CMR–Derived Extracellular Volume Fraction as a Marker for Myocardial Fibrosis: The Importance of Coexisting Myocardial Inflammation

Objectives

The aim of the present study was to evaluate whether extracellular volume fraction (ECV) can reliably inform on the extent of diffuse fibrosis in the simultaneous presence of myocardial inflammation, which has not been verified to date.

Proportion of Patients With Hypertension Resolution Following Adrenalectomy for Primary Aldosteronism: A Systematic Review and Meta‐Analysis

Unilateral primary aldosteronism (PA) is often treated with adrenalectomy, but hypertension resolution rates are variable. A valid estimate of the postoperative normotension rate is necessary to inform the utility of PA testing and treatment. The authors searched MEDLINE In‐Process & Other Non‐Indexed Citations, Embase, and Cochrane Central Register of Controlled Trials. Prospective adult cohort studies with surgically treated PA that reported resolution of hypertension without the aid of medications were included. Among 2620 abstracts identified by the search, 25 studies in the systematic review with data on 1685 patients were investigated. The pooled proportion of normotension following adrenalectomy was 52% (95% confidence interval, 0.44–0.60). Meta‐regression demonstrated a significant negative association between length of follow‐up and proportion of normotension, with normotension dropping by 6.7% per year of follow‐up (coefficient −0.006; 95% confidence interval, −0.01 to 0.002). Overall, approximately half of the patients experienced hypertension resolution, although this outcome may not be durable in all patients.

Primary aldosteronism (PA) is defined as a form of drug‐resistant and potentially curable hypertension with evidence of excess aldosterone secretion, suppressed plasma renin activity, and often hypokalemia.¹ Initially thought to be rare, PA is the leading cause of secondary hypertension. With increased screening and detection, the incidence of PA among hypertensive patients is currently reported at approximately 10%.² This syndrome has multiple etiologies, including inherited gene mutations,³ development of autoantibodies,⁴ and ectopic aberrant functional adrenal receptors.⁵ The clinical management is guided by the definition of unilateral vs bilateral adrenal involvement. With rare exception, adrenalectomy is reserved for unilateral adrenal disease.The proportion “cured” following adrenalectomy for patients with PA has been reported to range from 0% to 100%.⁶ However, “cure” is variably defined in the literature. These definitions include normal blood pressure (BP), normal BP without aid of antihypertensive medications, a reduced need for antihypertensive medications, and biochemical normalization, among others. Biochemical normalization of the aldosterone‐renin ratio is likely a necessary part of a definition of “cure.” At this time, however, there is no global consensus on the interpretation of postoperative aldosterone‐renin ratios with the existence of variable assays and cutoffs for even initial diagnosis. Therefore, from the patient''s perspective and in the absence of patient‐level clinical end point data, attainment of medication‐free normotension may be the most uniform and recognizable health benefit of surgical PA treatment. Individually reported results of long‐term resolution of hypertension without antihypertensive medications are between 30% and 70% following adrenalectomy.⁷ The primary aim of this systematic review and meta‐analysis was to determine the proportion of hypertension resolution without the aid of antihypertensive agents following adrenalectomy in patients with PA. To our knowledge, no previous meta‐analysis has been performed. A secondary objective was to identify patient‐level factors reported to be associated with hypertension resolution in patients managed with adrenalectomy.     

Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia

Parkinson’s disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn–antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

Parkinson’s disease (PD) is characterized by accumulation of α-synuclein (αSyn; encoded by the SNCA gene) (1). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal cell death in part via microglial activation (2, 3). Moreover, misfolded proteins in general are thought to interact with brain microglia, triggering microglial activation that contributes to neurodegenerative disorders, although microglial phagocytosis may also initially clear aberrant proteins to afford some degree of protection (2, 4). Additionally, in Alzheimer’s disease (AD), amyloid-β peptide (Aβ) is thought to trigger similar processes in microglia (5–7); however, the mechanism for this trigger is still poorly understood.Microglial cells contribute to neuroinflammation, specifically that mediated by the inflammasome. In particular, the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome has been associated with several neurodegenerative disorders, although other types of inflammation may also be important in this regard (8). The NLRP3 inflammasome is a multiprotein complex that responds to cell stress and pathogenic stimuli to promote activation of caspase-1, which in turn mediates maturation and release of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18 (9–11). NLRP3 inflammasome activation is a two-step process, involving an initial priming step and a secondary trigger. Priming involves a proinflammatory stimulus, such as endotoxin, a ligand for Toll-like receptor 4 (TLR4), that increases the abundance of NLRP3 and promotes de novo synthesis of pro–IL-1β via nuclear factor κB (11). The secondary trigger promotes inflammasome complex assembly and caspase-1 activation that in turn mediates the cleavage of pro–IL-1β and subsequent release of mature IL-1β. There are various secondary triggers, including adenosine triphosphate (ATP), microparticles, and bacterial toxins, all of which somehow lead to mitochondrial damage and release of oxidized mitochondrial DNA (11). Neuroinflammation has been reported in both human PD and AD brains (12–15), and NLRP3 inflammasome activation in particular has been observed in mouse models of PD and AD (7, 16). Importantly, in these PD models, dopaminergic (DA) neurons in the substantia nigra are resistant to damage in NLRP3-deficient mice compared with wild-type (WT) mice (16). Interestingly, a recent report identified an NLRP3 polymorphism that confers decreased risk in PD (17). Several groups have reported that fibrillar αSyn can activate the NLRP3 inflammasome in mice and in human monocytes (18–22), but it remains unknown if human brain microglia can be activated in this manner. Critically, antibodies targeting misfolded proteins are being tested in human clinical trials for several neurodegenerative diseases, including AD and PD; however, it is still unclear how antibodies to αSyn might affect this inflammatory response. In this study, we characterized the response of human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) to oligomeric/fibrillar αSyn in vitro and in vivo, using engraftment of hiMG in humanized mice. We used these immunocompromised mice because they prevent human cell rejection and express three human genes that support human cell engraftment (23). We show that αSyn and, even more so, αSyn–antibody complexes activate the NLRP3 inflammasome. Moreover, this process is further sensitized by the presence of Aβ and its cognate antibodies. These observations are of heightened interest because recent studies have shown that both misfolded Aβ and αSyn are present in several neurodegenerative disorders such as AD and Lewy body dementia (LBD), a form of dementia that can occur in the setting of PD (24–26).     

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis. CYP3A is of key importance in human drug metabolism, being involved in presystemic extraction of more than 50% of all drugs currently available and of various endogenous compounds. Therefore, we compared the induction potential of UDCA with that of the prototypical inducer rifampicin in a human model study with the CYP3A substrates budesonide and cortisol. Twelve patients with early-stage primary biliary cirrhosis and eight healthy volunteers were treated with UDCA (15 mg/kg daily) for 3 weeks and subsequently with rifampicin (600 mg/d) for 1 week. Extensive pharmacokinetic profiling of oral budesonide (3 mg) was performed by determination of budesonide and phase I metabolites (6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone) in plasma and urine at baseline and at the end of each treatment. In parallel, urinary 6beta-hydroxycortisol, a validated marker of CYP3A induction, was determined. UDCA did not affect biotransformation of budesonide and urinary excretion of 6beta-hydroxycortisol either in patients or in healthy volunteers. Ratios of areas under plasma concentration-time curves (AUC(0-12 h) during UDCA/AUC(0-12 h) before UDCA) of both metabolites were not higher than those of budesonide itself. In contrast, administration of rifampicin markedly induced CYP3A metabolism, resulting in abolished budesonide plasma levels and high urinary excretion of 6beta-hydroxycortisol. Metabolite formation was enhanced by rifampicin, but not by UDCA (e.g., AUC(16alpha-hydroxyprednisolone)/AUC(budesonide) in patients: baseline, 8.6 +/- 3.9; UDCA, 10.7 +/- 7.1; rifampicin, 527.0 +/- 248.7). In conclusion, UDCA is not a relevant inducer of CYP3A enzymes in humans.     

Aseptic colon resection by an invagination technique

A new aseptic colon resection by an invagination technique is presented. The bowel to be resected is invaginated down into the healthy intestine, and the anastomosis is sutured in one layer of continuous suture before transection by a diathermy wire, placed in the intestinal lumen via the anus. Sections of bowel that cannot be invaginated,e.g.,because of a tumor, are first removed by transection between pairs of cable ties, which close the lumen. Twenty dogs were operated on without receiving prophylactic antibiotics. In 10, the intestine was transected between cable ties. An imprint, taken from the anastomosis and subcutis, was cultured. The bacterial count at the anastomosis exceeded 100 in only three cases; in the subcutis, this was the case in one dog. One wound infection developed. Serial barium enemas at 1, 2, 3, and 4 weeks revealed no anastomotic leakage. One early death because of a total anastomotic dehiscence was encountered, and two dogs were killed because of wound dehiscence and anastomotic stricture, respectively. It is concluded that, in dogs, the method is easily and safely performed, but further experimental studies are needed.This study was supported with grants from Fonden til Laegevidenskabens Fremme, Kraeftens Bekaempelse, Sygekassernes Helsefond, and Aarhus Universitets Forskningsfond.     

Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia

Summary. Human T lymphotrophic virus type 1 (HTLV-I) associated leukaemia has a poor prognosis even with chemotherapy. We describe a patient with adult T-cell leukaemia treated with allogeneic bone marrow transplantation from an HTLV-I negative identical sibling donor. During follow-up after bone marrow transplantation, HTLV-I could be repeatedly isolated inspite of anti-viral prophylaxis. The patient died of an acute encephalitis and HTLV-I could be detected in autopsy material from the brain. By a PCR-based technique using short tandem repeats (STRs) it was shown that the patient's haemopoiesis was of donor origin. This shows the infection of donor cells in vivo by an aetiological agent which has been implicated in the leukaemogenic process for adult T-cell leukaemia.     

Continuing Medical Education: May 2007

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Article Title: Impact of Etiology of Cirrhosis on the Survival of Patients Diagnosed With Hepatocellular Carcinoma During Surveillance