neuroradiology; clinical specialty; neurohospitalist; clinical specialty; endocrinology; clinical specialty
Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.
Akt, protein kinase B; AMPKα, AMP-activated protein kinase α; AUC, area-under the curve; BAT, brown adipose tissue; BZA, bazedoxifene; CE, conjugated equine estrogens; E2, 17β-estradiol; ER, estrogen receptor; FAS, fatty acid synthase; FGF21, fibroblast growth factor 21; GIR, glucose infusion rate; H&E, hematoxylin and eosin; HFD, high-fat diet; HGP, hepatic glucose production; ITT, insulin tolerance test; Lcn2, lipocalin 2; LPL, lipoprotein lipase; NAFLD, non-alcoholic fatty liver disease; OGTT, oral glucose tolerance test; OVX, ovariectomy; PTT, pyruvate tolerance test; RBP4, retinol binding protein 4; Rd, rate of whole-body glucose disappearance; RER, respiratory exchange ratio; SERM, selective estrogen receptor modulator; TBARS, thiobarbituric acid reactive substances; TG, triacylglycerol; TSEC, tissue-selective estrogen complex; UCPs, uncoupling proteins; VO2, oxygen consumption; WAT, white adipose tissue.; Tissue-selective estrogen complexes; Bazedoxifene; Menopause; Metabolic syndrome; Insulin resistance; Type 2 diabetes
Report of a case of young immunocompetent male adult with autopsy proven acanthamoeba meningoencephalitis. The patient presented with a protracted febrile illness of 3 months duration with features of meningoencephalitis, this was followed by rapid deterioration while on anti tuberculous therapy and steroids and ended fatally. His magnetic resonance imaging showed features of hemorrhagic meningoencephalitis and magnetic resonance spectroscopy showed choline peak. Autopsy revealed necrotizing meningoencephalitis and intraocular colonization due to acanthamoeba.
Acanthamoeba meningoencephalitis; immunocompetent; intraocular colonization; magnetic resonance imaging; magnetic resonance spectroscopy
The diagnostic accuracy of the currently available tools carries poor sensitivity resulting in significant delay in specific diagnosis of cortical dementias. Considering the properties of default mode networking of the brain it is highly probable that specific changes may be seen in frontotemporal dementias (FTDs) and Alzheimer's disease sufficiently early.
The aim of this study is to look for changes in Transcranial Magnetic Stimulation (TMS) in cortical dementia.
Materials and Methods:
Evaluated with a single pulse TMS with the figure of eight coil and recorded from right first dorsal interossei (FDI). Resting Motor Threshold (RMT) was estimated on the opposite motor cortex (T1). Second site of stimulation was cervical spine at C7-T2. Central motor conduction time (CMCT) is equal toT1-T2. Silent Period (SP) identified by applying TMS pulse to contracting FDI.
RMT was reduced in seven out of eight Alzheimer's dementias. CMCT was in the upper limit of normal in both patients with FTD. The most consistent observation was that SP was reduced and there were escape discharges noticed during the SP suggesting increased cortical excitability and decreased cortical inhibition. This suggests probable early asymptomatic changes in the gamma-aminobutyric acid (GABA) nergic and cholinergic system is taking place. This if confirmed may give some insight into early diagnosis and therapeutic role of GABA agonists in these disorders.
Alzheimer's dementia; central motor conduction time; cortical inhibition; fronto-temporal dementias; transcranial magnetic stimulation
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
Heart failure; Anaemia
The majority of breast cancer cases ultimately become unresponsive to endocrine therapies, and this progression of breast cancer from hormone-responsive to hormone-independent represents an area in need of further research. Additionally, hormone-independent carcinomas are characterized as being more aggressive and metastatic, key features of more advanced disease. Having previously shown the ability of the stromal-cell derived factor-1 (SDF-1)-CXCR4 signaling axis to promote primary tumorigenesis and hormone independence by overexpressing CXCR4 in MCF-7 cells, in this study we further examined the role of SDF-1/CXCR4 in the endogenously CXCR4-positive, estrogen receptor α (ER-α)-positive breast carcinoma cell line, MDA-MB-361. In addition to regulating estrogen-induced and hormone-independent tumor growth, CXCR4 signaling stimulated the epithelial-to-mesenchymal transition, evidenced by decreased CDH1 expression following SDF-1 treatment. Furthermore, inhibition of CXCR4 with the small molecule inhibitor AMD3100 induced CDH1 gene expression and inhibited CDH2 gene expression in MDA-MB-361 cells. Further, exogenous SDF-1 treatment induced ER-α-phosphorylation in both MDA-MB-361 and MCF-7-CXCR4 cells, demonstrating ligand-independent activation of ER-α through CXCR4 crosstalk. qPCR microRNA array analyses of the MDA-MB-361 and MCF-7-CXCR4 cell lines revealed changes in microRNA expression profiles induced by SDF-1, consistent with a more advanced disease phenotype and further supporting our hypothesis that the SDF-1/CXCR4 signaling axis drives ER-α-positive breast cancer cells to a hormone independent and more aggressive phenotype. In this first demonstration of SDF-1-CXCR4-induced microRNAs in breast cancer, we suggest that this signaling axis may promote tumorigenesis via microRNA regulation. These findings represent future potential therapeutic targets for the treatment of hormone-independent and endocrine-resistant breast cancer.
SDF-1; CXCR4; microRNA; breast carcinoma; hormone independence; AMD3100
The oral cavity is a challenging area for radiological diagnosis. Soft-tissue, glandular structures and osseous relations are in close proximity and a sound understanding of radiological anatomy and common pathways of disease spread is required. In this pictorial review we present the anatomical and pathological concepts of the oral cavity with emphasis on the complementary nature of diagnostic imaging modalities.
Of the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.
TNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.
Panobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.
This study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.
Panobinostat; LBH589; triple-negative breast cancer; xenograft; histone deacetylase inhibitor; E-cadherin; CDH1; epithelial-to-mesenchymal transition
This study was conducted to evaluate the effect of a reduced-dose 7-valent pneumococcal conjugate vaccine (PCV) primary series followed by a 23-valent pneumococcal polysaccharide vaccine (23vPPS) booster on nasopharyngeal (NP) pneumococcal carriage. For this purpose, Fijian infants aged 6 weeks were randomized to receive 0, 1, 2, or 3 PCV doses. Within each group, half received 23vPPS at 12 months. NP swabs were taken at 6, 9, 12, and 17 months and were cultured for Streptococcus pneumoniae. Isolates were serotyped by multiplex PCR and a reverse line blot assay. There were no significant differences in PCV vaccine type (VT) carriage between the 3- and 2-dose groups at 12 months. NP VT carriage was significantly higher (P, <0.01) in the unvaccinated group than in the 3-dose group at the age of 9 months. There appeared to be a PCV dose effect in the cumulative proportion of infants carrying the VT, with less VT carriage occurring with more doses of PCV. Non-PCV serotype (NVT) carriage rates were similar for all PCV groups. When groups were pooled by receipt or nonreceipt of 23vPPS at 12 months, there were no differences in pneumococcal, VT, or NVT carriage rates between the 2 groups at the age of 17 months. In conclusion, there appeared to be a PCV dose effect on VT carriage, with less VT carriage occurring with more doses of PCV. By the age of 17 months, NVT carriage rates were similar for all groups. 23vPPS had no impact on carriage, despite the substantial boosts in antibody levels.
The genome of rabies virus encodes five proteins; the nucleoprotein, the phosphoprotein, the matrix protein, the glycoprotein, and the RNA-dependent RNA polymerase. Among these, the glycoprotein is the most important as it is the major contributor to pathogenicity and virus neutralizing antibody response. Keeping in mind that glycoprotein is the only protein exposed on the surface of virus and is thought to be responsible for the interaction with the cell membrane, it was attempted to target glycoprotein by a ligand polyethylene glycol 4000, which blocks its active site, as seen by molecular operating environment software, so that it may be possible to prevent the spread of virus into the host. The ligand polyethylene glycol 4000 was retrieved from Research Collaboratory for Structural Bioinformatics protein data bank by providing the glycoprotein sequence to the databank. In this study it was observed that the ligand was successfully docked on a major portion of antigenic site II of glycoprotein by mimicking the virus neutralizing antibodies. This knowledge may be important for the development of novel therapies for the treatment of rabies and other viral diseases in the future.
Docking; glycoprotein; molecular operating environment; polyethylene glycol 4000; rabies; RVG
Adrenocortical carcinoma (ACC) is a rare malignancy, especially in children. The overall incidence is approximately 2 cases per million per year. In children, the incidence is 0.3 cases per million per year, except in southern Brazil where the incidence is 3.4–4.2 cases per million per year. We describe a giant nonfunctioning metastasized ACC in a 6-year-old girl who presented with a history of increasing abdominal girth incidentally noticed by her mother since 1 week. Ultrasound abdomen showed a large right suprarenal tumor with calcifications and necrosis. Empty left renal fossa and compensatory enlarged right kidney were seen. Computed tomography (CT) scan revealed a large heterogenously enhancing right suprarenal mass with calcification and necrosis with pulmonary metastasis. Histopathology report from the right suprarenal mass revealed an ACC. With a stage IV disease, the patient died after 2 months from diagnosis.
Adrenocortical carcinoma; adrenocortical tumor; nonfunctioning
Swarnabhasma, an Ayurvedic preparation containing Calotropis gigantea R. Br. (Asclepiadaceae) is extensively used by Ayurvedic physicians for treatment of diabetes mellitus, bronchial asthma, rheumatoid arthritis and nervous disorders. In the present study, we report the effect of chloroform extracts of Calotropis gigantea leaf and flower on free radical scavenging activity, and lipid profile in streptozotozin-induced diabetic rats. The lipid peroxidation, superoxide dismutase, and catalase were measured in liver homogenate and serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, lipid profile were measured in blood serum. Administration of single dose of streptozotozin (55 mg/kg, i.p.) caused significant increases in lipid peroxidation, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, cholesterol and triglyceride levels, while superoxide dismutase and catalase levels were significantly decreased. Further, administration of chloroform extracts of Calotropis gigantea leaf and flower to streptozotocin-induced diabetes rats at a dose of 10, 20 and 50 mg/kg orally for 27 d lead to a significant decrease in lipid peroxidation, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, cholesterol and triglyceride levels. Consequently, superoxide dismutase and catalase levels were significantly increased. Glibenclamide was used as a positive control (10 mg/kg). It was observed that the effect of chloroform extracts of Calotropis gigantea on alkaline phosphatase, cholesterol, superoxide dismutase, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, levels are comparable to that of those produced by the positive control.
Calotropis gigantea; diabetes; oxidative stress; swarnabhasma
Testicular lymphoma is a rare neoplasm of the testis that is most commonly seen in older patients. It metastasizes preferentially to extranodal sites, including the skin, central nervous system, Waldeyer ring, contralateral testis, and lung. Two case reports of patients with a history of testicular lymphoma who developed involvement of the vitreous and retina are presented. These are interesting cases as the testis, central nervous system, and eye are all immune privileged organs, which may account for occurrence of disease in these sites. Histopathologic examination of diagnostic vitrectomy specimens from both cases showed atypical lymphoid cells with immunoglobulin heavy chain (IgH) gene rearrangements, consistent with the diagnosis of intraocular B-cell lymphoma. The results of a literature review of all reports of ocular involvement with testicular lymphoma are discussed. Patients with testicular lymphoma are at risk for relapse, particularly in the central nervous system. Clinicians should be suspicious for intraocular lymphoma in patients with a history of testicular lymphoma who present with vitritis or retinal lesions.
immune privileged organ; immunohistochemistry; intraocular lymphoma; microdissection; PCR; retina; testicular lymphoma; vitreous
Polyamine-assisted deprotection conditions have been developed for the rapid and clean cleavage of oligonucleotide chains from a cis-diol group bearing universal polymer support, making it compatible with modern oligonucleotide synthesis via all types of phosphoramidite synthons, including base labile protecting group bearing synthons as well. The synthesized oligonucleotides were found to be comparable with the corresponding standard oligomers with respect to their retention time on HPLC, mass on MALDI-TOF and biological activity in PCR amplification.
Centbutindole is a new antipsychotic agent related to butyrophenone group. The drug is dopamine antagonist but it also blocks 5HT2 receptors. Clinically the drug has passed through phase I, II & III clinical trials successfully and it has shown effective antipsychotic activity in schizophrenic patients. In the present study the drug was compared with risperidone in a double blind manner for a period of 8 weeks to assess the efficacy in schizophrenic patients. Patients of schizophrenia evaluated on PANSS, CGI & UKU side effect rating scale weekly Out of 44 patients included in study, 38 completed the trial. The intergroup comparison of two drugs showed that centbudindole and risperidone have similar onset of antipsychotic action as both the drugs showed significant decrease in the total PANSS score as well as positive syndrome score, negative syndrome score and general psychopathology score from 2nd week onwards. The scores in both the groups showed a steady and significant decline from 2nd week to 8th week of study. The present study showed that centbutindole has similar improvement on clinical global impression with risperidone. The side effect profile was similar in the two drugs except dystonia (5 patients in centbutindole vs 1 patient in risperidone group). The findings of present study shows that Centbutindole could be used as a promising new drug for treatment of schizophrenia in place of a typical antipsychotics as it has shown improvement on negative symptoms similar to risperidone.
Centbutindole; Risperidone; Atypical Antipsychotics and Extrapyramidal symptoms
The progressively increasing number of elderly people in the Canadian population and the disproportionate expenditure on their health care has stimulated interest in prevention of common illnesses observed in this age group. It is now recognized that nutrition plays an important role in health status, and both undernutrition and overnutrition are associated with greater risk of morbidity and mortality. Nutritional problems in the elderly can be suspected if there are several high-risk factors present--for example, living alone, physical or mental disability, recent loss of spouse or friend, weight loss, use of multiple medications, poverty, and high consumption of alcohol. Physical examination, anthropometry, and measurements of serum albumin levels and hemoglobin and lymphocyte counts are simple but helpful tools in confirming the presence of nutritional disorders. The prevention and correction of nutritional problems is likely to prove beneficial in the management of common geriatric illnesses. In these efforts, it is desirable to have a team approach in which the physician, the dietitian and the nurse each have a defined interactive role. Home care support services are important adjuncts in continuing care. Nutrition should receive a greater emphasis in the training of physicians and other health professionals.
A randomized cross-over study was made of 32 young healthy Hong Kong Chinese to compare the incidence and nature of dysrhythmias that occurred during third molar surgery done under local anesthesia, alone or supplemented with midazolam sedation. The incidence of dysrhythmias during surgery was not significantly different during the two procedures. However prior to surgery, 25% of the patients had dysrhythmias during sedation with midazolam. The majority of dysrhythmias were infrequent unifocal ventricular ectopics. During sedation with midazolam it may be beneficial to monitor the electrocardiogram, especially in high risk patients such as those suffering from ischaemic heart disease, cardiomyopathy, and those on antidysrhythmic drugs.
Presented here is the case report of a lady who was referred for evaluation and management of frank psychotic manifestations. A carefully taken history and physical findings pointed to the presence of hypothyroidism. This was later confirmed by laboratory evaluation. The patient improved after thyroxine supplementation.
OBJECTIVE--To examine the effects of maternal diet during lactation and the use of formula feeds on the development of atopic eczema in infants at risk. DESIGN--Mothers who planned to breast feed exclusively were randomly allocated to either a restricted diet (avoiding milk and other dairy products, eggs, fish, peanuts, and soybeans) or a diet without restrictions. Mothers who did not plan to breast feed were randomly allocated to using one of three formula feeds. SETTING--Child health centre in Canada. SUBJECTS--97 Mothers who chose to breast feed and 124 mothers who did not. INTERVENTIONS--Restricted diet for 49 mothers who breast fed. Casein hydrolysate formula, soy milk formula, or cows' milk formula for infants not breast fed. MAIN OUTCOME MEASURE--Development of eczema in babies. RESULTS--Infants were followed up over 18 months and examined for eczema. Eczema was less common and milder in babies who were breast fed and whose mothers were on a restricted diet (11/49 (22%) v 21/48 (48%)). In infants fed casein hydrolysate, soy milk, or cows' milk 9/43 (21%), 26/41 (63%), and 28/40 (70%), respectively, developed atopic eczema. CONCLUSIONS--In families with a history of atopic disease [corrected] mothers who breast feed should avoid common allergenic foods during lactation. If they choose not to breast feed a hydrolysate formula should be used.
Dysrhythmias with general anesthesia during dental surgery have been frequently reported. The incidence appears higher in spontaneously breathing patients lightly anesthetized with halothane. Anxiety, sitting posture, hypoxia, Chinese race, and heart disease appear to aggravate the condition. Use of beta blockers or lidocaine prior to anesthesia, intravenous induction, controlled ventilation with muscle relaxants, and use of isoflurane or enflurane in spontaneously breathing patients appear to decrease the incidence. It is stressed that continuous cardiac monitoring should be done in patients undergoing dental surgery under anesthesia in order to detect diagnose and treat any dysrhythmia. The great majority of dysrhythmias disappear either spontaneously or when the stimulus is stopped. In some cases there may be an obvious cause that should be immediately corrected. The need for drug intervention is rare and must be used with great care when used.
For people of Chinese descent, facial configuration differs from that of other Asians as well as Caucasians, and the standard nasal masks used in dentistry do not fit their faces well. A simple, easily sterilizable nasal mask has been developed for this purpose and is adaptable to existing nitrous oxide machines.
Nutrition is a major determinant of host resistance. Both deficiencies and excesses impair immune responses and lead to increased risk of infection and other diseases. Changes in immunity occur early in the development of nutritional deficiency; thus immunocompetence can be used as a sensitive functional index of undernutrition and as a prognostic marker of post-operative complications. Nutritional support enhances antibody response to common immunization procedures in such populations at risk of malnutrition as the elderly.
malnutrition; immune response; surgery; immunization