Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 119
Filter
1.
Indian J Endocrinol Metab ; 26(3): 206-212, 2022.
Article in English | MEDLINE | ID: mdl-36248052

ABSTRACT

Chronic consumption of a large quantity of alcohol often results in the disruption of the communication between the nervous, endocrine and immune systems leading to profound and serious consequences at the physiological and behavioral levels. The overall impact of excessive alcohol consumption on bone health, metabolic profile and body composition, especially at moderate levels, is not well understood. Chronic excessive alcohol consumption adversely affects bone health through multiple mechanisms leading to low bone mass. It may also be significantly associated with various components on the metabolic syndrome. This review summarizes the findings from published studies that provide consistent evidence on the various effects of alcohol abuse on the bone health and metabolism.

2.
Arch Osteoporos ; 17(1): 32, 2022 02 05.
Article in English | MEDLINE | ID: mdl-35122523

ABSTRACT

This study from southern India showed that proximal hip geometry was significantly impaired in postmenopausal women with femoral neck fracture. The trabecular bone score (TBS), which is reflective of bone microarchitecture, was also significantly impaired in patients with fracture. INTRODUCTION: There is limited information with regard to comprehensive bone health in Indian postmenopausal women with neck of femur fracture. We studied the bone mineral density (BMD), trabecular bone score (TBS), proximal hip geometry, and bone mineral biochemistry in postmenopausal women with and without femoral neck fractures. METHODS: This was a cross-sectional study conducted at a tertiary care center in South India. BMD, TBS, and hip structural analysis (HSA) were assessed using a dual-energy X-ray absorptiometry (DXA) scanner. Bone mineral biochemical profiles were also studied. RESULTS: A total of 90 postmenopausal women with acute femoral neck fracture with mean (SD) age of 63.2 (6.1) years and 90 age-matched controls were included. The prevalence of osteoporosis was higher among cases as compared to controls (83.3% vs 47.8%; P < 0.001). Degraded bone microarchitecture (TBS value < 1.200) was more frequent among women with hip fracture as compared to controls (46.7% vs 31.1%; P = 0.032). Cross-sectional moment of inertia (CSMI) was significantly lower at the narrow neck (NN) and inter-trochanteric (IT) region in cases (P < 0.05) and buckling ratio (BR) was significantly higher at all three sites in postmenopausal women with femoral neck fracture as compared controls. Multivariate logistic regression analysis showed that femoral neck osteoporosis, low CSMI at NN and high BR at NN and femoral shaft emerged as factors significantly associated with femoral neck fractures. CONCLUSION: This study highlights that impaired parameters of proximal hip geometry and a low trabecular bone score may be significantly associated with femoral neck fractures in postmenopausal women.


Subject(s)
Hip Fractures , Osteoporosis, Postmenopausal , Absorptiometry, Photon , Bone Density , Cross-Sectional Studies , Female , Femur Neck/diagnostic imaging , Hip Fractures/complications , Hip Fractures/diagnostic imaging , Hip Fractures/epidemiology , Humans , Middle Aged , Osteoporosis, Postmenopausal/complications , Osteoporosis, Postmenopausal/diagnostic imaging , Osteoporosis, Postmenopausal/epidemiology , Postmenopause
3.
J Family Med Prim Care ; 9(7): 3770-3772, 2020 Jul.
Article in English | MEDLINE | ID: mdl-33102369

ABSTRACT

We present the case of a 45-year-old lady with long standing hypothyroidism who was euthyroid on replacement for many years, but stopped responding even to supraphysiological doses of LT4 since the last five years. She complained of abdominal discomfort, bloating, and nausea. She did not have diarrhea or weight loss. Levothyroxine absorption test was done which was suggestive of malabsorption and she was started on triple therapy for H. pylori eradication after confirmation of diagnosis. After 10 days of treatment initiation, she developed symptoms of thyrotoxicosis with her supraphysiological dose of LT4, which was then tapered to a lower dose. Euthyroid state was ultimately achieved with lower doses of LT4 replacement.

4.
J Family Med Prim Care ; 9(8): 4451-4453, 2020 Aug.
Article in English | MEDLINE | ID: mdl-33110883

ABSTRACT

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipoprotein metabolism caused by defects in the low-density lipoprotein receptor (LDLR) gene. It is characterized by high low-density lipoprotein (LDL) cholesterol levels, premature cardiovascular disease (CVD), and tendon xanthomas. We present the case of a 26-year-old gentleman who presented with multiple nodular eruptions over the extensor aspects of upper and lower limbs and was diagnosed as FH on the basis of positive family history, typical lipid profile abnormalities, and biopsy of the nodule consistent with tendon xanthomas. The diagnosis and management of this case is deftly feasible at the primary care level.

5.
BMJ Case Rep ; 13(3)2020 Mar 12.
Article in English | MEDLINE | ID: mdl-32169989

ABSTRACT

Paraganglioma of the bladder is a rare tumour accounting for less than 0.06% of all urinary bladder tumours and has varied presentations. It may present with clinical symptoms of phaeochromocytoma, may be non-functioning and asymptomatic or may present with haematuria. Hence, paragangliomas are occasionally misdiagnosed, and this results in unanticipated intraoperative hypertensive crisis. We present the case of a 44-year-old woman with urinary bladder paraganglioma who presented with young onset hypertension, recurrent micturition syncope with prior history of coronary artery disease and stroke. She was stabilised preoperatively with alpha blocking agents and subsequently underwent successful transurethral resection of the same.


Subject(s)
Paraganglioma/surgery , Syncope/etiology , Urinary Bladder Neoplasms/complications , 3-Iodobenzylguanidine/metabolism , Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Adult , Diagnosis, Differential , Diagnostic Errors , Female , Humans , Hypertension/complications , Normetanephrine/urine , Prazosin/therapeutic use , Preoperative Care , Syncope/drug therapy , Tomography, X-Ray Computed/methods , Treatment Outcome , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/pathology
6.
Oncogenesis ; 6(5): e336, 2017 May 15.
Article in English | MEDLINE | ID: mdl-28504693

ABSTRACT

High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts. The cellular processes affected by CDK7 inhibition were analyzed by reverse transcriptase-quantitative PCR, western blot, flow cytometry and immunofluorescence. THZ1 perturbed the transcriptome and disabled CDK activation, leading to cell cycle arrest at G2 and DNA damage. THZ1 halted transcription of the nuclear-encoded mitochondrial ribosomal genes, reducing mitochondrial translation and oxidative respiration. It also inhibited the expression of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFR-α), reducing signaling flux through the AKT, extracellular-signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) downstream pathways. Finally, THZ1 disrupted nucleolar, Cajal body and nuclear speckle formation, resulting in reduced cytosolic translation and malfunction of the spliceosome and thus leading to aberrant mRNA processing. These findings indicate that CDK7 is crucial for gliomagenesis, validate CDK7 as a therapeutic target and provide new insight into the cellular processes that are affected by THZ1 and induce antitumor activity.

7.
Cell Death Discov ; 2: 16016, 2016.
Article in English | MEDLINE | ID: mdl-27551510

ABSTRACT

Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.

8.
Article in English | MEDLINE | ID: mdl-26236384

ABSTRACT

Background. Inflammation, together with related oxidative stress, is linked with the etiology of kwashiorkor, a form of severe acute malnutrition in children. A diet rich in anti-inflammatory and antioxidant phytochemicals may offer potential for the prevention and treatment of kwashiorkor. We selected and assayed five leafy green vegetables, two wild fruits, and six medicinal plants from Kenya for their antioxidant and anti-inflammatory properties. Consensus regarding medicinal plant use was established from ethnobotanical data. Methods. Antioxidant activity and phenolic content were determined using the oxygen radical absorbance capacity (ORAC) assay and Folin-Ciocalteu procedure, respectively. Anti-inflammatory activity was assessed in vitro targeting the inflammatory mediator tumour necrosis factor-alpha (TNF-α). Results. Mangifera indica (leaves used medicinally) showed the greatest antioxidant activity (5940 ± 632 µM TE/µg) and total phenolic content (337 ± 3 mg GAE/g) but Amaranthus dubius (leafy vegetable) showed the greatest inhibition of TNF-α (IC50 = 9 ± 1 µg/mL), followed by Ocimum americanum (medicinal plant) (IC50 = 16 ± 1 µg/mL). Informant consensus was significantly correlated with anti-inflammatory effects among active medicinal plants (r (2) = 0.7639, P = 0.0228). Conclusions. Several plant species commonly consumed by Kenyan children possess activity profiles relevant to the prevention and treatment of kwashiorkor and warrant further investigation.

9.
Oncogene ; 34(41): 5277-87, 2015 Oct 08.
Article in English | MEDLINE | ID: mdl-25659577

ABSTRACT

A truncation mutant of the epidermal growth factor receptor, EGFRvIII, is commonly expressed in glioma, an incurable brain cancer. EGFRvIII is tumorigenic, in part, through its transactivation of other receptor tyrosine kinases (RTKs). Preventing the effects of this transactivation could form part of an effective therapy for glioma; however, the mechanism by which the transactivation occurs is unknown. Focusing on the RTK MET, we show that MET transactivation in U87MG human glioma cells in vitro is proportional to EGFRvIII activity and involves MET heterodimerization associated with a focal adhesion kinase (FAK) scaffold. The transactivation of certain other RTKs was, however, independent of FAK. Simultaneously targeting EGFRvIII (with panitumumab) and the transactivated RTKs themselves (with motesanib) in an intracranial mouse model of glioma resulted in significantly greater survival than with either agent alone, indicating that cotargeting these RTKs has potent antitumor efficacy and providing a strategy for treating EGFRvIII-expressing gliomas, which are usually refractory to treatment.


Subject(s)
Brain Neoplasms/metabolism , ErbB Receptors/physiology , Glioma/metabolism , Transcriptional Activation , Analgesics/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Apoptosis , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Cell Line, Tumor , ErbB Receptors/antagonists & inhibitors , Female , Focal Adhesion Kinase 1/metabolism , Glioma/drug therapy , Glioma/genetics , Indoles/pharmacology , Mice, Inbred BALB C , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Oligonucleotides , Panitumumab , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction , Xenograft Model Antitumor Assays
10.
Cell Death Dis ; 6: e1664, 2015 Feb 26.
Article in English | MEDLINE | ID: mdl-25719248

ABSTRACT

Mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation so that cells with a high requirement for ATP generated through oxidative phosphorylation have high mtDNA copy number, whereas those with a low requirement have few copies. Using immunoprecipitation of DNA methylation on 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which distinguish between de novo DNA methylation and demethylation, respectively, we set out to determine whether DNA methylation at exon 2 of the human mtDNA-specific polymerase (DNA polymerase gamma A (POLGA)) regulates cell-specific mtDNA copy number in highly proliferative and terminally differentiated cells. Highly proliferative cancer and pluripotent and multipotent cells possessed low mtDNA copy number and were highly methylated at exon 2 of POLGA in contrast to post-mitotic cells. Unlike neural stem cells, cancer cells were unable to differentiate and remained extensively DNA methylated at exon 2 of POLGA. However, mtDNA depletion of cancer cells reduced DNA methylation at exon 2 of POLGA as they replenished mtDNA to form tumours in mice. Glioblastoma cells treated with the DNA demethylation agent 5-azacytidine over 28 days of astrocyte-induced differentiation demethylated exon 2 of POLGA leading to increased mtDNA copy number and expression of the astrocyte endpoint marker glial fibrillary acidic protein (GFAP). However, the demethylation agent vitamin C (VitC) was unable to sustain increased mtDNA copy number and differentiation, as was the case when VitC was withdrawn after short-term treatment. These data demonstrate that DNA demethylation of POLGA is an essential regulator of mtDNA copy number and cellular fate and that cancer cells are only able to modulate DNA methylation of POLGA and mtDNA copy number in the presence of a DNA demethylation agent that inhibits de novo methyltransferase 1 activity.


Subject(s)
DNA Methylation/genetics , DNA, Mitochondrial/genetics , DNA-Directed DNA Polymerase/genetics , Ascorbic Acid/pharmacology , Azacitidine/pharmacology , Blotting, Western , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line , Cell Line, Tumor , Chromatin Immunoprecipitation , DNA Copy Number Variations/genetics , DNA Methylation/drug effects , DNA Polymerase gamma , DNA-Directed DNA Polymerase/metabolism , Humans , Immunoprecipitation , Real-Time Polymerase Chain Reaction
11.
Cell Death Discov ; 1: 15028, 2015.
Article in English | MEDLINE | ID: mdl-27551460

ABSTRACT

MAPK-activated protein kinase 2 (MK2) is a checkpoint kinase involved in the DNA damage response. MK2 inhibition enhances the efficacy of chemotherapeutic agents; however, whether MK2 inhibition alone, without concurrent chemotherapy, would attenuate survival of cancer cells has not been investigated. CMPD1 is a widely used non-ATP competitive inhibitor that prevents MK2 phosphorylation. We employed CMPD1 together with MK2 knock-down and ATP-competitive MK2 inhibitor III (MK2i) in a panel of glioblastoma cells to assess whether MK2 inhibition could induce cancer cell death. While CMPD1 was effective at selective killing of cancer cells, MK2i and MK2 knock-down had no effect on viability of glioblastoma cells. CMPD1 treatment induced a significant G2/M arrest but MK2i-treated cells were only minimally arrested at G1 phase. Intriguingly, at doses that were cytotoxic to glioblastoma cells, CMPD1 did not inhibit phosphorylation of MK2 and of its downstream substrate Hsp27. These results suggest that CMPD1 exhibits cytotoxic activity independently of MK2 inhibition. Indeed, we identified tubulin as a primary target of the CMPD1 cytotoxic activity. This study demonstrates how functional and mechanistic studies with appropriate selection of test compounds, combining genetic knock-down and pharmacological inhibition, coordinating timing and dose levels enabled us to uncover the primary target of an MK2 inhibitor commonly used in the research community. Tubulin is emerging as one of the most common non-kinase targets for kinase inhibitors and we propose that potential tubulin-targeting activity should be assessed in preclinical pharmacology studies of all novel kinase inhibitors.

12.
Oncogene ; 34(13): 1658-66, 2015 Mar 26.
Article in English | MEDLINE | ID: mdl-24747966

ABSTRACT

A feature of many gliomas is the amplification of the epidermal growth factor receptor (EGFR), resulting in its overexpression. Missense mutations or deletions within the extracellular domain are associated with this amplification and can lead to constitutive activation of the receptor, with the Domain I/II deletion, EGFRvIII, being the most common. These changes have also been associated with increased sensitivity to EGFR inhibition using small molecule inhibitors. We have expressed, in human glioma cells, EGFR containing four glioma-specific EGFR missense mutations within Domain IV (C620Y, C624F, C628Y and C636Y) to analyze their biological properties and sensitivity to EGFR inhibition. One of these mutants, C620Y, exhibited an enhanced basal phosphorylation, which was partially dependent on an EGFR-ligand autocrine loop. All Domain IV mutants responded equally as well as wildtype EGFR (wtEGFR) to ligand stimulation. Biochemical analysis revealed that a pre-formed, disulfide-bonded dimer associated with these mutations was underglycosylated, inactive and cytoplasmically retained. Ligand stimulation resulted in the formation of a tyrosine-phosphorylated, disulfide-bonded dimer for all Domain IV mutants but not for wtEGFR. Following treatment with the next-generation, irreversible pan-ErbB inhibitor dacomitinib, the C620Y, C624F and EGFRvIII mutants were inactivated, covalently dimerized and were retained in the cytoplasm, resulting in cell-surface receptor loss and, for C620Y and C624F, decreased binding of EGF. Dacomitinib treatment significantly reduced the in vivo growth of human glioma xenografts bearing C620Y, but not wtEGFR. Collectively, these data indicate that the unique biochemical traits of Domain IV EGFR cysteine mutants can be exploited for enhanced sensitivity to EGFR small molecule inhibitors, with potential clinical applications.


Subject(s)
ErbB Receptors/genetics , Glioma/drug therapy , Mutation , Protein Multimerization , Quinazolinones/therapeutic use , Animals , Cell Line, Tumor , Cysteine , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , Female , Glioma/genetics , Glioma/pathology , Humans , Ligands , Mice , Mice, Inbred BALB C , Phosphorylation , Protein Structure, Tertiary , Quinazolinones/pharmacology
13.
Hum Reprod ; 29(7): 1375-9, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24812320

ABSTRACT

Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1-2 doses of i.m. methotrexate (50 mg/m² on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.


Subject(s)
Methotrexate/administration & dosage , Pregnancy, Ectopic/drug therapy , Quinazolines/administration & dosage , Abortifacient Agents, Nonsteroidal/administration & dosage , Acneiform Eruptions/chemically induced , Adult , Cesarean Section/adverse effects , Chorionic Gonadotropin/blood , Fallopian Tubes/physiopathology , Female , Gefitinib , Humans , Pregnancy , Pregnancy Outcome , Ultrasonography, Prenatal , Young Adult
14.
Cell Death Differ ; 20(12): 1644-53, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23995230

ABSTRACT

As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme.


Subject(s)
Brain Neoplasms/genetics , DNA Copy Number Variations/genetics , DNA, Mitochondrial/genetics , Glioblastoma/genetics , Animals , Biomarkers, Tumor/genetics , Brain Neoplasms/pathology , Cell Differentiation/genetics , Cell Line, Tumor , Cell Nucleus/genetics , Cell Respiration/genetics , DNA Replication/genetics , Gene Expression Regulation, Neoplastic , Glial Fibrillary Acidic Protein/metabolism , Glioblastoma/pathology , Humans , Mice , Neural Stem Cells/metabolism , Up-Regulation/genetics
15.
Scand J Surg ; 99(3): 153-61, 2010.
Article in English | MEDLINE | ID: mdl-21044933

ABSTRACT

INTRODUCTION: current studies suggest immunonutrition decreases the inflammatory process, infection rates and reduces length of hospital stay in surgical patients, however studies are often conducted on heterogeneous groups of patients with varying composition of the immuno-nutrition. We aim to investigate the effect of immunonutrition on patients undergoing major upper gastrointestinal surgery by assessment of (i) the inflammatory and immune response and (ii) changes in clinical outcome when compared to a randomised control receiving conventional feeding. METHOD: a prospective double-blind randomised controlled study was undertaken to compare a feed supplemented with glutamine, arginine, -3 fatty acids and tributyrin, vitamin C, E and B-carotene and micronutrients (zinc, selenium and chromium) to an isonitrogenous, isocaloric control feed in patients undergoing major upper GI surgery. The primary end-points were defined as C-reactive protein (CRP), prealbumin and retinol binding protein (RBP) levels. Secondary end-points included performance scoring systems, length of hospital stay, adverse events and protein and nutrient assays. Variables were measured pre-operatively and routinely up to the 4th post-operative day. RESULTS: there was no statistically significant change in primary end-points between the immunonutrition group and the control group. There was no difference in length of hospital stay between the groups. The vitamin C level in the study group was significantly higher at the end of the study period. Both groups tolerated the feeds well with adequate target feeding rate. There were no other significant changes in clinical outcomes between the two groups. CONCLUSION: this study has not shown a benefit of immunonutrition through changes in inflammatory or nutritional markers, a decrease in length of hospital stay, or other morbidity. This may be because of inadequate numbers recruited to the study. Further, multi-centre, randomised trials on homogeneous patient groups are necessary to investigate the role of immunonutrition in major upper GI surgery.


Subject(s)
Digestive System Surgical Procedures , Enteral Nutrition/methods , Postoperative Care/methods , Aged , Amino Acids/blood , Arginine/administration & dosage , Ascorbic Acid/blood , C-Reactive Protein/analysis , Chromium/administration & dosage , Double-Blind Method , Energy Intake , Fatty Acids, Omega-3/administration & dosage , Female , Glutamine/administration & dosage , Humans , Length of Stay , Male , Micronutrients/administration & dosage , Middle Aged , Postoperative Care/standards , Prospective Studies , Retinol-Binding Proteins/analysis , Selenium/administration & dosage , Triglycerides/administration & dosage , Zinc/administration & dosage
16.
J Wound Care ; 18(12): 497-503, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20081574

ABSTRACT

OBJECTIVE: To establish the feasibility of conducting a home-based progressive resistance exercise programme to improve calf muscle pump function in community-based patients with venous leg ulcers. METHOD: Participants were randomised to receive a 12-week progressive resistance exercise programme using heel raises in addition to compression. The control was usual care in addition to compression. Randomisation was stratified by ulcer duration and ulcer size. Air plethysmography was used to determine changes in calf muscle pump function from baseline. Changes in ulcer parameters were measured using the SilhouetteMobile device. RESULTS: Forty participants were randomised. There were significantly greater improvements in ejection fraction of the calf muscle in the exercise group compared with the control (usual care) group (mean difference 18.5%, 95% CI 0.03 to 36.6%, p<0.05). Other parameters improved in the exercise group but the mean differences were not significant. Adherence with prescribed exercises was 81% and there was no significant difference in the numbers reporting adverse events. There were also no significant differences in ulcer healing parameters (change in area, percentage change in area, number healed at 12 weeks, time to healing). CONCLUSION: A community-based randomised trial of progressive resistance exercise is feasible. The prescribed exercises appeared to increase ejection fraction, but the effect of exercise on ulcer healing requires further investigation.


Subject(s)
Resistance Training , Varicose Ulcer/therapy , Female , Humans , Male , Middle Aged , Muscle, Skeletal/blood supply , Patient Compliance , Resistance Training/adverse effects , Wound Healing
17.
Br J Cancer ; 99(2): 294-304, 2008 Jul 22.
Article in English | MEDLINE | ID: mdl-18594532

ABSTRACT

TRAIL/Apo-2L has shown promise as an anti-glioma drug, based on investigations of TRAIL sensitivity in established glioma cell lines, but it is not known how accurately TRAIL signalling pathways of glioma cells in vivo are reproduced in these cell lines in vitro. To replicate as closely as possible the in vivo behaviour of malignant glioma cells, 17 early passage glioma cell lines and 5 freshly resected gliomas were exposed to TRAIL-based agents and/or chemotherapeutic drugs. Normal human hepatocytes and astrocytes and established glioma cell lines were also tested. Cross-linked TRAIL, but not soluble TRAIL, killed both normal cell types and cells from three tumours. Cells from only one glioma were killed by soluble TRAIL, although only inefficiently. High concentrations of cisplatin were lethal to glioma cells, hepatocytes and astrocytes. Isolated combinations of TRAIL and chemotherapy drugs were more toxic to particular gliomas than normal cells, but no combination was generally selective for glioma cells. This study highlights the widespread resistance of glioma cells to TRAIL-based agents, but suggests that a minority of high-grade glioma patients may benefit from particular combinations of TRAIL and chemotherapy drugs. In vitro sensitivity assays may help identify effective drug combinations for individual glioma patients.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Glioma/drug therapy , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Adult , Aged , Antineoplastic Agents/administration & dosage , Astrocytes/drug effects , Carboplatin/administration & dosage , Cell Line, Tumor , Cisplatin/administration & dosage , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Drug Screening Assays, Antitumor , Etoposide/administration & dosage , Female , Glioblastoma/drug therapy , Glioblastoma/pathology , Glioma/pathology , Hepatocytes/drug effects , Humans , Lomustine/administration & dosage , Male , Membrane Glycoproteins/administration & dosage , Middle Aged , Procarbazine/administration & dosage , Recombinant Fusion Proteins/administration & dosage , TNF-Related Apoptosis-Inducing Ligand/administration & dosage , Temozolomide , Tumor Necrosis Factor-alpha/administration & dosage , Vincristine/administration & dosage
18.
J Med Food ; 10(1): 73-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17472470

ABSTRACT

Standardized extracts of Echinacea, cat's claw, and saw palmetto were each evaluated for ability to activate macrophage and natural killer cells, in vitro, using two independent measures of activation for each immune cell population. A standard series of exposure concentrations were tested for each herbal extract in a panel of four assays that evaluated macrophage phagocytosis, macrophage synthesis of interleukin-12, natural killer (NK) cell cytocidal activity (synthesis of granzyme B), and NK cell synthesis of interferon-gamma. Macrophage phagocytosis was stimulated by all three herbs tested: saw palmetto (up to 2.3-fold, P < .05), Echinacea (up to 3.6-fold, P < .01), and cat's claw (up to 4.7-fold, P < .01). Additionally, NK cell synthesis of interferon-gamma was stimulated by saw palmetto (up to 6.3-fold, P < .01) and Echinacea (up to 8.1 fold, P < .01) but not by exposure to cat's claw. None of the three herbs stimulated macrophage synthesis of interleukin-12 or NK cell synthesis of granzyme B. Comparison of the in vitro data with our earlier observations that cat's claw and Echinacea (but not saw palmetto) were each effective in reducing B16/F10 lung tumor colony formation in C57BL/6J mice suggests macrophage activation is the primary means by which these herbs modulate the immune system. Thus, macrophage activation (phagocytosis) may provide a potentially higher throughput method to identify herbal extracts with in vivo stimulatory effects.


Subject(s)
Immunologic Factors/pharmacology , Macrophage Activation/drug effects , Plant Extracts/pharmacology , Cat's Claw/chemistry , Cell Line , Echinacea/chemistry , Granzymes/biosynthesis , Humans , Interferon-gamma/biosynthesis , Interleukin-12/biosynthesis , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Macrophages/drug effects , Macrophages/immunology , Phagocytosis/drug effects , Phytotherapy , Serenoa/chemistry
19.
Biochem Pharmacol ; 71(10): 1422-34, 2006 May 14.
Article in English | MEDLINE | ID: mdl-16522318

ABSTRACT

The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.


Subject(s)
Enzyme Inhibitors/pharmacokinetics , ErbB Receptors/antagonists & inhibitors , Protein Tyrosine Phosphatases/antagonists & inhibitors , Tyrphostins/pharmacokinetics , Animals , Area Under Curve , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Injections, Intravenous , Injections, Subcutaneous , Mice , Molecular Structure , Quinazolines , Rats , Thymidine/metabolism , Tyrphostins/chemistry , Tyrphostins/pharmacology , Xenograft Model Antitumor Assays
20.
Biol Neonate ; 89(2): 133-8, 2006.
Article in English | MEDLINE | ID: mdl-16210848

ABSTRACT

BACKGROUND: The medicinal benefits of Echinacea sp. plants in several disease conditions, including insect bites, respiratory ailments, and even cancer and AIDS, have been touted for decades. Echinacea sp.-based phytoceuticals are among the top selling herbals in the Western marketplace today. However, evidence is very scant concerning the effects of using Echinacea species herbals during pregnancy. While available data indicates that fetal malformations do not occur during pregnancy in humans consuming this herb, there are no formal studies aimed at assessing the possibility that consuming Echinacea herbals may promote spontaneous abortions, thereby reducing the number of live births upon which to assess the presence or absence of malformations. OBJECTIVES: We undertook a study in which pregnant mice were fed daily Echinacea purpurea from pregnancy onset until gestational days 10, 11, 12, 13, and 14. METHODS: Maternal spleen and bone marrow were taken for enumeration of cells in each of five separate hemopoietic lineages/organ, and fetal status was recorded. RESULTS: The data indicate that the significant, pregnancy-induced elevation in splenic lymphocytes and nucleated erythroid cells was all but eliminated in those females which consumed E. purpurea daily throughout their pregnancy. Moreover, consuming E. purpurea during pregnancy reduced the number of viable fetuses. CONCLUSIONS: The data may be extrapolated to suggest that in humans, abstention from consuming Echinacea products during the early/mid stages of pregnancy, may be prudent.


Subject(s)
Diet , Echinacea/adverse effects , Fetal Development , Hematopoiesis , Animals , Bone Marrow Cells , Erythroblasts , Erythrocyte Count , Female , Gestational Age , Lymphocyte Count , Mice , Pregnancy , Spleen/cytology
SELECTION OF CITATIONS
SEARCH DETAIL
...