Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506) is a safe and effective treatment for the prevention of rejection of renal allografts. Mycophenolate mofetil (MMF) has been used as adjunct immunosuppressive therapy with cyclosporine and corticosteroids for the same purpose. The objective of this study was to investigate the safety and efficacy of FK506 and MMF in renal transplant recipients. METHODS: After cadaveric renal transplant, patients were randomized to receive tacrolimus in combination with either azathioprine (AZA, n=59), MMF 1 g/day (n=59), or MMF 2 g/day group (n=58). Patients were followed for 1 yr posttransplant for the incidence of biopsy-confirmed acute rejection, patient and graft survival, and adverse events. RESULTS: Tacrolimus doses and trough concentrations were similar between treatment groups at all time points; 80% of patients were maintained within a range of 5.0-13.9 ng/ml at 12 months posttransplant. The mean dose of MMF decreased in the 2 g/day group to 1.5 g/day by 6 months posttransplant, primarily due to gastrointestinal GI-related disorders. The incidence of biopsy-confirmed acute rejection at 1 year was 32.2%, 32.2%, and 8.6% in the AZA, MMF 1 g/day, and MMF 2 g/day groups, respectively (P<0.01). The use of antilymphocyte antibodies for the treatment of rejection was comparable across treatment groups. The incidence of most adverse events was similar across treatment groups and comparable with previous reports. The overall incidence of posttransplant diabetes mellitus was 11.9%, with the lowest rate observed in the MMF 2 g/day group (4.7%), and was reversible in 40% of patients. The incidence of malignancies and opportunistic infections was low and not different across treatment groups. CONCLUSION: Tacrolimus in combination with an initial dose of MMF 2 g/day is a very effective and safe regimen in cadaveric kidney transplant recipients.     

Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome

BACKGROUND: Select pancreatic enzymes, primarily elastase, precipitate pulmonary injury similar to pancreatitis-associated adult respiratory distress syndrome and stimulate leukocyte cytokine production in vitro via nuclear factor kappa B (NF-kappaB) activation. This study explores the effect of systemic pancreatic enzymes on pulmonary NF-kappaB and inhibitory kappa B (IkappaB) proteins and their role in enzyme-induced pulmonary injury. METHODS: Mice received pancreatic elastase, amylase, lipase, or trypsin intraperitoneally. Bronchoalveolar lavage IkappaBalpha/IkappaBbeta proteins were measured by immunoblot. Pulmonary NF-kappaB activation, tumor necrosis factor (TNF) gene expression, and neutrophil infiltration (myeloperoxidase) were determined and myeloperoxidase experiments repeated in p55 TNF receptor-deficient (TNF KO) animals. Additional animals received pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB activation, and TNF protein and pulmonary microvascular permeability were measured after elastase administration. RESULTS: Pancreatic elastase induced pulmonary IkappaBalpha/IkappaBbeta degradation (30 minutes), NF-kappaB activation (60 minutes), and TNF gene expression (60 minutes) with subsequent neutrophilic inflammation (4 hours) and microvascular leakage (24 hours), whereas amylase, lipase, and trypsin did not. Furthermore, lung injury was markedly reduced in TNF KO animals and PDTC significantly attenuated TNF production and pulmonary microvascular leakage. CONCLUSIONS: Pancreatic elastase induces cytokine-mediated lung injury and this pathway involves the NF-kappaB second messenger system, further supporting elastase as a factor linking pancreatic inflammation to systemic illness during severe acute pancreatitis.     

Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft

The current transplantation strategy in experimental and clinical Parkinson's disease (PD) has been to place nigral dopaminergic grafts not in their ontogenic site (substantia nigra) but in their target area (striatum). Although intrastriatal dopaminergic grafts are capable of reinnervating the striatum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patients. We have previously shown that simultaneous intrastriatal and intranigral dopaminergic grafts (double grafts) may provide a more complete restoration of the nigrostriatal circuitry (Mendez et al. [1996] J Neurosci 16:7216-7227; Mendez and Hong [1997] Brain Res 778:194-205). In the present study, we investigated the contribution of the intranigral graft to functional recovery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were divided into two groups and received either double grafts (n = 10) or intrastriatal grafts alone (n = 10). Following transplantation, both intrastriatally and double-grafted animals had a significant decrease in rotational behavior. However, only animals with double grafts exhibited a significant increase in contralateral adjusting step performance. The intranigral graft was subsequently lesioned by a second 6-OHDA injection. Following the second lesion, animals with double grafts exhibited a significant reversal of rotational behavior and a 51% reduction in contralateral adjusting step performance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest that the intranigral graft has an important role in the functional recovery of double-grafted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a superior strategy in neural transplantation for PD.     

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line--derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.     

Hearing Function and Nutritional Status in Aviation Pilots from Spain Exposed to High Acoustic Damage

Noise-induced hearing loss is the most frequent and preventable occupational disease. Aviation pilots are a vulnerable population, as they spend many hours exposed to noise pollution in their working environment. Different studies suggest that certain dietary compounds may play a key role in the etiology and prevention of this pathology. We aimed to study the relationship linking auditory function, dietary intake, and some serum biomarkers in pilots, exposed to noise in the work environment. A total of 235 pilots, who undergo a periodic medical examination at the Centro de Instrucción de Medicina Aeroespacial (Madrid, SPAIN), were evaluated. Auditory function was assessed by tonal audiometry. Energy and nutrient intakes were estimated by 24 h recall (DIAL^TM program). Serum homocysteine (Hcy) was determined in a Cobas 6000^TM multi-analyzer while folate, vitamin B₁₂, and D were analyzed in a Cobas e411^TM. The prevalence of hearing loss (HL) was 64.3%. HL was significantly related to age (r = 0.588, p ≤ 0.001) and flight hours (r = 0.283, p ≤ 0.001). A multiple linear regression model was used to assess the relationship among HL, flight hours, serum folate, and Hcy serum levels. HL was significantly (p < 0.050) associated with flight hours (β = 0.246), serum folate (β = −0.143), and serum Hcy (β = 0.227). Nutritional interventions would be of great interest to monitor and slow down the HL progression in populations exposed to noise pollution in their workplace.     

Association of Lifetime Exposure to Glyphosate and Aminomethylphosphonic Acid (AMPA) with Liver Inflammation and Metabolic Syndrome at Young Adulthood: Findings from the CHAMACOS Study

Background: The prevalence of liver disorders and metabolic syndrome has increased among youth. Glyphosate, the most widely used herbicide worldwide, could contribute to the development of these conditions.Objective: We aimed to assess whether lifetime exposure to glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), is associated with elevated liver transaminases and metabolic syndrome among young adults.Methods: We conducted a prospective cohort study (n=480 mother–child dyads) and a nested case–control study (n=60 cases with elevated liver transaminases and 91 controls) using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We measured glyphosate and AMPA concentrations in urine samples collected during pregnancy and at child ages 5, 14, and 18 y from cases and controls. We calculated glyphosate residue concentrations: [glyphosate +(1.5×AMPA)]. We estimated the amount of agricultural-use glyphosate applied within a 1-km radius of every residence from pregnancy to age 5 y for the full cohort using California Pesticide Use Reporting data. We assessed liver transaminases and metabolic syndrome at 18 y of age.Results: Urinary AMPA at age 5 y was associated with elevated transaminases [relative risk (RR) per 2-fold increase=1.27, 95% confidence interval (CI): 1.06, 1.53] and metabolic syndrome (RR=2.07, 95% CI: 1.38, 3.11). Urinary AMPA and glyphosate residues at age 14 y were associated with metabolic syndrome [RR=1.80 (95% CI: 1.10, 2.93) and RR=1.88 (95% CI: 1.03, 3.42), respectively]. Overall, a 2-fold increase in urinary AMPA during childhood was associated with a 14% and a 55% increased risk of elevated liver transaminases and metabolic syndrome, respectively. Living near agricultural glyphosate applications during early childhood (birth to 5 y of age) was also associated with metabolic syndrome at age 18 y in the case–control group (RR=1.53, 95% CI: 1.16, 2.02).Discussion: Childhood exposure to glyphosate and AMPA may increase risk of liver and cardiometabolic disorders in early adulthood, which could lead to more serious diseases later in life. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP11721","term_id":"372011122","term_text":"EHP11721"}}EHP11721     

Community‐based health literacy focused intervention for cervical cancer control among Black women living with human immunodeficiency virus: A randomized pilot trial

BackgroundHealth literacy plays an essential role in how individuals process health information to make decisions about health behaviours including cancer screening. Research is scarce to address health literacy as a strategy to improve cancer screening participation among women living with human immunodeficiency virus (HIV), particularly Black women who, despite the heavy burden of cervical cancer, report consistently low screening rates.AimTo assess the feasibility, acceptability and preliminary efficacy of a health literacy‐focused intervention called CHECC‐uP—Community‐based, HEalth literacy focused intervention for Cervical Cancer control—among women living with HIV.MethodsWe conducted a community‐based, single‐blinded randomized pilot trial. A total of 123 eligible women were enrolled and randomized to one of two conditions, control (i.e., cervical cancer brochure) or intervention (cervical cancer brochure plus 30–60 min health literacy‐focused education followed by monthly phone counselling and navigation assistance for 6 months). Study assessments were done at baseline, 3 and 6 months. The final analysis sample included 58 women who completed all data points and whose Papanicolaou (Pap) test status was confirmed by medical records.ResultsAll intervention participants who completed the programme would recommend the CHECC‐uP to other women living with HIV. However, adherence in the experimental conditions was low (49.6% attrition rate including 20 women who dropped out before the intervention began) due, in large part, to phone disconnection. Those who had received the intervention had a significantly higher Pap test rate compared to women in the control group at 6 months (50% vs. 21.9%, p = .025). Participation in the intervention programme was associated with improved health literacy and other psychosocial outcomes at 3 months but the trend was attenuated at 6 months.ConclusionsThe CHECC‐uP was highly acceptable and led to improved Pap testing rates among Black women living with HIV. Future research should consider addressing social determinants of health such as phone connectivity as part of designing a retention plan targeting low‐income Black women living with HIV.ImplicationsThe findings should be incorporated into a future intervention framework to fulfil the unmet needs of Black women living with HIV to facilitate their decision‐making about Pap test screening.Patient or Public ContributionNineteen community members including women living with HIV along with HIV advocates and care providers participated in four focus groups to develop cervical cancer screening decision‐relevant information and the health literacy intervention. Additionally, a community advisory board was involved to provide guidance in the general design and conduct of the study.