CRP, Fibrinogen, White Blood Cells, and Blood Cell Indices as Prognostic Biomarkers of Future COPD Exacerbation Frequency: The TIE Cohort Study.

Background/Objective: Systemic inflammation is common in chronic obstructive pulmonary disease (COPD), and evidence suggests that inflammatory biomarkers can predict acute exacerbations (AECOPDs). The aim of this study was to analyse whether C-reactive protein (CRP), fibrinogen, white blood cell count (WBC), or the blood cell indices PLR (platelet-to-lymphocyte ratio), SII (systemic immune inflammation index), SIRI (systemic inflammation response index), and AISI (aggregate index of systemic inflammation) can predict future AECOPDs. Methods: In the Tools Identifying Exacerbations (TIE) cohort study, participants with spirometry-confirmed COPD were recruited from primary and secondary care in three Swedish regions and assessed during a stable phase of COPD. AECOPD frequency during the three-year follow-up was reviewed in medical records. Associations were analysed via ordinal logistic regressions. Results: Of the 571 participants, 46% had ≥1 AECOPD during follow-up, and the mean ± SD AECOPD frequency was 0.63 ± 1.2/year. In unadjusted analyses, high levels of CRP (odds ratio 1.86, 95% CI 1.29-2.67), fibrinogen (2.09, 1.38-3.16), WBCs (2.18, 1.52-3.13), SII (1.52, 1.05-2.19), SIRI (1.76, 1.23-2.52), and AISI (1.99, 1.38-2.87) were associated with a higher AECOPD frequency. After adjustment for AECOPD history, age, sex, smoking, body mass index, COPD Assessment Test score, lung function, and inhaled corticosteroid use, associations remained for high levels of CRP (adjusted odds ratio of 1.64; 95% CI of 1.08-2.49), fibrinogen (1.55; 1.07-2.24), and WBC (1.65; 1.10-2.47). Conclusions: CRP, fibrinogen, and WBC, assessed during stable-phase COPD, enhanced AECOPD prediction, whereas PLR, SII, SIRI, and AISI did not.

Total Nitrite and Nitrate Concentration in Human Milk and Saliva during the First 60 Days Postpartum-A Pilot Study.

Nitric oxide (NO) in human milk may have important functions in lactation and infant health. This longitudinal pilot cohort study investigated the total nitrite and nitrate (NOx) concentration in human milk and maternal saliva during the first 60 days postpartum. Additionally, we explored the association between selected breastfeeding variables and milk and saliva NOx concentration. Human milk and maternal saliva samples were collected on days 2, 5, 14, 30, and 60 postpartum and analyzed for NOx concentration. Breastfeeding data were collected through self-assessed questions. Data analyses were performed using mixed models. The concentration of NOx in milk was significantly higher during the first 30 days compared to day 60, and there was a positive association between milk and saliva NOx concentrations throughout the entire study period. In absolute numbers, partially breastfeeding mothers had a lower concentration of NOx in milk on day 2 compared to exclusively breastfeeding mothers (8 vs. 15.1 µM, respectively). Partially breastfeeding mothers reported a later start of secretory activation and fewer mothers in this group started breastfeeding within the first hour after birth. Due to the small numbers, these differences could not be statistically evaluated. Further research is warranted to elucidate the role of NO in lactation success and breastfeeding outcomes.

Symptom Duration, Recurrence, and Long-Term Effects of Swimming-Induced Pulmonary Edema: A 30-Month Follow-Up Study.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) has been reported to subside within 24 to 48 h, but comprehensive follow-up studies on symptom duration and long-term effects are missing. RESEARCH QUESTION: What are the symptom duration, recurrence, and long-term effects of SIPE? STUDY DESIGN AND METHODS: A follow-up study was conducted, based on 165 cases of SIPE from Sweden's largest open-water swimming event with 26,125 individuals participating during 2017-2019. Data on patient characteristics, clinical findings, and symptoms were collected at admission. Telephone interviews at 10 days and 30 months were performed to explore symptom duration, recurrence of SIPE symptoms, need for medical evaluation, and long-term effects of self-assessed general health and physical activity level. RESULTS: Follow-up at 10 days was performed for 132 cases and at 30 months for 152 cases. Most of the patients were women, and their mean age was 48 years. At the 10-day follow-up, symptom duration > 2 days after the swimming race was reported by 38%. The most common symptoms were dyspnea and cough. In patients at 30-month follow-up, recurrence of respiratory symptoms during open-water swimming was reported by 28%. In multivariable logistic regression, asthma was independently associated with both symptom duration > 2 days and recurrence of SIPE symptoms (P = .045 and P = .022, respectively). Most participants reported equal or improved general health (93%) and physical activity level (85%) after experiencing SIPE, but 58% had not swum in open water since the event. INTERPRETATION: The present large cohort study challenges the established hallmark of SIPE symptom duration < 48 h, whereas SIPE recurrence was in the previously reported range. At 30 months, most patients reported unchanged self-assessed general health and physical activity level. These findings add to our understanding of the course of SIPE and can provide evidence-based information to swimmers and health care professionals.

Challenges of primary health care leadership during the COVID-19 pandemic in Sweden: a qualitative study of managers' experiences.

PURPOSE: At the outbreak of the COVID-19 pandemic, health care was at the centre of the crisis. New demands made existing organizational practices and services obsolete. Primary health care had a great deal of responsibility for COVID-19-related care. The pandemic demanded effective leadership to manage the new difficulties. This paper aims to explore experiences and perceptions of managers in primary health care in relation to their efforts to manage the COVID-19 crisis in their everyday work. DESIGN/METHODOLOGY/APPROACH: The authors used a qualitative approach based on 14 semi-structured interviews with managers in primary health care from four regions in Sweden. The interviews were conducted during September to December 2020. Data were analysed using conventional qualitative content analysis. FINDINGS: Data analysis yielded three categories: lonely in decision-making; stretched to the limit; and proud to have coped. The participants felt lonely in their decision-making, and they were stretched to the limit of their own and the organization's capacity. The psychosocial working conditions in primary care worsened considerably during the pandemic because demands on leaders increased while their ability to control the work situation decreased. However, they also expressed pride that they and their employees had managed the situation by being flexible and having a common focus. ORIGINALITY/VALUE: Looking ahead and using lessons learnt, and apart from making wise decisions under pressure, an important implication for primary health-care leaders is to not underestimate the power of acknowledging the virtues of humanity and justice during a crisis. Continuing professional education for leaders focusing on crisis leadership could help prepare leaders for future crises.

Swimming-Induced Pulmonary Edema: Evaluation of Prehospital Treatment With CPAP or Positive Expiratory Pressure Device.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) occasionally occurs during swimming in cold open water. Although optimal treatment for SIPE is unknown, non-invasive positive pressure ventilation (NPPV) is an option for prehospital treatment. RESEARCH QUESTION: Is NPPV a feasible and safe prehospital treatment for SIPE, and which outcome measures reflect recovery after treatment? STUDY DESIGN AND METHODS: A prospective observational study was conducted at Vansbrosimningen, Sweden's largest open water swimming event, from 2017 through 2019. Swimmers with a diagnosis of SIPE and with peripheral oxygen saturation (Spo2) of ≤ 95%, persistent respiratory symptoms, or both were eligible for the study. NPPV was administered on site as CPAP by facial mask or as positive expiratory pressure (PEP) by a PEP device. Discharge criteria were Spo2 of > 95% and clinical recovery. Four outcome measures were evaluated: Spo2, crackles on pulmonary auscultation, pulmonary edema on lung ultrasound (LUS), and patient-reported respiratory symptoms. RESULTS: Of 119 treated individuals, 94 received CPAP, 24 received treatment with a PEP device, and one required tracheal intubation. In total, 108 individuals (91%) were discharged after NPPV for a median of 10 to 20 min and 11 individuals (9%) required hospital transfer. NPPV resulted in increased Spo2 from a median of 91% to 97% (P < .0001) together with improvement of six patient-reported respiratory symptoms (median numerical rating scales, 1-7 to 0-1; P < .0001). No significant decrease in auscultation of crackles (93% vs 87%; P = .508) or pulmonary edema on LUS (100% vs 97%; P = .500) was seen during NPPV treatment. INTERPRETATION: NPPV administered as CPAP or via a PEP device proved feasible and safe as prehospital treatment for SIPE with a vast majority of patients discharged on site. Spo2 and patient-reported respiratory symptoms reflected recovery after treatment, whereas pulmonary auscultation or LUS findings did not.

Working conditions in primary healthcare during the COVID-19 pandemic: an interview study with physicians in Sweden.

OBJECTIVE: The aim of this study was to explore how the COVID-19 pandemic changed the working conditions of physicians in Swedish primary healthcare. DESIGN: This is a descriptive, qualitative study with individual semistructured interviews. Data were analysed using inductive content analysis. SETTING: Swedish primary healthcare units in both rural and urban areas. PARTICIPANTS: A total of 11 primary care physicians fulfilled participation. RESULTS: Two main categories emerged: 'work organisation and routines' and 'psychosocial work environment', containing three and five subcategories, respectively. The pandemic enforced changes in work organisation and routines. Increased flexibility, including more patient-oriented delivery of care, and novel means of interorganisational and intraorganisational interactions were perceived as positive by physicians. The pandemic also caused several changes in physicians' psychosocial work environment. Increased workload, information overload, as well as ethical considerations and feelings of uncertainty made the work environment stressful for physicians. CONCLUSIONS: The COVID-19 pandemic affected the working conditions of physicians in Swedish primary healthcare in numerous ways. The pandemic enforced changes in work organisation and routines for physicians in primary healthcare. Further research is needed to investigate how the pandemic will affect primary healthcare in the longer term. Learning from the pandemic is important because this will not be the last crisis that primary care and its healthcare professionals will face.

From chaos to control - experiences of healthcare workers during the early phase of the COVID-19 pandemic: a focus group study.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has caused overwhelming challenges to healthcare systems worldwide. Healthcare workers (HCWs) have faced particular challenges: being exposed to the coronavirus SARS-CoV-2 and caring for patients having a new and potentially life-threatening disease. The aim of this study was to explore how HCWs in the Swedish healthcare system perceived their work situation during the first phase of the COVID-19 pandemic in 2020. METHODS: Focus group discussions and interviews with HCWs were performed from June to October 2020 in one Swedish healthcare region. A purposeful sampling approach was used to select a variety of professions (physicians, nurses, nurse aides and cleaners) and workplaces (hospital inpatient wards, emergency department, nursing home and home care service). Qualitative content analysis was used for data analysis. RESULTS: In total, 51 HCWs participated in eight focus group discussions and one HCW participated in an individual interview. The content analysis identified two main categories: 'Concerns about the risk of infection and transmission of infection to others', and 'Transition from chaos to managing in a new and challenging work situation'. The findings revealed how HCWs perceived working conditions, including experiences of fear for personal health, confusion and uncertainty regarding personal protective equipment and infection prevention and control (PPE/IPC), and fear of infecting others. Both fearful and appreciating attitudes were achieved from the surrounding community. Helpful strategies for transition from chaos to control were lifted i.e. present and supportive leadership, and finding comfort and strength in the working team. Both helplessness and meaningfulness were described when caring for COVID-19 patients. CONCLUSIONS: This study provides unique insights into HCWs experiences of an extremely challenging work situation during the first phase of the COVID-19 pandemic, including feelings of stress and insecurity in a chaotic and hazardous working environment. But there is also mitigation of these challenges and even positive experiences including feelings of safety and meaningfulness. To enhance safety among HCWs in healthcare crises such as the COVID-19 pandemic, the findings highlight the importance of avoiding confusion about PPE/IPC, having a supportive healthcare leadership and ensuring accurate information provision about virus transmission to the public.

Incidence of Swimming-Induced Pulmonary Edema: A Cohort Study Based on 47,600 Open-Water Swimming Distances.

BACKGROUND: Despite increasing awareness of swimming-induced pulmonary edema (SIPE), large population-based studies are lacking and the incidence is unknown. RESEARCH QUESTION: What is the incidence of SIPE in a mixed group of competitive and recreational swimmers during a large open-water swimming event? METHODS: In four consecutive years (2016-2019), a prospective cohort study was conducted during Sweden's largest open-water swimming event, Vansbrosimningen. All swimmers seeking medical care with acute respiratory symptoms were eligible for the study. SIPE diagnosis was based on clinical findings in 2016 and 2017 and pulmonary edema assessed by lung ultrasound in 2018 and 2019. Data on patient characteristics, clinical findings, and information about the race were collected. RESULTS: Based on 47,573 consecutive swimming distances, 322 patients with acute respiratory symptoms (0.68%; CI, 0.61%-0.75%) were treated at the mobile medical unit. Of these, 211 patients (0.44%; CI, 0.39%-0.51%) received a diagnosis of SIPE. The annual incidence of SIPE was 0.34%, 0.47%, 0.41%, and 0.57%, respectively, from 2016 through 2019. Most patients diagnosed with SIPE were women (90%), despite about equal percentages of men and women participating (47% men and 53% women). The incidence of SIPE overall was 0.75% in women and 0.09% in men. The incidence increased with age, from 0.08% in the youngest age group (18-30 years) to 1.1% in the oldest age group (≥ 61 years). Based on multiple logistic regression analysis, the adjusted odds for SIPE occurring was 8.59 times higher for women compared with men and 12.74 times higher for the oldest age group compared with the youngest age group. INTERPRETATION: The incidence of SIPE over 4 years during a large open-water swimming event in Sweden was 0.44%. The incidence was higher in women than in men and increased with age.

Lung Ultrasound for Identification of Patients Requiring Invasive Mechanical Ventilation in COVID-19.

OBJECTIVES: Indication for invasive mechanical ventilation in COVID-19 pneumonia has been a major challenge. This study aimed to evaluate if lung ultrasound (LUS) can assist identification of requirement of invasive mechanical ventilation in moderate to severe COVID-19 pneumonia. MATERIALS AND METHODS: Between April 23 and November 12, 2020, hospitalized patients with moderate to severe COVID-19 (oxygen demand ≥4 L/min) were included consecutively. Lung ultrasound was performed daily until invasive mechanical ventilation (IMV-group) or spontaneous recovery (non-IMV-group). Clinical parameters and lung ultrasound findings were compared between groups, at intubation (IMV-group) and highest oxygen demand (non-IMV-group). A reference group with oxygen demand <4 L/min was examined at hospital admission. RESULTS: Altogether 72 patients were included: 50 study patients (IMV-group, n = 23; non-IMV-group, n = 27) and 22 reference patients. LUS-score correlated to oxygen demand (SpO2 /FiO2 -ratio) (r = 0.728; p < .0001) and was higher in the IMV-group compared to the non-IMV-group (20.0 versus 18.0; p = .026). Based on receiver operating characteristic analysis, a LUS-score of 19.5 was identified as cut-off for requirement of invasive mechanical ventilation (area under the curve 0.68; sensitivity 56%, specificity 74%). In 6 patients, LUS identified critical coexisting conditions. Respiratory rate and oxygenation index ((SpO2 /FiO2 )/respiratory rate) ≥4.88 identified no requirement of invasive mechanical ventilation with a positive predictive value of 87% and negative predictive value of 100%. CONCLUSIONS: LUS-score had only a moderate diagnostic value for requirement of invasive mechanical ventilation in moderate to severe COVID-19. However, LUS proved valuable as complement to respiratory parameters in guidance of disease severity and identifying critical coexisting conditions.

Swimming-Induced Pulmonary Edema: Diagnostic Criteria Validated by Lung Ultrasound.

BACKGROUND: Despite the increasing popularity of open water swimming worldwide, swimming-induced pulmonary edema (SIPE) is a poorly recognized condition lacking established diagnostic criteria. RESEARCH QUESTION: The aim of this study was to identify diagnostic criteria of SIPE during a large open water swimming event. STUDY DESIGN AND METHODS: In this cross-sectional study, 17,904 individuals swam 1,000, 1,500, or 3,000 m in cold open water during Sweden's largest open water swimming event in 2018 and 2019. Of 166 swimmers seeking medical attention for acute respiratory symptoms, 160 were included in the study. Medical history, symptoms, and clinical findings were collected. On-site lung ultrasound (LUS) was performed to verify pulmonary edema. RESULTS: Pulmonary edema was confirmed by LUS in 102 patients (64%); findings were unilateral in 11 (7%). Peripheral oxygen saturation was identified as a strong independent diagnostic test for pulmonary edema, with ≤ 95% as the suggested cut off based on receiver-operating characteristic curve analysis (area under the curve, 0.893; P < .0001). Crackles on lung auscultation, predominantly over the anterior chest, identified 88% of patients with edema. Peripheral oxygen saturation ≤ 95% or auscultation findings of crackles identified pulmonary edema with a sensitivity of 97% and a specificity of 86%. A specificity of 98% and a positive predictive value of 99% for LUS-verified pulmonary edema were reached if patients presented with both oxygen saturation ≤ 95% and auscultation of crackles. INTERPRETATION: We suggest a clinical algorithm for diagnosis of SIPE for swimmers with acute respiratory symptoms during swimming in cold open water. Novel features of focally distributed edema in the anterior parts of the lungs, sometimes unilateral, add to this unique dataset of an underreported condition.

Late onset hyperornithinemia-hyperammonemia-homocitrullinuria syndrome - how web searching by the family solved unexplained unconsciousness: a case report.

BACKGROUND: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a rare inherited urea cycle disorder, can remain undiagnosed for decades and suddenly turn into an acute life-threatening state. Adult presentation of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome has rarely been described, but is potentially underdiagnosed in the emergency room. In the case of acute hyperammonemia, prompt diagnosis is essential to minimize the risk of brain damage and death. CASE PRESENTATION: We present the diagnostics, clinical course, and treatment of a 48-year-old Caucasian man presenting with unexplained unconsciousness in the emergency room. A web search by a family member led to the suspicion of urea cycle disorder. Subsequent analysis of plasma ammonia and amino acids in plasma and urine demonstrated a pattern typical for hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. The diagnosis was confirmed by genetic analysis which revealed two heterozygous mutations in the SLC25A15 gene. The cause of the hyperammonemia crisis was acute upper gastrointestinal hemorrhage, leading to protein overload and subsequent cerebral edema. Continuous renal replacement therapy, scavenger treatment, and tightly controlled nutrition were useful in preventing hyperammonemia and recurrence of cerebral edema. CONCLUSIONS: The case emphasizes the importance of taking rare metabolic genetic disorders into consideration in patients with prolonged unexplained unconsciousness.

[Swimming-induced pulmonary edema in Swedish conditions has been insufficiently studied]. / Simningsorsakat lungödem vid svenska förhållanden otillräckligt studerat - Erfarenheter från Vansbrosimningen 2016.

Swimming-induced pulmonary edema (SIPE) has been described in sports and military medicine during strenuous swimming in open water. Symptoms include dyspnea, cough, frothy mucus and hemoptysis. Hypertension, a tight wetsuit, overhydration and previous episodes of SIPE are suggested risk factors. Immediate interruption of swimming prevents more serious symptoms. In the open water race at Vansbro 2016, 69 swimmers (of 13,878 in total) were treated for symptoms suspected for SIPE. Continuous positive airway pressure (CPAP) was successfully used to treat suspected SIPE in 46 patients in the on-site emergency care center. Open water swimming races are increasingly popular and also attract many unexperienced swimmers. There is a need of validated guidelines for organizers of open water races, swimmers and health professionals.

Characterization of Innate Immunity in an Extended Whole Blood Model of Human Islet Allotransplantation.

The instant blood-mediated inflammatory reaction (IBMIR) has been studied in whole blood models of human allo-islet transplantation for short periods (<6 h). Beyond this time frame the innate response to intraportally transplanted islets is less well described. A novel whole blood model was applied to study blood-islet-graft interactions up to 48 h. Heparinized polyvinyl chloride tubing was sealed into small bags containing venous blood together with allogeneic human islets and exocrine tissue, respectively. The bags were attached to a rotating wheel (37°C). Concentrated glucose and sodium hydrogen carbonate were added every 12 h to maintain physiological limits for sustained immune cell functions. Plasma was collected at repeated time points for analyses of coagulation/complement activation and chemokine/cytokine production. Immune cell infiltration was analyzed using immunohistochemistry. Coagulation and platelet activation markers, thrombin-antithrombin complex (TAT) and soluble CD40 ligand (sCD40L) showed early high concentrations (at 6-12 h). sC5b-9 steadily increased over 48 h. At 6 h neutrophils and monocytes surrounded the clotted cellular grafts with a following massive infiltration of neutrophils. High and increasing concentrations of CXCR1/2 ligands [IL-8 and growth-regulated oncogene α/ß/γ (Gro-α/ß/γ)] and IL-6 were produced in response to human islets and exocrine tissue. The CCR2 ligand monocyte chemoattractant protein 1 (MCP-1) exhibited increasing concentrations in response to exocrine tissue. The CXCR3 ligand interferon-inducible T cell α chemoattractant (I-TAC) was produced in response to both human islets and exocrine tissue from 6 h. Monokine induced by γ interferon (Mig) and interferon γ-induced protein 10 (IP-10) showed a later response, preferentially to exocrine tissue and with larger variations among preparations. An extended blood model of clinical islet transplantation allowed characterization of early immune activation in response to human islets and exocrine tissue. Increased production of chemokines targeting CXCR1/2, CCR2, and CXCR3 was observed, accompanied by massive intraislet neutrophil infiltration over 48 h. The model proved to be useful in exploring early blood-mediated reactions to cellular transplants and has relevance for evaluation of pharmacological interventions to prevent graft loss.

A novel model for studies of blood-mediated long-term responses to cellular transplants.

AIMS: Interaction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h. METHODS: Heparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability. RESULTS: Basic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen. CONCLUSION: A novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.

Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates.

Cell-based diabetes therapy requires an abundant cell source. Here, we report reversal of diabetes for more than 100 d in cynomolgus macaques after intraportal transplantation of cultured islets from genetically unmodified pigs without Gal-specific antibody manipulation. Immunotherapy with CD25-specific and CD154-specific monoclonal antibodies, FTY720 (or tacrolimus), everolimus and leflunomide suppressed indirect activation of T cells, elicitation of non-Gal pig-specific IgG antibody, intragraft expression of proinflammatory cytokines and invasion of infiltrating mononuclear cells into islets.

Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts.

BACKGROUND: We have previously shown that pig-to-primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non-immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non-human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation. METHODS: Liver specimens were collected at sacrifice from seven non-immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real-time reverse transcription polymerase chain reaction (RT-PCR) for species-specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer-efficiencies and normalized to cyclophilin expression. RESULTS: Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post-transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon-inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig), significantly increased between early and late time points together with expression of MIP-1alpha, regulated on activation normal T expressed and secreted protein (RANTES) and MCP-1. CCR5 showed only a marginal, non-significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post-transplant. CONCLUSIONS: Our data suggest that CXCR3, with ligands IP-10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non-human primates. Upregulation of RANTES and MIP-1alpha transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP-1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T-cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3-mediated chemoattractant pathway as an immunosuppressive target in pig-to-primate islet xenotransplantation.

Hyperlipidemia in pediatric kidney transplant recipients treated with cyclosporine.

Hyperlipidemia is a risk factor for cardiovascular disease in adult kidney transplant (Tx) recipients. We sought to determine the prevalence of, and the risk factors associated with, hyperlipidemia in pediatric kidney Tx recipients on cyclosporine (CsA). We identified 59 patients (mean age 8.2+/-5.7 years) transplanted between 1 January 1991 and 31 December 1993. Pre Tx, 34% had elevated total cholesterol [TC >200 mg/dl (5.17 mmol/l)]; 54% had elevated triglycerides [TG >200 mg/dl (2.26 mmol/L)]. Mean TG was higher pre Tx in dialysis (versus nondialysis) patients: 306 mg/dl (3.46 mmol/l) versus 228 mg/dl (2.58 mmol/l) ( P=0.04). Mean TC was higher in peritoneal dialysis than hemodialysis patients: 222 mg/dl (5.74 mmol/l) versus 169 mg/dl (4.37 mmol/l) ( P=0.03). Pre Tx and 3-year values correlated (TC, r=0.49, P=0.0008; TG, r=0.41, P=0.001); 3- and 5-year TC values correlated ( r=0.57, P=0.003). At 5 years post Tx, 41% of the recipients had elevated TC; 14% had elevated TG. Recipients with elevated TC had higher mean CsA concentrations at 1 year post Tx ( P=0.03). Recipients with elevated TG tended to receive more prednisone ( P=0.06). At 5 years post Tx, recipients had a high prevalence of hyperlipidemia. The identification and treatment of hyperlipidemia should be included in pediatric kidney Tx protocols.