Studying rod photoreceptor development in zebrafish.
The zebrafish has rapidly become a favored model vertebrate organism, well suited for studies of developmental processes using large-scale genetic screens. In particular, zebrafish morphological and behavioral genetic screens have led to the identification of genes important for development of the retinal photoreceptors. This may help clarify the genetic mechanisms underlying human photoreceptor development and dysfunction in retinal diseases. In this review, we present the advantages of zebrafish as a vertebrate model organism, summarize retinal and photoreceptor cell development in zebrafish, with emphasis on the rod photoreceptors, and describe zebrafish visual behaviors that can be used for genetic screens. We then describe some of the photoreceptor cell mutants that have been isolated in morphological and behavioral screens and discuss the limitations of current screening methods for uncovering mutations that specifically affect rod function. Finally, we present some alternative strategies to target the rod developmental pathway in zebrafish.


The Persian version of Community Integration Questionnaire in persons with multiple sclerosis: translation, reliability, validity, and factor analysis.
To culturally translate and validate the Community Integration Questionnaire (CIQ) in persons with multiple sclerosis (MS). After a forward-backward translation, 105 persons with MS completed the Persian versions of the CIQ and MS Quality of Life (MSQOL) questionnaires in the first visit. The CIQ was re-administered to a sample of 45 persons with MS 7-10 days after the first session. Test-retest reliability and internal consistency were assessed using intraclass correlation coefficient (ICC) and Cronbach's α coefficient, respectively. Construct validity was assessed by measuring associations between subscales of the Persian CIQ (including Home Integration (HI), Social Integration (SI), and Productivity (P)) and MSQOL (including Physical and Mental Components). Dimensionality was assessed through two methods of corrected item-subscale correlation and factor analysis. The acceptable level of test-retest reliability (ICC ≥0.70) was obtained for the Persian CIQ. However, Cronbach's α coefficient of ≥0.70 was only seen for the HI. The correlations between the Persian CIQ and the Physical MSQOL were higher than those of Persian CIQ and the Mental MSQOL. The corrected item-subscale Spearman's correlation coefficient of 0.40 was exceeded by most items of the HI and 2 items of P. A total of four factors were detected and similar to the results of item-subscale correlation, the most variability was seen for the items of SI which loaded on different factors. Persian CIQ seems to be a reliable and valid instrument for monitoring the level of community integration following rehabilitation in persons with MS. Some modifications need to be made in the SI of the Persian CIQ to improve extraction of information regarding community integration of persons with MS.


Cerebrovascular Correlates of Subclinical Attentional Disturbances in Non-stroke Cardiovascular Disease.
Evidence suggests that cerebrovascular hemodynamic disturbances underlie cognitive deterioration secondary to cardiovascular disease (CVD), including manifestations other than stroke, but the mechanisms remain unclear. To date, the majority of studies have used neuropsychological measures validated for the detection of clinically significant cognitive decline but lack the sensitivity to accurately detect subclinical or subtle cognitive changes. The N2 and P3 components of the event-related potential are sensitive markers of attention and cognitive processing, and are valuable in the assessment of age-related cognitive changes and neurodegenerative disease. The aims of this study were to test (a) the sensitivity of N2 and P3 components in differentiating older adults with CVD from healthy controls, and (b) whether cerebrovascular hemodynamics are associated with alterations in attention in persons with non-stroke CVD. Older adults with CVD (n = 20) and healthy older adults (n = 20) without cognitive impairment or history of stroke and matched for age, were recruited. Cerebral blood flow velocity of the middle cerebral artery (MCAv) and Gosling's Pulsatility Index (PI) were assessed using Transcranial Doppler ultrasound (TCD). ERPs were elicited using a two-tone auditory oddball task. N2 amplitude was significantly reduced in the CVD group at midline frontal, central and parietal sites (p < .05, d > 0.6). No significant group differences were observed in N2 latency, P3 amplitude, or P3 latency. Further, MCAv and PI were strongly associated with N2 amplitude in the CVD group, such that greater MCAv was associated with reductions in N2 amplitude (b = -0.58, p = .018), whilst PI was associated with increases in N2 amplitude (b = 0.66, p = .006). No relationships between MCAv or PI with N2 or P3 ERP components were observed in the healthy control group. The data reported here suggest that a reduction in N2 amplitude may be an important objective indicator of subclinical cognitive and attentional alterations in non-stroke CVD, and support the notion that cerebrovascular hemodynamic disturbances play a role in the pathogenesis of cognitive deterioration secondary to non-stroke CVD.


Comparison of 90-day complication rates and readmissions of primary total elbow arthroplasty in elective and traumatic cases: a single center experience.
The purpose of this study is to compare the 90 day complication rates of primary Total Elbow Arthroplasty (TEA) performed for arthritis (primary-OA; rheumatoid arthritis-RA) versus those performed for distal humerus fractures (DHF). Patients who underwent a TEA from 2015 to 2021 were identified from our institutional database and placed into cohorts based on surgical indications (TEA-OA, TEA-RA and TEA-DHF). Chart review was conducted to analyze the prevalence of complications, emergency department (ED) visits, readmissions, and secondary procedures in the first 90 day post-operative period. Complications included but were not limited to wound complications, hematoma, infection (superficial or deep), nerve palsy, periprosthetic fracture/failure and others. 49 patients who underwent TEA were included in this study: (DHF = 19, OA = 14, RA = 16). Six complications occurred within the first 90 days of surgery. There were two periprosthetic joint infections (PJI) in the OA group, requiring irrigation and debridement (I & D) within the first 90 days of surgery. There were three post-operative ulnar nerve palsies and one PJI requiring I & D in the TEA-RA group. Compared to the TEA-DHF and TEA-OA groups, the RA group had higher rates of all-cause complications (p = 0.03) and nerve palsy (p = 0.03). There were no significant differences between groups in readmissions (p = 0.27) or secondary interventions (p = 0.27). The 90-day complication/readmission rates of TEA preformed for DHFs is lower than those preformed for OA and RA. These differences could be related to the underlying chronic inflammatory etiology and side effect of treatments (intraarticular steroid injection, and biologics) received by patients with arthritis. Retrospective Cohort Study, level IV.


Third-generation cephalosporins and vancomycin as risk factors for postoperative vancomycin-resistant enterococcus infection.
To examine use of third-generation cephalosporins (3GCs) alone and in association with vancomycin hydrochloride as a risk factor for vancomycin-resistant enterococcus (VRE) infection in surgical patients. Case-control retrospective study analyzing antibiotic use in the 30 days preceding culture of VRE or vancomycin-sensitive enterococcus from an infected site. A large tertiary care teaching hospital. Surgical inpatients with VRE infections between September 3, 1993, and January 29, 1997, were matched with patients with vancomycin-sensitive enterococcus infections. Matches were based on surgical procedure, initial infection site, and immunosuppression. Matches were found for 32 of 50 surgical patients with VRE. Twenty matched pairs of patients were recipients of solid organ transplants. Multivariate logistic regression analysis was done to examine 3GCs and vancomycin as risk factors for VRE infection. Univariate analysis of use of other antibiotic agents and demographic data was also performed. Multivariate analysis showed significant differences in the use of 3GCs both alone and concurrently with vancomycin. Univariate analysis also showed higher use of metronidazole, concurrent vancomycin and metronidazole, concurrent vancomycin and ceftazidime, and all antibiotics combined in patients with VRE infections. This matched control study showed that use of 3GCs, alone (P=.05) or concurrently with vancomycin (P=.05), was a risk factor for VRE infection in surgical patients. Judicious administration of third-generation antibiotics is warranted in surgical patients with other risk factors for VRE.


Adolescent's stress responses and psychological functioning when a parent has early breast cancer.
To identify factors associated with psychological functioning in adolescent children of early-stage breast cancer patients. Adolescents' self-reported psychological functioning using the Child Behaviour Checklist (YSR), Mental Health subscale of the Child Health Questionnaire (CHQ-MH) and Child Impact of Events (C-IES) scale. The Family Assessment Device (FAD) and the Family Environment Scale (FES cohesion subscale) assessed family functioning. Maternal depression was assessed on the Beck Depression Inventory (BDI) and quality of life using the SF8. Using a cross-sectional within-groups design, assessments were obtained for 56 adolescents of 11-17 years . High rates of stress were found (C-IES) in 33% males and 45% females. Thirty percent of adolescents reported psychological problems (YSR) (28% males and 32% females) when compared with published norms. Poor family functioning was linked with YSR internalising and externalising problems; poor family cohesion with higher externalising and total YSR psychological problems. Maternal depression was linked with adolescent-reported internalising problems. When mothers have breast cancer, a substantial minority of their adolescent children have psychological and stress response-related problems linked with poor family functioning. These results argue in favour of a family-oriented approach to psychological support of breast cancer patients.


Management of Percutaneous Coronary Intervention Complications.
With the recent increase in complex coronary interventions including percutaneous coronary intervention (PCI) for chronic total occlusions and complex higher risk (and indicated) patients, the spectrum of potential periprocedural complications and their prompt management has become even more relevant. Vascular access-related problems remain the most prevalent of all PCI complications and with randomized controlled trial data from over 20,000 patients supporting the superiority of radial over femoral access in reducing bleeding and vascular complications, a default radial strategy should be promoted. The European Society of Cardiology guidelines have acknowledged this by giving a class 1 (level of evidence: A) recommendation for a radial approach for PCI. The US society guidelines, however, have thus far lagged behind. Each individual patient undergoing a PCI should be risk-stratified objectively using available risk prediction models based on patient comorbidities and anatomical and procedural complexities. Customized informed consent should therefore be provided to all patients and should include the potential risks from radiation injury. Here, we review the current data related to common periprocedural complications related to PCI.


Effects of aromatherapy and music therapy on patients' anxiety during MRI examinations: a randomized controlled trial.
Many patients experience anxiety during MRI examinations. However, little attention has been focused on decreasing patient anxiety and minimizing on-site cancellations. Here, we aimed to investigate the effects of aromatherapy and music therapy on alleviating anxiety during MRI examinations. This single-center, double-blinded, randomized control trial was conducted between November 1, 2021, and January 10, 2022. Patients undergoing MRI examinations were assigned randomly into either the aromatherapy group (AG), music therapy group (MG), aromatherapy plus music therapy group (AMTG), or routine care group (RG) at a ratio of 1:1:1:1. Aromatherapy was conducted through inhalation of lavender oil. Music therapy was performed using Pachelbel's Canon in D major. The primary outcome was the change in anxiety before and after the MRI scan, assessed using both the State-Trait Anxiety Inventory form 1 (STAI-1) and Self-Rating Anxiety Scale (SAS). The second outcome was the participant's comfort, measured using Kolcaba's General Comfort Questionnaire (GCQ). A total of 200 participants (mean age: 48.3 ± 14.9 years; 126 [63.0%] females) were enrolled, with 50 per group. The mean anxiety scores of the AMTG showed greater reduction compared with the AG, MG, and RG (ΔSTAI-1: 6.5 vs 2.6 vs 2.7 vs 1.9, p < 0.001; ΔSAS: 4.0 vs 1.4 vs 1.7 vs 0.6, p < 0.001). The mean GCQ score of the AMTG was higher compared with the AG, MG, and RG (98.0 vs 92.6 vs 91.2 vs 89.2, respectively, p < 0.001). Aromatherapy combined with music therapy is effective for reducing patients' anxiety and improving their comfort level during MRI scans. • In this randomized control trial of 200 participants undergoing MRI scans, aromatherapy plus music therapy is effective in reducing STAI-1 and SAS, as well as improving GCQ scores. • Although there was a significant difference between the aromatherapy plus music therapy and the single-intervention modalities, no significant differences were observed between the aromatherapy and music therapy themselves for state anxiety and comfort score. • Aromatherapy plus music therapy is a safe, non-invasive, nonpharmacological, and inexpensive patient-centered intervention for reducing anxiety and improving comfort in adults undergoing MRI examinations.


A novel method for freezing and storing research tissue bank specimens.
Preserving small pieces of frozen tissue for possible future ancillary studies ("tumor banking") usually involves either placing a small piece of tissue in a cryovial and snap freezing it in liquid nitrogen or embedding and freezing the tissue in a block of cryopreservation medium, such as optimal cutting temperature (OCT) compound. The cryovial storage method leaves an irregularly shaped piece of tissue frozen to the side of the plastic vial, where it is exposed to air, subject to desiccation ("freezer burn"), and difficult to remove, but the vials are easy to store. The OCT method results in good morphological preservation, but yields a large awkwardly stored block from which it may be difficult to locate and recover small specimens. We have proposed a novel method of storing tissue bank specimens, the "capsule-freeze" method, which combines the advantages of OCT specimen preservation with those of cryovial specimen storage. Using this method, a tissue specimen is "snap-frozen" in OCT within a size "00" VCap pharmaceutical capsule, then the capsule is stored within a 1.5-mL cryovial. The specimen is harvested by simply cutting a slice out of the capsule and sealing the cut ends with OCT before their return to the freezer. The slice is then embedded en face within an OCT block before frozen sectioning. Morphological preservation is excellent, and the capsules are very easy to store. Occasional cracking that we found with the use of gelatin capsules is greatly diminished with the use of VCaps cellulose-walled capsules. The OCT can be easily removed by rinsing in cold 70% ethanol solutions. This method of tissue storage is ideal for the small specimens that are now commonly archived in these days of tissue sparing surgery.


Effectiveness of bulking agents for co-composting penicillin mycelial dreg (PMD) and sewage sludge in pilot-scale system.
Penicillin mycelial dreg (PMD) has a distinguishing characteristic of the high content of penicillin residue and nutrients. The existing handling of PMD used as feed additive of livestock and poultry is facing a direct challenge of penicillin transportation into environment due to the inadequate absorption through the digestive system. This work aims at examining the feasibility of co-composting of PMD with sewage sludge (SWS) in a pilot-scale system and evaluating the effect of four bulking agents. Seven treatments were co-composted over a 32-day period in 390-L reactors using the same PMD and SWS with different bulking agents, corresponding to the seven formulas (T-1: PMD + SWS + RS; T-2: PMD + SWS + WS; T-3: PMD + SWS + RS + SD; T-4: PMD + SWS + WS + SD; T-5: PMD + SWS + SD; T-6: PMD + SWS + RS + WS; control: PMD + SWS). The parameters monitored over this period included temperature, organic matter (OM), TN, NH4(+)-N, NO3(-)-N, pH, EC, penicillin residue, as well as germination index (GI). The results showed that co-composting PMD and SWS with BA is feasible. The highest rate of OM mineralization was observed in T-3, while below 30% for T-2, T-4, and T-5. Furthermore, the SD addition resulted in both the increase in the duration of thermophilic stage and maximum temperature and the decrease in TN losses, particularly in T-3, suggesting that the formula of the T-3 is very suitable option for the co-composting of PMD and SWS.


Histones are incorporated in trans during reassembly of the yeast PHO5 promoter.
In yeast, remodeling of PHO5 promoter chromatin upon activation is accompanied by transient hyperacetylation and subsequent eviction of histones from the promoter in trans. In the course of rerepression, nucleosomes have to be reassembled on the promoter. We have analyzed where the histones for reassembly of the inactive promoter chromatin come from. The use of a strain with two differently tagged and differently regulated versions of histone H3 allowed us to discriminate between histones originating from the chromatin fraction and histones arising from the soluble histone pool. In this way, we show that the incorporated histones originate from a source in trans. Promoter closure occurs very rapidly, and the histone chaperones Asf1 and Hir1 as well as the SWI/SNF nucleosome remodeling complex appear to be important for rapid reassembly of nucleosomes at the PHO5 promoter.


Understanding the Transcriptomic Landscape to Drive New Innovations in Musculoskeletal Regenerative Medicine.
RNA-sequencing (RNA-seq) is a novel and highly sought-after tool in the field of musculoskeletal regenerative medicine. The technology is being used to better understand pathological processes, as well as elucidate mechanisms governing development and regeneration. It has allowed in-depth characterization of stem cell populations and discovery of molecular mechanisms that regulate stem cell development, maintenance, and differentiation in a way that was not possible with previous technology. This review introduces RNA-seq technology and how it has paved the way for advances in musculoskeletal regenerative medicine. Recent studies in regenerative medicine have utilized RNA-seq to decipher mechanisms of pathophysiology and identify novel targets for regenerative medicine. The technology has also advanced stem cell biology through in-depth characterization of stem cells, identifying differentiation trajectories and optimizing cell culture conditions. It has also provided new knowledge that has led to improved growth factor use and scaffold design for musculoskeletal regenerative medicine. This article reviews recent studies utilizing RNA-seq in the field of musculoskeletal regenerative medicine. It demonstrates how transcriptomic analysis can be used to provide insights that can aid in formulating a regenerative strategy.


HLA DR and DQ expression on human retinal pigment epithelial cells in vitro.
In a previous immunohistopathological study, we demonstrated a deviant expression of class II antigens on the uveal pigment epithelial cells of patients with proliferative diabetic retinopathy. The mechanisms triggering this abnormal expression by epithelial cells are not well known, and we tried to induce this phenomenon on primary cultures of human retinal pigment epithelial (RPE) cells. Confluent RPE-cell monolayers were supplemented with several biological or chemical reagents [recombinant interferon gamma, phytohemagglutinin A-P (PHA-P), phorbol-myristate acetate (PMA), recombinant interleukin-2, fibroblast growth factor (FGF), Insulin], to investigate their ability to induce HLA DR and DQ expression. On days 1, 3 and 5 after stimulation, the cells were incubated with monoclonal antibodies directed against human class II antigens: all reagents used failed to induce class II antigen: all reagents used failed to induce class II antigen expression. However, on day 7, we demonstrated the presence of numerous positive HLA DR and HLA DQ cells stimulated by gamma interferon, the percentages being closely related to the dose of this lymphokine. These findings, together with those of other investigators and our previous work on uveal pigmented epithelial cells in diabetic patients, may shed light on the exact implication of RPE in many poorly documented ocular diseases.


Improved compact representation method for Monte Carlo phase spaces.
Phase space files used in particle Monte Carlo simulations can be large, and thereby awkward to distribute and slow to load into memory. To circumvent this, compact source models and phase space representations have been developed. In this study, the aim is to increase the versatility of a previously presented method, based on principal component analysis whitening, by evaluating several modifications to the method on simulated cone-beam computed tomography projection images. Scaling the phase space components before whitening was seen to give the largest improvement and allowed for accurate modelling of phase spaces with a shifted detector and/or a bowtie filter present, configurations where the original method struggled. The modified method reproduced results using the original phase space to within a few percent both in energy fluence on the detector and in simulated projection and scatter images of a patient pelvis, without obvious position-dependence of the errors. Hence, the modified method was deemed sufficiently accurate for most applications relying on cone-beam computed tomography simulations. The final aim is to use the more versatile method for a broader range of phase space-based applications such as linear accelerator beam simulations and room shielding calculations.


Laryngeal paracoccidioidomycosis presenting as solitary true vocal fold disease.
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis or P. lutzii. It is a neglected tropical infectious disease that poses a major public health burden in endemic areas of Latin America. Mucosae of the upper digestive and respiratory tracts are commonly involved and many patients have disease at multiple mucosal sites, with or without lung involvement. Mucosal PCM presenting as solitary true vocal fold disease is relatively rare. We present the case of a 67-year-old Brazilian forest guard who presented with a 6-month history of hoarseness and globus pharyngeus due to a solitary left true vocal fold infiltration and vegetation diagnosed as PCM. Silent pulmonary disease was also present. A laryngoscopy video is offered as supplemental material to this report. He completely remitted after surgical removal and amphotericin B deoxycholate treatment.


3D visualization of epidermal Langerhans cells.
Langerhans cells (LCs) are intraepidermal dendritic cells that extend their dendrites between keratinocytes to form a dense network that covers the entire body. The mammalian epidermis has two diffusion barriers, the stratum corneum and tight junctions (TJs). In their resting state, LCs sit underneath these two barriers. Once activated, LCs elongate their dendrites to dock with, or penetrate through, TJs, which allows them to survey the environment between the two barriers. Here, we describe a method to visualize this dynamic interaction of TJs and LCs in 3D by using mouse ear epidermal sheets.


Linking public leadership with project management effectiveness: Mediating role of goal clarity and moderating role of top management support.
Grounding on social learning theory (SLT), this study examines the effect of public leadership on project management effectiveness (PME). Further, this study examines the mediating role of goal clarity and moderating role of top management support. Hierarchical linear regressions were used to investigate the relationships. PROCESS Hayes (2003) Model 7 was used for the moderation and mediation analysis. The data was collected from 322 Pakistani public sector developmental project employees. The results show that public leadership positively affects goal clarity (β = 0.049, p < 0.001) and project management effectiveness (0.032, p < 0.001). In addition, goal clarity mediates the association between public leadership and project management effectiveness (0.36, p < 0.001). Furthermore, the strength of the mediated relationship between public leadership and project management effectiveness (via goal clarity) depends on top management support. The indirect effect of public leadership on project management effectiveness is high when top management support is high (compared to low). The role of public leadership contributes significantly to the project's success. The project leader recognises, enlists, and promotes the organisation's core competencies, identifies, corrects, and controls key rigidities, places a high value on goal clarity, and continually lines up procedures with the project's overarching goals. Public leadership is crucial in project management effectiveness, especially in the public sector, where projects often involve multiple stakeholders, limited resources, and complex regulatory requirements. Effective public leadership ensures that projects are aligned with the organization's mission and goals and carried out efficiently, on time, and within budget.


A new method of alternating shooting of two different seismic sources for deep geophysical surveys.
In the latest geophysical survey crossing the Ninety East Ridge of the Indian Ocean, a new method was employed to perform proportional double seismic source excitation and synchronously receive signals from the sea surface and the seabed. The two seismic sources used for excitation were two sets of gun arrays with different energies and dominant frequencies, a G gun array and a Bolt gun array. The G gun array consisted of 3 G.II guns with a total capacity of 450 in3 and a dominant frequency of 20-100 Hz. The Bolt gun array consisted of 4 Bolt 1500LL air guns with a total capacity of 6000 in3 and a dominant frequency of 10-40 Hz. The seismic receiving system comprised a 480-channel seismic streamer towed from the sea surface and 21 ocean bottom seismometers (OBS). During offshore operations, the integrated navigation system produced equidistant trigger signals at an interval of 50 m. The trigger signals were distributed to the G gun array and Bolt gun array at a ratio of 3:1 after passing through a pulse signal proportional distributor. The two sets of gun arrays fired alternatingly at a given ratio. The receiving equipment on the sea surface and seabed simultaneously received the seismic signals excited by the two sets of gun arrays. After targeted data processing, in addition to the seismic profile generated by the conventional G gun seismic source, the deep seismic profile generated by the Bolt gun seismic source and the survey profile of the active-source OBS were obtained simultaneously. The penetration depths of the three sets of profiles reach 2 km, 6 km, and 30 km, respectively, greatly improving the efficiency of offshore deep-sea seismic surveys.


Utility of thin-layer preparations in the endometrial cytology: evaluation of benign endometrial lesions.
The purpose of the current study was to examine the use of thin-layer cytologic (TLC) preparation compared to conventional cytologic preparation (CCP) in the normal endometrium (proliferative, secretory, atrophic) and endometrial glandular and stromal breakdown (EGBD). During a 6-month period, we compiled 158 cases by collecting a direct endometrial sample using the Uterobrush. The material comprised 40 cases of proliferative endometrium, 42 cases of secretory endometrium, 46 cases of atrophic endometrium, and 30 cases of EGBD. The following points were investigated: (1) number of endometrial epithelial cell clumps; (2) presence of TLC > CCP cases on number of epithelial cell clumps; (3) number of condensed cluster of stromal cells; (4) presence of TLC > CCP cases on number of condensed cluster of stromal cells; (5) presence of metaplastic clumps with irregular protrusion-containing condensed stromal cluster; (6) presence of a clear background; (7) presence of blood vessel in TLC; (8) presence of blood vessel of length more than diameter of a field in object x20 glasses in TLC. (1) In all phases, the number of epithelial cell clumps per a unit area of a preparation of TLC is greater than in CCP. (2) Cells (condensed cluster of stromal cells and metaplastic clumps with irregular protrusion-containing condensed stromal cluster) of useful and adequate numbers for a diagnosis of EGBD were observed in TLC. (3) In all phases, TLC was significantly higher than CCP on the appearance of a clear background. (4) The proliferative endometrium and secretory endometrium were highly significant in comparison with atrophic endometrium and EGBD, respectively, in terms of the occurrence of a blood vessel of length more than diameter of a field in object x20 glasses. Although the preparation area of TLC is smaller than that of CCP, the preparation has a clean background so that an accurate report on the patient's condition is possible. Therefore, TLC preparation is a useful tool for the accurate and reliable diagnosis of normal endometrial phase and EGBD, because the preparation area is confined and identification of the target cell clumps is easy.


Predominant cytosolic distribution of serotonin in rat pineal gland in contrast to biogenic monoamine localization in midbrain and adrenal gland.
The subcellular distribution of serotonin and norepinephrine in the rat pineal gland was studied by tissue fractionation and compared with that of biogenic monoamines in the adrenal gland and midbrain. Homogenized tissues were fractionated by ultracentrifugation or by filtration through cellulose ester membranes. Most of the epinephrine (70-80%) and norepinephrine (62-82%) present in the adrenal glands was detected in the particulate fraction. The same distribution was found for serotonin (68.5%) and norepinephrine (59%) in the midbrain and for norepinephrine (62.5%) in the pineal gland. However, most of the serotonin in the pineal was found in the soluble fraction (89.5-98%). This suggests that the great majority of serotonin in the rat pinealocytes is cytosolic and thus is not stored in subcellular vesicles, in contrast to the biogenic monoamines in the midbrain or adrenal gland.


Reversibility of chronic alcohol cardiac depression: 31P magnetic resonance spectroscopy in hamsters.
In order to investigate the reversibility of chronic alcohol cardiac depression, hamsters were fed with 50% ethanol for 3 1/2 months, reaching serum alcohol levels of 0.13 +/- 0.11 g/dl (mean +/- SD). Alcohol was then withdrawn for 2 days. Isolated hearts were perfused according to a modified Langendorff method. Energy metabolites were studied using 31P magnetic resonance spectroscopy of isolated perfused hearts standardized by HPLC analysis of freeze-clamped tissue. Total intracellular calcium [Ca2+]i was measured with atomic absorption spectrophotometry, marking the extracellular space in vivo with K(CoEDTA). In alcohol-treated hamster hearts developed pressure was significantly depressed compared to controls. End-diastolic pressure was significantly increased. Coronary flow was not changed, whereas oxygen consumption and high-energy phosphate levels were significantly depressed. Intracellular pH was significantly decreased. [Ca2+]i was significantly increased. Heart weights were significantly lower. After alcohol withdrawal ventricular function, high-energy phosphate levels, and [Ca2+]i were not significantly different from control. The results indicate that chronic alcohol consumption depresses ventricular function and energy levels and also leads to myocardial acidosis. The increase in intracellular calcium likely causes mitochondrial dysfunction. Withdrawal of alcohol is associated with reversibility of functional and energetic cardiac depression.


Experimental coronary artery fistula.
Despite numerous clinical reports of coronary artery fistulas, there have been no laboratory models. A circumflex coronary-pulmonary artery fistula was constructed with a vein graft in 11 adult foxhounds. A temporary intravascular shunt obviated the need for cardiopulmonary bypass. Measurements of aortic flow, arterial pressure, left ventricular pressure and its derivative, heart rate, and flow in the proximal coronary, distal coronary, and fistula were made with the fistula open and closed in 9 animals. Mean fistula flow was 89 c.c. per minute, representing a 1.1:1 left-to-right shunt. Mean proximal coronary flow increased 211 per cent, and there was a relative steal of 26 per cent of distal coronary flow with the fistula functioning. Phasic flow patterns showed continuous systolic and diastolic flow in the proximal coronary artery and fistula. Despite the striking changes in coronary flow patterns, there was no significant effect on measured left ventricular function. Futher uses for this model and variations of it aresuggested.


[Genetic divergence of chars of the genus Salvelinus from Kronotsky Lake (Kamchatka Peninsula)].
Chars from the genus Salvelinus, inhabiting lakes and lake-river systems, belong to morphologically and ecologically different forms whose taxonomic status is under dispute. In the present work, we have examined genetic variation and divergence in various chars from the Kronotsky lake basin: the lacustrine chars (white, nose, and long-head) and Dolly Varden char Salvelinus malma. The study was conducted using analysis of allozyme and microsatellite loci, myogens, RAPD, and restriction analysis of two mtDNA segments. The estimates of heterozygoisty at allozyme and microsatellite loci were similar to the corresponding parameters in populations of northern Dolly Varden and Arctic char. Heterozygote deficit was recorded in both samples of individual forms, and in the combined sample of all chars from Kronotsky Lake. For both markers, appreciable genetic differentiation among the samples of different char forms was found, which was comparable to that among the spatially isolated populations of northern Dolly Varden. This result indicates reproductive isolation among the char forms examined. However, this isolation is not complete, because no fixed differences between the forms by any of the genetic systems analyzed was found. The genetic differentiation among different forms of lacustrine chars, which corresponds to the interpopulation rather than interspecies level, is thought to be explained by their comparatively recent divergence.


Singers' Vocal Function Knowledge Levels, Sensorimotor Self-awareness of Vocal Tract, and Impact of Functional Voice Rehabilitation on the Vocal Function Knowledge and Self-awareness of Vocal Tract.
This study investigated vocal function knowledge and vocal tract sensorimotor self-awareness and the impact of functional voice rehabilitation on vocal function knowledge and self-awareness. This is a prospective, randomized study. Twenty singers (study group [SG]) completed a questionnaire before and after functional voice rehabilitation. Twenty additional singers, representing the control group, also completed the questionnaire without functional voice rehabilitation at a 3-month interval. The questionnaire consisted of three parts. The first part evaluated the singers' attitude to the anatomical and physiological knowledge of the vocal tract and their self-esteem of the knowledge level. The second part assessed the theoretical knowledge of the singers' vocal tract physiology. The third part of the questionnaire assessed singers' sensorimotor self-awareness of the vocal tract. The results showed that most singers indicated that knowledge of the vocal tract's anatomy and physiology is useful (59% SG, 67% control group). However, 75% of all participants defined their knowledge of the vocal tract's anatomy and physiology as weak or inadequate. In the SG, vocal function knowledge at the first assessment was 45%. After rehabilitation, the level increased to 67.7%. Vocal tract sensorimotor self-awareness initially was 38.9% in SG but rose to 66.7%. Findings of the study suggest that classical singers lack knowledge about the physiology of the vocal mechanism, especially the breathing patterns. In addition, they have low sensorimotor self-awareness of their vocal tract. The results suggest that singers would benefit from receiving services from phoniatrists and speech-language pathologists during their voice training.


The effect of economical phenomenon on informal construction workers earnings within Covid-19 pandemic: A mixed method analysis.
The informal sector is an alternative to getting a job without special conditions such as education level or job skills. These informal workers are often found in the construction sector. Informal construction workers have no social protection and are economically marginalized, making their economy worse during the Covid-19 pandemic. This study investigates informal construction workers' economic phenomenon, from big cities in Java Island, Indonesia, when facing difficult situations due to the pandemic of Covid-19 with the mixed method. First, the quantitative method gathered the questionnaire from 225 informal workers in the construction sector who experienced a drastic reduction in their regular income, even weekly or monthly. They take advantage of savings and increase debt to cover the reduced income. Then, the qualitative method was conducted to investigate the informal construction worker's economical phenomenon with in-depth interviews with five foremen and five construction field managers. During the pandemic, government programs to provide income support for informal workers have contributed less to informal sector workers. Thus, the results of this research can be used by the government or other parties to help provide better social protection to informal sector workers from a more significant economic recession due to the pandemic.


Effect of aged garlic extract on APP processing and tau phosphorylation in Alzheimer's transgenic model Tg2576.
Multiple components present in garlic and various garlic preparations are known to exert pleiotropic protective effects as demonstrated in various in vitro and in vivo model systems. However, garlic pleiotropy in relation to Alzheimer's pathophysiology has not been explored extensively. Current study investigated anti-amyloidogenic, anti-inflammatory and anti-tangle effects of dietary aged garlic extract (AGE) (2%) and compared with its prominent constituents, i.e. S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS) (20 mg/kg) in Alzheimer's Swedish double mutant mouse model (Tg2576). Possible cholesterol-dependent and cholesterol-independent mechanisms of actions of AGE, SAC and DADS in exerting anti-amyloidogenic, anti-inflammatory and anti-tangle effects are discussed. Finally, ameliorative effects of dietary interventions were found to be in the order of AGE>SAC>DADS. If validated pre-clinically, dietary intervention with herbal alternative such as AGE having pleiotropic useful properties and least adverse effects may provide greater therapeutic benefit over a single-ingredient synthetic pharmaceutical drug having serious side effects in treating Alzheimer's disease.


beta-Casomorphins induce apnea and irregular breathing in adult rats and newborn rabbits.
Bovine beta-casomorphin, beta-casomorphin, morphiceptin or morphine were administered systemically (i.v. or i.p.) and intracerebroventricularly (lateral or IVth ventricles) to anesthetized adult rats and preterm newborn rabbits. All agents caused dose-related depressions of respiratory frequency and tidal volume. Morphiceptin and beta-casomorphin were approximately equipotent to morphine while beta-casomorphin was 10 times as potent after intracerebroventricular injection. The beta-casomorphins decreased inspiratory drive and prolonged the expiratory phase by delaying the setpoint for inspiration. A respiratory depression could be elicited by systemic administration of morphiceptin but not by beta-casomorphin or beta-casomorphin. All ventilatory effects induced by the beta-casomorphins could be readily reversed or prevented by naloxone. Intracerebroventricular but not intraperitoneal injection of beta-casomorphin depressed ventilation in preterm newborn rabbits in a similar pattern with apnoic periods to that seen in the adult rats. In addition, an irregular breathing pattern was elicited. Thus, the bovine beta-casomorphins possess potent central respiratory depressive effects. However, after systemic administration, only morphiceptin which is more metabolically stable induced a shortlasting effect on ventilation in adult rats.


Clinical results of the foraminotomy as described by Frykholm for the treatment of lateral cervical disc herniation.
During the period between 1980 and 1989, foraminotomy as described by Frykholm was performed on 230 patients suffering from lateral cervical disc herniation with exclusively radicular symptomatology. Following an average postoperative period of 3.5 years, the subjective alleviation of symptoms and the neurological symptomatology were examined in 161 patients. The mortality was nil; the morbidity was 5%, with a rapid full recovery in 4% of cases. In addition to the intra-operative findings of soft and hard disc lesions, a third group with combined findings was created. Excellent or good results were obtained in 98% of the patients with soft disc lesions, in 91% of the patients with combined findings, and in 84% of those with hard disc lesions. In 93% of the cases, there was a complete or marked improvement of paresis; in 82%, of the sensory deficits. A total of 92% of the patients were able to carry out their previous occupation to the full extent. The high efficacy of foraminotomy and the low incidence of complications described in previous studies was thereby confirmed.


Acute response of parathyroid hormone in congenital osteopetrosis.
Indices of calcium and phosphorus metabolism were studied in 3 children with osteopetrosis before and after infusion of bovine parathyroid hormone extract. Basal plasma concentrations of calcium, alkaline phosphatase and 25-hydroxy vitamin D tended to be low. Plasma immunoreactive PTH levels were at the upper normal range in two patients. A marked increase in urinary cyclic AMP in all patients was solely due to an increase in the nephrogenous cAMP. After vitamin D treatment urinary cAMP was essentially unchanged with the same preponderance of nephrogenous cAMP. Following PTH infusion plasma cAMP showed a brisk rise. There was also a prompt rise in urinary cAMP and a distinct decrease in the calcium to sodium clearance ratio indicating increased calcium reabsorption. Phosphaturic effect was only observed when PTH was given in the highest dose level. The findings are consistent with a state of low grade hyperparathyroidism which could not be related to the plasma levels of 25-hydroxy vitamin D or calcium.


Insulin-like growth factor I-dependent regulation of prolidase activity in cultured human skin fibroblasts.
Prolidase [E.C.22.214.171.124] is a cytosolic exopeptidase that catalyses the hydrolysis of C-terminal proline containing dipeptides or tripeptides. The enzyme plays an important role in the recycling of proline for collagen synthesis. Increase in enzyme activity is correlated with increased rates of collagen turnover but the mechanism and endpoints by which this enzyme is regulated remain largely unknown. We have found that insulin-like growth factor-I (IGF-I), potent stimulator of collagen biosynthesis, induces prolidase activity in cultured human skin fibroblasts. Supporting evidence comes from the following observations: (1) Serum of fasted rats, (IGF-I, 72 +/- 16 ng/ml) showed about 50% reduced ability to stimulate prolidase activity and collagen biosynthesis in confluent fibroblasts in comparison to the effect of control rat serum (IGF-I, 168 +/- 29). (2) An addition of IGF-I (100 ng/ml) to fasted rat serum restored its ability to stimulate prolidase activity and collagen biosynthesis to control values. (3) In confluent human skin fibroblasts, cultured for 48 h with serum free medium prolidase activity was decreased to 50% of control cells, cultured in the presence of normal rat serum. Supplementation of serum free medium with EGF, PDGF and IGF-I (factors that can replace growth promoting activity of serum) stimulated prolidase activity to control values while the medium deprived IGF-I had no such effect. (4) The relative differences in prolidase activity due to specific treatment of confluent cells with above growth factors were accompanied by parallel differences in the amount of the enzyme protein recovered from these cells as shown by western immunoblot analysis. Thus we conclude that prolidase activity is regulated by IGF-I in confluent fibroblasts.


Hyalomma anatolicum resistance against ivermectin and fipronil is associated with indiscriminate use of acaricides in southwestern Balochistan, Pakistan.
Ivermectin and fipronil have been used regularly to control the hard tick Hyalomma anatolicum (Acari: Ixodidae) in domestic ruminants for more than a half-decade in Balochistan, Pakistan. Inappropriate and indiscriminate use of these acaricides has resulted in the development of resistances in tick species. In this work, acaricides (ivermectin and fipronil) resistance was evaluated in H. anatolicum through in vitro and in vivo bioassays in a horse farm of Quetta, Balochistan province, Pakistan. A participatory epidemiological survey was conducted to assess potential risk factors associated with the development of acaricide resistance in H. anatolicum. The results of the epidemiological survey revealed that the horse keepers did not follow the manufacturer's instructions for the use of acaricides and applied indiscriminate doses of acaricides. The results of in vitro bioassays (adult immersion test and larval immersion test) showed that fipronil and ivermectin have protective efficacy against H. anatolicum. The results of in vivo bioassay (adult-tick mortality assay) revealed that fipronil had a higher efficacy (78.16%) than ivermectin (49.94%). More than 80% of tick mortality was not achieved in any bioassays, even for the highest acaricide concentration (100 ppm), which suggests the development of acaricide resistance against fipronil and ivermectin. This study highlights the urgency to implement a country-wide awareness about resistance monitoring and effective tick control. Graphical abstract.


Effects of hirami lemon, Citrus depressa Hayata, leaf meal in diets on the immune response and disease resistance of juvenile barramundi, Lates calcarifer (bloch), against Aeromonas hydrophila.
The present study was conducted to evaluate the dietary supplementation of leaf meal from Citrus depressa Hayata on the growth, innate immune response, and disease resistance of juvenile barramundi, Lates calcarifer. Four diets were formulated to contain 0% (control), 1% (C1), 3% (C3), and 5% (C5) leaf meal, respectively. During a 56 d feeding trial, fish survival, growth performance, and feed efficiency were not significantly different among all groups. For immune response, respiratory burst, superoxide dismutase and lysozyme activities were not significantly different among all groups. However, fish fed the C5 diet for 56 d had significantly higher phagocytic activity. Also, fish fed C3 and C5 diets had significantly higher Mx gene expressions in spleens and head kidneys with nerve necrosis virus injections after 24 h. Disease resistance against Aeromonas hydrophila was increased by the C5 diet. In this study, barramundi fed on a diet containing 5% C. depressa Hayata leaf meal had significantly better innate immune response and disease resistance against A. hydrophila.


Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.
Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.


Long-term outcome following surgery for colorectal cancers in octogenarians: a single institution's experience of 204 patients.
The incidence of colorectal cancer in elderly patients is likely to increase with an aging population. The aims of this study are to review our experience in the surgical management of octogenarians with colorectal cancers and to identify factors that influence the short-term and long-term outcomes. A retrospective review of all octogenarians who underwent surgery for colorectal cancer from December 2002 to October 2008 was performed. We identified 204 patients with a median age of 84 years (range, 80-97 years). The majority of patients had an American Society of Anesthesiologists score ≥3 (n = 142, 69.6%) and a Charlson Comorbidity Index of ≤3 (n = 128, 62.7%). Emergency surgery was performed in 83 (40.7%) patients. Left-sided malignancy was seen in 138 patients (67.6%). Most of the patients had either stage II (n = 75, 36.8%) or III (n = 69, 33.8%) diseases. The 30-day mortality rate was 16.2% (n = 33). After multivariate analysis, the independent variables predicting worse perioperative complications and death were age >85 years old, emergency surgery, and Charlson Comorbidity Index >3. The median follow-up for the 171 remaining patients was 27 months (range, 2-92 months). The 30-day readmission rate was 2.9% (n = 5). Thirty-one (21.2%) of 146 patients who survived curative surgery developed recurrent disease. Seventy (34.3%) patients died from various etiologies after their first 30 days postoperatively (60% cancer-specific with median survival of 15 months and 40% noncancer-related with median survival of 14 months). Overall and disease-free survivals were adversely affected in patients with advanced malignancy and in those with severe perioperative complications. Surgery for octogenarians with colorectal cancers is associated with significant morbidity and mortality rates which are associated with advanced age, emergency surgery, and Charlson Comorbidity Index >3. Long-term survival is dependent on the stage of the malignancy and the presence of severe perioperative complications.


Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration.
Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease progression can be managed, if not prevented, either by blocking neovascularization ("wet" form of AMD) or by preserving retinal pigment epithelium and photoreceptor cells ("dry" form of AMD). Although current therapeutic modalities are moderately successful in delaying the progression and management of the disease, advances over the past years in regenerative medicine using iPSC, embryonic stem cells, advanced materials (including nanomaterials) and organ bio-printing show great prospects in restoring vision and efficient management of either forms of AMD. This review focuses on the molecular mechanism of the disease, model systems (both cellular and animal) used in studying AMD, the list of various regenerative therapies and the current treatments available. The article also highlights on the recent clinical trials using regenerative therapies and management of the disease.


A distinct alleles and genetic recombination of pmrCAB operon in species of Acinetobacter baumannii complex isolates.
To investigate pmrCAB sequence divergence in 5 species of Acinetobacter baumannii complex, a total of 80 isolates from a Korean hospital were explored. We evaluated nucleotide and amino acid polymorphisms of pmrCAB operon, and phylogenetic trees were constructed for each gene of prmCAB operon. Colistin and polymyxin B susceptibility was determined for all isolates, and multilocus sequence typing was also performed for A. baumannii isolates. Our results showed that each species of A. baumannii complex has divergent pmrCAB operon sequences. We identified a distinct pmrCAB allele allied with Acinetobacter nosocomialis in gene trees. Different grouping in each gene tree suggests sporadic recombination or emergence of pmrCAB genes among Acinetobacter species. Sequence polymorphisms among Acinetobacter species might not be associated with colistin resistance. We revealed that a distinct pmrCAB allele may be widespread across the continents such as North America and Asia and that sporadic genetic recombination or emergence of pmrCAB genes might occur.


Timolol plus maximum tolerated antiglaucoma therapy: a one-year followup study.
Thirty-three eyes of 22 patients with primary open-angle glaucoma or severe ocular hypertension had topical timolol maleate added to their maximally tolerated medical regimens. With minimal side effects, 25 eyes (76%) could be treated medically for one year, and only eight eyes (24%) required filtering surgery. Thirteen (39%) of the medically treated eyes achieved intraocular pressures of 21 mm Hg or less. After the addition of timolol, 17 of the 33 eyes (52%) completed the one-year protocol with final mean intraocular pressure decreases of 5 mm Hg or more on medical therapy.


[Clinico-roentgenological characteristics of renal hemorrhage in hemophilia].
The observation over 20 cases of hemophilia with severe renal bleedings proved the possibility of rendering an effective surgical aid to these patients. Besides, on the grounds of the observations the authors concluded that in all the cases of hematuria and microhematuria constitute indications for x-ray examination of the kidneys and the urinary tract.


Predicting repetition of deliberate self-harm: a review of the literature in the light of a current study.
Three hundred and sixty-five patients exhibiting deliberate self-harm (DSH) were rated for DSH repetition on the six-item predictive scale of Buglass & Horton and on a five-point predictive scale developed from a previous study by the author. The Buglass & Horton scale was more sensitive and more specific overall and for female patients, but the five-point scale predicted better for males, especially those aged under 35. The results are discussed in relation to previous work on the prediction of DSH repetition.


Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis.
The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients' baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit-risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist.


Laparoscopic Resection of a Splenic Artery Aneurysm with Vascular Reconstruction During Pregnancy.
Splenic artery aneurysms (SAA) are more frequent in women and have a high rupture risk during pregnancy, with catastrophic outcomes. It is advisable to treat these aneurysms in pregnant and fertile women, whatever their diameter, given their increased risk for rupture. There are several therapeutic approaches: endovascular surgery using coil embolization or stent graft coverage; laparoscopic or open surgical resection with arterial reconstruction and ligation followed by splenectomy when necessary. This paper aims to report the successful treatment of SAA in second-trimester pregnant women using a laparoscopic approach with aneurysm resection and arterial reconstruction. This is a unique report of a minimally invasive approach with arterial reconstruction in a pregnant woman, thus reducing the risk of spleen infarction and potentially avoiding splenectomy.


Quantitative grading of nerve fiber layer photographs.
The authors have developed a simple method for semi-quantitative grading of atrophy of the peripapillary nerve fiber layer (NFL) in black and white photographs. An experienced observer read sets of NFL photographs using a four-level grading system. Five observers with varying levels of experience at ophthalmic examination were taught the grading system in approximately 4 hours, and their readings were compared with those of the expert. The reproducibility of readings by an experienced observer was excellent. The validity of the grading system was confirmed by comparisons to visual field findings, as well as to cup-to-disc ratios in the same eyes. The agreement with the expert by the five trained graders was good. Grading of the NFL could be useful both to monitor development of early glaucoma damage clinically and to measure progression of glaucoma damage in clinical trials research. The grading system can be taught readily to other observers.


Drug-polyester conjugated nanoparticles for cancer drug delivery.
We report here the synthesis of camptothecin-polylactide conjugate via camptothecin-initiated lactide polymerization and the formation of nanoconjugates for drug delivery applications.


Gonadotropin receptors: role of post-translational modifications and post-transcriptional regulation.
This review focuses on the post-translational modifications of LH and FSH receptors and recent studies on the regulation of LH receptor expression mediated by an RNA binding protein. Both LH and FSH receptors undergo extensive post-translational modifications. N-linked glycosylation occurs co-translationally and plays a role in the maturation and processing of the receptor, while palmitoylation is involved in receptor endocytosis and post-endocytic trafficking. A third type of post-translational modification is phosphorylation and its function has been reviewed. Finally, the regulation of LH receptor at the mRNA level by an RNA binding protein is discussed in the context of ovarian function.


Perception of syllable stress in esophageal speech.
This study is part of a larger investigation designed to assess the ability of esophageal speakers to effect systematic changes in listener perceptions of syllable stress. Ten male functional esophageal speakers and ten normal speakers were instructed to produce 25 repetitions of the disyllable/mama/ using five different conditions of syllable stress, ranging from strong first syllable stress through strong second syllable stress. Nine normal listeners judged both relative and absolute syllable stress of the disyllables, using a nine-point scale for each syllable. The results indicated that highly reliable judgments can be made when judging relative and absolute syllable stress in disyllables produced by both normal and esophageal speakers. In response to experimenter direction, both normal and esophageal speakers are able to effect systematic changes of direction and degree in listener perceptions of relative stress.


Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression.
To understand how neural-immune-associated genes and pathways contribute to neurodegenerative disease pathophysiology, we performed a systematic functional genomic analysis in purified microglia and bulk tissue from mouse and human AD, FTD, and PSP. We uncover a complex temporal trajectory of microglial-immune pathways involving the type 1 interferon response associated with tau pathology in the early stages, followed by later signatures of partial immune suppression and, subsequently, the type 2 interferon response. We find that genetic risk for dementias shows disease-specific patterns of pathway enrichment. We identify drivers of two gene co-expression modules conserved from mouse to human, representing competing arms of microglial-immune activation (NAct) and suppression (NSupp) in neurodegeneration. We validate our findings by using chemogenetics, experimental perturbation data, and single-cell sequencing in post-mortem brains. Our results refine the understanding of stage- and disease-specific microglial responses, implicate microglial viral defense pathways in dementia pathophysiology, and highlight therapeutic windows.


INDETERMINATE DOMAIN PROTEIN binding sequences in the 5'-untranslated region and promoter of the SCARECROW gene play crucial and distinct roles in regulating SCARECROW expression in roots and leaves.
SCARECROW (SCR) and SHORT-ROOT (SHR), which belong to the GRAS transcription factor family, are key regulators of root and leaf growth and development. Despite the importance of SCR expression for proper plant development, the mechanism of SCR regulation has not been clarified. A previous study showed that an INDETERMINATE DOMAIN transcription factor, JACKDAW (JKD), is essential for the expression of SCR in combination with SCR and SHR. In this study, we characterized possible binding sequences of INDETERMINATE DOMAIN PROTEIN in the 1.5 kb upstream region of SCR. Mutation in a binding sequence 340 bp upstream of the ATG increased transcriptional activation by JKD in transient assays using Arabidopsis cultured cells. However, the activity was not enhanced by SCR/SHR. Histochemical analysis of promoter activity in transgenic Arabidopsis plants carrying a fusion of the promoter and the β-glucronidase reporter gene showed that mutation of the -340 bp sequence eliminated most of the promoter activity, indicating that this sequence was indispensable for SCR expression. Promoter deletion of downstream sequences from -280 bp lost the enhanced activity by SCR/SHR in transient assays and activity in root tips and the bundle sheath (BS) in plants. Conversely, mutation at -480 bp did not significantly influence transcriptional activity in transient assays. However, most of SCR expression was lost except for the root tip in plants. The sequences around -1 kb appeared to regulate SCR expression negatively in plants. Together, these INDETERMINATE DOMAIN PROTEIN binding sequences have crucial and distinct functions in regulating SCR expression.


Automated patient-robot assignment for a robotic rehabilitation gym: a simplified simulation model.
A robotic rehabilitation gym can be defined as multiple patients training with multiple robots or passive sensorized devices in a group setting. Recent work with such gyms has shown positive rehabilitation outcomes; furthermore, such gyms allow a single therapist to supervise more than one patient, increasing cost-effectiveness. To allow more effective multipatient supervision in future robotic rehabilitation gyms, we propose an automated system that could dynamically assign patients to different robots within a session in order to optimize rehabilitation outcome. As a first step toward implementing a practical patient-robot assignment system, we present a simplified mathematical model of a robotic rehabilitation gym. Mixed-integer nonlinear programming algorithms are used to find effective assignment and training solutions for multiple evaluation scenarios involving different numbers of patients and robots (5 patients and 5 robots, 6 patients and 5 robots, 5 patients and 7 robots), different training durations (7 or 12 time steps) and different complexity levels (whether different patients have different skill acquisition curves, whether robots have exit times associated with them). In all cases, the goal is to maximize total skill gain across all patients and skills within a session. Analyses of variance across different scenarios show that disjunctive and time-indexed optimization models significantly outperform two baseline schedules: staying on one robot throughout a session and switching robots halfway through a session. The disjunctive model results in higher skill gain than the time-indexed model in the given scenarios, and the optimization duration increases as the number of patients, robots and time steps increases. Additionally, we discuss how different model simplifications (e.g., perfectly known and predictable patient skill level) could be addressed in the future and how such software may eventually be used in practice. Though it involves unrealistically simple scenarios, our study shows that intelligently moving patients between different rehabilitation robots can improve overall skill acquisition in a multi-patient multi-robot environment. While robotic rehabilitation gyms are not yet commonplace in clinical practice, prototypes of them already exist, and our study presents a way to use intelligent decision support to potentially enable more efficient delivery of technologically aided rehabilitation.


Ionic liquid-regenerated macroporous cellulose monolith: Fabrication, characterization and its protein chromatography.
Macroporous cellulose monolith as chromatographic support was successfully fabricated from an ionic liquid dissolved cellulose solution by an emulsification method and followed by the cross-linking reaction and DEAE modification. With the physical characterization, the cellulose monolith featured by both the interconnected macropores in range of 0.5-2.5μm and the diffusion pores centered at about 10nm. Given the bimodal pore system, the monolith possessed the specific surface area of 36.4m2g-1 and the column permeability of about 7.45×10-14m2. After the DEAE modification, the anion cellulose monolith was evaluated for its chromatography performances. It demonstrated that the static and dynamic adsorption capacity of BSA reached about 66.7mgmL-1 and 43.9mgmL-1 at 10% breakthrough point, respectively. The results were comparable to other chromatographic adsorbent. In addition, the proteins mixture with different pI was well separated at high flow velocity (611.0cmh-1) and high protein recovery (over 97%), proving the macroporous cellulose monolith had excellent separation performance. In this way, the prepared cellulose monolith with bimodal pores system is expected for the potential application in high-speed chromatography.


BuOH fraction of Salix Babylonica L. extract increases pancreatic beta-cell tumor death at lower doses without harming their function.
Salix babylonica L. is a species of the willow tree. Insulinoma is a tumor originating from pancreatic beta cells. This study aims to research the effect of different fractions of Salix babylonica L. leaf extract on INS-1 cells for treating pancreatic tumors. Cell death occurred at lower doses in the EtOAc fraction. The cells are functional in the BuOH fraction but not in EtOAc and H2O fractions. The EtOAc fraction has a higher percentage of necrosis and ROS. INS1, INS2, and AKT gene expressions in the H2O fraction, GLUT2, IR, HSP70 gene expressions, and WNT4 protein levels increased in the BuOH fraction. HSP90 gene expression, Beta-actin, GAPDH, insulin, HSP70, HSP90, HSF1, Beta-Catenin, and WNT7A protein levels were decreased, while IR immunolabelling intensity increased in both fractions. Ca+2, K+, Na+, and CA-19-9 in the cell, Ca+2 and K+ in secretion increased. The secondary metabolites in the EtOAc fraction cause more damage in INS-1 cells. Since the water fraction also causes the cells to die in high doses, cell function is damaged. The secondary metabolites in the BuOH fraction kill INS-1 cells with less damage. This makes the BuOH fraction of Salix babylonica L. more valuable.


AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C.
Type 4C Charcot-Marie-Tooth (CMT4C) demyelinating neuropathy is caused by autosomal recessive SH3TC2 gene mutations. SH3TC2 is highly expressed in myelinating Schwann cells. CMT4C is a childhood-onset progressive disease without effective treatment. Here, we generated a gene therapy for CMT4C mediated by an adeno-associated viral 9 vector (AAV9) to deliver the human SH3TC2 gene in the Sh3tc2-/- mouse model of CMT4C. We used a minimal fragment of the myelin protein zero (Mpz) promoter (miniMpz), which was cloned and validated to achieve Schwann cell-targeted expression of SH3TC2. Following the demonstration of AAV9-miniMpz.SH3TC2myc vector efficacy to re-establish SH3TC2 expression in the peripheral nervous system, we performed an early as well as a delayed treatment trial in Sh3tc2-/- mice. We demonstrate both after early as well as following late treatment improvements in multiple motor performance tests and nerve conduction velocities. Moreover, treatment led to normalization of the organization of the nodes of Ranvier, which is typically deficient in CMT4C patients and Sh3tc2-/- mice, along with reduced ratios of demyelinated fibers, increased myelin thickness and reduced g-ratios at both time points of intervention. Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment.


Clopidogrel therapy in patients undergoing coronary stenting: value of a high-loading-dose regimen.
The objective of this study was to assess the value of a clopidogrel regimen based on a high loading dose initiated before the stent placement procedure. A consecutive series of 864 patients treated with a high-loading-dose clopidogrel regimen (600 mg given 2-4 hr prior to intervention) was compared with 870 patients treated with conventional ticlopidine therapy. Abciximab was given periprocedurally in 62% of the patients. The composite endpoint of death, myocardial infarction, or urgent revascularization was reached by 39 (4.5%) clopidogrel patients and 59 (6.8%) ticlopidine patients. Clopidogrel therapy was associated with a 35% reduction of the risk for early adverse events (odds ratio 0.65; 95% confidence interval, 0.43-0.98). Thus, a high-loading-dose clopidogrel regimen in patients undergoing coronary artery stenting was safe and led to a more favorable clinical outcome than conventional therapy with ticlopidine regardless of concomitant treatment with abciximab.


Wideband and Large Angle Electromagnetically Induced Transparency by the Equivalent Transmission Line in a Metasurface.
A classical structure for a U-shaped metasurface exhibiting a wideband and large angle electromagnetically induced transparency (EIT) effect in the terahertz range is proposed. One horizontal and two vertical strips, which represent the bright and dark modes, respectively, are created for the U-shaped structure. The finite integration time domain (FITD) and equivalent circuit method are compared with the EIT result. The EIT effect is affected by the length of the vertical bar and by the distance from the vertical bar to the symmetry axis. The results show that the asymmetry of the main structure in the x and y axes makes it easier to achieve the EIT effect. In addition, by changing the incident angle, the EIT effect always exists until the angle of the incidental electromagnetic wave is 85 degrees. These results have many potential applications for terahertz filtering, large-angle switching and sensors.


A randomized controlled trial evaluating same-day mifepristone and misoprostol compared to misoprostol alone for cervical preparation prior to second-trimester surgical abortion.
We evaluated initial cervical dilation with the addition of oral mifepristone to vaginal misoprostol as cervical preparation for same-daysecond-trimester dilation and evacuation (D&E). Women desiring abortion between gestational ages 14weeks 0days and 19weeks 6days were randomized to 200-mg mifepristone or identical placebo immediately followed by 400-mcg misoprostol vaginally 4-6h prior to D&E. Primary outcome was cervical dilation assessed by largest Hegar dilator passed without resistance. Secondary outcomes included total procedure time and participant and provider perceptions. We had 90% power to detect a 2-mm change in initial cervical dilation with a mean of 10mm (SD=3.0mm), requiring 48 participants in each arm. Of 100 women enrolled, 96 were randomized and completed the study. Age, race, gestational age (mean 17.4weeks, SD=1.3) and parity did not significantly differ. Mean initial Hegar dilation measurements were 11.7 and 10.9mm in the mifepristone and placebo groups, respectively, with difference of 0.8 [95% CI=-0.4, 2.0mm]. We found total procedure times of 11.8 and 13.0min, respectively (difference of 1.2min [95% CI=-2.4, 4.8min]. Participant and provider perceptions did not differ. All 96 procedures were completed without hemorrhage, cervical laceration or other observed complications. The addition of mifepristone to vaginal misoprostol did not provide a significant increase in cervical dilation compared to misoprostol alone as cervical preparation 4-6h prior to D&E at 14weeks through 19weeks 6days. Adding mifepristone for a short interval (4-6h) did not improve cervical preparation with misoprostol prior to D&E at 14-19weeks. Future studies should evaluate alternative timing intervals of medications for this purpose.


Changes in Muscle Mass in Patients With Renal Transplants Based on Ultrasound: A Prospective Study.
This original research aimed to investigate the value of ultrasound (US), including grayscale US and shear wave elastography (SWE), in quantitatively evaluating muscle mass after kidney transplantation. A total of 52 patients and 54 healthy control participants were recruited. High-frequency US was used to evaluate the echo intensity and muscle morphologic features. Muscle stiffness in the rectus femoris was assessed with SWE. Interclass and intraclass correlation coefficients were used for evaluating measurement reliability. The diagnostic performance of SWE was determined by a receiver operating characteristic curve analysis. The intraobserver and interobserver repeatability was excellent (all correlation coefficients >0.940; P < .05). The best evaluation point after right iliac fossa transplantation was at the lower third of the right leg. In patients, the skin (0.154 versus 0.192 cm) and rectus femoris (0.700 versus 0.905 cm) were thinner, and the pinnate angle (6.500° versus 8.000°) and area (0.965 versus 1.270 cm2 ) were smaller (all P < .05). The US results showed that, compared with the controls, all patients' rectus femoris echo intensity (P < .001 in the transverse section) and elastic modulus (P < .001 in the Young modulus and shear wave speed) increased significantly. The cutoff values were 10.05 and 10.37, and the areas under the receiver operating characteristic curves were 0.843 and 0.845 for predicting kidney transplant and sarcopenia, respectively. This noninvasive and convenient technique might be effective for objectively evaluating the muscle mass of patients after kidney transplantation.


Concurrent ulnar plastic deformity and ipsilateral humeral condylar fracture: A case report.
Plastic deformities usually occur in skeletally immature bones not completely ossified due to longitudinal forces on their distal ends, especially the forearm and lower legs. Pediatric lateral humeral condylar fractures (LHCFs) constitute the second most common intra-articular fracture in the upper extremity. Nevertheless, plastic deformities accompanied by other traumatic injuries, including LHCFs, are atypical and rare. This study presents an exceedingly rare case of the concurrence of a plastic deformity and an ipsilateral fracture of the lateral condyle of the humerus in a 6-year-old Persian boy. The 6-year-old Persian injured boy referred to orthopedic clinic with an obvious deformity in the right upper limb with a limited motion range in the ipsilateral elbow. The patient underwent open-fixation surgery for LHCF fixation and suitable maneuvers to rectify the ulnar plastic deformity. Our findings indicated an acceptable outcome for this approach. His injured limb was reformed without deformities, and the complete union of the fractured area was accomplished eight weeks after surgery. The case is remarkable as reminding that we have to care concomitant "minor" injuries to the main fracture and to correctly treat them. Furthermore, open fixation surgery for LHCF rectification before fixing the ulnar deformity with the aid of a suitable maneuver led to good outcome and acceptable rehabilitation in a case of concurrent ulnar plastic deformity and an ipsilateral fracture of the external condyle of the humerus. Our approach helps to avoid further tissue damage and prevent the 2-stage surgical process.


Observations of ultrasound-induced effects in the fish Xiphophorous maculatus.
Tails of the fish Xiphophorous maculatus have been studied by transmission light microscopy during irradiation with continuous wave ultrasound (frequencies 0.78-3 MHz, spatial average intensities 0.01-3 Wcm-2). Blood flow started to increase a few minutes after the start of an irradiation, reaching a maximum after 5-10 min. Periodic variations in blood flow rate were often seen, and the response varied considerably among individual specimens. Acoustic microstreaming, which resulted in rapid rotation of clusters of cells, was observed in blood vessels adjacent to cartilaginous rods in the tail. The threshold average spatial intensities to initiate this were a few hundred mW cm-2 at 0.78, 1.5 and 3 MHz. The microstreaming resembled that occurring around ultrasonically stimulated microbubbles, but no evidence of any association was found. Microbubbles, possibly originating in water, were sometimes seen in the tissue of the fish following treatment with ultrasound.


Demand for vaccination in Sub-Saharan Africa: The vertical legacy of the slave trade.
We combine historical data on the slave trade by ethnic group with individual-level data geolocated at the cluster level from the 2010-2014 Demographic and Health Surveys to examine the relationship between ancestors' exposure to the slave trade and children vaccination status against measles. Exploiting within-location variation, and hence isolating the vertical cultural transmission channel of the slave trade, we find that children from mothers whose ancestors were exposed to the slave trade are less likely to be vaccinated than children living in the same location but with mothers from a slave-free ethnic group. The effect is larger than that of standard determinants of health demand, such as education or revenue. Exploiting other health behaviors, we point to mistrust as the channel through which the slave trade affects current demand for vaccination. We find evidence of increased adverse effect of slave trade exposure on contemporaneous demand for vaccination among the descendants whose family has a higher preference for traditional practices and higher incentives to transmit their inherited cultural traits. While we know that there is not a uniform health policy code deemed appropriate for all geographical areas, our results suggest that there is space to integrate ethnic groups' historical-specificity in health policy design and communication.


Neurobehavioral symptoms in children born extremely preterm: A Swedish National Study.
To determine the prevalence of neurobehavioral symptoms at 6.5 years in children born extremely preterm (EPT, <27 weeks' gestation). Population-based cohort study of infants born EPT in Sweden from 2004 to 2007. Of 486 survivors 375 were assessed and compared with 369 matched term-born controls. EPT children free from neurosensory and intellectual disabilities (neurodevelopmental disabilities [NDD]-free, n = 236) were compared separately. Standardised questionnaires were used to assess parental ratings of hyperactivity and attention, emotional, peer-relation, conduct and social problems; and deficits in perception, language and memory. EPT children had more reported problems in all assessed neurobehavioral domains than controls, with more than three times greater odds for most outcomes. Except for conduct problems, increased problems were identified also in NDD-free children. The odds of having neurobehavioral problems in ≥3 co-occurring domains were five (whole EPT group) and three (NDD-free group) times higher than in controls. EPT children with or without NDD have more neurobehavioral problems in multiple domains than term peers. Ongoing assessments of behaviour until school age or beyond should recognise early symptoms of attention, everyday social problems, perceptual, emotional or language difficulties.


A cluster validity framework for genome expression data.
This paper presents a method for the assessment of expression cluster validity.


Esophageal actinomycosis after allogeneic peripheral blood stem cell transplantation for extranodal natural killer/T cell lymphoma, nasal type.
We report a 19-year-old man with extranodal natural killer (NK)/T cell lymphoma, nasal type treated by allogeneic peripheral blood stem cell transplantation (allo-PBSCT). His lymphoma was chemoresistant, and disseminated during local radiotherapy. The patient received allo-PBSCT from his HLA-1 locus mismatched sister using busulfan (BU), cyclophosphamide (CY) and VP-16 as the conditioning regimen. His course was complicated by esophageal actinomycosis 9 months after transplantation, which resulted in the rupture of the right common carotid artery. These observations suggest that actinomycosis should be monitored carefully after transplantation in patients who have received local radiation therapy before the procedure.


Using pre-surgical suspicion to guide insula implantation strategy.
Insular epilepsy can be a challenging diagnosis due to overlapping semiology and scalp EEG findings with frontal, temporal, and parietal lobe epilepsies. Stereotactic electroencephalography (sEEG) provides an opportunity to better localize seizure onset. The possibility of improved localization is balanced by implantation risk in this vascularly rich anatomic region. We review both safety and pre-implantation factors involved in insular electrode placement across four years at an academic medical center. Presurgical data, operative reports, and invasive EEG summaries were retrospectively reviewed for patients undergoing invasive epilepsy monitoring on the insula from 2016 through 2019. EEG reports were reviewed to record the presence of insula ictal and interictal involvement. We recorded which presurgical findings suggested insular involvement (insula lesion on MRI, insula changes on PET/SPECT/scalp EEG, characteristic semiology, or history of failed anterior temporal lobectomy). The likelihood of pre-sEEG insular onset was categorized as low suspicion if no presurgical findings were present ("rule out"), moderate suspicion if one finding was present, and high suspicion if two or more findings were present. 76 patients received 189 insular electrodes as part of their implantation strategy for 79 surgical cases. Seven patients (8.9%) had insular ictal onset. One clinically significant complication (left hemiparesis) occurred in a patient with moderate suspicion for insular onset. There were 38 low suspicion cases, 36 moderate suspicion cases, and 5 high suspicion cases for pre-sEEG insula ictal onset. Two low suspicion (5.3%), three moderate suspicion (8.6%), and two high suspicion (40%) cases had insular ictal onset. The insula can safely receive sEEG. Having two or more presurgical factors indicating insular onset is a strong, albeit incomplete, predictor of insular seizure onset. Using pre-implantation clinical findings can offer clinicians predictive value for targeting the insula during invasive EEG monitoring.


Assessment of Implanon insertion and removal.
This report describes the proper technique and the time required for insertion and removal of Implanon. Implanon was inserted into 330 female volunteers for an assessment of efficacy, safety and tolerability over a 2-year period. Implanon was inserted subdermally using a unique, specially designed, preloaded, disposable applicator, and removal was accomplished either by the "pop-out" method or by grasping the implant with a small hemostat and removing it through a small incision. The average length of time required for insertion was 0.5 min. The average length of time required for removal was 3.6 min. There were no reported pregnancies when Implanon was in situ. Implanon is a single-rod subdermal contraceptive that is usually easily inserted and removed. Insertion and removal represent brief office procedures associated with a low rate of complications. Following proper insertion and removal procedures will minimize the possibility of complications.


Prenatal detection of unbalanced chromosomal rearrangements by array CGH.
Karyotype analysis has been the standard method for prenatal cytogenetic diagnosis since the 1970s. Although highly reliable, the major limitation remains the requirement for cell culture, resulting in a delay of as much as 14 days to obtaining test results. Fluorescent in situ hybridisation (FISH) and quantitative fluorescent PCR (QF-PCR) rapidly detect common chromosomal abnormalities but do not provide a genome wide screen for unexpected imbalances. Array comparative genomic hybridisation (CGH) has the potential to combine the speed of DNA analysis with a large capacity to scan for genomic abnormalities. We have developed a genomic microarray of approximately 600 large insert clones designed to detect aneuploidy, known microdeletion syndromes, and large unbalanced chromosomal rearrangements. This array was tested alongside an array with an approximate resolution of 1 Mb in a blind study of 30 cultured prenatal and postnatal samples with microscopically confirmed unbalanced rearrangements. At 1 Mb resolution, 22/30 rearrangements were identified, whereas 29/30 aberrations were detected using the custom designed array, owing to the inclusion of specifically chosen clones to give increased resolution at genomic loci clinically implicated in known microdeletion syndromes. Both arrays failed to identify a triploid karyotype. Thirty normal control samples produced no false positive results. Analysis of 30 uncultured prenatal samples showed that array CGH is capable of detecting aneuploidy in DNA isolated from as little as 1 ml of uncultured amniotic fluid; 29/30 samples were correctly diagnosed, the exception being another case of triploidy. These studies demonstrate the potential for array CGH to replace conventional cytogenetics in the great majority of prenatal diagnosis cases.


Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer.
Hypermethylation of CpG islands is well known as a major inactivation mechanism of tumor suppressor genes. E-cadherin (E-cad) as a tumor invasion suppressor has been reported in several invasive and metastatic carcinomas. However, its significance in carcinogenesis of primary non-small cell lung cancer (NSCLC) is not well documented. This study was designed to assess the significance with 95 pairs of carefully collected NSCLC tumors and corresponding nonmalignant tissue samples. We carried out PCR-SSCP (single-strand conformation polymorphism) and PCR-RFLP (restriction fragment length polymorphism) screening for DNA variants, bisulfite conversion-specific MSP for methylation analysis, reverse transcription (RT)-PCR for mRNA and immunohistochemistry (IHC) for protein expression assays. To investigate effect of promoter-hypermethylation on E-cad expression, we also did demethylation experiment in six cell lines. First, we found that the -160A carriers (a single nucleotide polymorphism (SNP) in the promoter region of E-cad) had an increased risk for lung cancer development when compared to DNA from healthy volunteers (OR (odds ratio)=2.81; 95% CI (confidence interval), 1.36-5.86). Methylation of E-cad occurred with a significantly higher frequency in tumors than corresponding normal peritumoral tissues (P<10(-5)). Reduced expression of E-cad was detected as a distinct molecular feature of tumors in comparison to corresponding counterparts. Moreover, the methylation alteration was detected more frequently in low-differentiated tumors than in well-differentiated ones. Defective expression of E-cad in methylated cell lines was markedly recovered after treated with 5-Aza-dC (5-aza-2'-deoxycytidine). Thus, promoter-hypermethylation of E-cad is significantly associated with its defective expression and tumor differentiation, and the demethylating observation proposes a therapeutic strategy to reverse the tumor's malignancy by restoring normal expression of E-cad.


A single-chain magnet formed by a twisted arrangement of ions with easy-plane magnetic anisotropy.
A unique "single-chain quantum magnet" was formed by an alternating arrangement of high-spin FeII/low-spin FeIII ions. Although the predominant spin-carrier components (high-spin FeII) possess easy-plane magnetic anisotropy (D > 0), twisted arrangement of easy-planes along the chain axis defines a novel class of one-dimensional Ising system.


X-linked retinal disorders and the Lyon hypothesis.
The heterozygous states in X-linked ocular albinism, choroideremia and X-linked retinitis pigmentosa are described. Their fundus appearances differ, to a greater or lesser extent, from those of hemizygous (affected) males and a possible explanation for these differences is briefly discussed.


Pre-operative intravenous cholangiography as an alternative to routine operative cholangiography in elective cholecystectomy.
Pre-operative intravenous cholangiography as an alternative to routine operative cholangiography at elective cholecystectomy has been assessed in a retrospective manner in 286 patients. Most of the examinations were technically satisfactory (94.7%) and of these 1.8% proved incorrect. A small number of patients developed transient skin rashes (1.3%), the only side effect recorded. Preoperative intravenous cholangiography offers an alternative to routine operative cholangiography with the potential saving of both operating staff and radiologists' time, without sacrificing accuracy.


Miliary tuberculosis and adult respiratory distress syndrome.
Although, miliary tuberculosis is an unusual cause of severe acute respiratory failure, we describe nine patients with miliary tuberculosis who developed adult respiratory distress syndrome. This complication occurred in seven patients despite treatment with antituberculous drugs. In two patients who developed the syndrome, miliary tuberculosis was diagnosed only at postmortem. The presence of pulmonary hypertension in all cases and disseminated intravascular coagulation in seven cases suggests a possible pathophysiologic relationship with severe pulmonary vascular damage. The high mortality rate (88.8%) was associated with nonpulmonary organ system failure. Miliary tuberculosis should be considered in patients with adult respiratory distress syndrome of unknown etiology, and simple diagnostic procedures such as sputum, bronchial brushing, and gastric examination should be followed by invasive diagnostic procedures to confirm this etiology. Since untreated miliary tuberculosis is usually fatal, early recognition of this disease is of great importance, and specific therapy may play a lifesaving role.


Kinetics of preneoplastic epithelia of the the intestinal mucosa induced in Buffalo rats by oral administration of N,N'-2,7-fluorenylenebisacetamide.
A diet containing 0.025% of N,N'-2,7-fluorenylenebisacetamide (2,7-FAA) was administered orally to 18 Buffalo rats for 3 months and to 21 rats for 5 months which corresponded to non-neoplastic stage and preneoplastic stage of carcinogenesis of the intestinal mucosa, respectively. The mitotic index, labeling index, and generation time of the epithelia of the intestinal mucosa of these stages were examined by autoradiography. 1) The mitotic index and labeling index decreased in the rats fed 2,7-FAA for 3 months than those of the non-treated controls. 2) Decrease of both indices was also observed in the rats fed 2,7-FAA for 5 months, except for the proximal part of the colon. 3) Around 1-hr prolongation of the generation time was observed in the epithelia of rats fed 2,7-FAA for 3 months compared with the non-treated control rats, and this was mainly due to the prolongation of the duration of the G1 phase. 4) Two- or three-hour prolongation of the generation time was observed in the epithelia of rats fed 2,7-FAA for 5 months compared with the non-treated control rats, and this was mainly due to the prolongation of the duration of the S phase.


HLA-B8/DR3 phenotype and the primary immune response.
Increased frequency of HLA-B8/DR3 has been reported in many organ-specific and systemic autoimmune diseases. Immune responsiveness in 11 normal subjects with and 22 without the B8/DR3 phenotype was studied. The IgA class immune response after immunization with the primary test immunogen alpha-Helix pomatia hemocyanin (HPH) was increased in B8/DR3-positive subjects compared to the non-B8/DR3 group. Also, IgG class antibody levels tended to be higher in the former group. The in vitro lymphocyte proliferative response to optimal concentrations of HPH did not differ between the groups nor did the response to allogeneic cells. Lymphocyte proliferation on stimulation with pokeweed mitogen and suboptimal concentration of phytohemagglutinin was increased in B8/DR3 individuals. It is concluded that the phenotype B8/DR3 is associated with a high humoral immune response.


Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.
Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.


The formation of a chiral supramolecular structure acting as a template for chirality transfer.
Spontaneous mirror symmetry breaking in self-assembled achiral trimers under a nonequilibrium state induces supramolecular chirality, which is stabilized by a polymer network to produce a homochiral material. Chirality is transferred to the polymer film in the course of polymerization of achiral reactive monomers on the surface.