Pharmacological profile of upacicalcet, a novel positive allosteric modulator of calcium-sensing receptor, in vitro and in vivo.
Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca2+) concentration without exhibiting an agonistic action when the extracellular Ca2+ level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca2+. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03-3mg/kg and 0.3-30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca2+ levels; however, the effect of upacicalcet on the reduction in serum Ca2+ disappeared at extracellular Ca2+ levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.


Architecture in cortical bone and ultrasound transmission velocity.
The square of ultrasound transmission velocity in a material is correlated to the modulus of elasticity, which is an indicator of its mechanical properties. This might make the measurement of ultrasound transmission velocity useful in the noninvasive diagnosis of bone diseases. Bone, however, is not an isotropic material but is architecturally structured. The aim of our study was to investigate and especially to quantify the influence of architecture in cortical bone on ultrasound transmission velocity. Twenty-two rectangular, flat specimens of cortical bone were prepared from diaphysis of fresh pig radius. Ultrasound transmission velocity was measured parallel and perpendicular to direction of Haversian channels. It was found to be 3647 +/- 41 m/s parallel to and 2821 +/- 29 m/s perpendicular to Haversian channels respectively (p < 0.001). Our results clearly indicate that there is an important influence of architecture in cortical bone on ultrasound transmission velocity which has to be taken into account in its clinical use.


Infectious tolerance develops after intrathymic alloantigen-induced acceptance of rat heart allografts can be adoptively transferred.
We have shown that intrathymic (IT) injection of alloantigen with antirat lymphocyte serum (ALS) treatment can induce donor-specific allograft acceptance. The purpose of this study was to investigate whether T-regulatory (T-reg) cells play a role in the maintenance of donor-specific heart graft tolerance that develops after IT injection of Lewis (LEW, RT1(l)) alloantigen into a Dark Agouti (DA, RT1(a)). Naïve DA rats were injected IT with 2.5 x10(7) LEW donor splenocytes and injected intraperitoneally with 1 mL ALS. Twenty-one days after pretreatment, a LEW or Brown Norway (BN, RT1(n)) heart was transplanted into a treated DA recipient. Splenocytes (1 x 10(8) or 5 x 10(7)) from a LEW heart-tolerant long-term survivor (LTS; >60 days) DA recipient were harvested and adoptively transferred (AT) into an irradiated (450 rad) naïve DA rat 24 hours before transplanting a LEW heart. All LEW heart allografts were rejected by untreated DA rats in a mean survival time (MST) of 7.4 +/- 1.7 days (n=7). In contrast, 66.7% of LEW heart grafts into IT+ALS-pretreated DA recipients were accepted indefinitely (n=24). When either 1 x 10(8) (n=5) or 5 x 10(7) (n=5) splenocytes from a LEW heart graft-tolerant LTS (>60 days) DA recipient were AT into a new naïve DA rat, all new LEW heart grafts were accepted indefinitely. The donor-specific tolerance that develops after IT+ALS-induced LEW heart acceptance by DA recipients can be transferred adoptively to new naïve DA recipients, thus indicating that it is infectious tolerance.


Heparin-resistance in AL amyloidosis: a case report.
Non-AT-III mediated heparin-resistance during CPB occurs by complex-forming with heparin-binding proteins. Currently, there are no specific recommendations for non-AT-III mediated heparin-resistance. We present a fatal case of a 70-yr-old male-patient undergoing cardiac-surgery in which refractory heparin-resistance was observed. The massive AL amyloidosis found at autopsy is thought to be responsible and illustrates that awareness and knowledge of the etiology and perioperative strategies of non-AT-III mediated heparin-resistance is important. For anticoagulation during cardiopulmonary bypass surgery in case of a non-AT-III medicated heparin resistance, we refer to the decision tree added to this manuscript and if necessary to consider direct thrombin inhibitors, such as bivalirudin or argatroban, as it bypasses the complexing pathway.


COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis.
Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness 1-4 . Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown.In an established hamster model of intranasal infection with SARS-CoV-2 5 , and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons.Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.


Somatic complications of epilepsy surgery over 25 years at a single center.
Epilepsy surgery is an effective treatment for refractory focal epilepsy. Risks of surgery need to be considered when advising individuals of treatment options. We describe the frequency and nature of physical adverse events associated with epilepsy surgery in a single center. We reviewed the prospectively maintained records of adults who underwent epilepsy surgery at our center between 1990 and 2014 to identify peri/postsurgical adverse events. These were categorized into neurological deficits and those related to surgery (e.g. wound infections). Neurological deficits were categorized as expected or unexpected and into transient (≤3 months) or persistent (>3 months), RESULTS: There were 911 procedures with no peri-operative deaths. Persistent neurological adverse events were seen following 157 (17.2%) procedures. The most common persistent expected complication was quadrantanopia after temporal lobe resections (72/764, 9.4%). Unexpected persistent neurological complications occurred in 20 procedures (2.2%) and included: quadrantanopia (6, 0.7%); hemianopia (2, 0.2%); hemi/mono-paresis/sensory loss (9, 1%); dysphasia (10, 1%); frontalis muscle weakness (2, 0.2%); and oculomotor weakness (1, 0.1%). 106 surgery related adverse events occurred in 83 procedures, with severe infections requiring bone-flap removal in 24 (2.6%) procedures and intracranial infections in 8 (0.9%). The risk of post-resective severe infection increased by 4 fold (OR 4.32, 95% CI 2.1-8.9, p<0.001) with use of subdural EEG monitoring prior to resection. In consequence, in August 2011 we introduced antibiotic coverage in all individuals undergoing intracranial monitoring. Also, after August 2011 there was greater use of Stereo-EEG (SEEG) than subdural (OR 9.0 CI 0.36-224.2, p=0.18ns). One complicated by severe infection. Other surgical complications included haematoma (0.3%), hydrocephalus (0.3%) and CSF leak (1.2%). None had permanent complications. Adverse event rates are similar to other series. Epilepsy surgery carries well defined surgical and neurological risks. The risks of somatic adverse events, in addition to neuropsychiatric and neuropsychological complications need to be made clear to individuals considering this treatment option.


[Human Umbilical Cord-Derived Mesenchymal Stem Cells Prevent Acute Graft-Versus-Host Disease after Hematopoietic Stem Cell Transplantation Via Exosome-Mediated MicroRNA and Its Mechanism].
To explore molecular mechanisms by which umbilical cord-derived mesenchymal stem cells suppress the development of GVHD after bone marrow hematopoietic stem cell transplantation. A mouse model of aGVHD was constructed after bone marrow hematopoietic stem cell transplantation, and the umbilical cord-derived mesenchymal stem cells were cultured, and then injected into the aGVHD mouse model, so as to investigate its prophylactic efficacy. Prophylactic effect of the exosomes isolated from umbilical cord-derived mesenchymal stem cells on aGVHD mice was assessed. Sequencing analysis of miRNA from exosomes was performed. aGVHD model was successfully constructed after hematopoietic stem cell transplantation. By injecting umbilical cord-derived mesenchymal stem cells into the GVHD mouse model, it was found that the treatment significantly prolonged survival time of mice compared to the untreated group. Injection exosomes derived from umbilical cord-derived mesenchymal stem cells into the GVHD mouse model significantly prolonged the survival time of mice compared to the untreated group. High-throughput sequencing data showed that microRNA such as miR-21 in exosomes isolated from umbilical cord-derived mesenchymal stem cells, which mainly affected the signaling pathways such as cell adhesion, RNA degradation. The umbilical cord-derived mesenchymal stem cells can prevent the occurrence of aGVHD after HSCT, which is mediate by MicroRNA in the exosomes derived from umbilical cord-derived mesenchymal stem cells.


Cell-free DNA for detection of clonal B cells in diffuse large B cell lymphoma by sequencing.
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in the western world. It is highly heterogeneous with a variable clinical course, but curable with chemo-immunotherapy in up to 70% of all cases. The lymphoma presents in lymph nodes and/or extranodal lymphoid tissue, and the diagnosis is based on invasive procedures for histopathologic evaluation. In this technical study, we evaluated cell-free DNA (cfDNA) from blood plasma to detect clonal B cells in patients with DLBCL using rearranged immunoglobulin heavy chain gene as targets by next-generation sequencing. Clonal B cell sequences and frequencies were determined from blood plasma cfDNA and cellular DNA from matched excised lymphoma tissues and mononuclear cells isolated from diagnostic bone marrow and blood samples from 15 patients. We showed that identical clonal rearrangements could be detected in blood plasma and excised lymphoma tissue and that plasma cfDNA was superior in detecting clonal rearrangements compared to blood or bone marrow-derived cellular DNA. These findings consolidate the role of blood plasma as a reliable and easily accessible source for detecting neoplastic cells in DLBCL.


Preclinical Assessment of the Efficacy of Anti-Angiogenic Therapies in Hepatocellular Carcinoma.
Diffuse hepatocellular carcinoma (HCC) is a complex affliction in which comorbidities can bias global outcome of cancer therapy. Better methods are thus warranted to directly assess effects of therapy on tumor angiogenesis and growth. As tumor angiogenesis is invariably associated with changes in local blood flow, we assessed the utility of ultrasound imaging in evaluation of the efficacy of anti-angiogenic therapy in a spontaneous transgenic mouse model of HCC. Blood flow velocities were measured monthly in the celiac trunk before and after administration of sorafenib or bevacizumab at doses corresponding to those currently used in clinical practice. Concordant with clinical experience, sorafenib, but not bevacizumab, reduced microvascular density and suppressed tumor growth relative to controls. Evolution of blood flow velocities correlated with microvascular density and with the evolution of tumor size. Ultrasound imaging thus provides a useful non-invasive tool for preclinical evaluation of new anti-angiogenic therapies for HCC.


[Perioperative cardiac arrhythmias in patients undergoing surgical treatment for lung cancer].
Thoracic surgery is associated with a high risk of morbidity and mortality. Cardiac arrhythmias are the most common and severe complications in early postoperative period. Evaluation of the prevalence and causes of cardiac arrythmias, factors that predispose to their occurrence and their influence on general state of health in short-term postoperative period. The study was performed in 80 patients with proven primary non-small cell lung cancer. We analyzed demographic data, type of carcinoma, presence of other diseases, laboratory results, and echocardiograms performed 2 times before and after operation and 24-hour Holter monitoring obtained 3 times--a day before thoracotomy and on the 1st and 5th postoperative day. There were no significant changes in a total number of supraventricular ectopic beats during 3 consecutive 24-hour Holter recordings. The second Holter recording performed on the 1st postoperative day showed a statistically significant increase (p < 0.05) in the number of ventricular premature beats, which persisted on a similar, higher level on the 5th day. Twenty-four patients (30%) developed atrial fibrillation (AF) in the postoperative period. The average time of the duration of AF was 2.62 days with the peak incidence during 1st and 2nd day after operation (total 62.5%). Apart from cigarette smoking, no other epidemiological and clinical variables affected the occurrence of postoperative AF (p > 0.05). Paroxysmal atrial fibrillation is the most common type of arrhythmias in early postoperative period after thoracic surgery. Patients who underwent thoracic surgery should be under cardiological surveillance during the first postoperative days. Routine prevention with anticoagulants in patients after pulmonary tumor resection should be implemented based on their current clinical condition.


Management of a Mass Casualty Event Caused by Electrocution Using Doctor Helicopters.
This is the first report to show the use of doctor helicopters in a mass casualty event induced by electrocution. We performed a narrative review. Two children obtained electrocution burns by breaking an electric fence. Five adults also received electrocution burns. Emergency medical technicians at the scene requested additional dispatch of an ambulance and the doctor helicopter. Two adult men with cardiopulmonary arrest were transported by 2 ambulances to a nearby hospital. One adult woman was in a restless confusional state, intubated, and transferred to another hospital using the doctor helicopter. One boy, who was initially in a coma, and his mother were transferred to our hospital by 1 ambulance. Another boy, who had finger amputation, was transferred to the other hospital by another doctor helicopter. A remaining elderly woman was transported to the other local hospital by ambulance. All the victims, except the 2 fathers who fell into cardiac arrest, survived. Early confirmation of the safety of the scene, early establishment of command and control, early request for dispatch of other parties and the doctor Helicopter, appropriate triage, appropriate treatment at the scene, selecting appropriate medical facilities, and dispersion transportation were crucial.


Biventricular upgrading in patients with conventional pacing system and congestive heart failure: results and response predictors.
There are few studies on cardiac resynchronization therapy (CRT) in heart failure (HF) patients with preexisting right ventricular (RV) pacing. The purpose of this study was to determine the efficacy of CRT upgrading in RV-paced patients and the predictivity of electromechanical dyssynchrony parameters (EDP) evaluated by standard echocardiography (ECHO) and tissue Doppler imaging (TDI). Thirty-eight consecutive patients with HF [New York Heart Association (NYHA) class III or IV, LVEF < 35%], prior continuous RV pacing, and absence of atrial fibrillation were enrolled in the presence of a paced QRS > or = 150 ms and evaluated by ECHO and TDI. A responder was defined as a patient with a favorable change in NYHA class and neither HF hospitalization nor death, plus an absolute increase of LVEF > or = 10 units. At six-months follow-up, the whole study population had significant improvement in symptoms, systolic function, and QRS duration (P < 0.001); 32 (84%) patients had a favorable clinical outcome, 25 (66%) were considered responders according to the previous definition. Postimplant QRS was similarly reduced in both responders and nonresponders, whereas EDP had a significant improvement only in responders (P < 0.05). Using EDP, 23 (79%) patients were responders compared with 2 (22%) patients without mechanical dyssynchrony (P = 0.002). In HF patients with previous RV pacing, CRT is effective to improve clinical, functional outcome, and LV performance and to reduce electromechanical dyssynchrony in a large proportion of patients. Dyssynchrony evaluated by standard and TDI ECHO can be useful for CRT selection of paced patients.


Real-time, automated, fluorophore mediated multi-cardiac marker biosensing system with nano-metallic particle reagent.
Cardiovascular disease (CVD) is the leading cause of death in U.S. Early and accurate diagnosis of CVD is crucial to save many lives, especially for the patients suffering the heart attack. Accurate and fast quantification of cardiac muscle specific biomarkers in the blood enables accurate diagnosis and prognosis and timely treatment of the patients. A prototype of fiber-optic, multi-analyte, immuno-biosensing system integrated with an automatic flow control unit has been in development to quantify four important cardiac markers in blood plasma accurately, rapidly and simultaneously. The validity of the sensor was, however, challenged because the concentrations of two markers are only at tens of picomolar level. Here, plasmon rich nano-metallic particles and selected biocompatible solvents were developed for fluorescence enhancement to improve the sensitivity of our fluorophore mediated biosensing. By applying the nanometal particle and the solvent, the sensitivity of single cardiac marker sensors were increased by 1.5 - 3 times. By using the fluorescence enhancing nano-metallic particle reagents, simultaneous quantification of four cardiac markers in plasma is currently possible, using 3-cm-sensor within 10 minutes at an average signal-to-noise ratio of 20.


Can HDL cholesterol be replaced by paraoxonase 1 activity in the prediction of severe coronary artery disease in patients with type 2 diabetes?
Novel biomarkers are required to improve cardiovascular disease prediction in patients with type 2 diabetes (T2D) as a high-risk population. This study was conducted to examine whether coronary artery disease (CAD) risk assessment can be improved by substituting high-density lipoprotein (HDL)-bound paraoxonase 1 (PON1) activity for HDL cholesterol (HDL-C) concentration in patients with T2D. In this study, we studied 139 patients with T2D (mean age 64.12 ± 8.17 years) who underwent coronary angiographic examination. The initial rate of substrate hydrolysis was spectrophotometrically assayed in kinetic mode for measuring PON1 activity. Receiver operating characteristic (ROC) graphs are created by plotting true positivity versus false positivity. In patients with HbA1c ≥ 7%, PON1 (AUC = 0.7, p = 0.029) and nonHDL-C/PON1 (AUC = 0.75, p = 0.013) were significantly more capable of differentiating patients with CAD from those without CAD compared to HDL-C and nonHDL-C/HDL-C. Also, the predictive power of PON1 (AUC = 0.64, p = 0.029) and nonHDL-C/PON1 (AUC = 0.71, p = 0.004) were significantly higher in comparison with HDL-C and nonHDL-C/HDL-C for CAD characterization in patients aged ≥50 years. Moreover, PON1 and nonHDL-C/PON1 are associated with the incidence of CAD with an AUC of 0.7 (p = 0.026) and AUC of 0.64 (p = 0.087), respectively, among subjects with low HDL-C. PON1 and the ratio of nonHDL-C/PON1 significantly improve the prediction of severe CAD in T2D patients and in patients with HbA1c ≥ 7%, age ≥50 years, or low HDL-C. PON1 activity and lipid ratios using this enzyme may be valuable as substitutes of HDL-C for increasing clinical efficacies in cardiovascular risk assessment.


Clinical effects of remimazolam alone or in combination with dexmedetomidine in patients receiving bronchoscopy and influences on postoperative cognitive function: a randomized-controlled trial.
Remimazolam and dexmedetomidine are commonly used as sedatives. However, the effects and safety of remimazolam alone or in combination with dexmedetomidine have not been investigated. We sought to investigate the clinical effects of remimazolam alone or in combination with dexmedetomidine in bronchoscopy, and their influence on cognitive function. Ninety eligible patients who underwent bronchoscopy under intravenous anesthesia were randomly divided into three groups: propofol control, remimazolam, and remimazolam plus dexmedetomidine. The primary outcome was the incidence of perioperative hypoxemia. Secondary outcomes included induction and maintenance doses of remimazolam, hemodynamic variables, scores for modified Observer's Assessment of Alertness/Sedation (MOAA/S), coughing, limb movement, incidence of adverse events, patient satisfaction, bronchoscopist satisfaction, incidence of post-operative cognitive dysfunction (POCD), time to loss of consciousness (LoC), and time to awake. The incidence of hypoxemia, hypotension, and bronchoscopist satisfaction score were significantly decreased, and time to LoC and time to awake were markedly longer in the remimazolam and remimazolam plus dexmedetomidine groups than in the propofol control group (p < 0.05). The remimazolam group had significantly decreased induction and maintenance doses of remimazolam and a shorter time to LoC than the remimazolam plus dexmedetomidine group (p < 0.05). Scores for coughing, limb movement, MOAA/S, and post-operative patient satisfaction were comparable among the three groups. POCD was not induced in any of the groups. Remimazolam is safe and effective for painless bronchoscopy, with a low incidence of adverse reactions, and exhibits a good synergistic effect with dexmedetomidine. This trial protocol had been registered on Chinese Clinical Trial Registry (ChiCTR2000041435, date: 2020 12 26.


Choline acetyltransferase- and peptide immunoreactivity of submucous neurons in the small intestine of the guinea-pig.
The peptides cholecystokinin (CCK), neuropeptide Y (NPY), somatostatin (SOM), substance P (SP) and vasoactive intestinal peptide (VIP), and the synthesizing enzyme for acetylcholine, choline acetyltransferase (ChAT) were localized immunohistochemically in nerve cell bodies of the submucous ganglia in the small intestine of the guinea-pig. VIP-like immunoreactivity was found in 45% of submucous neurons. ChAT immunoreactivity was observed in a separate group of nerve cells, which made up 54% of the total population. There were three subsets of neurons immunoreactive for ChAT: (1) ChAT neurons that also contained immunoreactivity for each of the peptides CCK, SOM and NPY, representing 29% of all submucous neurons; (2) ChAT neurons that also contained SP-like immunoreactivity, representing 11% of all submucous neurons, and (3) ChAT cells that did not contain any detectable amount of the peptides that were localized in this study.


Positive selection scanning reveals decoupling of enzymatic activities of carbamoyl phosphate synthetase in Helicobacter pylori.
In an effort to detect factors which may be under positive selection, a survey for such genes in two pathogenic strains of Helicobacter pylori (J99 and 26695) was performed. Based on an analysis of synonymous and nonsynonymous substitutions, we identified 19 candidate genes under positive selection. A search for homologues with known crystallographic structures revealed Escherichia coli carbomoyl phosphate synthetase as a homologue of H. pylori carbamoyl phosphate synthetase. Carbamoyl phosphate synthetase as isolated from E. coli is a heterodimeric enzyme that possesses two different but coupled functionalities and is involved in the first committed step in the separate biosynthetic pathways for arginine and pyrimidine nucleotides. In this study, we provide evidence indicating that one of these functionalities appears to be under selective pressure. Reports from previously published site-directed mutagenesis studies point to a decoupling of amidotransferase and synthetase activities. Implications of these findings for a metabolic enzyme under positive selection are discussed in terms of the mechanisms of H. pylori pathogenesis.


Re-construction layer effect of LiNi0.8Co0.15Mn0.05O2 with solvent evaporation process.
The solvent evaporation method on the structural changes and surface chemistry of the cathode and the effect of electrochemical performance of Li1.0Ni0.8Co0.15Mn0.05O2 (NCM) has been investigated. After dissolving of Li residuals using minimum content of solvent in order to minimize the damage of pristine material and the evaporation time, the solvent was evaporated without filtering and remaining powder was re-heated at 700 °C in oxygen environment. Two kinds of solvent, de-ionized water and diluted nitric acid, were used as a solvent. The almost 40% of Li residuals were removed using solvent evaporation method. The NCM sample after solvent evaporation process exhibited an increase in the initial capacity (214.3 mAh/g) compared to the pristine sample (207.4 mAh/g) at 0.1C because of enhancement of electric conductivity caused by decline of Li residuals. The capacity retention of NCM sample after solvent evaporation process (96.0% at the 50th cycle) was also improved compared to that of the pristine NCM sample (90.6% at the 50th cycle). The uniform Li residual layer after solvent treated and heat treatment acted like a coating layer, leading to enhance the cycle performance. The NCM sample using diluted nitric acid showed better performance than that using de-ionized water.


Early pregnancy uninterrupted by laparoscopic bipolar coagulation of uterine vessels.
Laparoscopic bipolar coagulation of uterine vessels (LBCUV) is reported to treat clinically symptomatic myomas that caused severe menorrhagia, but the viability of pregnancy after operation is unknown. A woman with clinically diagnosed uterine myomas, possibly with adenomyosis, had unexpected early pregnancy diagnosed at the time of LBCUV. The procedure resulted in improvement of menorrhagia to normal menstruation and reductions in the volume of both uterus and myomas. The intrauterine pregnancy was terminated at the woman's request. Pregnancy may be possible after LBCUV, although none has been reported.


Involvement of post-translational modification of neuronal plasticity-related proteins in hyperalgesia revealed by a proteomic analysis.
To clarify roles of an endogenous pain modulatory system of the central nervous system (CNS) in hyperalgesia, we tried to identify qualitative and quantitative protein changes by a proteomic analysis using an animal model of hyperalgesia. Specifically, we first induced functional hyperalgesia on male Wistar rats by repeated cold stress (specific alternation of rhythm in temperature, SART). We then compared proteomes of multiple regions of CNS and the dorsal root ganglion between the hyperalgetic rats and non-treated ones by 2-D PAGE in the pI range of 4.0-7.0. We found that SART changed the proteomes prominently in the mesencephalon and cerebellum. We thus analyzed the two brain regions in more detail using gels with narrower pI ranges. As a result, 29 and 23 protein spots were significantly changed in the mesencephalon and the cerebellum, respectively. We successfully identified 12 protein spots by a MALDI-TOF/TOF MS and subsequent protein database searching. They included unc-18 protein homolog 67K, collapsin response mediator protein (CRMP)-2 and CRMP-4, which were reported to be involved in neurotransmitter release or axon elongation. Interestingly, mRNA expression levels of these three proteins were not changed significantly by the induction of hyperalgesia. Instead, we found that the detected changes in the protein spots are caused by the post-translational modification (PTM) of proteolysis or phosphorylation. Taken together, development of the hyperalgesia would be linked to PTM of these three CNS proteins. PTM regulation may be one of the useful ways to treat hyperalgesia.


Effects of Sleep Deficiency on Risk, Course, and Treatment of Psychopathology.
This article reviews the literature on the relationship between sleep deficiency and unipolar and bipolar depression, anxiety disorders, and posttraumatic stress disorder. We consider the evidence for sleep as a contributory causal factor in the development of psychiatric disorders, as well as sleep as an influential factor related to the outcome and recurrence of psychopathology. A case for sleep deficiency being an important treatment target when sleep and psychiatric disorders are comorbid is also made. Our recommendation is that sleep deficiency is recognized as a means to positively impact the development and course of psychopathology and, as such, is routinely assessed and treated in clinical practice.


Adolescent suicide attempts in three diverse island nations: patterns, contextual differences and demographic associations.
Most epidemiological studies on suicidal behavior have been focused on high-income country settings. This study examine factors associated with suicidal behaviors among school-attending adolescents in three island nations. In this secondary analysis of the publicly available 2015 nationally representative GSHS data, we tested demographic, social, and behavioral attributes using multivariable logistic regression to association with suicide attempts. Within the recall period, 13.6% of participants reported having attempted suicide one or more times in the Cook Islands, 10.8% in Curaçao, and 9.8% in East Timor. In the Cook Islands, suicide ideation (AOR = 19.42, 95% CI = 9.11-41.41), anxiety (AOR = 2.51, 95% CI = 1.08-5.82), physical bullying (AOR = 3.3, 95% CI = 1.10-9.91), and cigarette smoking (AOR = 3.82, 95% CI = 1.38-10.54) were associated with suicide attempts. For Curaçaoo, suicide ideation (AOR = 7.88, 95% CI = 5.20-11.95) and suicide planning (AOR = 7.01, 95% CI = 4.24-11.60) were statistically significant. While for East Timor, suicide ideation (AOR = 4.59, 95% CI = 2.14-9.88), suicide planning (AOR = 3.36, 95% CI = 1.76-6.29), bullying victimization (AOR = 2.69, 95% CI = 1.02-7.12), and serious injuries (AOR = 2.22, 95% CI = 1.31-3.74) were statistically significant. Suicide attempt is relatively common in each of the three island nations. The socioeconomic context of adolescents might play a significant role in moderating suicidal behavior. Therefore, prevention efforts should be grounded in view of geographic, demographic, and socioeconomic contexts of the populations at risk.


In vivo calibration of a transcutaneous oxygen electrode in adult patients.
Transcutaneous oxygen tension (tcPO2) has been compared with arterial oxygen tension (PaO2 in 14 haemodynamically stable patients in an intensive care unit. Two calibration methods have been compared: (1) "In vitro" calibration, a two point calibration procedure carried out before attachment to the skin. (2) "In vivo" calibration, calibration using a single arterial sample, to recalibrate the upper point after attachment of the electrode to the skin and stabilisation of the electrical output. After "in vitro" calibration the regression equation was given by tcPO2 (mmHg) = 0.58 PaO2 + 13.4 (95% confidence limits +/- 19.6). After "in vivo" calibration, the regression equation for 55 comparisons over the range 50 to 120 mmHg was given by: tcPO2 (mmHg) = 0.98 PaO2 + 1.6 (95% confidence limits +/- 6.6). The "in vivo" calibration method therefore allows a close estimate of PaO2 to be made from tcPO2 values in adult patients providing strict operating criteria observed.


Why do sulfate-reducing bacteria outcompete methanogenic bacteria for substrates?
The apparent Ks values for H2 of several phylogenetically distant strains of both methanogenic bacteria and sulfate-reducing bacteria were measured. The sulfate reducers had Ks values of about 2 μM whereas the Ks values of the methanogens were 6-20 μM. This indicates that probably all sulfate-reducing bacteria have a higher substrate affinity for H2 than the methanogenic bacteria. Difference in substrate affinity can thus account for the inhibition of methanogenesis from H2 and CO2 in sulfate-rich ecosystems (mainly saltwater marshes), where the H2 concentration is well below 5 μM. Possible explanations for this general phenomenon are discussed.


The influence of social norms in the context of reducing sugar-sweetened beverages consumption.
This study aimed to examine the factors associated with low sugar-sweetened beverage (SSB) consumption and intention to avoid these products as well as investigate the role of different types of social norms in the adoption of this behaviour. This study reports the results of a secondary data analysis from a cross-sectional telephone survey. A total of 1000 adults were randomly recruited in the province of Québec, Canada, using a random-digit dialling procedure. Eligibility criteria were to be aged between 18 and 64 years; able to answer a questionnaire in French or English; and to reside in the province of Québec. SSB consumption, social norms and variables from the theory of planned behaviour were assessed by means of a questionnaire. Logistic regression analyses were conducted to examine factors associated with behaviour and intention. Consuming <1 SSB per day was significantly associated with intention, perceived behavioural control, and risk perception about tooth decay. Descriptive (perceived prevalence in the close surroundings of one person) and perceived societal norms (perceived broad societal approval/disapproval of the behaviour) were associated with behaviour. All theory of planned behaviour variables (including injunctive norm) and risk perception pertaining to chronic diseases predicted intention to avoid the consumption of ≥1 SSB per day. Sex, age, income, and risk perception pertaining to chronic diseases were associated with perceived societal disapproval of SSB consumption. This study confirms the importance of social norms in the prediction of SSB consumption but also highlights the need to address motivation and capacities in public health interventions to reduce SSB consumption.


Chronotype and mortality - a 37-year follow-up study in Finnish adults.
The UK Biobank study on chronotype and mortality suggested small increases of all-cause and cardiovascular mortality in a 6.5-year follow-up. Our aim was to constructively replicate findings from it in a longer follow-up. A questionnaire was administered to the population-based adult Finnish Twin Cohort in 1981 (response rate 84%). The study population included 23 854 participants who replied to the question: "Try to assess to what extent you are a morning person or an evening person," with four response alternatives (anchored from "clearly a morning person" to "clearly an evening person"). Vital status and cause of death data were provided by nationwide registers up to the end of 2018. Hazard ratios for mortality were computed based on 8728 deaths. Adjustments were made for education, alcohol, smoking, BMI, and sleep duration. The covariate adjusted model showed a 9% increase of all-cause mortality for the evening-type group (HR = 1.09, 95% CI 1.01-1.18), with attenuation mainly due to smoking and alcohol. Their importance was highlighted by observing no increased mortality among non-smokers who were at most light drinkers. There was no increase in any cause-specific mortality. Our results suggest that there is little or no independent contribution of chronotype to mortality.


Assessment of heterologous membrane protein polarity in transiently transfected MDCK cells.
We have evaluated transient transfection of MDCK cells by the DEAE-dextran/chloroquine method as a rapid method for study of heterologous plasma membrane protein polarity. Transiently transfected cells reseeded onto permeable supports formed confluent monolayers with normal tight junctions and normal distribution of endogenous apical and basolateral surface markers. Transfected monolayers reseeded onto opaque polycarbonate filters attained cell heights 3 times greater than on transparent filters. Conventional and confocal immunofluorescence microscopy were used to assess polarity of transient expression of heterologous proteins previously defined in stably transfected cell lines as apical (DAF-CD55), basolateral (VSV-G), and nonpolarized (CD7) in distribution. Through each transiently expressed protein exhibited a polarity phenotype in most cells which resembled the stable phenotype, consistency of polarized localization was less than in stably transfected cells. Similar results were obtained by lipofection. We conclude that transient transfection of MDCK cells may be useful as a rapid screen, but is not sufficiently reliable for definitive assessment of heterologous membrane proein polarity.


A subclass IgG4-specific antigen-binding radioimmunoassay (RIA): comparison between IgG and IgG4 antibodies to food and inhaled antigens in adult atopic dermatitis after desensitization treatment and during development of antibody responses in children.
A liquid-phase, antigen-binding radioimmunoassay measuring subclass IgG4 antibody (ab) to allergens has been developed. This assay, which uses monoclonal anti-IgG4 to bind IgG4, allows direct comparison of class (IgG)- and subclass (IgG4)-specific ab levels. These assays used radiolabeled purified allergens, Der p I (Ag P1) from the dust mite Dermatophagoides pteronyssinus, Lol p I (Rye 1), from ryegrass pollen, hen's egg ovalbumin, and beta-lactoglobulin from cow's milk. We have investigated IgG4 abs in several clinical situations. The results confirm that IgG ab responses to both inhalants and food proteins unequivocally include IgG4 ab. On average, the proportion of IgG4 ab to these antigens is far higher than the contribution of IgG4 to total IgG. In patients with adult atopic dermatitis, levels of both class and subclass ab were higher than in control subjects; however, the ratio of IgG4:IgG varied widely in patients and control subjects. During desensitization treatment of patients with perennial rhinitis, levels of IgG4 ab to Der p 1 increased sharply, but there were also increases in the total IgG ab responses so that the percentage contribution of IgG4 was only moderately increased (mean values: before, 29%; after, 36%). In a prospective study of children from atopic families, IgG4 abs to food proteins were detectable as early as 3 months. IgG abs to hen's egg ovalbumin and beta-lactoglobulin from cow's milk increased to a maximum at 3 years and declined by 5 years. However, specific IgG4 as a percentage of specific IgG increased progressively from a mean value of approximately 15% at 6 months to approximately 50% at 5 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)


A radioimmuno-chromatographic scanning method for the analysis of testosterone conjugates in urine and serum.
A method for the analysis of testosterone (and 5alpha-dihydrotestosterone) conjugates in human serum and urine samples is described. The samples were grought to pH 1 and extracted with a diethyl ether-methanol mixture. After evaporation the residues were run in a thin-layer chromatography system, individual samples' paths were cut into 1-cm long pieces and eluted with methanol. The methanol was evaporated and the residue subjected to acid hydrolysis. The released steroid was extracted by diethyl ether and measured by radioimmunoassay. The methodology described represents a new approach to the qualitative and quantitative study of steroid conjugates in serum and urine, and can easily be applied to the study of steroid conjugates in other biological mateiral.


The Effects of Conscious Movement Processing on the Neuromuscular Control of Posture.
Maintaining balance is thought to primarily occur sub-consciously. Occasionally, however, individuals will direct conscious attention towards balance, e.g., in response to a threat to balance. Such conscious movement processing (CMP) increases the reliance on attentional resources and may disrupt balance performance. However, the underlying changes in neuromuscular control remain poorly understood. We investigated the effects of CMP (manipulated using verbal instructions) on neural control of posture in twenty-five adults (11 females, mean age = 23.9, range = 18-33). Participants performed 90-s, bipedal stance balance trials in high- and low-CMP conditions, during both stable (solid surface) and unstable (foam) task conditions. Postural sway amplitude, frequency and complexity were used to assess postural control. Surface EMG was recorded bilaterally from lower leg muscles (Soleus, Tibialis Anterior, Gastrocnemius Medialis, Peroneus Longus) and intermuscular coherence (IMC) was assessed for 12 muscle pairs across four frequency bands. We observed significantly increased sway amplitude, and decreased sway frequency and complexity in the high- compared to the low-CMP conditions. All sway variables increased in the unstable compared to the stable conditions. We observed reduced beta band IMC between several muscle pairs during high- compared to low-CMP, but these findings did not remain significant after controlling for multiple comparisons. Finally, IMC significantly increased in the unstable conditions for most muscle combinations and frequency bands. In all, results tentatively suggest that CMP-induced changes in sway outcomes may be facilitated by reduced beta-band IMC, but these findings need to be replicated before they can be interpreted more conclusively.


Experience of Low Dose Perampanel to Add-on in Glioma Patients with Levetiracetam-uncontrollable Epilepsy.
After introduction of levetiracetam (LEV), treatment of seizures in patients with malignant brain tumors has prominently improved. On the other hand, we still experience some cases with LEV-uncontrollable epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptor antagonist that has recently been approved for treating focal epilepsy as a secondary drug of choice. Available literature reporting PER medication in patients with gliomas is still sparse. Here, we report our initial experience with glioma patients and report efficacy of adding low dose 2-4 mg PER to LEV in patients whose seizure were uncontrollable with LEV monotherapy. Clinical outcome data of 18 consecutive patients were reviewed. This included nine males and nine females aged 24-76 years (median, 48.5 years), treated for glioma between June 2009 to December 2018. We added PER to patients with LEV-uncontrollable epilepsy. Adverse effects, irritability occurred in two patients, but continuous administration was possible in all cases. Though epileptic seizures occurred in four cases receiving 2 mg PER, 17 cases achieved seizure freedom by dose increments; final dose, 2-4 mg PER added to LEV 500-3000 mg. Our study revealed anti-epileptic efficacy of low dose PER 2-4 mg as first add-on therapy to LEV in glioma patients who have failed or intolerable to LEV monotherapy. Low dose PER added on to LEV may have favorable efficacy with tolerable adverse effects in glioma patients with LEV-uncontrollable epilepsy.


Effect of insulin on NO production by monocytes from patients with metabolic cardiovascular syndrome.
Basal and insulin-induced production of NO by monocytes significantly increased in patients with metabolic cardiovascular syndrome. Plasma insulin concentration in these patients was below the control. No intergroup differences were found in C-peptide concentration. A negative correlation was revealed between insulin-induced NO production by monocytes and C-peptide/insulin ratio in patients. The role of monocytes on the regulation of vascular tone via NO production in patients with metabolic cardiovascular syndrome is discussed.


Monosialoganglioside GM1 reduces toxicity of Ptx and increase anti-metastasic effect in a murine mammary cancer model.
Having demonstrated the ability of monosialoganglioside GM1 micelles as oncology drug transporter, this work focuses on evaluating its application in an in vivo system, studying the toxicity and antitumoral effect of GM1-Ptx micellar formulation. The maximum tolerated dose (MTD) obtained after intravenous administration of GM1-Ptx in mice was 55 mg/kg and the 50% lethal dose (LD50) was 70 mg/kg. This value is higher than those described for the commercial formulations TAXOL and ABRAXANE, with LD50 of 30 and 45 mg/kg respectively. The antitumor activity, mortality and incidence of metastasis were studied on a murine model of mammary gland cancer. The GM1-Ptx formulation was administered i.v. at different doses for 9 weeks using empty GM1 micelles and saline as treatment controls. Once the treatments were completed, biochemical markers were quantified and histological tissue tests were performed. The most promising results were obtained with the treatment at a dose of 15 mg/kg/twice a week, condition in which a longer survival and significant reduction in the incidence of animals with metastasis, since only one 25% of the mice showed presence of pulmonary micro metastases.


Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae Infections in Children: A Two-Center Case-Case-Control Study of Risk Factors and Outcomes in Chicago, Illinois.
Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae infections are an emerging problem in children. We sought to identify risk factors and describe outcomes associated with pediatric ESBL-producing bacterial infections at 2 hospitals in Chicago, IL from 2008 to 2011. A case-case-control study of children aged 0-17 years was conducted. Cases of Escherichia coli, Klebsiella, and Proteus spp. ESBL-producing bacterial infections (n = 30) were compared to uninfected controls and in parallel, cases of non-ESBL-producing bacterial infections (n = 30) were compared to uninfected controls (n = 60). We then qualitatively compared these results. Median age of cases was 1.06 years; 62% of isolates were from urine, and 60% were E. coli. By multivariable analysis, ESBL cases were 5.7 and 3.3 times more likely to have gastrointestinal (P = .001; 95% confidence interval [CI] 1.9-17.0) and neurologic (P = .001; 95% CI 1.1-3.7) comorbidities, respectively, than controls; non-ESBL cases were also more likely to have gastrointestinal comorbidities than controls (P = .014; odds ratio 3.6; 95% CI 1.2-10.1). Study period prevalence remained stable (1.7%). Most (60%) infections occurred in the intensive care unit; however, 30% of children presented in the outpatient setting. Seventy-seven percent of isolates were multidrug resistant (ie, resistant to ≥3 antibiotic classes). Recurrence of infection occurred in 17% of ESBL cases. Crude mortality rates (7%) did not differ between cases and controls. The incidence of pediatric infection due to ESBL-positive Enterobacteriaceae was stable at 2 large tertiary-care medical centers over a 4-year period. Multidrug resistance in pediatric ESBL isolates is common. Risk factors for infection due to ESBL-producing bacteria include neurologic medical conditions.


Metabolism of liver CYP450 and ultrastructural changes after long-term administration of aspirin and ibuprofen.
Worldwide, aspirin and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs). Some adverse reactions, including gastrointestinal reactions, have been concerned extensively. Nevertheless, the mechanism of liver injury remains unclear. In the present study, we focused on the metabolism of liver cytochrome P450 (CYP450) and ultrastructural morphology of liver cells. A total of thirty rats were divided into three groups of 10. Rats in the aspirin and ibuprofen groups were given enteric-coated aspirin (15 mg/kg) and ibuprofen (15 mg/kg), respectively by gavage for four weeks. The body weights were recorded every two days. Liver function and metabolic capacity of CYP450 were studied on days 14 and 28. We then conducted ultrastructural examinations. Body weights in the Ibuprofen group were lower than those of the Control group, and ALT and AST levels were significantly higher (P < 0.05). There were no significant differences in terms of body weight, ALT or AST between the Aspirin and Control groups. The metabolic capacity of CYP450 was evaluated using five probe drugs, phenacetin, tolbutamide, metoprolol, midazolam, and bupropion. We found that ibuprofen and aspirin induced metabolism of the probe drugs. Moreover, according to the pharmacokinetic data, the Control, Aspirin and Ibuprofen groups could be discriminated accurately. Ultrastructural examination showed that the number of mitochondria was increased in both the Ibuprofen and Aspirin groups. Long-term administration of enteric-coated aspirin and ibuprofen induced the metabolic activity of the CYP450 enzyme. Aspirin had better tolerability than did ibuprofen, as reflected by pharmacokinetic data of probe drug metabolism.


Allergy in long-term hemodialysis. II. Allergic and atopic patterns of a population of patients undergoing long-term hemodialysis.
Maintenance hemodialysis is widely used throughout the world, and anaphylactic reactions appear to be increasing in number and severity. However, the exact incidence of sensitization and the role of atopy in these reactions are not yet fully understood. All of the 111 patients routinely dialyzed in a center were tested. All patients had a complete investigation of atopy, RAST to chemicals released during the procedure of dialysis (ethylene oxide (Eto), formaldehyde, phthalic anhydride, and toluene diisocyanate), skin tests with the effluent, and the titration of blood eosinophils. The incidence of atopy was found to be lower (13.5%) than in the normal population of the area. Skin tests with either histamine or allergens are significantly (p less than 0.001) smaller than those of nondialyzed subjects, and this method does not appear to be ideal in this population of patients. Eto sensitivity ranked first (5.5%), followed by phthalic anhydride sensitivity (3.6%); 5/6 patients who had a sensitivity to Eto and/or phthalic anhydride presented symptoms during dialysis, but they never were life threatening. Formaldehyde RAST was only found in one patient who had a life-threatening reaction. Finally, three patients presenting pruritus had positive skin prick tests with the effluent of the dialyzer. All patients having a first use syndrome and 80/81 symptom-free patients did not have serum-specific IgE against the released chemicals, 5/17 patients who had a pruritus during dialysis had either positive RAST to released chemicals or skin tests to the effluent, 5/8 patients who suffered from anaphylaxis had positive RAST to released chemicals, but only those who had a positive RAST presented a severe reaction.(ABSTRACT TRUNCATED AT 250 WORDS)


Variable-Internal-Stores models of microbial growth and metabolism with dynamic allocation of cellular resources.
Variable-Internal-Stores models of microbial metabolism and growth have proven to be invaluable in accounting for changes in cellular composition as microbial cells adapt to varying conditions of nutrient availability. Here, such a model is extended with explicit allocation of molecular building blocks among various types of catalytic machinery. Such an extension allows a reconstruction of the regulatory rules employed by the cell as it adapts its physiology to changing environmental conditions. Moreover, the extension proposed here creates a link between classic models of microbial growth and analyses based on detailed transcriptomics and proteomics data sets. We ascertain the compatibility between the extended Variable-Internal-Stores model and the classic models, demonstrate its behaviour by means of simulations, and provide a detailed treatment of the uniqueness and the stability of its equilibrium point as a function of the availabilities of the various nutrients.


Associations between meeting 24-hour movement guidelines and academic achievement in Australian primary school-aged children.
Few studies have investigated associations between academic achievement and meeting recommendations from the 24-hour (24-h) movement guidelines. The specific guidelines associated with the most benefit academic achievement are unknown. Utilizing both self-report and objective movement data, this study examined associations between academic achievement and meeting individual recommendations and combinations of recommendations from the 24-h movement guidelines (sleep, physical activity, and screen time). Data from CheckPoint, a cross-sectional study nested between Waves 6 and 7 of the Longitudinal Study of Australian Children, were used. Movement behaviors were measured using 24-h wrist-worn accelerometry (GENEActiv (Activinsights, Kimbolton, UK)) and were self-reported by children using the Multimedia Activity Recall for Children and Adolescents. Academic achievement was measured using a nationally administered standardized test in literacy and numeracy. Analysis of covariance, with t tests with sequential Bonferroni adjustments, was used to compare academic achievement with all possible combinations of meeting recommendations, adjusting for demographic confounders. Two models were considered: guideline compliance assessed by self-report (n = 1270, mean age = 11.99 years, 52% males) and by accelerometry (for moderate-to-vigorous intensity physical activity (MVPA) and sleep)) and self-report (screen time) in combination (n = 927, mean age = 11.97 years, 52% males). Literacy achievement significantly differed based on self-report (F(7, 1258) = 3.08, p = 0.003) and accelerometer derived (F(7, 915) = 2.40, p = 0.02) guideline compliance. Numeracy achievement significantly differed based on self-report (F(7, 1258) = 2.92, p = 0.005) but not accelerometer derived guideline compliance (F(7, 915) = 0.80, p = 0.58). When assessed by self-report, children who met all guidelines (t(334) = -4.05, p = 0.0001) or met the screen time and sleep guidelines in combination (t(125) = -5.02, p < 0.001) had superior literacy achievement. Meeting the self-report MVPA guideline in any combination was associated with higher numeracy scores (p < 0.05). Post-hoc analyses showed no differences in academic achievement for any category of accelerometer derived guideline compliance. The findings suggest that limiting recreational screen time is important for literacy achievement and that encouraging compliance with the MVPA guideline is important for numeracy achievement.


User-designed device with programmable release profile for localized treatment.
Three-dimensional printing enables precise and on-demand manufacture of customizable drug delivery systems to advance healthcare toward the goal of personalized medicine. However, major challenges remain in realizing personalized drug delivery that fits a patient-specific drug dosing schedule using local drug delivery systems. In this study, a user-designed device is developed as implantable therapeutics that can realize personalized drug release kinetics by programming the inner structural design on the microscale. The drug release kinetics required for various treatments, including dose-dense therapy and combination therapy, can be implemented by controlling the dosage and combination of drugs along with the rate, duration, initiation time, and time interval of drug release according to the device layer design. After implantation of the capsular device in mice, the in vitro-in vivo and pharmacokinetic evaluation of the device is performed, and the therapeutic effect of the developed device is achieved through the local release of doxorubicin. The developed user-designed device provides a novel platform for developing next-generation drug delivery systems for personalized and localized therapy.


Improving electroautotrophic ammonium production from nitrogen gas by simultaneous carbon dioxide fixation in a dual-chamber microbial electrolysis cell.
Microbial electrosynthesis is a promising technology for high-value added products generation from organic and inorganic waste. In this work, autotrophic dual-chamber microbial electrolysis cells (MECs) were set up for N2 fixation at -0.9 V vs Ag/AgCl (sat. KCl) cathodic potential under ambient conditions. Higher NH4+ production yield (average value of 0.35 µmol h-1 cm-2, normalized to cathode surface area) and higher faradaic efficiency (FE, 20.25%) were obtained with intermittent addition of N2 and CO2, while the yield and FE were only 0.018 µmol h-1 cm-2 and 4.21% in the absence of CO2. Furthermore, cyclic voltammograms (CV) explained the bioelectrochemical behavior of N2 reduction was coupled with CO2 reduction in the autotrophic MECs. Microbial community analysis and functional prediction in the cathodic chamber revealed that Xanthobacter and Hydrogenophaga played as producers for N2 and CO2 fixation and Pannonibacter acting as a decomposer for converting organic nitrogen to ammonium. This work not only provided an optional bioelectrocatalytic method for N2 fixation with negative CO2-emissions but also revealed the mechanism of simultaneous fixation of N2 and CO2 via Calvin cycle in autotrophic MECs.


Unexpected Solitary Subcutaneous Metastasis From Esophageal Carcinoma Revealed by MDP Bone Scintigraphy.
A 60-year-old man with back pain underwent 99m Tc-MDP to evaluate bone metastases from newly esophageal carcinoma. No bone metastasis was found on the whole-body bone scan. Unexpectedly, subcutaneous metastasis revealed increased 99m Tc-MDP activity.


Screening of the bioactive compounds in Amphora coffeaeformis extract and evaluating its protective effects against deltamethrin toxicity in rats.
Pyrethroids are synthetic chemicals similar to the pyrethrins, but more toxic to insects and mammals and persistent in the environment than pyrethrins. This study aimed to identify the bioactive compounds of Amphora coffeaeformis extract (ACE) and to determine their potential protective activity against deltamtherin (DEL) insecticide in rats. Six groups of male albino rats were treated for 4 weeks included the control group, ACE-treated group (772 mg/kg b.w.), DEL-exposed group (13.5 mg/kg b.w.), DEL plus ACE-treated group, and the groups treated with ACE for 14 days before or after DEL. At the end of treatment, blood and tissue samples were collected for biochemical assays. The GC-MS identified 18 compounds; most of them are fatty acid methyl ester, and the HPLC identified 8 polyphenols and significant amounts of vitamins A, C, B1, B2, B9, and E. The in vivo results revealed that DEL induced significant alterations in hematological and serum biochemical parameters, oxidative stress markers, proinflammatory cytokines, and NF-κB. ACE protects against DEL toxicity, and the protection was more pronounced in the groups treated with ACE plus DEL or ACE after DEL suggesting that ACE could be used for the prevention or the treatment of DEL toxicity. It could be concluded that ACE is a promising candidate for the production of bioactive compounds and should be considered in the pharmaceutical and food application.


Electronic residency application service scores: do they correlate with the rank order list for the match?
To investigate the relationship between ERAS-based preinterview scores, residency program postinterview scores and candidate rank order for the match. Two hundred sixty-three candidates' preinterview and postinterview scores and rank order were evaluated. The rank order was stratified as 1-4, 5-8, 9-12, > 13 and unranked. Spearman's p statistical analysis was used. There was a moderate relationship, r2 = 0.543, between preinterview and postinterview scores for all applicants. There was a significant inverse correlation between preinterview score and rank order, r2 = -0.763, and for the postinterview and rank order, r2 = -0.768. However, there were no significant relationships between factors significant for the top 4 ranked candidates. Preinterview and postinterview scores significantly correlated with each other and with the rank order list except for top-ranked candidates. Other factors may influence the rank order list.


Phytophagous and predaceous mites associated with vegetable crops from Riyadh, Saudi Arabia.
This study was conducted to investigate phytophagous and predatory mites associated with vegetable plants in Riyadh, Saudi Arabia. Eight phytophagous and 10 predacious mites were collected from 14 species of vegetable crops covering five major production localities. Out of these 18 mite species, 13 species are new to the mite fauna of Saudi Arabia. In addition, the two species, Tenuipalpus punicae and Agistemus exsertus, are reported for the first time on vegetable crops in Saudi Arabia. For each mite species found, notes on host plant association and occurrence period are given. An illustrated key for the identification of the 18 mite species reported in this study is provided and this can be used to improve the IPM programs by applying the local natural predatory mites in controlling mite pests in Saudi Arabia.


Gelsolin binds to polymeric actin at a low rate.
Association of gelsolin with actin filament subunits was investigated by the decrease of the fluorescence intensity of a 7-nitro-2-oxa-1,3-diazole (NBD) label covalently linked to gelsolin. The rate constant of this reaction was found to be 4 x 10(3) M-1 s-1. Binding of NBD-labeled gelsolin to monomeric actin proceeds at a similar low rate. The rate of association of gelsolin that was unmodified to actin filament subunits was estimated too. Unmodified gelsolin was added to a mixture of actin filaments and actin-DNase I complex. The fractions of gelsolin that bound to actin filament subunits or to actin-DNase I complex depended on the relative rates of these two competing reactions. In this way it was possible to estimate the rate constant of association of unmodified gelsolin with actin filament subunits (2 x 10(4) M-1 s-1). Thus, gelsolin associates with actin filament subunits at a rate that is considerably slower than diffusion-controlled and similar to the rate of binding of gelsolin to monomeric actin.


A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2020: 30-Year anniversary of gaining knowledge about folic acid's prevention potential for neural tube defects.
Spina bifida and anencephaly are major neural tube defects largely preventable through maternal periconceptional intake of folic acid. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of cereal grains, including wheat flour, maize flour, and rice, at the end of year 2020, a time point marking the 30th anniversary of the publication of landmark British Medical Research Council (MRC) study providing unequivocal knowledge on folic acid's FAP SBA prevention potential. The Food Fortification Initiative database was used to identify countries with mandatory fortification policies with folic acid added to cereal grains. We examined the status of FAP SBA prevention assuming mandatory folic acid fortification at 200 mcg/day of folic acid protects against FAP SBA and reduces their prevalence to a minimum achievable rate of 0.5 cases/1000 live births. Our analysis showed that 61,680 FAP SBA cases were prevented in the year 2020 through mandatory folic acid fortification of cereal grains in 58 countries, translating to 22% prevention of total possible FAP SBA prevention globally. Many countries in Africa, Asia, and Europe are yet to implement fortification. In 2020, 30 years after the MRC study was published, 218,270 preventable FAP SBA cases still occurred globally. Global prevention efforts for FAP SBA are inadequate even after three decades of knowledge on their prevention. Universal mandatory fortification of staples should be urgently implemented to prevent thousands of FAP SBA and associated elective terminations, stillbirths, and child mortality.


Contribution of low skeletal muscle mass in predicting cardiovascular events: A prospective cohort study.
We aimed to explore the association between skeletal muscle mass and cardiovascular events, and its additional value on the assessment of cardiovascular diseases (CVD) over traditional risk scores. The study included 1365 community-based participants aged over 50 years and free of CVDs at baseline. Participants completed detailed assessments at baseline and received a follow-up assessment in 2021-2022 via phone calls or electronic medical records. Skeletal muscle mass was measured using an automatic bioelectric analyzer. Predicted probabilities of 10-year atherosclerotic cardiovascular disease (ASCVD) risk were estimated individually with the China-PAR equation. After a mean follow-up of 7.6 years, 144 cardiovascular events were identified. The fully-adjusted hazard ratios (HRs) of cardiovascular events were 0.93 (0.88-0.98) and 1.08 (1.04-1.12) for skeletal muscle mass and predicted 10-year risk, respectively. Among participants over 60 years and with two or more risk factors, cardiovascular events risk increased progressively with each decreasing skeletal muscle tertile. Receiver operating characteristic curves showed that the C-statistic of predicting cardiovascular events for a 10-year risk assessment was slightly increased after adding skeletal muscle mass. The categorical net reclassification improvement (NRI) showed a 56.7% increase in the reclassification. The continuous NRI and integrated discrimination improvement increased as well. Participants with low skeletal muscle mass were more likely to have cardiovascular events. Low muscle mass improved the predictive power of CVD incidence over the original risk score, indicating that muscle mass could be a valuable parameter and a declining value needed early detection in the population.


Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE.
Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.


The relationship of sleep complaints risk factors with sleep phase, quality, and quantity in Japanese workers.
Numerous studies have determined that lifestyle factors (smoking, drinking, snacking, etc.) and the bedroom environment can influence sleep. We developed a new sleep scale-the 3-Dimensional Sleep Scale (3DSS)-which measures three elements of sleep: phase, quality, and quantity. The purpose of this study is to determine which risk factors of sleep complaints are associated with these sleep elements. Data were obtained from 366 Japanese day workers (302 men and 64 women). Sleep condition was assessed with the 3DSS, and we also assessed various habits within 2 h of going to bed, including smoking, drinking, snacking, caffeine intake, mobile phone use, and working. We also asked about bedroom environmental conditions (noise, lighting, and temperature and humidity). Multivariate logistic regression analysis using the backward selection method (likelihood ratio) was used, with 3DSS scores as the outcome (i.e., over or under the cutoff). The results showed that smoking was associated with significantly greater odds ratio [2.71 (1.65-4.44)] of disordered sleep phase, while lighting as well as temperature and humidity led to greater odds [3.67 (1.55-8.68), 1.93 (1.20-3.11)] of poor sleep quality. Finally, only noise was significantly related to greater odds [1.98 (1.13-3.46)] of low sleep quantity. These findings indicated the various risk factors of sleep complaints could be associated with different sleep elements. This might help in the effective treatment of sleep complaints.


Extramedullary leukemia with central facial palsy originated from poorly differentiated abdominal lymphoma.
An 8-year-old boy was presented with central facial palsy caused by extramedullary leukemia which had originated from poorly differentiated abdominal lymphoma. On cerebral tomographic scanning, there were adherences in the basal area of the brain. The occurrence of central facial palsy is very rare in childhood leukemia. However, in this case facial palsy was central in type and appeared as the presenting sign. The occurrence of central facial palsy was confirmed by the absence of clinical, radiological and audiological signs of peripheral involvement. The contralateral stapedius reflex test (500, 1000, and 2000 Hz) was present in this case.


Mechanisms of Xiong-Pi-Fang in treating coronary heart disease associated with depression: A systematic pharmacology strategy and in vivo pharmacological validation.
Coronary heart disease (CHD) and depression are very common and often co-existing disorders. Xiong-Pi-Fang (XPF), a therapeutic classical traditional Chinese medicine (TCM) formula, has shown satisfactory efficacy in treating CHD associated with depression. However, its mechanism of action is still unknown. To employ a systematic pharmacology approach for identifying the action mechanisms of XPF in treating CHD associated with depression. We used a systematic pharmacology approach to identify the potential active mechanisms of XPF in treating CHD with depression. Potential active compounds in XPF and the diseases targets were screened using relevant databases to build corresponding pathways, following the experiments that were conducted to confirm whether the presumptive results of systemic pharmacology were correct. Network pharmacology predicted 42 key targets and 20 signaling pathways involved in XPF-mediated treatment, with IL-6/JAK2/STAT3/HIF-1α/VEGF-A pathway significantly affected. The common influences were hypothalamic-pituitary-adrenal axis (HPA axis) and glucocorticoid signaling, validated through chronic unexpected mild stress (CUMS) with isoprenaline (ISO) for inducing CHD within the depression model in rats. In addition, XPF intake reduced depressive-like behaviors and improved ECG ischemic changes. Furthermore, XPF exerted some anti-inflammatory effects by inhibiting the interleukin-6 (IL-6) induced phosphorylation of janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), ultimately downregulating hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) activation. The dysfunctional HPA axis feedback loop was also regulated, which enhanced the glucocorticoid receptor (GR) expression. In contrast, it improved glucocorticoid resistance by reducing the mineralocorticoid receptor expression. Suppressing IL-6 release and maintaining the HPA feedback loop balance could be the primary mechanism of XPF against CHD with depression. The significance of the IL-6 and HPA axis identified indicates their potential as essential targets for CHD therapy with depression.


Preliminary experience with abdominal dual-energy CT (DECT): true versus virtual nonenhanced images of the liver.
The aim of this work was to compare the quality and noise of true non-enhanced (TNE) and virtual non-enhanced (VNE) images in patients undergoing dual-energy computed tomography (DECT) of the liver. Twenty consecutive patients (mean age 54.7±19.9 years) prospectively underwent abdominal DECT to assess the liver using a triphasic protocol consisting of precontrast, arterial-phase and portal-phase acquisitions. Exclusion criteria were allergy to iodinated contrast material, impaired renal function and a body mass index (BMI) >35 kg/m(2). The DE portal-phase acquisition was performed with automatic dose modulation (CARE Dose 4D). Nonionic iodinated contrast material (Iomeron 400) was administered at 0.625 gI/kg with a flow rate of 3.5 ml/s. Axial VNE images were reconstructed based on the portal data set using a collimation and an increment of 5 mm and were compared with TNE images reconstructed with the same parameters. The average image quality and noise were analysed by two radiologists in separate reading sessions. No statistically significant difference (p>0.05) in image quality was observed between VNE (4.00±0.85) and TNE images (4.35±0.58). A sufficient diagnostic quality was found in 95.0% (19/20) of VNE images and in 100% of TNE images. No statistically significant difference (p<0.05) was observed in the average image noise of VNE (9.5±0.7) and TNE (12.3±1.1) images. Abdominal DECT allows acquisition of liver VNE images with similar image quality and lower noise than TNE. Nevertheless, a few technical limitations related to the small field of view of the second detector in patients with a high BMI and heterogeneous iodine subtraction restrict the application of this technique to selected patients only.


The usefulness of exercise-induced QRS axis shift as a predictor of coronary artery disease.
The QRS axis of 101 patients with coronary artery disease (CAD) and 57 normal subjects without CAD who underwent coronary arteriograms were measured before and after exercise testing. There was no improvement in the sensitivity of positive axis shifts (15 degrees or greater) for CAD (18%) when compared to the value of positive ST depression (61%). However, the specificity of positive axis shifts for CAD was significantly increased (98%) when compared to the value of positive ST depression (77%). In addition, 39% of those patients with CAD (39 of 101) showed false negative ST depression, but 18% of these patients (7 of 39) showed a positive axis shift. In normal subjects 21% (12 of 57) showed false positive ST depression, but all of the 21% (12 of 12) showed negative axis shift. There was no significant difference in the increments of heart rate between positive ST depression, positive axis shift, and negative ST depression, negative axis shift. No statistical differences in the sensitivity of ST depression and an axis shift for one-, two- and three-vessel diseases were noted. The specificity of left-axis shift for the left anterior descending artery lesion was 98% and the specificity of right-axis shift for the right coronary artery and/or left circumflex artery lesion was 91%. Therefore, the axis shift response is no more sensitive for the detection of CAD than ST depression. However, when a positive axis shift is observed, one can predict two things: the CAD and the localization of the coronary stenosis.


Proposal of an algorithm for the management of rectally inserted foreign bodies: a surgical single-center experience with review of the literature.
Retained rectal foreign bodies (RFBs) are uncommon clinical findings. Although the management of RFBs is rarely reported in the literature, clinicians regularly face this issue. To date, there is no standardized management of RFBs. The aim of the present study was to evaluate our own data and subsequently develop a treatment algorithm. All consecutive patients who presented between January 2006 and December 2019 with rectally inserted RFBs at the emergency department of the Klinikum Stuttgart, Germany, were retrospectively identified. Clinicopathologic features, management, complications, and outcomes were assessed. Based on this experience, a treatment algorithm was developed. A total of 69 presentations with rectally inserted RFBs were documented in 57 patients. In 23/69 cases (33.3%), the RFB was removed transanally by the emergency physician either digitally (n = 14) or with the help of a rigid rectoscope (n = 8) or a colonoscope (n = 1). In 46/69 cases (66.7%), the RFB was removed in the operation theater under general anesthesia with muscle relaxation. Among these, 11/46 patients (23.9%) underwent abdominal surgery, either for manual extraction of the RFB (n = 9) or to exclude a bowel perforation (n = 2). Surgical complications occurred in 3/11 patients. One patient with rectal perforation developed pelvic sepsis and underwent abdominoperineal extirpation in the further clinical course. The management of RFBs can be challenging and includes a wide range of options from removal without further intervention to abdominoperineal extirpation in cases of pelvic sepsis. Whenever possible, RFBs should obligatorily be managed in specialized colorectal centers following a clear treatment algorithm.


A Functional Comparison of Treatment of Intrinsic Sphincter Deficiency with Muscle-Derived and Adipose Tissue-Derived Stem Cells.
This study investigated the effect of muscle-derived stem cells (MDSCs) and adipose tissue-derived stem cells (ADSCs) in the treatment of stress urinary incontinence (SUI) and their differences in a rat model. MDSCs and ADSC were isolated from rats (n = 10), examined for their properties, and labeled with enhanced green fluorescent protein (EGFP) and β-galactosidase (β-gal) gene. Rats received bladder-neck and transurethral sphincter injection of EGFP-labeled MDSCs and β-gal gene-labeled ADSC and injection of D-Hanks as a control (n = 24 each group). At 0, 15, 30, and 60 days after cells injection, urinary voiding function was assessed by urine dynamics detector. The rats were killed to harvest their urethras for tracking of MDSCs and ADSC. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) was performed to detect smooth muscle contents. Urodynamic test showed that MDSCs and ADSC improved the function of urination in rats with intrinsic sphincter deficiency (ISD), and effect of MDSCs-treatment was more pronounced. In addition, histologic analysis showed that the MDSCs and ADSC-treated groups had significantly higher myosin and α-smooth muscle actin (α-SMA) content than the control group. Compared with ADSC-treated groups, the MDSCs-treated groups in myosin and α-SMA content showed the tendency of increase. In summary, MDSCs and ADSCs have obvious effects in the treatment and/or prevention of ISD and transplantation of MDSCs is more effective than ADSC. © 2018 IUBMB Life, 70(10):976-984, 2018.


Antigenic relationships of Bence Jones proteins, myeloma globulins, and normal human gama-globulin.
By means of immunodiffusion and immunoelectrophoresis study has been made of antigenic relationships of Bence Jones proteins, and the three classes of normal and pathological immunoglobulins, 7S gamma, beta(2A), and beta(2M). All thirty-nine Bence Jones proteins studied could be classified into either one of two distinct antigenic types, A or B. Both types are related to the immunoelectrophoretically slow (S) fragment of a papain digest of normal gamma-globulin; B is related more closely than A, but neither has antigenic determinants in common with the fast (F) fragment. The 7S gamma myeloma globulins were either immunological type I or II. The papain digests of these proteins produced the S and F precipitin lines in immunoelectrophoresis but multiple bands in starch gel electrophoresis, especially in the F region. The S fraction of type I myeloma globulins is antigenically similar to Bence Jones protein of type B, and the S component of type II myeloma globulins has antigenic determinants in common with type A Bence Jones protein. Correspondingly, myeloma patients with type I globulins and proteinuria usually excrete type B Bence Jones proteins, whereas patients with type II excrete type A proteins. The F fragment is the part common to normal 7S gamma-globulin and types I and II myeloma globulins but is absent in beta(2A) and beta(2M) pathological globulins and in both types of Bence Jones proteins. Papain digests of beta(2A) myeloma globulins produced a single precipitin line in immunoelectrophoresis. beta(2A) myeloma globulins appeared to have two antigenic units, one in common with type B Bence Jones protein and normal gamma-globulin, and another specific to beta(2A). The beta(2A) myeloma patients excreted type B Bence Jones protein. The papain digest of a macroglobulin produced two precipitin lines, the faster of which had antigenic determinants in common with type B Bence Jones protein, the slower seemed specific for the macroglobulin. Five serum micromolecular globulins proved to be either type A or B Bence Jones proteins. From the above results, an antigenic map was constructed showing which determinants are shared and which are specific for normal 7S gamma-globulin, types I and II myeloma globulins, beta(2A) myeloma globulins, a macroglobulin, and types A and B Bence Jones proteins.


Diabetic autonomic neuropathy in patients with vascular disease.
An attempt has been made to determine the effect on vasomotor tone and sweating of peripheral neuropathy in the feet of diabetics with vascular disease. There was a loss of vasomotor tone in 48 per cent of patients with peripheral neuropathy and in 12 per cent of those without neuropathy (P less than 0.01). Complete loss of sudomotor activity was rare in both groups.


Role of glycine in the N-methyl-D-aspartate-mediated neuronal cytotoxicity.
Current evidence indicates that glutamate acting via the N-methyl-D-aspartate (NMDA) receptor/ion channel complex plays a major role in the neuronal degeneration associated with a variety of neurological disorders. In this report the role of glycine in NMDA neurotoxicity was examined. We demonstrate that NMDA-mediated neurotoxicity is markedly potentiated by glycine and other amino acids, e.g., D-serine. Putative glycine antagonists HA-966 and 7-chlorokynurenic acid were highly effective in preventing NMDA neurotoxicity, even in the absence of added glycine. The neuroprotective action of HA-966 and 7-chlorokynurenic acid, but not that of NMDA antagonists 3-(2-carboxypiperazine-4-yl)propylphosphonate and MK-801, could be reversed by glycine. These results indicate that glycine, operating through a strychinine-insensitive glycine site, plays a central permissive role in NMDA-mediated neurotoxicity.


The efficacy of anthelmintics against third stage larvae of Ancylostoma caninum in Mastomys natalensis.
Investigations have been carried out on the multimammate rat (Mastomys natalensis), orally infected with 1000 third stage larvae of Ancylostoma caninum per animal, to evaluate the larvicidal efficacy of anthelmintics in this paratenic host. The oral or subcutaneous administration of 19 anthelmintics and filaricides revealed good activity for levamisole, cambendazole, and mebendazole against 15-day-old Ancylostoma larvae which were located in the muscular tissue. Similarly, good results were obtained with levamisole and cambendazole against the migrating third stage larvae, by treatment two to six days after infection. The benzimidazole derivatives, thiabendazole, oxibendazole, parbendazole, and fenbendazole showed marked activity only at high dosage rates. The anthelmintics methyridine, amoscanate, pyrantel tartrate, morantel tartrate; the microfilaricidal organophosphates dichlorvos, fenthion, and haloxon; as well as the micro- or macrofilaricidal drugs diethylcarbamazine, nitrofurantoin, nifurtimox, suramin sodium, and thiacetarsamide sodium failed to show larvicidal activity even in high dosages. The average larval recovery rate after oral infection with 1000 third stage larvae, in untreated control animals, was 14.85%.


5-Year Collis-Nissen Gastroplasty Outcomes for Type III-IV Hiatal Hernia with Short Esophagus: A Prospective Observational Study.
To assess the 5-year outcomes of patients undergoing Collis-Nissen gastroplasty for type III-IV hiatal hernia with short esophagus. From a prospective observational cohort of patients who underwent antireflux surgery for type III-IV hiatal hernia between 2009 and 2020, those with short esophagus (abdominal length <2.5 cm) in whom a Collis-Nissen procedure was performed and reached at least 5 years of follow-up were identified. Hernia recurrence, patients' symptoms, and quality of life were assessed annually by barium meal x-ray, upper endoscopy, and validated symptoms and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaires. Of the 114 patients with Collis-Nissen gastroplasty, 80 patients who completed a 5-year follow-up were included (mean age 71 years). There were no postoperative leaks or deaths. Recurrent hiatal hernia (any size) was identified in 7 patients (8.8%). Heartburn, regurgitation, chest pain, and cough were significantly improved at each follow-up interval (p < 0.05). Preoperative dysphagia disappeared or improved in 26 of 30 patients, while new-onset dysphagia occurred in 6. Mean postoperative QOLRAD scores significantly improved at all dimensions (p < 0.05). Collis gastroplasty combined with Nissen fundoplication provides low hernia recurrence, good control of symptoms, and improved quality of life in patients with large hiatal hernia and short esophagus.


Emil Kraepelin and forensic psychiatry.
Kraepelin's main positions in forensic psychiatry, that are understandable only in the context of his underlying psychiatric and, especially, nosological theory, are the following: (1) Criminal behavior, especially if repeatedly shown by the same individual, should be regarded as (or, in the strongest version possible, is) mental illness; (2) above all, this viewpoint is due to Kraepelin's broad acceptance of degeneration theory in general, whereas he rejected simplifying concepts like Lombroso's early hypothesis of clinically observable "stigmata degenerations"; (3) Kraepelin voted for the acceptance of diminished responsibility to provide a more differentiated spectrum for the psychiatric expert and the judge; (4) because delinquency, in his view, was closely linked with mental illness, which should be treated instead of (only) being punished, he strictly objected to the death penalty; and (5) he suggested significantly increasing psychiatry's influence on decisions regarding the kind and length of imprisonment.


Inflammatory bone loss: pathogenesis and therapeutic intervention.
Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.


DNA damage and aging on hematopoietic stem cells: Impact of oxidative stress in ApoE-/- mice.
The effects of aging on ROS production and DNA damage were assessed in hematopoietic stem cells (HSCs) from apolipoprotein E-deficient (ApoE-/-) mice (2-, 12- and 24-month-old), a traditional experimental model of atherogenic dyslipidemia. HSCs from aged ApoE-/- mice were associated with increased ROS levels, leading to loss quiescence, DNA damage, apoptosis and telomere shortening. The concurrence of lack of ApoE and aging result in exhaustion and senescence of HSCs accompanied by increased oxidative stress and inflammation. Therefore, our data open avenues to a better understanding of age-related changes and genetic factors, which may synergistically compromise the efficacy of aged HSC recovery and/or transplantation.


HMG-CoA reductase inhibitors and the kidney.
HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors (statins) have been shown to reduce serum cholesterol and cardiovascular morbidity and mortality. The mechanisms of these beneficial effects are reviewed. Altered inflammatory responses and improved endothelial function mediated by statins are thought to be, in part, responsible for the reduction in cardiovascular events. It has not been well established whether statins confer similar benefits to the kidney. In this review, we critically consider the available data whereby dyslipidemia mediates renal dysfunction by modulating the inflammatory response to diverse cytokines. We also review the emerging database suggesting that statins may modulate renal dysfunction by altering the response of the kidney to dyslipidemia, particularly in patients with end-stage renal disease (ESRD) and post-kidney transplant.


Atomic view of the HIV-1 matrix lattice; implications on virus assembly and envelope incorporation.
During the late phase of HIV type 1 (HIV-1) infection cycle, the virally encoded Gag polyproteins are targeted to the inner leaflet of the plasma membrane (PM) for assembly, formation of immature particles, and virus release. Gag binding to the PM is mediated by interactions of the N-terminally myristoylated matrix (myrMA) domain with phosphatidylinositol 4,5-bisphosphate. Formation of a myrMA lattice on the PM is an obligatory step for the assembly of immature HIV-1 particles and envelope (Env) incorporation. Atomic details of the myrMA lattice and how it mediates Env incorporation are lacking. Herein, we present the X-ray structure of myrMA at 2.15 Å. The myrMA lattice is arranged as a hexamer of trimers with a central hole, thought to accommodate the C-terminal tail of Env to promote incorporation into virions. The trimer–trimer interactions in the lattice are mediated by the N-terminal loop of one myrMA molecule and α-helices I–II, as well as the 310 helix of a myrMA molecule from an adjacent trimer. We provide evidence that substitution of MA residues Leu13 and Leu31, previously shown to have adverse effects on Env incorporation, induced a conformational change in myrMA, which may destabilize the trimer–trimer interactions within the lattice. We also show that PI(4,5)P2 is capable of binding to alternating sites on MA, consistent with an MA–membrane binding mechanism during assembly of the immature particle and upon maturation. Altogether, these findings advance our understanding of a key mechanism in HIV-1 particle assembly.


Evaluation of trabecular bone formation in a canine model surrounding a dental implant fixture immobilized with an antimicrobial peptide derived from histatin.
JH8194 induces osteoblast differentiation, although it was originally designed to improve antifungal activity. This suggests that JH8194 is useful for implant treatment. Therefore, the aim of this study was to evaluate the osseointegration capacity of JH8194-modified titanium dental implant fixtures (JH8194-Fi). The implants were randomly implanted into the edentulous ridge of dog mandibles. Healing abutments were inserted immediately after implant placement. Three weeks later, peri-implant bone levels, the first bone-to-implant contact points, and trabecular bone formation surrounding the implants were assessed by histological and digital image analyses based on microcomputed tomography (microCT). The histological analysis revealed an enhancement of mature trabecular bone around the JH8194-Fi compared with untreated fixtures (control-Fi). Similarly, microCT combined with analysis by Zed View™ also showed increased trabecular bone formation surrounding the JH8194-Fi compared with the control-Fi (Student's t-test, P < 0.05). JH8194 may offer an alternative biological modification of titanium surfaces to enhance trabecular bone formation around dental implants, which may contribute to the transient acquirement of osseointegration and the long-term success of implant therapy.


Substrate specificity of eukaryotic signal peptidase. Site-saturation mutagenesis at position -1 regulates cleavage between multiple sites in human pre (delta pro) apolipoprotein A-II.
We have previously described a novel mutant of human preproapolipoprotein A-II (pre(delta pro)apoA-II) in which the wild-type 18-amino acid-long signal sequence (Gly18 decreases) was functionally redefined to 20 amino acids in length (Ala 20 decreases). We have used this mutant as a model preprotein to probe the substrate specificity of eukaryotic signal peptidase. Site-saturation mutagenesis was performed resulting in the substitution of 13 different amino acids (acidic, basic, aromatic, hydrophobic, and small-neutral) for Ala20 (or position -1). The effects of these substitutions were assessed using an in vitro transcription/translation/microsomal membrane processing system. NH2-terminal sequence analysis of the 13 mutant proteins demonstrated that amino acids which occupy position -1 in a signal peptide are critical in establishing a good context for signal peptidase cleavage and that two or more potential sites of cleavage may compete for recognition by signal peptidase.


Cholinergic markers in aged cognitively impaired Long-Evans rats.
Aged Long-Evans rats (24-25 months old) were classified into cognitively impaired or unimpaired subgroups based on their performances in the Morris Swim Maze task compared to young controls. Using quantitative in vitro receptor autoradiography, we investigated the status of various cholinergic markers in these two groups and in young adults (six months) animals. The apparent density of [3H]pirenzepine (muscarinic M1) sites was similar in the three groups of rats in various cortical areas, subfields of the hippocampus, medial septum and striatum. Similarly, choline acetyltransferase activity and the density of [3H]hemicholinium-3 (high-affinity choline uptake) and [3H]cytisine (nicotinic) binding sites were also unchanged in the brain regions studied between the aged cognitively impaired, unimpaired and young adult rats. In contrast, significant increases in [3H]AF-DX 384 (muscarinic M2) binding density were observed in various cortical areas and in the molecular layer of the dentate gyrus of aged cognitively impaired versus unimpaired rats and in few cortical regions of old as compared to young animals. Therefore, a selective alteration in the regulation of putative M2 receptor sites is apparent, particularly in the aged cognitively impaired rats. Increases in M2 binding sites could lead to a decrease in the capacity to release acetylcholine, as some of the M2 receptors are believed to act as negative autoreceptors. This could influence cognitive functions as selective M2 blockers have recently been reported to facilitate spatial memory in aged impaired rats [Doods et al. (1993) Life Sci. 52, 497-503: Quirion et al. (1995) J. Neurosci. 15, 1455-1462.


The FVB/N mice: A well suited strain to study learning and memory processes using olfactory cues.
The FVB/N mice are well suited to generate transgenic animals. These mice are also particularly sensitive to seizures and neurodegeneration induced by systemic administration of chemoconvulsants and are very useful to model epilepsy. However, previous studies report strong cognitive and visual impairments suggesting this background unsuitable for behavioral analysis. In this study, we assessed and compared learning abilities of FVB/N mice to the well characterized C57BL/6 strain using the olfactory tubing maze, a non-visual hippocampus-dependent task in which the mice were trained to learn odor-reward associations. Exploratory behavior and spontaneous locomotor activity were then compared using the open field test. We demonstrated that FVB/N mice were able to learn the task, reaching at the end of the test a high percentage of correct responses. Interestingly, the performance of the FVB/N mice was at least similar to that of the C57BL/6 mice. Moreover, in contrast to previous reports, the FVB/N mice displayed a spontaneous locomotor activity lower than C57BL/6 mice. Our study demonstrated that FVB/N mice are not cognitively impaired and that their learning and memory performance can be assessed when the task is based on olfaction rather than vision.


Resistance to anti-infective drugs and the threat to public health.
Increasing resistance of pathogens to anti-infective drugs is an urgent public health problem that must be addressed through more prudent use of these drugs in human medicine and in animal husbandry, agriculture, and aquaculture.