Gut Microbial Dysbiosis Differs in Two Distinct Cachectic Tumor-Bearing Models Consuming the Same Diet.

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), non-tumor-bearing ad libitum fed (NTB-AL), and non-tumor-bearing group pair-fed to the TB (NTB-PF). The TB group was implanted either with the Ward colon carcinoma or MCA-induced sarcoma, both transplantable tumor lines. Fecal samples were collected after the development of cachexia, and bacteria species were identified using 16S rRNA gene analysis. Both TB groups developed cachexia but had a differently altered gut microbiome. Beta diversity was unaffected by treatment (NTB-AL, TB, and NTB-PF) regardless of tumor type but was affected by diet. Also, diet consistently changed the relative abundance of several bacteria taxa, while treatment and tumor type did not. The control diet increased the abundance of A. Anaeroplasma, while the walnut diet increased the genus Ruminococcus. There were no common fecal bacterial changes characteristic of cachexia found. Diet consistently changed the gut microbiota, but these changes were insufficient to slow the progression of cachexia, suggesting cancer cachexia is more complex than a few gut microbiota shifts.

AZD1222-induced nasal antibody responses are shaped by prior SARS-CoV-2 infection and correlate with virologic outcomes in breakthrough infection.

The nasal mucosa is an important initial site of host defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, intramuscularly administered vaccines typically do not achieve high antibody titers in the nasal mucosa. We measure anti-SARS-CoV-2 spike immunoglobulin G (IgG) and IgA in nasal epithelial lining fluid (NELF) following intramuscular vaccination of 3,058 participants from the immunogenicity substudy of a phase 3, double-blind, placebo-controlled study of AZD1222 vaccination (ClinicalTrials.gov: NCT04516746). IgG is detected in NELF collected 14 days following the first AZD1222 vaccination. IgG levels increase with a second vaccination and exceed pre-existing levels in baseline-SARS-CoV-2-seropositive participants. Nasal IgG responses are durable and display strong correlations with serum IgG, suggesting serum-to-NELF transudation. AZD1222 induces short-lived increases to pre-existing nasal IgA levels in baseline-seropositive vaccinees. Vaccinees display a robust recall IgG response upon breakthrough infection, with overall magnitudes unaffected by time between vaccination and illness. Mucosal responses correlate with reduced viral loads and shorter durations of viral shedding in saliva.

An Executed Plan to Combat COVID-19 in the United States.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019. To date, this coronavirus is responsible for greater than 90 million cases in the United States and more than 1 million confirmed deaths. When this virus came to the United States, testing was unorganized, no effective treatments were known, and no vaccines had been discovered. A plan to correct these deficiencies through cooperative science and efficient clinical trials was implemented to combat this novel virus. This plan developed efficient and inexpensive tests, highly effective medicines to treat and prevent disease progression, and vaccines to immunize the population.

Anti-SARS-CoV-2 IgG and IgA antibodies in COVID-19 convalescent plasma do not enhance viral infection.

The novel coronavirus, SARS-CoV-2 that causes COVID-19 has resulted in the death of nearly 4 million people within the last 18 months. While preventive vaccination, and monoclonal antibody therapies have been rapidly developed and deployed, early in the pandemic the use of COVID-19 convalescent plasma (CCP) was a common means of passive immunization with a theoretical risk of antibody-dependent enhancement (ADE) of viral infection. Though vaccines elicit a strong and protective immune response and transfusion of CCP with high titers of neutralization activity are correlated with better clinical outcomes, the question of whether antibodies in CCP can enhance infection of SARS-CoV-2 has not been directly addressed. In this study, we analyzed for and observed passive transfer of neutralization activity with CCP transfusion. Furthermore, to specifically understand if antibodies against the spike protein (S) enhance infection, we measured the anti-S IgG, IgA, and IgM responses and adapted retroviral-pseudotypes to measure virus neutralization with target cells expressing the ACE2 virus receptor and the Fc alpha receptor (FcαR) or Fc gamma receptor IIA (FcγRIIA). Whereas neutralizing activity of CCP correlated best with higher titers of anti-S IgG antibodies, the neutralizing titer was not affected when Fc receptors were present on target cells. These observations support the absence of antibody-dependent enhancement of infection (ADE) by IgG and IgA isotypes found in CCP. The results presented, therefore, not only supports the therapeutic use of currently available antibody-based treatment, including the continuation of CCP transfusion strategies, but also the use of various vaccine platforms in a prophylactic approach.

Anti-SARS-CoV-2 IgG and IgA antibodies in COVID-19 convalescent plasma do not facilitate antibody-dependent enhance of viral infection.

The novel coronavirus SARS-CoV2, which causes COVID-19, has resulted in the death of nearly 4 million people within the last 18 months. While preventive vaccination and monoclonal antibody therapies have been rapidly developed and deployed, early in the pandemic the use of COVID-19 convalescent plasma (CCP) was a common means of passive immunization, with the theoretical risk of antibody-dependent enhancement (ADE) of viral infection remaining undetermined. Though vaccines elicit a strong and protective immune response, and transfusion of CCP with high titers of neutralization activity are correlated with better clinical outcomes, the question of whether antibodies in CCP can enhance infection of SARS-CoV2 has not been directly addressed. In this study, we analyzed for and observed passive transfer of neutralization activity with CCP transfusion. Furthermore, to specifically understand if antibodies against the spike protein (S) enhance infection, we measured the anti-S IgG, IgA, and IgM responses and adapted retroviral-pseudotypes to measure virus neutralization with target cells expressing the ACE2 virus receptor and the Fc alpha receptor (FcαR) or Fc gamma receptor IIA (FcγRIIA). Whereas neutralizing activity of CCP correlated best with higher titers of anti-S IgG antibodies, the neutralizing titer was not affected when Fc receptors were present on target cells. These observations support the absence of antibody-dependent enhancement of infection (ADE) by IgG and IgA isotypes found in CCP. The results presented, therefore, support the clinical use of currently available antibody-based treatment including the continued study of CCP transfusion strategies.

The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysis.

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized patients with COVID-19.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Donor Anti-Spike Immunity is Related to Recipient Recovery and Can Predict the Efficacy of Convalescent Plasma Units.

BACKGROUND: The novel coronavirus, SARS-CoV2 that causes COVID-19 has resulted in the death of more than 2.31 million people within the last year and yet no cure exists. Whereas passive immunization with COVID-19 convalescent plasma (CCP) provides a safe and viable option, selection of optimal units for therapy and lack of clear therapeutic benefit from transfusion remain as barriers to the use of CCP. STUDY DESIGN AND METHODS: To identify plasma that is expected to benefit recipients, we measured anti-SARS-CoV2 antibody levels using clinically available serological assays and correlated with the neutralizing activity of CCP from donors. Neutralizing titer of plasma samples was measured by assaying infectivity of SARS-CoV-2 spike protein pseudotyped retrovirus particles in the presence of dilutions of plasma samples. We also used this assay to identify evidence of passive transfusion of neutralizing activity in CCP recipients. RESULTS: Viral neutralization and anti-spike protein antibodies in 109 samples from 87 plasma donors were highly varied but modestly correlated with each other. Recipients who died of COVID-19 were found to have been transfused with units with lower anti-spike antibody levels and neutralizing activity. Passive transfer of neutralization activity was documented in 62% of antibody naive plasma recipients. CONCLUSIONS: Since viral neutralization is the goal of CCP transfusion, our observations not only support the use of anti-spike SARS-CoV2 serology tests to identify beneficial CCP units, but also support the therapeutic value of convalescent plasma with high titers of anti-spike antibodies.

The Effect of Convalescent Plasma Therapy on COVID-19 Patient Mortality: Systematic Review and Meta-analysis.

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials (RCT), 20 matched-control studies, two dose-response studies, and 96 case-reports or case series. Studies published between January 1, 2020 to January 16, 2021 were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of RCT and matched-control data demonstrated that COVID-19 patients transfused with convalescent plasma exhibited a lower mortality rate compared to patients receiving standard treatments. Additional analyses showed that early transfusion (within 3 days of hospital admission) of higher titer plasma is associated with lower patient mortality. These data provide evidence favoring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.

Unusual Cardiac Presentation of COVID-19 and Use of Convalescent Plasma.

COVID-19 infection caused by the SARS-CoV-2 virus has been associated with cardiac abnormalities, including conduction abnormalities. Convalescent plasma is emerging as a potentially safe and effective treatment option for patients severely or critically ill with COVID-19. Here, we describe a case of a COVID-19 patient with new-onset cardiac ectopy who had near resolution of his cardiac sequelae following convalescent plasma transfusion.

Hospitalized COVID-19 patients treated with convalescent plasma in a mid-size city in the Midwest.

BACKGROUND: SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge. METHODS: Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively. RESULTS: 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion. CONCLUSION: Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.

Hospitalized COVID-19 Patients treated with Convalescent Plasma in a Mid-size City in the Midwest.

Background: SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge. Methods: Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively. Results: 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion. Conclusion: Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.

Hospitalized COVID-19 patients treated with Convalescent Plasma in a mid-size city in the midwest.

Background SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge. Methods Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively. Results 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion. Conclusion Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.

Hospitalized COVID-19 Patients treated with Convalescent Plasma in a Mid-size City in the Midwest.

Background: SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge. Methods: Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively. Results: 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion. Conclusion: Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.

Persistent viral RNA shedding after COVID-19 symptom resolution in older convalescent plasma donors.

INTRODUCTION: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for a worldwide pandemic. While the medical community understands the mode of viral transmission, less is known about how long viral shedding occurs once viral symptoms have resolved. Our objective was to determine how long the SARS-CoV-2 remains detectable following self-reporting of viral symptom resolution. METHODS: This study was approved by the University of Wisconsin Institutional Review Board. A cohort of patients who were previously SARS-CoV-2 positive less than 28 days after self-reported symptom resolution were retested for proof of viral recovery by nasal swab reverse transcriptase polymerase chain reaction for SARS-CoV-2 RNA. RESULTS: A total of 152 potential participants were screened, of which 5 declined, 54 were ineligible, and 93 were recruited; 86 of 93 completed testing. Eleven of 86 (13%) were still positive at a median of 19 days (range, 12-24 days) after symptom resolution. Positive participants were significantly older than negative participants (mean, 54 years; 95% confidence interval [CI], 44-63 vs 42 years; 95% CI, 38-46; P = .024). CT values were significantly, inversely associated with age (ß = -.04; r2 = 0.389; P = .04). The number of days since symptom recovery was not apparently different between positive and negative participants. CONCLUSION: We found evidence of persistent viral shedding in nasopharyngeal secretions more than 2 weeks after resolution of symptoms from confirmed COVID-19 infection. Persistent shedding was more common in older participants, and viral load was higher among older positive participants. These results underscore the necessity of testing COVID-19 convalescent plasma donors less than 28 days after symptom resolution.

Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle.

BACKGROUND: Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). METHODS AND RESULTS: 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. CONCLUSIONS: Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

Percutaneous cryoablation of stage T1b renal cell carcinoma: technique considerations, safety, and local tumor control.

PURPOSE: To describe the technical methods, safety, and local tumor control rate associated with percutaneous cryoablation of stage T1b renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective review of a percutaneous renal ablation registry was used to identify 46 patients with a total of 46 biopsy-proven RCC lesions measuring 4.1-7.0 cm treated with cryoablation between 2003 and 2011. The main outcome parameters investigated were adjunctive maneuvers, complications, and local tumor progression, and cancer-specific survival rates. Complication rates were categorized and recorded using the Clavien-Dindo classification system. Progression-free and cancer-specific survival rates were estimated using the Kaplan-Meier method. RESULTS: The mean treated RCC size was 4.8 cm (range, 4.1-6.4 cm). Prophylactic tumor embolization was performed in 7 patients (15%), ipsilateral ureteral stents were placed in 7 patients (15%), and hydrodisplacement of bowel was performed in the treatment of 16 tumors (35%). A single technical failure (2.2%) was observed at the time of ablation. Thirty-six tumors (78%) had follow-up imaging at 3 months or later following ablation, including a single recurrence at 9 months after ablation. The mean duration of follow-up for the 35 RCC tumors that did not recur was 2.0 years (range, 0.3-6.1 y). Estimated local progression-free survival rate at 3 years was 96.4%. Of the 46 cryoablation procedures, there were 7 complications (15.2%) of grade II or worse. CONCLUSIONS: The results suggest that cryoablation represents a valid treatment alternative for select patients with clinical stage T1b RCC. Complications are frequent enough that multidisciplinary patient management should be considered.

The reward-based eating drive scale: a self-report index of reward-based eating.

Why are some individuals more vulnerable to persistent weight gain and obesity than are others? Some obese individuals report factors that drive overeating, including lack of control, lack of satiation, and preoccupation with food, which may stem from reward-related neural circuitry. These are normative and common symptoms and not the sole focus of any existing measures. Many eating scales capture these common behaviors, but are confounded with aspects of dysregulated eating such as binge eating or emotional overeating. Across five studies, we developed items that capture this reward-based eating drive (RED). Study 1 developed the items in lean to obese individuals (n = 327) and examined changes in weight over eight years. In Study 2, the scale was further developed and expert raters evaluated the set of items. Study 3 tested psychometric properties of the final 9 items in 400 participants. Study 4 examined psychometric properties and race invariance (n = 80 women). Study 5 examined psychometric properties and age/gender invariance (n = 381). Results showed that RED scores correlated with BMI and predicted earlier onset of obesity, greater weight fluctuations, and greater overall weight gain over eight years. Expert ratings of RED scale items indicated that the items reflected characteristics of reward-based eating. The RED scale evidenced high internal consistency and invariance across demographic factors. The RED scale, designed to tap vulnerability to reward-based eating behavior, appears to be a useful brief tool for identifying those at higher risk of weight gain over time. Given the heterogeneity of obesity, unique brief profiling of the reward-based aspect of obesity using a self-report instrument such as the RED scale may be critical for customizing effective treatments in the general population.

BDNF secretion by human pulmonary artery endothelial cells in response to hypoxia.

Within human pulmonary artery, neurotrophin growth factors [NTs; e.g. brain-derived neurotrophic factor (BDNF)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been reported, but their functional role is incompletely understood. We tested the hypothesis that BDNF is produced by human pulmonary artery endothelial cells (PAECs). In the context of hypoxia as a risk factor for pulmonary hypertension, we examined the effect of hypoxia on BDNF secretion and consequent autocrine effects on pulmonary endothelium. Initial ELISA analysis of circulating BDNF in 30 healthy human volunteers showed that 72 h exposure to high altitude (~11,000 ft, alveolar PO2 = 100 mmHg) results in higher BDNF compared to samples taken at sea level. Separately, in human PAECs exposed for 24h to normoxia vs. hypoxia (1-3% O2), ELISA of extracellular media showed increased BDNF levels. Furthermore, quantitative PCR of PAECs showed 3-fold enhancement of BDNF gene transcription with hypoxia. In PAECs, BDNF induced NO production (measured using an NO-sensitive fluorescent dye DAF2-DA) that was significantly higher under hypoxic conditions, an effect also noted with the TrkB agonist 7,8-DHF. Importantly, hypoxia-induced NO was blunted by neutralization of secreted BDNF using the chimeric TrkB-Fc. Both hypoxia and BDNF increased iNOS (but not eNOS) mRNA expression. In accordance, BDNF enhancement of NO in hypoxia was not blunted by 50 nM L-NAME (eNOS inhibition) but substantially lower with 100 µM L-NAME (eNOS and iNOS inhibition). Hypoxia and BDNF also induced expression of hypoxia inducible factor 1 alpha (HIF-1α), a subunit of the transcription factor HIF-1, and pharmacological inhibition of HIF-1 diminished hypoxia effects on BDNF expression and secretion, and NO production. These results indicate that human PAECs express and secrete BDNF in response to hypoxia via a HIF-1-regulated pathway.

Relationship between alkaline phosphatase and all-cause mortality in peritoneal dialysis patients.

Elevated levels of serum alkaline phosphatase (AlkPhos) have been reported to be associated with increased mortality risk in hemodialysis (HD) patients. We examined the association of serum AlkPhos with all-cause mortality in our PD patients. The study enrolled 90 PD patients beginning in 1995. On enrollment, demographics and clinical and biochemical data were recorded. Patients were followed to September 2011. Mean age of the enrollees was 52 years, with 61% being women, and most (81%) being of African descent. Mean and median AlkPhos were 135 U/L and 113 U/L respectively. Mean and maximum follow-up were 2.61 and 16 years respectively. As expected, AlkPhos correlated directly with serum intact parathyroid hormone (r = 0.36, p = 0.003). In a Cox multivariate regression analysis with adjustment for confounding variables, AlkPhos as a continuous (relative risk: 1.016; p = 0.004) anda categorical variable [> 120 U/L and < or = 120 U/L (relative risk: 6.0; p = 0.03)] remained a significant independent predictor of mortality. For each unit increase in enrollment AlkPhos, there was a 1.6% increase in the relative risk of death. Elevated serum AlkPhos is significantly and independently associated with increased mortality risk in our PD patients followed for up to 16 years. AlkPhos should be evaluated prospectively as a potential therapeutic target in clinical practice.