Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease.
Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.


Transient receptor potential melastatin 4 channel contributes to migration of androgen-insensitive prostate cancer cells.
Impaired Ca2+ signaling in prostate cancer contributes to several cancer hallmarks, such as enhanced proliferation and migration and a decreased ability to induce apoptosis. Na+ influx via transient receptor potential melastatin 4 channel (TRPM4) can reduce store-operated Ca2+ entry (SOCE) by decreasing the driving force for Ca2+. In patients with prostate cancer, gene expression of TRPM4 is elevated. Recently, TRPM4 was identified as a cancer driver gene in androgen-insensitive prostate cancer.We investigated TRPM4 protein expression in cancer tissue samples from 20 patients with prostate cancer. We found elevated TRPM4 protein levels in prostatic intraepithelial neoplasia (PIN) and prostate cancer tissue compared to healthy tissue. In primary human prostate epithelial cells (hPEC) from healthy tissue and in the androgen-insensitive prostate cancer cell lines DU145 and PC3, TRPM4 mediated large Na+ currents. We demonstrated significantly increased SOCE after siRNA targeting of TRPM4 in hPEC and DU145 cells. In addition, knockdown of TRPM4 reduced migration but not proliferation of DU145 and PC3 cells. Taken together, our data identify TRPM4 as a regulator of SOCE in hPEC and DU145 cells, demonstrate a role for TRPM4 in cancer cell migration and suggest that TRPM4 is a promising potential therapeutic target.


Effect of lidocaine patches on upper trapezius EMG activity and pain intensity in patients with myofascial trigger points: A randomized clinical study.
To compare the effects of 5% lidocaine patches and placebo patches on pain intensity and electromyographic (EMG) activity of an active myofascial trigger point (MTrP) of the upper trapezius muscle. Thirty-six patients with a MTrP in the upper trapezius muscle were randomly divided into two groups: 20 patients received lidocaine patches (lidocaine group) and 16 patients received placebo patches (placebo group). They used the patches for 12 h each day, for 2 weeks. The patch was applied to the skin over the upper trapezius MTrP. Spontaneous pain, pressure pain thresholds, pain provoked by a 4-kg pressure applied to the MTrP and trapezius EMG activity were measured before and after treatment. Baseline spontaneous pain values were similar in both groups and significantly lower in the lidocaine group than the placebo group after treatment. The baseline pressure pain threshold was significantly lower in the lidocaine group, but after treatment it was significantly higher in this group. Baseline and final values of the pain provoked by a 4-kg pressure showed no significant difference between the groups. Baseline EMG activity at rest and during swallowing of saliva was significantly higher in the lidocaine group, but no significant difference was observed after treatment. Baseline EMG activity during maximum voluntary clenching was similar in both groups, but significantly higher in the lidocaine group after treatment. These clinical and EMG results support the use of 5% lidocaine patches for treating patients with MTrP of the upper trapezius muscle.


The choroid plexus of the fourth ventricle and its arteries.
The choroid plexus of the fourth ventricle consists of two symmetrical parts located in the roof of the ventricle and protruding through its openings, the foramina of Luschka and Magendie. The arteries supplying the choroid plexus of the fourth ventricle are difficult to approach because of their deep location within the cerebellopontine angles and the cerebellomedullary fissure. They originate from multiple sites on the cerebellar arteries, and pass near the vital structures of the pons and medulla. The increasing use of the operating microscope and endoscopy during operations in the posterior cranial fossa has created a need for better understanding of the microsurgical anatomy of the plexus and its arteries. The arteries of 15 human brain-stems with cerebelli were injected with coloured gelatine and fixed in 10% formaldehyde solution. The specimens were studied under an operating microscope. The choroids plexus on each side of the midline was divided into four segments, the medial and lateral horizontal segments and the rostral and caudal sagittal segments, in order to facilitate the description of their blood supply. The anterior inferior cerebellar artery (AICA), the posterior inferior cerebellar artery (PICA) and the superior cerebellar artery (SCA) were the main supplying vessels. AICA supplied the portion of the plexus in the cerebellopontine angles and the adjacent part of the lateral recess of the fourth ventricle through the foramina of Luschka. PICA supplied most of the choroid plexus in the roof and the median opening of the fourth ventricle.


Long-Term Neurodevelopmental Outcomes of Premature Infants in Singapore.
Neonatal care advances have resulted in improved survival but have raised concerns of increase in neurodevelopmental impairment. This study looked at long-term neurodevelopmental outcomes at ages 5 and 8 years of very low birthweight infants born in the 2000s as compared to the 1990s. Neurodevelopmental assessment at 2 years old was compared to that at 5 and 8 years to determine if assessment at 2 years was predictive of later outcomes. A retrospective cohort study of consecutive infants with birthweight less than 1250 grams admitted to a tertiary centre in Singapore between January 1994 to December 1995 (Epoch I) and January 2004 to December 2005 (Epoch II) were included. Neurodevelopmental impairment was defined as having intelligence quotient (IQ) of less than 70, cerebral palsy, legal blindness, or hearing impairment requiring hearing aids. Mean gestational age was lower for Epoch II compared to Epoch I (28.1 ± 2.5 vs 29.4 ± 2.7 weeks, P = 0.004). Death or neurodevelopmental impairment rates did not differ (24.3% and 17.1% at 5 years old, P = 0.398; 29.1% and 25.0% at 8 years old, P = 0.709). There was improvement in visual impairment rate at 8 years in Epoch II (10.7% vs 34.0%, P = 0.024). Mean IQ was better in Epoch II (109 and 107 vs 97 and 99 at 5 [P = 0.001] and 8 years [P = 0.047], respectively). All infants with no neurodevelopmental impairment at 2 years remained without impairment later on. Over a decade, neurodevelopmental outcomes did not worsen despite lower mean gestational age. Long- term improvement in IQ scores and a reduction in visual impairment rates were seen. Our data suggests that children without neurodevelopmental impairment at 2 years are without impairment later on; therefore, they may need only developmental monitoring with targeted assessments instead of routine formal IQ assessments.


Oral (1-->3),(1-->4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma.
In vitro beta-glucan can enhance tumor cytotoxicity through iC3b receptors on leukocytes. We tested if (1-->3),(1-->4)-beta-D-glucan (beta-glucan) can synergize with anti-GD2 monoclonal antibody (MoAb) 3F8 (mouse IgG3) in therapy of human neuroblastoma xenografts. Athymic nude mice with established neuroblastoma xenografts were treated with daily i.p. or p.o. beta-glucan, in the presence/absence of i.v. MoAb twice a week, for 22-29 days. Serial tumor volumes and body weights were monitored. 3F8 plus beta-glucan produced near-complete tumor regression/disease stabilization, whereas 3F8 or beta-glucan alone did not significantly affect tumor growth. For NMB7 tumors, median survival of 3F8 plus beta-glucan group was 5.5-fold that of control groups (P < 0.001), and for LAN-1, the survival difference was 2.6-fold. Forty-seven percent of the mice with NMB7 and 18% with LAN-1 remained progression free in contrast to <3% of controls. Antitumor effect was seen at > or =40 microg of glucan dose, i.v. or p.o., and in all human neuroblastoma cell lines tested. No toxicities were noted in mice treated with either beta-glucan alone or 3F8 plus beta-glucan (4-4000 microg/dose). In contrast to anti-GD2 MoAb 3G6 (IgM), 3F8 F(ab')(2) and MoAb 8H9 (IgG1) did not activate complement and had no synergy with beta-glucan. Antitumor effect of 3F8 plus p.o. beta-glucan persisted after antiasialo-GM1 antibody treatment, as well as in NK-deficient host. p.o. 1,3-1,4-beta-glucan synergized with antitumor IgG and IgM MoAb in vivo. Because beta-glucan was well tolerated and inexpensive, its potential value in cancer therapy deserves further investigation.


Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective.
Besides acute respiratory distress syndrome, acute cardiac injury is a major complication in severe coronavirus disease 2019 (COVID-19) and is associated with a poor clinical outcome. Acute cardiac injury with COVID-19 can be of various etiologies, including myocardial ischemia or infarction and myocarditis, and may compromise cardiac function, resulting in acute heart failure or cardiogenic shock. Systemic inflammatory response increases heart rate (HR), which disrupts the myocardial oxygen supply/demand balance and worsens cardiac energy efficiency, thus further deteriorating the cardiac performance of the injured myocardium. In fact, the combination of elevated resting HR and markers of inflammation synergistically predicts adverse cardiovascular prognosis. Thus, targeted HR reduction may potentially be of benefit in cardiovascular pathologies associated with COVID-19. Ivabradine is a drug that selectively reduces HR via If current inhibition in the sinoatrial node without a negative effect on inotropy. Besides selective HR reduction, ivabradine was found to exert various beneficial pleiotropic effects, either HR-dependent or HR-independent, including anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative actions and the attenuation of endothelial dysfunction and neurohumoral activation. Cardioprotection by ivabradine has already been indicated in cardiovascular pathologies that are prevalent with COVID-19, including myocarditis, acute coronary syndrome, cardiogenic shock or cardiac dysautonomia. Here, we suggest that ivabradine may be beneficial in the management of COVID-19- related cardiovascular complications.


Cancerous inhibitor of protein phosphatase 2A regulates cisplatin resistance in ovarian cancer.
Ovarian cancer is the most aggressive type of gynecological cancer. The cause of the poor survival rate is the development of chemotherapy resistance to platinum-based therapies, including cisplatin. The present study aimed to investigate the mechanism of cancerous inhibitor of protein phosphatase 2A (CIP2A)-induced chemoresistance in ovarian cancer. The present study initially investigated the expression of CIP2A in the ovarian tumor tissue, cisplatin-sensitive SKOV-3 cell line, and cisplatin-resistant ovarian carcinoma SKOV-3CDDP/R cell line. In addition, CIP2A was knocked down using small interference RNA in ovarian cancer cells and the chemosensitivity of these cells was analyzed. The results demonstrated that CIP2A expression was significantly higher in patients with ovarian cancer and in the cisplatin-resistant ovarian carcinoma SKOV-3CDDP/R cell line at the mRNA and protein levels. The proliferation and chemosensitivity were decreased and enhanced, respectively, when CIP2A was knocked down. CIP2A silencing significantly promoted the apoptosis induced by cisplatin in SKOV-3CDDP/R cells, suggesting that CIP2A participated in the cisplatin resistance of ovarian cancer cells and that CIP2A silencing enhanced the apoptosis induced by cisplatin. CIP2A may be considered as a potential candidate for modulating cisplatin therapy in ovarian cancer.


Endless minds most beautiful.
The marriage of evolution and development to produce the new discipline 'evo-devo' in biology is situated in the general history of evolutionary biology, and its significance for developmental cognitive science is discussed. The discovery and description of the highly conserved, robust and 'evolvable' mechanisms that organize the vertebrate body plan and fundamental physiology have direct implications for what we should investigate in the evolution of behavior and cognition.


Direct human papillomavirus E6 whole-cell enzyme-linked immunosorbent assay for objective measurement of E6 oncoproteins in cytology samples.
A novel, whole-cell enzyme-linked immunosorbent assay (ELISA) based on a non-type-specific anti-human papillomavirus (HPV) E6 antibody was tested on 182 residual cytological specimens. For samples with a designation of more severe than cervical intraepithelial neoplasia grade 3 (CIN3+), 83% tested positive for E6; in a subset with paired testing for E6 ELISA and HPV DNA, 72% tested E6 positive and 92% tested high-risk (HR)-HPV DNA positive (P = 0.2). Among the women with a less than CIN3 diagnosis, 31% and 47% tested positive for E6 and HR-HPV DNA, respectively (P = 0.0006).


Massive deletion in AZFb/b+c and azoospermia with Sertoli cell only and/or maturation arrest.
Recent studies have revealed that AZF deletion in Y chromosome is the most common known molecular genetic cause of spermatogenetic failure leading to male infertility. Characteristics of AZFa, AZFb and AZFc deletions and their association with spermatogenic impairment have been reported in a large number of populations. However, the distributions of those larger deletions resulted from P5/proximal-P1, P5/distal-P1 and P4/distal-P1 recombinations are still unclear as the literature on their frequencies is limited, and the contribution of these deletions to spermatogenetic failure remain to be confirmed by population studies. In this study, we investigated such massive deletions in 387 idiopathic azoospermic, 269 oligozoospermic patients and 315 men with normal spermatogenesis using 21 AZFb/c specific sequence-tagged sites. As a result, nine uninterrupted massive deletions were observed exclusively in men with azoospermia caused by either Sertoli cell only (SCO) or maturation arrest (MA). Prevalence of the deletion was 2.33%, in which five deletions arose from non-allelic homologous recombination between the palindromes P5 and P1 and two between P4 and P1. In other two deletions, novel proximal breakpoints in the interval region between P4 and P3 were observed. Our findings strongly support that the massive deletions in the AZFb or AZFb+c regions are important genetic causes of SCO and/or MA resulting in azoospermia and, besides the P5/proximal-P1, P5/distal-P1 and P4/distal-P1 deletions there may be other massive deletions in these regions resulting in severe spermatogenic impairment.


Natural hydrophobicity and reversible wettability conversion of flat anatase TiO₂ thin film.
Flat anatase TiO2 thin film deposited at room temperature shows the natural hydrophobicity, which is destroyed by 400 °C vacuum annealing. On the basis of the analysis of surface composition and structure, the origin of hydrophobicity of the flat TiO2 film can be identified as (1) approximately fully stoichiometric TiO2 and (2) hydrocarbon adsorbates on the film surface. We further validate that interfacial water molecules near the surface of the as-prepared TiO2 film are oriented in the hydrophobic hydration structure via Fourier transform infrared/attenuated total reflection. Moreover, the as-prepared TiO2 film also shows a smart surface reversibly switched between hydrophobicity and super-hydrophilicity. During the recovery process of hydrophobicity, the irradiated films show the wettability with water contact angle of 107 ± 1.7, 72 ± 2.5, 80 ± 1.1, and 17 ± 1.3° corresponding to after a week of exposure to ambient air, O2, CF4, and Ar, respectively. It can be strongly reinforced that the stoichiometry and the adsorbates both play an important role in forming the hydrophobic TiO2 films.


Correlates of lifetime suicide attempts among individuals with affective disorders in a Chinese rural community.
The aim of this study was to compare the demographic and clinical characteristics of individuals with affective disorders who had attempted suicide at some time in their lives and those who had not made a suicide attempt. In a Chinese rural community, individuals with suicide attempt (N = 30) and those without suicide attempt (N = 166) were assessed with Present State Examination (PSE). Attempters had a significantly higher level of family economic status, higher rate of lifetime depressed mood and hopelessness, and delusions than nonattempters. The logistic regression models also indicated that depressed mood and hopelessness were the most important predictors of suicide attempts. No significant difference in treatment condition was found between attempters and non-attempters. Early identification and interventions focusing on reducing depressed mood, hopelessness, and controlling psychotic symptoms may be helpful in reducing the risk of suicide attempts among individuals with affective disorders residing in the community.


ECG Wave-Maven: An Internet-based Electrocardiography Self-Assessment Program for Students and Clinicians.
To create a multimedia internet-based ECG teaching tool, with the ability to rapidly incorporate new clinical cases. We created ECG Wave-Maven ( http://ecg.bidmc.harvard.edu ), a novel teaching tool with a direct link to an institution-wide clinical repository. We analyzed usage data from the web between December, 2000 and May 2002. In 17 months, there have been 4105 distinct uses of the program. A majority of users are physicians or medical students (2605, 63%), and almost half report use as an educational tool. The internet offers an opportunity to provide easily-expandable, open access resources for ECG pedagogy which may be used to complement traditional methods of instruction.


[Role of the family practitioner in the management of patients following a myocardial infarct].
Determining the role of the general practitioner (GP) in the management of the postinfarction patient, the factors that influence this role, and the relation between GP and cardiologist. Descriptive. Registration Network of Family Practice (RNF) of the University of Limburg, the Netherlands. Data were obtained from a sample of 284 patients from 30 GPs, all participating in the RNF. The GPs completed a questionnaire about their own patients while the data concerning the cardiac state of the patients were obtained from their problem lists. Postinfarction care was given in only 50% of the patients. Relatively more patients with a more severe cardiac condition were under regular medical follow-up than those with a less severe cardiac condition. However, the severity of the disease had no effect on the specialty of the doctor performing the follow-up (GP or cardiologist), nor had the time expired after the myocardial infarction. In almost 50% of the cases the GPs found continuation of the follow-up by the cardiologist not necessary, in 25% of the cases they were not satisfied with the complementary roles of both disciplines. Postinfarction care by the GPs was not uniform. They need guidelines for the management of such patients, based on the patient's risk profile. There is a need for better coordination between GP and cardiologist.


Aspergillus fumigatus meningitis in immunosuppressed patients; diagnosis, management, prevention and control.
Aspergillosis is a fungal disease that may be expressed by a diversity of clinical syndromes being produced by several of more than 170 Aspergillus species. The "Matei Balş" National Institute for Infectious Diseases has a long experience in diagnostic procedures and treatment of the immunosuppressed patients. Irrespective of the place of their residence, most patients with HIV infection and AIDS were investigated in the Institute in the last two decades. The first case of double central nervous infection (Mycobacterium tuberculosis and Aspergillus fumigatus) in a HIV positive patient is discussed.


[Evaluation of mycobacteria growth indicator tube (MGIT) for drug susceptibility testing of Mycobacterium tuberculosis isolates].
Fifty six clinical isolates of Mycobacterium tuberculosis were tested for drug susceptibility in Mycobacteria Growth Indicator Tube (MGIT) containing 0.1 microgram/ml of INH, 1.0 microgram/ml of RFP, 3.5 micrograms/ml of EB and 0.8 microgram/ml of SM. These results were compared with those obtained by testing the same M.tuberculosis isolates by the absolute concentration method using 1% Ogawa egg slant containing 0.1 microgram/ml of INH, 10 micrograms/ml of REP, 2.5 micrograms/ml of EB and 20 micrograms/ml of SM. Fifty six isolates consisted of 18 pansensitive strains, 27 multidrug resistant strains and 11 single drug resistant strains. The results of individual drugs showed excellent agreement between the MGIT and the Ogawa methods, and overall agreement rate of the two methods were 96.4%. The results were just the same for all drugs in 48 out of 56 strains studied. The drug resistance could be observed much earlier by the MGIT method (mean 5.9 days) than by the Ogawa method (more than 21 days). In conclusion, the MGIT system could be a promising new drug susceptibility test which might become available in Japan replacing the Ogawa method.


Utility of free/total prostate specific antigen (f/t PSA) ratio in diagnosis of prostate carcinoma.
The discovery that PSA exists in serum in both free and complexed forms led to development of immunoassays specific for different PSA forms. This helped in measuring free PSA in the presence of PSA-ACT (PSA-alpha antichymotrypsin), hence it was possible to calculate the percent free PSA or free to total PSA ratio, measurement of which was helpful in reducing the number of unnecessary biopsies significantly, while maintaining a high clinical sensitivity for detection of cancer. The study was performed on 103 consecutive male patients (mean age 68 +/- 10.8 years SD) comprising of 90 patients with benign disease (87%) and 13 prostate carcinoma patients (13%), who had histologically proven prostate cancer. Patients with total PSA between 2-25 ng/ml were included in the study. 30 normal healthy males with age 58 +/- 10 years, served as control. Serum total PSA and free PSA were analyzed using streptavidin biotin EIA method (M/s Roche Diagnostics, Germany). The mean total PSA in normal healthy control subjects was 1.86 +/- 1.07 ng/ml. It was increased significantly in diseased condition. Its mean concentration in carcinoma patients was 12.6 +/- 5.3 ng/ml and in benign patients it was 6.3 +/- 4.6 ng/ml. The free to total PSA ratio in all the three groups was significantly different (p < 0.004) from each other. In carcinoma patients, mean f/t PSA ratio was 0.12 +/- 0.06 as compared to 0.21 +/- 0.11 and 0.28 +/- 0.17 in benign patients and in control respectively. The sensitivity and specificity of the test was calculated at different f/t PSA ratio cutoff. At 0.1 cutoff value, sensitivity of the test was 54% and specificity was 83%. The positive predictive value (ppv) was 32% and negative predictive value (npv) was 92%. From cutoff value of 0.12 to 0.16, sensitivity was increased from 54% to 85% but specificity was reduced from 78% to 67%. The ppv did not show much change and npv was increased from 92% to 97%. Increasing the cut off value thereafter showed no change in sensitivity but specificity was further reduced to 40%, therefore in this patient series, f/t PSA ratio cutoff of 0.16 was found to be the appropriate cutoff value. Combination of this ratio cutoff with other parameters like serum total PSA, DRE and TRUS helped in increasing the sensitivity of the test and this also helped in reducing the number of unnecessary biopsies. In 103 men who were biopsied, 13 (12.6%) prostatic carcinoma were identified. Among these 13 cancer patients, 9 patients had abnormal findings in DRE.7 individuals out of these 9, also had free to total PSA ratio lower than 0.16 and would have been biopsied and diagnosed anyway. If we use only f/t PSA ratio less than 0.16, to decide whom to biopsy, we would have biopsied and diagnosed 11/13 cases i.e. sensitivity of 85% but If we decide to biopsy those patients who had abnormal DRE and those who had low f/t PSA ratio, we could identify 13/13 carcinoma i.e. 100% sensitivity. Combining the f/t PSA ratio with total PSA, DRE and TRUS findings could help in reducing the number of unnecessary biopsies. 37 patients who were negative for malignancy having total PSA in the range of 5-20 ng/ml, normal DRE and TRUS findings, have been biopsied but with combination of total PSA in the range of 5-20 ng/ml, normal findings in digital rectal examination and TRUS and f/t PSA ratio more than 0.16 (cutoff), we could have avoided 16 biopsies which were unnecessary that means there was 43% reduction in unnecessary biopsies.


High prevalence of torque teno sus virus in China and genetic diversity of the 5' non-coding region.
Members of the family Anelloviridae are emerging circular DNA viruses infecting many species of vertebrates including pigs. To date, members of two distinct genera, Iotatorquevirus, including torque teno sus virus 1a and torque teno sus virus 1b (TTSuV1a and TTSuV1b), and Kappatorquevirus, including torque teno sus virus k2a and torque teno sus virus k2b (TTSuVk2a and TTSuVk2b), have been identified in domestic pigs and wild boars. The goal of this study was to evaluate the prevalence and genetic diversity of these viruses based on 5' non-coding genes in Chinese swine herds experiencing clinical symptoms. One hundred eighty-five clinical samples from 11 different regions, collected during 2008-2009, were analyzed using a PCR method, and the results revealed a high TTSuV-positive rate of 78.9 % (146/185) in pigs. Moreover, we detected co-infection with multiple TTSuV strains in the same pig. Nucleotide sequencing results revealed greater genetic diversity within the genus Kappatorquevirus than within the genus Iotatorquevirus. In addition, TTSuVk2b, a novel virus discovered in New Zealand in 2012, was also identified in this study. In summary, the present work helps us obtain more knowledge about the epidemiology and genetic diversity of TTSuVs.


Effect of a physiotherapy rehabilitation program on knee osteoarthritis in patients with different pain intensities.
[Purpose] To examine the effect of physiotherapy rehabilitation program on moderate knee osteoarthritis in patients with different pain intensities. [Subjects and Methods] Sixty subjects (37 men and 23 women) with moderate knee osteoarthritis participated in the current study. Randomization software was used to select the participating subjects' numbers from the clinic records. They were classified into three groups according to pain intensity: mild, moderate, and severe pain groups. All groups underwent a standard set of pulsed electromagnetic field, ultrasound, stretching exercises, and strengthening exercises. Pain intensity, knee range of motion, knee function, and isometric quadriceps strength were evaluated using the visual analogue scale, universal goniometer, Western Ontario and McMaster Universities osteoarthritis index, and Jamar hydraulic dynamometer, respectively. The evaluation was performed before and after a 4-week rehabilitation program. [Results] All groups showed significant differences in pain intensity, knee range of motion, isometric quadriceps strength, and knee function. The score change in moderate pain group was significantly greater than those in mild and severe pain groups. [Conclusion] Pain intensity is one of the prominent factors that are responsible for the improvement of knee osteoarthritis. Consequently, pain intensity should be considered during rehabilitation of knee osteoarthritis.


Surface Plasmon Polariton Cross-Coupling Enhanced Forward Emission from Insulator-Metal-Capped ZnO Films.
Increasing light extraction efficiency in the forward direction is being extensively pursued due to its crucial role in realizing top-emitting organic and inorganic light emitting devices. Various surface plasmon polariton (SPP)-based strategies for emission enhancement and light extraction have been developed to improve the top-emitting efficiency of these devices. However, the role of surface roughness of both semiconductor film and metal electrode in improving the emission efficiency of a practical device has not been thoroughly studied yet. In this work, the influence of surface roughness of a top metal electrode on the photoluminescence enhancement of a ZnO thin film is investigated experimentally and numerically based on an insulator-metal-semiconductor system. It is found that the generic surface roughness of the metal electrode plays an encouraging role in increasing the forward-emission intensity by facilitating cross-coupling of SPPs on the two opposite sides of the metal layer. More importantly, the forward emission can be further enhanced by capping a high-index polymer layer on the metal electrode to bridge the momentum mismatch between the two SPPs modes. The experimental observations are well explained by the SPPs cross-coupling mechanism that models the radiation power of a dipolar emitter underneath the metal electrode as a function of the metal surface roughness. Our work opens up the possibility of using cross-coupling of SPPs as an effective means to fabricate high-brightness top-emitting devices without the need of complicated nanoscale patterning.


[Meta-analysis of efficacy and safety of oral theophylline in chronic obstructive pulmonary disease].
To evaluate the efficacy and safety of oral theophylline versus placebo in patients with stable chronic obstructive pulmonary disease (COPD). The databases Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials and Chinese Biomedical Database were retrieved by using the key words "Uniphyl or Theophylline or Theo-Dur or theo or Theotrim or Elixophyllin or Elixophyllin or Phyllocontin or aminophylline or Methylxanthine or nuelin or doxofylline" and "obstructive or bronchitis or pulmonary emphysema or bronchial hyperreactivity or COPD or COLD or emphysema" so as to search the materials about the randomized controlled clinical trials comparing the effectiveness of stable COPD treated by oral theophylline and placebo. A meta-analysis was conducted. For continuous variables, the results of individual studies were pooled using fixed-effect weighted mean difference (WMD) with a corresponding 95% confidence interval (CI). Where the results were expressed as dichotomous variables, the relative risk (RR) with 95%CI was calculated. Thirty-four documents about randomized controlled clinical trials, including a total of 2087 patients, from the retrieved 2010 documents accorded to the demand of enrollment. The results of meta-analysis showed that theophylline significantly improved the forced expiratory volume in 1 s, forced vital capacity and peak expiratory flow rate (WMD 0.09 L, 95%CI 0.09 - 0.09; WMD 0.14 L, 95%CI 0.13 - 0.14; WMD 17.0 L/min and 95%CI 6.9 - 27.2 respectively). Arterial oxygen tension and arterial carbon dioxide tension at rest both improved with treatment (WMD 2.89 mm Hg, 95%CI 1.11 - 4.66; WMD -2.05 mm Hg and 95%CI -3.59 to -1.42 respectively). Six-minute walk distance significantly improved (WMD 38.89 meters, 95%CI 21.55 - 56.22) in treatment group. The RR of acute exacerbations was smaller between both groups (RR 0.74, 95%CI 0.59 - 0.93). The RR of total adverse events was similar (RR 1.05, 95%CI 0.95 - 1.16) while RR of drug-related adverse events was greater (RR 2.54, 95%CI 1.37 - 4.70). And there was significant statistical difference. Compared with the placebo, theophylline can improve lung function, arterial blood gas tensions and walking distance while the incidence of drug-related adverse events is higher.


Intraperitoneal chemotherapy for advanced epithelial ovarian cancer: A Canadian perspective.
The objectives of this study were to: a) assess the position of Canadian gynecological oncologists (GOC) toward intraperitoneal (IP) chemotherapy as primary treatment for ovarian cancer, b) initiate a process of communication among GOC, and c) assess the perception of barriers to implementing IP chemotherapy across Canada. An electronic practice survey was mailed to all GOC in January 2006. The response rate was 62%. GOC accept IP chemotherapy as the standard of care in the primary treatment of optimally debulked epithelial ovarian cancer. The majority of respondents were working on implementation strategies at their local institutions. The cost of administration and use of additional resources were identified as sources of moderate and high concerns, respectively. Moderate concerns were expressed with regard to the management of systemic and local toxicity, catheter complications, patients' acceptance, and quality of life. Catheter insertion issues were of low concern to most respondents. Previous experience with IP administration did not significantly impact the perceived level of concern. GOC support the use of IP chemotherapy for appropriate patients with ovarian cancer. This survey identifies important implementation challenges of IP therapy for Canada, and processes must be developed before successful delivery of IP chemotherapy can be realized. This survey serves to initiate a process of communication among GOC. A collaborative effort will be needed to facilitate this change in practice. Further study of the implementation process is warranted as more experience is gained with this modality of treatment.


Core-excitation energy calculations with a long-range corrected hybrid exchange-correlation functional including a short-range Gaussian attenuation (LCgau-BOP).
We report the calculations of core-excitation energies of first-row atoms using the time-dependent density functional theory (DFT) and the long-range correction (LC) scheme for exchange-correlation functionals, including LC-BOP, Coulomb-attenuated method BLYP, and our recently developed LCgau-BOP method, which includes a flexible portion of short-range Hartree-Fock (HF) exchange through the inclusion of a Gaussian function in the LC scheme. We show that the LC scheme completely fails to improve the poor accuracy of conventional generalized gradient approximation functionals, while the LCgau scheme gives an accuracy which is an order of magnitude better than BLYP and significantly better than B3LYP. A reoptimization of the two parameters controlling the inclusion of short-range HF exchange in the LCgau method enables the errors to be reduced to the order of 0.1 eV which is competitive with the best DFT methods we are aware of. This reparametrization does not affect the LC scheme and therefore maintains the high accuracy of predicted reaction barrier heights. Moreover, while there is some loss in accuracy in thermochemical predictions compared to the previously optimized LCgau-BOP, rms errors in the atomization energies over the G2 test set are found to be comparable to B3LYP. Finally, we attempt to rationalize the success of the LC and LCgau schemes in terms of the well-known self-interaction error (SIE) of conventional functionals. To estimate the role of the SIE, we examine the total energy calculations for systems with a fractional number of electrons, not only in the highest occupied molecular orbital but also in the 1s-characterized core orbital. Our conclusion is that the inclusion of short-range HF exchange in LC-type functionals can significantly alleviate the problems of the SIE in the core region. In particular, we confirm that the absence of the SIE diagnostics in the core orbital energies correlates with the accurate prediction of core-excitation energies using the newly optimized LCgau approach.


Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation.
Mast cells (MCs) develop from hematopoietic progenitors and differentiate into mature MCs that reside within connective or mucosal tissues. Though the number of MCs in tissues usually remains constant, inflammation and asthma disturb this homeostasis, leading to proliferation of MCs. Understanding the signaling events behind this proliferative response could lead to the development of novel strategies for better management of allergic diseases. MC survival, proliferation, differentiation, and migration are all maintained by a MC growth factor, stem cell factor (SCF) via its receptor, KIT. Here, we explored how protein kinase C (PKC) redundancy influences MC proliferation in bone marrow-derived MC (BMMC). We found that SCF activates PKCα and PKCβ isoforms, which in turn modulates KIT phosphorylation and internalization. Further, PKCα and PKCβ activate p38 mitogen activated protein kinase (MAPK), and this axis subsequently regulates SCF-induced MC cell proliferation. To ascertain the individual roles of PKCα and PKCβ, we knocked down either PKCα or PKCβ or both via short hairpin RNA (shRNA) and analyzed KIT phosphorylation, p38 MAPK phosphorylation, and MC viability and proliferation. To our surprise, downregulation of neither PKCα nor PKCβ affected MC viability and proliferation. In contrast, blocking both PKCα and PKCβ significantly attenuated SCF-induced cell viability and proliferation, suggesting that PKCα and PKCβ compensate for each other downstream of SCF signaling to enhance MC viability and proliferation. Our results not only suggest that PKC classical isoforms are novel therapeutic targets for SCF/MC-mediated inflammatory and allergic diseases, but they also emphasize the importance of inhibiting both PKCα and β isoforms simultaneously to prevent MC proliferation.


Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior.
Therapeutic nanoparticles (NPs) can deliver cytotoxic chemotherapeutics and other drugs more safely and efficiently to patients; furthermore, selective delivery to target tissues can theoretically be accomplished actively through coating NPs with molecular ligands, and passively through exploiting physiological "enhanced permeability and retention" features. However, clinical trial results have been mixed in showing improved efficacy with drug nanoencapsulation, largely due to heterogeneous NP accumulation at target sites across patients. Thus, a clear need exists to better understand why many NP strategies fail in vivo and not result in significantly improved tumor uptake or therapeutic response. Multicolor in vivo confocal fluorescence imaging (intravital microscopy; IVM) enables integrated pharmacokinetic and pharmacodynamic (PK/PD) measurement at the single-cell level, and has helped answer key questions regarding the biological mechanisms of in vivo NP behavior. This review summarizes progress to date and also describes useful technical strategies for successful IVM experimentation.


Circular RNA LONP2 regulates proliferation, invasion, and apoptosis of bladder cancer cells by sponging microRNA-584-5p.
Bladder cancer (BC) is the most frequent type of urinary tumor and a barely treatable disease. Although extensive efforts have been invested in the research of BC, the underlying etiology and pathophysiology remain unclear. CircLONP2 is a circular RNA implicated in the development of many cancers, and miR-584-5p and YAP1 have been reported to contribute to the progression of BC. In this research, we presented novel evidence supporting circLONP2/miR-584-5p/YAP1 axis as a novel regulatory module in the progression of BC. We analyzed the expression of circLONP2 between precancerous BC samples and normal tissues using a published RNA-seq dataset. The expression of circLONP2 was also validated in clinical samples and cell lines by quantitative RT-PCR. Small interfering RNA (siRNA) and miRNA inhibitor was utilized to modulate the expression of circLONP2 and miR-584-5p and investigate their functions on cell proliferation and invasion. Luciferase reporter assay and RNA pull-down were performed to confirm the functional interactions among circLONP2/miR-584-5p/YAP1. CircLONP2 was significantly upregulated in precancerous BC tissues and BC cells. CircLONP2 depletion inhibited cell viability, proliferation, and invasion of BC cell lines, which could be partially rescued by miR-584-5p inhibitor. Further experiments indicated that miR-584-5p regulates cell viability, proliferation, and invasion via directly targeting YAP1. In summary, our work indicates that circLONP2 plays an oncogenic function in BC by regulating miR-584-5p/YAP1 axis, and its interaction with miR-584-5p provides a potential strategy to target BC.


The effect of subtherapeutic chlortetracycline on antimicrobial resistance in the fecal flora of swine.
The aims of this research were to determine the association between inclusion of subtherapeutic chlortetracycline in the diets of swine and the prevalence and antimicrobial resistance of Salmonella; define the association between inclusion of subtherapeutic chlortetracycline and antimicrobial resistance in the aerobic Gram-negative fecal flora of swine; and estimate the proportion of total model variance attributable to farm, pig, and colony level effects. There was no association between subtherapeutic chlortetracycline exposure and Salmonella prevalence. There were increased odds for an aerobic Gram-negative fecal isolate to be resistant to ampicillin, ceftriaxone, and tetracycline if isolated from a pig that received chlortetracycline. There was a positive association between inclusion of subtherapeutic chlortetracycline in the diet and resistance to multiple antimicrobials. The proportion of total variance associated with farm, pig, and colony varied based on the resistance phenotype. Because farm-level variance contributed a small proportion to total variance in all models, effects of antimicrobial use interventions observed in this study may be predictive of anticipated impact of interventions on most swine farms. Resources for future investigations may be better allocated to sampling more pigs and more bacterial colonies per pig in relationship to the number of farms.


Investigating Philosophies Underpinning Dietetic Private Practice.
There is limited theory or knowledge regarding dietitians' practice philosophies and how these philosophies are generated and incorporated into their professional practices. For the purposes of this study, a conceptual framework will explain and define the 'philosophies' as three different types of knowledge; episteme, techne, and phronesis. This study aimed to develop an explanatory theory of how dietitians in private practice source, utilise, and integrate practice philosophies. A grounded theory qualitative methodology was used to inform the sampling strategy, data collection, and analytical processes. Semi-structured interviews with dietitians in private practice were undertaken and data were collected and analysed concurrently. The results show that dietitians form collaborative relationships with their clients, in order to nurture change over time. They use intrinsic and intertwined forms of episteme, techne, and phronesis, which allow them to respond both practically and sensitively to their clients' needs. The learning and integration of these forms of knowledge are situated in their own practice experience. Dietitians adapt through experience, feedback, and reflection. This study highlights that private practice offers a unique context in which dietitians deal with complex issues, by utilising and adapting their philosophies.


The Nrf2 inhibitor brusatol has a protective role in a rat model of oxygen-induced retinopathy of prematurity.
Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been testified to be involved in the development of retinopathy of prematurity (ROP), which can cause childhood visual impairment. Whether brusatol, an Nrf2 inhibitor, could be utilized to treat ROP was unknown. The oxygen-induced retinopathy rat model was established to mimic ROP, which was further intravitreal administrated with brusatol. Vessel morphology and microglial activation in the retina were assessed with histology analysis. The relative expression levels of angiogenesis and inflammation-related molecules were detected with Western blot and real-time polymerase chain reaction methods. Intravitreal brusatol administration could alleviate both angiogenesis and microgliosis induced by hyperoxia, along with down-regulation of vascular endothelial growth factor, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, cluster of differentiation molecule 11B, tumor necrosis factor alpha, inducible nitric oxide synthase, glial fibrillary acidic protein, and IBA-1 expression. It was further revealed that Nrf2 and heme oxygenease-1 were diminished by brusatol administration. The results demonstrate the potential of intravitreal brusatol deliver to treat ROP with down-regulation of angiogenesis and microgliosis.


Haemogregarina podocnemis sp. nov.: description of a new species of Haemogregarina Danilewsky 1885 (Adeleina: Haemogregarinaidae) in free-living and captive yellow-spotted river turtles Podocnemis unifilis (Testudines: Podocnemididae) from Brazil.
Based on morphological, morphometric, and molecular data, we describe a new hemoparasite of the genus Haemogregarina Danilewsky 1885, isolated from the Brazilian aquatic turtle Podocnemis unifilis (Testudines: Podocnemididae). The new species, Haemogregarina podocnemis sp. nov. (Apicomplexa: Haemogregarinidae), is characterized by small trophozoites with a single cytoplasmic vacuole on one side; pre-meronts with nuclear chromatin dispersed in the cytoplasm, with or without cytoplasmic vacuoles; meronts that are usually broad and slightly curved (kidney-shaped), with an average of eight small rectangular nuclei; immature gamonts (bean-shaped) with two morphological types: one with nuclear chromatin dispersed in the cytoplasm and the other with nuclei in the middle of the cell; mature gamonts of two morphological types: one with a length equal to or greater than that of the erythrocyte and the width of the nuclei similar to that of the hemoparasite and the other smaller than the erythrocyte with the width of the nuclei less than that of the hemoparasite. This is the first hemogregarine species described that infects the Brazilian turtle Po. unifilis. These findings highlight the need for further studies of Haemogregarina spp. to better determine the biodiversity of this understudied parasite group.


Biosynthesis of pulcherriminic acid.
1. Candida pulcherrima was grown on a complex medium to which various compounds had been added to determine their effect on the biosynthesis of pulcherriminic acid. Most of the pulcherriminic acid synthesized by C. pulcherrima PRL2019 was derived from the l-[1-(14)C]leucine added to the medium. 2. The cyclic dipeptide of l-leucine (cyclo-l-leucyl-l-leucyl) was shown, by trapping experiments involving cycloleucyl-leucyl isomers, to be synthesized by strain PRL2019. Cyclo-l-leucyl-l-leucyl was derived from l-leucine and was converted into pulcherriminic acid. Cyclo-l-leucyl-l-leucyl was a precursor of pulcherriminic acid in strain PRL2007 also. 3. The results supported the hypothesis that pulcherriminic acid is derived from l-leucine and that cyclo-l-leucyl-l-leucyl is an intermediate in the biosynthesis.


High risk of death in elderly patients with extensive bullous pemphigoid.
To evaluate survival and factors predicting death in bullous pemphigoid. Retrospective analysis of cohort. Three referral centers (university hospitals). Among 237 patients recruited between January 1, 1985, and December 31, 1992, 20 were excluded because of doubtful diagnosis. The 217 remaining patients were 79+/-11 years old (mean+/-SD); 120 were women and 97 were men; and 79% had been treated with oral corticosteroids, 40 to 90 mg/d. Missing information on follow-up was minimized by letters and/or telephone calls to patients, families, nursing homes, and physicians. Actuarial survival curve, compared with the expected curve as derived from census data, and evaluation of prognostic factors by comparing initial characteristics between patients alive at 6 months and these who died before that point. Survival curve demonstrated an early increased mortality: 17% at 3 months and 31% at 6 months, mainly from sepsis and cardiovascular diseases. Of the factors related to bullous pemphigoid activity (duration; pruritus; and number and extent of blisters, eosinophilia, and serum antibodies) only generalized pemphigoid was predictive of death in comparison with localized forms. In multivariate analysis, age of 86 years or more (relative risk, 7.1; 95% confidence interval [CI], 2.0-25.4; P < or = .01), poor general condition (relative risk, 8.2; 95% CI, 3.0-22.4; P < or = .001), female sex (relative risk, 2.4; 95% CI, 1.1-5.4; P < or = .05), and generalized disease (relative risk, 4.4; 95% CI, 1.4-13.7; P < or = .01) were associated with increased risks of death at 6 months. In this series, generalized bullous pemphigoid had a poor prognosis especially in older patients and those in poor general condition.


Assessment of B-type natriuretic peptide in patients with pneumonia.
The mammalian heart synthesises and secretes B-type natriuretic peptide (BNP), which has potent diuretic, natriuretic and vascular smooth muscle-relaxing effects as well as complex interactions with the hormonal and nervous systems. Recent studies described that BNP was acute phase reactant. In this study, we aimed to evaluate BNP levels in patients with pneumonia. Twenty-one patients with pneumonia and 21 healthy control subjects were enrolled in this study. Their serum levels of BNP were measured in addition to the standard evaluations. Leucocyte count [19.3 (13.2-25.7) 10(6)/ml vs. 9.55 (3.7-13.9) 10(6)/ml, p < 0.001], erythrocyte sedimentation rate [73 (57-81) mm/h vs. 35 (4-55) mm/h, p < 0.001], C-reactive protein (CRP) [127.72 (27-290) mg/l vs. 13.19 (3-41) mg/l, p < 0.001] and BNP [53.1 (17-91) pg/ml vs. 16.24 (1-38) pg/ml, p < 0.001] levels significantly decreased after treatment period. Initial BNP levels were significantly higher than control groups (53.10 +/- 15.07 pg/ml vs. 18.62 +/- 14.05 pg/ml, p < 0.001) and decreased after treatment to the levels comparable with control subjects. BNP levels correlated with CRP levels at admission (r = 0.716, p < 0.001). We have shown that BNP levels show a transient increase in patients with pneumonia and correlate well with CRP.


Case report: forced eruption and implant site development.
It is now possible to use the orthodontic extrusion of periodontally compromised teeth to facilitate the development of a future implant site in an area where the amount of bone in the inciso-apical dimension would otherwise have been inadequate. The purpose of this case report was to analyze the hard and soft tissue changes when forced eruption is used for implant site development.


Progress in acute pancreatitis.
Pancreatic necrosis and sepsis are the major causes of death in instances of acute pancreatitis. No widely accepted definition of these conditions in individuals exists, and, yet, accurate differentiation is mandatory for effective therapy. A series of operational definitions conforming to known clinopathologic factors are proposed for the necrotizing septic complications of acute pancreatitis. These complications, as distinguished from acute interstitial pancreatitis, are fat sequestra, pancreatic necrosis, infected pancreatic necrosis, pancreatic abscess and acute pseudocyst. Imprecise definitions of these complications of necrotizing pancreatitis make inter-institutional comparisons of previously identified data dubious.


New cruciform structures: toward coordination induced single molecule switches.
New cruciform structures 1-4 were synthesized to investigate a new single molecule switching mechanism arising from the interplay between the molecule and the electrode surface. These molecular cruxes consist of two rod-type substructures, namely an oligophenylenevinylene and an oligophenyleneethynyl. While the oligophenylenevinylene rods are functionalized with acetyl protected sulfur anchor groups, the oligophenyleneethynyl rods provide terminal pyridine units. The hypothesized switching mechanism should arise from the electrochemical potential dependent coordination of the pyridine unit to the electrode surface. The assembly of the oligophenylenevinylene substructure was based on a Wittig reaction whereas its perpendicular oligophenyleneethynyl rod was assembled by Sonogashira-Hagihara coupling reactions. Preliminary transport investigations with molecular cruciforms 2 and 4 in a mechanical controllable break junction in a liquid environment displayed the trapping of single molecules between two gold electrodes via the terminally sulfur functionalized oligophenylenevinylene rod.


TWEAKing death.
Smac mimetics (inhibitor of apoptosis [IAP] antagonists) are synthetic reagents that kill susceptible tumor cells by inducing degradation of cellular IAP (cIAP) 1 and cIAP2, nuclear factor kappaB activation, tumor necrosis factor (TNF) alpha production, TNF receptor 1 occupancy, and caspase-8 activation. In this issue of The Journal of Cell Biology, Vince et al. (see p. 171) report remarkable similarities in the events leading to tumor cell death triggered by the cytokine TWEAK (TNF-like weak inducer of apoptosis) and IAP antagonists. Although the mechanistic details differ, a common and necessary feature that is also shared by TNF receptor 2 signaling is reduction in the level of cIAP1 and, in some cases, cIAP2 and TNF receptor-associated factor 2. These findings not only extend our appreciation of how cell death pathways are kept in check in tumors, they reinforce the possible utility of induced cIDE (cIAP deficiency) in the selective elimination of neoplastic cells.


Bioelectronome. Integrated approach to receptor chemistry, radicals, electrochemistry, cell signaling, and physiological effects based on electron transfer.
Bioelectronome refers to the host of electron transfer (ET) reactions that occur in living systems. This review presents an integrated approach to receptor chemistry based on electron transfer, radicals, electrochemistry, cell signaling, and end result. First, receptor activity is addressed from the unifying standpoint of redox transformations in which various receptors are discussed. After a listing of receptor-binding modes, receptor chemistry is treated with focus on generation of reactive oxygen species (ROS), activation by ROS, and subsequent cell signaling involving ROS. A general electrostatic mechanism is proposed for receptor-ligand action with supporting evidence. Cell-signaling processes appear to entail electron transfer, ROS, redox chains, and relays. The widespread involvement of phosphate from phosphorylation may be rationalized electrostatically by analogy with DNA phosphate. Extensive evidence supports important participation of ET functionalities in the mechanism of drugs and toxins. The integrated approach is applied to the main ET classes, namely, quinones, metal complexes, iminium species, and aromatic nitro compounds.


Intussusception of the reconstructed bladder neck leads to earlier continence after radical prostatectomy.
Although there is no evidence that the reconstructed bladder neck actively contributes to post-radical prostatectomy continence, we set out to determine whether buttressing sutures, which prevent the bladder neck from pulling open as the bladder fills, would result in the earlier return of urinary control. Forty-five men (mean age 57 years, range 37 to 67) with clinical localized prostate cancer underwent anatomic radical retropubic prostatectomy with standard tennis racket bladder neck reconstruction. The bladder neck was then intussuscepted using two 2-0 Maxon Lembert sutures placed lateral and posterior to the reconstructed bladder neck. Filling of the bladder with saline at this point revealed little leakage. Patient-reported continence at 3 months was compared with the published outcome of 64 men using the same quality-of-life instrument (the UCLA Prostate Cancer Index). At 3 months, 82% of men who underwent intussusception of the bladder neck were continent (no pad/dry pad) compared with 54% in our prior report (P = 0.0035). The occurrence of bladder neck contracture was similar: 7% versus 5%. Intussusception of the bladder neck led to a significant improvement in urinary control at 3 months postoperatively. Longer follow-up will be necessary to determine whether this approach may eliminate the 2% probability of long-term significant problems with urinary control.


Identification of Major Effect QTLs for Agronomic Traits and CSSLs in Rice from Swarna/Oryza nivara Derived Backcross Inbred Lines.
Backcross inbred lines (BILs) derived from elite x wild crosses are very useful for basic studies and breeding. The aim of this study was to map quantitative trait loci (QTLs) associated with yield and related traits and to identify chromosomal segment substitution lines (CSSLs) from unselected BC2F8 BILs of Swarna/Oryza nivara IRGC81848. In all, 94 BILs were field evaluated in 2 years (wet seasons, 2014 and 2015) for nine traits; days to 50% flowering, days to maturity (DM), plant height (PH), number of tillers, number of productive tillers, panicle weight, yield per plant, bulk yield, and biomass. BILs were genotyped using 111 polymorphic simple sequence repeats distributed across the genome. Fifteen QTLs including 10 novel QTLs were identified using composite interval mapping, Inclusive composite interval mapping and multiple interval mapping (MIM). O. nivara alleles were trait-enhancing in 26% of QTLs. Only 3 of 15 QTLs were also reported previously in BC2F2 of the same cross. These three included the two major effect QTLs for DM and PH detected in both years with 13 and 20% phenotypic variance. Further, a set of 74 CSSLs was identified using CSSL Finder and 22 of these showed significantly higher values than Swarna for five yield traits. CSSLs, 220S for panicle weight and 10-2S with consistent high yield in both years are worthy of large scale field evaluation. The major QTLs and 22 significantly different CSSLs are a useful resource for rice improvement and dissecting yield related traits.


[Effects of hyaluronan tetrasaccharide on the differentiation of neuronal cells and oligodendrocyte precursor cells].
It has been reported that hyaluronan tetrasaccharide (HA4) has an ability to accelerate the healing process of spinal cord injuries and to mitigate the symptoms of experimental autoimmune encephalitis (EAE) in animal models. However, the precise mechanisms of the effect of HA4 are unclear. This study examined the in vitro effects of HA4 on the differentiation of PC12 cells and neuronal progenitor cells from mouse embryo. The effect of HA4 on the proliferation and differentiation of rat oligodendrocyte precursor cells was examined. HA4 upregulated neurite-outgrowth of cultured PC12 cells in the presence of Nerve Growth Factor (NGF), which induces neuronal differentiation in PC12. HA4 also upregulated beta III-tubulin positive cells and increased the expression of neurofilament M, two of the marker proteins of nerve differentiation. The activation was observed in an HA4 dose-dependent manner, and the effect was observed at levels as low as femtogram/L. Furthermore, the enhancement of neurite-outgrowth was not observed in the presence of hyaluronan disaccharide, hexasaccharide, 12 mer or high molecular weight hyaluronan. Upregulation of neurite-outgrowth was observed only in the presence of NGF. While HA4 accelerated neurite-outgrowth of primary mouse neural progenitor cells, it did not enhance the proliferation or differentiation of oligodendrocyte precursor cells derived from rat primary neuronal progenitor cells in culture. These results suggest that the effects of HA4 alleviating some neuronal diseases may be ascribable, at least in part, to its capacity to enhance differentiation of neurons.


The Na+/H+ exchange inhibitor HOE642 prevents stress-induced epithelial barrier dysfunction.
Recently, evidence has been obtained that the Na+/H+ exchange (NHE) inhibitor HOE642 may stabilize endothelial and epithelial barrier function in vivo. However, the underlying mechanisms are not known. Therefore, we studied the influence of HOE642 on the barrier function of the epithelial cell line CaCo2. The phorbolester phorbol 12-myristate 13-acetate (PMA) was used to induce hyperpermeability of the epithelial layer which was indirectly determined by measuring the transepithelial electrical resistance (TER). Confocal laser scan microscopy (LSM) served to analyze the intracellular localization of adherens and tight junction molecules. In five independent experiments we found that HOE642 increased TER in non-treated CaCo2 cells (control: 350 +/- 28 Omega/cm2; HOE642: 444 +/- 53 Omega/cm2) and prevented PMA-induced barrier dysfunction (PMA: 33 +/- 12 Omega/cm2; PMA plus HOE642: 496 +/- 47 Omega/cm2). LSM showed that HOE642 prevented the PMA-induced disassociation of the zonula adherens molecule beta-catenin from the cell membrane and the decreased expression of the zonula occludens molecule ZO-1. From our data we conclude that HOE642 may prevent stress-induced epithelial dysfunction by stabilization of cell membrane-associated junction molecules.


Current Status of National Institutes of Health Research Funding for Women Surgeon-Scientists.
Women have made substantial advancements in academic surgery, but research funding disparities continue to hamper their progress, and current literature on the status of National Institutes of Health (NIH) funding awarded to women surgeon-scientists appears to be conflicting. To examine gender-based differences in NIH funding awarded to surgeon-scientists by comparing total grant amounts awarded and the distribution of grants by gender and research type. This cross-sectional study was performed using a previously created database of NIH-funded surgeons from 2010 to 2020. Active physician data from the Association of American Medical Colleges were used to calculate total surgeon populations. This study was performed at the NIH using the NIH internal data platform, iSearch Grants. A total of 715 men and women surgeon-scientists funded by the NIH in 2010 and 1031 funded in 2020 were included in the analysis. The main outcome was the number of women among the total number of surgeons who received NIH grants and the total grant amounts awarded to them. Bivariate χ2 analyses were performed using population totals and substantiated by z tests of population proportions. This study included 715 physicians (n = 579 men [81.0%]) in 2010 and 1031 physicians (n = 769 men [74.6%]) in 2020. In 2020, women comprised 27.4% of the surgical workforce and 25.4% of surgeons with research funding in the US, but they received only 21.7% of total NIH research funding awarded to all surgeons. The number of funded women surgeon-scientists, however, significantly increased from 2010 to 2020 (262 [25.4%] in 2020 vs 136 [19.0%] in 2010; P < .001) as did their funding ($189.7 million [21.7%] in 2020 vs $75.9 million [12.3%] in 2010; P < .001). Furthermore, the proportion of US women surgeons overall with NIH funding significantly increased in 2020 vs 2010 (0.7% vs 0.5%; P < .001). Basic science, clinical outcomes, and clinical trial R01 grants also increased among women surgeon-scientists. Women and men K grant holders had a similar mean (SD) number of R01 application attempts before success (2.7 [3.01] vs 2.3 [3.15]; P = .60) and similar K-to-R award conversion rates (23.5% vs 26.7%; P = .55). This cross-sectional study found an increasing number of women surgeon-scientists receiving NIH funding in 2020 vs 2010 as well as increases in the median grant amounts awarded. Although these results are promising, a discrepancy remains in the proportion of women in the surgical workforce compared with those funded by the NIH and the total grant amounts awarded to them.


Effect of the Japanese diet during pregnancy and lactation or post-weaning on the risk of metabolic syndrome in offspring.
We examined the effects on offspring of ingestion of the 1975 Japanese diet during pregnancy and lactation and after weaning in mice. Pregnant dams were divided into groups that were fed the Japanese diet or a control diet and raised until offspring were weaned. The offspring after weaning were further divided into groups that were raised on the Japanese diet or the control diet. Ingestion of the Japanese diet after weaning suppressed accumulation of visceral fat in offspring, and reduced the amount of lipids in serum and liver. This effect was weakened if the Japanese diet was only ingested during pregnancy and lactation. Therefore, it was suggested that ingestion of the Japanese diet of mothers during pregnancy and lactation weakens the lipid accumulation inhibitory effect of the Japanese diet in children.


Peptide YY directly inhibits ghrelin-activated neurons of the arcuate nucleus and reverses fasting-induced c-Fos expression.
The hypothalamic arcuate nucleus (Arc) monitors and integrates hormonal and metabolic signals involved in the maintenance of energy homeostasis. The orexigenic peptide ghrelin is secreted from the stomach during negative status of energy intake and directly activates neurons of the medial arcuate nucleus (ArcM) in rats. In contrast to ghrelin, peptide YY (PYY) is released postprandially from the gut and reduces food intake when applied peripherally. Neurons in the ArcM express ghrelin receptors and neuropeptide Y receptors. Thus, PYY may inhibit feeding by acting on ghrelin-sensitive Arc neurons. Using extracellular recordings, we (1) characterized the effects of PYY on the electrical activity of ghrelin-sensitive neurons in the ArcM of rats. In order to correlate the effect of PYY on neuronal activity with the energy status, we (2) investigated the ability of PYY to reverse fasting-induced c-Fos expression in Arc neurons of mice. In addition, we (3) sought to confirm that PYY reduces food intake under our experimental conditions. Superfusion of PYY reversibly inhibited 94% of all ArcM neurons by a direct postsynaptic mechanism. The PYY-induced inhibition was dose-dependent and occurred at a threshold concentration of 10(-8)M. Consistent with the opposite effects of ghrelin and PYY on food intake, a high percentage (50%) of Arc neurons was activated by ghrelin and inhibited by PYY. In line with this inhibitory action, peripherally injected PYY partly reversed the fasting-induced c-Fos expression in Arc neurons of mice. Similarly, refeeding of food-deprived mice reversed the fasting-induced activation in the Arc. Furthermore, peripherally injected PYY reduced food intake in 12-hour fasted mice. Thus the activity of Arc neurons correlated with the feeding status and was not only reduced by feeding but also by administration of PYY in non-refed mice. In conclusion, our current observations suggest that PYY may contribute to signaling a positive status of energy intake by inhibiting Arc neurons, which are activated under a negative status of energy intake by signals such as ghrelin.


Responsiveness to live M. tuberculosis, and common antigens, of sonicate-stimulated T cell lines from normal donors.
Live mycobacteria are more efficient vaccines against mycobacterial disease than killed ones. A possible explanation is the existence of important protective antigens released by live bacilli, which are not present in any significant quantity in dead ones. Conversely, internal mycobacterial antigens may be irrelevant to protection if not released by live bacilli. We show here, using T cell lines derived by limiting dilution from the peripheral blood of normal donors stimulated with sonicated BCG, that a variable percentage of sonicate responsive T cells is unable to respond to live M. tuberculosis. The possibility that such lines have an immunopathological, rather than protective role, is discussed.


[1-(L-2-hydroxy-3-mercaptopropanoic acid)] analogues of arginine-vasopressin, [8-D-arginine]vasopressin, and [4-valine,8-D-arginine]vasopressin.
[1-(L-2-Hdroxy-3-mercaptopropanic acid)]arginine-vasopressin (hydroxy-AVP), [1-(L-2-hydroxy-3-mercaptopropanoic acid),8-D-arginine]vasopressin (hydroxy-DAVP), and [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-valine,8-D-arginine]vasopressin (hydroxy-VDAVP) were synthesized by a combination of the solid-phase and solution methods of peptide synthesis. Protected octapeptides synthesized by the solid-phase method were further acylated by 1 + 8 couplings in solution to furnish the key intermediates. Hydroxy-AVP has antidiuretic potency of 470 units/mg and activity in the rat vasopressor assay of 550 units/mg, representing a small enhancement of activity over that of arginine-vasopressin (AVP) in each case. Hydroxy-DAVP and hydroxy-VDAVP have essentially the same high antidiuretic activity (900 units/mg) and very low vasopressor potencies (0.9 and less than 0.02 units/mg, respectively). Hydroxy-AVP, hydroxy-DAVP, and hydroxy-VDAVP thus have antidiuretic-pressor selectivity (A/P) of 1, 1000, and greater than 45 000, respectively. These data are compared with those of other vasopressin analogues. Hydroxy-VDAVP is a highly specific antidiuretic peptids and may be useful in pharmacological studies of antidiuresis.


Chitin and Its Effects on Inflammatory and Immune Responses.
Chitin, a potential allergy-promoting pathogen-associated molecular pattern (PAMP), is a linear polymer composed of N-acetylglucosamine residues which are linked by β-(1,4)-glycosidic bonds. Mammalians are potential hosts for chitin-containing protozoa, fungi, arthropods, and nematodes; however, mammalians themselves do not synthetize chitin and thus it is considered as a potential target for recognition by mammalian immune system. Chitin is sensed primarily in the lungs or gut where it activates a variety of innate (eosinophils, macrophages) and adaptive immune cells (IL-4/IL-13 expressing T helper type-2 lymphocytes). Chitin induces cytokine production, leukocyte recruitment, and alternative macrophage activation. Intranasal or intraperitoneal administration of chitin (varying in size, degree of acetylation and purity) to mice has been applied as a routine approach to investigate chitin's priming effects on innate and adaptive immunity. Structural chitin present in microorganisms is actively degraded by host true chitinases, including acidic mammalian chitinases and chitotriosidase into smaller fragments that can be sensed by mammalian receptors such as FIBCD1, NKR-P1, and RegIIIc. Immune recognition of chitin also involves pattern recognition receptors, mainly via TLR-2 and Dectin-1, to activate immune cells to induce cytokine production and creation of an immune network that results in inflammatory and allergic responses. In this review, we will focus on various immunological aspects of the interaction between chitin and host immune system such as sensing, interactions with immune cells, chitinases as chitin degrading enzymes, and immunologic applications of chitin.


Psychosocial registry for persons with cancer: a method of facilitating quality of life and symptom research.
Research focused on the psychosocial aspects of the experience of persons with cancer and their family caregivers is hampered by the methodological challenges inherent in quality of life research. A data registry offers a potential solution to many of these problems in providing a large, comprehensive database, using standardized instruments. We report here our preliminary experience with establishing a Psychosocial Registry designed to advance research in the psychological, social, and spiritual aspects of quality of life of newly diagnosed cancer patients and their family caregivers. The first six months of enrollment demonstrated that the majority of newly diagnosed patients approached for consent (68%) and their primary family caregiver (92%) were willing to participate in the registry; of these, 80% also agreed to be contacted in the future for additional studies. Face-to-face interview was the preferred method of data collection. Our preliminary experience suggests that continuation of the registry with the current modest level of resources would generate a sample of approximately 1000 patients in three years. The long-range goal is to establish a national psychosocial data registry that will enroll patients at diagnosis and follow them through the entire cancer experience, including end of life or survivorship.


Biological and genomic analysis of a symbiotic nitrogen fixation defective mutant in Medicago truncatula.
Medicago truncatula has been selected as one of the model legume species for gene functional studies. To elucidate the functions of the very large number of genes present in plant genomes, genetic mutant resources are very useful and necessary tools. Fast Neutron (FN) mutagenesis is effective in inducing deletion mutations in genomes of diverse species. Through this method, we have generated a large mutant resource in M. truncatula. This mutant resources have been used to screen for different mutant using a forward genetics methods. We have isolated and identified a large amount of symbiotic nitrogen fixation (SNF) deficiency mutants. Here, we describe the detail procedures that are being used to characterize symbiotic mutants in M. truncatula. In recent years, whole genome sequencing has been used to speed up and scale up the deletion identification in the mutant. Using this method, we have successfully isolated a SNF defective mutant FN007 and identified that it has a large segment deletion on chromosome 3. The causal deletion in the mutant was confirmed by tail PCR amplication and sequencing. Our results illustrate the utility of whole genome sequencing analysis in the characterization of FN induced deletion mutants for gene discovery and functional studies in the M. truncatula. It is expected to improve our understanding of molecular mechanisms underlying symbiotic nitrogen fixation in legume plants to a great extent.


Artificial intelligence-assisted reduction in patients' waiting time for outpatient process: a retrospective cohort study.
Many studies suggest that patient satisfaction is significantly negatively correlated with the waiting time. A well-designed healthcare system should not keep patients waiting too long for an appointment and consultation. However, in China, patients spend notable time waiting, and the actual time spent on diagnosis and treatment in the consulting room is comparatively less. We developed an artificial intelligence (AI)-assisted module and name it XIAO YI. It could help outpatients automatically order imaging examinations or laboratory tests based on their chief complaints. Thus, outpatients could get examined or tested before they went to see the doctor. People who saw the doctor in the traditional way were allocated to the conventional group, and those who used XIAO YI were assigned to the AI-assisted group. We conducted a retrospective cohort study from August 1, 2019 to January 31, 2020. Propensity score matching was used to balance the confounding factor between the two groups. And waiting time was defined as the time from registration to preparation for laboratory tests or imaging examinations. The total cost included the registration fee, test fee, examination fee, and drug fee. We used Wilcoxon rank-sum test to compare the differences in time and cost. The statistical significance level was set at 0.05 for two sides. Twelve thousand and three hundred forty-two visits were recruited, consisting of 6171 visits in the conventional group and 6171 visits in the AI-assisted group. The median waiting time was 0.38 (interquartile range: 0.20, 1.33) hours for the AI-assisted group compared with 1.97 (0.76, 3.48) hours for the conventional group (p < 0.05). The total cost was 335.97 (interquartile range: 244.80, 437.60) CNY (Chinese Yuan) for the AI-assisted group and 364.58 (249.70, 497.76) CNY for the conventional group (p < 0.05). Using XIAO YI can significantly reduce the waiting time of patients, and thus, improve the outpatient service process of hospitals.


Bacillus cereus, a volatile human pathogen.
Bacillus cereus is a Gram-positive aerobic or facultatively anaerobic, motile, spore-forming, rod-shaped bacterium that is widely distributed environmentally. While B. cereus is associated mainly with food poisoning, it is being increasingly reported to be a cause of serious and potentially fatal non-gastrointestinal-tract infections. The pathogenicity of B. cereus, whether intestinal or nonintestinal, is intimately associated with the production of tissue-destructive exoenzymes. Among these secreted toxins are four hemolysins, three distinct phospholipases, an emesis-inducing toxin, and proteases. The major hurdle in evaluating B. cereus when isolated from a clinical specimen is overcoming its stigma as an insignificant contaminant. Outside its notoriety in association with food poisoning and severe eye infections, this bacterium has been incriminated in a multitude of other clinical conditions such as anthrax-like progressive pneumonia, fulminant sepsis, and devastating central nervous system infections, particularly in immunosuppressed individuals, intravenous drug abusers, and neonates. Its role in nosocomial acquired bacteremia and wound infections in postsurgical patients has also been well defined, especially when intravascular devices such as catheters are inserted. Primary cutaneous infections mimicking clostridial gas gangrene induced subsequent to trauma have also been well documented. B. cereus produces a potent beta-lactamase conferring marked resistance to beta-lactam antibiotics. Antimicrobials noted to be effective in the empirical management of a B. cereus infection while awaiting antimicrobial susceptibility results for the isolate include ciprofloxacin and vancomycin.


DNA fragmentation in spermatozoa: a historical review.
Sperm DNA Fragmentation has been extensively studied for more than a decade. In the 1940s the uniqueness of the spermatozoa protein complex which stabilizes the DNA was discovered. In the fifties and sixties, the association between unstable chromatin structure and subfertility was investigated. In the seventies, the impact of induced DNA damage was investigated. In the 1980s the concept of sperm DNA fragmentation as related to infertility was introduced as well as the first DNA fragmentation test: the Sperm Chromatin Structure Assay (SCSA). The terminal deoxynucleotidyl transferase nick end labelling (TUNEL) test followed by others was introduced in the nineties. The association between DNA fragmentation in spermatozoa and pregnancy loss has been extensively investigated spurring the need for a therapeutic tool for these patients. This gave rise to an increased interest in the aetiology of DNA damage. The present decade continues within this research area. Some of the more novel methods recently submerging are sorting of cells with increased DNA fragmentation and hyaluronic acid (HA) binding techniques. The clinical value of these tests remains to be elucidated. In spite of half a century of research within the area, this analysis is not routinely implemented into the fertility clinics. The underlying causes are multiple. The abundance of methods has impeded the need for a clinical significant threshold. One of the most promising methods was commercialized in 2005 and has been reserved for larger licensed laboratories. Myriads of reviews and meta-analyses on studies using different assays for analysis of DNA fragmentation, different clinical Artificial Reproductive Treatments (ART), different definitions of successful ART outcome and small patient cohorts have been published. Although the area of DNA fragmentation in spermatozoa is highly relevant in the fertility clinics, the need for further studies focusing on standardization of the methods and clinical implementation persists.


Carbonic Anhydrase from Porphyromonas Gingivalis as a Drug Target.
Periodontitis originates from a microbial synergy causing the development of a mouth microbial imbalance (dysbiosis), consisting of a microbial community composed of anaerobic bacteria. Most studies concerning the treatment of periodontitis have primarily take into account the Gram-negative bacterium Porphyromonas gingivalis, because it is a prominent component of the oral microbiome and a successful colonizer of the oral epithelium. Here, we focus our attention on the study of the carbonic anhydrases (CAs, EC 188.8.131.52) encoded in the genome of this pathogen as a possible drug target. Carbonic anhydrases are a superfamily of metalloenzymes, which catalyze the simple but physiologically crucial reaction of carbon dioxide hydration to bicarbonate and protons. Bacterial CAs have attracted significant attention for affecting the survival, invasion, and pathogenicity of many microorganisms. The P. gingivalis genome encodes for two CAs belonging to β-CA (PgiCAβ) and γ-CA (PgiCAγ) families. These two enzymes were cloned, heterologously expressed in Escherichia coli, and purified to homogeneity. Moreover, they were subject to extensive inhibition studies using the classical CA inhibitors (sulfonamides and anions) with the aim of identifying selective inhibitors of PgiCAβ and PgiCAγ to be used as pharmacological tools for P. gingivalis eradication.


Cope rearrangement versus a novel tandem retro-Diels-Alder-Diels-Alder reaction with role reversal.
[reaction: see text] A reinvestigation of the thermolysis of 4,4-dibromotetracyclo[184.108.40.206(2,7).0(3,5)]undec-9-ene (2) affords diene 8 with a completely rearranged hydrocarbon skeleton via the isolable intermediate 4, along with cyclopentadiene and bromobenzene. DFT calculations show that the novel tandem retro-Diels-Alder-Diels-Alder reaction with role reversal is slightly less favored than the overall single-step Cope rearrangement.


Cell cycle-dependent regulation of histone precursor mRNA processing by modulation of U7 snRNA accessibility.
Histone gene expression is regulated both during and after transcription, with the turnover of histone messenger RNA and the regulation of its 3' processing being the principal factors that determine the size of the histone mRNA pool during the cell cycle. The mature ends of the replication-dependent histone mRNAs are generated during 3' processing by endonucleolytic cleavage of a large primary transcript. This reaction depends on a highly conserved stem-loop structure also included in the mature RNA, and a purine-rich sequence lying downstream within the spacer transcript. Three factors involved in this reaction which act in trans have been identified: the U7 small nuclear ribonucleoprotein particle (snRNP), the heat-labile factor, and the hairpin-binding factor. Here we show how U7 snRNP participates in the regulation of 3' processing: the 5' sequences of the U7 snRNA that hybridize with the downstream spacer motif during 3' processing are occluded in the G0 stage of the cell cycle but are exposed and free to interact with histone pre-mRNA during S phase, when histone mRNA synthesis is at its peak.


Definite orthogonal modular forms: computations, excursions, and discoveries.
We consider spaces of modular forms attached to definite orthogonal groups of low even rank and nontrivial level, equipped with Hecke operators defined by Kneser neighbours. After reviewing algorithms to compute with these spaces, we investigate endoscopy using theta series and a theorem of Rallis. Along the way, we exhibit many examples and pose several conjectures. As a first application, we express counts of Kneser neighbours in terms of coefficients of classical or Siegel modular forms, complementing work of Chenevier-Lannes. As a second application, we prove new instances of Eisenstein congruences of Ramanujan and Kurokawa-Mizumoto type.


Development and implementation of a three-dimensional (3D) printing elective course for health science students.
Three-dimensional (3D) printing technology has become more affordable, accessible, and relevant in healthcare, however, the knowledge of transforming medical images to physical prints still requires some level of training. Anatomy educators can play a pivotal role in introducing learners to 3D printing due to the spatial context inherent to learning anatomy. To bridge this knowledge gap and decrease the intimidation associated with learning 3D printing technology, an elective was developed through a collaboration between the Department of Anatomy and the Makers Lab at the University of California, San Francisco. A self-directed digital resource was created for the elective to guide learners through the 3D printing workflow, which begins with a patient's computed tomography digital imaging and communication in medicine (DICOM) file to a physical 3D printed model. In addition to practicing the 3D printing workflow during the elective, a series of guest speakers presented on 3D printing applications they utilize in their clinical practice and/or research laboratories. Student evaluations indicated that their intimidation associated with 3D printing decreased, the clinical and research topics were directly applicable to their intended careers, and they enjoyed the autonomy associated with the elective format. The elective and the associated digital resource provided students with the foundational knowledge of 3D printing, including the ability to extract, edit, manipulate, and 3D print from DICOM files, making 3D printing more accessible. The aim of disseminating this work is to help other anatomy educators adopt this curriculum at their institution.


Zebrafish Models of Diamond-Blackfan Anemia: A Tool for Understanding the Disease Pathogenesis and Drug Discovery.
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome characterized by red blood cell aplasia. Currently, mutations in 19 ribosomal protein genes have been identified in patients. However, the pathogenic mechanism of DBA remains unknown. Recently, several DBA models were generated in zebrafish (Danio rerio) to elucidate the molecular pathogenesis of disease and to explore novel treatments. Zebrafish have strong advantages in drug discovery due to their rapid development and transparency during embryogenesis and their applicability to chemical screens. Together with mice, zebrafish have now become a powerful tool for studying disease mechanisms and drug discovery. In this review, we introduce recent advances in DBA drug development and discuss the usefulness of zebrafish as a disease model.


How long is the peer review process for journal manuscripts? A case study on Angewandte Chemie International Edition.
One of the most frequently raised criticisms of the review process for manuscripts is that the length of time between submission of a manuscript and the editorial decision is overly long. Taking the journal Angewandte Chemie International Edition as an example and based on nearly 2000 manuscripts, the present study examined just how long the peer review process takes.


Photocatalysed C-H amidation of indoles enabled by tert-butyl alkyl((perfluoropyridin-4-yl)oxy)carbamate.
Development of a new catalytic and straightforward strategy to construct C-N bonds is playing a pivotal role in synthetic chemistry. Here, we report a photocatalysed protocol to access direct C-H amidation of indoles, enabled by a rationally designed tert-butyl alkyl((perfluoropyridin-4-yl)oxy)carbamate. A series of biologically important aminoindoles were prepared under mild conditions with excellent regioselectivity and broad substrate scope.


High immunogenecity and erythrocyte-binding activity in the tryptophan-rich domain (TRD) of the 74-kDa Plasmodium vivax alanine-tryptophan-rich antigen (PvATRAg74).
Plasmodium vivax is the most widespread species of human malaria parasite affecting 70-80 million people worldwide each year. In recent years, some potential vaccine candidate antigens from P. vivax have been identified including tryptophan-rich antigens PvTRAg and PvTARAg55. We report here the identification and partial characterization of a 74 kDa P. vivax alanine-tryptophan-rich antigen (PvATRAg74) which is expressed by all asexual blood stages of the parasite. This protein contains two major domains, i.e. alanine-rich domain (ARD) in N-terminal region and the tryptophan-rich domain (TRD) at C-terminus. PvATRAg74 also contains variable numbers of octa-peptide repeats in the ARD region. The C-terminal PvATRAg74 containing TRD was highly conserved among 32 P. vivax isolates while N-terminal ARD showed genetic polymorphisms. The 36 kDa TRD was expressed in E. coli and named here as His6-TRD. The purified recombinant His6-TRD showed binding with uninfected human erythrocytes. This antigen was also recognized by all 38 P. vivax patients' sera on ELISA thus showing a very high seropositivity rates. In vitro stimulation of lymphocytes with purified His6-TRD indicated that it induced T cell immune response in majority (94%, n=16) of P. vivax exposed individuals. The stimulated T cells produced higher amount of IL-4 and IL-10 than IFN-gamma, TNF-alpha, and IL-12 indicating a Th2 type of response bias. Unlike PvTARAg55, this antigen is more immunogenic in humans and possesses the erythrocyte-binding activity. Immunogenecity of PvATRAg74 is similar to PvTRAg whose erythrocyte-binding activity still remains unknown.


[Symptoms and upper limb work-related musculo-skeletal disorders among 173 supermarket cashiers].
Cashiers in supermarket chains have long been considered at risk for the development of work related musculo-skeletal disorders of the upper limbs (UL-WMSDs). The aim of this study was to assess the prevalence of UL-WMSDs among workers operating supermarket cash tills and, after clinical tests, their frequency. A standardized questionnaire was given to a random group of 173 workers in order to collect information regarding symptoms in the upper limbs (pain and parasthesia). Among the 111 workers who reached a "positive clinical history threshold" we selected a random sample of subjects to undergo clinical tests (professional medical care, ultrasound examination, electro-neurographic examination). 64% of the workers had a positive clinical history for UL-WMSDs. The most frequently reported disorder was pain, especially in the shoulder, while 37% of workers suffered from one or more disorders of the upper limbs. Clinical tests were performed on 51 workers (47 women) whose average length of service was 20 years and 2/3 were part-time workers; a total of 43 UL-WMSDs (59%) were diagnosed in 30 workers, including 13 (30.2%) cases of compressive neuropathies, 13 cases of hand/elbow tendinitis (30.2%) and 17 cases of shoulder tendinitis (39.5%). The average age of these 30 subjects was 47 years, with a length of service of 23 years, mostly part-time workers. We found a high prevalence of general disorders and cases of UL-WMSDs among the workers investigated, including part-time workers and workers who were not working exclusively as cashiers. The study also revealed a poor health surveillance programme to identify/ UL-WMSDs that should be the responsibility of the occupational physician and a consequent underestimation of risk and lack of the information needed to adopt preventive measures.


Talking about Climate Change and Global Warming.
The increasing prevalence of social networks provides researchers greater opportunities to evaluate and assess changes in public opinion and public sentiment towards issues of social consequence. Using trend and sentiment analysis is one method whereby researchers can identify changes in public perception that can be used to enhance the development of a social consciousness towards a specific public interest. The following study assessed Relative search volume (RSV) patterns for global warming (GW) and Climate change (CC) to determine public knowledge and awareness of these terms. In conjunction with this, the researchers looked at the sentiment connected to these terms in social media networks. It was found that there was a relationship between the awareness of the information and the amount of publicity generated around the terminology. Furthermore, the primary driver for the increase in awareness was an increase in publicity in either a positive or a negative light. Sentiment analysis further confirmed that the primary emotive connections to the words were derived from the original context in which the word was framed. Thus having awareness or knowledge of a topic is strongly related to its public exposure in the media, and the emotional context of this relationship is dependent on the context in which the relationship was originally established. This has value in fields like conservation, law enforcement, or other fields where the practice can and often does have two very strong emotive responses based on the context of the problems being examined.


Physapubescin B Exhibits Potent Activity against Human Prostate Cancer In Vitro and In Vivo.
The present data showed that a natural compound isolated from the plant Physalis pubescens L. (Solanaceae), physapubescin B, exhibited antitumor activity against prostate cancer in vitro and in vivo. Treating prostate cancer cells with physapubescin B resulted in the accumulation of cells in the G2/M phase, which was associated with reduced Cdc25C levels and increased levels of CyclinB1, P21 as well as p-Cdk1 (Tyr15). Additionally, reactive oxygen species (ROS) generation was increased in physapubescin B-treated PC-3 cells. Furthermore, the physapubescin B-induced decrease of Cdc25C protein expression together with the G2/M phase cell cycle arrest were significantly abrogated by antioxidant NAC and GSH. Our data also demonstrated that physapubescin B exhibited strong in vivo antitumor efficacy in human prostate cancer PC3 xenograft. In conclusion, our results provide clear evidence that physapubescin B exhibits antitumor activity both in vitro and in vivo and deserves further development as an anticancer agent.


Renal Transplantation in the Gulf Co-operation Council Countries.
The Gulf Co-operation Council (GCC) which has six member-countries was established in 1981 to promote mutual co-operation on various aspects including health care. Efforts are ongoing to have active co-ordination among the member-countries in the field of organ transplantation. Islamic scholars in these countries have approved organ donation from living related and cadaveric donors after obtaining consent from the families concerned. This has paved the way for the implementation of successful renal transplantation programs in many of the GCC countries. The results of the operations performed locally in these countries are encouraging and similar. However, the demand for organs is still high and only 30% of the need is being met at present. Commercial organ donation is strictly prohibited in all these countries. In Saudi Arabia, the Saudi Center for Organ Transplantation (SCOT), erstwhile National Kidney Foundation, was established in 1985. The main objective was to coordinate organ transplantation program in the Kingdom and in the last ten years, the center has gathered remarkable experience in this field. Other GCC countries need to establish cadaveric renal transplantation programs in their countries on similar lines as SCOT.


Somatization and conversion: distinct or overlapping constructs?
The terms somatization and conversion are used descriptively to define specific diagnostic entities, and phenomenologically to denote pathologic processes that underlie somatic symptom formation. There is a lack of clarity, and even controversy, however, as to whether somatization and conversion should be considered distinct or overlapping constructs, and whether they contribute to the pathogenesis of certain organic diseases or solely to medically unexplained somatic symptoms. This article attempts to resolve some of this confusion by reviewing the origins of the terms somatization and conversion, and describing how their meanings and uses have evolved over the last century. Whereas some psychoanalysts and psychiatrists adopted Stekel's view that somatization involves a psychological process analogous to conversion, others maintained Freud's distinction between the psychoneuroses and the actual neuroses and view somatization as a physiological process. Recent psychoanalytic attempts to understand somatization are based on a modern theory of emotional processing, which is rooted in cognitive science and open to empirical research. Maintaining a conceptual distinction between somatization and conversion has important implications for psychoanalytic therapy.


Social Resources, Abortion, and Contraceptive Use Among Women With Criminal Justice Histories.
Women in the criminal legal system face structural barriers to social resources such as education, employment, and benefits. Little is known how these resources intersect with their reproductive lives, specifically with obtaining abortions. We explored the relationship between social resources and abortion history among women incarcerated in a county jail through a secondary analysis of survey data from a 2014 to 2016 jail-based sexual health intervention. Regression analyses determined correlates of having an abortion history. Thirty percent of participants had an abortion and were more likely to have at least a high school education (adjusted odds ratio [aOR] = 3.3; 95% confidence interval [CI] = 1.25-8.77) and a history of sexually transmitted infections (aOR = 3.2; 95% CI = 1.25-8.06). Appropriate systems-level efforts should be expanded to support women with criminal legal histories in their reproductive lives.