Lipid-lipid interactions as regulators of carboxylester lipase activity.
The hydrolysis of 1,3-dioleoylglycerol and related substrates by mammalian pancreatic carboxylester lipases was studied. Mixed lipid films of substrates with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine at the argon-buffer interface were exposed to relatively high levels of monomeric porcine pancreatic carboxylester lipase for a brief period. With either 1,3-dioleoylglycerol, 1,2-dioleoylglycerol, trioleoylglycerol, or oleoylmethanol as a substrate, the percentage of substrate hydrolysis increased abruptly from near zero to near 100% with increasing proportion of substrate in the film. The phospholipid was not hydrolyzed. Using 1,3-dioleoylglycerol as the substrate with either the dimeric, porcine pancreatic carboxylester lipase, human pancreatic carboxylester lipase, or human milk bile salt-stimulated lipase gave results identical to those obtained with the porcine monomer. Hydrolysis of 1,3-dioleoylglycerol by porcine monomeric carboxylester lipase was independent of the initial surface pressure of the film. However, a strong correlation was observed between hydrolysis and interfacial lipid composition at all surface pressures, even if bulk 1,3-dioleoylglycerol was also present. The ultrasensitive dependence of hydrolysis on interfacial lipid composition, i.e. lipid-lipid interactions, suggests that such "switching" may contribute to the regulation of diacylglycerol levels in cells where they function in signal transduction.


Atrioventricular nodal gap conduction as a manifestation of dual nodal pathways.
Electrophysiologic studies were performed in a 76 year old patient for evaluation of sinus bradycardia. Atrial extrastimuli were induced during sinus rhythm at progressively decreasing coupling (A1-A2) intervals. At an A1-A2 interval of 420 msec, right bundle branch block developed, and at 370 msec conduction failed below the His bundle. When the interval was reduced to 320 msec, conduction resumed with a normal QRS pattern with an abrupt increase in A-H intervals from 165 to 305 msec. These findings are interpreted as type I or atrioventricular (A-V) nodal gap conduction physiologically related to conversion from a rapid to a slow A-V nodal conduction mode.


Inhibitory effects of rHP-NAP IgY against Helicobacter pylori attachment to AGS cell line.
Helicobacter pylori is a major human pathogen related to gastric adenocarcinoma and gastroduodenal diseases. Treatment of H. pylori infections is complicated by the rise of antibiotic resistance, necessitating investigation of alternative therapies. One such alternative is passive immunization by oral administration of antibacterial immunoglobulin. In the present study, chicken immunoglobulin (IgY) was used for passive immunotherapy against a major virulence factor of H. pylori, namely recombinant HP-Nap protein. Recombinant HP-Nap was prepared and used to immunize hens. IgY was purified from the eggs by polyethylene glycol precipitation method with a total IgY-HP-NAP yield of 30 mg per egg. The inhibitory effect of specific IgY on H. pylori attachment was investigated in AGS cell line infected by the bacteria. The results demonstrate the potent effect of IgY- HP-NAP in inhibition of H. pylori attachment to the AGS cells.


Comparative trial of felodipine and nifedipine in refractory hypertension.
The aim of this study was to compare the new vasodilator felodipine with nifedipine in 18 patients with poorly controlled hypertension. The design was a double-blind, cross-over study using a double-dummy technique. Felodipine 5mg was given 3 times daily and nifedipine 10mg 3 times daily. In case of an unsatisfactory blood pressure reduction, the drug dose was doubled. 14 patients had the higher dose of felodipine and 16 the higher dose of nifedipine. Both agents had good antihypertensive effect. After 1 week's therapy, felodipine reduced the blood pressure by 18/12 mm Hg (supine) and 18/13 mm Hg (upright), and nifedipine by 19/11 and 24/14 mm Hg, respectively. After 4 weeks' therapy, 12 hours after drug intake, felodipine reduced the blood pressure by 11/8 mm Hg (supine) and 16/8mm Hg (upright), and nifedipine by 3/2 and 6/4 mm Hg, respectively. Two patients on nifedipine withdrew from the study due to adverse reactions. In general, however, there were few side effects, with no significant difference between the drugs.


Increased fibronectin-receptor expression in colon carcinoma-derived HT 29 cells decreases tumorigenicity in nude mice.
Following malignant transformation, epithelial cells of colorectal carcinomas, unlike normal colonic epithelial cells, no longer express the alpha 5 beta 1 fibronectin receptor. We hypothesized that the loss of alpha 5 beta 1 expression might facilitate the tumorigenicity of transformed colonic cells. To examine this hypothesis, we established subclones of the human colon adenocarcinoma cell line HT 29, which differ in their fibronectin receptor expression and tested their tumorigenicity in nude mice. Our data indicate that the capacity to form tumors in nude mice after subcutaneous injection was significantly lower for alpha 5-positive than for alpha 5-negative cell clones. In addition, tumors from clones expressing no detectable levels of alpha 5 beta 1 grew rapidly, whereas tumors expressing elevated levels of fibronectin receptor grew slowly. Despite similar rates of adhesion to fibronectin for alpha 5-positive and alpha 5-negative cell clones in vitro, deposition of fibronectin in tumor-surrounding stroma was increased in tumors derived from alpha 5-positive cells. Our results indicate that an increase of the alpha 5 beta 1-mediated interaction of malignant cells with the extracellular matrix may be responsible for decreased tumorigenicity of malignant transformed cells in colorectal carcinomas.


Cortical-chromaffin cell interactions in the adrenal gland.
Adrenal catecholamines and steroids are important regulators of the stress response, immune function, blood pressure, and energy homeostasis. Historically, the two cell populations within the adrenal gland-the steroid-producing adrenocortical cells and the catecholamine-producing chromaffin cells-have been regarded as two independent endocrine systems. Research on adrenal physiology and pathophysiology has therefore largely focused on the individual understanding of each cell type. However, adrenal cortex and medulla appear to be interwoven and show multiple contact zones without separation by connective tissue or interstitial membranes. In vitro studies, animal models, and the analysis of human adrenal pathophysiology have demonstrated critical importance of cortical-chromaffin crosstalk for adrenal function and disease. Thus, chromaffin cells regulate steroid-hormone release by the adrenal cortex and steroids induce catecholamine production in the medulla. Consequently, disorders of the adrenal cortex have been shown to affect chromaffin cell function and vice versa. Mouse models of adrenal cortical dysfunction, such as the targeted disruption of the 21-hydroxylase- or the CRHR1 genes, show alterations in chromaffin cell function, while disruption of tyrosine hydroxylase, a key enzyme in catecholamine synthesis, impairs adrenal cortical function. Accordingly, patients with congenital adrenal hyperplasia (CAH) and Addison's disease show reduced catecholamine biosynthesis. Immense progress in characterizing the mechanisms of chromaffin-cortical interactions has been achieved in recent years. Here, we summarize the current view on intraadrenal communication with respect to adrenal pathophysiology.


A rare presentation of IgG4 related disease as a gastric antral lesion: Case report and review of the literature.
Immunoglobulin G4 related disease is a recently recognized systemic fibro-inflammatory disorder affecting virtually every organ in the body, characterized by lympho-plasmacytic dense infiltrates rich in IgG4 positive plasmacytes along with storiform fibrosis, inconstantly associated with elevated serum IgG4 levels. Few cases of Immunoglobulin G4 related disease occurring solely in the stomach have been published. We herein present a rare case of a 57 year old male patient presenting with an incidentally discovered asymptomatic pre-pyloric submucosal gastric lesion confused with a gastro-intestinal stromal tumor with failed endoscopic biopsy attempts due to tumor mobility. The patient underwent wedge resection of the lesion which was diagnosed postoperatively as Immunoglobulin G4 related disease. Immunoglobulin G4 related disease presenting as a solitary lesion in the stomach is a very rare condition. It should be kept in the differential diagnosis of a submucosal mass or polyp. The treatment is medical with systemic steroid therapy. Obtaining a tissue biopsy is of extreme importance to avoid unnecessary surgery.


Role of FOXM1 in vascular smooth muscle cell survival and neointima formation following vascular injury.
Accelerated smooth muscle cell (SMC) proliferation is the primary cause of intimal hyperplasia (IH) following vascular interventions. Forkhead Box M1 (FOXM1) is considered a proliferation-associated transcription factor. However, the presence and role of FOXM1 in IH following vascular injury have not been determined. We examined the expression of FOXM1 in balloon-injured rat carotid arteries and investigated the effect of FOXM1 inhibition in SMCs and on the development of IH. FOXM1 was detected by immunofluorescent staining in balloon-injured rat carotid arteries where we observed an upregulation at day 7, 14, and 28 compared to uninjured controls. Immunofluorescence staining revealed FOXM1 coincided with proliferating cell nuclear antigen (PCNA). FOXM1 was also detectable in human carotid plaque samples. Western blot showed an upregulation of FOXM1 protein in serum-stimulated SMCs. Inhibition of FOXM1 using siRNA or chemical inhibition led to the induction of apoptosis as measured by flow cytometry and western blot for cleaved caspase 3. Perturbations in survival signaling were measured by western blot following FOXM1 inhibition, which showed a decrease in phosphorylated AKT and β-catenin. The chemical inhibitor thiostrepton was delivered by intraperitoneal injection in rats that underwent balloon injury and led to reduced intimal thickening compared to DMSO controls. FOXM1 is an important molecular mediator of IH that contributes to the proliferation and survival of SMCs following vascular injury.


Behavioral characteristics and early temperament of premature infants with intracranial hemorrhage.
Behavioral characteristics of 12 full-term and 44 premature infants with and without intracranial hemorrhage (ICH) were studied. Cranial ultrasonography prospectively documented Grade I-II ICH in 14, Grade III-IV in 19 and no ICH in 11 premature infants. Examination at corrected age of 40 +/- 2 weeks using the Neonatal Behavioral Assessment Scale showed that infants in the ICH groups had lower levels of arousal and more abnormal reflexes than full-terms. Infants with ICH III-IV displayed less optimal motor responses than full-term infants and diminished orientation responses, especially to visual stimuli. Thus, lower level of arousal, immature motoric processes, and poor visual orientation differentiated premature with ICH from full-term infants, although premature infants without these sequelae, did not differ significantly from full-term infants. The above may represent early manifestations of visual-perceptual and motor problems noted in the follow-up of ICH infants. Further, neonatal behavior was found to affect parent ratings of infant temperament (via the Bates Infant Characteristics Questionnaire) at 3 months corrected age, and the relationships between neonatal behavior and parental ratings differed depending upon the infant's gestational age and severity of hemorrhage. We conclude that neonatal behaviors are less optimal in premature infants, and least optimal in premature infants with severe intracranial hemorrhage when compared to fullterm infants.


Analgesic, anti-inflammatory, antipyretic and haematological effects of aethiopinone, an o-naphthoquinone diterpenoid from Salvia aethiopis roots and two hemisynthetic derivatives.
Aethiopinone (1), an o-naphthoquinone diterpene from Salvia aethiopis L. roots and two hemisynthetic derivatives 2 and 3 have been evaluated for toxicity, anti-inflammatory, analgesic, antipyretic, and haemostatic activities. The compounds tested showed low toxicity and a pharmacological profile similar to other NSAI substances on reducing the edema induced by carrageenan and contractions induced by phenyl-p-quinone; the most active compounds were 1 and 2. In the same way and as expected with these types of substances, the bleeding time increased. In the TPA-induced ear inflammation model, the three compounds showed a moderate reduction of edema, and 1 produced a significant increase in the reaction time against thermal painful stimuli in the tail immersion test. The results demonstrated strong anti-inflammatory, peripheral and central analgesic properties for 1, as well as antiedematose topical action and peripheral analgesic properties for 2 and 3.


Identification of a potentially avoidable cardiopulmonary resuscitation in hematology and oncology wards.
In-hospital cardiopulmonary resuscitation (CPR) is one of undesirable situations. We tried to identify and characterize a potentially avoidable CPR in cancer patients who were hospitalized in hematology and oncology wards. A potentially avoidable CPR was determined based on chemotherapy setting, disease status and clinical situation at the time when a cardiopulmonary arrest occurred, by using a consensus-driven medical records review of two physicians. One hundred thirty-seven patients among 12,437 patients hospitalized at hematology and oncology wards between March 2003 and June 2015 (1.1%) underwent a CPR. Eighty-eight patients (64.2%) were men. The majority of patients with a CPR had lung cancer (41, 29.9%), hematologic malignancy (24, 17.5%), stomach cancer (23, 16.8%) or lymphoma (20, 14.6%). A potentially avoidable CPR was identified in 51 patients (37.2%). In a multivariate analysis, advanced diseases and certain tumor types (e.g., lung cancer, lymphoma) were significant risk factors for a potentially avoidable CPR. Of patients who received a potentially avoidable CPR, 29 patients (56.9%) did not have a do-not-resuscitate documentation. A first return of spontaneous circulation rate (ROSC) and in-hospital survival rate (IHSR) were much lower in patients with a potentially avoidable CPR than those with a CPR that was not avoidable (ROSC: 39.2% vs 53.5%, P = 0.106; IHSR: 2.0% vs 12.8%, P = 0.032, respectively). A potentially avoidable CPR was common at hematology and oncology wards. A potentially avoidable CPR frequently occurred in advanced diseases and certain tumor types. Furthermore, cancer patients who received a potentially avoidable CPR showed the worse prognosis.


Chemical changes during in vivo degradation of poly(anhydride-imide) matrices.
The in vivo degradation characteristics of a novel class of biodegradable polymers, poly(anhydride-imides), were investigated. The poly(anhydride-imides) examined were poly[trimellitylimidoglycine-co-1,6-bis(p-carboxyphenoxy)hex ane] (TMA-gly:CPH) in 10:90, 30:70 and 50:50 molar ratios and poly[pyromellitylimidoalanine-co-1,6-bis(p-carboxyphenoxy)he xane] (PMA-ala:CPH) in 10:90 and 30:70 molar ratios. The polymer matrices were compression-molded into circular discs, then implanted in rat subcutaneous tissues for nearly two months. At defined time intervals, the animals were sacrificed and explants analyzed. Proton NMR spectroscopic analysis revealed a complete absence of imide monomer units in PMA-ala: CPH compositions after 28 d and complete removal of imide units at 56 d from TMA-gly matrices. Gross observation of the implants closely correlated to the imide content: with decreasing imide content, the explants darkened and fragmented at a faster rate. The chemical compositions of the poly(anhydride imide) explants were also monitored using IR spectroscopy. The residual amount of anhydride bonds in the polymer backbone following implantation were calculated from peaks specific to the anhydride bonds relative to the total amount of carbonyl bonds present. Initially, the imide (TMA-gly or PMA-ala) anhydride bonds were rapidly hydrolyzed then solubilized, followed by the slower hydrolysis of the CPH monomer anhydride bonds.


Detection of human norovirus in cherry tomatoes, blueberries and vegetable salad by using a receptor-binding capture and magnetic sequestration (RBCMS) method.
In this study, we developed a sensitive receptor-binding capture and magnetic sequestration (RBCMS) method capable of concentrating human norovirus (HuNoV) from various food samples within few hours. We found that distilled water was suitable for the elution of HuNoV from inoculated tomatoes and blueberries, and glycine buffer improved the elution of HuNoV from inoculated salad. A significant improvement in post-extraction RNA yield was achieved by sequentially heat-releasing and column-extracting over either technique alone. The viral recovery of the RBCMS method was significantly higher than both the same-day PEG method (90 min PEG precipitation) and the two-day PEG method (overnight PEG precipitation) with a recovery rate of 8.75%, 1.03% and 5.40%, respectively. The detection limit of HuNoV by RBCMS method was significantly improved to 0.056 RTU. The estimated minimal concentration powers (MCPs) were 6.11, 30.48, and 63.60-fold for the same-day PEG, two-day PEG, and RBCMS methods, respectively. RNase protection assay suggests that the viral genome was protected from RNase attack by remaining within the viral capsid. The signal detected by the RBCMS method might be more biologically relevant, as it requires both intact viral capsid to bind to HBGA receptors and the presence of viral genome to be amplified. Overall, the RBCMS method takes significantly less time than current PEG precipitation methods, recovers a higher yield of HuNoV from various food samples, and hence exhibits higher sensitivity.


The two-component system CesRK controls the transcriptional induction of cell envelope-related genes in Listeria monocytogenes in response to cell wall-acting antibiotics.
The two-component system CesRK of Listeria monocytogenes responds to cell wall-acting antibiotics. We show here that CesRK controls the transcription of several cell envelope-related genes. The CesRK-dependent induction of these genes may be viewed as an attempt by L. monocytogenes to protect itself against the damaging effects of cell wall-acting antibiotics.


Non-response in a population study after an environmental disaster.
After the grounding of the tanker MV Braer off the coast of Shetland an epidemiological study was rapidly instigated to determine any immediate or long-term health effects on the exposed resident population. The study was carried out in two phases, at the time of the grounding and five months later. The objective of this study is to determine the reasons for non-response in both phases of the Shetland Health Study. A telephone survey was performed on a systematic sample of non-responders from the exposed population in both phases of the study. The setting was the south mainland of Shetland. Fifty-nine of the 215 non-responders in the first phase of the study and 16 of the 86 non-responders in the second phase were surveyed. The main reasons for non-response were attitudinal rather than situational or organisational. Non-responders did not feel their health was affected, were not interested in the study or did not think the study was useful. Some were put off by the biological tests involved and some had difficulties with appointment times. Practical issues such as flexible appointment systems are easier to address than client characteristics but factors relating to distrust and indifference must be addressed if non-response rates are to be minimised.


Axillary nerve injuries in contact sports: recommendations for treatment and rehabilitation.
Axillary nerve injuries are some of the most common peripheral nerve injuries in athletes who participate in contact sports. Resulting deltoid muscle paralysis is secondary to nerve trauma which occurs following shoulder dislocation or a direct blow to the deltoid muscle. Compression neuropathy has been reported to occur in quadrilateral space syndrome as the axillary nerve exits this anatomic compartment. The axillary nerve is also extremely vulnerable during any operative procedure involving the inferior aspect of the shoulder, and iatrogenic injury to the axillary nerve remains a serious complication of shoulder surgery. Accurate diagnosis of axillary nerve injury is based on a careful history and physical examination as well as an understanding of the anatomy of the shoulder and the axillary nerve in particular. Inspection, palpation and neurological testing provide the bases for diagnosis. A clinically suspected axillary nerve injury should be confirmed by electrophysiological testing, including electromyography and nerve conduction studies. During the acute phase of injury, the athlete should be rested and any ligamentous or bony injury should be treated as indicated. Patients should undergo an extensive rehabilitation programme emphasising active and passive range of motion as well as strengthening of the rotator cuff, deltoid and periscapular musculature. Shoulder joint contracture should be avoided at all costs as a loss of shoulder mobility may ultimately affect functional outcome despite a return of axillary nerve function. If no axillary nerve recovery is observed by 3 to 4 months following injury, surgical exploration is indicated. Athletes who sustain injury to the axillary nerve have a variable prognosis for nerve recovery, although the return of function of the involved shoulder is typically good to excellent. We recommend that athletes who sustain axillary nerve injury may return to contact sport participation when they achieve full active range of motion of the shoulder and when shoulder strength is documented to be good to excellent by isometric or manual muscle testing.


Is reporting of recurrence data important in pancreatic cancer?
Therapeutic approaches to patients with pancreatic cancer have undergone a paradigm shift in recent years. However, little is known about the outcome of patients with recurrent pancreatic cancer who undergo treatment. The purpose of this study was to identify patients with recurrent pancreatic cancer and to determine whether treatment after recurrence had any effect on outcome. A review of all patients undergoing surgical resection with curative intent revealed 70 patients with documented recurrence and complete medical records. Patients were grouped into three categories: group 1 included those who received treatment after recurrence (n = 45), group 2 included those who were not offered treatment (n = 9), and group 3 included those with poor performance status who received no treatment (n = 16). The median overall survival for the three groups was 26, 18, and 14.5 months for groups 1, 2, and 3, respectively (P <.00001). The median survival after recurrence was 10 months, 6 months, and 1 month, respectively, for the three groups (P <.0001). This is the first series we are aware of that compares the outcomes of patients who received treatment after recurrence of pancreatic cancer with the outcomes of those who received no treatment. In this series, it seems that patients who were well enough to tolerate additional therapy had a longer survival than those who received supportive care only. This may be important in the analysis of adjuvant therapy trials of pancreatic cancer with survival as an end point.


11C-choline positron emission tomography/computerized tomography for preoperative lymph-node staging in intermediate-risk and high-risk prostate cancer: comparison with clinical staging nomograms.
Conventional imaging (CI) techniques are inadequate for lymph node (LN) staging in prostate cancer (PCa). To assess the accuracy of (11)C-Choline positron emission tomography/computerized tomography (PET/CT) for LN staging in intermediate-risk and high-risk PCa and to compare it with two currently used nomograms. From January 2007 to September 2007, 57 PCa patients at intermediate risk (n=27) or high risk (n=30) were enrolled at two academic centres. All patients underwent preoperative PET/CT and radical prostatectomy with extended pelvic LN dissection (PLND). Risk of LN metastasis (LNM) was assessed using available nomograms. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and number of correctly recognized cases for LNM detection at PET/CT were assessed. The accuracy of PET/CT for LNM detection was compared with the accuracy of nomograms for LNM prediction by using receiver operating characteristic (ROC) analysis. Fifteen patients (26%) had LNMs, and a total of 41 LNMs were identified. On a patient analysis, sensitivity, specificity, PPV, NPV, and number of correctly recognized cases at PET/CT were 60.0%, 97.6%, 90.0%, 87.2%, and 87.7% while, on node analysis, these numbers were 41.4%, 99.8%, 94.4%, 97.2%, and 97.1%. The mean diameter (in mm) of the metastatic deposit of true-positive LNs was significantly higher than that of false-negative LNs (9.2 vs 4.2; p=0.001). PET/CT showed higher specificity and accuracy than the nomograms; however, in pairwise comparison, the areas under the curve (AUCs) were not statistically different (all p values >0.05). In patients with intermediate-risk and high-risk PCa, (11)C-Choline PET/CT has quite a low sensitivity for LNM detection but performed better than clinical nomograms, with equal sensitivity and better specificity.


Candida dubliniensis encrustation of an obstructing upper renal tract calculus.
We present the case of a 53-year-old man, with a history of alcohol abuse, requiring intensive care unit admission, with an obstructing right upper renal calculus and Klebsiella pneumoniae urosepsis. Ureteroscopic treatment of this obstruction displayed a small calculus within the renal pelvis completely encapsulated within a fungal bezoar. Laboratory analysis of the fungal mass found it to be Candida dubliniensis.


[Periarticular knee osteotomies for pre-arthritic deformities in the frontal plane : Indications and surgical techniques].
Currently, periarticular knee joint osteotomies are an integral part of the treatment of early arthritic deformities in the knee joint. Analysis of the deformity is performed with a standardized full-leg standing x‑ray of both legs, as well as a lateral x‑ray of the knee joint that includes 2/3 of the proximal tibial shaft. An MRI examination of the knee joint is obtained to assess the articular cartilage, the ligaments and menisci. Torsion angle measurements with the CT/MRT supplement the diagnostics if necessary. Knowledge of normal physiological values and their standard deviations of the mechanical leg axis and the joint angles around the knee is obligatory. The osteotomy is performed as close as possible to the femoral and/or tibial deformity. Postsurgical deformities including pathological patella position or a significant difference in leg length must be prevented. A description of proximal tibia opening or closing wedge osteotomies based on the nomenclature of the joint angles by Paley is presented. The indications for the various osteotomy techniques in the coronary plane are discussed in detail.


Primary screw perforation or subsequent screw cut-out following proximal humerus fracture fixation using locking plates: a review of causative factors and proposed solutions.
The surgical treatment of proximal humerus fractures remains controversial primarily due to the high complication rate associated with the available fixation methods. In an attempt to reduce the incidence of serious complications and subsequent poor clinical outcomes, proximal humerus locking plates have become popular but even these implants cannot overcome the risk of complications, especially those associated with loss of fracture reduction and screw cut-out/migration through the humeral head. In an attempt to address these issues, we have reviewed the literature, investigating the most likely causes for these predominantly mechanical complications and propose technical solutions.


The Challenges of Switching Therapies in an Evolving Multiple Biosimilars Landscape: A Narrative Review of Current Evidence.
With the increasing availability of biosimilars, the practice of switching therapies for non-medical reasons between an originator biologic and an analogous biosimilar has become more common. The evidence to support this practice mostly comes from single-switch randomized controlled trials (RCTs) and real-world (RW) evidence studies. However, as more biosimilars of the same originator enter the market, multiple switching events between originators and biosimilars is becoming a reality, despite limited evidence to support the efficacy and safety of such practice. Some countries have established guidelines, policies, or laws related to interchangeability and/or automatic substitution, whereas others have left these practices unregulated or controlled by other components of the healthcare system. Collectively, guidelines on single non-medical switching are often vague, with even less focus given to multiple non-medical switching, leaving this practice mostly unregulated. This narrative review will first discuss the current regulatory perspectives on non-medical switching and challenges associated with switching therapies, particularly with the availability of multiple biosimilars. We will then review the current evidence from RCTs and RW studies in the light of three different multiple-switch scenarios currently taking place in clinical practice: switching between an originator and a single biosimilar, switching between biosimilars of the same originator, and the clinical practice of switching back to the originator (i.e., switchbacks) after a failure of the initial non-medical switch to the analogous biosimilar.


Extracting a large live freely floating cysticercosis cyst from the anterior chamber of the eye using visco expression technique: A case report.
Ocular involvement by cysticercosis is uncommon and rare in the anterior chamber. It can give rise to iridocyclitis which can be potentially blinding to the patient. The management is usually surgical. We report a case of 18-year-old girl with large cysticercosis cyst in the anterior chamber. The cyst was removed intact by viscoexpression technique from the anterior chamber of the eye and the patient achieved visual acuity of 6/9 post-operatively.


BiP mRNA expression is upregulated by dehydration in vasopressin neurons in the hypothalamus in mice.
The immunoglobulin heavy chain binding protein (BiP) is an endoplasmic reticulum (ER) chaperone that facilitates the proper folding of newly synthesized secretory and transmembrane proteins. Here we report that BiP mRNA was expressed in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in wild-type mice under basal conditions. Dual in situ hybridization in the SON and PVN demonstrated that BiP mRNA was expressed in almost all the neurons of arginine vasopressin (AVP), an antidiuretic hormone. BiP mRNA expression levels were increased in proportion to AVP mRNA expression in the SON and PVN under dehydration. These data suggest that BiP is involved in the homeostasis of ER function in the AVP neurons in the SON and PVN.


The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism.
Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions. To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism. We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up. Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 μmol/L (median); range 823-1647 μmol/L (normal value <50 μmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI. Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma.


Use of 2-dimensional cell monolayers and 3-dimensional microvascular networks on microfluidic devices shows that iron increases transendothelial adiponectin flux via inducing ROS production.
Iron excess is a risk factor for cardiovascular diseases and it is important to understand the effect of iron on vascular permeability, particularly for the transport of large metabolic hormones such as adiponectin. We used 2-dimensional monolayers of cultured human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells (HUVEC) as well as 3-dimensional microvascular networks to measure transendothelial flux. Iron supplementation reduced transendothelial electric resistance (TEER). Flux analysis indicated that under control conditions permeability of 70 kDa dextran and oligomeric forms of adiponectin were restricted in comparison with a 3 kDa dextran, however upon iron treatment permeability of the larger molecules was increased. The increased permeability and size-dependent trans-endothelial movement in response to iron was also observed in 3-dimensional microvascular networks. Mechanistically, the alteration in barrier functionality was associated with increased oxidative stress in response to iron since alterations in TEER and permeability were rescued when reactive oxygen species production was attenuated by pre-treatment with the antioxidant N-acetyl cysteine.]. Iron supplementation induced ROS production resulting in increased transendothelial permeability. Altogether, this suggests that the oxidative stress associated with iron excess could play an important role in the regulation of endothelial functionality, controlling hormone action in peripheral tissues by regulating the first rate-limiting step controlling hormone access to target tissues.


Simultaneous determination of intramolecular distance distributions and conformational dynamics by global analysis of energy transfer measurements.
Fluorescence energy transfer is widely used for determination of intramolecular distances in macromolecules. The time dependence of the rate of energy transfer is a function of the donor/acceptor distance distribution and fluctuations between the various conformations which may occur during the lifetime of the excited state. Previous attempts to recover both distance distributions and segmental diffusion from time-resolved experiments have been unsuccessful due to the extreme correlation between fitting parameters. A method has been developed, based on global analysis of both donor and acceptor fluorescence decay curves, which overcomes this extreme cross-correlation and allows the parameters of the equilibrium distance distributions and intramolecular diffusion constants to be recovered with high statistical significance and accuracy. Simulation studies of typical intramolecular energy transfer experiments reveal that both static and dynamic conformational distribution information can thus be obtained at a single temperature and viscosity.


[Extragenital endometriosis--abdominal manifestations and complications (a general review)].
This paper describes the aetiology, symptoms, diagnosis and therapeutic management of extragenital endometriosis and discusses the abdominal complications on the basis of the case histories of several patients with severe manifestation of this condition.


Prevalence of orofacial dysfunction in cerebral palsy and its association with gross motor function and manual ability.
To investigate the prevalence of orofacial dysfunction (OFD) and explore factors associated with OFD in young individuals with cerebral palsy (CP). We conducted a cross-sectional study on a population with CP in a Swedish county (132 individuals, mean age 14y 2mo [SD 4y 5mo], range 5-22y) using the Nordic Orofacial Test - Screening (NOT-S), Gross Motor Function Classification System (GMFCS), and Manual Ability Classification System (MACS). The NOT-S interview was completed by 129 individuals (76 males, 53 females) of whom 52 (30 males, 22 females) also agreed to complete the NOT-S examination. OFD occurred in at least one NOT-S domain in about 80% of the individuals and was present in all subdiagnoses, GMFCS levels, and MACS levels. Prevalence of OFD increased with increasing levels of GMFCS and MACS from level I=55% to level V=100%. Within the 12 NOT-S domains, the prevalence of OFD varied between 19% and 69%, wherein seven of them were at least 40%: 'Drooling', 'Nose breathing', 'Chewing and swallowing', 'Face at rest', 'Oral motor function', 'Speech', and 'Facial expression' (in ascending order). OFD is common in CP. The use of OFD screening in health service planning would assist detection of areas in need of further evaluation.


Promoting culturally appropriate interventions among vulnerable populations.
Evidence-based practice is critical for the improvement of interventions for culturally diverse and disadvantaged groups in the community. Nurses are strategically located in the line of patient care and must be grounded in knowledge related to the delivery of culturally appropriate intervention strategies. Although many of the health care disciplines have failed to conduct or disseminate culturally competent interventions among vulnerable populations, it is important to note that nursing has long been engaged in such activities. Clearly, all health care professionals must be provided with the tools that they need to give appropriate and effective care to patients and to conduct and disseminate relevant research about vulnerable populations. This chapter focuses on culturally competent interventions for ethnic and racial minority groups, women, and the mentally ill.


Microplastics in decapod crustaceans sourced from Australian seafood markets.
Microplastic abundance and characteristics were assessed in five decapod crustaceans purchased from seafood markets and collected in coastal waters around Australia (South Australia, New South Wales, Queensland, Northern Territory, and Western Australia). Three species of prawns (king, banana and tiger prawns) and two species of crabs (blue-swimmer and mud crabs) were analysed. Muscle tissues and gastro-intestinal tracts in prawns, and gastro-intestinal tracts in crabs, were chemically digested, with microplastic identification verified using Fourier Transform Infrared spectroscopy. Forty-eight percent of crustaceans contained microplastics. Prawns and crabs had 0.8 ± 0.1 and 1.6 ± 0.1 pieces per individual, respectively, with spatial patterns evident. Microplastics were predominantly fibres (98%) of blue (58%) and black (24%) colours with polyolefin including polyester the most prevalent polymers. Overall, compared to a systematic review we performed of microplastics in decapod crustaceans worldwide, microplastic loads in crustaceans from Australia were in the lower range of plastic contamination.


Pesticide poisoning cases in Ankara and nearby cities in Turkey: an 11-year retrospective analysis.
Since they are available in open markets and pharmacies, pesticides have been widely used all over the country. (Un)intentional poisoning with these compounds is one of the most common causes of chemical poisoning, especially in rural agricultural areas. Pesticide poisonings reported by various countries showed that it is a worldwide health problem with 250,000-370,000 associated deaths each year. In this study, medico-legal deaths between the years 2001 and 2011 in Ankara and nearby cities in Turkey were investigated retrospectively. The autopsies were partly carried out by Ankara Branch of Council of Forensic Medicine. Data were collected from reports of the Morgue Department whose toxicological analyses were performed in the Chemistry Department. The data revealed that 70 cases out of 10,720 autopsied ones had been attributed to fatal pesticide poisoning. The age range was 1-80 years (mean ± SD, 41.33 ± 17.42 years). Most of the cases (60%) were reported from Ankara. Insecticides were the most common (94%) cause of fatal pesticide poisonings, most of them (63%) being organophosphate insecticides. The percentages of pesticide-induced deaths are quite high in our society and should therefore not be underestimated. Accordingly, intensive efforts to reduce occupational and intentional pesticide poisonings are urgently needed in Ankara and nearby cities.


Effectiveness of health care workers and peer engagement in promoting access to health services among population at higher risk for HIV in Tanzania (KPHEALTH): study protocol for a quasi experimental trial.
While there are indications of declining HIV infection rates in the general population globally, Tanzania included, men who have sex with men (MSM), female sex workers (FSW) and people who inject drugs (PWID), now called Key Populations (KP) for HIV epidemic have 2-20 times higher infections rates and contributes up to 30% of new HIV infection. Tanzania have developed a Comprehensive Guideline for HIV prevention among key population (CHIP) to address the epidemic among KPs. However, these populations are stigmatized and discriminated calling for innovative approaches to improve access to CHIP. This project seeks to test the effectiveness of healthcare workers and peer-to-peer engagement in promoting access to CHIP among HIV at risk populations in Tanzania. A quasi-experimental design involving Dar es Salaam City as an intervention region and Tanga as a control region will be done. Using respondent driven sampling, 1800 at risk population (900 from Intervention site and 900 from control site) will be recruited at baseline to identify pull and push factors for health services access. Stakeholder's consultation will be done to improve training contents for CHIP among health care workers and peers. Effectiveness of healthcare workers training and peer engagement will be tested using a quasi-experimental design. The results are expected to co-create service provision and improve access to services among KPs as a human right, reverse HIV infection rates among KPs and the general population, and improve social and economic wellbeing of Tanzanian. Retrospectively registered on 28th August, 2019 with International Standard Randomized Clinical Trial Number ( ISRCTN11126469 ).


Contrast-enhanced computed tomography for demonstration of bilateral renal cortical necrosis.
Bilateral renal cortical necrosis as a rare form of acute renal failure was encountered in two patients with sepsis and acute renal failure. In both cases contrast-enhanced computed tomography showed characteristic findings: absent specification of the renal cortex and enhancement of subcapsular and juxtamedullary areas and of the medulla without excretion of contrast medium. Establishing an early diagnosis and visualizing the extent of renal cortical necrosis by means of contrast-enhanced computed tomography allow a prognostic evaluation of renal function and further planning of therapy.


The epidemiology and clinical implications of genetic variation in prostate cancer.
There is strong evidence of a genetic predisposition to prostate cancer. Recent advances in genetic sequencing technologies have permitted significant advances in the field. This article reviews the genetic basis underlying prostate cancer, and highlights the epidemiology and potential clinical usefulness of both rare and common genetic variations. In addition, recent findings related to the understanding of prostate cancer genetics are discussed.


Invasive meningococcal capsular group Y disease, England and Wales, 2007-2009.
Enhanced national surveillance for invasive meningococcal disease in England and Wales identified an increase in laboratory-confirmed capsular group Y (MenY) disease from 34 cases in 2007 to 44 in 2008 and 65 in 2009. For cases diagnosed in 2009, patient median age at disease onset was 60 years; 39% of patients had underlying medical conditions, and 19% died. MenY isolates causing invasive disease during 2007-2009 belonged mainly to 1 of 4 clonal complexes (cc), cc23 (56% of isolates), cc174 (21%), cc167 (11%), and cc22 (8%). The 2009 increase resulted primarily from sequence type 1655 (cc23) (22 cases in 2009, compared with 4 cases each in 2007 and 2008). cc23 was associated with lpxL1 mutations and meningitis in younger age groups (<25 years); cc174 was associated with nonmeningitis, particularly pneumonia, in older age groups (>65 years). The increase in MenY disease requires careful epidemiologic and molecular monitoring.


Adverse birth outcomes in Victoria, Australia in association with maternal exposure to low levels of ambient air pollution.
The relationship between maternal exposure to air pollution and birth outcomes is not well characterised where ambient air pollution is relatively low. We aimed to explore the association between maternal exposure to ambient nitrogen dioxide (NO2) and fine particulate matter (PM2.5) and a range of birth outcomes in Victoria, Australia. Secondary aims were to explore whether obstetric conditions, such as gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy, were effect modifiers in observed relationships. We included all singleton births occurring in Victoria, Australia from 1st March 2012 to 31st December 2015 using routinely collected government data. Outcomes included birth weight, small for gestational age (SGA), term low birth weight (tLBW), large for gestational age (LGA), and spontaneous preterm birth (sPTB). We estimated exposure to annual ambient NO2 and PM2.5 concentrations, assigned to maternal residence at time of birth. Confounders included maternal, meteorological and temporal variables. Multivariable linear regression and log-binomial regression were used for continuous and dichotomous outcomes, respectively. There were 285,594 births during the study period. Average NO2 exposure was 6.0 parts per billion (ppb, median 5.6; interquartile range (IQR) 3.9) and PM2.5 was 6.9 μg/m3 (median 7.1, IQR 1.3). IQR increases in ambient NO2 and PM2.5 were associated with fetal growth restriction, including decrements in birth weight (NO2 β -22.8 g; 95%CI -26.0, -19.7; PM2.5 β -14.8 g; 95%CI -17.4, -12.2) and increased risk of SGA (NO2 RR 1.08; 95%CI 1.06, 1.10; PM2.5 RR 1.05; 95%CI 1.04, 1.07) and tLBW (NO2 RR 1.06; 95%CI 1.01, 1.10; PM2.5 RR 1.04; 95%CI 1.03, 1.08). Women with GDM and hypertensive disorders of pregnancy had greater decrements in birth weight in association with pollutant exposure. In this exploratory study using an annual metric of exposure, maternal exposure to low-level ambient air pollution was associated with fetal growth restriction, which carries substantial public health implications.


Carmustine-induced phosphatidylserine translocation in the erythrocyte membrane.
The nitrosourea alkylating agent, carmustine, is used as chemotherapeutic drug in several malignancies. The substance triggers tumor cell apoptosis. Side effects of carmustine include myelotoxicity with anemia. At least in theory, anemia could partly be due to stimulation of eryptosis, the suicidal death of erythrocytes, characterized by cell shrinkage and breakdown of phosphatidylserine asymmetry of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]i). The present study tested whether carmustine triggers eryptosis. To this end [Ca²⁺]i was estimated from Fluo3 fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin V binding, and hemolysis from hemoglobin release. As a result a 48 h exposure to carmustine (≥25 µM) significantly increased [Ca²⁺]i, decreased forward scatter and increased annexin V binding. The effect on annexin V binding was significantly blunted in the absence of extracellular Ca²⁺. In conclusion, carmustine stimulates eryptosis at least partially by increasing cytosolic Ca²⁺ activity.


Phosphorylation and function of DGAT1 in skeletal muscle cells.
Aberrant intramuscular triacylglycerol (TAG) storage in human skeletal muscle is closely related to insulin insensitivity. Excessive lipid storage can induce insulin resistance of skeletal muscle, and under severe conditions, lead to type 2 diabetes. The balance of interconversion between diacylglycerol and TAG greatly influences lipid storage and utilization. Diacylglycerol O-acyltransferase 1 (DGAT1) plays a key role in this process, but its activation and phosphorylation requires further dissection. In this study, 12 putative conserved phosphorylation sites of DGAT1 were identified by examining amino acid conservation of DGAT1 in different species. Another 12 putative phosphorylation sites were also found based on bioinformatics predictions and previous reports. Meanwhile, several phosphorylation sites of DGAT1 were verified by phosphorylation mass spectrometry analysis of purified DGAT1 from mouse myoblast C2C12 cells. Using single point mutations, a regulatory role of 3 putative phosphorylation sites was dissected. Finally, using truncation mutations, a potential domain of DGAT1 that was involved in the regulation of enzymatic activity was revealed. This study provides useful information for further understanding DGAT1 activity regulation.


Increased activity of rat liver messenger RNA and of albumin messenger RNA modulated by thioacetamide.
Administration of thioacetamide to rats was found to increase the activity of liver messenger RNA in the wheat germ protein synthesis assay. The synthesis of total protein was increased about 2.5-fold after 4 days of treatment. The treatment was associated with an increase in the relative quantity of polyadenylic acid-containing RNA. Immunoprecipitation studies showed that albumin synthesis directed by the messenger RNA was increased disproportionately, reaching a level 5 to 6 times the control after 4 days of thioacetamide administration.


Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors.
This paper describes SAR studies involved in the transformation of the NSAID meclofenamic acid into potent and selective cyclooxygenase-2 (COX-2) inhibitors via neutralization of the carboxylate moiety in this nonselective COX inhibitor.


Magnetic resonance nanoparticles for cardiovascular molecular imaging and therapy.
Molecular vascular imaging represents a novel tool that promises to change the current medical paradigm of 'see and treat' to a 'detect and prevent' strategy. Nanoparticle agents, such as superparamagnetic nanoparticles and perfluorocarbon nanoparticle emulsions, have been developed for noninvasive imaging, particularly for magnetic resonance imaging. Designed to target specific epitopes in tissues, these agents are beginning to enter clinical trials for cardiovascular applications. The delivery of local therapy with these nanoparticles, using mechanisms such as contact-facilitated drug delivery, is in the advanced stages of preclinical research. Ultimately, combined diagnostic and therapeutic nanoparticle formulations may allow patients to be characterized noninvasively and segmented to receive custom-tailored therapy. This review focuses on recent developments of nanoparticle technologies with an emphasis on cardiovascular applications of magnetic resonance imaging.


Education for health: case studies of two multidisciplinary MPH/MSc public health programmes in the UK.
Amidst the winds of change that are blowing across the UK public health (PH) landscape in relation to the essential abilities and national standards that are required for the 'art and science' of PH, the preparation for a new cadre of 'PH professionals' is already underway. Several postgraduate masters programmes in public health (MPH) have taken on board the challenge of addressing the requisite sets of skills and expertise as a guide to their content and delivery. Although there are recommendations regarding teaching PH to undergraduate medical students, little consensus seems to exist on teaching postgraduate PH to non-medically qualified professionals, health managers and administrators. Employing a case study approach, this article analyses the methods used, philosophies and processes, structure and organization, outcomes to date, and lessons learnt from MPH programmes implemented at two institutions in the UK. The programmes have been initiated recently, and have had the opportunity to take on board the recent national guidelines about training standards. The findings indicate that preparatory work of the programmes, and the challenges and strengths in meeting the recent policy developments in PH training are pertinent points. The MPH programmes highlight key issues in interprofessional education and its purpose, its process and its outcomes in relation to multidisciplinary specialist practice. These programmes provide a variety of models for others wishing to develop or restructure their postgraduate PH teaching programmes. The finalization of the national standards for specialist practice in PH in the UK is encouraged, along with clearer working definitions of the domains of expertise required. Collectively, attention to these measures can ensure that the processes which teaching programmes embrace to refine their content and delivery will equip tomorrow's professionals with PH knowledge and skills.


Alkali-metal mediated reactivity of a diaminobromoborane: mono- and bis-borylation of naphthalene versus boryl lithium or hydroborane formation.
Reaction of lithium with PDABBr [PDA = C(6)H(4)-1,2-(NTripp)(2), Tripp = 2,4,6-Pr(i)(3)C(6)H(2)] and naphthalene afforded 2- and 2,6-borylated naphthalenes; conversely, use of high-sodium lithium (0.5% Na) afforded the lithium boryl [(PDAB)Li(THF)(2)]; this work establishes that main group reagents can achieve selective borylations of fused polycyclic aromatics under mild conditions in good yields.


Properties of epinephrine-induced activation of cardiac adenosine 3',5'-monophosphate-dependent protein kinase.
The effects of epinephrine on cyclic AMP content and protein kinase activity were examined in an in situ rat heart preparation. Bolus injection of epinephrine into the superior vena cava caused an increase in the activity ratio (-cyclic AMP/"cyclic AMP) of 12 000 X g supernatant protein kinase. The increase was significant within 5 s and maximal in 10 s. Epinephrine produced a dose-dependent increase in both protein kinase activity ratio and cyclic AMP content. The increases in both parameters exhibited a high degree of correlation. The increase in protein kinase activity ratio observed with low doses of epinephrine (less than or equal to 1 microgram/kg) resulted from an increase in independent protein kinase activity (-cyclic AMP) without a change in total protein kinase activity (+cyclic AMP). However, the increase in the activity ratio observed with higher doses of epinephrine (greater than 1 microgram/kg) was due mainly to a decrease in total protein kinase activity rather than a further increase in independent protein kinase activity. The loss of supernatant total protein kinase activity could be accounted for by an increase in activity associated with particulate fractions obtained from the homogenates. A similar redistribution of protein kinase could be demonstrated by the addition of cyclic AMP to homogenates prepared from hearts not stimulated with epinephrine. These results demonstrate that epinephrine over a wide dose range produces a parallel increase in the content of cyclic AMP and the activation of soluble protein kinase. The findings also suggest that protein kinase translocation to particulate material may depend on the degree of epinephrine-induced enzyme activation.


Robotic-assisted laparoscopic cholecystectomy.
We report a case of laparoscopic cholecystectomy that was performed using a robotic surgical system. A 70-year-old woman underwent laparoscopic robotic cholecystectomy ZEUS, the robotic system used in our study, has three interactive robotic arms fixed to the side of the operating table. The arms are controlled by the surgeon, who sits at a remote computer console. The surgeon's movements can be scaled down, and tremor is filtered out. The robotic-assisted laparoscopic cholecystectomy was completed in 42 min. The time to set up the robot was 22 mins. All of the surgically reproducible robotic maneuvers were performed without any particular difficulty. The robotic movements were stable, accurate, and reliable, as well as easy to control with precision. Our preliminary experience indicates that robotic laparoscopic cholecystectomy is safe and can be as fast as conventional laparoscopic cholecystectomy. However, further clinical applications of robotic surgery are needed to confirm this observation.


Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin-3 and BM-40/SPARC genes.
The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas.


Responsiveness and accountability in long-term care: strategies for policy development and empowerment.
This paper presents a model for engaging planners, service providers and consumers in a collaborative process of improving quality of life in long-term care facilities, discussing the implications of this approach for standards of care and policy development. This empowerment model was refined and tested in a large system of skilled-nursing-care facilities using a matched-pair comparison group design. The rationale, theory base and the relationship of the empowerment model to current concepts of health promotion are shown. Subsequent follow-up indicated examples of the impact of the model on broader aspects of public policy.


Polysaccharide-based electroconductive hydrogels: Structure, properties and biomedical applications.
Architecting an appropriate platform for biomedical applications requires setting a balance between simplicity and complexity. Polysaccharides (PSAs) play essential roles in our life in food resources, structural materials, and energy storage capacitors. Moreover, the diversity and abundance of PSAs have made them an indispensable part of food ingredients and cosmetics. PSA-based hydrogels have been extensively reviewed in biomedical applications. These hydrogels can be designed in different forms to show optimum performance. For instance, electroactive PSA-based hydrogels respond under an electric stimulus. Such performance can be served in stimulus drug release and determining cell fate. This review classifies and discusses the structure, properties, and applications of the most important polysaccharide-based electroactive hydrogels (agarose, alginate, chitosan, cellulose, and dextran) in medicine, focusing on their usage in tissue engineering, flexible electronics, and drug delivery applications.


Mycobacterium avium infection and immune restoration disease after highly active antiretroviral therapy in a patient with HIV and normal CD4+ counts.
A patient infected with HIV who had normal CD4+ T-cell counts developed Mycobacterium avium complex lymphadenitis associated with restoration of delayed-type hypersensitivity responses to mycobacterial antigens after commencing highly active antiretroviral therapy (Mycobacterium avium immune restoration disease). This case provides further evidence that delayed-type hypersensitivity responses and CD4+ T-cell counts are independent indicators of the cellular immune defects induced by HIV infection and that Mycobacterium avium immune restoration disease may occur in patients with persistently normal CD4+ T-cell counts.


Functional outcome of total knee arthroplasty after periprosthetic distal femoral fracture.
A prospective matched cohort study was performed to compare functional outcomes between 28 patients with periprosthetic femoral fractures and 28 with primary total knee arthroplasties (TKA). The mean follow-up was 6.7 years (range, 5-9). Radiographic osteopenia was a predisposing factor, but not notching, body mass index, or preinjury knee scores or motion. At last follow-up, the Knee Society scores, knee motion, Womac, and SF-12 were significantly lower in the fracture group, and were significantly decreased compared to the preinjury status. We found that periprosthetic distal femoral fracture after TKA worsens functional outcomes at the medium term, but arthroplasty complication and survival rates were similar in both groups.


Pooled human platelet lysate versus fetal bovine serum-investigating the proliferation rate, chromosome stability and angiogenic potential of human adipose tissue-derived stem cells intended for clinical use.
Because of an increasing focus on the use of adipose-derived stem cells (ASCs) in clinical trials, the culture conditions for these cells are being optimized. We compared the proliferation rates and chromosomal stability of ASCs that had been cultured in Dulbecco's modified Eagle's Medium (DMEM) supplemented with either pooled human platelet lysate (pHPL) or clinical-grade fetal bovine serum (FBS) (DMEM(pHPL) versus DMEM(FBS)). ASCs from four healthy donors were cultured in either DMEM(pHPL) or DMEM(FBS), and the population doubling time (PDT) was calculated. ASCs from two of the donors were expanded in DMEM(pHPL) or DMEM(FBS) and cultured for the final week before harvesting with or without the addition of vascular endothelial growth factor. We assessed the chromosomal stability (through the use of array comparative genomic hybridization), the expression of ASC and endothelial surface markers and the differentiation and angiogenic potential of these cells. The ASCs that were cultured in pHPL exhibited a significantly shorter PDT of 29.6 h (95% confidence interval, 22.3-41.9 h) compared with those cultured in FBS, for which the PDT was 123.9 h (95% confidence interval, 95.6-176.2 h). Comparative genomic hybridization analyses revealed no chromosomal aberrations. Cell differentiation, capillary structure formation and cell-surface marker expression were generally unaffected by the type of medium supplement that was used or by the addition of vascular endothelial growth factor. We observed that the use of pHPL as a growth supplement for ASCs facilitated a significantly higher proliferation rate compared with FBS without compromising genomic stability or differentiation capacity.


In vitro photodynamic effect of aluminum tetrasulfophthalocyanines on melanoma skin cancer and healthy normal skin cells.
Photodynamic therapy is a medical treatment that uses an inactive dye/drug and lasers as a light source to activate the dye/drug to produce a toxic form of oxygen that destroys the cancer cells. This study aimed at investigating the cytotoxic effects of different concentrations of aluminum tetrasulfophthalocyanines in its inactive and active state (laser induced) on melanoma skin cancer cells, healthy normal skin fibroblast and keratinocyte cells. Experimentally, 3 × 10⁴ cells/ml were seeded in 24-well plates before treatment with different concentrations of aluminum tetrasulfophthalocyanines. After 2h, cells were irradiated with a light dose of 4.5 J/cm². Post-irradiated cells were incubated for 24h before cell viability was measured using the CellTiter-Blue Viability Assay. Results showed that aluminum tetrasulfophthalocyanines at high concentrations were cytotoxic to melanoma cells in the absence of laser activation. In the presence of laser activation of aluminum tetrasulfophthalocyanines at a concentration of 40 μg/ml decreased cell viability of melanoma cells to 45%, fibroblasts to 78% and keratinocytes to 73%. At this photosensitizing concentration of aluminum tetrasulfophthalocyanines the efficacy of the treatment light dose 4.5 J/cm² and the cell death mechanism induced by photoactivated aluminum tetrasulfophthalocyanines was evaluated. A light dose of 4.5 J/cm² was more efficient in killing a higher number of melanoma cells and a lower number of fibroblast and keratinocyte cells than the other light doses of 2.5 J/cm², 7.5 J/cm² and 10.5 J/cm². Apoptosis features such as blebbing, nucleus condensation, nucleus fragmentation and the formation of apoptotic bodies were seen in the photodynamic therapy treated melanoma skin cancer cells. This in vitro photodynamic therapy study concludes that using aluminum tetrasulfophthalocyanines at a photosensitizing concentration of 40 μg/ml in combination with a laser dose of 4.5 J/cm² was potentially lethal for melanoma skin cancer cells and less harmful for the normal healthy skin cells.


Sequential domain refolding of pig muscle 3-phosphoglycerate kinase: kinetic analysis of reactivation.
Slow refolding of 3-phosphoglycerate kinase is supposed to be caused mainly by its domain structure: folding of the C-terminal domain and/or domain pairing has been suggested to be the rate-limiting step. A slow isomerization has been observed during refolding of the isolated C-terminal proteolytic fragment (larger than the C-domain of about 22 kDa by 5 kDa) of the pig muscle enzyme. Here, the role of this step in the reformation of the active enzyme species is investigated. The time course of reactivation during refolding of 3-phosphoglycerate kinase or its complementary proteolytic fragments (residues 1-155 and 156-416) exhibits a pronounced lag-phase indicating the formation of an inactive folding intermediate. The whole process, which leads to a high (60-85%) recovery of the enzyme activity, can be described by two consecutive first-order steps (with rate constants 0.012+/-0.0035 and 0.007+/-0.0020 s(-1)). A prior renaturation of the C-fragment restores MgATP binding by the C-domain and abolishes the faster step, allowing the separate observation of the slower step. In accordance with this, refolding of the C-domain as monitored by a change in Trp fluorescence occurs at a rate similar to that of the faster step. In addition to the previously observed slow refolding step (0.012 s(-1)) within the C-domain, the occurrence of another slow step (0.007 s(-1)), probably within the N-domain, is detected. The independence of the folding of the C-domain is demonstrated whereas, from the comparative kinetic analysis, independent folding of the N-domain looks less probable. Our data are more compatible with a sequential, rather than random, mechanism and suggest that folding of the C-domain, leading to an inactive intermediate, occurs first, followed by folding of the N-domain.


B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer.
This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.


The use of acridine orange as a rapid method for the quantitation of bacteremia in laboratory animals.
A rapid technique has been developed to quantitate the degree of bacteremia in laboratory animals. Direct staining of blood smears with acridine orange and enumeration using fluorescent microscopy allowed quantitation of Haemophilus influenzae in blood at densities from 10(5) to 10(8) cfu/ml. This technique will facilitate the accuracy with which therapeutic trials are conducted in laboratory models of infection.


Arterioureteral fistula--a rare complication of ureterolithotomy: treatment with embolization.
Fistula formation between a ureteral branch of a renal artery and the ipsilateral ureter is rare. We describe a case that followed ureterolithotomy of an impacted stone. Selective angiography with embolization of the bleeding branch was curative.


A Rare Presentation of Plexiform Schwannoma of the Thumb.
Plexiform schwannomas are rare, benign, neural crest-derived tumors that commonly occur in the hand and upper extremities. They may be sporadic or associated with neurofibromatosis type 2. Although previous literature has described plexiform schwannomas occurring in fingers, nerve and tendon sheaths, and intraosseous lesions, this is the first known case of a plexiform schwannoma of the thumb. This is a case of a growing, painless, subungual mass of the thumb in a 54-year-old patient. After surgical excision and subsequent immunohistochemical examination, the patient was diagnosed with a plexiform schwannoma. This highlights the importance of maintenance a broad differential before surgery and obtaining a proper diagnosis using histopathology.


Circadian rhythm in c-fos protein expression in the rat adrenal cortex.
The circadian variation in the expression of c-fos protein(s) in the adrenal cortex of adult rats was investigated immunocytochemically. The animals were maintained in standard laboratory facilities with a 12:12 h light:dark schedule (07.00-19.00 h) until sacrificed. The number of c-fos immunoreactive (c-fos IR) cells was statistically constant in the zona fasciculata and zona reticulata at 20.00 h and 24.00 h, and 04.00 h, but was decreased to 52% at 08.00 h and to 18% at 12.00 h, respectively, when compared to the 24.00 h value. At 16.00 h, the number of c-fos IR cells was increased again to 63% of the 24.00 h value. In the zona granulosa c-fos IR was observed only at 20.00 h and 24.00 h. Administration of dexamethasone, a potent inhibitor of ACTH release, significantly reduced the number of c-fos IR cells. As the circadian rhythm of c-fos expression in the adrenal cortex correlates to that reported for ACTH secretion from the pituitary, the results suggest that c-fos gene is involved in mediating physiological ACTH-induced responses in the adrenal cortical cells.


Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours.
Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.


The electromicrophysiology of delta waves induced by systemic atropine.
Delta waves in the EEG can be induced by the intravenous administration of atropine. In cats we have investigated with several computer averaging programs the relationship of extracellular unit discharge to the EEG on the surface and within the cortex. We have also studied the laminar profiles and the vertical current density profiles of these slow waves. Our results indicate that surface-positive delta waves are related to events associated with excitation of cortical neurons, while surface-negative delta waves are related to a decreased probability of unit firing suggesting the possibility of inhibition. Laminar analysis of atropine-induced slow waves indicated that these were probably generated by pyramidal cells in a similar way to delta waves induced by brain lesions. These results suggest that a disturbance in cholinergic input to the cortex might be responsible for delta waves in the EEG.


Differential response of satellite cells and embryonic myoblasts to a tumor promoter.
Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) reversibly suppressed myotube formation and expression of acetylcholine receptors in cultures of Day 15 mouse embryo presumptive myoblasts, but was totally ineffective in cultures of adult mouse satellite cells. A subpopulation of TPA-resistant myogenic cells became apparent in cultures prepared from older embryos or newborn mice. Thus, limb presumptive myoblasts are a heterogeneous population, and part of the distinct TPA-resistant subpopulation may represent satellite cell precursors.


Endogenous prostaglandin F2α concentrations in bovine whole semen, seminal plasma, and extended semen.
A series of experiments were conducted to quantify PGF2α in bovine semen, seminal plasma, and extended semen, and to determine if PGF2α was synthesized or released during extension of bovine semen. Concentrations of PGF2α were measured in paired samples of whole and extended semen from beef and dairy bulls. Concentrations of PGF2α did not differ between beef and dairy (mean±SEM, 273.8±42.8 vs. 210.3±18.5 pg/mL, respectively; P=0.12), but tended (P=0.08) to be greater for whole compared with extended semen (255.5±29.8 vs. 194.5±17.0 pg/mL). Whole semen was extended at eight dilution rates (regardless of initial sperm concentration), using a diluent consisting of two fractions. Samples collected after each dilution step resulted in four subsamples. Concentrations of PGF2α in subsamples decreased (P<0.001) at higher dilution rates and later steps of extension. Subsequently, whole semen and seminal plasma were extended at three dilution rates. Initial PGF2α concentration was greater (P<0.001) for whole semen compared with seminal plasma. During extension, PGF2α synthesis or release resulted in less disparity, but the amount synthesized or released was greater (P=0.03) for semen compared with seminal plasma. We concluded that synthesis or release of PGF2α during extension resulted in concentrations similar to whole semen.


Characteristics of Laboratory Confirmed Ethylene Glycol and Methanol Exposures Reported to a Regional Poison Control Center.
Ethylene glycol (EG) and methanol (MET) exposures are rare but can cause significant morbidity and mortality. Though frequently treated similarly, EG and MET exposures have characteristics that are not well differentiated in the literature. We sought to describe the clinical characteristics of EG and MET exposures, confirmed with quantitative serum levels. An IRB-approved retrospective review of the University of Kansas Health System Poison Control Center database from July 2005 to July 2015 identified all EG/MET exposures evaluated at a health care facility. Initial measurements were EG/MET levels, serum pH, serum creatinine, anion gap, serum ethanol level, max anion gap, max osmolar gap, therapy performed (hemodialysis, fomepizole, ethanol) and death. The search identified 75 cases, with 59 cases having only detectable EG levels and 15 cases having only detectable MET levels. The average EG level was 126 mg/dL (range 5 - 834). The average detectable methanol level was 78 mg/dL (range 5 - 396). The average maximum anion gap of the EG positive group was 20 mEq/L (range 8 - 35). The average maximum anion gap of the MET positive group was 14 mEq/L (range 6 - 34). One death was reported in the EG positive group, with an initial level of 266 mg/dL. In this study of EG/MET exposures, EG exposures were more common than MET exposures, but they had similar demographics, laboratory findings, and interventions. Continued studies are warranted to characterize these uncommon exposures further.


The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex.
Phosphoinositide (PI) 3-kinase is required for most insulin and insulin-like growth factor (IGF) 1-dependent cellular responses. The p85 regulatory subunit of PI 3-kinase is required to mediate the insulin-dependent recruitment of PI 3-kinase to the plasma membrane, yet mice with reduced p85 expression have increased insulin sensitivity. To further understand the role of p85, we examined IGF-1-dependent translocation of p85alpha by using a green fluorescence protein (GFP)-tagged p85alpha (EGFP-p85alpha). In response to IGF-1, but not to PDGF signaling, EGFP-p85alpha translocates to discrete foci in the cell. These foci contain the insulin receptor substrate (IRS) 1 adaptor molecule, and their formation requires the binding of p85 to IRS-1. Surprisingly, monomeric p85 is preferentially localized to these foci compared with the p85-p110 dimer, and these foci are not sites of phosphatidylinositol-3,4,5-trisphosphate production. Ultrastructural analysis reveals that p85-IRS-1 foci are cytosolic protein complexes devoid of membrane. These results suggest a mechanism of signal down-regulation of IRS-1 that is mediated by monomeric p85 through the formation of a sequestration complex between p85 and IRS-1.


Multimorbidity and loneliness. Longitudinal analysis based on the GSOEP.
Our aim was to examine the longitudinal association between multimorbidity and loneliness in the general adult population (and in different age groups) in Germany. Longitudinal data were used from the German Socio-Economic Panel (n= 44,385 observations in the years 2013 and 2017) - a nationally representative sample including adults aged 18 years and above. Respondents are re-surveyed annually. Loneliness was quantified using the established UCLA-3. Multimorbidity was defined as the coexistence of two or more conditions and was indicated by a list containing 13 somatic and mental diseases. Asymmetric linear fixed effects regressions (also stratified by three age groups: 18 to 44 years; 45 to 64 years, 65 years and older) were used to examine the association between the onset and end of multimorbidity as well as loneliness. After adjusting for possible confounders, regression analysis revealed that the onset of multimorbidity is associated with an increase in loneliness in the total sample (β = 0.07, p < 0.001) and among individuals aged 65 years and older (β = 0.13, p < 0.001), whereas no significant association was found in the other age groups. The end of multimorbidity was not associated with loneliness neither in the total group nor in the individual age groups. This study revealed an association between the onset of multimorbidity and higher loneliness particularly among individuals in late life. Thus, preventing or delaying multimorbidity may be beneficial to avoid loneliness among older adults.


The relationship between obstructive sleep apnea, nocturia, and daytime overactive bladder syndrome in women.
The purpose of this study was to corroborate the association between obstructive sleep apnea (OSA) and nocturia in a clinical sample of urogynecologic patients and to explore whether night-time urine concentration predicts the presence of OSA. Patients with nocturia and control subjects underwent a home sleep study, completed validated nocturia questionnaires, and provided evening and morning urine specimens that were analyzed for osmolarity. Twenty-one patients with nocturia (16 of whom also had daytime overactive bladder [OAB] symptoms) and 10 control subjects were studied. OSA was present in 17 of 21 women (81%) with nocturia: 13 women (81%) with OAB, 4 women (80%) with nocturia/no OAB, and 4 control subjects (40%; P < .001). The percentage of rapid eye movement sleep time was correlated inversely with nocturic frequency (rho = -.51; P < .004). The presence of diluted nighttime urine in a patient with nocturia was 88% sensitive for the presence of OSA. We should consider a diagnosis of OSA in all patients with nocturia, even those patients with daytime OAB.


Atomic force microscopy of an organic monolayer.
Atomic force microscope images of polymerized monolayers of n-(2-aminoethyl)-10,12-tricosadiynamide revealed parallel rows of molecules with a side-by-side spacing of approximately equal to 0.5 nanometer. Forces used for imaging (10(-8) newton) had no observable effect on the polymer strands. These results demonstrate that atomic force microscope images can be obtained for an organic system.


Effect of fasting and feeding a high-sucrose, fat-free diet on the synthesis of hepatic glycerolipids in vivo and in isolated hepatocytes.
1. The synthesis of glycerolipids from a number of radioactive precursors, such as [2-3H] glycerol, [32P]phosphate, [Me-14C]choline and [1,2-14C2]ethanolamine proceeds in enzymatically isolated hepatocytes with a specificity that agrees very well with that observed in the liver in vivo. 2. The nutritional state of the rat has a profound influence on the glycerolipid metabolism of isolated hepatocytes. Fasting strongly decreased the incorporation of glycerol via sn-glycerol 3-phosphate into triacylglycerols whereas the formation of phosphatidylcholine and, particularly, phosphatidylethanolamine was much less affected by food deprivation. Refeeding a high-sucrose, fat-free diet caused a tremendous increase in the synthesis of diacylglycerols and triacylglycerols to values exceeding those found in hepatocytes from normally fed animals. The formation of phosphatidylcholine increased more slowly and the synthesis of phosphatidylethanolamine was even depressed by refeeding a high-sucrose, fat-free diet. 3. Alteration of the nutritional state resulted in similar changes in the amounts and metabolism of hepatic glycerolipids in vivo. The formation and, consequently, the amount of diacyglycerol and triacylglycerol were decreased by fasting and increased to values above normal in rats refed a high-sucrose, fat-free diet. The formation and the amounts of phospholipids in the liver decreased slightly by fasting which was mainly due to a decrease in phosphatidylcholine. Refeeding caused a significant increase in the formation and amount of phosphatidylcholine. The amount of phosphatidylethanolamine was even further diminished by feeding a high-sucrose, fat-free diet to 48-h-fasted rats. 4. These results show that the alterations, induced in the in vivo metabolism of hepatic glycerolipids, by changes of the dietary state, are also reflected in the isolated hepatocytes. This finding strengthens the potential significance of isolated hepatocytes in studies on the regulation of hepatic lipid metabolism.


Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections.
Necrotising soft-tissue infections due to group A streptococcus (GAS) are rare (about 0.2 cases per 100000 people). The disease progresses rapidly, causing severe necrosis and hydrolysis of soft tissues. Histopathological analysis of necrotic tissue debrided from two patients (one with necrotising fasciitis and one with myonecrosis) showed large quantities of bacteria but no infiltrating neutrophils. We aimed to investigate whether the poor neutrophil chemotaxis was linked with the ability of group A streptococcus (GAS) to degrade host chemokines. We did RT-PCR, ELISA, and dot-blot assays to establish whether GAS induces synthesis of interleukin 8 mRNA, but subsequently degrades the released chemokine protein. Class-specific protease inhibitors were used to characterise the protease that degraded the chemokine. We used a mouse model of human soft-tissue infections to investigate the pathogenic relevance of GAS chemokine degradation, and to test the therapeutic effect of a GAS pheromone peptide (SilCR) that downregulates activity of chemokine protease. The only isolates from the necrotic tissue were two beta-haemolytic GAS strains of an M14 serotype. A trypsin-like protease released by these strains degraded human interleukin 8 and its mouse homologue MIP2. When innoculated subcutaneously in mice, these strains produced a fatal necrotic soft-tissue infection that had reduced neutrophil recruitment to the site of injection. The M14 GAS strains have a missense mutation in the start codon of silCR, which encodes a predicted 17 aminoacid pheromone peptide, SilCR. Growth of the M14 strain in the presence of SilCR abrogated chemokine proteolysis. When SilCR was injected together with the bacteria, abundant neutrophils were recruited to the site of infection, bacteria were cleared without systemic spread, and the mice survived. The therapeutic effect of SilCR was also obtained in mice challenged with M1 and M3 GAS strains, a leading cause of invasive infections. The unusual reduction in neutrophils in necrotic tissue of people with GAS soft-tissue infections is partly caused by a GAS protease that degrades interleukin 8. In mice, degradation can be controlled by administration of SilCR, which downregulates GAS chemokine protease activity. This downregulation increases neutrophil migration to the site of infection, preventing bacterial spread and development of a fulminant lethal systemic infection.


Pregnancy complicated by severe osteogenesis imperfecta: a report of two cases.
This case report discusses the anesthetic management of two parturients with severe osteogenesis imperfecta who presented for cesarean delivery. Although the anesthetic management for milder forms of the disease has been previously reported, anesthetic options for cases of this severity have not.


IL-7 and lymphopenia.
Interleukin-7 (IL-7) is a growth and anti-apoptotic factor for T-lymphocytes, with potential for clinical use in the treatment of immunodeficiencies due to loss of T-cells. Lymphopenia induced by disease (HIV infection, hemodialysis or Idiopathic CD4+ lymphopenia) or by treatment (high dose chemotherapy or depleting antibodies) for cancer or auto-immune diseases results in increased circulating levels of IL-7 which decline with T-cell recovery, however, the mechanism of such response remains to be elucidated. Furthermore, IL-7 is a major player in the regulation of peripheral T-cell homeostasis and as such is an important candidate cytokine for therapy aimed at improving T-cell reconstitution following lymphopenia. Anti- IL-7 is on the other hand proposed to treat conditions where IL-7 may play a more direct role in pathogenesis such as autoimmune disease like Rheumatoid Arthritis, Multiple Sclerosis or Inflammatory Bowel disease.


Asian perspectives on personal recovery in mental health: a scoping review.
Personal recovery is a relatively novel concept in many Asian countries, and recovery-oriented interventions are usually adapted from western conceptualizations of recovery. To understand what personal recovery in mental health means to people in Asia, what meanings they give to their conditions, and what factors they perceive as hindering or facilitating their recovery. The review focused on peer-reviewed papers published in English between the years 2000 and 2020. Arksey and O'Malley 5-stage method was used to guide the review. Thirty studies were included. Personal recovery in Asia meant a return to a pre-illness state and involved a transformative process. Mental illness was explained as being biomedically oriented, although religious/culturally bound explanations were also present in some studies. Social support, religion, meaningful activities, supportive professionals, and personalized coping strategies were viewed as supporting recovery. Religious stigma, discrimination, gendered norms, and negative societal perceptions of mental illness hindered recovery. The concept of personal recovery in Asia is extremely diverse. Studies exploring personal recovery among people experiencing mental illness in Asia remains in its early stages and more research is needed to better understand how it is conceptualized. Such knowledge could benefit frontline implementation of recovery-oriented services.


Brugia malayi cystatin therapeutically ameliorates dextran sulfate sodium-induced colitis in mice.
Helminth immunomodulation in the host has been shown to have therapeutic implications in inflammatory bowel diseases. In this study we aimed to evaluate the therapeutic effect of Brugia malayi recombinant cystatin (rBmCys) in a dose-dependent manner on dextran sulfate sodium (DSS)-induced colitis in mice. The anti-inflammatory activity of rBmCys on mice peritoneal exudate cells was initially analyzed in vitro. BALB/c mice were fed with 5% DSS for 7 days to induce colitis. The colitis mice were treated intraperitoneally with rBmCys (10, 25 or 50 µg for the three different groups of mice) on days 1, 3 and 5 of the DSS administration. Disease severity was assessed by the disease activity index (DAI) and macroscopic and histopathological scores of colon and myeloperoxidase activity in colonic mucosa. Cytokine profiles were measured in sera and cultured splenocytes of treated mice followed by stimulation with rBmCys. rBmCys showed anti-inflammatory activity in vitro. Treatment of DSS-induced colitis with rBmCys in mice ameliorated the overall disease severity as reflected by a significant reduction in weight loss, the DAI, mucosal edema, colon damage and myeloperoxidase activity of the colonic mucosa. While the mRNA expressions of IFN-γ, TNF-α, interleukin (IL)-5, IL-6 and IL-17 were downregulated, IL-10 expression was upregulated in the splenocytes of colitis mice treated with rBmCys. The amelioration of DSS-induced colitis occurred in a dose-dependent manner. The results of this study indicate an anti-inflammatory potential of rBmCys and provide evidence for using this protein as a promising therapeutic agent in ulcerative colitis.


Consciousness and the consolidation of motor learning.
It is no secret that motor learning benefits from repetition. For example, pianists devote countless hours to performing complicated sequences of key presses, and golfers practice their swings thousands of times to reach a level of proficiency. Interestingly, the subsequent waking and sleeping hours after practice also play important roles in motor learning. During this time, a motor skill can consolidate into a more stable form that can lead to improved future performance without intervening practice. Though it is widely believed that sleep is crucial for this consolidation of motor learning, this is not generally true. In many instances only day-time consolidates motor learning, while in other instances neither day-time nor sleep consolidates learning. Recent studies have suggested that conscious awareness during motor training can determine whether sleep or day-time plays a role in consolidation. However, ongoing studies suggest that this explanation is also incomplete. In addition to conscious awareness, attention is an important factor to consider. This review discusses how attention and conscious awareness interact with day and night processes to consolidate a motor memory.


Balancing diversity and tolerance: lessons from patients with systemic lupus erythematosus.
The autoimmune disease systemic lupus erythematosus (SLE) is caused by a failure of B cell tolerance. Recent studies in mouse models of SLE have identified several distinct tolerance checkpoints that must each function appropriately to protect against disease. However, studies of B cell repertoire selection in humans are essential to understand which checkpoints are defective in human autoimmune diseases.


Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.
Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.


[Quantifiable morphokinesis of parts of the hypothalamo-adenohypophyseal-gonadal axis in hormonally castrated boars. 3. Studies of boars following treatment with steroid test substance 547].
Morphokinetic effects caused in parts of the hypothalamic adenohypophyseogonadal axis of boars by treatment, using No. 547 steroid test substance (ZIMET, Jena) were to some extent identical with those resulting from analogous CAP application (inhibition of testicular androgen producers, anterior lobe of the pituitary gland, nucleus praeopticus medialis) or those following analogous norgestrel treatment (testes weight, tubule length). The findings recorded were largely attributed to the androgenic properties of No. 547 steroid test substance.


Evaluation of 3 different agar media for rapid detection of extended-spectrum β-lactamase-producing Enterobacteriaceae from surveillance samples.
Rapid detection of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli in surveillance samples of high-risk patients allows early optimization of antimicrobial therapy and timely introduction of infection control procedures. This study evaluated the BLSE (AES Chemunex), chromID ESBL (bioMérieux), and Brilliance ESBL agar (Oxoid) for rapid detection of ESBL-producing Enterobacteriaceae from surveillance samples. A total of 139 perineal and nose samples were processed. Isolated bacterial strains were identified by mass spectrometry. ESBL confirmation was performed by phenotypical and molecular tests. Overall, 16 ESBL-producing Enterobacteriaceae were recovered. The sensitivities after 24 h of incubation were comparable (BLSE, 87.5%; Brilliance ESBL, 87.5%; and chromID, 81.3%). The specificity of chromogenic media (80.7-82.1%) was significantly higher compared to BLSE (60.8%). All 3 media are reliable to screen for ESBL-producing Enterobacteriaceae from surveillance samples. Yet, the main advantages of chromogenic media over BLSE reside in their chromogenic character and higher specificity, reducing the total number of isolates that require further identification and ESBL confirmation testing.