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1.
J Immunol ; 210(7): 972-980, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36779805

ABSTRACT

The anemia of critical illness (ACI) is a nearly universal pathophysiological consequence of burn injury and a primary reason burn patients require massive quantities of transfused blood. Inflammatory processes are expected to drive postburn ACI and prevent meaningful erythropoietic stimulation through iron or erythropoietin supplementation, but to this day no specific inflammatory pathways have been identified as a critical mechanism. In this study, we examined whether secretion of G-CSF and IL-6 mediates distinct features of postburn ACI and interrogated inflammatory mechanisms that could be responsible for their secretion. Our analysis of mouse and human skin samples identified the burn wound as a primary source of G-CSF and IL-6 secretion. We show that G-CSF and IL-6 are secreted independently through an IL-1/MyD88-dependent mechanism, and we ruled out TLR2 and TLR4 as critical receptors. Our results indicate that IL-1/MyD88-dependent G-CSF secretion plays a key role in impairing medullary erythropoiesis and IL-6 secretion plays a key role in limiting the access of erythroid cells to iron. Importantly, we found that IL-1α/ß neutralizing Abs broadly attenuated features of postburn ACI that could be attributed to G-CSF or IL-6 secretion and rescued deficits of circulating RBC counts, hemoglobin, and hematocrit caused by burn injury. We conclude that wound-based IL-1/MyD88 signaling mediates postburn ACI through induction of G-CSF and IL-6 secretion.


Subject(s)
Anemia , Burns , Humans , Granulocyte Colony-Stimulating Factor/metabolism , Interleukin-6/metabolism , Myeloid Differentiation Factor 88/metabolism , Anemia/etiology , Burns/complications , Iron/metabolism , Interleukin-1/metabolism
2.
BJS Open ; 4(3): 380-390, 2020 06.
Article in English | MEDLINE | ID: mdl-32181587

ABSTRACT

BACKGROUND: Immediate implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure in the UK, but almost one in ten women experience implant loss and reconstructive failure after this technique. Little is known about how implant loss impacts on patients' quality of life. The first phase of the Loss of implant Breast Reconstruction (LiBRA) study aimed to use qualitative methods to explore women's experiences of implant loss and develop recommendations to improve care. METHODS: Semistructured interviews were conducted with a purposive sample of women who experienced implant loss after immediate IBBR, performed for malignancy or risk reduction across six centres. Interviews explored decision-making regarding IBBR, and experiences of implant loss and support received. Thematic analysis was used to explore the qualitative interview data. Sampling, data collection and analysis were undertaken concurrently and iteratively until data saturation was achieved. RESULTS: Twenty-four women were interviewed; 19 had surgery for malignancy and five for risk reduction. The median time between implant loss and interview was 42 (range 22-74) months. Ten women had undergone secondary reconstruction, two were awaiting surgery, and 12 had declined further reconstruction. Three key themes were identified: the need for accurate information about the risks and benefits of IBBR; the need for more information about 'early-warning' signs of postoperative problems, to empower women to seek help; and better support following implant loss. CONCLUSION: Implant loss is a devastating event for many women. Better preoperative information and support, along with holistic patient-centred care when complications occur, may significantly improve the experience and outcome of care.


ANTECEDENTES: La reconstrucción mamaria inmediata con prótesis (implant-based breast reconstruction, IBBR) es el procedimiento reconstructivo más utilizado en el Reino Unido, pero casi una de cada diez mujeres presentará pérdida de la prótesis y fallo del procedimiento reconstructivo tras esta técnica. Se sabe poco de cómo la pérdida de la prótesis afecta la calidad de vida de las pacientes. La primera fase del estudio LiBRA tuvo como objetivo explorar la percepción de las mujeres ante la pérdida de la prótesis, utilizando métodos cualitativos, y proponer una serie de medidas para mejorar la atención sanitaria de estas pacientes. MÉTODOS: Se realizaron entrevistas semiestructuradas en una muestra de mujeres que padecieron la pérdida de la prótesis tras una IBBR inmediata, realizada por neoplasia o como procedimiento de reducción de riesgo, en seis centros. Las entrevistas analizaron la toma de decisiones con respecto a la IBBR inmediata, así como la percepción ante la pérdida del implante y el soporte recibido. Se utilizó un análisis por temas para examinar los datos de la entrevista cualitativa. El muestreo, la recopilación de datos y el análisis se realizaron de forma simultánea e iterativa hasta que se logró la saturación de datos. RESULTADOS: Se entrevistaron 24 pacientes; 19 en las que la indicación quirúrgica fue por cáncer y 5 por reducción de riesgo. La mediana del tiempo entre la pérdida del implante y la entrevista fue de 42 (rango 22-52) meses. Diez mujeres se habían sometido a una reconstrucción secundaria; dos estaban a la espera de la cirugía y 12 habían rechazado la reconstrucción posterior. Se identificaron tres temas clave, siendo las necesidades de: i) información precisa sobre los riesgos y beneficios de la IBBR, ii) más información sobre los signos de "alarma precoz" de las complicaciones postoperatorias que permitiesen a las mujeres buscar ayuda, y iii) mejor soporte tras la pérdida de la prótesis. CONCLUSIÓN: La pérdida de una prótesis es una complicación catastrófica para muchas mujeres. Una mejor información y apoyo preoperatorios, junto con una atención holística centrada en la paciente cuando se presentan las complicaciones, podrían mejorar significativamente la experiencia y el resultado de la atención.


Subject(s)
Breast Implants/adverse effects , Breast Neoplasms/psychology , Mammaplasty/adverse effects , Prosthesis Failure , Quality of Life , Adult , Aged , Breast Implantation/methods , Breast Neoplasms/surgery , Female , Humans , Interviews as Topic , Mammaplasty/methods , Middle Aged , Postoperative Complications/etiology , Qualitative Research , United Kingdom
3.
Br J Surg ; 107(7): 832-844, 2020 06.
Article in English | MEDLINE | ID: mdl-32073654

ABSTRACT

BACKGROUND: Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR. METHODS: The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy. RESULTS: A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P < 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment. CONCLUSION: TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.


ANTECEDENTES: La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante. RESULTADOS: Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P < 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.


Subject(s)
Mammaplasty , Mastectomy , Adult , Aged , Aged, 80 and over , Female , Humans , Kaplan-Meier Estimate , Logistic Models , Mammaplasty/adverse effects , Mammaplasty/methods , Mastectomy/adverse effects , Mastectomy/methods , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Proportional Hazards Models , Treatment Outcome , Young Adult
4.
Vet J ; 214: 14-20, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27387720

ABSTRACT

The relationships between diet, obesity and insulin dysregulation in equids require further investigation due to their association with laminitis. This study examined the effect of dietary glycaemic load and increased adiposity on insulin sensitivity and adipokine concentrations in different equine breeds. Equal numbers of Standardbred horses, mixed-breed ponies and Andalusian horses were provided with ad libitum hay plus either cereal-rich (CHO; n = 12), fat-rich (FAT; n = 12) or control (CON; n = 9) meals over 20 weeks. The isocaloric CHO and FAT diets were fed to induce obesity by gradually increasing the supplementary feeds to provide 200% of daily digestible energy requirements by Week 20. The CON group were fed a basal ration only and maintained moderate body condition. At Week 20, the CHO and FAT groups demonstrated significantly increased body condition score, bodyweight, total body fat mass and plasma leptin concentrations compared with the CON group (P <0.001). The CHO group had lower insulin sensitivity (SI; P <0.001) and higher acute insulin response to glucose (P = 0.002) than the CON group. In contrast, the FAT group was no different to the control group. Ponies and Andalusians had lower SI values compared with Standardbreds, regardless of diet group (P = 0.001). Adiponectin concentrations were similar between the FAT and CON groups, but were significantly lower in the CHO group (P = 0.010). The provision of cereal-rich meals appeared to be a more important determinant of insulin sensitivity than the induction of obesity per se. Whether hypoadiponectinaemia is a cause or consequence of insulin dysregulation warrants further investigation.


Subject(s)
Adipokines/metabolism , Adiposity , Dietary Fats/analysis , Edible Grain , Glycemic Load , Horse Diseases/physiopathology , Insulin Resistance/physiology , Animal Feed/analysis , Animal Nutritional Physiological Phenomena/drug effects , Animals , Diet/veterinary , Dietary Supplements/analysis , Female , Horse Diseases/genetics , Horses , Male
5.
Free Radic Res ; 49(1): 45-56, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25377300

ABSTRACT

Peroxisome proliferator-activated receptor gamma (PPARγ) is known to be activated via exercise-associated transient increases in oxidative stress. However, the precise mechanism(s) triggering PPARγ activation in monocytes during/following exercise remain to be confirmed. Here, two cohorts of five healthy male individuals undertook exercise bouts (cycling; 70% VO2max; 45 min) in the presence/absence of dietary antioxidant supplementation (vitamins C (1000 mg/day) and E (400IU/day) for four weeks before exercise); monocytic 5' adenosine monophosphate-activated protein kinase (AMPK)/PPARγ co-activator-1alpha (PGC-1α)/PPARγ signalling was investigated in samples obtained before exercise and up to 24 h after exercise, while THP-1 cells were cultured as an in vitro monocyte model. In THP-1 cells, AMPKα1 was phosphorylated within 1h of menadione (15 µM)-triggered increases in [reactive oxygen species (ROS)]cyto, an effect which was followed by upregulation of PPARγ and several of its target genes (PGC-1α, liver X receptor alpha [LXRα] and ATP-binding cassette subfamily A, member 1 [ABCA1]; 24-72 h), with these effects being blunted by co-administration of vitamin C (62.5 µM). Conversely, treatment with oxidised low-density lipoprotein (oxLDL) (1 µg/mL; 24-72 h), but not non-oxidised LDL, upregulated the above PPARγ-regulated genes without affecting AMPKα1 phosphorylation. In vivo, dietary antioxidant supplementation (which is known to prevent exercise-triggered increases in oxLDL levels) blunted exercise-associated upregulation of the above PPARγ-regulated genes, but had no effect on exercise-associated transient [ROS]cyto increases, or on AMPK phosphorylation. These data suggest that exercise-associated PPARγ signalling effects appear, at least in monocytes, to be mediated by increased generation of PPARγ ligands via oxidation of lipoproteins (following exercise-associated transient increases in oxidative stress), rather than via [ROS]cyto-mediated AMPK activation. These findings may be of clinical relevance, as PPARγ activation in monocytes is associated with beneficial effects related to type-2 diabetes and its cardiovascular complications.


Subject(s)
AMP-Activated Protein Kinases/blood , Exercise/physiology , Lipoproteins, LDL/blood , Monocytes/metabolism , PPAR gamma/blood , Adult , Antioxidants/administration & dosage , Cells, Cultured , Cohort Studies , Humans , Lipoproteins, LDL/pharmacology , Male , Oxidative Stress/physiology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phosphorylation , Reactive Oxygen Species/metabolism , Signal Transduction , Transcription Factors/blood
7.
Am J Clin Nutr ; 70(3): 338-45, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10479195

ABSTRACT

BACKGROUND: A new intravenous lipid emulsion (ILE) prepared from a mixture of soybean and olive oils contains only long-chain triacylglycerols, with a low proportion (20%) of polyunsaturated fatty acids and 60% monounsaturated fatty acids. OBJECTIVE: The goal of this randomized, double-blind clinical trial was to assess in children the efficacy and safety of this new ILE compared with a control group receiving a soybean-oil emulsion. DESIGN: Eighteen children received for 2 mo 24% of nonprotein energy (1.80 g kg (-)(1) d(-)(1)) either as the new ILE or a soybean oil-based emulsion. Assessments were performed on days -30, 0, 30, and 60 and the changes (day 60 - day 0) assessed by analysis of variance. RESULTS: There were no significant differences in triacylglycerol, apolipoproteins A-I and B, or HDL cholesterol between the 2 groups, whereas total and LDL cholesterol were higher in the soybean oil group on day 60. The pattern of 20:4n-6 in erythrocyte membranes did not change significantly, nor did the ratio of 20:3n-9 to 20:4n-6. On day 60, 18:1n-9 was significantly higher in the olive oil group, the ratio of Sigma(n)-6 > C(18) + 18:3n-6 to 18:2n-6 was 2.20 +/- 0.09 in the olive oil group and 1.33 +/- 0.16 in the soybean-oil group, and Sigma(n)-3 > C(18) was 3.83 +/- 0.30 in the olive oil group and 4. 03 +/- 0.33 in the soybean-oil group. The peroxidation index was lower after the olive oil treatment. CONCLUSIONS: The olive oil-based emulsion was well tolerated, maintained a normal EFA status, and may be more suitable for prevention of lipid peroxidation than the soybean-oil-based emulsion.


Subject(s)
Dietary Fats, Unsaturated/pharmacology , Fat Emulsions, Intravenous/pharmacology , Parenteral Nutrition , Plant Oils/pharmacology , Child , Child, Preschool , Dietary Fats, Unsaturated/adverse effects , Double-Blind Method , Fat Emulsions, Intravenous/adverse effects , Female , Humans , Infant , Male , Olive Oil , Plant Oils/adverse effects
8.
Dev Biol ; 211(1): 64-76, 1999 Jul 01.
Article in English | MEDLINE | ID: mdl-10373305

ABSTRACT

We describe the successful application of a strategy that potentially provides for an efficient and universal screen for downstream gene targets. We used the promoter of the Gsh-1 homeobox gene to drive expression of the SV40 T-antigen gene in transgenic mice. We have previously shown that the Gsh-1 homeobox gene is expressed in discrete domains of the ganglionic eminences, diencephalon, and hindbrain during brain development. Gsh-1-SV40 T transgenic mice showed cellular hyperplasia in regions of the brain coincident with Gsh-1 expression. The Gsh-1-SV40 T transgene was introduced, by breeding, into Gsh-1 homozygous mutant mice, and Gsh-1 -/- cell lines were made. Clonal cell lines were generated and analyzed by Northern blot hybridizations and Affymetrix GeneChip probe arrays to determine gene expression profiles. The results indicate that the cell lines remain representative of early developmental stages. Further, immunocytochemistry showed uniformly high levels of nestin expression, typical of central nervous system progenitor cells, and the absence of terminal differentiation markers of neuronal cells. One clonal cell line, No. 14, was then stably transfected with a tet-inducible Gsh-1 expression construct and subcloned. The starting clone 14, together with the uninduced and induced subclones, provided cell populations with varying levels of Gsh-1 expression. Differential display and Affymetrix GeneChip probe arrays were then used to identify transcript differences that represent candidate Gsh-1 target genes. Of particular interest, the drm and gas1 genes, which repress cell proliferation, were observed to be activated in Gsh-1-expressing cells. These observations support models predicting that homeobox genes function in the regulation of cell proliferation.


Subject(s)
Homeodomain Proteins/genetics , Hypothalamus/embryology , Stem Cells/metabolism , Animals , Antigens, Polyomavirus Transforming/genetics , Biosensing Techniques , Cell Differentiation , Cell Division , Cell Line , Clone Cells , Doxycycline/pharmacology , Gene Expression Regulation , Gene Targeting , Histocytochemistry , Hypothalamus/cytology , Immunohistochemistry , Mice , Mice, Transgenic , RNA, Messenger/genetics , Transfection
9.
Nutr Rev ; 56(8): 231-5, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9735676

ABSTRACT

Soy protein, when substituted for animal protein in the diet, will lower blood cholesterol. Recent research also provides evidence that soy protein and/or isoflavones may improve endothelial functioning and attenuate events leading to both lesion and thrombus formation.


Subject(s)
Cardiovascular Diseases/prevention & control , Hypercholesterolemia/diet therapy , Isoflavones/pharmacology , Soybean Proteins/therapeutic use , Animals , Female , Humans , Thrombosis/prevention & control
10.
Am J Clin Nutr ; 68(3): 545-51, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9734729

ABSTRACT

The long-term clinical effects of soy protein containing various amounts of isoflavones on lipoproteins, mononuclear cell LDL receptor messenger RNA concentrations, and other selected cardiovascular risk factors are not well known. Sixty-six hypercholesterolemic, free-living, postmenopausal women were investigated during a 6-mo parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, all subjects were randomly assigned to 1 of 3 dietary groups (all with 40 g protein): a National Cholesterol Education Program (NCEP) Step 1 diet with protein from casein and nonfat dry milk (control), an NCEP Step 1 diet with protein from isolated soy protein containing moderate amounts of isoflavones (ISP56), or an NCEP Step 1 diet with protein from isolated soy protein containing high amounts of isoflavones (ISP90). Non-HDL cholesterol in both the ISP56 and ISP90 groups was reduced compared with the control group (P < 0.05), whereas total cholesterol was not changed. HDL cholesterol increased in both the ISP56 and ISP90 groups (P < 0.05), whereas the ratio of total to HDL cholesterol decreased significantly in both groups compared with the control (P < 0.05). Mononuclear cell LDL receptor messenger RNA concentrations increased in subjects consuming ISP56 or ISP90 compared with the control (P < 0.05). These results indicate that soy protein, with different amounts of isoflavones, may decrease the risk of cardiovascular disease via improved blood lipid profiles, and that the mechanism by which apolipoprotein B-containing lipoproteins were depressed may be via alterations in LDL receptor quantity or activity.


Subject(s)
Cholesterol/blood , Hypercholesterolemia/diet therapy , Isoflavones/pharmacology , Receptors, LDL/drug effects , Soybean Proteins/therapeutic use , Aged , Aged, 80 and over , Body Mass Index , Cardiovascular Diseases/prevention & control , Double-Blind Method , Female , Humans , Hypercholesterolemia/metabolism , Isoflavones/administration & dosage , Middle Aged , Postmenopause , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/isolation & purification , Receptors, LDL/metabolism , Soybean Proteins/administration & dosage
11.
Clin Nutr ; 16(3): 109-12, 1997 Jun.
Article in English | MEDLINE | ID: mdl-16844581

ABSTRACT

Inappropriate parenteral iron intake in children on long-term parenteral nutrition can be responsible for iron overload. This study was carried out to monitor iron status changes when iron parenteral intake was stopped in case of iron overload. Seven children with serum ferritin concentrations above 800 ng/ml (6 with documented liver iron overload) were prospectively studied after total discontinuation of parenteral iron intake and without chelation therapy. Iron status was assessed, by means of ferritin and iron plasma concentrations, 8-15 months (T(1)) and 24-30 months (T(2)) after withdrawal of parenteral iron. Ferritin and iron concentrations declined at T(1), or T(2) in all but two children. At T(2) ferritin and iron concentrations were significantly lower (P < 0.05) than before iron parenteral discontinuation with a yearly reduction of 22 +/- 15% and 15 +/- 16%, respectively, for ferritin concentration and iron concentration. This fall in serum ferritin concentration is comparable to thalassemic subjects after bone marrow transplantation. The total withdrawal of parenteral iron intake improves iron status in children with iron overload. Nevertheless, iron overload related parenteral nutrition should be avoided by lowering iron intake in case of long-term total parenteral nutrition and by careful monitoring.

12.
Dev Biol ; 176(2): 284-99, 1996 Jun 15.
Article in English | MEDLINE | ID: mdl-8660867

ABSTRACT

We report the cloning, characterization, and targeting of an Sp1-related zinc finger transcription factor gene from the distal arm of mouse chromosome 12. This gene, previously identified in rats and humans and designated sp4, is homologous to the Drosophila buttonhead (btd) gene, which is expressed in the head region of developing flies. Similarly, in situ hybridizations show that sp4 is highly expressed in mouse embryos in the developing central nervous system (CNS). Expression of sp4 is seen as early as Day 9 of development, where transcripts are abundant in the posterior neuropore. Expression in later embryos is detected throughout the CNS as well as in other structures, including the nasal mucosa, the vomeronasal organ, the epithelium of the lung and intestinal tract, the testes, and the developing teeth. Northern blot analysis showed sp4 expression in the adult brain and other tissues. Gene targeting by homologous recombination was used to determine the role of sp4 during mouse development. Two-thirds of homozygous mutants die within the first few days after birth and those that survive are smaller than their wild-type littermates. While fertility of the female mutants appears normal, homozygous mutant males do not breed, despite having histologically intact testes containing mature sperm. sp4/sp4 mutant males fail to copulate, indicating that this gene is required for normal male reproductive behavior.


Subject(s)
Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/physiology , Transcription Factors/genetics , Transcription Factors/physiology , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA, Complementary/genetics , Drosophila , Female , Fertility/genetics , Fertility/physiology , Gene Deletion , Gene Expression Regulation, Developmental , Gene Targeting , Growth/genetics , Growth/physiology , Homozygote , Humans , In Situ Hybridization , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Rats , Sequence Homology, Amino Acid , Sp4 Transcription Factor , Zinc Fingers/genetics , Zinc Fingers/physiology
13.
Z Kardiol ; 84(8): 621-32, 1995 Aug.
Article in German | MEDLINE | ID: mdl-7571769

ABSTRACT

Exercise echocardiography and exercise electrocardiography were performed to test the anti-ischemic effects of isosorbide dinitrates (2 x 40 mg) und nisoldipine (2 x 10 mg) using a randomized, double-blind, placebo-controlled crossover trial. A total of 24 patients with symptomatic coronary artery disease and exercise-induced ST segment depression underwent 144 investigations (6 in each patient) at the first placebo treatment, 1st and 8th day during treatment with the first drug and the second placebo treatment 1st and 8th day during treatment with the second drug. A wall motion score (sum of 14 segments; wall motion grading: normal = 1, hypokinetic = 2, akinetic = 3, dyskinetic = 4) and ST depression at the exercise were used to assess the anti-ischemic effects. Both drugs reduced the number of exercise-induced wall motion abnormalities on the maximal comparable exercise level in comparison to placebo treatment. The wall motion score on the maximal comparable exercise level during placebo treatment was 25.5 +/- 6.9, during isosorbide dinitrate treatment (1 day) 23.5 +/- 7.2 and 23 +/- 6.7 (8th day; for both treatment days, p < or = 0.001 vs. placebo treatment), and during nisoldipine treatment (1st day) 23.6 +/- 5.9 and 23 +/- 6.8 (8th day; p < or = 0.001). ST segment depression changed at exercise during first placebo treatment to 0.153 +/- 0.068 mV, during ISDN treatment to 0.102 +/- 0.055 (1st day, p < 0.001) and to 0.117 +/- 0.056 (8th day, p < 0.001). ST segment depression during nisoldipine treatment was 0.121 +/- 0.075 mV on the 1st day (p < or = 0.002) and 0.120 +/- 0.071 mV on the 8th day (p < 0.001). Exercise echocardiography can be used to test anti-ischemic drug effects. There were no differences in the reduction of exercise-induced ischemia between the two drugs.


Subject(s)
Coronary Disease/drug therapy , Echocardiography/drug effects , Exercise Test/drug effects , Isosorbide Dinitrate/therapeutic use , Nisoldipine/therapeutic use , Vasodilator Agents/therapeutic use , Aged , Coronary Disease/diagnostic imaging , Cross-Over Studies , Double-Blind Method , Electrocardiography/drug effects , Female , Hemodynamics/drug effects , Humans , Isosorbide Dinitrate/adverse effects , Male , Middle Aged , Myocardial Contraction/drug effects , Nisoldipine/adverse effects , Vasodilator Agents/adverse effects , Ventricular Function, Left/drug effects
14.
Dev Biol ; 164(1): 277-89, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8026630

ABSTRACT

This manuscript reports on the limb malformations and axial skeleton alterations found in legless fetuses and their heterozygote and wild-type littermates transplacentally exposed to all-trans-retinoic acid via a single intraperitoneal injection on Day 7, 8, 9, 9.5, 10, 10.5, or 11 of gestation. The most surprising aspect of the results was the temporal sensitivity of the legless mouse limb to exogenous retinoic acid. On Day 11, when both fore- and hindlimbs of nonmutant embryos can be made abnormal by retinoic acid and other teratogens, retinoic acid did not increase the frequency or severity of legless hindlimb defects and forelimb malformations were only slightly enhanced. On the other hand, retinoic acid administration on Day 7 exacerbated forelimb malformations in legless fetuses at a time when visible emergence of the affected structure is still 48 hr away. Heterozygote and wild-type fetuses had no limb malformations at this time point. A similar phenomenon was observed with hindlimb malformations after retinoic acid exposure on Day 8 except for a few mild limb malformations in heterozygotes at a high dose of retinoic acid. This early hypersensitivity of fore- and hindlimbs was followed by a period of reduced sensitivity (Day 8 forelimb; Day 9 hindlimb) when even very high doses (50 mg/kg) induced minimal changes in the typical legless malformation pattern. Subsequently, at the time of visible limb bud emergence (Day 9 forelimbs; Day 10 hindlimbs), sensitivity to exogenous retinoic acid was again detected. Surprisingly, the altered malformation patterns induced by retinoic acid in lgl mutants were nearly identical to those from earlier, pre-emergence exposure. A number of axial skeleton alterations were induced in legless fetuses by retinoic acid, especially after exposure on Days 7, 8, or 9. Posterior truncations were particularly noteworthy, showing a graded response in which frequency and severity of truncation were worst in lgl/lgl fetuses; heterozygotes gave an intermediate response, and wild-type fetuses were least affected. This exacerbation of the legless phenotype by exogenous retinoic acid coupled with the similarity between legless and retinoid malformations suggest that the legless mutation has altered endogenous retinoid homeostasis or a downstream retinoid-responsive gene.


Subject(s)
Abnormalities, Drug-Induced , Bone and Bones/abnormalities , Limb Deformities, Congenital , Tretinoin/toxicity , Animals , Extremities/embryology , Female , Gestational Age , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Pregnancy
15.
Plant Foods Hum Nutr ; 40(4): 297-308, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2247435

ABSTRACT

The objective of the study was to determine the effects of methionine and cysteine supplementation of soy protein isolate and casein on serum and tissue lipid levels in rats. Sixty male, weanling, Wistar-Kyoto rats were fed two sources of protein (casein or soy protein isolate) and three variations of sulfur-amino acid supplementation (none, methionine, or cysteine). At this level of protein intake (10% by weight), rats fed soy-based diets had similar serum lipid concentrations than rats fed casein-based diets. Choline was not added to the diet in order to be able to assess independent influences of methionine and cysteine on lipid metabolism. Overall, serum lipid values were greater in rats fed proteins supplemented with methionine while the addition of cysteine produced lower lipid levels. Liver lipid concentrations were increased tremendously upon cysteine supplementation of soy protein isolate. Protein quality, as determined by protein efficiency ratio, was improved by supplementation of either sulfur-amino acid; however, methionine had the greatest effect. Results indicate that the sulfur-amino acids influence lipid metabolism in the absence of dietary choline. The mechanism by which this occurs is not known.


Subject(s)
Caseins/metabolism , Cysteine/administration & dosage , Lipids/analysis , Methionine/administration & dosage , Plant Proteins/metabolism , Animals , Cholesterol/blood , Cholesterol, HDL/blood , Intestines/chemistry , Lipids/blood , Liver/chemistry , Male , Phospholipids/blood , Rats , Rats, Inbred WKY , Glycine max , Weight Gain
16.
Nutrition ; 6(4): 309-12, 1990.
Article in English | MEDLINE | ID: mdl-2134547

ABSTRACT

The object of this study was to determine the effect of calcium carbonate or calcium phosphate supplements on dietary protein and fat utilization from low and high manganese diets. During the 63-day study, the 14 human adult subjects ate a constant laboratory controlled diet. In separate periods, subjects consumed the basal diet alone or with supplements of calcium carbonate, calcium carbonate plus manganese gluconate, calcium phosphate, or calcium phosphate plus manganese gluconate. Contrast analyses of data indicated that manganese gluconate supplementation of diets, when combined with either calcium phosphate or calcium carbonate, increased fecal losses of fat. When used as single supplements, both calcium phosphate and calcium carbonate depressed fecal fat loss in comparison with values when no supplements were used. Manganese gluconate supplements depressed fecal nitrogen losses calculated as a percentage of dry fecal weight.


Subject(s)
Calcium/pharmacology , Dietary Fats/metabolism , Dietary Proteins/metabolism , Adult , Calcium Carbonate/administration & dosage , Calcium Carbonate/pharmacology , Calcium Phosphates/administration & dosage , Calcium Phosphates/pharmacology , Female , Gluconates/administration & dosage , Gluconates/pharmacology , Humans , Intestinal Absorption/drug effects , Male
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