Opposite associations of age-dependent insulin-like growth factor-I standard deviation scores with nutritional state in normal weight and obese subjects.
Insulin-like growth factor-I (IGF-I) has been suggested to be a prognostic marker for the development of cancer and, more recently, cardiovascular disease. These diseases are closely linked to obesity, but reports of the association of IGF-I with measures of obesity are divergent. In this study, we assessed the association of age-dependent IGF-I standard deviation scores with body mass index (BMI) and intra-abdominal fat accumulation in a large population. A cross-sectional, epidemiological study. IGF-I levels were measured with an automated chemiluminescence assay system in 6282 patients from the DETECT study. Weight, height, and waist and hip circumference were measured according to the written instructions. Standard deviation scores (SDS), correcting IGF-I levels for age, were calculated and were used for further analyses. An inverse U-shaped association of IGF-I SDS with BMI, waist circumference, and the ratio of waist circumference to height was found. BMI was positively associated with IGF-I SDS in normal weight subjects, and negatively associated in obese subjects. The highest mean IGF-I SDS were seen at a BMI of 22.5-25 kg/m2 in men (+0.08), and at a BMI of 27.5-30 kg/m2 in women (+0.21). Multiple linear regression models, controlling for different diseases, medications and risk conditions, revealed a significant negative association of BMI with IGF-I SDS. BMI contributed most to the additional explained variance to the other health conditions. IGF-I standard deviation scores are decreased in obesity and underweight subjects. These interactions should be taken into account when analyzing the association of IGF-I with diseases and risk conditions.


Effectiveness of an ear and hearing care training program for frontline health workers: A before and after study.
Delegating ear and hearing care (EHC) tasks to frontline health workers may help to improve muchneeded access to this specialized care. Primary healthcare workers (PHCWs) need to acquire relevant knowledge and skill to recognize, refer, and/or treat simple ear problems. This study aims to evaluate the effectiveness of an EHC training program for PHCWs. The training intervention was a 2day course based on an adapted WHO training resource in EHC for frontline workers. A pre and posttest study design was undertaken with the assessment of EHC at two time points using the same questionnaire at baseline and at completion of the training. One hundred and ninety PHCWs were recruited for the study. Overall, there was a statistically significant improvement from baseline to course completion. However, participants' scores in the domain of knowledge for risk factors were slightly low compared to other domains (54.3%, 95% confidence interval [CI]: 52.0%-56.6%), and this improved significantly following the training (72.7%, 95% CI: 71.0%-74.0%). A potential confounder in this evaluation may be that of the scores recorded at pretest, which may change in the posttest due to regression to the mean phenomenon. The findings from this study indicate that the training program demonstrated the potential to be an effective way to improve knowledge of EHC, and we suggest the inclusion of "primary ear care" as a component of primary health care.


LONG TERM RESULTS AFTER STAPLED HEMORRHOIDOPEXY ALONE AND COMPLEMENTED BY EXCISIONAL HEMORRHOIDECTOMY: A RETROSPECTIVE COHORT STUDY.
Stapled hemorrhoidopexy is associated with less postoperative pain and faster recovery. However, it may be associated with a greater risk of symptomatic recurrence. We hypothesized that undertaking a limited surgical excision of hemorrhoid disease after stapling may be a valid approach for selected patients. To compare long-term results after stapled hemorrhoidopexy with and without complementation with closed excisional technique. In a retrospective uni-institutional cohort study, sixty-five (29 men) patients underwent stapled hemorrhoidopexy and 21 (13 men) underwent stapled hemorrhoidopexy with excision. The same surgeons operated on all cases. Patients underwent stapled hemorrhoidectomy associated with excisional surgery if symptoms attributable to external hemorrhoid piles were observed preoperatively, or if residual prolapse or bulky external disease was observed after the firing of the stapler. A closed excisional diathermy hemorrhoidectomy without vascular ligation was utilized in all complemented cases. All clinical variables were obtained from a questionnaire evaluation obtained through e-mail, telephone interview, or office follow-up. The median duration of postoperative follow-up was 48.5 (6-40) months. Patients with grades 3 and 4 hemorrhoid disease were operated on more frequently using stapled hemorrhoidopexy complemented with excisional technique (95.2% vs. 55.4%, p=0.001). Regarding respectively stapled hemorrhoidopexy and stapled hemorrhoidopexy complemented with excision, there was no difference between the techniques in relation to symptom recurrence (43% and 33%, p=0.45) and median interval between surgery and symptom recurrence (30 (8-84) and 38.8 (8-65) months, p=0.80). Eight (12.3%) patients were re-operated after stapled hemorrhoidopexy and 2 (9.6%), after hemorrhoidopexy with excision (p=0.78). Patient distribution in both groups according to the degree of postoperative satisfaction was similar (p=0.97). Stapled hemorrhoidopexy combined with an excisional technique was effective for more advanced hemorrhoid disease. The combination may have prevented symptomatic recurrence associated to stapled hemorrhoidopexy alone.


Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese Glaucoma Societies.
To investigate practice patterns among glaucoma subspecialists in the American Glaucoma Society (AGS) and the Japanese Glaucoma Society (JGS), regarding use of antifibrosis agents and glaucoma drainage devices. An anonymous survey incorporating 10 clinical situations was mailed to all AGS and JGS members in December 1995. Half of the AGS (105 of 210), and JGS (25 of 50) members returned surveys. Most respondents (51-87%) preferred trabeculectomy with adjunctive mitomycin for all 10 clinical situations. Mitomycin concentrations varied from 0.1 to 0.8 mg/ml (range of means for 10 situations 0.31-0.39 mg/ml) and intraoperative application times ranged from 5 s to 7 min (range of means for 10 situations 2.5-4.6 min). Preferences for either no antifibrosis agent (up to 39%) or 5-fluorouracil (up to 29%) were highest in primary trabeculectomy. Thirty-seven percent to 64% of AGS members used glaucoma drainage devices, especially after complicated postsurgical glaucomas (after penetrating keratoplasty, scleral buckling, or pars plana vitrectomy) and in neovascular glaucoma, but few JGS members used them. Large differences between university- and private practice-based AGS members were found only in mitomycin use for primary trabeculectomy (33% vs. 52%, respectively; p = 0.07) and for complicated postsurgical glaucomas (46% vs. 70%, respectively; p = 0.03). Trabeculectomy with mitomycin was the preferred surgical procedure among AGS and JGS members in the clinical situations surveyed. Mitomycin concentration and time of application varied widely. Many respondents used 5-fluorouracil or no antimetabolite in primary trabeculectomy. Glaucoma drainage devices were widely used for complicated glaucomas in the United States.


The Smith-Lemli-Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology.
The brief history of the Smith-Lemli-Opitz syndrome (SLOS) (MIM 270400) reflects that of latter 20th century dysmorphology and biochemical and molecular genetics: from its first description as a rare but characteristic multiple malformation syndrome known only to a handful of dysmorphologists, to a relatively common Garrodian defect with a complex molecular basis that has captured the attention of researchers and basic scientists from the fields as diverse as embryology, developmental biology, sterol biochemistry, epidemiology, and teratology. The discovery of the underlying biochemical defect - deficiency of 3beta-hydroxysteroid-Delta7-reductase (DHCR7), an enzyme catalyzing the last step of cholesterol biosynthesis, and the resultant generalized cholesterol deficiency - has led to an explosion of knowledge of this biochemical pathway and to a paradigm shift in the recognition of metabolic deficiencies as causes of dysmorphic syndromes. Characterization of the human DHCR7 gene and the identification of mutations in patients with SLOS have revealed a complex picture of molecular heterogeneity and provided insights into the structure and function of DHCR7. SLOS is the first metabolic malformation syndrome with profound effects on the body plan, and its discovery has paved the way to the discovery of a number of other defects of the cholesterol synthetic pathway.


Effects of Saccharomyces cerevisiae on alleviating cytotoxicity of porcine jejunal epithelia cells induced by deoxynivalenol.
Deoxynivalenol (DON) is one of the mycotoxins most frequently encountering in cereal-based foods throughout the world. Saccharomyces cerevisiae was used to alleviate porcine jejunal epithelia cell (IPEC-J2) injury induced by DON in this study. The results indicated that cell viability and proliferation rates were significantly decreased when DON concentrations were increased from 0 to 64 µM after 24 h incubation (p < 0.05). The longer incubation time and higher DON concentrations would cause more serious effects on cell viability. S. cerevisiae could significantly degrade DON and decrease lactic dehydrogenase (LDH) release in the cells induced by DON (p < 0.05). DON (4 µM) could increase necrotic and apoptotic cell rates as well as decrease viable cell rates, compared with the control group (p < 0.05). However, S. cerevisiae addition in the DON group could decrease necrotic, late apoptotic and early apoptotic cell rates by 38.05%, 46.37% and 44.78% respectively, increase viable cell rates by 2.35%, compared with the single DON group (p < 0.05). In addition, S. cerevisiae addition could up-regulate mRNA abundances of IL-6, IL-8 and IL-10 in IPEC-J2 cells (p < 0.05), but down-regulate mRNA abundances of tight junction proteins (TJP-1) and occludin by 36.13% and 50.18% at 1 µM of DON (p < 0.05). It could be concluded that S. cerevisiae was able to alleviate IPEC-J2 cell damage exposed to DON.


Sleep apnea in the elderly.
Sleep apnea syndrome (SAS) in the elderly presents varied clinical symptoms and also has many complications. Moreover, there are many hospital departments related to these symptoms. This article uses literature to provide an outline on SAS observed in the elderly. SAS sufferers often have complications with so-called lifestyle-related diseases, such as hypertension, hyperlipidemia, diabetes mellitus and metabolic syndrome. These symptoms, along with SAS, recede as a result of continuous positive airway pressure treatment. Some have also reported recession of depression symptoms and delay in deterioration of cognitive functions. The elderly tends to develop SAS through coexistence of chronic respiratory organ disorders, increase in upper airway collapse, strokes, cardiovascular diseases, hypertension, diabetes mellitus and other physiological anatomical changes that accompany aging. However, judgment on the severity and effects regarding prognosis by each remedy used in the diagnosis and treatment of SAS in the elderly is still being developed, and it is considered necessary to accumulate more evidence and establish new standards.


Inhibition of the transforming ability of cigarette smoking condensate-treated human fetal lung DNA induced by oltipraz.
Rat-1 cells transfected by genomic DNA of human fetal lung explants treated with 100 micrograms/ml of oltipraz (5-(2-pyrazimyl)-4-methyl-1, 2-dithiol-3-thione) for 14 hr or 100 micrograms/ml of cigarette smoking condensate for 6 hr formed 0 to 8 transformation foci, respectively. If 100 micrograms/ml of oltipraz was added to culture of human fetal lung explants 8 hr prior to the treatment of cigarette smoking condensate, the Rat-1 cells transfected by genomic DNA of human fetal lung explants formed only two foci. In addition, the growth speed of Rat-1 cells transfected by genomic DNA of human fetal lung treated with both oltipraz and cigarette smoking condensate was lower than that transfected by cigarette smoking condensate-treated human fetal lung DNA. Our results indicate that oltipraz can block the irreversible change of human fetal lung DNA caused by cigarette smoking condensate, and the results suggest the possibility of using oltipraz as control in the experimental initiation of human lung carcinogenesis.


The dualism of psychology.
Dualism (the separation of the mind from the body) as related to psychology, particularly the division of disorders into organic and functional and how these terms are related to a tendency toward dualism in various schools of psychology, is explored in this article. The possibility of biological substratums for dualistic thinking is proposed, and this biological tendency is related to religion and mythology. Despite this biological tendency, the inadequacy of the dualistic concept is discussed and an alternative perspective is offered that attempts to satisfy the proposed function that dualism serves: self-preservation. This perspective is identified as monism or the idea that mind and body reflect an identical reality. This proposition is explored historically, and monism is explored as a perspective that has the potential of uniting us with nature and each other, making struggle, competition, and strife meaningless.


Varicocele--the most common cause of male factor infertility?
Varicocele is often cited as the most common cause of male factor infertility. Arguments in support of this statement include reports of increased prevalence of varicocele in populations of infertile men compared with fertile or otherwise unselected men, association of varicocele with abnormal semen parameters, and improvements in semen parameters and/or pregnancy rates after varicocele repair. Logically, there would appear to be three possibilities regarding the relationship between varicocele and fertility: (i) varicocele has no association with or effect on male fertility; (ii) varicocele may be associated with, but is not the cause of, male subfertility; and (iii) varicocele is a direct cause of male subfertility. In the following, we review evidence from the literature for and against these three possibilities: at the current time, available evidence appears inadequate to confirm or deny any of these three possibilities. Since the ultimate goal of infertile couples is to conceive, it seem logical that future varicocele research should focus primarily on adequately powered, controlled clinical trials in well-characterized infertile couples, randomized to intervention or appropriate controlled observation, with pregnancy as the primary outcome.


Acute Oncologic Complications: Clinical-Therapeutic Management in Critical Care and Emergency Departments.
Introduction. It is now known that cancer is a major public health problem; on the other hand, it is less known, or rather, often underestimated, that a significant percentage of cancer patients will experience a cancer-related emergency. These conditions, depending on the severity, may require treatment in intensive care or in the emergency departments. In addition, it is not uncommon for a tumor pathology to manifest itself directly, in the first instance, with a related emergency. The emergency unit proves to be a fundamental and central unit in the management of cancer patients. Many cancer cases are diagnosed in the first instance as a result of symptoms that lead the patient's admittance into the emergency room. Materials and Methods. This narrative review aims to analyze the impact of acute oncological cases in the emergency setting and the role of the emergency physician in their management. A search was conducted over the period January 1981-April 2023 using the main scientific platforms, including PubMed, Scopus, Medline, Embase and Google scholar, and 156 papers were analyzed. Results. To probe into the main oncological emergencies and their management in increasingly overcrowded emergency departments, we analyzed the following acute pathologies: neurological emergencies, metabolic and endocrinological emergencies, vascular emergencies, malignant effusions, neutropenic fever and anemia. Discussion/Conclusions. Our analysis found that a redefinition of the emergency department connected with the treatment of oncology patients is necessary, considering not only the treatment of the oncological disease in the strict sense, but also the comorbidities, the oncological emergencies and the palliative care setting. The need to redesign an emergency department that is able to manage acute oncological cases and end of life appears clear, especially when this turns out to be related to severe effects that cannot be managed at home with integrated home care. In conclusion, a redefinition of the paradigm appears mandatory, such as the integration between the various specialists belonging to oncological medicine and the emergency department. Therefore, our work aims to provide what can be a handbook to detect, diagnose and treat oncological emergencies, hoping for patient management in a multidisciplinary perspective, which could also lead to the regular presence of an oncologist in the emergency room.


Adolescent Waterpipe Use is Associated with Greater Body Weight: The Irbid-TRY.
Adult waterpipe smokers are at increased risk of obesity. However, it is unclear if adolescents, who are at the epicenter of the global waterpipe epidemic, are at similar risk. Therefore, the current study examined the waterpipe smoking relationship with obesity among adolescents. A sample of 2,313 boys and girls in grades 7-10 were surveyed about waterpipe and cigarette use in Jordan. Weight, body mass index (BMI), waist circumference, waist-to-hip ratio, and waist-to-height ratio were measured. Obesity indices were assessed as a function of smoking status (never used tobacco, current waterpipe only, current cigarettes only, and current dual smoking) as well as frequency of use of each tobacco product. About 51.5% of adolescents smoked waterpipe whereas 29.8% were overweight/obese. Students who smoked waterpipe weekly had twofold greater odds of being obese than never-smokers (OR = 2.14; 95% CI = 1.08-4.21). Approximately 12% of students currently smoked waterpipe but not cigarettes, 2% smoked cigarettes but not waterpipe, and 11% smoked both. Body weight and age- and gender-specific BMI were greater for waterpipe and dual users compared to never users, especially for dual vs. never users (58.6 ±.8 vs. 55.6 ±.4 and.48 ±.07 vs..29 ±.03, respectively; p <.005). For dual users, greater frequency of tobacco use was associated with greater weight and BMI. Waterpipe and dual use is associated with greater obesity, BMI, and body weight among Jordanian adolescents. Given the rising epidemics of both tobacco use and obesity among Middle Eastern adolescents, the clustering of these risk factors warrants public health action.


Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis.
To evaluate the efficacy and safety of an oral phosphodiesterase 4 inhibitor, apremilast, in treatment of ankylosing spondylitis (AS) by monitoring symptoms and signs in a pilot study including exploratory investigation of effects of PDE4 inhibition on blood biomarkers of bone biology. In this double-blind, placebo-controlled, single-centre, Phase II study, patients with symptomatic AS with active disease on MRI were randomised to apremilast 30 mg BID or placebo over 12 weeks. Bath Indices were monitored serially. Patients were followed for 4 weeks after stopping medication. Bone biomarkers were assessed at baseline and day 85. 38 subjects were randomised and 36 subjects completed the study. Although the primary end-point (change in BASDAI at week 12) was not met, apremilast was associated with numerically greater improvement from baseline for all clinical assessments compared with placebo with mean change in BASDAI (-1.59±1.48 vs -0.77±1.47), BASFI (-1.74±1.91 vs -0.28±1.61) and BASMI (-0.51±1.02 vs -0.21±0.67); however, differences did not achieve statistical significance. The clinical indices returned to baseline values by 4 weeks after cessation of apremilast. Six apremilast patients (35.3%) vs 3 placebo (15.8%) achieved ASAS20 responses (p=0.25). There were statistically significant decreases in serum RANKL and RANKL:osteoprotegrin ratio and plasma sclerostin but no significant changes in serum DKK-1, bone alkaline phosphatase, TRAP5b, MMP3, osteoprotegrin, or osteocalcin. Although a small pilot study, these results suggest that apremilast may be effective and well tolerated in AS and modulates biomarkers of bone biology. These data support further research of apremilast in axial inflammation.


Surface plasmon resonance-based real-time bioaerosol detection.
Rapid and precise bioaerosol detection in different environments has become an important research and technological issue over last decades. Previously, we employed a real-time PCR protocol in conjunction with personal bioaerosol sampler for rapid detection of airborne viruses. The approach has been proved to be specific and sensitive. However, a period of time required for entire procedure was in manner of hours. Some new developments are required to decrease the detection time down to real-time protocols. Presently, a surface plasmon resonance (SPR)-based immunosensor that coupled with a specific antigen-antibody reaction could offer sensitive, specific, rapid and label-free detection. This study describes the possibility of combining the personal sampler with SPR technology for qualitative and extremely rapid detection of airborne micro-organisms. Common viral surrogate MS2 bacteriophage, frequently used in bioaerosol studies, was employed as a model organism. The results of the sensor functionalizing procedure with monoclonal anti-MS2 antibody and optimization of the chip performance are presented. The SPR-based detection of the airborne virus was found to be very fast; the viral presence was detected in less than 2 min, and the entire procedure (sampling and analysis) was undertaken in 6 min, which could be considered as real-time detection for this type of measurements. The combination of SPR with the personal sampler targeted towards bioaerosol detection was proven to be feasible. The SPR sensor was found to be highly stable and suitable for multiple utilizations without significant decrease in response. The suggested approach opens new possibilities for the development of portable and rapid (almost real time) bioaerosol monitors. This technology is the first in the world real-time bioaerosol monitor. This outcome would be of strong interest to individuals representing public health, biosecurity, defence forces, environmental sciences and many others.


The use of intrauterine balloon therapy in reproductive medicine and surgery: a guidance for practice.
The use of balloon therapy in obstetric practice especially in postpartum haemorrhage (PPH) is well established and has recently been reviewed. However, little attention has been drawn regarding the use of intrauterine balloon (IUB) in gynaecological practice. This study focuses on the various usage of IUB in gynaecological practice. An electronic literature search through Medline, EMBASE and Clinicaltrial.gov from inception to August 2022 was conducted. The study focuses on the three following areas: (1) Indications: prevention and removal of intrauterine adhesions, management of ectopic pregnancy, facilitation of endoscopic surgery and other clinical usages; (2) Practical aspects of balloon therapy including ultrasound guidance, choice of balloon, inflation volume, duration of balloon therapy; and (3) Potential complications including pain, infection, uterine rupture and how they can be avoided. IUB therapy is a simple, inexpensive and effective method that can be applied in various gynaecological conditions ranging from IUA to intrauterine haemorrhage. Complications are rare, but in most cases can be avoided with correct use.


Reconstruction with tenodesis in an adult flatfoot model. A biomechanical evaluation of four methods.
Six fresh-frozen adult cadaveric specimens were mounted in an Instron materials testing machine with use of a cemented intramedullary rod. Angular relationships between the first metatarsal and the talus were recorded with a sonic digitizer. A flatfoot deformity was created by dividing the talonavicular joint capsule (superiorly, medially, and inferiorly), the spring ligament, the anteromedial aspect of the subtalar joint capsule, and the plantar fascia. Angular displacement in the sagittal and transverse planes was recorded at no load and at 100, 350, and 700-newton plantar loads. Each specimen was subjected to four different reconstructions with tenodesis, and the angular relationship between the first metatarsal and the talus was measured at the four levels of load. A reconstruction with use of the peroneus longus tendon was performed by preserving its insertion into the first metatarsal, rerouting the tendon and passing it from medial to lateral through a calcaneal bone tunnel, and anchoring it to the lateral aspect of the calcaneus. A reconstruction with the tibialis tendon was performed by passing the medial third of the tendon from dorsal to plantar through the navicular and from medial to lateral through the calcaneal bone tunnel and securing it to the lateral aspect of the calcaneus. The reconstruction with the tibialis anterior tendon was repeated with the tendon graft routed along the medial aspect of the navicular, directly through the calcaneal bone tunnel. The fourth reconstruction was done with use of an Achilles tendon allograft.(ABSTRACT TRUNCATED AT 250 WORDS)


The place of culture in forensic psychiatry.
Members of a multicultural society must all be subject to the same equitable system of justice. However, culture exerts profound influences on human behavior, and cultural considerations have a place in determinations of capacity and in appropriate sentencing. Cultural psychiatry can contribute to forensic psychiatry by helping to contextualize individuals' actions and experiences. This contextualizing can be done through cultural consultations that employ interpreters and culture brokers to identify the role of culture in individuals' psychopathology. Clarifying how cultural background has affected individuals' capacity to form a criminal intent or control their behavior may allow a better determination of level of culpability and guide appropriate sentencing. However, framing behavior as culturally influenced may also stereotype and stigmatize specific groups. To avoid this, culture must be understood in terms of power relationships between minority groups and the dominant society. Cultural factors are not only relevant to the experience of specific groups but pervade the entire judicial system shaping the process of moral and legal reasoning.


Measuring the switching dynamics and energy efficiency of tantalum oxide memristors.
We measured the real-time switching of metal-oxide memristors with sub-nanosecond resolution and recorded the evolution of the current and voltage during both ON (set) and OFF (reset) events. From these we determined the dynamical behavior of the conductivity for different applied bias amplitudes. Quantitative analysis of the energy cost and switching dynamics showed 115 fJ for ON-switching and 13 pJ for OFF-switching when resistance change was limited to 200%. Results are presented that show a favorable scaling with speed in terms of energy cost and reducing unnecessary damage to the devices.


Improved inhibitors of glucosylceramide synthase.
Previous work has led to the identification of inhibitors of glucosylceramide synthase, the enzyme catalyzing the first glycosylation step in the synthesis of glucosylceramide-based glycosphingolipids. These inhibitors have two identified sites of action: the inhibition of glucosylceramide synthase, resulting in the depletion of cellular glycosphingolipids, and the inhibition of 1-O-acylceramide synthase, resulting in the elevation of cell ceramide levels. A new series of glucosylceramide synthase inhibitors based on substitutions in the phenyl ring of a parent compound, 1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), was made. For substitutions of single functional groups, the potency of these inhibitors in blocking glucosylceramide synthase was primarily dependent upon the hydrophobic and electronic properties of the substituents. An exponential relationship was found between the IC50 of each inhibitor and the sum of derived hydrophobic (pi) and electronic (sigma) parameters. This relationship demonstrated that substitutions that increased the electron-donating characteristics and decreased the lipophilic characteristics of the homologues enhanced the potency of these compounds in blocking glucosylceramide formation. A novel compound was subsequently designed and observed to be even more active in blocking glucosylceramide formation. This compound, D-threo-4'-hydroxy-P4, inhibited glucosylceramide synthase at an IC50 of 90 nM. In addition, a series of dioxane substitutions was designed and tested. These included 3',4'-methylenedioxyphenyl-, 3',4'-ethylenedioxyphenyl-, and 3'4'-trimethylenedioxyphenyl-substituted homologues. D-threo-3', 4'-Ethylenedioxy-P4-inhibited glucosylceramide synthase was comparably active to the p-hydroxy homologue. 4'-Hydroxy-P4 and ethylenedioxy-P4 blocked glucosylceramide synthase activity at concentrations that had little effect on 1-O-acylceramide synthase activity. These novel inhibitors resulted in the inhibition of glycosphingolipid synthesis in cultured cells at concentrations that did not significantly raise intracellular ceramide levels or inhibit cell growth.


[Occurrence and course of condylomata of the cervix during pregnancy].
This study analyses the frequency and the way cervical condylomata develop during pregnancy. We looked at 102 case notes of patients with condylomata in pregnancy which were diagnosed between September 1979 and September 1982. The incidence of pregnancy in patients with these condylomatous conditions is 1.3% and the incidence of these condylomatous conditions in pregnant women is 2.12%, which is three times that found in the general population. The authors analyse the distribution of straightforward condylomata and atypical ones and the way they evolve in pregnancy. Pure condylomata regress in 83% of cases. There has never been a case of invasion during the observation we have carried Out on carcinomata in situ. The distribution between pure condylomata (50%) and condylomata associated with various degrees of dysplasia (50%) has been studied and compared with that in the general population.


[Patellofemoral pain. Diagnosis and treatment].
Patellofemoral pain is a frequent complaint among recreational and competitive athletes. Studies from Sweden and Norway among junior and senior high school students showed that every third to fourth student currently suffers, or has previously suffered, from patellofemoral pain. This paper presents current trends in diagnosis and treatment of patellofemoral pain. It describes the clinical examination, and discusses the additional information obtained from tests like radiography, CT and MT. Arthroscopy can establish the degree of cartilage damage and joint articulation, but should not be used as a general diagnostic tool. Treatment of patellofemoral pain should consist of patient education and a carefully designed rehabilitation programme emphasizing eccentric quadriceps exercises, primarily in close chain modes. A knee sleeve with a lateral cushion seems to alleviate symptoms in some patients. If the problems are not reduced by a well executed exercise programme over six months, surgical intervention should be discussed on the basis of a specific diagnosis. The article includes a review of recent studies on patellar shaving, spongialization, lateral release, proximal/distal realignment, tibial tubercle elevation and medialization, and patellectomy.


Erythromycin Releasing PVA/sucrose and PVA/honey Hydrogels as Wound Dressings with Antibacterial Activity and Enhanced Bio-adhesion.
The present study deals with preparation and characterization of thermally crosslinked PVA-based hydrogels containing honey and sucrose for the purpose of erythromycin delivery. The hydrogels have been characterized and compared by scanning electron microscopy, Fourier transform infrared spectroscopy, and bio-adhesion tests. Swelling measurements showed that addition of sucrose and honey decreased the equilibrium swelling of the hydrogels. Results of release studies showed that the amount of erythromycin, released at the early hours was higher for PVA/sucrose and PVA/honey hydrogels compared to PVA hydrogel while the drug released at later times was highly reduced for PVA/honey hydrogel. Both Peppas-Sahlin and Korsmeyer-Peppas models fitted well to the release data. Fitting Peppas-Sahlin model to the release data showed that at the initial times, release of drug from the hydrogel network was mainly governed by Fickian mechanism; however, at later times the drug is dominantly released by relaxational mechanism due to swelling of the network,. Addition of honey improved the bio-adhesion of PVA/honey hydrogel as compared to PVA/sucrose and pure PVA hydrogel. Results of antibacterial tests showed growth inhibitory action of erythromycin-loaded PVA hydrogels against Pseudomonas aeruginosa and Staphylococcus aureus bacteria. This study indicates that these hybrid hydrogels are capable of being used as functional wound dressings aiming to control the rate of antibiotic delivery to the wound site and prevent the wounds from infection.


Respiratory syncytial virus hospitalization and incurred morbidities the season after prophylaxis.
The primary objective of this study was to determine the incidence and incurred morbidities of Respiratory syncytial virus (RSV)-related hospitalization (RSVH), the season following completion of prophylaxis. A retrospective study was conducted of all infants enrolled in a prophylaxis clinic in one institution during the 2009 to 2014 RSV seasons. RSV infection was identified by Diseases codes and confirmed by RSV-positivity. Data were classified into five groups based on indications for prophylaxis. The incidence of RSVH was calculated. For each subgroup, differences in characteristics between children with and without RSVH were analyzed by independent t test or chi-square test. During five RSV seasons, 827 infants were enrolled. RSVH incidence the season following prophylaxis was 2.1% (n=17/827). Children with chronic lung disease (CLD) had the highest RSVH incidence (7.7%; n=4/52) followed by preterms 33 to 35 weeks gestation (2.5%; n=4/162), those with complex medical disorders (2.2%; n=3/135), those with congenital heart disease (1.5%; n=1/66) and preterms less than or equal to 32 weeks gestation (1.2%; n=5/412). There was no statistically significant association between indications for prophylaxis and RSVH (Fisher exact test, P=0.060). The odds of RSVH were 4.9 times greater (odds ratio [OR]=4.9; 95% CI: 1.53, 15.55; P=0.007) in CLD compared to those without CLD. The median length of RSVH stay was 4 days; 58.8% (n=10/17) required oxygen (median 1 day); 29.4% (n=5/17) required intensive care. Infants with CLD are at highest risk for RSVH in the season postprophylaxis and may merit palivizumab for more than two seasons dependent on disease severity. However, larger prospective studies are necessary to confirm the findings before embarking on a strategy of providing prophylaxis for a third RSV season.


Genetic analysis of genes controlling natural variation of seed coat and flower colors in soybean.
Soybean exhibits natural variation in flower and seed coat colors via the deposition of various anthocyanin pigments in the respective tissues. Although pigmentation in seeds or flowers has been well dissected at molecular level in several plant species, the genes controlling natural variation in anthocyanin traits in the soybean are not completely understood. To evaluate the genetic correlation between genetic loci and genes, 8 enzyme-encoding gene families and a transcription factor were localized in a soybean genome-wide genetic map. Among the seed coat color-controlling loci, the genetic location of the gene encoding for W1 was substantiated in the context of the current soybean molecular genetic map and O was postulated to correspond to anthocyanidin reductase. Among the genetic loci that regulate flower pigmentation, the genetic locations of the genes encoding for W1, W4, and Wp were identified, W3 was mapped on soybean linkage group B2 (chromosome 14), and W2 was postulated to correspond to an MYB transcription factor. Correlation studies between the developed markers and 3 color-controlling loci provided important empirical data that should prove useful in the design of marker-assisted breeding schemes as well as future association studies involving soybean.


Treatment of pigmented villonodular synovitis of the knee with yttrium-90 silicate: prospective evaluations by arthroscopy, histology, and 99mTc pertechnetate uptake measurements.
The diffuse form of pigmented villonodular synovitis of eight knee joints of eight patients was treated by intra-articular injection of 185 MBq yttrium-90 silicate (90Y). Six patients had a recurrence of disease after one or two surgical synovectomies. After treatment with 90Y once or twice four knees showed clinical improvement with an accompanying decrease of the inflammatory activity as measured by the technetium-99m pertechnetate (99mTcO4-) uptake ratio and the severity of the diseased synovial tissue. Arthroscopy was performed before and six months after each 90Y treatment. The ratio of 99mTcO4- uptake in the inflamed compared with the normal knee joint correlated well with the macroscopical grading of pigmented villonodular synovitis. In all cases areas of persistent synovitis were found after the 90Y injection and this was confirmed both by histological examination and 99mTcO4- uptake measurements. Biopsy specimens taken from the diseased synovial areas showed histologically mostly less prominent and less numerous villi. The cartilage damage was slightly increased in only two cases. No radiological deterioration was found during follow up (mean 24 months, range 12-41). No complications of the radiosynoviortheses were noted.


Discriminating biomolecules with coherent control strategies.
The activity of the GAP-Biophotonics research group at the University of Geneva in the field of coherent control for discriminating similar biomolecules, such as flavins, proteins and DNA bases, is presented and future developments are discussed.


Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma.
The purpose of this study was to identify poor prognostic factors of low-risk stage IB1 cervical adenocarcinoma . All women diagnosed with stage IB1 cervical adenocarcinoma between 1982 and 2002 were identified at our three institutions. Data were extracted from medical records. Patients were retrospectively assigned to a low- or intermediate/high-risk cohort based on the surgical-pathologic eligibility criteria of two randomized controlled trials of adjuvant therapy in early stage cervical cancer, Gynecologic Oncology Group protocols 92 and 109. Multivariate analysis was performed. Two hundred thirty women diagnosed with stage IB1 cervical adenocarcinoma had an overall 5-year survival of 89%. Adenosquamous cell type (P < 0.01) was the only independent risk factor of disease recurrence in the low-risk group (n = 178). The 5-year disease-free survival for low-risk adenosquamous patients was 79%, compared to 96% for other histologic subtypes (P < 0.01). Low-risk case subjects developed fewer disease recurrences than those in the intermediate/high-risk (n = 52) category (7% vs 46%; P < 0.01). The 5-year disease-free survival for intermediate/high-risk patients was 51% and no additional risk factors were identified. Adenosquamous histology is predictive of disease recurrence and decreased survival in low-risk stage IB1 cervical adenocarcinoma. This risk factor should be considered in future clinical trials of adjuvant therapy.


Catheter Ablation Improves Mortality and Other Outcomes in Real-World Patients With Atrial Fibrillation.
Background It is still controversial whether catheter ablation for atrial fibrillation (AF) improves survival and other outcomes in patients with AF. This study evaluated whether ablation reduces death and other events in nationwide real-world Asian patients with AF. Methods and Results From the Korean National Health Insurance Service database, 194 928 adult patients (aged ≥18 years) with newly diagnosed AF were treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between January 1, 2005, and December 1, 2015. Among these patients, this study included 9185 with ablation and 18 770 with medical therapy. The time at risk was counted from the first medical therapy, and ablation was analyzed as a time-varying covariate. Inverse probability of treatment weighting was used to correct for differences between the groups. After weighting, the 2 cohorts had similar background characteristics. During a median (25th, 75th percentiles) follow-up of 43 (19, 81) months, ablation of AF was associated with lower incidence and risk of composite outcome, including death, heart failure admission, and stroke/systemic embolism (2.5 and 6.4 per 100 person-years, respectively; hazard ratio [HR], 0.47; 95% CI, 0.43-0.52; P<0.001), all-cause death (1.0 and 3.6 per 100 person-years; HR, 0.41; 95% CI, 0.36-0.47; P<0.001), heart failure admission (0.7 and 1.9 per 100 person-years; HR, 0.43; 95% CI, 0.37-0.50), and ischemic stroke/systemic embolism (1.1 and 2.8 per 100 person-years; HR, 0.39; 95% CI, 0.34-0.44) than medical therapy. Conclusions Ablation may be associated with lower risk of death, heart failure admission, and ischemic stroke/systemic embolism in real-world Asian patients with AF.


Responses of fibroblasts to anchorage of dorsal extracellular matrix receptors.
Fibroblasts in 2D cultures differ dramatically in behavior from those in the 3D environment of a multicellular organism. However, the basis of this disparity is unknown. A key difference is the spatial arrangement of anchored extracellular matrix (ECM) receptors to the ventral surface in 2D cultures and throughout the entire surface in 3D cultures. Therefore, we asked whether changing the topography of ECM receptor anchorage alone could invoke a morphological response. By using polyacrylamide-based substrates to present anchored fibronectin or collagen on dorsal cell surfaces, we found that well spread fibroblasts in 2D cultures quickly changed into a bipolar or stellate morphology similar to fibroblasts in vivo. Cells in this environment lacked lamellipodia and large actin bundles and formed small focal adhesions only near focused sites of protrusion. These responses depend on substrate rigidity, calcium ion, and, likely, the calcium-dependent protease calpain. We suggest that fibroblasts respond to both spatial distribution and mechanical input of anchored ECM receptors. Changes in cell shape may in turn affect diverse cellular activities, including gene expression, growth, and differentiation, as shown in numerous previous studies.


Health-related quality of life and symptom assessment in randomized controlled trials of patients with leukemia and myelodysplastic syndromes: What have we learned?
Health-related quality of life (HRQOL) and other patient-reported outcomes (PROs) are crucial for a comprehensive evaluation of treatment effectiveness. A systematic review of randomized controlled trials (RCTs) with a PRO endpoint conducted in patients with leukemia and myelodysplastic syndromes (MDS) was performed. Eligible studies were evaluated independently, according to a pre-defined coding scheme, by two reviewers. Thirteen RCTs, enrolling overall 3380 patients were identified. There were four RCTs involving acute myeloid leukemia patients (AML), one with acute lymphoid leukemia (ALL), five with chronic lymphocytic leukemia (CLL) and three with MDS. Six RCTs accurately documented PRO methodology assessment and were thus considered likely to robustly inform clinical decision-making. Of these, three RCTs dealt with AML, two with CLL, one with MDS. A growing number of RCTs in leukemia and MDS have included a PRO component in recent years. Inclusion of PROs in RCTs is feasible and can provide unique information to facilitate clinical decision-making.


Explaining Discrepancies Between the Digit Triplet Speech-in-Noise Test Score and Self-Reported Hearing Problems in Older Adults.
The purpose of this study is to determine which demographic, health-related, mood, personality, or social factors predict discrepancies between older adults' functional speech-in-noise test result and their self-reported hearing problems. Data of 1,061 respondents from the Longitudinal Aging Study Amsterdam were used (ages ranged from 57 to 95 years). Functional hearing problems were measured using a digit triplet speech-in-noise test. Five questions were used to assess self-reported hearing problems. Scores of both hearing measures were dichotomized. Two discrepancy outcomes were created: (a) being unaware: those with functional but without self-reported problems (reference is aware: those with functional and self-reported problems); (b) reporting false complaints: those without functional but with self-reported problems (reference is well: those without functional and self-reported hearing problems). Two multivariable prediction models (logistic regression) were built with 19 candidate predictors. The speech reception threshold in noise was kept (forced) as a predictor in both models. Persons with higher self-efficacy (to initiate behavior) and higher self-esteem had a higher odds to being unaware than persons with lower self-efficacy scores (odds ratio [OR] = 1.13 and 1.11, respectively). Women had a higher odds than men (OR = 1.47). Persons with more chronic diseases and persons with worse (i.e., higher) speech-in-noise reception thresholds in noise had a lower odds to being unaware (OR = 0.85 and 0.91, respectively) than persons with less diseases and better thresholds, respectively. A higher odds to reporting false complaints was predicted by more depressive symptoms (OR = 1.06), more chronic diseases (OR = 1.21), and a larger social network (OR = 1.02). Persons with higher self-efficacy (to complete behavior) had a lower odds (OR = 0.86), whereas persons with higher self-esteem had a higher odds to report false complaints (OR = 1.21). The explained variance of both prediction models was small (Nagelkerke R2 = .11 for the unaware model, and .10 for the false complaints model). The findings suggest that a small proportion of the discrepancies between older individuals' results on a speech-in-noise screening test and their self-reports of hearing problems can be explained by the unique context of these individuals. The likelihood of discrepancies partly depends on a person's health (chronic diseases), demographics (gender), personality (self-efficacy to initiate behavior and to persist in adversity, self-esteem), mood (depressive symptoms), and social situation (social network size). Implications are discussed.


The role of the synovial fibroblast in rheumatoid arthritis pathogenesis.
Synovial fibroblasts continue to grow in prominence both as the subjects of research into the pathogenesis of rheumatoid arthritis and as novel therapeutic targets. This timely review aims to integrate the most recent findings with existing paradigms of fibroblast-related mechanisms of disease. Linking the role of synovial fibroblasts as innate sentinels expressing pattern recognition receptors such as toll-like receptors to their effector roles in joint damage and interactions with leukocyte subpopulations has continued to advance. Understanding of the mechanisms underlying increased fibroblast survival in the inflamed synovium has led to therapeutic strategies such as cyclin-dependent kinase inhibition. Major advances have taken place in understanding of the interactions between epigenetic and micro-RNA regulation of transcription in synovial fibroblasts, improving our understanding of the unique pathological phenotype of these cells. Finally, the impact of new markers for fibroblast subpopulations is beginning to become apparent, offering the potential for targeting of pathological cells as the roles of different populations become clearer. Over the past 2 years, major advances have continued to emerge in understanding of the relationship between synovial fibroblasts and the regulation of inflammatory pathways in the rheumatoid arthritis synovium.


Searching efficient protection strategies for the eutrophied Gulf of Finland: the combined use of 1D and 3D modeling in assessing long-term state scenarios with high spatial resolution.
An experiment combining the use of two ecosystem models was conducted to search for effective protection strategies for the Gulf of Finland (Baltic Sea). Reference and scenario simulations were first run with a one-dimensional (1D) model for seven main basins of the entire Baltic Sea until steady state was achieved. The obtained basinwise distributions of inorganic nitrogen (N) and phosphorus (P), as well as sediment labile P, were then used to initiate 5-y simulations with a three-dimensional (3D) ecosystem model. The results suggest that relatively small local load reductions (the "Finland" scenario) would improve only the state of adjacent coastal waters significantly. This would be the case, even for runs covering several decades, which clearly exceed the residence times of nutrients in the Gulf of Finland. A significant decrease from a substantial loading source to the Gulf (the "St. Petersburg" scenario) would decrease cyanobacterial biomasses in the entire Gulf of Finland and also immediately outside it. A reduction in the current Polish nutrient loads would improve the situation in the whole Baltic Proper and cause an extensive decline in cyanobacterial biomasses in the Gulf of Finland, as well. However, it would take several decades until the improvement caused by reducing loads in the "Poland" scenario is seen, while in the "St. Petersburg" scenario the corresponding time lag would only be a few years. Our results suggest that the common water protection policy in the Baltic Sea region should have the largest nutrient sources as its primary target, regardless of their location and country.


Effects of long-term exercise and diet intervention on plasma adipokine concentrations.
In a randomized, controlled, 2 x 2 factorial trial on the effect of long-term changes in diet and exercise, a significant reduction in body weight and fat mass was observed. Alterations in leptin and plasminogen activator inhibitor-1 concentrations were previously reported from this study. We examined the separate and combined effects of a 1-y exercise and diet intervention on several adipokines; adiponectin, interleukin-6 and -8, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, hepatocyte growth factor, nerve growth factor, C-reactive protein, and resistin. One hundred eighty-eight men with several risk factors for diabetes and cardiovascular disease were randomly allocated to 4 groups: diet, exercise, combined diet and exercise, and control. Plasma adiponectin concentrations remained unchanged, whereas body mass index and fat mass decreased after dietary changes and an increase in physical activity. In the control group, adiponectin concentrations were reduced. Analyzed according to the factorial design, only diet intervention had a significant (P = 0.03) positive effect on plasma adiponectin relative to control, and this effect was largely explained by changes in fat mass. After adjustment for change in percentage body fat, there were significant positive effects on tumor necrosis factor-alpha in all 3 intervention groups (P = 0.01 for the diet group, 0.03 for the exercise group, and 0.05 for the combined diet and exercise group). Minor changes were observed for the other adipokines. Neither baseline concentrations of nor changes in adiponectin and plasminogen activator inhibitor-1 were significantly correlated to the other adipokines, whereas concentrations of and changes in the other adipokines were significantly correlated. Diet intervention had a significant positive effect on adiponectin concentrations, which is largely explained by a reduction in fat mass.


Molecular recognition and modification of the 30S ribosome by the aminoglycoside-resistance methyltransferase NpmA.
Aminoglycosides are potent, broad spectrum, ribosome-targeting antibacterials whose clinical efficacy is seriously threatened by multiple resistance mechanisms. Here, we report the structural basis for 30S recognition by the novel plasmid-mediated aminoglycoside-resistance rRNA methyltransferase A (NpmA). These studies are supported by biochemical and functional assays that define the molecular features necessary for NpmA to catalyze m(1)A1408 modification and confer resistance. The requirement for the mature 30S as a substrate for NpmA is clearly explained by its recognition of four disparate 16S rRNA helices brought into proximity by 30S assembly. Our structure captures a "precatalytic state" in which multiple structural reorganizations orient functionally critical residues to flip A1408 from helix 44 and position it precisely in a remodeled active site for methylation. Our findings provide a new molecular framework for the activity of aminoglycoside-resistance rRNA methyltransferases that may serve as a functional paradigm for other modification enzymes acting late in 30S biogenesis.


Therapeutic modalities for treatment resistant depression: focus on vagal nerve stimulation and ketamine.
Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years is vagal nerve stimulation (VNS). The present review briefly describes the relevance of this treatment in the light of other existing pharmacological and non-pharmacological options. It then summarizes clinical findings with respect to the efficacy of VNS. The anatomical rationale for its efficacy and other potential mechanisms of its antidepressant effects as compared to those employed by classical antidepressant drugs are discussed. VNS has been approved in some countries and has been used for patients with TRD for quite some time. A newer, fast-acting, non-invasive pharmacological option called ketamine is currently in the limelight with reference to TRD. This drug is currently in the investigational phase but shows promise. The clinical and preclinical findings related to ketamine have also been summarized and compared with those for VNS. The role of neurotrophin factors, specifically brain derived neurotrophic factor and its receptor, in the beneficial effects of both VNS and ketamine have been highlighted. It can be concluded that both these therapeutic modalities, while effective, need further research that can reveal specific targets for intervention by novel drugs and address concerns related to side-effects, especially those seen with ketamine.


Longitudinal imaging of T cell-based immunotherapy with multi-spectral, multi-scale optoacoustic tomography.
Most imaging studies of immunotherapy have focused on tracking labeled T cell biodistribution in vivo for understanding trafficking and homing parameters and predicting therapeutic efficacy by the presence of transferred T cells at or in the tumour mass. Conversely, we investigate here a novel concept for longitudinally elucidating anatomical and pathophysiological changes of solid tumours after adoptive T cell transfer in a preclinical set up, using previously unexplored in-tandem macroscopic and mesoscopic optoacoustic (photoacoustic) imaging. We show non-invasive in vivo observations of vessel collapse during tumour rejection across entire tumours and observe for the first time longitudinal tumour rejection in a label-free manner based on optical absorption changes in the tumour mass due to cellular decline. We complement these observations with high resolution episcopic fluorescence imaging of T cell biodistribution using optimized T cell labeling based on two near-infrared dyes targeting the cell membrane and the cytoplasm. We discuss how optoacoustic macroscopy and mesoscopy offer unique contrast and immunotherapy insights, allowing label-free and longitudinal observations of tumour therapy. The results demonstrate optoacoustic imaging as an invaluable tool in understanding and optimizing T cell therapy.


Operative techniques for the treatment of neonatal necrotizing enterocolitis.
Operative management of infants with necrotizing enterocolitis and its complications requires a repertoire of surgical techniques, many of which are unique to pediatric surgery. Survival rates for infants with this once deadly illness are improving. Choice of the correct operative procedure and precise technical performance of the technique are mandatory for survival of the infant.


Burkholderia cepacia Complex Infections in Urgently Referred Neonates from Syrian Border Regions to a Hospital in Turkey: A Cross-Border Cluster.
Burkholderia cepacia complex (BCC) is a rare cause of sepsis in neonates, but infections are usually severe. It can be encountered unexpectedly when adequate health care is not provided. In this study, 49 neonatal cases with blood culture-proven BCC bacteremia within the first 72 h following admission to the neonatal intensive care unit between June 2017 and December 2018 were retrospectively analyzed in detail. All but one of the cases were born in Jarabulus, Al Bab, or Aleppo in Syria and were referred to Turkey due to urgent medical treatment needs. The rate of BCC bacteremia among the neonates transferred from across the border was 16.1% (48/297). The most common coexisting problems in the cases were multiple congenital malformations (12.2%), gastrointestinal system atresia (8.2%), and congenital heart diseases (4.1%). The median age at the time of their admission in Turkey was three days, and the median length of stay in another center before the referral was 11.5 h. The case fatality rate was 14.3%. In this study, a high rate of BCC infection and associated mortality was seen in neonates referred from cross-border regions. For centers accepting cases from conflict-affected regions, it is crucial to be careful regarding early detection of bacteremia, planning appropriate treatments, and preventing cross-contamination risks within the unit.


Recent advances in nano-based electrochemical biosensors: application in diagnosis and monitoring of diseases.
Based on biological molecules combined with nanostructured components, the news generations of electrochemical biosensors can employ different transducers (potentiometric, amperometric and impedimetric) converting the chemical information into a measurable amperometric signal. Following this contemporary theme, our main focus in this review is to discuss different methodologies for application in biosensing, whose signal transduction is based on electrochemical principles. We apply a discussion on recent trends involving different nanostructured materials, but without daring to contemplate all nanomaterials incessantly cited in literature, which leads us to believe that this moment is an unprecedented revolution in the preparation of electrochemical biodevices. Besides, some structures of bio-nano interface and different electrochemical biosensors involved in diagnosis systems are also discussed. We outline in several parts of the report how nanoscience technologies are emerging in diagnostic medicine, as well as convergence of electrochemistry and bio-nanoscience. Our hopes for this review are that it can help different categories of researchers to understand the broad application area of electrochemistry and bioelectrochemistry, in order to detecting several types of diseases and biological phenomena.


Watermelon origin solved with molecular phylogenetics including Linnaean material: another example of museomics.
Type specimens are permanently preserved biological specimens that fix the usage of species names. This method became widespread from 1935 onwards and is now obligatory. We used DNA sequencing of types and more recent collections of wild and cultivated melons to reconstruct the evolutionary history of the genus Citrullus and the correct names for its species. We discovered that the type specimen of the name Citrullus lanatus, prepared by a Linnaean collector in South Africa in 1773, is not the species now thought of as watermelon. Instead, it is a representative of another species that is sister to C. ecirrhosus, a tendril-less South African endemic. The closest relative of the watermelon instead is a West African species. Our nuclear and plastid data furthermore reveal that there are seven species of Citrullus, not four as assumed. Our study implies that sweet watermelon originates from West, not southern Africa as previously believed, and that the South African citron melon has been independently domesticated. These findings affect and explain numerous studies on the origin of these two crops that led to contradictory results because of the erroneous merging of several distinct species.


Baculovirus replication: phosphorylation of polypeptides synthesized in Trichoplusia ni nuclear polyhedrosis virus-infected cells.
A number of polypeptides synthesized specifically in Trichoplusia ni multiple nucleocapsid nuclear polyhedrosis virus (T. ni MNPV)-infected Spodoptera frugiperda cells are phosphorylated both early and late in infection. Certain non-structural proteins and the major basic internal protein are the main phosphoproteins detected in infected cells. The polyhedron protein was not phosphorylated. Many cell proteins continue to be phosphorylated throughout infection. Pulse-chase experiments have shown that some polypeptides are stably phosphorylated whereas other polypeptides (including the major basic protein) have phosphates which cycle on and off. One polypeptide was substantially labelled only after a chase with unlabelled orthophosphate. Fractionation of cells into nucleus and cytoplasm showed that polypeptides located in both the cytoplasm and nucleus were phosphorylated.


Insulin-like growth factor and interleukin-1beta levels and subsequent fetal size in response to chronic Porphyromonas gingivalis exposure in the pregnant rabbit.
The purpose of this study was to describe maternal insulin-like growth factor, interleukin-1beta, and fetal size in a rabbit model of Porphyromonas gingivalis exposure. With the use of a previously described model, 8 New Zealand White rabbits were exposed to either P gingivalis or media during pregnancy and killed at term. Kit and placenta weight were compared between groups. Doe serum insulin-like growth factor system protein and interleukin-1beta levels were compared by analysis of variance for repeated measures; a probability value of <.05 was considered to be significant. No significant differences in kit and placental weights between exposed and unexposed groups were observed. Insulin-like growth factor system proteins increased significantly as pregnancy progressed, but there were no significant differences in insulin-like growth factor system proteins or interleukin-1beta between exposed and unexposed does. Chronic P gingivalis exposure does not disrupt insulin-like growth factor system proteins or systemic inflammation and does not impair fetal growth in the pregnant rabbit. Gestational age changes in doe insulin-like growth factor system proteins occur, and the timing of exposure to oral pathogens may influence fetal growth.


Environmental factors and risk of idiopathic dilated cardiomyopathy: a multi-hospital case-control study in Japan.
Detailed epidemiological investigations on the relationship of environmental factors, especially occupational and microbiological factors, to the development of idiopathic dilated cardiomyopathy (IDC) are scarce. A multi-hospital case-control study was conducted in 38 hospitals throughout Japan in order to survey IDC cases and age, sex-matched outpatient controls at each hospital. Crude and adjusted odds ratios (ORs) by various environmental factors were calculated in 135 pairs of cases and controls. Univariate analyses revealed significantly increased ORs for lower education, passive smoking in the workplace, cold and/or hot workplace, symptoms of fatigue and history of bacterial infection; in contrast, decreased ORs were associated with a history of rubella and gastroduodenal diseases. Based on multivariate adjusted analyses, lower education (OR 1.96, 95% confidence interval (CI) 1.13-3.40), cold or hot workplace (OR 1.84, 95%CI 1.08-3.12) and history of measles (OR 1.78, 95%CI 1.01-3.08) exhibited a significant positive relationship with IDC risk. History of rubella (OR 0.17, 95%CI 0.06-0.52) and gastroduodenal diseases (OR 0.14, 95%CI 0.07-0.29) were inversely related to the risk. Some occupational and microbiological factors appear to relate independently to the development of IDC and further investigation is required to establish their respective mechanisms.


Salmonella Infection in Mesenteric Lymph Nodes of Breeding Sows.
Salmonellosis is one of the main foodborne diseases worldwide. Breeding sows asymptomatically infected with Salmonella can transmit the pathogen to piglets and humans. The isolation of Salmonella from mesenteric lymph nodes (MLNs) is considered a demonstration of asymptomatic infection in swine. As previous breeding sow studies have been performed using feces, the aim of this work was to study the occurrence of Salmonella infections by sampling MLNs, in comparison to their serological status. First, Salmonella fecal shedding was studied in 12/16 large breeding farms to establish the framework of study. Then, MLN (n = 264) and blood (n = 237) samples were obtained at an abattoir from sows of 15 of these 16 breeding farms. Additionally, risk factors associated with Salmonella MLN infection were analyzed. A total of 6.1% (16/264) sows, distributed in 40% (6/15) of the farms, had the pathogen in MLN. Salmonella Typhimurium was the most frequent serovar isolated. Interestingly, 43.8% (7/16) of MLN isolates were susceptible to all the antimicrobials tested and were found distributed throughout all farms with at least one sow positive. As well, one isolate of the emerging DT195 clone was detected and found to be resistant to six antibiotic families (ASSuTNx-Cfx). The serovars and the resistance profiles of the Salmonella isolates from feces were completely different to those obtained from MLNs. The seroprevalence (41.8% of sows and 100% of farms) was higher than that of MLN infections, showing no concordance (k = 0.15) between these two diagnostic tests in sows. Strategies directed to correct two risk factors (i.e., administration of dry food and old premises) would most likely help to reduce Salmonella infections in breeding sows.


Effect of 7,8-dihydroxyflavone as an antioxidant on in vitro maturation of oocytes and development of parthenogenetic embryos in pigs.
One of the factors that impairs in vitro produced porcine embryos is the oxidative stress that is mainly caused by the imbalance between reactive oxygen species (ROS) generation and antioxidants activity, especially that of glutathione (GSH). Here, we examined the effect of 7,8-dihydroxyflavone (7,8-DHF), a kind of flavonoid antioxidant, on porcine oocyte maturation and its developmental competence. Porcine oocytes were cultured in media supplemented with 0, 1, 5 and 10 μM 7,8-DHF during both in vitro maturation (IVM) and in vitro culture (IVC) after parthenogenetic activation. Maturation of oocytes was evaluated based on first polar body (PB) extrusion and intracellular GSH level, and developmental competence was assessed through observing cleavage and blastocyst formation. In each step, the levels of intracellular GSH and ROS were assessed by fluorescence intensity, and the apoptosis-related gene expression was examined using semiquantitative RT-PCR. The group treated with 1 μM 7,8-DHF during IVM and IVC showed increased cytoplasmic maturation and reached the blastocysts stage (36.1%) at a higher rate than the other groups (24.7, 16.0 and 10.3% for 0, 5 and 10 μM, P<0.05). In that group, the intracellular GSH level was significantly increased while ROS generation was significantly decreased after IVM and IVC (P<0.05). Moreover, it showed high expression of an anti-apoptotic gene (BCL2L1) and low expression of a pro-apoptotic gene (BAK1) (P<0.05). In conclusion, treatment with 1 μM 7,8-DHF during IVM and IVC showed an anti-apoptotic effect by increasing intracellular GSH synthesis and scavenging ROS and therefore improved the developmental competence of porcine embryos.


Impact of plasma transfusion in trauma patients who do not require massive transfusion.
For trauma patients requiring massive blood transfusion, aggressive plasma usage has been demonstrated to confer a survival advantage. The aim of this study was to evaluate the impact of plasma administration in nonmassively transfused patients. Trauma patients admitted to a Level I trauma center (2000-2005) requiring a nonmassive transfusion (<10 U packed RBC [PRBC] within 12 hours of admission) were identified retrospectively. Propensity scores were calculated to match and compare patients receiving plasma in the first 12 hours with those who did not. The 1,716 patients (86.1% of 1,933 who received PRBC transfusion) received a nonmassive transfusion. After exclusion of 31 (1.8%) early deaths, 284 patients receiving plasma were matched to patients who did not. There was no improvement in survival with plasma transfusion (17.3% versus 14.1%; p = 0.30) irrespective of the plasma-to-PRBC ratio achieved. However, the overall complication rate was significantly higher for patients receiving plasma (26.8% versus 18.3%, odds ratio [OR] = 1.7; 95% CI, 1.1-2.4; p = 0.016). As the volume of plasma increased, an increase in complications was seen, reaching 37.5% for patients receiving >6 U. The ARDS rate specifically was also significantly higher in patients receiving plasma (9.9% versus 3.5%, OR = 3.0; 95% CI, 1.4-6.2; p = 0.004]. Patients receiving >6 U plasma had a 12-fold increase in ARDS, a 6-fold increase in multiple organ dysfunction syndrome, and a 4-fold increase in pneumonia and sepsis. For nonmassively transfused trauma patients, plasma administration was associated with a substantial increase in complications, in particular ARDS, with no improvement in survival. An increase in multiple organ dysfunction, pneumonia, and sepsis was likewise seen as increasing volumes of plasma were transfused. The optimal trigger for initiation of a protocol for aggressive plasma infusion warrants prospective evaluation.


The effect of N-bromosuccinimide on the sub-unit structure of acidin and its complexes with biotin.
1. Each molecule of biotin bound to avidin protected four tryptophan residues from oxidation by N-bromosuccinimide, regardless of the occupancy of neighbouring binding sites in the four-sub-unit avidin molecule. 2. The oxidation products from avidin molecules in which some of the sites were occupied were separated on columns of Sephadex G-100. In the absence of biotin, oxidized avidin broke down into sub-units, which partly aggregated. When some of the sites were occupied by biotin, the only detectable products were completely oxidized avidin (sub-units and large aggregates) and unoxidized avidin-biotin complex (tetramer). Since the biotin-containing sub-units were randomly distributed before oxidation took place, they must have dissociated from the molecules containing oxidized sub-units and then reassociated to form the tetrameric avidin-biotin complex. 3. This reassociation still occurred in 3.5m-guanidinium chloride, which prevents the reassociation of unoccupied sub-units. During their brief existence in this medium, the sub-units of avidin-biotin complex were protected from oxidation by N-bromo-succinimide to the same extent as was the tetrameric complex. 4. It is concluded that sub-units of avidin-biotin complex do not readily lose their biotin, even in 3.5m-guanidinium chloride, and that monomeric biotin-binding species are probably present in solutions of avidin sub-units at guanidinium chloride concentrations between 3.0m and 3.5m.


A comparative study of egg recognition signature mixtures in Formica ants.
Processing of information from the environment, such as assessing group membership in social contexts, is a major determinant of inclusive fitness. For social insects, recognizing brood origin is crucial for inclusive fitness in many contexts, such as social parasitism and kin conflicts within colonies. Whether a recognition signature is informative in kin conflicts depends on the extent of a genetic contribution into the cues. We investigated colony- and matriline-specific variation in egg surface hydrocarbons in seven species of Formica ants. We show that chemical variance is distributed similarly to genetic variation, suggesting a significant genetic contribution to eggs odors in the genus. Significant among matriline components, and significant correlations between chemical and genetic similarity among individuals also indicate kin informative egg odors in several species. We suggest that egg odor surface variation could play a large role in within colony conflicts, and that a comparative method can reveal novel insight into communication of identity.


A mutant collagen XIII alters intestinal expression of immune response genes and predisposes transgenic mice to develop B-cell lymphomas.
Epithelial cells of mucosal surfaces are critical for maintaining immune homeostasis by aiding in the discrimination of pathogenic and commensal microorganisms and modulating the activities of antigen-presenting cells and lymphocytes. Functional breakdowns resulting in chronic infection and inflammation are associated with the development of hematologic and solid neoplasms for which detailed pathogenetic mechanisms are poorly understood. Mice heterozygous for a transgene Col13a1(del) expressing a mutant collagen XIII developed clonal mature B-cell lineage lymphomas originating in mesenteric lymph nodes (MLN). The tumors were associated with T cells and macrophages. The incidence of disease was reduced 2-fold in transgenic mice raised under specific pathogen-free conditions, suggesting a role for infectious agents. The lymphomas did not express the mutant collagen XIII, indicating that its influence on tumorigenesis was B-cell extrinsic and likely to be associated with collagen XIII-positive tissues drained by the MLN. Studies of the small intestines of transgenic mice showed that the subepithelial basement membranes (BM) were highly abnormal and that they exhibited heightened expression of genes involved in immune responses. These results define collagen XIII-dependent maintenance of the intestinal BM as a previously unappreciated component of immune responses and a critical determinant of cancer susceptibility.


Endoscopic pancreatography in management of relapsing acute pancreatitis.
Endoscopic retrograde cholangiopancreatography (E.R.C.P.) was attempted in 31 patients suffering from repeated attacks of acute pancreatitis. Pancreatograms were obtained in 25 patients. Twelve showed definite "surgical lesions" (obstructions, strictures, or pseudocysts). In at least three patients failure to obtain a pancreatogram was due to obstruction of pancreatic duct close to the papilla. Two patients, both with pseudocysts, developed a mild relapse of pancreatitis after the procedure. Surgical intervention based on the x-ray findings seemed beneficial in the short follow-up period.Endoscopic pancreatography can be of value in deciding when surgery is advisable for patients with relapsing acute pancreatitis and in determining the operative appreach. It is an advance in the management of a difficult clinical condition.


Cox model and decision trees: an application to breast cancer data.
To evaluate, using semiparametric methodologies of survival analysis, the relationship between covariates and time to death of patients with breast cancer, as well as the determination discriminatory power in the conditional inference tree of patients who had cancer. A retrospective cohort study was conducted using data collected from medical records of women who had breast cancer and underwent treatment between 2005 and 2015 at the Hospital da Fundação de Assistencial da Paraíba in Campina Grande, State of Paraiba, Brazil. Survival curves were estimated using the Kaplan-Meier method, Cox regression, and conditional decision tree. Women with triple-negative molecular subtypes had a shorter survival time compared to women with positive hormone receptors. The addition of hormone therapy reduced the risk of a patient dying by 5.5%, and the risk of a HER2-positive patient dying was 34.5% lower compared to those who were negative for this gene. Patients undergoing hormone therapy had a median survival time of 4 753 days. This paper shows a favorable scenario for the use of immunotherapy for patients with HER2 overexpression. Further studies could assess the effectiveness of immunotherapy in patients with other conditions, to favor the prognosis and better quality of life for the patient.


Detection, characterization, and enrollment of donors of Ebola convalescent plasma in Sierra Leone.
Passive therapy with convalescent plasma provides an early opportunity to intervene in Ebola virus disease (EVD). Methods for field screening and selection of potential donors and quantifying plasma antibody are needed. Recombinant Ebola virus glycoprotein (EBOV GP) was formatted into immunoglobulin G-capture, competitive, and double-antigen bridging enzyme immunoassays (EIAs). EVD survivors in Freetown, Sierra Leone, were recruited as potential plasma donors and assessed locally using sera alone and/or paired sera and oral fluids (ORFs). Uninfected controls comprised unexposed Gambians and communities in Western Area, Sierra Leone. Antibody neutralization in selected sera was measured retrospectively in a pseudotype virus assay. A total of 115 potential donors were considered for enrollment: 110 plasma samples were concordantly reactive in the three EIAs; three were concordantly unreactive and two were reactive in two of three EIAs (98.2% agreement; 95% confidence interval [CI], 93.9%-99.8%). In 88 donors with paired ORF and plasma, G-capture EIA reactivity correlated well in the two analytes (R2 = 0.795). Plasma and ORF from 44 Gambians were unreactive. ORF samples from 338 of 339 unexposed Western Area community controls were unreactive (specificity, 99.7%; 95% CI, 98.4%-99.7%); ORF samples from 113 of 116 Kerry Town EVD survivors were reactive (sensitivity, 97.4%; 95% CI, 92.5%-99.5%). Strong reactivity in G-capture and/or competitive EIAs identified donors with high plasma EBOV GP antibody levels in the double-antigen bridging assay, correlating with high levels of neutralizing antibody. In-field testing can qualify convalescent donors for providing high-titer antibody.


Polyaniline and CN-functionalized polyaniline as organic cathodes for lithium and sodium ion batteries: a combined molecular dynamics and density functional tight binding study in solid state.
We present the first atomistic-scale simulation of the discharge process of polymeric cathode materials for electrochemical batteries in solid state. The oxidation of polyaniline (PANI) and of cyano groups (CN) functionalized PANI induced by coordination to the electrolyte anions is computed and voltage curves are estimated. To deal with the large required numbers of atoms and structures, a combination of molecular dynamics and density functional tight binding (DFTB) is used. The DFTB is benchmarked to density functional theory (DFT) calculations using different functionals to confirm its accuracy. The voltages computed with the solid state model are in good agreement with available experimental data and ab initio models based on oligomers. The solid state model also predicts substantially increased voltage with PANI functionalized with cyano groups.


Defective NDUFA9 as a novel cause of neonatally fatal complex I disease.
Mitochondrial disorders are associated with abnormalities of the oxidative phosphorylation (OXPHOS) system and cause significant morbidity and mortality in the population. The extensive clinical and genetic heterogeneity of these disorders due to a broad variety of mutations in several hundreds of candidate genes, encoded by either the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), impedes a straightforward genetic diagnosis. A new disease gene is presented here, identified in a single Kurdish patient born from consanguineous parents with neonatally fatal Leigh syndrome and complex I deficiency. Using homozygosity mapping and subsequent positional candidate gene analysis, a total region of 255.8 Mb containing 136 possible mitochondrial genes was identified. A pathogenic mutation was found in the complex I subunit encoding the NDUFA9 gene, changing a highly conserved arginine at position 321 to proline. This is the first disease-causing mutation ever reported for NDUFA9. Complex I activity was restored in fibroblasts of the patient by lentiviral transduction with wild type but not mutant NDUFA9, confirming that the mutation causes the complex I deficiency and related disease. The data show that homozygosity mapping and candidate gene analysis remain an efficient way to detect mutations even in small consanguineous pedigrees with OXPHOS deficiency, especially when the enzyme deficiency in fibroblasts allows appropriate candidate gene selection and functional complementation.


Collaborative telemedicine between optometry and ophthalmology: an initiative from the University of Houston.
The University of Houston College of Optometry (UHCO) has developed a strong Telemedicine Optometry/Ophthalmology program. Patient care, clinical teaching and research benefit from utilizing Telemedicine technology. This initiative between Optometry and Ophthalmology is at the forefront of eyecare! Presented here: clinical teaching opportunities via tele-education including retinal, uveitic, neuro-ophthalmic disorders and glaucoma. Seminars introduce students to this technology and enhance their clinical experience through exposure to eye pathologies often related to systemic diseases. UHCO's affiliated clinics include multidisciplinary centers staffed by optometrists: the Frost Eye Clinic (HIV multidisciplinary care), Good Neighbor Health Clinic and Rusk School Health Promotion Project (indigent multidisciplinary care). These centers can converse on line with eyecare professionals. Large sites interested in low vision/visual rehabilitation include: The Institute for Rehabilitation and Research (TIRR), the Social Security Hospital (Lima, Peru), the Matagorda General Hospital and the Quentin Mease Hospital. These sites, do offer quality care but require visual rehabilitation programs provided by UHCO. These sites also provide exposure to pathology for the students. A residency program trains optometrists in Telemedicine. The research program focuses on optics and imaging necessary to diagnose glaucoma, diabetic retinopathy, and neuro-ophthalmic disorders through Telemedicine. UHCO supports the advancement of standards in tele-eyecare.


Behavioural profiles in captive-bred cynomolgus macaques: towards monkey models of mental disorders?
To date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non-human primates have remained largely underexplored. The present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering. The study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation. No interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups.


Improving the emission efficiency of MBE-grown GaN/AlN QDs by strain control.
The quantum-confined stark effect induced by polarization has significant effects on the optical properties of nitride heterostructures. In order to improve the emission efficiency of GaN/AlN quantum dots [QDs], a novel epitaxial structure is proposed: a partially relaxed GaN layer followed by an AlN spacer layer is inserted before the growth of GaN QDs. GaN/AlN QD samples with the proposed structure are grown by molecular beam epitaxy. The results show that by choosing a proper AlN spacer thickness to control the strain in GaN QDs, the internal quantum efficiencies have been improved from 30.7% to 66.5% and from 5.8% to 13.5% for QDs emitting violet and green lights, respectively.


Safety, Tolerability, and Pharmacokinetics of Ibuprofenamine Hydrochloride Spray (NSAIDs), a New Drug for Rheumatoid Arthritis and Osteoarthritis, in Healthy Chinese Subjects.
Ibuprofenamine hydrochloride spray is novel transdermal nonsteroidal anti-inflammatory drugs (NSAIDs), under clinical development for the treatment of Rheumatoid Arthritis and Osteoarthritis as a novel transdermal drug. A single and multiple ascending dose study investigated the safety, tolerability and pharmacokinetics of ibuprofenamine hydrochloride in healthy Chinese subjects. A total of 34 subjects (single-dose study: 34 subjects and multiple-dose study: 20 subjects) were involved in the trial. In the single-dose study, subjects were assigned to one of the four groups received 35, 70, 140, 280 mg. In the 70 mg and 140 mg treatment groups, subjects received one dose on the first day and twice a day from day 6 to 12. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts. After a single dose, both ibuprofenamine and ibuprofen plasma exposure showed a more than dose-proportional increase across a dose range of 35-280 mg. After multiple dosing, both ibuprofenamine and ibuprofen steady-state exposure increased obviously more than dose-proportional manner across the evaluated dose range (twice a day for 7 days) resulted in obvious accumulation. Single or multiple doses of ibuprofenamine hydrochloride were generally well tolerated and no obvious skin irritation was observed. Ibuprofenamine hydrochloride exhibited a safety and pharmacokinetic profile that supports its future investigation as a potential therapeutic for Rheumatoid Arthritis and Osteoarthritis.


Phenotypic and functional analysis of T-cell precursors in the human fetal liver and thymus: CD7 expression in the early stages of T- and myeloid-cell development.
It has been proposed that the CD7 molecule is the first antigen expressed on the membrane of cells committed to the T-cell lineage during human fetal T-cell ontogeny. To further identify the pre-T cell subpopulation that migrates to the thymus early in ontogeny, we analyzed the phenotypic and functional characteristics of the fetal liver populations separated on the basis of CD7 expression. Three populations expressing different levels of CD7 were observed: CD7bright, CD7dull, and CD7-. A CD7bright population depleted of mature T, B, and myeloid cells (lineage negative, lin-) and mostly composed of CD56+ CD34- natural killer cells did not mature into T cells in a fetal thymic organ culture (FTOC) assay and was devoid of myeloid progenitors in a clonal colony-forming cell assay. In contrast, the CD7-/dull CD34+ lin- populations were capable of differentiating into phenotypically mature T cells after injection into FTOC and contained early myeloid progenitors. Here we phenotypically compared the fetal liver CD7 populations with the most immature fetal thymic subset that differentiated in the FTOC assay, namely the triple negative (TN, CD3-CD4-CD8-) thymocytes. Fetal TN lin- expressed high levels of CD34 marker and were further subdivided by their expression of CD1 antigen, because CD1- TN thymocytes express higher levels of CD34 antigen compared with CD1+ TN cells. CD1- lin -TN thymocytes are characterized by expressing high levels of CD2, CD7, and CD34 markers and dull levels of CD5, CD10, and CD28 molecules. We could not find fetal liver pre-T cells with a phenotype equivalent to that of TN thymocytes. Our data show that CD7 does not necessarily identify T-cell precursors during fetal T-cell development and strongly support the hypothesis that the acquisition of early T-cell markers as CD2, CD28, and CD5 molecules on the cell surface of T-cell progenitors takes place intrathymically.


Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins.
Suppression of red blood cell production is a common complication of chemotherapy, causing anemia in a significant number of cancer patients. We have evaluated the sensitivity of human hematopoietic progenitors and erythroid precursor cells to chemotherapeutic drugs and found that probasophilic erythroblasts represent the stage of erythroid differentiation more vulnerable to the cytotoxic effects of myelosuppressive agents. Stem cell factor (SCF) supports proliferation and survival of early hematopoietic cells by binding to the c-kit receptor. In unilineage erythropoietic culture of CD34+ progenitors, short-term pretreatment of immature erythroid precursors with SCF results in protection from apoptosis induced by chemotherapeutic agents and restores normal proliferation and differentiation after removal of the cytotoxic stimulus. The levels of drug-induced caspase processing are significantly reduced in erythroblasts treated with SCF, indicating that activation of the c-kit receptor generates antiapoptotic signals acting before amplification of the caspase cascade. Accordingly, we found that SCF up-regulates Bcl-2 and Bcl-X L in erythroid precursors and that exogenous expression of these proteins protects erythroblasts from caspase activation and death induced by chemotherapeutic agents. These results suggest a possible mechanism for SCF-mediated protection of erythroid precursor cells from apoptosis and may contribute to devise new strategies for prevention and treatment of chemotherapy-induced anemia.


Transnational access to large prospective cohorts in Europe: Current trends and unmet needs.
Biobank samples and data from studies of large prospective cohorts (LPC) represent an invaluable resource for health research. Efficient sharing and pooling of samples and data is a central pre-requisite for new advances in biomedical science. This requirement, however, is not compatible with the present scattered and traditional access governance structures, where legal and ethical frameworks often form an obstacle for effective sharing. Moreover, the EU General Data Protection Regulation (GDPR) is demanding increasingly rigorous administration from all those organisations processing personal data. The BBMRI-LPC project (Biobanking and Biomolecular Research Infrastructure - Large Prospective Cohorts) assembled 21 LPCs from 10 countries and two EU-wide multinational cohort networks with a key objective to promote collaborative innovative transnational research proposed by external researchers on the broad field of common chronic diseases, and analyze the gaps and needs involved. BBMRI-LPC organized three scientific calls to offer European investigators an opportunity to gain free of charge transnational access to research material available in the participating cohorts. A total of 11 high-quality research proposals involving multiple prospective cohorts were granted, and the access process in the individual projects carefully monitored. Divergent access governance structures, complex legal and ethical frameworks and heterogeneous procedures were identified as currently constituting substantial obstacles for sample and data transfer in Europe. To optimize the scientific value and use of these research resources, practical solutions for more streamlined access governance in collaborative projects are urgently needed. A number of infrastructure developments could be made to improve time-efficiency in access provision.


The effect of various concentrations of nucleobases, nucleosides or glutamine on the incorporation of [3H]thymidine into DNA in rat mesenteric-lymph-node lymphocytes stimulated by phytohaemagglutinin.
1. The rate of [3H]thymidine incorporation into DNA was measured in phytohaemagglutinin-stimulated lymph-node lymphocytes of the rat. 2. Addition of nucleobases or nucleosides to culture medium that already contained 0.2 mM-glutamine had a small stimulatory effect on incorporation. At lower concentrations of glutamine, adenosine (even at 1 microM) caused a marked increase in the rate of incorporation. 3. In the absence of added glutamine, addition of nucleosides or nucleobases markedly increased the rate of incorporation: nucleosides were more effective than nucleobases; and the rate of proliferation in the presence of 10 microM-adenosine plus 10 microM-uridine was similar to that in the presence of optimal concentrations of glutamine. 4. The rate of incorporation was dramatically decreased by an inhibitor of the pathway of pyrimidine nucleotide synthesis de novo. Addition of the pyrimidine nucleosides completely overcame the inhibition; addition of the pyrimidine nucleobases was much less effective. 5. These results indicate that, for proliferation of lymphocytes, glutamine is not essential and can be partially or totally replaced by nucleosides and, to some extent, by nucleobases.


Deriving bio-equivalents from in vitro bioassays: assessment of existing uncertainties and strategies to improve accuracy and reporting.
Bio-equivalents (e.g., 17β-estradiol or dioxin equivalents) are commonly employed to quantify the in vitro effects of complex human or environmental samples. However, there is no generally accepted data analysis strategy for estimating and reporting bio-equivalents. Therefore, the aims of the present study are to 1) identify common mathematical models for the derivation of bio-equivalents from the literature, 2) assess the ability of those models to correctly predict bio-equivalents, and 3) propose measures to reduce uncertainty in their calculation and reporting. We compiled a database of 234 publications that report bio-equivalents. From the database, we extracted 3 data analysis strategies commonly used to estimate bio-equivalents. These models are based on linear or nonlinear interpolation, and the comparison of effect concentrations (ECX ). To assess their accuracy, we employed simulated data sets in different scenarios. The results indicate that all models lead to a considerable misestimation of bio-equivalents if certain mathematical assumptions (e.g., goodness of fit, parallelism of dose-response curves) are violated. However, nonlinear interpolation is most suitable to predict bio-equivalents from single-point estimates. Regardless of the model, subsequent linear extrapolation of bio-equivalents generates additional inaccuracy if the prerequisite of parallel dose-response curves is not met. When all these factors are taken into consideration, it becomes clear that data analysis introduces considerable uncertainty in the derived bio-equivalents. To improve accuracy and transparency of bio-equivalents, we propose a novel data analysis strategy and a checklist for reporting Minimum Information about Bio-equivalent ESTimates (MIBEST).


Interpreting NK cell transcripts versus T cell transcripts in renal transplant biopsies.
NK cell transcripts are increased in biopsies with antibody-mediated rejection, whereas T cell transcripts are increased in T cell-mediated rejection. However, NK and T cells share many features, creating potential ambiguity. Therefore to estimate the NK- versus T cell transcript burdens separately, we defined nonoverlapping transcripts selective for NK cells (N = 4) or T cells (N = 5). We compared NK- versus T cell transcript burdens in microarrays from 403 kidney transplant biopsies (182 early, 221 late). In late biopsies, high NK-cell transcript expression was associated with antibody-mediated rejection, correlating with microvascular inflammation and donor specific HLA antibody. However, some early biopsies with T cell-mediated rejection had high NK-cell transcript expression, as well as T cell transcripts, without evidence of antibody-mediated rejection or DSA, correlating with interstitial inflammation and tubulitis. Both NK-cell and T cell transcripts were moderately increased in many kidneys with inflammation secondary to injury or atrophy scarring. These results support the distinct role of NK cells in late antibody-mediated rejection, but indicate a role for NK-transcript expressing cells (NK cells or T cells with NK features) both in T cell-mediated rejection and in inflammation associated with injury and atrophy scarring.