Preclinical discovery and development of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection: the rise and fall.
The ongoing COVID19 pandemic represents an unprecedented opportunity to test the feasibility of monoclonal antibody (mAb) therapies against respiratory viruses. While many hurdles were easily predictable (e.g. time to develop, scalability, and economic sustainability), mAb cocktails (i.e. the combination of two mAbs) were finally deployed in 2021, one year after the beginning of the pandemic. Of them, the REGN-COV-2 cocktail was likely the most successful experience and contributed at saving lives at the time of the wave sustained by the Delta variant of concern (VOC). Herein, the authors review the preclinical and clinical history of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection. The authors furthermore provide the reader with their perspectives on this cocktail including its current place in the treatment armamentarium. Unfortunately, results from clinical trials highlighted a very limited efficacy in inpatients; furthermore, the current evidence with regards to its lack of effectiveness against the current dominant VOC (omicron) suggests a very limited use of these drugs in the future. In the authors' opinion, this story reminds us of the limitations of mAb therapies in pandemic settings, and of the inferiority of monoclonal versus polyclonal antibody-based therapeutics in such scenarios.


The meiotic recombination checkpoint is regulated by checkpoint rad+ genes in fission yeast.
During the course of meiotic prophase, intrinsic double-strand breaks (DSBs) must be repaired before the cell can engage in meiotic nuclear division. Here we investigate the mechanism that controls the meiotic progression in Schizosaccharomyces pombe that have accumulated excess meiotic DSBs. A meiotic recombination-defective mutant, meu13Delta, shows a delay in meiotic progression. This delay is dependent on rec12+, namely on DSB formation. Pulsed-field gel electrophoresis analysis revealed that meiotic DSB repair in meu13Delta was retarded. We also found that the delay in entering nuclear division was dependent on the checkpoint rad+, cds1+ and mek1+ (the meiotic paralog of Cds1/Chk2). This implies that these genes are involved in a checkpoint that provides time to repair DSBs. Consistently, the induction of an excess of extrinsic DSBs by ionizing radiation delayed meiotic progression in a rad17(+)-dependent manner. dmc1Delta also shows meiotic delay, however, this delay is independent of rec12+ and checkpoint rad+. We propose that checkpoint monitoring of the status of meiotic DSB repair exists in fission yeast and that defects other than DSB accumulation can cause delays in meiotic progression.


Factors associated with acute-phase response of bisphosphonate-naïve or pretreated women with osteoporosis receiving an intravenous first dose of zoledronate or ibandronate.
A first intravenous dose of bisphosphonates may be associated with an acute-phase response (APR). In bisphosphonate-naïve women with postmenopausal osteoporosis, the characteristics and frequency of APR may differ by compound. Prior bisphosphonate exposure was predictive of APR risk and severity. Intravenous (IV) administration of bisphosphonates (BP), such as zoledronate (ZOL) and ibandronate (IBN), may be associated with an APR. The characteristics of APR may differ by compound. The aim of the present study was to evaluate the characteristics of APR (rates, signs and symptoms, severity), in the absence of any preventive measure, after a first IV application of ZOL or IBN in patients naïve or previously exposed to BP in a real-world clinical setting. This is an open-label prospective exploratory study with two cohorts of consecutive postmenopausal women with osteoporosis treated with either IV ZOL or IBN at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Intravenous BP was administered to 725 women (411 ZOL and 314 IBN). Prior oral or IV BP use was less frequent in the ZOL group (61.8 vs. 71.7%, p = 0.005). In total, 301 women (41.5%) reported the presence of one or more signs or symptoms of APR with rates for ZOL and IBN of 47.7 and 33.4%, respectively (p < 0.001). Corresponding APR rates in the subgroup of BP-naïve patients were 55.6 and 32.4%, respectively (p < 0.001). The leading APR clinical sign was the presence of post-dose myalgia or arthralgia (68.1%). Prior BP exposure was predictive of both APR risk and severity, and lower serum 25-hydroxy vitamin D (25(OH)D) levels were possibly predictive of severity. In a real-world setting, APR rates with ZOL and IBN may be higher than reported in randomised controlled trials and may differ by compound, prior BP exposure, and serum 25(OH)D levels.


The evidence for a neurobiological model of childhood antisocial behavior.
Children with persistent antisocial and aggressive behavior are diagnosed as having disruptive behavior disorder. The authors review evidence that antisocial children, and especially those who persist with this behavior as they grow older, have a range of neurobiological characteristics. It is argued that serotonergic functioning and stress-regulating mechanisms are important in explaining individual differences in antisocial behavior. Moreover, low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may help to explain poor conditioning and socialization. The authors propose a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between early adversity and antisocial behavior problems in childhood. Implications for intervention programs are discussed.


Effect of Antiretroviral Therapy on Bone and Renal Health in Young Adults Infected With HIV in Early Life.
HIV antiretroviral (ARV) therapy is associated with renal and bone toxicity, but little is known about the potential cumulative effects in adults exposed to ARVs from birth. To prospectively evaluate renal and bone health in young adults with lifelong HIV and extensive ARV exposure. Cross-sectional comparison of bone mineral density (BMD) by dual-energy X-ray absorptiometry, bone turnover, and renal function in young adults infected with HIV in early life (n = 65) to matched healthy controls (n = 23) and longitudinal evaluation (mean follow-up = 4.4 years) within a subset of the HIV cohort (n = 33). Government outpatient research clinic. Albumin/creatinine ratio, protein/creatinine ratio, anion gap, N-terminal telopeptides, and osteocalcin were significantly increased in persons with HIV compared with controls, whereas whole-body BMD and BMD z scores were lower. Within the HIV group, duration of tenofovir disoproxil fumarate (TDF) correlated with higher anion gap but did not correlate with bone parameters. Longer duration of didanosine and stavudine use correlated with lower BMD and BMD z scores. Longitudinal analyses revealed that BMD and bone metabolism significantly improved over time. No subject had an estimated glomerular filtration rate (eGFR) <60, but decline in eGFR correlated with increasing years of TDF exposure. Subclinical markers of renal dysfunction were increased in HIV-infected young adults and associated with TDF exposure, whereas lower bone density was associated with didanosine and stavudine exposure. The tendency for improvement in markers of bone health over time and the availability of less toxic ARV alternatives may herald improvements in renal and bone health for perinatally infected patients in adulthood.


[Visual symptoms by syphilis].
This case presents a 42-year-old homosexual man with weight loss, urticaria type rash, tinnitus/phonophobia, dizziness and blurred vision and scotoma on the left side. Visual acuity was affected and a left papillitis was present. The patient was tested positive for antibodies against Treponoma pallidum. This case illustrates that symptoms of the syphilis disease can come from different organ systems and cross medical specialties. We encourage clinicians to more readily think of syphilis whenever there is a sexual active patient with complaints from different parts of the body.


Intrapopulation differences in ant eating in the mountain gorillas of Bwindi Impenetrable National Park, Uganda.
Variability in ant eating has been observed in several populations of eastern and western gorillas. We investigated the occurrence of ant (Dorylus sp.) eating in two groups of mountain gorillas (Gorilla beringei beringei) with overlapping home ranges within Bwindi Impenetrable National Park, Uganda from September 2001 to August 2002. We calculated the frequency of ant eating by an indirect method of analyzing fecal samples from silverbacks, adult females, and juveniles. One group consumed ants significantly more often than the other (3.3 vs 17.6% of days sampled). Furthermore, the group that consumed ants more often also consumed them on a seasonal basis (September-February monthly range: 0-8%; March-August monthly range: 30-42.9%). Finally, females and juveniles of this group consumed ants significantly more often than did the silverback (total samples containing ants: silverback, 2.1%; adult female, 13.2%; juvenile, 11.2%). Differences in ant eating between groups are likely due to variability in use of habitats where ants occur (particularly secondary forests). Surveys of ant densities in differing habitats, nutritional analysis of ants, and quantification of the amount of ants in their diets are necessary to understand if ant consumption is due to availability, nutritional value, group traditions, or taste preference.


Vulvar aggressive angiomyxoma: a surgical challenge.
Aggressive angiomyxoma is a rare and locally aggressive mesenchymal tumour, predominantly occurring in women of reproductive age group. The term aggressive is attributed to the infiltrative nature and frequent local recurrences. They arise commonly from the vulvovaginal region, perineum or pelvis and are usually misdiagnosed as other common entities in these regions. Radiological investigations aid in the diagnosis and planning of surgery. However, the final diagnosis in most of the cases is established by histopathological examination. We herein report a case of a middle-aged woman presenting with recurrent large right vulvar mass highlighting the surgical challenges posed by its intrapelvic extension.


Dietary sources of polyphenols in the Mediterranean healthy Eating, Aging and Lifestyle (MEAL) study cohort.
The aim of this study was to estimate the dietary intake and major food sources of polyphenols in the Mediterranean healthy Eating, Aging and Lifestyles (MEAL) study cohort. A total of 1937 individuals (18 + y) of urban population of Catania, Italy, completed a validated 110-item food frequency questionnaire; Phenol-Explorer database was used to estimate polyphenol intake. Mean intake of polyphenols was 663.7 mg/d; the most abundant classes were phenolic acids (362.7 mg/d) and flavonoids (258.7 mg/d). The main dietary sources of total polyphenols were nuts, followed by tea and coffee as source of flavanols and hydroxycinnamic acids, respectively, fruits (i.e. cherries were sources of anthocyanins and citrus fruits of flavanones) and vegetables (i.e. artichokes and olives were sources of flavones and spinach and beans of flavonols); chocolate, red wine and pasta contributed to flavanols and tyrosols, respectively. These findings will be useful to assess the potential benefits of foods with high polyphenol content.


Mortality of Creole kids during infection with gastrointestinal strongyles: a survival analysis.
Mortality due to strongyles infection in small ruminants is a critical component of flock productivity in a tropical climate. In goat production, few experiments have been conducted to estimate the variability of this trait. A survival analysis study was carried out in the Creole experimental flock of INRA-Gardel (Moule, Guadeloupe) to identify management and genetic factors influencing mortality of kids reared at pasture and infected with gastrointestinal strongyles, predominantly Haemonchus contortus and Trichostrongylus colubriformis. Survival curves from 3 and 11 mo of age were analyzed for 837 kids sired by 48 bucks and 250 does. The causes of death were recorded. Mortality due to gastrointestinal strongyles was the variable considered. The flock management included drenchings with levamisole every 8 wk. Fecal egg counts and packed cell volume were regularly measured after 7 wk of natural infection. All but 6.7% of the records were uncensored, with an average failure time of 165 d. The probability of death following gastrointestinal infection was more than three times greater in males than in females. Kids raised by their mother before weaning had a lower (P < 0.05) relative risk of dying than those reared in nursery (0.40 vs. 1). Parity of the dam and litter size effects were not significant. The risk of death was reduced by approximately 80% during the 3 wk that followed a drenching (P < 0.01). Risk decreased by about 25% for each additional kilogram of body weight at weaning. Live weight, fecal egg counts, and packed cell volume all had significant effects on risk of death when introduced as time-dependent covariates in the model (P < 0.0001 for live weight and packed cell volume, and P < 0.01 for fecal egg counts). The estimated genetic variability was small and inaccurate. These results demonstrated that risk of death from gastrointestinal infection could be reduced with appropriate flock management. High infection levels increased the risk of death, but they were not the direct cause. The important mediation of reduced body weight and anemia in likelihood of death is highlighted. More data are needed to better assess the possibility for genetic improvement of viability in Creole kids during gastrointestinal strongyle infection.


Complications, reoperations, and nutrient deficiencies two years after sleeve gastrectomy.
Background. The aim of this study was to investigate patient outcomes and nutritional deficiencies following sleeve gastrectomy (SG) during a follow-up of two years. Methods. Over a period of 56 months, all consecutive patients who underwent SG were documented in this prospective, single-center, observational study. The study endpoints included operative time, complication rates, nutritional deficiencies and percentage of excess weight loss (%EWL). Results. From September 26, 2005 to May 28, 2009, 82 patients (female : male = 48 : 34) with a mean age of 43.3 years (range: 22-64) and a preoperative BMI of 52.5 kg/m² (range: 36.8-77.0) underwent SG. Major complications were observed in 9.8% of the patients, with 1 death. During follow up 51.2% of patients were supplemented with iron, 36.6% with zinc, 37.8% with calcium, 26.8% with vitamin D, 46.3% with vitamin B12 and 41.5% with folic acid. %EWL was 54.3, 65.3 and 62.6% after 6, 12 and 24 months. Conclusion. SG as a single step procedure is an effective bariatric intervention. Nutritional deficiencies after SG can be detected by routine nutritional screening. Our results show that Vitamin B12 supplementation should suggest routinely after SG.


Corporeal elements and principles in the learned German chymical tradition.
This paper explores diverse conceptions of the physicality and tangibility of elements and principles in early modern chymistry. By tracing the development of natural philosophical and corpuscular ideas about material elements and principles among several physicans and chymists, including Thomas Erastus, Andreas Libavius, Daniel Sennert, and Anton Günther Billich, this article locates a learned tradition that developed predominantly in Germany, and which directly challenged a common understanding of matter held by major Paracelsians as well as authors from the French textbook tradition. Likewise, conceptions of incorporeal elements or principles are shown to have developed from the ideas of Paracelsus and Petrus Severinus, whereas authors in the learned tradition emphasised a particular interpretation of Aristotle. The article concludes by suggesting that chymical interpretations of material composition had an important influence throughout the seventeenth and eighteenth centuries, and that this provides further evidence that the so-called "compositional revolution" in chemistry was well underway prior to the eighteenth century.


Improving medical students' success in promoting health behavior change: a curriculum evaluation.
Effective behavior change counseling is an important component of the optimal care of patients, yet only a minority of medical schools currently include such training in their curriculum. To design and evaluate a formal curriculum to teach medical students the principles of motivational interviewing (MI) that will improve knowledge, skills, and confidence in the area of counseling patients for health behavior change. Fifty-three 3rd year medical students at the University of California, San Diego. A 4-week curriculum consisting of four 2-h sessions, in a small group format (8-12 students). Educational strategies included a combination of short didactics, video demonstrations, small group role plays, and interactive exercises. Students completed identical pre- and post-assessments, consisting of a questionnaire measuring confidence and knowledge, and a performance assessment using the Video Assessment of Simulated Encounters-Revised (VASE-R) tool. Knowledge improved significantly (pre-mean: 7.04, post-mean: 11.54; P < 0.001), as did skill development (pre-mean: 7.02, post-mean: 9.47; P < 0.001). Student satisfaction with behavior change counseling training improved from 3.6 to 8.1 (P < 0.001). Students were significantly more confident (P < 0.001) in their abilities to assess a patient's readiness for change and counsel the patient on behavior change after the course. Participation in a focused curriculum on the use of motivational interviewing techniques significantly improved 3rd year medical students' knowledge, confidence, and skills in the area of behavior change counseling. These gains may help students succeed in promoting good health habits in their future patients.


Breast-feeding duration and infant atopic manifestations, by maternal allergic status, in the first 2 years of life (KOALA study).
To investigate the potential effect of modification by maternal allergic status on the relationship between breast-feeding duration and infant atopic manifestations in the first 2 years of life. Data from 2705 infants of the KOALA Birth Cohort Study (The Netherlands) were analyzed. The data were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Total and specific immunoglobulin E measurements were performed on venous blood samples collected during home visits at age 2 years. Relationships were analyzed using logistic regression analyses. Longer duration of breast-feeding was associated with a lower risk for eczema in infants of mothers without allergy or asthma (P(trend) = .01) and slightly lower risk in those of mothers with allergy but no asthma (P(trend) = .14). There was no such association for asthmatic mothers (P(trend) = .87). Longer breast-feeding duration decreased the risk of recurrent wheeze independent of maternal allergy (P(trend) = .02) or asthma status (P(trend) = .06). Our findings show that the relationship between breast-feeding and infant eczema in the first 2 years of life is modified by maternal allergic status. The protective effect of breast-feeding on recurrent wheeze may be associated with protection against respiratory infections.


The Dynamic of Staphylococcus aureus Nasal Carriage in Central Iran.
Nasal carriage of Staphylococcus aureus plays an important role in the pathogenesis of staphylococcal infections. Anterior nasal region is a primary origin of S. aureus. In longitudinal studies, three types of S. aureus nasal carriers can be distinguished: persistent carriers, intermittent or transient carriers, and noncarriers. This study was designed to determine the dynamic of S. aureus nasal carriage in healthy carriers of central Iran. A total of 813 healthy adults were subjected to this cross-sectional study from November 2011 to January 2012 in Arak University of Medical Sciences. Two anterior nasal swabs were taken with a week interval from each participant. All the isolates were identified as S. aureus phenotypically by standard laboratory methods. The isolates were reconfirmed by amplification of sa442 gene as the identification marker. All the isolates were screened for the presence of the PVL (Panton-Valentine leukocidin) virulence genes and arginine catabolic mobile element (ACME-arc). Among the 813 subjects screened, 83 (10.2%) were persistent carriers, 86 (10.6%) were transient carriers and 644 (79.2%) cases were found as noncarriers. A total of 169 (20.8%) participants had colonized S. aureus. The frequency of ACME-arc A and PVL genes in S. aureus strains were 17% and 20%, respectively. Carriage of PVL-positive S. aureus is common in this region, even in the low frequency of MRSA colonization. The detection of ACME-arcA gene in S. aureus isolates is a public-health concern and demands continued surveillance and close monitoring.


Monte-Carlo simulation combined with density functional theory to investigate the equilibrium thermodynamics of electrode materials: lithium titanates as model compounds.
By using lithium titanate (LTO) as a model electrode material, the present study proposes a method to describe its equilibrium thermodynamics based on the Monte-Carlo simulation (MC), for which the energetic parameters are determined by the density functional theory (DFT). The electrochemical potential profile is simulated by a simple topological model which consists only of three parameters representing the Li site energies; namely, the potential energy of the 8a site (ε8a), the difference in the site energy between the 8a and 16c sites (Δε) and the repulsion between two Li atoms situated at the adjacent 8a and 16c sites (J). Parameter physics by the MC revealed that the term Δε plays a decisive role, with a collateral effect from J, for characterizing the shape of the potential profile whereas the term ε8a determines its position along the electrochemical potential. For instance, if Δε exceeds the thermal energy at the temperature under consideration, i.e., if Δε > 3kT, the first-order phase transition takes place during which two phases coexist, resulting in a plateau region in the potential profile. On the other hand, if Δε < 3kT, the lithiation of LTO is viewed as a phenomenon above the critical point, above which the material is in a homogeneous uniphasic state. A multiple regression analysis of a set of the total energy calculated by DFT allows us to determine these energetic terms. The MC simulation with the determined parameters well reproduces the shape and position of the experimental potential profile of LTO. Since the determined value, Δε/eV ∼ 0.4, far exceeds the thermal energy at ambient temperature, the potential plateau of LTO is explained by the first-order phase transition as long as the equilibrium state is concerned.


Micro-to-Nano Oncolytic Microbial System Shifts from Tumor Killing to Tumor Draining Lymph Nodes Remolding for Enhanced Immunotherapy.
Because the tumor-draining lymph nodes (TDLNs) microenvironment is commonly immunosuppressive, oncolytic microbe-induced tumor antigens aren't sufficiently cross-primed tumor specific T cells through antigen-presenting cells (e.g., dendritic cells (DCs)) in TDLNs. Herein, this work develops the micro-to-nano oncolytic microbial therapeutics based on pyranose oxidase (P2 O) overexpressed Escherichia coli (EcP) which are simultaneously encapsulated by PEGylated mannose and low-concentrated photosensitizer nanoparticles (NPs). Following administration, P2 O from this system generates toxic hydrogen peroxide for tumor regression and leads to the release of tumor antigens. The "microscale" EcP is triggered, following exposure to the laser irradiation, to secrete the "nanoscale" bacterial outer membrane vesicles (OMVs). The enhanced TDLNs delivery via OMVs significantly regulates the TDLNs immunomicroenvironment, promoting the maturation of DCs to potentiate tumor antigen-specific T cells immune response. The micro-to-nano oncolytic microbe is leveraged to exert tumor killing and remold TDLNs for initiating potent activation of DCs, providing promising strategies to facilitate microbial cancer vaccination.


Myosin VI is required for targeted membrane transport during cytokinesis.
Myosin VI plays important roles in endocytic and exocytic membrane-trafficking pathways in cells. Because recent work has highlighted the importance of targeted membrane transport during cytokinesis, we investigated whether myosin VI plays a role in this process during cell division. In dividing cells, myosin VI undergoes dramatic changes in localization: in prophase, myosin VI is recruited to the spindle poles; and in cytokinesis, myosin VI is targeted to the walls of the ingressing cleavage furrow, with a dramatic concentration in the midbody region. Furthermore, myosin VI is present on vesicles moving into and out of the cytoplasmic bridge connecting the two daughter cells. Inhibition of myosin VI activity by small interfering RNA (siRNA)-mediated knockdown or by overexpression of dominant-negative myosin VI tail leads to a delay in metaphase progression and a defect in cytokinesis. GAIP-interacting protein COOH terminus (GIPC), a myosin VI binding partner, is associated with the function(s) of myosin VI in dividing cells. Loss of GIPC in siRNA knockdown cells results in a more than fourfold increase in the number of multinucleated cells. Our results suggest that myosin VI has novel functions in mitosis and that it plays an essential role in targeted membrane transport during cytokinesis.


Urinary biomarkers in hydronephrosis.
Hydronephrosis is diagnosed in 0.5-1% of all newborns, and ureteropelvic junction obstruction (UPJO) accounts for 35% of those cases. A urinary tract obstruction that occurs during early kidney development affects renal morphogenesis, maturation, and growth, and in the most severe cases, this will ultimately lead to progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The clinical management of these patients remains a controversial topic. The aim is to preserve renal function by identifying the 15-20% of children who require early surgical intervention from those for whom watchful waiting may be appropriate because of spontaneous resolving/stabilization without significant loss of renal function. Although the patients attend regular follow-ups, including repetitive blood tests, ultrasonographies, and the more invasive diuretic renograms, the surgeons still miss reliably biomarkers that could be used as predictors for renal parenchymal damage and decreased renal function, and thereby provide more clear indications for surgical intervention. The aim of this PhD thesis was to further elucidate the pathophysiology of obstructive nephropathy (study I) and to search for potential candidate biomarkers that may have a predictive and/or diagnostic value in the management of hydronephrosis (study II). Study I: Urine and kidney cytokine profiles in experimental unilateral acute and chronic hydronephrosis. To study the dynamics of the urinary secretion of cytokines after the release of unilateral ureteral obstruction, and to study whether the urinary concentrations of these compounds reliably reflects changes in the renal parenchyma. This was tested in 2 experimental rat models: an acute obstruction model and a chronic obstruction model. The acute obstruction model demonstrated significant differences in the renal levels of IL-1β, IL-6, TNF-α, and IL-10 in comparison with controls, and these differences were associated with similar differences in their urinary excretion. Such results were not obtained in the chronic obstruction model in which significant differences were only demonstrated in the urinary concentrations of IL-6. Study II: Candidate urinary biomarkers in hydronephrosis - a clinical study. To study the dynamics of the urinary excretion of selected potential biomarkers in children after the relief of UPJO, and to compare their findings with healthy controls. Twenty-eight children with UPJO were included in the study from 2007-2011 together with 13 healthy children. Pre-, peri- and post-operatively (1 year) urine samples were collected. The median age of the patients was 8.1 (3.5-14.5) years. Five proteins (EGF, IP-10, MCP-1, RANTES, and MIP-1α) were examined in study IIa, and 4 proteins (NGAL, CyC, βM-2, and OPN) were examined in study IIb. In brief, significantly increased urinary concentrations of EGF and MCP-1 were demonstrated in children with UPJO compared to controls, which was followed by a decline in the post-operative period to levels similar to the controls. This indicates that the urinary concentrations of EGF and MCP-1 are regulated as a response to the obstruction, suggesting that they may have a potential as urinary biomarkers in hydronephrosis. In general, urine from the obstructed kidney exhibited higher concentrations of the proteins compared to urine from the nonobstructed kidney. Furthermore, CyC, β-2M, and OPN were negatively correlated with age, and IP-10 and MCP-1 were negatively correlated with DRF. In conclusion, this PhD study confirmed increased concentrations of selected proteins in urine from kidneys suffering from obstruction. Interestingly, it was observed that some urinary proteins had an age-dependent excretion. Further investigations are required to test the ability of the examined proteins to identify an obstruction and reveal disease progression and, thereby, be useful clinical tools.


Recognizing Inadequate Response in Patients With Major Depressive Disorder.
  Being able to recognize inadequate response to antidepressant treatment and distinguish it from treatment-resistant depression is key in order for clinicians to provide appropriate therapies. Although definitions vary, nonresponse is often defined as less than 25% improvement on a standardized rating scale, and partial response, as more than 25% but less than 50% improvement. Residual symptoms characteristic of inadequate response (less than 50% improvement) include low mood, anxiety, irritability, guilt, and somatic symptoms. Various factors that may contribute to inadequate response to an antidepressant include inadequate dose or duration, poor adherence, and misdiagnosis. .


The essential oil of Lippia alba: analysis of samples from French overseas departments and review of previous works.
This paper contains new data on the chemical composition of the essential oil of Lippia alba (Mill.) N. E. Brown, as well as an overview of the available literature. Although the composition of the essential oil of this species is well-documented, discrepancies between the reported results suggest that many chemotypes and morphotypes exist. The analysis of essential oils obtained from the leaves of samples from three different locations in the French Overseas Departments (French Guiana, Martinique, and two different places in Guadeloupe) have shown that the composition of each one is quite different. This new data, along with a review and discussion of published studies, enabled us to establish seven distinct chemotypes. Possible connections between these chemotypes and morphotypes already described were also investigated.


Involvement of a conserved GFG motif region in substrate binding by RseP, an Escherichia coli S2P protease.
RseP, an Escherichia coli S2P family intramembrane cleaving protease, is involved in regulation of the extracytoplasmic stress response and membrane quality control through specific cleavage of substrates. Recent research suggested that the PDZ domains and the MRE β-loop (membrane-reentrant β-loop) are involved in substrate discrimination; the former would serve to prevent cleavage of substrates with a large periplasmic domain, whereas the latter would directly interact with the substrate's transmembrane segment and induce its conformational change. However, the mechanisms underlying specific substrate recognition and cleavage by RseP are not fully understood. Here, the roles of the N-terminal part of the first cytoplasmic loop region (C1N) of RseP that contains a highly conserved GFG motif were investigated. A Cys modifiability assay suggested that C1N is partly membrane-inserted like the MRE β-loop. Pro, but not Cys, substitutions in the GFG motif region compromised the proteolytic function of RseP, suggesting the importance of a higher order structure of this motif region. Several lines of evidence indicated that the GFG motif region directly interacts with the substrate and also aids the function of the MRE β-loop that participates in substrate recognition by RseP. These findings provide insights into the substrate recognition mechanisms of S2P proteases.


Early Evolution of Vertebrate Mybs: An Integrative Perspective Combining Synteny, Phylogenetic, and Gene Expression Analyses.
The genes in the Myb superfamily encode for three related transcription factors in most vertebrates, A-, B-, and c-Myb, with functionally distinct roles, whereas most invertebrates have a single Myb. B-Myb plays an essential role in cell division and cell cycle progression, c-Myb is involved in hematopoiesis, and A-Myb is involved in spermatogenesis and regulating expression of pachytene PIWI interacting RNAs, a class of small RNAs involved in posttranscriptional gene regulation and the maintenance of reproductive tissues. Comparisons between teleost fish and tetrapods suggest that the emergence and functional divergence of the Myb genes were linked to the two rounds of whole-genome duplication early in vertebrate evolution. We combined phylogenetic, synteny, structural, and gene expression analyses of the Myb paralogs from elephant shark and lampreys with data from 12 bony vertebrates to reconstruct the early evolution of vertebrate Mybs. Phylogenetic and synteny analyses suggest that the elephant shark and Japanese lamprey have copies of the A-, B-, and c-Myb genes, implying their origin could be traced back to the common ancestor of lampreys and gnathostomes. However, structural and gene expression analyses suggest that their functional roles diverged between gnathostomes and cyclostomes. In particular, we did not detect A-Myb expression in testis suggesting that the involvement of A-Myb in the pachytene PIWI interacting RNA pathway is probably a gnathostome-specific innovation. We speculate that the secondary loss of a central domain in lamprey A-Myb underlies the functional differences between the cyclostome and gnathostome A-Myb proteins.


Implications of polyploidy events on the phenotype, microstructure, and proteome of Paulownia australis.
Polyploidy events are believed to be responsible for increasing the size of plant organs and enhancing tolerance to environmental stresses. Autotetraploid Paulownia australis plants exhibit superior traits compared with their diploid progenitors. Although some transcriptomics studies have been performed and some relevant genes have been revealed, the molecular and biological mechanisms regulating the predominant characteristics and the effects of polyploidy events on P. australis remain unknown. In this study, we compared the phenotypes, microstructures, and proteomes of autotetraploid and diploid P. australis plants. Compared with the diploid plant, the leaves of the autotetraploid plant were longer and wider, and the upper epidermis, lower epidermis, and palisade layer of the leaves were thicker, the leaf spongy parenchyma layer was thinner, the leaf cell size was bigger, and cell number was lower. In the proteome analysis, 3,010 proteins were identified and quantified, including 773 differentially abundant proteins. These results may help to characterize the P. australis proteome profile. Differentially abundant proteins related to cell division, glutathione metabolism, and the synthesis of cellulose, chlorophyll, and lignin were more abundant in the autotetraploid plants. These results will help to enhance the understanding of variations caused by polyploidy events in P. australis. The quantitative real-time PCR results provided details regarding the expression patterns of the proteins at mRNA level. We observed a limited correlation between transcript and protein levels. These observations may help to clarify the molecular basis for the predominant autotetraploid characteristics and be useful for plant breeding in the future.


First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi.
Segmental vitiligo is often ascribed to the neurogenic theory of melanocyte destruction, although data about the initial etiopathological events are scarce. Clinical, histopathological and T-cell phenotypic analyses were performed during the early onset of a segmental vitiligo lesion in a patient with associated halo nevi. Histopathological analysis revealed a lymphocytic infiltrate, mainly composed of CD8+ T-cells and some CD4(+) T-cells around the dermo-epidermal junction. Flow cytometry analysis of resident T-cells revealed a clear enrichment of pro-inflammatory IFN-gamma producing CD8+ T-cells in lesional skin compared to the non-lesional skin. Using human leukocyte antigen-peptide tetramers (MART-1, tyrosinase, gp100), increased numbers of T cells, recognizing melanocyte antigens were found in segmental vitiligo lesional skin, as compared with the non-lesional skin and the blood. Our findings indicate that a CD8+ melanocyte specific T cell-mediated immune response, as observed in generalized vitiligo, also plays a role in segmental vitiligo with associated halo nevi.


Sister Mary Joseph's nodule as the first and only sign of recurrence in a case of stage Ia carcinoma ovary.
Sister Mary Joseph's nodule, a term coined by Sir Hamilton Bailey, describes the umbilical nodule associated with advanced intra-abdominal malignancy. It signifies extensive intra-abdominal disease with a poor prognosis and a median survival of 4-14 months. We describe a case in which discharge from umbilical nodule was the first sign of recurrence in carcinoma ovary. On laparotomy, besides extra-abdominal umbilical deposit there was no peritoneal disease.


Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum.
Tripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.


Utility of acetyldithio-CoA in detecting the influence of active site residues on substrate enolization by 3-hydroxyl-3-methylglutaryl-CoA synthase.
Hydroxymethylglutaryl-CoA synthase-catalyzed condensation of acetyl-CoA with acetoacetyl-CoA requires enolization/carbanion formation from the acetyl C-2 methyl group prior to formation of a new carbon-carbon bond. Acetyldithio-CoA, a readily enolizable analog of acetyl-CoA, was an effective competitive inhibitor of avian hydroxymethylglutaryl-CoA synthase (Ki = 28 microm). In the absence of cosubstrate, enzyme catalyzed the enolization/proton exchange from the C-2 methyl group of acetyldithio-CoA. Mutant enzymes that exhibited impaired formation of the covalent acetyl-S-enzyme reaction intermediate exhibited diminished (D159A and D203A) or undetectable (C129S) rates of enolization of acetyldithio-CoA. The results suggest that covalent thioacetylation of protein, which has not been detected previously for other enzymes that enolize this analog, occurs with hydroxymethylglutaryl-CoA synthase. Enzyme catalyzed the transfer of the thioacetyl group of this analog to 3'-dephospho-CoA suggesting the intermediacy of a covalent thioacetyl-S-enzyme species, which appears to be important for proton abstraction from C-2 of the thioacetyl group. Avian enzyme glutamate 95 is crucial to substrate condensation to form a new carboncarbon bond. Mutations of this invariant residue (avian enzyme E95A and E95Q; Staphylococcus aureus enzyme E79Q) correlated with diminished ability to catalyze enolization of acetyldithio-CoA. Enolization by E95Q was not stimulated in the presence of acetoacetyl-CoA. These observations suggest either a direct (proton abstraction) or indirect (solvent polarization) role for this active site glutamate.


Ciliary defects: cell biology and clinical perspectives.
Considerable progress has been made in achieving a perspective of the pathophysiology of ciliary defects in human disease in the interval between Siewert's and Kartagener's early descriptions of KS. Not only have we achieved a better understanding of some of the mechanisms involved in the pathogenesis of congenital ciliary syndromes, but also we have come to appreciate a new spectrum of ciliary defects, those of acquired etiology. The advent of modern electron microscopy has been a significant element to this progress and its importance is reflected by the numerous studies of ciliary defects that have come in the wake of the pioneering ultrastructural investigations of Afzelius and colleagues. However, each discovery appears to generate additional questions. This is indicative of the importance of the subject to both basic and clinical science and of the vitality of the investigators in this field as a comprehensive understanding of ciliary diseases is sought.


Recognition and laboratory characteristics of an atypical oocyst of Cryptosporidium.
Feces from some patients with clinically unremarkable cryptosporidiosis contained an unusual variety of oocyst not previously recognized. These atypical oocysts were shown by electron microscopy to have a distinctive three-layered outer coat and, by immunofluorescence with a monoclonal antiserum, to lack an antigen present on the surface of typical oocysts. In contrast to typical oocysts, the atypical variety is very fragile and quickly collapses when suspended in solutions of high osmotic pressure or in lipid solvents. Atypical oocysts cannot be stained by methods used to stain typical oocysts, but their appearance in sucrose-phenol is characteristic. Their stability in this solution, though much less than that of typical oocysts, is sufficient for them to be recognized and for cases to be diagnosed by microscopy. Patients who excreted atypical oocysts never excreted the typical variety. General findings in patients who excreted atypical oocysts were no different from those who excreted typical oocysts.


The sensory basis of roost finding in a forest bat, Nyctalus noctula.
Tree cavities are a critical resource for most forest-dwelling bats. Yet, it is not known how bats search for new sites and, in particular, find entrances to cavities. Here, we evaluated the importance of different sensory channels for the detection of tree roosts by the noctule bat Nyctalus noctula. Specifically, we tested the role of three non-social cues (echo information, visual information and temperature-related cues) and two social sensory cues (conspecific echolocation calls and the presence of bat olfactory cues). We set up an experiment in a flight room that mimicked natural conditions. In the flight room, we trained wild-caught bats kept in captivity for a short while to find the entrance to an artificial tree cavity. We measured the bats' hole-finding performance based on echolocation cues alone and then presented the bat with one of four additional sensory cues. Our data show that conspecific echolocation calls clearly improved the bats' performance in finding tree holes, both from flying (long-range detection) and when they were crawling on the trunk (short range detection). The other cues we presented had no, or only weak, effects on performance, implying that detection of new cavities from a distance is difficult for noctules if no additional social cues, in particular calls from conspecifics, are present. We conclude that sensory constraints strongly limit the effectiveness of finding new cavities and may in turn promote sociality and acoustic information transfer among bats. As acoustic cues clearly increased the bats' detection performance, we suggest that eavesdropping is an important mechanism for reducing the costs of finding suitable roosts.


Prospective hatching of embryos developed from oocytes exhibiting difficult oolemma penetration during ICSI.
The hormonal milieu during ovarian stimulation is known to affect oolemma behaviour as well as zona pellucida thickness and structure. This led us to investigate whether a special subgroup of patients with oocytes where penetration of the oolemma is difficult during ICSI may benefit from assisted hatching. A total of 77 couples (mean age: 32.9 +/- 4.6 years; range: 22-38) had oocytes that could hardly be penetrated by the ICSI pipette. Nineteen patients underwent two ICSI cycles, giving a total number of 96 cycles, which were randomly split into either the study group (n = 52) or the non-hatching group (n = 44). Hatching was done using a non-contact 1.48 mm wavelength diode laser. Implantation and pregnancy rates were recorded. The pregnancy rate was 36.6% (19/52) in the study group and 13.6% (6/44) in the non-hatching group (P < 0.05). In addition, a higher number (P < 0.05) of embryos implanted in the study group (23/106; 21.7%) than in the non-hatching group (9/92; 9.8%). Once oolema penetration during ICSI has proven difficult, prospective hatching of embryos considered for transfer may increase their implantation behaviour.


Activity-based funding in mental health: a disastrous path.
On the basis of the experience of the Netherlands, this critical commentary will argue why activity-based funding (ABF) in mental health care is a disastrous path that Australia should not take. ABF leads to an exponential growth in health care spending as it encourages diagnostic inflation and overproductivity. It also leads to fraud and an increased bureaucracy that goes hand in hand with demoralisation among health workers. And finally, the increasing treatment claims leads to the reintroduction of productivity limitations, waiting lists and ultimately austerity measures in order to halt the untamed growth of spending.


Optimal electron doping of a C60 monolayer on Cu(111) via interface reconstruction.
We demonstrate the charge state of C60 on a Cu(111) surface can be made optimal, i.e., forming C60(3-) as required for superconductivity in bulk alkali-doped C60, purely through interface reconstruction rather than with foreign dopants. We link the origin of the C60(3-) charge state to a reconstructed interface with ordered (4x4) 7-atom vacancy holes in the surface. In contrast, C60 adsorbed on unreconstructed Cu(111) receives a much smaller amount of electrons. Our results illustrate a definitive interface effect that affects the electronic properties of molecule-electrode contact.


Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters.
The radio-iodinated noradrenaline analogue meta-iodobenzylguanidine (MIBG) can be used for scintigraphy and radiation therapy of neuroendocrine (NE). The aim of the present study was to study the importance of vesicular monoamine transporters (VMATs) for the uptake of (123)I-MIBG in NE tumours. In nude mice, bearing the human transplantable midgut carcinoid GOT1, all organs and xenografted tumours accumulated (123)I after i.v. injection of (123)I-MIBG. A high concentration of (123)I was maintained in GOT1 tumours and adrenals, which expressed VMATs, but rapidly decreased in all other tissues. In the VMAT-expressing NE tumour cell lines GOT1 and BON and in VMAT-expressing primary NE tumour cell cultures (carcinoids, n=4 and pheochromocytomas, n=4), reserpine significantly reduced the uptake of (123)I-MIBG. The membrane pump inhibitor clomipramine had no effect on the uptake of (123)I-MIBG in GOT1 and BON cells, but inhibited the uptake in one out of four primary carcinoid cell cultures and three out of four primary pheochromocytoma cell cultures. In conclusion, VMATs and secretory granules are of importance for the uptake and retention of (123)I-MIBG in NE tumours. Information about the type and degree of expression of VMATs in NE tumours may be helpful in future to select patients suitable for radiation therapy with radio-iodinated MIBG.


The Association Between Environmental Perchlorate, Nitrate, and Thiocyanate Exposure and Oral Pain in NHANES.
To examine the human exposure to perchlorate, nitrate, and thiocyanate, and their associations with oral pain (OP) in the general population from the U.S. A total of 13,554 participants were enrolled in the National Health and Nutrition Examination Survey. The urinary perchlorate, nitrate, and thiocyanate were measured using ion chromatography coupled with an electrospray tandem mass spectrometry. The multivariable linear and logistic regressions were performed to explore the associations of the urinary perchlorate, nitrate, and thiocyanate, with the prevalence of oral pain. Restricted cubic splines were used to explore the non-linearity. There are 3,129 OP cases. There was a higher urinary level of perchlorate, nitrate, and thiocyanate in OP. We found that urinary thiocyanate was positively associated with OP (odds ratio [OR] = 1.06; [1, 1.13]; p = 0.049). Restricted cubic spines revealed that urinary thiocyanate was in a U-shape association with OP. Urinary thiocyanate was in a U-shape association with OP, suggesting that we should keep the exposure of thiocyanate under a reasonable range.


LOXL2 from human amniotic mesenchymal stem cells accelerates wound epithelialization by promoting differentiation and migration of keratinocytes.
In this study, we identified wound healing-related proteins secreted by human amniotic epithelial cells (hAECs) and human amniotic mesenchymal stem cells (hAMSCs). We observed increased migration and reduced proliferation and differentiation when keratinocytes were co-cultured in media conditioned by hAECs (hAECs-CM) and hAMSCs (hAMSCs-CM). Label-free mass spectrometry and bioinformatic analyses of the hAECs-CM and hAMSCs-CM proteome revealed several proteins associated with wound healing, angiogenesis, cellular differentiation, immune response and cell motility. The levels of the proteins related to wound healing, including CTHRC1, LOXL2 and LGALS1, were significantly higher in hAMSCs-CM than hAECs-CM. LOXL2 significantly enhanced in vitro keratinocyte migration and differentiation compared to CTHRC1 and LGALS1. Moreover, LOXL2 enhanced keratinocyte migration and differentiation by activating the JNK signaling pathway. We observed significant reduction in the in vitro migration and differentiation of keratinocytes when co-cultured with medium conditioned by LOXL2-silenced hAMSCs and when treated with 10 μM SP600125, a specific JNK inhibitor. Treatment with hAMSCs-CM and LOXL2 significantly accelerated wound healing in the murine skin wound model. These findings show that LOXL2 promotes wound healing by inducing keratinocyte migration and differentiation via a JNK signaling pathway.


Effect of omega-3 supplementation on inflammatory parameters in patients on chronic ambulatory peritoneal dialysis.
End stage renal disease (ESRD) is a state of micro inflammation that attenuates patient's life span and quality of life. Inflammatory markers like interlukin 6 (IL-6) and C- reactive protein (CRP) can predict inflammatory state in ESRD patients. Dietary limitations are risk factors for omega-3 deficiency in these patients. Omega-3 supplementation is an attractive material that proposed in inflammation modulation. The aim of this study is evaluation of effect of omega-3 supplementation on IL-6 and CRP level in chronic ambulatory peritoneal dialysis (CAPD) patients. This randomized controlled double-blind clinical trial is performed in 40 CAPD patients in two academic hospitals in Isfahan, Iran. One group received 1000 mg omega-3 capsule (each capsule contains 180 mg Eicosapentanoic and 120 mg Dosahexanoic acid) three times a day orally for 8 weeks (n = 20) and the other matched group by placebo (n = 20). Serum level of IL-6 and quantitative CRP (Q-CRP) were measured in beginning and the end of the study. Finally all data were analyzed by SPSS version 18. Mean age of patients was 53 years old in omega-3 group patients and 54 years old in placebo group. There were not any differences in CRP and IL-6 level in the beginning and the end of study between two groups (P: 0.81 and 0.10 for CRP and 0.26 and 0.23 for IL-6, respectively). Omega-3 supplementation did not effect on inflammatory markers (Q-CRP and IL-6) in CAPD patients after 8 weeks.


Static Non-articulating Knee Spacers Are Associated with a High Degree of Morbidity in Challenging Clinical Scenarios.
The morbidity associated with the use of static non-articulating knee spacers for the treatment of periprosthetic joint infection (PJI) in challenging clinical scenarios has not been well described. From 2011-2019, 63 molded block static spacers were utilized at two academic institutions for the treatment of PJI with associated severe soft tissue compromise (59%), collateral ligament deficiency (49%), extensor mechanism compromise (48%), or type 3 bone defects (44%). Complications and outcomes were assessed. Complications with the use of static spacers were common and included further bone loss (46%), spacer migration (16%), extensor mechanism compromise (16%), cast or related soft tissue injuries (16%), fracture (13%), and spacer breakage (3%). Ultimately, 22% of patients underwent amputation. Patient variables such as age and body mass index were not associated with outcomes. Static knee spacers are associated with substantial morbidity in challenging clinical scenarios and alternatives may need to be considered. (Journal of Surgical Orthopaedic Advances 32(2):122-126, 2023).


Prognostic Factors and Models for Elderly (≥70 Years Old) Primary Operable Triple-Negative Breast Cancer: Analysis From the National Cancer Database.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. In the elderly (≥70 years old) primary operable (T1-3N0-1M0) TNBC, individualized treatment modalities for this population are pivotal and important, but limited studies are explored. The clinicopathological features of elderly primary operable TNBC patients were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database between January 2010 and December 2015. Kaplan-Meier curves were used to show the survival patterns in the different subgroups. Multivariate Cox analysis was used to identify independent risk factors in the 3-, 5-, and 7- year overall survival (OS) and cancer-specific survival (CSS) in this subpopulation. The predictive model was further developed and validated for clinical use. Between 2010 and 2015 years, a total of 4,761 elderly primary operable TNBC patients were enrolled for the study, with a mean age of 76 years and a median follow-up of 56 months. The multivariate Cox analysis showed that age (increased per year: hazard ratio (HR) = 1.05), race (Asian/Pacific Islander and American Indian/Alaska Native, HR = 0.73), differentiation grade (grade II: HR = 2.01; grade III/IV: HR = 2.67), larger tumor size (T1c: HR = 1.83; T2: HR = 2.78; T3: HR = 4.93), positive N stage (N1mi: HR = 1.60; N1: HR = 1.54), receiving radiation therapy (HR = 0.66), and receiving adjuvant chemotherapy (HR = 0.61) were the independent prognostic factors for OS, and a similar prognostic pattern was also determined in CSS. Besides, two nomograms for predicting the 3-, 5-, and 7-year OS and CSS in this population were developed with a favorable concordance index of 0.716 and 0.746, respectively. The results highlight that both radiation and adjuvant chemotherapy are significantly associated with favorable long-term OS and CSS probability in elderly primary operable TNBC patients. Based on the determined independent prognostic factors, the novel nomograms could assist the oncologists to make individualized clinical decisions for the subpopulation at different risks.


Diagnostic capability of peripapillary retinal nerve fiber layer parameters in time-domain versus spectral-domain optical coherence tomography for assessing glaucoma in high myopia.
To evaluate and compare the diagnostic capabilities of peripapillary retinal nerve fiber layer (p-RNFL) parameters of Spectralis optical coherence tomography (OCT) versus Stratus OCT to detect glaucoma in patients with high myopia. This is a retrospective, cross-sectional study. Sixty highly myopic eyes of 60 patients were enrolled, with 30 eyes in the glaucoma group and 30 eyes in the control group. All eyes received peripapillary imaging of the optic disc using Stratus and Spectralis OCT. Areas under the receiver operating characteristic curve (AUROC) and the sensitivity at specificity of >80% and >95% for p-RNFL parameters obtained using the two devices to diagnose glaucoma were analysed and compared. In Spectralis OCT, p-RNFL thickness parameters with the largest AUROC were the temporal-inferior sector (0.974) and the inferior quadrant (0.951), whereas in Stratus OCT, the best parameters were the 7-o'clock sector (0.918) and the inferior quadrant (0.918). Compared to the Stratus OCT parameters, the Spectralis OCT parameters demonstrated generally higher AUROC; however, the difference was not statistically significant. The best p-RNFL parameters for diagnosing glaucoma in patients with high myopia were the temporal-inferior sector on Spectralis OCT and the 7-o'clock sector on Stratus OCT. There were no significant differences between the AUROCs for Spectralis OCT and Stratus OCT, which suggest that the glaucoma diagnostic capabilities of these two devices in patients with high myopia are similar.


Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia.
The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from EmuSRalpha-TEL-JAK2 transgenic mice present an aberrant CD8(+) differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4(-)CD8(-) double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3epsilon- and pTalpha-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRalphabeta transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCRalphabeta expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs.


[Eisleben and the Mansfeld area in the medical history aspect. A contribution to Luther year 1983].
The homeland of the reformer Martin Luther which since the middle ages has been acting as the centre of a mining industry is at the same time also one of the starting points for the organisation of a mining medicine with its medical measures directed to the treatment of the miners. On the occasion of the Luther memorial year 1983 is reported on several physicians and pharmaceutists of the Eisleben-Mansfeld district who distinguished themselves by particular activities and thus for ever stay in the history of science.


Newer therapies for asthma: a focus on anti-IgE.
The prevalence of asthma and other allergic disorders has been on the increase not only in the western world but also in the developing countries. This increasing prevalence has lead research into the discovery and development of various new therapeutic strategies. The improved understanding about the pathophysiology of asthma has prompted the developments of novel molecules to tackle this problem. These include newer phosphodiesterase inhibitors, cytokine modulation strategies, allergen immunotherapy, and anti-IgE. Immunoglobulin E plays a major role in airway inflammation in asthma. Omalizumab, a novel humanised monoclonal antibody directed against the high affinity FcepsilonRI portion of the IgE has shown a lot of promise in the control of asthma symptoms and as a steroid sparing agent in the management of allergic asthma. This new molecule has an excellent safety profile and could play an important role in the management of patients with severe asthma. This review gives a brief overview of the newer therapies under investigation with special reference to omalizumab in the treatment of allergic asthma.


Technical devices in jejunal pouch reconstruction following total gastrectomy, including postoperative results.
Either straight Roux-en-Y anastomosis or jejunal interposition used to be adopted following total gastrectomy. However, dissatisfaction with regard to postoperative quality of life has prompted the development of new techniques. The purpose of this study is to describe and assess the authors' technical devices in jejunal pouch (J-pouch) reconstruction following total gastrectomy and the results of these operations. A prospective study of 17 patients with malignant gastric disease (nine with J-pouch interposition, eight with J-pouch Roux-en-Y reconstruction) was performed. To facilitate the side-to-side anastomosis of the jejunal loop, the authors used an autosuture instrument. The anastomosis was then checked for hemostasis using a vaginoscope. An Endo GIA with a 60-mm long white cartridge (closed height of staples, 1.0 mm) is the instrument of choice to create the J-pouch. This autosuture instrument fires triple staggered staple lines, which minimizes bleeding from the anastomosed site and reduces operative time. No anastomotic leaks were associated with the autosuture instrument. The vaginoscope facilitates a direct observation of the staple lines internally and if necessary, enables secure hemostasis with sutures. Bowel motility was satisfactory for both surgical procedures, as measured by the percentage of radiopaque markers which were expelled from the pouch. There were no serious complications, and all patients have currently survived, a maximum of 5 years and 6 months after surgery, except for one patient who died from recurrent disease. The authors' procedures for J-pouch reconstruction are advantageous due to a favorable postoperative quality of life, with low complication rates.


Cardioembolic strokes resulting from a self-inflicted needle puncture involving both sides of the heart.
Foreign bodies in the heart are rare occurrences with a limited evidence base to guide recommendations on management. We report a case of multiple cardioembolic strokes as a result of a self-inflicted sewing needle puncture from the anterior chest through the right ventricle and interventricular septum with its tip in the left ventricle close to the subvalvular apparatus in a 39-year-old psychiatric patient. We discuss issues surrounding decision making and ongoing care and highlight the importance of further follow-up and reporting of cases to form a robust evidence base to guide future recommendations.


Ultrastructural study of the ciliated cells from renal tubular epithelium in acute progressive glomerulonephritis.
Light microscopic examination of the renal tubular epithelium of a female with a rapid progressive glomerulonephritis revealed in several areas the presence of cells bearing ciliumlike structures. At transmission electron microscopy, normal tubular cells appeared to be partially replaced by epithelial cells showing numerous 9 X 2 cilia and a normally developed basal apparatus. The cilia showed several ultrastructural details (i.e., outer dynein arms, spokes) such as observed in kinocilia of the respiratory epithelium. In addition, a number of poorly differentiated cells showing cilia with a 9 + 0 pattern and at the same time cilia with a 9 + 2 pattern of microtubular arrangement were also seen. The possible biologic significance of these cilia is discussed.


Is type of work associated with physical activity and sedentary behaviour in women with fibromyalgia? A cross-sectional study from the al-Ándalus project.
To analyse the association between the type of work (productive vs reproductive work) and the levels of physical activity and sedentary behaviour in women with fibromyalgia. This cross-sectional study involved 258 women with fibromyalgia from southern Spain. Of them, 55% performed reproductive work (unpaid, associated with caregiving and domestic roles) exclusively, while 45% had productive job (remunerated, that results in goods or services). Physical activity of light, moderate and vigorous intensity in the leisure time, at home, at work, and totally were measured through the leisure time physical activity instrument and with the physical activity at home and work instrument, respectively. Sedentary behaviour was measured by the Sedentary Behaviour Questionnaire. After adjusting for age, fat percentage, education level and marital status, the multivariate analysis of covariance model informed the existence of significant differences between type of work groups (p<0.001). Women with productive work engaged in more light physical activity at work (mean difference =448.52 min; 95 % CI 179.66 to 717.38; p=0.001), and total physical activity of light (809.72 min; 535.91 to 1085.53; p<0.001) and moderate (299.78 min; 97.31 to 502.25; p=0.004) intensity. Women with reproductive work engaged in more light physical activity at home (379.14; 175.64 to 582.64; p<0.001). Leisure time physical activity and sedentary behaviour were similar in both groups (p>0.05 for all comparisons). Women with productive work had greater levels of physical activity compared with those who only did reproductive work, except for physical activity at home. Having productive work might facilitate movement of women with fibromyalgia towards a more active lifestyle.


Clinical use of a new mitral disc valve.
A disc valve of new design was used successfully for the replacement of the mitral valve in patients with rheumatic mitral valve disease. This valve would appear to have the following advantages over the mitral ball valve prosthesis:* Lower left atrial pressure after replacement.* Elimination of the hazard of left ventricular outflow tract obstruction with mitral valve replacement.* Decreased incidence of thromboembolization.* Abolition of possibility of ventricular septal irritation. Despite the better outlook for this valve compared with the ball valve for mitral valve substitution, the mitral valve should always be repaired whenever feasible. Repair is possible in the majority of patients.


OC-STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis.
Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.


Short-term inhalation toxicity of polyisocyanate aerosols in rats: comparative assessment of irritant-threshold concentrations by bronchoalveolar lavage.
The object of this study was to compare the relative potency of respirable aerosols of the aliphatic hexamethylene 1,6-diisocyanate homopolymer of the isocyanurate type (HDI-IC) and the aromatic polymeric methylenediphenyl-4,4'-diisocyanate (pMDI) to elicit early changes in bronchoalveolar lavage fluid (BALF). The validity of the concentration x time (C x t) concept was addressed in rats exposed to concentrations from 3.4 to 58.1 mg pMDI/m3 and exposure durations of 6 h to 23 min, respectively (C x t approximately 1200 mg/m3-min). One additional group of rats was exposed to 2.7 mg MDA/m3 for 1 x 6 h, a putative product of hydrolysis of pMDI. In rats repeatedly exposed to 12.9 mg pMDI/m3 (6 h/day, 5 days/wk for 14 days), cumulative exposure-related changes were examined. Results show that total protein and angiotensin-converting enzyme (ACE) in BALF were among the most sensitive endpoints to probe early effects caused by exposure to irritant polyisocyanate aerosols. In the repeated-exposure study, BALF protein was maximal after the first exposure day. Based on these most sensitive endpoints in BALF, a benchmark no-effect threshold concentration of 0.5 and 3 mg/m3 was estimated for the pMDI and HDI-IC aerosol, respectively. The slope of the concentration-effect curve was steeper following exposure to HDI-IC than to pMDI. These estimated acute no-observed-effect levels (NOELs) were almost identical to those observed in longer term inhalation studies using conventional endpoints. It is concluded that pulmonary irritation caused by polyisocyanate aerosols can readily be quantified in an acute rat bioassay by the analysis of total protein in BALF.


University Students' Perceptions of Child Sexual Offenders: Impact of Classroom Instruction.
Research with the public suggests that knowledge about sexual offenders, especially child sexual offenders, is limited and often inaccurate. In general, the public tends to believe that adults who commit sex crimes against children are pedophiles or monstrous strangers who cannot be rehabilitated. However, there is some evidence to suggest that these perceptions can be changed through curricular intervention. The current study was designed to determine whether a course on sex crimes against children could influence college students' knowledge and attitudes toward child sexual offenders. In a pretest-post-test design, students enrolled in the sex crimes course endorsed fewer stereotypes had more positive attitudes toward treatment and offender rehabilitation, along with reduced support for punitive sentencing compared with students enrolled in a general psychology class. Implications for improving public attitudes and suggestions for informing public policies are offered.


Impact of climate change on human infectious diseases: Empirical evidence and human adaptation.
Climate change refers to long-term shifts in weather conditions and patterns of extreme weather events. It may lead to changes in health threat to human beings, multiplying existing health problems. This review examines the scientific evidences on the impact of climate change on human infectious diseases. It identifies research progress and gaps on how human society may respond to, adapt to, and prepare for the related changes. Based on a survey of related publications between 1990 and 2015, the terms used for literature selection reflect three aspects--the components of infectious diseases, climate variables, and selected infectious diseases. Humans' vulnerability to the potential health impacts by climate change is evident in literature. As an active agent, human beings may control the related health effects that may be effectively controlled through adopting proactive measures, including better understanding of the climate change patterns and of the compound disease-specific health effects, and effective allocation of technologies and resources to promote healthy lifestyles and public awareness. The following adaptation measures are recommended: 1) to go beyond empirical observations of the association between climate change and infectious diseases and develop more scientific explanations, 2) to improve the prediction of spatial-temporal process of climate change and the associated shifts in infectious diseases at various spatial and temporal scales, and 3) to establish locally effective early warning systems for the health effects of predicated climate change.


Cytokines regulate beta-2-adrenergic receptor responsiveness in airway smooth muscle via multiple PKA- and EP2 receptor-dependent mechanisms.
Beta2AR desensitization in airway smooth muscle (ASM) mediated by airway inflammation has been proposed to contribute to asthma pathogenesis and diminished efficacy of beta-agonist therapy. Mechanistic insight into this phenomenon is largely conceptual and lacks direct empirical evidence. Here, we employ molecular and genetic strategies to reveal mechanisms mediating cytokine effects on ASM beta2AR responsiveness. Ectopic expression of inhibitory peptide (PKI-GFP) or a mutant regulatory subunit of PKA (RevAB-GFP) effectively inhibited intracellular PKA activity in cultured human ASM cells and enhanced beta2AR responsiveness by mitigating both agonist-specific (beta-agonist-mediated) desensitization and cytokine (IL-1beta and TNF-alpha)-induced heterologous desensitization via actions on multiple targets. In the absence of cytokine treatment, PKA inhibition increased beta2AR-mediated signaling by increasing both beta2AR-G protein coupling and intrinsic adenylyl cyclase activity. PKI-GFP and RevAB-GFP expression also conferred resistance to cytokine-promoted beta2AR-G protein uncoupling and disrupted feed-forward mechanisms of PKA activation by attenuating the induction of COX-2 and PGE2. Cytokine treatment of tracheal ring preparations from wild-type mice resulted in a profound loss of beta-agonist-mediated relaxation of methacholine-contracted rings, whereas rings from EP2 receptor knockout mice were largely resistant to cytokine-mediated beta2AR desensitization. These findings identify EP2 receptor- and PKA-dependent mechanisms as the principal effectors of cytokine-mediated beta2AR desensitization in ASM.


Enhancement of L-selectin, but not P-selectin, bond formation frequency by convective flow.
L-selectin-mediated leukocyte rolling has been proposed to require a high rate of bond formation compared to that of P-selectin to compensate for its much higher off-rate. To test this hypothesis, a microbead system was utilized to measure relative L-selectin and P-selectin bond formation rates on their common ligand P-selectin glycoprotein ligand-1 (PSGL-1) under shear flow. Using video microscopy, we tracked selectin-coated microbeads to detect the formation frequency of adhesive tether bonds. From velocity distributions of noninteracting and interacting microbeads, we observed that tether bond formation rates for P-selectin on PSGL-1 decreased with increasing wall shear stress, from 0.14 +/- 0.04 bonds/microm at 0.2 dyn/cm(2) to 0.014 +/- 0.003 bonds/microm at 1.0 dyn/cm(2). In contrast, L-selectin tether bond formation increased from 0.017 +/- 0.005 bonds/microm at 0.2 dyn/cm(2) to 0.031 +/- 0.005 bonds/microm at 1.0 dyn/cm(2). L-selectin tether bond formation rates appeared to be enhanced by convective transport, whereas P-selectin rates were inhibited. The transition force for the L-selectin catch-slip transition of 44 pN/bond agreed well with theoretical models (Pereverzev et al. 2005. Biophys. J. 89:1446-1454). Despite catch bond behavior, hydrodymanic shear thresholding was not detected with L-selectin beads rolling on PSGL-1. We speculate that shear flow generated compressive forces may enhance L-selectin bond formation relative to that of P-selectin and that L-selectin bonds with PSGL-1 may be tuned for the compressive forces characteristic of leukocyte-leukocyte collisions during secondary capture on the blood vessel wall. This is the first report, to our knowledge, comparing L-selectin and P-selectin bond formation frequencies in shear flow.


Organic Monomolecular Layers Enable Energy-Level Matching for Efficient Hole Transporting Layer Free Inverted Perovskite Solar Cells.
High-efficiency hole transport layer free perovskite solar cells (HTL-free PSCs) with economical and simplified device structure can greatly facilitate the commercialization of PSCs. However, eliminating the key HTL in PSCs results usually in a severe efficiency loss and poor carrier transfer due to the energy-level mismatching at the indium tin oxide (ITO)/perovskite interface. In this study, we solve this issue by introducing an organic monomolecular layer (ML) to raise the effective work function of ITO with the assistance of an interface dipole created by Sn-N bonds. The energy-level alignment at the ITO/perovskite interface is optimized with a barrier-free contact, which favors efficient charge transfer and suppressed nonradiative carrier recombination. The HTL-free PSCs based on the ML-modified ITO yield an efficiency of 19.4%, much higher than those of HTL-free PSCs on bare ITO (10.26%), comparable to state-of-the-art PSCs with a HTL. This study provides an in-depth understanding of the mechanism of interfacial energy-level alignment and facilitates the design of advanced interfacial materials for simplified and efficient PSC devices.


Separate and combined effects of airflow and rehydration during exercise in the heat.
To determine whether airflow is required to obtain the beneficial effects of rehydration (thermoregulatory and cardiovascular) during exercise in dry heat. Ten moderately trained (VO2max = 55 +/- 8 mL.kg(-1).min(-1)) heat acclimated males pedaled for 60 min at 60% VO2max in a hot-dry environment (36 +/- 1 degrees C; 29 +/- 2% relative humidity) on four different occasions: 1) without rehydration or forced airflow (control trial; CON); 2) rehydrating 100% of sweat losses by ingestion of a 6% carbohydrate-electrolyte solution (rehydration trial; REH); 3) receiving airflow at a velocity of 2.55 m.s(-1) (wind trial; WIND); and 4) combining airflow and rehydration (W + R). Without airflow, rehydration alone (REH) did not lower rectal temperature below CON (39.0 +/- 0.1 vs 39.1 +/- 0.1 degrees C at 60 min; respectively). However, with airflow, rehydration reduced final rectal temperature (38.8 +/- 0.1 vs 38.5 +/- 0.1 degrees C; P < 0.05; WIND vs W + R). In the trials with wind (WIND and W + R), skin temperature was reduced by about 0.6 degrees C (P < 0.05), and heart rate drift was prevented. In the trials with rehydration (REH and W + R trials), cardiac output (CO2-rebreathing technique) was maintained higher than CON (16.5 +/- 0.4 and 17.0 +/- 0.7 vs 15.4 +/- 0.4 L.min(-1), respectively; P < 0.05). When exercising in a hot-dry environment, airflow is required for rehydration to improve thermoregulation and cardiovascular function.


Suicide medical malpractice: an educational overview.
A malpractice lawsuit is in the legal category of an action in tort, which is a demand for compensation for the damages that have occurred. For a physician to be found liable to a patient for malpractice, four essential elements must be proved to sustain an assertion of malpractice: duty, negligence, harm, and causation. The incidence of malpractice litigation in the field of psychiatry is increasing. The most common malpractice claim related to psychiatric practice is the failure to provide reasonable protection to patients from killing themselves. A psychiatrist should be able to evaluate suicide risk on the basis of all available information, including patient responses to direct and indirect questions, known risk factors, information on how the patient behaved under similar circumstances in the past, and collateral information. Reasonable care necessitates that a patient who is either thought of being or established to be suicidal must be the subject of some precautions. A failure either to soundly assess a patient's suicide risk or to employ an appropriate safety plan after the suicide potential becomes foreseeable is likely to make a physician liable if the patient is harmed because of a suicide event. It is imperative for a psychiatric office or facility to have a good documentation. Careful documentation of evaluations and treatment interventions with a description of changes related to the patient's clinical condition indicates clinically and legally appropriate psychiatric care.


Involvement of ICOS-B7RP-1 costimulatory pathway in the regulation of immune responses to Leishmania major and Nippostrongylus brasiliensis infections.
The ICOS-B7RP-1-mediated T cell costimulatory pathway has been implicated crucial for T cell activation and differentiation. In this study, we investigated the role of this costimulation in the regulation of immune responses to parasitic infections by using blocking antibody against B7RP-1 as well as ICOS-deficient mice. The administration of anti-B7RP-1 monoclonal antibody (mAb) significantly suppressed the footpad swelling in susceptible BALB/c mice upon Leishmania major infection. The observation was consistent not only with the significant suppression of IL-4, IL-5 and IL-10 secretion from lymph node cells, which were derived from L. major-infected mice, but also with the significant reduction of total serum IgE and IgG(1) in anti-B7RP-1 mAb-treated BALB/c mice. Infection of ICOS-deficient mice with L. major also suggested the impaired Th2 immune responses in the absence of this costimulation. The immunological function of ICOS-B7RP-1 costimulatory pathway in infection was further confirmed by infecting anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice with Nippostrongylus brasiliensis. The characteristic elevation of total serum IgE and eosinophilia upon N. brasiliensis infection was suppressed by blocking this costimulation. Moreover, the protection to N. brasiliensis adult worms was suppressed in anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice. These results suggest the crucial role of this costimulatory pathway in the regulation of Th2-biased T cell differentiation and in host immune responses against L. major and N. brasiliensis infections.


disLocate: tools to rapidly quantify local intermolecular structure to assess two-dimensional order in self-assembled systems.
Order classification is particularly important in photonics, optoelectronics, nanotechnology, biology, and biomedicine, as self-assembled and living systems tend to be ordered well but not perfectly. Engineering sets of experimental protocols that can accurately reproduce specific desired patterns can be a challenge when (dis)ordered outcomes look visually similar. Robust comparisons between similar samples, especially with limited data sets, need a finely tuned ensemble of accurate analysis tools. Here we introduce our numerical Mathematica package disLocate, a suite of tools to rapidly quantify the spatial structure of a two-dimensional dispersion of objects. The full range of tools available in disLocate give different insights into the quality and type of order present in a given dispersion, accessing the translational, orientational and entropic order. The utility of this package allows for researchers to extract the variation and confidence range within finite sets of data (single images) using different structure metrics to quantify local variation in disorder. Containing all metrics within one package allows for researchers to easily and rapidly extract many different parameters simultaneously, allowing robust conclusions to be drawn on the order of a given system. Quantifying the experimental trends which produce desired morphologies enables engineering of novel methods to direct self-assembly.


Environmental Sampling for Influenza A Viruses in Turkey Barns.
We have examined a variety of sampling strategies for detecting pathogens in turkey flocks undergoing infections with low pathogenicity avian influenza virus (LPAIV). We found that viral RNA was widely distributed in the barn environment of turkey flocks undergoing an active LPAIV infection and was in both water and drinker biofilm samples. Viral RNA was concentrated in drinker biofilm and sediment and was detectable using real-time reverse-transcription polymerase chain reaction (RRT-PCR) and by virus isolation. Drinker biofilm sample results correlated with concurrently collected oropharyngeal (OP) sample results from flocks on a farm with LPAI in which the two sampling strategies were directly compared. To evaluate the utility of biofilm sampling for the detection of highly pathogenic avian influenza virus (HPAIV), biofilm and OP swabs from mortality pools were collected daily from negative turkey flocks on an HPAI-positive premise. The biofilm swabs were positive 1-2 days prior to positives appearing in the OP sample pools. The drinker biofilm sampling strategy overcame the difficulty of finding a subclinical infectious bird in a population by collecting material from a large number of individuals and testing a sample in which a positive signal persists for several days to weeks. The sampling method is convenient for use in turkey barns and has been reliably used in both active and passive surveillance programs for LPAIV and HPAIV using RRT-PCR.


[Paediatric case report of an acquired autoimmune thrombotic thrombocytopenic purpura].
Thrombotic thrombocytopenic purpura (TTP), when accompanied by regenerative anaemia with schizocytosis, thrombopenia and neurological manifestations, is a disease whose main characteristic is the absence of the von Willebrand factor (vWF) cleaving protease. The two types of TTP are distinguishable by the presence or absence of antiprotease inhibitors, which are, respectively, either acquired or constitutional. The acquired autoimmune form is most frequently observed in adults. An adolescent with a previous history of moderate, isolated thrombopenia first showed symptoms of TTP at the age of 14. Positive antiprotease inhibitors in combination with a degeneration of protease activity confirmed the diagnosis of acquired autoimmune TTP. A treatment consisting of daily plasma exchange led to rapid improvement; however, a failed attempt to space out plasma exchanges necessitated the introduction of 4 weekly injections of Rituximab beginning on day 40, which was successful. Indeed, since the second injection of Rituximab on day 51, the number of platelets stabilized at a normal level, thereby allowing for the complete cessation of plasma exchange. At this writing - day 89 - the patient remains in persistent remission. Given the different therapeutic and prognostic implications of the 2 types of TTP in child patients, it is mandatory to end at an accurate biological diagnosis: whereas the constitutional form is effectively treated with plasma injections, the acquired form, while initially requiring plasma exchange, often necessitates the use of immunosuppressors during acute or relapse phase. The present study concerns a paediatric case of acquired TTP treated successfully with Rituximab during an acute dependant phase.


Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro.
Studies in embryonic development have guided successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro. For example, human PSCs have been differentiated into monolayer cultures of liver hepatocytes and pancreatic endocrine cells that have therapeutic efficacy in animal models of liver disease and diabetes, respectively. However, the generation of complex three-dimensional organ tissues in vitro remains a major challenge for translational studies. Here we establish a robust and efficient process to direct the differentiation of human PSCs into intestinal tissue in vitro using a temporal series of growth factor manipulations to mimic embryonic intestinal development. This involved activin-induced definitive endoderm formation, FGF/Wnt-induced posterior endoderm pattering, hindgut specification and morphogenesis, and a pro-intestinal culture system to promote intestinal growth, morphogenesis and cytodifferentiation. The resulting three-dimensional intestinal 'organoids' consisted of a polarized, columnar epithelium that was patterned into villus-like structures and crypt-like proliferative zones that expressed intestinal stem cell markers. The epithelium contained functional enterocytes, as well as goblet, Paneth and enteroendocrine cells. Using this culture system as a model to study human intestinal development, we identified that the combined activity of WNT3A and FGF4 is required for hindgut specification whereas FGF4 alone is sufficient to promote hindgut morphogenesis. Our data indicate that human intestinal stem cells form de novo during development. We also determined that NEUROG3, a pro-endocrine transcription factor that is mutated in enteric anendocrinosis, is both necessary and sufficient for human enteroendocrine cell development in vitro. PSC-derived human intestinal tissue should allow for unprecedented studies of human intestinal development and disease.


Reliability and Correlation of Static and Dynamic Foot Arch Measurement in a Healthy Pediatric Population.
Measurement of the medial longitudinal foot arch in children is a controversial topic, as there are many different methods without a definite standard procedure. The purpose of this study was to 1) investigate intraday and interrater reliability regarding dynamic arch index and static arch height, 2) explore the correlation between both arch indices, and 3) examine the variation of the medial longitudinal arch at two different times of the day. Eighty-six children (mean ± SD age, 8.9 ± 1.9 years) participated in the study. Dynamic footprint data were captured with a pedobarographic platform. For static arch measurements, a specially constructed caliper was used to assess heel-to-toe length and dorsum height. A mixed model was established to determine reliability and variation. Reliability was found to be excellent for the static arch height index in sitting (intraday, 0.90; interrater, 0.80) and standing positions (0.88 and 0.85) and for the dynamic arch index (both 1.00). There was poor correlation between static and dynamic assessment of the medial longitudinal arch (standing dynamic arch index, r = -0.138; sitting dynamic arch index, r = -0.070). Static measurements were found to be significantly influenced by the time of day (P < .001), whereas the dynamic arch index was unchanged (P = .845). This study revealed some further important findings. The static arch height index is influenced by gender (P = .004), whereas dynamic arch index is influenced by side (P = .011) and body mass index (P < .001). Dynamic and static foot measurements are reliable for medial longitudinal foot arch assessment in children. The variation of static arch measurements during the day has to be kept in mind. For clinical purposes, static and dynamic arch data should be interpreted separately.


Expression and functional analysis of Brucella outer membrane protein 25 in recombinant goat pox virus.
The Capripoxvirus (CaPV) has a large double‑stranded DNA genome and a restricted host‑range. At present, it is being investigated as an ideal vaccine vector. In the present study, a novel recombinant goat pox virus (rGTPV) was constructed to express Brucella outer membrane protein (OMP)25, and was validated by in vitro and in vivo immunization assays. A novel rGTPV vector was created, in which the thymidine kinase gene was used as a flanking sequence, I1L was inserted as a promoter element to enhance Brucella OMP25 expression, and p7.5 as another promoter element was used to regulate guanine phosphoribosyl‑transferase as a selection maker. The rGTPV vector was transfected into sheep fetal fibroblast/lamb testis cells pre‑infected with GTPV G14‑STV44‑55 to recombine. Brucella OMP25 protein was expressed in cells by rGTPV, and activated immune reactivity to Brucella OMP25 protein, as detected by western blotting. Furthermore, rGTPV elicited, anti‑Brucella‑specific immunoglobulin G responses, as determined by ELISA. Mice vaccinated with rGTPV did not exhibit pathology alterations in the kidney and liver. These results suggested that the novel rGTPV was able to efficiently drive Brucella OMP25 protein expression and activate immune reactivity, and may have applications in CaPV live vector vaccines and associated research.


Nonpenetrating Deep Sclerectomy for Progressive Glaucoma: Long-term (5-year) Follow-up of Intraocular Pressure Control and Visual Field Survival.
To monitor 5-year outcomes of nonpenetrating deep sclerectomy (NPDS) with mitomycin C (MMC) in a new consecutive patient cohort. All eyes undergoing NPDS surgery between 1/08 and 6/12 were monitored for intraocular pressure (IOP), number of antiglaucoma medications (meds), and visual field indices [mean deviation (MD) and corrected pattern standard deviation (CPSD)], relative to the preoperative baseline using the two-tailed paired Student's t test. Of 106 eyes undergoing NPDS with MMC, mean IOP was 19.7 ± 0.5 [sem] mm Hg preoperatively, 11.9 ± 0.5 at 3 months, 12.5 ± 0.6 at 6 months, 12.4 ± 0.5 at 12 months, 12.6 ± 0.6 at 18 months, 11.1 ± 0.6 at 2 years, 11.8 ± 0.5 at 2.5 years, 11.0 ± 0.5 at 3 years, 11.7 ± 0.5 at 3.5 years, 10.7 ± 0.7 at 4 years, 11.6 ± 0.5 at 4.5 years, and 12.4 ± 0.7 at 5 years (average IOP reduction of 7.8 mm Hg or 37%; p < 10-6) at 5 years. About 92% of eyes had stable IOP ≥5 and ≤21 mm Hg at 5 years. Mean preoperative meds 2.7 ± 0.1 was reduced to 0.40 ±0.09 at 3 months, 0.51 ± 0.1 at 6 months, 0.38 ± 0.08 at 12 months, 0.49 ± 0.09 at 18 months, 0.41 ± 0.09 at 2 years, 0.39 ± 0.09 at 2.5 years, 0.49 ± 0.1 at 3 years, 0.58 ± 0.1 at 3.5 years, 0.49 ± 0.1 at 4 years, 0.64 ± 0.1 at 4.5 years, and 0.52 ± 0.1 at 5 years, corresponding to mean reduction of 2.2 meds (81%; p < 10-22) at 5 years. Mean deviation and CPSD were stable relative to baseline at all time intervals (R = 0.83-0.94; p < 0.0001). With appropriate postoperative management, eyes undergoing NPDS can maintain excellent IOP control with minimal medication use and maintain very stable visual fields over an extended time frame. Slagle G, Groth SL, Montelongo M, et al. Nonpenetrating Deep Sclerectomy for Progressive Glaucoma: Long-term (5-year) Follow-up of Intraocular Pressure Control and Visual Field Survival. J Curr Glaucoma Pract 2020;14(1):3-9.


Insights from space: potential role of diet in the spatial organization of chromosomes.
We can now sequence and identify genome wide epigenetic patterns and perform a variety of "genomic experiments" within relatively short periods of time-ranging from days to weeks. Yet, despite these technological advances, we have a poor understanding of the inter-relationships between epigenetics, genome structure-function, and nutrition. Perhaps this limitation lies, in part, in our propensity to study epigenetics in terms of the linear arrangement of elements and genes. Here we propose that a more complete understanding of how nutrition impacts on epigenetics and cellular development resides within the inter-relationships between DNA and histone modification patterns and genome function, in the context of spatial organization of chromatin and the epigenome.


The role of the lateral prefrontal cortex in inhibitory motor control.
Research on inhibitory motor control has implicated several prefrontal as well as subcortical and parietal regions in response inhibition. Whether prefrontal regions are critical for inhibition, attention or task-set representation is still under debate. We investigated the influence of the lateral prefrontal cortex (PFC) in a response inhibition task by using cognitive electrophysiology in prefrontal lesion patients. Patients and age- and education-matched controls performed in a visual Stop-signal task featuring lateralized stimuli, designed to challenge either the intact or lesioned hemisphere. Participants also underwent a purely behavioral Go/Nogo task, which included a manipulation of inhibition difficulty (blocks with 50 vs. 80% go-trials) and a Change-signal task that required switching to an alternative response. Patients and controls did not differ in their inhibitory speed (stop-signal and change-signal reaction time, SSRT and CSRT), but patients made more errors in the Go/Nogo task and showed more variable performance. The behavioral data stress the role of the PFC in maintaining inhibitory control but not in actual inhibition. These results support a dissociation between action cancellation and PFC-dependent action restraint. Laplacian transformed event-related potentials (ERPs) revealed reduced parietal activity in PFC patients in response to the stop-signals, and increased frontal activity over the intact hemisphere. This electrophysiological finding supports altered PFC-dependent visual processing of the stop-signal in parietal areas and compensatory activity in the intact frontal cortex. No group differences were found in the mu and beta decrease as measures of response preparation and inhibition at electrodes over sensorimotor cortex. Taken together, the data provide evidence for a central role of the lateral PFC in attentional control in the context of response inhibition.