After conversion from chronic AF to sinus rhythm in this canine model, electrical remodeling occurs rapidly. However, gross and ultrastructural anatomic changes persist, as does vulnerability to induced AF. Vulnerability to AF initiation 7 to 14 days after cardioversion is more dependent on persisting structural abnormalities than on electrophysiological abnormalities.

Background & Aims Hepatocellular ballooning is a key finding in nonalcoholic steatohepatitis (NASH). It is conventionally defined by hemotoxylin and eosin (H&E) staining showing enlarged cells with rarefied cytoplasm and recently by changes in the cytoskeleton. Fat droplets are emerging as important organelles in cell metabolism. To address a possible relation between fat droplets and ballooning, we studied fat staining, H&E, and keratin 18 staining in human NASH. Methods Sequential staining and high resolution imaging were used to study freshly prepared cryo-sections from 10 patients with histologically confirmed steatohepatitis using oil red O for fat droplet identification, H&E to identify ballooning, and anti-K18 to confirm cytoskeletal changes. High resolution images were captured at each stage using the Aperio Scanscope. To provide ultrastructural correlation, glutaraldehyde-fixed specimens were studied using transmission electron microscopy (TEM) with serial sectioning for localization of ballooned cells by light microscopy and TEM in identical specimens. Results Serial staining consistently demonstrated that hepatocellular ballooning is associated with fat droplet accumulation evident by oil red O positivity and depletion of cytoplasmic keratin 18 with K-18 positive Mallory-Denk bodies (MDB). TEM confirmed the association between osmium stained fat droplets, MDB formation and cellular enlargement and suggested droplet-associated dilation of the endoplasmic reticulum. Conclusion These results indicate a relationship between cellular ballooning, fat droplet accumulation and cytoskeletal injury in NASH. We speculate that injury to multiple organelles including fat droplets and endoplasmic reticulum contribute to this characteristic finding.

Endotoxin-induced lung injury is characterized by neutrophil infiltration of the lungs. The various mechanisms which mediate movement of neutrophils from vascular space to lung interstitium and alveoli remain unclear. Macrophage-inflammatory protein 2 (MIP-2) is a potent chemoattractant for neutrophils and may play a significant role in recruiting neutrophils in acute lung injury in rats. Experiments were performed in male Sprague Dawley rats to: (1) evaluate the kinetics of neutrophil influx in the lung following intraperitoneal administration of Salmonella enteritidis lipopolysaccharide (LPS); (2) determine the expression of transcripts for chemokines and adhesion molecules in the lung following intraperitoneal LPS; and (3) elucidate the effects of intra-alveolar instillation of recombinant rat MIP-2 on neutrophil influx into the lung. Intraperitoneal LPS resulted in an increase in neutrophil sequestration in the lung capillaries of rats as early as 45 min following administration, and there was a parallel increase in lung myeloperoxidase activity. There were also major increases in mRNA in whole-lung homogenates of LPS-treated rats for chemokines MIP-2 and KC (cytokine-induced neutrophil chemoattractant) and adhesion molecules P- and E-selectin at 1 and 2 h following LPS. When recombinant rat MIP-2 was instilled into the alveolar space of rats through a catheter wedged into a bronchus, there was profound neutrophil localization both in the vascular and alveolar space which significantly differed (P < 0.05) from the contralateral lungs of the same animals, and lungs of control animals instilled with control buffer. These observations reveal that MIP-2 is a potent chemoattractant in rat lungs, and suggest that chemoattractants locally released in alveoli can recruit neutrophils to those alveoli. This suggests that alveolar macrophages may play an important role in neutrophil sequestration in sepsis and other inflammatory lung diseases which produce a neutrophilic alveolitis.

Megamitochondria with crystalline inclusions (MMC) have been previously described in nonalcoholic fatty liver; however, their distribution within hepatic zones is unknown. We sought to determine this distribution from the core liver biopsy specimens of 31 patients: 8 males and 23 females, age range 21 to 72 years. Twenty-nine showed evidence of nonalcoholic steatohepatitis (NASH) on biopsy with steatosis, inflammation, varying degree of fibrosis, ballooned hepatocytes, and Mallory hyaline, and two patients had cryptogenic cirrhosis thought to represent "burned out" NASH. Identified by transmission electron microscopy, the abundance of MMC was compared between low-stage (fibrosis stages 1 and 2) and high-stage (fibrosis stages 3 and 4) groups and between zones with or without difference in fibrosis stage. Regardless of stage, the MMC were distributed equally in all zones and were abundant similarly in low-and high-stage groups. This abundance did not correlate with the degree of oxidative stress (4-hydroxynonenal staining) or with the abundance of ballooned hepatocytes. Consistent with age as a risk factor for more severe disease, the median age for the low-stage group was significantly lower than that of the high-stage group (P ‫؍‬ .003). In conclusion, in NASH, the MMC seem to be distributed randomly among zones and without variation in abundance, regardless of the fibrosis stage. The exact function of these structures remains to be defined. In this study, their presence did not seem to correlate with the light microscopic injury pattern represented by ballooned hepatocytes or degree of oxidative stress defined by immunostaining for 4-hydroxynonenal. (HEPATOLOGY

Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.