Effect of intimate partner violence during pregnancy on maternal mental health: a cohort study in central Vietnam.

This study aims to explore the effects of intimate partner violence during pregnancy (p-IPV) on postpartum depression among women in central Vietnam. p-IPV was defined among 150 women aged 18 years and older in the third trimester of their pregnancy. Baseline data was collected between February and May 2019, and then those women were followed up to 3-5 months after childbirth to assess depression using the Patient Health Questionnaire-9 (PHQ-9). Data collection was completed in September 2019. Relative risk was estimated to identify the effect of p-IPV on maternal postpartum depression. Twenty-one women reported IPV during pregnancy. In the follow-up assessment, 8 of 21 mothers exposed to p-IPV and 23 of 127 mothers not exposed to p-IPV developed postpartum depression. p-IPV including emotional and physical violence were increased the risk of postpartum depression. The findings support evidence that p-IPV increases the risk of postpartum depression among women in central Vietnam.

Community-based Interventions to Prevent Dental Caries among Kindergarten Children in Vietnam: A 12-month Study of Field Trial.

AIM: To investigate the status of dental caries and assess the effectiveness of dental caries prevention interventions in children from 3 to 5-year-old in Hue City, Vietnam. MATERIALS AND METHODS: The subjects were 464 children and their direct caregivers at some kindergartens in Hue City from June 2020 to October 2021. The study included two consecutive phases: the first one was a cross-sectional study to identify the rate of dental caries and related factors in the studied kindergartens, and phase 2 was a controlled comparative interventional study for a period of 12 months. RESULTS: The mean of decayed, missing, filled, and DMFT index was 8.25, 0.09, 0.48, and 8.82, respectively, with no statistically significant difference in these figures between the living areas. The multivariable logistic regression model revealed some factors related to dental caries, including age, frequency of toothbrushing per day, parent-assisted toothbrushing, and eating and drinking sweets. Results showed the effectiveness of a community-based intervention for preventing dental caries, gingivitis, and plaque in the intervention group, compared to the control group. CONCLUSION: The rate of dental caries among Vietnamese children was remarkably high. A comprehensive intervention to prevent early childhood dental caries was effective and might be considered a necessary program in healthcare prophylaxis. CLINICAL SIGNIFICANCE: This intervention was consistent with the guidelines of WHO and based on evidences of related factors of dental caries identified in a previous cross-sectional study.

Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways.

Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.

Investigation of long wavelength mid-infrared generation in the tight focusing limit.

An ultrafast coherent long wavelength MIR source based on difference frequency generation was demonstrated. An average power of 2.5 mW at ∼18 µm was achieved. The angular distribution of the generated MIR source under the condition of tight-focusing limit shows the onset of conical emission of the MIR beam due to on-axis phase mismatching.

Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors.

Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.

Cyclin C interacts with steroid receptor coactivator 2 and upregulates cell cycle genes in MCF-7 cells.

Steroid receptor coactivator 2 (SRC-2) is a coactivator that regulates nuclear receptor activity. We previously reported that SRC-2 protein is degraded through the action of cAMP-dependent protein kinase A (PKA) and cAMP response element binding protein (CREB). In the study presented here, we aimed to identify proteins that interact with and thereby regulate SRC-2. We isolated cyclin C (CCNC) as an interacting partner with the SRC-2 degradation domain aa 347-758 in a yeast two-hybrid assay and confirmed direct interaction in an in vitro assay. The protein level of SRC-2 was increased with CCNC overexpression in COS-1 cells and decreased with CCNC silencing in COS-1 and MCF-7 cells. In a pulse-chase assay, we further show that silencing of CCNC resulted in a different SRC-2 degradation pattern during the first 6 h after the pulse. Finally, we provide evidence that CCNC regulates expression of cell cycle genes upregulated by SRC-2. In conclusion, our results suggest that CCNC temporarily protects SRC-2 against degradation and this event is involved in the transcriptional regulation of SRC-2 cell cycle target genes.

Association between facility characteristics and the process of care delivered to patients with hepatitis C virus infection.

BACKGROUND: Available data suggest problems in the process of care provided to patients with chronic hepatitis C (HCV). However, the solutions to these problems are less obvious. Healthcare facility factors are potentially modifiable and may enhance process quality in HCV treatment. METHODS: We evaluated the relationship between the process of HCV care and facility factors including number of weekly half-day HCV clinics per 1,000 HCV patients, HCV-specific quality-improvement initiatives, and administrative service of the HCV clinic (gastroenterology, infectious disease, primary care) for a cohort of 34,258 patients who sought care in 126 Veterans Affairs facilities during 2003-2006. We measured HCV care on the basis of 23 HCV-specific process measures capturing pretreatment (seven measures), preventive and/or comorbid (seven measures), and treatment and treatment monitoring care (nine measures). RESULTS: Patients seen at a facility with >8 half-day clinics were 52 % more likely to receive overall indicated care (OR 1.52, 95 % CI 1.13-2.05). Patients seen at a facility with >3 HCV quality improvement initiatives were more likely to receive better preventive and/or comorbid care (OR 1.32, 95 % CI 1.00-1.74). Compared with patients in facilities with no dedicated HCV clinic, patients at facilities with gastroenterology-based clinics received better pretreatment care (OR 1.36, 95 % CI 1.01-1.85) and more antiviral treatment (OR 1.45, 95 % CI 1.06-1.97) whereas those at facilities with infectious disease-based or primary care-based clinics received better preventive and/or comorbid care (OR 1.59, 95 % CI 1.06-2.39 and 1.84, 95 % CI 1.21-2.79 respectively). CONCLUSION: Several facility factors affected the process of HCV care. These factors may serve as targets for quality-improvement efforts.

Effectiveness-implementation hybrid trial of Spanish language, digital cognitive-behavioral therapy (dCBT) intervention for depression and anxiety - protocol for the SUPERA (SUpport from PEeRs to expand Access) study.

BACKGROUND: Limited English Proficiency (LEP) Latinxs experience a longer duration of untreated depression and anxiety. LEP Latinxs have difficulty accessing mental healthcare due to insufficient Spanish-speaking behavioral/mental health clinicians to meet demand. These under-resourced healthcare systems are less likely to be the site for the implementation of innovations. Digital interventions can provide an effective option for overcoming these barriers; yet, when digital evidence-based treatments are available, uptake and engagement is often low. This manuscript presents the protocol for the SUPERA (SUpport from PEeRs to expand Access) study which will evaluate the implementation of an evidence-based, Spanish language, digital cognitive-behavioral therapy (dCBT) intervention (i.e., SilverCloud) in safety-net primary care clinics for LEP Latinx patients with depression or anxiety. METHODS: We will conduct an effectiveness-implementation hybrid trial (Type 2) design comparing engagement and clinical outcomes in two modalities of dCBT delivery (peer-supported vs. unsupported). We will also compare provider-level outreach (using a clinic patient registry) versus inreach (traditional provider referral) to compare rates of initiation, completion, and cost. Participants will be 426 LEP Latinx adults ≥18 years of age, PHQ-9 ≥ 10 or GAD-7 ≥ 8, with access to the internet via smartphone, and not currently receiving individual psychotherapy. We will collect baseline, post-intervention (8 weeks), and follow up (3 months) data. CONCLUSION: The long-term goal of this research is to aid in the implementation of digital mental health interventions that can be sustainably implemented in low-resourced settings, while reducing the reliance on professionals, overcoming workforce deficits, and increasing relevance for diverse populations.

Central implementation strategies outperform local ones in improving HIV testing in Veterans Healthcare Administration facilities.

BACKGROUND: Pilot data suggest that a multifaceted approach may increase HIV testing rates, but the scalability of this approach and the level of support needed for successful implementation remain unknown. OBJECTIVE: To evaluate the effectiveness of a scaled-up multi-component intervention in increasing the rate of risk-based and routine HIV diagnostic testing in primary care clinics and the impact of differing levels of program support. DESIGN: Three arm, quasi-experimental implementation research study. SETTING: Veterans Health Administration (VHA) facilities. PATIENTS: Persons receiving primary care between June 2009 and September 2011 INTERVENTION: A multimodal program, including a real-time electronic clinical reminder to facilitate HIV testing, provider feedback reports and provider education, was implemented in Central and Local Arm Sites; sites in the Central Arm also received ongoing programmatic support. Control Arm sites had no intervention MAIN MEASURES: Frequency of performing HIV testing during the 6 months before and after implementation of a risk-based clinical reminder (phase I) or routine clinical reminder (phase II). KEY RESULTS: The adjusted rate of risk-based testing increased by 0.4 %, 5.6 % and 10.1 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). During phase II, the adjusted rate of routine testing increased by 1.1 %, 6.3 % and 9.2 % in the Control, Local and Central Arms, respectively (all comparisons, p < 0.01). At study end, 70-80 % of patients had been offered an HIV test. CONCLUSIONS: Use of clinical reminders, provider feedback, education and social marketing significantly increased the frequency at which HIV testing is offered and performed in VHA facilities. These findings support a multimodal approach toward achieving the goal of having every American know their HIV status as a matter of routine clinical practice.

Implementation of nurse-initiated rapid HIV testing at high-prevalence primary care sites within the U.S. Veterans Affairs Health Care System.

Nurse-initiated HIV rapid testing (NRT) increases testing/receipt of results compared with traditional testing. We implemented NRT in primary care clinics at 2 Veterans Affairs hospitals.At site 1, 2364 tests were conducted; 5 HIV positives were identified. At site 2, 2522 tests were conducted; 9 HIV positives were identified. Success varied across demographic/clinical strata.

Case of Esophageal Actinomycosis Occurred after Endoscopic Mucosal Resection for Subepithelial Tumor.

Esophageal actinomycosis is a rare, chronic granulomatous disease caused by Actinomyces species. Endoscopy and biopsy are essential for making a diagnosis. This paper reports a case of esophageal actinomycosis that developed after an endoscopic mucosal resection (EMR) for a subepithelial tumor (SET). A 74-year-old male patient had a 3 cm flat, smooth elevation in the esophagus without symptoms. The SET was partially resected, and histology revealed "nonspecific degenerated mesenchymal tissue". Three months later, the patient exhibited a persistently large ulceration at the EMR site, and a biopsy revealed actinomycosis. CT of the chest and abdomen revealed no abnormal findings. Ampicillin treatment was administered for six months, and the ulceration on the esophageal SET improved.

Selective detection of HBV pre-genomic RNA in chronic hepatitis B patients using a novel RT-PCR assay.

In chronic hepatitis B (CHB) patients, quantification of HBV pgRNA in plasma has the potential to provide information on disease prognosis and liver injury or histopathology. However, current methods for detecting HBV pgRNA present technical difficulties due to the co-existence of HBV DNA in plasma samples. We have successfully established a novel one-step RT-PCR assay that allows selective quantification of HBV pgRNA. Two cohorts of participants were recruited for assay validation, including treatment-naïve patients with CHB and HBeAg-positive CHB patients who were treated with Tenofovir and monitored for 6 months to assess the predictive value of baseline HBV RNA for HBeAg seroclearance. Statistical analysis was performed using MedCalc version 20.019 software. The novel selective one-step RT-PCR assay for detecting HBV pgRNA was validated with a limit of detection of 100 copies/mL. The assay was able to selectively measure HBV pgRNA even in the presence of excess HBV rcDNA. In treatment-naïve CHB patients, HBV pgRNA levels were significantly lower than HBV DNA concentration. Serum HBV DNA levels and HBeAg status were positively associated with HBV pgRNA. Baseline serum HBV pgRNA levels were found to be strong predictors of HBeAg seroclearance after 6 months of Tenofovir treatment. The study presents a novel RT-PCR assay that allows accurate measurement of plasma HBV pgRNA in chronic hepatitis B patients, even in the presence of excess HBV DNA. The assay is highly selective and represents a significant advancement with potential for further breakthroughs in understanding the clinical significance of HBV pgRNA.

Typhoid fever, complicated by syncope due to relative bradycardia: A case report.

In a United Nations (UN) staff member headquarters in South Sudan, we present a rare typhoid fever complicated by syncope due to relative bradycardia. A 25-year-old male presented to our hospital with a high fever, diarrhea, and no vomiting. He had no substantial medical background. He was diagnosed with an unspecified digestive disorder and received initial treatment. Two syncope episodes were recorded in the Level 1 hospital. He was referred to our hospital at the 30th hour and the third fainting occurred. Electrocardiogram showed bradycardia with a heart rate of 40 beats/min. The atropine test was negative; the initial diagnosis was sinus sickness syndrome. Microbiology tests later suggested typhoid infection. Then, the diagnosis changed to relative bradycardia caused by Salmonella typhi; and he was orally treated with the third-generation Quinolone antibiotic. He significantly improved and got discharged on the seventh day. In conclusion, typhoid remains a real and present threat to UN staff and civilians in South Sudan.

Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.

Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.

Process of care for hepatitis C infection is linked to treatment outcome and virologic response.

BACKGROUND & AIMS: Process of care-based measures are used commonly to assess the quality of medical care provided to patients with chronic hepatitis C virus (HCV) infection. However, the links between these processes and patient outcomes are not clear. METHODS: We conducted a large retrospective cohort study of 34,749 patients with HCV infection identified from the national Veterans Administration HCV Clinical Case Registry between 2003 and 2006. We examined the relationship between meeting process-based measures of HCV care (categorized into pretreatment, preventive or comorbid care, and treatment monitoring domains) and antiviral treatment-related outcomes. For each domain, we defined optimum care as receipt of all indicated care processes in that domain. Study end points were rates of antiviral treatment, treatment completion, and sustained virologic response (SVR), adjusted for patient demographics, comorbidities, use of health services, and intrafacility clustering. RESULTS: Patients who received optimum pretreatment care were significantly more likely to receive antiviral treatment (odds ratio [OR], 3.2; 95% confidence interval [CI], 2.9-3.5), complete treatment (OR, 1.26; 95% CI, 1.13-1.43), and achieve an SVR (OR, 1.29; 95% CI, 1.01-1.65), than those with suboptimum pretreatment care. Optimum preventive or comorbidity care also independently was associated with receipt of antiviral treatment (OR, 1.36; 95% CI, 1.23-1.51), but not with completion of treatment or SVR. Optimum treatment monitoring was associated with a nonsignificant trend toward achieving an SVR (OR, 1.22; 95% CI, 0.95-1.56). CONCLUSIONS: Optimum care for HCV infection-particularly the care delivered before treatment-is associated with increased rates of treatment and SVR. These data could be used to guide clinical policy as newer, more-effective treatments become available.

Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection.

BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infection are at risk for developing costly and morbid complications, although the actual prevalence of these complications is unknown. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular carcinoma (HCC). METHODS: We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least one physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort as well as sex and changes in clinical characteristics. RESULTS: In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. The prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly. CONCLUSIONS: The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years. An aging cohort of patients with HCV could partly explain our findings. Clinicians and health care systems should develop strategies to provide timely and effective care to this high-risk population of patients.

The performance of process measures in hepatitis C.

OBJECTIVES: Previous evaluations regarding the extent to which standard chronic hepatitis C virus (HCV) care processes are delivered during routine clinical care are scant and have primarily relied on automated data--the validity of which is unknown. METHODS: We examined adherence to 24 explicit modified Delphi panel-derived HCV-specific process measures in a cohort of 122,744 patients enrolled in the automated Veterans Administration HCV Clinical Case Registry between 2000 and 2006. We reviewed medical charts of 717 patients to compare the agreement between Registry and charts. We also estimated the effect of justifiable exceptions on measured performance in HCV by determining the proportion of patients who failed a measure but met a valid exception (i.e., patient refusal, outside care, or treatment contraindications). RESULTS: The percentage of patients who met the individual measures varied. For example, 74% of patients received HCV genotype testing, 23% received antiviral treatment, 28% received liver biopsy, and 16% received hepatitis A vaccination. We found excellent agreement between the Registry and charts in all measures (agreement coefficients >0.75). However, exceptions to indicated care documented in charts were common for genotype testing, liver biopsy, and antiviral treatment. After accounting for these exceptions, the measure rates increased from 75 to 93% for genotype testing, 31 to 50% for liver biopsy, and from 26 to 64% for antiviral treatment. Treatment contraindications were the most common reasons for not meeting indicated care. CONCLUSIONS: Automated data missed several exceptions to care that are documented only in providers' notes, thus underestimating process of care. These results have implications for future quality assessment initiatives-most of which will likely rely on automated data for process-based quality reporting. After accounting for automated data and medical record reviews, vaccinations and antiviral treatment rates in the Veterans Administration left room for improvement.

Adherence to COVID-19 Preventive Measures among Dental Care Workers in Vietnam: An Online Cross-Sectional Survey.

An online cross-sectional survey using a "snowball" sampling method was carried out to assess the adherence to COVID-19 preventive measures among dental care workers (DCWs) during the pandemic. Six questions concerning the COVID-19 preventive guidelines issued by the Vietnam Ministry of Health were used to evaluate DCWs' adherence to preventive measures at dental care clinics. The quality of life of DCWs was assessed using the WHO-5 questionnaire and was defined as low if the total score was less than 13 points. Factors relating to adherence to COVID-19 prevention measures of DCWs were determined by multivariate linear regression analysis. In total, 514 DCWs completed the questionnaire. A total of 37% DCWs rated their quality of life as low. Regression analysis suggested that older age, a better quality of life, living in an urban area, and training on COVID-19 prevention were associated with better adherence to COVID-19 preventive measures, while being a dentist and lack of personal protective equipment was associated with less adherence to COVID-19 preventive measures. The pandemic had a significant negative impact on the physical and mental health of DCWs. Therefore, specific national guidelines for the prevention and control of the spread of COVID-19 in dental facilities should be issued.

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells.

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18-2.6 µM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.

cAMP-mediated regulation of HNF-4alpha depends on the level of coactivator PGC-1alpha.

Hepatocyte nuclear factor-4 alpha (HNF-4alpha) is a member of the nuclear receptor superfamily with important roles in hepatic metabolism. Fasting induces the cAMP/protein kinase A (PKA)-signaling pathway. The mechanisms whereby cAMP regulates HNF-4alpha transcriptional activity are incompletely understood. We have therefore investigated the role of cAMP/PKA in regulation of HNF-4alpha in COS-1 cells and the hepatoma HepG2 cell line. cAMP/PKA inhibited the transcriptional activity of HNF-4alpha in COS-1 cells, whereas a stimulatory effect was observed in HepG2 cells. The cAMP-induced inhibition of HNF-4alpha in COS-1 cells was counteracted by overexpression of the nuclear receptor coactivator PGC-1alpha, and cAMP/PKA-dependent induction of the PGC1A gene in HepG2 cells seems to explain the cell specific differences. This was further supported by knock-down of PGC-1alpha in HepG2 cells, which abolished the stimulatory effect of PKA on HNF-4alpha transcriptional activity. Similar to the cAMP/PKA-mediated regulation of HNF-4alpha, overexpression of the cAMP-response element binding protein (CREB) inhibited the transcriptional activity of HNF-4alpha in COS-1 cells, regardless of cAMP/PKA activation and CREB phosphorylation. Moreover, activation of CREB by cAMP/PKA further stimulated HNF-4alpha transactivation in HepG2 cells. cAMP induced the expression of the HNF-4alpha target genes PCK1 and G6Pase in these cells. In conclusion, our results suggest that the level of PGC-1alpha determines whether the cAMP/PKA-pathway overall stimulates or inhibits HNF-4alpha transcriptional activation.