Simon Hannam

The role of Toll-like receptors in renal diseases

Toll-like receptors (TLRs) have a key role in innate immunity. These receptors recognize both pathogen-associated molecular patterns and molecules that are released from damaged tissue. TLRs mediate signal transduction pathways through the activation of transcription factors that regulate the expression of proinflammatory cytokines and chemokines and are required for the development of adaptive immune responses. TLRs might have an important role in the pathogenesis of renal diseases: their exaggerated activation is associated with ischemic kidney damage, acute kidney injury, end-stage renal failure, acute tubulointerstitial nephritis, acute renal transplant rejection and delayed allograft function. As the results of previous studies concerning the role of TLRs in renal diseases are conflicting, further work is needed to determine the exact role of these receptors and to evaluate strategies to prevent TLR-mediated local inflammation. This Review discusses the evidence supporting a role for TLRs in contrasting bacterial infections and in causing or aggravating renal conditions when TLR activation leads to a harmful inflammatory response.

Takotsubo cardiomyopathy — The current state of knowledge

Takotsubo cardiomyopathy is defined as acute chest pain during stressful incidents which is associated with ST-segment abnormalities and/or increased serum troponin levels. There is also regressive systolic dysfunction which is usually localized in the apical and medial left ventricles but there are no significant coronary artery lesions. The ventricular asynergy is also described in the right ventricle but is less common. Almost all the patients are women. The onset of this disease is typically triggered by an acute emotional or stress event or by an accumulation of trivial and repetitive stresses. The etiology of this syndrome remains unclear. Myocardial ischemia and reperfusion due to microvascular spasm, aborted myocardial infarction and related no-reflow phenomenon have been proposed as inducers of Takotsubo cardiomyopathy. The temporal relationship between the stressful event and the triggering of the clinical syndrome as well as the report of elevated catecholamine plasma levels during the acute phase suggest a possible involvement of the sympathetic nervous system. A smaller left ventricular size and hormonal disturbances in women may also play a role.

Effect of prone and supine position on sleep, apneas, and arousal in preterm infants.

OBJECTIVE. Prematurely born compared with term born infants are at increased risk of sudden infant death syndrome, particularly if slept prone. The purpose of this work was to test the hypothesis that preterm infants with or without bronchopulmonary dysplasia being prepared for neonatal unit discharge would sleep longer and have less arousals and more central apneas in the prone position. METHODS. This was a prospective observational study in a tertiary NICU. Twenty-four infants (14 with bronchopulmonary dysplasia) with a median gestational age of 27 weeks were studied at a median postconceptional age of 37 weeks. Video polysomnographic recordings of 2-channel electroencephalogram, 2-channel electro-oculogram, nasal airflow, chest and abdominal wall movements, limb movements, electrocardiogram, and oxygen saturation were made in the supine and prone positions, each position maintained for 3 hours. The duration of sleep, sleep efficiency (total sleep time/total recording time), and number and type of apneas, arousals, and awakenings were recorded. RESULTS. Overall, in the prone position, infants slept longer, had greater sleep efficiency (89.5% vs 72.5%), and had more central apneas (median: 5.6 vs 2.2), but fewer obstructive apneas (0.5 vs 0.9). The infants had more awakenings (9.7 vs 3.5) and arousals per hour (13.6 vs 9.0) when supine. There were similar findings in the bronchopulmonary dysplasia infants. CONCLUSIONS. Very prematurely born infants studied before neonatal unit discharge sleep more efficiently with fewer arousals and more central apneas in the prone position, emphasizing the importance of recommending supine sleeping after neonatal unit discharge for prematurely born infants.

Metabolic syndrome and renal disease

The metabolic syndrome (MetS) is a cluster of risk factors including insulin resistance, dyslipidemia and hypertension which are also relevant for the development of chronic kidney disease (CKD). It has proven difficult to elucidate whether the renal dysfunction in MetS is due to the MetS itself or the individual risk factors. For example, obesity - which is also part of the MetS - may enhance the risk of renal dysfunction development probably through mechanisms associated with renal hyperfiltration, hyperperfusion and focal glomerulosclerosis. Insulin resistance also promotes kidney disease by worsening renal hemodynamics. In patients with MetS, tubular atrophy, interstitial fibrosis, and arteriolar sclerosis indicating the presence of vascular damage, have also been described. As yet, there has been little evidence that preventing or treating symptoms of the MetS protects patients from renal impairment.

Malignancy-Associated Dyslipidemia

Cholesterol and triglycerides, important lipid constituents of cell, are essential to carry out several vital physiological functions. Lipids might be associated with cancers because they play a key role in the maintenance of cell integrity. The pathway for cholesterol synthesis may also produce various tumorigenic compounds and cholesterol serves as a precursor for the synthesis of many sex hormones linked to increased risk of various cancers. In some malignant diseases, blood cholesterol undergoes early and significant changes. The mechanism for the link between cancer and cholesterol remains controversial. The dates from studies are confusing because both hypolipidemia and hypercholesterolemia might be connected with malignancy. Not only cancers but also antineoplastic therapies have an influence on lipid profile. There are also dates suggesting that antihyperlipemic drugs might nfluenced malignancy.

Sleeping position, oxygen saturation and lung volume in convalescent, prematurely born infants

Objective: To determine whether the effects of sleeping position on lung volume and oxygenation are influenced by postmenstrual age (PMA) and oxygen dependency in convalescent prematurely born infants. Design: Prospective study. Setting: Tertiary neonatal unit. Patients: 41 infants (21 oxygen dependent), median gestational age 28 weeks (range 24–31 weeks) and birth weight 1120 g (range 556–1780 g). Intervention: Infants were studied both supine and prone at two-weekly intervals from 32 weeks’ PMA until discharge. Each posture was maintained for 1 h. Main outcome measures: Pulse oximeter oxygen saturation (Spo2) was monitored continuously, and at the end of each hourly period functional residual capacity (FRC) was measured. Results: Overall, lung volumes were higher in the prone position throughout the study period; there was no significant effect of PMA on lung volumes. Overall, Spo2 was higher in the prone position (p = 0.02), and the effect was significant in the oxygen-dependent infants (p = 0.03) (mean difference in Spo2 between prone and supine was 1.02%, 95% CI 0.11% to 1.92%), but not in the non-oxygen-dependent infants. There was no significant influence of PMA on Spo2. Conclusion: In the present study, prone sleeping did not improve oxygenation in prematurely born infants, 32 weeks’ PMA or older and with no ongoing respiratory problems. However, the infants were monitored in each position for an hour, thus it is recommended that oxygen saturation should continue to be monitored after 32 weeks’ PMA to be certain that longer periods of supine sleeping are not associated with loss of lung volume and hypoxaemia.

Left atrial size in hypertension and stroke.

Introduction An enlarged left atrium is associated with increased risk for stroke. However, there are controversies regarding how left atrial size should be measured. Material and methods Echocardiography and carotid artery ultrasound were performed in 120 patients with essential hypertension (HT group) and in 64 hypertensive patients admitted with a first-ever ischemic stroke (HT-stroke group). Left atrial size was measured as antero-posterior diameter (LAD) and as left atrial volume (LAV) and indexed to body surface area (LADi/LAVi). All patients were in sinus rhythm and without mitral valve disease. Results In the HT-stroke group, LAVi and LADi were significantly larger as compared with the HT group (P ⩽ 0.03 for all). In bivariate correlations, larger left atrial size was associated with higher SBPs and DBPs and significant carotid artery stenosis both in HT and HT-stroke groups (all P < 0.05). In multivariate logistic regression analysis, stroke was associated significantly with larger LAVi [odds ratio (OR) 1.73, 95% confidence interval (CI) 1.06–2.65]; left ventricular mass index (OR 1.11, 95% CI 1.03–1.21); significant carotid artery stenosis (OR 1.09, 95% CI 1.03–1.24); and any carotid artery stenosis (OR 1.07, 95% CI 1.03–1.14). Analysis of receiver operating characteristic curves revealed that LAVi was the best left atrial measurement for prediction of stroke (OR 0.77, 95% CI 0.70–0.84). Conclusion In hypertensive patients, a first-ever ischemic stroke was associated with larger left atrial size, left ventricular mass index and internal carotid artery stenosis. LAVi was the left atrial measurement most closely associated with ischemic stroke.

Acid Gastroesophageal Reflux in Convalescent Preterm Infants: Effect of Posture and Relationship to Apnea

Concerns regarding gastroesophageal reflux (GER) and associated apnea episodes result in some practitioners having convalescent, prematurely born infants sleep in the prone position. We have tested the hypothesis that such infants would not suffer from clinically important acid GER or associated apnea episodes more in the supine compared with the prone position. Lower esophageal pH was measured and videopolysomnographic recordings of nasal airflow, chest and abdominal wall movements, electrocardiographic activity, and oxygen saturation were made on two successive days of 21 premature infants (median gestational age 28 wk) at a median postmenstrual age (PMA) of 36 wk. On each day, the infants were studied prone and supine. The acid reflux index was higher in the supine compared with the prone position (median 3% versus 0%, p = 0.002), but was low in both positions. The number of obstructive apnea episodes per hour was higher in the supine position (p = 0.008). There were, however, no statistically significant correlations between the amount of acid GER and the number of either obstructive or total apnea episodes in either the supine or prone position. Supine compared with prone sleeping neither increases clinically important acid GER nor obstructive apnea episodes associated with acid GER in asymptomatic, convalescent, prematurely born infants.

Nasal and lower airway levels of nitric oxide in prematurely born infants

BACKGROUND Nitric oxide (NO) is produced by various cells in the respiratory tract, but the majority is released from the paranasal sinuses in adults. The paranasal sinuses in infants are only partially pneumatised. Thus, nasal NO would be predicted to be low in infants measured soon after birth and/or born very prematurely; this has implications for the measurement of exhaled NO and interpretation of the results obtained. OBJECTIVES To determine whether nasal NO could be detected in very immature infants, particularly soon after birth, and whether nasal or lower airway NO levels were influenced by gestational age or postnatal age. PATIENTS Fifteen infants, with median gestational age of 27 weeks (range 25-32 weeks). METHODS Nasal and lower airway NO measurements were attempted on days 1, 3, 5, 7, 14, 21, and 28 after birth. Measurements were only made while the infants remained ventilated. Nasal NO was sampled directly from the nasal space and lower airway. NO was sampled from a catheter positioned so that its tip lay at the lower end of the endotracheal tube. RESULTS Nasal NO was detected in all infants on all study occasions and the levels were greater than those from the lower airway. Nasal and lower airway NO levels did not correlate significantly with gestational age, but lower airway NO levels correlated with postnatal age (r=0.86, p=0.014). CONCLUSION Even in very immature infants examined in the first day after birth, care must be taken to avoid contamination with nasal NO, if lower airway levels are to be accurately assessed.

A possible role for the Hering-Breuer deflation reflex in apnea of prematurity.

BACKGROUND The vagally mediated Hering-Breuer deflation reflex terminates expiration and initiates inspiration when lung volume is reduced to less than functional residual capacity. The effects of prematurity on this reflex are not known. STUDY DESIGN Fifteen term and 20 preterm nonventilated infants were studied. Lung deflation was achieved by chest compression using an inflatable jacket. Relative changes in expiratory time and inspiratory time on chest compression were calculated from airflow recordings. Esophageal pressure changes in the term infants and chest wall movements in the preterm infants were also measured. RESULTS The term infants had a mean prolongation of inspiratory time on squeezing of 15% versus a 24% shortening in the preterm infants (p < 0.001). The term infants had a mean shortening of expiratory time on squeezing of 35% versus 18% in the preterm infants (p < 0.001). Fifteen of the 20 preterm infants demonstrated a tendency to have short apneas (2 to 5 seconds) on squeezing, 88% of which were central in origin. In these infants shortening of inspiratory time was greater than that seen in the preterm infants not having apneas (p < 0.05). CONCLUSIONS Preterm infants responded to a rapid reduction in lung volume with a shortened inspiratory effort and a tendency to have central apneas. This may be due to an immaturity in part of the reflex arc responsible for transmitting the Hering-Breuer deflation reflex.