Persistence and determinants of statin therapy among middle-aged patients free of cardiovascular disease.
Statins have been shown to significantly reduce morbidity and mortality both in patients with coronary artery disease and in those with dyslipidemia when they are taken regularly. Middle-aged patients have the highest level of forecasting benefit, and little is known about the persistence rate of these therapies in a real-life setting.Objective. To evaluate the persistence rate of middle-aged patients initiating statin therapy as well as its relation to patients' demographic and clinical characteristics. A cohort of 25,733 patients was reconstructed from prescription data recorded in the Régie de l'assurance maladie du Québec administrative database. All patients aged 50-64 years old who received at least one statin prescription between January 1, 1998 and December 31, 2000 for a new intention of treatment for dyslipidemia were included in the cohort and followed up until June 30, 2001. The date of the first prescription of statin was defined as the index date. The cumulative persistence rate was estimated using a Kaplan-Meier analysis. Cox regression models were used to estimate the rate ratio of ceasing statins after adjustment. Mean age of patients initiating statin agents was 58 years; 39%were male, 24% received social assistance, 19% had diabetes, 30% had hypertension and 11% had a respiratory disease at cohort entry. Persistence with statin therapy fell to 67% in the first 6 months after treatment and continued to decline over the next 3 years to 39%. At 3 years, persistence varied significantly with statin agents. After controlling for individual patients' demographic and clinical characteristics, we found that patients who were prescribed fluvastatin, lovastatin and atorvastatin had a higher rate of cessation than those on simvastatin and pravastatin. The adjusted rate ratio of ceasing statin agents in patients with other risk factors of cardiovascular disease, such as diabetes (HR: 0.78; 0.75-0.82) or hypertension (HR: 0.72; 0.69-0.74), demonstrated a lower cessation rate. We observed lower persistence in patients who used the greatest number of pharmacies and prescribing physicians. This analysis indicates that barriers to persistence occur early in the therapeutic course. Overall persistence with statins is low, particularly among patients with few other cardiovascular risk factors.


Overlapping connections within the motor cortico-basal ganglia circuit: fMRI-tractography analysis.
Contribution of the subcortical nuclei to the coordination of human behavior is dependent on the existence of appropriate anatomical architecture. Interpretations of available data have led to opposing 'information funneling' and 'parallel processing' hypotheses. Using motor circuit as a model, we examined whether cortico-subcortical circuits, especially cortico-basal ganglia circuits, are funneled or parallel in the control of volitional movement. Twenty-five healthy subjects underwent functional magnetic resonance imaging (fMRI). Activated clusters during self-initiated, sequential finger-to-thumb opposition movements of the left hand were identified in the bilateral supplementary motor area (SMA), right lateral premotor cortex (PM) and primary motor cortex (M1), and in the right striatum and thalamus. These functionally defined clusters were applied to probabilistic tractography based on diffusion-weighted MRI to examine patterns of connectivity. Striatal and thalamic sub-regions with high probabilities of connection to the motor cortices partially overlapped, with connection to the two premotor areas outspreading rostrally relative to M1. We suggest that, on a macroscopic anatomical level, there is overlap as well as segregation among connections of the motor cortices with the striatum and thalamus. This supports the notion that neuronal information of the motor cortices is funneled, and parallel processing is not an exclusive principle in the basal ganglia.


L-dopa impairs learning, but spares generalization, in Parkinson's disease.
In this study we examined the effect of dopaminergic modulation on learning and memory. Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.


Blood Biochemical and Erythrocytic Morpho-pathological Consequences of Naphthalene Intoxication in Indian Teleost, Anabas testudineus (Bloch).
Anabas testudineus (Bloch) was exposed to 0.71 mg/L and 1.42 mg/L (25 and 50% of LC50 value respectively) naphthalene, a polycyclic aromatic hydrocarbon (PAH), for 21 days. Blood biochemical parameters and erythrocytic morphological alterations were assessed to describe the naphthalene toxicity. Biochemical analysis showed a significant increase in glutamic pyruvic transaminase, GPT (576.7 ± 11.79 and 608.9 ± 12.08 U/L, respectively) and alkaline phosphatase, ALP (12.9 ± 0.69 and 13.4 ± 0.64 U/L, respectively) activities under two doses compared with control. Protein and albumin (ALB) content in blood decreased significantly, in comparison with control value in the tune of 22.67 ± 1.04 and 23.97 ± 1.24 g/dl, respectively and 10.7 ± 0.79 and 11.1 ± 0.67 g/dl, respectively. Erythrocytes showed varied symptomatic morphological changes under naphthalene exposure, which included severe denaturation, swelling in cells, appearance of sickle and tear drop cells, and cellular vacuolation. In particularly, the changes were more prominent under higher naphthalene exposure. Following the results, it has been able to establish that GPT, ALP, protein and ALB, and the morphological manifestations of erythrocytes would be good tools of biomarker in monitoring toxicological paradigm, especially to naphthalene exposure in aquatic bodies.


Plant tropisms as a window on plant computational processes.
Plants are living information-processing organisms with highly adaptive behavior, allowing them to prosper in a harsh and fluctuating environment in spite of being sessile. Lacking a central nervous system, plants are distributed systems orchestrating complex computational processes performed at the tissue level. Here I consider plant tropisms as a useful input-output system boasting a robust mathematical description, naturally permitting a dialogue between mathematical modeling and biological observations. I propose tropisms as an ideal framework for the study of plant computational processes, allowing us to infer the relationship between observed tropic responses and known stimuli. I concentrate on macroscopic models, and elucidate this approach by presenting recent examples focusing on computational processes involved at different hierarchical levels of interactions: a plant's interaction with itself and its internal state, with the abiotic environment, and with neighboring plants.


A selective detection approach for copper(ii) ions using a hydrazone-based colorimetric sensor: spectroscopic and DFT study.
The development of an efficient and miniaturized analytical approach to determine trace levels of toxic ions in aqueous fluids presents a current research challenge. Hydrazone-based chemosensors are considered potential candidates due to their high sensitivity and selectivity towards heavy metal ions. Computational techniques can be properly implemented to elucidate possible modes of ligand-metal interaction and provide an in-depth understanding of the chemistry involved. The present study reports the use of 3-hydroxy-5-nitrobenzaldehyde-4-hydroxybenzoylhydrazone (3-HNHBH) ligand for highly sensitive, quick and re-usable colorimetric sensing of copper(ii) ions in aqueous media. DFT calculations suggest that the complexation of 3-HNHBH with copper(ii) ions adopts a seesaw coordination geometry and results in the largest HOMO-LUMO gap and most effective coulombic interaction compared to Zn and Ni counterparts. It demonstrated a high selectivity towards copper ions with a detection limit of 0.34 μg L-1. The ligand was readily regenerated using a 0.5 M HCl solution, indicating its feasibility to be used as a re-usable sensor for the convenient detection of copper ions in aqueous media. The influence of metal interference, pH and solvents on the selectivity and regeneration of the ligand was also investigated.


Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.
Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.


Therapeutic potential and limitations of curcumin as antimetastatic agent.
Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.


Selective cytotoxic activity of immunotoxins composed of a monoclonal anti-Thy 1.1 antibody and the ribosome-inactivating proteins bryodin and momordin.
The ribosome-inactivating proteins, bryodin, from Bryonia dioica, and momordin, from Momordica charantia, were coupled by a disulphide bond to a monoclonal anti-Thy 1.1 antibody (OX7). Both immunotoxins were specifically cytotoxic to the Thy 1.1-expressing mouse lymphoma cell line AKR-A in vitro. The OX7-bryodin immunotoxins were the more powerfully toxic and reduced protein synthesis in AKR-A cells by 50% at a concentration of 1-4 x 10(-11) M as compared with 1 x 10(-9) M for the OX7-momordin immunotoxins. Neither of the immunotoxins was toxic to mouse lymphoma EL4 cells, which lack the Thy 1.1 antigen, at concentrations up to 3 x 10(-8) M. Further, bryodin and momordin immunotoxins made from an antibody (R10) of irrelevant specificity were without effect on AKR-A cells.


Vascularized fibular osteocutaneous grafts in the treatment of severely infected wrist arthritis.
The authors successfully treated two cases of wrist arthritis severely infected by Staphylococcus aureus and Mycobacterium tuberculosis with vascularized fibular osteocutaneous grafts. The surgical procedure was divided into two stages, with extensive debridement of the infected wrist joint, and reconstruction with a vascularized fibular osteocutaneous flap. This two-staged surgery yielded complete amelioration of the severely infected wrist arthritis, and permanent stabilization of the wrist joint.


White blood cell count is positively associated with benign prostatic hyperplasia.
To determine whether low-grade systemic inflammation is associated with prostatic enlargement/benign prostatic hyperplasia. Prostate volume was measured by transrectal ultrasonography in 576 Japanese men. The association between prostate volume and routine clinical inflammatory markers (C-reactive protein level, white blood cell count, or the differential white cell count [neutrophils, lymphocytes, basophils, eosinophils, and monocytes]) were analyzed. Contributors to prostate volume were identified in univariate and multivariable linear regression models. Prostate volume was found to have a positive association with serum prostate-specific antigen level (P < 0.001), white blood cell count (P = 0.027) and absolute neutrophil count (P = 0.010). In univariate linear regression models, a large prostate volume was associated with older age, higher prostate-specific antigen, and higher white blood cell and neutrophil counts. A multivariable model adjusted for age, prostate-specific antigen, and C-reactive protein showed that the white blood cell count and the neutrophil count were independently associated with prostate volume. An increased white blood cell count was also associated with higher total International Prostatic Symptom Scores (P < 0.001). White blood cell count seems to be associated with the degree of prostate enlargement and lower urinary tract symptoms. Chronic low-grade systemic inflammation might be involved in the etiology of benign prostatic hyperplasia.


Insulin therapy for depressed myocardial contractility after prolonged ischemia.
Insulin was administered to two patients whose diminished myocardial contractility made it difficult to terminate cardiopulmonary bypass. In both instances, bypass was successfully terminated shortly after the insulin injection. These clinical observations led to experiments under the controlled conditions provided by the isolated, working rat heart preparation. The recovery of contractility after 30 minutes of severe ischemia was assessed in all 11 control and 11 insulin-treated hearts. Myocardial performance, as judged by the product of heart rate and peak systolic blood pressure, was significantly greater in the insulin-treated hearts. These clinical observations and experimental findings suggest the need for more extensive study of the potential value of insulin in treating depressed contractility after prolonged myocardial ischemia.


Inflammatory pseudotumor causing intestinal obstruction: diagnostic and therapeutic aspects.
The authors report an unusual presentation of inflammatory pseudotumor (IPT) that caused intestinal obstruction in a 9-year-old boy, and discuss the clinicopathologic features of this rare entity with emphasis on diagnosis and treatment. There are no specific presumptive clinical and laboratory findings, including tumor markers and imaging techniques, that distinguish mesenteric IPT from other abdominal mass lesions. The most important diagnostic aid is to bear this entity in mind when a child presents with intestinal obstruction associated with an abdominal mass. Radical unnecessary surgical procedures or potentially harmful therapy should be avoided, and appropriate treatment is achieved by total excision of the lesion in most of the cases.


Metabolome analysis of Saccharomyces cerevisiae and optimization of culture medium for S-adenosyl-L-methionine production.
S-Adenosyl-L-methionine (SAM) is a fine chemical used as a nutritional supplement and a prescription drug. It is industrially produced using Saccharomyces cerevisiae owing to its high SAM content. To investigate the optimization of culture medium components for higher SAM production, metabolome analysis was conducted to compare the intracellular metabolite concentrations between Kyokai no. 6 (high SAM-producing) and laboratory yeast S288C (control) under different SAM production conditions. Metabolome analysis and the result of principal component analysis showed that the rate-limiting step for SAM production was ATP supply and the levels of degradation products of adenosine nucleotides were higher in Kyokai 6 strain than in the S288C strain under the L-methionine supplemented condition. Analysis of ATP accumulation showed that the levels of intracellular ATP in the Kyokai 6 strain were also higher compared to those in the S288C strain. Furthermore, as expected from metabolome analysis, the SAM content of Kyokai 6 strain cultivated in the medium without yeast extract increased by 2.5-fold compared to that in the additional condition, by increasing intracellular ATP level with inhibited cell growth. These results suggest that high SAM production is attributed to the enhanced ATP supply with L-methionine condition and high efficiency of intracellular ATP consumption.


Modeling studies on the role of vitamins B1 (thiamin), B3 (nicotinamide), B6 (pyridoxamine), and caffeine as potential leads for the drug design against COVID-19.
In response to the COVID-19 pandemic, and the lack of effective and safe antivirals against it, we adopted a new approach in which food supplements with vital antiviral characteristics, low toxicity, and fast excretion have been targeted. The structures and chemical properties of the food supplements were compared to the promising antivirals against SARS-COV-2. Our goal was to exploit the food supplements to mimic the topical antivirals' functions but circumventing their severe side effects, which has limited the necessary dosage needed to exhibit the desired antiviral activity. On this line, after a comparative structural analysis of the chemicals mentioned above, and investigation of their potential mechanisms of action, we selected caffeine and some compounds of the vitamin B family and further applied molecular modeling techniques to evaluate their interactions with the RDB domain of the Spike protein of SARS-CoV-2 (SC2Spike) and its corresponding binding site on human ACE-2 (HssACE2). Our results pointed to vitamins B1 and B6 in the neutral form as potential binders to the HssACE2 RDB binding pocket that might be able to impair the SARS-CoV-2 mechanism of cell invasion, qualifying as potential leads for experimental investigation against COVID-19.


Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.
We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance.


Lack of otolith involvement in balance responses evoked by mastoid electrical stimulation.
Passing current through mastoid electrodes (conventionally termed galvanic vestibular stimulation; GVS) evokes a balance response containing a short- and a medium-latency response. The origins of these two responses are debated. Here we test the hypotheses that they originate from net signals evoked by stimulation of otolith and semi-circular canal afferents, respectively. Based on anatomy and function, we predicted the directions of the stimulus-evoked net head rotation vector from the canals and the linear acceleration net vector from the otoliths. We tested these predictions in healthy adults by obtaining responses with the head in strategic postures to alter the relevance of the signals to the balance system. Cross-covariance between a stochastic waveform of stimulating current and motor output was used to assess the balance responses. Consistent with the canal hypothesis, with the head pitched down the medium-latency EMG response was abolished while the short-latency EMG response was maintained. The results, however, did not support the otolith hypothesis. The direction of the linear acceleration signal from the otoliths was predicted to change substantially when using monaural stimuli compared to binaural stimuli. In contrast, short-latency response direction measured from ground-reaction forces was not altered. It was always directed along the inter-aural axis irrespective of whether the stimulus was applied binaurally or monaurally, whether the head was turned in yaw through 90 deg, whether the head was pitched down through 90 deg, or combinations of these manipulations. We conclude that a net canal signal evoked by GVS contributes to the medium-latency response whilst a net otolith signal does not make a significant contribution to either the short- or medium-latency responses.


Robust habit learning in the absence of awareness and independent of the medial temporal lobe.
Habit memory is thought to involve slowly acquired associations between stimuli and responses and to depend on the basal ganglia. Habit memory has been well studied in experimental animals but is poorly understood in humans because of their strong tendency to acquire information as conscious (declarative) knowledge. Here we show that humans have a robust capacity for gradual trial-and-error learning that operates outside awareness for what is learned and independently of the medial temporal lobe. We tested two patients with large medial temporal lobe lesions and no capacity for declarative memory. Both patients gradually acquired a standard eight-pair object discrimination task over many weeks but at the start of each session could not describe the task, the instructions or the objects. The acquired knowledge was rigidly organized, and performance collapsed when the task format was altered.


[When patients' sexuality finds its way into daily care activities].
The sexual life and desire of patients manifest themselves in the care environment in various ways. These different situations open up debates and undermine convictions. This article presents some nurses' testimonies.


Plasma Clot Properties in Patients with Pancreatic Cancer.
Pancreatic cancer is one of the most prothrombotic malignancies. Plasma clot properties may be altered in patients with pancreatic cancer, and circulating tissue factor (TF) may play an important role. We applied a modified plasma clot formation assay (only CaCl2 and phospholipids were added to initiate clotting) and a standard clotting assay (lipidated TF was also added) to investigate whether plasma clot properties are altered in pancreatic cancer patients (n = 40, 23 female) compared to sex-matched healthy controls. The modified assay was also performed in the presence of a TF blocking antibody. With this modified assay, we detected an increased plasma clot formation rate (Vmax) and an increased delta absorbance (ΔAbs, indicating fibrin fiber thickness) in patients compared to controls. These differences were not detected with the standard clotting assay. Following addition of a TF blocking antibody in in our modified assay, Vmax decreased significantly in patients only, ΔAbs significantly decreased in patients and in healthy controls, the lag phase did not change, and the time to peak fibrin generation increased in patients only. Taken together, these findings indicate the presence of a prothrombotic state in pancreatic cancer patients, which depends on TF and is detectable with our modified assay but not with a standard clotting assay.


Pinealectomy blocks vernal courtship behavior in red-sided garter snakes.
Male red-sided garter snakes (Thamnophis sirtalis parietalis) court only on emergence from winter dormancy. The salient proximate factor responsible for the initiation of courtship behavior appears to be warm ambient temperatures subsequent to sustained exposure to cold temperatures. In the present study, autumn-captured garter snakes were pinealectomized or sham-pinealectomized 1-2 weeks prior to hibernation. After 17 weeks of maintenance in several ambient lighting and temperature conditions, all males were tested for the presence of courtship behavior. No pinealectomized animals exhibited any indications of reproductive behavior, whereas 53% of sham-pinealectomized males actively courted females. Photoperiod did not influence the prevalence of mating behavior. These results suggest that the pineal gland mediates non-photoperiodic seasonal information in the garter snake. This is the first demonstration, in any vertebrate species, that the pineal gland can directly influence reproductive behavior.


Effects of pentachlorophenol on the detoxification system in white-rumped munia (Lonchura striata).
Pentachlorophenol (PCP), a priority pollutant due to its persistence and high toxicity, has been used worldwide as a pesticide and biocide. To understand the adverse effects of PCP, adult male white-rumped munias (Lonchura striata) were orally administrated commercial PCP mixed with corn oil at dosages of 0, 0.05, 0.5, and 5mg/(kg·day) for 42day. Gas chromatography-mass spectrometry (GC-MS) analysis found that PCP was preferentially accumulated in the kidney rather than in the liver and muscle in all exposure groups. To examine the function of CYP1A in pollutant metabolism, we isolated two full-length cDNA fragments (designated as CYP1A4 and CYP1A5) from L. striata liver using reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. PCP induced the expression of CYP1A5, although no obvious change was observed in CYP1A4 expression. Furthermore, PCP significantly elevated the activities of ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase and decreased the activity of benzyloxy-trifluoromethyl-coumarin, with no significant responses observed in benzyloxyresorufin O-debenzylase. PCP induced significant changes in antioxidant enzyme (superoxide dismutase and catalase) activities and malondialdehyde content, but decreased glutathione peroxidase (GSH-Px) and glutathione S-transferase activities and GSH content in the liver of L. striata. The present study demonstrated that PCP had hepatic toxic effects by affecting CYP1As and anti-oxidative status.


Searching for replication origins in mammalian DNA.
The attempts at identifying precise replication origins (ori) in mammalian DNA have been pursued mainly through physico-chemical and biochemical approaches, in view of the essential failure of the search for autonomously replicating sequences in cultured cells. These approaches involve the mapping of short stretches of nascent DNA, the identification of the regions where either leading or lagging strands switch polarity, or the localization of replication intermediates by two-dimensional gel electrophoresis. Due to the complexity of animal cell genomes, most of these studies have been performed on amplified domains and with the use of synchronization procedures. The results obtained have been controversial. In order to avoid the use of experimental procedures potentially affecting the physiological mechanism of DNA replication, we have developed a method for the localization of ori in single-copy loci in exponentially growing cells. This method entails the absolute quantification of the abundance of selected DNA fragments along a genomic region within samples of newly synthesized DNA by competitive polymerase chain reaction (PCR); the latter is immune to all the uncontrollable variables which severely affect the reproducibility of conventional PCR. The application of this method to SV40 ori-driven plasmid replication precisely identifies the known ori localization. Using the same approach, we have mapped an ori for bi-directional DNA replication in a 13.7-kb locus of human chromosome 19 encoding lamin B2.


Effect of valproate and add-on levetiracetam on inflammatory biomarkers in children with epilepsy.
Contemporary research indicates the role of neuroinflammation/inflammatory markers in epilepsy. In addition, comorbidities such as anxiety and poor health-related quality of life are vital concerns in clinical care of pediatric patients with epilepsy. This open-label, prospective, observational study evaluated the effect of valproate and add-on levetiracetam on serum levels of C-C motif ligand 2 (CCL2) and Interleukin-1 beta (IL-1β) in pediatric patients with epilepsy. We also studied effect of valproate and add-on levetiracetam on anxiety and health-related quality of life (HRQoL) in specified age subgroups. Children aged 1 to 12 years, diagnosed with epilepsy (generalized or focal seizures), treated with valproate (n = 40) and valproate with add-on levetiracetam (n = 40) were included. All patients were followed up for 16 weeks and assessed for changes in serum CCL2 and IL-1β levels. Spence Children Anxiety Scale short version (SCAS-S) and QOLCE-16 scales were used to measure anxiety and HRQoL, respectively, in specific age groups. The serum CCL2 level decreased significantly (p < .001) from 327.95 ± 59.07 pg/ml to 207.02 ± 41.50 pg/ml in the valproate group and from 420.65 ± 83.72 pg/ml to 250.06 ± 46.05 pg/ml in the add-on levetiracetam group. Serum IL-1β level did not change significantly in both groups. Spence Children Anxiety Scale short version scores were decreased and QOLCE-16 scores were increased significantly (p < .001) in both valproate and add-on levetiracetam groups. The results of our study suggest that valproate and levetiracetam led to decrease serum CCL2 levels without any change in serum IL-1β levels in children with epilepsy. Anti-inflammatory property of valproate and levetiracetam might underlie their antiepileptic effect and CCL2 could be a potential marker of drug efficacy in epilepsy. Also, valproate and levetiracetam reduced anxiety and improved quality of life in children with epilepsy in the age groups evaluated.


Machine learning analysis predicts a person's sex based on mechanical but not thermal pain thresholds.
Sex differences in pain perception have been extensively studied, but precision medicine applications such as sex-specific pain pharmacology have barely progressed beyond proof-of-concept. A data set of pain thresholds to mechanical (blunt and punctate pressure) and thermal (heat and cold) stimuli applied to non-sensitized and sensitized (capsaicin, menthol) forearm skin of 69 male and 56 female healthy volunteers was analyzed for data structures contingent with the prior sex structure using unsupervised and supervised approaches. A working hypothesis that the relevance of sex differences could be approached via reversibility of the association, i.e., sex should be identifiable from pain thresholds, was verified with trained machine learning algorithms that could infer a person's sex in a 20% validation sample not seen to the algorithms during training, with balanced accuracy of up to 79%. This was only possible with thresholds for mechanical stimuli, but not for thermal stimuli or sensitization responses, which were not sufficient to train an algorithm that could assign sex better than by guessing or when trained with nonsense (permuted) information. This enabled the translation to the molecular level of nociceptive targets that convert mechanical but not thermal information into signals interpreted as pain, which could eventually be used for pharmacological precision medicine approaches to pain. By exploiting a key feature of machine learning, which allows for the recognition of data structures and the reduction of information to the minimum relevant, experimental human pain data could be characterized in a way that incorporates "non" logic that could be translated directly to the molecular pharmacological level, pointing toward sex-specific precision medicine for pain.


Downregulation of fibronectin transcription in highly metastatic adenocarcinoma cells.
Silencing of fibronectin (FN) expression seems to be one of the key mechanisms underlying metastatic behaviour. An inverse correlation exists between FN expression levels and the metastatic potential of two related murine mammary adenocarcinomas, M3 and MM3. Primary cultures of M3 tumour, which is moderately metastatic to lung (40% incidence), show a conspicuous FN extracellular matrix (ECM) and high levels of FN mRNA, while primary cultures of the highly metastatic MM3 tumour (95% lung incidence) are negative for FN in immunofluorescence and show at least 40-fold lower levels of FN mRNA, only detectable by RT-PCR, with a different pattern of alternatively spliced EDI isoforms compared to M3 cells. We show that the FN promoter sequence is not altered in MM3 cells. Transfection experiments with CAT constructs indicate that silencing occurs at the transcriptional level, involving the 220-bp proximal promoter region.


Regioselectivity-reversal in acylation of 6-azauridine catalyzed by Burkholderia cepacia lipase.
3'-O-stearoylation of 6-azauridine was achieved enzymatically for the first time. Among eight commercially available lipases, that from Burkholderia cepacia displayed a 3'-regioselectivity of 80% towards the acylation of 3-hydroxyl of 6-azauridine. Using an immobilized lipase from Burkholderia cepacia, the 3'-regioselectivities of the acylations could be reversed by lengthening the aliphatic chain of the acyl donors (C2-C18). The possible reason might be the presence of the interaction between the base moiety and the acyl group.


Microwave treatment of the cornea leads to localised disruption of the extracellular matrix.
Microwave keratoplasty is a thermo-refractive surgical procedure that can correct myopia (short-sightedness) and pathologic corneal steepening by using microwave energy to cause localised shrinkage around an annulus of the cornea leading to its flattening and vision correction. The effects on the corneal extracellular matrix, however, have not yet been evaluated, thus the current study to assess post-procedure ultrastructural changes in an in-vivo rabbit model. To achieve this a series of small-angle x-ray scattering (SAXS) experiments were carried out across whole transects of treated and untreated rabbit corneas at 0.25 mm intervals, which indicated no significant change in collagen intra-fibrillar parameters (i.e. collagen fibril diameter or axial D-period), whereas inter-fibrillar measures (i.e. fibril spacing and the degree of spatial order) were markedly altered in microwave-treated regions of the cornea. These structural matrix alterations in microwave-treated corneas have predicted implications for corneal biomechanical strength and tissue transparency, and, we contend, potentially render microwave-treated corneas resistant to surgical stabilization using corneal cross-linking procedures currently employed to combat refractive error caused by corneal steepening.


The impact of modified tongue base suspension on CPAP levels in patients with severe OSA.
The aim of this study was to evaluate the effects of modified tongue base suspension (mTBS) procedure on continuous positive airway pressure (CPAP) levels in patients with severe obstructive sleep apnea (OSA). From November 2011 to December 2012, a total of 31 patients with severe OSA who underwent mTBS were included into this prospective case series with planned data collection. Prior to surgery, all the patients were subjected to a polysomnography (PSG) and CPAP titration on two separate nights. Following the surgery, patients were subjected to a control PSG and CPAP titration at the sixth month of follow-up period. The preoperative and postoperative mean apnea hypopnea index (AHI), CPAP titration values, AHI during CPAP use and amount of sleeping time with CPAP were compared. Median age was 48 years (range 31-66), and most patients were male (87.0 %). Postoperative mean AHI (44.73 ± 17.05 vs. 19.96 ± 19.52), optimal CPAP value (12.64 ± 1.60 vs. 8.00 ± 1.77) and AHI during CPAP use (3.79 ± 1.78 vs. 2.25 ± 1.81) were decreased, and the amount of sleeping time with CPAP (5.29 ± 0.84 vs. 6.52 ± 0.89) was increased significantly (p < 0.001 for all parameters). The surgery was considered to be successful when 50 % reduction in the mean AHI and/or the decrease of AHI below 20/h were obtained. A total of 24 patients (77.4 %) met the surgical success criteria. The mTBS is a safe and feasible procedure with favorable effects on CPAP levels in patients with severe OSA.


The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress.
In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.


Pathogenesis and therapy of traction detachment in various retinal vascular diseases.
We examined six patients with retinal vasculopathies (two cases each of angiomatosis retinae [von Hippel-Lindau disease], exudative vitreoretinopathy, and Coats' disease), who developed preretinal and vitreal membranes, retinal traction detachment, and exudation under the retina. The membranes consisted of a core of collagen of various diameter fibers usually covered on both sides by cells that displayed glial cell characteristics. The retina reattached spontaneously and exudates disappeared when traction was eliminated by vitreous surgery. Membrane formation did reoccur after vitrectomy if the vessels continued to leak, leading again to traction and subretinal exudation. Treatment consisted of surgical removal of vitreal and preretinal membranes and destruction of leaking vessels.


A Comparison of Major Petroleum Life Cycle Models.
Many organizations have attempted to develop an accurate well-to-pump life cycle model of petroleum products in order to inform decision makers of the consequences of its use. Our paper studies five of these models, demonstrating the differences in their predictions and attempting to evaluate their data quality. Carbon dioxide well-to-pump emissions for gasoline showed a variation of 35%, and other pollutants such as ammonia and particulate matter varied up to 100%. Differences in allocation do not appear to explain differences in predictions. Effects of these deviations on well-to-wheels passenger vehicle and truck transportation life cycle models may be minimal for effects such as global warming potential (6% spread), but for respiratory effects of criteria pollutants (41% spread) and other impact categories, they can be significant. A data quality assessment of the models' documentation revealed real differences between models in temporal and geographic representativeness, completeness, as well as transparency. Stakeholders may need to consider carefully the tradeoffs inherent when selecting a model to conduct life cycle assessments for systems that make heavy use of petroleum products.


Pathways into chronic multidimensional poverty amongst older people: a longitudinal study.
The use of multidimensional poverty measures is becoming more common for measuring the living standards of older people. However, the pathways into poverty are relatively unknown, nor is it known how this affects the length of time people are in poverty for. Using Waves 1 to 12 of the nationally representative Household, Income and Labour Dynamics in Australia (HILDA) survey, longitudinal analysis was undertaken to identify the order that key forms of disadvantage develop - poor health, low income and insufficient education attainment - amongst Australians aged 65 years and over in multidimensional poverty, and the relationship this has with chronic poverty. Path analysis and linear regression models were used. For all older people with at least a Year 10 level of education attainment earlier mental health was significantly related to later household income (p = 0.001) and wealth (p = 0.017). For all older people with at less than a Year 10 level of education attainment earlier household income was significantly related to later mental health (p = 0.021). When limited to those in multidimensional poverty who were in income poverty and also had poor health, older people generally fell into income poverty first and then developed poor health. The order in which income poverty and poor health were developed had a significant influence on the length of time older people with less than a Year 10 level of education attainment were in multidimensional poverty for. Those who developed poor health first then fell into income poverty spend significantly less time in multidimensional poverty (-4.90, p < .0001) than those who fell into income poverty then developed poor health. Knowing the order that different forms of disadvantage develop, and the influence this has on poverty entrenchment, is of use to policy makers wishing to provide interventions to prevent older people being in long-term multidimensional poverty.


The relationship between parental alcohol use and college students' alcohol-related cognitions.
This study examined how parental and cognitive factors are structurally related to college students' intention to drink alcohol as well as possible gender differences in these relationships. Multiple-group comparison was used in structural equation modeling to assess data-to-model fit of the hypothesized model. Perceived parental alcohol use, positive expectancies, abstinence self-efficacy in social situations, and intent to drink alcohol were structurally modeled and examined in 714 college students based on self-report measures. Results showed good fit of the hypothesized model in both men and women. Invariance of model fit was found across genders, although a more detailed analysis of the results suggested gender-specific influence of parental alcohol use over students' cognitions. Perceptions of greater parental alcohol use were associated with higher positive expectancies for alcohol use, which, in turn, were significantly related to lower drink refusal self-efficacy. Both higher expectancies and lower refusal self-efficacy were related to the intention for future use. Results of the study shed light on the development of alcohol-related cognitions in male and female college students and contribute to our understanding of the structural relationship between expectancies and self-efficacy in alcohol use.


The association of coffee consumption and oxygen desaturation index during sleep among Japanese male workers.
Coffee is a major caffeine-containing food source that can be used for treatment of apnea in prematurity. However, few studies have examined the association between coffee consumption and sleep-disordered breathing (SDB). We investigated whether coffee consumption is associated with the oxygen desaturation index (ODI) as a marker of SDB among middle-aged Japanese male workers. The subjects were 1126 male local government workers aged 22-59 who participated in SDB screening in 2011-2012. Daily coffee consumption was assessed by a self-administered questionnaire. We measured 3% oxygen desaturation (3%ODI) during a night's sleep using a pulse oximeter. A general linear model was used to calculate the multivariate-adjusted means of 3%ODI per quartile of coffee consumption. We further analyzed the data after stratifying by overweight and current smoking status. A inverse association between coffee consumption and 3%ODI was found. The multivariate-adjusted mean of 3%ODI for the lowest and highest coffee consumption groups were 11.9 times/h and 10.6 times/h (p for trend = 0.06), respectively; 14.6 and 11.5 times/h (p for trend = 0.01) in overweight participants; and 12.7 and 11.0 times/h (p for trend = 0.06) in non-smokers. No associations were found in non-overweight and smoking workers. Our results suggest that higher coffee consumption was associated with lower 3% ODI as a marker of SDB in overweight and non-smoking workers.


Nitrogen-doped carbon encapsulating Fe7Se8 anode with core-shell structure enables high-performance sodium-ion capacitors.
With the associated advantages of low costs and abundant resources, sodium-ion capacitors (SICs) present a suitable means for large-scale energy storage. However, their practical application is still significantly limited by the sluggish electrochemical reaction kinetics of battery-type anodes. Herein, the nitrogen-doped carbon-encapsulated Fe7Se8 nanorods (Fe7Se8@NC) with a core-shell structure were prepared via an in-situ self-polymerization and carbonization-selenization approach, which improves ion transport and maintains the structural stability of the nanorods. The designed Fe7Se8@NC nanorods exhibit desirable rate capability with a capacity of 290.7 mAh/g at 10 A/g and long-term cyclability with 84.6 % retention over 6000 cycles at 5 A/g. Moreover, research has shown that the diffusion dynamics of Na+ is improved in ether-based electrolytes and that the irreversible reactions at low voltages can be inhibited by a high discharge cut-off voltage. Furthermore, we demonstrated the specific sodium storage mechanism and excellent electrochemical reversibility of the Fe7Se8@NC electrode through in-situ and ex-situ characterization techniques. As expected, the assembled SICs with the Fe7Se8@NC anode and active carbon cathode deliver prominent energy/power densities and an ultra-long cycle life over 5000 cycles, shedding new light on the design of transition metal dichalcogenides as anode materials for advanced energy storage systems.


Cough Characteristics and Healthcare Journeys of Chronic Cough Patients in Community-Based Populations in South Korea and Taiwan.
This study aimed to understand the cough characteristics and health journeys among community-based chronic cough (CC) patients, and their characteristics associated with healthcare visits. A population-based cross-sectional study was conducted in 2020, using the South Korea and Taiwan National Health and Wellness Survey (NHWS) and CC surveys. Patients with current CC were defined by daily coughing for > 8 weeks in the past 12 months and currently coughing at the time of survey. The survey items pertained to CC patients' treatment journey and cough characteristics. Patients with current CC in South Korea and Taiwan, respectively, had cough duration for 3.45 ± 5.13 years and 5.75 ± 7.28 years and cough severity visual analogue scale (VAS) scores of 4.50 ± 2.15 and 4.46 ± 1.92 out of 0-10 scale, with 70.3% and 57.9% having spoken with a physician about cough. Compared to CC patients who had not visited healthcare professionals for cough, those who visited reported more severe cough (VAS: 3.89 ± 1.71 vs. 4.6 ± 2.02; p = 0.009), worse cough-specific quality of life (Leicester Cough Questionnaire: 16.20 ± 3.23 vs.13.45 ± 2.68, p < 0.001), greater symptom severity (Hull Airway Reflux Questionnaire: 16.73 ± 15.16 vs. 24.57 ± 13.38; p < 0.001), and more urinary incontinence (13.6 vs. 26.5%, p = 0.027). More than 50% of patients perceived cough medication(s) as not or a little useful and 25% felt their physicians did not well understand how CC impacts their life. Cough is frequently severe and persistent among community-based CC patients. They experience several issues in their health journey, including treatment ineffectiveness and physician's understanding. Further efforts are warranted to reduce CC burden in the community.


Parental social-cognitive correlates of preschoolers' oral hygiene behavior: A systematic review and meta-analysis.
Regular and consistent parental involvement in children's oral hygiene practices is crucial to prevent oral diseases in young children. This emphasizes the need for interventions targeting parental-supervised oral hygiene behavior. To inform the design of future interventions, this meta-analysis aimed to identify the parental social-cognitive factors associated with oral hygiene behavior of preschoolers. Five bibliographic databases were searched. A study was eligible for inclusion when it reported an association between a parental social-cognitive factor and an oral hygiene behavior in the targeted age cohort. Meta-analyses were performed when there were at least four independent effect sizes (k > 3). Of the 5945 records identified, 25 studies contained eligible data to be included in four meta-analyses: attitude (k = 12); self-efficacy (k = 12); intention (k = 6), and sense of coherence (k = 5). The results showed that greater frequency of preschoolers' oral hygiene behavior is significantly associated with parental attitudes (r+ = 0.18), self-efficacy (r+ = 0.34), and intention (r+ = 0.29), and not significantly associated with parental sense of coherence (r+ = 0.08). Self-efficacy, attitudes, and intention were identified as significant correlates of parental-supervised oral hygiene behavior. However, this is a limited evidence base and many social-cognitive factors, such as self-regulatory processes including planning and action control, have yet to be explored in this context. The significant social-cognitive correlates identified in this study, as well as potential other self-regulatory factors, should be targeted in future intervention studies aimed at improving this important preventive behavior.


Two structural states of the vertebrate Z band.
Ultrastructural analysis of the vertebrate Z band suggests that two reversible states of a single intricate lattice are essential for the contractile process. The two structural states of the Z band lattice (ss and bw) have been described in cross section in skeletal and cardiac muscle in different physiological states. The lattice responds to active tension but resists passive deformation. Changes in Z band form and dimension are correlated with cross-bridge binding. Two-dimensional image processing techniques show enhanced structural features that vary with the observed changes in lattice dimension. All projected images from all lattices show an approximate four-fold symmetry. Each image reveals differences in the appearance of axial filaments which enter from opposite sides of the Z band and cross-connecting filaments of similar curvature which appear to connect each axial filament to four nearest axial filaments. In the ss images, the apparent diameter of cross-cut axial filaments and the Z band interaxial filament spacing are smaller than in bw images. Cross-connecting filaments appear to overlap in the region half-way between axial filaments in ss images. We conclude that the Z band is an essential and dynamic part of the sarcomere, uniquely suited to transmit tension while maintaining dimensions appropriate for cross-bridge interaction.


Prenatal diagnosis of thalassaemia by haemoglobin chromatography on Biorex. An evaluation of the method.
The applicability of the chromatographic separation of haemoglobin F, A and S on Biorex 70 ( Blouquit et al., 1982) for the prenatal diagnosis of thalassaemia and related conditions was evaluated in comparison to the conventional globin chain separation technique. The method proved reliable, inexpensive and rapid and should be considered as a valuable alternative in laboratories carrying out great numbers of tests and those being newly set up for this purpose.


Extended investigation of tau and mutation screening of other candidate genes on chromosome 17q21 in a Swedish FTDP-17 family.
Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive and motor disturbances. It was recently discovered that the majority of the FTDP-17 families carry missense or 5' splice mutations in the exons coding for the microtubule-binding domains of the tau protein. However, in at least five FTDP-17 families, no such mutations could be identified. In the present study, we aimed at further investigate abnormalities in the tau gene in a Swedish FTDP-17 family, where no mutations in the tau gene previously have been identified. Initially, we searched for larger deletions by Southern blot hybridization. Furthermore, possible abnormal splicing events was investigated by RT-PCR from brain tissue of affected individuals. In addition, we investigated the presence of mutations in other genes in the FTDP-17 candidate region on chromosome 17q21; Gamma-tubulin, Glial Fibrillary Acid Protein (GFAP), Human dual specificity phosphatase tyrosine/serine (VHR), Rap-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. In conclusion, no pathological changes in the tau gene were observed, neither was any mutations segregating with the disease detected in the investigated candidate genes. Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP-17.


Is it necessary to separate clinical stage T1c from T2 prostate adenocarcinoma?
To test the hypothesis that prostate cancer patients with clinical stage cT1c and cT2 have similar outcomes and clinicopathological features, and should be grouped together. From a series of men with prostate cancer who had a radical retropubic prostatectomy (RP), we assessed those with cT1c (223) and cT2 (65) adenocarcinoma. All RP specimens were totally embedded and whole-mounted; tumour volume was measured using the grid method. Clinical and pathological characteristics were analysed. Patients with cT2 tumours were more likely to have a higher Gleason score (P = 0.04) and final pathological stage (P = 0.05) than those with cT1c tumours. There was no significant difference in age (P = 0.92), preoperative PSA level (P = 0.17), prostate weight (P = 0.34), tumour volume (P = 0.16), surgical margin status (P = 0.86), multifocality (P = 0.92), the presence of perineural invasion (P = 0.09), or high-grade prostatic intraepithelial neoplasia (P = 0.99) between patients with clinical stage cT1c and those with cT2 tumours. There was no difference in PSA recurrence between patients with clinical stage T1c and those with cT2 tumours (P = 0.27). Patients with clinical stage cT2 tumours have a higher Gleason score and advanced pathological stage than tumours detected because of a high serum PSA level (cT1c). These results suggest that clinical stage cT1c tumours should be separated from clinical stage cT2 disease, but the PSA recurrence rate for both tumour stages is similar, indicating a need for further evaluation and refinement of the current clinical staging system.


The vasorelaxant effect of deuterium oxide is secondary to calcium-induced liberation of nitric oxide by endothelial cells.
To test the hypothesis that deuterium oxide (D2O) might induce endothelium-dependent and nitric oxide-mediated vasodilation by altering intracellular calcium concentration ([Ca2+]i) in vascular endothelial cells. The endothelium-dependent and nitric oxide-mediated regulation of vascular tone by D2O was first examined in perfused rat mesenteric arterial beds. Direct effects of D2O on [Ca2+]i in cultured vascular endothelial cells were then examined in order to elucidate a cellular mechanism for D2O-induced vasodilation. Vascular reactivity was assayed by measuring the perfusion pressure of isolated rat mesenteric arterial beds. [Ca2+]i in cultured bovine and rat vascular endothelial cells was measured with the fura-2 fluorescence technique. D2O relaxed precontracted rat mesenteric arterial beds with an intact endothelium. This effect of D2O was either inhibited by N omega-nitro-L- arginine (a nitric oxide synthase inhibitor) or eliminated by the removal of endothelium. In cultured bovine aortic, rat aortic, and rat tail artery endothelial cells, D2O induced a biphasic increase in [Ca2+]i, with a characteristic initial transient increase followed by various patterns of sustained [Ca2+]i increase. The sustained phase was entirely dependent on the extracellular calcium entry. A direct effect of D2O on [Ca2+]i in vascular endothelial cells may be responsible for the endothelium-dependent, presumably nitric oxide-mediated, vasodilation induced by D2O in precontracted vessels. From these results new mechanisms can be explored for the antihypertensive effect of D2O and new avenues can be developed to study the functional integrity of the endothelium-dependent regulation of the vascular tone.


Effects of concomitant aspirin administration on the pharmacokinetics of indomethacin in man.
Ten healthy volunteers each received single and multiple 50-mg doses of indomethacin orally and a single 25-mg dose of [14C]indomethacin intravenously in the absence of and concomitantly with 1200 mg of aspirin as a single dose and in a chronic t.i.d. regimen. Systematic analysis of the data resulted in the isolation and quantification of aspirin's effects on the absorption, distribution, biotransformation, excretion, enterohepatic circulation, and accumulation of indomethacin. The effects of chronic aspirin were to suppress the renal clearance, to increase the biliary clearance, to decrease the efficiency of gastrointestinal absorption, and to enhance the enterohepatic circulation of indomethacin. On concomitant administration of 1200 mg of aspirin t.i.d., mean plasma levels of indomethacin were depressed by 20% after a single oral dose, by a smaller margin after multiple oral doses, and not at all after a single intravenous dose of indomethacin. The mean plasma concentration of orally administered indomethacin was decreased by 8% when given concurrently with a single 1200 mg dose of aspirin. Concomitant chronic therapeutic dosages of indomethacin had no effect on salicylate accumulation from repetitive doses of aspirin.


Targeted Next Generation Sequencing Revealed Novel Variants in the PKD1 and PKD2 Genes of Iranian Patients with Autosomal Dominant Polycystic Kidney Disease.
Autosomal dominant polycystic kidney disease (ADPKD), one of the common inherited disorders in humans, is characterized by the development and enlargement of renal cysts, often leading to end-stage renal disease (ESRD). In this study, Iranian ADPKD families were subjected to high-throughput DNA sequencing to find potential causative variants facilitating the way toward risk assessment and targeted therapy. Our protocol was based on the targeted next generation sequencing (NGS) panel previously developed in our center comprising 12 genes involved in PKD. This panel has been applied to investigate the genetic causes of 32 patients with a clinical suspicion of ADPKD. We identified a total of 31 variants for 32 individuals, two of which were each detected in two individuals. Twenty-seven out of 31 detected variants were interpreted as pathogenic/likely pathogenic and the remaining 4 of uncertain significance with a molecular diagnostic success rate of 87.5%. Among these variants, 25 PKD1/2 pathogenic/likely pathogenic variants were detected in 32 index patients (78.1%), and variants of uncertain significance in four individuals (12.5% in PKD1/2). The majority of variants was identified in PKD1 (74.2%). Autosomal recessive PKD was identified in one patient, indicating the similarities between recessive and dominant PKD. In concordance with earlier studies, this biallelic PKD1 variant, p.Arg3277Cys, leads to rapidly progressive and severe disease with very early-onset ADPKD. Our findings suggest that targeted gene panel sequencing is expected to be the method of choice to improve diagnostic and prognostic accuracy in PKD patients with heterogeneity in genetic background.


Application of a Standard Cross-Specialty Workup for Diagnosis and Metabolic Screening of Obese Adolescents With Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a common disorder. The used diagnostic criteria and screening for related metabolic disease in adolescent girls with PCOS vary with medical specialty, causing discrepancies in care. We sought to improve and standardize care to guidelines for adolescents with PCOS and obesity. This is a quality improvement project in a multispecialty, tertiary care children's hospital. Providers in Adolescent Medicine, Gynecology, Pediatric Endocrinology, and Endocrine-Metabolic clinics participated. Diagnostic testing and metabolic screening data were collected for new patient encounters with PCOS and obesity, with two improvement cycles from December 2012 to March 2017. Providers received education on diagnostics tests and metabolic screening recommendations, and electronic medical record tools were created. The number of diagnostic and metabolic screening tests ordered per cycle and per clinic were analyzed and compared with baseline. The preintervention cycle included 74 encounters-44 in Cycle 1 and 58 in Cycle 2. Diagnostic test completeness improved by Cycle 2 (46%-68%) for all clinics. Screening for metabolic disease only improved in Gynecology (27%-71%). Adolescent Medicine, Endocrinology, and Endocrine-Metabolic used note templates, and Adolescent Medicine and Gynecology used order sets. Note templates were associated with more diagnostic tests ordered in Endocrinology (30%-88%; p = .002). Implementation of quality improvement measures improved the number of diagnostic and metabolic screening tests performed in new patient encounters for PCOS, although the most effective strategy varied by clinic type and electronic medical record habits. Similar efforts should be implemented to standardize care at other institutions.


Noise correlation and its impact on the performance of multi-material decomposition-based spectral imaging in photon-counting CT.
It has been known that noise correlation plays an important role in the determination of the performance of spectral imaging based on two-material decomposition (2-MD). To further understand the basics of spectral imaging in photon-counting CT toward optimal design and implementation, we study the noise correlation in multi-MD (m-MD) and its impact on the performance of spectral imaging. We derive the equations that characterize the noise and noise correlation in the material-specific (basis) images in m-MD, followed by a simulation study to verify the derived equations and study the noise correlation's impact on the performance of spectral imaging. Using a specially designed digital phantom, the study of noise correlation runs over the cases of two-, three-, and four-MD (2-MD, 3-MD, and 4-MD). Then, the noise correlation's impact on the performance of spectral imaging in photon-counting CT is investigated, using a modified Shepp-Logan phantom. The results in 2-MD show that, in-line with what has been reported in the literature, the noise correlation coefficient between the material-specific images corresponding to the basis materials approaches -1. The results in m-MD (m ≥ 3) are more complicated and interesting, as the noise correlation coefficients between a pair of the material-specific images alternate between ±1, and so do in the case of 4-MD. The m-MD data show that the noise in virtual monochromatic imaging (a form of spectral imaging) is moderate even though the noises in material-specific (basis) images vary drastically. The observation of noise correlation in 3-MD, 4-MD, and beyond (i.e., m-MD) is informative to the community. The relationship between noise correlation and the performance of spectral imaging revealed in this work may help clinical medical physicists understand the fundamentals of spectral imaging based on MD and optimize the performance of spectral imaging in photon-counting CT and other X-ray imaging modalities.


Greening automation: Wash and Re-use of disposable 384-well liquid handling tips to enable sustainable high-throughput vaccine development.
Laboratory automation uses large amounts of plastic consumables, generating substantial single-use plastic waste. Automated ELISAs are an indispensable analytical tool in vaccine formulation and process development. Current workflows, however, rely on disposable liquid handling tips. In progress toward sustainability, we developed workflows for washing 384-well format liquid handling tips, using nontoxic reagents, for re-use during ELISA testing. We estimate that this workflow reduces plastic and cardboard waste in our facility by 989 kg/year and 202 kg/year, respectively, without introducing new chemicals into our waste steam.


Central nervous system action of calcitonin to alter experimental gastric ulcers in rats.
The central nervous system action of calcitonin to influence various experimental models of gastric ulcers and gastric function was studied in rats fasted for 24 h. Intracisternal injection of salmon calcitonin (5 micrograms) completely suppressed gastric ulcerations induced by exposure to cold restraint stress, intracisternal injection of a stable thyrotropin-releasing hormone analogue, or peroral administration of aspirin. By contrast, intracisternal calcitonin enhanced gastric lesions elicited by peroral administration of 40% ethanol or 0.6 N HCl. Calcitonin action was dose-dependent (0.01-1 microgram) and central nervous system mediated inasmuch as intravenous calcitonin, given at a dose 50-fold higher than that effective intracisternally, did not significantly modify gastric mucosal injuries elicited by aspirin or ethanol. Intracisternal injection of calcitonin at 0.01 microgram inhibited gastric acid output by 90% in pylorus-ligated rats and suppressed gastric emptying of a liquid meal by 63%-94% in doses ranging from 0.01 to 5 micrograms. Prostaglandin generation in the gastric mucosa was not modified by intracisternal injection of calcitonin. These results demonstrate that intracisternal calcitonin acts within the brain to potently prevent ulcer formation elicited by stress, thyrotropin-releasing hormone analogue, or aspirin, but is not cytoprotective against necrotizing agents. Calcitonin action is not related to modification of gastric prostaglandin generation but it may involve the inhibition of gastric secretory and motor function.


Anatomical assessment of the bladder outlet and proximal urethra using ultrasound and videocystourethrography.
In a prospective blinded comparative clinical study 125 women underwent videocystourethrography and cystometry as well as transperineal ultrasound as part of their diagnostic work-up for urinary incontinence or after incontinence-correcting surgery. Comparisons between ultrasound and X-ray imaging were carried out on 117 women for whom complete data sets were available. Mean bladder neck descent was significantly greater with ultrasound compared to VCU (US: 2.1 +/- 1.2 cm vs. VCU: 1.8 +/- 0.9; P = 0.003). Rotation of the proximal urethra was not always seen on X-ray, but when it was (44 patients) there was good correlation with US (US rotation 55 +/- 27 degrees vs. VCU rotation 55 degrees +/- 29). There was also good agreement between both tests regarding visualization of funneling or opening of the proximal urethra, with both tests showing equivalent results in 95 out of 117 patients (Cohen's kappa 0.58). On comparing extensive funneling to the midurethra on US with frank leakage on VCU the methods were in agreement for 90 out of 117 patients (kappa 0.54). Overall a good correlation between ultrasound and radiological findings was observed. Both methods allow anatomic assessment of the bladder neck and have different strengths and weaknesses. Ultrasound imaging may be preferable as it is cheaper, requires less technological back-up and avoids the risks of radiation exposure and allergic reactions to contrast medium.


Structure and dynamic of a natterjack toad metapopulation (Bufo calamita).
The migratory and reproductive behaviour ofBufo calamita was studied at four neighbouring breeding sites in the northern Rhineland, Germany, from 1986 to 1991. Radio telemetry and marking systems based on toe-clipping and on microchips were used to follow the tracks of toads and for individual recognition. Emphasis lay on estimates of (1) the exchange of reproductive individuals between neighbouring sites, and (2) the reproductive success at each site. Allozyme electrophoresis served to assess the genetic diversity of local populations. More than 90% of all reproductive males showed a lifelong fidelity to the site of first breeding, whereas females did not prefer certain breeding sites. Due to the female-biased exchange of individuals among neighbouring sites the genetic distance between local populations was generally low but increased with geographical distance. This pattern of spatial relations is consistent with the structure of a metapopulation. Morever, up to three mass immigrations of males per breeding period, replacing previously reproductive individuals, suggested the existence of temporal populations successively reproducing at the same locality. Genetic distances were considerably greater between temporal populations than between local ones, indicating partial reproductive isolation. In fact, an exchange of reproductive individuals between the temporal populations at each site was not detected, but gene flow due to the recruitment of first-breeders originating from offspring other than their own seems probable. Thus, natterjack metapopulations consist of interacting local and temporal populations. The reproductive success differed considerably among the four sites and also between the temporal populations. Three out of four local populations had low reproductive success as well as the latest temporal population. The persistence of these populations depended entirely on the recruitment of juveniles from the only self-sustaining local population. This "rescue-effect" impeded local extinction. The discussion focuses on the modifications required to fit the classical metapopulation concept to the empirical findings and their consequences for the dynamics of amphibian metapopulations.


Inflammatory response to cardiopulmonary bypass.
This article reviews the roles of the contact and complement systems and of neutrophils and monocytes in the inflammatory response to cardiopulmonary bypass and open heart operation. These blood proteins and cells, together with other blood elements, produce the vasoactive and cytotoxic substances and microemboli that cause the morbidity associated with cardiopulmonary bypass and open heart operation.


Peginterferon plus Ribavirin for HIV-infected Patients with Treatment-Naïve Acute or Chronic HCV Infection in Taiwan: A Prospective Cohort Study.
Data are limited on the effectiveness and safety of peginterferon plus ribavirin in HIV-infected Asian patients with acute or chronic HCV infection. HIV-infected Taiwanese patients with acute HCV infection received peginterferon plus weight-based ribavirin for 24 weeks (n = 24), and those with chronic HCV genotype 1 or 6 (HCV-1/6) and HCV genotype 2 or 3 (HCV-2/3) infection received response-guided therapy for 12-72 and 24-48 weeks, respectively (n = 92). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA 24 weeks off-therapy. The SVR rates were 83% and 72% in patients with acute and chronic HCV infection (p = 0.30), and 68% and 72% in patients with chronic HCV-1/6 and HCV-2/3 infection (p = 0.48), respectively. While no factors predicted SVR in acute HCV and chronic HCV-2/3 infection, age (odds ratio [OR] per 1-year increase: 0.88, 95% confidence interval [CI]: 0.78-0.99, p = 0.04), HCV RNA (OR per 1-log10 increase: 0.18, 95% CI: 0.03-0.98, p = 0.03), IL28B genotype (OR: 5.52, 95% CI: 1.55-12.2, p = 0.02), and RVR (OR: 9.62, 95% CI: 3.89-15.3, p = 0.007) predicted SVR in chronic HCV-1/6 infection. In conclusion, the SVR rates of peginterferon plus ribavirin for 24 weeks and for response-guided 12-72 weeks are satisfactory in HIV-infected Taiwanese patients with acute and chronic HCV infection.


Nanofibers doped with a novel red-emitting Europium complex: synthesis, characterization, photophysical property and sensing activity toward molecular oxygen.
In this paper, we synthesize a novel diamine ligand of DIQ-Et and its corresponding Eu(III) complex of Eu(TTA)(3)DIQ-Et, where DIQ-Et=N-ethyl-10H-dipyrido-[f,h]-indolo-[3,2-b]-quinoxaline, and TTA=2-thenoyltrifluoroacetonate. The UV-vis absorption, photoluminescence, low temperature phosphorescence, energy transfer mechanism, and excited state lifetime of Eu(TTA)(3)DIQ-Et are investigated in detail. Data suggest that the emission of Eu(TTA)(3)DIQ-Et is quenchable by molecular oxygen due to the back-energy transfer process. By doping Eu(TTA)(3)DIQ-Et into a polymer matrix of poly(vinylpyrrolidone) (PVP), oxygen sensing performance of the resulted nanofibers is investigated. Finally, the 0.7 wt% doped sample exhibits a linear response toward molecular oxygen, with a sensitivity of 2.4 and response/recovery time of 12s/16s.


Covalent Immobilization of Human Placental 17β-Hydroxysteroid Dehydrogenase Type 1 onto Glutaraldehyde Activated Silica Coupled with LC-TOF/MS for Anti-Cancer Drug Screening Applications.
Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), a potential target in breast cancer prevention and therapy, was extracted from human placenta and immobilized on nonporous silica (∼5 μm) with a covalent method for the first time. The optimum initial enzyme concentration and immobilization time during the immobilization process were 0.42 mg mL-1 and 12 h, repectively. The binding was confirmed by scanning electron microscope (SEM) and infrared spectroscopy (FT-IR). It could improve the pH, thermal and storage stability compared to free enzyme. Moreover, the immobilized enzyme could be reused at least four times. A screening method based on it coupled with liquid chromatography-time-of-flight mass spectrometer (LC-TOF/MS) was established, and the half-maximal inhibitory concentration (IC 50) of apigenin for the immobilized enzyme was 291 nM. Subsequently, 10 natural products were evaluated leading to inhibition of the activity of 17β-HSD1 at the concentration of 25 μM, and six of them inhibit the activity over 50%.


Comparison of Lamiaceae medicinal uses in eastern Morocco and eastern Andalusia and in Ibn al-Baytar's Compendium of Simple Medicaments (13th century CE).
Transmission of traditional knowledge over time and across culturally and historically related territories is an important topic in ethnopharmacology. Here, we contribute to this knowledge by analysing data on medicinal uses in two neighbouring areas of the Western Mediterranean in relation to a historical text that has been scarcely mentioned in historical studies despite its interest. This paper discusses the sharing of popular knowledge on the medicinal uses of plants between eastern Morocco and eastern Andalusia (Spain), focusing on one of the most useful plant families in the Mediterranean area: Lamiaceae. Moreover, we used the classical work of Ibn al-Baytar (13th century CE) The Compendium of Simple Medicaments and Foods as a basis to contrast the possible link of this information, analysing the influence of this historical text on current popular tradition of medicinal plant use in both territories. For data collection, we performed ethnobotanical field research in the eastern part of Morocco, recording current medicinal uses for the Lamiaceae. In addition, we systematically reviewed the ethnobotanical literature from eastern Andalusia, developing a database. We investigated the possible historical link of the shared uses and included in this database the information from Ibn al-Baytar's Compendium. To compare the similarity and diversity of the data, we used Jaccard's similarity index. Our field work provided ethnobotanical information for 14 Lamiaceae species with 95 medicinal uses, serving to treat 13 different pathological groups. Of the total uses recorded in Morocco, 30.5% were shared by eastern Andalusia and found in Ibn al-Baytar's work. There was a higher similarity when comparing current uses of the geographically close territories of eastern Morocco and eastern Andalucía (64%) than for eastern Morocco and this historical text (43%). On the other hand, coincidences between current uses in eastern Andalusia and the ones related in the Compendium are lower, 28%. The coincidence of the current ethnobotanical knowledge in the two territories is high for the Lamiaceae. Probably the shared historical background, recent exchanges, information flow, and the influence of the historical herbal texts have influenced this coincidence. In this sense, there is a high plant-use overlap between Ibn al-Baytar's text and both territories: nearly half of the uses currently shared by eastern Morocco and eastern Andalusia were included in the Compendium and are related to this period of Islamic medicine, indicating a high level of preservation in the knowledge of plant usage. The study of 14 species of Lamiaceae suggests that this classical codex, which includes a high number of medicinal plants and uses, constitutes a valuable bibliographical source for comparing ancient and modern applications of plants.


When glycaemic targets can no longer be achieved with basal insulin in type 2 diabetes, can simple intensification with a modern premixed insulin help? Results from a subanalysis of the PRESENT study.
The aim of this analysis was to assess the efficacy and safety of intensifying insulin therapy from a basal-only regimen to biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes previously failing to reach glycaemic targets. The analysis is based on data from a subpopulation of the Physicians' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy (PRESENT) study, which was a 6-month observational study in 15 countries. This subanalysis included patients previously receiving long-acting analogue insulin (AB; n = 348), or human basal insulin (long and intermediate acting) (HB; n = 3414), who were transferred to BIAsp 30. Efficacy end-points included change in glycated haemoglobin (HbA(1c)), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), from baseline to the end of the study. Episodes of hypoglycaemia, adverse events, and physician and patient satisfaction were also recorded. End-points were considered separately by previous basal regimen (AB or HB). After 6 months' treatment with BIAsp 30, HbA(1c) was significantly lowered in both groups (-1.60% and -1.42% in the AB and HB groups; p < 0.0001 compared with baseline). Reductions in FPG and PPG were also statistically significant in both groups. The rate (events/patient/year) of overall hypoglycaemia remained relatively constant in patients switching from AB, but it was statistically lower in patients switching from HB (change from baseline -3.8; p < 0.001). In routine clinical practice, patients with type 2 diabetes who are failing to reach glycaemic targets on basal insulin can achieve better glycaemic control without an increase in overall hypoglycaemia by intensifying with BIAsp 30.


Light-Based Neuronal Activation: The Future of Cranial Nerve Stimulation.
Despite advances in implant hardware, neuroprosthetic devices in otolaryngology have sustained evolutionary rather than revolutionary changes over the past half century. Although electrical stimulation has the capacity for facile activation of neurons and high temporal resolution, it has limited spatial selectivity. Alternative strategies for neuronal stimulation are being investigated to improve spatial resolution. In particular, light-based neuronal stimulation is a viable alternative and complement to electrical stimulation. This article provides a broad overview of light-based neuronal stimulation technologies. Specific examples of active research on light-based prostheses, including cochlear implants, auditory brainstem implants, retinal implants, and facial nerve implants, are reviewed.


Machine learning for the prediction of osteopenia/osteoporosis using the CT attenuation of multiple osseous sites from chest CT.
To use machine learning and the CT attenuation of all bones visible on chest CT scans to predict osteopenia/osteoporosis. We retrospectively evaluated 364 patients with CT scans of the chest, and Dual-energy X-ray absorptiometry (DXA) scans within 6 months of each other. Studies were performed between 01/01/2015 and 08/01/2021. Volumetric segmentation of the ribs, thoracic vertebrae, sternum, and clavicle was performed using 3D Slicer to obtain the mean CT attenuation of each bone. The study sample was randomly split into training/validation (80 %, n = 291 patients) and test (20 %, n = 73 patients) datasets. Univariate analyses were used to identify the optimal CT attenuation thresholds to diagnose osteopenia/osteoporosis. We used penalized multivariable logistic regression models including Least Absolute Shrinkage and Selection Operator (LASSO), Elastic Net, and Ridge regression, and Support Vector Machines (SVM) with radial basis functions (RBF) to predict osteopenia/osteoporosis and compared these results to the CT attenuation threshold at T12. There were positive correlations between the CT attenuation between all bones (r > 0.6, P < 0.001 for all). There were positive correlations between CT attenuation of the bones and the L1-L4 BMD T-score, total hip T-score, and femoral neck T-scores (r > 0.4, P < 0.001 for all). A CT attenuation threshold of 170.2 Hounsfield units (HU) at T12 had an AUC of 0.702, while a threshold of 192.1 HU at T4 had an AUC of 0.757. The SVM with RBF had the highest AUC (AUC = 0.864) and was better than the LASSO (P = 0.011), Elastic Net (P = 0.011), Ridge regression (P = 0.011) but was not better than using the CT attenuation at T12 (P = 0.060). The CT attenuation of the ribs, thoracic vertebra, sternum, and clavicle can be used individually and collectively to predict BMD and to predict osteopenia/osteoporosis.


Prevention of Iron Overload and Long Term Maintenance of Normal Iron Stores in Thalassaemia Major Patients using Deferiprone or Deferiprone Deferoxamine Combination.
Decrease in mortality and morbidity is observed in thalassaemia major patients with reduced iron load in comparison to heavy iron loaded patients. Effective and complete treatment of transfusional iron overload can be achieved by chelation protocols that can eliminate excess iron and maintain normal iron stores (NIS). The maintenance of NIS, i. e., serum ferritin (350 μg/L >), MRI T2* cardiac (>20 ms) and liver (>6.3 ms) relaxation time levels was monitored in 16 thalassaemia major patients (32-53 years, 12 splenectomized, 10 male, erythrocyte transfusions 120-323 ml/kg/year) for about 90 patient years. The patients were treated with individualised tailor-made deferiprone or deferiprone/deferoxamine combination protocols. In 8 patients deferiprone (50-100 mg/kg/day) was sufficient for maintaining NIS and withdrawal of deferiprone for 28 months in total was necessary in 4 patients for preventing iron deficiency. In 3 other patients intermittent deferoxamine (50-75 mg/kg/8-30 h, 1-4 days/week) in combination with deferiprone (75-100 mg/kg/day) was sufficient for maintaining NIS. In the remaining 5 patients deferiprone (75-100 mg/kg/day) and deferoxamine (50-60 mg/kg/8-15 h, 1-7 days/week) combination was used for maintaining NIS, as a result of increased transfusions which were caused mainly by splenomegaly and infections. No toxic side effects were detected during the study. Lower chelation doses were used for the maintenance of NIS in comparison to iron loaded categories of patients. The safe maintenance of NIS using deferiprone and deferiprone/deferoxamine combinations should be considered as an optimum therapy for the complete treatment of iron overload in the majority of thalassaemia patients.


Calcium binding sites of hamster parasympathetic neurons.
Sites of Ca localization in hamster submandibular ganglion cells have been studied by electron microscopy using the technique of Oschman et al. [11]. Electron-dense deposits, which we assume to contain Ca, are found: (i) on axonal plasma membranes; (ii) on the plasma membranes of neuron soma and its processes; (iii) on the membrane of clear vesicles in the nerve terminal; and (iv) in the matrix of mitochondria. Intracellularly injected Ca accumulates in the mitochondria. Caffeine reduces the electron-dense deposits seen in mitochondria. Caffeine induces a swelling of Golgi apparatus when applied with CaCl2, but this swelling is not observed without CaCl2. These results are discussed in the light of Ca-activated K-conductance increases, which induce 4 types of membrane potential changes [18, 19].


Expired Tidal Volume and Respiratory Rate During Postnatal Stabilization of Newborn Infants Born at Term via Cesarean Delivery.
To retrieve evolving respiratory measures in the first minutes after birth in normal neonates born at term using a respiratory function monitor. We evaluated newborn babies delivered at term via cesarean after uncomplicated pregnancies. Immediately after birth, a respiratory function monitor with an adapted flowmeter and a face mask were applied at 2, 5, and 10 minutes after birth for 90 seconds in each period. We analyzed expired and inspired tidal volume, respiratory rate (RR), percentage of leakage, and number of analyzed breaths in each individual infant's recording using a respiratory research software. A total of 243 infants completed the study. The final data set included 59 058 (48.35%) valid observations for each of the variables representing the analysis of 32 801 breaths. With these data, we constructed a reference range with 10th, 25th, 50th, 75th, and 90th percentiles for expired tidal volume and RR. Tidal volumes plateaued earlier in female than in male infants. No correlation with delayed cord clamping, gestational age, maternal morbidity, or indication for cesarean delivery were established. We have constructed a reference range with percentiles for inspired and expired tidal volumes and RR in newborn babies born at term for the first 10 minutes after birth. Reference ranges can be employed for research and can be useful in the clinical setting to guide positive pressure ventilation in the delivery room.


The impact of radiosensitivity on clinical outcomes of spinal metastases treated with stereotactic body radiotherapy.
To evaluate the impact of radiosensitivity on outcomes of spinal metastases treated with stereotactic body radiotherapy (SBRT) and identify the correlated prognostic factors. The authors retrospectively reviewed the records of all patients who underwent SBRT with no prior radiation for spinal metastases between October 2015 and October 2020 at Sun Yat-sen University Cancer Center. On the basis of radiosensitivity, patients were divided into two groups-radiosensitive and radioresistant. The endpoints included local control (LC), overall survival (OS), pain relief, and time to pain relief. A total of 259 (82.5%) patients with 451 lesions were assessable with a median follow-up time of 10.53 months. The 1-, 2-, and 3-year OS rates were 59%, 52%, and 44%, respectively. The median survival was 33.17 months. Higher Karnofsky Performance Scale score and shorter time to diagnosis of spinal metastases from primary cancer at consult predicted for better OS (p = 0.02 and p < 0.001, respectively). The presence of other metastases (p = 0.04) and pain at enrollment assessed by the Brief Pain Inventory predicted for worse OS (p = 0.01). The 6-, 12-, and 24-month LC rates were 88%, 86%, and 82%, respectively. Younger age was identified for better LC and pain relief (p < 0.001 and p = 0.04, respectively). There was no variable independently associated with time to pain relief. As for toxicity, no Grade ≥3 toxicity was observed. Regardless of radiosensitivity, SBRT is feasible and appears to be an effective treatment paradigm for patients with spinal metastases, with limited accepted toxicities.


Molecular paleoparasitological diagnosis of Ascaris sp. from coprolites: new scenery of ascariasis in pre-Colombian South America times.
Paleoparasitological studies using microscopy showed that Ascarisand Trichuris trichiura are the human intestinal parasites most found in archaeological sites. However, in pre-Columbian South American archaeological sites, Ascaris is rare. In this work we standardized a molecular methodology for Ascaris diagnosis directly from ancient DNA retrieved from coprolites. Using cythochrome b gene (142 bp) target, ancient DNA sequences were retrieved from South American samples, negative by microscopy. Moreover, the methodology applied was sensitive enough to detect ancient DNA extracted from 30 Ascaris eggs from an European coprolite. These results revealed a new scenery for the paleodistribution of Ascaris in South America.


Vibrio deploys type 2 secreted lipase to esterify cholesterol with host fatty acids and mediate cell egress.
Pathogens find diverse niches for survival including inside a host cell where replication occurs in a relatively protective environment. Vibrio parahaemolyticus is a facultative intracellular pathogen that uses its type 3 secretion system 2 (T3SS2) to invade and replicate inside host cells. Analysis of the T3SS2 pathogenicity island encoding the T3SS2 appeared to lack a mechanism for egress of this bacterium from the invaded host cell. Using a combination of molecular tools, we found that VPA0226, a constitutively secreted lipase, is required for escape of V. parahaemolyticus from the host cells. This lipase must be delivered into the host cytoplasm where it preferentially uses fatty acids associated with innate immune response to esterify cholesterol, weakening the plasma membrane and allowing egress of the bacteria. This study reveals the resourcefulness of microbes and the interplay between virulence systems and host cell resources to evolve an ingenious scheme for survival and escape.


The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: Epithelial Ovarian Cancer.
We report the results of an international consensus on hyperthermic intraperitoneal chemotherapy (HIPEC) regimens for epithelial ovarian cancer (EOC) performed with the following goals: To define the indications for HIPEC To identify the most suitable HIPEC regimens for each indication in EOC To identify areas of future research on HIPEC To provide recommendations for some aspects of perioperative care for HIPEC METHODS: The Delphi technique was used with two rounds of voting. There were three categories of questions: evidence-based recommendations [using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system with the patient, intervention, comparator, and outcome (PICO) method], an opinion survey, and research recommendations. Seventy-three (67.5%) of 108 invited experts responded in round I, and 68 (62.9%) in round II. Consensus was achieved for 34/38 (94.7%) questions. However, a strong positive consensus that would lead to inclusion in routine care was reached for only 6/38 (15.7%) questions. HIPEC in addition to interval cytoreductive surgery (CRS) received a strong positive recommendation that merits inclusion in routine care. Single-agent cisplatin was the only drug recommended for routine care, and OVHIPEC-1 was the most preferred regimen. The panel recommended performing HIPEC for a minimum of 60 min with a recommended minimum intraabdominal temperature of 41°C. Nephroprotection with sodium thiosulfate should be used for cisplatin HIPEC. The results of this consensus should guide clinical decisions on indications of HIPEC and the choice and various parameters of HIPEC regimens and could fill current knowledge gaps. These outcomes should be the basis for designing future clinical trials on HIPEC in EOC.


Human-associated extended-spectrum β-lactamase in the Antarctic.
Escherichia coli bacteria with extended-spectrum β-lactamase (ESBL) type CTX-M resistance were isolated from water samples collected close to research stations in Antarctica. The isolates had bla(CTX-M-1) and bla(CTX-M-15) genotypes and sequence types (ST) indicative of a human-associated origin. This is the first record of ESBL-producing enterobacteria from Antarctica.


Quantitative assessment of dendritic branching and spine densities of neurons of hippocampal embryonic tissue transplanted into juvenile neocortex.
Embryonic 18-day-old hippocampal tissue was transplanted into a fresh cavity in frontal neocortex in 18-day-old (juvenile) Wistar rats. The transplant was examined after 2-5 months. The rapid Golgi procedure was used to assess quantitatively the dendritic branching (intersections and branching orders) and spine numbers per neuronal region, and spine densities (per 20 microns segment) on the pyramidal neurons, granule neurons and other types. The results revealed that the graft neurons generally have significant deviations from those of normal native hippocampal neurons. The aberrations were present in both pyramidal and granule cells. There were also many neurons which could not be classified into the known types. The pyramidal neurons showed a significant deficiency in dendritic branching, more often in basal dendrites than in apical dendrites. Apical dendrites of the graft pyramidal neurons also developed spine densities relatively better than basal dendrites, and sometimes significantly higher than even normal neurons. The significant deficiency in spine numbers of basal dendrites was primarily due to deficiency in dendritic branching rather than to spine density. On the contrary, the granule cells developed significantly less of both dendritic branching and spine densities (hence spines per neuron) than normal hippocampal granule neurons. The unclassifiable neuronal types had generally high dendritic branching and spine densities relative to the other neurons of the graft. The study discusses the importance and necessity of making quantitative assessments of neurons to understand whether the apparently normal neurons of transplants are really normal, and how far they are deviant. So far, quantitative assessments have been seldom reported in this important area of research, hence, this study is the first of its kind to highlight it.


Prognostic significance of pretreatment serum lactate dehydrogenase-to-albumin ratio in gastric cancer.
To investigate the prognostic role of lactate dehydrogenase-to-albumin ratio (LAR) in gastric cancer patients undergoing curative resection. A retrospective study was conducted including resectable gastric cancer patients. According to the time-dependent receiver operating characteristics (ROC) analysis, the optimal threshold for pretreatment LAR was 5.5. The Kaplan-Meier method, Cox regression univariate and multivariate analyses were used to analyze the prognostic factors for disease-free survival and overall survival (OS). The study cohort consisted of 81 patients, mean age was 60.2 ±13.8 (range, 29-87) years and 55 (67.9%) were male. The median OS time was 34.8 and 45 months in patients with LAR ≥ 5.5 (n = 50) and LAR < 5.5 (n = 31), respectively. Kaplan-Meier curves showed that with the increase in LAR there was reduced survival, but it was not statistically significant (p = 0.278). Multivariate analyses revealed that the positive lymph node ratio above 20% was an independent predictor in resectable gastric cancer patients (OR = 6.281, 95% CI: 1.135-34.767, p = 0.035). With the increase in LAR survival in gastric cancer decreased, but it was not statistically significant. Studies involving a large patient series are needed.


Eliminative split of pectic substances by phytopathogenic soft-rot bacteria.
Culture filtrates of Erwinia carotovora and Bacillus polymyxa split pectic substances to yield a product that absorbs at 230 mmicro, and which reacts with thiobarbituric acid to form a substance that absorbs at 547 mmicro. This product is believed to be a C-4,5-unsaturated oli-gouronide. The preferred substrate is polygalacturonic acid rather than pectin; the enzyme, provisionally named polygalacturonic-trans-eliminase, is activated by calcium.


Polyketones from the endophytic fungus Cytospora rhizophorae.
Cytosporaphenones D (1) and E (2), two new polyketones, and one new natural product 1,7-dihydroxy-6-methyl-8-formylxanthone (3), along with four known compounds, were isolated from Cytospora rhizophorae, an endophytic fungus from Morinda officinalis. Their structures were elucidated by extensive spectroscopic analyses and X-ray diffraction technique.