The snare technique: a novel atraumatic method for the removal of difficult nasal foreign bodies.
Nasal foreign bodies (NFBs) are a common occurrence, particularly in children between 2 and 4 years old. Many techniques have been developed to remove NFBs, though intranasal batteries, in particular, possess characteristics such as round shape, smooth surface, and limited visibility that make attempts at removal significantly more difficult. In the context of intranasal batteries, a considerable local soft tissue reaction and potential necrosis may exist to further complicate removal. To present a technique for removal of difficult intranasal foreign bodies that may be utilized by health care practitioners, particularly in the Emergency Department setting. We present a case of a 4-year-old child presenting with intranasal battery with mucosal necrosis. After conventional techniques failed, we utilized a novel wire snare technique to dissect the NFB free from the nasal mucosa safely and in an atraumatic fashion. This technique is noted to be a rapid, atraumatic, and effective means for the removal of difficult NFBs.


Repair of UV-irradiated plasmid DNA in mutants of Saccharomyces cerevisiae and Escherichia coli deficient in repair of pyrimidine dimers.
The repair of in vitro UV-irradiated DNA of plasmid pBB29 was studied in excision defective yeast mutants rad1, rad2, rad3, rad4, rad10 and in Escherichia coli mutants uvr- and recA-, by measuring the cell transformation frequency. Rad2, rad3, rad4, and rad10 mutants could repair plasmid DNA despite their inability to repair nuclear DNA, whereas the reduced ability of rad1 mutant for plasmid DNA repair demonstrated alone the same dependence on the host functions that are needed for nuclear DNA repair. In E. coli the repair of UV-irradiated plasmid DNA is carried out only by the excision-repair system dependent on uvr genes. Treatment of UV-irradiated plasmid DNA with UV endonuclease from Micrococcus luteus greatly enhances the efficiency of transformation of E. coli uvr- mutants. Similar treatment with cell-free extracts of yeast rad1 mutant or wild-type strains as well as with nuclease BaL31, despite their ability for preferential cutting of UV damaged DNA, showed no influence on cell transformation.


Blocking by picrotoxin of nigra-evoked inhibition of neurons of ventromedial nucleus of the thalamus.
The transmitter substance realeased by nigro-thalamic fibres is proposed to be gamma-aminobutyric acid, since picrotoxin blocked nigra-evoked monosynaptic inhibition of thalamic neurons.


Dosimetric comparison of carbon ion radiotherapy and stereotactic body radiotherapy with photon beams for the treatment of hepatocellular carcinoma.
The purpose of this study was to compare carbon ion radiotherapy (C-ion RT) and stereotactic radiotherapy (SBRT) with photon beams for the treatment of hepatocellular carcinoma (HCC), specifically with regard to the dose volume parameters for target coverage and normal tissue sparing. Data of 10 patients who were treated using C-ion RT with a total dose of 60 Gy(RBE) in four fractions were used. The virtual plan of SBRT was simulated on the treatment planning computed tomography images of C-ion RT. Dose volume parameters such as minimum dose covering 90% of the planning target volume (PTV D90), homogeneity index (HI), conformity index (CI), mean liver dose (MLD), volume of the liver receiving 5 to 60 Gy (V5-60), and max point dose (Dmax) of gastrointestinal (GI) tract were calculated from both treatment plans. The PTV D90 was 59.6 ± 0.2 Gy(RBE) in C-ion RT, as compared to 56.6 ± 0.3 Gy in SBRT (p < 0.05). HI and CI were 1.19 ± 0.03 and 0.79 ± 0.06, respectively in C-ion RT, as compared to 1.21 ± 0.01 and 0.37 ± 0.02, respectively in SBRT. Only CI showed a significant difference between two modalities. Mean liver dose was 8.1 ± 1.4 Gy(RBE) in C-ion RT, as compared to 16.1 ± 2.5 Gy in SBRT (p < 0.05). V5 to V50 of liver were higher in SBRT than C-ion RT and significant differences were observed for V5, V10 and V20. Dmax of the GI tract was higher in SBRT than C-ion RT, but did not show a significantly difference. C-ion RT provides an advantage in both target conformity and normal liver sparing compared with SBRT.


Pulmonary hypertension: work in progress.
Pulmonary arterial hypertension is a rare disorder defined by mean pulmonary artery pressures that exceed 25 mm Hg at rest or are greater than 30 mm Hg with exercise. The mortality rate is high for untreated patients, mainly as a result of progressive right heart dysfunction. Pulmonary arterial hypertension has been historically classified as primary pulmonary hypertension or pulmonary hypertension resulting from an underlying disease process. Ongoing research in the nuclear medicine field holds great promise for understanding the pathophysiologic pathways for this condition, as well as the monitoring of the continually evolving therapeutic options.


Isolation of Listeria monocytogenes from goat cheese associated with a case of listeriosis in goat.
Listeria monocytogenes was isolated from the brain of a goat, which was euthanized due to listeriosis. A few weeks later a similar subtype of L. monocytogenes was isolated from an on-farm manufactured fresh cheese which did not contain any milk from the goat which had suffered from listeriosis. A similar subtype was also found on 1 of the shelves in the refrigerator where cheeses were stored. Prior to the onset of listeriosis, 1 fresh cheese had been made of milk from the actual goat, which may have excreted L. monocytogenes in her milk. Thus, the cheese made of this milk may have contaminated the shelves in the refrigerator which then has served as a Listeria reservoir for new cheeses during several weeks.


Nostril Surgery: Indications, Surgical Procedures and Outcomes-A Systematic Review of Published Cases.
To achieve adequate nasal proportions, nostril surgery can be a complementary technique useful in facial surgery. To help surgeons with the decision to realize nostril surgery, we conducted a systematic review to summarize reported cases on surgical procedures with a specific interest on indications, surgical procedures and postoperative outcomes. A therapeutic algorithm is also proposed. We carried out this review in accordance with the PRISMA criteria. Twenty-two eligible studies were identified using Medical databases, including 1599 patients. A qualitative and quantitative analysis was carried out. Excision techniques were realized on 728 patients (45.5%), followed by cinching sutures on 642 patients (40%) and combined techniques: excision techniques with flap advancement techniques in 189 cases (12%), excision techniques with flap advancement techniques and cinching suture in 40 patients (2.5%). When excessive alar flaring was present, alar wedge resection was preferred in the 92% of followed by alar and sill resection. Cinching sutures were realized when excessive alar flaring was associated with a vertical alar axis, in cases of wide alar base, of associated orthognathic surgery. When excessive alar flaring was associated with wide alar bases, indications changed basing on the associated deformities. In 795 patients, nostril surgery was conducted simultaneously with rhinoplasty. Nostril surgery through excision techniques, cinching sutures or flaps advancement techniques, reveals good outcomes and can be complementary to rhinoplasty or orthognathic surgery. Through this systematic review, we tried to orient surgeons to find the best treatment for nostril base surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


A biliary endoscopy model.
Intraoperative biliary endoscopy (choledochoscopy) is often not practiced by surgeons despite the availability of both rigid and flexible endoscopes in many operating rooms. The main reasons for this reluctance are lack of familiarity and experience with endoscopic techniques. A biliary model was designed that permits the procedure to be learned. Its important features are mobilization of the duodenum, the use of irrigation, and the possibility of practicing the removal of calculi under visual control. We stress that the use of the choledochoscope is important to reduce the incidence of retained stones after common bile duct explorations.


FOXP3 and scurfy: how it all began.
It has been 65 years since the scurfy mutation arose spontaneously in mice at the Oak Ridge National Laboratory in the United States, and it is 13 years since the molecular cloning of the forkhead box P3 (FOXP3) gene was reported. In this Timeline article, we review the events that have occurred during and since this time. This is not meant as an exhaustive review of the biology of FOXP3 or of regulatory T cells, rather it is an attempt to highlight the landmark events that have demonstrated the importance of FOXP3 in immune function. These events have driven, and continue to drive, the extensive research effort to fully understand the role of regulatory T cells in the immune system.


Shifts in Higher-Order Unions and Stepfamilies among Currently Cohabiting and Married Women of Childbearing Age.
Shifts in union formation and childbearing have undoubtedly altered the prevalence and structure of higher-order unions and stepfamilies, but no study has examined trends over time. Comparing the 1988 and 2011-2013 cycles of the National Survey of Family Growth (NSFG), I produce estimates of repartnering and stepfamily formation among currently partnered women aged 15-44. The percentage of intact unions that are remarriages stayed stable (around 27-28%), but a growing proportion of currently married and cohabiting women had another cohabiting partner in the past. The percentage of intact unions that are stepfamilies increased from 24% to 31%, with an increase in cohabiting stepfamilies from 19% to 39% of all stepfamilies. Further, while the majority of remarriages are stepfamilies, the majority of women's stepfamilies are no longer remarriages due to union formation among never-married parents. Cohabiting (but not marital) stepfamilies also exhibited changes in which partner had children and in shared childbearing.


Racial and ethnic disparities in clinical research and the dermatology workforce: Part 2.
Although racial and ethnic demographics are shifting in this country, it is not reflected in the diversity of clinical trial research participants; science, technology, engineering, and mathematics pipeline programs; or the workforce in the field of dermatology. Barriers to recruitment of minority patients for research studies also exist for numerous reasons including lack of education of prospective subjects, lack of awareness of ongoing trials, and mistrust within the health care system. Gaps in the science, technology, engineering, and mathematics pipeline for racial and ethnic minorities, particularly Black, Hispanic/Latinx, and American Indian or Alaska Native, are due in large part to structural racism. Lack of exposure as well as lack of educational, mentorship, and research opportunities contribute to gaps in the dermatology workforce. Having a representative population in the dermatology workforce and in clinical research trial patients is essential for optimum patient care, excellence in the specialty, and knowledge of appropriate treatments for minority populations. This article will discuss knowledge gaps for increasing minority subjects who participate in clinical research trials and discuss mechanisms to engage this community in trial recruitment. Additionally, this article addresses lack of racial and ethnic diversity of the dermatology workforce and performance gaps in the recruitment of racial/ethnic minorities into dermatology.


Classic chordoma coexisting with benign notochordal cell rest demonstrating different immunohistological expression patterns of brachyury and galectin-3.
Increasing numbers of studies support the hypothesis that chordoma arises from notochordal cell rests, although the mechanism awaits further research. Brachyury is the first specific molecule linking chordoma with the notochord, and galectin-3 has been widely used as a marker of notochordal cells. We conducted a histological study of the expression of these two molecules in 46 classic chordoma specimens and unexpectedly found that classic chordoma tumor cells coexisted with benign notochordal cell rests in six specimens. Brachyury and galectin-3 expression were investigated by immunohistochemistry. All specimens contained atypical chordoma tumor cells set within an abundant myxoid matrix, which strongly expressed brachyury and galectin-3. However, brachyury and galectin-3 were not expressed in the notochordal cells. Benign notochordal cells, present as notochord rests, could undergo malignant transformation to form chordoma; however, the cause and role of brachyury and galectin-3 expression in chordoma tumorigenesis requires further careful study.


Radiation therapy of pineal region tumors: 25 new cases and a review of 208 previously reported cases.
Malignant pineal region tumors are rare neoplasms arising in midline structures of the brain. This report analyzes the influence of histology, tumor location, radiation dose, treatment volume, age and cerebrospinal fluid findings on freedom from relapse, freedom from spinal relapse and survival. Patient and treatment parameters of 25 cases of pineal region tumors managed at Stanford University are presented, and an additional 208 published cases were reviewed. Univariate and multivariate analysis were performed to delineate parameters predictive of freedom from relapse, freedom from spinal relapse, and survival for all 233 patients. The 5- and 10-year freedom from relapse for Stanford patients was 63% and 46%, respectively. The 5- and 10-year survival for Stanford patients was 67% and 61%, respectively. The 5- and 10-year freedom from relapse for the total 233 cases was 66% and 61%, respectively. The 5- and 10-year survival for all patients was 74% and 68%, respectively. For the entire group, biopsy confirmed germinoma and non-biopsied tumors had superior freedom from relapse compared to non-germinoma germ cell tumors (p = 0.03, p = 0.005, respectively). Non-biopsied patients had improved survival compared to non-germinoma germ cell tumors (p = 0.004). Pineal parenchymal tumors had worse freedom from relapse compared to non-biopsied patients (p = 0.04). For patients with suprasellar tumors, germinomas were associated with improved freedom from relapse compared to non-germinoma germ cell tumors (p = 0.02). Simultaneous pineal and suprasellar tumors had superior survival compared to solitary tumors of pineal (p = 0.04), suprasellar (p = 0.03), or third ventricle location (p = 0.03). Twenty-two patients (9.4%) developed isolated spinal relapse. Five- and 10-year spinal relapse rates for all patients were 11% and 13%. Survival after spinal relapse was 19%. Pineal parenchymal tumors had lower freedom from spinal relapse compared to non-biopsied patients (p = 0.001). For tumors located in the pineal gland, germinomas and pineal parenchymal tumors had lower freedom from spinal relapse than did non-biopsied patients (p = 0.006, p = 0.004, respectively). Pineal germinomas had lower freedom from spinal relapse than germinomas with suprasellar location (p = 0.04). Univariate and multivariate analysis identified tumor histology as the most significant predictor of freedom from relapse, freedom from spinal relapse and survival. Histologic type had the greatest impact on outcome. Treatment recommendations should be based on assessment of histologic type and extent of disease.


Approaches to Mixed Methods Dissemination and Implementation Research: Methods, Strengths, Caveats, and Opportunities.
Limited translation of research into practice has prompted study of diffusion and implementation, and development of effective methods of encouraging adoption, dissemination and implementation. Mixed methods techniques offer approaches for assessing and addressing processes affecting implementation of evidence-based interventions. We describe common mixed methods approaches used in dissemination and implementation research, discuss strengths and limitations of mixed methods approaches to data collection, and suggest promising methods not yet widely used in implementation research. We review qualitative, quantitative, and hybrid approaches to mixed methods dissemination and implementation studies, and describe methods for integrating multiple methods to increase depth of understanding while improving reliability and validity of findings.


ASA III osteoporotic fracture in 62 patients treated with vertebroplasty under local anesthesia.
Vertebroplasty is a minimally invasive procedure that may be performed under either local or general anesthesia. In this study, we aimed at assessing the outcomes of the vertebroplasty performed under local anesthesia in patients at high risk of general anesthesia. Vertebroplasty was performed under local anesthesia in the treatment of a total of 62 patients (68 vertebrae in total) with osteoporotic vertebral fractures between 2011 and 2013. None of the patients had a history of trauma. Patients who were classified as ASA III during the preoperative examinations were included in the study. VAS scores were evaluated before the surgery, on the first postoperative day, and in week 1 and in month 1 after the surgery. The average age was 77.5 years (age range 53-102). An average of 2 cc of cement was injected to 22 patients (35.5 %), and an average of 3 cc of cement was injected to 40 patients (64.5 %). The mean VAS scores were 7.52 (6-9) before the procedure, 3.55 (2-5) on the first day, 2.03 (0-4) in week 1 and 0.87 (0-2) in month 1 postoperatively. Asymptomatic cement embolism was detected in one patient. No other complications were observed in the study group. Vertebroplasty performed under local anesthesia is an effective and safe procedure in terms of pain control and early ambulation and is bereft of the complications associated with general anesthesia.


Is the modality of the supersensitivity after sympathectomy age and duration dependent?
Sympathetic denervation of the rat parotid gland was performed neonatally or in adult fully developed animals on one side. The contralateral gland served as control. Two and 9 weeks later the glands were used for in vitro amylase secretory studies. The neonatally denervated glands displayed an enhanced response to high concentrations of noradrenaline, without significant changes in the lower concentration range. In adult sympathectomized animals no significant alteration could be recorded in secretory response 9 weeks after denervation. Two weeks after adult ganglionectomy a striking leftward shift of the noradrenaline concentration-response curve was observed without changes in the maximal response. Thus, the modality of the supersensitivity appears to be influenced by the age of the animal when the surgical procedure is performed, as well as by the duration of the denervation.


[Vertebral erosions in abdominal aortic aneurysms as a cause of chronic low back pain. A series of 5 cases].
Chronic low back bain is a common cause of medical consultation, and is often associated with degenerative vetebral disease. Despite this, we must not forget other diseases even in those cases where the imaging tests may suggest chronic degenerative changes in the lumbar spine, including the possible presence of an abdominal aortic aneurysm with a contained rupture must be ruled out due to its prognostic and therapeutic implications. We present 5 cases of chronic low back pain associated with serious lytic lesions in the vertebral body due to chronic rupture of an abdominal aortic aneurysm.


The Role of Palliative Care in Burns: A Scoping Review.
Patients with severe burns may face distressing symptoms with a high risk of mortality as a result of their injury. The role of palliative care in burns management remains unclear. To appraise the literature on the role of palliative care in burns management. We used scoping review with searches in 12 databases from their inception to August 2019. The citation retrieval and retention are reported in a PRISMA statement. 39 papers comprising of 30 primary studies (26 from high-income and four from middle-income countries), four reviews, two editorials, two guidelines, and one expert board review document were retained in the review. Palliative care is used synonymously with comfort and end-of-life care in burns literature. Comfort care is mostly initiated when active treatment is withheld (early deaths) or withdrawn (late deaths), limiting its overall benefits to burn patients, their families, and health care professionals. Futility decisions are usually complex and challenging, particularly for patients in the late death category, and it is unclear if these decisions result in timely commencement of comfort care measures. Three comfort care pathways were identified, but it remained unclear how these pathways evaluated "good death" or supported the family which creates the need for the development of other evidence-based guidelines. Palliative care is applicable in burns management, but its current role is mostly confined to the end-of-life period, suggesting that it is not been fully integrated in the management process. Evidence-based guidelines are needed to support the integration and delivery of palliative care in the burn patient population.


Host-pathogen interaction unveiled by immune, oxidative stress, and cytokine expression analysis to experimental Saprolegnia parasitica infection in Nile tilapia.
The present study evaluated the pathogenicity, immunological, and oxidant/antioxidant responses against Saprolegnia parasitica (S. parasitica) infection in Nile tilapia (Oreochromis niloticus). Three groups of Nile tilapia were assigned as the control group (no zoospores exposure). The other two groups were challenged by Saprolegnia zoospores; one was used for sampling, and the other for mortality monitoring. The study lasted 3 weeks and was sampled at three point times at 1, 2, and 3 weeks. Results showed that S. parasitica zoospores were pathogenic to Nile tilapia, causing a cumulative mortality rate of 86.6%. Immunoglobulin M and C- reactive protein (IgM and CRP) levels showed a similar trend being significantly (P < 0.05, P < 0.001) higher in the infected group at weeks 1, 2, and 3, respectively, compared to the control group. Oxidant and antioxidant parameters in gills revealed that Malondialdehyde (MDA) level was significantly higher in the infected group compared to the control group. While catalase, glutathione peroxidase, and superoxide dismutase (CAT, GSH, and SOD) levels were significantly decreased in the infected group compared to the control group. Compared to the control, the tumor necrosis factor-α (TNF-α) gene was firmly upregulated in gill tissue at all-time points, particularly at day 14 post-infection. Meanwhile, Interleukin 1-β (IL-1 β) gene was significantly upregulated only at days 7 and 14 post-infection compared to control. Histopathological examination revealed destructive and degenerative changes in both skin and gills of experimentally infected Nile tilapia. Our findings suggest that Nile tilapia-S. parasitica infection model was successful in better understanding of pathogenicity and host (fish)-pathogen (oomycete) interactions, where the induced oxidative stress and upregulation of particular immune biomarkers in response to S. parasitica infection may play a crucial role in fish defense against oomycetes in fish.


Cytotoxic Evaluation and Molecular Docking Studies of Aminopyridine Derivatives as Potential Anticancer Agents.
The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure. The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2- aminopyridine could attenuate tumor development using colorectal cancer cell lines. Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay. The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1μM and 3.27-7.7 μM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 μg/ml. In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.


A Case of Woolly Hair Nevus Associated with Pigmentary Demarcation Lines and Heterochromia Iridis: Coincidence or a New Association?
We report a case of woolly hair nevus with pigmentary demarcation lines and heterochromia iridis. Woolly hair nevus is a rare abnormality of the scalp hair characterized by the patch of hair, which is curlier and light colored than the rest of the scalp hair. Association of woolly hair nevus with some other ectodermal defects effecting skin and eyes has been reported before. Here, woolly hair nevus associated with demarcation lines and heterochromia iridis, to our knowledge, have not been previously reported.


Topotecan: a new topoisomerase I inhibiting antineoplastic agent.
To review the pharmacologic, pharmacokinetic, therapeutic, and safety aspects of topotecan, a new antineoplastic agent, and to assess its role in the treatment of cancer. MEDLINE database English language only, January 1990-March 1998; SmithKline Beecham Pharmaceuticals; published articles, books, and abstracts. Studies in humans with cancer, clinical case reports, open clinical trials, and controlled clinical studies. Efficacy studies were limited primarily to trials with at least 20 evaluable patients: Relevant data were extracted only from published reports. Data were obtained from studies in both articles and abstracts. Only articles written in English were reviewed. Topotecan is an effective second- or third-line therapy for patients with advanced ovarian cancer and is comparable to ifosfamide, liposomal doxorubicin, and paclitaxel. Activity in combination with other agents and as a first-line agent is yet to be determined. Limited data indicate activity in small-cell lung cancer, cancers of the breast and uterus, and in nonlymphocytic leukemia. The dose-limiting toxicity is myelosuppression. Topotecan is an effective second-line agent for patients with unresponsive or relapsed cancer of the ovary. It appears to be similar to other active agents in patients with this disease status. Its ultimate role in ovarian cancer and other neoplasms awaits additional evaluation in combination with other agents and as first-line therapy.


Plain radiographs are inadequate to identify overlengthening with a radial head prosthesis.
A correctly sized radial head implant helps restore more normal elbow motion and load distribution and allows the collateral ligaments to heal in an anatomic position. No single method of measurement has been agreed on. We hypothesized that plain radiographs could be used to evaluate the appropriate length of a radial head prosthesis when we simulated different patterns of ligament disruption. Osteotomies of the medial and lateral condyles were created in 6 cadaver specimens to simulate 4 conditions: ulnar collateral ligament (UCL) and lateral ulnar collateral ligament (LUCL) intact, UCL intact, LUCL intact, and UCL and LUCL disrupted. Radial heads were resected and replaced with correctly or incorrectly sized monopolar radial head implants. Radiographs were taken after simulated ligament injury with a radial head prosthesis that was either 2 mm too short, the appropriate length, or too long by either 2 or 4 mm. Measurements were recorded between radiographic markers to determine ulnohumeral joint displacement. A 4 x 4 x 2 repeated-measures analysis of variance was performed, as well as post hoc analyses using Tukey's honest significant difference test, to determine statistically significant changes in our radiographic measurements. Results showed that disruption of at least 1 ligament alters the ulnohumeral joint separation on the lateral but not on the anteroposterior radiograph. Overlengthening the radial head did not result in a statistically significant change in ulnohumeral space. Replicating radial length is an important but sometimes difficult step during radial head replacement. Standard radiographic assessment of the ulnohumeral joint will not demonstrate marked changes in the ulnohumeral space when the implant is underlengthened by 2 mm or overlengthened by as much as 4 mm, as long as the joint remains located. Disruption of at least 1 collateral ligament alters the ulnohumeral joint separation on the lateral but not on the anteroposterior radiograph.


Third year medical student knowledge gaps after a virtual surgical rotation.
This study describes perceived knowledge gaps of third-year medical students after participating in a virtual surgical didactic rotation (EMLR) and shortened in-person surgery rotation during the COVID-19 Pandemic. Open-ended and Likert questions were administered at the end of the virtual rotation and inperson-surgical rotation to medical students. Three blinded coders identified themes by semantic analysis. 82 students (51% of all MS3s) participated in the EMLR. Semantic analysis revealed gaps in perioperative management (Post-EMLR:18.4%, Post-Inpatient:26.5%), anatomy (Post-EMLR:8.2%, PostInpatient:26.5%). and surgical skills (Post-EMLR: 43.0%, Post-Inpatient: 44.1%). Students also described gaps related to OR etiquette (Post-EMLR: 12.2%, Post-Inpatient: 8.8%) and team dynamics/the hidden curriculum (Post- Inpatient:26.6%). There was a significant improvement in perceived confidence to perform inpatient tasks after completing the inpatient clinical experience (p ≤ 0.01). Virtual interactive didactics for cognitive skills development cannot replace a full clinical surgical experience for third-year medical students. Future curricula should address perceived gaps.


[Diagnosis of HER2 gene amplification in breast carcinoma].
Amplification of the HER2 gene, mapping to 17q21.1, is present in about 20 % of breast carcinomas. Amplification leads to an overexpression of the protein that made it possible to develop a targeted therapy by the monoclonal antibody trastuzumab (Herceptin). A good response to the treatment requires a stringent assessment of the gene status in tumours; only patients whose tumour shows a high expression of the protein or an amplification of the gene are eligible. Cases with intermediate level expression are checked by in situ hybridization, mainly by FISH, to identify amplifications in this subset of tumours. Results are sometimes difficult to interpret due to the frequent aneuploidy of the tumours. Moreover, copy number cut-offs of the gene for defining an amplification are variable according to the studies. A tumour is considered now as amplified when showing more than six HER2 copies per nucleus, or a ratio HER2 to centromere 17 greater than 2.2. The phenomenon of HER2 amplification in breast cancers is discussed in this paper, and distinguished from gene overrepresentation. It is recommended that tumours showing six to seven copies of HER2 are assessed with a kit including the centromere 17. Clusters of signals are characteristic of amplifications. The process designed for the assessment of HER2 is a model of strategies that will be used for the evaluation of markers involved in future targeted therapies.


[Useful tests to assess the clinical usefulness of new prognostic markers: the example of heart failure].
Identification of risk factors is one of the most frequent questions in medical research currently. Several reports showed "significant" and "independent" prognostic factors in a variety of human conditions, however, those were not tested about predictive information in addition to standard risk markers. Recently novel statistical approaches (reclassification) have been developed to test the performance and usefulness of new risk factors and prognostic markers. There are several established methods to test the prognostic models. The aim of this work was to present the application of these novel statistical approaches by re-analyzing previously reported results of the authors. The authors analyzed the prognostic role of two markers: red cell distribution width and heat shock protein 70 in patients with heart failure. Using Cox regression analyses the authors have reported previously that both markers are independent predictors. In the present study they re-analyzed the role of red cell distribution width and heat shock protein 70 by reclassification tests. Incorporating red cell distribution width to the reference model the authors found a significant improvement in discrimination . However, the reclassification analysis provided ambiguous results with heat shock protein 70. Interpretation of results on new prognostic factors has to be done carefully, and appropriate reclassification approaches may help to confirm clinical usefulness only.


Adiponectin receptor 1 gene (ADIPOR1) variant is associated with advanced age-related macular degeneration in Finnish population.
Adiponectin is an adipocyte-expressed protein that regulates the glucose, lipid, and energy metabolism via adiponectin receptors 1 and 2. Obesity is a known risk factor for age-related macular degeneration (AMD). We, therefore, examined associations of single nucleotide polymorphisms in Adiponectin (ADIPOQ) and Adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) genes with the prevalence of advanced AMD in Finnish population. Thirty-seven markers for ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in a sample collection of 91 men and 177 women having exudative AMD and 18 men and 26 women having severe atrophic AMD. Patients were diagnosed by fundus photographs and fluorescein angiography. The control group (no signs of AMD in fundus photographs) consisted of 55 men and 111 women. Inclusion criteria age was over 65 years old without diabetes diagnosis. Out of the tested SNPs, rs10753929 located in intron of ADIPOR1 gene was significantly associated (p=0.0471) with AMD status when using a permutation procedure that controlled for the number of tested genotypes and genetic models. Odds ratio (OR) for the association was 1.699 (95% CI 1.192-2.423). The SNP consists of C/T alleles and the risk allele T had a minor allele frequency (MAF) of 20.4%. Distribution of proportion of cases/controls between alleles revealed an additive genetic model. Our findings reveal that rs10753929 ADIPOR1 variant is a novel candidate for AMD genetic risk factor in Finnish population.


Pyruvate inhibits zinc-mediated pancreatic islet cell death and diabetes.
We have shown that zinc ion (Zn2+) in secretory granules of pancreatic beta cells could act as a paracrine death effector in streptozotocin-induced diabetes. As Zn2+ has been reported to perturb glycolysis, we studied if pyruvate could inhibit Zn(2+)-mediated islet cell death in vitro and streptozotocin-induced diabetes in vivo by normalizing intracellular energy metabolism. Cell death was measured by quantitative viable cell staining and Hoechst/propidium iodide staining. ATP was measured by bioluminescence determination. Pyruvate was infused through the tail vein 1 h before streptozotocin administration. Beta-cell volume was measured by point counting of the insulin-containing cells. Zn2+ induced classical necrosis on MIN6N8 insulinoma cells which was associated with a rapid decline of intracellular ATP levels. Pyruvate inhibited Zn(2+)-induced necrosis of insulinoma cells and depletion of intracellular ATP by Zn2+. Pyruvate did not inhibit other types of necrosis or apoptosis. Energy substrates such as oxaloacetate, alpha-ketoglutarate and succinic acid dimethylester also attenuated Zn(2+)-induced insulinoma cell death. Methylpyruvate that does not generate NAD+ in the cytoplasm or alpha-ketoisocaproate that stimulates ATP generation exclusively in mitochondria also protected insulinoma cells from Zn(2+)-induced necrosis. Pyruvate infusion inhibited the development of diabetes by protecting beta-cell mass after streptozotocin administration. These results indicate that pyruvate inhibits Zn(2+)-induced necrosis of beta cells in vitro by protecting intracellular ATP levels and also streptozotocin-induced diabetes in vivo where Zn2+ has been reported to act as a paracrine death effector.


Involvement of suppressor of cytokine signalling-1-mediated degradation of MyD88-adaptor-like protein in the suppression of Toll-like receptor 2-mediated signalling by the murine C-type lectin SIGNR1-mediated signalling.
Dendritic cells recognize pathogens through pattern recognition receptors such as Toll-like receptors and phagocytose and digest them by phagocytic receptors for antigen presentation. This study was designed to clarify the cross-talk between recognition and phagocytosis of microbes in dendritic cells. The murine dendritic cell line XS106 cells were stimulated with the murine C-type lectin SIGNR1 ligand lipoarabinomannan and the Toll-like receptor 2 ligand FSL-1. The co-stimulation significantly suppressed FSL-1-mediated activation of NF-κB as well as production of TNF-α, IL-6 and IL-12p40 in a dose-dependent manner. The suppression was significantly but not completely recovered by knock-down of SIGNR1. SIGNR1 was associated with Toll-like receptor 2 in XS106 cells. The co-stimulation upregulated the expression of suppressor of cytokine signalling-1 in XS106 cells, the knock-down of which almost completely recovered the suppression of the FSL-1-mediated cytokine production by lipoarabinomannan. In addition, it was found that the MyD88-adaptor-like protein in XS106 cells was degraded by co-stimulation with FSL-1 and lipoarabinomannan in the absence, but not the presence, of the proteasome inhibitor MG132 and the degradation was inhibited by knock-down of suppressor of cytokine signalling-1. This study suggests that Toll-like receptor 2-mediated signalling is negatively regulated by SIGNR1-mediated signalling in dendritic cells, possibly through suppressor of cytokine signalling-1-mediated degradation of the MyD88-adaptor-like protein.


Antipodean aquaculture agents.
Parallel features exist among diseases in Antipodean hosts when compared with those in other tropical and temperate regions. These features can be associated between infections in fish and prawns and between infections in freshwater and saltwater systems. Both fish and prawns are prone to physical stress, to behavioural stress, and to both introduced and native disease agents, agents that are limiting factors in several established aquaculture ventures. Both types of hosts are reared in a variety of facilities, each allowing for a different dynamic predisposition for disease. These diseases include those caused by native freshwater, estuarine and marine agents in both introduced and native hosts, and by introduced agents in those hosts. Some infections reflect unexpected or unidentifiable agents and host responses. Much can be learned in Australia and New Zealand from the infections, successes, failures and innovative methodologies experienced or used in the rest of the world. Potential in the Antipodes for production of unique and abundant fishery products is immense for both local and export markets. Approaches, however, should remain cautious regarding introductions and persistent regarding the investigation of potential diseases, host responses, diagnostic methods and management techniques.


Long Noncoding RNAs as Targets and Regulators of Nuclear Receptors.
Intensive research has been directed at the discovery, biogenesis, and expression patterns of long noncoding RNAs , yet their biochemical functions have remained elusive for the most part. Nuclear receptors that interpret signaling mediated by small molecule hormones play a role in regulating the expression of some long noncoding RNAs. More importantly, these RNAs have also been shown to effect hormone-affected gene transcription regulated by the nuclear receptors. In this chapter, we summarize the current knowledge that has been acquired on hormonal signaling inducing expression of long noncoding RNAs and how they then may act in trans or in cis to modulate gene transcription. We highlight a few of these noncoding RNA molecules in terms of how they may impact hormone-driven cancers. Future directions critical for moving this field forward are presented, with a clear emphasis on the need for better biochemical approaches to address the mechanism of action of these exciting RNAs.


Maternal self-confidence during the first four months postpartum and its association with anxiety and early infant regulatory problems.
Maternal self-confidence has become an essential concept in understanding early disturbances in the mother-child relationship. Recent research suggests that maternal self-confidence may be associated with maternal mental health and infant development. The current study investigated the dynamics of maternal self-confidence during the first four months postpartum and the predictive ability of maternal symptoms of depression, anxiety, and early regulatory problems in infants. Questionnaires assessing symptoms of depression (Edinburgh Postnatal Depression Scale), anxiety (State-Trait Anxiety Inventory), and early regulatory problems (Questionnaire for crying, sleeping and feeding) were completed in a sample of 130 women at three different time points (third trimester (T1), first week postpartum (T2), and 4 months postpartum (T3). Maternal self-confidence increased significantly over time. High maternal trait anxiety and early infant regulatory problems negatively contributed to the prediction of maternal self-confidence, explaining 31.8% of the variance (R=.583, F3,96=15.950, p<.001). Our results emphasize the transactional association between maternal self-confidence, regulatory problems in infants, and maternal mental distress. There is an urgent need for appropriate programs to reduce maternal anxiety and to promote maternal self-confidence in order to prevent early regulatory problems in infants.


Sectoral assessment of greenhouse gas emissions in Pakistan.
In this study, an attempt has been made to develop inventory of greenhouse gas (GHG) emissions for Pakistan at the national and sectoral level. The emission profile includes carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). In 2012, GHG emissions from different sectors of economy are estimated at 367 Tg CO2eq. Out of this, CO2 emissions were 179 Tg; CH4 emissions were 107 Tg CO2eq; and N2O emissions were 81 Tg CO2eq. Energy and agriculture sectors contribute approximately 89% of national GHG emissions. Industrial processes, waste, and land use change and forestry (LUCF) sectors contribute the remaining 11% GHG emissions. A comparison with the 1994 GHG emission inventory of Pakistan shows that GHG emissions in Pakistan from 1994 to 2012 have increased at an annual growth rate of 4.1% and yet anticipated to increase further for meeting the national developmental goals; however, the per capita emissions in Pakistan will remain low when compared with the global average.


Diagnostic and Management Strategies for Common Neurobehavioral and Psychiatric Disturbances Among Patients with Cognitive Impairment and the Dementias.
Neurobehavioral and neuropsychiatric symptoms are highly prevalent among individuals diagnosed with cognitive impairment or dementia and impact the quality of life for patients and caregivers alike. Diagnosis and management of these conditions (including primarily depression, anxiety, apathy, psychosis, agitation, and aggression) is crucial to optimal patient care outcomes in clinical practice. The present article provides a practical review of diagnostic approaches and management strategies for behavioral and neuropsychiatric disorders arising in patients with cognitive impairment, up to and including dementia.


Analysis of signaling pathways controlling flagellar movements in mammalian spermatozoa.
The mammalian sperm flagellum is an example of organelles where sensory and signaling functions are integrated with motility. Structurally related to other ciliary appendages, it has unique cytoskeletal structures that serve to assemble signaling complexes as well as components of metabolic pathways. Flagellar motility is regulated by signaling events that control sperm ion milieu, energy production, and classical second messenger-dependent phosphorylation cascades. Here, we will concentrate on the cAMP signaling pathway associated with flagellar motility. We will describe methods to analyze the properties of a unique adenylyl cyclase termed sAC (gene name Sacy, Adcy10), which plays an essential function in cAMP accumulation in spermatozoa. This soluble adenylyl cyclase (sAC) is a sensor for bicarbonate, pH, and Ca(2+) and is likely involved in coupling energy homeostasis with signaling events. We will also describe methods to investigate the macromolecular complexes that bring together sAC and other signaling molecules.


[Global management of melanoma in the palliative phase].
The priority of the care management of people with melanoma in the palliative stage is to treat symptoms causing discomfort and to provide psychological support. The commitment of caregivers is important, both on the professional as well as human level. A team in Lyon shares its practices.


Relation between the number of image planes and the accuracy of three-dimensional echocardiography for measuring left ventricular volumes and ejection fraction.
The relation between accuracy of 3-dimensional echocardiography (3DE) in determining left ventricular end-diastolic volume, end-systolic volume, and ejection fraction (compared with magnetic resonance imaging) and the number of component planes used for 3DE ventricular reconstruction was evaluated in 41 adult subjects with normal (n = 24) and abnormal (n = 17) left ventricles. Accuracy and confidence of 3DE gradually increased with use of additional component planes, so that > or = 10 planes from both parasternal and apical windows provided 3DE reconstructions that accurately predict magnetic resonance imaging-measured left ventricular volumes and ejection fraction with confidence.


Association of Sex With Outcomes in Patients Undergoing Percutaneous Coronary Intervention: A Subgroup Analysis of the GLOBAL LEADERS Randomized Clinical Trial.
Women experience worse ischemic and bleeding outcomes after percutaneous coronary intervention (PCI). To assess the association of sex with patient outcomes at 2 years after contemporary PCI and with the efficacy and safety of 2 antiplatelet strategies. This study is a prespecified subgroup analysis of the investigator-initiated, prospective, randomized GLOBAL LEADERS study evaluating 2 strategies of antiplatelet therapy after PCI in an unselected population including 130 secondary/tertiary care hospitals in different countries. The main study enrolled 15 991 unselected patients undergoing PCI between July 2013 and November 2015. Patients had an outpatient clinic visit at 30 days and 3, 6, 12, 18, and 24 months after the index procedure. Data were analyzed between January 1, 2019, and March 31, 2019. Eligible patients were randomized to either the experimental or reference antiplatelet strategy. Experimental strategy consisted of 1 month of dual antiplatelet therapy (DAPT) followed by 23 months of ticagrelor monotherapy, while the reference strategy comprised of 12 months of DAPT followed by 12 months of aspirin monotherapy. The primary efficacy end point was the composite of all-cause mortality and new Q-wave myocardial infarction at 2 years. The secondary safety end point was Bleeding Academic Research Consortium type 3 or 5 bleeding. Of the 15 968 patients included in this study, 3714 (23.3%) were women. The risk of the primary end point at 2 years was similar between women and men (adjusted hazard ratio [HR], 1.00; 95% CI, 0.83-1.20). Compared with men, women had higher risk of Bleeding Academic Research Consortium type 3 or 5 bleeding (adjusted HR, 1.32; 95% CI, 1.04-1.67) and hemorrhagic stroke at 2 years (adjusted HR, 4.76; 95% CI, 1.92-11.81). At 2 years, there was no between-sex difference in the efficacy and safety of the 2 antiplatelet strategies. At 1 year, compared with DAPT, ticagrelor monotherapy was associated with a lower risk of bleeding in men (HR, 0.72; 95% CI, 0.53-0.98) but not in women (HR, 1.23; 95% CI, 0.80-1.89; P for interaction = .045). Compared with men, women experienced a higher risk of bleeding and hemorrhagic stroke after PCI. The effect of 2 antiplatelet strategies on death and Q-wave myocardial infarction following PCI did not differ between the sexes at 2 years. ClinicalTrials.gov identifier: NCT01813435.


Frequency of gamma H2AX foci in healthy volunteers and health workers occupationally exposed to X-irradiation and its relevance in biological dosimetry.
Gamma-H2AX (γ-H2AX) assay is a marker to measure double-strand breaks in the deoxyribonucleic acid. Variables such as age, oxidative stress, temperature, genetic factors and inter-individual variation have been reported to influence the baseline γ-H2AX focus levels. Therefore, knowledge on baseline frequency of γ-H2AX foci in a targeted population would facilitate reliable radiation triage and dose estimation. The objective of the present study was to establish the baseline data using blood samples from healthy volunteers (n = 130) differing in age, occupation and lifestyle as well as from occupationally exposed health workers (n = 20). The γ-H2AX focus assay was performed using epifluorescence microscopy. In vitro dose-response curve for γ-H2AX foci was constructed in blood samples (n = 3) exposed to X-rays (30 min post-exposure). The mean γ-H2AX focus frequency obtained in healthy volunteers was 0.042 ± 0.001 and showed an age-related increase (p < 0.001). Significantly higher (p < 0.005) focus frequencies were observed in health workers (0.066 ± 0.005) than in healthy volunteers. A sub-group analysis did not show a significant (p > 0.1) difference in γ-H2AX focus frequency among sexes. Blood exposed in vitro to X-rays showed dose-dependent increase in γ-H2AX foci frequency (Y = 0.1902 ± 0.1363 + 2.9020 ± 0.3240 * D). Baseline frequency of γ-H2AX foci obtained from different age groups showed a significant (p < 0.01) influence on the dose-response coefficients. The overall results demonstrated that the γ-H2AX assay can be used as a reliable biomarker for radiation triage and estimating the radiation absorbed dose by considering variables such as age, occupation and lifestyle factors.


Validation of the Japanese Society for Surgery of the Hand version of the Disability of the Arm, Shoulder, and Hand questionnaire.
The Disability of the Arm, Shoulder and Hand (DASH) questionnaire is a region-specific self-administered questionnaire that consists of a disability/symptom (DASH-DS) scale, and two optional modules, the work (DASH-W) and the sport/music (DASH-SM) modules. The DASH was cross-culturally adapted and developed by the Impairment Evaluation Committee, Japanese Society for Surgery of the Hand. The purpose of this study was to test the reliability, validity, and responsiveness of the Japanese version of DASH (DASH-JSSH). A series of 72 patients with upper extremity disorders completed the DASH-JSSH, the medical outcomes study 36-item short-form health survey (SF-36), and the Visual Analog Scale (VAS) for pain. Thirty-eight of the patients were reassessed for test-retest reliability 1 or 2 weeks later. Reliability was investigated by reproducibility and internal consistency. To analyze the validity, a principal component analysis and correlation coefficients between the DASH-JSSH and the SF-36 were obtained. Responsiveness was examined by calculating the standardized response mean (mean change/SD) and effect size (mean change/SD of baseline value) after carpal tunnel release of the 17 patients with carpal tunnel syndrome. Cronbach's alpha coefficients in the DASH-DS and DASH-W were 0.962 and 0.967, respectively. The intraclass correlation coefficients for the same were 0.82 and 0.85, respectively. The unidimensionality of the DASH-DS and DASH-W were confirmed. The correlations between the DASH-DS score and the subscale of the SF-36 scale ranged from -0.29 to -0.73. The correlation coefficient between the DASH-DS and the DASH-W was 0.79. The standardized response mean/effect size of DASH-DS, DASH-W, and VAS for pain were -0.48/-0.26, -0.68/-0.41, and -0.40/-0.40, respectively. DASH-DS and DASH-W were as moderately sensitive as VAS for pain. The DASH-DS and DASH-W Japanese version have evaluation capacities equivalent to those of the original and other language versions of the DASH.


Ki: a key to transform the century of death to the century of life.
This is my response to the commentary written by Mr James Flowers with the title of 'What is Qi?' in the issue 4 of Vol.3 (2006) of eCAM. I will explain my opinions regarding the importance of Ki research, philosophical aspects of Ki and a possible role of Ki now and in the future.


Important methodological aspects that should be taken into account during the research of isolated mitochondria.
Isolated mitochondria have been widely used for the study of energetic functioning of these important cellular organelles in a physiological or pathophysiological state. This is due, on the one part, to the fact that isolated mitochondria are relatively easy to isolate from a great variety of animal tissues, and on the other part to the fact that their energetic functioning is relatively easy to study experimentally. Nevertheless, they have a great disadvantage because of the fact that these biological structures can easily undergo structural-functional changes during their in vitro handling, causing many conclusions reported in the research of isolated mitochondria to be merely the fruit of experimental artifacts. The present review describes a series of important methodological aspects that should be taken into account in order to obtain reliable results in the study of the energetic functioning (and of other aspects) of isolated mitochondria.


Xenogenic transplantation of human bladder- and renal-cell carcinoma into NMRI mice treated with cyclosporin A and into NMRI nu/nu mice. Introduction of a new experimental cancer model.
128 tumors from three different human renal-cell carcinomas and from one human transitional bladder cancer were transplanted into NMRI mice treated with cyclosporin A at various dosages. Their acceptance rate, proliferation rate, and morphologic and growth characteristics were studied and compared with those of the same human tumors after transplantation into NMRI nu/nu mice. The acceptance rate was 80% in mice treated with cyclosporin A at 100 mg/kg-1 and 150 mg/kg-1/day. The highest acceptance rate was observed after transplantation into nu/nu (thymus-aplastic) mice (100%). Morphologically, the transplanted tumor was similar in the two animal groups and identical with the primary tumors. Metastases were not seen in either animal model. The NMRI mice treated with cyclosporin A had leukocyte infiltration into the transplanted tumor. The growth rate of the human tumors in normal mice depended on the cyclosporin A dosage, and was highest in the nu/nu mice. The proliferation rates of the transplanted human tumors, as judged by flow cytometry, were rather similar in all groups.


Pattern of ventilation during halothane anaesthesia in infants less than two months of age.
To examine the breathing pattern of infants aged less than two months in order to understand better the effect of halothane on ventilation in infants. The inspiratory flow waveform, the CO2 waveform and occluded inspiratory pressure waveform were recorded at different inspired concentrations of halothane using a washout of halothane in two groups of infants undergoing elective herniorrhaphy. Data were analyzed for minute ventilation (Vi) and tidal volume (VT), parameters of timing of the breath [Total time (Ttot), Inspiratory time (Ti), and the ratio of the occluded to unoccluded inspiratory time (TiOCC/Ti)], parameters of Amplitude of the neural output [mean inspiratory flow (VT/Ti)] and parameters of the Shape of the inspiratory breath profile [the inspiratory flow centroid (Ci/Ti), the inspiratory duty cycle (Ti/Ttot)]. The airway was occluded at end expiration and the slope of the initial 100 msec of occlusion (dP/dt) together with the maximal negative pressure (PMAX) and occluded inspiratory time (TiOCC) were obtained. We studied ten infants < 48 wk post-conceptional age (PCA) and ten infants > 48 wk. PCA Flow (V), pressure (Pao) and carbon dioxide tension (PCO2) were recorded at three concentrations of inspired halothane (FiH): 0%, 1% and 2% which corresponded to an end-tidal halothane concentration of about 0.2%, 0.8% and 1.2% respectively. In both groups Vi, VT and VT/Ti decreased whereas dP/dt, did not, suggesting that the respiratory pump was impaired. The parameters of breath Shape did not change. Importantly the parameters of Timing showed different tendencies. In infants > 48 wk PCA TiOCC/Ti decreased. In infants < 48 wk PCA, TiOCC/Ti did not change. The different response in the timing parameter TiOCC/Ti is consistent with a different effect of halothane on parameters of ventilatory timing in infants < 48 wk PCA and this may represent a maturational effect.


Bistability and switching in the lysis/lysogeny genetic regulatory network of bacteriophage lambda.
Bistability and switching are two important aspects of the genetic regulatory network of lambda phage. Positive and negative feedbacks are key regulatory mechanisms in this network. By the introduction of threshold values, the developmental pathway of lambda phage is divided into different stages. If the protein level reaches a threshold value, positive or negative feedback will be effective and regulate the process of development. Using this regulatory mechanism, we present a quantitative model to realize bistability and switching of lambda phage based on experimental data. This model gives descriptions of decisive mechanisms for different pathways in induction. A stochastic model is also introduced for describing statistical properties of switching in induction. A stochastic degradation rate is used to represent intrinsic noise in induction for switching the system from the lysogenic pathway to the lysis pathway. The approach in this paper represents an attempt to describe the regulatory mechanism in genetic regulatory network under the influence of intrinsic noise in the framework of continuous models.


Surface expression of neutrophil adhesion molecules in pregnant women at risk for hypertensive complications.
To determine if neutrophil activation is a pathogenetic factor in hypertensive disorders in pregnancy, the neutrophil expression of adhesion molecules was prospectively investigated in pregnant women at risk, prior to the development of hypertensive complications. Two neutrophil activation parameters, beta2-integrin (CD11b) and l-selectin (CD62L), were assessed at admission between 14 and 24 weeks of gestation in 82 pregnant women at risk of preeclampsia and other hypertensive complications. Results were compared to those in 20 healthy normotensive women. Of the 82 women at risk, 23 (28%) developed hypertensive complications: 9 (11%) preeclampsia and 14 (17%) others, such as intrauterine growth restriction (n = 6), fetal or neonatal loss (n = 8), and preterm delivery (< or = 30 weeks of gestation) (n = 8). All pregnancy outcome measures were significantly worse in the patients with complications than in those at risk but without complications or the healthy controls. Expression of beta2-integrin was significantly higher in early stages of pregnancy in the women who eventually developed complications than the women who did not, P =.019, or the healthy controls, P =.049. Surface expression of beta2-integrin is increased in pregnant women at risk for hypertensive complications before the clinical manifestations of the disorder.


A triple suicide gene strategy that improves therapeutic effects and incorporates multimodality molecular imaging for monitoring gene functions.
Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly, all the three genes (thymidine kinase, cytosine deaminase and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron emission tomography, magnetic resonance spectroscopy and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple suicide gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo.


Expression of the β1-adrenergic receptor (ADRB1) gene in the myocardium and β-adrenergic reactivity of the body in patients with a history of myocardium infraction.
β1-adrenergic receptors (β1-AR) directly affect on intracardiac hemodynamic and the ability of the heart to tolerate physical activity by regulating its inotropic and chronotropic functions. Severe hypersympathicotonia, specific to coronary artery disease (CAD) and chronic heart failure (HF), leads to impaired functioning of β1-AR. The aim of this research was to assess the expression level of the β1-AR ADRB1 gene in the myocardium, to evaluate the β-adrenergic reactivity of the membrane (β-ARM) of erythrocytes, and to analyze the association of these parameters with myocardial contractile dysfunction in patients with a myocardial infarction (MI) in the past and without it. The study included 126 patients with chronic CAD. Among the patients, 55.6 % had a history of MI at least 6 months ago. The expression of the ADRB1 gene was assessed using real-time polymerase chain reaction. With this purpose, we isolated RNA from the right atrial appendage, which was excised when a heart-lung machine was connected during a planned coronary bypass surgery. β-ARM was evaluated in 57 patients. This method is based on the fact of inhibition of hemolysis of erythrocytes, placed in a hyposmotic medium, in the presence of a β-blocker. Within the whole sample of patients, the expression of the ADRB1 gene is comparable in different functional classes of HF. There was no linear correlation between the expression of the ADRB1 gene and left ventricle ejection fraction (LVEF). In patients with a history of MI, the expression of the ADRB1 gene was elevated when compared to a group of patients without MI (p = 0.017). Patients with a history of MI had higher values of β-ARM than those without MI (p = 0.017). The reverse correlation between β-ARM and LVEF (r = -0,570, p = 0,002) was revealed in the group of patients without MI but not in the group of patients with a history of MI (r = -0,137, p = 0,479). In the sample of patients with chronic CAD, in the myocardium of subjects with a history of MI, the relative expression of ADRB1 gene was higher compared to the group of patients without MI. In patients with different functional classes (FC) of HF and with different ejection fraction, both with MI and without it, ADRB1 gene expression was comparable. In the group of patients with a history of MI, an increase in β-ARM was observed, i.e. decrease in the number or sensitivity of β-AR. Among patients without MI, an inverse correlation was found between β-ARM and LVEF.


Correlation Analysis of the Microbiome and Immune Function in the Lung-Gut Axis of Critically Ill Patients in the ICU.
Critical illnesses in the intensive care unit (ICU) have been a global burden. We aimed to determine the correlation between the lung and gut in critically ill patients to find novel evidence of the lung-gut axis, which may be a new treatment for patients with critical illness in the ICU. We collected bronchoalveolar lavage specimens and fecal samples of 31 patients with critical illness within 24 h after admission. Metagenomics was used to detect lung and intestinal samples. Immune cells were detected by flow cytometry. There are 86 common species in both lung and gut. The abundance of Enterococcus faecium is high in both the lung and gut of patients with critical illness in the respiratory intensive care unit (RICU). Corynebacterium striatum in the lung and gut is correlated with different immune cells. In addition, C. striatum in the lung and gut might share the same source, supporting the concept of a gut-lung axis in humans. The microbiome in the lung and gut showed a correlation to some extent, and C. striatum in the lung and gut might share the same source. In addition, the microbiome showed a correlation with immunity, indicating a potential therapeutic target in patients with critical illness. The lung-gut axis might play an important role in patients with critical illness in the RICU.


Mechanisms involved in symptomatic myocardial bridging: Value of sequential testing for endothelial function, flow reserve measurements and dobutamine stress angiography.
In patients with extensive myocardial bridging, evaluation of its clinical significance remains a challenge. Sequential invasive testing is feasible and gives more insight into the pathophysiological mechanism of bridging-related angina. Twelve patients with chest pain, proven ischaemia and extensive myocardial bridging were assessed. Myocardial bridging was evaluated at rest, during intracoronary acetylcholine infusion, through coronary flow velocity and flow reserve measurements, and during dobutamine stress. The mean length of the bridging segment was 24.9 mm (QCA; range 8.4-48.0 mm). Acetylcholine infusion caused severe vasospasm in two patients. In these two patients anginal symptoms were related to vasospasm and sequential testing was discontinued. In the remaining ten patients sequential testing was continued. Coronary flow reserve was normal in all patients: 3.3+/-0.6. In six patients reliable quantitative measurements could be performed during dobutamine stress. The mean systolic diameter of the bridging segment was 1.6+/-0.4 at baseline and 1.3+/-0.3 during dobutamine stress (mean of differences 0.38 (95% CI 0.1-0.7)). The difference between the diastolic and systolic diameter in the bridging segment increased from 0.3+/-0.2 mm at baseline to 1.0+/-0.5 mm during dobutamine infusion (mean of differences 0.6 (95% CI 0.3 to 0.9)). Sequential testing for bridging is feasible and may disclose endothelial dysfunction or spasm as an underlying mechanism in a minority of patients. Coronary flow reserve was preserved. Dobutamine stress unmasked further lumen reduction and may give further insight into the clinical significance of myocardial bridging in individual patients. (Neth Heart J 2008;16:10-5.).


Spatial and temporal variations of vegetation cover and its influencing factors in Shandong Province based on GEE.
Economic development has rapidly progressed since the implementation of reform and opening up policies, posing significant challenges to sustainable development, especially to vegetation, which plays a crucial role in maintaining ecosystem service functions and promoting green low-carbon transformations. In this study, we estimated the fractional vegetation cover (FVC) in Shandong Province from 2000 to 2020 using the Google Earth Engine (GEE) platform. The spatial and temporal changes in FVC were analyzed using gravity center migration analysis, trend analysis, and geographic detector, and the vegetation changes of different land use types were analyzed to reveal the internal driving mechanism of FVC changes. Our results indicate that vegetation cover in Shandong Province was in good condition during the period 2000 to 2020. The high vegetation cover classes dominated, and overall changes were relatively small, with the center of gravity of vegetation cover generally shifting towards the southwest. Land use type, soil type, population density, and GDP factors had the most significant impact on vegetation cover change in Shandong Province. The interaction of these factors enhanced the effect on vegetation cover change, with land use type and soil type having the highest degree of influence. The observational results of this study can provide data support for the policy makers to formulate new ecological restoration strategies, and the findings would help facilitate the sustainability management of regional ecosystem and natural resource planning.


Emergency department patient literacy and the readability of patient-directed materials.
There are 20 million American adults who cannot read. The demographics of the illiterate population suggest that they represent a significant proportion of patients cared for in a teaching hospital emergency department. This study was designed to assess whether readability of written material given to patients in a university hospital ED matched the literacy level of these patients. Data were gathered from 111 consecutive adult ED patients. Results of the survey showed that although the median education level of ED patients was 10th grade, more than 40% could not be expected to read at the 8th grade level, and at least 20% could be considered functionally illiterate. Readability of ED patient-directed materials was measured using the Fry index. Hospital and commercially generated patients education materials ranged from 8th to 13th grade level; a patient-directed brochure from Virginia ACEP is written at a college reading level. Comprehension of the "leaving against medical advice" (AMA) form or a consent for surgery would require at least an 11th grade education. This study shows that there is an alarming discrepancy between ED patient literacy levels in our sample and the reading skills required to comprehend important written medical and legal information. More than 50% of ED patients in a teaching hospital may read below the level required to understand standard discharge instructions. In addition, understanding the "operative consent" and leaving AMA forms requires a level of education beyond that of the majority of ED patients. If patient-directed written material is to serve its purpose, then ED patient populations should be surveyed and the reading level of written material adjusted accordingly.


Synthesis and degradation of hepatic metallothionein in mice differing in susceptibility to cadmium mortality.
We have confirmed the observations of Tsunoo et al. (Toxicol. Lett. 4:253, 1979) that (a) DBA/2 mice are resistant to cadmium mortality than C3H mice and (b) DBA/2 mice accumulate more 109Cd into hepatic metallothionein than do C3H mice in response to an injection of 30 mumol CdCl2/kg, a dose of CdCl2 which is lethal to C3H mice. We now report, using a nonlethal dose of 8 mumol CdCl2/kg, that the rates of both the synthesis and the degradation of cadmium-induced hepatic metallothionein are increased in C3H mice. The rate of metallothionein synthesis, measured 6 hr after cadmium administration and expressed as the percentage of injected [35S]cysteine incorporated into metallothionein/g liver, was 0.33 +/- 0.04% (SD) in C3H mice, compared to 0.19 +/- 0.06% in DBA/2 mice (significantly different rates by Students' t test. P less than 0.01). Also, at this dose, hepatic 35S-labeled metallothionein was degraded with a half-life of 22.5 +/- 0.7 hr in C3H mice, compared to 30.1 +/- 2.5 hr in DBA/2 mice (significantly different half-lives by F test, within 95% confidence limits). The increased accumulation of metallothionein in resistant DBA/2 mice compared to sensitive C3H mice after cadmium exposure appears to be due primarily to a difference in metallothionein degradation, rather than metallothionein synthesis.


Unperturbing a non-helically perturbed bacterial flagellar filament: Salmonella typhimurium SJW23.
Salmonella typhimurium SJW23 has a right-handed, non-helically perturbed filament of serotype gt with a unique surface pattern. Non-helical perturbations involve symmetry reduction along the five-start helical lines resulting in layer lines of fractional Bessel orders and a consequent seam. The flagellin gene, fliC(23), which we sequenced, differs from the sequence of the canonic, plain SJW1655 flagellin, fliC(1655). We modified discrete components of fliC(23) in order to localize, in the expressed filament, the submolecular site responsible for the non-helical perturbation. These modifications include (i) deleting the outermost domain D3(23), (ii) replacing D3(23) with D3(1655), (iii) substituting a hydrophilic α-helix at the interface between the neighboring domains D1 and D2 with a hydrophobic one from fliC(1655), and (iv) substituting a serine/glycine pair in the loop connecting the modified α-helix to its neighbor; these modifications were made in the presence and absence of D3(23). We used S. typhimurium SJW1655 both as a reference and as a source for 'spare parts'. The symmetry of the constructs was assessed from the power spectra through changes in the layer lines at a height of 1/105 and 1/35 Å(-1), unique to the non-helical perturbation. Deleting D3(23), either alone or in combination with various substitutions, or replacing it with D3(1655) transforms the non-helically perturbed filament into a plain one as judged by the disappearance of the typical layer lines from the power spectra. We conclude that the non-helical perturbation is a product of unique interactions in the D3(23) density shell. Whereas other minor structural changes may occur at the filaments interior, they are all helically symmetric.


Development and optimization of a system for comprehensive two-dimensional liquid chromatography with UV and mass spectrometric detection for the separation of complex samples by multi-step gradient elution.
Comprehensive two-dimensional liquid chromatography (LC x LC) is a powerful tool for the separation of complex biological samples. This technique offers the advantage of simplified automation and greater reproducibility in a shorter analysis time than off-line two-dimensional separation systems. In the present study, an LC x LC system is developed enabling simultaneous UV and MS detection, and which can be easily converted to a conventional reversed-phase LC-UV/MS system. In LC x LC, a 60-min reversed-phase LC separation with a linear solvent gradient in the first dimension is coupled to a second-dimension separation on a mixed-mode cation-exchange/reversed-phase column with a modulation time of 60s. The isocratic separation in the second-dimension column is optimized by the use of a multi-step gradient where the organic and the ionic modifier are varied independently. Intraday (n=3) and interday (n=4) variability of the retention times were evaluated with the complete system and found to be 0.5% and 0.7%, respectively. Good linearity was observed in calibration curves for three different compounds varying in polarity.


The FDA's new procedures for the use of investigational drugs in treatment.
The Food and Drug Administration has established new procedures to make promising investigational drugs available for treatment of patients with immediately life-threatening or serious diseases as early in the drug development process as possible and well before general marketing begins. The purpose of this article is to inform the medical community about these new procedures and to facilitate their implementation. Examples of immediately life-threatening and serious diseases are given and the procedures that physicians should use to obtain a drug under the new regulations are described. The treatment use of zidovudine (Retrovir), while still in the investigational phase, is described as a case study. The article also summarizes the Food and Drug Administration's new procedures under which drug sponsors can charge for investigational drugs.


The Impact of Prostate Volume in Open Radical Prostatectomy: A Single Centre Experience.
Even the most experienced surgeons experience technical difficulties and challenges when operating on very large prostates, regardless of surgical technique. Our goal was to determine whether preoperative prostate volume has an impact on functional and oncological outcomes after open radical prostatectomy. We reviewed the records of 909 patients who underwent open radical prostatectomy by a single surgeon at our institution. Variables were compared across quartile distributions of prostate volume as defined by preoperative transrectal ultrasound examination, including group A with prostate volume < 30ccm 3, group B with prostate volume ≥ 30ccm 3 and < 50ccm 3, group C with prostate volume ≥ 50ccm 3 and < 70ccm 3 and group D with prostate volume ≥ 70ccm3. Factors assessed in this analysis were patient age, preoperative prostate specific antigen (p-PSA), Gleason score, pathological stage, margin status, operative time, cystography leakage, early continence, biochemical recurrence (BCR)-free, and overall-survival (OS). The complication rates were classified using Clavien Dindo classification. There were no statistically relevant differences between the groups considering preoperative factors such as age, p-PSA, Gleason score, and tumor stadium. Patients with a very large prostate had slightly higher percentage of anastomosis leakage, severe Clavien Dindo complication rates (≥ 3), longer operation time and severe early incontinence (IV°) rates, simultaneously having lower positive margin rates. Nevertheless, the early continence rates, BCR-free and OS were similar regardless of the prostate size. open radical prostatectomy for patients with very large prostate is a viable therapy option with slightly higher urinary leakage-, early incontinence- and complication-rates that takes slightly more operation time. However, the functional and oncological outcomes are similar when compared to smaller prostates.


RA-induced prominence-specific response resulted in distinctive regulation of Wnt and osteogenesis.
Proper retinoic acid (RA) signaling is essential for normal craniofacial development. Both excessive RA and RA deficiency in early embryonic stage may lead to a variety of craniofacial malformations, for example, cleft palate, which have been investigated extensively. Dysregulated Wnt and Shh signaling were shown to underlie the pathogenesis of RA-induced craniofacial defects. In our present study, we showed a spatiotemporal-specific effect of RA signaling in regulating early development of facial prominences. Although inhibited Wnt activities was observed in E12.5/E13.5 mouse palatal shelves, early exposure of excessive RA induced Wnt signaling and Wnt-related gene expression in E11.5/E12.5 mouse embryonic frontonasal/maxillary processes. A conserved regulatory network of miR-484-Fzd5 was identified to play critical roles in RA-regulated craniofacial development using RNA-seq. In addition, subsequent osteogenic/chondrogenic differentiation were differentially regulated in discrete mouse embryonic facial prominences in response to early RA induction, demonstrated using both in vitro and in vivo analyses.


Quantum oscillations of nitrogen atoms in uranium nitride.
The vibrational excitations of crystalline solids corresponding to acoustic or optic one-phonon modes appear as sharp features in measurements such as neutron spectroscopy. In contrast, many-phonon excitations generally produce a complicated, weak and featureless response. Here we present time-of-flight neutron scattering measurements for the binary solid uranium nitride, showing well-defined, equally spaced, high-energy vibrational modes in addition to the usual phonons. The spectrum is that of a single atom, isotropic quantum harmonic oscillator and characterizes independent motions of light nitrogen atoms, each found in an octahedral cage of heavy uranium atoms. This is an unexpected and beautiful experimental realization of one of the fundamental, exactly solvable problems in quantum mechanics. There are also practical implications, as the oscillator modes must be accounted for in the design of generation IV nuclear reactors that plan to use uranium nitride as a fuel.


[Pathoanatomical and clinical aspects of the placenta in preterm birth].
Prematurely born children show a clearly elevated risk for perinatal morbidity, long-term pediatric morbidities and development of chronic diseases in adulthood compared to babies born at term. The pathoanatomical investigation of placentas from preterm births is useful for assessing the etiology, the risk of recurrence and the prognosis for the child. The focus is on presenting the clinical and pathoanatomical characteristics of acute chorioamnionitis as a frequent cause of preterm induction of labor and pregnancy-induced hypertension, in particular preeclampsia as a frequent reason for elective cesarean section. Other lesions, sometimes of unclear etiology associated with preterm birth and substantially elevated risk of recurrence are reviewed. The clinical correlations and therapeutic options of the various diseases are discussed taking the risk of recurrence into consideration. Examination of placentas, association with the clinical course and a literature search. Acute chorioamnionitis and omphalovasculitis can be histologically subdivided into different stages which correlate with the clinical severity and the prognosis for the newborn child. Chronic deciduitis, chronic chorioamnionitis, villitis of unknown etiology, massive perivillous fibrin deposition and chronic histiocytic intervillositis are entities of unclear etiology associated with recurrent abortion and preterm birth. Autoimmune diseases and thrombophilia are occasionally associated with these pathologically defined lesions. Pregnancy-associated hypertensive disease and particularly preeclampsia as the cause of intrauterine developmental delay and elective cesarean section often show characteristic pathoanatomical placental lesions, which can give indications for the severity and duration of the disease and the prognosis for the child. Early onset (<34 weeks of gestation) and late onset preeclampsia show clinical and morphological differences. Subsequent pregnancies are classified as being at risk and screening for preeclampsia should be clinically performed.


Macrophage membrane-mediated targeted drug delivery for treatment of spinal cord injury regardless of the macrophage polarization states.
Targeted delivery of therapeutics for spinal cord injury (SCI) has been a long-term challenge due to the complexity of the pathological procession. Macrophage, as an immune cell, can selectively accumulate at the trauma site after SCI. This intrinsic targeting, coupled with good immune-escaping capacity makes macrophages an ideal source of biomimetic delivery carrier for SCI. Worth mentioning, macrophages have multiple polarization states, which may not be ignored when designing macrophage-based delivery systems. Herein, we fabricated macrophage membrane-camouflaged liposomes (RM-LIPs) and evaluated their abilities to extend drug circulation time and target the injured spinal cord. Specially, we detected the expression levels of the two main targeted receptors Mac-1 and integrin α4 in three macrophage subtypes, including unactivated (M0) macrophages, classically activated (M1) macrophages and alternatively activated (M2) macrophages, and compared targeting of these macrophage membrane-coated nanoparticles for SCI. The macrophage membrane camouflage decreased cellular uptake of liposomes in RAW264.7 immune cells and strengthened binding of the nanoparticle to the damaged endothelial cells in vitro. RM-LIPs can prolong drug circulation time and actively accumulate at the trauma site of the spinal cord in vivo. Besides, RM-LIPs loaded with minocycline (RM-LIP/MC) showed a comprehensive therapeutic effect on SCI mice, and the anti-pyroptosis was found to be a novel mechanism of RM-LIP/MC treatment of SCI. Moreover, the levels of Mac-1 and integrin α4 in macrophages and the targeting of RM-LIP for SCI were found to be independent of macrophage polarization states. Our study provided a biomimetic strategy via the biological properties of macrophages for SCI targeting and treatment.


[Anesthesiology and palliative medicine. Structured results of a prospective questionnaire-based survey in German hospitals].
Anesthesiology departments were often integrated into the primary formation of palliative activities in Germany. The aim of this study was to present the current integration of anesthesiology departments into palliative care activities in Germany. The objective was to determine current activities of anesthesiology departments in in-hospital palliative care. A quantitative study was carried out based on a self-administered structured questionnaire used during telephone interviews. A total of 168 out of 244 hospitals consented to participate in the study and the response rate was 69%. In-hospital palliative care activities were reported for most of the surveyed hospitals. Only two hospitals in the maximum level of care reported no activities. Participation in these activities by anesthesiology departments was described in up to 92%. Historically, most activities are due to the commitment of individuals, whereas the development of palliative care of cancer pain services and hospital support teams took place in the university hospitals by 2005. Until 2005 many university palliative care activities had their origins in cancer pain services. These were often integrated into anesthesiology departments. Currently, anesthesiology departments work as an integrative part of palliative medicine. However, it appears from the present results that there is a domination of internal medicine (especially hematology and oncology) in palliative activities in German hospitals. This allows the focus of palliative activities to be formed by subjective specialist interests. Such a state seems to be reduced by the integration of anesthesiology departments because of their neutrality with respect to faculty-specific medical interests. Advantages or disadvantages of these circumstances are not considered by the present investigation.


The art and science of abrasive finishing and polishing in restorative dentistry.
Effective use of rotary cutting burs and bonded, coated, and loose abrasives can greatly simplify and improve the effectiveness of finishing and polishing procedures. Fluted carbide finishing burs appear to be the optimal rotary contouring devices for posterior composite resins. Finishing diamonds are preferred for gross finishing of adjusted porcelain. Coated abrasive discs and strips provide unique interproximal and incisal access and are preferred for finishing and polishing of microfil resins. Rubberized bonded abrasives have evolved to provide a greater range of finishing and polishing action on composite resin and for polishing porcelain. A wide selection of aluminum oxide and diamond polishing pastes, together with highly effective felt and foam application devices, are now available to polish composite and porcelain to an enamel-like appearance. Aluminum oxide composite polishing pastes are highly effective and strongly recommended for use on highly filled hybrid composites but have limited utility on microfil resins, with use of extrafine (0.3-mu) pastes clearly contraindicated.


Clinical outcomes in the surgical treatment of idiopathic normal pressure hydrocephalus.
Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of gait disturbance, dementia and urinary incontinence. Outcomes after ventriculoperitoneal shunting for INPH are variable due to a lack of reliable, quantitative outcome data and inconsistent methods of selecting shunt candidates. The aim of this retrospective cohort study was to assess objective and quantitative clinical outcomes of ventriculoperitoneal shunting for INPH. From 2008 to 2013, consecutive patients diagnosed with INPH based on clinical and radiological criteria were included in this single-centre study. All patients received programmable-valve ventriculoperitoneal shunts. Outcome measures were assessed at baseline, 3, 6 and 12months post-operatively. Outcomes included gait time and scores on the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), the Addenbrooke's Cognitive Examination Revised (ACE-R) and the Mini-Mental State Examination (MMSE). Thresholds for improvements were set a priori as ⩾20% decrease in gait time, ⩾10point decrease in UPDRS-III score, ⩾5point increase in ACE-R score and ⩾2point increase in MMSE score at last follow-up. The proportion of patients improving varied between measures, being gait time (60%), UPDRS-III (69%), MMSE (63%), and ACE-R (56%). Overall, improvement in at least one outcome measure was observed in 85% of patients and 38% improved in gait time, UPDRS-III score and cognitive scores. Only 15% of patients experienced no improvement on any measure. This study demonstrates that the majority of INPH patients can sustain improvements in multiple symptoms up to 12months after shunting.


Mapping, quantitative distribution and origin of substance p- and VIP-containing nerves in the uvea of guinea pig eye.
VIP- and substance P-like immunoreactivities were found in considerable concentrations (VIP: 17.3 +/- 4.8 pmol/g, mean +/- SEM; substance P:11.1 +/- 1.8 pmol/g) in the uveal portion of the guinea pig eye. Immunocytochemistry localised these two regulatory peptides to nerve fibres found principally in a plexus in the iris (substance P) and in an extensive network surrounding the blood vessels of the choroid (VIP). A remarkable anatomical demarcation of the two types of peptide-containing nerves was established by the staining of substance P-containing nerves, which stops at the level of the ciliary body. This uveal area is known to be involved in the ocular responses to nociceptive stimuli. At the ultrastructural level, immunoreactivity for both peptides was localised to distinct subpopulations of p-type nerves, distinguishable by the size of their large dense-cored vesicles. Those immunoreactive for VIP were significantly larger (p less than 0.0005) than those immunoreactive for substance P (95 +/- 7 nm and 82 +/- 9 nm respectively; mean +/- SD). Interruption of the trigeminal pathway produced a remarkable decrease of substance P immunoreactivity in the anterior portion of the uvea (9.1 +/- 1.5 pmol/g, mean +/- SEM, control; 5.3 +/- 1.3 pmol/g, denervated), but not of VIP immunoreactivity in the choroid. Following colchicine treatment, VIP-immunoreactive neuronal cell bodies were localised in the choroid. The separate anatomical localisations and distributions of the two uveal peptides appear to be related to their different origins and functional roles in the response of the eye to noxious stimuli.


Risk factors for developing both primary breast and primary ovarian cancer: A systematic review.
Women with breast cancer have an increased risk of primary ovarian cancer (BR→OV), and women with ovarian cancer have an increased risk of primary breast cancer (OV→BR). This systematic review summarizes risk factors for developing BR→OV and OV→BR. We searched PubMed and Embase until June 2022. We identified 23 articles meeting our inclusion criteria. Studies observed a lower risk of BR→OV for Black versus White women, alcohol consumption, radiotherapy and hormone therapy, BRCA2 versus BRCA1, and ER/PR positive versus negative breast tumors, and a higher risk with family history of breast/ovarian cancer, triple negative versus luminal breast cancer, and higher grade breast tumors. There was an increased risk of OV→BR with family history of cancer. Tumor characteristics, and genetic and familial factors are associated with risk of BR→OV and OV→BR. These results could aid clinicians in decision-making for breast and ovarian cancer patients, including risk-reducing strategies.


Altered activity of plasma hemopexin in patients with minimal change disease in relapse.
Since an active isoform of plasma hemopexin (Hx) has been proposed to be a potential effector molecule in minimal change disease (MCD), we tested plasma and urine samples from subjects with MCD in relapse (n = 18) or in remission (n = 23) (after treatment with prednisolone) for presence or activity of Hx. For comparison, plasma or urine from proteinuric subjects with focal and segmental glomerulosclerosis (FSGS, n = 11), membranoproliferative glomerulonephritis (MPGN, n = 9), IgA nephropathy (n = 5) or healthy control donors (n = 10), were incorporated into the study. Electrophoresis and Western blotting methods were used for evaluation of the Hx status, whereas protease activity of Hx was tested upon kidney tissue in vitro according to standard methods. The results show (1) a decreased mean titer of plasma Hx exclusively in MCD relapse subjects as compared with MCD in remission (0.21+/-0.14 mg/ml vs 0.44+/-0.06 mg/ml; p < 0.01). Mean Hx titers in other proteinuric subjects ranged from 0.38+/-0.05 mg/ml to 0.40+/- 0.06 mg/ml, whereas, the mean titer of healthy controls was 0.59+/-0.03 mg Hx/ml; (2) an increased Hx activity (expressed in arbitrary units) exclusively in plasma from MCD relapse subjects (3.3+/-0.72 vs 1.16+/-0.56, MCD remission; p < 0.01); (3) different Western blot patterns in MCD relapse vs remission plasma; (4) reduced stainability or virtual absence of the 80-kD Hx band in blots of urine from MCD relapse in contrast to urine samples from other proteinuric subjects with FSGS, MPGN, or IgA nephropathy. It is concluded that Hx in MCD relapse subjects may exist in an altered isoform, showing enhanced protease activity as compared with subjects in remission, subjects with other forms of primary glomerulopathy, or healthy control individuals.


Tumorigenic properties of neurofibromin-deficient Schwann cells in culture and as syngrafts in Nf1 knockout mice.
Neurofibromatosis type 1 (NF1) is one of the most common dominantly inherited genetic diseases associated with the nervous system. Functional loss of the NF1 tumor suppressor is frequently associated with the generation of benign neurofibromas that can progress to malignancy. Recent evidence in genetic mouse models indicates that the development of neurofibromas requires a loss of Nf1 in the cells destined to become neoplastic as well as heterozygosity in nonneoplastic cells. We tested this hypothesis in a newly developed syngraft mouse model in which Nf1-/- Schwann cells isolated from knockout embryos were grafted into the sciatic nerves of Nf1+/- mice, corresponding to the genetic background of NF1 patients. Furthermore, we also characterized in vitro growth of these cells. We found that embryonic mouse Nf1-/- Schwann cells exhibit increased proliferation and less growth factor-dependence in vitro compared with heterozygous and wild-type counterparts. Moreover, Nf1-/- Schwann cells showed tumorigenic growth when implanted into nerve of adult Nf1 heterozygous mice. These findings support the conclusion that loss of Nf1 in embryonic mouse Schwann cells is sufficient for tumor development in the heterozygous environment of adult mouse nerve. In addition, this syngraft model provides a practical means for the controlled induction of neurofibromas, greatly facilitating localized application of therapeutic agents and gene delivery.


Magnesium bromide mediated highly diastereoselective heterogeneous hydrogenation of olefins.
Palladium on carbon combined with magnesium bromide catalyzed hydrogenation of Baylis-Hillman olefins to afford the corresponding aldol derivatives in a highly syn-diastereoselective manner is described. [reaction: see text]


Pregnancy outcomes following periconceptional or gestational exposure to ustekinumab: Review of cases reported to the manufacturer's global safety database.
Ustekinumab, a human immunoglobulin G1 monoclonal antibody that binds to and inhibits interleukin (IL)-12/IL-23, is indicated for multiple immune-mediated diseases. Ustekinumab is actively transported across the placenta and theoretically could impact pregnancy outcomes. Limited data on pregnancy outcomes with ustekinumab exposure are available. To assess pregnancy outcomes in patients exposed to ustekinumab during pregnancy METHODS: Cumulative data on medically confirmed ustekinumab-exposed pregnancies from the manufacturer's Global Safety Database were summarised. Descriptive data for pregnancy outcomes were presented overall and by patient subgroups. As of 31 August 2020, 408 medically confirmed, prospective, maternal ustekinumab-exposed pregnancies with reported outcomes were identified. The mean maternal age was 31 years. Of the 420 pregnancy outcomes (including 4 sets of twins),a , b 340 (81%) were live births, 51 (12.1%) spontaneous abortions, 25 (6%) elective/induced abortions, 3 (0.7%) stillbirths and 1 (0.2%) ongoing pregnancy with foetal congenital anomaly (CA). Among 340 live births, 33 (9.7%) were born pre-term. The rate of major CAs was similar by indication (Crohn's disease vs psoriasis), ustekinumab dose (45 mg vs 90 mg) and timing and duration of maternal exposure to ustekinumab. Prospective outcomes of pregnancies with paternal periconceptional ustekinumab exposure (n = 87) included 92% live births (1.2% major CA), 5.7% spontaneous abortions and 2.3% elective/induced abortions. Rates of adverse pregnancy outcomes or CAs with ustekinumab exposure were consistent with rates reported for the US general population and do not suggest a higher risk associated with maternal or paternal exposure to ustekinumab.