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1.
Hered Cancer Clin Pract ; 20(1): 32, 2022 Sep 06.
Article in English | MEDLINE | ID: mdl-36068545

ABSTRACT

Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in ~ 52% of reads in DNA extracted from tumour, ~ 10% of reads in DNA extracted from peripheral blood leukocytes and ~ 10% of reads in DNA extracted from buccal mucosa. The second BRCA1 c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in ~ 59% of reads in DNA extracted from tumour, ~ 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in ~ 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.

2.
Diabetologia ; 57(10): 2066-75, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24989997

ABSTRACT

AIMS/HYPOTHESIS: EGF and gastrin co-administration reverses type 1 diabetes in rodent models. However, the failure of this to translate into a clinical treatment suggests that EGF-mediated tissue repair is a complicated process and warrants further investigation. Thus, we aimed to determine whether EGF receptor (EGFR) feedback inhibition by mitogen-inducible gene 6 protein (MIG6) limits the effectiveness of EGF therapy and promotes type 1 diabetes development. METHODS: We treated Mig6 (also known as Errfi1) haploinsufficient mice (Mig6 (+/-)) and their wild-type littermates (Mig6 (+/+)) with multiple low doses of streptozotocin (STZ), and monitored diabetes development via glucose homeostasis tests and histological analyses. We also investigated MIG6-mediated cytokine-induced desensitisation of EGFR signalling and the DNA damage repair response in 832/13 INS-1 beta cells. RESULTS: Whereas STZ-treated Mig6 (+/+) mice became diabetic, STZ-treated Mig6 (+/-) mice remained glucose tolerant. In addition, STZ-treated Mig6 (+/-) mice exhibited preserved circulating insulin levels following a glucose challenge. As insulin sensitivity was similar between Mig6 (+/-) and Mig6 (+/+) mice, the preserved glucose tolerance in STZ-treated Mig6 (+/-) mice probably results from preserved beta cell function. This is supported by elevated Pdx1 and Irs2 mRNA levels in islets isolated from STZ-treated Mig6 (+/-) mice. Conversely, MIG6 overexpression in isolated islets compromises glucose-stimulated insulin secretion. Studies in 832/13 cells suggested that cytokine-induced MIG6 hinders EGFR activation and inhibits DNA damage repair. STZ-treated Mig6 (+/-) mice also have increased beta cell mass recovery. CONCLUSIONS/INTERPRETATION: Reducing Mig6 expression promotes beta cell repair and abates the development of experimental diabetes, suggesting that MIG6 may be a novel therapeutic target for preserving beta cells.


Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Haploinsufficiency/physiology , Intracellular Signaling Peptides and Proteins/physiology , Animals , Diabetes Mellitus, Experimental/genetics , Haploinsufficiency/genetics , Humans , Immunoblotting , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Islets of Langerhans/metabolism , Male , Mice , Mice, Inbred C57BL , Rats , Reverse Transcriptase Polymerase Chain Reaction
3.
Br J Cancer ; 110(2): 313-9, 2014 Jan 21.
Article in English | MEDLINE | ID: mdl-24263063

ABSTRACT

BACKGROUND: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer. METHODS: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative. RESULTS: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ≥70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27-2.78, P=0.002). CONCLUSION: Patients aged ≥70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Pancreatic Neoplasms/drug therapy , Age Factors , Aged , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Chemotherapy, Adjuvant , Cohort Studies , Female , Humans , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis
4.
Am J Physiol Endocrinol Metab ; 304(12): E1281-90, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23592481

ABSTRACT

Diabetes manifests from a loss in functional ß-cell mass, which is regulated by a dynamic balance of various cellular processes, including ß-cell growth, proliferation, and death as well as secretory function. The cell cycle machinery comprised of cyclins, kinases, and inhibitors regulates proliferation. However, their involvement during ß-cell stress during the development of diabetes is not well understood. Interestingly, in a screen of multiple cell cycle inhibitors, p21 was dramatically upregulated in INS-1-derived 832/13 cells and rodent islets by two pharmacological inducers of ß-cell stress, dexamethasone and thapsigargin. We hypothesized that ß-cell stress upregulates p21 to activate the apoptotic pathway and suppress cell survival signaling. To this end, p21 was adenovirally overexpressed in pancreatic rat islets and 832/13 cells. As expected, p21 overexpression resulted in decreased [(3)H]thymidine incorporation. Flow cytometry analysis in p21-transduced 832/13 cells verified lower replication, as indicated by a decreased cell population in the S phase and a block in G2/M transition. The sub-G0 cell population was higher with p21 overexpression and was attributable to apoptosis, as demonstrated by increased annexin-positive stained cells and cleaved caspase-3 protein. p21-mediated caspase-3 cleavage was inhibited by either overexpression of the antiapoptotic mitochondrial protein Bcl-2 or siRNA-mediated suppression of the proapoptotic proteins Bax and Bak. Therefore, an intact intrinsic apoptotic pathway is central for p21-mediated cell death. In summary, our findings indicate that ß-cell apoptosis can be triggered by p21 during stress and is thus a potential target to inhibit for protection of functional ß-cell mass.


Subject(s)
Apoptosis/physiology , Diabetes Mellitus, Type 2/metabolism , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/physiology , Oncogene Protein p21(ras)/metabolism , Animals , Cell Cycle/physiology , Cell Line, Tumor , Cell Proliferation , Dexamethasone/pharmacology , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/physiopathology , Enzyme Inhibitors/pharmacology , Gene Expression/drug effects , Gene Expression/physiology , Glucocorticoids/pharmacology , Insulinoma , Mitochondria/physiology , Oncogene Protein p21(ras)/genetics , Pancreatic Neoplasms , Rats , Signal Transduction/drug effects , Signal Transduction/physiology , Thapsigargin/pharmacology , Up-Regulation/physiology
5.
Endocrinology ; 154(3): 1039-46, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23384834

ABSTRACT

Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional ß-cell mass, which is influenced by changes in ß-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional ß-cell mass by decreasing ß-cell function, survival, and proliferation. However, the mechanism by which Dex decreases ß-cell proliferation is unknown. Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (also known as gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs ß-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor. We found that Dex induced Mig6 and decreased [(3)H]thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets. Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets, we were able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication. We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked the G(1)/S transition of the cell cycle. In conclusion, Mig6 functions as a molecular brake for ß-cell proliferation during glucocorticoid treatment in ß-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional ß-cell mass.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Carrier Proteins/metabolism , Dexamethasone/pharmacology , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/drug effects , Intracellular Signaling Peptides and Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/genetics , Cell Line , Cell Proliferation/drug effects , G1 Phase Cell Cycle Checkpoints/drug effects , Glucocorticoids/pharmacology , Humans , Insulin-Secreting Cells/metabolism , MAP Kinase Signaling System/drug effects , Male , Mice , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , Rats , Rats, Wistar , Receptors, Glucocorticoid/metabolism
6.
Mol Endocrinol ; 27(1): 162-71, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23204325

ABSTRACT

The increased insulin secretory burden placed on pancreatic ß-cells during obesity and insulin resistance can ultimately lead to ß-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6(+/-)) to study the role of Mig6 in regulating ß-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6(+/-) pancreatic islets was lower than wild-type islets despite having comparable ß-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in ß-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced ß-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing ß-cell survival.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis , Endoplasmic Reticulum Stress , Insulin-Secreting Cells/physiology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Apoptosis Regulatory Proteins/metabolism , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Intracellular Signaling Peptides and Proteins , Mice , Mice, Inbred C57BL , Mice, Knockout , Protein Biosynthesis , Rats , Transcriptional Activation
7.
J Vis Exp ; (64)2012 Jun 25.
Article in English | MEDLINE | ID: mdl-22760342

ABSTRACT

Glucose homeostasis is primarily controlled by the endocrine hormones insulin and glucagon, secreted from the pancreatic beta and alpha cells, respectively. Functional beta cell mass is determined by the anatomical beta cell mass as well as the ability of the beta cells to respond to a nutrient load. A loss of functional beta cell mass is central to both major forms of diabetes (1-3). Whereas the declining functional beta cell mass results from an autoimmune attack in type 1 diabetes, in type 2 diabetes, this decrement develops from both an inability of beta cells to secrete insulin appropriately and the destruction of beta cells from a cadre of mechanisms. Thus, efforts to restore functional beta cell mass are paramount to the better treatment of and potential cures for diabetes. Efforts are underway to identify molecular pathways that can be exploited to stimulate the replication and enhance the function of beta cells. Ideally, therapeutic targets would improve both beta cell growth and function. Perhaps more important though is to identify whether a strategy that stimulates beta cell growth comes at the cost of impairing beta cell function (such as with some oncogenes) and vice versa. By systematically suppressing or overexpressing the expression of target genes in isolated rat islets, one can identify potential therapeutic targets for increasing functional beta cell mass (4-6). Adenoviral vectors can be employed to efficiently overexpress or knockdown proteins in isolated rat islets (4,7-15). Here, we present a method to manipulate gene expression utilizing adenoviral transduction and assess islet replication and beta cell function in isolated rat islets (Figure 1). This method has been used previously to identify novel targets that modulate beta cell replication or function (5,6,8,9,16,17).


Subject(s)
Insulin-Secreting Cells/physiology , Transduction, Genetic/methods , Adenoviridae/genetics , Animals , Cell Growth Processes/physiology , Genetic Vectors/genetics , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Rats
8.
Ann Oncol ; 23(7): 1713-22, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22241899

ABSTRACT

BACKGROUND: Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used. METHODS: We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC. RESULTS: By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P=0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels>90 U/ml did not benefit from adjuvant chemotherapy (P=0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P=0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P=0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%. CONCLUSIONS: Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.


Subject(s)
Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Carcinoma, Pancreatic Ductal/blood , Neoplasm Recurrence, Local , Pancreatic Neoplasms/blood , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/therapy , Chemotherapy, Adjuvant , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pancreatectomy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Perioperative Period , Prognosis , Proportional Hazards Models , Retrospective Studies
9.
Exp Hematol ; 38(12): 1178-88, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20826193

ABSTRACT

OBJECTIVE: The standard of care for promyelocytic leukemia includes use of the differentiating agent all-trans retinoic acid (RA) and chemotherapy. RA induces cell differentiation through retinoic acid receptor (RAR) transcription factors. Because redox mechanisms influence how readily transcription factors bind to DNA response elements (RARE), the impact of small molecule (E3330) inhibition of the redox regulatory protein, apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) on RAR DNA binding and function in RA-induced myeloid leukemia cell differentiation and apoptosis was investigated. MATERIALS AND METHODS: The redox function of APE1 was studied using the small molecule inhibitor E3330 in HL-60 and PLB acute myeloid leukemia cells. Electrophoretic mobility shift assays were employed to determine effect of inhibitor on APE1/Ref-1 redox signaling function. Trypan blue assays, Annexin-V/propidium iodide and CD11b staining, and real-time polymerase chain reaction analyses were employed to determine survival, apoptosis, and differentiation status of cells in culture. RESULTS: RARα binds to its RARE in a redox-dependent manner mediated by APE1/Ref-1 redox regulation. Redox-dependent RAR-RARE binding is blocked by E3330, a small molecule redox inhibitor of APE1/Ref-1. Combination treatment of RA + E3330 results in a profound hypersensitivity of myeloid leukemia cells to RA-induced differentiation and apoptosis. Additionally, redox inhibition by E3330 results in enhanced RAR target gene, BLR-1, expression in myeloid leukemia cells. CONCLUSIONS: The redox function of APE1/Ref-1 regulates RAR binding to its DNA RAREs influencing the response of myeloid leukemia cells to RA-induced differentiation. Targeting of APE1/Ref-1 redox function may allow manipulation of the retinoid response with therapeutic implications.


Subject(s)
Apoptosis/drug effects , DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors , Leukemia, Myeloid/drug therapy , Tretinoin/pharmacology , Benzoquinones/pharmacology , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , DNA-(Apurinic or Apyrimidinic Site) Lyase/physiology , Humans , Leukemia, Myeloid/pathology , Oxidation-Reduction , Propionates/pharmacology , Receptors, CXCR5/analysis , Receptors, Retinoic Acid/metabolism , Response Elements , Retinoic Acid Receptor alpha
10.
Br J Cancer ; 98(3): 537-41, 2008 Feb 12.
Article in English | MEDLINE | ID: mdl-18231110

ABSTRACT

Identification of a biomarker of prognosis and response to therapy that can be assessed preoperatively would significantly improve overall outcomes for patients with pancreatic cancer. In this study, patients whose tumours exhibited high LMO4 expression had a significant survival advantage following operative resection, whereas the survival of those patients whose tumours had low or no LMO4 expression was not significantly different when resection was compared with operative biopsy alone.


Subject(s)
Adenocarcinoma/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Homeodomain Proteins/metabolism , Pancreatic Neoplasms/metabolism , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Carcinoma, Pancreatic Ductal/surgery , Cohort Studies , Female , Humans , LIM Domain Proteins , Male , Middle Aged , Pancreatectomy , Pancreatic Neoplasms/surgery , Prognosis , Survival Analysis , Treatment Outcome
11.
Eur J Pharmacol ; 432(1): 9-17, 2001 Nov 30.
Article in English | MEDLINE | ID: mdl-11734182

ABSTRACT

1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [3H]5-hydroxytryptamine ([3H]5-HT) uptake into rat cortical synaptosomes (pIC(50)=8.48+/-0.12). It produces a dextral shift of the 5-HT dose-response curves for the binding of GTPgamma[35S] to human 5-HT(1B) (pK(b)=9.05+/-0.14) and 5-HT(1D) (pK(b)=8.98+/-0.07) receptors and inhibits the contractile response of the rabbit saphenous vein to the 5-HT(1B/D) receptor agonist, sumatriptan (pK(b)=8.4+/-0.2). In addition, it is an antagonist at the 5-HT(2A) (pK(i)=7.29+/-0.19) and 5-HT(2B) (pK(i)=7.35+/-0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K(+)-induced outflow of [3H]5-HT from guinea pig cortical slices (pEC(50)=7.74+/-0.05 nM) in which the 5-HT transporter had been inhibited by a maximally effective concentration of paroxetine. It is concluded that LY393558 should be an effective antidepressant with the potential to produce an earlier onset of efficacy than selective serotonin uptake inhibitors.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Cyclic S-Oxides/pharmacology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Thiadiazines/pharmacology , Animals , Binding, Competitive , Carrier Proteins/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cyclic S-Oxides/metabolism , Dose-Response Relationship, Drug , Drug Synergism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , In Vitro Techniques , Male , Membrane Glycoproteins/metabolism , Mice , Norepinephrine/pharmacokinetics , Potassium/pharmacology , Rabbits , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/metabolism , Saphenous Vein/drug effects , Saphenous Vein/physiology , Serotonin/metabolism , Serotonin/pharmacokinetics , Serotonin Antagonists/metabolism , Serotonin Plasma Membrane Transport Proteins , Serotonin Receptor Agonists/pharmacology , Sulfur Radioisotopes , Sumatriptan/pharmacology , Thiadiazines/metabolism , Tritium , Vasoconstriction/drug effects
12.
Nephrol Nurs J ; 28(3): 295-300, 2001 Jun.
Article in English | MEDLINE | ID: mdl-12143451

ABSTRACT

A qualitative examination of the beliefs and experiences of nephrology nurses was conducted by interviewing 22 nurses in dialysis units. The interviews were transcribed and content analysis of the transcripts was conducted. Seven propositions are reported: (a) The relationship between nephrology nurses and nephrology patients, in some ways, is similar to a psychotherapeutic patient/therapist relationship; (b) End-of-life decisions are conducted within the matrixes of ongoing relationships; (c) What draws nurses to nephrology practice is different from what keeps them in nephrology practice; (d) Nephrology nurses are engaged in ongoing learning at both a technical and interpersonal level; (e) Both internal and external support systems aid the mental health of nephrology nurses; (f) Nephrology nurses see their professional experiences as unique; and (g) Nephrology nurses see themselves as different from their colleagues. These findings, if supported by further research, have important implications for recruiting, training, and supporting nephrology nurses.


Subject(s)
Ambulatory Care/psychology , Attitude of Health Personnel , Nurse-Patient Relations , Nursing Staff, Hospital/psychology , Renal Dialysis/nursing , Renal Dialysis/psychology , Career Choice , Decision Making , Female , Health Knowledge, Attitudes, Practice , Humans , Job Satisfaction , Mental Health , Midwestern United States , Nephrology/education , Nurse's Role , Nursing Methodology Research , Nursing Staff, Hospital/education , Self Concept , Social Support , Surveys and Questionnaires , Terminal Care/psychology
13.
Eur J Pharmacol ; 407(1-2): 39-46, 2000 Oct 27.
Article in English | MEDLINE | ID: mdl-11050288

ABSTRACT

The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)=0.81 nM) receptor than the clinically effective antidepressant, nefazodone. It is a potent inhibitor of [3H]5-HT uptake into rat cortical synaptosomes (IC(50)=3.1 nM) and shows selectivity over that for [3H]noradrenaline (IC(50)>1000 nM). It potentiates potassium-induced [3H]5-HT outflow from prelabelled guinea pig cortical slices both in the presence (EC(50)=950 nM) and absence (EC(50)=250 nM) of a saturating concentration of the 5-HT transport inhibitor, paroxetine, indicating a low level of activity at the 5-HT(1B/1D) autoreceptor. These studies indicate that LY367265 is a putative antidepressant which, because of its 5-HT(2A) receptor antagonist activity, has the potential to produce less sleep disturbance and sexual dysfunction than selective serotonin uptake inhibitors.


Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Carrier Proteins/antagonists & inhibitors , Membrane Glycoproteins/antagonists & inhibitors , Membrane Transport Proteins , Nerve Tissue Proteins , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Thiadiazoles/pharmacology , Triazoles/pharmacology , Animals , Antidepressive Agents, Second-Generation/metabolism , Carrier Proteins/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cyclic S-Oxides/pharmacology , Guinea Pigs , Humans , Male , Membrane Glycoproteins/metabolism , Norepinephrine/metabolism , Piperazines , Rats , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Serotonin/metabolism , Serotonin Antagonists/metabolism , Serotonin Plasma Membrane Transport Proteins , Synaptosomes/drug effects , Synaptosomes/metabolism , Triazoles/metabolism
14.
J Matern Fetal Med ; 8(4): 147-50, 1999.
Article in English | MEDLINE | ID: mdl-10406295

ABSTRACT

OBJECTIVE: To identify prenatally diagnosed cases of hypoplastic left heart syndrome (HLHS) and then to determine postnatal outcomes after surgical interventions. METHODS: An ultrasound and pediatric cardiology database was used to identify all fetuses diagnosed prenatally from 1991-1996 with HLHS. Fetal karyotypes were performed on cultured amniocytes. After diagnosis, parents were given several management options: pregnancy termination before 22 weeks, postnatal hospice care, or surgery using the Norwood procedure or cardiac transplantation. Ultrasound and echocardiography findings were later compared to karyotype results and postnatal outcome data. RESULTS: Fifteen fetuses with HLHS were identified. Two (16%) chromosome abnormalities and three (20%) structural defects were detected. Three mothers (20%) opted for pregnancy termination, two (13%) chose postnatal hospice care, and one aneuploid fetus had an intrauterine death. Nine parents (60%) chose surgery for their infants; however, one infant was not an appropriate surgical candidate due to a coexisting diaphragmatic hernia. Eight infants underwent surgery and two survived (25%). Of the four infants scheduled to undergo the Norwood procedure, one died preoperatively, two died intraoperatively, and one infant survived and is doing well at age 8 months. Of the four infants scheduled for cardiac transplantation, two died awaiting transplant and one died postoperatively. One infant survived cardiac transplantation but has microcephaly and developmental delay at age two. CONCLUSIONS: In prenatally diagnosed HLHS at our institution, the survival rate following surgery for infants felt to be the best candidates was only 25%.


Subject(s)
Hypoplastic Left Heart Syndrome/diagnosis , Hypoplastic Left Heart Syndrome/surgery , Abortion, Legal , Amnion/cytology , Cells, Cultured , Female , Gestational Age , Humans , Karyotyping , Pregnancy , Retrospective Studies , Treatment Outcome , Ultrasonography, Prenatal
15.
Circulation ; 98(17): 1769-75, 1998 Oct 27.
Article in English | MEDLINE | ID: mdl-9788832

ABSTRACT

BACKGROUND: This report describes the complication of pulmonary vein stenosis with resultant severe pulmonary hypertension that developed in 2 patients after successful catheter ablation of chronic atrial fibrillation. METHODS AND RESULTS: Three months after successful catheter ablation of atrial fibrillation, both patients developed progressive dyspnea and pulmonary hypertension. Both were found to have severe stenosis of all 4 pulmonary veins near the junction with the left atrium. Balloon dilation of the stenotic pulmonary veins was performed in these patients, with improvement in dyspnea and pulmonary hypertension. CONCLUSIONS: The complication of pulmonary vein stenosis is potentially life-threatening, and the application of radiofrequency current within the pulmonary veins with standard catheter technology should be avoided. This complication can be treated with balloon dilation, although the long-term course is unknown.


Subject(s)
Atrial Fibrillation/surgery , Catheter Ablation , Hypertension, Pulmonary/etiology , Pulmonary Veno-Occlusive Disease/complications , Adult , Constriction, Pathologic , Electrocardiography , Female , Humans , Male , Middle Aged
16.
J Pediatr Surg ; 33(3): 454-6, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9537556

ABSTRACT

BACKGROUND: The use of centrally positioned venous catheters plays an indispensable role in the care of infants and children. METHODS: Since 1992 the authors have seen nine patients who experienced fragmentation and migration of catheter fragments into the central circulation. The patients ranged in age from 6 days to 15 years. RESULTS: Sites of migration included pulmonary artery (five patients), superior vena cava (two patients), hepatic vein and innominate vein (one patient). The elapsed time from recognition of retained catheter fragments until retrieval ranged from a few hours to 6 weeks. CONCLUSION: All retained fragments were successfully removed during cardiac catheterization without complications.


Subject(s)
Blood Vessels , Catheterization, Central Venous/instrumentation , Foreign-Body Migration/therapy , Heart Ventricles , Adolescent , Brachiocephalic Veins , Catheters, Indwelling/adverse effects , Child , Child, Preschool , Equipment Failure , Foreign-Body Migration/diagnosis , Hepatic Veins , Humans , Infant , Infant, Newborn , Pulmonary Artery , Vena Cava, Superior
17.
ANNA J ; 25(6): 583-7, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10188391

ABSTRACT

Events at the bedside of a dying patient form lasting memories for families and friends. What is said, who is there, and how care is delivered prevail when individuals are recalling the dying event. The La Crosse Advance Directive Study (LADS) (Hammes & Rooney, 1998) was conducted to examine end-of-life planning in a Midwestern community where an extensive advance directive education program exists. The results indicated that families and friends wanted to be present at death; wanted to give their loved one permission to die; and wanted to have consistent, thorough, and honest communications with their providers. Families also felt compelled to keep the promises they made to their dying loved ones. This study provides an opportunity for families and friends to tell their stories of the events at the bedside of dying patients. Their stories identify a need for more medical, nursing, patient, and family education in end-of-life care.


Subject(s)
Attitude to Death , Family/psychology , Survivors/psychology , Terminal Care/psychology , Adaptation, Psychological , Advance Directives , Decision Making , Humans , Needs Assessment , Nursing Methodology Research
18.
Br J Rheumatol ; 35(10): 951-7, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8883432

ABSTRACT

This study investigated the synovial fluid concentrations of glycosaminoglycan (GAG), keratan sulphate (KS) epitope 5D4 and chondroitin sulphate (CS) sulphation patterns in healthy volunteers and patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Synovial fluids were collected from knee joints of healthy volunteers (n = 24), and patients with OA (n = 28) and RA (n = 29). Concentrations of GAG and the keratan sulphate epitope 5D4 were measured in 15 of the healthy volunteers, and all of the OA and RA synovial fluids. Total GAG was measured using a dye-binding method and 5D4 by an ELISA. The unsaturated CS disaccharides delta C4 and delta C6 were measured by capillary electrophoresis in all synovial fluids. The concentrations of GAG, 5D4 and delta C6 in the normal synovial fluid were higher but that of delta C4 lower than those of the disease groups. The delta C6:delta C4 ratios correlated with age (r = -0.437, P < 0.001) and the mean value was lower in females than males (2.92 compared with 5.22, P < 0.001). After allowing for age and sex, the delta C6:delta C4 ratio in the control group was significantly elevated (P < 0.001) compared to both OA and RA. The ratio was also related to proteoglycan markers (r = 0.383 for 5D4 and r = 0.357 for GAG). The finding that 5D4 and delta C6:delta C4 ratios are higher in synovial fluid from healthy volunteers compared to OA and RA suggests that they may be markers of the susceptibility of articular cartilage to early damage in arthritis.


Subject(s)
Arthritis, Rheumatoid/metabolism , Chondroitin/analysis , Keratan Sulfate/analysis , Osteoarthritis/metabolism , Synovial Fluid/chemistry , Adult , Age Factors , Aged , Analysis of Variance , Biomarkers/analysis , Cartilage/chemistry , Cartilage/metabolism , Cartilage/physiopathology , Disaccharides/analysis , Epitope Mapping/standards , Female , Glycosaminoglycans/analysis , Humans , Linear Models , Male , Middle Aged , Sex Factors , Sulfur/metabolism
19.
Cathet Cardiovasc Diagn ; 37(2): 215-7, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8808086

ABSTRACT

A method of obtaining a vegetation sample in a culture-negative endocarditis is described. A combination of fluoroscopy and transesophageal echocardiography was utilized to obtain the sample. The results positively influenced the diagnosis and treatment in this 16-yr-old male with complex congenital heart disease.


Subject(s)
Biopsy/methods , Echocardiography, Transesophageal , Endocarditis/diagnosis , Adolescent , Endocarditis/etiology , Humans , Male
20.
Am J Perinatol ; 11(5): 334-6, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7993511

ABSTRACT

All fetal echocardiograms performed at our institution between January 1, 1986, and June 1, 1991, were reviewed. The echocardiogram referral indication and results were verified for all women studied. Historic risk factors under consideration were pregestational diabetes, anticonvulsant or lithium ingestion in the first trimester, and a family history of congenital heart disease. Women with historic risk factors who had either a fetal abnormality on antenatal sonography or a known aneuploid fetus prior to the fetal echocardiograph were excluded. Of the 994 women who had a fetal echocardiogram performed during this study period, 486 (48.9%) were evaluated solely on the basis of a historic risk factor. Four of the 486 women (0.8%) were diagnosed as having a significant fetal structural cardiac malformation. Two of the four fetuses succumbed to obstetric complications. The remaining two infants were delivered at term and are doing well after postnatal cardiac surgery. In this select group of women with risk factors but no recognized fetal abnormality, the incidence of significant cardiac lesions was low. Although indications for fetal echocardiography must be evaluated on an individual basis, our data do not support a recommendation for the routine use of fetal echocardiography as a screening test in all women with historic risk factors.


Subject(s)
Echocardiography , Fetal Diseases/diagnostic imaging , Fetal Heart/diagnostic imaging , Heart Defects, Congenital/epidemiology , Ultrasonography, Prenatal , Female , Fetal Diseases/epidemiology , Heart Defects, Congenital/diagnostic imaging , Humans , Pregnancy , Pregnancy, High-Risk , Risk Factors
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