Epidemiology of hepatocellular carcinoma

Year 2000 estimates of the incidence of cancer indicate that primary liver cancer remains the fifth most common malignancy in men and the eighth in women. The number of new cases has been predicted as 564,000, corresponding to 398,000 in men and 166,000 in women. The geographic areas at highest risk are located in Eastern Asia, Middle Africa, and some countries of Western Africa. Changes in incidence among migrant populations underline the predominant role of environmental factors in the etiology of primary liver cancer. In high-risk countries, the early cases of primary liver cancer occur already at ages 20 and above, underlying the impact of viral exposures early in life. In countries at low risk, primary liver cancer is rare before the 50s, translating the impact of late exposures with moderate risks and long latency intervals. Sex ratios are typically between 2 and 4. The incidence of primary liver cancer is increasing in several developed countries including the United States, and the increase will likely continue for several decades. The trend has a dominant cohort effect related to exposures to hepatitis B and C viruses. The variability of primary liver cancer incidence is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.     

Cumulative Systolic BP and Changes in Urine Albumin-to-Creatinine Ratios in Nondiabetic Participants of the Multi-Ethnic Study of Atherosclerosis

Background and objectives

Cumulative exposure to elevated systolic BP (cumSBP) may affect progression of urine albumin excretion in the absence of diabetes. The objective of this study was to examine the association between cumSBP exposure and progression of spot urine albumin-to-creatinine ratio (UACR) in a multi-ethnic cohort of adults without diabetes.

Design, setting, participants, & measurements

The analysis included 3789 participants without severely increased urine albumin excretion or diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 adults aged 45–84 years. UACR was measured at baseline and approximately 1.6, 3.1, and 9.4 years after the baseline examination. cumSBP was calculated as the summed average systolic BP (SBP; mmHg) between two consecutive examinations multiplied by the time between the two examinations (mmHg×year) and categorized as ≤1128 (SBP<120 mmHg), 1129–1222 (SBP≥120–129 mmHg), 1223–1316 (SBP≥130–130 mmHg), and >1316 (SBP≥140 mmHg). Baseline UACR was categorized as normal, mildly increased, or moderately increased, and definite progression of UACR was defined as a persistently higher UACR category at subsequent examinations. No UACR progression was defined as remaining in the same UACR category across all examinations or regressing.

Results

In fully adjusted models, compared with cumSBP≤1128 mmHg, cumSBP 1223–1316 and >1316 mmHg was associated with a 85% and 130% significantly higher odds of definite UACR progression (95% confidence interval, 24% to 178% and 56% to 243%, respectively) versus no UACR progression. Every 100-mmHg higher level of cumSBP was associated with a 1.23-fold higher odds of definite UACR progression (95% confidence interval, 1.13 to 1.34) versus no UACR progression.

Conclusion

Exposure to higher cumSBP was associated with increased UACR progression among adults without diabetes.     

Viral inoculum dose impacts memory T‐cell inflation

Memory T‐cell inflation develops during certain persistent viral infections and is characterized by the accumulation and maintenance of large numbers of effector‐memory T cells, albeit with varying degrees in size and phenotype among infected hosts. The underlying mechanisms that control memory T‐cell inflation are not yet fully understood. Here, we dissected CMV‐specific memory T‐cell formation and its connection to the initial infectious dose by varying the inoculum size. After low dose inoculum with mouse CMV, the accumulation of inflationary memory T cells was severely hampered and correlated with reduced reservoirs of latent virus in nonhematopoietic cells and diminished antigen‐driven T‐cell proliferation. Moreover, lowering of the initial viral dose turned the characteristic effector memory‐like inflationary T cells into more central memory‐like cells as evidenced by the cell‐surface phenotype of CD27^high, CD62L⁺, CD127⁺, and KLRG1^?, and by improved secondary expansion potential. These data show the impact of the viral inoculum on the degree of memory T‐cell inflation and provide a rationale for the observed variation of human CMV‐specific T‐cell responses in terms of magnitude and phenotype.     

Peroxisome proliferator‐activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE^−/− model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE^−/− mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus-associated atherosclerosis in gld.apoE^−/− mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease.     

BRUGADA SYNDROME

Brugada syndrome is a rare cardiac arrhythmia characterized by electrocardiographic right bundle branch block and persistent ST-segment elevation in the right precordial leads. It is associated with ventricular fibrillation and a high risk for sudden cardiac death, predominantly in younger males with structurally normal hearts. Patients can remain asymptomatic, and electrocardiographic patterns can occur both spontaneously or after pharmacological induction. So far, several pathogenic genes have been identified as associated with the disease, but SCN5A is the most prevalent one. Two consensus reports to define the diagnostic criteria, risk stratification, and management of patients have been published in the last few years. This brief review focuses on the recent clinical diagnosis, genetic basis, and advances in pharmacological treatment of Brugada syndrome.     

Trypanosoma cruzi nucleoside triphosphate diphosphohydrolase 1 (TcNTPDase-1) biochemical characterization,immunolocalization and possible role in host cell adhesion

Previous work has suggested that Trypanosoma cruzi diphosphohydrolase 1 (TcNTPDase-1) may be involved in the infection of mammalian cells and serve as a potential target for rational drug design. In this work, we produced recombinant TcNTPDase-1 and evaluated its nucleotidase activity, cellular localization and role in parasite adhesion to mammalian host cells. TcNTPDase-1 was able to utilize a broad range of triphosphate and diphosphate nucleosides. The enzyme's K_m for ATP (0.096 mM) suggested a capability to influence the host's ATP-dependent purinergic signaling. The use of specific polyclonal antibodies allowed us to confirm the presence of TcNTPDase-1 at the surface of parasites by confocal and electron microscopy. In addition, electron microscopy revealed that TcNTPDase-1 was also found in the flagellum, flagellum insertion region, kinetoplast, nucleus and intracellular vesicles. The presence of this enzyme in the flagellum insertion region and vesicles suggests that it may have a role in nutrient acquisition, and the widespread distribution of TcNTPDase-1 within the parasite suggests that it may be involved in other biological process. Adhesion assays using anti-TcNTPDase-1 polyclonal antibodies as a blocker or purified recombinant TcNTPDase-1 as a competitor revealed that the enzyme has a role in parasite–host cell adhesion. These data open new frontiers to future studies on this specific parasite–host interaction and other unknown functions of TcNTPDase-1 related to its ubiquitous localization.     

Heart rate variability analysis indicates preictal parasympathetic overdrive preceding seizure‐induced cardiac dysrhythmias leading to sudden unexpected death in a patient with epilepsy

Evidence for seizure‐induced cardiac dysrhythmia leading to sudden unexpected death in epilepsy (SUDEP) has been elusive. We present a patient with focal cortical dysplasia who has had epilepsy for 19 years and was undergoing presurgical evaluation. The patient did not have any cardiologic antecedents. During long‐term video–electroencephalography (EEG) monitoring, following a cluster of secondarily generalized tonic–clonic seizures (GTCS), the patient had prolonged postictal generalized EEG suppression, asystole, followed by arrhythmia, and the patient died despite cardiopulmonary resuscitation. Analysis of heart rate variability showed a marked increase in the parasympathetic activity during the period preceding the fatal seizures, compared with values measured 1 day and 7 months before, and also higher than the preictal values in a group of 10 patients with GTCS without SUDEP. The duration of the QTc interval was short (335–358 msec). This unfortunate case documented during video‐EEG monitoring indicates that autonomic imbalance and seizure‐induced cardiac dysrhythmias contribute to the pathomechanisms leading to SUDEP in patients at risk (short QT interval). A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young‐adult Ts65Dn and disomic mice

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age‐related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 months of age. Ts65Dn dams were maintained on a choline‐supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75‐neurotrophin receptor (p75^NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn‐unsupplemented mice displayed region‐ and immunolabel‐dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal‐diet choline supplementation attenuates some of the genotype‐dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. J. Comp. Neurol. 522:1390–1410, 2014. © 2013 Wiley Periodicals, Inc.