Association between novel MRI-estimated pancreatic fat and liver histology-determined steatosis and fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Ectopic fat deposition in the pancreas and its association with hepatic steatosis have not previously been examined in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD). AIM: To quantify pancreatic fat using a novel magnetic resonance imaging (MRI) technique and determine whether it is associated with hepatic steatosis and/or fibrosis in patients with NAFLD. METHODS: This is a cross-sectional study including 43 adult patients with biopsy-proven NAFLD who underwent clinical evaluation, biochemical testing and MRI. The liver biopsy assessment was performed using the NASH-CRN histological scoring system, and liver and pancreas fat quantification was performed using a novel, validated MRI biomarker; the proton density fat fraction. RESULTS: The average MRI-determined pancreatic fat in patients with NAFLD was 8.5% and did not vary significantly between head, body, and tail of the pancreas. MRI-determined pancreatic fat content increased significantly with increasing histology-determined hepatic steatosis grade; 4.6% in grade 1; 7.7% in grade 2; 13.0% in grade 3 (P = 0.004) respectively. Pancreatic fat content was lower in patients with histology-determined liver fibrosis than in those without fibrosis (11.2% in stage 0 fibrosis vs. 5.8% in stage 1-2 fibrosis, and 6.9% in stage 3-4 fibrosis, P = 0.013). Pancreatic fat did not correlate with age, body mass index or diabetes status. CONCLUSIONS: In patients with NAFLD, increased pancreatic fat is associated with hepatic steatosis. However, liver fibrosis is inversely associated with pancreatic fat content. Further studies are needed to determine underlying mechanisms to understand if pancreatic steatosis affects progression of NAFLD.

Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD.

BACKGROUND: Conventional magnetic resonance imaging (MRI) techniques that measure hepatic steatosis are limited by T1 bias, T(2)* decay and multi-frequency signal-interference effects of protons in fat. Newer MR techniques such as the proton density-fat fraction (PDFF) that correct for these factors have not been specifically compared to liver biopsy in adult patients with non-alcoholic fatty liver disease (NAFLD). AIM: To examine the association between MRI-determined PDFF and histology-determined steatosis grade, and their association with fibrosis. METHODS: A total of 51 adult patients with biopsy-confirmed NAFLD underwent metabolic-biochemical profiling, MRI-determined PDFF measurement of hepatic steatosis and liver biopsy assessment according to NASH-CRN histological scoring system. RESULTS: The average MRI-determined PDFF increased significantly with increasing histology-determined steatosis grade: 8.9% at grade-1, 16.3% at grade-2, and 25.0% at grade-3 with P ≤ 0.0001 (correlation: r(2) = 0.56, P < 0.0001). Patients with stage-4 fibrosis, when compared with patients with stage 0-3 fibrosis, had significantly lower hepatic steatosis by both MRI-determined PDFF (7.6% vs. 17.8%, P < 0.005) and histology-determined steatosis grade (1.4 vs. 2.2, P < 0.05). NAFLD patients with grade 1 steatosis were more likely to have characteristics of advanced liver disease including higher average AST:ALT (0.87 vs. 0.60, P < 0.02), GGT (140 vs. 67, P < 0.01), and INR (1.06 vs. 0.99, P < 0.01), higher stage of fibrosis and hepatocellular ballooning. CONCLUSIONS: MRI-determined proton density-fat fraction correlates with histology-determined steatosis grade in adults with NAFLD. Steatosis is non-linearly related to fibrosis progression. In patients with NAFLD, a low amount of hepatic steatosis on imaging does not necessarily indicate mild disease.

Number of portal tract macrophages correlates with the modified hepatic activity index in chronic hepatitis C infection.

The Ishak modified hepatic activity index (mHAI) is widely used to score disease activity in chronic hepatitis C infection. However, the scoring of the mHAI components is subjective and prone to interobserver variation. Liver injury results in increased numbers of portal tract macrophages, which are easily identified via periodic acid-Schiff with diastase digestion stain. Evaluation of 30 liver biopsies from patients with chronic hepatitis C revealed increasing numbers of portal tract macrophages as scores of liver inflammation increased. Specifically, the number of PASD-positive portal tract macrophages per centimeter of biopsy length correlated with the level of portal inflammation and total mHAI score, and these correlations were statistically significant (P = .039 and .029, respectively). Although the portal macrophage count appeared to correlate with the interface activity and lobular necroinflammatory score, this did not meet statistical significance (P = .073 and .079, respectively). Interobserver agreement by κ analysis was greater for the portal macrophage count than for any individual component of the mHAI score. In summary, the number of periportal ceroid-laden macrophages correlates with liver inflammation as measured using the mHAI, with better interobserver agreement. This technique may serve as a useful adjunct to the mHAI in the assessment of liver injury in hepatitis C.

Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993-1996).

OBJECTIVE: To determine causes of death or reasons for euthanasia in a population of military working dogs. DESIGN: Retrospective study. ANIMALS: 927 military working dogs. PROCEDURE: Records of all military working dogs that died during the period from 1993 to 1996 were evaluated for cause of death or reason for euthanasia by review of necropsy and histopathology reports, death certificates, and daily clinical treatment sheets. A single primary cause of death or euthanasia was determined. RESULTS: Although sexually intact male dogs were more numerous in the study population, castrated male dogs typically lived longer than spayed females or sexually intact males. Leading causes of death or euthanasia (76.3% of all dogs) were appendicular degenerative joint disease, neoplasia, spinal cord disease, nonspecific geriatric decline, and gastric dilatation-volvulus. Compared with German Shepherd Dogs, Belgian Shepherd Dogs were at increased risk for death attributable to neoplasia, behavior, and respiratory tract disease. German Shepherd Dogs had nearly twice the risk for death associated with spinal cord diseases, compared with Belgian Shepherd Dogs. CONCLUSIONS AND CLINICAL RELEVANCE: For most military working dogs, death or euthanasia results from a few diseases commonly associated with advanced age. Some breed differences in risk for these diseases may exist, which clinicians should consider in the procurement and long-term management of these dogs.

A comparison of cervical pathology between United States Air Force women who did and did not serve in the Persian Gulf War.

PURPOSE: The purpose of this study was to look objectively at cervical cytological differences between women Gulf War female veterans (GWFV) and Gulf War-era active duty females not deployed to the Gulf (NDF) during Operation Desert Shield/Desert Storm using Pap smear results. METHODS: A cohort of 6715 active duty Air Force women who also served on active duty between August 7, 1990-March 1, 1991 provided at least one Pap smear as part of routine medical care during 1994. Of these, 1446 were identified as GWFV and 5269 were identified as NDF. Diagnoses were compared using Chi-square tests with Yate's continuity correction. RESULTS: There were no differences between the two groups, overall, in the diagnosis of other than within normal limits (OTWNL), the diagnoses of significant disease or in Bethesda system diagnoses in each of the three years for which comparisons were made. GWFV diagnosed in the 26-30 age group were significantly more likely to have a diagnosis of OTWNL than were NDF in the same age group in 1994. There were no differences between the two groups in any other age category. CONCLUSIONS: The data provide little support for the hypothesis that a difference exists between GWFV and NDF with respect to abnormal cervical cytology.

Estrogen increases hyperemic microvascular blood flow velocity in postmenopausal women.

BACKGROUND: Epidemiologic studies suggest that estrogen replacement therapy (ERT) is protective against vascular disease. ERT confers this benefit by lowering lipid levels and improving arterial function. However, its effect on the microvasculature in vivo is unknown. Thus the purposes of this study were to evaluate effect of estrogen status on the hyperemic response of the microvasculature in vivo in postmenopausal women and to compare the hyperemic response of the microvasculature in postmenopausal women taking ERT with that of premenopausal women. METHODS: We measured forearm microvasculature flow velocity by using a laser Doppler in a cross section of 64 healthy premenopausal and postmenopausal women 23 to 72 years old. Microvasculature blood flow velocity was measured at baseline. throughout 2 minutes of ischemia, and immediately after the ischemic period was terminated (i.e., during the peak hyperemic response). RESULTS: The peak of the hyperemic flow velocity (PHFV) in the postmenopausal women who were taking long-term ERT at usual doses was greater than that of postmenopausal women who were not currently taking ERT (p < .0001). Moreover, the PHFV of postmenopausal women taking ERT was similar to that of premenopausal women. Multivariate regression analysis showed estrogen status and baseline flow velocity to be independent predictors of PHFV. CONCLUSIONS: Current, long-term ERT at usual replacement doses is associated with improved microvascular responses in postmenopausal women, which may explain some of its beneficial vascular effects.

A study of the lifetime occurrence of neoplasia and breed differences in a cohort of German Shepherd Dogs and Belgian Malinois military working dogs that died in 1992.

The population of U.S. Department of Defense military working dogs provides an opportunity to study the lifetime occurrence of neoplasia in 2 breeds of dogs--the German Shepherd Dog and the Belgian Malinois. Medical records were reviewed for all dogs that died or were euthanized in 1992 (135 German Shepherd Dogs and 106 Belgian Malinois). Histologically confirmed neoplasms were recorded. More than 30% of both breeds (41 German Shepherd Dogs and 33 Belgian Malinois) developed at least 1 primary neoplasm during their lives, with 10% developing more than 1 neoplasm. Nearly 57% of the neoplasms were benign, and approximately 43% were malignant. German Shepherd Dogs lived 9.7 years, on average, and Belgian Malinois lived 7.9 years, on average. Of the dogs that developed any neoplasm, Belgian Malinois had a mean age at 1st diagnosis that was 1.1 years younger and a mean age at 1st diagnosis of malignancy that was 1.7 years younger than those in German Shepherd Dogs. The risk of a malignancy being the cause of death or euthanasia of a Belgian Malinois was 4.21 times the risk in German Shepherd Dogs (95% CI: 1.32, 13.47). Seminoma was the malignancy that occurred most frequently. Hemangioma was the benign neoplasm that occurred most frequently. Veterinarians identified masses clinically at equal rates in both groups.

Regional anesthesia. Nerve blocks of the extremities and face.

Regional nerve blocks are useful for anesthetizing the hand and fingers, the foot and toes, and the face and mouth. These simple procedures may be performed prior to wound repair or surgery of the affected area. The authors discuss the indications, techniques, dosages, and potential complications of regional anesthesia.

Vac1p coordinates Rab and phosphatidylinositol 3-kinase signaling in Vps45p-dependent vesicle docking/fusion at the endosome.

The vacuolar protein sorting (VPS) pathway of Saccharomyces cerevisiae mediates transport of vacuolar protein precursors from the late Golgi to the lysosome-like vacuole. Sorting of some vacuolar proteins occurs via a prevacuolar endosomal compartment and mutations in a subset of VPS genes (the class D VPS genes) interfere with the Golgi-to-endosome transport step. Several of the encoded proteins, including Pep12p/Vps6p (an endosomal target (t) SNARE) and Vps45p (a Sec1p homologue), bind each other directly [1]. Another of these proteins, Vac1p/Pep7p/Vps19p, associates with Pep12p and binds phosphatidylinositol 3-phosphate (PI(3)P), the product of the Vps34 phosphatidylinositol 3-kinase (PI 3-kinase) [1] [2]. Here, we demonstrate that Vac1p genetically and physically interacts with the activated, GTP-bound form of Vps21p, a Rab GTPase that functions in Golgi-to-endosome transport, and with Vps45p. These results implicate Vac1p as an effector of Vps21p and as a novel Sec1p-family-binding protein. We suggest that Vac1p functions as a multivalent adaptor protein that ensures the high fidelity of vesicle docking and fusion by integrating both phosphoinositide (Vps34p) and GTPase (Vps21p) signals, which are essential for Pep12p- and Vps45p-dependent targeting of Golgi-derived vesicles to the prevacuolar endosome.

A role for synaptotagmin (p65) in regulated exocytosis.

Proteins that are specifically localized to synaptic vesicles in the nervous system have been proposed to mediate aspects of synaptic transmission. Antibodies raised against the cytoplasmic domains of five of these proteins, vamp, rab3A, synaptophysin, synaptotagmin, and SV2, were used to investigate their function. Microinjection of monoclonal and polyclonal antibodies raised against synaptotagmin (p65), but not the other vesicle proteins, decreases K+/Ca(2+)-mediated dopamine beta-hydroxylase surface staining, a measure of regulated secretion in PC12 cells. Microinjection of a soluble fragment of synaptotagmin encompassing one of the domains homologous to the C2 regulatory region of protein kinase C, but lacking the membrane anchor, also inhibits evoked dopamine beta-hydroxylase surface staining. These results provide support for the hypothesis that synaptotagmin, a Ca(2+)- and phospholipid-binding protein, is important for regulated exocytosis in neurons.

Standardized comparisons of the use of alcohol, drugs, and cigarettes among military personnel and civilians.

BACKGROUND: Understanding the effectiveness of policies and programs aimed at combating substance abuse in the military requires comparison with the civilian population from which military personnel are drawn. METHODS: Standardized comparisons of the use of alcohol, drugs, and cigarettes among military personnel and civilians were conducted with data from the 1985 Worldwide Survey of Alcohol and Nonmedical Drug Use among Military Personnel and the 1985 National Household Survey on Drug Abuse. The two data sets were equated for age and geographic location of respondents, and civilian substance use rates were standardized to reflect the sociodemographic distribution of the military. RESULTS: Military personnel were significantly less likely than civilians to use drugs, but were significantly more likely to use alcohol and cigarettes and to engage in heavy use of alcohol and cigarettes. Heavy drinking was especially likely among young military men. Military women were similar to military men in their smoking and drug use patterns. CONCLUSIONS: Findings suggest that military policies and programs have been notably effective in reducing drug use, but that efforts to limit alcohol and cigarette use should be intensified. Military efforts directed against alcohol abuse should be targeted toward younger men, while smoking and drug prevention programs should be directed toward both men and women.

D1-dopamine receptor agonists selectively activate striatal c-fos independent of rotational behaviour.

L-Dopa and dopaminergic agonists selective for the D1- or D2-dopamine receptor subtype induce contraversive rotation in rats which have been unilaterally lesioned with injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. D-Amphetamine, which releases dopamine from neurones on the unlesioned side of the animal, causes ipsiversive rotation. These increases in rotational behaviour are mediated, at least in part, by dopamine receptors in the striatum. In unilaterally lesioned animals, L-dopa and the D1-selective agonists SKF 38393 and CY 208-243 produce contralateral rotation and induction of the nuclear proto-oncogene c-fos in the lesioned striatum. D-Amphetamine induces both ipsilateral rotation and c-fos activation in the intact striatum. Three lines of evidence, however, dissociate fos induction and rotation. First, LY 171555, a selective D2-dopamine receptor agonist, also induces contraversive rotation but this rotation is not accompanied by c-fos activation in striatum. Second, D1-dopamine agonists produce activation of striatal c-fos even if rotation is prevented by an anaesthetic. Third, rotation induced by injection of SKF 38393 into substantia nigra is not accompanied by c-fos induction. These results suggest a mechanism by which D1-dopamine receptor mechanisms may regulate long-term changes in dopaminergic systems.

The role of heme oxygenase and aryl hydrocarbon hydroxylase in the protection by cysteamine from acetaminophen hepatotoxicity.

Administration of cysteamine to rats depressed hepatic aryl hydrocarbon hydroxylase (AHH) activity, cytochrome P-450, and total heme at 24 hr. Total heme remained decreased at 48 hr when all other parameters returned to control values. A significant 5-fold increase in heme oxygenase activity occurred in rat liver 5 hr after treatment, when AHH activity and total heme were unchanged. Histological examination of liver biopsies from rats treated with cysteamine revealed normal hepatic architecture. The observed effects of cysteamine on hepatic drug-metabolizing enzymes in vivo were not due to cysteamine-induced hepatotoxicity. Our results indicate that cysteamine increases heme oxygenase activity in rat liver, with a subsequent decrease in total heme, AHH activity, and cytochrome P-450 content. The depression of P-450 by cysteamine is likely to be an important mechanism for its protection in acetaminophen overdose. The protection studies illustrate this mechanism. Centrilobular hepatic necrosis and elevation in transaminase activity following a toxic dose of acetaminophen were prevented by treatment with cysteamine. The hepatoprotective effect of cysteamine was evident when acetaminophen was administered 24 hr after cysteamine but did not occur when acetaminophen was administered 5 hr after cysteamine or simultaneously. All groups of rats receiving cysteamine showed decreased mortality compared to the group receiving acetaminophen alone.

Pyogenic granulomas of the cornea.

Pyogenic granulomas are vasoproliferative, inflammatory lesions composed of granulation tissue, which occur on cutaneous or mucosal tissues, often arising secondary to other processes such as trauma or infection. Conjunctival pyogenic granulomas are not rare, but corneal involvement is very unusual and can occasionally lead to problems in the differential diagnosis of corneal masses. We report three cases of pyogenic granuloma involving the cornea. The clinicopathologic features of these cases and a review of the literature on the ocular manifestations of this condition are presented.