[Malignant midline granuloma and T-cell lymphoma. Apropos of a case].
Malignant granuloma of the face, a rare condition with many clinical designations of controversial etiopathology, would in fact appear to correspond, in the majority of recently published cases, to a T malignant lymphoma pathology. The freezing of a sample for immunohistochemical analysis, and more effective therapeutic choices, even though their aggressivity may seem out of proportion to the patient's condition, should make it possible to improve the prognosis of this condition which is still dangerous as the reported case shows.


Amyotrophic lateral sclerosis progression: Iran-ALS clinical registry, a multicentre study.
This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p = 0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender.


[Identification of Candida species causing vaginitis in Mexican patients].
The increasing frequency of candidiasis due Candida spp. other than C. albicans suggests that these organisms may also have emerged as a cause of vaginitis. The aim of this study was to investigate the species of Candida most frequently isolated from Mexican patients with vaginal candidiasis. A total of 631 isolates of Candida were identified by the API 20C system and standard bacteriological tests. The most frequently identified species were C. albicans (39.0%), C. glabrata (35.9%), and C. tropicalis (16.2%). The results of this study show that in addition to C. albicans, C. glabrata and C. tropicalis can also be considered important vaginal pathogens in Mexican patients.


A Diet Score Assessing Norwegian Adolescents' Adherence to Dietary Recommendations-Development and Test-Retest Reproducibility of the Score.
Assessment of adolescents' dietary habits is challenging. Reliable instruments to monitor dietary trends are required to promote healthier behaviours in this group. The purpose of this cross-sectional study was to assess adolescents' adherence to Norwegian dietary recommendations with a diet score and to report results from, and test-retest reliability of, the score. The diet score involved seven food groups and one physical activity indicator, and was applied to answers from a semi-quantitative food frequency questionnaire (FFQ) administered twice. Reproducibility of the score was assessed with Cohen's Kappa (κ statistics) at an interval of three months. The setting was eight lower-secondary schools in Hordaland County, Norway, and subjects were adolescents (n = 472) aged 14-15 years and their caregivers. Results showed that the proportion of adolescents consistently classified by the diet score was 87.6% (κ = 0.465). For food groups, proportions ranged from 74.0% to 91.6% (κ = 0.249 to κ = 0.573). Less than 40% of the participants were found to adhere to recommendations for frequencies of eating fruits, vegetables, added sugar, and fish. Highest compliance to recommendations was seen for choosing water as beverage and limit the intake of red meat. The score was associated with parental socioeconomic status. The diet score was found to be reproducible at an acceptable level. Health promoting work targeting adolescents should emphasize to increase the intake of recommended foods to approach nutritional guidelines.


Transforming stealthy to sticky nanocarriers: a potential application for tumor therapy.
Nanomedicine has shown remarkable progress in preclinical studies of tumor treatment. Over the past decade, scientists have developed various nanocarriers (NCs) for delivering drugs into the tumor area. However, the average amount of accumulated drugs in tumor sites is far from satisfactory. This limitation is strongly related to the corona formation during blood circulation. To overcome this issue, NCs should be designed to become highly stealthy by modifying their surface charge. However, at the same time, stealthy effects not only prevent protein formation but also alleviate the cellular uptake of NCs. Therefore, it is necessary to develop NCs with switchable properties, which are stealthy in the circulation system and sticky when arriving at tumor sites. In this review, we discuss the recent strategies to develop passive and active charge-switchable NCs, known as chameleon-like drug delivery systems, which can reversibly transform their surface from stealthy to sticky and have various designs.


Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase.
Acetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer's disease. Colorimetric Ellman's method was used for determination of IC50 value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action. A new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC50 = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC50 = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM. It is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstract A new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.


The Fat Mass- and Obesity-Associated (FTO) Gene to Obesity: Lessons from Mouse Models.
Genetic variants at the fat mass- and obesity-associated (FTO) locus are strongly associated with obesity-related traits by regulating neighboring genes. Nevertheless, it is possible that FTO protein is directly involved in mechanisms regulating body composition and adiposity. Here, the in vivo biological functions of FTO in the risk for obesity were studied by reviewing murine models. The effects of the locus-specific manipulations of the murine Fto gene on metabolic-related phenotypes in genetically modified mouse models were reviewed and summarized into the following three categories: growth and body composition, eating behaviors, and metabolic homeostasis. The mouse models showed different phenotypes depending on target tissues and methods for gene manipulation. Mice harboring deletions or point mutations at the Fto locus had high metabolic rates, while FTO-overexpressing mice showed dyslipidemia. Both deletion and overexpression of the Fto gene led to abnormal eating behaviors. Intriguingly, several phenotypes were differently expressed depending on developmental timing of the genetic manipulations. For instance, a germ line deletion decreased total body fat mass, while the deletion in adult mice increased it. The results highlight that FTO is critical not only for body composition but also normal development, and its function might differ depending on the stage of development.


The Healthy Neighborhoods Project: a local health department's role in catalyzing community development.
Studies show that community development approaches to health education may lead not only to improved social, economic, and health status but also to increased individual participation in health education and preventive health care activities. However, because of categorical funding restraints and philosophical issues, local health departments have rarely given control of defining project outcomes to the community. One such project was in a low-income urban neighborhood in the San Francisco Bay Area. In this Healthy Neighborhoods Project, the health department catalyzed community development and organization in a multiethnic public housing complex. As a result, an empowered community successfully advocated to improve public safety by installing street speed humps and increased street lighting. After project completion, residents initiated several additional health actions, including the removal of a neighborhood tobacco billboard. This article describes the project, which may serve as a model for other urban public health programs to explore their role in community empowerment.


United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn.
The aim of this study was to describe the early phase United Kingdom (UK) clinical experience with a novel entirely subcutaneous implantable cardioverter-defibrillator (S-ICD). A questionnaire was sent to all UK hospitals implanting S-ICDs. Nineteen of 25 (76%) hospitals responded with the details of 111 implanted patients [median 5/hospital (range 1-18)]. Mean duration of follow-up was 12.7 ± 7.1 months. Median patient age was 33 years (range 10-87 years). Underlying pathology was primary electrical disease in 43%, congenital heart disease 12%, hypertrophic cardiomyopathy 20%, ischaemic cardiomyopathy 14%, idiopathic dilated cardiomyopathy 5%, and other cardiomyopathies 7% patients. Nineteen (17%) patients required 20 re-operations, including permanent device explantation in 10 (9%). Twenty-four appropriate shocks were delivered in 13 (12%) patients, including 10 for ventricular fibrillation. One patient suffered arrhythmic death, but there were no failures to detect or terminate ventricular arrhythmias above the programmed detection rate. Fifty-one inappropriate shocks were delivered in 17 (15%) patients. Forty-one (80%) were for T-wave over-sensing and 1 (2%) for atrial flutter-wave over-sensing. The 11 patients who received inappropriate shocks due to T-wave over-sensing were significantly younger than patients who did not (24 ± 10 vs. 37 ± 19 years; P = 0.02). The S-ICD is an important innovation in ICD technology. However, these data indicate that adverse event rates are significant during early clinical adoption. Important lessons in patient selection, implant technique, and device programming can be learnt from this experience.


Resorcinol derivatives from Ardisia maculosa.
Besides a series of known sterols and triterpenoids, a new resorcinol (1) and a known resorcinol (2) have been isolated from ethanol extract of Ardisia maculosa for the first time. The structures of these resorcinol derivatives were elucidated as 2-methyl-5-(Z-heptadec-8-enyl) resorcinol and 5-Z-heptadec-8-enyl) resorcinol by HRESI-MS, NMR ((1)H, (13)C, HSQC, HMBC) experiments. In our in vitro assay, compounds 1 and 2 showed no antimicrobial activities, however, compound 2 exhibited cytotoxity activity against human cancer cell line with GI(50) value of 2.14 x 10(- 4) mmol/ml.


Experimental and theoretical studies on the excess capacity of Photosystem II.
It has been recently suggested that compensatory changes in Photosystem II (PS II) electron turnover rates can protect photosynthesis from photoinhibition [Behrenfeld et al. (1998) Photosynth Res 58: 259-268]. We have further explored this feature of PS II using a rate electrode for simultaneous measurements of the steady-state rate of oxygen evolution and the oxygen flash yield depending on the background irradiance in both control and photoinhibited algal cells of Chlorella Böhm. Theoretical simulations based on the two-electron gate model agree qualitatively with experimental data if we assume an increase of the electron turnover rate in the remaining functional PS II centers of the photoinhibited sample. Our results confirm the hypothesis that the compensatory effect enables cells to maintain the maximal rates of photosynthesis even in the presence of moderate photoinhibition (decrease of up to 50% in the number of functional centers) and that the effect originates from the inner capacity of electron transport through PS II. The origin of the compensatory effect is briefly discussed.


Comparison of ultrasonography, computerized tomography (EMI scan), and radiographic techniques in evaluation of exophthalmos.
A series of 342 consecutive patients with unilateral exophthalmos of confirmed etiology have been studied with a combination of clinical investigative techniques. High resolution B-scan ultrasonography and computerized tomography proved to be the most valuable tests for detecting orbital tumors and inflammatory conditions. Ultrasonography demonstrated primary orbital tumors but failed to show intracranial and some secondary tumors. Computerized tomography demonstrated primary, secondary, and intracranial tumors but not cystic masses. Inflammatory conditions such as Graves' disease and pseudotumor were characterized by ultrasonography also, while computerized tomography was not reliable for this. Correct diagnosis of orbital abnormalities in this series was 82% with ultrasonography and 72% with computerized tomography. Combined accuracy of these two complementary tests was 97% for tumor diagnosis. Conventional radiography and polytomography revealed secondary bony changes but not primary orbital tumors and inflammation. Orbital venography and arteriography had a low yield with tumors but were essential for demonstrating arteriovenous abnormalities. Orbital diagnosis has been improved significantly with the two newer techniques of ultrasonography and computerized tomography.


How Should Clinicians Respond When Different Standards of Care Are Applied to Undocumented Patients?
A challenge in caring for patients in resource-poor settings is the ethical discomfort and discouragement clinicians might experience when they're unable to provide optimal care due to lack of resources. This case, in which a resident is faced with rationalizing substandard care for certain classes of patients, probably represents the top of a slippery slope. This article argues that physicians should identify and advocate for optimal care for each patient. Moreover, physicians should advocate to improve the health system that allows for substandard care. Physicians should disclose to patients all available evaluation and treatment options, even those that seem cost prohibitive or unrealistic for some other reason. Transparency and objectivity in the patient-clinician relationship require good communication skills and are central to avoiding harm.


[Efficacy of Aceneuramic Acid for Distal Myopathy with Rimmed Vacuoles].
Distal myopathy with rimmed vacuoles (DMRV), also known as GNE myopathy, is a rare disease affecting the distal muscles, such as the tibialis anterior muscle. The GNE gene, which codes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in a homozygous or compound heterozygous manner, and the lack of sialic acid in skeletal muscle is the critical underlying mechanism in DMRV pathogenesis. DMRV mouse models were established, and supplementation with sialic acid improved the phenotypes of the models. A phase 1 clinical trial using aceneuramic acid was conducted at Tohoku University Hospital, Japan, followed by trials using a slow-release product. A phase II/III study, subsequent extended trial, and confirmatory trial were also conducted. Regulatory approval is currently under review.


Clinical and functional comparison between stapled colonic J-pouch low rectal anastomosis and hand-sewn colonic J-pouch anal anastomosis for very low rectal cancer.
We investigated intersphincteric resection with hand-sewn coloanal anastomosis, which may be an alternative to standard low anterior resection for very low rectal cancer when stapled anastomosis is technically impossible. The present study compared the clinical and functional results of 16 patients who underwent stapled colonic J-pouch low rectal anastomosis (CJLRA) with those of 15 patients who underwent intersphincteric excision and hand-sewn colonic J-pouch anal anastomosis (CJAA). After a median follow-up period of 59 months, local recurrence was found in four patients from the CJAA group, three of whom subsequently underwent curative abdominoperineal resection. Defecatory function 6 and 12 months after surgery did not differ between the groups, although pads were used significantly more frequently in the CJAA group. Anorectal physiologic study before and 12 months after surgery revealed that the internal anal sphincter function was impaired to a larger extent after CJAA than after CJLRA, probably due to the partial or subtotal resection of the internal sphincter, and the anal dilatation during resection and anastomosis. Although the prevention of intraoperative tumor implantation and the early detection of local recurrence is of utmost importance, CJAA may be an acceptable sphincter-preserving procedure for selected patients in whom stapled anastomosis is impossible.


The feedback loop between miR-21, PDCD4 and AP-1 functions as a driving force for renal fibrogenesis.
Renal fibrosis is a final common pathway of chronic kidney disease. Sustained activation of fibroblasts is considered to play a key role in perpetuating renal fibrosis but the driving force in the perpetuation stage is only partially understood. To date, some investigations have specifically identified overexpression of microRNA 21 (miR-21) in the progression of kidney fibrosis. Nevertheless, the precise role of miR-21 in fibroblast activation remains largely unknown. In this study, we found that miR-21 was significantly upregulated in activated fibroblasts and that it maintained itself at constant high levels by employing an auto-regulatory loop between miR-21, PDCD4 and AP-1. Persistently upregulated miR-21 suppressed protein expression of Smad7 and, eventually, enhanced the TGF-β1/Smad pathway to promote fibroblast activation. More importantly, we found miR-21 sequestration with miR-21 antagomir or AP-1 inhibitors attenuated unilateral ureteral obstruction (UUO)-induced renal fibrosis. miR-21-knockout mice also suffered far less interstitial fibrosis in response to kidney injury. Altogether, these data suggest that miR-21 is a main driving force of fibroblast activation and keeps its high expression level by employing a double negative autoregulatory loop. Targeting this aberrantly activated feedback loop may provide new therapeutic strategy in treating fibrotic kidneys.


The acoustic structure of male giant panda bleats varies according to intersexual context.
Although the acoustic structure of mammal vocal signals often varies according to the social context of emission, relatively few mammal studies have examined acoustic variation during intersexual advertisement. In the current study male giant panda bleats were recorded during the breeding season in three behavioural contexts: vocalising alone, during vocal interactions with females outside of peak oestrus, and during vocal interactions with peak-oestrous females. Male bleats produced during vocal interactions with peak-oestrous females were longer in duration and had higher mean fundamental frequency than those produced when males were either involved in a vocal interaction with a female outside of peak oestrus or vocalising alone. In addition, males produced bleats with higher rates of fundamental frequency modulation when they were vocalising alone than when they were interacting with females. These results show that acoustic features of male giant panda bleats have the potential to signal the caller's motivational state, and suggest that males increase the rate of fundamental frequency modulation in bleats when they are alone to maximally broadcast their quality and promote close-range contact with receptive females during the breeding season.


ACE2, Much More Than Just a Receptor for SARS-COV-2.
The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.


Casein kinase 2α regulates multidrug resistance-associated protein 1 function via phosphorylation of Thr249.
We have shown previously that the function of Ycf1p, yeast ortholog of multidrug resistance-associated protein 1 (MRP1), is regulated by yeast casein kinase 2α (Cka1p) via phosphorylation at Ser251. In this study, we explored whether casein kinase 2α (CK2α), the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semiconserved site Thr249. Knockdown of CK2α in MCF7-derived cells expressing MRP1 [MRP1 CK2α(-)] resulted in increased doxorubicin sensitivity. MRP1-dependent transport of leukotriene C(4) and estradiol-17β-d-glucuronide into vesicles derived from MRP1 CK2α(-) cells was decreased compared with MRP1 vesicles. Moreover, mutation of Thr249 to alanine (MRP1-T249A) also resulted in decreased MRP1-dependent transport, whereas a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings, showing increased intracellular doxorubicin accumulation in MRP1 CK2α(-) and MRP1-T249A cells compared with MRP1 cells. Inhibition of CK2 kinase by 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2α(-), MRP1-T249A, or MRP1-T249E cells, suggesting that CK2α regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2α and MRP1 interact physically, and recombinant CK2 phosphorylates MRP1-derived peptide in vitro in a Thr249-dependent manner, whereas knockdown of CK2α results in decreased phosphorylation at MRP1-Thr249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin and increased doxorubicin cytotoxicity. This study supports a model in which CK2α potentiates MRP1 function via direct phosphorylation of Thr249.


Developmental variation and amino acid sequences of cytochromes c of the fruit fly Drosophila melanogaster and the flesh fly Boettcherisca peregrina.
The amino acid sequences of cytochromes c purified from the fruit fly Drosophila melanogaster and the flesh fly Boettcherisca peregrina were determined. In contrast with the case of the housefly, isocytochromes c were not detected in these flies at any developmental stage. The sequence of fruit fly cytochrome c differed from that reported previously but was identical with that predicted from the nucleotide sequence of the fruit fly cytochrome c gene (DC4) (Limbach, K.J. & Wu, R. (1985) Nucl. Acids Res. 13, 631-644). Isocytochrome c of the fruit fly, reported to be encoded by the DC3 gene, was not detected as a functional cytochrome c molecule.


Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management.
Acute tubular necrosis (ATN) is a form of acute renal failure (ARF) that is common in hospitalized patients. In critical care units, it accounts for about 76% of cases of ARF. Despite the introduction of hemodialysis > 30 years ago, the mortality rates from ATN in hospitalized and ICU patients are about 37.1% and 78.6%, respectively. The purpose of this review is to discuss briefly the cause, diagnosis, and epidemiology of ARF, and to review in depth the clinical trials performed to date that have examined the influence of growth factors, hormones, antioxidants, diuretics, and dialysis. In particular, the role of the dialysis modality, dialyzer characteristics, and dosing strategies are discussed.


A self-aligning knee joint for walking assistance devices.
This paper presents a novel self-aligning knee mechanism for walking assistance devices for the elderly to provide physical gait assistance. Self-aligning knee joints can assist in flexion/extension motions of the knee joint and compensate the knee's transitional movements in the sagittal plane. In order to compensate the center of rotation, which moves with the flexion/extension motion of the human knee joint, a self-aligning knee joint is proposed that adds redundant degrees of freedom (i.e., 2-DoF) to the 1-DoF revolute joint. The key idea of the proposed mechanism is to decouple joint rotations and translations for use in lower-extremity wearable devices. This paper describes the mechanical design of this self-aligning knee mechanism and its implementation on a wearable robot and in preliminary experiments. The performance of the proposed mechanism is verified by simulations and experiments.


Beyond chronic kidney disease: the diagnosis of Renal Disease in the Elderly as an unmet need. A position paper endorsed by Italian Society of Nephrology (SIN) and Italian Society of Geriatrics and Gerontology (SIGG).
The dramatic increase in prevalence of chronic kidney disease (CKD) with ageing makes the recognition and correct referral of these patients of paramount relevance in order to implement interventions preventing or delaying the development of CKD complications and end-stage renal disease. Nevertheless, several issues make the diagnosis of CKD in the elderly cumbersome. Among these are age related changes in structures and functions of the kidney, which may be difficult to distinguish from CKD, and multimorbidity. Thus, symptoms, clinical findings and laboratory abnormalities should be considered as potential clues to suspect CKD and to suggest screening. Comprehensive geriatric assessment is essential to define the clinical impact of CKD on functional status and to plan treatment. Correct patient referral is very important: patients with stage 4-5 CKD, as well as those with worsening proteinuria or progressive nephropathy (i.e. eGFR reduction > 5 ml/year) should be referred to nephrologist. Renal biopsy not unfrequently may be the key diagnostic exam and should not be denied simply on the basis of age. Indeed, identifying the cause(s) of CKD is highly desirable to perform a targeted therapy against the pathogenetic mechanisms of CKD, which complement and may outperform in efficacy the general measures for CKD.


An unusual cause of tonsillar asymmetry.
We present the first reported case of tonsillar asymmetry secondary to a mandibular osteoma. Computed tomography rather than tonsillectomy for histology prevented the distress and risk of unnecessary surgery, and the patient was managed conservatively.


Unusual Aggregates Formed by the Self-Assembly of Proline, Hydroxyproline, and Lysine.
There is a plethora of significant research that illustrates toxic self-assemblies formed by the aggregation of single amino acids, such as phenylalanine, tyrosine, tryptophan, cysteine, and methionine, and their implication on the etiology of inborn errors of metabolisms (IEMs), such as phenylketonuria, tyrosinemia, hypertryptophanemia, cystinuria, and hypermethioninemia, respectively. Hence, studying the aggregation behavior of single amino acids is very crucial from the chemical neuroscience perspective to understanding the common etiology between single amino acid metabolite disorders and amyloid diseases like Alzheimer's and Parkinson's. Herein we report the aggregation properties of nonaromatic single amino acids l-proline (Pro), l-hydroxyproline (Hyp), and l-lysine hydrochloride (Lys). The morphologies of the self-assembled structures formed by Pro, Hyp, and Lys were extensively studied by various microscopic techniques, and controlled morphological transitions were observed under varied concentrations and aging times. The mechanism of structure formation was deciphered by concentration-dependent 1H NMR analysis, which revealed the crucial role of hydrogen bonding and hydrophobic interactions in the structure formation of Pro, Hyp, and Lys. MTT assays on neural (SHSY5Y) cell lines revealed that aggregates formed by Pro, Hyp, and Lys reduced cell viability in a dose-dependent manner. These results may have important implications in the understanding of the patho-physiology of disorders such as hyperprolinemia, hyperhydroxyprolinemia, and hyperlysinemia since all these IEMs are associated with severe neurodegenerative symptoms, including intellectual disability, seizures, and psychiatric problems. Our future studies will endeavor to study these biomolecular assemblies in greater detail by immuno-histochemical analysis and advanced biophysical assays.


beta2-microglobulin serum level is not a marker of disease activity in multiple sclerosis.
Beta2-microglobulin (beta2-MG) is a pharmacodynamic marker of interferon-beta activity in multiple sclerosis (MS). Its role in the natural course of the disease is not fully known. We analyzed the spontaneous fluctuation of beta2-MG in free-treatment MS patients during a short-time course to quantify beta2-MG as a marker of disease activity/progression. Thirty MS patients were clinically assessed and imaged monthly over a 3-month period. Sera were collected concomitantly for the evaluation of beta2-MG, by means of an enzyme-linked immunosorbent assay. Sera from 20 healthy individuals (HI) were drawn and used as controls. The Mann-Whitney test was used when appropriate and time effect on radiological and biological measures was assessed by means of the random effect models. Eight (26.7%) patients experienced a clinical relapse but three (10%) required steroid treatment. A reduction in the contrast-enhancing lesion load (P = 0.02) and a trend (P = 0.07) toward a decrease in brain parenchyma fraction were observed. Baseline levels of beta2-MG were similar in patients and HI. Patients' beta2-MG values increased over the 3-month time period (P = 0.05) but did not exceed those detected in HI at any time point. These results failed to demonstrate the validity of beta2-MG as a surrogate marker of disease in MS.


Behaviors of dentists in regard to dental and medical appointments. ADA Health Foundation Research Institute.
During the Health Screening Program at the ADA's annual session, 1,160 dentists completed questionnaires about their personal medical and dental visits within the past year. Findings from this study were compared with findings from other surveys of these behaviors in the general population. Results indicated that dentists visited dentists more often than did members of the general population. Dentists' visits to physicians were fewer than those reported by the general population.


Serum parathyroid hormone (PTH) in pregnant women determined by an immunoradiometric assay for intact PTH.
Most studies of circulating PTH levels using traditional RIAs have supported the concept of physiological hyperparathyroidism of pregnancy, with pregnant women having serum immunoreactive PTH levels significantly higher than those in nonpregnant subjects. However, such RIAs are insensitive and often detect inactive PTH fragments, so that the correlation between PTH immunoreactivity and bioactivity is poor. Employing a new intact PTH immunoradiometric assay (Allegro-Nichols), we reassessed the effects of pregnancy on parathyroid function. The mean serum PTH level in 81 pregnant women was 14.4 +/- 6.3 (+/- SD) compared to 24.8 +/- 9.0 ng/L in 11 normally cycling nonpregnant women (P less than 0.001). The mean serum total and ionized calcium levels in the 2 groups were similar. In 5 of the pregnant women, serum bioactive PTH, determined by cytochemical bioassay, was slightly lower (7.7 +/- 3.4 ng/L) than in normal individuals (11.1 +/- 1.9 ng/L). Our findings suggest, in contrast with the results of most previous studies, that serum intact PTH may decline during pregnancy.


[Treatment of cardiac arrhythmias in aged patients (author's transl)].
The most often causes of cardiac arrhythmias in aged patients are heart failure as a consequence of coronary or of hypertensive heart disease, hypersensitive carotis-sinus, digitalisintoxication and hypokalemia. Out of that, the different tachyarrhythmias and bradyarrhythmias and often also a tachycardia-bradycardia-syndrome may develop. Appropriately it results the most often kinds of antiarrhythmic therapy as the treatment of heart failure with digitalis, diuretics and nitrates, the handling of electrostimulation with pacemakers, the removal of digitalis and the supply of potassium. Beyond of that, there are many antiarrhythmic drugs, selected for therapy of "first choice". These are betablockers in sinustachycardia, ajmaline in supraventricular ectopic beats, verapamile in supraventricular tachycardia, lidoflazine with propafenone in atrial fibrillation, propafenone in ventricular ectopic beats, lidocaine in ventricular tachycardia, electrodefibrillation in ventricular fibrillation, orciprenaline, atropine and electrostimulation in bradyarrhythmias. The relation of advantage and risk of an antiarrhythmic therapy has to be considered carefully, especially in higher decades. Mostly it is already sufficient, to avoid arrhythmias by a critical and controlled prescription of digitalis, diuretics and laxatives.


Opioid usage and COVID-19 prognosis: A systematic review and meta-analysis.
The COVID-19 pandemic continues to have profound health, social, psychological, and economic ramifications. Infection by COVID-19 has been of concern in people who use opioids, as opioid use has been known to mediate immunosuppression and is associated with respiratory depression and end-organ damage. With differing modalities of opioid usage, the association between opioids and COVID-19 outcomes is not well understood. We performed a comprehensive systematic search of seven health science databases, including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang Data, up to December 15, 2021. We identified a total of five related articles, which were included in this study. The meta-analysis showed that opioids have a significant association with ICU admission for COVID-19 patients (OR = 5.41, 95%CI: 1.85 to 15.79, P = 0.002). Use of opioids was also associated with higher mortality among patients with COVID-19 compared to non-users (OR = 2.74, 95%CI: 1.34 to 5.62, P = 0.034), while use of opioids was not significantly associated with need for mechanical ventilation (OR = 3.68, 95%CI: 0.85 to 15.90, P = 0.081). Furthermore, the adjusted analysis indicated that COVID-19 patients with a history of opioid use were more likely to be admitted to the ICU (OR = 3.57, 95%CI: 3.05 to 4.17, P<0.001) and have higher mortality rates (OR = 1.72, 95%CI: 1.09 to 2.72, P = 0.02), while there was no significant association with need for mechanical ventilation (OR = 2.09, 95%CI: 0.77 to 5.64, P = 0.146). Significant heterogeneity existed across the included studies. Patients using opioids with COVID-19 were at higher risk of ICU admission and mortality. Prospective studies are required to confirm these findings.


New insights into the FGF23-Klotho axis.
Abnormal mineral metabolism is a hallmark in patients with advanced chronic kidney disease (CKD). Hyperphosphatemia, and the homeostatic mechanisms controlling phosphate metabolism, have received particular attention over the past decade. The phosphate-regulating hormone fibroblast growth factor-23 (FGF23) was discovered through studies of rare hypophosphatemic disorders, whereas Klotho, which subsequently turned out to be a co-receptor for FGF23, was identified in a mouse model showing hyperphosphatemia and multiple aging-like traits. The FGF23-Klotho endocrine axis is a pivotal regulator of mineral metabolism. In CKD, early onset of Klotho deficiency contributes to renal FGF23 resistance and a maladaptive increase in circulating FGF23. FGF23 is an early biomarker of renal injury and increased FGF23 predicts adverse clinical outcomes, in particular cardiovascular disease. A paradigm of FGF23 excess and Klotho deficiency is proposed, in which FGF23 preferentially stimulates left ventricular hypertrophy, and loss of Klotho augments fibrosis, endothelial dysfunction, and vascular calcification. The clinical benefit of FGF23 and Klotho measurements remain uncertain, nevertheless, the FGF23-Klotho axis is a solid candidate for a novel diagnostic and therapeutic target in CKD.


Differential signaling pathways are initiated in macrophages during infection depending on the intracellular fate of Chlamydia spp.
Chlamydia muridarum and Chlamydia caviae have equivalent growth rates in mouse epithelial cells but only C. muridarum replicates inside mouse macrophages, while C. caviae does not. Macrophages infected with C. muridarum or C. caviae were used to address the hypothesis that the early signaling pathways initiated during infection depend on the fate of chlamydiae in the host cell. Transmission electron microscopy of C. muridarum-infected macrophages showed intact chlamydial elementary bodies and reticulate bodies 2 h postinfection in compact vacuoles. Conversely, in macrophages infected with C. caviae, chlamydiae were observed in large phagocytic vacuoles. Furthermore, C. caviae infections failed to develop into inclusions or produce viable bacteria. Expression of proinflammatory cytokines TNFα, IL-1β and MMP13 was similar in C. caviae- or C. muridarum-infected macrophages at 3 h postinfection, indicating that chlamydial survival is not required for initiation of these responses. IL-1β secretion, dependent on inflammasome activation, occurred in C. caviae-infected macrophages despite no chlamydial growth. Conversely, IFNβ mRNA was observed only in C. muridarum- but not in C. caviae-infected macrophages. These data demonstrate that differential signaling events are initiated during a productive versus nonproductive chlamydial infection in a macrophage.


Evidence of Low Adherence to Stimulant Medication Among Children and Youths With ADHD: An Electronic Health Records Study.
The objective of this study was to evaluate rates and correlates of stimulant medication adherence in a sample of pediatric patients using data derived from electronic medical records (EMRs) from a large health care organization in a large metropolitan area. The study relied on a novel definition of medication adherence as a timely renewal of an index prescription determined using the electronically recorded issuance of a stimulant prescription in the EMR ("refill"). Prescription and sociodemographic data were extracted from the Partners HealthCare Research Patient Data Registry to calculate adherence to stimulant medication treatment. In the EMR, 2,206 patients with prescriptions for central nervous system stimulant medication were identified. Results showed that 46% of the index prescriptions were refilled within the timeframe necessary for the patient to be considered consistently medicated. A multivariable logistic regression model predicting medication adherence from patient demographic and treatment characteristics yielded an area-under-the-curve statistic of 0.57, indicating that these characteristics predicted adherence only modestly better than chance. EMR data from a large health care organization showed that 46% of pediatric patients were adherent to treatment with stimulants. Rates of medication adherence were worse among patients receiving care from a primary care provider than among those receiving care from a psychiatrist, in older patients, and in female patients and did not appear to be influenced by racial-ethnic group, economic class, stimulant type, or medication formulation (short or long acting). These findings, which show low rates of medication adherence among children and adolescents with ADHD, suggest the need for efforts to improve these rates.


Development of a new, more sensitive immunoassay for human tryptase: use in systemic anaphylaxis.
Tryptase, a neutral protease, is selectively concentrated in the secretory granules of human mast cells, and its release into the circulation serves as a clinical marker of mast cell activation. The current study describes a new, more sensitive ELISA utilizing a newly developed, mouse monoclonal IgG1 antibody for capture called B12 and capable of detecting tryptase in normal plasma and serum. The greater sensitivity of the new immunoassay results in part from a greater portion of tryptase being detected. Mean levels of tryptase in serum from normal subjects from Richmond, Virginia (4.9 ng/ml; n = 56), Munich, Germany (3.8 ng/ml; n = 19), and Amersfoort, The Netherlands (1.9 ng/ml; n = 8) were as indicated. In 62 subjects with ongoing allergic rhinitis, tryptase levels were no different in serum than for 19 normal controls, indicating that local mast cell activation is not necessarily reflected in the circulation. In 61 subjects sensitive to honey bee or yellow jacket venom by history, the 17 destined to have a severe, hypotensive response to a sting challenge had higher levels of tryptase at baseline than mild reactors, nonreactors, and controls, suggesting that baseline levels of tryptase may predict the severity of the clinical response to allergen in sensitive subjects.


Subcellular distribution of trace elements in kidney of a mother-fetus pair of Dall's porpoises (Phocoenoides dalli).
Total and subcellular renal Zn, Cu, Se, Mn, V, Hg, Cd and Ag were determined by a mother-fetus pair of Dall's porpoises (Phocoenoides dalli). All element concentrations in the maternal individual were higher than those in the fetal individual. Most of total renal elements studied were present in the cytosol of both animals. In maternal cytosol, Mn, Hg and Ag were present in high molecular weight substances (HMW); Se was in low molecular weight substances (LMW); Zn, Cu, and Cd were in metallothionein (MT), mostly; and the distribution of V in percentage among the three renal cytosolic fractions was similar. In fetal cytosol, Zn, Mn, Hg, V, Cd, and Ag were present in HMW, Cu was present in MT, mostly. In contrast, Se was observed mostly in both LMW and HMW. MT isoforms were characterized. Three obvious peaks in retention time were found in either the maternal or fetal MT. The highest elemental ion intensities were in the 7.8min peak for the mother, and in the 4.3min peak for the fetus, respectively, implying that different MT isoforms may be closely associated with elemental accumulation between maternal and fetal renal cytosols.


Using PCR and Real-Time PCR (LightCycler) for Diagnosis and Follow up of Invasive Fungal Infections in Patients with Hematological Malignancies and Transplantation.
In modern medicine, for early diagnosis of infections, tests that have high specificity and sensitivity should be preferred. For this reason, especially for patients with hematological malignancies and transplantation, that have high mortality and morbidity ratios, some molecular biological techniques are coming into use today for differential diagnosis and follow up of invasive fungal infections. In the coming years it will become easier to early diagnose and also to plan optimal treatments, by using these techniques for diagnosis of fungal infections. In this study, we made fungal DNA isolation from blood samples, which were taken from patients, in immunodeficiency state, with hematological malignancies and transplantation. For polymerase chain reaction (PCR), we used universal fungal primers. By using real-time PCR samples from 20 patients, which were found positive by PCR, the amount of DNA was measured. In real-time PCR, we used Aspergillus colonies as our standard, and for this purpose, SDA petri dishes were incubated for 72 hours at 30°C and; 101-106 cfu/mL serial dilutions were made by using hemocytometry. We performed DNA isolation and PCR from these dilutions. Fungal species specific products giving one band of 500 bp, were fixed in 2% agarose gel. We measured the DNA amounts by real-time PCR by using Sybr Green I. Standard dilution series and extraction samples were studied at the same time by real-time PCR. Measurement of the DNA quantities in the separate samples, one at the time of first day and the other after 15 days were interpreted by the LightCycler system. Results of real-time PCR in these two different samples were compared; it was noted that fungal DNA was increased in 5, decreased in 6 and equivalent in 9 patients. These findings showed that real-time PCR is a new, specific and a sensitive method among the other quantitative PCR systems. This method was also quicker than the other quantitative PCR systems. Currently, the investigators prefer this method because, it gives early idea about patient condition, for early diagnosis of infections and treatment patients who are under risk of some kind of infection, and for follow up treatment results. Additionally for diagnosis of fungal infections serial samples in PCR, together with other conventional diagnostic methods, should used.


Kinetic and thermodynamic stability of acenes: Theoretical study of nucleophilic and electrophilic addition.
To understand the reactivity of acenes, particularly pentacene, the addition of HCl and water to acenes was studied for the benzene-nonacene series at the B3LYP/6-31G(d) level of theory. Surprisingly, the reactivity of the acenes increases along the series up to hexacene and remains constant from hexacene and above due to the biradical character of the ground state of higher acenes. While the exothermicity of HCl and water additions are very similar, the activation barriers for HCl and water additions differ by a constant factor of ca. 27 kcal/mol. The barrier for the addition of HCl varies from 44 kcal/mol for benzene to 16-18 kcal/mol for pentacene-nonacene, whereas the barrier for the addition of water varies from 71 kcal/mol for benzene to 43-46 kcal/mol for pentacene-nonacene. The transition states (TSs) for the addition of water to acenes are relatively "late" on the reaction coordinate, compared to the "earlier" TSs for the addition of HCl. There is a substantial substituent effect on the energy barriers for these reactions. HCl behaves as an electrophile, with rhoHCl (vs rho p) = -4.48 and -3.39 for anthracenes and pentacenes, respectively, while water behaves as a nucleophile, with rhoHCl (vs rho p) = 2.35 and 1.39 for anthracenes and pentacenes, respectively.


[Treatment of pneumonia in childhood (author's transl)].
It is necessary to start with antibiotic treatment in infections of the lower respiratory system, especially pneumonias. The finding of the infectious agent is difficult and without security. With simple investigations, as sedimentation rate, white blood cell count and cell differentiation there is a possibility of 80% to get a diagnosis of bacterial infection. In 25 patients aged 1 1/2 to 9 years with x-ray diagnosis of pneumonia the results of treatment with cephacetril (100 mg/kg/d) are given. Clinical symptoms disappeared after 5 days, the average time of illness was 12 days. One patient got a severe pleural effusion.


Exercise training improves vascular function and secondary health measures in survivors of pediatric oncology related cerebral insult.
Adolescent and young adult (AYA) survivors of pediatric oncology related cerebral insult are vulnerable to numerous treatment-induced deficits that significantly enhance cardiovascular disease risk. Regular exercise improves endothelial function, fitness, body composition and musculoskeletal function which may reduce predisposition for cardiovascular disease. Here we assessed the feasibility and effectiveness of a 24-week exercise intervention on cardiovascular, physical and metabolic outcomes in this population. Thirteen survivors (6 male, 7 female; median age 19 y (range 16-23 y) were recruited to participate in a 48-week study consisting of a 24-week control period (regular care) followed by a 24-week exercise intervention. Outcome measures were collected at entry (week 0) and following regular care (24-week) and exercise (48-week). Assessed variables included endothelial function (flow mediated dilation, FMD), blood pressure, heart rate (HR), aerobic capacity, anthropometry, body composition, muscular strength (3 repetition maximum testing), muscular endurance (repetitions/min) and physical activity levels (accelerometry). Compared to baseline, delta diameter (p = 0.008) and FMD (p = 0.029) of the brachial artery increased following exercise. Bicep-curl strength also increased following exercise compared to baseline (p = 0.019), while submaximal (6 min mark) measures of ventilation (p = 0.012), rating of perceived exertion (p = 0.012), HR (p = 0.001), absolute (p = 0.000) and relative (p = 0.000) aerobic capacity decreased. Breaks in sedentary time increased (p = 0.043) following exercise compared to regular care. Although the sample was small and heterogeneous, this study demonstrates that exercise is achievable and has positive effects on vascular function, submaximal fitness, local strength and physical activity in a population of AYA survivors of pediatric oncology related cerebral insult.


Lubrication with Soft and Hard Two-Dimensional Colloidal Arrays.
Normal and friction forces between immobilized two-dimensional (2D) homogeneous non-close-packed colloidal arrays made of different particles are compared in aqueous media. Soft pH-responsive (microgels) and nonresponsive hard (silica) particles of different sizes were used to create the 2D arrays. The results show that the friction of soft responsive structured layers can be successfully modulated by varying the pH, with a friction coefficient varying by nearly 3 orders of magnitude (10-2 to 1). This important change in lubricating properties is mainly correlated with the particle swelling behavior, i.e., the friction coefficient decreasing exponentially with an increase in the swelling ratio regardless of the size, surface coverage, and degree of ionization of the particles. In addition, the robustly attached microgel particles were able to sustain high pressure (up to 200 atm) without significant surface damage. The 2D arrays of nonresponsive hard particles also gave rise to a very low friction coefficient (μ ≈ 10-3) under similar experimental conditions and could sustain a larger pressure without damage (≤600 atm). The low friction dissipation observed between the hard arrays resulted from a rolling mechanism. Even though rolling requires nonimmobilized particles on the substrates, the results show the importance of attaching a certain proportion of particles on the surfaces to reduce friction.


Room temperature fabrication of dielectric Bragg reflectors composed of a CaF2/ZnS multilayered coating.
We describe the design, fabrication, and characterization of mechanically stable, reproducible, and highly reflecting distributed Bragg reflectors (DBR) composed of thermally evaporated thin films of calcium fluoride (CaF2) and zinc sulfide (ZnS). CaF2 and ZnS were chosen as the low and high refractive index components of the multilayer DBR structures, with n = 1.43 and n = 2.38 respectively, because neither material requires substrate heating during the deposition process in order to produce optical quality thin films. DBRs consisting of seven pairs of CaF2 and ZnS layers, were fabricated with thicknesses of 96 and 58 nm, respectively, as characterized by high-resolution scanning electron microscopy (HR-SEM), and exhibited a center wavelength of λc = 550 nm and peak reflectance exceeding 99%. The layers showed good adhesion to each other and to the glass substrate, resulting in mechanically stable DBR coatings. Complete optical microcavities consisting of two such DBR coatings and a CaF2 spacer layer between them could be fabricated in a single deposition run. Optically, these structures exhibited a resonator quality factor of Q > 160. When a CaF2/ZnS DBR was grown, without heating the substrate during deposition, on top of a thin film containing the fluorescent dye Rhodamine 6G, the fluorescence intensity showed no degradation compared to an uncoated film, in contrast to a MgF2/ZnS DBR coating grown with substrate heating which showed a 92% reduction in signal. The ability to fabricate optical quality CaF2/ZnS DBRs without substrate heating, as introduced here, can therefore enable formation of low-loss high-reflectivity coatings on top of more delicate heat-sensitive materials such as organics and other nanostructured emitters, and hence facilitate the development of nanoemitter-based microcavity device applications.


Ticarcillin-induced cystitis. Cross-reactivity with related penicillins.
Two children had dysuria, sterile pyuria, and microscopic hematuria develop during treatment with ticarcillin disodium. With the exception of a predominance of pyuria over hematuria, the clinical course and laboratory findings in this disorder were similar to those observed in hemorrhagic cystitis, a potential complication of the use of several semisynthetic penicillins and penicillin G potassium. One patient had urinary abnormalities develop during two courses of ticarcillin therapy and subsequently after initiation of piperacillin sodium therapy. A second patient in whom hemorrhagic cystitis due to carbenicillin disodium developed experienced this related disorder four years later when first exposed to ticarcillin. Neither reduction of the dose nor substitution of one semisynthetic penicillin for another (piperacillin for ticarcillin, ticarcillin for carbenicillin) prevented recurrence of the disorder. The clinical importance of either form of cystitis induced by semisynthetic penicillins is uncertain, as is the risk for progression to interstitial nephritis.


Gravitational waves from a first-order electroweak phase transition: a brief review.
We review the production of gravitational waves by an electroweak first-order phase transition. The resulting signal is a good candidate for detection at next-generation gravitational wave detectors, such as LISA. Detection of such a source of gravitational waves could yield information about physics beyond the Standard Model that is complementary to that accessible to current and near-future collider experiments. We summarize efforts to simulate and model the phase transition and the resulting production of gravitational waves.This article is part of the Theo Murphy meeting issue 'Higgs cosmology'.


Cost-sensitive Bayesian control policy in human active sensing.
An important but poorly understood aspect of sensory processing is the role of active sensing, the use of self-motion such as eye or head movements to focus sensing resources on the most rewarding or informative aspects of the sensory environment. Here, we present behavioral data from a visual search experiment, as well as a Bayesian model of within-trial dynamics of sensory processing and eye movements. Within this Bayes-optimal inference and control framework, which we call C-DAC (Context-Dependent Active Controller), various types of behavioral costs, such as temporal delay, response error, and sensor repositioning cost, are explicitly minimized. This contrasts with previously proposed algorithms that optimize abstract statistical objectives such as anticipated information gain (Infomax) (Butko and Movellan, 2010) and expected posterior maximum (greedy MAP) (Najemnik and Geisler, 2005). We find that C-DAC captures human visual search dynamics better than previous models, in particular a certain form of "confirmation bias" apparent in the way human subjects utilize prior knowledge about the spatial distribution of the search target to improve search speed and accuracy. We also examine several computationally efficient approximations to C-DAC that may present biologically more plausible accounts of the neural computations underlying active sensing, as well as practical tools for solving active sensing problems in engineering applications. To summarize, this paper makes the following key contributions: human visual search behavioral data, a context-sensitive Bayesian active sensing model, a comparative study between different models of human active sensing, and a family of efficient approximations to the optimal model.


Laparoscopic extraperitoneal para-aortic lymphadenectomy.
Lymph nodes are the main pathway in the spread of gynaecological malignancies, being a well-known prognostic factor. Lymph node dissection is a complex surgical procedure and requires surgical expertise to perform the procedure, thereby minimising complications. In addition, lymphadenectomy has value in the diagnosis, prognosis, and treatment of patients with gynaecologic cancer. Therefore, a video focused on the para-aortic retroperitoneal anatomy and the surgical technique of the extraperitoneal para-aortic lymphadenectomy is presented.


Interaction of hydrocortisone and caerulein on pancreatic size and composition in the rat.
To determine the effects of hydrocortisone and caerulein (separately and in combination) on the exocrine pancreas of suckling, recently weaned, growing, and adult rats, we administered hydrocortisone (0.5 mg/100 g body wt), caerulein (1 microgram/kg), and a combination of these two hormones for 3 days. The rats were killed, and the pancreas was weighed and analyzed for DNA, protein, amylase, and chymotrypsinogen. Caerulein alone was associated with significant decreases in amylase, chymotrypsinogen, and protein concentration in suckling rats; after weaning, it produced significant increases of these same parameters, representative of pancreatic hypertrophy. Hydrocortisone caused significant increases in DNA content and enzyme and protein concentrations in suckling rats; after weaning, the steroid significantly decreased DNA content in 26-day-old rats, but increases in enzyme and protein concentration were observed. Using an increase in DNA content as an index of hyperplasia and cellular mass and enzyme and protein concentrations as indices of hypertrophy, we conclude that over a 3-day period 1) caerulein produced pancreatic hypertrophy after weaning while potentiating the hyperplastic and hypertrophic action of hydrocortisone in suckling rats; and 2) hydrocortisone potentiated the hypertrophic effect of caerulein after weaning. The data suggest that these two hormones may regulate acinar cell proliferation and enzyme synthesis of the exocrine pancreas.


Successes and challenges of implementing a cancer care delivery intervention in community oncology practices: lessons learned from SWOG S1415CD.
Cancer Care Delivery (CCD) research studies often require practice-level interventions that pose challenges in the clinical trial setting. The SWOG Cancer Research Network (SWOG) conducted S1415CD, one of the first pragmatic cluster-randomized CCD trials to be implemented through the National Cancer Institute (NCI) Community Oncology Program (NCORP), to compare outcomes of primary prophylactic colony stimulating factor (PP-CSF) use for an intervention of automated PP-CSF standing orders to usual care. The introduction of new methods for study implementation created challenges and opportunities for learning that can inform the design and approach of future CCD interventions. The order entry system intervention was administered at the site level; sites were affiliated NCORP practices that shared the same chemotherapy order system. 32 sites without existing guideline-based PP-CSF standing orders were randomized to the intervention (n = 24) or to usual care (n = 8). Sites assigned to the intervention participated in tailored training, phone calls and onboarding activities administered by research team staff and were provided with additional funding and external IT support to help them make protocol required changes to their order entry systems. The average length of time for intervention sites to complete reconfiguration of their order sets following randomization was 7.2 months. 14 of 24 of intervention sites met their individual patient recruitment target of 99 patients enrolled per site. In this paper we share seven recommendations based on lessons learned from implementation of the S1415CD intervention at NCORP community oncology practices representing diverse geographies and patient populations across the U. S. It is our hope these recommendations can be used to guide future implementation of CCD interventions in both research and community settings. NCT02728596 , registered April 5, 2016.


Health literacy of Dutch adults: a cross sectional survey.
Relatively little knowledge is available to date about health literacy among the general population in Europe. It is important to gain insights into health literacy competences among the general population, as this might contribute to more effective health promotion and help clarify socio-economic disparities in health. This paper is part of the European Health Literacy Survey (HLS-EU). It aims to add to the body of theoretical knowledge about health literacy by measuring perceived difficulties with health information in various domains of health, looking at a number of competences. The definition and measure of health literacy is still topic of debate and hardly any instruments are available that are applicable for the general population. The objectives were to obtain an initial measure of health literacy in a sample of the general population in the Netherlands and to relate this measure to education, income, perceived social status, age, and sex. The HLS-EU questionnaire was administered face-to-face in a sample of 925 Dutch adults, during July 2011. Perceived difficulties with the health literacy competences for accessing, understanding, appraising and applying information were measured within the domains of healthcare, disease prevention and health promotion. Multiple linear regression analyses were applied to explore the associations between health literacy competences and education, income, perceived social status, age, and sex. Perceived difficulties with health information and their association with demographic and socio-economic variables vary according to the competence and health domain addressed. Having a low level of education or a low perceived social status or being male were consistently found to be significantly related to relatively low health literacy scores, mainly for accessing and understanding health information. Perceived difficulties with health information vary between competences and domains of health. Health literacy competences are associated with indicators of socio-economic position and with the domain in which health information is provided.


The role of surgical staging in esophageal carcinoma.
Given the overall poor prognosis of patients with esophageal carcinoma and considering the new therapeutic options, surgeons should accurately stage patients preoperatively to appropriately tailor their treatment. CT, MRI, PET and EUS are still inaccurate in evaluating local surgical resectability and in detecting abdominal and thoracic lymph node metastases. Minimally invasive surgical staging is a promising adjunct to esophageal cancer staging. The thoracoscopic and laparoscopic staging provide more accurate information for evaluating local invasion, lymph node and distant metastasis. The greater accuracy afforded by minimally invasive staging is essential for patients who should undergo radical surgical or multimodal treatment. According to data reported by many authors, it seems most useful to combine nonoperative staging procedures as CT/MRI and EUS with minimally invasive staging techniques.


MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia.
Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and a decrease in the synthesis of the encoded protein IKAP (also known as ELP1). Small non-coding RNAs known as microRNAs (miRNAs) are important post-transcriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP loss, we examined expression of miRNAs in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from five control individuals and five FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative PCR (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs had been previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP, supporting a potential interaction between NOVA1 and IKAP. Taken together, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be a regulator of FD pathophysiology.


Integrating quantitative and qualitative methods in patient care information system evaluation: guidance for the organizational decision maker.
The aim of this paper is twofold. First, we describe two important dimensions of patient care information systems (PCIS) evaluation: the domain of evaluation and the different phases of the PCIS implementation. Second, we claim that, though Randomized Controlled Trials (RCTs) are often still seen as the standard approach, this type of design hardly generates relevant information for the organizational decision maker. Interpretive study of evaluation literature. The field of evaluation is scattered and the types of questions that can be asked and methods that can be used seem infinite and badly demarcated. Different stakeholders, moreover, often have different priorities in evaluating ICT. The most important reason for the lack of relevance of RCTs is that they are ill suited for investigating why and how a PCIS is being used, or not, and what the (often unplanned) effects and consequences are. Subsequently, our aim is to contribute to the discussion about the viability of qualitative versus quantitative methods in PCIS evaluation, by arguing for a specific integration of quantitative and qualitative research methods. The joint utilization of these methods, we claim, yields the richest results.


Canga biodiversity, a matter of mining.
Brazilian name canga refers to the ecosystems associated with superficial iron crusts typical for the Brazilian state of Minas Gerais (MG) and some parts of Amazon (Flona de Carajas). Iron stone is associated with mountain plateaux and so, in addition to high metal concentrations (particularly iron and manganese), canga ecosystems, as other rock outcrops, are characterized by isolation and environmental harshness. Canga inselbergs, all together, occupy no more than 200 km(2) of area spread over thousands of km(2) of the Iron Quadrangle (MG) and the Flona de Carajas, resulting in considerable beta biodiversity. Moreover, the presence of different microhabitats within the iron crust is associated with high alpha biodiversity. Hundreds of angiosperm species have been reported so far across remote canga inselbergs and different micro-habitats. Among these are endemics such as the cactus Arthrocereus glaziovii and the medicinal plant Pilocarpus microphyllus. Canga is also home to iron and manganese metallophytes; species that evolved to tolerate high metal concentrations. These are particularly interesting to study metal homeostasis as both iron and manganese are essential plant micro-elements. Besides being models for metal metabolism, metallophytes can be used for bio-remediation of metal contaminated sites, and as such are considered among priority species for canga restoration. "Biodiversity mining" is not the only mining business attracted to canga. Open cast iron mining generates as much as 5-6% of Brazilian gross domestic product and dialog between mining companies, government, society, and ecologists, enforced by legal regulation, is ongoing to find compromise for canga protection, and where mining is unavoidable for ecosystem restoration. Environmental factors that shaped canga vegetation, canga biodiversity, physiological mechanisms to play a role, and ways to protect and restore canga will be reviewed.


ESTIMATING THE FORM OF NATURAL SELECTION ON A QUANTITATIVE TRAIT.
The fitness function f relates fitness of individuals to the quantitative trait under natural selection. The function is useful in predicting fitness differences among individuals and in revealing whether an optimum is present within the range of phenotypes in the population. It may also be thought of as describing the ecological environment in terms of the trait. Quadratic regression will approximate the fitness function from data (e.g., Lande and Arnold, 1983), but the method does not reliably indicate features of f such as the presence of modes (stabilizing selection) or dips (disruptive selection). I employ an alternative procedure requiring no a priori model for the function. The method is useful in two ways: it provides a nonparametric estimate of f, of interest by itself, and it can be used to suggest an appropriate parametric model. I also discuss measures of selection intensity based on the fitness function. Analysis of six data sets yields a variety of forms of f and provides new insights for some familiar cases. Low amounts of variation and a low density of data points near the tails of many phenotype distributions emerge as limitations to gaining information on fitness functions. An experimental approach in which the distribution of a quantitative trait is broadened through manipulation would minimize these problems.


[Hypoxic brain damage after prolonged cardiac arrest during anesthesia--changes in CT and serum NSE concentration].
A 48-year-old woman was scheduled for total hysterectomy under spinal anesthesia in a local hospital. Large doses of diazepam (20 mg) and pentazocine (30 mg) were administered for sedation five minutes after starting the operation. Four minutes later, cardiac arrest occurred. The patient did not respond to closed chest massage and was transferred to our institution. As closed chest massage was not effective because the patient was moderately obese and her abdomen was open, open chest massage was initiated with administration of a large dose of epinephrine. Five minutes later, cardiac rhythm was restored, but it had taken a total of 75 minutes to restore cardiac rhythm and the patient suffered brain death. The cause of cardiac arrest was suspected to be a lethal dose of sedatives under spinal anesthesia. CT revealed massive cerebral edema soon after resuscitation. Serum NSE (neuron specific enolase) was within normal limits (< 10 ng.ml-1) at that time, but on the following day the CT demonstrated low attenuation area of white matter and gray matter in the cerebrum and brainstem, and serum NSE increased to 357 ng.ml-1, indicating massive necrosis of neuronal cells. The high concentration of serum NSE persisted for four days, and subsequently decreased to 112 ng.ml-1. This may have been a sign of completion of washout after brain death with no cerebral perfusion. It was concluded that if a case of cardiac arrest does not respond to closed chest massage, immediate open chest massage should be considered and that serum NSE may be an indicator of prognosis of hypoxic cerebral injury.


Perspectives From Patients and Care Providers on the Management of Fecal Incontinence: A Needs Assessment.
A large proportion of Canadians experience fecal incontinence, with no avenue for effective treatments. The Ottawa Hospital has recently started a percutaneous tibial nerve stimulation program for patients who have not improved with conservative efforts. As part of this program implementation, a qualitative needs assessment was undertaken to better define successful outcomes and to identify barriers for program sustainability. This was a cross-sectional, qualitative study involving standardized, semistructured interviews. The study was conducted at a single tertiary care center. Patients experiencing fecal incontinence, as well as nurses, physical therapists, and physicians, were enrolled in the study. Interview questions revolved around success definitions, barriers, and promoters of fecal incontinence care. Transcripts were analyzed to develop themes surrounding fecal incontinence care. Twelve interviews were undertaken raising a total of 17 different themes. Barriers to fecal incontinence care included education for both the care provider and patients. Access issues for treatments were also highlighted. Promoters of fecal incontinence care were reflected by the impact that it has on quality of life, personal hygiene, psychological burden, and activity and productivity. The definition of fecal incontinence success was focused on improvements in quality of life rather than a numerical reduction of incontinence episodes. This study was limited in its small number of interviews conducted. We were unable to identify patients who were unable to seek out care for fecal incontinence. Patient and care provider education surrounding fecal incontinence is lacking. Furthermore, access for effective treatments is a real barrier for Canadians experiencing fecal incontinence. Programs should focus on improvement of overall quality of life rather than a reduction of incontinence episodes.


Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer's disease brain.
Previously, we identified protein kinase FA/glycogen synthase kinase-3 alpha (GSK-3 alpha) as a brain microtubule-associated tau kinase that phosphorylates Ser235 and Ser404 of tau and causes its electrophoretic mobility shift in gels, a unique property characteristic of paired helical filament-associated pathological tau (PHF-tau) in Alzheimer's disease brains. In this study, we found that the activity of kinase FA/GSK-3 alpha towards phosphorylation of brain tau could be stimulated approximately fourfold by heparin. The phosphorylation molar ratio was increased simultaneously up to 9 mol of phosphates/mol of tau, resulting in a reduced mobility of tau with an apparent molecular mass shift to approximately 68 kDa in sodium dodecyl sulfate gels, which is very similar to that observed in Alzheimer-tau. Tryptic digestion of 32P-labelled tau, followed by HPLC and two-dimensional separation on TLC cellulose plates, revealed eight major phosphopeptides. Phosphoamino acid analysis together with sequential manual Edman degradation and protein sequence analysis further revealed that, in addition to Ser235 and Ser404, heparin generated Thr212, Thr231, Ser262, Ser324, and Ser356, the five extra phosphorylation sites in tau. As Ser235, Ser262, Ser324, Ser356, and Ser404 (particularly the site of Ser262) have been identified as five of the most potent sites in tau responsible for reducing microtubule binding possibly involved in neuronal degeneration, and Thr231, Ser235, Ser262, and Ser404 are four of the most well documented sites abnormally phosphorylated in Alzheimer-tau, the results provide initial evidence that protein kinase FA/GSK-3 alpha after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau in Alzheimer's disease brains.


Advanced Image Analysis Methods for Automated Segmentation of Subnuclear Chromatin Domains.
The combination of ever-increasing microscopy resolution with cytogenetical tools allows for detailed analyses of nuclear functional partitioning. However, the need for reliable qualitative and quantitative methodologies to detect and interpret chromatin sub-nuclear organization dynamics is crucial to decipher the underlying molecular processes. Having access to properly automated tools for accurate and fast recognition of complex nuclear structures remains an important issue. Cognitive biases associated with human-based curation or decisions for object segmentation tend to introduce variability and noise into image analysis. Here, we report the development of two complementary segmentation methods, one semi-automated (iCRAQ) and one based on deep learning (Nucl.Eye.D), and their evaluation using a collection of A. thaliana nuclei with contrasted or poorly defined chromatin compartmentalization. Both methods allow for fast, robust and sensitive detection as well as for quantification of subtle nucleus features. Based on these developments, we highlight advantages of semi-automated and deep learning-based analyses applied to plant cytogenetics.


Ion permeation pathway within the internal pore of P2X receptor channels.
P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1-4 and P2X7 receptor channels are cation-selective, whereas P2X5 has been reported to have both cation and anion permeability. P2X receptor channel structures reveal that each subunit is comprised of two transmembrane helices, with both N-and C-termini on the intracellular side of the membrane and a large extracellular domain that contains the ATP binding sites at subunit interfaces. Recent structures of ATP-bound P2X receptors with the activation gate open reveal the unanticipated presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be largely buried within the membrane as potential pathways for ions to permeate the intracellular end of the pore. In the present study, we identify a critical residue within the intracellular lateral fenestrations that is readily accessible to thiol-reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Taken together, our results demonstrate that ions can enter or exit the internal pore through lateral fenestrations that play a critical role in determining the ion selectivity of P2X receptor channels.


Fulminant course of infectious mononucleosis with virus-associated hemophagocytic syndrome.
A fatal case of infectious mononucleosis due to serologically verified Epstein-Barr virus infection in a previously healthy 30-year-old man is presented. The clinical course was characterized by severe prostration, persistently high spiking fever, and continuous development of enlarged lymph nodes. Hematologic examination revealed peripheral leukopenia and thrombocytopenia, and in the bone marrow an increased number of benign histiocytes showed marked hemophagocytosis. At autopsy abnormal lymphoid infiltrates were present in several tissues. The pathogenesis of this infection-associated hemophagocytic syndrome is discussed in terms of the possibility of an impaired immune response to infectious agents.


Enhancing Oral Performance of Paclitaxel Lipid-Mimic Prodrug via Modulating Type of Fatty Acids.
Owing to the serious clinical side effects of intravenous Taxol, an oral chemotherapeutic strategy is expected to be promising for paclitaxel (PTX) delivery. However, its poor solubility and permeability, high first-pass metabolism, and gastrointestinal toxicity need to be overcome. A triglyceride (TG)-like prodrug strategy facilitates oral drug delivery by bypassing liver metabolism. However, the effect of fatty acids (FAs) in sn-1,3 on the oral absorption of prodrugs remains unclear. Herein, a series of TG-mimetic prodrugs of PTX is explored with different carbon chain lengths and degrees of unsaturation of FAs at the sn-1,3 position in an attempt to enhance oral antitumor effect and to guide the design of TG-like prodrugs. Interestingly, the different FA lengths exhibit great influence on in vitro intestinal digestion behavior, lymph transport efficiency, and up to fourfold differences in plasma pharmacokinetics. The prodrug with long-chain FAs shows a more effective antitumor effect, whereas the degree of unsaturation has a negligible impact. The findings illustrate how FAs structures affect the oral delivery efficiency of TG-like PTX prodrugs and thus provide a theoretical basis for their rational design.


Routine versus selective use of intraoperative angiography during thromboembolectomy for acute lower limb ischemia: analysis of outcomes.
The success of thromboembolectomy for acute lower limb ischemia depends on the complete removal of all thromboembolic material accessible to the Fogarty catheter. Intraoperative arteriography can be used during arterial thromboembolectomy as a guide for extension of procedure to ensure complete clearance of the arterial tree and distal patency. However, it is still matter of debate if intraoperative angiography should be routinely performed in all cases or only in selected cases, depending on intraoperative findings, when the surgeon suspects an incomplete desobstruction. Details of 380 thromboembolectomies in 361 patients with acute lower limb ischemia due to native vessel occlusion were prospectively recorded over a 12-year period in a central hospital vascular unit setting. The relevance of intraoperative angiography was retrospectively analyzed. The procedures were divided into two groups: group A, when intraoperative angiography was performed in selected cases (selective angiography), and group B, when angiography was performed as a routine procedure in all cases (routine angiography). Thrombectomy and embolectomy cases were separately analyzed. "On-table" angiography was used in 57 (26.4%) of 216 cases in group A and in all 164 cases (100%) of group B. Included in this study were 225 embolectomies and 155 thrombectomies of native vessels. After thrombectomy, the adoption of routine intraoperative angiography (group B) resulted in a statistically significant higher intraoperative reintervention rate than did selective intraoperative angiography (group A) (53.4% vs. 29.9%; p < 0.05). Also, after embolectomy extension of procedure, the rate was higher in group B than in group A (17% vs. 9.2%), but it did not reach statistical significance (p > 0.05). Considering the overall casuistic, at 24 months after thromboembolectomy, group B resulted in a lower incidence of reocclusion in comparison with group A (p < 0.05), whereas there was no statistical difference between the two groups in terms of amputation (p > 0.05) or of mortality (p > 0.05). Considering separately patients treated by embolectomy and by thrombectomy, reocclusion rate at 24 months was lower in group B than in group A, after thrombectomy and after embolectomy, with a statistical significance (p < 0.05). Amputation rate at 24 months was similar in group A and group B after embolectomy (10.7% vs. 8.9%; p > 0.05). After thrombectomy, there was in group B a slight advantage in comparison with group A, although not reaching statistical significance (31.3% vs. 46.2%; p > 0.05). There was no difference in mortality rate according to treatment group. Routine use of intraoperative angiography influences outcome after thromboembolectomy for lower limb acute arterial occlusion. Routine use of intraoperative angiography, compared with selective use, results in higher rate of extension of the procedure for residual lesion and in a lower reocclusion rate at 24 months.


Effects of standardized ileal digestible tryptophan: lysine ratio on growth performance of nursery pigs.
Two experiments were conducted to estimate the standardized ileal digestible (SID) Trp:Lys ratio requirement for growth performance of nursery pigs. Experimental diets were formulated to ensure that lysine was the second limiting AA throughout the experiments. In Exp. 1 (6 to 10 kg BW), 255 nursery pigs (PIC 327 × 1050, initially 6.3 ± 0.15 kg, mean ± SD) arranged in pens of 6 or 7 pigs were blocked by pen weight and assigned to experimental diets (7 pens/diet) consisting of SID Trp:Lys ratios of 14.7%, 16.5%, 18.4%, 20.3%, 22.1%, and 24.0% for 14 d with 1.30% SID Lys. In Exp. 2 (11 to 20 kg BW), 1,088 pigs (PIC 337 × 1050, initially 11.2 kg ± 1.35 BW, mean ± SD) arranged in pens of 24 to 27 pigs were blocked by average pig weight and assigned to experimental diets (6 pens/diet) consisting of SID Trp:Lys ratios of 14.5%, 16.5%, 18.0%, 19.5%, 21.0%, 22.5%, and 24.5% for 21 d with 30% dried distillers grains with solubles and 0.97% SID Lys. Each experiment was analyzed using general linear mixed models with heterogeneous residual variances. Competing heteroskedastic models included broken-line linear (BLL), broken-line quadratic (BLQ), and quadratic polynomial (QP). For each response, the best-fitting model was selected using Bayesian information criterion. In Exp. 1 (6 to 10 kg BW), increasing SID Trp:Lys ratio linearly increased ( 0.05) ADG and G:F. For ADG, the best-fitting model was a QP in which the maximum ADG was estimated at 23.9% (95% confidence interval [CI]: [<14.7%, >24.0%]) SID Trp:Lys ratio. For G:F, the best-fitting model was a BLL in which the maximum G:F was estimated at 20.4% (95% CI: [14.3%, 26.5%]) SID Trp:Lys. In Exp. 2 (11 to 20 kg BW), increasing SID Trp:Lys ratio increased ( 0.05) ADG and G:F in a quadratic manner. For ADG, the best-fitting model was a QP in which the maximum ADG was estimated at 21.2% (95% CI: [20.5%, 21.9%]) SID Trp:Lys. For G:F, BLL and BLQ models had comparable fit and estimated SID Trp:Lys requirements at 16.6% (95% CI: [16.0%, 17.3%]) and 17.1% (95% CI: [16.6%, 17.7%]), respectively. In conclusion, the estimated SID Trp:Lys requirement in Exp. 1 ranged from 20.4% for maximum G:F to 23.9% for maximum ADG, whereas in Exp. 2 it ranged from 16.6% for maximum G:F to 21.2% for maximum ADG. These results suggest that standard recommendations may underestimate the SID Trp:Lys requirement for nursery pigs from 11 to 20 kg BW.


What co-morbidities do people with malaria have and what are their patterns of health seeking in Nigeria?
This study assessed the comorbidities associated with malaria and patterns of health seeking in southeast Nigeria. The survey was undertaken in Enugu state, Southeast Nigeria. Data were collected from 500 householders, 200 in-patient and outpatient exit surveys and data abstraction from 125 inpatient and outpatient records. A total of 307 (64.2%) households had an episode of malaria within 1 month of the interview. The most common malaria comorbidities were upper respiratory tract infection and diarrhea. Most patients first sought treatment from patent medicine vendors. The average monthly cost of treating the comorbidities was 270 Naira (1.75 USD) and 601 Naira (3.89 USD) for outpatient department and inpatient department respectively. The economic burden of malaria is compounded by comorbidities and inappropriate health seeking behavior. Interventions to control malaria are required to also control common comorbidities.


Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.
Basel-Vanagaite-Smirin-Yosef syndrome (OMIM 616449) is a rare autosomal recessive genetic disorder characterized by severe developmental delay and variable craniofacial, neurological, cardiac, and ocular anomalies in the presence of variants in the MED25 gene. So far, only a handful of patients have been reported with this condition globally. Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies. By whole-exome sequencing (WES), a homozygous variant was found in the MED25 gene, c.518T>C, predicted to result in a p.Ile173Thr change in the MED25 protein. This change has recently been reported in another Lebanese family. Review of the literature, the importance of this mutation in the Lebanese population, and the possibility that this condition may be underdiagnosed and only effectively detected using molecular techniques such as WES are discussed.


Involvement of polyamines in root development at low temperature in the subantarctic cruciferous species Pringlea antiscorbutica.
Polyamine involvement in root development at low temperature was studied in seedlings of Pringlea antiscorbutica R. Br. This unique endemic cruciferous species from the subantarctic zone is subjected to strong environmental constraints and shows high polyamine contents. In the present study, free polyamine levels were modified by inhibitors of polyamine biosynthesis (D-arginine, difluoromethylornithine, cyclohexylammonium, and methylglyoxal-bis-guanylhydrazone) and variations of the endogenous pools were compared to changes in root growth. The arginine decarboxylase pathway, rather than that of ornithine decarboxylase, seemed to play a major role in polyamine synthesis in Pringlea antiscorbutica seedlings. Root, but not shoot, phenotypes were greatly affected by these treatments, which modified polyamine endogenous levels according to their expected effects. A positive correlation was found between agmatine level and growth rate of the primary root. Spermidine and spermine contents also showed positive correlations with primary root growth whereas the putrescine level showed neutral or negative effects on this trait. Free polyamines were therefore found to be differentially involved in the phenotypic plasticity of root architecture. A comparison of developmental effects and physiological concentrations suggested that agmatine and spermine in particular may play a significant role in the control of root development.


The innervation and neuroendocrine cell population of the appendix in total colonic aganglionosis.
There is little published information on changes in the appendix in Hirschsprung's disease despite the presence within the mucosa of nerves and neuroendocrine cells together forming a 'neuroendocrine ganglion'. The innervation and neuroendocrine cell population of 11 appendices (two from patients with total colonic aganglionosis, six from patients with short segment Hirschsprung's disease and three normal controls) were examined using H & E, a standard Grimelius silver stain and immunocytochemistry for S-100 protein, neuron-specific enolase, neurofilament and synaptophysin. Compared with both normal and short segment Hirschsprung's disease controls, the total colonic aganglionosis appendices showed decreased numbers of nerve bundles around the muscle layers and within the submucosa, markedly decreased numbers of smaller fibres within the circular muscle and absence of the finer fibres within the lamina propria. There was no change in the overall number of epithelial neuroendocrine cells but subepithelial neuroendocrine cells, normally found in association with mucosal nerve fibres, were totally absent. The concomitant loss of nerve fibres and neuroendocrine cells from the lamina propria in total colonic aganglionosis suggests a different embryological origin for epithelial and sub-epithelial neuroendocrine cells.


Injectable Nanoreinforced Shape-Memory Hydrogel System for Regenerating Spinal Cord Tissue from Traumatic Injury.
Traumatic injury in the central nervous system can lead to loss of functional neurons. Transplantation of neural progenitors is a promising therapeutic strategy. However, infusion of dissociated cells often suffers from low viability, uneven cell distribution, and poor in vivo engraftment that could be reinforced by a better cell delivery system. Here, we develop an injectable composite hydrogel system for use as a minimally invasive treatment of spinal cord injury (SCI) using motor neurons (MNs) derived from embryonic stem cells (ESCs). The composite hydrogel is based on a modified gelatin matrix integrated with shape-memory polymer fibers. The gelatin matrix creates a local microenvironment for cell assembly and also acts as a lubricant during injection through a fine catheter. Notably, shape-memory fiber scaffolds are able to recover to maintain the microstructures even after dramatic deformation from injection operation, providing the necessary support and guidance for motor neuron differentiation. We find that the composite hydrogel with an aligned fiber scaffold greatly improves the viability of ESCs and their differentiation toward MNs both in vitro and in vivo. When transplanted to SCI animals by injection, the ESC-loaded composite hydrogels are identified to significantly enhance tissue regeneration and motor function recovery in mice. With this proof-of-concept study, we believe that the injectable composite hydrogel system provides a promising solution for in vivo cell delivery with minimum invasiveness and can be readily extended to other stem-cell-based regenerative treatments.


Radioimmunoassay of hydromorphone and hydrocodone in human plasma.
A radioimmunoassay for hydromorphone in human plasma was developed using a commercially available morphine-6-antiserum and tritiated dihydromorphine. In the assay, free and bound drug are separated using dextran-coated charcoal. The method quantitates hydromorphone in the 2.5-20-ng/ml range with minimum sensitivity at 1.0 ng/ml. Within-run precision for hydromorphone as shown by the standard error of the estimate of the linear regression equation is +/- 1.01 ng/ml. Between-run precision data for hydromorphone at the 2,5-, 10-, and 20-ng/ml levels gave percent relative standard deviations of 22.35, 10.96, and 8.55%, respectively. A plasma concentration-time curve from a subject administered a single oral dose of hydromorphone demonstrates the usefulness of the assay in monitoring drug levels in a bioavailability study. The method also is applicable to the analysis of hydrocodone in human plasma in the 10-80-ng/ml range with minimum sensitivity at 3.0 ng/ml. Within-run precision for hydrocodone as shown by the standard error of the estimate of the linear regression equation is +/- 1.06 ng/ml. Between-run precision data at the 15-, 30, and 60-ng/ml levels gave percent relative standard deviations of 12.48, 7.67, and 6.03%, respectively.


NLRP12 attenuates tumor necrosis factor-α production in Burkholderia pseudomallei-infected RAW264.7 macrophages.
NLRP12 has been shown to play an essential role as a negative regulator in several bacterial infection. The purpose of this study is to elucidate the role of NLRP12 in B. pseudomallei-infected RAW264.7 macrophages. The protein expression and the level of TNF-α production were determined by immunoblotting and ELISA assay, respectively. The results demonstrated that unlike the LPS-mutant strain which lacks O antigenic polysaccharide, the wild-type B. pseudomallei was able to upregulate NLRP12 protein expression in RAW264.7 macrophages. NLRP12 expression also correlated with the suppression of TNF-α production as demonstrated in wild-type B. pseudomallei-infected Nlrp12-depleted macrophages when compared to that of the control siRNA-transfected cells. The expression of NLRP12 was also inhibited in cytochalasin D treated cells. Our findings showed that wild-type B. pseudomallei can activate NLRP12 expression leading to the suppression of TNF-α production. It is possible that the regulation of NLRP12 may contribute to the pathogenesis of B. pseudomallei infection in melioidosis patients.


Cognitive inference device for activity supervision in the elderly.
Human activity, life span, and quality of life are enhanced by innovations in science and technology. Aging individual needs to take advantage of these developments to lead a self-regulated life. However, maintaining a self-regulated life at old age involves a high degree of risk, and the elderly often fail at this goal. Thus, the objective of our study is to investigate the feasibility of implementing a cognitive inference device (CI-device) for effective activity supervision in the elderly. To frame the CI-device, we propose a device design framework along with an inference algorithm and implement the designs through an artificial neural model with different configurations, mapping the CI-device's functions to minimise the device's prediction error. An analysis and discussion are then provided to validate the feasibility of CI-device implementation for activity supervision in the elderly.