Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.
The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.


The genetic and environmental contributions to attention deficit hyperactivity disorder as measured by the Conners' Rating Scales--Revised.
The majority of published reports on twin studies of attention deficit hyperactivity disorder (ADHD) have indicated robust additive genetic influences and unique environmental influences. These studies typically used DSM ADHD symptoms collected by telephone or interviews with mothers. The purpose of this study was to test the genetic architecture of ADHD by using the ADHD index from Conners' Rating Scales-Revised. From the Conners' scale forms, data for the ADHD index were collected from the mothers of 1,595 7-year-old twin pairs from the Netherlands Twin Registry. Rates of ADHD diagnoses were computed by using Conners' gender- and age-specific cutoff points. Contributions from additive, dominant, unique environmental, interaction, and gender effects were computed by using gender-genetic models. The prevalence of ADHD across the sample of 7-year-old twin pairs was about 4% according to the mothers' reports, consistent with other reported rates of ADHD. However, using the gender norms provided with the ADHD index, the authors found slightly higher rates of ADHD in girls than previously reported. Genetic analyses yielded a model that includes genetic dominance (48%), additive genetic factors (30%), and unique environmental factors (22%). The ADHD index from Conners' Rating Scales-Revised identified an appropriate percentage of children across this epidemiologic twin sample as being at risk for ADHD. The results of the genetic analyses are consistent with prior reports that ADHD is predominantly influenced by genetic factors that are both dominant and additive.


Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons.
The expansion of a polyglutamine (polyQ) tract in the N-terminal region of ataxin-7 (atxn7) is the causative event in spinocerebellar ataxia type 7 (SCA7), an autosomal dominant neurodegenerative disorder mainly characterized by progressive, selective loss of rod-cone photoreceptors and cerebellar Purkinje and granule cells. The molecular and cellular processes underlying this restricted neuronal vulnerability, which contrasts with the broad expression pattern of atxn7, remains one of the most enigmatic features of SCA7, and more generally of all polyQ disorders. To gain insight into this specific neuronal vulnerability and achieve a better understanding of atxn7 function, we carried out a functional analysis of this protein in the teleost fish Danio rerio. We characterized the zebrafish atxn7 gene and its transcription pattern, and by making use of morpholino-oligonucleotide-mediated gene inactivation, we analysed the phenotypes induced following mild or severe zebrafish atxn7 depletion. Severe or nearly complete zebrafish atxn7 loss-of-function markedly impaired embryonic development, leading to both early embryonic lethality and severely deformed embryos. More importantly, in relation to SCA7, moderate depletion of the protein specifically, albeit partially, prevented the differentiation of both retina photoreceptors and cerebellar Purkinje and granule cells. In addition, [1-232] human atxn7 fragment rescued these phenotypes showing strong function conservation of this protein through evolution. The specific requirement for zebrafish atxn7 in the proper differentiation of cerebellar neurons provides, to our knowledge, the first in vivo evidence of a direct functional relationship between atxn7 and the differentiation of Purkinje and granule cells, the most crucial neurons affected in SCA7 and most other polyQ-mediated SCAs. These findings further suggest that altered protein function may play a role in the pathophysiology of the disease, an important step toward the development of future therapeutic strategies.


Alleles at four HLA class II loci determined by oligonucleotide hybridization and their associations in five ethnic groups.
The use of polymerase chain reaction (PCR) and oligonucleotide hybridization offers a new approach for the definition of HLA class II alleles. It has been possible to determine 43 alleles of DRB1, four of DRB3, two of DRB4, four of DRB5, eight of DQA1, and 14 of DQB1. These alleles are inherited together in members of families and form closely associated groups which are found repeatedly and in characteristic patterns in different populations. We have determined the HLA class II alleles and analyzed their association in 431 healthy unrelated subjects including 161 North American Caucasians, 53 Latin Americans, 61 Blacks, 88 Chinese, and 68 Israeli Jews. For-locus haplotypes (DRB1; DRB3/4/5; DQA1; DQB1) were derived from 79 B cell lines and the analysis of segregation in 34 nuclear families. The B-cell lines yielded 37 and the families showed the same, and 20 other, haplotypic combinations. In addition to these 57 haplotypes, associated alleles were assigned in the unrelated panels following certain rules. The resulting haplotypes were assigned to groups known to share associated alleles. The groups were: 1) DR1, DR2, and DRw10 (13 haplotypes); 2) DR3 and DRw6 (26 haplotypes); 3) DR5 and DRw8 (24 haplotypes); 4) DR4, DR7, and DR9 (24 haplotypes). Their distribution in populations with different ethnic backgrounds was analyzed. The expressed DRB4 allele and its null mutant were determined by PCR and oligonucleotide hybridization. The different DR7 haplotypes resulting from these determinations were analyzed in a panel of 130 North American Caucasoids. This comprehensive analysis of class II HLA haplotypes in human populations should be useful in understanding the role of these genes and in various applications including anthropology, disease susceptibility, and transplantation of allogeneic organs and tissues.


[Tactics and strategy of malaria control].
Tactics and strategy of malaria control. Both from the qualitative and quantitative point of view malaria can be regarded as one of the most serious medical problems of developing countries. In spite of decades of endeavours by the endemic countries and the World Health Organization using various tactics and strategies malaria prevalence and incidence could not be decreased essentially in tropical developing countries. The author analyses the reasons for this failure and gives realistic recommendations for lowering malaria morbidity and mortality taking into consideration the socio-economic conditions prevailing in the Third World.


Primary prevention of eating disorders: might it do more harm than good?
The aim of this pilot study was to evaluate a new school-based eating disorder prevention program designed to reduce dietary restraint. Forty-six school-girls, aged 13-14 years, took part. The intervention consisted of eight weekly sessions of 45 min duration. A battery of self-report questionnaires was administered before and after the intervention and 6 months later. Unlike previous prevention studies, there was not only an increase in knowledge at postintervention but there was also a decrease in target behavior and attitudes. However, these effects were short-lived since they had disappeared 6 months later: indeed, at 6-month follow-up there was an increase in dietary restraint compared with baseline. These findings suggest that the intervention had been counterproductive since it led to an increase in dietary restraint. They imply that school-based prevention programs may do more harm than good.


Palliative care in the cardiac intensive care unit.
Patients admitted to today's cardiac intensive care units (CICUs) have increasingly complex medical conditions; consequently, palliative care is becoming an integral component of their care. Although there is a robust body of literature emanating from other intensive care unit settings, there has been less discussion about the role of palliative care in the CICU. This study examined all admissions to the Mount Sinai Hospital CICU from January 1 through December 31, 2012. Of the 1,368 patients admitted, there were 117 CICU patient deaths. End-of-life discussions were carried out in 85 patients (72.6%) who died during that hospital admission; the primary CICU team led these discussions and helped with decision making in >1/2 of them. For the 85 patients who had goals of care (GOC) discussions, there was a higher rate of redirected GOC toward comfort care or no escalation of care (38.8% vs 3.1%, p <0.001) and withdrawal of life-sustaining treatments, such as mechanical ventilation and vasopressors (23.5% vs 6.3%, p = 0.02) compared with patients for whom no GOC discussions were held. Among patients who had GOC discussions, there was no statistically significant difference for patients who had their mechanical circulatory support, defibrillator, or pacing therapies turned off compared with patients who were not involved in GOC discussions. With the exception of discontinuation of mechanical circulatory support which took place for 6 of the 7 patients in the CICU, end-of-life interventions were split evenly between the palliative care unit and the CICU. There was no difference in CICU length of stay or days to mortality from the time of CICU admission between the 2 groups. In conclusion, our study demonstrates the effect of palliative care and end-of-life decision making in the CICU. As such, we advocate for increased palliative care education and training among clinicians who are involved in cardiac critical care.


A prospective study of injuries and training amongst the England 2003 Rugby World Cup squad.
To assess the aetiology, incidence, severity, and causes of injuries to England rugby union players during preparation for and participation in the 2003 Rugby World Cup. A 63 week prospective design was employed to study the training practices and injuries of England rugby players. The team physician reported all training and match injuries and provided details of the location, diagnosis, severity, and mechanism of each injury. The team fitness coach reported details of the number and duration of training sessions and the time dedicated to rugby and conditioning training. Players' stature, body mass, and skinfolds were measured at the beginning and end of the study period. The overall incidence of injury was 17 injuries/1000 h of exposure (match: 218 injuries/1000 h; training: 6.1 injuries/1000 h). The major locations of injuries were the lower (60%) and upper (17%) limbs and the most common diagnoses were muscle and tendon (50%) and joint (non-bone) and ligament (41%) injuries. The highest incidences of match injuries occurred whilst being tackled (50 injuries/1000 h) and in a ruck or maul (35 injuries/1000 h), whilst the greatest incidences of training injuries occurred during endurance running (24 injuries/1000 h) and contact activities (20 injuries/1000 h). Players' average body mass increased and skinfold measurement decreased significantly over the study period. The incidence of match injuries at international level was found to be higher than previously reported. The tackle, ruck, and maul elements of match play and the endurance running and contact elements of training presented the highest risk of injury for all players.


Double-blind comparison of alprazolam and diazepam for subchronic withdrawal from alcohol.
The efficacy and safety of a new triazolobenzodiazepine, alprazolam, was compared to diazepam in 46 alcoholics in a double-blind study. The drugs were administered for 21 days starting on the fifth day after the last drink. The mean optimal daily oral dose of alprazolam was 2.2 mg and of diazepam 20.2 mg given in a t.i.d. fashion. Alprazolam was as effective as diazepam in the relief of anxiety as measured by the Hamilton Anxiety Rating Scale, Physician's Global Impressions, Patient's Global Impressions, Hopkins Symptom Checklist and Target Symptoms Record. At the end of the trial 95% of patients in both groups experienced moderate to marked therapeutic effect and felt much or very much better as compared to the start of the study. The number of side effects was similar in both groups and they were mostly described by patients as "mild".


In vivo, in vitro, and in silico studies suggest a conserved immune module that regulates malaria parasite transmission from mammals to mosquitoes.
Human malaria can be caused by the parasite Plasmodium falciparum that is transmitted by female Anopheles mosquitoes. "Immunological crosstalk" between the mammalian and anopheline hosts for Plasmodium functions to control parasite numbers. Key to this process is the mammalian cytokine transforming growth factor-β1 (TGF-β1). In mammals, TGF-β1 regulates inducible nitric oxide (NO) synthase (iNOS) both positively and negatively. In some settings, high levels of NO activate latent TGF-β1, which in turn suppresses iNOS expression. In the mosquito, ingested TGF-β1 induces A. stephensi NOS (AsNOS), which limits parasite development and which in turn is suppressed by activation of the mosquito homolog of the mitogen-activated protein kinases MEK and ERK. Computational models linking TGF-β1, AsNOS, and MEK/ERK were developed to provide insights into this complex biology. An initial Boolean model suggested that, as occurs in mammalian cells, MEK/ERK and AsNOS would oscillate upon ingestion of TGF-β1. An ordinary differential equation (ODE) model further supported the hypothesis of TGF-β1-induced multiphasic behavior of MEK/ERK and AsNOS. To achieve this multiphasic behavior, the ODE model was predicated on the presence of constant levels of TGF-β1 in the mosquito midgut. Ingested TGF-β1, however, did not exhibit this behavior. Accordingly, we hypothesized and experimentally verified that ingested TGF-β1 induces the expression of the endogenous mosquito TGF-β superfamily ligand As60A. Computational simulation of these complex, cross-species interactions suggested that TGF-β1 and NO-mediated induction of As60A expression together may act to maintain multiphasic AsNOS expression via MEK/ERK-dependent signaling. We hypothesize that multiphasic behavior as represented in this model allows the mosquito to balance the conflicting demands of parasite killing and metabolic homeostasis in the face of damaging inflammation.


Swallowing dysfunction in myotonic dystrophy: a retrospective study of symptomatology and radiographic findings.
Swallowing dysfunction is a common symptom of myotonic dystrophy, but it is poorly documented in large patient series. This retrospective study was designed to investigate the presence of swallowing symptoms in a large study population and to describe a specific pattern of clinical and radiographic abnormalities. A retrospective analysis was made of 169 files of patients with confirmed MD. Neuromuscular assessment was made by means of a standardised neurological examination; clinical swallowing symptoms were listed, and video-fluoroscopic images were analysed. More than half the patients reported swallowing complaints. The major symptoms were frequent choking, difficult pharyngeal transport and piecemeal deglutition. The pharyngeal phase of swallowing was most frequently compromised. This was shown radiographicaly in reduced pharyngeal peristalsis, hypopharyngeal stasis and fragmented swallowing. Aspiration was seen in half of the patients, mostly during swallowing. A typical 'hung position' of the hyoid was also seen. Different onset types of MD seem to be accompanied by comparable subjective complaints and radiographic symptoms. Pharyngeal transport was most affected in this patient population. Muscular weakness seems to be the major contributor to swallowing impairment in MD. Swallowing abnormalities may be present even if patients report only a few symptoms and even if the severity of the disease is not pronounced.


Comparison of the zygoma anchorage system with cervical headgear in buccal segment distalization.
This prospective study aimed to evaluate the effects of the zygoma anchorage system (ZAS) in buccal segment distalization in comparison with cervical headgear (CH). Thirty patients with Class II dental malocclusions were included in the study and were divided into two equal groups: the first group (10 females and 5 males, mean age 14.74 years at T1) received buccal segment distalization with ZAS and the second group (8 females and 7 males, mean age 15.26 years at T1) with CH. The skeletal, dental, and soft tissue changes were measured on cephalograms obtained before (T1) and after (T2) distalization, and these changes were statistically evaluated using a repeated measures analysis of variance, Mann-Whitney U-test, and Wilcoxon test. The Class II buccal segment relationship was corrected to a Class I in an average period of 9.03 +/- 0.62 months in the ZAS group and 9.00 +/- 0.76 months in the CH group. Significant distalization was observed for the posterior teeth in both groups (P < 0.001). Distal tipping of all posterior teeth occurred in the CH group (P < 0.001), but only for the molars in the ZAS group (P < 0.001). The upper incisors retroclined, overjet decreased, and the upper and lower lips retruded in both groups. The ZAS provided absolute anchorage for distalization of the maxillary posterior teeth and can be used as an aesthetic and non-compliant alternative to extraoral traction in the treatment of Class II malocclusions.


[Genetics of pancreatic cancer: recent advances in molecular diagnosis].
Pancreatic cancer is an important cause of death from cancer throughout the world. Until recently, pancreatic cancer was a poorly understood disease. Research in the past decade has shown conclusively, however, that pancreatic cancer is primarily genetic in nature. Inactivation with a variety of tumor-suppressor genes such as p53, p16, and DPC4, and genome-maintenance genes such as BRCA2, coupled with the activation of oncogenes such as K-ras, are a few of the mutations that trigger the growth of cancerous cells. The genetic profile of pancreatic cancer has reshaped the nomenclature describing histological progression in pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, whereas changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53 and DPC4 genes and activation of telomerase occur late in the neoplastic progression. Although the majority of pancreatic cancers occur sporadically, a minority has been shown to aggregate in families and has aided our understanding of pancreatic tumorigenesis. An improved understanding of the genetics of pancreatic cancer should lead to the development of gene-based screening tests and novel rational therapies.


Salivary nitrate, nitrite and N-nitroso compounds in patients with cancer of the upper aerodigestive tract.
N-nitroso compounds are carcinogens that can be ingested directly or synthesized from nitrites and nitrates. The possible role of N-nitroso compounds in the induction of upper aerodigestive tract tumours was considered in a case-control study conducted in the Valle d'Aosta, an Italian region with a high incidence of these neoplasms. Nitrate, nitrite, labile and stable N-nitroso compounds were analysed in the saliva of 36 patients with cancers of the upper aerodigestive tract and 23 healthy individuals. After allowing for tobacco, salivary nitrate, nitrite and N-nitroso compounds were not associated with an increased risk of upper aerodigestive tract cancers. The odds ratio for continuous units of total N-nitros compounds was 0.99 (95% confidence interval 0.9-1.1). Thus, salivary nitrate, nitrite and N-nitroso compounds might not be suitable markers for the assessment of the risk of cancer of the upper aerodigestive tract, although a role for N-nitroso compounds cannot be excluded.


Comparison of skin-to-skin (kangaroo) and traditional care: parenting outcomes and preterm infant development.
To examine whether the kangaroo care (KC) intervention in premature infants affects parent-child interactions and infant development. Seventy-three preterm infants who received KC in the neonatal intensive care unit were matched with 73 control infants who received standard incubator care for birth weight, gestational age (GA), medical severity, and demographics. At 37 weeks' GA, mother-infant interaction, maternal depression, and mother perceptions were examined. At 3 months' corrected age, infant temperament, maternal and paternal sensitivity, and the home environment (with the Home Observation for Measurement of the Environment [HOME]) were observed. At 6 months' corrected age, cognitive development was measured with the Bayley-II and mother-infant interaction was filmed. Seven clusters of outcomes were examined at 3 time periods: at 37 weeks' GA, mother-infant interaction and maternal perceptions; at 3-month, HOME mothers, HOME fathers, and infant temperament; at 6 months, cognitive development and mother-infant interaction. After KC, interactions were more positive at 37 weeks' GA: mothers showed more positive affect, touch, and adaptation to infant cues, and infants showed more alertness and less gaze aversion. Mothers reported less depression and perceived infants as less abnormal. At 3 months, mothers and fathers of KC infants were more sensitive and provided a better home environment. At 6 months, KC mothers were more sensitive and infants scored higher on the Bayley Mental Developmental Index (KC: mean: 96.39; controls: mean: 91.81) and the Psychomotor Developmental Index (KC: mean: 85.47; controls: mean: 80.53). KC had a significant positive impact on the infant's perceptual-cognitive and motor development and on the parenting process. We speculate that KC has both a direct impact on infant development by contributing to neurophysiological organization and an indirect effect by improving parental mood, perceptions, and interactive behavior.


Responsiveness of various reservoir species to oral rabies vaccination correlates with differences in vaccine uptake of mucosa associated lymphoid tissues.
Oral rabies vaccination (ORV) is highly effective in foxes and raccoon dogs, whereas for unknown reasons the efficacy of ORV in other reservoir species is less pronounced. To investigate possible variations in species-specific cell tropism and local replication of vaccine virus, different reservoir species including foxes, raccoon dogs, raccoons, mongooses, dogs and skunks were orally immunised with a highly attenuated, high-titred GFP-expressing rabies virus (RABV). Immunofluorescence and RT-qPCR screenings revealed clear differences among species suggesting host specific limitations to ORV. While for responsive species the palatine tonsils (tonsilla palatina) were identified as a main site of virus replication, less virus dissemination was observed in the tonsils of rather refractory species. While our comparison of vaccine virus tropism emphasizes the important role that the tonsilla palatina plays in eliciting an immune response to ORV, our data also indicate that other lymphoid tissues may have a more important role than originally anticipated. Overall, these data support a model in which the susceptibility to oral live RABV vaccine infection of lymphatic tissue is a major determinant in vaccination efficacy. The present results may help to direct future research for improving vaccine uptake and efficacy of oral rabies vaccines under field conditions.


[Pattern analysis of 5641 microcalcifications in 100 mammary duct carcinomas: polymorphism].
5641 micro-calcifications in 100 mammary duct carcinomas were magnified 20 times and then classified according to their shape. Four readily definable configurations were recognised: punctate, bean-shaped, linear and branching. In 95% of cases at least two of these configurations were identified next to each other within individual groups (polymorphy). Monomorphic punctate micro-calcifications occurred almost exclusively in the small papillary/cribriform carcinomas measuring a few millimetres. Larger examples of this type of carcinoma showed a polymorphic picture which was, however, dominated by punctate micro-calcifications. Comedo carcinomas showed linear and branching patterns. This phenomenon can be explained by the histological structure of these two ductal carcinomas.


Effect of latanoprost on the expression of matrix metalloproteinases and tissue inhibitor of metalloproteinase 1 on the ocular surface.
To investigate the effect of topical latanoprost on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase 1 (TIMP-1) on the ocular surface. Tears were collected from 39 patients with glaucoma who used latanoprost, 0.005%, eyedrops (Xalatan) and 28 healthy volunteers. The MMP-9 concentration was measured. Conjunctival epithelial cells were collected from 10 eyes of 10 patients before and 1 to 3 months after starting to take topical latanoprost, 0.005%, and MMP-1, MMP-9, and TIMP-1 messenger RNA (mRNA) expression was analyzed. Both eyes of 48 mice were treated once a day with latanoprost, 0.005%, timolol gel, 0.5%, eyedrops, vehicle of Xalatan, or phosphate-buffered saline, and MMP-9 and TIMP-1 mRNA expression was analyzed. The median MMP-9 concentration in latanoprost-treated cases was 91.2 ng/mL (in controls, 19.7 ng/mL; P < .001). In latanoprost-treated cases, the relative ratio of MMP-9 to glyceraldehyde 3-phosphate dehydrogenase mRNA was significantly increased from 6.42 to 21.3 (P = .04, paired t test) and the relative amount of TIMP-1 was significantly decreased from 154 to 105 (P = .009). The relative amount of MMP-1 to GAPDH mRNA before and after latanoprost use was not significantly different (P = .16). In mice, MMP-9 expression was increased and TIMP-1 expression was decreased on the ocular surface at 8 weeks after latanoprost use. The topical use of latanoprost increases MMP-1 and MMP-9 and decreases TIMP-1 on the ocular surface. The use of topical latanoprost might not be recommended in patients with keratoconus or after laser-assisted in situ keratomileusis.


[Mesenchymal chondrosarcoma. Anatomico-clinical, immunohistochemical and ultrastructural study. Apropos of a case].
One case of mesenchymal chondrosarcoma of the mandible is reported in a 18 years-old man. The patient noted swelling and pain and roentgenography showed an osteolytic lesion of the right mandible. Histologically, the feature was obvious with chondroid sheets of round ovoid or elongated cells. Immunohistochemically, numerous cells had positive S-100 protein and vimentin. The electron microscopy showed numerous undifferentiated cells and also fibroblastic and cartilaginous cells. The prognosis of this tumor, usually bad, cannot be yet appreciated in this case (follow-up of only 3 months). The histogenesis of this peculiar variety of chondrosarcoma is discussed.


Human papillomavirus vaccination in the prevention of cervical neoplasia.
Cervical cancer remains a major cause of morbidity and mortality for women worldwide. Although the introduction of comprehensive screening programs has reduced the disease incidence in developed countries, it remains a major problem in the developing world. The recent licensing of 2 vaccines against human papillomavirus (HPV) type 16 and HPV-18, the viruses responsible for 70% of cervical cancer cases, offers the hope of disease prevention. In this article, we review the role of HPV in the etiology of cervical cancer and the evidence to support the introduction of vaccination programs in young women and discuss the potential obstacles to widespread vaccination. In addition, we discuss the issues that remain to be elucidated, including the potential need for booster doses of the vaccine and the role of concomitant vaccination in men.


Increased Anxiety and Depression Symptoms in Post-Acute Care Patients with Stroke during the COVID-19 Pandemic.
This study aimed to explore the quality and stability of post-acute care for patients with stroke, including their functional outcomes, mental health and medical care in Taiwan during the COVID-19 pandemic. In this retrospective case-control study-based on propensity score matching-we assessed 11 patients admitted during the pandemic period (in 2021) and 11 patients admitted during the non-pandemic period (in 2020). Functional outcomes, including the scores of the modified Rankin Scale, Barthel Index, EuroQoL-5 Dimension, Lawton-Brody instrumental activities of daily living, Berg Balance Scale, 5-metre walking speed and 6-min walking distance, were determined. Data on the length of acute care, length of post-acute care, destination after discharge and 14-days readmission were used to evaluate the quality of medical care. The Wilcoxon signed-rank test was used to compare functional performance before and after rehabilitation. The pandemic group showed no significant improvement in the scores of EuroQoL-5 Dimension, a self-reported health status assessment (p = 0.13), with the anxiety or depression dimension showing a negative effect (r = 0.21). Post-acute care programmes can efficiently improve the functional performance of patients with stroke during the COVID-19 pandemic in Taiwan. Mental health should therefore be simultaneously maintained while rehabilitating physical function.


Modelling focused electron beam induced deposition beyond Langmuir adsorption.
In this work, the continuum model for focused electron beam induced deposition (FEBID) is generalized to account for multilayer adsorption processes. Two types of adsorption energies, describing both physisorption and spontaneous chemisorption, are included. Steady state solutions under no diffusion are investigated and compared under a wide range of conditions. The different growth regimes observed are fully explained by relative changes in FEBID characteristic frequencies. Additionally, we present a set of FEBID frequency maps where growth rate and surface coverage are plotted as a function of characteristic timescales. From the analysis of Langmuir, as well as homogeneous and heterogeneous multilayer maps, we infer that three types of growth regimes are possible for FEBID under no diffusion, resulting into four types of adsorption isotherms. We propose the use of these maps as a powerful tool for the analysis of FEBID processes.


Haemostasis with the FISH Vascular Closure Device after 6 French Transfemoral Accesses in Interventional Radiology: Clinical Results.
Endovascular procedures have increased for different indications over the recent years. To achieve a safe haemostasis after arterial puncture and for more comfort for the patients different vascular closure devices have been developed. To evaluate the effectiveness and safety of a percutaneous closure system based on a matrix patch for achieving haemostasis. In this study from 2014 to 2015 a percutaneous vascular closure system Femoral Introducer Sheath and Haemostasis (FISH) was used in 54 patients (mean age 69.0±10.7 years), in an antegrade and retrograde technique within the context of an angiographic intervention. The system was used in conjunction with transfemoral approaches with a sheath size of 6F. Postinterventionally (on the following day and after 6 weeks), follow-up was conducted clinically and using colour coded ultrasound. Immediate haemostasis was achieved in 50/54 patients (92.6 %). In 4 cases, an immediate haemostasis was not achieved. In these cases, manual compression was successful. There was one major complication, a retroperitoneal bleeding requiring transfusion. Minor complications were not observed. Safe and effective haemostasis is possible with the percutaneous FISH closure system at puncture sizes of 6 F. An immediate re-puncture after using FISH is possible.


Osteocytic osteolysis in a cretaceous reptile.
Bone resorption through osteocytic activity already recognized in all classes of Vertebrates, has been demonstrated in fragments of long bones from a non-identified reptile found in an Upper Cretaceous rock formation in Dinosaur National Park, Patricia, Alberta.


Treatment of Kaposi's sarcoma after solid organ transplantation.
This retrospective review of all patients who developed Kaposi's sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.


[The nervous system function of patients with periodontitis].
Analysis of the function of the nervous system, based on clinical, neurological, and psychological studies in 78 patients with generalized periodontitis, revealed central regulation disorders without signs of organic lesions of the brain in 76% patients. The authors claim that stress and a high level of personal anxiety may be responsible for the development of these disorders, which was confirmed by the results of psychological testing.


Benign mucocele-like lesion of the breast: how to differentiate from mucinous carcinoma before surgery.
The aim of the study was to improve the pre-operative diagnosis of mammary mucinous lesions. All mucinous lesions detected by fine needle aspiration (FNA) and confirmed by histological examination were reviewed by cytological findings, mammographic appearances and sonographic findings. Twenty aspirates had corresponding pathology, including 12 mucinous carcinomas, two mucocele-like lesions (MLL) with atypical ductal hyperplasia, three MLL with ductal hyperplasia and three simple MLL. Simple MLL and mucocele-like with ductal hyperplasia showed scant cellularity, no or rare intact single tumour cells, monolayered arrangement and absence of nuclear atypia. In contrast, most mucinous carcinomas showed higher cellularity, more single tumour cells, three-dimensional clusters, and mild to marked nuclear atypia. However, MLL with atypical ductal hyperplasia showed cytological features overlapping with mucinous carcinoma. MLL had a non-specific mammographic appearance and showed a cystic lesion on sonography. Mucinous carcinoma appeared as a solid mass on sonography and as a distinct nodule on mammography. Based on the combination of FNA cytology and image findings, benign MLL can be correctly distinguished from mucinous carcinoma before surgery.


Dinosaurs on the north slope, alaska: high latitude, latest cretaceous environments.
Abundant skeletal remains demonstrate that lambeosaurine hadrosaurid, tyrannosaurid, and troodontid dinosaurs lived on the Alaskan North Slope during late Campanian-early Maestrichtian time (about 66 to 76 million years ago) in a deltaic environment dominated by herbaceous vegetation. The high ground terrestrial plant community was a mild- to cold-temperate forest composed of coniferous and broad leaf trees. The high paleolatitude (about 70 degrees to 85 degrees North) implies extreme seasonal variation in solar insolation, temperature, and herbivore food supply. Great distances of migration to contemporaneous evergreen floras and the presence of both juvenile and adult hadrosaurs suggest that they remained at high latitudes year-round. This challenges the hypothesis that short-term periods of darkness and temperature decrease resulting from a bolide impact caused dinosaurian extinction.


Expression of cell kinetics and death during monocyte-macrophage differentiation: effects of Actinomycin D and Vinblastine treatments.
The different effects of two cytostatic drugs, Actinomycin D and Vinblastine, during macrophage-like differentiation induced in THP-1 monocytic cell line by phorbol ester phorbol 12-myristate 13-acetate (PMA) (6, 30, and 60 nM), were studied by morpho-cytochemical approaches. In PMA-unstimulated monocytic cells, the cytostatic effects of Actinomycin D (an antimetabolic drug) were characterized by a drastic reduction of the G2/M cells accompanied by dramatic death of the G1 cells; on the contrary, Vinblastine (a microtubule-depolymerizating drug) induced an accumulation of the G2/M cells with the appearance of aneugenic micronuclei and scarce cell death mainly from the G1 cells. After 60 nM PMA stimulation, the culture was mostly composed by macrophagic cells characterized by low proliferation and the appearance of mono-/binucleated polyploid cells; in this condition, the cytotoxicity of the two drugs, more effective for Vinblastine, induced cell death in the different ploidy classes (2c, 4c, 8c). Cell death appeared to be of apoptotic nature, but with some morpho-phenotypic differences due to the action mechanism of the drugs and dependent on cell culture growth and differentiation. As a consequence of the different block-action of the two drugs on the cell cycle phases and in relation to the different subcellular targets, the effects changed during the transition from not-adhering/proliferating monocytes to adhering/low-proliferating differentiated macrophages.


Role of histone deacetylase 1 in distant metastasis of pancreatic ductal cancer.
Current therapies for pancreatic ductal cancer (PDAC) do not sufficiently control distant metastasis. Thus, new therapeutic targets are urgently needed. Numerous studies have suggested that the epithelial-mesenchymal transition (EMT) is pivotal for metastasis of carcinomas. The fact that the EMT is reversible suggests the possibility that it is induced by an epigenetic mechanism. In this study, we aimed to investigate the role of histone deacetylase 1 (HDAC1), which is an epigenetic mechanism on distant metastasis of PDAC. We investigated the HDAC1 expression in 103 resected PDAC specimens obtained from patients who were treated with/without preoperative therapy using immunohistochemistry. To validate the findings in the clinical samples, we evaluated the HDAC1 activity, the EMT-associated genes and the migration/invasion ability in vitro, and performed an HDAC1 inhibitor assay. The high expression of HDAC1 in clinical samples was significantly associated with poor progression-free survival, especially distant metastasis-free survival. In vitro, HDAC1 inhibitors decreased the invasion ability and reversed the EMT change; the only factor to show a concomitant decrease was the expression of SNAIL. We confirmed that the HDAC1 expression was associated with the SNAIL expression in clinical samples. Moreover, the resistant cells and parental cells did not show any significant differences in the expression of HDAC1; this was consistent with the finding that preoperative therapy did not alter the HDAC1 expression in clinical samples. The targeting of HDAC1, which could suppress metastasis by inhibiting the EMT, is a promising treatment option for PDAC.


Thermosipho affectus sp. nov., a thermophilic, anaerobic, cellulolytic bacterium isolated from a Mid-Atlantic Ridge hydrothermal vent.
A novel obligately anaerobic, extremely thermophilic, organotrophic bacterium, strain ik275mar(T), was isolated from a Mid-Atlantic Ridge deep-sea hydrothermal vent. Cells were rods surrounded by a sheath-like structure (toga), 0.4-0.9 µm in width and 1.2-6.0 µm in length. Strain ik275mar(T) grew at 37-75 °C, pH 5.6-8.2 and at NaCl concentrations of 10-55 g l(-1). Under optimum conditions (70 °C, pH 6.6, NaCl 20 g l(-1)), doubling time was 32 min. The isolate was able to ferment carbohydrates including starch, cellulose and cellulose derivatives. Acetate, H(2) and CO(2) were the main products of glucose fermentation. G+C content of DNA was 27 mol%. Phylogenetic analysis of 16S rRNA gene sequences showed that strain ik275mar(T) is a member of the genus Thermosipho. 16S rRNA gene sequence identity with the other species of the genus Thermosipho ranged from 93.7 to 94.5 %. Based on the phylogenetic analysis and physiological properties of the novel isolate, we propose a novel species, Thermosipho affectus sp. nov., with type strain ik275mar(T) ( = DSM 23112(T) = VKM B-2574(T)).


Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
Certain changes in TCR contact residues have been shown to have profound effects on the capacity of a peptide Ag to stimulate a T cell response. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial agonist activity (e.g., cytokine production without proliferation) or antagonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was associated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation of low molecular mass TCRzeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those previously described for partial agonists. Thus, a partial agonist phenotype such as anergy induction cannot be ascribed in a causal manner to this pattern of tyrosine phosphorylation. We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCRzeta isoforms and differential phosphorylation of p120 proto-oncogene c-Cbl. Another early event following TCR engagement by Ag, down-modulation of the TCR, was studied with antagonist peptides. We show that antagonist peptides do not cause TCR down-modulation. This failure may represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.


LAMP2 microdeletions in patients with Danon disease.
Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated. We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5'-untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)(n) simple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2. This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.


Precision Medicine in Myeloma: Challenges in Defining an Actionable Approach.
Recently, large sequencing studies have provided insights into the mutational landscape of multiple myeloma (MM), identifying actionable mutations and giving a precious opportunity for exploring new targeted therapies. The main goal of precision medicine, matching patients with the right drug, seems to be closer than ever. However, no targeted therapies in MM are approved yet. Several clinical trials testing targeted drugs and enrolling patients with MM are currently ongoing and will provide predictive biomarkers that might support clinical decision making. In this review, we evaluate the evidence supporting the implementation of precision medicine in MM and we discuss the challenges that should be dealt with in this imminent and promising new era.


Microtubule-severing ATPase spastin in glioblastoma: increased expression in human glioblastoma cell lines and inverse roles in cell motility and proliferation.
We studied the expression and distribution of the microtubule-severing enzyme spastin in 3 human glioblastoma cell lines (U87MG, U138MG, and T98G) and in clinical tissue samples representative of all grades of diffuse astrocytic gliomas (n = 45). In adult human brains, spastin was distributed predominantly in neuronsand neuropil puncta and, to a lesser extent, in glia. Compared with normal mature brain tissues, spastin expression and cellular distribution were increased in neoplastic glial phenotypes, especiallyin glioblastoma (p < 0.05 vs low-grade diffuse astrocytomas). Overlapping punctate and diffuse patterns of localization wereidentified in tumor cells in tissues and in interphase and mitotic cells ofglioblastoma cell lines. There was enrichment of spastin in the leading edges of cells in T98G glioblastoma cell cultures and in neoplastic cell populations in tumor specimens. Real-time polymerase chain reaction and immunoblotting experiments revealed greater levels of spastin messenger RNA and protein expression in theglioblastoma cell lines versus normal human astrocytes. Functional experiments indicated that spastin depletion resulted in reduced cell motility and higher cell proliferation of T98G cells. Toour knowledge, this is the first report of spastin involvement incellmotility. Collectively, our results indicate that spastinexpression in glioblastomas might be linked to tumor cell motility, migration, and invasion.


Assessment of antimicrobial use and prescribing practices among pediatric inpatients in Zimbabwe.
This study aims to assess antimicrobial consumption in the pediatric department of a tertiary care public hospital in Zimbabwe. Clinical records of pediatric inpatients admitted to Harare Central Hospital over a 3-week period were reviewed prospectively. Antimicrobial consumption was described as days of therapy per 100 inpatient days (DOT/100 PD). Adherence of antimicrobial drug prescriptions to the National Guidelines was also evaluated. A total of 121 (93.1%) children were prescribed at least one antimicrobial out of 130 children admitted. The median age was 14 months (IQR: 3 - 48 months). Overall antimicrobial consumption was 155.4 DOT/100 PD (95% CI 146-165.2). The most frequently prescribed antimicrobials were benzylpenicillin, gentamicin and ceftriaxone. Prescriptions were adherent to national guidelines in 57.7% of children. This study shows that there is high antimicrobial drug usage in hospitalized children in Zimbabwe and a considerable proportion of prescriptions are non-adherent with national guidelines.


Comparison of metal bioaccumulation in crop types and consumable parts between two growth periods.
A high proportion of populations in most developing countries live below the poverty line and those near refuse grounds resort to dumpsite farming to grow food. Consequently, high levels of waste-derived contaminants are found in crops consumed by these people. This study investigates the extent to which crops cultivated on the Mbale dumpsite (Uganda) were contaminated by 11 metals and 2 non-metals: iron (Fe), aluminum (Al), zinc (Zn), manganese (Mn), copper (Cu), mercury (Hg), lead (Pb), nickel (Ni), cobalt (Co), cadmium (Cd), selenium (Se), chromium (Cr), and arsenic (As). We investigated how element bioaccumulation in crops was influenced by the growth period (short- and long-term crop maturity). The short-term crops were Zea mays and Amaranthus cruentus, whereas the long-term crops were Manihot esculenta, Colocasia esculenta, Musa acuminata, Carica papaya, Coffea arabica, and Saccharum officinarum. Results showed that nine metals were present at concentrations above World Health Organization/Food and Agriculture Organization (WHO/FAO) food safety recommendations and hence may pose health risks to consumers. In this study, leaves contained higher metal concentrations than other analyzed consumable parts. Pb and Co were found at higher concentrations in leaves of short-term crops than in long-term crops. Among short-term crops, only Z. mays seeds contained permissible metal concentrations by WHO/FAO standards. The growth period was also found to influence metal bioaccumulation in crop types. Pb, Co, Fe, Al, and Cu concentrations were significantly higher in the short-term crops than in long-term crops, while Mn, Ni, and Cr concentrations were higher in long-term crops than in short-term crops. Overall, public awareness about the health risks associated with consuming short-term leafy crops grown on dumpsites should be improved to reduce toxic metal exposure. While implementing such a campaign, the food supply of individuals whose survival depends on such crops should not be jeopardized. Therefore, farmers need alternative farming areas outside dumpsites. Integr Environ Assess Manag 2022;18:1056-1071. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Surgical management of neglected bilateral obligatory patella dislocation.
Congenital dislocation of the patella may present as an isolated anomaly or may be associated with other lower limb deformities as part of a more complex malformative or dystrophic syndrome. One type is the congenitally dislocated patella fixed irreducibly from birth in a lateral position, and second is the obligatory patella dislocation that is hypoplastic to start with and gradually gets fixed into the lateral position as the child grows. We report the surgical management of a 16-year-old boy with neglected obligatory dislocation of bilateral patellae with 2-year follow-up results.


Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides.
In Drosophila, neurosecretory cells that release peptide hormones play a prominent role in the regulation of development, growth, metabolism, and reproduction. Several types of peptidergic neurosecretory cells have been identified in the brain of Drosophila with release sites in the corpora cardiaca and anterior aorta. We show here that in adult flies the products of three neuropeptide precursors are colocalized in five pairs of large protocerebral neurosecretory cells in two clusters (designated ipc-1 and ipc-2a): Drosophila tachykinin (DTK), short neuropeptide F (sNPF) and ion transport peptide (ITP). These peptides were detected by immunocytochemistry in combination with GFP expression driven by the enhancer trap Gal4 lines c929 and Kurs-6, both of which are expressed in ipc-1 and 2a cells. This mix of colocalized peptides with seemingly unrelated functions is intriguing and prompted us to initiate analysis of the function of the ten neurosecretory cells. We investigated the role of peptide signaling from large ipc-1 and 2a cells in stress responses by monitoring the effect of starvation and desiccation in flies with levels of DTK or sNPF diminished by RNA interference. Using the Gal4-UAS system we targeted the peptide knockdown specifically to ipc-1 and 2a cells with the c929 and Kurs-6 drivers. Flies with reduced DTK or sNPF levels in these cells displayed decreased survival time at desiccation and starvation, as well as increased water loss at desiccation. Our data suggest that homeostasis during metabolic stress requires intact peptide signaling by ipc-1 and 2a neurosecretory cells.


Identification and characterization of an Xq26-q27 duplication in a family with spina bifida and panhypopituitarism suggests the involvement of two distinct genes.
We investigated a family with a duplication, dup(X)q26-q27, that was present in two brothers, their mother, and their maternal grandmother. The brothers carrying the duplication displayed spina bifida and panhypopituitarism, whereas a third healthy brother inherited the normal X chromosome. Preferential inactivation of the X chromosome containing the duplication was evident in healthy carrier females. We determined the boundaries of the Xq26-q27 duplication. Via interphase FISH analysis we narrowed down each of the two breakpoint regions to approximately 300-kb intervals. The proximal breakpoint is located in Xq26.1 between DXS1114 and HPRT and is contained in YAC yWXD599, while the distal breakpoint is located in Xq27.3 between DXS369 and DXS1200 and contained in YAC yWXD758. The duplication comprises about 13 Mb. Evidence from the literature points to a predisposing gene for spina bifida in Xq27. We hypothesize that the spina bifida in the two brothers may be due to interruption of a critical gene in the Xq27 breakpoint region. Several candidate genes were mapped to the Xq27 critical region but none was shown to be disrupted by the duplication event. Recently, M. Lagerström-Fermér et al. (1997, Am. J. Hum. Genet. 60, 910-916) reported on a family with X-linked recessive panhypopituitarism associated with a duplication in Xq26; however, no details were reported on the extent of the duplication. Our study corroborates their hypothesis that X-linked recessive panhypopituitarism is likely to be caused by a gene encoding a dosage-sensitive protein involved in pituitary development. We place the putative gene between DXS1114 and DXS1200, corresponding to the interval defined by the duplication in the present family.


Latitudinal countergradient variation in the common frog (Rana temporaria) development rates--evidence for local adaptation.
Adaptive genetic differentiation along a climatic gradient as a response to natural selection is not necessarily expressed at phenotypic level if environmental effects on population mean phenotypes oppose the genotypic effects. This form of cryptic evolution--called countergradient variation--has seldom been explicitly demonstrated for terrestrial vertebrates. We investigated the patterns of phenotypic and genotypic differentiation in developmental rates of common frogs (Rana temporaria) along a ca. 1600 km latitudinal gradient across Scandinavia. Developmental rates in the field were not latitudinally ordered, but displayed large variation even among different ponds within a given latitudinal area. In contrast, development rates assessed in the laboratory increased strongly and linearly with increasing latitude, suggesting a genetic capacity for faster development in the northern than the southern larvae. Experiments further revealed that environmental effects (temperature and food) could easily override the genetic effects on developmental rates, providing a possible mechanistic explanation as to why the genetic differentiation was not seen in the samples collected from the wild. Our results suggest that the higher developmental rates of the northern larvae are likely to be related to selection stemming from seasonal time constrains, rather than from selection dictated by low ambient temperatures per se. All in all, the results provide a demonstration of environmental effects concealing substantial latitudinally ordered genetic differentiation understandable in terms of adaptation to clinal variation in time constrains.


Clinical utility of a screening protocol for blunt cerebrovascular injury using computed tomography angiography.
OBJECTIVE Blunt cerebrovascular injury (BCVI) occurs in approximately 1% of the blunt trauma population and may lead to stroke and death. Early vascular imaging in asymptomatic patients at high risk of having BCVI may lead to earlier diagnosis and possible stroke prevention. The objective of this study was to determine if the implementation of a formalized asymptomatic BCVI screening protocol with CT angiography (CTA) would lead to improved BCVI detection and stroke prevention. METHODS Patients with vascular imaging studies were identified from a prospective trauma registry at a single Level 1 trauma center between 2002 and 2008. Detection of BCVI and stroke rates were compared during the 3-year periods before and after implementation of a consensus-based asymptomatic BCVI screening protocol using CTA in 2005. RESULTS A total of 5480 patients with trauma were identified. The overall BCVI detection rate remained unchanged postprotocol compared with preprotocol (0.8% [24 of 3049 patients] vs 0.9% [23 of 2431 patients]; p = 0.53). However, postprotocol there was a trend toward a decreased risk of stroke secondary to BCVI on a trauma population basis (0.23% [7 of 3049 patients] vs 0.53% [13 of 2431 patients]; p = 0.06). Overall, 75% (35 of 47) of patients with BCVI were treated with antiplatelet agents, but no patient developed new or progressive intracranial hemorrhage despite 70% of these patients having concomitant traumatic brain injury. CONCLUSIONS The results of this study suggest that a CTA screening protocol for BCVI may be of clinical benefit with possible reduction in ischemic complications. The treatment of BCVI with antiplatelet agents appears to be safe.


Solvation of dried dentin matrix by water and other polar solvents.
To develop a simple method for measuring the degree of solvation of dried, demineralized dentin matrix by water and other polar solvents. The null hypothesis was that there are no differences in expansion forces produced by different polar solvents. Midcoronal dentin discs were prepared from extracted, unerupted human third molars. The discs were cut into square specimens with surface areas of 2 x 2, 3 x 3 and 4 x 4 mm and thicknesses of 0.5, 1.0 and 1.5 mm. After demineralization in 0.5 M EDTA (pH 7), the dimensions of the specimens were measured both wet and dry. Dry specimens were held between two parallel steel plates connected to a 50 N load cell which measured the solvation force when water or other polar solvents were added. After measuring the expansion force induced by water, the specimens were fixed in glutaraldehyde and the trials repeated. On additional specimens, repeated measures of expansion forces were obtained using water, methanol, ethanol, n-propanol, n-butanol, ethylene glycol, formamide, hydroxyethylmethacrylate, N,N-dimethyl formamide and acetone in unfixed specimens. Water produced hydration forces as high as 204 g before, and 428 g after glutaraldehyde treatment. The hydration force correlated better with specimen thickness than with surface area. Water solvated the matrix faster than methanol > ethanol > formamide > ethylene glycol. Hydroxyethylmethacrylate, N,N-dimethyl formamide and acetone were unable to solvate the dried matrix. Regression analysis of solvation force vs. Hansen's solubility parameters for dispersive, polar and hydrogen bonding forces demonstrated that solvation force correlations were highest with hydrogen bonding solubility parameters. Measurements of solvation forces provides a simple method for determining solvent-collagen matrix interactions.


Factors contributing to medication errors: a literature review.
Drug administration is an integral part of the nurse's role. Responsibility for correct administration of medication rests with the nurse, yet medication errors are a persistent problem associated with nursing practice. This review examines what constitutes a medication error and documents contributory factors in medication errors. These factors have been derived from reported medication errors and opinions of nurses as to factors which predispose to errors. A number of definitions exist as to what constitutes a medication error. The definition used should facilitate interpretation and comparison of a wide range of research reports. Medication errors are a multidisciplinary problem and a multidisciplinary approach is required in order to reduce the incidence of errors.


Optimization and Evaluation of a Multiplex Quantitative PCR Assay for Detection of Nucleic Acids in Human Blood Samples from Patients with Spotted Fever Rickettsiosis, Typhus Rickettsiosis, Scrub Typhus, Monocytic Ehrlichiosis, and Granulocytic Anaplasmosis.
Spotted fever group rickettsioses (SFGR), typhus group rickettsioses (TGR), scrub typhus (caused by Orientia tsutsugamushi), ehrlichiosis, and anaplasmosis often present as undifferentiated fever but are not treated by agents (penicillins and cephalosporins) typically used for acute febrile illness. Inability to diagnose these infections when the patient is acutely ill leads to excess morbidity and mortality. Failure to confirm these infections retrospectively if a convalescent blood sample is not obtained also impairs epidemiologic and clinical research. We designed a multiplex real-time quantitative PCR (qPCR) assay to detect SFGR, TGR, O. tsutsugamushi, and infections caused by Anaplasma phagocytophilum and Ehrlichia chaffeensis with the ompA, 17-kDa surface antigen gene, tsa56, msp2 (p44), and vlpt gene targets, respectively. Analytical sensitivity was ≥2 copies/μl (linear range, 2 to 2 × 105) and specificity was 100%. Clinical sensitivities for SFGR, TGR, and O. tsutsugamushi were 25%, 20%, and 27%, respectively, and specificities were 98%, 99%, and 100%, respectively. Clinical sensitivities for A. phagocytophilum and E. chaffeensis were 93% and 84%, respectively, and specificities were 99% and 98%, respectively. This multiplex qPCR assay could support early clinical diagnosis and treatment, confirm acute infections in the absence of a convalescent-phase serum sample, and provide the high-throughput testing required to support large clinical and epidemiologic studies. Because replication of SFGR and TGR in endothelial cells results in very low bacteremia, optimal sensitivity of qPCR for these rickettsioses will require use of larger volumes of input DNA, which could be achieved by improved extraction of DNA from blood and/or extraction of DNA from a larger initial volume of blood.


HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1.
RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-κB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-κB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKε) after viral infection and impaired the association between TRAF3 and IKKε, which further decreased the phosphorylation of IKKε and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-β transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity.


Management of Arteriovenous Malformations Associated with Developmental Venous Anomalies: A Literature Review and Report of 2 Cases.
Classification of cerebrovascular malformations has revealed intermediary lesions that warrant further review owing to their unusual presentation and management. We present 2 cases of arteriovenous malformation (AVM) associated with a developmental venous anomaly (DVA), and discuss the efficacy of previously published management strategies. Two cases of AVMs associated with DVA were identified, and a literature search for published cases between 1980 and 2016 was conducted. Patient demographic data and clinical features were documented. In case 1, a 29-year-old female presenting with parenchymal hemorrhage and left homonymous hemianopia was found to have a right parieto-occipital AVM fed from the anterior cerebral, middle cerebral, and posterior cerebral arteries, with major venous drainage to the superior sagittal sinus. In case 2, imaging in a 34-year-old female evaluated for night tremors and incontinence revealed a left parietal AVM with venous drainage to the superior sagittal sinus. Including our 2 cases, 22 cases of coexisting AVMs and DVAs have been reported in the literature. At presentation, 68% had radiographic evidence of hemorrhage. Stereotactic radiosurgery was performed in 7 cases, embolization in 6 cases, surgical resection in 4 cases, and multimodal therapy in 5 cases. Radiography at follow-up demonstrated successful AVM obliteration in 67% of cases (12 of 18). Patients with coexisting AVMs and DVAs tend to have a hemorrhagic presentation. Contrary to traditional AVM management, in these cases it is important to preserve the draining vein via the DVA to ensure a safe, sustained circulatory outflow of the associated brain parenchyma while achieving safe AVM obliteration.


Method for measuring the threshold value of stimulated Brillouin scattering in water.
A new method for accurate measurement of the threshold value of stimulated Brillouin scattering (SBS) in water in terms of pump laser intensity is investigated. The threshold value of SBS is determined by the point of the deviation of the value of the attenuation coefficients of wide- and narrow-linewidth lasers rather than the intensity of the backscattered SBS signal in the material.


Knowledge of AIDS and self-efficacy to high-risk sexual practices among Lebanese males in New York.
The relationship of AIDS knowledge and self-efficacy to high-risk sexual practices among Lebanese males in NewYork was examined. Self-administered questionnaires were completed by a convenience sample. Relationships between AIDS-knowledge and self-efficacy and high-risk sexual practices for the 25 homosexual men were rarely significant, probably because of the small sample. The 261 heterosexual participants had statistically significant relationships between AIDS-knowledge and 9 high-risk sexual practices and between self-efficacy and 18 high-risk sexual practices. For heterosexuals, and to a lesser degree for homosexuals, high-risk sexual practices increased as drug-related behaviours and sex with prostitutes increased.


PM2.5 chemical composition and health risks by inhalation near a chemical complex.
Particulate matter (PM2.5) samples were collected in the vicinity of an industrial chemical pole and analysed for organic and elemental carbon (OC and EC), 47 trace elements and around 150 organic constituents. On average, OC and EC accounted for 25.2% and 11.4% of the PM2.5 mass, respectively. Organic compounds comprised polycyclic aromatic hydrocarbons (PAHs), alkylated PAHs, anhydrosugars, phenolics, aromatic ketones, glycerol derivatives, aliphatic alcohols, sterols, and carboxyl groups, including aromatic, carboxylic and dicarboxylic acids. Enrichment factors > 100 were obtained for Pb, Cd, Zn, Cu, Sn, B, Se, Bi, Sb and Mo, showing the contribution of industrial emissions and nearby major roads. Principal component analysis revealed that vehicle, industrial and biomass burning emissions accounted for 66%, 11% and 9%, respectively, of the total PM2.5-bound PAHs. Some of the detected organic constituents are likely associated with plasticiser ingredients and thermal stabilisers used in the manufacture of PVC and other plastics in the industrial complex. Photooxidation products of both anthropogenic (e.g., toluene) and biogenic (e.g., isoprene and pinenes) precursors were also observed. It was estimated that biomass burning accounted for 13.8% of the PM2.5 concentrations and that secondary OC represented 37.6% of the total OC. The lifetime cancer risk from inhalation exposure to PM2.5-bound PAHs was found to be negligible, but it exceeded the threshold of 10-6 for metal(loi)s, mainly due to Cr and As.


Pay-it-forward influenza vaccination among older adults and children: A cost-effectiveness analysis in China.
A quasi-experimental study was conducted to evaluate the effectiveness of a pay-it-forward strategy for increasing influenza vaccination among children and older adults compared to a self-paid vaccination strategy in China. Pay-it-forward is an innovative community-engaged intervention in which participants receive a free influenza vaccination and are then asked if they would like to donate or create a message to support subsequent vaccinations. This economic evaluation used a decision-tree model to compare pay-it-forward to a standard of care arm in which patients had to pay for their own influenza vaccine. The analysis was performed from the healthcare provider perspective and costs were calculated with 2020 United States dollars. The time horizon was one year. In the base case analysis, pay-it-forward was more effective (111 vs 55 people vaccinated) but more costly than standard-of-care ($4477 vs $2725). Pay-it-forward spurred 96.4% (107/111) of individuals to voluntarily donate to support influenza vaccination for high-risk groups in China. Further costing and implementation research is needed to inform scale up.


Cyclin D- and E-dependent kinases and the p57(KIP2) inhibitor: cooperative interactions in vivo.
This study examines in vivo the role and functional interrelationships of components regulating exit from the G1 resting phase into the DNA synthetic (S) phase of the cell cycle. Our approach made use of several key experimental attributes of the developing mouse lens, namely its strong dependence on pRb in maintenance of the postmitotic state, the down-regulation of cyclins D and E and up-regulation of the p57(KIP2) inhibitor in the postmitotic lens fiber cell compartment, and the ability to target transgene expression to this compartment. These attributes provide an ideal in vivo context in which to examine the consequences of forced cyclin expression and/or of loss of p57(KIP2) inhibitor function in a cellular compartment that permits an accurate quantitation of cellular proliferation and apoptosis rates in situ. Here, we demonstrate that, despite substantial overlap in cyclin transgene expression levels, D-type and E cyclins exhibited clear functional differences in promoting entry into S phase. In general, forced expression of the D-type cyclins was more efficient than cyclin E in driving lens fiber cells into S phase. In the case of cyclins D1 and D2, ectopic proliferation required their enhanced nuclear localization through CDK4 coexpression. High nuclear levels of cyclin E and CDK2, while not sufficient to promote efficient exit from G1, did act synergistically with ectopic cyclin D/CDK4. The functional differences between D-type and E cyclins was most evident in the p57(KIP2)-deficient lens wherein cyclin D overexpression induced a rate of proliferation equivalent to that of the pRb null lens, while overexpression of cyclin E did not increase the rate of proliferation over that induced by the loss of p57(KIP2) function. These in vivo analyses provide strong biological support for the prevailing view that the antecedent actions of cyclin D/CDK4 act cooperatively with cyclin E/CDK2 and antagonistically with p57(KIP2) to regulate the G1/S transition in a cell type highly dependent upon pRb.


A Modular Implementation for the Simulation of 1D and 2D Solid-State NMR Spectra of Quadrupolar Nuclei in the Virtual Multifrequency Spectrometer-Draw Graphical Interface.
We present the implementation of the solid state (SoS)NMR module for the simulation of several 1D and 2D NMR spectra of all the elements in the periodic table in the virtual multifrequency spectrometer (VMS). This module is fully integrated with the graphical user interface of VMS (VMS-Draw) [Licari et al., J. Comput. Chem. 36, 2015, 321-334], a freeware tool which allows a user-friendly handling of structures and analyses of advanced spectroscopical properties of chemical compounds-from model systems to real-world applications. Besides the numerous modules already available in VMS for the study of electronic, optical, vibrational, vibronic, and EPR properties, here the simulation of NMR spectra is presented with a particular emphasis on those techniques usually employed to investigate solid state systems. The SoSNMR module benefits from its ability to work under both periodic and nonperiodic conditions, such that small molecules/molecular clusters can be treated, as well as extended three-dimensional systems enforcing (or not) translational periodicity. These features allow VMS to simulate spectra resulting from NMR calculations by some popular quantum chemistry codes, namely Gaussian09/16, Castep, and Quantum Espresso. The effectiveness of the SoSNMR module of VMS is examined throughout the manuscript, and applied to simulate 1D static, MAS, and VAS NMR spectra as well as 2D correlation (90°, MAS) and MQMAS spectra of active NMR nuclei embedded in different amorphous and crystalline systems of actual interest in chemistry and material science. Finally, the program is able to simulate the spectra of both the total ensemble of spin-active nuclei present in the system and of subensembles differentiated depending on the chemical environment of the first and second coordination sphere in a very general way applicable to any kind of systems.


Failure strength of human vertebrae: prediction using bone mineral density measured by DXA and bone volume by micro-CT.
Significant relationships exist between areal bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) and bone strength. However, the predictive validity of BMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA in the lumbar spine may be improved by assessing BMD from lateral-projection scans, as these might better approximate the objective of measuring the trabecular-rich bone in the vertebral body, compared to the commonly-used posterior-anterior (PA) projections. Nowadays, X-ray micro-computed tomography (μCT) allows non-destructive three-dimensional structural characterization of entire bone segments at high resolution. In this study, human lumbar cadaver spines were examined ex situ by DXA in lateral and PA projections, as well as by μCT, with the aims (1) to investigate the ability of bone quantity measurements obtained by DXA in the lateral projection and in the PA projection, to predict variations in bone quantity measurements obtained by μCT, and (2) to assess their respective capabilities to predict whole vertebral body strength, determined experimentally. Human cadaver spines were scanned by DXA in PA projections and lateral projections. Bone mineral content (BMC) and BMD for L2 and L3 vertebrae were determined. The L2 and L3 vertebrae were then dissected and entirely scanned by μCT. Total bone volume (BV(tot)=cortical+trabecular), trabecular bone volume (BV), and trabecular bone volume fraction (BV/TV) were calculated over the entire vertebrae. The vertebral bodies were then mechanically tested to failure in compression, to determine ultimate load. The variables BV(tot), BV, and BV/TV measured by μCT were better predicted by BMC and BMD measured by lateral-projection DXA, with higher R(2) values and smaller standard errors of the estimate (R(2)=0.65-0.90, SEE=11%-18%), compared to PA-projection DXA (R(2)=0.33-0.53, SEE=22%-34%). The best predictors of ultimate load were BV(tot) and BV assessed by μCT (R(2)=0.88 and R(2)=0.81, respectively), and BMC and BMD from lateral-projection DXA (R(2)=0.82 and R(2)=0.70, respectively). Conversely, BMC and BMD from PA-projection DXA were lower predictors of ultimate load (R(2)=0.49 and R(2)=0.37, respectively). This ex vivo study highlights greater capabilities of lateral-projection DXA to predict variations in vertebral body bone quantity as measured by μCT, and to predict vertebral strength as assessed experimentally, compared to PA-projection DXA. This provides basis for further exploring the clinical application of lateral-projection DXA analysis.


Synthetic vaccines: the role of adjuvants in immune targeting.
A clear understanding of the mechanism of function of immune stimulatory adjuvants, which commonly accompany vaccines, is beginning to emerge. Recent investigations have demonstrated that Toll-like receptors (TLRs) are the critical link between the innate and the adaptive immunity. This link, which is normally activated as a result of collaboration between adjuvants and TLRs in triggering adaptive immunity, has been a subject of several recent investigations. With the advent of well-defined synthetic small molecules, which are designed to either mimic the adjuvants or, as in many cases, to structurally represent pathogen associated molecular patterns, it is now possible to design reproducible experiments and to draw credible conclusions. An adjuvant alerts the host immune system through a mechanism similar to that of an infection by a pathogen, which involves interaction with a TLR followed by a lsqou;danger signal' to the immune system. Secretion of cytokines and regulation of the expression of co-stimulatory molecules induced by innate response shape the magnitude and quality of adaptive response. Synthetic vaccines containing specific epitopes to which immune responses are desired, are expected to be far superior in target specificity while the benefits may be long-lasting. The immune responses by therapeutic vaccines are generally adaptive in nature and such responses often require the participation of the components of innate immunity, most importantly the TLRs and their pathogen-associated binding compliments. Structurally well-defined synthetic molecules derived from lipid A, muramyl di-peptide (MDP), and CpG motifs from bacterial DNA offer a wide range of immune stimulants for the development of fully synthetic vaccines. Lipo-peptide and self-adjuvanted antigens, in combination with additional immune stimulatory adjuvants in liposome delivery system, may be important in vaccine design. Combinations of synthetic mimics of microbial products are known to display synergistic effects in stimulating the immune system. Either alone or in combination with chemotherapy, innate immune therapy using TLR ligands to stimulate the immune system may offer an alternate therapeutic approach against rapidly mutating viral infections-(HIV/AIDS), and cancers.


GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells.
The bone marrow microenvironment comprises multiple cell niches derived from bone marrow mesenchymal stem cells. However, the molecular mechanism of bone marrow mesenchymal stem cell differentiation is poorly understood. The transcription factor GATA2 is indispensable for hematopoietic stem cell function as well as other hematopoietic lineages, suggesting that it may maintain bone marrow mesenchymal stem cells in an immature state and also contribute to their differentiation. To explore this possibility, we established bone marrow mesenchymal stem cells from GATA2 conditional knockout mice. Differentiation of GATA2-deficient bone marrow mesenchymal stem cells into adipocytes induced accelerated oil-drop formation. Further, GATA2 loss- and gain-of-function analyses based on human bone marrow mesenchymal stem cells confirmed that decreased and increased GATA2 expression accelerated and suppressed bone marrow mesenchymal stem cell differentiation to adipocytes, respectively. Microarray analysis of GATA2 knockdowned human bone marrow mesenchymal stem cells revealed that 90 and 189 genes were upregulated or downregulated by a factor of 2, respectively. Moreover, gene ontology analysis revealed significant enrichment of genes involved in cell cycle regulation, and the number of G1/G0 cells increased after GATA2 knockdown. Concomitantly, cell proliferation was decreased by GATA2 knockdown. When GATA2 knockdowned bone marrow mesenchymal stem cells as well as adipocytes were cocultured with CD34-positive cells, hematopoietic stem cell frequency and colony formation decreased. We confirmed the existence of pathological signals that decrease and increase hematopoietic cell and adipocyte numbers, respectively, characteristic of aplastic anemia, and that suppress GATA2 expression in hematopoietic stem cells and bone marrow mesenchymal stem cells.


[The perception of health professionals of two definitions of frailty in elderly people].
The objective of this study was to understand the perception of health professionals of two definitions of frailty in elderly people. The sample consisted of twelve health professionals, who work in a Geriatrics Ambulatory. The tools used for data collection were individual semi-structured interviews, and the questionnaire Definitions of Frailty, developed for that purpose. Data were organized and analyzed using the Collective Subject Discourse method, which consists of key-expressions, central-ideas and collective subject discourse. The results indicated that the health professionals have got difficulties to accept a one-dimensional definition of frailty, which is in accordance with the international literature. The six Central Ideas (CI) that emerged from the discourses were: 1) the definitions are complementary; 2) there is no potential for prevention; 3) defining frailty is a complex task; 4) what is the concept of frailty? 5) the multidimensional definition is complete; 6) frailty is a state that can last for life. The participants believe that these definitions complement each other, since frailty encompasses an interaction of biological, psychological, and social factors throughout the lifespan. Only one professional accepted the multidimensional definition as complete. Defining frailty is a rather complex task.


Improved procedures for immunoferritin labeling of ultrathin frozen sections.
In employing fixed frozen ultrathin sections as substrates for immunoferritin labeling of intracellular antigens, we have found that conventional glutaraldehyde fixation sometimes permits very little specific staining of the sections, either because it inactivates certain protein antigens, or because it renders them inaccessible to the antibody stains. We have developed several fixation procedures that are chemically milder and allow a uniform but less extensive cross-linking of the specimen. With these procedures and precautions in the handling of the more fragile frozen sections, excellent structural preservation and specific immunoferritin labeling has been achieved with several systems.


Cyanide Ligand Assembly by Carbon Atom Transfer to an Iron Nitride.
The new iron(IV) nitride complex PhB(iPr2Im)3Fe≡N reacts with 2 equiv of bis(diisopropylamino)cyclopropenylidene (BAC) to provide PhB(iPr2Im)3Fe(CN)(N2)(BAC). This unusual example of a four-electron reaction involves carbon atom transfer from BAC to create a cyanide ligand along with the alkyne iPr2N-C≡C-NiPr2. The iron complex is in equilibrium with an N2-free species. Further reaction with CO leads to formation of a CO analogue, which can be independently prepared using NaCN as the cyanide source, while reaction with B(C6F5)3 provides the cyanoborane derivative.


[Asymmetric dimethylarginine: predictor of cardiovascular diseases?].
Cardiovascular diseases are the most common diseases worldwide. They are responsible for one third of global deaths and they are the leading cause of disability, too. The usage of different levels of prevention in combination with effective risk assessment improved these statistical data. Risk assessment based on classic risk factors has recently been supported with several new markers, such as asymmetric dimethylarginine, which is an endogenous competitive inhibitor of nitric oxide synthase. Elevated levels of asymmetric dimethylarginine have been reported in obese, smoker, hypercholesterolemic, hypertensive and diabetic patients. According to previous studies, asymmetric dimethylarginine is a suitable indicator of endothelial dysfunction, which is held to be the preceding condition before atherosclerosis. Several researches found positive correlation between higher levels of asymmetric dimethylarginine and coronary artery disease onset, or progression of existing coronary disease. According to a study involving 3000 patients, asymmetric dimethylarginine is an independent risk factor of cardiovascular mortality in patients with coronary artery disease. This article summarizes the role of asymmetric dimethylarginine in prediction of cardiovascular diseases, and underlines its importance in cardiovascular prevention.


The effects of nalidixic acid on respiratory activity of asynchronous and synchronous cultures of Alcaligenes eutrophus.
Nalidixic acid inhibited DNA synthesis and cell division during asynchronous growth of Alcaligenes eutrophus but treated cells continued to grow as monitored by A550, respiratory activity and cell volume. Differential effects on cell division were seen when the antibiotic was added at different times during synchronous growth. The earlier in the cell cycle the time of addition the greater the inhibition of cell division. These results suggests that chromosome replication is confined to the first half of the cell cycle in A. eutrophus grown at 30 degrees C. Respiration rates of cells selected by continuous-flow centrifugation and immediately treated with nalidixic acid increased in a stepwise fashion. These steps were similar to those observed in untreated control cells and imply that the DNA-division cycle is not the causal factor for the periodicities in respiration rates and ATPase activity that have been previously reported in this bacterium.


Socio-Demographic, Clinical, and Mortality Differences between HIV-Infected and HIV/HTLV-1 Co-Infected Patients in Peru.
In Peru, the estimated prevalence of human immunodeficiency virus (HIV) and human T-lymphotropic virus-1 (HTLV-1) co-infection has been reported to be as high as 18%. Despite the endemicity of HTLV-1 in Peru, few studies have assessed the impact of HIV/HTLV-1 co-infection. Our study compared socio-demographic and clinical characteristics, and mortality rates between HIV-infected and HIV/HTLV-1 co-infected patients. We reviewed the medical records of patients aged 18 years and older belonging to the HIV and HTLV-1 cohorts in Lima during a 30-year period: 1989-2019. Each HIV/HTLV-1 co-infected patient was randomly matched with two HIV-infected patients with similar characteristics (same sex, age ± 5 years, and same year of HIV diagnosis). Allegedly co-infected patients without a confirmatory diagnosis of HIV and HTLV-1 were excluded. Most of the patients in the HIV-infected group did not have a negative test result for HTLV-1 infection, so we used two probabilistic sensitivity analysis models to correct for potential HTLV-1 exposure misclassification bias in the group of HIV-infected patients. Of 162 patients enrolled, 54 were HIV/HTLV-1 co-infected and 108 were HIV-infected. The median age was 42 years (IQR = 34-51 years) and the majority were male (61.1%), single (44.4%), heterosexual (71%), born in Lima (58%), educated at the secondary school level (55.6%), and receiving antiretroviral treatment (91.4%). HIV/HTLV-1 co-infection was associated with an increased risk of death (HR: 11.8; 95% CI: 1.55-89.00; p = 0.017) while antiretroviral treatment was associated with a decreased risk of death (HR: 0.03; 95% CI: 0.003-0.25; p = 0.001). The overall mortality rate was 13.6 per 100 persons and the survival time for co-infected patients (median = 14.19 years) was significantly shorter than that of HIV-infected patients (median = 23.83 years) (p < 0.001). HIV/HTLV-1 co-infected patients had a significantly shorter survival time compared to HIV-infected patients, suggesting that the immune alterations caused by HTLV-1 in CD4 cell count may have contributed to late initiation of antiretroviral treatment and prophylaxis against opportunistic infections over the decades, and thus reducing their benefits in these patients.


An 85-kilodalton surface antigen gene family of Trypanosoma cruzi encodes polypeptides homologous to bacterial neuraminidases.
We have determined the sequence of a cDNA (Tt34c1) encoding a Trypanosoma cruzi trypomastigote stage-specific 85-kDa surface glycoprotein (gp85). Within the peptide sequence of Tt34c1 are two 8-amino acid motifs, Ser-X-Asp-X-Gly-X-Thr-Trp, that are characteristic of bacterial neuraminidases. Analysis of the Tt34c1 sequence predicts the presence of an amino-terminal signal sequence and a hydrophobic carboxy-terminus that is probably replaced by a glycosyl phosphatidylinositol membrane anchor. Gp85 is encoded by an extensive multigene family that is distributed throughout the genome and can be divided into subsets on the basis of oligonucleotide hybridisation patterns. By sequencing products of polymerase chain reaction (PCR) amplification of the 5' end of trypomastigote gp85 mRNA we show that multiple copies of the gene family are transcribed simultaneously in a trypanosome population. Comparison of the sequence of the PCR clones and another gp85 cDNA showed a highly conserved region 5' of the first methionine extending 180 nt into the coding sequence. Insertions and point mutations were observable outside these homologous sequences demonstrating the variant nature of the gp85 mRNAs.


Effect of a fixed combination of nimodipine and betahistine versus betahistine as monotherapy in the long-term treatment of Ménière's disease: a 10-year experience.
Despite an abundance of long-term pharmacological treatments for recurrent vertigo attacks due to Ménière's disease, there is no general agreement on the their efficacy. We present the results of a retrospective study based on a 10-year experience with two long-term medical protocols prescribed to patients affected by Ménière's disease (diagnosed according to the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium guidelines) who completed treatments in the period 1999-2009. A total of 113 medical records were analysed; 53 patients received betahistine-dihydrochloride at on-label dosage (32 mg die) for six months, and 60 patients were treated with the same regimen and nimodipine (40 mg die) as an add-therapy during the same period. Nimodipine, a 1,4-dihydropyridine that selectively blocks L-type voltage-sensitive calcium channels, has previously been tested as a monotherapy for recurrent vertigo of labyrinthine origin in a multinational, double-blind study with positive results. A moderate reduction of the impact of vertigo on quality of life (as assessed by the Dizziness Handicap Inventory) was obtained in patients after therapy with betahistine (p < 0.05), but a more significant effect was achieved in patients treated by combined therapy (p < 0.005). In the latter group, better control of vertigo was seen with a greater reduction of frequency of attacks (p < 0.005). Both protocols resulted in a significant improvement of static postural control, although a larger effect on body sway area in all tests was obtained by the fixed combination of drugs. In contrast, no beneficial effect on either tinnitus annoyance (as assessed by the Tinnitus Handicap Inventory) and hearing loss (pure-tone average at 0.5, 1, 2, 3 kHz frequencies of the affected ear) was recorded in patients treated with betahistine as monotherapy (p > 0.05), whereas the fixed combination of betahistine and nimodipine was associated with a significant reduction of tinnitus annoyance and improvement of hearing loss (p < 0.005). It was concluded that nimodipine represents not only a valid add-therapy for Ménière's disease, and that it may also exert a specific effect on inner ear disorders. Further studies to investigate this possibility are needed.


Effect of linagliptin versus placebo on cardiovascular and kidney outcomes in nephrotic-range proteinuria and type 2 diabetes: the CARMELINA randomized controlled trial.
Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP. Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5 mg or placebo (PBO). The primary endpoint [time to first occurrence of 3-point major adverse cardiac events (3P-MACE)], and kidney outcomes, were evaluated by NRP status [urinary albumin:creatinine ratio (UACR) ≥2200 mg/g] at baseline (BL) in participants treated with one or more dose of study medication. NRP was present in 646/6979 [9.3% (LINA/PBO n = 317/n = 329); median UACR 3486 (Q1: 2746/Q3: 4941) mg/g] participants, who compared with no-NRP were younger (62.3/66.1 years) and had lower estimated glomerular filtration rate (eGFR) (39.9/56.1 mL/min/1.73 m2). Over a median of 2.2 years, 3P-MACE occurred with a 2.0-fold higher rate in NRP versus no-NRP (PBO group), with a neutral LINA effect, regardless of NRP. The composite of time to renal death, end-stage kidney disease (ESKD) or decrease of ≥40 or ≥50% in eGFR, occurred with 12.3- and 13.6-fold higher rate with NRP (PBO group); evidence of heterogeneity of effects with LINA was observed for the former [NRP yes/no: hazard ratio 0.80 (0.63-1.01)/1.25 (1.02-1.54); P-interaction 0.005], but not the latter [0.83 (0.64-1.09)/1.17 (0.91-1.51), P-interaction 0.07]. No heterogeneity was observed for renal death or ESKD [0.88 (0.64-1.21)/0.94 (0.67-1.31), P-interaction 0.79]. Glycated haemoglobin A1c (HbA1c) was significantly reduced regardless of NRP, without increasing hypoglycaemia risk. Regression to normoalbuminuria [1.20 (1.07-1.34)] and reduction of UACR ≥50% [1.15 (1.07-1.25)] from BL, occurred more frequently with LINA, regardless of NRP status (P-interactions >0.05). Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk.


Distribution and number of epidermal growth factor receptors in skin is related to epithelial cell growth.
Epidermal growth factor (EGF), a low-molecular-weight polypeptide (G. Carpenter and S. Cohen, 1979, Annu. Rev. Biochem. 48, 193-216), stimulates the proliferation and keratinisation of cultured embryonic epidermis (S. Cohen, 1965, Dev. Biol. 12, 394-407) and promotes epidermal growth, thickening, and keratinisation when injected into neonatal mice (S. Cohen and G.A. Elliott, 1963, J. Invest. Dermatol, 40, 1-5). We have determined the distribution of the available receptors for epidermal growth factor in rat skin using autoradiography following incubation of explants with 125I-labelled mouse EGF. EGF receptors are detected on the epithelial cells overlying the basement membranes of the epidermis, sebaceous gland, and regions of the hair follicle all of which have proliferative capacity. In marked contrast, tissues which have started to differentiate and lost their growth potential, carry either an undetectable or sharply reduced number of EGF receptors. The EGF receptor number and receptor affinity of epidermal basal cells freshly isolated from rats of increasing age has also been determined. We find that receptor affinity remains unchanged (3.3 nM) but that basal cell surface receptor number decreases markedly with age. This decrease in receptor number is similar in trend to the known drop in basal cell [3H]thymidine labelling index which occurs over the same time period. The data suggest that the distribution of EGF receptors and EGF cell surface receptor number in skin are important in the spatial and temporal control of epithelial proliferation.