We describe a case of a patient whose clozapine was discontinued after a “red result” following R-CHOP (rituximab with cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone) chemotherapy for large B-cell lymphoma. In some cases, manufacturers grant permission, on compassionate grounds, for clozapine to be continued or reinitiated following assessment by their consultant hematologist. Other than a recent case report, there is not much literature surrounding this medical issue. However, since the two leading causes of mortality in schizophrenia are cancer and cardiac disease, this is not an uncommon occurrence. Clinicians are reluctant to prescribe clozapine in view of its side-effect profile, despite its proven efficacy for managing treatment-resistant schizophrenia. The alternative is to prescribe two antipsychotics to manage symptoms. This approach may be associated with increased side effects, and evidence for actual benefits is scant. The consequences were disastrous in this case, as the individual not only relapsed following clozapine discontinuation, but the therapy for this treatable form of lymphoma had to be delayed. He was eventually admitted to an inpatient unit after having been stable for 15 years. We managed to stabilize him with olanzapine and aripiprazole which enabled the heme-oncology group to resume R-CHOP therapy with filgrastim (granulocyte colony-stimulating factor). Even so, he continued to exhibit severe psychotic symptoms, with religious delusions and auditory hallucinations. We therefore applied for permission to rechallenge him on clozapine. Permission was granted when protocol conditions were met, and reinitiation went without any adverse events. The patient’s symptoms showed improvement within a few weeks, and the other antipsychotics were discontinued once clozapine was titrated up to 300 mg. The decision to reinitiate clozapine following a red result is not to be taken lightly, but needs to be considered in terms of the risks versus benefits. More literature surrounding this issue would be of great benefit to clinicians, patients, and their families.
clozapine agranulocytosis; clozapine discontinuation; red result; clozapine rechallenge; R-CHOP chemotherapy
Sheehan's syndrome manifests as hypopituitarism following a child birth usually preceded by postpartum hemorrhage. The symptoms range from vague feelings of ill health to symptoms of a full blown panhypopituitarism. A large series of such patients is not described in the literature.
Materials and Methods:
We present the details of ten women with partial Sheehan's syndrome. They presented with post-partum hemorrhage and lactation failure.
After delivery, seven out of ten patients had regular menstrual cycles indicating preservation of gonadotroph function. Lactotroph, thyrotroph, and somatotroph failure were present in all and corticotrophs preservation was documented in four out of ten patients. The hypophysial magnetic resonance imaging (MRI) confirmed empty sella in all.
lactotroph, somatotroph and thyrotroph failure are common in patients with Sheehan's syndrome. In addition to known preservation of gonadotroph axis, corticotroph axis may be preserved in some of these patients arguing against the universal treatment of these patients with glucocorticoids.
Corticotrophs; empty sella; postpartum hemorrhage; regular cycles; Sheehan's syndrome
The asymmetric unit of the title compound, C13H11ClN2, contains two geometrically distinct molecules; one molecule is close to planar [dihedral angle between the aromatic rings = 2.44 (18)°] and the other is twisted about the linking hydrazide group [dihedral angle = 14.08 (19)°]. In the crystal, the N—H groups do not form hydrogen bonds and the molecules are linked by weak C—H⋯π interactions.
In the title compound, C17H19NO2, the aromatic rings are oriented at a dihedral angle of 59.27 (12)°. In the crystal, inversion dimers linked by pairs of weak C—H⋯O interactions generate R
In the title compound, C14H10FNO3, the dihedral angle between the two benzene rings is 32.66 (14)°. An S(6) ring motif is formed due to an intramolecular O—H⋯O hydrogen bond between the hydroxy and carbonyl groups. In the crystal, molecules are consolidated into dimers with R
2(8) ring motifs by pairs of O—H⋯O hydrogen bonds.
In the title compound, C14H11Cl2N, the dihedral angle between the 4-methylanilinic and 2,4-dichlorobenzaldehyde moieties is 7.37 (8)°. In the crystal, C—H⋯π interactions between the terminal methyl group and a symmetry-related ring of the anilinic group help to establish the packing.
In the title compound, C15H15NO, the almost planar 2,3-dimethylaniline unit and the salicylaldehyde group (r.m.s. deviations of 0.0156 and 0.0109 Å, respectively) are oriented at a dihedral angle of 43.69 (9)° with respect to each other. An S(6) ring motif is formed due to intramolecular O—H⋯N hydrogen bonding. In the crystal, C—H⋯π interactions occur between the 2,3-dimethylaniline unit and the salicylaldehyde group, where the CH is from the o-methyl group.
The asymmetric unit of the title compound, C15H14ClNO2, contains two molecules with significantly different conformations: the dihedral angles between the 4-chloroaniline and 3,4-dimethoxyphenyl (excluding C atoms) moieties are 19.68 (7) and 45.54 (4)°. In the crystal, the molecules are linked by C—H⋯O hydrogen bonds and weak C—H⋯π interactions.
In the title compound, C13H14N2, the dihedral angle between the aromatic rings is 69.73 (14)°. In the crystal, inversion dimers linked by pairs of N—H⋯N hydrogen bonds generate R
2(10) loops. A weak C—H⋯π interaction also occurs.
AIM: To investigate whether the iron stores regulator hepcidin is implicated in colon cancer-associated anaemia and whether it might have a role in colorectal carcinogenesis.
METHODS: Mass spectrometry (MALDI-TOF MS and SELDI-TOF MS) was employed to measure hepcidin in urine collected from 56 patients with colorectal cancer. Quantitative Real Time RT-PCR was utilized to determine hepcidin mRNA expression in colorectal cancer tissue. Hepcidin cellular localization was determined using immunohistochemistry.
RESULTS: We demonstrate that whilst urinary hepcidin expression was not correlated with anaemia it was positively associated with increasing T-stage of colorectal cancer (P < 0.05). Furthermore, we report that hepcidin mRNA is expressed in 34% of colorectal cancer tissue specimens and was correlated with ferroportin repression. This was supported by hepcidin immunoreactivity in colorectal cancer tissue.
CONCLUSION: We demonstrate that systemic hepcidin expression is unlikely to be the cause of the systemic anaemia associated with colorectal cancer. However, we demonstrate for the first time that hepcidin is expressed by colorectal cancer tissue and that this may represent a novel oncogenic signalling mechanism.
Iron; Hepcidin; Colon; Cancer; Anaemia; Mass spectrometry
In the present study, oxidative stress and lymphocytic DNA damage in both pre-op and post-op benign prostrate hyperplasia (BPH) patients with age >50 years was evaluated and compared with normal healthy subjects (controls- without any evidence of disease) of the same sex and age group. From December 2007 to November 2009, oxidative stress in 45 BPH patients were evaluated both before (pre-op patients) and after 7 days of surgery (post-op patients) in terms of measurements of plasma levels of (1) various anti-oxidative enzymes, (2) non-enzymatic antioxidants and (3) malondialdehyde which is a product of lipid peroxidation. The lymphocyte DNA damage was also evaluated by single cell alkaline gel electrophoresis in terms of tail length migration in these patients. These values were compared with their respective control subjects of similar sex and age group. The activities of antioxidant enzymes and the levels of antioxidant, reduced glutathione were found significantly decreased (p < 0.05) in serum samples of pre-operative group of BPH patients as compared to the controls. These altered parameters increased significantly (p < 0.05) and returned to their near normal control values, but not up to baseline values, in post operative patients i.e. after the cancer load was decreased by surgery. Lymphocytic DNA damage was found to be significantly increased in pre-op group as compared to controls and was reduced after surgery in post-op group. The present study therefore, shows significantly increased levels of oxidative stress and DNA damage in BPH patients which were reduced after removal of tumour load. Thus oxidative damage plays an important role in prostate tumourogenesis and timely management of oxidative stress can be of importance in preventing the occurrence of BPH.
BPH; Oxidative stress; Antioxidants; Lipid peroxidation; DNA damage
Highly ionic metal oxide nanostructures are attractive, not only for their physiochemical properties but also for antibacterial activity. Zinc oxide (ZnO) nanostructures are known to have inhibitory activity against many pathogens but very little is known about doping effects on it. The antibacterial activity of undoped ZnO and tin (Sn) doped ZnO nanostructures synthesized by a simple, versatile, and wet chemical technique have been investigated against Escherichia coli, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa bacterial strains. It has been interestingly observed that Sn doping enhanced the inhibitory activity of ZnO against S. aureus more efficiently than the other two bacterial strains. From cytotoxicity and reactive oxygen species (ROS) production studies it is found that Sn doping concentration in ZnO does not alter the cytotoxicity and ROS production very much. It has also been observed that undoped and Sn doped ZnO nanostructures are biosafe and biocompatible materials towards SH-SY5Y Cells. The observed behavior of ZnO nanostructures with Sn doping is a new way to prevent bacterial infections of S. aureus, especially on skin, when using these nanostructures in creams or lotions in addition to their sunscreen property as an ultraviolet filter. Structural investigations have confirmed the formation of a single phase wurtzite structure of ZnO. The morphology of ZnO nanostructures is found to vary from spherical to rod shaped as a function of Sn doping. The excitation absorption peak of ZnO is observed to have a blue shift, with Sn doping leading toward a significant tuning in band gap.
nanostructures; Sn doped ZnO; S. aureus; antibacterial activity
The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient’s life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn’s disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.
•Reanalysis of GWAS data identifies a SNP associated with outcome in Crohn’s disease•This SNP modulates inflammatory responses in monocytes via a FOXO3-driven pathway•The mild disease-associated allele reduces TNFα and increases IL-10 production•Prognosis in RA and malaria (also TNFα-related diseases) is also linked to this SNP
An analysis of GWAS data of patients with Crohn’s disease distinguishes SNPs associated with disease risk from those associated with outcome. Functional studies indicate that a noncoding SNP associated with FOXO3A influences a cytokine inflammatory pathway that impacts outcome, not only in Crohn’s but also other diseases such as rheumatoid arthritis and malaria.
We are reporting a case of 71-year old lady with a dual chamber demand pacemaker, who developed acute pulmonary edema due to an acute left ventricular (LV) dysfunction and worsening in mitral valve regurgitation after atrioventricular nodal ablation for uncontrolled atrial fibrillation. This was attributed to right ventricular apical pacing leading to LV dyssynchronization. Patient dramatically improved within 12-24 h after upgrading her single chamber pacemaker to biventricular pacing. Our case demonstrates that biventricular pacing can be an effective modality of treatment of acute congestive heart failure. In particular, it can be used when it is secondary to LV dysfunction and severe mitral regurgitation attributed to significant dyssynchrony created by right ventricular pacing in patients with atrioventricular nodal ablation for chronic atrial fibrillation.
Acute congestive heart failure; Cardiac resynchronization therapy pacemaker; Pacing; Cardiac biventricular pacing
AIM: To find a non-invasive strategy for detecting choledocholithiasis before cholecystectomy, with an acceptable negative rate of endoscopic retrograde cholangiopancreatography.
METHODS: All patients with symptomatic gallstones were included in the study. Patients with abnormal liver functions and common bile duct abnormalities on ultrasound were referred for endoscopic retrograde cholangiopancreatography. Patients with normal ultrasound were referred to magnetic resonance cholangiopancreatography. All those who had a negative magnetic resonance or endoscopic retrograde cholangiopancreatography underwent laparoscopic cholecystectomy with intraoperative cholangiography.
RESULTS: Seventy-eight point five percent of patients had laparoscopic cholecystectomy directly with no further investigations. Twenty-one point five percent had abnormal liver function tests, of which 52.8% had normal ultrasound results. This strategy avoided unnecessary magnetic resonance cholangiopancreatography in 47.2% of patients with abnormal liver function tests with a negative endoscopic retrograde cholangiopancreatography rate of 10%. It also avoided un-necessary endoscopic retrograde cholangiopancreatography in 35.2% of patients with abnormal liver function.
CONCLUSION: This strategy reduces the cost of the routine use of magnetic resonance cholangiopancreatography, in the diagnosis and treatment of common bile duct stones before laparoscopic cholecystectomy.
Magnetic resonance cholangiopancreatography; Endoscopic retrograde cholangiopancreatography; Choledocholithiasis; Liver function tests; Laparoscopic cholecystectomy; Obstructive jaundice
Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate-refractory gastrointestinal stromal tumors). This single-institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty-eight patients were enrolled, and 35% were heavily pretreated (≥2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression-free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1, and 2.5 and 13.6 months, respectively. The 3-month progression-free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma, and MFH were 75% and 69.2%, 60%, and 62.5%, and and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low-grade disease could have been included and the small numbers, a 3-month progression-free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.
soft tissue sarcoma; targeted therapy; sunitinib malate; progression-free rate; survival; tyrosine kinase inhibitor
In vitro cultures of loquat cultivar Mardan were established using shoot apices after treating with NaOCl (5%, 7%, 10%, 12%, 14% (v/v)) for 12 min and HgCl2 (0.01%, 0.05%, 0.10%, 0.20%, 0.25% (w/v)) for 2 min. A maximum survival rate of 70% was recorded after surface sterilization with 10% NaOCl. Caulogenic response was assessed on Murashige and Skoog (MS) medium fortified with assorted combinations of the cytokinins, benzylaminopurine (BAP), kinetin, and N6-(2-isopentyl)adenine (2iP). Treatment of BAP 1.5 mg/L combined with 2iP 9.0 mg/L and kinetin 1.5 mg/L was found to be optimum for shoot morphogenesis in terms of the number and subsequent growth of shoots, while the highest shoot length was yielded by the combination of BAP 0.5 mg/L, kinetin 0.5 mg/L, and 2iP 3 mg/L. Higher levels of cytokinins induced callogenesis, vitrification and stunted growth to some extent. For rhizogenesis, uniform sized micro-shoots were excised and transferred to half-strength MS medium containing auxins. The best rooting expression was observed with naphthaleneacetic acid (NAA) 1 mg/L combined with indole-3-butyric acid (IBA) 2 mg/L and paclobutrazol (PBZ) 1 mg/L.
Eriobotrya japonica; Micropropagation; Sterilization of loquat; Plant growth regulator; Shoot proliferation; Rhizogenesis
Multiple emulsions are excellent and exciting potential systems for the delivery of useful cosmetic agents. The work describes stability of a multiple emulsion for cosmetic purpose, loaded with extract of Camellia sinensis L. (Theaceae) in concentration of 5%. The formulation constitutes of cetyl dimethicone copolyol and polyoxyethylene (20) cetyl ether as emulsifiers and was characterised and monitored for various physicochemical aspects. Centrifugation has no devastating effect on physical destabilization/phase separation observed for 30 days. Mean globule sizes of multiple droplets were found in the range of 10.29 ± 4.4 μm to 12.77 ± 5.1 μm and of inner droplets were in the range of 0.8 ± 0.4 μm to 1.6 ± 0.8 μm. All samples exhibited shear thinning behavior with increase in shear stress. The results of the present study indicate that multiple emulsions can be used as carrier of 5% Camellia sinensis L. extract to enhance desired effects. The developed physically and chemically stable system is an effective system for targeting skin layers; however, long-term stability at elevated temperatures may be needed with suitable modifications, if required.
Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, and to what extent gene expression configures multiple trajectories into commitment. Importantly, the transient nature of the commitment transition confounds the experimental capture of committing cells. We develop a computational framework that simulates stochastic commitment events, and affords mechanistic exploration of the fate transition. We use a combined modeling approach guided by gene expression classifier methods that infers a time-series of stochastic commitment events from experimental growth characteristics and gene expression profiling of individual hematopoietic cells captured immediately before and after commitment. We define putative regulators of commitment and probabilistic rules of transition through machine learning methods, and employ clustering and correlation analyses to interrogate gene regulatory interactions in multipotent cells. Against this background, we develop a Monte Carlo time-series stochastic model of transcription where the parameters governing promoter status, mRNA production and mRNA decay in multipotent cells are fitted to experimental static gene expression distributions. Monte Carlo time is converted to physical time using cell culture kinetic data. Probability of commitment in time is a function of gene expression as defined by a logistic regression model obtained from experimental single-cell expression data. Our approach should be applicable to similar differentiating systems where single cell data is available. Within our system, we identify robust model solutions for the multipotent population within physiologically reasonable values and explore model predictions with regard to molecular scenarios of entry into commitment. The model suggests distinct dependencies of different commitment-associated genes on mRNA dynamics and promoter activity, which globally influence the probability of lineage commitment.
Stem cells have the capacity to both self-renew and differentiate into specialized cell lineages, thus sustaining tissue formation during embryonic development and permitting tissue homeostasis throughout adult life. Previous studies have suggested that stem cell commitment to a specific lineage may constitute a discrete event of stochastic activation of a small number of key regulator genes. Experimental exploration of this question is challenging, in face of the elusive nature of the commitment transition and due to considerable gene expression heterogeneity between cells. Here, we implement a computational model that simulates gene expression variation through time and affords the capture of in silico commitment events. This model integrates statistical analysis of experimental single-cell gene expression data with dynamical modeling methods to implement a mechanistic framework for stochastic regulation of gene transcription and a probabilistic approach for the commitment rules. Applied to blood cells, our method identifies potential commitment-associated genes, explores how their expression patterns can define alternative commitment regimes, and suggests how differences in regulation of gene expression dynamics can impact the frequency of commitment.
To explore the evidence available of poor-quality (counterfeit and substandard) medicines in the literature.
Databases used were EMBASE, MEDLINE, PubMed and the International Pharmaceutical Abstracts, including articles published till January 2013.
Prevalence studies containing original data. WHO definitions (1992) used for counterfeit and substandard medicines.
Study appraisal and synthesis
Two reviewers independently scored study methodology against recommendations from the MEDQUARG Checklist. Studies were classified according to the World Bank classification of countries by income.
Data extracted: place of study; type of drugs sampled; sample size; percentage of substandard/counterfeit medicines; formulations included; origin of the drugs; chemical analysis and stated issues of counterfeit/substandard medicines.
44 prevalence studies were identified, 15 had good methodological quality. They were conducted in 25 different countries; the majority were in low-income countries (11) and/or lower middle-income countries (10). The median prevalence of substandard/counterfeit medicines was 28.5% (range 11–48%). Only two studies differentiated between substandard and counterfeit medicines. Prevalence data were limited to antimicrobial drugs (all 15 studies). 13 studies involved antimalarials, 6 antibiotics and 2 other medications. The majority of studies (93%) contained samples with inadequate amounts of active ingredients. The prevalence of substandard/counterfeit antimicrobials was significantly higher when purchased from unlicensed outlets (p<0.000; 95% CI 0.21 to 0.32). No individual data about the prevalence in upper middle-income countries and high-income countries were available.
Studies with strong methodology were few. The majority did not differentiate between substandard and counterfeit medicines. Most studies assessed only a single therapeutic class of antimicrobials.
The prevalence of poor-quality antimicrobial medicines is widespread throughout Africa and Asia in lower income countries and lower middle-income countries . The main problem identified was inadequate amounts of the active ingredients.
counterfeit drug; substandard drug; fake drug; anti-infective ; drug counterfeiting
Timely information about disease severity can be central to the detection and management of outbreaks of acute respiratory infections (ARI), including influenza. We asked if two resources: 1) free text, and 2) structured data from an electronic medical record (EMR) could complement each other to identify patients with pneumonia, an ARI severity landmark.
A manual EMR review of 2747 outpatient ARI visits with associated chest imaging identified x-ray reports that could support the diagnosis of pneumonia (kappa score = 0.88 (95% CI 0.82∶0.93)), along with attendant cases with Possible Pneumonia (adds either cough, sputum, fever/chills/night sweats, dyspnea or pleuritic chest pain) or with Pneumonia-in-Plan (adds pneumonia stated as a likely diagnosis by the provider). The x-ray reports served as a reference to develop a text classifier using machine-learning software that did not require custom coding. To identify pneumonia cases, the classifier was combined with EMR-based structured data and with text analyses aimed at ARI symptoms in clinical notes.
370 reference cases with Possible Pneumonia and 250 with Pneumonia-in-Plan were identified. The x-ray report text classifier increased the positive predictive value of otherwise identical EMR-based case-detection algorithms by 20–70%, while retaining sensitivities of 58–75%. These performance gains were independent of the case definitions and of whether patients were admitted to the hospital or sent home. Text analyses seeking ARI symptoms in clinical notes did not add further value.
Specialized software development is not required for automated text analyses to help identify pneumonia patients. These results begin to map an efficient, replicable strategy through which EMR data can be used to stratify ARI severity.
Objective The aim of this study was to assess the assumed advantage of endoscopic assistance to the standard subtemporal approach. The idea was to measure qualitatively and quantitatively visibility versus operability.
Design We performed eight subtemporal dissections on four cadaver heads. Our dissections integrated an operating microscope, endoscope, and neuronavigation. Comparison was made between visibility and operability afforded by the microscope alone or by the microscope–endoscope combination. Visibility was recorded as complete or incomplete and was quantified for key structures using linear measurements taken by the navigation system. Operability was determined by whichever maneuvers could be safely and comfortably accomplished in the space afforded.
Results From our survey, the structures whose visibility most benefitted from the addition of the endoscope include: contralateral third nerve, posterior perforated substance, mammillary bodies, and contralateral superior cerebellar artery. With regard to quantitative evaluation, we found increased visibility of both basilar artery and posterior cerebral artery. With regard to the operability, no objective advantage was afforded by the addition of the endoscope. Subjectively, the maneuvers were easier to perform while using the endoscope.
Conclusion Using the endoscope as an assistance tool during conducting classical subtemporal approach can help in overcome a lot of the classical subtemporal approach limitations.
subtemporal; endoscope; endoscope-assisted; interpeduncular; operability
Cocaine or Benzoylmethylecgonine is an alkaloid extracted from the leaves of the Erythroxylon plant, which can cause gastrointestinal ischemia from severe arterial vasoconstriction via stimulation of alpha-adrenergic receptors in the gastric and mesenteric arteries. We report this case of a 65-year-old man who presented with a single massive ulcer at the incisura of the stomach as a result of cocaine use. The size and location of this ulcer were atypical and illustrate the potential for serious gastrointestinal manifestations from cocaine use.