospho-ERK levels and that injury increased the phospho-ERK levels at different stages of both diapause eggs and eggs in which diapause initiation was prevented by HCl. Effects of anaerobiosis on dechorionation-stimulated phospho-ERK levels showed that the mechanical injury itself but not the dramatic increase in oxygen uptake upon injury is involved in a rapid activation of ERK. Chemical anaerobiosis on dechorionation-stimulated phospho-ERK levels and the in vivo effect of anaerobiosis showed that the supply of oxygen also plays a role in ERK signaling. In addition, injury induced the phosphorylation of c-jun N-terminal kinases (JNKs) and p38 kinase, components of two parallel MAPK pathways. A kinase assay showed a dramatic increase in JNK kinase activity in egg lysates upon injury. When newly hatched first instar larvae were injured, an increase in the phospho-ERK levels similar to that in dechorionated eggs was observed. From the results, we hypothesize that the injury-induced rapid activation of MAPK signaling, which serves as a natural signal for embryonic development, is related to diapause termination in dechorionated eggs.


Evidence for a functional interaction between 5-HT1A and 5-HT2 receptors in rats.
Evidence of a functional interaction between serotonin 5-HT1A and 5-HT2 receptor subtypes has been compromised by incomplete experimental designs and conflicting data. To test for such an interaction, combinations of the 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonist DOI were administered to rats prior to testing of locomotor activity in the Behavioral Pattern Monitor (BPM). The BPM is an activity and holeboard chamber that enables analyses of quantitative and qualitative changes in locomotor and investigatory activity. Dose-response studies of 8-OH-DPAT and DOI alone and in the presence of selected doses of the other drug were performed in order to allow isobolographic analysis, which characterizes the relationship of two drugs as either additive (no interaction), supra-additive, or infra-additive. Rats treated with saline, 8-OH-DPAT (6.25, 12.5, 25, or 50 microg/kg SC), DOI (0.15, 0.3, or 0.6 mg/kg SC), or selected combinations of both drugs were tested in the BPM for 1 h. Isobolographic analysis of the effects on locomotor activity revealed that 8-OH-DPAT and DOI interact in an infra-additive manner. Thus, at a functional level, 5-HT1A and 5-HT2 receptors interact antagonistically in the modulation of locomotor activity.


Fibrillin-containing microfibrils are key signal relay stations for cell function.
Fibrillins constitute the backbone of microfibrils in the extracellular matrix of elastic and non-elastic tissues. Mutations in fibrillins are associated with a wide range of connective tissue disorders, the most common is Marfan syndrome. Microfibrils are on one hand important for structural stability in some tissues. On the other hand, microfibrils are increasingly recognized as critical mediators and drivers of cellular signaling. This review focuses on the signaling mechanisms initiated by fibrillins and microfibrils, which are often dysregulated in fibrillin-associated disorders. Fibrillins regulate the storage and bioavailability of growth factors of the TGF-β superfamily. Cells sense microfibrils through integrins and other receptors. Fibrillins potently regulate pathways of the immune response, inflammation and tissue homeostasis. Emerging evidence show the involvement of microRNAs in disorders caused by fibrillin deficiency. A thorough understanding of fibrillin-mediated cell signaling pathways will provide important new leads for therapeutic approaches of the underlying disorders.


Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery.
Despite strong evidence that human genetic variants affect the expression of many key transcription factors involved in autoimmune diseases, establishing biological links between non-coding risk variants and the gene targets they regulate remains a considerable challenge. Here, we combine genetic, epigenomic, and CRISPR activation approaches to screen for functional variants that regulate IRF8 expression. We demonstrate that the locus containing rs2280381 is a cell-type-specific enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter regulating IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to regulate AC092723.1 and IRF8 expression differentially. Our work illustrates an integrative strategy to define functional genetic variants that regulate the expression of critical genes in autoimmune diseases and decipher the mechanisms underlying the dysregulation of IRF8 expression mediated by lupus risk variants.


Clinical cases in AIDS. 2.
As the human immunodeficiency virus (HIV) epidemic continues, there are increasing numbers of patients with HIV-related disease. Those doctors studying for the MRCP exam will need to be familiar with the common manifestations of HIV infection and acquired immunodeficiency syndrome.


[Study of pathological morphology in chronic sinusitis].
To study the pathological characteristics and regularity of chronic sinusitis (CS) in different clinical types, tc estimate the reliability and feasibility of CS classification on the pathologic basis. HE, Van Gieson's, alcian blue-periodic acid-schiff(AB-PAS) staining was used to observe the changes of epithelium, to measure the thickness of basement membrane and the area of mucous glands. The ultrastructural changes of pseudostratified ciliated columnar epithelium were observed under transmission electron microscope (TEM) and scanning electron microscope (SEM). The epithelial fiber tissue was increased, the basement membrane was thickened, and the mucous glands were obviously increased in CS under the light microscope. Subepithelial fibrosis and thickened basement membrane were most obviously seen in type III of CS and the hyperplasia of mucous glands was most distinct in type II. Under the TEM, abnormal structure of cilia, decrease of ciliated cells, increase of goblet cells were detected in all three CS types. Under the SEM, the cilia of every types showed the ingravescenced process of pathological changes from slight cilium disorder, disorientation, to desquamation of most cilia and replacement of microvilli. There is significant distinction of mucous membrane structure among three types. The Chinese classification of CS has pathological basis, it represents the occurrence, development and regularity of CS, and it can be used as basis in further study, communication and evaluation for surgical effect of CS.


Ruthenium red: differential effects on excitation and excitation-contraction coupling in frog skeletal muscle.
The effects of purified ruthenium red (RR6+) on action potentials, resting potentials, twitches, tetani and potassium contractures in fibre bundles dissected from frog leg muscles were compared to the effects of supranormal concentrations of Ca2+. The effects of RR6+ include a shift of action potential threshold and reduction in rates of depolarization, repolarization and conduction velocity. Resting potentials and action potential overshoots are unaffected by RR6+ in concentrations of 10 microM or less. Higher RR6+ concentrations cause membrane depolarization. Low concentrations of RR6+ cause twitch potentiation but do not affect tetanus tension. Unlike Ca2+, RR6+ has no effect on the mechanical activation curve. However, crude preparations of RR6+ contain an unidentified contaminant which does shift the mechanical activation curve to the right, i.e. it increases mechanical threshold. RR6+ itself appears to be largely excluded from the t-system.


BNIP3 induces IL6 and calcineurin/NFAT3 hypertrophic-related pathways in H9c2 cardiomyoblast cells.
Ischemia/reperfusion injury causes cardiomyocyte apoptosis, ventricular remodeling, leading to a dilated heart. Hypoxia is one of the causes involved in ischemia damage, and BNIP3 is a hypoxia-inducible marker and also a sensor to induce mitochondria-dependent apoptosis. Recent reports discussed ablating BNIP3 can restrain cardiomyocytes apoptosis and post-infarction remodeling. BNIP3 is a crucial therapeutic target. However, the BNIP3-induced hypertrophy aspect is rarely investigated. Here, we transiently transfected BNIP3 plasmids into H9c2 cardiomyoblast cells to evaluate the molecular signaling and hypertrophy markers using Western blot. We measured the cell size change using actin staining. We disclose that BNIP3 overexpression induced an increase in cell size, activated the pathological-related hypertrophy signaling pathways, such as IL6-MEK5-ERK5, IL6-JAK2-STAT1/3, calcineurin/NFAT3 and p38β MAPK resulting in the fetal genes, ANP and BNP expressing. Concluding above, BNIP3 acts as a pathological hypertrophy inducer, which might be a potential therapeutic target for heart damage prevention.


Comparison of the vasodepressor action of ZK 36 374, a stable prostacyclin derivative, PGI2 and PGE1 with their effect on platelet aggregation and bleeding time in rats.
ZK 36 374, a new, chemically stable prostacyclin derivative, was compared with PGE1 and PGI2 with respect to its action on platelet aggregation in vitro, on bleeding time and on arterial blood pressure in conscious rats. The time of occlusion of a hole in a polyethylene (PE) tube of an AV-shunt between the left carotid artery and the right jugular vein by a microthrombus was considered as an index of bleeding time. All three substances inhibited the ADP-induced aggregation of human and rat platelets. In human PRP, ZK 36 374 was 17 times more active than PGE1 and 2 - 5 times as potent as PGI2. In contrast, in rat PRP, PGI2 was 9.2 and 3.4 times as potent as PGE1 and ZK 36 374, respectively. Similar differences in potency were found in the in vivo experiments where these substances given by an intravenous infusion to conscious rats prolonged bleeding time and depressed mean arterial pressure in a dose-dependent manner. ZK 36 374 was also orally active. At oral doses of 1, 2 and 3 mg/kg this new compound caused a dose-dependent prolongation of bleeding time and a fall in arterial blood pressure. In conclusion, the results show that ZK 36 374 is an intravenously and orally active prostacyclin derivative which may be of therapeutic value for occlusive peripheral vascular diseases.


Confirmation of Transcriptional Read-Through Events by RT-PCR.
Chimeric RNAs can be formed by trans-splicing from different transcripts or cis-splicing of adjacent genes (cis-SAGe). Cis-SAGe results from read-through transcription of two neighbor genes. To investigate the mechanisms underlying intergenic splicing of adjacent genes, it is important to develop an assay to detect transcriptional read-through. Here, we describe a general RT-PCR based method to confirm the process for cis-SAGe candidates. In this method, we use PCR to amplify cDNA that is reverse transcribed from the read-through precursor mRNA. The result provides a foundation for further downstream mechanistic studies.


Methods to Assess the Impact of Hsp90 Chaperone Function on Extracellular Client MMP2 Activity.
Secreted, or extracellular, heat shock protein 90 (eHsp90) is considered a recent discovery in eukaryotes. Over the last two decades, studies have provided significant supporting evidence that implicates eHsp90 both in normal cellular processes such as wound healing and in the development of human pathologies and diseases including fibrosis and cancer. In the early 2000s, Eustace et al. demonstrated that eHsp90 promotes the invasion of breast cancer cells by binding to and regulating the activity of an extracellular matrix (ECM) remodeling enzyme, the matrix metalloproteinase 2 or MMP2. Interestingly, inside mammalian cells, Hsp90 is an essential chaperone that interacts with hundreds of newly synthesized proteins, known as "clients," that require Hsp90's assistance to perform their function. Several methods are routinely used to characterize the role and impact of Hsp90 on a client protein's functionality in vitro and in vivo. However, the mechanistic role of eHsp90 is less well-defined since, so far, only a handful of extracellular client proteins have been identified. Here, we describe methods to characterize the impact of the secreted chaperone on MMP2 activity, the most characterized extracellular client of eHsp90. The procedures described here can be applied and adapted to characterize other extracellular clients, particularly members of the MMP family.


Production and characterization of monoclonal antibodies to oxidized LDL.
Oxidized low density lipoprotein (LDL) seems to take a part in atherogenesis through direct interactions with macrophages, endothelial cells, and smooth muscle cells, and is thought to participate in renal glomerular injury. For the purpose of illustrating the role of oxidized LDL in the human diseases, monoclonal antibodies were developed and characterized, recognizing oxidized LDL-specific epitopes that do not exist on native LDL. LDL was oxidized by the incubation with CuSO4, and used as immunogen. Splenocytes from the immunized mouse and mouse myeloma cells were fused to produce hybridomas, which were screened for the secretion of oxidized LDL-specific antibodies. Immunoblot analysis and binding affinity assay showed that these monoclonal antibodies recognize malondialdehyde-conjugated peptide epitopes.


Hospital Volume Versus Good Clinical Practice.
This letter to the editor comments on a recently published article that assessed the treatment of patients with soft tissue sarcoma in high‐volume versus low‐volume centers.


Health Care Access, Utilization, and Management in Adult Chinese, Koreans, and Vietnamese with Cardiovascular Disease and Hypertension.
Asians are often pooled together when evaluating disparities in health care indicators (access, utilization, and management), though substantial variation may exist across different Asian ethnicities. The aim of this study was to compare health care indicators among Chinese, Korean, Vietnamese, and non-Hispanic white (NHW) adults with cardiovascular disease and hypertension (CVD/HTN). We analyzed health care indicators using multivariable logistic regression in a sample of Asians and NHWs with CVD/HTN from the 2011-2012 California Health Interview Survey (CHIS). Koreans had the lowest utilization of emergency room (ER) or inpatient hospital services; Vietnamese had the lowest access to a personal doctor; Chinese had the lowest adjusted odds of having seen a doctor in the prior 12 months; and all Asians received fewer written heart disease care plans compared to NHWs. Even when utilization of ER for heart disease appeared to be similar, lack of access to a doctor was a more common reason noted by Asians versus NHWs. However, a lower proportion of Asians reported delays in receiving prescription or care. Accounting for differences across groups did not diminish these disparities. Health care indicators varied by race and across Asian ethnicities even after controlling for sociodemographic factors, insurance coverage, and health status. Future studies should consider oversampling other Asian ethnicities and assessing more in depth the potential impact of ethnicity-related factors on disparities in health care indicators.


Influence of enzymatic phospholipid cleavage on the permeability of the erythrocyte membrane. II. Protein-mediated transfer of monosaccharides and anions.
In order to investigate the influence of membrane lipids on transport via the protein domain of the erythrocyte membrane, a number of facilitated diffusion processes was studied by tracer flux techniques in whole cells after cleavage of up to 65% of the phosphatidylcholine or the sphingomyelin by phospholipase A2 from Naja naja or bee venom, or by sphingomyelinase, respectively. The mediated fluxes of L-arabinose, which is transported by the glucose carrier, and of L-lactate, which uses a specific monocarboxylate carrier, were markedly inhibited by cleavage of either phosphatidylcholine or sphingomyelin. These phospholipid dependencies are in line with earlier data on cholesterol dependencies (Deuticke, B. (1977) Rev. Physiol. Biochem. Pharmacol. 78, 1-97). They can only in part be explained by changes of membrane fluidity. More specific interactions of the degradation products with the carrier proteins seem also to play a role. Sulfate and oxalate transfer, which proceed via the inorganic anion-exchange system, are essentially unaffected by cleavage of phosphatidylcholine and less sensitive to sphingomyelin cleavage than the two other processes. This also agrees with earlier data on cholesterol independency of sulfate transfer. The inorganic anion-exchange protein thus seems to be less dependent on the surrounding lipids in its conformation and its mode of action than the two other carriers.


Variations in flow and intraalveolar pressure during jet ventilation: theoretical and experimental analysis.
Alteration in flow and pressure in a chest-lung model during jet ventilation was studied from a theoretical and experimental standpoint. The model consisted of a stiff box, with an inserted cast of the bronchial tree, simulating either normal or low compliance of the human chest-lung. Airway resistances in the model could be altered. A constant driving flow (Vd) was applied through the opening of the trachea at various rates. The driving flow drew in a constant flow (entrained flow = Ve) and increased the box pressure (PA), which in turn induced an increasing back flow (Vr). Vd, Ve-Vr and PA were measured. Theoretical analysis of time variation in box pressure showed a monoexponential pattern which was confirmed experimentally. Tr, the time at which back flow and entrained flow become equal could be predicted taking the physical characteristics of the experimental set-up and the values of Vd and Ve into account. Tr values depended mainly on the compliance of the experimental set-up. Increasing the resistances was found to reduce Ve. In practice, the efficiency of jet ventilation for gas exchange at a frequency below 4 Hz is known to be mainly related to the volume of gas flowing in the trachea towards the alveoli. This efficiency generally depends on the values of Tr and the inspiratory period (TI). A value of TI less than or equal to Tr will thus improve the jet ventilation efficiency.


Rate of neuronal fallout in a transsynaptic cerebellar model.
Quantitative analyses of transsynaptic granule cell death subsequent to the genetically determined degeneration of Purkinje cells in the cerebellum of pcd/pcd mutant mice show that granule neuron fallout follows a typical mathematical pattern of elemental decay. Biological and theoretical connotations are discussed in light of the empirical observations and a simulation model.


Genomic data provide a robust phylogeny backbone for Rhodiola L. (Crassulaceae) and reveal extensive reticulate evolution during its rapid radiation.
The Tibetan Plateau and adjacent mountain regions (TP; including the Tibetan Plateau, Himalaya, Hengduan Mountains and Mountains of Central Asia) harbor great biodiversity, some lineages on which may have undergone rapid radiations. However, only a few studies have investigated the evolutionary pattern of such diversification in depth using genomic data. In this study, we reconstructed a robust phylogeny backbone of Rhodiola, a lineage that may have undergone rapid radiation in the TP, using Genotyping-by-sequencing data, and conducted a series of gene flow and diversification analyses. The concatenation and coalescent-based methods yield similar tree topologies, and five well-supported clades were revealed. Potential gene flow and introgression events were detected, both between species from different major clades and closely related species, suggesting pervasive hybridization and introgression. An initial rapid and later slowdown of the diversification rate was revealed, indicating niche filling. Molecular dating and correlation analyses showed that the uplift of TP and global cooling in the mid-Miocene might have played an important role in promoting the rapid radiation of Rhodiola. Our work demonstrates that gene flow and introgression might be an important contributor to rapid radiation possibly by quickly reassembling old genetic variation into new combinations.


Cardiovascular magnetic resonance for the diagnosis and management of heart failure with preserved ejection fraction.
Heart failure with preserved ejection fraction (HFpEF) is characterized by an impaired ventricular filling resulting in the development of dyspnea and other HF symptoms. Even though echocardiography is the cornerstone to demonstrate structural and/or functional alterations of the heart as the underlying cause for the clinical presentation, cardiovascular magnetic resonance (CMR) represents the noninvasive gold standard to assess cardiac morphology, function, and tissue changes. Indeed, CMR allows quantification of biventricular volumes, mass, wall thickness, systolic function, and intra- and extracardiac flows; diastolic functional indices include transmitral and pulmonary venous velocities, left ventricular and left atrial filling velocities from volumetric changes, strain analysis from myocardial tagging, tissue phase contrast, and feature tracking. Moreover, CMR allows superior tissue characterization of the myocardium and the pericardium, which are crucial for a noninvasive etiological and histopathological assessment of HFpEF: conventional T1-weighted, T2-weighted, and post-contrast sequences are now complemented by quantitative mapping sequences, including T1 and T2 mapping as well as extracellular volume quantification. Further experimental sequences comprise diffusion tensor analysis, blood oxygenation-dependent sequences, hyperpolarized contrast agents, spectroscopy, and elastography. Finally, artificial intelligence is beginning to help clinicians deal with an increasing amount of information from CMR exams.


Lack of correlation between anticardiolipin antibodies and peripheral autonomic nerve involvement in systemic lupus erythematosus.
The presence of anticardiolipin antibodies has recently been related to a clinical complex in which both central and peripheral neurologic damage is included. A series of 27 female patients affected by systemic lupus erythematosus (SLE) was tested for the presence of peripheral autonomic neuropathy and serum anticardiolipin antibody (ACA) levels were determined in each patient by ELISA. Peripheral autonomic impairment was detected in 40.7% of SLE patients and a large number (77.7%) of patients had elevated levels of ACA. No relationship was found between presence of ACA (both for IgG and IgM classes) and the autonomic neuropathy.


Retracted: Benefit Modeling and Analysis of Wind Power Generation under Social Energy Economy and Public Health.
[This retracts the article DOI: 10.1155/2022/5635853.].


Beta-NAP, a cerebellar degeneration antigen, is a neuron-specific vesicle coat protein.
We have identified a target antigen in autoimmune cerebellar degeneration, beta-NAP, that is closely related to the beta-adaptin and beta-COP coat proteins. Beta-NAP is a nonclathrin-associated phosphoprotein expressed exclusively in neurons, from E12 through adulthood. Beta-NAP is present in the neuronal soma and nerve terminal as soluble and membrane-bound pools and is associated with a discrete set of nerve-terminal vesicles. These results establish beta-NAP as a neuron-specific vesicle coat protein. We propose a model in which beta-NAP mediates vesicle transport between the soma and the axon terminus and suggest that beta-NAP may represent a general class of coat proteins that mediates apical transport in polarized cells.


Letterer-Siwe disease with lipid-containing vacuolated cells--an autopsy case.
A case of Letterer-Siwe disease of a 1-year-2-month-old boy, which clinicopathologically satisfied 7 out of the 8 characteristics of the disease by Siwe's criteria, excluding pathologic changes in the bone is reported. The vacuolated histiocytes appeared in the proliferating reticuloendothelial cells in this case; the cells were positive by general fat reaction; the fats consisted of cholesterol fats, phospholipids and neutral lipid. Electron microscopy showed the occurrence of lipid droplets with cholesterol crystals and atypical form of Langerhans cell granule. Granulomatous changes were found in the lymph nodes and spleen, and this case was also similar in part to chronic granulomatous disease; however, celoid and lipofuscin pigments were negative in the proliferating cells. Cytomegalic inclusion disease as a complication was found in the lungs and intestine, and bilirubin stones in the liver.


Development of electrospun beaded fibers from Thai silk fibroin and gelatin for controlled release application.
Thai silk fibroin and gelatin are attractive biomaterials for tissue engineering and controlled release applications due to their biocompatibility, biodegradability, and bioactive properties. The development of electrospun fiber mats from silk fibroin and gelatin were reported previously. However, burst drug release from such fiber mats remained the problem. In this study, the formation of beads on the fibers aiming to be used for the sustained release of drug was of our interest. The beaded fiber mats were fabricated using electrospinning technique by controlling the solution concentration, weight blending ratio of Thai silk fibroin/gelatin blend, and applied voltage. It was found that the optimal conditions including the solution concentration and the weight blending ratio of Thai silk fibroin/gelatin at 8-10% (w/v) and 70/30, respectively, with the applied voltage at 18 kV provided the fibers with homogeneous formation of beads. Then, the beaded fiber mats obtained were crosslinked by the reaction of carbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS). Methylene blue as a model active compound was loaded on the fiber mats. The release test of methylene blue from the beaded fiber mats was carried out in comparison to that of the smooth fiber mats without beads. It was found that the beaded fiber mats could prolong the release of methylene blue, comparing to the smooth fiber mats without beads. This was possibly due to the beaded fiber mats that would absorb and retain higher amount of methylene blue than the fiber mats without beads. Thai silk fibroin/gelatin beaded fiber mats were established as an effective carrier for the controlled release applications.


Nucleoside and glucose transport in erythrocytes from new-born lambs.
1. Glucose and inosine transport by erythrocytes from new-born lambs and adult sheep were compared. Uptake of both permeants was considerably faster in the new-born. Inosine uptake by erythrocytes from nucleoside-permeable and impermeable lambs were not significantly different at birth. The difference between the two phenotypes was first apparent 30 days after birth.2. The post-natal changes in glucose and inosine transport activity closely paralleled the progressive decrease in the percentage of fetal erythrocytes (i.e. cells containing fetal haemoglobin) in the circulation. Cell fractionation studies confirmed that the permeability changes were directly related to changes in the relative proportions of fetal and adult haemoglobin containing erythrocytes.3. The results demonstrate that fetal cells are highly permeable to both glucose and inosine. These cells are replaced by erythrocytes which contain adult haemoglobin and which have a much lower, but still significant, glucose permeability and either low or negligible inosine transport activity depending on the genotype of the animal.4. Inosine transport by fetal erythrocytes from both nucleoside-permeable and impermeable animals was mediated by a nucleoside transport system which had similar properties to that responsible for nucleoside transport in adult nucleoside-permeable cells. Glucose transport in both fetal and adult cells was highly stereo-specific, indicating the presence of a selective transport system.5. It is suggested that the regulatory mechanism responsible for initiating the switch from fetal to adult haemoglobin synthesis may also be responsible for the changes in glucose and nucleoside transport activity.


Maturation of chronic lymphocytic leukemia B cells: correlation between the capacity of responding to T-cell factors in vitro and the stage of maturation reached in vivo.
Circulating malignant cells from 15 patients with B-cell chronic lymphocytic leukemia (B-CLL) were examined by the electron microscope (EM) and tested for their capacity to produce immunoglobulin (Ig) molecules using endogenous labeling techniques in vitro. In agreement with previous observations, B-CLL clones from various patients could be subdivided in three distinct groups: immature (type 1) clones, that comprised mainly small resting lymphocytes which synthesized, but degraded Ig of the secretory type intracellularly; mature (type 3) clones consisting mainly of cells with an extended Golgi apparatus and numerous strands of rough endoplasmic reticulum (RER) that secreted Ig molecules; and clones (type 2) at an intermediate maturational stage. When stimulated with T-cell supernatants that contained T-cell replacing factor(s) (TRF), type 3 and, to a lesser extent, type 2 clones differentiated further and secreted increased amounts of Ig. This maturation was not observed when type 1 clones were stimulated with the same supernatants. However, these cells were not incapable of further maturation since they could differentiate in response to phorbol ester (TPA). The present data reinforce the concept that different CLL clones undergo a process of maturation in vivo that may be arrested at different levels and demonstrate that the various clones respond differently to physiological stimuli depending upon the level of maturation already reached in vivo.


Transnasogastric drainage of a perforated duodenal ulcer: technical note.
Perforated peptic ulcers are usually managed surgically after failure of more conservative medical treatment of ulcer disease. This case illustrates transnasogastric placement of a drainage catheter through a perforated ulcer, which was successful as definitive therapy.


Electrical noise from lipid bilayer membranes in the presence of hydrophobic ions.
In the presence of the hydrophobic ion dipicrylamine, lipid bilayer membranes exhibit a characteristic type of noise spectrum which is different from other forms of noise described so far. The spectral density of current noise measured in zero voltage increases in proportion to the square of frequency at low frequencies and becomes constant at high frequencies. The observed form of the noise spectrum can be interpreted on the basis of a transport model for hydrophobic ions in which it is assumed that the ions are adsorbed in potential-energy minima at either membrane surface and are able to cross the central energy barrier by thermal activation. Accordingly, current-noise results from random fluctuations in the number of ions jumping over the barrier from right to left and from left to right. On the basis of this model the rate constant ki for the translocation of the hydrophobic ion across the barrier, as well as the mean surface concentration Nt of adsorbed ions may be calculated from the observed spectral intensity of current noise. The values of ki obtained in this way closely agree with the results of previous relaxation experiments. A similar, although less quantitative, agreement is also found for the surface concentration Nt.


The burden of anxiety among a nationally representative US adult population.
Anxiety disorders are highly prevalent and are associated with a significant humanistic and economic burden. This study evaluates the impact of anxiety symptoms on direct and indirect costs and quality of life in individuals with self-reported and unrecognized anxiety symptoms. The 2019 US National Health and Wellness Survey database was analyzed to compare individuals with anxiety symptoms to individuals without symptoms, stratified by responses to a yes/no question about experiencing anxiety symptoms, and further stratified by severity of symptoms based on GAD-7 scores. Individuals who responded 'yes' were characterized as having self-reported anxiety symptoms, and those who responded 'no' were screened for unrecognized anxiety symptoms. Overall, 44.0 % of the population experienced anxiety symptoms, of which 32.5 % self-reported experiencing anxiety, while an additional 11.5 % had mild to severe symptoms but did not self-identify as having anxiety. Both groups experienced significantly worse quality of life, and higher direct and indirect costs than a control group who had no anxiety symptoms (GAD-7 ≤ 4). Individuals with more severe anxiety symptoms experienced worse outcomes. The data were cross-sectional, so causality could not be determined. Outcomes were based on self-report, and are therefore subject to reporting and recall bias. Prevalence and severity were assessed using the GAD-7, and not clinically validated. A substantial proportion of the population experiences anxiety symptoms without recognizing it. Anxiety symptoms had a significant impact on quality of life, direct costs, and indirect costs, representing a considerable burden that increased with severity of illness.


The validity of self-initiated, event-driven infectious disease reporting in general population cohorts.
The 2009/2010 pandemic influenza highlighted the need for valid and timely incidence data. In 2007 we started the development of a passive surveillance scheme based on passive follow-up of representative general population cohorts. Cohort members are asked to spontaneously report all instances of colds and fevers as soon as they occur for up to 9 months. Suspecting that compliance might be poor, we aimed to assess the validity of self-initiated, event-driven outcome reporting over long periods. During two 8 week periods in 2008 and 2009, 2376 and 2514 cohort members in Stockholm County were sent one-week recall questionnaires, which served as reference method. The questionnaires were completed by 88% and 86% of the cohort members. Whilst the false positive proportion (1-specificity) in the reporting was low (upper bound of the 95% confidence interval [CI] ≤ 2% in each season), the false negative proportion (failure to report, 1-sensitivity) was considerable (60% [95% CI 52%-67%] in each season). Still, the resulting epidemic curves for influenza-like illness compared well with those from existing General Practitioner-based sentinel surveillance in terms of shape, timing of peak, and year-to-year variation. This suggested that the error was fairly constant. Passive long-term surveillance through self-initiated, event-driven outcome reporting underestimates incidence rates of common upper respiratory tract infections. However, because underreporting appears predictable, simple corrections could potentially restore validity.


The effect of paclitaxel on 2-aminofluorene-DNA adducts formation and arylamine N-acetyltransferase activity and gene expression in human lung tumor cells (A549).
In this study, paclitaxel was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity, gene expression and 2-aminofluorene-DNA adduct formation in a human lung tumor cell line (A549). The activity of NAT was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (2-AAF) and remaining 2-aminofluorene (2-AF). Human lung tumor cell cytosols and intact cells were used for examining NAT activity and carcinogen-DNA adduct formation. The results demonstrated that NAT activity, gene expression (NAT1 mRNA) and 2-AF-DNA adduct formation in human lung tumor cells were inhibited and decreased by paclitaxel in a dose-dependent manner. The effects of paclitaxel on the values of the apparent Km and Vmax of NAT from human lung tumor cells were also determined in both examined systems. The result also indicated that paclitaxel decreased the apparent values of Km and Vmax from human lung tumor cells in both cytosol and intact cells. Thus, paclitaxel is an uncompetitive inhibitor to NAT enzyme.


Induced-membrane femur reconstruction after resection of bone malignancies: three cases of massive graft resorption in children.
Bone reconstruction after surgical resection of bone malignancies in children remains a difficult challenge. Induced-membrane reconstruction as described by Masquelet et al. was originally reported in traumatic or septic bone defects and is now adapted to this field. We report here three cases of massive femoral graft resorption requiring surgical revision in two boys aged 3 and 6 years and a 9-year-old girl. Hypotheses include the long delay between the two stages, nature of the bone graft, high varus loads specific to this location, and lack of stability of the fixation. This technique has recently provided promising preliminary results when applied to the field of bone tumours. However, reconstruction of the femur seems to be specifically associated with a risk of graft resorption. Identification of the origin of this major complication is needed to amend the technique or its indications.


Circulating immune complex, endotoxin, and biliary infection in patients with biliary obstruction.
Immunoglobulin A-containing circulating immune complexes, immunoglobulin G-containing circulating immune complexes, and endotoxin were measured in the sera of patients with obstructive jaundice. The bile of patients with percutaneous transhepatic biliary drainage was also cultured for bacteriologic studies. There was a significantly positive correlation between the endotoxin levels and both immunoglobulin A-containing circulating immune complex and immunoglobulin G-containing circulating immune complex. The endotoxin levels of the patients with gram-negative infections were significantly increased compared with those of the patients with sterile cultures. The immunoglobulin G-containing circulating immune complex levels of the patients with bacteria in bile were significantly increased compared with those of the patients with sterile cultures. The immunoglobulin A-containing circulating immune complex levels of the patients with bacteria in bile were slightly increased, but the difference did not reach statistical significance. These results indicate that one of the causes of increased circulating immune complex levels may be endotoxemia in combination with biliary infection in patients with biliary obstruction.


Solubility and stability of sterigmatocystin in aqueous solutions.
In the present work we studied the ability of phosphate buffer to solubize sterigmatocystin (ST) at different pH values. We observed a higher solubility of ST at acid pH values, specially in pH 4.5. The ST adsorbed to glass was maximum at alkaline pH values.Also we studied the stability of different concentrations of ST in phosphate buffer at different pH values. After 24 h, ST can be considered stable at alkaline, neutral and 3.5 pH values. At pH 4.5, 5.5 and 6.5, ST recovered after 24 h was lower, specially at pH 4.5, when only 44% was recovered. At day 7, ST was stable only at pH 7.5 (91%). The lowest recovery was at pH 4.5 (25%).


Arterial blood pressure and its measurement.
Pressure is defined as force per unit area. The actual value of the recorded pressure depends on dynamic influences, like acceleration and friction in a moving fluid, and on static influences like the effect of a gravitational field. In the arterial system, four mechanisms exert the main influence on the measured pressure: (1) cardiac output and peripheral resistance, on which the mean value of the pressure depends; (2) the flow amplitude and the characteristic impedance of the artery, on which the pressure amplitude depends; (3) the orthostatic pressure component; (4) the local velocity of flow, on which the recorded pressure depends, and is described by the Bernoulli equation. Under normal conditions, this influence is rather small. The measurement of arterial pressure can be done either invasively or with one of the following noninvasive methods: occlusive cuff method, vascular unloading, arterial tonometry, or measurement of the arterial pulse wave velocity. Each of these methods has certain advantages and disadvantages. It seems necessary to point out the fact that due to wave reflections in the arterial system, pressure values depend on local influences and differ from location to location. Most markedly, the influence of wave reflection can be demonstrated proximally, as well as distally, to the occlusive cuff in the Riva Rocci method. Once the blood pressure has been measured in a person, the problem of the assessment and interpretation of the measured values has to be considered. According to the decision of the WHO, certain limits are defined which permit a distinction between normotension and hypertension. In each case, of course, a physician has to consider the importance of individual conditions.


High expectancy influences the role of cognitive load in inattentional deafness during landing decision-making.
Neglecting a critical auditory alarm is a major obstacle to maintaining a safe environment, especially in aviation. Earlier studies have indicated that tasks with a higher perceptual or cognitive load in the visual modality influence the processing of auditory stimuli. It is unclear, however, whether other factors, such as memory failure, active neglect, or expectancy influence the effect of cognitive load on auditory alarm detection sensitivity during aeronautical decision-making. In this study, we investigated this issue in three laboratory experiments using the technique of signal detection analysis, in which participants were asked to make a landing decision based on indicators of the instrument landing system while also trying to detect an audible alarm. We found that the sensitivity of auditory alarm detection was reduced under conditions of high cognitive load and that this effect persisted even when the auditory detection response occurred first (before the landing decision response) and when the probability of an auditory alarm was 40%. However, the sensitivity of auditory detection was not influenced by cognitive load under high expectancy conditions (60% probability of alarm presentation). Furthermore, the value of the response bias was reduced under high cognitive load conditions when the probability of an auditory alarm was low (20%). With an increase in the level of expectancy (40% and 60% probability of alarm presentation), it was found that cognitive load did not influence the response bias. These findings indicate that visual cognitive load affects the sensitivity to an auditory alarm only at a low expectancy level (20% and 40% probability of alarm presentation). The effect of cognitive load on the sensitivity to an auditory alarm was not due to memory failure or active neglect and the response bias was more sensitive to the expectancy factor.


Arginine-chitosan/DNA self-assemble nanoparticles for gene delivery: In vitro characteristics and transfection efficiency.
Chitosan (Cs) is a natural cationic polysaccharide that has shown potential as non-viral vector for gene delivery because of its biocompatibility and low toxicity. However, chitosan used for gene delivery is limited due to its poor water solubility and low transfection efficiency. The purpose of this work was to prepare Arginine-chitosan (Arg-Cs)/DNA self-assemble nanoparticles (ACSNs), and determine their in vitro characteristics and transfection efficiency against HEK 293 and COS-7 cells. Our experimental results showed that the particle size and zeta potential of ACSNs prepared with different N/P ratios were 200-400nm and 0.23-12.25mV, respectively. The in vitro transfection efficiency of ACSNs showed dependence on pH of transfection medium, and the highest expression efficiency was obtained at pH 7.2. The transfection efficiency increased with the ratio of chitosan-amine/DNA phosphate (N/P ratio) from 1 to 5, and reached the highest level with the N/P ratio 5. Effect of plasmid dosage on the transfection efficiency showed the highest transfection efficiency was obtained at 4microg/well for HEK 293 cells and 6microg/well for COS-7 cells. The transfection efficiency of ACSNs was much higher than that of Cs/DNA self-assemble nanoparticles (CSNs). The average cell viability of ACSNs was over 90%. These results suggested that ACSNs could be a safe and effective non-viral vector for gene delivery.


Human 'Ia' antigen populations defined by monoclonal antibodies.
The relationships between the antigens recognized by four monoclonal anti-human 'Ia'-like antibodies were investigated using sequential immunoprecipitation and capping techniques. Two of the antibodies were 'monomorphic' and have previously been shown to recognize epitopes in which carbohydrate residues are involved, whereas the two 'polymorphic' antibodies recognized protein-defined epitopes--one of these epitopes being present on MB+DR- molecules. In the absence of an indisputable anti-DR monoclonal antibody, it was not possible to conclusively verify which 'Ia'-encoded antigens were detected by the anti-'Ia'-like monoclonal antibodies. Nevertheless, several firm conclusions could be drawn: (a) so-called 'monomorphic' antibodies do not necessarily react with all 'Ia' molecules encoded by a single locus--from the results using the two monomorphic antibodies, B5.1 and 3F1.1, described herein, two populations of antigens being B5.1+3F1.1+ and B5.1+3F1.1- were identified; (b) cross-reactivity of a polymorphic determinant expressed on antigenically-separable 'Ia' molecules was noted--using the two polymorphic antibodies, 26.1 and F5C9, molecules which were 26.1+F5C9+ and 26.1-F5C9+ were identified; and (c) the data clearly point to the existence of at least two loci coding for 'Ia'-like antigens (one of which may or may not be the HLA-DR locus). Given that polymorphisms can now include protein- and carbohydrate-defined epitopes, that cross-reactions occur and that the definition of DR itself by monoclonal antibodies is not clear, the complexity of the human 'Ia' antigens is apparent.


Potential recruitment into a clinical trial of vascular secondary prevention medications in cerebral small vessel disease, based on concomitant medication use.
Blood pressure-lowering medications, antiplatelet drugs and statins are often prescribed to asymptomatic patients with white matter hyperintensities (WMH). A clinical trial is needed, but potential trial participants would be excluded if they already had another indication to take the medication. It is likely that many patients with WMH would already have a recognised vascular-related indication for these drugs.We used data from the UK Biobank study to determine what proportion of people with WMH were not taking these drugs and would be potentially able to enter a clinical trial of antiplatelet drugs, statins, or BP-lowering medication. We used the UK Biobank MRI sub-study of healthy volunteers aged 40-70 years as our cohort. We considered that WMH volumes in the top quartile (2.7-89 mls) were severe enough for a patient to be at risk of progression and be offered treatment. Such patients could also be included in a hypothetical clinical trial if there were no contraindications. Using the product licenses, we defined exclusion criteria for four hypothetical clinical trials of aspirin, clopidogrel, statins, and tight BP control. We then calculated what proportion of patients would still be eligible if these criteria were applied. 5794/23,179 patients had WMH in the top quartile. Of these, 4006/5794 69% (95% CI 68-70%) would be eligible for a trial of aspirin; with 81% (95% CI 80-82%) eligible for a trial of clopidogrel; 56% (95% CI 55-58%) of patients would be eligible to enter into a trial of a lower BP target, and 58% (95%CI 57-59%) would be able to enter a trial of a statin. Over 80% of patients with WMH in the UK biobank would be eligible to enter a trial of an antiplatelet and just over half would be eligible to enter a trial of a statin or BP-lowering medication.


Modeling variations of medium porosity in rotating drum biofilter.
Rotating drum biofilters (RDBs) mounted with reticulated polyurethane sponge media has showed high removal efficiencies over a long period of time when used for volatile organic compound (VOC) removal. Due to the accumulation of biomass within the sponge medium, the porosity of a filter bed usually changes dynamically, which makes it difficult to predict and to control. In this paper, the porosity of a multi-layer RDB bed was investigated by a diffusion-reaction model in which biofilm growth and decay were taken into account at the pore scale of the sponge medium. Temporal and spatial changes of porosity were studied under various organic loadings and gas empty bed contact times (EBCTs). The porosity of the biofilter bed was assumed to be a function of biofilm thickness, and all the pores were assumed to be uniform. Toluene was selected as the model VOC. The model was solved using numerical methods through the MATLAB software. Results show that the porosity decreased with increased time of operation, increased toluene loading, or decreased gas EBCT value. The porosity in the outermost medium layer was less than that in the inner medium layers. Toluene removal efficiencies and porosities calculated from this model correlated with the experimental data well. Porosity variation was proposed to be an indicator for prediction of biofilter performance in biofilters as a consequence.


Rainfall-induced nutrient losses from manure-fertilized farmland in an alluvial plain.
Nutrient transport and loss in farmlands are affected by factors such as land cover, fertilization, soil type, rainfall, and management practices. We investigated the temporal and spatial changes in macronutrient transport and loss after fertilization and precipitation in manure-fertilized eggplant farmland in an alluvial plain. Upon adding topical fertilizer, concentrations of most nutrients in runoff and groundwater increased, and nitrogen runoff increased from 22.11 to 35.81 kg/ha, although eggplant yield did not increase correspondingly. Incorporation of fertilizer by plowing reduced nutrient losses (nitrogen runoff/fertilizer decreased from 18.40 to 12.29 %). Measurements taken along the nutrient transport route (runoff, drainage ditch, groundwater, river water, and finally rainfall) revealed that concentrations of most nutrients declined at each stage. Nutrient characteristics varied by transport, and the forms of nitrogen and phosphorus differed greatly between runoff and groundwater (nitrate/nitrogen in runoff was ~43.49 %, while in groundwater ~5.41 %). Most nutrient concentrations in runoff decreased greatly during the planting season (total nitrogen decreased from 62.25 to 4.17 mg/L), correlated positively with temperature and stage of plant growth, but little temporal change was observed in groundwater. This field investigation during one planting season exemplifies the basic principles of nutrient loss and transport from manure-fertilized farmland in an alluvial plain.


Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.
In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. ClinicalTrials.gov Identifier: NCT01835236.


Publisher Correction: The molecular landscape of head and neck cancer.
The article as originally published contained errors in Figure 3. The direction of the arrows associated with the labels for p53 and RB were incorrect. This has now been corrected in all versions of the article.


Initiation of human parturition. VIII. Metabolism of progesterone by fetal membranes of early and late human gestation.
A decreased rate of progesterone metabolism is detected in human fetal membranes several weeks preceding normal parturition at term. A 10- to 20-fold decrease in 20alpha-hydroxysteroid oxidoreductase activity and a 2- to 6-fold decrease in 5alpha-reductase activity are observed in human amnion and chorion laeve after 33 weeks' gestation.


Unveiling the potential of prohibitin in cancer.
Recently, research has shed new light on the role of Prohibitin (PHB) in cancer pathogenesis across an array of cancer types. Important mechanisms for PHB have been unveiled in several cancers, especially with regard to the androgen independent state of prostate cancer (PC) and oestrogen dependent breast cancer. However, PHB is often overlooked due to its complex but subtle roles within the cell. Having gathered both historical and current research exploring PHB's role in different cancer types including prostate and breast, here we aim to pair this information with its molecular properties in the hope of translating this information into a clinical perspective, thus discussing its possible use in future cancer therapy.


[Hypothenar hammer syndrome: A recurrent case report after surgery].
Hypothenar hammer syndrome is a rare entity secondary to ulnar artery damage in the wrist, affecting mainly those exposed to repeated hand-palm trauma. Surgery is discussed in case of severe symptoms, resistant to medical treatment, and/or when anatomical lesions with emboligenic potential are demonstrated in the radiological exams. In this case, resection of the pathological zone with revascularization by autologous vein graft is the best option. We report the case of a 60-year-old patient who had a recurrence of symptoms more than 10 years after the completion of a surgical treatment. There was an aneurysmal thrombosed vein graft with extensive thrombus extending from the ulnar artery upstream of the Guyon's canal to the superficial palmar arch. The digital revascularization was provided by the radial superficial palmar arch and the presence of a collateral vascular supply. This late complication was responsible for compression of the ulnar nerve in Guyon's canal. A new surgery was performed consisting of the resection of the thrombosed zone, including the vein graft, without vascular reconstruction given the good vascularization of all the fingers, and release of the ulnar nerve to the wrist. The operative follow-up was uneventful with the disappearance of pain and sensory-motor deficits. Good digital vascularization was confirmed by imaging at 3 months postoperatively; nerve recovery by electromyogram at 6 months with normal conduction.


Trends in HbA1c and other biochemical outcomes of individuals with newly diagnosed type 1 diabetes.
There is limited data on glycaemic control and cardiovascular risk factor management in newly diagnosed individuals with type 1 diabetes in the first 2 years. Retrospective, single centre study from the North West of England, newly diagnosed with type 1 diabetes between 2014 and 2018 (n = 58). HbA1c, blood pressure, lipids and body mass index (BMI) data were collected from electronic patient records from the time of diagnosis until the end of 2 years, stratified by age 16-24 years or ≥ 25 years at presentation. For those aged 16-24 years (n = 31), median (IQR), HbA1c improved at 6 months from 83 (63-93) to 51.5 (46-75) mmol/mol (p = 0.001) and remained stable 6-24 months. For those ≥ 25 years (n = 27), HbA1c declined from 91 (70-107) to 65 (50-89) mmol/mol, (p < 0.01) at 6 months and declined further to 52 mmol/mol (44-70) at 24 months. At 24 months, 27.8% of all individuals had an HbA1c ≥ 69 mmol/mol. Approximately, a third met LDL (< 2 mmol/L) and total cholesterol (< 4 mmol/L) targets. A total of 58.6% of individuals were overweight/obese (BMI > 25 kg/m2) at 24 months compared to 45.8% at baseline. There were no significant blood pressure changes during the follow-up. In both age groups, significant improvement of HbA1c occurred within the first 6 months of diagnosis with no statistical difference between the two groups at any of the time points up to 24 months. Despite significant improvements in HbA1c, majority had levels > 53 mmol/mol at 24 months. Alongside the high incidence of obesity and dyslipidaemia, our data support the need for further intensification of therapy from diagnosis of type 1 diabetes.


C-C chemokines in the vitreous of patients with proliferative vitreoretinopathy and proliferative diabetic retinopathy.
To investigate the presence of three C-C chemokines (monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein-1alpha [MIP-1alpha], and MIP-1beta) in vitreous samples from eyes with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), or retinal detachment (RD). Vitreous samples were obtained and assayed by solid phase enzyme-linked immunosorbent assay for the chemokines MCP-1, MIP-1alpha, and MIP-1beta in a prospective study of 43 consecutive patients. Eighteen samples from cadaveric control eyes were also assayed. Monocyte chemotactic protein-1 was detected in all samples. The vitreous of eyes with vitreoretinal disorders showed significantly higher levels than the vitreous of cadaveric control eyes (P < or = 0.05). Median level (5th-95th percentile) in the PVR cases (n = 20) was 890.18 pg/mL (286.04-1806.20); in RD (n = 8), 296.69 pg/mL (171.44-1310.02); and in PDR (n = 15), 434.60 pg/mL (124.56-1092.94). In the cadaveric control eyes (n = 18), median level was 83.97 pg/mL (26.09-208.38). Macrophage inflammatory protein-1alpha and MIP-1beta were not detected in any samples. Monocyte chemotactic protein-1 might be involved in the recruitment of macrophages and monocytes into the vitreous of eyes with proliferative vitreoretinal disorders.


Inhibition of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid oxidation and of bile acid secretion in rat liver by fatty acids.
In isolated rat hepatocytes, fatty acids inhibited the side chain oxidation, but not the uptake, of exogenously added 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid (THCA). THCA did not inhibit fatty acid oxidation. In liver homogenates, fatty acids inhibited THCA activation to its CoA ester (THC-CoA) and THCA oxidation. THCA did not influence fatty acid activation or oxidation. Comparison of the THC-CoA concentrations present in the incubation mixtures during THCA oxidation, with substrate concentration curves determined for THC-CoA oxidation, indicated that the inhibition of THCA oxidation by fatty acids was at least partly exerted at the activation step. The inhibition of THCA activation by fatty acids was noncompetitive. Palmitoyl-CoA at concentrations found in the incubation mixtures during THCA oxidation in the presence of palmitate inhibited THC-CoA oxidation, but not sufficiently to fully explain the fatty acid-induced inhibition of THCA oxidation. The inhibition of THC-CoA oxidation by palmitoyl-CoA did not seem to be competitive. Acyl-CoA oxidase, the first enzyme of peroxisomal beta-oxidation (which catalyzes the side chain oxidation of THCA), was enhanced 15-fold in liver homogenates from clofibrate-treated rats when palmitoyl-CoA was the substrate, but the oxidase activity remained unaltered when THC-CoA was the substrate. In the perfused liver, oleate, infused after a wash-out period of 60 min, markedly inhibited bile acid secretion. The results 1) suggest that fatty acids inhibit THCA metabolism both at the activation step and at the peroxisomal beta-oxidation sequence and that separate enzymes may be involved in both the activation and peroxisomal beta-oxidation of fatty acids and THCA and 2) raise the question whether fatty acids might (indirectly?) affect overall bile acid synthesis via their inhibitory effect on THCA metabolism.


An initiator protein for plasmid R6K DNA replication. Mutations affecting the copy-number control.
Two kinds of mutations affecting the copy-number control of plasmid R6K were isolated and identified in an initiator pi protein by DNA sequencing. Firstly, a temperature-sensitive replication mutation, ts22, with decreased copy number results in a substitution of threonine to isoleucine at position 138 of the 305-amino-acid pi protein. Secondly, a high-copy-number (cop21) mutant was isolated from this ts mutant and was identified by an alteration of alanine to serine at position 162. This cop21 mutation suppressed the Ts character and was recessive to the wild-type allele in the copy control.


A case report of Pasteurella multocida meningitis in a patient with non-traumatic skull base defect.
Pasteurella multocida is a gram-negative coccobacillus that is primarily found in oropharynx of dogs, cats and other animals. It causes infections in human beings through contact with animal saliva in the form of licks, bites and scratches of animals colonized by the bacteria. Meningitis due to Pasteurella multocida is rare in immunocompetent individuals. We report a case of meningitis due to Pasteurella multocida in an immunocompetent patient. A 30-year-old gentleman presented with 2-day history of fever and neck stiffness. 6 weeks earlier, he was treated as a case of bacterial meningitis. During that hospital stay, he was diagnosed to have bony defect in the sellar floor based on MRI head performed to evaluate for a prolonged history of CSF rhinorrhea. He was discharged and scheduled for an elective endoscopic endonasal/open repair of the skull base defect after resolution of meningitis. CSF findings during current admission also showed features of bacterial meningitis. CSF culture showed Pasteurella multocida sensitive to penicillin, ampicillin and ceftriaxone. Retrospective history revealed patient's contact with stray cats as he used to feed them but there was no history of licks, bites. He was treated with intravenous ceftriaxone 2 g twice a day for 14 days with complete resolution of his symptoms. Pasteurella multocida is an important cause of bacterial meningitis in patients with skull defect. Patients with traumatic or non-traumatic bony defect of skull should avoid contact with dogs and cats to prevent the spread of infection the central nervous system.


Chemical approaches to define the structure-activity relationship of heparin-like glycosaminoglycans.
Heparin, the drug of choice for the prevention and treatment of thromboembolic disorders, has been shown to interact with many proteins. Despite its widespread medical use, little is known about the precise sequences that interact with specific proteins. The minimum heparin binding sequence for FGF1 and FGF2 necessary to promote signaling was investigated. A characteristic pentasaccharide sequence, DEFGH, is required to accelerate the inhibition of thrombin and factor Xa in the blood-coagulation cascade. The first synthetic heparin pentasaccharide drug has been approved in Europe and the US and is sold under the trade name Arixtra. Other oligosaccharides with different composition are under clinical investigation. The enormous interest in the assembly of heparin oligosaccharides will stimulate the development of new synthetic approaches. Heparin-oligosaccharide-synthesis automation similar to that of DNA or peptide synthesis will play an important role.


Rearrangement of synaptic connections with inhibitory neurons in developing mouse visual cortex.
Cortical inhibition is determined in part by the organization of synaptic inputs to gamma-aminobutyric acidergic (GABAergic) neurons. In adult rat visual cortex, feedforward (FF) and feedback (FB) connections that link lower with higher areas provide approximately 10% of inputs to parvalbumin (PV)-expressing GABAergic neurons and approximately 90% to non-GABAergic cells (Gonchar and Burkhalter [1999] J. Comp. Neurol. 406:346-360). Although the proportions of these targets are similar in both pathways, FF synapses prefer larger PV dendrites than FB synapses, which may result in stronger inhibition in the FF than in the FB pathway (Gonchar and Burkhalter [1999] J. Comp. Neurol. 406:346-360). To determine when during postnatal (P) development FF and FB inputs to PV and non-PV neurons acquire mature proportions, and whether the pathway-specific distributions of FF and FB inputs to PV dendrites develop from a similar pattern, we studied FF and FB connections between area 17 and the higher order lateromedial area (LM) in visual cortex of P15-42 mice. We found that the innervation ratio of PV and non-PV neurons is mature at P15. Furthermore, the size distributions of PV dendrites contacted by FF and FB synapses were similar at P15 but changed during the third to sixth postnatal weeks so that, by P36-42, FF inputs preferred thick dendrites and FB synapses favored thin PV dendrites. These results suggest that distinct FF and FB circuits develop after eye opening by rearranging the distribution of excitatory synaptic inputs on the dendritic tree of PV neurons. The purpose of this transformation may be to adjust differentially the strengths of inhibition in FF and FB circuits.


Bio-evaluation of poly(lactic-co-glycolic) acid nanoparticles loaded with radiolabelled rifampicin.
The poly(lactic-co-glycolic) acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have a sustained release profile over 7 days. There is no information on the location or mode of release of these nanoparticles in living systems. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. We aim to study the distribution pattern of PLGA-loaded nano-formulation of radiolabelled rifampicin in humans. Rifampicin was labelled with 99m Tc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. Following a single oral dosage of the rifampicin nanoformulation, the pharmacokinetic (PK) parameters were significantly different between the nanoparticle and conventional groups: area under the concentration-time curve (AUC = 113.8 vs. 58.6; P < .001), mean residence time (MRT = 16.2 vs. 5.8; P < .01) and elimination rate constant (Ke = 0.04 vs. 0.10; P < .05). Also, Single-photon emission computed tomography/computed tomography (SPECT/CT) images revealed biodistribution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis. Significant difference in PK parameters and biodistribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in the large intestine. The nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node tuberculosis (TB) and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.


Natural killer activity of peripheral blood lymphocytes and its relation to histopathological factors of lung cancer.
This investigation was intended to determine whether the natural killer (NK) activity of peripheral blood lymphocytes (PBL) correlated with the histopathological factor, which is thought to be a result of a balance between tumor aggression and host resistance. The NK activity of PBL from 60 patients with lung cancer was measured by the lysis of 51Cr-labelled K562 target cells. The activity was significantly decreased with advancing stages of the disease, and inversely correlated with increased immunosuppressive substance levels of the serum. Histopathological factors, such as low grade pleural invasion of the tumor and abundant lymphoid cell infiltration around the tumor, were significantly associated with the high NK activity of PBL. These results show that a decrease in NK activity may play a role in identifying those individuals with a greater risk of cancer development.


fastMRI+, Clinical pathology annotations for knee and brain fully sampled magnetic resonance imaging data.
Improving speed and image quality of Magnetic Resonance Imaging (MRI) using deep learning reconstruction is an active area of research. The fastMRI dataset contains large volumes of raw MRI data, which has enabled significant advances in this field. While the impact of the fastMRI dataset is unquestioned, the dataset currently lacks clinical expert pathology annotations, critical to addressing clinically relevant reconstruction frameworks and exploring important questions regarding rendering of specific pathology using such novel approaches. This work introduces fastMRI+, which consists of 16154 subspecialist expert bounding box annotations and 13 study-level labels for 22 different pathology categories on the fastMRI knee dataset, and 7570 subspecialist expert bounding box annotations and 643 study-level labels for 30 different pathology categories for the fastMRI brain dataset. The fastMRI+ dataset is open access and aims to support further research and advancement of medical imaging in MRI reconstruction and beyond.


The unstable painful shoulder (UPS) as a cause of pain from unrecognized anteroinferior instability in the young athlete.
The etiology of shoulder pain in the overhead athlete is often difficult to determine. This study hypothesized that (1) instability can present in a purely painful form, without any apparent history of instability, but with anatomic lesions indicative of instability, termed unstable painful shoulder (UPS), and that (2) arthroscopic shoulder stabilization is effective. The study evaluated 20 patients (mean age, 22 ± 8 years) at a mean of 38 months postoperatively (range, 24-69 months). Inclusion criteria were painful shoulder with lesions indicative of instability on imaging or at surgery, minimum 2-year follow-up. Exclusion criteria were recognized instability, other associated pathologies, and previous shoulder surgery. Patients were young, hyperlax athletes who complained of deep, anterior shoulder pain and denied any instability. Pain was reproduced with the arm in an anterior apprehension position and relieved by a relocation test; however, no actual apprehension was experienced. Patients often had glenohumeral laxity and hyperlaxity. Lesions indicative of instability confirmed that at least 1 unapparent shoulder subluxation occurred. The Rowe, Walch-Duplay, and University of California, Los Angeles scores improved significantly (P < .05); 19 patients (95%) were satisfied, and 15 (75%) returned to their previous level of sports. The diagnosis of UPS is often missed but is important to consider in the young hyperlax athlete. Soft tissue and/or bony lesions consistent with instability are necessary to confirm the diagnosis. Arthroscopy certainly deserves a significant place in this form of anteroinferior instability because it allows both the assessment of lesions (ie, diagnosis) and a satisfactory functional result and return to sport.


A data-driven approach for predicting the impact of drugs on the human microbiome.
Many medications can negatively impact the bacteria residing in our gut, depleting beneficial species, and causing adverse effects. To guide personalized pharmaceutical treatment, a comprehensive understanding of the impact of various drugs on the gut microbiome is needed, yet, to date, experimentally challenging to obtain. Towards this end, we develop a data-driven approach, integrating information about the chemical properties of each drug and the genomic content of each microbe, to systematically predict drug-microbiome interactions. We show that this framework successfully predicts outcomes of in-vitro pairwise drug-microbe experiments, as well as drug-induced microbiome dysbiosis in both animal models and clinical trials. Applying this methodology, we systematically map a large array of interactions between pharmaceuticals and human gut bacteria and demonstrate that medications' anti-microbial properties are tightly linked to their adverse effects. This computational framework has the potential to unlock the development of personalized medicine and microbiome-based therapeutic approaches, improving outcomes and minimizing side effects.


Long-term prospective evaluation of intestinal anastomosis using stainless steel staples in 14 dogs.
This prospective clinical study evaluated the use, complications, and clinical and ultrasonographic follow-ups of end-to-end intestinal anastomoses with skin staples in naturally occurring diseases in canine small and large intestines. Intestinal anastomoses were performed in 14 dogs and pre-, peri-, and postoperative data were recorded. Postoperative clinical and ultrasound evaluations were performed at regular intervals for 1 year. The mean time taken to construct the anastomosis was 5 min. There were no intraoperative complications. Hemorrhage and colonic stricture were the main postoperative complications. Staple loss occurred in 2 cases. Absence of wall layering and focal wall thickening were observed in all cases at each ultrasonographic follow-up. Hyperechoic fat was observed in all but 1 of the cases at month 1. Nine dogs were alive with normal digestive function at the end of the study. The skin stapler technique enabled rapid construction of consistent anastomoses with inexpensive stapling material.


Normal activation of frontotemporal language cortex in dyslexia, as measured with oxygen 15 positron emission tomography.
To assess the ability of dyslexic men to activate left middle to anterior language cortex normally. Positron emission tomography using oxygen 15-labeled water as a tracer during rest and during a syntax task involving sentence comprehension. Research hospital. Fifteen right-handed, severely dyslexic men (mean [+/- SD] age, 27 +/- 5 years) and 20 matched controls. None. Cerebral blood flow. During rest, dyslexics showed reduced blood flow (relative to controls) in one left parietal region near the angular/supramarginal gyri, but otherwise normal flow. During syntactic processing, dyslexics and controls showed similar, significant activation of left middle to anterior temporal and inferior frontal cortex. These results, together with the previously reported failure of dyslexics to activate left temporoparietal cortex during phonologic processing, argue for dysfunction of left cortical language areas restricted to posterior language regions in dyslexia.


Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.
Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2lox/lox) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.