Effects of dopaminergic depletion and brain atrophy on neuropsychiatric symptoms in de novo Parkinson's disease.
Neuropsychiatric symptoms impact the patients' quality of life and caregivers' burdens in Parkinson's disease (PD). We aimed to investigate the effects of striatal dopaminergic depletion and brain atrophy on the neuropsychiatric symptoms of patients with PD. Two hundred and seven patients with de novo drug-naïve PD underwent dopamine transporter (DAT) positron emission tomography and brain MRI scanning. In addition, the patients were assessed with caregiver-administered neuropsychiatric inventory (NPI) questionnaires. To evaluate the effects of DAT uptake, subcortical volume and cortical thinning on the patients' neuropsychiatric symptoms, we performed logistic regression and negative binomial regression analyses on the NPI data after controlling for possible confounders. Frontal cortical thinning was associated with the presence of nighttime behaviour and irritability, and the thinning correlated with the severity of the nighttime behaviour. Temporal cortical thinning was associated with the presence of aggression/agitation, and it correlated with the severity of the aggression/agitation. Subcortical atrophy in the accumbens was associated with the presence of disinhibition and correlated with the severity of the disinhibition. Putamen atrophy and insular thinning were independently associated with the presence of apathy, but only insular thinning correlated with the severity of the apathy. Of the predictors, only frontal cortical thinning correlated with the total NPI score. The results of this study suggested that accumbens atrophy and frontotemporal cortical thinning, especially frontal cortical thinning, independently contributed to neuropsychiatric symptoms in patients with PD, while DAT uptake did not affect the neuropsychiatric symptoms.


Primary total knee arthroplasty for periarticular fractures.
We present a series of 6 patients with periarticular fractures of the knee that were treated by primary total joint arthroplasty. These fractures around in 6 elderly women, three in the proximal tibia and three in the distal femoral. All the patients had osteoarthritis and osteopenia. In five patients, a hinged total knee arthroplasty was performed, and in one case an unconstrained prosthesis was performed. Cementing techniques were used in all. Postoperatively, immediate mobilization with full weight bearing was initiated. No radiographic or clinical evidence of loosening was seen, and the functional outcome was satisfying. The results suggest that another treatment option for intra-articular distal femoral or intra-articular proximal tibial fractures in elderly patients with severe osteopenia and osteoarthritis is primary total knee arthroplasty. Furthermore, this primary total knee arthroplasty may require some degree of constraint.


Detainees in Amsterdam, a target population of the Public Mental Health System?
The Forensic Medical Service of the Public Health Service offers health care to detainees in police cells in Amsterdam. This study describes the registered mental health, addiction and social problems and compares them to the self-reported problems among a sample of detainees. Registers of the Forensic Medical Service are related to information from registers of police detention episodes. A general assessment of substance use, mental health and social problems is obtained by interviewing a sample of 264 detainees. The Forensic Medical Service was contacted in 24% of the 17,321 detention episodes. In 14% of the episodes mental or substance related disorders were observed. Within the sample 59% scored positively on indicators of substance abuse or mental health problems, 35% had additional social problems (debts, unemployment, housing). This proportion increased with age. It is concluded that substance abuse and mental health problems combined with social problems are highly prevalent among detainees, especially among the older ones. This urges for a close cooperation between Public Mental Health Care and Forensic Medical Services.


H3 K27M Mutations in Thalamic Pilocytic Astrocytomas with Anaplasia.
The revised World Health Organization classification of central nervous system tumors, published in 2016, has recognized the H3 K27M mutation as a critical genetic signature defining a new group of infiltrative astrocytomas designated as diffuse midline glioma, H3 K27M mutant. Although most H3 K27M mutations arise in the setting of diffusely infiltrative tumors, there are rare reports of compact tumors with low-grade histologic features harboring this mutation. The prevalence and clinical significance of this mutation in pilocytic astrocytomas remain unclear. We report 2 young adult patients with H3 K27M-mutated thalamic pilocytic astrocytomas who presented to medical attention with symptomatic hydrocephalus requiring urgent intervention. We present our experience with this unusual tumor and recommend a treatment paradigm of maximal safe surgical resection followed by chemotherapy and radiation. Stereotactic biopsies may undergrade some adult thalamic pilocytic astrocytomas. Therefore, we recommend that all these tumors be evaluated for the H3 K27M mutation. Further, we think H3 K27M-mutant thalamic pilocytic astrocytomas require aggressive multimodality treatment and these treatments should be guided by the molecular findings, as opposed to the histologic ones.


Shaken baby syndrome: identification, intervention, and prevention.
More than 1 million children are severely abused annually. Shaken baby syndrome (SBS), one example of physical abuse, is a leading cause of morbidity and mortality in infants. There is a national annual incidence in the United States of 750 to 3,750 cases of SBS. Shaken baby syndrome is defined as vigorous manual shaking of an infant who is being held by the extremities or shoulders, leading to whiplash-induced intracranial and intraocular bleeding with no external signs of head trauma. Shaken baby syndrome should be suspected in infants with a wide spectrum of clinical signs and symptoms. The classic findings of SBS are retinal hemorrhages, usually bilateral, and intracranial injury. One third of the victims of SBS survive with few or no sequelae, one third suffer permanent injury, and one third die. Parental behaviors, environmental factors, and child characteristics all may contribute to a shaking event. The nurse practitioner, in a wide variety of clinical settings, is in a strategic position for the early identification and intervention for families at risk for SBS. Prevention through parent, caregiver, and community-wide education programs is the only option for infants who are at risk for SBS.


E-space preservation.
To determine the relationship of E-space preservation with lingual holding arches to mandibular permanent second molar impaction. Two hundred consecutively treated patients undergoing nonextraction treatment for incisor crowding were entered into the study. Lower incisor crowding was assessed by the Little Irregularity Index. Treatment involved E-space preservation via a passive lingual arch placed prior to exfoliation of the second primary molar. Panoramic and cephalometric radiographs were analyzed for any significant relationship of mandibular permanent second molar impaction relative to molar angulation, spacing, growth pattern, and skeletal relationships. Twenty-nine patients had at least one impacted second molar (14.5%). Of a possible 400 mandibular second molars, 34 were determined to be impacted (8.5%). Only the mandibular first molar-second molar angulation was found to be significant (P < .001). Pretreatment intermolar angulation of 24 degrees had a positive predictive value of 1. Impaction of permanent second mandibular molars in patients undergoing nonextraction via E-space preservation with a passive lingual arch is 10 to 20 times more prevalent than that observed in the general population. Risk of impaction is best predicted by the pretreatment intermolar angulation between first and second permanent mandibular molars.


Tumor necrosis factor-alpha and interleukin-4 gene polymorphisms in Chinese patients with gout.
The purpose of this study was to examine whether polymorphisms of interleukin-4 (IL-4) (promoter-590 and intron 3) and tumor necrosis factor-alpha (TNF-alpha) promoter-308 genes are markers of susceptibility to or clinical manifestations of gout in Taiwanese patients. The study included 196 Taiwanese patients with gout and 103 unrelated healthy control subjects living in central Taiwan. Polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha (promoter-308) genes were typed from genomic DNA. Allelic frequencies and carriage rates were then compared between gout patients and control subjects. The correlation between allelic frequencies, carriage rates and clinical manifestations of gout were evaluated. No significant differences were observed in the allelic frequencies and carriage rates of the IL-4 (promoter-590 and intron 3) and TNF-alpha gene polymorphisms between patients with gout and healthy control subjects. Furthermore, the IL-4 (promoter-590 and intron 3) and TNF-alpha genotypes were not found to be associated with the clinical and laboratory profiles in gout patients. However, there was a significant difference in the TNF-alphapolymorphism genotype between patients with and without hypertriglyceridemia (P=0.001, xi2=11.47, OR=10.3, 95%CI=3.57-29.7). The results of our study suggest that polymorphisms of the IL-4 (promoter-590 and intron 3) and TNF-alpha promoter-308 genes are not related to gout in Chinese patients in Taiwan.


Post-Operative Endonasal Debridement May Improve Outcomes of Endoscopic Dacryocystorhinostomy.
Background: Endoscopic dacryocystorhinostomy (endoDCR) has proven to be an effective minimally invasive surgical procedure for treatment of nasolacrimal duct obstruction. Post-surgical endonasal debridement has not yet been independently assessed for its impact on functional success. Methods: A retrospective review was performed of all patients who underwent endoDCR by an experienced oculofacial plastic surgeon over 7 years (2012-2019). Post-operative intranasal debridement was not routinely performed from March 2012 to February 2016. From March 2016 to June 2019, all patients underwent routine ipsilateral intranasal debridement at post-operative week 2. Surgical success was determined based upon subjective assessment of epiphora resolution at the patient's final post-operative visit. Results: A total of 69 patients (88 surgeries) were included. Thirty-five patients had standard post-operative follow-up without debridement, whereas 34 underwent endonasal debridement at post-operative week 2. Demographics and follow-up were similar between the 2 groups. Functional success was achieved in 84.1% of patients without debridement, and in 97.7% with debridement (P = .058). Conclusion: This review demonstrates a trend toward improvement in the rate of surgical success of endoDCR when routine endonasal debridement was instituted 2 weeks following surgery. We believe that removal of nasal crusts, clots, and residual absorbable gelatin sponge at the osteotomy site improves tear outflow and reduces cicatricial healing enhancing patency of the surgically derived lacrimal-nasal fistula. We advocate for postoperative debridement in the perioperative management of endoDCR patients to optimize successful outcomes.


Electromyographic analysis of goal-directed grasping behavior in the American lobster.
Animals spontaneously initiate goal-directed behavior including foraging action based on their appetitive motivation. The American lobster Homarus americanus exhibits grasping behavior with its crusher claw as feeding behavior that can be initiated after appropriate operant conditioning. In order to quantitatively characterize the goal-directed grasping behavior with a time resolution fine enough for neurophysiological analysis of its initiation and control mechanisms, we made simultaneous electromyographic (EMG) recording from grasping- and reaching-related muscles of the crusher claw while animals initiated grasping behavior. We developed an in vivo extracellular recording chamber that allowed the animal under a semi-restrained condition to perform operant reward learning of claw grasping. Three muscles in the crusher claw (propodite-dactyl closer/opener and coxal protractor) were found to be closely associated with spontaneous grasping behavior. In spontaneous grasping, the activation of those muscles consistently preceded the grasping onset time and exhibited different activity patterns from the grasp induced by a mechanical stimulus. Furthermore, we found that the timing of coxal protractor activation was closer to the grasp onset and its activity was briefer for goal-directed grasping behavior in trained and hungry animals than for non-goal-directed spontaneous grasping behavior in naive or satiated animals. It is suggested that the goal-directed grasping behavior of lobster is characterized, at least partly, by experience-dependent briefer activity of specific muscles involved in reaching action.


Hazard Identification and Characterization: Criteria for Categorizing Shiga Toxin-Producing Escherichia coli on a Risk Basis†.
Shiga toxin-producing Escherichia coli (STEC) comprise a large, highly diverse group of strains. Since the emergence of STEC serotype O157:H7 as an important foodborne pathogen, serotype data have been used for identifying STEC strains, and this use continued as other serotypes were implicated in human infections. An estimated 470 STEC serotypes have been identified, which can produce one or more of the 12 known Shiga toxin (Stx) subtypes. The number of STEC serotypes that cause human illness varies but is probably higher than 100. However, many STEC virulence genes are mobile and can be lost or transferred to other bacteria; therefore, STEC strains that have the same serotype may not carry the same virulence genes or pose the same risk. Although serotype information is useful in outbreak investigations and surveillance studies, it is not a reliable means of assessing the human health risk posed by a particular STEC serotype. To contribute to the development of a set of criteria that would more reliably support hazard identification, this review considered each of the factors contributing to a negative human health outcome: mild diarrhea, bloody diarrhea, and hemolytic uremic syndrome (HUS). STEC pathogenesis involves entry into the human gut (often via ingestion), attachment to the intestinal epithelial cells, and elaboration of Stx. Production of Stx, which disrupts normal cellular functions and causes cell damage, alone without adherence of bacterial cells to gut epithelial cells is insufficient to cause severe illness. The principal adherence factor in STEC is the intimin protein coded by the eae gene. The aggregative adherence fimbriae adhesins regulated by the aggR gene of enteroaggregative E. coli strains are also effective adherence factors. The stx2a gene is most often present in locus of enterocyte effacement ( eae)-positive STEC strains and has consistently been associated with HUS. The stx2a gene has also been found in eae-negative, aggR-positive STEC that have caused HUS. HUS cases where other stx gene subtypes were identified indicate that other factors such as host susceptibility and the genetic cocktail of virulence genes in individual isolates may affect their association with severe diseases.


Synthesis and biological activities of oligo(8-bromoadenylates) as analogues of 5'-O-triphosphoadenylyl(2'----5')adenylyl(2'----5')adenosine.
The 8-bromoadenosine analogue of 5'-O-triphosphoadenylyl(2'----5')adenylyl(2'----5')adenosine (2-5A) and its derivatives were synthesized, and their biological activity was evaluated in mouse L cell extracts. All compounds, except 5'-dephosphorylated "cores" bound to the 2-5A-dependent endonuclease with a relative activity, depending on the derivative, of 1 to 0.035 of that of 2-5A trimer. 8-Bromoadenylate trimer 5'-mono-, -di, and -triphosphates inhibited protein synthesis with a relative activity of 0.0023, 0.050, and 0.015 compared to 2-5A. Tetramer 5'-monophosphate also inhibited protein synthesis (relative activity 0.0033). The corresponding pentamer 5'-monophosphate did not; however, the pentamer 5'-diphosphate was able to inhibit translation (relative activity 0.0092). All compounds that possessed inhibitory activity in the protein synthesis inhibition assay gave ribosomal RNA cleavage patterns characteristic of the action of 2-5A-dependent endonuclease. Thus, 8-bromination of the all of the adenine rings of 2-5A leads to 20- to 70-fold reduction in the biological activity of the corresponding 5'-di- and -triphosphate, respectively; however, this same alteration of the three adenine moieties gives rise to a 5'-monophosphate with much enhanced translational inhibitory activity compared to the parent 2-5A trimer 5'-monophosphate.


Synthesis of methotrexate-betulonic acid hybrids and evaluation of their effect on artificial and Caco-2 cell membranes.
An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (tert-butoxycarbonylamino)-3,6-dioxa-8-octanamine (Boc-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by 1H NMR, 13C spectra, FAB mass spectrometry and elemental analysis. The identity of conjugates was confirmed by LC-MS data. Membranotropic properties of the new hybrids were assessed on the basis of their interactions with artificial lipid membranes by differential scanning calorimetry (DSC) method. The ability of the conjugates to penetrate Caco-2 cells is inferior to methotrexate. Probably, this is due to the increasing lipophilicity, the affinity of these hybrid molecules for the lipid bilayer increases, which is confirmed by experiments with artificial membranes.


Development and preliminary evaluation of an intraoral Tongue Drive System.
Tongue Drive System (TDS) is a wireless tongue-operated assistive technology (AT), developed for people with severe physical impediments to control their environments using their tongue motion. We have developed a new intraoral TDS (iTDS) in a form of a dental retainer, which can tightly clasp onto the upper teeth, completely hidden inside the mouth, using commercial off-the-shelf components (COTS). The iTDS retainer was tested by two healthy subjects and their performance was compared with that of an external TDS (eTDS) implemented in the form of a headset. The iTDS retainer showed comparable performance with the eTDS headset. The iTDS is expected to improve the stability and robustness of the TDS, while giving users a certain degree of privacy.


Indentation test for free-flowable powder excipients.
Indentation of a sphere into nonconsolidated powder excipients is a suitable complementary method for the evaluation of flow properties of the free-flowable noncohesive powders. To use the standard penetrometry method to indentation of nonconsolidated powder layer by a glass sphere of 16 mm in diameter, the suitable geometry of the measurement container is required to prevent undesirable moving in a direction opposite to that in which the indenting sphere moves. Thus, the powder indentation by a sphere seems to be similar to indentation by the Brinell hardness tester. In this work, the depth of indentation was measured for five pharmaceutical powder excipients: sodium chloride, sodium citrate, potassium citrate, sorbitol, and boric acid with the three size fractions in the range of 0.315-0.630 mm. To express powder flowability, the uniform mass and/or volume flow rate from the 10-mm cylindrical outlet of the cylindrical testing hopper was used. The relationships between the powder flow rate and its bulk density and/or the different characteristics of indentation were modeled by using linear regression. Out of the indentation characteristics, the mass of indentation calculated as the multiple of the volume of indentation and the powder bulk density could be recommended to estimate the powder mass flow rate due to the linear regression with the coefficient of determination equal to 0.973 and the accuracy of 4.3%. In conclusion, the indentation by the sphere could be recommended as a quick simple method for the comparison of flow properties of the nonconsolidated, noncohesive powder excipients.


Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2: laboratory investigation.
Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice. Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control. Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM.


Toll-like receptor 9 signaling in chronic lymphocytic leukemia cell lines.
Chronic lymphocytic leukemia (CLL) is a prototypic neoplasia in which malignant cells strongly depend on microenvironmental stimulations in the lymphoid tissues where they accumulate; leukemic cells are exposed to interaction with bystander and accessory cells, as well as inflammatory soluble mediators. Cell lines are frequently used to model the pathobiology of this disease; however, they do not always recapitulate leukemic cell growth and response to stimulation, and no data are available on Toll-like receptors (TLR) signaling in CLL cell lines. To address this gap, we analyzed HG3, MEC2, and PCL12 cell lines, before and after CpG stimulation, by RNA-sequencing followed by bioinformatic analyses and validation experiments. We identified NFKBIZ mRNA and the corresponding IkBz protein as robust markers of TLR9 activation in both MEC2 and PCL12, but not in HG3 cells. Next, we compared our current results with previous results obtained with primary CLL patient samples and were able to conclude that MEC2 is most similar to the patients' cells in terms of global responsiveness to TLR stimulation; in particular, MEC2 better resembles the samples of patients, as it is characterized by high expression levels of IkBz, but with a lower number of genes regulated.


Effect of vitamin E, vitamin C, and beta-carotene on stroke risk.
In a recent prospective observational study, vitamins C and E and beta-carotene did not elicit protective effects on stroke risk. Lutein, however, may elicit such protection. Nevertheless, these nutrients may be important modulators of the outcome after the occurrence of a stroke. At present, optimal control of the classic stroke risk factors in combination with increased consumption of fruits, vegetables, and antioxidant nutrients may represent the safest and most efficient strategy to control stroke risk.


Evaluation of an inpatient psychiatric hospital physician education program and adherence to American Diabetes Association practice recommendations.
This study evaluated adherence to American Diabetes Association (ADA) recommendations for diabetes monitoring following an educational intervention for physicians in an inpatient psychiatric hospital. This retrospective chart review was conducted in an inpatient psychiatric institution from July 1, 2010-January 15, 2011. A total of 120 subjects (60 subjects each in the pre- and post-intervention groups) meeting the inclusion criteria served as the study sample. Included subjects were admitted and discharged from an inpatient psychiatric institution within 90 days prior to (pre-intervention) and following (post-intervention) the physician education program. The medical staff was presented an educational program intervention, consisting of a 30 minute overview of the ADA 2010 Standards of Care recommendations and distribution of laminated treatment reminders. Electronic grouped order sets for patients with diabetes were also created and implemented. The primary outcome was change (pre-intervention to post-intervention) in frequency of hemoglobin A1c documentation on admission following the intervention. Secondary outcomes included the change in frequency of documentation of fasting plasma glucose, serum creatinine, urine creatinine/microalbumin ratio (UMA), fasting lipid profile (FLP), and change in days on sliding scale insulin. Regarding change in frequency of documentation of A1c values on admission, chi-square analysis revealed a significant increase from pre-intervention to post-intervention period of 30% (n = 18) to 61.7% (n = 37), respectively (p = 0.0005). Documentation of FLP also significantly increased [73.3% vs. 91.7% (p = 0.0082)]. There were no significant differences in the documentation of fasting plasma glucose, serum creatinine, and UMA or days treated with sliding scale insulin. The physician education program was successful in increasing the assessment of A1c values and lipid profiles for patients with diabetes mellitus in a psychiatric institution.


Crosslinked network microstructure of carbon nanomaterials promotes flaw-tolerant mechanical response.
Carbon nanomaterials, such as carbon nanotubes (CNTs) and carbon nanofibers (CNFs), are chemically inert in their highly graphitic forms. Various post processing methods can activate their surfaces to enhance their interactions with a host matrix in a nanocomposite. Chemical surface functionalization is used often. This method however can lead to major strength loss in nanomaterials stemming from induced surface defects (changing sp2 bonds to sp3 bonds). In this manuscript, we have experimentally studied the mechanical properties of the individual, pyrolysis-fabricated CNFs. These CNFs have a highly crosslinked 3D network of C-C bonds. The strength of CNFs has been studied as a function of O/C ratio. The loss in strength due to functionalization has been compared to that of other carbon nanomaterials with layered strcutures (CNT and graphene). Comparisons were also made with carbon microfibers. Fracture strength estimations of the critical flaw size in CNFs, CNTs and graphene were also made. The results revealed that despite having high surface area, carbon nanomaterials with crosslinked microstructure are resilient to flaws as big (deep) as 10-30 nm, while nanomaterials with layered structure (such as CNTs) experience a dramatic loss in strength with much lower flaw sizes. Hence, it seems that graphitic nanomaterials such as graphene and CNT have high strenght that, although higher than CNFs, comes at a cost to flaw tolerance and robustness. Since failure is often progressive, this work demonstrates a benefit that crosslinked nanomaterials have over highly graphitic ones, such as CNTs, in load bearing applications.


Pride: adaptive social emotion or seventh sin?
This experiment examined the ability of pride to serve as an adaptive emotion within the context of social interaction. After an in vivo induction of pride or a neutral state, participants engaged in a group problem-solving task. In contrast to a conventional view that pride is often associated with negative interpersonal outcomes, results confirmed that proud individuals not only took on a dominant role within the group problem-solving task, but also were perceived as the most likeable interaction partners. These findings suggest that pride, when representing an appropriate response to actual performance (as opposed to overgeneralized hubris), constitutes a functional social emotion with important implications for leadership and the building of social capital.


Functional analysis of mouse keratin 8 in polyoma middle T-induced mammary gland tumours.
Keratin 8 and 18 are commonly used as tumorigenic markers for various types of carcinomas. They are known to be involved in cell migration, cell invasiveness, plasminogen activity and drug and radiation resistance. To ascertain a potential function for simple epithelium keratins in mammary adenocarcinoma in vivo, keratin-8-deficient mice (mK8) were mated with transgenic mice carrying the middle T oncogene driven by the MMTV promoter. The resulting mK8 knockout and control progeny carrying the middle T transgene developed mammary gland tumours with the same incidence. However, the onset of palpable mammary gland tumours occurred earlier in mK8 mutant than in control mice. This effect was prominent in males where the onset in control animals is delayed overall, because of the lower hormonal inducibility of the MMTV promoter. Metastatic foci were observed in the lungs of all females and of a few males, independently of the genotype. Histological analysis revealed no morphological differences of the tumorigenic cells in primary tumours nor in metastatic foci. As expected, keratin 8 was absent in the mK8 tumours. Keratin 7 (mK7), keratin 18 (mK18) and keratin 19 (mK19) protein were observed in both primary and metastatic foci. These results constitute the first in vivo analysis of the role of simple epithelium keratins in mammary carcinogenesis. It demonstrates that the latency, but not the incidence nor the morphological features, of PyV middle T-induced mammary gland tumours is affected by keratin 8 deficiency.


Education for integrated working: A qualitative research study exploring and contextualizing how practitioners learn in practice.
Integrated working can be a means of providing efficient and cost-effective care, which benefits both service users and health professionals. However, it does require readiness of practitioners to work in new and innovative ways to achieve integration. This paper describes the findings of a qualitative study exploring the nature of practice-based education and training underpinning successful integrated care teams using an ecological systems theory lens. Nine teams in the West Midlands region of the United Kingdom (UK) participated in this study. A total of 27 participants were involved in semi-structured interviews during which they shared their views and experiences of learning in practice. Thematic analysis of interview transcripts highlighted the shifting context of working in integrated teams impacting on learning, the influence of leadership on education and training, the nature of in-service training, and the knowledge-sharing culture. The findings highlight that the learning climate is highly dependent on the leadership ethos in the practice context, which influences the allocation of time and resources for training and clinical supervision. Whilst formal education and training has an important role to play in fostering integrated working, informal learning is pivotal to successful integration and potentially has greater impact making it worthy of further study.


Racial difference in cochlear pigmentation is associated with hearing loss risk.
The goals of this study are to characterize the distribution of melanin pigmentation in the human cochlea and to investigate differences in pigment content between races. Human temporal bone specimens from the Johns Hopkins Temporal Bone Collection were examined. Demographic, clinical, and audiometric data were analyzed. Melanin pigmentation in the cochlea was quantified in each specimen. Nineteen African-American (AA) and 27 Caucasian specimens were selected for the study. The mean ages were 64 and 70 years for AA and Caucasian specimens, respectively (p = 0.21). At all cochlear turns, AA specimens contained significantly more pigmentation in the stria vascularis (p = 0.0003) and Rosenthal's canal (p < 0.0001) compared with Caucasian specimens. Strial melanin content increased significantly with age. Cochlear pigmentation content was not associated with sex or hearing thresholds. Melanin pigmentation is significantly more abundant in AA cochleae than in Caucasian cochleae. This study provides a detailed description of pigmentation in the cochlea and may help to explain the observed racial differences in hearing thresholds.


Should patients be screened for asymptomatic carotid artery stenosis?
To evaluate, against published guidelines, the potential role of screening to reduce the risk of stroke and death from asymptomatic carotid artery stenosis (ACAS). Papers selected for review were identified through a GRATEFUL MED literature search, from personal files and from references documented in identified papers. Population studies concerning disease prevalence, natural history studies related to risk of stroke, randomized controlled trials related to carotid endarterectomy and natural history studies related to the risk of developing ACAS were considered for review. An estimate was made of the potential for stroke resulting from ACAS in the general population. This was evaluated against the positive predictive value of duplex scanning, and the number of patients needing to be screened to prevent a stroke was estimated. The prevalence of ACAS in the general population was estimated to range from 2% to 8% for ACAS 50% or greater and to range form 1% to 2% for ACAS 80% or greater. The yearly risk of stroke or death from undetected ACAS was estimated to be 0.16% for ACAS 50% or greater and 0.06% for ACAS 80% or greater. The estimated number of patients needing to be screened to prevent 1 stroke would range from 850 to 1700 (and potentially as high as 8500). General screening for ACAs to prevent stroke and death cannot be recommended when evaluated against guidelines. The decision to screen individual patients will require judgement, continued evaluation and surveillance of the results of such screening by the treating physician.


Projections from the Cerebral Cortex to the Red Nucleus of the Guinea-pig. A Retrograde Tracing Study.
The origin and the topographic distribution of corticorubral (CR) projections in the guinea-pig were studied by using the retrograde axonal transport of a tracer, colloidal gold-labelled, enzymatically inactive horseradish peroxidase conjugated to wheat-germ agglutinin (WGAapoHRP - Au), which was injected in the red nucleus (RN). It was found that the bulk of the CR projections arise from layer V neurons of the agranular frontal cortex in both its medial (Agm) and lateral (Agl) subdivisions; in the Agm labelled neurons are preferentially located in the upper part of layer V, whereas in the Agl they are more concentrated in the central band of the layer. Fewer projections originate from areas of the granular parietal and the agranular cingulate and retrobulbar cortices. CR projections have a bilateral origin, with a large ipsilateral predominance. The pattern of retrograde cortical labelling observed after injection of WGAapoHRP - Au in different portions of the RN indicates that CR projections are distributed throughout the entire rostrocaudal extent of the nucleus, but are slightly more concentrated in the rostral parvocellular area. The morphological arrangement of CR projections in the guinea-pig, as demonstrated in the present study, shows several analogies with other mammals. The functional characteristics of the cortical areas in which CR neurons are located indicate that CR projections may play a significant role in the central organization of movement.


An evaluation of compound-specific isotope analyses for assessing the biodegradation of MTBE at Port Hueneme, CA.
The use of compound-specific isotope analysis (CSIA) as a diagnostic tool for MTBE biodegradation in aquifers was tested at the Port Hueneme, CA site. There, a 1500-m long dissolved MTBE plume and associated engineered aerobic flow-through biobarrier have been well-studied, leading to delineation of regions of known significant and limited bioattenuation. This allowed comparison of field-scale CSIA results with a priori knowledge of aerobic MTBE biodegradation, leading to conclusions concerning the utility of CSIA as a diagnostic tool for other aerobic biodegradation sites. Groundwater samples were collected and analyzed for both 13C and 2H (D) in MTBE through the bioactive treatment zone and within the larger MTBE plume. For reference, the 13C enrichment factor for MTBE biodegradation in laboratory-scale microcosms using site groundwater and sediments was also quantified. Aerobic microcosms showed a 13C enrichment of 5.5 to 6.4 +/- 0.2 per thousand over a two-order of magnitude concentration decrease, with an average isotope enrichment factor (epsilon(c)) of -1.4 per thousand, in agreement with other aerobic microcosm studies. Less 13C enrichment (about 25%) was observed for similar MTBE concentration reductions in groundwater samples collected within the aerobic biotreatment zone, and this enrichment was comparable to the scatter in delta13C values within the source zone. Increasing enrichment with decreasing MTBE concentration seen in microcosm data was not evident in either the 13C or D field data. The discrepancy between field and laboratory data may reflect small-scale (<1 m) spatial heterogeneity in MTBE biodegradation activity and the mixing of water from adjacent strata during groundwater sampling; for example, relatively nonattenuated MTBE-impacted water from one stratum could be mixed with highly attenuated/low-MTBE concentration from another, and this could produce a sample with both reduced MTBE concentration and low enrichment. Overall, the results suggest that 13C data alone may produce inconclusive results at sites where MTBE undergoes aerobic biodegradation, and that even with two-dimensional CSIA (13C and D), an increase in the confidence of data interpretation may only be possible with data sets larger than those typically collected in practice.


Enhancing adherence to antipsychotic treatment for bipolar disorders. Comparison of mobile app-based psychoeducation, group psychoeducation, and the combination of both: protocol of a three-arm single-blinded parallel-group multi-centre randomised trial.
Group Psychoeducation (PE) is an effective strategy to enhance adherence to antipsychotic treatment in Bipolar Disorders (BD). However, it requires attendance to weekly sessions during a period of about 6 months. This may impede its application for those patients living far from mental health centres, resulting inequality in access to evidence-based care. Therefore, there is an increasing need to find new efficient strategies to deliver and extend PE programs to a wider population of BD patients. Mobile apps are a cost-effective way to deliver PE. In the Italian healthcare context, no evidence about the use of apps is available. The current paper presents the protocol about the development of a smartphone app to deliver PE for BD and the protocol for a trial assessing its effectiveness. In euthymic BD patients, the study will compare the adherence rates to antipsychotics between PE delivered through Bipolar mobile Application (Bip.App), group PE and a combination of both, will investigate demographic, socio-cultural and clinical predictors of lower adherence in the arms, and will investigate whether PE combined with Bip.App is associated with lower risk of recurrence of (hypo)manic and depressive episodes than group PE alone, and assess the feasibility and satisfaction for Bip.App. Participants will be recruited from mental health centres and included if they are 18-65 year-old, have primary BD in the euthymic phase, they have been prescribed a second-generation oral antipsychotic as a maintenance/prophylactic therapy for at least 1 year, they have not undergone a structured protocol of PE for BD, they have access to a smartphone and sufficient competence in using it. Participants will be excluded if they have neurological disease, mental retardation or learning disability, psychosis, limited fluency in Italian. Adherence will be assessed through count pills, blood levels, and self-reported adherence. A single-blinded parallel-group superiority multi-centre randomised controlled trial design will be used.


[The effect of recombinant human erythropoietin on the treatment of anemia of prematurity]
OBJECTIVE: To assess the efficacy of erythropoietin in the prevention and treatment of anemia of prematurity, correlating the use of this drug with weight gain, length, and head circumference and comparing two administration schemes of he same weekly dose: daily use and twice a week. METHODS: The study comprised 42 premature newborns with gestational age up to 33 weeks, birthweight up to 1550 g, and postnatal age between 10 and 35 days. The newborns were randomized into three groups: patients in group 1 received seven daily doses of 100 U/kg erythropoietin per week; patients in group 2 received two 350 U/kg erythropoietin doses per week; and patients in group 3 did not receive the drug. Hematologic measurements, blood transfusion requirements, and growth rates were followed during therapy. RESULTS: Cases and controls did not differ with respect to weight, length, head circumference, and total time of hospital stay. At the end of the study, no significant difference was observed in the platelet count measurement means, white blood cell count, and ferritin levels in the three groups. However, the final hematocrit and hemoglobin values of patients who did not receive erythropoietin were significantly lower than those of patients who received the drug. The absolute reticulocyte count mean was significantly higher in patients who received erythropoietin after two weeks of treatment when compared with those patients who did not receive the drug. Patients in group 1 e 2 received fewer excessive transfusions (2 or more) than patients in group 3. The administration of 700 U/kg/week erythropoietin significantly reduced the number of excessive blood transfusions. There is no significant difference in blood transfusion volume between patients who received erythropoietin on a daily basis and those who received the drug twice weekly. CONCLUSIONS: the use of erythropoietin did not influence weight gain and growth. The administration of 700 U/kg/week erythropoietin in premature infants with gestational age up to 33 weeks and birthweight up to 1550 g stimulates erythropoiesis and significantly reduces excessive blood transfusion requirements. Erythropoietin showed to be a safe and well tolerated medication, with no short-term side effects in the study population.


A meta-analysis of Parkinson's disease and exposure to pesticides.
This study examined the association between Parkinson's disease (PD) and exposure to pesticides. A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999. Prior to the meta-analysis, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random effect model. The majority of the studies reported consistent elevation in the risk of PD with exposure to pesticides. The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53] for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed in United States. Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Our findings suggest that exposure to pesticides may be a significant risk factor for developing PD.


The creation of an assessment tool for the analysis of two forms of heat damage in animal hair.
Animal cruelty cases can involve a variety of mistreatment to domestic animals. A common source of abuse is the use of heat sources, such as ovens, hot surfaces and microwaves. Analysis of damage to skin by a veterinarian is a key aspect of these investigations but additional information can be provided by observing the hair of the animal, including heat source type and exposure time. This study developed an objective grading system for the analysis of heat damage in hairs which can be used to quantify different damage characteristics including bubbling, discolouration, expansion of hair, fractures, changes to the medulla and scales and scale removal/melting. This grading scheme was applied to the investigation of dog (Canis familiaris) skin samples with full pelage and loose hairs exposed to microwaves and a heated environment in order to identify any distinguishing damage characteristics from the two different heated environments. Samples were exposed to a furnace for 1min at different temperature ranges (50-350°C with 50°C intervals) and also a microwave at maximum power for different time periods (15, 30, 45, 60, 120, 180, 240 and 300s). Hairs were extracted for examination using high powered light microscopy and scanning electron microscopy. Overall, it can be determined that the type of damage observed is influenced by the nature of heat applied and the context and substrate in which the hair is situated at the time of exposure. Using principal component analysis (PCA) it was concluded that as temperature increases in a furnace so does the severity of each of the damage characteristics observed. It can be noted that with furnace exposure, any one of the characteristics could be used to indicate the temperature to which it has been exposed. For furnace exposed samples there was no significant difference between loose or embedded hairs. PCA analysis determined that there are two independent forms of damage that occur when hairs are exposed to microwave radiation, these are: increased bubbling and discolouration in the root and increased bubbling and discolouration of the shaft and tip. Exposure time is correlated with both the root and shaft/tip observations. The results indicated some clear distinctions between heat source and exposure useful for the objective interpretation of such evidence. This standardised approach for the observation of heat damage characteristics in animal hair provides investigators with a tool to differentiate between methods of abuse, providing a greater understanding of the crime committed.


Exposure of pelagic seabirds to Toxoplasma gondii in the Western Indian Ocean points to an open sea dispersal of this terrestrial parasite.
Toxoplasma gondii is a protozoan parasite that uses felids as definitive hosts and warm-blooded animals as intermediate hosts. While the dispersal of T. gondii infectious oocysts from land to coastal waters has been well documented, transmission routes to pelagic species remain puzzling. We used the modified agglutination test (MAT titre ≥ 10) to detect antibodies against T. gondii in sera collected from 1014 pelagic seabirds belonging to 10 species. Sampling was carried out on eight islands of the Western Indian Ocean: Reunion and Juan de Nova (colonized by cats), Cousin, Cousine, Aride, Bird, Europa and Tromelin islands (cat-free). Antibodies against T. gondii were found in all islands and all species but the great frigatebird. The overall seroprevalence was 16.8% [95% CI: 14.5%-19.1%] but significantly varied according to species, islands and age-classes. The low antibody levels (MAT titres = 10 or 25) detected in one shearwater and three red-footed booby chicks most likely resulted from maternal antibody transfer. In adults, exposure to soils contaminated by locally deposited oocysts may explain the detection of antibodies in both wedge-tailed shearwaters on Reunion Island and sooty terns on Juan de Nova. However, 144 adults breeding on cat-free islands also tested positive. In the Seychelles, there was a significant decrease in T. gondii prevalence associated with greater distances to cat populations for species that sometimes rest on the shore, i.e. terns and noddies. This suggests that oocysts carried by marine currents could be deposited on shore tens of kilometres from their initial deposition point and that the number of deposited oocysts decreases with distance from the nearest cat population. The consumption of fishes from the families Mullidae, Carangidae, Clupeidae and Engraulidae, previously described as T. gondii oocyst-carriers (i.e. paratenic hosts), could also explain the exposure of terns, noddies, boobies and tropicbirds to T. gondii. Our detection of antibodies against T. gondii in seabirds that fish in the high sea, have no contact with locally contaminated soils but frequent the shores and/or consume paratenic hosts supports the hypothesis of an open-sea dispersal of T. gondii oocysts by oceanic currents and/or fish.


Is the human dystrophin gene's intron structure related to its intron instability?
To study the human dystrophin gene molecular deletion mechanism, we analyzed breakpoint regions within junction fragments of deletion-type patients and investigated whether the dystrophin gene's intron structure might be related to intron instability. Junction fragments corresponding to exon 46 and 51 deletions were cloned. The breakpoint regions were sequenced, and the features of introns with available Genebank sequences were analyzed. An analysis of junction fragment sequences corresponding to exon 46 and 51 deletions showed that all 5' and 3' breakpoints are located within repeat sequences. No small insertions, small deletions, or point mutations are located near the breakpoint junctions. By analyzing the secondary structure of the junction fragments, we demonstrated that all junction fragment breakpoints are located in non-matching regions of single-stranded hairpin loops. A high concentration of repetitive elements is found to be a key feature of many dystrophin introns. In total, 34.8% of the overall dystrophin intron sequences is composed of repeat sequences. Repeat elements in many dystrophin gene introns are the key to their structural bases and reflect intron instability. As a result of the primary DNA sequences, single-stranded hairpin loops form, increasing the instability of the gene, and forming the base for breaks in the DNA. The formation of the single-stranded hairpins can result in reattachment of two different breakpoints, producing a deletion.


Permanganate (PM) pretreatment improves medium-chain fatty acids production from sewage sludge: The role of PM oxidation and in-situ formed manganese dioxide.
Medium-chain fatty acids (MCFAs) production from sewage sludge is mainly restricted by the complex substrate structure, competitive metabolism and low electron transfer rate. This study proposes a novel permanganate (PM)-based strategy to promote sludge degradation and MCFAs production. Results show that PM pretreatment significantly increases MCFAs production, i.e., attaining 12,036 mg COD/L, and decreases the carbon fluxes of electron acceptor (EA)/electron donor (ED) to byproducts. Further analysis reveals that PM oxidation enhances the release and biochemical conversion of organic components via disrupting extracellular polymers (EPS) structure and reducing viable cells ratio, providing directly available EA for chain elongation (CE). The microbial activity positively correlated with MCFAs generation are apparently heightened, while the competitive metabolism of CE (i.e., methanogensis) can be completely inhibited. Accordingly, the functional bacteria related to critical bio-steps and dissimilatory manganese reduction are largely enriched. Further mechanism exploration indicates that the main contributors for sludge solubilization are 1O2 (61.6 %) and reactive manganese species (RMnS), i.e., Mn(V)/Mn(VI) (22.3 %) and Mn(III) (∼16.1 %). As the main reducing product of PM reaction, manganese dioxide (MnO2) can enable the formation of microbial aggregates, and serve as electron shuttles to facilitate the carbon fluxes to MCFAs during CE process. Overall, this strategy can achieve simultaneous hydrogen recovery, weaken competitive metabolisms and provide electron transfer accelerator for CE reactions.


Clinical comparison of postoperative sensitivity for an adhesive resin cement containing 4-META and a conventional glass-lonomer cement.
The aim of this clinical 2-year follow-up study was to compare the postoperative sensitivity of abutment teeth restored with full coverage restorations retained with either conventional glass-ionomer cement or a new adhesive resin cement containing 4-methacrylolyloxyethyl trimellitate anhydride (4-META). Sixty patients received 120 full-coverage restorations on vital abutment teeth, cemented with either a glass-ionomer cement (Ketac-Cem) or a new adhesive resin cement (Chemiace II). A randomized split-mouth design and a patient double-blind data acquisition protocol were used. The teeth were examined before cementation, after 1 week, and after 6, 12, and 24 months. With regard to postcementation sensitivity, a low incidence was observed for both groups. With the adhesive resin cement, little postoperative hypersensitivity was observed after 1 week (13.3%), 6 months (5.9%), 12 months (2.1%), and 24 months (none); results were similar with the conventional glass-ionomer cement Ketac-Cem after 1 week (5.9%), 6 months (5.9%), 12 months (6.4%), and 24 months (none). After 6 months, 2 teeth of the Chemiace II group showed no sensitivity. Endodontic treatment was carried out for these 2 abutment teeth. After 24 months, no cases of postoperative hypersensitivity were recorded for either group. In this study, the incidence of postoperative hypersensitivity after cementation of full-crown restorations with a conventional glass-ionomer cement and a new adhesive resin cement was similar.


p16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri.
The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (< or = 25%) and as diffuse positive (> 25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P < 0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.


Children's Understanding of Self-Focused Humor Styles.
It has been proposed that four main styles of humor exist, two which are thought to be adaptive (affiliative, self-enhancing) and two which are thought to be maladaptive (aggressive, self-defeating). Whilst the existence of these four humor styles has been supported in older children, it is suggested that for younger children, self-enhancing and self-defeating humor may develop at a later point. To investigate this further, the current research involved five semi-structured paired interviews with children aged eight to eleven years to explore the use and understanding of self-enhancing and self-defeating humor in this age group. Findings indicated that use of both self-enhancing and self-defeating humor were apparent in some children, but not all. It therefore seems appropriate that attempts to investigate humor in this age group should aim to include all four styles of humor. The current research also demonstrated the value of paired interviews when carrying out this sort of research with children.


Nurse characteristics and inferences about children's pain.
The purpose of this study was to describe pediatric nurses' projected responses to children's pain as described in vignettes of hospitalized children and to explore nurse characteristics that might influence those responses. A survey was mailed to a national random sample of 700 RNs, and 334 nurses responded. The survey included case reports of three hospitalized school-aged children experiencing pain. Nurses were asked to rate their perceptions of the children's pain levels and to indicate how much analgesia they would recommend. Contrary to earlier studies, in response to the scenarios, nurses in this sample perceived high levels of pain, said they would administer doses of analgesia close to the maximum prescribed by physicians, and recommended an array of non-pharmacologic methods to treat pain. Variation in pain perceptions and decisions was not related to key personal and professional characteristics of the nurses, including their education level, race/ethnicity, age, years of clinical experience, and receipt of continuing education about pain. Findings from this large national study suggest that most nurses would make appropriate decisions relating to the treatment of children's pain, perhaps reflecting changes in the emphasis on pain management.


Definitions, methods, and applications in interpretable machine learning.
Machine-learning models have demonstrated great success in learning complex patterns that enable them to make predictions about unobserved data. In addition to using models for prediction, the ability to interpret what a model has learned is receiving an increasing amount of attention. However, this increased focus has led to considerable confusion about the notion of interpretability. In particular, it is unclear how the wide array of proposed interpretation methods are related and what common concepts can be used to evaluate them. We aim to address these concerns by defining interpretability in the context of machine learning and introducing the predictive, descriptive, relevant (PDR) framework for discussing interpretations. The PDR framework provides 3 overarching desiderata for evaluation: predictive accuracy, descriptive accuracy, and relevancy, with relevancy judged relative to a human audience. Moreover, to help manage the deluge of interpretation methods, we introduce a categorization of existing techniques into model-based and post hoc categories, with subgroups including sparsity, modularity, and simulatability. To demonstrate how practitioners can use the PDR framework to evaluate and understand interpretations, we provide numerous real-world examples. These examples highlight the often underappreciated role played by human audiences in discussions of interpretability. Finally, based on our framework, we discuss limitations of existing methods and directions for future work. We hope that this work will provide a common vocabulary that will make it easier for both practitioners and researchers to discuss and choose from the full range of interpretation methods.


A replication study and genome-wide scan of single-nucleotide polymorphisms associated with pancreatic cancer risk and overall survival.
To explore the effects of single-nucleotide polymorphisms (SNP) on pancreatic cancer risk and overall survival (OS). The germ line DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on OS. Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Finally, we conducted a genome-wide association study (GWAS) of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively. Among seven risk SNPs analyzed, two (rs505922 and rs9543325) were associated with risk (P < 0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (P < 0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Furthermore, our GWAS identified a novel SNP [rs1482426, combined stage I and II, P = 1.7 × 10(-6), per-allele HR, 1.74; 95% confidence interval (CI), 1.38-2.18] to be putatively associated with OS. The effects of SNPs on pancreatic cancer risk and OS were replicated in our study, although further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer.


Mucin-like peptides from Echinococcus granulosus induce antitumor activity.
There is substantial evidence suggesting that certain parasites can have antitumor properties. We evaluated mucin peptides derived from the helminth Echinococcus granulosus (denominated Egmuc) as potential inducers of antitumor activity. We present data showing that Egmuc peptides were capable of inducing an increase of activated NK cells in the spleen of immunized mice, a fact that was correlated with the capacity of splenocytes to mediate killing of tumor cells. We demonstrated that Egmuc peptides enhance LPS-induced maturation of dendritic cells in vitro by increasing the production of IL-12p40p70 and IL-6 and that Egmuc-treated DCs may activate NK cells, as judged by an increased expression of CD69. This evidence may contribute to the design of tumor vaccines and open new horizons in the use of parasite-derived molecules in the fight against cancer.


Effectiveness of a Stroke Risk Self-Management Intervention for Adults with Prehypertension.
The aim of this study was to evaluate the effectiveness of a community-based intervention for prehypertensive adults, to enhance stroke risk awareness and to adopt a preventive lifestyle for primary stroke prevention. This was a single-blinded, repeated measures quasi-experimental study with 47 participants (23 in the experimental group and 24 in the control group) recruited through convenience sampling from two urban areas. The stroke risk self-management intervention consisted of three weekly, 2-hour, face-to-face sessions and two booster telephone sessions, utilizing strategies to enhance motivation for behavioral changes based on the Self-Determination Theory. All participants completed a pretest, a 1-month and a 3-month post test of stroke risk awareness and preventive lifestyle including blood pressure self-monitoring, healthy diet, and regular physical activity. Data were analyzed using descriptive statistics, chi-square test, two sample t test, repeated measures analysis of variance, and Friedman test with PASW Statistics 18.0. After the intervention, significant improvements were found in the experimental group for stroke risk awareness, blood pressure self-monitoring and regular physical activity, and were sustained over time. Our preliminary results indicate that the stroke risk self-management intervention is feasible and associated with improvement in self-management of stroke risk factors for primary stroke prevention among a prehypertensive population.


Online Information on the Treatment of Burning Mouth Syndrome: Quality and Readability.
To evaluate the quality and readability of online information about the treatment of burning mouth syndrome (BMS). An internet search using the phrase "burning mouth syndrome treatment" was carried out on the Google search engine (www.google.co.uk) on 8 June 2015, and the first 100 websites listed were examined. Data collection included DISCERN score, the Journal of the American Medical Association (JAMA) benchmarks for website analysis score, the presence of the Health on the Net (HON) Foundation seal, and the Flesch Reading Ease Score (FRES). Descriptive statistics were performed using Microsoft Office Excel. The search strategy initially yielded 635,000 links; following the application of the exclusion criteria, 53 sites remained for analysis. The overall DISCERN score varied between websites, with half of all websites achieving an overall score of 2 and none of these websites achieving the maximum score of 5. The mean score ± standard deviation (SD) was 2.4 ± 0.7. Only 10 (18.9%) of the websites achieved the four JAMA benchmarks while 3 (5.7%) of the websites did not achieve any of them. Only 9 (17%) displayed the HON seal. The FRES of the websites ranged from 32.4 to 82.2; the mean ± SD rating was 55.4 ± 10.7, which is considered to reflect fairly difficult reading. The information available online about BMS is of questionable quality and content. Perhaps engaging patients in determining what type and format of information they desire when searching online for health information could guide clinicians and researchers alike in providing reliable and readable information sources.


Nonexponential kinetics of ion pair dissociation in electrofreezing water.
Temporally- or spatially-heterogeneous environments can participate in many kinetic processes, from chemical reactions and self-assembly to the forced dissociation of biomolecules. Here, we simulate the molecular dynamics of a model ion pair forced to dissociate in an explicit, aqueous solution. Triggering dissociation with an external electric field causes the surrounding water to electrofreeze and the ion pair population to decay nonexponentially. To further probe the role of the aqueous environment in the kinetics, we also simulate dissociation events under a purely mechanical force on the ion pair. In this case, regardless of whether the surrounding water is a liquid or already electrofrozen, the ion pair population decays exponentially with a well-defined rate constant that is specific to the medium and applied force. These simulation data, and the rate parameters we extract, suggest the disordered kinetics in an electrofreezing medium are a result of the comparable time scales of two concurrent processes, electrofreezing and dissociation.


Evaluation of portability and cost of a fluorescent PCR ribotyping protocol for Clostridium difficile epidemiology.
Clostridium difficile is the most commonly identified pathogen among health care-associated infections in the United States. There is a need for accurate and low-cost typing tools that produce comparable data across studies (i.e., portable data) to help characterize isolates during epidemiologic investigations of C. difficile outbreaks and sporadic cases of disease. The most popular C. difficile-typing technique is PCR ribotyping, and we previously developed methods using fluorescent PCR primers and amplicon sizing on a Sanger-style sequencer to generate fluorescent PCR ribotyping data. This technique has been used to characterize tens of thousands of C. difficile isolates from cases of disease. Here, we present validation of a protocol for the cost-effective generation of fluorescent PCR ribotyping data. A key component of this protocol is the ability to accurately identify PCR ribotypes against an online database (http://walklab.rcg.montana.edu) at no cost. We present results from a blinded multicenter study to address data portability across four different laboratories and three different sequencing centers. Our standardized protocol and centralized database for typing of C. difficile pathogens will increase comparability between studies so that important epidemiologic linkages between cases of disease and patterns of emergence can be rapidly identified.


How Behavior Change Strategies are Used to Design Digital Interventions to Improve Medication Adherence and Blood Pressure Among Patients With Hypertension: Systematic Review.
Information on how behavior change strategies have been used to design digital interventions (DIs) to improve blood pressure (BP) control or medication adherence (MA) for patients with hypertension is currently limited. Hypertension is a major modifiable risk factor for cardiovascular diseases and can be controlled with appropriate medication. Many interventions that target MA to improve BP are increasingly using modern digital technologies. This systematic review was conducted to discover how DIs have been designed to improve MA and BP control among patients with hypertension in the recent 10 years. Results were mapped into a matrix of change objectives using the Intervention Mapping framework to guide future development of technologies to improve MA and BP control. We included all the studies regarding DI development to improve MA or BP control for patients with hypertension published in PubMed from 2008 to 2018. All the DI components were mapped into a matrix of change objectives using the Intervention Mapping technique by eliciting the key determinant factors (from patient and health care team and system levels) and targeted patient behaviors. The analysis included 54 eligible studies. The determinants were considered at two levels: patient and health care team and system. The most commonly described determinants at the patient level were lack of education, lack of self-awareness, lack of self-efficacy, and forgetfulness. Clinical inertia and an inadequate health workforce were the most commonly targeted determinants at the health care team and system level. Taking medication, interactive patient-provider communication, self-measurement, and lifestyle management were the most cited patient behaviors at both levels. Most of the DIs did not include support from peers or family members, despite its reported effectiveness and the rate of social media penetration. This review highlights the need to design a multifaceted DI that can be personalized according to patient behavior(s) that need to be changed to overcome the key determinant(s) of low adherence to medication or uncontrolled BP among patients with hypertension, considering different levels including patient and healthcare team and system involvement.


[Minimum amounts of suitable habitat for wheat aphid, parasitoid, and hyperparasitoid in facility-based agricultural landscapes].
Minimum amount of suitable habitat (MASH) is the minimum habitat area that a population requires to persist in a given environmental setting for a long time, being an important aspect of population viability analysis (PVA). In this paper, we estimated the MASH for wheat aphids, parasitoids, and hyperparasitoids in facility-based agricultural landscapes in Yinchuan Plain of Northwest China, based on the relationships between population density and habitat area, and by using regression analysis. It was found that the population density and growth rate were consistently inversely related to area, but the exact mathematical functions varied with different species, especially those at different trophic levels. The MASH values for Macrosiphum avenae, Schizaphis graminum, Aphidius avenae, Aphidius gifuensis, and Pachyneuron aphidis were estimated with a polynormal regression model of density-area relationship, and the results were similar to those estimated from an inverse relationship between population and area. The differences of MASH between trophic levels were significant. It was concluded that these species had different values of MASH, which reflected their different habitat requirements and their differences in body size, migration, trophic position, and habitat quality. For parasitoids, the highest parasitic rates always took place at a spatial scale of 800-1000 m2, which could be considered as the base of aphids control with parasitoids, while the difference of MASH among trophic levels could be used to suppress the pest population.


Does gene deletion of AMPA GluA1 phenocopy features of schizoaffective disorder?
Glutamatergic dysfunction is strongly implicated in schizophrenia and mood disorders. GluA1 knockout (KO) mice display schizophrenia- and depression-related abnormalities. Here, we asked whether GluA1 KO show mania-related abnormalities. KO were tested for behavior in approach/avoid conflict tests, responses to repeated forced swim exposure, and locomotor responses under stress and after psychostimulant treatment. The effects of rapid dopamine depletion and treatment with lithium or a GSK-3β inhibitor (SB216763) on KO locomotor hyperactivity were tested. Results showed that KO exhibited novelty- and stress-induced locomotor hyperactivity, reduced forced swim immobility and alterations in approach/avoid conflict tests. Psychostimulant treatment and dopamine depletion exacerbated KO locomotor hyperactivity. Lithium, but not SB216763, treatment normalized KO anxiety-related behavior and partially reversed hyperlocomotor behavior, and also reversed elevated prefrontal cortex levels of phospho-MARCKS and phospho-neuromodulin. Collectively, these findings demonstrate mania-related abnormalities in GluA1 KO and, combined with previous findings, suggest this mutant may provide a novel model of features of schizoaffective disorder.


Facile synthesis of nanogels modified Fe3O4@Ag NPs for the efficient adsorption of bovine & human serum albumin.
This article describes the preparation of Fe3O4 nanoparticles and its decoration with a layer of tiny Ag nanoparticles at room temperature. Later on, the synthesized Fe3O4@Ag heterostructures were protected with Silica and finally modified with Poly(N-isopropyl acrylamide) (PNIPA) nanogels through post-synthesis method to get multifunctional (superparamagnetic, plasmonic and thermosensitive) nanocomposite. The structural characteristics of Fe3O4@Ag@SiO2-PNIPA nanogels composite were investigated by instrumental techniques such as Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Diffraction (XRD) and Vibrating Sample Magnetometer (VSM). The average particles diameter was calculated from XRD data through Scherer formula and it was found as 14 nm. The Fe3O4@Ag@SiO2-PNIPA polymeric composites were assessed for the adsorption of Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA) proteins from aqueous media. The adsorption data of BSA and HSA were best explained by Langmuir isotherm model with maximum adsorption capacities of 322 and 166 (mg/g) respectively showing mono-layer adsorption. The kinetics data for both the proteins were fairly interpreted by pseudo-second-order model. Thermodynamics studies revealed that the adsorption phenomena of BSA and HSA on the surface of Fe3O4@Ag@SiO2-PNIPA nanogels composite are spontaneous and exothermic.


Report of a case of 46,xx/45,xx,-20 mosaicism.
A 46,XX/45,XX,-20 mosaicism was observed in a phenotypically normal female who had three grossly malformed children (two stillbirths and a perinatal death).


Lipid imaging within the normal rat kidney using silver nanoparticles by matrix-assisted laser desorption/ionization mass spectrometry.
The well-characterized cellular and structural components of the kidney show distinct regional compositions and distribution of lipids. In order to more fully analyze the renal lipidome we developed a matrix-assisted laser desorption/ionization mass spectrometry approach for imaging that may be used to pinpoint sites of changes from normal in pathological conditions. This was accomplished by implanting sagittal cryostat rat kidney sections with a stable, quantifiable and reproducible uniform layer of silver using a magnetron sputtering source to form silver nanoparticles. Thirty-eight lipid species including seven ceramides, eight diacylglycerols, 22 triacylglycerols, and cholesterol were detected and imaged in positive ion mode. Thirty-six lipid species consisting of seven sphingomyelins, 10 phosphatidylethanolamines, one phosphatidylglycerol, seven phosphatidylinositols, and 11 sulfatides were imaged in negative ion mode for a total of seventy-four high-resolution lipidome maps of the normal kidney. Thus, our approach is a powerful tool not only for studying structural changes in animal models of disease, but also for diagnosing and tracking stages of disease in human kidney tissue biopsies.


Alteration of lens electrolyte transport parameters following transient oxidative perturbation.
Rabbit lenses were incubated, in vitro, for 20 hr. During the first 60 min of the incubation period, the lenses were exposed to hydrogen peroxide at specified concentrations. Deranged electrolyte balance was observed in lenses exposed to hydrogen peroxide concentrations exceeding 0.1 mM. Lenticular sodium pump activity, as evidenced by lens 86Rb uptake, was reduced to 61% of control when examined immediately after exposure to 0.5 mM hydrogen peroxide for 1 hr. Upon further incubation in peroxide-free medium, the sodium pump activity of hydrogen peroxide treated lenses continued to deteriorate. The deterioration of sodium pump activity in lenses transiently challenged with hydrogen peroxide was not altered by supplementation of the incubation medium with antioxidants or by substitution of calcium in the medium. Lenticular potassium permeability, as evidenced by the rate of 86Rb efflux from the lens, was found to be elevated immediately after exposure to 0.5 mM hydrogen peroxide for 1 hr. However, no further change in the rate of 86Rb efflux was noted when the hydrogen peroxide treated lens was incubated for an additional 19 hr in peroxide-free medium. Na,K-ATPase and Ca-ATPase activities were measured in membrane preparations isolated from lenses that had been exposed to 0.5 mM hydrogen peroxide and then cultured in control medium for 19 hr. Neither of the transport enzyme activities was diminished in the hydrogen peroxide treated lenses indicating that the deterioration in sodium pump activity in lenses temporarily exposed to hydrogen peroxide is not due to a progressive loss of Na,K-ATPase enzyme.


The Met Needs for Pediatric Surgical Conditions in Sierra Leone: Estimating the Gap.
In low- and middle-income countries, there is a gap between the need for surgery and its equitable provision, and a lack of proxy indicators to estimate this gap. Sierra Leone is a West African country with close to three million children. It is unknown to what extent the surgical needs of these children are met. To describe a nationwide provision of pediatric surgical procedures and to assess pediatric hernia repair as a proxy indicator for the shortage of surgical care in the pediatric population in Sierra Leone. We analyzed results from a nationwide facility survey in Sierra Leone that collected data on surgical procedures from operation and anesthesia logbooks in all facilities performing surgery. We included data on all patients under the age of 16 years undergoing surgery. Primary outcomes were rate and volume of surgical procedures. We calculated the expected number of inguinal hernia in children and estimated the unmet need for hernia repair. In 2012, a total of 2381 pediatric surgical procedures were performed in Sierra Leone. The rate of pediatric surgical procedures was 84 per 100,000 children 0-15 years of age. The most common pediatric surgical procedure was hernia repair (18%), corresponding to a rate of 16 per 100,000 children 0-15 years of age. The estimated unmet need for inguinal hernia repair was 88%. The rate of pediatric surgery in Sierra Leone was very low, and inguinal hernia was the single most common procedure noted among children in Sierra Leone.


Advances in refractive surgery: 1975 to the present.
To review the major advances in the field of refractive surgery occurring over the past 25 years. Literature review. The major developments in refractive surgery over the past 25 years are reviewed. The past 25 years have witnessed great changes in refractive surgery. As a result of advancements in technology, instrumentation, and technique, we have seen improvements in the treatment of all types of ametropias. In this article, we review some of the successes and failures of the past quarter-century.


Photochemical conversion of a cytidine derivative to a thymidine analog via [2+2]-cycloaddition.
Epigenetic information is encoded in the mammalian genome in the form of cytosines methylated at the 5 position. Cytosine methylation has multiple biological effects, but our understanding of these effects has lagged because extant methods for mapping methylation sites genome-wide have severe shortcomings. For instance, the gold standard bisulfite sequencing approach suffers from the use of harsh reaction conditions resulting in DNA cleavage and incomplete conversion of unmethylated cytosine to uracil. We report here on a new photochemical method in which a DNA (cytosine-5)-methyltransferase can be used to covalently attach reactive functionalities which upon irradiation at ∼350 nm initiate photoinduced intramolecular reactions that convert modified C to T analogues. We synthesized a model compound, a cinnamyl ether-containing cytidine derivative, and demonstrated its conversion to a thymidine analogue using mild conditions and a DNA-compatible wavelength (∼350 nm), enabled by the use of a triplet sensitizer, thioxanthone. Transfer of a cinnamyl ether or comparable reactive functionality from an AdoMet analog to cytosine followed by the use of this photoconversion method would require only small amounts of DNA and allow complete methylation profiling on both long and short read sequencing platforms.


Papillomavirus research update: highlights of the Barcelona HPV 2000 international papillomavirus conference.
The 18th international papillomavirus conference took place in Barcelona, Spain in July 2000. The HPV clinical workshop was jointly organised with the annual meeting of the Spanish Association of Cervical Pathology and Colposcopy. The conference included 615 abstracts describing ongoing research in epidemiology, diagnosis/screening, treatment/prognosis, immunology/human immunodeficiency virus, vaccine development/trials, transformation/progression, replication, transcription/translation, viral protein functions, and viral and host interactions. This leader summarises the highlights presented at the conference (the full text of the abstracts and lectures can be found at www.hpv2000.com). Relevant material in Spanish can be found at www.aepcc.org.


Long-term impact of plain packaging of cigarettes with larger graphic health warnings: findings from cross-sectional surveys of Australian adolescents between 2011 and 2017.
To assess the long-term impact of plain packaging (PP) of cigarettes with larger graphic health warnings (HW) introduced in December 2012 on adolescents' relevant tobacco-related perceptions. Cross-sectional school-based surveys of 12 to 17 year olds in 2011 (n=4413), 2013 (n=4423), 2014 (n=4576) and 2017 (n=4266). Students rated the character of four popular cigarette brands, indicated their agreement regarding brand differences in smoking ease, quitting, addictiveness, harmfulness and pack attractiveness and positive/negative perceptions of pack image. The frequency of students reading, attending to, thinking and talking about HW was assessed. Responses of students seeing cigarette packs in the previous 6 months (2011: 63%; 2013: 67%, 2014: 56%, 2017: 56%) were examined. Smoking prevalence declined from 2011 to 2017. Among students who had recently seen packs, cigarette packs were rated less positively and more negatively in 2017 than in 2011 (p<0.001) with ratings similar between 2013 and 2017. Positive character ratings for each brand reduced between 2011 and 2013 (ps<0.05) with further reductions between 2013 and 2017 (ps<0.05). Fewer students agreed, and more were uncertain, that brands differed in their smoking ease, addictiveness, harmfulness and pack attractiveness in 2017 than 2011. The frequency of students reading, attending, talking or thinking about HW did not change between 2011 and 2017. PP's initial impact in reducing adolescent's positive perceptions of cigarette packs and brand differences continued in the following years with tobacco packaging less appealing to young people in 2017 than 2011 and students more uncertain about brand differences.


[Registration with piezoelectric sensors of the normal in vivo activity of the contractile element of the right ventricle].
A new method employed for registration with piezoelectric sensors of the force developed or acceleration of shortening velocity of the contractile element, throughout the right cardiac cycle, is described. The normal activity of the contractile element shows different aspects in both ventricles. SPz curve of the right ventricle is compared with the correspondent SPz curve of the left ventricle. The former curve shows that blood ejection to pulmonary artery is essentially due to developed force or acceleration of shortening velocity of the contractile element, during the isometric contraction phase of the cardiac cycle. Ejection period, with quite constant shortening velocity, seems to complete the blood expulsion. Left ventricular blood flow to systemic circuit is mainly due to early ejection phase, where developed force or acceleration of the shortening velocity of the contractile element appears to be higher, to impulse blood to the aortic artery.


Evolutionary Conserved Cysteines Function as cis-Acting Regulators of Arabidopsis PIN-FORMED 2 Distribution.
Coordination of plant development requires modulation of growth responses that are under control of the phytohormone auxin. PIN-FORMED plasma membrane proteins, involved in intercellular transport of the growth regulator, are key to the transmission of such auxin signals and subject to multilevel surveillance mechanisms, including reversible post-translational modifications. Apart from well-studied PIN protein modifications, namely phosphorylation and ubiquitylation, no further post-translational modifications have been described so far. Here, we focused on root-specific Arabidopsis PIN2 and explored functional implications of two evolutionary conserved cysteines, by a combination of in silico and molecular approaches. PIN2 sequence alignments and modeling predictions indicated that both cysteines are facing the cytoplasm and therefore would be accessible to redox status-controlled modifications. Notably, mutant pin2C-A alleles retained functionality, demonstrated by their ability to almost completely rescue defects of a pin2 null allele, whereas high resolution analysis of pin2C-A localization revealed increased intracellular accumulation, and altered protein distribution within plasma membrane micro-domains. The observed effects of cysteine replacements on root growth and PIN2 localization are consistent with a model in which redox status-dependent cysteine modifications participate in the regulation of PIN2 mobility, thereby fine-tuning polar auxin transport.


The envelope of intracellular African swine fever virus is composed of a single lipid bilayer.
African swine fever virus (ASFV) is a member of a family of large nucleocytoplasmic DNA viruses that include poxviruses, iridoviruses, and phycodnaviruses. Previous ultrastructural studies of ASFV using chemical fixation and cryosectioning for electron microscopy (EM) have produced uncertainty over whether the inner viral envelope is composed of a single or double lipid bilayer. In this study we prepared ASFV-infected cells for EM using chemical fixation, cryosectioning, and high-pressure freezing. The appearance of the intracellular viral envelope was determined and compared to that of mitochondrial membranes in each sample. The best resolution of membrane structure was obtained with samples prepared by high-pressure freezing, and images suggested that the envelope of ASFV consisted of a single lipid membrane. It was less easy to interpret virus structure in chemically fixed or cryosectioned material, and in the latter case the virus envelope could be interpreted as having two membranes. Comparison of membrane widths in all three preparations indicated that the intracellular viral envelope of ASFV was not significantly different from the outer mitochondrial membrane (P < 0.05). The results support the hypothesis that the intracellular ASFV viral envelope is composed of a single lipid bilayer.


The importance of microbiological investigations, medications and artificial feeding in diarrhoea evaluation.
Diarrhoea in hospitalised patients is usually attributed to medications especially antibiotics, enteral tube feeding or enteropathogenic bacteria particularly Clostridium difficile. The aim of this study was to evaluate the investigations performed on patients who developed diarrhoea during their stay in an acute general hospital. Over 18 working days, an unselected group of adult inpatients who developed diarrhoea following their admission to hospital were reviewed. Symptoms, medications, nutritional support and any investigations performed were assessed. Eighty-one patients developed diarrhoea. Forty-nine (60%) were receiving antibiotics prior to the development of symptoms, 30 (37%) were being enterally tube fed, 14 (17%) had positive stool for Clostridium difficile A and B toxin and 3 (4%) had salmonella species positive stool. The majority of cases of diarrhoea were related to medications and enteral tube feeding. A small but significant number did develop bacterial infections. In contrast to some suggested guidelines, when investigating hospital acquired diarrhoea, it is considered worthwhile to perform microbiological stool examinations.


A search for potential antitumor agents: biological effects and DNA binding of a series of anthraquinone derivatives.
In an effort to establish a relationship between mechanism of binding and affinity to DNA, cytotoxic activity, and genotoxic activity, we have studied four new anthracenedione derivatives bearing charged side chain groups at various positions of the polycyclic aromatic system. Cytotoxicity, genotoxicity, and thermodynamic DNA binding parameters were shown to be directly related, indicating the polynucleotide as an important target for drug action, rather than a minor, subterminal interacting site. This finding was further supported by the observation of extensive anthraquinone accumulation occurring in the nuclear compartment. The relative binding affinities of the drugs are discussed in terms of nature and position of side-chain substituents. Different binding modes were found: three compounds intercalate into the nucleic acid double helix, and one interacts with the exterior of the macromolecule. The biological results suggest that the mode of complex formation plays a less relevant role than DNA binding efficiency.


The release of genetically modified crops into the environment. Part II. Overview of ecological risk assessment.
Despite numerous future promises, there is a multitude of concerns about the impact of GM crops on the environment. Key issues in the environmental assessment of GM crops are putative invasiveness, vertical or horizontal gene flow, other ecological impacts, effects on biodiversity and the impact of presence of GM material in other products. These are all highly interdisciplinary and complex issues. A crucial component for a proper assessment is defining the appropriate baseline for comparison and decision. For GM crops, the best and most appropriately defined reference point is the impact of plants developed by traditional breeding. The latter is an integral and accepted part of agriculture. In many instances, the putative impacts identified for GM crops are very similar to the impacts of new cultivars derived from traditional breeding. When assessing GM crops relative to existing cultivars, the increased knowledge base underpinning the development of GM crops will provide greater confidence in the assurances plant science can give on the risks of releasing such crops.


A Flow-Through Cell Electroporation Device for Rapidly and Efficiently Transfecting Massive Amounts of Cells in vitro and ex vivo.
Continuous cell electroporation is an appealing non-viral approach for genetically transfecting a large number of cells. Yet the traditional macro-scale devices suffer from the unsatisfactory transfection efficiency and/or cell viability due to their high voltage, while the emerging microfluidic electroporation devices is still limited by their low cell processing speed. Here we present a flow-through cell electroporation device integrating large-sized flow tube and small-spaced distributed needle electrode array. Relatively large flow tube enables high flow rate, simple flow characterization and low shear force, while well-organized needle array electrodes produce an even-distributed electric field with low voltage. Thus the difficulties for seeking the fine balance between high flow rate and low electroporation voltage were steered clear. Efficient in vitro electrotransfection of plasmid DNA was demonstrated in several hard-to-transfect cell lines. Furthermore, we also explored ex vivo electroporated mouse erythrocyte as the carrier of RNA. The strong ability of RNA loading and short exposure time of freshly isolated cells jointly ensured a high yield of valid carrier erythrocytes, which further successfully delivered RNA into targeted tissue. Both in vitro and ex vivo electrotransfection could be accomplished at high cell processing speed (20 million cells per minute) which remarkably outperforms previous devices.


High numerical aperture imaging with different polarization patterns.
The modulation transfer function (MTF) is calculated for imaging with linearly, circularly and radially polarized light as well as for different numerical apertures and aperture shapes. Special detectors are only sensitive to one component of the electric energy density, e.g. the longitudinal component. For certain parameters this has advantages concerning the resolution when comparing to polarization insensitive detectors. It is also shown that in the latter case zeros of the MTF may appear which are purely due to polarization effects and which depend on the aperture angle. Finally some ideas are presented how to use these results for improving the resolution in lithography.


Depression in the medical setting: biopsychological interactions and treatment considerations.
This article examines depression in 6 medical conditions: coronary artery disease (CAD), cancer, human immunodeficiency virus (HIV) infection, Parkinson's disease, pain, and the sex hormone changes of aging. Research is beginning to define specific biological and psychological mechanisms underlying the adverse interactions between depression and these medical conditions. Antidepressant medications, psychosocial therapies, and hormonal manipulations are effective in reducing depressive symptoms. Specific psychosocial interventions may increase longevity in CAD and cancer and may enhance quality of life in HIV infection. Newer antidepressants appear to be safer and better tolerated than older agents for medically ill patients, but do not appear to be as effective for neuropathic pain. Dopamine agonists may benefit depression associated with Parkinson's disease. Hormone replacement therapy may improve subsyndromal depressive symptoms in postmenopausal women and may enhance antidepressant response for older women with major depression.


Membrane biophysics define neuron and astrocyte progenitors in the neural lineage.
Neural stem and progenitor cells (NSPCs) are heterogeneous populations of self-renewing stem cells and more committed progenitors that differentiate into neurons, astrocytes, and oligodendrocytes. Accurately identifying and characterizing the different progenitor cells in this lineage has continued to be a challenge for the field. We found previously that populations of NSPCs with more neurogenic progenitors (NPs) can be distinguished from those with more astrogenic progenitors (APs) by their inherent biophysical properties, specifically the electrophysiological property of whole cell membrane capacitance, which we characterized with dielectrophoresis (DEP). Here, we hypothesize that inherent electrophysiological properties are sufficient to define NPs and APs and test this by determining whether isolation of cells solely by these properties specifically separates NPs and APs. We found NPs and APs are enriched in distinct fractions after separation by electrophysiological properties using DEP. A single round of DEP isolation provided greater NP enrichment than sorting with PSA-NCAM, which is considered an NP marker. Additionally, cell surface N-linked glycosylation was found to significantly affect cell fate-specific electrophysiological properties, providing a molecular basis for the cell membrane characteristics. Inherent plasma membrane biophysical properties are thus sufficient to define progenitor cells of differing fate potential in the neural lineage, can be used to specifically isolate these cells, and are linked to patterns of glycosylation on the cell surface.