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Biomedical subjects

Peter Hauser

Publications and source records attributed to Peter Hauser.

36 records · Page 2Linked to original sources
PubMed2005

Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing.

Expression of the small heat shock protein alphaB-crystallin in differentiated thyroid tumors has been described recently. In this study, we investigated the molecular mechanisms that affect the expression of alphaB-crystallin in benign goiters (n = 7) and highly malignant anaplastic thyroid carcinomas (ATCs) (n = 3). AlphaB-crystallin expression was compared with that of Hsp27-1. Immunoblot and quantitative real-time (RT) polymerase chain reaction revealed marked downregulation of alphaB-crystallin in all the tested ATCs and the ATC-derived cell line C-643 . In contrast, considerable expression of Hsp27-1 in benign and malignant thyroid tissue was demonstrated. Immunofluorescence analysis revealed no relevant topological differences between benign and malignant thyrocytes in the cytoplasmic staining of both proteins. Consistent and marked downregulation of TFCP2L1 was identified as one of the main mechanisms contributing to CRYAB gene silencing in ATCs. In addition, CRYAB gene promoter methylation seems to occur in distinct ATCs. In silico analysis revealed that the differential expression of alphaB-crystallin and Hsp27-1 results from differences between the alphaB-crystallin and Hsp27-1 promoter fragments (712 bp upstream from the transcriptional start site). Biological activity of the analyzed promoter element is confirmed by its heat shock inducibility. In conclusion, we demonstrate downregulation of alphaB-crystallin expression in highly dedifferentiated ATCs because of a tumor-specific transcription factor pattern. The differential expression of alphaB-crystallin and Hsp27-1 indicates functional differences between both proteins.

Animals↗
PubMed2004

The phenomenology and treatment of interferon-induced depression.

Interferon (IFN)-alpha, IFN-beta, and IFN-gamma are currently available for the treatment of malignancies, viral infections (e.g., hepatitis C virus), multiple sclerosis (MS), and skin conditions. In addition to their therapeutic effects, IFNs commonly cause various side effects. Most common among the side effects of IFN are "flu-like" symptoms such as chills, fever, and muscle soreness. However, IFN can also cause significant neuropsychiatric side effects, particularly symptoms of depression. A literature search was conducted in order to summarize current information on (1) the frequency, characteristics, and risk factors of IFN-induced depression, (2) possible biochemical mechanisms associated with IFN-induced depression, and (3) the treatment strategies for IFN-induced depression. Review of the literature suggests that symptoms of depression induced by IFN therapy, in particular IFN-alpha therapy, are common and can limit the treatment utility, often necessitating discontinuation of IFN therapy or the use of psychopharmacologic agents. Depression is also a suspected side effect of therapy with IFN-beta and IFN-gamma; however, the association has not been as convincingly confirmed. Importantly, IFNs affect neurochemical pathways putatively involved in the etiology of depression. While these depressive side effects usually resolve after the completion of IFN therapy, they can persist or reappear with dose escalations. It is recommended that health care providers, patients and their families be informed about the potential risk of the psychiatric disturbances that can occur with IFN-alpha therapy. Screening and monitoring, ideally using symptom rating scales for depression, and early antidepressant treatment intervention appear necessary to optimize IFN therapy for the majority of patients.

Brain↗
PubMed2004

Association of interferon-alpha-induced depression and improved treatment response in patients with hepatitis C.

Thirty-nine patients with hepatitis C viral infection on interferon-alpha (IFN-alpha) therapy were monitored weekly using the Beck Depression Inventory (BDI). Thirteen of thirty-nine patients (33%) developed IFN-alpha-induced major depressive disorder (MDD). During the course of IFN-alpha therapy, patients who became depressed were treated with citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant. Results indicated that: (1) IFN-alpha response rates were significantly higher in those patients who developed IFN-alpha-induced MDD than in those who did not (end-of-treatment response (ETR) rates: 61.5% versus 26.9% and sustained viral response (SVR) rates: 38.5% versus 11.5%), (2) male patients with ETR to IFN-alpha therapy were, on average, approximately 33 pounds lighter in body weight than male patients who did not respond, and (3) gender, race, past history of MDD, and past history of substance abuse were not significantly associated with ETR. In conclusion, our findings suggest that IFN-alpha-induced MDD may be a predictor of a positive response to IFN-alpha therapy, or an indication of optimal dosing.

Adult↗
PubMed2004

Neuropsychiatric side effects of HCV therapy and their treatment: focus on IFN alpha-induced depression.

Psychiatric disorders, particularly depression, and substance-use disorders (SUDs) are common comorbidities in patients who have chronic hepatitis C virus (HCV) infection. Patients who are infected with HCV who are treated with interferon alfa (IFNalpha) are also at significant risk for IFNalpha-induced depression (incidence, ~20-30%) and other neuropsychiatric side effects that can affect treatment adherence, require dose reduction or discontinuation, and impact patient quality of life adversely. Because psychiatric illness and SUD comorbidities are so common, patients who have hepatitis C should be screened for these disorders. If these disorders are present, patients should be referred to a mental health care provider for appropriate treatment before therapy with IFNalpha is considered. Having a comanagement model of care that involves mental health care providers should help identify appropriate candidates for IFNalpha therapy. If preexisting depression responds to antidepressant treatment IFNalpha therapy can then be initiated. Patients who have other active psychiatric disorders can probably be offered IFNalpha therapy safely with appropriate monitoring and management involving a mental health care professional; however, there is a paycity of research in this area, and the few published studies have small sample sizes. If depression develops during IFNalpha therapy, most patients respond to treatment with selective serotonin-reuptake inhibitors, often allowing patients to continue receiving IFNalpha therapy. In addition to screening patients and treating those who have psychiatric disorders before IFNalpha therapy is started, early recognition of psychiatric disorders and neuropsychiatric side effects during IRNalpha therapy through continued screening and monitoring, with appropriate management, can potentially maximize HCV treatment adherence and possibly improve antiviral therapy outcomes.

Antiviral Agents↗
PubMed2004

Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function.

Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

Acute Kidney Injury↗
PubMed2004

Co-occurring Hepatitis C, substance use, and psychiatric illness: treatment issues and developing integrated models of care.

Hepatitis C virus (HCV) infection is transmitted by injection drug use and associated with psychiatric conditions. Patients with drug use or significant psychiatric illness have typically been excluded from HCV treatment trials noting the 1997 National Institutes of Health Consensus Statement on HCV that indicated active drug use and major depressive illness were contraindications to treatment of HCV infection. However, the 2002 NIH Consensus Statement recognized that these patients could be effectively treated for HCV infection and recommended that treatment be considered on a case-by-case basis. Treating HCV infection in these patients is challenging, with drug use relapse possibly leading to psychosocial instability, poor adherence, and HCV reinfection. Interferon therapy may exacerbate preexisting psychiatric symptoms. Co-occurring human immunodeficiency virus or hepatitis B virus provide additional challenges, and access to ancillary medical and psychiatric services may be limited. Patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention. Clinicians must integrate early interventions for psychiatric conditions and drug use into their treatment algorithm. Few programs or treatment models are designed to manage co-occurring substance use, psychiatric illness, and HCV infection and therapy. The National Institute on Drug Abuse convened a panel of experts to address the current status and the long-range needs through a 2-day workshop, Co-occurring Hepatitis C, Substance Abuse, and Psychiatric Illness: Addressing the Issues and Developing Integrated Models of Care. This conference report summarizes current data, medical management issues, and strategies discussed.

Behavior, Addictive↗
PubMed2004

Alterations in gene expression in cadaveric vs. live donor kidneys suggest impaired tubular counterbalance of oxidative stress at implantation.

Recipients of live donor transplant kidneys (LIV) exhibit a significantly longer allograft half-life compared with cadaveric donor organs (CADs). The reasons are incompletely understood. Therefore this study sought to elucidate the genome-wide gene expression profiles in microdissected transplant kidney biopsies obtained from five cadaveric and five matched live donors before transplantation. cDNA microarrays were used to determine the transcripts in isolated glomeruli (G) and the tubulointerstitial (TI) compartment. Data were subjected to hierarchical clustering, maxT adjustment and a jackknife procedure to ensure robustness of reported findings; validation was performed by independent analysis of split biopsies and TaqMan-PCR. One hundred and thirteen sequences representing 62 unique genes (17 redundant features), and 34 ESTs separated G from TI. No difference in gene expression was found in G between LIV and CAD kidneys, but nine genes (two represented twice) and three ESTs were abundantly expressed in the CAD TI compared with LIV. The main biological function of these genes is counter regulation of oxidative stress. Promoter analysis of significant features suggested coregulated gene groups. These data suggest that CAD kidneys exhibit a distinctly different set of transcripts in the TI compartment but not in the G compartment when compared with LIV kidneys.

Cadaver↗
PubMed2004

Treatment outcomes in depression: comparison of remote treatment through telepsychiatry to in-person treatment.

OBJECTIVE: Telepsychiatry is an increasingly common method of providing psychiatric care, but randomized trials of telepsychiatric treatment compared to in-person treatment have not been done. The primary objective of this study was to compare treatment outcomes of patients with depressive disorders treated remotely by means of telepsychiatry to outcomes of depressed patients treated in person. Secondary objectives were to determine if patients' rates of adherence to and satisfaction with treatment were as high with telepsychiatric as with in-person treatment and to compare costs of telepsychiatric treatment to costs of in-person treatment. METHOD: In this randomized, controlled trial, 119 depressed veterans referred for outpatient treatment were randomly assigned to either remote treatment by means of telepsychiatry or in-person treatment. Psychiatric treatment lasted 6 months and consisted of psychotropic medication, psychoeducation, and brief supportive counseling. Patients' treatment outcomes, satisfaction, and adherence and the costs of treatment were compared between the two conditions. RESULTS: Hamilton Depression Rating Scale and Beck Depression Inventory scores improved over the treatment period and did not differ between treatment groups. The two groups were equally adherent to appointments and medication treatment. No between-group differences in dropout rates or patients' ratings of satisfaction with treatment were found. Telepsychiatry was more expensive per treatment session, but this difference disappeared if the costs of psychiatrists' travel to remote clinics more than 22 miles away from the medical center were considered. Telepsychiatry did not increase the overall health care resource consumption of the patients during the study period. CONCLUSIONS: Remote treatment of depression by means of telepsychiatry and in-person treatment of depression have comparable outcomes and equivalent levels of patient adherence, patient satisfaction, and health care cost.

Delivery of Health Care↗
PubMed2003

Impaired tubulointerstitial expression of endothelin-1 and nitric oxide isoforms in donor kidney biopsies with postischemic acute renal failure.

BACKGROUND: About 30% of cadaveric renal allografts, but almost never living-donor kidneys, develop postischemic acute renal-transplant failure (ARF). We therefore quantified the expression of essential reperfusion regulators in different compartments of cadaveric and living-donor kidney biopsies. METHODS: Specimens were obtained from donor kidneys at the end of the cold ischemia time before implantation and categorized into three groups according to donor source and early posttransplant function. Ten living-donor biopsies (LIV) were compared with nine cadaveric kidney biopsies (CAD) with primary posttransplant function (CAD-PF) and to nine with ARF (CAD-ARF). Laser capture microdissection was used to isolate glomeruli from tubulointerstitium. The gene expression of intercellular adhesion molecule (ICAM)-1, interleukin (IL)-1beta, endothelin (ET)-1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) was quantified in glomeruli and tubulointerstitium by real-time polymerase chain reaction (TaqMan). RESULTS: Tubulointerstitial areas of all CAD kidneys revealed significantly lower mRNA levels of all investigated genes compared with LIV. Tubulointerstitial ET-1, iNOS, and eNOS in CAD-ARF averaged only half of the expression in CAD-PF kidneys. ICAM-1 and IL-1beta mRNA concentrations were equal in CAD-PF and CAD-ARF. Glomerular expression of the investigated genes was equal in CAD and LIV kidneys with the exception of ICAM-1 and ET-1, which were two times higher in CAD-PF compared with LIV and CAD-ARF. CONCLUSION: These data suggest that CAD compared with LIV kidneys have an impaired expression of immune and vasoregulatory genes in the tubulointerstitium, which may represent reduced cellular vitality and capacity to adaptation. The observed further reduction of ET-1, iNOS, and eNOS expression in CAD-ARF might contribute to reperfusion injury and delayed allograft function.

Acute Kidney Injury↗
PubMed2003

Strategies to decrease costs of prescribing selective serotonin reuptake inhibitors at a VA Medical Center.

OBJECTIVE: The authors examined the efficacy of a multifaceted intervention designed to contain the cost of prescribing selective serotonin reuptake inhibitors (SSRIs) to inpatients and outpatients served by a Veterans Affairs (VA) medical center. METHODS: Elements of the intervention included identification of a preferred agent, tablet splitting, education and feedback for prescribers, and an electronic record and ordering system to facilitate changes in prescriber behaviors. VA databases were searched for information on use and costs of antidepressants. RESULTS: Over 35 months the number of patients treated with SSRIs and the amount spent on SSRIs increased. However, the mean monthly cost per patient decreased from $57.12 to $42.19. The projected cost savings over the 35 months was approximately $700,000; one-fourth of the savings was due to tablet splitting and three-fourths to changes in the proportions of the various SSRIs prescribed. A survey of the top 75 antidepressant prescribers showed that after the educational interventions, 91 percent were aware that citalopram was the medical center's preferred antidepressant, and 59 percent identified it as their own preferred first-line treatment. DISCUSSION AND CONCLUSIONS: The results suggest that multifaceted interventions can influence antidepressant costs through provider education and changes in pharmacy and computerized information processes, resulting in substantial cost savings for institutions.

Citalopram↗
PubMed2003

Prenatal PCB exposure, the corpus callosum, and response inhibition.

The present study reports the association between prenatal exposure to polychlorinated biphenyls (PCBs), the corpus callosum, and response inhibition in children who are 4.5 years old. Children (n = 189) enrolled in the Oswego study were tested using a continuous performance test. We measured (square millimeters) the splenium of the corpus callosum, a pathway implicated in the regulation of response inhibition, using magnetic resonance imaging. Results indicated a dose-dependent association between cord blood PCBs and errors of commission. Splenium size but not other brain areas predicted errors of commission (r(2) = 0.20), with smaller size associated with more errors of commission. There was an interaction between splenium size and PCB exposure. The smaller the splenium, the larger the association between PCBs and errors of commission. If the association between PCBs and response inhibition is indeed causal, then children with suboptimal development of the splenium are particularly vulnerable to these effects. These data await replication.

Child Behavior Disorders↗
PubMed2002

Tubular apoptosis in the pathophysiology of renal disease.

Apoptosis of renal tubular epithelial cells plays a major role in acute renal failure. Several external and internal signals can induce apoptosis, which is then effectuated via several pathways. These pathways are either the FAS/FAS-L pathway and downstream MAPK (mitogen-activated protein kinases) and JNK (c-Jun N-terminal kinase) signal transduction, or the RANK/RANK-L (receptor activator of NFkB) pathway via activation of the caspase cascade. Other pathways, especially for apoptosis induction by toxins, include the mitochondrial permeability transition pore activation and Bcl-2 superfamily member differential regulation. An important final, irreversible branch of these pathways is the release of cytochrome c from the mitochondria, leading to nuclear fragmentation. Therapeutic interventions of acute tubular injury focus on the prevention of apoptosis by either modulation of the balance of the bcl-2 family or by selectively blocking angiotensin receptors. It is not clear yet, which receptor blockade or combination of receptor blockers are most effective in apoptosis prevention. In chronic renal failure, tubular apoptosis has been found in biopsies from polycystic kidneys, but not in a quantitatively meaningful amount in other chronic human renal diseases. On the other hand, given the short half-life of apoptotic cells of few hours, even low numbers over time might turn out to be important modulators of chronic kidney disease, which are characterized by tubular cell loss. Potential therapeutic interventions to prevent tubular apoptosis in chronic renal disease include angiotensin system inhibition, whereby the angiotensin II AT2 receptor blockade seems more promising in apoptosis inhibition than the inhibition of other receptor subtypes.

Acute Kidney Injury↗
PubMed2002

Effects of AT1 and AT2 receptor blockade on angiotensin II induced apoptosis of human renal proximal tubular epithelial cells.

BACKGROUND: Tubular atrophy is a common histological feature of chronic renal failure, and epithelial cell death by apoptosis might play an important role in its pathogenesis. Angiotensin II contributes to the progressive nature of many kidney diseases and treatment with angiotensin converting enzyme inhibitors preserves the structure of the tubulointerstitial compartment in human and experimental renal diseases. METHODS: Primary cultures of human renal proximal tubular epithelial cells were co-incubated with angiotensin II alone or in combination with the angiotensin II AT1 receptor antagonist losartan or/and the AT2 antagonist PD123319. Apoptosis was determined after 20 hours by TUNEL staining and flow cytometry. RESULTS: Angiotensin II at concentrations of 10(-9) M induced apoptosis (control vs. angiotensin II 4 +/- 3% vs. 73 +/- 11%; p < 0.05). This effect was completely offset by co-incubation with the angiotensin II AT2 receptor blocker at concentrations 10(-7) M (control vs. PD123319 4 +/- 3% vs. 8 +/- 3%; p < 0.05); AT1 blockade was ineffective in apoptosis inhibition. When both angiotensin receptors were blocked, no additional effect on apoptosis inhibition could be detected. CONCLUSION: We provided evidence, that physiological concentrations of angiotensin II can induce apoptosis of human renal proximal tubule epithelial cells. This effect is mediated via AT2 receptors.

Angiotensin II↗
PubMed2002

Treatment of cytokine-induced depression.

A high proportion of cancer and hepatitis C patients who receive cytokine immunotherapy develop symptoms of depression that are indistinguishable from those found in major depressive disorders. These symptoms are alleviated by anti-depressant treatment. Moreover, preventive treatment with anti-depressants, in particular selective serotonin reuptake inhibitors (SSRIs) attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. The intermediate mechanisms of these effects are still unclear. Studies suggest that the state of depression is associated with an increase in plasma levels of various cytokines and soluble cytokine receptors. Furthermore, anti-depressants have been shown to shift the cytokine network towards a decreased production of pro-inflammatory cytokines and an increased production of anti-inflammatory cytokines. Other studies suggest that anti-depressants can also modify immune reactivity by acting on neural structures involved in neuroimmunomodulation. It is possible that anti-depressants could help to normalize the serotoninergic neurotransmission that is likely disrupted during immunotherapy due to the potent effects of cytokines on the metabolism of the amino acid precursor tryptophan. Further work is needed to optimize strategies for preventing neuropsychiatric side effects of cytokine immunotherapy, to clarify the mechanisms involved in the alleviating effects of anti-depressants on cytokine-induced depression, as well as to assess the possible consequences of anti-depressant therapy on the efficacy of immunotherapy on the disease process.

Antidepressive Agents↗
PubMed2002

Failure of BCL-2 up-regulation in proximal tubular epithelial cells of donor kidney biopsy specimens is associated with apoptosis and delayed graft function.

SUMMARY: In renal transplantation, postischemic acute renal failure (ARF) develops in more than 20% of patients. We investigated whether tubular epithelial cells obtained from donor kidneys without subsequent ARF express a different pattern of survival genes, compared with cells from kidneys exhibiting ARF. Donor kidney biopsy specimens were obtained before transplantation from eight recipients of cadaveric kidneys with primary graft function (CAD-PF), eight patients with biopsy-proven ARF without rejection (CAD-ARF), and eight recipients of living donor kidneys with primary graft function (LIV). One thousand proximal tubular epithelial cells per biopsy specimen were isolated by laser capture microdissection. Quantitative analysis of apoptosis and the apoptosis regulatory genes Bcl-2, Bcl-xL, and Bax were performed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling staining and real-time PCR, respectively. Primary cultures of human proximal tubular epithelial cells served as calibrator. The number of apoptotic cells was significantly higher in CAD-ARF compared with LIV and CAD-PF (1.5 +/- 1.1% [p < 0.05] vs. 0.3 +/- 0.2% vs. 0.4 +/- 0.2%; mean +/- SD). The apoptosis inhibitors Bcl-2 and Bcl-xL were significantly up-regulated in renal tubular cells of recipients without ARF compared with CAD-ARF. The ratios of Bcl-2/GAPDH normalized to calibrator were as follows: LIV 48 +/- 30, CAD-PF 38 +/- 55, and CAD-ARF 5 +/- 7 (p < 0.05). The corresponding ratios for Bcl-xL were as follows: LIV 6 +/- 6, CAD-PF 5 +/- 3, and CAD-ARF 1 +/- 1 (p < 0.05). No difference in the expression of the proapoptotic Bax could be observed. These data suggest that failure of proximal tubular cells to respond to injury by up-regulation of survival factors from the Bcl-2 family contributes to postischemic ARF in patients after cadaveric renal transplantation.

Apoptosis↗
PubMed2002

Effects of microinjection of synthetic Bcl-2 domain peptides on apoptosis of renal tubular epithelial cells.

Bcl-2 protein family members are among the key regulators of the apoptosis effector phase. Therefore, we investigated the ability of synthetic peptides derived from proteins of the Bcl-2 family, namely, the NH2-terminal region of Bcl-2 (Bcl2_syn), a central domain of Bax (Bax_syn), and a central domain of Bak (Bak_syn) to interfere with the apoptotic process in LLC-PK1 cells. Apoptosis was induced by tacrolimus or lipopolysaccharide treatment, and microinjection of Bcl2_syn into stimulated LLC-PK1 cells significantly reduced the percentage of apoptotic cells detected within 4 h after the treatment. Microinjection of Bax_syn or Bax_syn, in contrast, induced apoptosis in otherwise untreated LLC-PK1 cells during the same period of time. A random sequence control peptide (Control_syn), which served as a negative control, as well as FITC-labeled dextran, which was coinjected in all experiments for visualization, were ineffective in either preventing or inducing apoptosis. These results suggest that synthetic peptides mimicking the functional domains of proteins of the Bcl-2 family are capable of regulating apoptosis when microinjected into LLC-PK1 cells in vivo. Analogs to these regulatory peptides could therefore provide valuable lead compounds in the therapeutical context.

Animals↗