Handedness in twins reared apart: A review of the literature and new data.
Reared-apart twin studies are a powerful means for identifying the relative contributions of heredity and environment to variation in human physical and behavioural traits. One such characteristic is handedness, for which it has long been noted that approximately 20% of twin pairs are comprised of one right-handed cotwin and one left-handed cotwin. Reared-together twin studies suggest a slightly greater concordance in monozygotic (MZT) than dizygotic (DZT) twins, implying that genetics influences hand preference. We report here two studies of handedness in reared-apart twins. Study 1 synthesizes the available data and estimates that at least N = 560 same-sex reared-apart twin pairs (for which zygosity is known with reasonable confidence) have been identified. Of these, handedness data are available for both members of n = 415 pairs. We observed similar levels of concordance/discordance for reared-apart monozygotic (MZA) and dizygotic (DZA) twins. However, although direction of handedness (right or left) has frequently been examined, strength of handedness (strong or weak) has not. Study 2 examined strength of hand preference and relative hand skill, as well as right- and left-hand speed, information available for participants in the Minnesota Study of Twins Reared Apart (MISTRA). We provide evidence of heritability for right-hand and left-hand speed. We also found hand preference strength was more alike than chance in DZA, but not MZA, twins. Findings are discussed in relation to genetic and environmental influences on human handedness.


Detection of mustard gas bis(2-chloroethyl)-sulfide in urine.
Extraction procedure and detection of bis(2-chloroethyl)sulfide from urine samples of two patients are described using gas chromatography-mass spectrometry. Concentrations are found in the low ppb-range. The result is discussed in connection with the reactivity of this substance and the corresponding metabolites.


Do patient-reported outcome measures cover personal factors important to people with rheumatoid arthritis? A mixed methods design using the International Classification of Functioning, Disability and Health as frame of reference.
Personal factors (PFs) are internal factors that determine functioning and the individuals' experience of disability. Their coverage by patient-reported outcome measures (PROMs) has not been examined in rheumatoid arthritis (RA) so far. The aims of this study were to identify PFs important in the life stories of people with RA and to determine their coverage by PROMs used in RA. The qualitative data of people with RA was explored to identify PFs. Additionally a systematic literature search was conducted to find PROMs used in RA. PROMs items were linked to the components, domains and categories of the International Classification of Functioning, Disability and Health (ICF) to determine the coverage of important PFs by PROMs. Twelve PFs were found to be important in the life stories of people with RA. The PFs coping and reflecting about one's life in an optimistic way were covered most frequently, each by 14 of the 42 explored PROMs, while job satisfaction was not covered at all. The London Coping with Rheumatoid Arthritis Questionnaire, General Self-Efficacy Scale, Arthritis Self-Efficacy Scale, Rheumatoid Arthritis Self-Efficacy Questionnaire and Revised Ways of Coping Inventory covered most PFs. Nineteen PROMs did not cover any of the PFs. Several PFs were identified as important in the life stories of people with RA, but only 55% of the PROMS covered some of these PFs. When evaluating PFs important to people with RA, health professionals should be alert on which PROMs can be used to assess which PFs.


Increased Accumulation of α-Synuclein in Inflamed Appendices of Parkinson's Disease Patients.
The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (PD) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of PD. This study investigated appendix abnormality in patients with PD. We assessed appendix morphology in 100 patients with PD and 50 control subjects by multislice spiral computed tomography. We analyzed the clinical characteristics of patients with PD with diseased appendices, which was confirmed in seven patients by histopathological analysis. Chronic appendicitis-like lesions were detected in 53% of patients with PD, but these were not associated with the duration of motor symptoms. Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder were risk factors for PD. The following clinical symptoms could be used to identify patients with PD with appendicitis-like lesions: first motor symptoms were bradykinesia/rigidity, onset of motor symptoms in the central axis or left limb, prodromal constipation, high ratio of Unified Parkinson's Disease Rating Scale Part III score to symptom duration, low Montreal Cognitive Assessment score, and high Epworth Sleepiness Scale score. The seven patients with PD who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation. These results indicate an association between chronic appendicitis-like lesions and PD, and suggest that α-Syn accumulation in the diseased appendix occurs in PD. © 2021 International Parkinson and Movement Disorder Society.


NHWD-1062 ameliorates inflammation and proliferation by the RIPK1/NF-κB/TLR1 axis in Psoriatic Keratinocytes.
Psoriasis is a common chronic inflammatory skin disease. RIPK1 plays an important role in inflammatory diseases. At present, the clinical efficacy of the RIPK1 inhibitor is limited and the regulatory mechanism is unclear in the treatment of psoriasis. Therefore, our team developed a new RIPK1 inhibitor, NHWD-1062, which showed a slightly lower IC50 in U937 cells than that of GSK'772 (a RIPK1 inhibitor in clinical trials) (11 nM vs. 14 nM), indicating that the new RIPK1 inhibitor was no less inhibitory than GSK'772. In this study, we evaluated the therapeutic effects of NHWD-1062 using an IMQ-induced mouse model of psoriasis and explored the precise regulatory mechanism involved. We found that gavage of NHWD-1062 significantly ameliorated the inflammatory response and inhibited the abnormal proliferation of the epidermis in IMQ-induced psoriatic mice. We then elucidated the mechanism of NHWD-1062, which was that suppressed the proliferation and inflammation of keratinocytes in vitro and in vivo through the RIPK1/NF-κB/TLR1 axis. Dual-luciferase reporter assay indicated that P65 can directly target the TLR1 promoter region and activate TLR1 expression, leading to inflammation. In summary, our study demonstrates that NHWD-1062 alleviates psoriasis-like inflammation by inhibiting the activation of the RIPK1/NF-κB/TLR1 axis, which has not been previously reported and further provides evidence for the clinical translation of NHWD-1062 in the treatment of psoriasis.


Exploitation of the redundancy of the conventional limb lead electrocardiograms for prolongation of the record length.
A method is described for duplicating the usable record length for computer analysis of the conventional limb lead ECGs. The method is based on the use of the extensive redundancy contained in the limb leads when they are recorded by sequencing in groups of two or three leads at a time. The resultant increase in the number of ECG complexes available for computer analysis facilitates noise reduction procedures and improves the precision and repeatability of ECG measurements. A similar scheme is proposed for duplicating or triplicating the useful record length of lead VI or any other chest lead used for rhythm analysis. Finally, it is noted that the present formats of grouping of the conventional ECG leads are all suboptimal and a transition to simultaneous acquisition of all eight independent components of the 12-lead ECG is encouraged.


Enhanced electrochemical properties of Ni-rich layered cathode materials via Mg2+ and Ti4+co-doping for lithium-ion batteries.
To optimize the electrochemical performance of Ni-rich cathode materials, the 0.005 mol of Mg2+ and 0.005 mol of Ti4+co-doping LiNi0.83Co0.11Mn0.06O2 composite powders, labeled as NCM-11, are successfully prepared by being calcinated at 750 °C for 15 h following by an appropriate post-treatment, which are confirmed by XRD, EDS and XPS. The results suggest that NCM-11 presents a well-ordered layered structure with a low Li+/Ni2+ mixing degree of 1.46% and Mg2+ and Ti4+ ions are uniformly distributed across the lattice. The cell assembled with NCM-11 can deliver an initial discharge specific capacity of 194.2 mAh g-1 and retain a discharge specific capacity of 163.0 mAh g-1 after 100cycles at 2.0C at 25 °C. Furthermore, it still maintains a discharge specific capacity of 166.7 mAh g-1 after 100cycles at 2.0C at 60 °C. More importantly, it also exhibits a higher discharge specific capacity of about 150.7 mAh g-1 even at 5.0C. Those superior electrochemical performance can be mainly ascribed to the synergistic effect of Mg2+ and Ti4+co-doping, in which Mg2+ ions can occupy the Li+ layer to act as pillar ions and Ti4+ ions can occupy the transition metal ions layer to enlarge the interplane spacing. Thus, the heterovalent cations co-doping strategy can be considered as a simple and practical method to improve the electrochemical performance of Ni-rich layered cathode materials for lithium-ion batteries.


Comparisons of 25 cerebrospinal fluid cytokines in a case-control study of 106 patients with recent-onset depression and 106 individually matched healthy subjects.
Neuroinflammation has been suggested as a contributor to the pathophysiology of depression; however, large case-control studies investigating cytokine levels in the cerebrospinal fluid (CSF) from patients with recent-onset depression by multiplex analyses are missing. An individually matched (sex and age) prospective case-control study comparing patients with recent-onset depression to healthy controls. CSF was analyzed with the Mesoscale V-PLEX Neuroinflammation Panel 1. comparisons of analyte levels in the CSF between groups with interleukin (IL)-6 and IL-8 as primary outcomes and 23 other cytokines as secondary outcomes. We included 106 patients (84.0% outpatients) with recent-onset depression and 106 healthy controls. There were no significant differences in the primary outcomes IL-6 (relative mean difference (MD): 1.10; 95% confidence interval (CI) 0.93-1.30; p = 0.276) or IL-8 levels (MD: 1.05; 95% CI 0.96-1.16; p = 0.249) relative to healthy controls. IL-4 was 40% higher (MD: 1.40; 95% CI 1.14-1.72; p = 0.001), monocyte chemoattractant protein (MCP)-1 was 25% higher (MD: 1.25; 95% CI 1.06-1.47; p = 0.009) and macrophage inflammatory protein (MIP)-1β was 16% higher (MD: 1.16; 95% CI 1.02-1.33; p = 0.025) in patients with depression relative to healthy controls. However, only IL-4 was significantly elevated after correction for multiple testing of secondary outcomes (p = 0.025). We found no significant differences in CSF levels of the co-primary outcomes IL-6 and IL-8, however, the higher CSF levels of IL-4, MCP-1 and MIP-1β among patients with recent-onset depression compared to healthy controls indicate a potential role of these cytokines in the neuroinflammatory response to depression.


The relationship of cyst type to risk factors for breast cancer and the subsequent development of breast cancer in patients with breast cystic disease.
The frequency of epithelial hyperplasia and papillary apocrine change in patients with palpable breast cysts lined by either apocrine or flattened epithelium has been compared. Hyperplasia of any degree, severe hyperplasia with or without atypia and papillary apocrine change were all seen significantly more frequently in patients with clinically palpable apocrine cysts. Twelve patients were identified with breast cancer with a history of cyst aspiration, in whom all cysts aspirated could be classified as apocrine or flattened on the basis of cytology or electrolyte composition of cyst fluid. Eleven patients had single or multiple apocrine cysts and one had a single flattened cyst. This represents a significantly increased preponderance of apocrine cysts as compared with that normally seen in patients with cystic disease. The mastectomy specimens of those 11 patients with a history of apocrine cyst aspiration more frequently contained hyperplastic changes and non-invasive carcinoma than age- and menopausal-matched controls who did not have a history of cystic disease. This study suggests that patients who develop cysts lined by apocrine epithelium may be at a greater risk of subsequent breast cancer than those with flattened epithelial cysts.


Direct modelling of age standardized marginal relative survival through incorporation of time-dependent weights.
When quantifying the probability of survival in cancer patients using cancer registration data, it is common to estimate marginal relative survival, which under assumptions can be interpreted as marginal net survival. Net survival is a hypothetical construct giving the probability of being alive if it was only possible to die of the cancer under study, enabling comparisons between populations with differential mortality rates due to causes other the cancer under study. Marginal relative survival can be estimated non-parametrically (Pohar Perme estimator) or in a modeling framework. In a modeling framework, even when just interested in marginal relative survival it is necessary to model covariates that affect the expected mortality rates (e.g. age, sex and calendar year). The marginal relative survival function is then obtained through regression standardization. Given that these covariates will generally have non-proportional effects, the model can become complex before other exposure variables are even considered. We propose a flexible parametric model incorporating restricted cubic splines that directly estimates marginal relative survival and thus removes the need to model covariates that affect the expected mortality rates. In order to do this the likelihood needs to incorporate the marginal expected mortality rates at each event time taking account of informative censoring. In addition time-dependent weights are incorporated into the likelihood. An approximation is proposed through splitting the time scale into intervals, which enables the marginal relative survival model to be fitted using standard software. Additional weights can be incorporated when standardizing to an external reference population. The methods are illustrated using national cancer registry data. In addition, a simulation study is performed to compare different estimators; a non-parametric approach, regression-standardization and the new marginal relative model. The simulations study shows the new approach is unbiased and has good relative precision compared to the non-parametric estimator. The approach enables estimation of standardized marginal relative survival without the need to model covariates that affect expected mortality rates and thus reduces the chance of model misspecification.


Unplanned extracapsular cataract extraction in postvitrectomy eyes.
A 70-year-old man, a 59-year-old woman, and a 57-year-old woman underwent pars plana vitrectomy. In all three cases, cataracts developed in the eyes that had been operated on. During cataract extraction, which included massage of the globe after retrobulbar anesthesia and a conventional ab externo incision, loss of lens material into the vitreous cavity occurred in all three postvitrectomy eyes.


ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis.
Epidermal necrolysis (EN)--either Stevens-Johnson syndrome (SJS) or toxic EN (TEN)--is a severe drug reaction. We constructed and evaluated a specific algorithm, algorithm of drug causality for EN (ALDEN), in order to improve the individual assessment of drug causality in EN. ALDEN causality scores were compared with those from the French pharmacovigilance method in 100 cases and the case-control results of the EuroSCAR study. Scores attributed by ALDEN segregated widely. ALDEN pointed to a "probable" or "very probable" causality in 69/100 cases as compared to 23/100 with the French method (P < 0.001). It scored "very unlikely" causality for 64% of medications vs. none with the French method. Results of ALDEN scores were strongly correlated with those of the EuroSCAR case-control analysis for drugs associated with EN (r = 0.90, P < 0.0001), with probable causality being reported in 218/329 exposures. ALDEN excluded causality in 321 drugs that the case-control analysis had described as "probably not associated" and in 22/233 drugs that had been described as inconclusive exposures. Being more sensitive than a general method, ALDEN, which correlates well with case-control analysis results, can be considered a reference tool in SJS/TEN.


Knockdown of CTRP6 reduces the deposition of intramuscular and subcutaneous fat in pigs via different signaling pathways.
The regulation of porcine subcutaneous (SC) and intramuscular (IM) fat deposition significantly affects pork quality and the lean meat percentage of the carcass, respectively. The adipokine C1q/tumor necrosis factor-related protein 6 (CTRP6), plays a significant role in regulating animal fat deposition. The purpose of this study was to understand the effects of CTRP6 gene knockdown in IM and SC adipocytes by RNA-seq analysis. A total of 1830 and 2936 differentially expressed genes (DEGs) were identified in SC and IM adipocytes, respectively. 844 were down- and 2092 were upregulated in SC adipocytes, while 648 were down- and 1182 were upregulated in IM adipocytes. Furthermore, 1778 DEGs were detected only in SC adipocytes, 672 DEGs only in IM adipocytes, and 1158 DEGs in both types of adipocytes. GO analysis indicated that DEGs involved in adipocyte differentiation were significantly enriched in both SC and IM adipocytes following treatment with CTRP6-siRNA. Moreover, KEGG pathway enrichment analysis revealed differences of metabolic regulation between IM and SC adipocytes. With CTRP6-silencing, the signaling pathways related to Ras and arachidonic acid metabolism were significantly enriched in IM adipocytes, while four other signaling pathways, encompassing the TNF, MAPK, p53 and adipokine pathway were specifically enriched in SC adipocytes. Interestingly, the effect of CTRP6-siRNA treatment was attenuated by the specific Ras activator ML-097 in IM adipocytes, while the specific p53 activator SJ-172550 had the corresponding effect in SC adipocytes. Altogether, we suggest that CTRP6 may be a differential regulator of the development and metabolism of IM and SC adipose tissues.


Failure of antibody-coated bacteria and bladder washout tests to localize infection in spinal cord injury patients.
The validity of the antibody-coated bacteria test and Fairley washout procedure to determine whether urinary tract infections were of kidney or bladder origin in spinal cord injury patients was assessed by comparing test results with those obtained from culture of ureteral urine specimens. It was concluded that neither the presence of antibody-coated bacteria nor a positive bladder washout test can be considered as definitive evidence that bacteriuria is of renal origin in these patients.


Pain management in patients with cancer: focus on opioid analgesics.
Cancer pain is generally treated with pharmacological measures, relying on using opioids alone or in combination with adjuvant analgesics. Weak opioids are used for mild-to-moderate pain as monotherapy or in a combination with nonopioids. For patients with moderate-to-severe pain, strong opioids are recommended as initial therapy rather than beginning treatment with weak opioids. Adjunctive therapy plays an important role in the treatment of cancer pain not fully responsive to opioids administered alone (ie, neuropathic, bone, and visceral colicky pain). Supportive drugs should be used wisely to prevent and treat opioids' adverse effects. Understanding the pharmacokinetics, pharmacodynamics, interactions, and cautions with commonly used opioids can help determine appropriate opioid selection for individual cancer patients.


Manifestation of Endocrine Deficiency after Sterilization
Sterilizations have increased during the past 3 years in the new federal countries of Germany. Whereas approximately 800 procedures were performed in the years 1989/90, our current study revealed that approximately 20,000 procedures were performed from 5/31/91-6/1/92. This development and the fact that we coagulated the uterine tubes with endocoagulation and bipolar high frequency methods prompted us to undertake a study to determine whether endocrine deficiency resulted after sterilization. The results revealed that the sterilization caused postoperative changes of menstruation in more than 20% of the women. Climacteric difficulties were present in about 4% of the cases. We concluded endocrine evaluation of these patients which confirmed our clinical results.


Artificial Grassland Had Higher Water Use Efficiency in Year with Less Precipitation in the Agro-Pastoral Ecotone.
Improving plant water use efficiency is a key strategy for the utilization of regional limited water resources as well as the sustainable development of agriculture industry. To investigate the effects of different land use types on plant water use efficiency and their mechanisms, a randomized block experiment was designed in the agro-pastoral ecotone of northern China during 2020-2021. The differences in dry matter accumulation, evapotranspiration, soil physical and chemical properties, soil water storage and water use efficiency and their relationships among cropland, natural grassland and artificial grassland were studied. The results show that: In 2020, the dry matter accumulation and water use efficiency of cropland were significantly higher than those of artificial and natural grassland. In 2021, dry matter accumulation and water use efficiency of artificial grassland increased significantly from 364.79 g·m-2 and 24.92 kg·ha-1·mm-1 to 1037.14 g·m-2 and 50.82 kg·ha-1·mm-1, respectively, which were significantly higher than cropland and natural grassland. The evapotranspiration of three land use types showed an increasing trend in two years. The main reason affecting the difference of water use efficiency was that land use type affected soil moisture and soil nutrients, and then changed the dry matter accumulation and evapotranspiration of plants. During the study period, the water use efficiency of artificial grassland was higher in years with less precipitation. Therefore, expanding the planted area of artificial grassland may be one of the effective ways to promote the full utilization of regional water resources.


Collective occupation in public spaces and the construction of the social fabric: L'occupation collective dans les espaces publics et la construction du tissu social.
Contemporary research is expanding understandings of occupation beyond that of the individual's doing, including the shared and social nature of occupation. The concept of collective occupation has been introduced to capture this broader understanding. This study aimed to explicate the concept of occupation in a Greek town. Ethnographic methodology was used and primary data were collected through observation, participation, and informal interviews. Analysis involved a hermeneutic process to develop a narrative of occupation in the town, including action, setting, and plots. Occupation, a dynamic and multidimensional process, served to maintain the self, family, and social fabric and balance between and within them. Collective occupation maintained the social fabric through three forms: informal daily encounters in public spaces, organization and associations, and celebration and commemoration. Occupational therapists may consider engaging with the potential power of such collective occupation when working toward social change to enable just and inclusive societies.


Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.
Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.


[An assessment of the immunoepidemiological efficacy of a liquid cultured killed vaccine against tick-borne encephalitis virus strain 205 in the Maritime Territory].
Inactivated vaccine against tick-borne encephalitis (TBE), prepared on the basis of strain 205, is characterized by epidemiological (53%) and immunobiological activity. The appearance of a few TBE cases among the vaccinees is probably due to different maturation rate of immune response to various strains (different specificity of immune response). A suggestion has been made that no inactivated vaccine prepared from a single strain can produce a reliable protective effect because of pronounced heterogeneity of the population of TBE virus.


Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase Cε with Stat3 involve integration with ERK1/2.
We have reported that protein kinase C epsilon (PKCε) expression level in epidermis dictates the susceptibility of mice to the development of squamous cell carcinomas (SCC) elicited either by repeated exposure to ultraviolet radiation (UVR) or by the DMBA-TPA tumor promotion protocol. To find clues about the mechanism by which PKCε mediates susceptibility to UVR-induced development of SCC, we found that PKCε-over-expressing transgenic mice, as compared to their wild-type littermates, when exposed to UVR, elicit enhanced phosphorylation of Stat3 at Ser727 residues. Stat3 is constitutively activated in SCC and UVR fails to induce SCC in Stat3 mutant mice. Stat3Ser727 phosphorylation is essential for Stat3 transcriptional activity (Cancer Res. 67: 1385, 2007). We now present several novel findings including that PKCε integrates with its downstream partner ERK1/2 to phosphorylate Stat3Ser727. In these experiments, mice were either exposed to UVR (2 kJ/m(2)/dose) emitted by Kodacel-filtered FS-40 sun lamps or treated with TPA (5 nmol). Both UVR and TPA treatment stimulated PKCε-Stat3 interaction, Stat3Ser727 phosphorylation and Stat3-regulated gene COX-2 expression. PKCε-Stat3 interaction and Stat3Ser727 phosphorylation was also observed in SCC elicited by repeated UVR exposures of mice. PKCε-Stat3 interaction was PKCε specific. UVR or TPA-stimulated Stat3Ser727 phosphorylation accompanied interaction of PKCε with ERK1/2 in intact mouse skin in vivo. Deletion of PKCε in wild-type mice attenuated both TPA and UVR-induced expression of phosphoforms of ERK1/2 and Stat3Ser727. These results indicate that PKCε integrates with ERK1/2 to mediate both TPA and UVR-induced epidermal Stat3Ser727 phosphorylation. PKCε and Stat3 may be potential molecular targets for SCC prevention.


Mitigating arrhythmia risk in Hydroxychloroquine and Azithromycin treated COVID-19 patients using arrhythmia risk management plan.
To assess cardiac safety in COVID-19 patients treated with the combination of Hydroxychloroquine and Azithromycin using arrhythmia risk management plan. We retrospectively examined arrhythmia safety of treatment with Hydroxychloroquine and Azithromycin in the setting of pre-defined arrhythmia risk management plan. The data was analyzed using R statistical package version 4.0.0. A two-tailed p-value<0.05 was considered significant. 81 patients were included from March 23rd to May 10th 2020. The median age was 59 years, 58.0% were female. The majority of the study population (82.7%) had comorbidities, 98.8% had radiological signs of pneumonia. Fourteen patients (17.3%) experienced QTc ≥ 480 ms and 16 patients (19.8%) had an increase of QTc ≥ 60 ms. Seven patients (8.6%) had QTc prolongation of ≥ 500 ms. The treatment was discontinued in 4 patients (4.9%). None of the patients developed ventricular tachycardia. The risk factors significantly associated with QTc ≥ 500 ms were hypokalemia (p = 0.032) and use of diuretics during the treatment (p = 0.020). Three patients (3.7%) died, the cause of death was bacterial superinfection with septic shock in two patients, and disseminated intravascular coagulation with multiple organ failure in one patient. None of these deaths were associated with cardiac arrhythmias. We recorded a low incidence of QTc prolongation ≥ 500 ms and no ventricular tachycardia events in COVID-19 patients treated with Hydroxychloroquine and Azithromycin using cardiac arrhythmia risk management plan.


[Giant Brunner's gland hamartoma: diagnosis and endoscopic treatment].
Brunner's gland hamartoma is a polypoid lesion typically composed of an increased quantity of normal-appearing Brunner's glands, accompanied by a variable proportion of smooth muscle. Most of these masses are asymptomatic and behave as benign tumors. Occasionally tumoral growth can provoke gastrointestinal problems which, together with the possibility of malignant transformation, will require resection after a broad differential diagnosis has been made with solitary duodenal mass. Both clinical and radiographic studies are nonspecific and often do not allow diagnosis of these tumors. Basic endoscopic studies (upper endoscopy) with adequate characterization of the lesion by endoscopic ultrasound (EUS) can establish a high diagnostic suspicion and determine the best therapeutic option (endoscopy or surgery). We present a case of giant Brunner's gland hamartoma. The initial manifestation was iron-deficiency anemia with no evidence of bleeding. After adequate characterization of the lesion, EUS allowed complete and safe endoscopic resection, avoiding more invasive surgical treatment.


Pediatric surgical neuro-oncology: current best care practices and strategies.
Significant advances have been made in the diagnosis and treatment of childhood brain tumors. Gross total surgical resection combined with appropriate adjuvant therapies can achieve a high rate of disease control for low grade gliomas, ependymomas and medulloblastomas. High grade gliomas, tumors involving the optic apparatus or diencepahalic structures, diffuse brainstem lesions, and recurrent or metastatic disease still pose considerable therapeutic challenges. We review the current treatment strategies of the three most common types of pediatric brain tumors: gliomas, medulloblastomas and ependymomas, and discuss current and future diagnostic and therapeutic modalities.


Effects of development and aging on the concentration of a human brain antigen.
The concentration of a glycoprotein reactive with monoclonal antibody 44D10 was studied during development and aging in 19 normal brains. Little change in the concentration of the antigen was found in white matter of brains ranging from the age of 1 to 54 years. However, a linear increase in the concentration of antigen was observed between the ages of 54 and 80 years. By the age of 80 years, the concentration of the glycoprotein had increased 2-3-fold. In contrast to white matter, gray matter did not contain detectable levels of antigen at ages from 1 to 54 years. Low levels of antigen were detected in brains of all older individuals examined. However, the relative concentration of this glycoprotein in gray matter was less than 5% of that in white matter. An examination of white matter homogenates from guinea pig and bovine brain showed that monoclonal antibody 44D10 was not reactive in these species.


Investigation of MRI-based radiomics model in differentiation between sinonasal primary lymphomas and squamous cell carcinomas.
To develop and validate an MRI-based radiomics model in differentiation between sinonasal primary lymphomas and squamous cell carcinomas (SCCs). One-hundred-and-fifty-four patients were enrolled (74 individuals with SCCs and 80 with lymphomas). After feature analysis and feature selection with variance threshold and least absolute shrinkage and selection operator (LASSO) methods, an MRI-based radiomics model with the support vector machine (SVM) classifier was constructed in differentiation between lymphomas and SCCs. Areas under the receiver operating characteristic curves (AUCs) of the MRI-based radiomics model were compared with those of radiologists using Delong test. Five features (T1 original shape Compactness2, T1 wavelet-HHH first-order Total Energy, T2 wavelet-HLH GLCM Informational Measure of Correlation1, T1 wavelet-LHL GLCM Inverse Variance and T1 square GLRLM Long Run Low Gray Level Emphasis) were finally selected in the radiomics model. The AUC values in differentiation between lymphomas and SCCs were 0.94 for the training dataset and 0.85 for the validation dataset, respectively. For all the patient datasets, the AUC values of radiomics model, readers 1, 2 and 3 were 0.92, 0.76, 0.77 and 0.80, respectively. For the validation datasets, no significant difference was found between the AUCs of the radiomics model and those of the three radiologist (P = 0.459, 0.469, 0.738 for radiologist 1, 2 and 3, respectively). An MRI-based radiomics model can help to differentiate sinonasal lymphomas from SCCs with high accuracy.


Phenotypic characterization and ERIC-PCR based genotyping of Paenibacillus larvae isolates recovered from American foulbrood outbreaks in honey bees from Italy.
Paenibacillus larvae is the etiological agent of American foulbrood (AFB), a widespread and severe bacterial brood disease of honey bees. The genomic characterization of P. larvae strains by enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) is able to differentiate four genotypes (ERIC I, ERIC II, ERIC III, ERIC IV). The information on the presence of P. larvae ERIC genotypes worldwide is few. We have characterized P. larvae strains isolated in Italy from AFB outbreaks to obtain information on ERIC genotypes and phenotypes of the strains circulating in the country. A total of 117 P. larvae isolates from 115 AFB outbreaks occurring in 2008-2012 were subjected to phenotypic and genetic characterization. The genomic characterization allowed the identification of ERIC I and ERIC II genotypes. Examining the data of Northern and Central Italy separately it was noted that in Northern Italy most outbreaks were caused by the ERIC I genotype (78.6%), followed by the ERIC II genotype (18.6%) and by co-infections (ERIC I + ERIC II) (2.6%). In Central Italy, only outbreaks caused by the ERIC I genotype were observed. With regard to phenotypic characteristics all examined strains of ERIC II genotype fermented fructose while no strains of ERIC I genotype possessed this ability. Both P. larvae ERIC I and ERIC II genotypes were isolated from the AFB outbreaks, but ERIC II genotype was isolated only in Northern Italy. The fermentation of fructose seems to be a genotype-specific biochemical marker.


Evolution of structure and function of Class I peroxidases.
The phylogenetics of Class I of the heme peroxidase-catalase superfamily currently representing over 940 known sequences in all available genomes of prokaryotes and eukaryotes has been analysed. The robust reconstructed tree for 193 Class I peroxidases with 6 selected Class II representatives reveals all main trends of molecular evolution. It suggests how the ancestral peroxidase gene might have been transferred from prokaryotic into eukaryotic genomes. Besides well known families of catalase-peroxidases, cytochrome c peroxidases and ascorbate peroxidases, the phylogenetic analysis shows for the first time the presence of two new well separated clades of hybrid-type peroxidases that might represent evolutionary bridges between catalase-peroxidases and cytochrome c peroxidases (type A) as well as between ascorbate peroxidases and Class II peroxidases (type B). Established structure-function relationships are summarized. Presented data give useful hints on the origin and evolution of catalytic promiscuity and specificity and will be a valuable basis for future functional analysis of Class I enzymes as well as for de novo design.


Is Housing a Health Insult?
In seeking to understand the relationship between housing and health, research attention is often focussed on separate components of people's whole housing 'bundles'. We propose in this paper that such conceptual and methodological abstraction of elements of the housing and health relationship limits our ability to understand the scale of the accumulated effect of housing on health and thereby contributes to the under-recognition of adequate housing as a social policy tool and powerful health intervention. In this paper, we propose and describe an index to capture the means by which housing bundles influence health. We conceptualise the index as reflecting accumulated housing 'insults to health'-an Index of Housing Insults (IHI). We apply the index to a sample of 1000 low-income households in Australia. The analysis shows a graded association between housing insults and health on all outcome measures. Further, after controlling for possible confounders, the IHI is shown to provide additional predictive power to the explanation of levels of mental health, general health and clinical depression beyond more traditional proxy measures. Overall, this paper reinforces the need to look not just at separate housing components but to embrace a broader understanding of the relationship between housing and health.


Low toxicity superparamagnetic magnetite nanoparticles: One-pot facile green synthesis for biological applications.
Superparamagnetic magnetite nanoparticles have been synthesized by a highly reproducible polyvinyl alcohol (PVA)-based modified sol-gel process using water as the only solvent. The synthesis method has proven to be effective, time and cost saving and environmental friendly, resulting in PVA-coated magnetite nanoparticles as direct product from the synthesis, without any special atmosphere or further thermal treatment. X-ray diffraction and transmission electron microscopy revealed that the biocompatible PVA-coating prevents the nanoparticle agglomeration, giving rise to spherical crystals with sizes of 6.8nm (as-cast) and 9.5nm (heat treated) with great control over size and shape with narrow size distribution. Complementary compositional and magnetic characterizations were employed in order to study the surface chemistry and magnetic behavior of the samples, respectively. Cytotoxicity endpoints including no observed adverse effect concentration (NOAEC), 50% lethal concentration (LC50) and total lethal concentration (TLC) of the tested materials on cell viability were determined after 3, 24 and 48h of exposure. The PVA coating improved the biocompatibility of the synthesized magnetite nanoparticles showing good cell viability and low cytotoxicity effects on the MTT assay performed on BHK cells. Preliminary assessment of nanoparticles in vivo effects, performed after 48h on Balb/c mice, exposed to a range of different sub-lethal doses, showed their capacity to penetrate in liver and kidneys with no significant morphological alterations in both organs.


Computer simulation of the dynamics of cell populations.
A modified version of the program of Valleron and Friendel is presented for the computer simulation of growing populations of cells. The method effects a sizable reduction of the storage requirement and allows one to follow the growth and division of cell clones for a large number of generations. Moreover, it is particularly useful to simulate specific biological events assumed to occur in the cell under various hypotheses and to compare them. Examples of this are also given.


Semi-rational protein engineering of a novel esterase from Bacillus aryabhattai (BaCE) for resolution of (R,S)-ethyl indoline-2-carboxylate to prepare (S)-indoline-2-carboxylic acid.
A gene encoding an esterase from Bacillus aryabhattai (BaCE) was identified, synthesized and efficiently expressed in the Escherichia coli system. A semi-rational protein engineering was applied to further improve the enzyme's enantioselectivity. Under the guidance of the molecular docking result, a single mutant BaCE-L86Q and a double mutant BaCE-L86Q/G284E were obtained, with its Emax value 6.4 times and 13.9 times of the wild-type BaCE, respectively. The recombinant BaCEs were purified and characterized. The overwhelming E value demonstrated that BaCE-L86Q/G284E was a promising biocatalyst for the biological resolution to prepare (S)-indoline-2-carboxylic acid.


GABAergic/glutamatergic-glial/neuronal interaction contributes to rapid adaptation in pacinian corpuscles.
Pacinian corpuscles (PCs) are tactile receptors composed of a nerve ending (neurite) that is encapsulated by layers of lamellar cells. PCs are classified as primary mechanoreceptors because there is no synapse between the transductive membrane and the site of action-potential generation. These touch receptors respond in a rapidly adapting manner to sustained pressure (indentation or displacement), which until now was believed to be attributable solely to the mechanical properties of the capsule. However, evidence of positive immunoreactivity for GABA receptors on the neurite, as well as evidence for gene expression of synaptobrevin in the lamellar cells led to the hypothesis that GABAergic inhibition originating from the lamellar cells is involved in the rapid adaptation process of PCs. Electrophysiological data from isolated PCs demonstrates that, in the presence of either gabazine or picrotoxin (GABA receptor antagonists), many action potentials appear during the static portion of a sustained indentation stimulus (similar to slowly adapting receptors) and that these "static" spikes completely disappear in the presence of GABA. It was consequently hypothesized that glutamate, released by either the neurite itself or the lamellar cells, caused these action potentials. Indeed, the glutamate receptor blocker kynurenate either decreased or totally eliminated the static spikes. Together, these results suggest that GABA, emanating from the modified Schwann cells of the capsule, inhibits glutamatergic excitation during the static portion of sustained pressure, thus forming a "mechanochemical," rather than purely mechanical, rapid adaptation response. This glial-neuronal interaction is a completely novel finding for the PC.


Music as social bonding: A cross-cultural perspective.
We extend Savage et al.'s music and social bonding hypothesis by examining it in the context of Chinese music. First, top-down functions such as music as political instrument should receive more attention. Second, solo performance can serve as important cues for social identity. Third, a right match between the tones in lyrics and music contributes also to social bonding.


Understanding multidisciplinary care for people with rheumatic disease in British Columbia, Canada, through patients, nurses and physicians voices: a qualitative policy evaluation.
In 2011, the province of British Columbia (BC) moved to allow patients with complex rheumatic disease to be seen by nurses along with their rheumatologist by introducing a 'Multidisciplinary Care Assessments' (MCA) billing code (G31060). To describe multidisciplinary care introduced as part of MCAs across BC and investigate the perceived impact of this intervention, the addition of nurses to the care team, on patient care from the perspective of patients, nurses, and rheumatologists. We conducted semi-structured interviews, informed by a qualitative evaluation approach with patients, nurses, and rheumatologists from September 2019 - August 2020. Interviews investigated 1) the experiences of all stakeholders with adopting the multidisciplinary care billing code, 2) the perceived role of the nurse in the care team, and 3) the perceived impact of multidisciplinary care on patient experience and outcomes. We purposefully sampled practices for maximum variation of geographical location (rural vs. urban), size of practice (i.e., patient caseload), and number of nurses employed. We interviewed 21 patients, 13 nurses, and 12 rheumatologists from across BC. Our analysis identified variation in the way rheumatologists adopted multidisciplinary care across BC. Our analysis showed some heterogeneity in the way the MCA was delivered in rheumatology practices; however, patient education was identified as the core role of nurses across practices. We identified six core themes describing the impact of this model of care, all representing improvements in the way practices functioned, from improved efficiency to access, patient experience, time management, clinician experience, and patient health outcomes. Contextual factors that influenced the presence of these themes were related to the time the nurses spent with patients and the professional roles they performed. Our results suggest nurse care can complement physician care by extending contact time for patients and promoting the efficient use of health care professionals' skills, time, and resources. These data may encourage future uptake of the billing code to help ensure the policy delivers maximum benefits to patients given the wide range of perceived benefits described by clinicians and patients.


Developing a diagnostic and intervention package for 2- to 3-year-olds with autism: outcomes of the frameworks for communication approach.
The aim of the research was to develop and evaluate a model of good practice which would make an explicit link between diagnosis and intervention, and so give parents a very clear rationale for the autism-specific yet individualized programme that they were carrying out. It employed an action research design, which essentially is responsive to participants, thus developing a user-friendly model of service. The programme was based on the developmental perspective that the pragmatics of language are the precursors of speech itself and enable both communication and relationship between child and parents. Since these are impaired in autism they should therefore be prioritized in early intervention. Ten children aged 1:10 to 2:9 at assessment, and with a diagnosis of autism, underwent an intervention based on home visits, modelling, workshops and written information, with parents as 'therapists' in naturally occurring situations. Within 18 months all children made substantial progress in social interaction and expressive communication, including gestural and verbal communication.


Treatment of Candida peritonitis by peritoneal lavage with amphotericin B.
A 14-year-old girl, who was a renal transplant recipient, developed Candida tropicalis peritonitis during peritoneal dialysis and immunosuppressive and broad-spectrum antibiotic therapy. Therapeutic cure of the peritonitis followed a ten-day course of amphotericin B administered solely by peritoneal lavage.


Cloning of yeast lysyl- and phenylalanyl-tRNA synthetase genes.
Cloning of yeast lysyl- and phenylalanyl-tRNA synthetase genes was accomplished by probing a lambda gt11 recombinant DNA expression library with antibodies directed against the purified enzymes. Several DNA clones encoding either the alpha or the beta subunit of phenylalanyl-tRNA synthetase were isolated. In each case, the inserted DNA was oriented in the same direction with respect to the lambda gt11 lacZ transcription unit, giving rise to the expression of hybrid proteins. The corresponding DNA fragments constitute suitable hybridization probes for the isolation of complete nucleotide sequences encoding the alpha and beta subunits of the enzyme. Recombinant DNA lambda gt11 clones encoding lysyl-tRNA synthetase were also selected. One of these contained yeast DNA inserted with the opposite orientation with respect to lacZ. The lysogen corresponding to that recombinant DNA phage produced an active, native lysyl-tRNA synthetase. The 3.6 kbp DNA insert contained all the information necessary for the expression of yeast lysyl-tRNA synthetase in E. coli.


Trends in Off-Label Drug Use in Ambulatory Settings: 2006-2015.
Off-label drug use in children is common and potentially harmful. In most previous off-label use research, authors studied hospitalized children, specific drug classes, or non-US settings. We characterized frequencies, trends, and reasons for off-label systemic drug orders for children in ambulatory US settings. Using nationally representative surveys of office-based physicians (National Ambulatory Medical Care Surveys, 2006-2015), we studied off-label orders of systemic drugs for children age <18 based on US Food and Drug Administration-approved labeling for age, weight, and indication. We characterized the top classes and diagnoses with off-label orders and analyzed factors and trends of off-label orders using logistic regression. Physicians ordered ≥1 off-label systemic drug at 18.5% (95% confidence interval: 17.7%-19.3%) of visits, usually (74.6%) because of unapproved conditions. Off-label ordering was most common proportionally in neonates (83%) and in absolute terms among adolescents (322 orders out of 1000 visits). Off-label ordering was associated with female sex, subspecialists, polypharmacy, and chronic conditions. Rates and reasons for off-label orders varied considerably by age. Relative and absolute rates of off-label orders rose over time. Among common classes, off-label orders for antihistamines and several psychotropics increased over time, whereas off-label orders for several classes of antibiotics were stable or declined. US office-based physicians have ordered systemic drugs off label for children at increasing rates, most often for unapproved conditions, despite recent efforts to increase evidence and drug approvals for children. These findings can help inform education, research, and policies around effective, safe use of medications in children.


Cellular uptake of covalent conjugates of oligonucleotide with membrane-modifying peptide, peptaibol.
Using the membrane-modifying peptide, trichorovin-XIIa (TV-XIIa), which is an 11-residual peptaibol isolated from the fungus Trichoderma viride, we synthesized covalent conjugates of 20-mer oligonucleotide with TV-XIIa to examine the potential use of TV-XIIa in cellular delivery. The results indicated that the conjugates were progressively taken up by human lung carcinoma A549 cells. Next, the antisense effects of the conjugates on p53 protein expression were examined. The p53 expression was significantly decreased by ca. 20-50% in the presence of the conjugates upon treatment with the transfection solution at the concentration of 5 μM.


Novel risk scoring system for metastatic renal cell carcinoma patients treated with cabozantinib.
Cabozantinib is an effective treatment for metastatic renal cell carcinoma (mRCC). The international mRCC database consortium (IMDC) criteria is the gold standard for risk stratification in mRCC. We created a risk scoring system specific for mRCC patients treated with cabozantinib. We conducted a retrospective review of 87 patients with mRCC treated with cabozantinib at Winship Cancer Institute from 2015 to 2019. Overall survival (OS) and progression free survival (PFS) were used to measure clinical outcomes. Upon variable selection in multivariable analysis (MVA), elevated baseline monocyte-to-lymphocyte ratio (MLR), sarcomatoid histologic component, ECOG PS > 1, and absence of bone metastases were each assigned 1 point. A three-group risk scoring system was then created: low (score=0-1), intermediate (score=2), and high risk (score=3-4). The Cox proportional hazard model and Kaplan-Meier method were used for survival analyses. The median age was 62 years-old and the majority were males (71%) with clear-cell RCC (75%). Most (67%) received at least 1 prior line of systemic therapy. High risk and intermediate risk pts had significantly shorter OS (high risk HR: 13.84, p<0.001; intermediate risk HR: 3.50, p = 0.004) and PFS (high risk HR: 7.31, p<0.001; intermediate risk HR: 1.87, p = 0.053) compared to low risk patients in MVA. RCC patients treated with cabozantinib may benefit from specific risk stratification criteria using RCC histology, ECOG PS, sites of metastatic disease, and MLR. These variables are easily accessible in the clinical setting and may be helpful to determine which mRCC patients may benefit from treatment with cabozantinib.


Attenuation of cardiopulmonary bypass-derived inflammatory reactions reduces myocardial reperfusion injury in cardiac operations.
In cardiac operations endopeptidase (protease) inhibitor may be beneficial in reducing myocardial injury when administered in the cardiopulmonary bypass prime. Nafamostat mesilate was evaluated in 20 patients who underwent coronary artery bypass grafting. The patients were divided into a control group (n = 10) and a nafamostat group (n = 10). Nafamostat (2 mg/kg per hour) was continuously given during cardiopulmonary bypass in the nafamostat group. The age, number of grafts, cardiopulmonary bypass time, and aortic crossclamp time were similar between groups. In the control group, neither tumor necrosis factor-alpha nor interleukin-1 levels showed any significant change during cardiopulmonary bypass, whereas interleukin-6 and interleukin-8 levels, percent expression of adhesion molecule (CD18) on neutrophils, and CH50 assay results increased significantly during cardiopulmonary bypass. As compared with the control group, the nafamostat group showed significantly lower levels of interleukin-6 (123 +/- 57 versus 40 +/- 22 pg/ml, respectively) and interleukin-8 (96 +/- 13 versus 66 +/- 14 pg/ml, respectively). The nafamostat group showed a significantly lower difference of CH50 assay results and malondialdehyde levels between coronary sinus blood and arterial blood and peak values of creatine kinase MB (43 +/- 12 IU/L versus 19 +/- 6 IU/L) during the postoperative course compared with findings in the control group. These results demonstrated that inflammatory reactions induced by cardiopulmonary bypass had adverse effects on myocardial recovery after aortic crossclamping and that nafamostat mesilate given during cardiopulmonary bypass appeared to reduce myocardial reperfusion injury by attenuating such inflammatory reactions. Attenuation of inflammatory reactions of cardiopulmonary bypass should be considered in the strategy of myocardial protection.


The failure of immunosuppression withdrawal: patient benefit is not detectable, inducible, or reproducible.
(1) Immunosuppression is responsible for excellent patient outcomes. (2) Immunosuppression withdrawal fails in most patients. (3) Patients who may benefit from immunosuppression withdrawal cannot currently be identified. (4) No data suggest that immunosuppression withdrawal decreases patient morbidity (ie, nephrotoxicity). (5) The minimization of immunosuppression instead of withdrawal may be adequate for improving patient outcomes.


A cryptic deletion in 5q31.2 provides further evidence for a minimally deleted region in myelodysplastic syndromes.
Recurrent deletions of 5q in myeloid malignancies encompass two separate regions: deletion of 5q33, which is associated with the 5q− syndrome and haploinsufficiency of RPS14, and deletion of a more proximal locus at 5q31. We present a case with a cryptic 1.3 Mb deletion in 5q31.2 identified by array comparative genomic hybridization that places the proximal boundary of the deletion proximal and close to the candidate EGR1 gene. The patient was diagnosed initially with a myelodysplastic syndrome, with a del(20)(q11.2q13.3) as the sole abnormality identified by karyotyping. The patient progressed to acute myeloid leukemia with no change to the G-banded karyotype. The 1.3 Mb deletion on the long arm of one chromosome 5 was confirmed to have been present both at presentation with myelodysplastic syndrome and at transformation. This is an interesting case because there are few array studies identifying cryptic 5q deletions, and the study of these small deletions helps to refine the common deleted region. This case, together with previously published studies, suggests that the proximal boundary of the common deleted region may lie within the KDM3B gene.


[Monitoring of cerebral electrical activity during cardiac surgery (author's transl)].
Continuous recording of cerebral activity by the Cerebral Function Monitor is a useful supplementation to anaesthetic monitoring in cardiac surgery. It is a simple and reliable method for early detection of cerebral damage during heart surgery and in other situations with possible cerebral impairment. The operating principles of the Cerebral Function Monitor and the interpretation of the electrical activity tracings are presented. Therapeutic considerations to minimize or to prevent anoxic brain damage are offered.


Primary care--opportunities and threats. Developing professional knowledge: making primary care education and research more relevant.
The trio of recent government white papers heralds a new world for primary care. Many changes in the education of future primary health care professionals and in the research ethos of the discipline will be needed to realise this vision. New skills and attitudes, not least in multidisciplinary working; lifelong learning; and greater understanding of and participation in primary care research will have to emerge from educational efforts in the next few years.


Stereoscopic fluorescein angiography of the fundus.
The fundus of the eye is a three-dimensional organ. The usual two-dimensional representation of the angiogram provides us with incomplete information. It is true that it is usually possible by indirect means to deduce at which level the pathological process is taking place, but a simple technique enables one to register and project the angiogram stereoscopically. This gives the observer a direct visual impression of the spatial proportions of the pathological process.


Behavioral characteristics to airborne particles generated from commercial spray products.
Commercial spray products are commonly used in daily life and airborne particles generated by these products may cause adverse health effects. Our study was aimed to characterize the behaviors of airborne particles from spray products and to determine the deposition loss rate. Four categories of spray products with highly frequent use - air fresheners, fabric deodorants, window cleaners, and a bathroom cleaner - were selected for the study. The products were applied in a cleanroom according to the instructions for use. Airborne particles (10-10,000 nm) were measured within the breathing zone of a user with a scanning mobility particle sizer and an optical particle spectrometer. Additionally, filter sampling was performed to examine the morphological characteristics of the particles using a field emission-scanning electron microscope (FE-SEM). The initial concentration and particle size distribution varied among different spray types and products. Two propellant-type air fresheners that we tested showed a high initial concentration of smaller sized particles. However, one of these and all hand-pressure type propellants showed a low initial concentration in all size ranges. We observed that particles in nucleation mode (10-31.6 nm) decreased and aggregated particles shifted to accumulation mode (100-1,000 nm) over time. The FS-SEM analysis confirmed the aggregation of nano-sized particles for all products. The deposition loss rates of various particle sizes depended on the initial concentration and distribution of particle sizes. For two air fresheners with high initial concentrations, the loss rate of small-sized particles was higher than that of the other products whereas the particle loss rate of large-sized particles was higher, regardless of initial concentration. The results of this study can give us useful information in the behaviors of airborne particles in the consumer spray products and resulting exposure assessment especially in the application to the exposure modeling of spray products.


Laryngeal reconstruction by composite nasal mucoseptal graft after partial laryngectomy. three years follow-up.
We have used autogenous nasal mucoseptal (NMS) graft for the reconstruction of the larynx after partial laryngectomy in glottic carcinoma invading the anterior commissure, for the past three years. The composite graft, readily available and obtained without sequela, provides satisfactory and large enough replacement tissue. It provides both a dependable rigid cartilaginous wall and a respiratory mucous lining of the lumen. The method was found to be simple and effective in bridging the laryngeal defect. The free NMS graft was used for reconstruction after extended frontal and frontolateral laryngectomy in 10 patients. The patients were successfully decannulated within 4 to 6 days after the operation and in none of the cases was nasogastric feeding tube or laryngeal stenting necessary. In eight patients anatomical and functional results were achieved; the neolarynx prevented a permanent tracheostomy and a fair voice was obtained.


Reduced Nonradiative Recombination Energy Loss Enabled Efficient Polymer Solar Cells via Tuning Alkyl Chain Positions on Pendent Benzene Units of Polymers.
Nonradiative recombination energy loss (ΔE3) plays a key role in enhancing device efficiencies for polymer solar cells (PSCs). Until now, there is no clear resolution for reducing ΔE3 via molecular design. Herein, we report two conjugated polymers, PBDB-P-p and PBDB-P-m, which are integrated from benzo[1,2-b:4,5-b']dithiophene with alkylthio chain substituted at para- or meta-position on pendent benzene and benzo[1,2-c:4,5-c']dithiophene-4,8-dione. Both the polymers have different temperature-dependent aggregation properties but similar molecular energy levels. When BO-4Cl was used as an acceptor to fabricate PSCs, the device of PBDB-P-p:BO-4Cl displayed a maximal power conversion efficiency (PCE) of 13.83%, while the best device of PBDB-P-m:BO-4Cl exhibited a higher PCE of 14.12%. The close JSCs and fill factors in both PSCs are attributed to their formation of effective nanoscale phase separation as confirmed by atomic force microscopy measurements. We find that the PBDB-P-m-based device has 1 order of magnitude higher electroluminescence quantum efficiency (EQEEL) than in the PBDB-P-p-based one, which could arise from the relatively weak aggregation in the PBDB-P-m-based film. Thus, the PBDB-P-m-based device has a remarkably enhanced VOC of 0.86 V in contrast to 0.80 V in the PBDB-P-p-based device. This study offers a feasible structural optimization way on the alkylthio side chain substitute position on the conjugated polymer to enhance VOC by reducing nonradiative recombination energy loss in the resulting PSCs.


Yaws in West Sumatra, Indonesia: clinical manifestations, serological findings and characterisation of new Treponema isolates by DNA probes.
The results of a yaws survey on the island of Sumatra in Indonesia are presented. The prevalence of yaws in the investigated region was found to be very high, a minimum of 300 cases per 100,000 individuals, which indicates that yaws is far from being eradicated and that campaigns for treatment are necessary. Patients suffering from early infectious yaws showed florid skin lesions. Of 101 serum samples from such patients, 100 had a positive reaction in one or more treponemal tests. The Treponema pallidum haemagglutination assay was found to be the most sensitive test (97% positive) in detecting antibodies against Treponema pallidum subsp. pertenue, followed by the fluorescent treponemal antibody absorption test (94%), the Venereal Disease Research Laboratory test and the TmpA enzyme immunoassay (91%), and analysis by Western blot using Treponema pallidum antigens (88%). Of 42 asymptomatic contacts of yaws patients 32 showed positive reactions in one or more tests, indicating that many people in the investigated region have been infected with treponemes. Eight new Treponema pallidum subsp. pertenue strains were isolated from yaws skin lesions. In vitro amplification of treponemal DNA and hybridisation with specific DNA probes showed that all eight strains were identical with Treponema pallidum subsp. pertenue CDC 2575, with regard to the subsp. pertenue specific tyfl gene.


Improving the thermal structure predictions in the Yellow Sea by conducting targeted observations in the CNOP-identified sensitive areas.
Targeted observation is an appealing procedure for improving model predictions. However, studies on oceanic targeted observations have been largely based on modeling efforts, and there is a need for field validating operations. Here, we report the results of a field targeted observation that is designed based on the sensitive areas identified by the Conditional Nonlinear Optimal Perturbation approach to improve the 7th day thermal structure prediction in the Yellow Sea. By introducing the technique of cycle data assimilation and the new concept of time-varying sensitive areas, an observing strategy is designed and validated by a set of Observing System Simulation Experiments. Then, the impact of targeted observations was investigated by a choreographed field campaign in the summer of 2019. The results of the in-field Observing System Experiments show that, compared to conventional local data assimilation, conducting targeted observations in the sensitive areas can yield more benefit at the verification time. Furthermore, dynamic analysis demonstrates that the refinement of vertical thermal structures is mainly caused by the changes in the upstream horizontal temperature advection driven by the Yellow Sea Cold Water Mass circulation. This study highlights the effectiveness of targeted observations on reducing the forecast uncertainty in the ocean.


Osteoarthritis as a disease of mechanics.
Mechanics means relating to or caused by movement or physical forces. In this paper, I shall contend that osteoarthritis (OA) is almost always caused by increased physical forces causing damage to a joint. While examples of joint injury causing OA are numerous, I shall contend that most or almost all OA is caused in part by mechanically induced injury to joint tissues. Further, once joint pathology has developed, as is the case for almost all clinical OA, pathomechanics overwhelms all other factors in causing disease progression. Treatments which correct the pathomechanics have long lasting favorable effects on pain and joint function compared with treatments that suppress inflammation which have only temporary effects. I shall lastly contend that the mechanically induced joint injury leads to variable inflammatory responses but that the role of this inflammation in worsening structural damage in an already osteoarthritic joint has not yet been proven.


Heterogeneous p27(Kip1) expression within primary renal cell cancers, their invasive margins and peritumoral renal parenchyma correlation with pathological and prognostic features.
The expression of the negative cell cycle regulator p27(Kip1) is frequently found to be deregulated in various human cancer types. Whether expression of p27(Kip1) can be used as prognostically relevant biological variables for renal cell cancer patients still remains to be clarified. Therefore, in the present investigation the expression within different tissue areas obtained from renal cell carcinomas was determined. For analysis of p27(Kip1) in 420 tumor nephrectomy specimens obtained from 420 consecutively included patients, tissue microarrays were used comprising of 1,260 tissue samples each obtained from the tumor itself, the invasive front as well as non-malignant surrounding parenchyma. A sufficient follow-up after surgical therapy was available in 251 cases. In univariate survival analysis, decreased expression of p27(Kip1) within tissue cores obtained from the invasion front was significantly correlated with the patients' disease-specific long-term survival (p = 0.02, log-rank test). In contrast, expression of p27(Kip1) protein within the primary tumors was not identified to reveal any prognostically important information. In Cox regression analysis, histological stage and grade (p < 0.01), the presence of regional lymph node (p < 0.01) or distant metastases at the time of surgery (p < 0.01) as well as decreased expression of p27(Kip1) (p = 0.04) within the invasion front tissue samples independently predicted the disease-specific long-term survival following surgery. Our analysis demonstrated that p27(Kip1) is heterogeneously expressed in renal cell carcinomas. Moreover, the result of the present study supports the prognostic value of p27(Kip1) protein expression for patients diagnosed with renal cell carcinoma.


Psychological effect of exercise in women with breast cancer receiving adjuvant therapy: what is the optimal dose needed?
Several meta-analyses have examined the role of exercise interventions in improving psychological outcomes in cancer survivors but most did not focus on adjuvant therapy period and did not investigate the optimal dose of exercise needed. The present meta-analysis examines the impact of exercise interventions delivered at this particular period on fatigue, anxiety, depression, and quality of life (QoL) as well as dose-response relationships between volume of prescribed exercise and these psychological outcomes. Randomized, controlled trials that proposed an exercise intervention to patients with breast cancer undergoing chemotherapy and/or radiotherapy were systematically identified and coded. Psychological outcomes effect sizes were calculated and analyzed for trends using linear and quadratic regressions. Pooled effects of the 17 included studies revealed improvement for all outcomes, significant for fatigue, depression, and QoL with pooled estimates ranging from 0.2 to 0.5 favoring intervention. Significant inverse associations of the volume of prescribed exercise with fatigue and QoL were observed. Exercise intervention improved fatigue, depression, and QoL in patients with breast cancer receiving adjuvant therapy. Prescription of relatively low doses of exercise (<12 MET h/week) consisting in ∼90-120 min of weekly moderate physical exercise seems more efficacious in improving fatigue and QoL than higher doses.


Requirement of heme to replace the sparking sterol function in the yeast Saccharomyces cerevisiae.
At least four distinctive sterol functions have been defined in the yeast Saccharomyces cerevisiae. One of these functions, identified as sparking, has the lowest quantitative requirement for sterol, but has the greatest structural specificity. Based on studies utilizing a yeast strain auxotrophic for both heme and sterol biosynthesis, it had been reported that a delta 5-sterol was essential for the growth of the organism. We demonstrate here that heme, and not a heme precursor, can replace the delta 5-sparking sterol requirement of heme auxotrophic strains of yeast.


Author Correction: Relationship between spectrotemporal modulation detection and music perception in normal-hearing, hearing-impaired, and cochlear implant listeners.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Are modified radical mastectomies done for T1 breast cancers because of surgeon's advice or patient's choice?
Clinical trials show that T1 breast cancers are equally well treated with breast-conserving surgery as with modified radical mastectomy. However, the Colorado Central Cancer Registry indicates that, for the past 5 years, the majority of women (72%) with T1 breast cancer in Colorado have undergone modified radical mastectomies. A questionnaire was sent to 175 general surgeons to determine the reasons for the high number of modified radical mastectomies still being performed. The results indicate that one group of surgeons (34% of those responding) believes each type of surgery has equal survival rates but unknowingly influences the patient to choose modified radical mastectomy, with a subtly biased presentation. Education of both surgeons and patients is needed to increase the number of patients with T1 breast lesions who can benefit from breast-conserving therapy.


Synthesis and Evaluation of 18F-Labeled Fluoroalkyl Triphenylphosphonium Salts as Mitochondrial Voltage Sensors in PET Myocardial Imaging.
We have previously reported that radiolabeled phosphonium cations accumulate in the mitochondria down a transmembrane potential gradient. We present an optimized procedure for synthesis of three [18F]-labeled fluoroalkyl triphenylphosphonium salts ([18F]FATPs) via two-step simple nucleophilic substitution reactions to develop new myocardial imaging agents for positron emission tomography (PET) . The total reaction time of [18F]FATPs was within 60 min, and the overall decay-corrected radiochemical yield was approximately 15-30% (decay corrected). Radiochemical purity was >98% according to analytical high-performance liquid chromatography (HPLC) . The specific activity of [18F]FATPs was >6.1 TBq/μmol. The [18F]FATPs exhibited higher first-pass extraction fraction values in isolated heart, higher uptake in the myocardium, and a more rapid clearance from the liver and lung than [13N]NH3 in normal rats. The images from rats with an occluded left coronary artery demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. This imaging technology may enable high-throughput, multiple studies daily and wide distribution of PET myocardial studies in clinic.


Giant Gartner duct cyst and elevated CA-125.
Gartner duct cysts represent vestigial remnants of the caudal end of the mesonephric (Wolffian) ducts. They are often associated with ureteral and renal abnormalities. In most cases they are solitary, less than 2 cm in diameter. Giant Gartner duct cysts are extremely rare. We present a girl with a giant Gartner duct cyst, without notable associated abnormalities or pathology, successfully treated by surgical excision. Preoperative aspiration revealed elevated level of CA-125 in the cyst fluid, with normal serum level of the same marker. Analyzing the aspirated fluid for CA-125 may be a useful tool for evaluation of cystic lesions in this region.


Covid-19 and international cooperation: IR paradigms at odds.
The Covid-19 pandemic is a global challenge calling for a global response. But the actual responses of states, while exhibiting considerable international cooperation, are predominantly competitive and self-centered. This raises important questions about the utility of our basic intellectual tools-in the form of International Relations Theory (IRT)-for understanding the pattern of these responses. IRT analyzes inter-state dynamics and explains the extent to which states and institutions do or do not cooperate. This critique focuses on theories that stress competition (realism), those that focus on cooperation (liberalism) and those emphasising ideational constructions that could go either way (constructivism and normative theory). It seeks to elucidate the relative strengths of these theories-what they can tell us and what they cannot-in understanding responses to the current pandemic. It concludes that, while all the identified approaches have something to offer, realist theory, which highlights the prioritization of national interests over collective action, provides the most optimal approach for a full understanding of global responses to Covid-19. The analysis helps draw lessons for policy responses to this and other global crises, such as climate change.


Evaluation of an inner city HIV pre-exposure prophylaxis service tailored to the needs of people who inject drugs.
HIV prevention strategies including pre-exposure prophylaxis (PrEP) must reach all in need to achieve elimination of transmission by 2030. Mainstream provision may inadvertently exclude key populations. Incidence of HIV in people who inject drugs (PWID) in Glasgow, Scotland's largest city, is increasing, partly due to sexual transmission. Scotland provides publicly funded oral PrEP for individuals at sexual risk of HIV through sexual health services; however, uptake by PWID has been negligible. We developed a tailored outreach PrEP service based in the local homeless health centre. We used active case finding, flexibility of assessment location, supervised community daily dispensing and active follow-up to optimise uptake and adherence. We describe a two-year service evaluation. We reviewed the case records of all PWID identified by the outreach team as being at higher risk of sexual acquisition for whom PrEP was considered between November 2018 and November 2020. Evaluation focused on PrEP uptake, adherence and monitoring. We conducted a descriptive statistical analysis. Of 41 PWID assessed as eligible, 32 (78.0%) commenced PrEP. The proportion of PrEP-covered days was 3320/3400 days (97.6%); 31/32 (96.9%) had regular HIV serology monitoring. The service was feasible to run, but it relied on outreach provision and liaison with other services. Tailored PrEP services can reach PWID effectively. Uptake and adherence were high but the model was resource-intensive. Appropriately tailored PrEP delivery may be required to meet the needs of this and other key populations who experience barriers to accessing mainstream services.


IgA coating of vaginal bacteria is reduced in the setting of bacterial vaginosis (BV) and preferentially targets BV-associated species.
Immunoglobulin (Ig) bacterial coating has been described in the gastrointestinal tract and linked to inflammatory bowel disease; however, little is known about Ig coating of vaginal bacteria and whether it plays a role in vaginal health including bacterial vaginosis (BV). We examined Ig coating in 18 women with symptomatic BV followed longitudinally before, 1 week, and 1 month after oral metronidazole treatment. Immunoglobulin A (IgA) and/or immunoglobulin G (IgG) coating of vaginal bacteria was assessed by flow cytometry, and Ig coated and uncoated bacteria were sorted and characterized using 16S rRNA sequencing. Despite higher levels of IgG compared to IgA in cervicovaginal fluid, the predominant Ig coating the bacteria was IgA. The majority of bacteria were uncoated at all visits, but IgA coating significantly increased after treatment for BV. Despite similar amounts of uncoated and IgA coated majority taxa ( >1% total) across all visits, there was preferential IgA coating of minority taxa (0.2%-1% total) associated with BV including Sneathia, several Prevotella species, and others. At the time of BV, we identified a principal component (PC) driven by proinflammatory mediators that correlated positively with an uncoated BV-associated bacterial community and negatively with an IgA coated protective Lactobacillus bacterial community. The preferential coating of BV-associated species, increase in coating following metronidazole treatment, and positive correlation between uncoated BV-associated species and inflammation suggest that coating may represent a host mechanism designed to limit bacterial diversity and reduce inflammatory responses. Elucidating the role of Ig coating in vaginal mucosal immunity may promote new strategies to prevent recurrent BV.


In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy.
Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.


Measurement of functional capacity requirements to aid in development of an occupation-specific rehabilitation training program to help firefighters with cardiac disease safely return to work.
We designed a study to measure the functional capacity requirements of firefighters to aid in the development of an occupation-specific training program in cardiac rehabilitation; 23 healthy male firefighters with no history of heart disease completed a fire and rescue obstacle course that simulated 7 common firefighting tasks. They wore complete personal protective equipment and portable metabolic instruments that included a data collection mask. We monitored each subject's oxygen consumption (VO(2)) and working heart rate, then calculated age-predicted maximum heart rates (220 - age) and training target heart rates (85% of age-predicted maximum heart rate). During performance of the obstacle course, the subjects' mean working heart rates and peak heart rates were higher than the calculated training target heart rates (t(22) = 5.69 [working vs target, p <0.001] and t(22) = 15.14 [peak vs target, p <0.001]). These findings, with mean results for peak VO(2) (3,447 ml/min) and metabolic equivalents (11.9 METs), show that our subjects' functional capacity greatly exceeded that typically attained by patients in traditional cardiac rehabilitation programs (5 to 8 METs). In conclusion, our results indicate the need for intense, occupation-specific cardiac rehabilitation training that will help firefighters safely return to work after a cardiac event.


Climate change impacts of introducing carbon capture and utilisation (CCU) in waste incineration.
Amending municipal solid waste incineration (MSWI) with carbon capture and utilisation (CCU) can simultaneously lower the climate change impacts of incineration and supply carbon for a range of uses. However, life cycle assessment (LCA) shows that technology choices and the benefits of CCU applied to MSWI depend on the energy system in which the MSWI operates throughout its lifetime, and on the markets for the CCU products. Carbon capture reduces up to 50% of the energy recovery of MSWI. We assessed different energy system scenarios, ranging from fossil- to non-fossil based. Direct utilisation of the captured CO2 is beneficial only on a local basis when substituting fossil-based CO2 (-700 kg CO2-eq/tonne waste), with benefits similar to carbon capture and storage. Hydrogenation of CO2 with the purpose of producing feedstock chemicals or fuels such as methane, methanol, dimethyl ether (DME) and formic acid provides much higher benefits (-2000 kg CO2-eq/tonne waste), but only in non-fossil-based energy systems, due to the dramatically high consumption of electricity (more than 6000 kWh/tonne waste). Use as feedstock chemicals provides more benefits than use as fuels, and CCU solutions focusing on methanol and DME are the most promising technologies. Although built on scarce and early-development data, the analysis highlights current crucial issues, at both the technological and system levels, for the future introduction of CCU in MSWI.


Reconstruction of parotid duct defect with autologous vein graft and vascular coupler after buccal mucosa cancer resection.
The distal end of parotid duct is often inevitably resected en-block with the buccal mucosa cancer to obtain safety margin and prevent local recurrence. Ligation of duct frequently causes complications like cheek swelling, fistula and gland function loss. The authors describe a novel procedure of combined use of autologous vein graft and vascular coupler to reconstruct the parotid duct defect for buccal mucosa cancer patients who undergo radical neck dissection and free-flap reconstruction, no lumen-stent or cannula is needed. Case examples are shown to illustrate the operative details and different outcomes for two kinds of orifice site choices. Key factors for success include the proper use of Coupler device, right choice of new orifice location and maintenance of lumen patency. For buccal mucosa cancer patients, this novel method for parotid duct reconstruction could effectively reduce postoperative complications and preserve the parotid gland function.


Current age and race adjusted prostate specific antigen threshold values delay diagnosis of high grade prostate cancer.
Age specific prostate specific antigen ranges have been advocated to increase the predictive value of prostate specific antigen based on increases that occur with aging. We suggest that prostate specific antigen is not a dichotomous biomarker and age specific reference ranges delays the diagnosis of high grade prostate cancer in older and black American men. Using the Prostate Cancer Prevention Trial risk calculator we evaluated the impact of age on the risk of high grade prostate cancer in white and black men. We created a hypothetical population of men by standardizing risk variables, including negative family history, normal digital rectal examination and no history of negative biopsy. Results were compared in the 2 populations using 5-year age increments from ages 55 to 75 years and increasing prostate specific antigen. Increasing age was associated with a higher risk of high grade prostate cancer in white and black men. The risk of high grade prostate cancer in a black man was twice that in a white man with the same prostate specific antigen at all prostate specific antigen values. Age specific and race specific prostate specific antigen ranges are flawed. Many patients who would not be considered for biopsy based on these prostate specific antigen ranges are at significant risk for high grade prostate cancer. The risk of high grade prostate cancer in black men is twice that in white men. Risk assessment in black men and older men is necessary to diagnose high grade prostate cancer when treatment can be effective.


ATP-binding cassette transporter A1 and HDL metabolism: effects of fatty acids.
Ample evidence indicates that dietary fatty acids alter the plasma levels of high-density lipoprotein cholesterol (HDL-C). However, the mechanisms underlying the effects of fatty acids still remain elusive. Recent advances in our understanding of ATP-binding cassette transporter A1 (ABCA1) function and regulation have provided a valuable insight into the mechanisms by which fatty acids may affect plasma HDL-C levels. ABCA1 mediates the assembly of phospholipids and free cholesterol with apolipoprotein A-I, which is a critical step for HDL biogenesis. Studies have shown that unsaturated fatty acids, but not saturated fatty acids, repress the expression of ABCA1 in vitro. Although information on mechanisms for the fatty-acid-mediated regulation of ABCA1 expression is still limited and controversial, recent evidence suggests that unsaturated fatty acids inhibit the expression of ABCA1 at the transcriptional and posttranscriptional levels. The transcriptional repression of ABCA1 expression by unsaturated fatty acids is likely liver X receptor dependent. Evidence also suggests that histone deacetylation may play a role in the repression. Posttranscriptionally, unsaturated fatty acids may facilitate ABCA1 protein degradation, which may involve phosphorylation of ABCA1 by protein kinases. Further studies are warranted to better understand the role of dietary fatty acids in HDL metabolism and their effects on cardiovascular health.


Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones.
Expression of N-methyl-d-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) in the CA1 region of the hippocampus can be divided into an early (1-2 h), protein synthesis-independent phase and a late (>4 h), protein synthesis-dependent phase. In this study we have addressed whether the de novo protein synthesis required for the expression of late-LTP can be sustained solely from the translation of mRNAs located in the dendrites of CA1 pyramidal neurones. Our results show that late-LTP, lasting at least 5 h, can be maintained in hippocampal slices where the dendrites located in stratum radiatum have been isolated from their cell bodies by a microsurgical cut. The magnitude of the potentiation of the slope of field EPSPs in these 'isolated' slices was similar to that recorded in 'intact' slices. Incubation of the slices with the mRNA translation inhibitor cycloheximide or the mammalian target of rapamycin (mTOR) inhibitor rapamycin blocked late-LTP in both 'intact' and 'isolated' slice preparations. In contrast, incubation of slices with the transcription inhibitor, actinomycin D, resulted in a reduction of sustained potentiation, at 4 h, in 'intact' slices while in 'isolated' slices the magnitude of potentiation was similar to that seen in untreated slices. These results indicate that late-LTP can be induced and maintained in 'isolated' dendritic preparations via translation of pre-existing mRNAs.


Behavioral readout of spatio-temporal codes in olfaction.
Neural recordings performed at an increasing scale and resolution have revealed complex, spatio-temporally precise patterns of activity in the olfactory system. Multiple models may explain the functional consequences of the spatio-temporal olfactory code, but the link to behavior remains unclear. Recent evidence in the field suggests a behavioral sensitivity to both fine spatial and temporal features in the code. How these features and combinations of features give rise to olfactory behavior is the subject of active research in the field. Modern genetic and optogenetic methods show great promise in testing the link between olfactory codes and behavior.


Response to neoadjuvant therapy for rectal cancer: influence on long-term results.
Pre-operative treatment with chemoradiotherapy (CRT) seems to improve local control and overall survival in patients with rectal cancer. The aims of the study were to analyse the impact on overall, disease free and cancer related survival of tumour response to pre-operative CRT and to analyse the influence of the degree of response on long-terms results. Patients with a locally advanced rectal cancer, treated by pre-operative CRT were studied. A radical resection of the rectal tumour with mesorectal excision was performed within 6-8 weeks. Judged on the final TNM classification patients were considered responders when the tumour showed histologically a complete response, microscopic residual disease or a partial response. Non-responders were those in whom the extent of disease remained stable or progressed. Results Radical excision was performed in 103 patients, and a palliative resection in five. Forty-three patients underwent abdominoperineal resection and 65 anterior resection of the rectum. Seventy-one (65.7%) patients showed a response to CRT, while 37 (34.3%) did not. The overall local and distant recurrence rates were 6.8% and 21.3%. Tumour recurrence (P < 0.008) and disease free survival (P < 0.007) were significantly different in responders and nonresponders. Of the 71 responders, 16 had a pathological complete response, 27 had persisting microscopic disease and 28 had macroscopic residual disease. No differences in cancer specific outcome were observed in these groups. Pathological response to pre-operative CRT is associated with improved tumour recurrence and disease-free survival rates. Any response to pre-operative CRT appears to improve outcomes as much as a complete response.


Tripolyphosphatase associated with S-adenosylmethionine synthetase isozymes from rat liver.
S-Adenosylmethionine (AdoMet) synthetase alpha and beta were purified to homogeneity, as judged by SDS-polyacrylamide gel electrophoresis from rat liver. When the purified enzymes were applied onto Sephacryl S-200, each synthetase was eluted together with a tripolyphosphatase. The activities of these isozymes in synthesizing AdoMet and in hydrolyzing tripolyphosphate decreased in parallel with increasing amounts of rabbit anti-(beta-form) IgG. The activity of the beta-form isozyme was markedly stimulated by the addition of tripolyphosphate, whereas that of the alpha-form isozyme was inhibited. The tripolyphosphatase activity of both the alpha- and the beta-form was markedly stimulated by the addition of AdoMet. The tripolyphosphatases of each isozyme showed some other similar properties.


Characterization of the DNA binding activity of stable RecA-DNA complexes. Interaction between the two DNA binding sites within RecA helical filaments.
The DNA-binding, annealing and recombinational activities of purified RecA-DNA complexes stabilized by ATP gamma S (a slowly hydrolysable analog of ATP) are described. Electrophoretic analysis, DNase protection experiments and observations by electron microscopy suggest that saturated RecA complexes formed with single- or double-stranded DNA are able to accommodate an additional single strand of DNA with a stoichiometry of about one nucleotide of added single-stranded DNA per nucleotide or base-pair, respectively, of DNA resident in the complex. This strand uptake is independent of complementarity or homology between the added and resident DNA molecules. In the complex, the incoming and resident single-stranded DNA molecules are in close proximity as the two strands can anneal in case of their complementarity. Stable RecA complexes formed with single-stranded DNA bind double-stranded DNA efficiently when the added DNA is homologous to the complexed strand and then initiate a strand exchange reaction between the partner DNA molecules. Electron microscopy of the RecA-single-stranded DNA complexes associated with homologous double-stranded DNA suggests that a portion of duplex DNA is taken into the complex and placed in register with the resident single strand. Our experiments indicate that both DNA binding sites within RecA helical filaments can be occupied by either single- or double-stranded DNA. Presumably, the same first DNA binding site is used by RecA during its polymerization on single- or double-stranded DNA and the second DNA binding site becomes available for subsequent interaction of the protein-saturated complexes with naked DNA. The way by which additional DNA is taken into RecA-DNA complexes shows co-operative character and this helps to explain how topological problems are avoided during RecA-mediated homologous recombination.


Genotype and retention of the ejaculatory reflex in castrated male mice.
Genotype proves to be an important factor affecting the retention of sexual responsiveness following castration. Male F1 hybrids between C57BL/6 females and DBA/2 males (B6D2F1) show very prolonged retention. Experiment 1 used a diallelic design using C57BL/6, DBA/2 and BALB/c strains and showed that heterosis per se is not an adequate explanation of the superior retention of the B6D2F1 genotype. Experiment 2 showed that neonatal injections of 100 mug TP to B6D2F1 male mice did not result in better retention of the ejaculatory reflex after castration in adulthood. B6D2F1 males from both experiments who exhibited the ejaculatory reflex for many months after castration went through a 'difficult period' in the first 10 to 12 postcastration weeks. During this time, ejaculation latency increased fourfold, and then returned to the original level. On the other hand, the proportion of males reaching the ejaculatory threshold during this period first declined then increased.


Collagenase inhibitors from Viola yedoensis.
Fractionation of acetone and methanol extracts of Viola yedoensis, under the guidance of inhibition against Clostridium histolyticum collagenase (ChC), resulted in the isolation of esculetin (1) (IC(50) 12 μM) and scopoletin (2) (IC(50) 1.8 μM) as the active constituents, together with trans-p-coumaric acid (3), cis-p-coumaric acid (4), 3-O-β-D-glucosyl-7-O-α-L-rhamnosylkaempferol (5), rutin (6), isovitexin (7), isoorientin (8), vicenin-2 (9), isoscoparin (10), vanillic acid (11) and adenosine (12). Modification of phenolic hydroxy groups of 1 showed that small O-alkyl groups largely increased the activity, whereas larger O-alkyl groups decreased the activity, and 6,7-dimethoxycoumarin (scoparone 13) potently inhibited ChC (IC(50) 24 nM).