Reasons for a Lower Rate of Epidural Anesthesia During Birth for Immigrant Women in the Eyes of Medical Staff: A Mixed-Methods Analysis.
Various studies have shown that immigrant women in comparison to non-immigrant women of the same parity have lower rates of epidural anesthesia (EDA). Data from two studies on immigrant obstetric care in Berlin, Germany were analyzed to answer the following question: What reasons do the medical staff see for the lower rate of EDA in immigrant women? Between May and August 2017, 34 interviews with obstetricians and midwives in four obstetric clinics in Berlin were conducted on the topic of obstetric care for immigrant women. After anonymizing the more than 20 h of interview material, transcripts were coded with MaxQDa and analyzed according to the qualitative content analysis.The quantitative data is from an online survey conducted between May and October 2017, in all but one obstetric clinic in Berlin with obstetricians and midwives. Regarding the research question, 121 questionnaires could be analyzed. In the online survey, (multiple answers were possible), the top reason for a lower rate of EDA given was mostly fear on the part of the immigrant women (64%). A language barrier, which results in logistic and time constrictions, is mentioned as the second most frequent reason (50%). The explorative analysis of the interviews shows that doctors and midwives regard cultural aspects such as different expectations on the birth experience as a reason for a lower EDA rate. Furthermore, within the medical staff the impression persists that in some cases the companion decides on the behalf of the patient about the application of an EDA, which from time to time is against the wish of the immigrant woman giving birth. In the view of the medical staff, the reasons for a lower rate of EDA during birth for immigrant women were varied. On one side, this is attributed to the wishes of the respective women ("demand") but on the other side this can be attributed to the health care system ("supply"). In the case of a language barrier, the "supply" and the access of EDA for immigrant women is limited and can be then shifted to the German-speaking companion to make a decision regarding EDA ("structural deprivation of self-determination").


Remarkable White Circularly Polarized Electroluminescence Based on Chiral Co-assembled Helix Nanofiber Emitters.
White circularly polarized organic light-emitting diodes (CP-WOLEDs) are of great significance in potential lighting sources and full-color 3D displays. However, High-performance white CP-EL sources are almost unexplored. We have constructed full-color CP-EL devices based on chiral co-assemblies by using three achiral conjugated pyrene-based dyes (BP, w-WP and c-WP) doped with chiral binaphthyl-based enantiomers (S-/R-M) as the EMLs through an intermolecular chirality induction mechanism. (S-/R-M)0.2 -(c-WP)0.8 films exhibit regular helix nanofibers under annealing treatment and emit strong white CPL. Significantly, remarkable CP-WOLEDs based on (S-/R-M)0.2 -(c-WP)0.8 were achieved with |gEL | values as high as 6.2×10-2 and an excellent CRI of 98 at the CIE coordinates of (0.33, 0.33). These are the highest gEL and CRI values of reported CP-WOLEDs to date. This is the first achievement of CP-WOLEDs based on chiral co-assembled helix nanofiber emitters, and provides a valuable strategy with which to develop white CP-EL for future practical applications.


Defining a role for systemic chemotherapy in local and advanced appendix adenocarcinoma.
Appendix adenocarcinomas (AAs) are rare tumours that often present late, with a propensity for peritoneal metastases (PMs). This study aimed to evaluate outcomes of AA patients undergoing cytoreductive surgery (CRS) with curative intent and determine the role of systemic chemotherapy. Data were collected from a prospective database and classified according to World Health Organization (WHO) 2019 classification. Tumour clearance from CRS was described using a completeness of cytoreduction (CC) score ranging from 0 [no residual disease (RD)] to 3 (>2.5 cm RD). Patients with CC0-2 CRS received hyperthermic intraperitoneal chemotherapy (HIPEC). Systemic chemotherapy was categorised as 'prior' (>6 months before), 'neoadjuvant' (<6 months before), 'adjuvant' (<6 months after CC0-1 CRS) or 'palliative' (after CC2-3 CRS). Analyses used Kaplan-Meier and Cox regression methods. Between January 2005 and August 2021, 216 AA patients were identified for inclusion. Median age was 59 years (21-81 years). CRS/HIPEC was carried out in 182 (84%) patients, of whom 164/182 (76%) had mitomycin C HIPEC. CC0-1 was achieved in 172 (80%) patients. Systemic chemotherapy was given to 97 (45%) patients from the whole cohort and to 37/46 (80%) patients with positive nodes. Median overall survival (OS) was 122 months (95% confidence interval 61-182 months). After multivariate analysis, patients with acellular and lower-grade PM had similar OS to those with localised (M0) disease (P = 0.59 and P = 0.19). For patients with positive nodes, systemic chemotherapy was associated with reduced risk of death compared to no chemotherapy (P < 0.0019). This study identifies AA patients with positive lymph nodes derive the most benefit from systemic chemotherapy. We confirm the prognostic importance of stage and peritoneal grade, with excellent outcomes in patients with acellular mucin and lower-grade PM.


Analyzing the value of IONM as a complex intervention: The gap between published evidence and clinical practice.
Intraoperative neurophysiological monitoring (IONM) was investigated as a complex intervention (CI) as defined by the United Kingdom Medical Research Council (MRC) in published studies to identify challenges and solutions in estimating IONM's effects on postoperative outcomes. A scoping review to April 2022 of the influence of setting on what was implemented as IONM and how it influenced postoperative outcomes was performed for studies that compared IONM to no IONM cohorts. IONM complexity was assessed with the iCAT_SR tool. Causal graphs were used to represent this complexity. IONM implementation depended on the surgical procedure, institution and/or surgeon. "How" IONM influenced neurologic outcomes was attributed to surgeon or institutional experience with the surgical procedure, surgeon or institutional experience with IONM, co-interventions in addition to IONM, models of IONM service delivery and individual characteristics of the IONM provider. Indirect effects of IONM mediated by extent of tumor resection, surgical approach, changes in operative procedure, shorter operative time, and duration of aneurysm clipping were also described. There were no quantitative estimates of the relative contribution of these indirect effects to total IONM effects on outcomes. IONM is a complex intervention whose evaluation is more challenging than that of a simple intervention. Its implementation and largely indirect effects depend on specific settings that are usefully represented in causal graphs. IONM evaluation as a complex intervention aided by causal graphs and multivariable analysis could provide a valuable framework for future study design and assessments of IONM effectiveness in different settings.


Molecular genetics and animal models in autistic disorder.
Autistic disorder is a behavioural syndrome beginning before the age of 3 years and lasting over the whole lifetime. It is characterised by impaired communication, impaired social interactions, and repetitive interests and behaviour. The prevalence is about 7/10,000 taking a restrictive definition and more than 1/500 with a broader definition, including all the pervasive developmental disorders. The importance of genetic factors has been highlighted by epidemiological studies showing that autistic disorder is one of the most genetic neuropsychiatric diseases. The relative risk of first relatives is about 100-fold higher than the risk in the normal population and the concordance in monozygotic twin is about 60%. Different strategies have been applied on the track of susceptibility genes. The systematic search of linked loci led to contradictory results, in part due to the heterogeneity of the clinical definitions, to the differences in the DNA markers, and to the different methods of analysis used. An oversimplification of the inferred model is probably also cause of our disappointment. More work is necessary to give a clearer picture. One region emerges more frequently: the long arm of chromosome 7. Several candidate genes have been studied and some gave indications of association: the Reelin gene and the Wnt2 gene. Cytogenetical abnormalities are frequent at 15q11-13, the region of the Angelman and Prader-Willi syndrome. Imprinting plays an important role in this region, no candidate gene has been identified in autism. Biochemical abnormalities have been found in the serotonin system. Association and linkage studies gave no consistent results with some serotonin receptors and in the transporter, although it seems interesting to go further in the biochemical characterisation of the serotonin transporter activity, particularly in platelets, easily accessible. Two monogenic diseases have been associated with autistic disorder: tuberous sclerosis and fragile X. A better knowledge of the pathophysiology of these disorders can help to understand autism. Different other candidate genes have been tested, positive results await replications in other samples. Animal models have been developed, generally by knocking out the different candidate genes. Behaviour studies have mainly focused on anxiety and learning paradigms. Another group of models results from surgical or toxic lesions of candidate regions in the brain, in general during development. The tools to analyse these animals are not yet standardised, and an important effort needs to be undertaken.


Extreme mitogenomic divergence between two syntopic specimens of Arremon aurantiirostris (Aves: Emberizidae) in central Panama suggests possible cryptic species.
We report the complete mitochondrial genome of two specimens of Orange-billed Sparrow Arremon aurantiirostris from Colón Province, in central Panama. The two specimens were collected on the same day, and at the same locality; however, they showed substantial divergence (6.3% average pairwise divergence among coding genes). A survey of ND2 sequence variation across Panama suggests that this divergence is the result of geographic differentiation and secondary contact. This high level of mitochondrial divergence among co-occurring individuals raises the possibility of multiple biological species in Orange-billed Sparrows. Our results are yet another demonstration that much remains to be discovered regarding avian biodiversity in Panama and throughout the Neotropics.


Rat heart in culture as a tool to elucidate the cellular origin of lipoprotein lipase.
Lipoprotein lipase was determined in 5-day old cell cultures derived from hearts of newborn rats. With the help of the preplating method the cells were subdivided into cultures containing predominantly cardiac myocytes and into those composed mainly of mesenchymal cells. Lipoprotein lipase activity, associated with the mesenchymal cells was ten times higher than the activity found in the cultures containing mainly the myogenic cells. It is suggested that the mesenchymal cells are the progenitors of lipoprotein lipase in rat heart.


Sleep Disturbance in Posttraumatic Stress Disorder: Epiphenomenon or Causal Factor?
The goal of this review is to integrate recent findings on sleep disturbance and PTSD, examine sleep disturbance as a causal factor in the development of PTSD, and identify future directions for research, treatment, and prevention. Recent research highlights a relationship between both objective and subjective sleep disturbance and PTSD across diverse samples. Sleep disturbance also predicts PTSD over time. Finally, treatments targeting sleep disturbance lead to decreased PTSD symptoms, while standard PTSD treatments conclude with residual sleep disturbance. Sleep disturbance may be more than a mere epiphenomenon of PTSD. Future research examining the causal role of sleep disturbance in the development of PTSD, as well as the utility of targeting sleep disturbance in prevention and treatment, is necessary to fully understand the likely bidirectional relationship between sleep disturbance and PTSD.


Duration of ischemia is a major determinant of transmurality and severe microvascular obstruction after primary angioplasty: a study performed with contrast-enhanced magnetic resonance.
This study sought to assess the relationship between duration of ischemia and both myocardial transmural necrosis (TN) and severe microvascular obstruction (SMO), by contrast-enhanced magnetic resonance (CE-MR), in patients with acute myocardial infarction (AMI) treated with angioplasty (PCI), and to estimate the risk of TN and SMO with the duration of ischemia. The impact of ischemic time on myocardial and microvascular injury is not well characterized in people. We performed CE-MR in 77 patients with first AMI, 5 +/- 3 days after successful PCI. The AMI was labeled as transmural if hyperenhancement at CE-MR was extended to > or =75% of the thickness in two or more ventricular segments. The SMO was identified as areas of late hypoenhancement surrounded by hyperenhanced tissue. The relationship between ischemic time and CE-MR evidence of SMO or TN was evaluated by logistic regression. Thirteen patients were excluded because of preprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery. For the remaining 64 patients, the mean time to treatment was 190 +/- 110 min, 45 (65%) patients had TN and 23 (39%) had SMO. Mean pain to balloon time was 90 +/- 40 min, 110 +/- 107 min, and 137 +/- 97 min in patients without TN and SMO, with TN but without SMO, or with both TN and SMO, respectively (p = 0.001). Multivariate analysis showed that time delay was significantly associated both with TN (odds ratio per 30 min, 1.37, p = 0.032), and SMO (odds ratio per 30 min, 1.21; p = 0.021). In AMI patients with impaired coronary perfusion undergoing PCI, the risk of TN and SMO increases with the duration of the ischemic time.


Comparison between the effects of dietary fat level and of calorie intake on methylnitrosourea-induced mammary carcinogenesis in female SD rats.
The aim of this study was to separate the effects of calorie intake on tumorigenesis from those of fat content and fat composition in an animal model. Our principal observations were the following. Decreasing the calorie level by 30% significantly inhibited tumor development in any observed parameter of tumorigenesis, independently of the level of fat. The fat content of semi-synthetic diets, although varying by 44.4%, did not significantly influence mammary tumorigenesis; in fact, carcinogenic expression was discontinuously related to the fat level. A plateau of tumor incidence was observed at the level of 35 energy percentage of fat. Fat composition did not influence tumorigenesis or body weight gain. The role of caloric restriction is thus stressed in relation to possible dietary prevention of cancer.


[The biopsychosocial understanding of health disorders and impairments in children with a focus on developmental neurological relationships].
The distinction between mental (spiritual and psychological) and physical health disorders is particularly difficult due to the special features of neurobiological development in children and adolescents. In this review article, the basics of developmental neurology are briefly described. On the basis of some congenital or early acquired neurological diseases, it is then shown to what extent mental processes can be impaired in interactions with the social context. Taking these aspects into account plays an important role in child and family-oriented counseling and support. The common occurrence of physical, mental, and psychological development disorders, which is also very variable between individuals and fluctuates over the course of a person's life, requires good interdisciplinary cooperation between conservative and surgical child and adolescent medicine and child and adolescent psychiatry.


Temporal phenotyping for transitional disease progress: An application to epilepsy and Alzheimer's disease.
Complicated multifactorial diseases deteriorate from one disease to other diseases. For example, existing studies consider Alzheimer's disease (AD) a comorbidity of epilepsy, but also recognize epilepsy to occur more frequently in patients with AD than those without. It is important to understand the progress of disease that deteriorates to severe diseases. To this end, we develop a transitional phenotyping method based on both longitudinal and cross-sectional relationships between diseases and/or medications. For a cross-sectional approach, we utilized a skip-gram model to represent co-occurred disease or medication. For a longitudinal approach, we represented each patient as a transition probability between medical events and used supervised tensor factorization to decompose into groups of medical events that develop together. Then we harmonized both information to derive high-risk transitional patterns. We applied our method to disease progress from epilepsy to AD. An epilepsy-AD cohort of 600,000 patients were extracted from Cerner Health Facts data. Our experimental results suggested a causal relationship between epilepsy and later onset of AD, and also identified five epilepsy subgroups with distinct phenotypic patterns leading to AD. While such findings are preliminary, the proposed method combining representation learning with tensor factorization seems to be an effective approach for risk factor analysis.


Imaging predictors of response to cardiac resynchronization therapy: left ventricular work asymmetry by echocardiography and septal viability by cardiac magnetic resonance.
Left ventricular (LV) failure in left bundle branch block is caused by loss of septal function and compensatory hyperfunction of the LV lateral wall (LW) which stimulates adverse remodelling. This study investigates if septal and LW function measured as myocardial work, alone and combined with assessment of septal viability, identifies responders to cardiac resynchronization therapy (CRT). In a prospective multicentre study of 200 CRT recipients, myocardial work was measured by pressure-strain analysis and viability by cardiac magnetic resonance (CMR) imaging (n = 125). CRT response was defined as ≥15% reduction in LV end-systolic volume after 6 months. Before CRT, septal work was markedly lower than LW work (P < 0.0001), and the difference was largest in CRT responders (P < 0.001). Work difference between septum and LW predicted CRT response with area under the curve (AUC) 0.77 (95% CI: 0.70-0.84) and was feasible in 98% of patients. In patients undergoing CMR, combining work difference and septal viability significantly increased AUC to 0.88 (95% CI: 0.81-0.95). This was superior to the predictive power of QRS morphology, QRS duration and the echocardiographic parameters septal flash, apical rocking, and systolic stretch index. Accuracy was similar for the subgroup of patients with QRS 120-150 ms as for the entire study group. Both work difference alone and work difference combined with septal viability predicted long-term survival without heart transplantation with hazard ratio 0.36 (95% CI: 0.18-0.74) and 0.21 (95% CI: 0.072-0.61), respectively. Assessment of myocardial work and septal viability identified CRT responders with high accuracy.


Splenectomy increases atherosclerotic lesions in apolipoprotein E deficient mice.
Atherosclerosis is an inflammatory immune disease associated with lipid accumulation in the intima layer of arteries. The spleen plays an important immune function, but its influence in development of atherosclerosis remains unclear. Evaluation of the role of the spleen in atherosclerosis is justified due to the high frequency of total splenectomies. In this work, the effect of splenectomy on the development of atherosclerosis in apolipoprotein E (ApoE) deficient mice was investigated. ApoE deficient mice were divided into a sham-operated control group (CT) and a splenectomized group (SP). Thirty days after surgery, animals were fed a high fat western diet. After 8 wk, mice were euthanized and their blood, heart, and aorta were subjected to analysis. Atherosclerotic lesion areas in the aortic root were stained with hematoxylin-eosin and quantified by morphometry. The atherosclerotic lesions in the thoracic and abdominal portions of aorta were determined by assessing the percentage of the luminal surface area stained by Sudan IV. Total serum cholesterol and anti-oxidized LDL antibodies were measured. Levels of total serum cholesterol did not vary significantly after splenectomy. Anti-oxidized LDL IgG antibodies were similar between groups. However, compared with the control group, lesions in the aortic root were significantly larger in splenectomized mice (P<0.01). These data were confirmed by the increase of atherosclerotic area in the thoracic and abdominal portions of aorta in splenectomized mice. These data indicate that splenectomy increases atherosclerotic lesions in ApoE deficient mice fed an atherogenic diet, suggesting an atheroprotector role of the spleen.


The effect of physical exercise on reverse cholesterol transport.
High-density lipoproteins (HDL) are recognized for their role in coronary artery disease (CAD) risk reduction. Plasma HDL plays a pivotal role in the reverse cholesterol transport (RCT) process. Physical exercise is well recognized as a modality that affects HDL metabolism. The purpose of this discussion is to describe the effects of physical exercise on RCT.


Changes in home care clients' characteristics and home care in five European countries from 2001 to 2014: comparison based on InterRAI - Home Care data.
Policymakers advocate extended residence in private homes as people age, rather than relocation to long-term care facilities. Consequently, it is expected that older people living in their own homes will be frailer and have more complex health problems over time. Therefore, community care for aging people is becoming increasingly important to facilitate prevention of decline in physical and cognitive abilities and unnecessary hospital admission and transfer to a nursing home. The aim of this study was to examine changes in the characteristic of home care clients and home care provided in five European countries between 2001 and 2014 and to explore whether home care clients who are most in need of care receive the care required. This descriptive study used data from two European research projects, Aged in Home Care (AdHOC; 2001-2002) and Identifying best practices for care-dependent elderly by Benchmarking Costs and outcomes of Community Care (IBenC; 2014-2016). In both projects, the InterRAI-Home Care assessment tool was used to assess a random sample of home care clients 65 years and older in five European countries. These data facilitate a comparison of physical and cognitive health and the provided home care between countries and study periods. In most participating countries, both cognitive (measured on the Cognitive Performance Scale) and functional ability (measured on the Activities of Daily Living Hierarchy scale) of home care clients deteriorated over a 10-year period. Home care provided increased between the studies. Home care clients who scored high on the physical and cognitive scales also received home care for a significantly higher duration than those who scored low. Older people in several European countries remain living in their own homes despite deteriorating physical and cognitive skills. Home care services to this group have increased. This indicates that the government policy of long-term residence at own home among older people, even in increased frailty, has been realised.


Steering molecular organization and host-guest interactions using two-dimensional nanoporous coordination systems.
Metal-organic coordination networks (MOCNs) have attracted wide interest because they provide a novel route towards porous materials that may find applications in molecular recognition, catalysis, gas storage and separation. The so-called rational design principle-synthesis of materials with predictable structures and properties-has been explored using appropriate organic molecular linkers connecting to metal nodes to control pore size and functionality of open coordination networks. Here we demonstrate the fabrication of surface-supported MOCNs comprising tailored pore sizes and chemical functionality by the modular assembly of polytopic organic carboxylate linker molecules and iron atoms on a Cu(100) surface under ultra-high-vacuum conditions. These arrays provide versatile templates for the handling and organization of functional species at the nanoscale, as is demonstrated by their use to accommodate C(60) guest molecules. Temperature-controlled studies reveal, at the single-molecule level, how pore size and chemical functionality determine the host-guest interactions.


Transcriptome aberration associated with altered locomotor behavior of zebrafish (Danio rerio) caused by Waterborne Benzo[a]pyrene.
Waterborne Benzo[a]pyrene (B[a]P) pollution is a global threat to aquatic organisms. The exposure to waterborne B[a]P can disrupt the normal locomotor behavior of zebrafish (Danio rerio), however, how it affect the locomotor behavior of adult zebrafish remains unclear. Herein, B[a]P at two concentrations (0.8 μg/L and 2.0 μg/L) were selected to investigate the molecular mechanisms of the affected locomotor behavior of zebrafish by B[a]P based on transcriptome profiling. Adverse effects of B[a]P exposure affecting locomotor behavior in zebrafish were studied by RNA sequencing, and the locomotion phenotype was acquired. The gene enrichment results showed that the differentially highly expressed genes (atp2a1, cdh2, aurka, fxyd1, clstn1, apoc1, mt-co1, tnnt3b, and fads2) of zebrafish are mainly enriched in adrenergic signaling in cardiomyocytes (dre04261) and locomotory behavior (GO:0007626). The movement trajectory plots showed an increase in the locomotor distance and velocity of zebrafish in the 0.8 μg/L group and the opposite in the 2.0 μg/L group. The results showed that B[a]P affects the variety of genes in zebrafish, including motor nerves, muscles, and energy supply, and ultimately leads to altered locomotor behavior.


Effect of exogenus protease on performance, nutrient digestibility, intestinal histomorphometric, meat quality characteristics, carcass yield in broilers fed low protein diets.
The objective of the present study was to evaluate the effects of increasing doses of protease on broilers from 1 to 42 days of age. A total of 1290 Ross AP broilers were used, distributed among five treatments: positive control diet, negative control diet (NC), NC + 50 ppm of protease, NC + 100 ppm of protease, and NC + 200 ppm of protease. Each treatment contained six replicates of 43 animals each. The inclusion of proteases in the diet had effects (P < 0.05) on body weight, feed intake, weight gain, and feed conversion in the 12 to 21 day period; body weight, weight gain, and feed intake in the 29 to 42 day period; nutrient digestibility (energy metabolizability coefficient and crude protein at 28 days); and intestinal parameters (crypt and muscle width of jejunum and ileum at 28 days and villus length, crypt length, and jejunum thickness muscle layer at 42 days). These results indicate that the inclusion of protease in broiler feed can improve production parameters when the amount of crude protein in the diet is reduced.


The verification of the reliability of a triglyceride-glucose index and its availability as an advanced tool.
The triglyceride-glucose (TyG) index has been considered as insulin resistance (IR) assessment index. The current study aimed to verify the reliability of the TyG index as an IR assessment marker; the study of plasma fatty acids and body fat composition to determine potential metabolic syndrome (MetS) participants with a body mass index (BMI) of between 25.0 and 29.9 kg/m2. The study included 378 overweight participants with a body mass index of between 25.0 and 29.9 kg/m2. They were divided into tertiles according to the homeostasis model assessment of IR (HOMA-IR) or the TyG index. The role of the IR assessment index and the relationship with IR-related diseases and the risk factors using gas chromatograph-mass spectrometry, computed tomography, and dual energy X-ray absorptiometry, was investigated. It was only in the TyG index tertile that the higher TyG index participants showed considerably higher LDL-cholesterol levels. More markedly, a close relationship was observed between the TyG index and the omega-6 polyunsaturated fatty acids compared with the HOMA-IR. Unlike HOMA-IR, with regard to the risks of developing chronic diseases, the MetS, the third tertile of the TyG index, showed an approximately 33.7 times greater odds ratio (OR) of the MetS occurring, compared with the first tertile of the TyG index. The TyG index may be considered as an IR assessment index. In addition, the TyG index is an advanced tool that reflects the relevance of pro-inflammation levels and the presence of IR-related chronic diseases.


Melatonin and psychiatry.
The pineal methoxyindole melatonin remains the most widely studied of the "pineal principles," and in subhuman species, the neuroendocrine status of this hormone is now generally acknowledged. In humans, however, no definitive functional activity for melatonin has yet been convincingly demonstrated, despite the description in recent years of marked changes in the metabolism of this hormone in several clinical categories. Currently, much interest is focused on the role that melatonin may play in various psychiatric disorders, and pineal research now represents one of the active areas of current psychiatry research. Investigators in this field have encountered many technical and practical difficulties, but the advent of the impressively sensitive and specific assay systems for melatonin has done much to facilitate the progress of research. Present ideas suggest a positive involvement of melatonin in affective disorders, possible involvement in the schizophrenic psychosis, and potential involvement of this hormone in other psychiatric categories. The present review discusses the etiological significance, diagnostic potential, and clinical utility of melatonin in psychiatry.


Lack of Improvement of Sperm Characteristics in Obese Males After Obesity Surgery Despite the Beneficial Changes Observed in Reproductive Hormones.
Even though obesity surgery normalizes circulating testosterone concentrations in males with obesity-associated secondary hypogonadism, its impact on spermatogenesis remains controversial. We aimed to evaluate sperm characteristics in obese men after bariatric surgery as well as changes in reproductive hormones. Twenty severely obese men (body mass index (BMI) ≥ 35 kg/m2) were evaluated before and 2 years after bariatric surgery. The serum was assayed for insulin, leptin, kisspeptin, and inhibin B, among other hormones. Homeostasis model assessment of insulin resistance (HOMA-IR) was estimated. We used World Health Organization reference values for sperm analysis. After surgery, serum total testosterone, calculated free testosterone, inhibin B, and kisspeptin increased, whereas fasting insulin, HOMA-IR, and leptin concentrations decreased. Despite these improvements, sperm volume showed a small decrease after surgery, while the rest of sperm characteristics remained mostly unchanged. Abnormal sperm concentration persisted in 60% of the patients. Sperm characteristics may not improve after bariatric surgery despite the beneficial changes of reproductive hormones.


[Shoulder arthrodesis using an external fixator in the treatment of chronic inflammatory complications of proximal humeral fractures].
Chronic osteomyelitis is a serious chronic condition that frequently results in permanent after-effects. Treatment is complex, lengthy and costly. Between the beginning of 2003 and the end of 2010, 438 operations of the proximal humerus were performed at our department using either angle-stable osteosynthesis or hemiarthroplasty. In four cases out of this group of patients, deep tissue infection affecting the bone developed. These four patients were treated with arthrodesis of the shoulder joint using an external fixation device. Arthrodesis was also the treatment method in a patient who previously received conservative treatment but developed chronic osteomyelitis. Healing of the infectious focus along with the formation of stable, painless shoulder was achieved in all five patients, with the arthrodesis offering full support for the limbs periphery. The above method represents an alternative to reverse arthroplasty of the shoulder joint usually performed after infection is cured. While function of the limb usually worsens after arthrodesis, the risk of recurring inflammation is substantially lower.


Assembly of synaptic active zones requires phase separation of scaffold molecules.
The formation of synapses during neuronal development is essential for establishing neural circuits and a nervous system1. Every presynapse builds a core 'active zone' structure, where ion channels cluster and synaptic vesicles release their neurotransmitters2. Although the composition of active zones is well characterized2,3, it is unclear how active-zone proteins assemble together and recruit the machinery required for vesicle release during development. Here we find that the core active-zone scaffold proteins SYD-2 (also known as liprin-α) and ELKS-1 undergo phase separation during an early stage of synapse development, and later mature into a solid structure. We directly test the in vivo function of phase separation by using mutant SYD-2 and ELKS-1 proteins that specifically lack this activity. These mutant proteins remain enriched at synapses in Caenorhabditis elegans, but show defects in active-zone assembly and synapse function. The defects are rescued by introducing a phase-separation motif from an unrelated protein. In vitro, we reconstitute the SYD-2 and ELKS-1 liquid-phase scaffold, and find that it is competent to bind and incorporate downstream active-zone components. We find that the fluidity of SYD-2 and ELKS-1 condensates is essential for efficient mixing and incorporation of active-zone components. These data reveal that a developmental liquid phase of scaffold molecules is essential for the assembly of the synaptic active zone, before maturation into a stable final structure.


Recent advances in paediatric sleep disordered breathing.
This article reviews the latest evidence pertaining to childhood sleep disordered breathing (SDB), which is associated with negative neurobehavioural, cardiovascular and growth outcomes. Polysomnography is the accepted gold standard for diagnosing SDB but is expensive and limited to specialist centres. Simpler tests such as cardiorespiratory polygraphy and pulse oximetry are probably sufficient for diagnosing obstructive sleep apnoea (OSA) in typically developing children, and new data-processing techniques may improve their accuracy. Adenotonsillectomy is the first-line treatment for OSA, with recent evidence showing that intracapsular tonsillectomy results in lower rates of adverse events than traditional techniques. Anti-inflammatory medication and positive airway pressure respiratory support are not always suitable or successful, although weight loss and hypoglossal nerve stimulation may help in select comorbid conditions. To understand the clinical impact of childhood sleep disordered breathing (SDB).To understand that, while sleep laboratory polysomnography has been the gold standard for diagnosis of SDB, other diagnostic techniques exist with their own benefits and limitations.To recognise that adenotonsillectomy and positive pressure respiratory support are the mainstays of treating childhood SDB, but different approaches may be indicated in certain patient groups.


Association of Bone Turnover Markers with Type 2 Diabetes Mellitus and Microvascular Complications: A Matched Case-Control Study.
The aim of this study was to evaluate the association of bone turnover markers (BTMs) with type 2 diabetes mellitus (T2DM) and microvascular complications. A total of 166 T2DM patients and 166 non-diabetic controls matched by gender and age were enrolled. T2DM patients were sub-classified into groups based on whether they had diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). Clinical data including demographic characteristics and blood test results [serum levels of osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and β-crosslaps (β-CTX)] were collected. Logistic regression and restrictive cubic spline curves were performed to examine the association of BTMs with the risk of T2DM and microvascular complications. After adjusting for family history of diabetes, sex and age, an inverse association was observed between elevated serum OC levels [O, p < 0.001] and increased serum P1NP levels , p < 0.001] with the risk of T2DM. Moreover, there was an inverse linear association of serum OC and P1NP levels with the risk of T2DM. However, β-CTX was not associated with T2DM. Further analysis showed a nonlinear association between OC and the risk of DR, while P1NP and β-CTX were not correlated with DR. Serum concentrations of BTMs were not associated with the risks of DPN and DKD. Serum OC and P1NP levels were negatively correlated with T2DM risk. Particularly, serum OC levels were associated with DR risk. Given that BTMs are widely used as markers of bone remodeling, the present finding provides a new perspective for estimating the risk of diabetic microvascular complications.


Phylogenetic Analysis and Codon Usage Bias Reveal the Base of Feline and Canine Chaphamaparvovirus for Cross-Species Transmission.
Chaphamaparvoviruses (ChPVs) are ancient viruses that have been detected in a variety of hosts. In this study, through a phylogenetic analysis and the adaptability of ChPV to multiple hosts, we evaluated the basis for the ability of feline (FeChPV) and canine ChPV (CaChPV) for cross-species transmission. Phylogenetic analysis showed that FeChPV and CaChPV were closely related. Notably, two strains of ChPVs isolated from domestic cats and two from dogs clustered together with CaChPVs and FeChPVs, respectively, suggesting that the stringent boundaries between canine and feline ChPV may be broken. Further analysis revealed that CaChPV and FeChPV were more adapted to dogs than to cats. Mutation analysis identified several shared mutations in cross-species-transmissible strains. Furthermore, the VP structures of FeChPV and CaChPV exhibited a high degree of similarity across both cross-species-transmissible and non-cross-species-transmissible strains. However, it is crucial to note that these results are largely computational, and limitations exist in terms of the number and diversity of samples analyzed; the capacity for cross-species transmission should be approached with caution and elucidated in further studies.


Correction: The Hog Cycle of Law Professors: An Econometric Time Series Analysis of the Entry-Level Job Market in Legal Academia.
[This corrects the article DOI: 10.1371/journal.pone.0159815.].


The role of biofilm on orthopaedic implants: the "Holy Grail" of post-traumatic infection management?
The development of post-traumatic infection is potentially a limb threatening condition. The orthopaedic trauma literature lags behind the research performed by our arthroplasty colleagues on the topic of implant-related infections. Surgical site infections in the setting of a recent ORIF are notoriously hard to eradicate due to biofilm formation around the implant. This bacteria-friendly, dynamic, living pluri-organism structure has the ability to morph and adapt to virtually any environment with the aim to maintain the causative organism alive. The challenges are twofold: establishing an accurate diagnosis with speciation/sensitivity and eradicating the infection. Multiple strategies have been researched to improve diagnostic accuracy, to prevent biofilm formation on orthopaedic implants, to mobilize/detach or weaken the biofilm or to target specifically bacteria embedded in the biofilm. The purpose of our paper is to review the patho-physiology of this mysterious pluri-cellular structure and to summarize some of the most pertinent research performed to improve diagnostic and treatment strategies in biofilm-related infections.


Composition and metabolism of phospholipids in Octopus vulgaris and Sepia officinalis hatchlings.
The objective of the present study was to characterise the fatty acid (FA) profiles of the major phospholipids, of Octopus vulgaris and Sepia officinalis hatchlings, namely phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylethanolamine (PE); and to evaluate the capability of both cephalopod species on dietary phospholipid remodelling. Thus, O. vulgaris and S. officinalis hatchlings were in vivo incubated with 0.3μM of L-∝-1-palmitoyl-2-[1-(14)C]arachidonyl-PC or L-∝-1-palmitoyl-2-[1-(14)C]arachidonyl-PE. Octopus and cuttlefish hatchlings phospholipids showed a characteristic FA profiles with PC presenting high contents of 16:0 and 22:6n-3 (DHA); PS having high 18:0, DHA and 20:5n-3 (EPA); PI a high content of saturated FA; and PE showing high contents of DHA and EPA. Interestingly, the highest content of 20:4n-6 (ARA) was found in PE rather than PI. Irrespective of the phospholipid in which [1-(14)C]ARA was initially bound (either PC or PE), the esterification pattern of [1-(14)C]ARA in octopus lipids was similar to that found in their tissues with high esterification of this FA into PE. In contrast, in cuttlefish hatchlings [1-(14)C]ARA was mainly recovered in the same phospholipid that was provided. These results showed a characteristic FA profiles in the major phospholipids of the two species, as well as a contrasting capability to remodel dietary phospholipids, which may suggest a difference in phospholipase activities.


The clinical significance of acquired jejunoileal diverticula.
Because of the relative rarity of acquired jejunoileal diverticulosis, including its symptomatology and complications, diagnosis is often difficult and delayed, resulting in unnecessary morbidity and mortality. The purpose of the present study was to draw attention to jejunoileal diverticula and their complications as a site of gastrointestinal symptoms. The records of 10 patients with symptomatic jejunoileal diverticula treated in our departments were reviewed. The clinical presentation was varying and nonspecific. Jejunoileal diverticula were diagnosed peroperatively in four patients operated on successfully for their acute complications. In one case the diagnosis was considered after a radiotargeted erythrocyte bleeding scan and in five other cases enteroclysis for chronic abdominal complaints demonstrated jejunoileal diverticula. The death of one patient operated on for massive hemorrhage from jejunal diverticula was probably related to delayed diagnosis and treatment. Jejunoileal diverticula should not always be dismissed as asymptomatic findings, as they may be the cause of vague, chronic symptomatology and acute complications, including intestinal obstruction, hemorrhage, and perforation. Awareness of the fact that jejunoileal diverticula may cause chronic nonspecific abdominal symptoms and serious acute complications may lead to earlier diagnosis and timely treatment with lower morbidity and mortality.


Morphometric MRI analysis enhances visualization of cortical tubers in tuberous sclerosis.
Focal cortical dysplasias (FCD) type IIb and cortical tubers in tuberous sclerosis complex (TSC) are histopathologically similar and are both epileptogenic lesions frequently causing pharmacoresistant epilepsies. Morphometric analysis of T1- and T2-weighted MRI volume data sets can enhance visualization of FCD. Here, we retrospectively investigated whether morphometric MRI analysis is of equal benefit for visualizing cortical tubers. Morphometric analysis was applied to T1- and partly also T2-weighted 1.5T or 3T MRI volume data sets of 15 TSC patients using a fully automated MATLAB(®) script (i.e. MAP07) commonly used for FCD detection. In this study, focus was on the most sensitive of the resulting morphometric feature maps (i.e. the 'junction image') which highlights blurring of the gray-white matter junction in comparison to a normal database. The visualization of tubers in these 'junction images' was quantitatively compared with that in conventional MR sequences. In all patients, morphometric analysis visualized almost all tubers detected in the normal MRI, and additionally highlighted on average 23% (range 3-50%) more tubers which were not detected by visual analysis of the conventional MR sequences. When T2 volume data sets from a 3T scanner were available for postprocessing, the rate of additionally detected tubers increased to 29% on average. These formerly overlooked tubers were usually smaller than the tubers already found in the conventional MRI. Morphometric analysis of MRIs in TSC can highlight cortical tubers which are likely to be overlooked in conventional MRI sequences alone. Additionally detected tubers may be of potential importance for both presurgical evaluation and initial diagnosis of TSC.


[DNA mutations associated to rifampicin or isoniazid resistance in M. tuberculosis clinical isolates from Sonora, Mexico].
To perform the analysis of specific regions of the major genes associated with resistance to isoniazid or rifampin. Twenty two M. tuberculosis strains, isolated from human samples obtained in Sonora, Mexico. Specific primers for hotspots of the rpoB, katG, inhA genes and the ahpC-oxyR intergenic region were used. The purified PCR products were sequenced. Mutations in the promoter of inhA, the ahpC-oxyR region, and codon 315 of katG and in 451 or 456 codons of rpoB, were identified. Detection of mutations not previously reported requires further genotypic analysis of Mycobacterium tuberculosis isolates in Sonora.


The influence of reward anticipation on conflict control in children and adolescents: Evidences from hierarchical drift-diffusion model and event-related potentials.
Reward is deemed a performance reinforcer. The current study investigated how social and monetary reward anticipation affected cognitive control in 39 children, 40 adolescents, and 40 adults. We found that cognitive control performance improved with age in a Simon task, and the reaction time (RT) was modulated by the reward magnitude. The conflict monitoring process (target N2 amplitudes) of adolescents and the attentional control processes (target P3 amplitudes) of adolescents and adults could be adjusted by reward magnitude, suggesting that adolescents were more sensitive to rewards compared to children. Reward magnitudes influenced the neural process of attentional control with larger P3 in congruent trails than that in incongruent trials only in low reward condition. The result of hierarchical drift-diffusion model indicated that children had slower drift rates, higher decision threshold, and longer non-decision time than adolescents and adults. Adolescents had faster drift rates in monetary task than in social task under the high reward condition, and they had faster drift rates under high reward condition than no reward condition only in the monetary task. The correlation analysis further showed that adults' non-decision time and decision threshold correlated with conflict monitoring process (N2 responses) and attentional control process on conflicts (P3 responses). Adolescents' drift rates associated with neural process of attentional control. The current study reveals that reward magnitude and reward type can modulate cognitive control process, especially in adolescents.


The preparation and characterization of novel human-like collagen metal chelates.
In order to develop the nutritional trace elements which could be absorbed and utilized effectively, protein chelates were adopted. Calcium, copper and manganese were considered based on their physiological functions, and the new chelates of HLC-Ca, HLC-Cu and HLC-Mn were formed in MOPS or MES buffer and purified by gel chromatography, and then freeze-dried. And they were detected and analyzed by atomic absorption spectrophotometry, ultraviolet-visible absorption (UV-vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, fluorescence quenching method, circular dichroism (CD) and differential scanning calorimetry (DSC). The results showed that some chemical reactions happened between HLC and the three metal ions to form new chemical compounds. The thermodynamic parameters, ∆H, ∆G and ∆S, showed that the chelation process between HLC and metal ions was performed spontaneously. Fluorescence quenching spectra of HLC indicated that the quenching mechanism was static in nature. According to the data of DSC, the new chelates were more stable than the free HLC. And HLC-metal complex was non-toxic to the BHK21 cell through MTT assay.


Evidence of acute inflammation in the periodontal ligament subsequent to orthodontic tooth movement in rats.
Experimental orthodontic tooth extrusion can result in red cell diapedesis through the PDL vascular wall. Diapedesis is an early sign of acute inflammation. At the ultrastructural level, red cell migration is demonstrated occurring through the endothelial junction of a postcapillary-sized venule. This phenomenon is considered to be indicative of unphysiological tooth loading.


Bionic Construction of Helical Bi2 O3 Microfibers for Highly Efficient CO2 Electroreduction.
Helical Bi2 O3 microfibers (HBM) were prepared with the assistance of cotton template through a simple heating treatment in air. This twisted structure induced the lattice strains, enriched the oxygen vacancies of Bi2 O3 , and promoted the sufficient exposure of active sites simultaneously, thus performing outstanding activity and selectivity as catalyst for CO2 electroreduction to formate. The faradaic efficiency (FE) of formate reached 100.4±1.9 % at -0.90 V vs. reversible hydrogen electrode (RHE) in an H-cell, and the partial current density was boosted to 226 mA cm-2 with FEformate of 96 % at -1.08 V vs. RHE in a flow cell. This work may open a new era for construction of metal oxide fibers by bionic strategy as high-performance electrocatalysts.


Evolution-inspired design of multicolored photoswitches from a single cyanobacteriochrome scaffold.
Cyanobacteriochromes (CBCRs) are small, bistable linear tetrapyrrole (bilin)-binding light sensors which are typically found as modular components in multidomain cyanobacterial signaling proteins. The CBCR family has been categorized into many lineages that roughly correlate with their spectral diversity, but CBCRs possessing a conserved DXCF motif are found in multiple lineages. DXCF CBCRs typically possess two conserved Cys residues: a first Cys that remains ligated to the bilin chromophore and a second Cys found in the DXCF motif. The second Cys often forms a second thioether linkage, providing a mechanism to sense blue and violet light. DXCF CBCRs have been described with blue/green, blue/orange, blue/teal, and green/teal photocycles, and the molecular basis for some of this spectral diversity has been well established. We here characterize AM1_1499g1, an atypical DXCF CBCR that lacks the second cysteine residue and exhibits an orange/green photocycle. Based on prior studies of CBCR spectral tuning, we have successfully engineered seven AM1_1499g1 variants that exhibit robust yellow/teal, green/teal, blue/teal, orange/yellow, yellow/green, green/green, and blue/green photocycles. The remarkable spectral diversity generated by modification of a single CBCR provides a good template for multiplexing synthetic photobiology systems within the same cellular context, thereby bypassing the time-consuming empirical optimization process needed for multiple probes with different protein scaffolds.


Simultaneous determination of all-trans and 13-cis retinoic acids and their 4-oxo metabolites by adsorption liquid chromatography after solid-phase extraction.
All-trans retinoic acid (all-trans RA), the active metabolite of vitamin A, has been demonstrated to be an efficient alternative to chemotherapy in the treatment of acute promyelocytic leukemia (APL), the AML3 subtype of the FAB cytological classification. Complete remission is obtained by inducing terminal granulocytic differentiation of the leukemic cells. To study all-trans RA pharmacokinetics in patients with APL, a rapid, precise and selective high-performance liquid chromatographic (HPLC) assay was developed. This method is easy and shows good repeatability (C.V. = 8.41-12.44%), reproducibility (C.V. = 9.19-14.73%), accuracy (C.V. = 3.5-11%) and sensitivity with a detection limit of 5 pmol/ml. The analysis is performed using normal-phase HPLC in an isocratic mode with UV detection after solid-phase extraction on octadecyl (C18) columns. The mobile phase is hexane-dichloromethane-dioxane (78:18:4, v/v) containing 1% acetic acid.


Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm.
A definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that warrant genetic testing. Electrical activity of the diaphragm (Edi) reflects neural respiratory drive from respiratory center to diaphragm. We evaluated the function of the respiratory center in CCHS by Edi monitoring. Monitoring of Edi was performed in six CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously. The Edi peak during wakefulness was 14.0 (10.3-21.0) µV and the Edi peak during sleep was 6.7 (3.8-8.0) µV. The Edi peak during sleep was significantly lower than the Edi peak during wakefulness, and patients were in a state of hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in the Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06μV/mmHg. Maximum EtCO2 or TcPco2 was 51 mmHg, and the average SpO2 was 91.5% during monitoring. We confirmed that Edi monitoring could evaluate the function of the respiratory center and reproduce the hypoventilation of CCHS. The present study suggested that Edi monitoring is a useful examination in deciding whether to perform genetic testing or not and it may lead to an early diagnosis of CCHS.


Sulfur containing derivatives from Ferula persica var. latisecta.
Two new sulfur containing derivatives, t-butyl 3-[(1-methylpropyl)dithio]-2-propenyl malonate (1), t-butyl 3-[(1-methylthiopropyl)thio]-2-propenyl malonate (2) were isolated from the roots of Ferula persica Willd. var. latisecta D. F. Chamberlain. Their structures were elucidated by spectral methods.


Anthraquinone Covalent Organic Framework Hollow Tubes as Binder Microadditives in Li-S Batteries.
The exploration of new application forms of covalent organic frameworks (COFs) in Li-S batteries that can overcome drawbacks like low conductivity or high loading when typically applied as sulfur host materials (mostly ≈20 to ≈40 wt % loading in cathode) is desirable to maximize their low-density advantage to obtain lightweight, portable, or high-energy-density devices. Here, we establish that COFs could have implications as microadditives of binders (≈1 wt % in cathode), and a series of anthraquinone-COF based hollow tubes have been prepared as model microadditives. The microadditives can strengthen the basic properties of the binder and spontaneously immobilize and catalytically convert lithium polysulfides, as proved by density functional calculations, thus showing almost doubly enhanced reversible capacity compared with that of the bare electrode.


Continuous hemodiafiltration therapy ameliorates LPS-induced systemic inflammation in a rat model.
Systemic inflammation can result in multiple organ dysfunction syndrome, a potentially life-threatening condition. Some reports suggest that continuous hemodiafiltration can effectively remove proinflammatory cytokines from circulation during systemic inflammation. In the present study, we investigated whether continuous hemodiafiltration therapy could prevent LPS-induced systemic inflammation and improve survival in a rat model. Male Wistar rats were injected with lipopolysaccharide (LPS; 7.5 mg/kg body weight), and 6 h later were treated with either single-pass hemofiltration (C group), continuous hemofiltration (CHF group), continuous hemodiafiltration (CHDF group), or mock filtration (Control group). We performed histologic examinations of lung and liver tissues, determined serum cytokine levels, and survival rates for each treatment group, and compared cytokine removal between CHF and CHDF therapies. Histologic examination revealed significant reduction in inflammation in lung and liver tissues harvested 24 h after CHDF compared with the Control group. Likewise, LPS-induced serum TNF-α and IL-6 levels decreased with continuous hemodiafiltration along with a significant improvement in survival. After 30 min of treatment, both CHF and CHDF removed significant amounts of TNF-α and IL-6 from the blood. However, serum cytokine levels measured before and after filtration were not significantly different. Continuous hemodiafiltration therapy lowered inflammatory cytokines and increased survival rates in a rat model of systemic inflammation. Therefore, continuous hemodiafiltration may be a potential therapy for use against various systemic inflammatory diseases.


Systematic review of drug utilization studies & the use of the drug classification system in the WHO-SEARO Region.
Information available on drug consumption is inadequate in most low and middle income countries. This systematic review was conducted to analyse published work on drug utilization research/studies (DUR) in the SEARO region of WHO for study objectives, methodology, results and recommendations and to identify the need for improving DUR and the use of the ATC/DDD system. A literature search for DUR was carried out in biomedical databases (PubMed, Scirus, Scopus and Google Scholar) up to May 2012. Publications were selected if those were in the English language, describing DUR or prescription practices, and study conducted in the WHO-SEARO countries. A total of 318 publications were included in the review. Of these, 67 per cent were from India and 13 per cent were from Thailand. Majority of the publications were hospital based; only 16 per cent were community based. The ATC/DDD system was used in only 20 per cent of the publications, of which 73 per cent publications used DDD indicators. Several publications focused on antibiotics (31%). Publications that recommended the need for a policy or intervention to improve prescription practices/rational drug use amounted to 35 per cent. Drug utilization studies using ATC/DDD system need to be promoted and carried out on an ongoing basis. DUR is important for rational use of drugs. Its relevance to policy making and resource allocation needs to be emphasized.


A comparison of multi-ligament reconstruction and isolated anterior cruciate ligament reconstruction at one year follow-up: results from the Danish Knee Ligament Reconstruction Registry.
The Danish Knee Ligament Reconstruction Registry (DKRR) has monitored the outcomes of surgeries for multi-ligament knee injuries (MLKI) since 2005. This study aimed to compare the subjective clinical outcomes of patients who had undergone surgery after MLKI with those of patients who had received isolated anterior cruciate ligament (ACL) reconstruction. This study used patient-reported outcome scores at 1-year follow-up as the primary outcome and contains the outcome data of knee ligament surgeries retrieved from the DKRR. Clinical subjective outcomes and knee function were evaluated with Knee Injury and Osteoarthritis Outcome Scores (KOOS) and Tegner Activity Scale (Tegner) scores. Demographic differences were examined using the Student's t-test and the chi-square test. Multiple linear regression was used to analyse the data and adjust for potentially confounding factors. P-values < 0.05 were considered to be statistically significant. A total of 31,686 knee ligament surgeries were registered in the DKRR between 2005 and 2017, resulting in 1,160 multi-ligament patients and 28,843 isolated ACL patients. The mean age of the MLKI group was significantly higher than that of the isolated ACL group (33.2 years [95% CI 32.5-33.9] vs. 28.3 years [95% CI 28.1-28.4]). The adjusted KOOS Sport and Quality of Life (QoL) sub-scores and Tegner scores of the MLKI group significantly improved from the baseline to the 1-year follow-up (16.7 points [95%CI 12.8;20.6], 12.6 points [95%CI 9.6;15.6] and 1.76 points [95%CI 1.43;2.08], respectively). The KOOS Sport and QoL sub-scores of the isolated ACL group were significant and increased more than those of the MLKI group. No differences in the Tegner scores were observed. Surgical reconstruction after multi-ligament knee injury resulted in significant subjective outcome improvements at 1- year follow-up. The KOOS Sport and QoL sub-scores of the isolated ACL group significantly increased compared to those of the MLKI group.


Temporal lobe resections in children.
Often, seizures in childhood are intractable to medical therapy. Intractable seizures and prolonged anticonvulsant medication can adversely affect intellectual development and psychosocial maturation in children. Temporal lobe resections for complex partial seizures and focal epilepsy in children can be performed with minimal morbidity. The higher morbidity lies with prolonged observation of these children with intractable seizures. The final result of surgical treatment shows that children can significantly benefit from an early developmental period without anticonvulsant medication or intractable seizures with improvements in both IQ and behavioral interactions. With improvements in neuroimaging techniques and evaluation procedures, more children can be identified who might benefit from a resective procedure. It is thus advocated that early evaluation and surgical intervention be performed to gain improvement in seizure control and psychosocial development.


A Systematic Review of the Efficacy and Safety of Ketamine in Total Joint Arthroplasty.
Ketamine is administered intraoperatively to treat pain associated with primary total hip (THA) and knee arthroplasty (TKA). The purpose of this study was to evaluate the efficacy and safety of ketamine in primary THA and TKA to support the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons (AAHKS), American Academy of Orthopaedic Surgeons (AAOS), Hip Society, Knee Society, and the American Society of Regional Anesthesia and Pain Management (ASRA). The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for studies published prior to 2020 on ketamine in THA and TKA. All included studies underwent qualitative assessment and quantitative homogeneity testing followed by a systematic review and direct comparison meta-analysis to assess the efficacy and safety of ketamine. After a critical appraisal of 136 publications, 7 high-quality studies were included for analyses. High-quality evidence demonstrates that intraoperative ketamine decreases postoperative opioid consumption. Four of 7 studies found that ketamine reduces postoperative pain. Intraoperative ketamine is not associated with an increase in adverse events and may reduce postoperative nausea and vomiting (relative risk [RR] 0.68; 95% CI 0.50-0.92). High-quality evidence supports the use of ketamine intraoperatively in THA and TKA to reduce postoperative opioid consumption. Most studies found ketamine reduces postoperative pain, nausea, and vomiting. Moderate quality evidence supports the safety of ketamine, but it should be used cautiously in patients at risk for postoperative delirium, such as the elderly.


Synthesis, characterization and biodistribution of a new hexadentate aminethiol ligand labeled with Tc-99m.
A new hexadentate aminethiol ligand (TACNS) derived from triazacyclononane was synthesized and characterized for the development of technetium radiopharmaceuticals. The ligand formed a neutral, lipophilic and stable complex with [99mTc]pertechnetate in the presence of tin(II)tartarate as a reducing agent. The biodistribution of [99mTc]TACNS indicates slight uptake in brain (0.23% ID/organ at 5 min) with a washout at 30 min to 0.14% ID/organ. A small uptake in heart (0.48% ID at 5 min) was also observed. The characterization of [99mTc]TACNS complex using single crystal x-ray analysis and mass spectroscopy has shown that an Sn-N3S3 complex was formed in which tin is oxidized from Sn(II) to Sn(IV). Pertechnetate was incorporated into the complex as counter anion. The nature of the species formed with Tc-99 and "no-carrier-added" [99mTc]pertechnetate is different as confirmed by ratio TLC. From these results, it is demonstrated that sometimes it may be difficult to predict the structure of new technetium radiopharmaceuticals, especially when stannous ion is used as a reducing agent. Moreover, the nature of the chemical species may not be the same at millimolar and at nanomolar levels.


Brief Report: Late-Onset Cryopyrin-Associated Periodic Syndrome Due to Myeloid-Restricted Somatic NLRP3 Mosaicism.
Gain-of-function NLRP3 mutations cause cryopyrin-associated periodic syndrome (CAPS), with gene mosaicism playing a relevant role in the pathogenesis. This study was undertaken to characterize the genetic cause underlying late-onset but otherwise typical CAPS. We studied a 64-year-old patient who presented with recurrent episodes of urticaria-like rash, fever, conjunctivitis, and oligoarthritis at age 56 years. DNA was extracted from both unfractionated blood and isolated leukocyte and CD34+ subpopulations. Genetic studies were performed using both the Sanger method of DNA sequencing and next-generation sequencing (NGS) methods. In vitro and ex vivo analyses were performed to determine the consequences that the presence of the variant have in the normal structure or function of the protein of the detected variant. NGS analyses revealed the novel p.Gln636Glu NLRP3 variant in unfractionated blood, with an allele frequency (18.4%) compatible with gene mosaicism. Sanger sequence chromatograms revealed a small peak corresponding to the variant allele. Amplicon-based deep sequencing revealed somatic NLRP3 mosaicism restricted to myeloid cells (31.8% in monocytes, 24.6% in neutrophils, and 11.2% in circulating CD34+ common myeloid progenitor cells) and its complete absence in lymphoid cells. Functional analyses confirmed the gain-of-function behavior of the gene variant and hyperactivity of the NLRP3 inflammasome in the patient. Treatment with anakinra resulted in good control of the disease. We identified the novel gain-of-function p.Gln636Glu NLRP3 mutation, which was detected as a somatic mutation restricted to myeloid cells, as the cause of late-onset but otherwise typical CAPS. Our results expand the diversity of CAPS toward milder phenotypes than previously reported, including those starting during adulthood.


Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma.
The objective of this study was to evaluate the efficacy and safety of icotinib in patients with brain metastases (BMs) from lung adenocarcinoma. Clinical data of 28 cases with BMs from lung adenocarcinoma were retrospectively analyzed. All the patients took 125 mg icotinib orally three times a day. Progression of disease, intolerable adverse reactions, and number of deaths were recorded. For all the patients, the remission rate of icotinib was 67.8% and the disease control rate was 96.4%. The median overall survival time of patients was 21.2 months, and the median progression-free survival time of patients was 10.9 months. Only mild adverse events of grade 1/2 were observed during the treatment. Icotinib was an effective and safe strategy to treat patients with BMs from lung adenocarcinoma.


Systemic cryptococcosis in an immune-competent child.
Crytococcus neoformans is an encapsulated yeast that frequently affects immune-compromised patients, although increasingly being detected in the immune-competent host as well. We report a case of disseminated cryptococcosis in a young child in whom no immune deficiency was yet identified. A 4-year-old child presented with high-grade fever, intermittent abdominal pain and generalized skin eruptions for the past two months. He had pallor, firm lymphadenopathy, skin lesions with scarring and firm hepatosplenomegaly. Magnetic resonance imaging of brain and bone-marrow aspiration were normal. Fine-needle-aspiration-cytology of cervical lymph nodes demonstrated Cryptococcus. Serum latex-agglutination test showed a positive titer (1:256). Cryptococcus culture was sterile. The patient received intravenous liposomal amphotericin-B and oral flucytosine for 8 weeks followed by oral fluconazole. Disseminated cryptococcosis with involvement of reticuloendothelial and dermatological systems is rare. Early diagnosis and timely management of associated complications would be life saving.


Can abdominal hypropressive technique improve stress urinary incontinence? an assessor-blinded randomized controlled trial.
To verify which one improves better stress urinary incontinence (SUI) symptoms: abdominal hypopressive technique (AHT) or pelvic floor muscle training (PFMT). Randomized controlled trial. Women with SUI who had not participated of physiotherapy program before were invited. The outcome measures were 7-day bladder diary, International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and pelvic floor muscles (PFM) function measured by Modified Oxford grading System with vaginal palpation and manometry with Peritron. Intervention consisted by 12 weeks of exercises program including PFMT or AHT program, in groups of maximum three women, twice a week, with physiotherapist supervision. AHT and PFMT groups reduced urinary leakage episodes in 7 days, -0.64 and -1.91, respectively, but PFMT was superior, whit mean difference -1.27 (95% confidence interval [CI]: -1.92 to -0,62) and effect size was 0.94 in favor to PFMT. Regarding to total score of ICIQ-SF, both groups improved, with mean difference between groups -4.7 (95% CI: -6.90 to -2.50) and effect size was 1.04 in favor to PFMT. Manometry also presented improvement after treatment for both groups with mean difference between them of 11 (95% CI: 6.33-15.67) and effect size was 1.15 also in favor to PFMT. Regarding to SUI symptoms, quality of life impact and PFM function both groups presented improvement, however, PFMT was superior to AHT among all of them.


Molecular cloning, expression pattern, and chemical analysis of heat shock protein 70 (HSP70) in the mudskipper Boleophthalmus pectinirostris: Evidence for its role in regulating spermatogenesis.
Heat shock protein 70 (HSP70) is molecular chaperone that is important for reproductive biological processes. In this study, a full length HSP70 from the mudskipper (Boleophthalmus pectinirostris) was characterized. It was found to contain: a 108 bp 5'-untranslated region, a 208 bp 3'-untranslated region, and a 1953 bp open reading frame, which encodes a protein of 650 amino acids with a theoretical molecular weight of 71.1 kDa and an isoelectric point of 5.17. RT-PCR analysis revealed that HSP70 was ubiquitously expressed in all major tissues with differential expression levels. This suggests that HSP70 has vital and conserved biological functions. HSP70 was localized mainly in the cytoplasm of germinal cells, indicating an important role of this protein during spermatogenesis. In response to heat stress, the testes presented abnormal morphology in connective tissues, in which HSP70 immunoreactivity was not observed. HSP70 mRNA expression in the gill, liver, and testes was significantly increased, which suggests that HSP70 plays an important role in protection against heat stress.


Role of beta2-containing nicotinic acetylcholine receptors in auditory event-related potentials.
Nicotine improves sensory processing in schizophrenic individuals, as measured by changes in auditory event-related potentials (ERPs). Nicotine administration also alters ERPs in mice by increasing the amplitude and gating of the P20 ERP component while decreasing the amplitude of the N40 ERP component. Less is known about the role of specific nicotinic acetylcholine receptor (nAChR) subtypes. In this study, we examined whether nAChRs containing the beta2 subunit contribute to nicotine's effects on auditory ERPs. We tested the effect of nicotine in wild-type mice and mice lacking the beta2 nAChR subunit. Mice underwent stereotaxic implantation of stainless steel electrodes located in the CA3 region of the hippocampus, and 50 paired click stimuli were delivered during each drug condition. There was no significant difference in P20 or N40 amplitude or gating between genotypes during the control condition, suggesting that beta2-containing receptors are not essential for the baseline auditory ERP response. Nicotine increased P20 amplitude and enhanced gating in wild-type and beta2 knockout mice, but only decreased N40 amplitude in wild-type mice. There was no effect of nicotine on N40 gating in either genotype. beta2-containing receptors are necessary for nicotine's effects on the N40 component of the mouse auditory ERP. These results suggest that beta2-containing nAChRs modulate sensory processing and may serve as a therapeutic target in schizophrenic individuals.


Cis-regulatory elements and transcription factors related to auxin signaling in the streptophyte algae Klebsormidium nitens.
The phytohormone auxin affects numerous processes in land plants. The central auxin signaling machinery, called the nuclear auxin pathway, is mediated by its pivotal receptor named TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFB). The nuclear auxin pathway is widely conserved in land plants, but auxin also accumulates in various algae. Although auxin affects the growth of several algae, the components that mediate auxin signaling have not been identified. We previously reported that exogenous auxin suppresses cell proliferation in the Klebsormidium nitens that is a member of streptophyte algae, a paraphyletic group sharing the common ancestor with land plants. Although K. nitens lacks TIR1/AFB, auxin affects the expression of numerous genes. Thus, elucidation of the mechanism of auxin-inducible gene expression in K. nitens would provide important insights into the evolution of auxin signaling. Here, we show that some motifs are enriched in the promoter sequences of auxin-inducible genes in K. nitens. We also found that the transcription factor KnRAV activates several auxin-inducible genes and directly binds the promoter of KnLBD1, a representative auxin-inducible gene. We propose that KnRAV has the potential to regulate auxin-responsive gene expression in K. nitens.


Antibiotic resistance rates and phenotypes among isolates of Enterobacteriaceae in French extra-hospital practice.
Antibiotic resistance among members of the family Enterobacteriaceae was prospectively surveyed by eight French private laboratories over a 5-month period in 1999. A total of 2,599 consecutive and nonduplicate strains were collected, mainly (60.9%) from patients in the community. Most strains (82.9%) derived from urine. Escherichia coli was the predominant (73.9%) organism isolated. The overall rates of antibiotic resistance were as follows: amoxicillin, 53.4%; amoxicillin-clavulanic acid, 27.3%; ticarcillin, 44.2%; piperacillin-tazobactam, 3.2%; cephalothin, 29.2%; cefuroxime, 14.7%; cefoxitin, 11.5%; ceftazidime, 3.6%; cefotaxime, 2.8%; cefepime, 0.3%; imipenem, 0.1%; gentamicin (G), 3.8%; tobramycin (T), 5.0%; netilmicin (Nt), 3.7%; amikacin (A), 0.7%; nalidixic acid, 14.3%; ofloxacin, 10.4%; cotrimoxazole, 21.1%; nitrofurantoin, 12.7%; fosfomycin, 5.2%; tetracycline, 50.1%; and colistin, 12.5%. Beta-lactam resistance phenotypes essentially comprised penicillinase production (33.9%), overexpression of chromosomal cephalosporinase (4.6%), and synthesis of inhibitor-resistant TEM/OXA enzymes (1.5%) or extended-spectrum beta-lactamases (1.5%). Aminoglycoside resistance phenotypes consisted of GTNt (93 strains), TNtA (68 strains), GTNtA (14 strains), T (4 strains), GT (3 strains), G (1 strain), and reduced uptake/permeability (3 strains). Most of the nalidixic acid-resistant strains were resistant to ofloxacin (72.8%). Antibiotic resistance rates and phenotypes varied widely according to the bacterial group and the source of the strains. Significantly higher rates were observed in private healthcare centers than in the community, due to a higher proportion of both resistant species and resistant strains. However, multidrug-resistant isolates, including five extended-spectrum beta-lactamase-producing strains, were also recovered from the community.


Disruption of the relationship between renin and atrial natriuretic peptide early in the course of ventricular dysfunction.
Plasma renin activity is normal in left ventricular dysfunction in the absence of diuretic therapy. In health there is a reciprocal relationship between renin and atrial natriuretic peptide (ANP) but a positive correlation in advanced heart failure. The relationship between renin and ANP in mild left ventricular dysfunction is unknown. Patients with left ventricular dysfunction (n = 35, 18 without diuretic therapy) were compared to 20 age-matched healthy subjects. Plasma concentrations of active renin (PARC), ANP and norepinephrine were measured after 20 min rest and 45 min after an infusion of normal saline (10 ml/kg body wt.). Basal plasma ANP was increased in patients with left ventricular dysfunction compared to healthy subjects, whether or not they were receiving diuretics. PARC was similar in healthy controls and patients untreated with diuretics but was increased in diuretic treated patients. After saline loading in healthy subjects PARC fell while ANP rose. Patients with left ventricular dysfunction had a smaller decline in PARC, that did not achieve statistical significance, but had a greater increase in plasma ANP compared to healthy subjects (P<0.05). The close reciprocal relationship between PARC and ANP observed in healthy subjects before and after saline loading (r = 0.8, P<0.001 and r = 0.6, P<0.01) was weakened in those not receiving diuretics (r = 0.4, P<0.05 and r = 0.24, ns) and lost in those receiving diuretics (r = 0.1 and r = 0.08). Patients with left ventricular dysfunction have a disturbance of the normal reciprocal relationship between PARC and ANP which antedates diuretic treatment. This should be taken into account when interpreting plasma neuroendocrine measurements in patients with ventricular dysfunction.


Enterohaemorrhagic E. coli modulates an ARF6:Rab35 signaling axis to prevent recycling endosome maturation during infection.
Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC/EHEC) manipulate a plethora of host cell processes to establish infection of the gut mucosa. This manipulation is achieved via the injection of bacterial effector proteins into host cells using a Type III secretion system. We have previously reported that the conserved EHEC and EPEC effector EspG disrupts recycling endosome function, reducing cell surface levels of host receptors through accumulation of recycling cargo within the host cell. Here we report that EspG interacts specifically with the small GTPases ARF6 and Rab35 during infection. These interactions target EspG to endosomes and prevent Rab35-mediated recycling of cargo to the host cell surface. Furthermore, we show that EspG has no effect on Rab35-mediated uncoating of newly formed endosomes, and instead leads to the formation of enlarged EspG/TfR/Rab11 positive, EEA1/Clathrin negative stalled recycling structures. Thus, this paper provides a molecular framework to explain how EspG disrupts recycling whilst also reporting the first known simultaneous targeting of ARF6 and Rab35 by a bacterial pathogen.


Multivariate analysis of survival, local control, and time to distant metastases in patients with unresectable non-small-cell lung carcinoma treated with 3-dimensional conformal radiation therapy with or without concurrent chemotherapy.
Three-dimensional (3D) conformal radiation therapy (CRT) and chemotherapy have recently improved lung cancer management. We reviewed outcomes in 68 patients with unresectable stage I-III non-small-cell lung cancer. Treatment consisted of 3D CRT alone or with concurrent chemotherapy (CCR). Concurrent chemotherapy improved survival, to a median of 17 months +/- 4.9 months, compared with 8 months+/- 4.1 months for the radiation therapy (RT) alone group (P=0.0347). The 2- and 5-year survival rates were 40.3%+/-7.7% and 14.1%+/-6.4%, respectively, with CCR, compared with 19.6%+/- 9.6% and 0, respectively, for RT alone. In a subgroup analysis for age > 65, patients who received CCR (n=20) had significantly improved survival and local control (P=0.005 and P=0.0286, respectively). Acute esophageal toxicity Radiation Therapy Oncology Group grade >or= 3 was significantly higher in the CCR group and correlated with the RT dose (19% in CCR vs. 0 in RT, P=0.0234; P=0.050). The overall incidences of esophageal and pulmonary toxicity grade >or= 3 were 20.6% and 5.9%, respectively. Our study confirms that CCR is associated with improved survival over RT alone, with a tolerable increase in acute toxicity.


A thumb opposition splint to improve manual dexterity and upper-limb functioning in Charcot-Marie-Tooth disease.
To assess initial efficacy and tolerability of a thumb opposition splint on manual dexterity, perceived upper limb functioning and occupational performance in patients with Charcot-Marie-Tooth disease. One group pre-post design. Thirteen patients were provided with a neoprene opposition splint for their dominant hand. Manual dexterity (Sollerman hand function test), perceived upper limb functioning (Michigan Hand Outcomes Questionnaire) and occupational performance (Canadian Occupational Performance Measure) were assessed after using the splint and compared with pre-treatment scores (paired t-tests). Usability and tolerability were assessed with a questionnaire. Sollerman test scores improved significantly from a mean of 47 (standard deviation (SD) 11) to 52 (SD 12) points (norm 80 points) (p = 0.006). Perceived functioning in the domain activities of daily living (scale 0-100) improved significantly from 51 (SD 20) to 60 (SD 17) points (p = 0.04). Both occupational performance and satisfaction scores improved significantly (p = 0.020). Efficacy did not relate to age, disease duration or severity. Subjects were satisfied with splint cosmesis and comfort. These results indicate that a thumb opposition splint can be applied effectively to improve upper limb functioning in patients with Charcot-Marie-Tooth disease.


Junctional epidermolysis bullosa associated with hypoplastic enamel and pervasive failure of tooth eruption: Oral rehabilitation with use of an overdenture.
This report describes a previously unreported case of generalized hypoplastic enamel and failure of eruption of the permanent maxillary teeth and only partial eruption of the permanent mandibular teeth in an 18-year-old male diagnosed with junctional epidermolysis bullosa. Similar anomalies were reported to have affected the deciduous dentition. Beginning at 4 years of age, oral rehabilitation has been conservatively managed with the fabrication of various maxillary complete overdentures. The use of this prosthesis has provided an economical, nonsurgical treatment option when oral soft tissue permits and with relative ease of construction.


Facile preparation and characterization of super tough chitosan/poly(vinyl alcohol) hydrogel with low temperature resistance and anti-swelling property.
Facile preparation of super tough hydrogels with low temperature tolerance and anti-swelling property is still a challenging task for researchers. Meanwhile, the vast majority of tough hydrogels were obtained though chemical crosslinking and complicated synthesis or processing method accompanying a large number of harmful chemical reagents. Herein, the super tough chitosan/poly(vinyl alcohol) (CS/PVA) hydrogels (the maximum compressive strength of 18.97 MPa at a strain of 80% and the maximum tensile strength of 4.02 MPa at a strain of 406.4%) were successfully prepared via a simple post-treatment method. CS/PVA hydrogels were firstly prepared by freezing-thawing process and then soaking in saturated sodium chloride aqueous solution. The resultant hydrogels possess excellent swelling resistance and low temperature tolerance. This work shows that the post-treatment of immersing in saline solution is a feasible way to prepare super tough hydrogels with low temperature tolerance and anti-swelling property. This also would enlarge the application areas of CS.


An overview of Mycoplasma bovis mastitis in Israel (2004-2014).
The prevalence of Mycoplasma bovis in milk samples submitted to the Israeli National Service for Udder Health and Milk Quality was determined during the period 2004-2014 and the genetic pattern of the obtained isolates was assessed by multilocus sequence typing (MLST). Mycoplasma spp. were identified in 66 herds including M. bovis (n = 60), M. cottewii (n = 3), M. bovigenitalium (n = 2), M. alkalescens (n = 2) and M. yeatsii (n = 1). The proportion of M. bovis infected herds was relatively low (0-0.68%) in 2004-2007, increased to 3.77% during the 2008 outbreak, and ranged from 0.77 to 2.77% during the 2009-2014 period. Since 2008, about eight M. bovis positive dairy herds have been identified in Israel annually, with six of which on average being newly infected. MLST of 57 M. bovis isolates revealed that sequence type 10 was the dominant genotype identified in 60% of the herds. In conclusion, these data show that M. bovis is the main mycoplasmal mastitic pathogen in Israel.


Prevalence of treated patients with Alzheimer's disease: current trends and COVID-19 impact.
There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population. To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic. Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019. Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020. The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.


Reevaluation of the contributions of reactive intermediates to the photochemical transformation of 17β-estradiol in sewage effluent.
Photodegradation of the natural steroid 17β-estradiol (E2), an endocrine-disrupting hormone that has been widely detected in aquatic environments, was investigated in wastewater effluents at various pH ranges under simulated solar irradiation. The rate of E2 degradation in the sewage effluents was stable at pH 6.0-7.0 but suddenly increased from pH 8.0-10.0. The second-order reaction rate constants of E2 with 3EfOM* and CO3•- were measured to increase 11.0-fold and 18.0-fold from pH 6.0 to 10.0, respectively. Two main reasons are proposed for this sharp increase. First, the change in the ionization state of E2 made it susceptible to oxidation by triplet-state effluent organic matter (3EfOM*) and carbonate radicals (CO3•-). Second, the steady-state concentration of CO3•- increased with increasing pH. Indirect photolysis was suggested to be the main degradation pathway in the sewage effluents, and 3EfOM* was proposed to play a major role at pH 8.0-9.0, while CO3•- played a significant role at pH 10.0. In this study, EfOM was shown for the first time to inhibit the oxidation of E2 initiated by 3EfOM* and CO3•-. Thus, we suggest that EfOM plays a dual role in the photodegradation of E2: EfOM can not only be activated as 3EfOM* to degrade E2 but also can inhibit the degradation of E2 by reducing the E2 oxidation intermediate back to E2. The estrogenic activity of the photodegradation products was also studied. The in vitro estrogenic activity of E2 solutions decreased approximately as fast as the E2 photodegradation occurred in the effluent water at various pH values, suggesting that solar photodegradation in sewage effluents reduces the risk of endocrine disruption in waters impacted by E2 and subject to continuing inputs. The results of this study are important for predicting the environmental fate of endocrine-disrupting chemicals and developing methods for their removal from aquatic environments.


Clinical experience with leuprorelin acetate before radiotherapy for prostatic cancer.
A total of 40 patients with stages A2 to C prostatic cancer were treated with leuprorelin acetate depot once a month for 2 months before being treated by pelvic irradiation or radical prostatectomy. In the 32 patients who were evaluable, seven (22%) were classified as minor responders after leuprorelin treatment and 23 (72%) as major responders when assessed by rectal examination. Prostate-specific antigens also returned to normal concentrations (5 ng/ml) in 26/31 (84%) patients. Leuprorelin acetate depot suppressed plasma testosterone concentrations to castration values during treatment, but concentrations returned to normal 2 months after completion of treatment. Following radical treatment, there were three deaths--one postoperative and two due to recurrent disease--but there was no isolated local relapse. It is concluded that the protocol was locally well tolerated and was effective in the treatment of stages B2 and C prostatic cancer patients.


Interactions of GYKI 52466 and NBQX with cyclothiazide at AMPA receptors: experiments with outside-out patches and EPSCs in hippocampal neurones.
In outside-out patches from cultured hippocampal neurones, glutamate (1 mM) applied for 1 ms evoked currents which rose rapidly (tau(on) 451 +/- 31 micros) to a peak and then deactivated with slower kinetics (1.95 +/- 0.13 ms). Offset time constants were significantly slower with longer application durations (tau(off) 3.10 +/- 0.19, 3.82 +/- 0.25, 4.80 +/- 0.65 and 7.56 +/- 0.65 ms with 10, 20, 100 and 500 ms applications respectively). Desensitization was complete within 100 ms with a similar rate for all application durations (4.74 +/- 0.34 ms with 100 ms applications). GYKI 52466 reduced inward peak currents with an IC50 of 11.7 +/- 0.6 microM and had similar potency on steady-state currents to longer glutamate applications. GYKI 52466 had no significant effect on desensitization or deactivation time constants but caused a modest and significant prolongation of onset kinetics at higher concentrations. Cyclothiazide (100 microM) potentiated steady-state currents 25-fold at 100 ms and caused a modest but significant slowing in onset kinetics (601 +/- 49 micros with 1 ms applications) but a more pronounced prolongation of deactivation time constants (5.55 +/- 0.66 ms with 1 ms applications). In 50% of neuronal patches cyclothiazide completely eliminated desensitization. In those patches with residual desensitization, the rate was not significantly different to control (5.36 +/- 0.43 ms with 100 ms applications). Following 100 ms applications of glutamate, GYKI 52466 had IC50s of 11.7 +/- 1.1 microM and 75.1 +/- 7.0 microM in the absence and presence of cyclothiazide (100 microM) respectively. Onset kinetics were slowed from 400 +/- 20 micros to 490 +/- 30 micros by cyclothiazide (100 microM) and then further prolonged by GYKI 52466 (100 microM) to a double exponential function (tau(on1) 1.12 +/- 0.13 ms and tau(on2) 171.5 +/- 36.5 ms). GYKI 52466 did not re-introduce desensitization but concentration-dependently weakened cyclothiazide's prolongation of deactivation time constants (1 ms applications: 5.01 +/- 0.71, 4.47 +/- 0.80 and 2.28 +/- 0.64 ms with GYKI 52466 30, 100 and 300 microM respectively). NBQX reduced peak current responses with an IC50 of 28.2 +/- 1.3 nM. Paradoxically, steady-state currents with 500 ms applications of glutamate were potentiated from 3.3 +/- 1.2 pA to 29.4 +/- 6.4 pA by NBQX (1 nM). Higher concentrations of NBQX then antagonized this potentiated response. The potency of NBQX in antagonizing steady-state currents to 500 ms applications of glutamate (IC50 120.9 +/- 30.2 nM) was 2-fold less than following 100 ms applications (IC50 67.7 +/- 2.6 nM). NBQX had no effect on rapid onset, desensitization or deactivation time constants. However, a slow relaxation of inhibition was seen with longer applications. NBQX was 2-5-fold less potent against inward currents in the presence of cyclothiazide (100 microM) depending on the application duration but had no effect on the rapid onset, desensitization or deactivation time constants. The same relaxation of inhibition was seen as with NBQX alone. NBQX (1 microM) reduced AMPA receptor-mediated EPSC amplitude to 7 +/- 1% of control with no effect on kinetics. Cyclothiazide (330 microM) caused a 2.8-fold prolongation of the decay time constant (control 26.6 +/- 2.2 ms, cyclothiazide 74.2 +/- 7.6 ms, n = 9). Additional application of NBQX (1 microM) partly reversed this prolongation to 1.9 fold (47.7 +/- 2.5 ms, n = 5). These results support previous findings that cyclothiazide also allosterically influences AMPA receptor agonist/antagonist recognition sites. There were no interactions between NBQX and cyclothiazide on desensitization or deactivation time constants of glutamate-induced currents but clear interactions on EPSC deactivation kinetics. This raises the possibility that the interactions of NBQX, GYKI 52466 and cyclothiazide on AMPA-receptor-mediated EPSC kinetics observed are due to modulation of glutamate-release at presynaptic AMPA receptors.


The clinical assessment of cancer tests: a statistical approach to the prediction of "false positive" rates from controls.
As the sensitivity of the new in vitro cancer detection techniques increases, a larger number of "false positive" results can be expected from control populations apparently free from malignant disease at the time of the test. An attempt is made to predict the number of unexplained positives, together with the expected age and sex distribution, using published cancer registration statistics. The predicted numbers are compared with the observed numbers of unexplained positives in two clinical trials of the MEM test.


Roles of the kidney in the formation, remodeling and repair of bone.
The relationship between the kidney and bone is highly complex, and the kidney plays an important role in the regulation of bone development and metabolism. The kidney is the major organ involved in the regulation of calcium and phosphate homeostasis, which is essential for bone mineralization and development. Many substances synthesized by the kidney, such as 1,25(OH)2D3, Klotho, bone morphogenetic protein-7, and erythropoietin, are involved in different stages of bone formation, remodeling and repair. In addition, some cytokines which can be affected by the kidney, such as osteoprotegerin, sclerostin, fibroblast growth factor -23 and parathyroid hormone, also play important roles in bone metabolism. In this paper, we summarize the possible effects of these kidney-related cytokines on bone and their possible mechanisms. Most of these cytokines can interact with one another, constituting an intricate network between the kidney and bone. Therefore, kidney diseases should be considered among patients presenting with osteodystrophy and disturbances in bone and mineral metabolism, and treatment for renal dysfunction may accelerate their recovery.


CSF hydrodynamic studies in man. 2 . Normal hydrodynamic variables related to CSF pressure and flow.
With the patient in the supine position, the subarachnoidal space was infused with artificial CSF at several constant pressure levels. The resulting flow of liquid was recorded. By draining CSF at a low pressure the CSF production rate was determined. Normal values are given and discussed for (1) the resting pressure, (2) the conductance of the CSF outflow pathways, (3) the formation rate of CSF, (4) the pressure difference across the CSF outflow pathways, and (5) the sagittal sinus pressure. None of the variables showed any age dependence, nor was there any sex difference.