bluuebunny/crossref_metadata_2025 huggingface dataset:
Ingested Foreign Bodies of the Gastrointestinal Tract: Retrospective Analysis of 542 Cases
Authors: Velitchkov Nadko G. , Grigorov Georgi I. , Losanoff Julian E. , Kjossev Kirien T.
Published: August 2002

Ingested foreign bodies (FBs) present a common clinical problem. As the incidence of FBs requiring operative removal varies from 1% to 14%, it was decided to perform this study and compare the data with those from the world literature, as well as to outline an algorithm for management, including indications for surgery. We reviewed all patients with FB ingestion from 1973 to 1993. There were 542 patients with 1203 ingestions, aged 15 to 82 years. Among them, 69.9% (n= 379) were jail inmates at the time of ingestion, 22.9% (n= 124) had a history of psychosis, and 7.2% (n= 39) were alcoholics or denture‐wearing elderly subjects. Most foreign bodies passed spontaneously (75.6%;n= 410). Endoscopic removal was possible in 19.5% (n= 106) and was not associated with any morbidity. Only 4.8% (n= 26) required surgery. Of the latter, 30.8% (n= 8) had long gastric FBs with no tendency for distal passage and were removed via gastrotomy; 15.4% (n= 4) had thin, sharp FBs, causing perforation; and 53.8% (n= 14) had FBs impacted in the ileocecal region, which were removed via appendicostomy. Conservative approach to FB ingestion is justified, although early endoscopic removal from the stomach is recommended. In cases of failure, surgical removal for gastric FBs longer than 7.0 cm is wise. Thin, sharp FBs require a high index of suspicion because they carry a higher risk for perforation. The ileocecal region is the most common site of impaction. Removal of the FB via appendicostomy is the safest option and should not be delayed more than 48 hours.
Diagnostic standards for acute pancreatitis
Authors: Ranson John H. C. , Shamamian Peter
Published: August 2002

An accurate history and thorough physical examination will often raise clinical suspicion of acute pancreatitis in the differential diagnosis of a patient presenting with acute abdominal pain. An accurate diagnosis is needed to eliminate etiologies of acute abdominal pain and to appropriately direct therapy. Confirmation of the diagnosis is most often made by evaluation of serum amylase and lipase levels. Although hyperamylasemia is found in the majority of patients with acute pancreatitis, other nonpancreatic acute abdominal conditions may be present with hyperamylasemia. CT scanning provides an accurate confirmation of clinical and laboratory findings and offers excellent anatomic and morphologic representation of the pancreas and peripancreatic tissue. The following article, written by the late John H.C. Ranson, presents a discussion of the modalities available for diagnosing acute pancreatitis.
Superconducting quantum interference device magnetometer for diagnosis of ischemia caused by mesenteric venous thrombosis
Authors: Allos Suhail H. , Staton Daniel J. , Bradshaw L. Alan , Halter Susan , Wikswo John P. , Richards William O.
Published: August 2002

Although mesenteric venous thrombosis carries a better prognosis than arterial thrombosis, mortality and morbidity are still high. Previous studies have shown that the basic electrical rhythm (BER) of the bowel decreases early after induction of arterial ischemia. Furthermore, our studies have shown that these changes occur prior to pathologic changes and that they can be recorded noninvasively using a superconducting quantum interference device (SQUID). SQUIDs measure magnetic fields that are created by the electrical activity of the gastrointestinal smooth muscle and have been used to measure the BER of the small intestine in human volunteers. This study was conducted to determine if a SQUID could be used for early noninvasive detection of mesenteric venous ischemia in an animal model. Simultaneous recordings from serosai electrodes and a SQUID outside the abdomen were taken from anesthetized New Zealand rabbits. Recordings were made for 15 minutes before and 90 minutes after injection of thrombin into the superior mesenteric vein. The basic electrical rhythm of the small bowel dropped from 16.42 ± 0.69 to 8.80 ± 0.74 cycles per minute at 30 minutes and to 6.82 ± 0.722 after 90 minutes (p < 0.0001, paired t‐test). The correlation coefficient between the SQUID and electrical recordings was 0.954 (p < 0.0001). These data suggest that the ischemia caused by mesenteric venous thrombosis results in changes in the bioelectrical activity, which can be noninvasively detected using a SQUID.
Future Role of the Pathologist in Reporting Colorectal Cancer
Authors: Jass Jeremy R.
Published: August 2002

A pathology report on a surgical specimen of colorectal cancer has prognostic implications and is assuming increasing importance in relation to decisions regarding postoperative adjuvant therapy. The classic pathologic report is a static description of the extent of spread within the surgical specimen. The clinician, on the other hand, needs to know how far the tumor has spread in the patient. For the radiotherapist the report on rectal cancer must include a detailed account of anatomic location and spread, including relations to peritoneum and extent of mesorectal involvement. The oncologist aims to improve survival of patients undergoing “curative” surgery. Untreated, a subset of such patients die of metastatic disease, occult hepatic metastases being present at the time of surgery. An estimate of the risk of micrometastatic disease requires a prognostic classification utilizing independent pathobiologic variables. Reporting of colorectal cancer needs to become more closely tailored to clinical endpoints relevant to therapeutic decision‐making. This paper looks critically at current practice and future directions.
Patterns of Injury in Victims of Urban Free‐Falls
Authors: Velmahos George C. , Demetriades Demetrios , Theodorou Demetrios , Cornwell Edward E. , Belzberg Howard , Asensio Juan , Murray James , Berne Thomas V.
Published: August 2002

The objective of this study was to identify the patterns of injury in urban free‐fall victims so as to establish guidelines of management. This prospective study at an academic level I trauma center included 187 consecutive patients who presented to our trauma center during a 9‐month period (September 1994 to June 1995) after a fall from a height of 5 to 70 feet. Only three falls were from heights of more than 40 feet. Of these patients, 116 (65.1%) suffered significant trauma. Fractures were the most common injuries, accounting for 76.2% of all injuries. Spinal fractures were detected in 37 patients and were associated with neurologic deficits in 7. Intraabdominal injuries occurred in 11 patients, requiring operative intervention in 9 of them. Solid organ lacerations prevailed, but small bowel perforation and bladder rupture were present in one case each. A significant retroperitoneal hematoma was detected in only one case and a thoracic aortic rupture in one more. The height of the fall correlated highly with the incidence of intoxication and severity of injury, the need for operation, the length of hospitalization, and mortality. Most urban free‐falls occur from moderate heights. The spinal column is frequently injured and therefore should be thoroughly assessed clinically and radiographically in all fall victims. Intraabdominal organ injuries are much more common than retroperitoneal ones. Thus the abdominal cavity should be the primary target of aggressive workup in hemodynamically unstable patients. The height of the fall is a good predictor of injury severity and outcome prognosis.
Ethics of Xenotransplantation: Animal Issues, Consent, and Likely Transformation of Transplant Ethics
Authors: Daar A.S.
Published: August 2002

The shortage of organs, breakthroughs in research, involvement of biotechnology companies, absence of ethically more acceptable alternatives, and a vaguely perceived “time to put man on the moon” feeling have contributed to the current reawakening of interest in xenotransplantation. The focus of ethical attention has changed from the moral correctness of using animals for research/therapy to an increasingly appreciated danger of the establishment and spread of xenozoonoses in recipients, their contacts, and the general public. The United Kingdom has established an embargo on clinical trials and has set up a national regulatory authority to oversee and coordinate the development of research, establish guidelines, and decide on when trials can proceed. In the United States, on the other hand, the overall attitude is to “proceed with caution,” and the Food and Drug Administration has approved a number of xenotransplant studies. The Public Health Service guidelines on reducing infection risk are still evolving and are likely to end up being more cautious than they are currently. There are a number of reasons for not using subhuman primates for xenotransplantation, including their closeness to humans, the likelihood of passing on infections, their depletability (gorillas, chimpanzees), their slow breeding, and the expense of breeding them under specified‐pathogen free conditions. The pig, although domesticated and familiar, is too distant to evoke the same feelings we have for primates, has the correct‐size organs, is probably less likely to pass on infections, breeds rapidly, and is not endangered; moreover, millions of them are eaten every year. Although drawing ethical conclusions is difficult, at this stage of knowledge and debate it seems acceptable to manipulate pigs genetically and to proceed to using their organs for xenotransplantation trials when infection control measures and the scientific base justify it. The question of informed consent is likely to be a vexing one. It might end up more of a binding legal contract than consent as we understand it now. Xenotransplantation is also unlikely to cost less than, or significantly alleviate the shortage of, cadaveric organs in the short term. The international dimension of the risk of infection is becoming obvious, but there has so far been no effort to convene an international forum to agree on universally acceptable guidelines.
Genetics of Inflammatory Bowel Disease: Implications for the Future
Authors: Peña A. Salvador , Crusius J. Bart A.
Published: August 2002

There is overwhelming evidence that genetic factors play a role in the predisposition to suffer the development of the chronic inflammatory bowel diseases. The genetic analysis of complex diseases, such as ulcerative colitis and Crohn's disease, is difficult. The presence of disease heterogeneity, the relative low frequency in the population, the degree to which first‐degree relatives are affected (approximately 10%), the presence of genes with minor genetic effects, and ethnic differences are some of the difficulties encountered when identifying disease susceptibility loci. Two major approaches to identifying these genes are being followed at present. The first, family‐based, consists of studying linkage analysis in sibling pairs and parental transmission in genome‐wide screening using microsatellite markers. These studies are appropriate and helpful for finding genes of major or moderate effects but may provide difficulty when identifying genes with minor effects. Risch and Merikangas have pointed to the power of association studies utilizing candidate genes in families. These studies should be considered in the future in genome‐wide screens when technologic advances permit. The second approach is based on classic epidemiologic designs, population‐based studies, using candidate genes in the framework of a biologic hypothesis. Recent data using both approaches in both Crohn's disease and ulcerative colitis are reviewed. The results of genome‐wide linkage studies have not reached consensus but suggest that these diseases are different and polygenic in nature. We have started our studies with the hypothesis that an abnormal immune dysbalance contributes to the biologic basis of disease. We therefore study polymorphisms in genes encoding proinflammatory and regulatory cytokines. Preliminary data of these association studies suggest the importance of several genes with small effects in determining the severity and prognosis of these diseases.
Late Outcome of 304 Consecutive Patients with Multiple Gland Enlargement in Primary Hyperparathyroidism Treated by Conservative Surgery
Authors: Proye Charles , Carnaille Bruno , Quievreux Jean‐Louis , Combemale Frederic , Oudar Christophe , Lecomte‐Houcke Martine
Published: August 2002

The aim of this study was to assess the late outcome of patients with primary hyperparathyroidism and multiple gland enlargement (MGE) treated by conservative surgery. MGE in primary hyperparathyroidism is the presence of two or more enlarged glands weighing more than 50 mg. Conservative surgery consists in resecting the grossly enlarged glands without biopsying the normal glands. Some authors have suggested that this approach overlooks minute hyperplasia, leading to late recurrences of hyperparathyroidism; conversely, it may result in the unnecessary resection of grossly enlarged, but not hyperfunctioning, glands. Altogether 1231 patients were operated on for primary hyperparathyroidism between 1966 and 1995. Of these patients, 304 (24.9%) had MGE, including 42 cases of multiple endocrine neoplasia (MEN), 12 familial cases, and 250 seemingly sporadic cases. Two, three, or four glands (or more) were involved in 61.8%, 21.4%, and 16.4% of cases, respectively. During the early postoperative period one patient died and ten were reoperated for persistent hypercalcemia. The pathologic diagnoses were double adenomas (13.5%), hyperplasia (35.8%), association of the two (39.8%), and a normal second gland (10.8%) on light microscopy findings. None of the 30 deaths that occurred during follow‐up was related to hyperparathyroidism. Altogether 190 patients (79%) were available for follow‐up (average 89.3 months): 90% were normocalcemic, 4.7% hypocalcemic, and 5.2% hypercalcemic. A late iPTH assay was done in 147. PTH was appropriate to the serum calcium level in 84.3% and appropriate to normal calcemia in 91.6% of 132 cases. Conservative surgery is thus an acceptable treatment for MGE in patients with hyperparathyroidism. Few late recurrences occur, for which there are no individual predictive criteria.
Significant Changes in Blood Pressure, Glucose, and Lipids with Gastric Bypass Surgery
Authors: Cowan George S.M. , Buffington Cynthia K.
Published: August 2002

The morbidly obese have a disproportionately greater risk of hypertension, diabetes, and coronary artery disease than their lean or less seriously obese counterparts. Roux‐en‐Y gastric bypass surgery has been found to be highly effective in inducing, and sustaining, weight loss in individuals with morbid obesity. The purpose of the present study was to examine the effects of weight loss with Roux‐en‐Y gastric bypass surgery (GBP) on blood pressure, fasting blood glucose, and the lipid/lipoprotein status of 61 morbidly obese women and 21 men. Anthropometric and blood pressure assessments and blood samples for glucose and lipid/lipoprotein analyses were obtained before surgery and at 6 to 12 months postoperatively. By this time, morbidly obese (MO) males and females had lost 33% and 30% of their initial body weight, respectively, along with significant reductions in fasting blood glucose (p < 0.01) and systemic blood pressure (p < 0.05). Weight loss with GBP was also associated with significant reductions in the apoprotein B‐containing lipoproteins and the triglyceride and cholesterol composition of these particles. There was a trend (p < 0.10) toward increased serum levels of high density lipoprotein (HDL)‐cholesterol following GBP, and significant (p < 0.05) improvement in HDL subfraction distribution and composition. These findings demonstrate the effectiveness of GBP in inducing metabolic changes in the MO population, which may reduce the risk of coronary artery disease, diabetes, and hypertension.
Transpelvic Gunshot Wounds: Routine Laparotomy or Selective Management?
Authors: Velmahos George C. , Demetriades Demetrios , Cornwell Edward E.
Published: August 2002

Mandatory exploration is the standard method for managing patients with gunshot wounds to the abdomen and back. This policy is associated with a high incidence of unnecessary laparotomies and significant morbidity. Reports from our center have shown that a policy of selective management, based on clinical findings, is safe in such patients. Patients with bullet trajectories that carry a high likelihood for intraabdominal organ injury may constitute a subgroup at particular risk. The need for routine or selective exploration in similar patients must be assessed. Therefore we decided to analyze patients with transpelvic gunshot wounds. The objective of the study was to examine if a policy of selective management of patients with transpelvic gunshot wounds is safe. This prospective study was conducted at an academic level I trauma center. We admitted 37 patients with transpelvic gunshot wounds over a 12‐month period. All patients were managed according to a protocol that dictated laparotomy in the presence of significant clinical findings (peritoneal signs, hemodynamic instability, gross hematuria, rectal bleeding) and observation in the absence of the above. Additional diagnostic workup was performed only in appropriate cases rather than routinely. Nineteen (51.3%) patients were immediately operated on the basis of clinical findings. Sixteen of these laparotomies were therapeutic. Eighteen (48.6%) patients were initially observed. Subsequently, three of them underwent exploration for development of abdominal tenderness. All three laparotomies were nontherapeutic. The remaining 15 (40.5%) patients were successfully managed nonoperatively. There were no delays in diagnosis or missed injuries. Clinical examination had a sensitivity of 100% and specificity of 71.4% in detecting the need for laparotomy. A policy of selective management is thus safe, even for patients who suffer gunshot wounds with a high likelihood for intraabdominal organ injury. Clinical examination, supported by additional studies in appropriate cases, is the main method of selecting patients for operation or nonoperative treatment.
Parathyroid Carcinoma: Sixteen New Cases and Suggestions for Correct Management
Authors: Favia Gennaro , Lumachi Franco , Polistina Francesco , D’Amico Davide F.
Published: August 2002

We undertook a retrospective study in 16 patients with parathyroid carcinoma, with the aim of conveying experience from management of this rare cause of hyperparathyroidism (HPT). From 1980 to 1996 we operated on 309 patients with HPT, 290 of whom had primary HPT, and parathyroid carcinoma was diagnosed in 16 (5.2%) cases. In none was the malignancy diagnosed preoperatively. The average serum calcium and parathyroid hormone levels were significantly higher (
p < 0.05) than in patients with parathyroid adenoma, and the mean tumor size was 2.9 cm (median 2.5 cm, range 1.5–4.5 cm). Twenty‐eight operations were performed with resulting normalization of serum calcium levels for more than 6 months in 11 patients. Six patients presented prolonged postoperative hypocalcemia (2–10 months), and five patients had persistent HPT. Ten patients experienced recurrent disease; the median disease‐free period was 24 months (range 4–72 months). None of the patients was treated with chemotherapy, one patient underwent radiation therapy (50 Gy in 25 sessions) but required reoperation for local recurrence 4 months later. Three patients are still alive (two with recurrence). Average survival was 40 months (median 31 months, range 11–131 months).
Recognizing, Scoring, and Predicting Blast Injuries RID="" ID="" This International Association for the Surgery of Trauma and Surgical Intensive Care (IATSIC) article was presented at the 37th World Congress of Surgery International Surgical Week (ISW97), Acapulco, Mexico, August 24–30, 1997.
Authors: Cernak Ibolja , Savic Jovan , Zunic Gordana , Pejnovic Nada , Jovanikic Olivera , Stepic Vladislav
Published: August 2002

The aim of this study was to find relevant signs and readily available parameters for the recognition of blast injuries and estimation of their severity. The injury severity, estimated by the Injury Severity Score (ISS), Red Cross Wound Classification (RCWC), and experimentally defined Pathology Scoring System for Blast Injuries (PSS/IS) according to Yelverton and modified for use in humans, was compared with a great number of subjective sensations, clinical signs, parameters of hemodynamic, metabolic, neuroendocrine and immune conditions. On the basis of these data, the confidence of the above‐mentioned methods was analyzed in the evaluation of blast injuries. This study included 1303 casualties, wounded by explosive devices and with suspected blast injuries, treated at the Military Medical Academy in Belgrade (MMA) from 1991 to 1994. The patients were examined on admission at the MMA (<18 hours) and during hospitalization (1, 2, 5, and 7 days after wounding). The casualties with confirmed blast injury (n= 665, 51%)
had an ISS ranging from 0 to 34 (mean 13) had wounds ranging from G1ST
(soft tissue wounds caused by low energy transfer) to G3VF (massive wounds with fractures and injury of vital structures) according to the RCWC, with PSS/IS scores from 2 to 105 (mean 60). Statistically significant correlation was found between ISS and PSS/IS as well as RCWC and PSS/IS. Cytokines (IL‐1, TNFalpha) and amino acids responded to a blast injury in similar manner as to gunshot wounds with a greater ISS or more severe RCWC injury type. The subjective sensations in blasted patients (deafness, thoracic pain, vertigo) and mediators, confirmed in previous experimental investigations as important factors in the pathogenesis of blast injuries
(TxA2, sulfidopeptide leukotrienes) were relationed only to the PSS/IS.RID="" ID="" Correspondence to: I. Cernak, M.D., Ph.D.
Palliative Chemotherapy and Radiotherapy for Pancreatic Cancer: Is It Worthwhile?
Authors: van der Schelling George P. , Jeekel Johannes
Published: August 2002

The role of palliative chemotherapy or radiotherapy (or both) in pancreatic cancer is discussed. In patients with disseminated pancreatic cancer chemoradiotherapy has so far not been effective in prolonging survival. Recent trials with gemcitabine has shown a modest improvement in clinical benefit and survival. Patients with locally advanced disease should be offered 5‐fluorouracil and radiation therapy, as valid data have repeatedly shown better median survival compared to no therapy. The option of a second‐look laparotomy to evaluate resectability after palliative chemoradiotherapy in patients with locally advanced disease should be applied liberally because currently available imaging techniques sometimes do not accurately reflect tumor size and tumor progression. New treatment strategies, such as regional perfusion, are being investigated.
Adrenal Gland and Renal Sonography
Authors: Little Andrew F.
Published: August 2002

Ultrasound (US) is an established imaging modality for the assessment of the kidneys and adrenal glands. The advantages include its lack of ionizing radiation, speed, multiplanar real time evaluation, and cost compared with more expensive modalities. The addition of color Doppler also permits accurate evaluation of blood flow, which is especially useful in renal assessment. As with all sonography, both renal and adrenal US are highly dependent on the operator's skill and experience and require meticulous scanning techniques. In particular, adrenal sonography can be difficult due to the lack of a satisfactory acoustic window through which the incident US beam passes. This review summarizes the various morphologic appearances seen in common renal and adrenal pathologies, many of which have characteristic US appearances enabling accurate diagnosis.
Hepatic Adenoma and Focal Nodular Hyperplasia: Differential Diagnosis and Treatment
Authors: Herman Paulo , Pugliese Vincenzo , Machado Marcel A.C. , Montagnini Andre L. , Salem Marcelo Z. , Bacchella Telesforo , D'Albuquerque Luis A.C. , Saad William A. , Machado Marcel C.C. , Pinotti Henrique W.
Published: August 2002

The diagnosis of benign hepatic tumors as hepatic adenoma (HA) and focal nodular hyperplasia (FNH) remains a challenge for clinicians and surgeons. The importance of differentiating between these lesions is based on the fact that HA must be surgically resected and FNH can be only observed. A series of 23 female patients with benign liver tumors (13 FNH, 10 HA) were evaluated, and a radiologic diagnostic algorithm was employed with the aim of establishing preoperative criteria for the differential diagnosis. All patients were submitted to surgical biopsy or hepatic resection to confirm the diagnosis. Based only on clinical and laboratory data, distinction was not possible. According to the investigative algorithm, the diagnosis was correct in 82.6% of the cases; but even with the development of imaging methods, which were used in combination, the differentiation was not possible in four patients. For FNH cases scintigraphy presented a sensitivity of 38.4% and specificity of 100%, whereas for HA the sensitivity reached 60% and specificity 85.7%. Magnetic resonance imaging, employed when scintigraphic findings were not typical, presented sensitivities of 71.4% and 80% and specificities of 100% and 100% for FNH and HA, respectively. Preoperative diagnosis of FNH was possible in 10 of 13 (76.9%) patients and was confirmed by histology in all of them. In one case, FNH was misdiagnosed as HA. The diagnosis of HA was possible in 9 of 10 (90%) adenoma cases. Surgical biopsy remains the best method for the differential diagnosis between HA and FNH and must be performed in all doubtful cases. Surgical resection is the treatment of choice for all patients with adenoma and can be performed safely. With the evolution of imaging methods it seems that the preoperative diagnosis of FNH may be considered reliable, thereby avoiding unnecessary surgical resection.
Changes in Intermediary Metabolism in Severe Surgical Illness
Authors: Wolfe Robert R. , Martini Wenjun Z.
Published: August 2002

Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state.
Uroporphyria In Hfe Mutant Mice Given 5–Aminolevulinate: A New Model of Fe–Mediated Porphyria Cutanea Tarda
Authors: Sinclair Peter R. , Gorman Nadia , Walton Heidi S. , Bement William J. , Sinclair Jacqueline F. , Gerhard Glenn S. , Szakacs Juliana G. , Andrews Nancy C. , Levy Joanne E.
Published: August 2002

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, it has been shown that many PCT patients carry mutations in the HFE gene, which is responsible for hereditary hemochromatosis. Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe–null mutation accumulated high levels of hepatic URO when fed 5–aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower rate. The amount of accumulated URO in the null mutant mice was similar to that in wild–type mice treated with iron carbonyl in the diet, or injected with iron dextran. Iron in both wild–type and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild–type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe–null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.
Plasma Membrane Ca2+ Release-Activated Ca2+ Channels With A High Selectivity for Ca2+ Identified by Patch–Clamp Recording in Rat Liver Cells
Authors: Rychkov Grigori , Brereton Helen M. , Harland Lyn M. , Barritt Gregory J.
Published: August 2002

Repetitive waves of increased cytoplasmic Ca2+ concentration play a central role in the process by which hormones regulate liver function. Maintenance of these Ca2+ waves requires Ca2+ inflow through store–operated Ca2+ channels. The properties and mechanism(s) of activation of these channels are not well understood. Store–operated Ca2+ channels (SOCs) in the H4–IIE rat liver cell line were studied by whole–cell patch clamping. Depletion of Ca2+ in intracellular stores by intracellular perfusion with either inositol 1,4,5–trisphosphate (InsP3) or thapsigargin in the presence of 10 mmol/L ethylene glycol–bis(β–aminoethyl ether)–N,N–tetraacetic acid (EGTA), or with 10 mmol/L EGTA alone, activated an inward current that reversed at a membrane potential above +40 mV. In physiologic extracellular medium, this inward current was carried exclusively by Ca2+ and was blocked by a variety of di– and trivalent cations. In the absence of extracellular Ca2+ and Mg2+, the inward current was carried by monovalent cations. This current was 10 to 30 times larger than that observed in the presence of extracellular Ca2+, and permitted the detection of single–channel events that corresponded to a single–channel conductance of about 40 pS. Both the Ca2+ and Na+ inward currents were blocked by the calmodulin antagonist, N–(6–amino hexyl)–5–chloro–1–naphthalenesulphonamide (W7), but not by calmidazolium or calmodulin–dependent protein kinase II fragment 290–309. It is concluded that liver cells possess plasma membrane Ca2+ channels that have a high selectivity for Ca2+, are activated by a decrease in the concentration of Ca2+ in intracellular stores through a mechanism that is unlikely to involve calmodulin, and are involved in re–filling intracellular Ca2+ stores during Ca2+ signaling.
Subcellular Site of Superoxide Dismutase Expression Differentially Controls Ap–1 Activity and Injury in Mouse Liver Following Ischemia/Reperfusion
Authors: Zhou Weihong , Zhang Yulong , Hosch Micaela S. , Lang Amie , Zwacka Ralf M. , Engelhardt John F.
Published: August 2002

Acute damage following ischemia and reperfusion (I/R) in the liver is in part caused by the generation of reactive oxygen species, such as superoxides, during the reperfusion event. Gene therapy directed at attenuating mitochondrial superoxide production following warm I/R injury in the liver has demonstrated great promise in reducing acute hepatocellular damage. In the present study, we have compared the therapeutic effects of ectopic expression of mitochondrial (MnSOD) and cytoplasmic (Cu/ZnSOD) superoxide dismutase using recombinant adenoviral vectors for reducing I/R damage in the liver. Consistent with previous observations, recombinant adenoviral delivery of MnSOD to the liver significantly attenuated both acute liver damage and AP–1 activation following I/R injury to the livers of mice. However, ectopic expression of Cu/ZnSOD diminished neither I/R–induced elevations in serum alanine transaminase (ALT) nor AP–1 activation. Interestingly, baseline activation of AP–1 before I/R–induced injury was seen in livers infected with recombinant Ad.Cu/ZnSOD, but not Ad.MnSOD or Ad.LacZ, vectors. The level of Cu/ZnSOD–induced AP–1 activation was significantly reduced by ablation of Kupffer cells or by coexpression of catalase, suggesting that increased H2O2 production facilitated by Cu/ZnSOD in hepatocytes and/or Kupffer cells may be responsible for AP–1 activation. In vitro reconstitution studies using hepatocyte and macrophage cell lines demonstrated that Cu/ZnSOD overexpression induces AP–1 in both cell types, and that secretion of a Cu/ZnSOD–induced macrophage factor is capable of elevating AP–1 in hepatocytes. In summary, our findings demonstrate that subcellular sites of superoxide production in the liver can differentially affect the outcome of I/R injury in the liver and selectively influence AP–1 activation.
Characterization of Autoantibodies Against Uridine–Diphosphate Glucuronosyltransferase in Patients With Inflammatory Liver Diseases
Authors: Bachrich Thomas , Thalhammer Therese , Jäger Walter , Haslmayer Petra , Alihodzic Belma , Bakos Silvia , Hitchman Eva , Senderowicz Adrian M. , Penner Edward
Published: August 2002

Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver–kidney microsomal autoantibodies and was termed LKM–3. To evaluate the nature of LKM–3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and 1 of 27 of the HCV patients. The anti–UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT–isoform involved in the bilirubin glucuronidation. Additionally, these sera were able to block UGT–mediated substrate glucuronidation in vitro. The prevalence for UGT1A1 was shown by 2 independent techniques: (1) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT–isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9–mediated biotransformation. In contrast, the serum from the HCV–patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT–mediated glucuronidation in vitro, but it is unlikely that anti–UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range.
Intrahepatic Hepatitis C Viral Rna Status of Serum Polymerase Chain Reaction-Negative Individuals With Histological Changes on Liver Biopsy
Authors: Barrett Sharon , Kieran Niamh , Ryan Eleanor , O'Keane Conor J. , Crowe John
Published: August 2002

For individuals testing anti–HCV positive but negative for HCV RNA in serum, diagnosis remains unclear. Debate exists over whether these individuals have resolved infection or have similar clinical, histological, and virological profiles as serum PCR-positive individuals. The aim of this study was to assess the significance of histological changes in the liver of 33 serum PCR-negative women by investigation of clinical, histological, and intrahepatic HCV RNA status. For comparison, clinical and histological data from 100 serum PCR-positive women is presented. Viral RNA status was determined in snap–frozen liver biopsies using a sensitive nested PCR with an internal control. Although serum PCR-positive and -negative individuals shared similar age at diagnosis, source, and duration of infection, they differed from a clinical, histological, and virological perspective. Mean serum ALT levels were significantly lower in serum PCR-negative women (27.4 IU/L ± 18 vs. 58.7 IU/L ± 40 P < .001). Similarly, although inflammation (82%) and mild fibrosis (15%) were observed in PCR-negative biopsies, the mean HAI/fibrosis scores were significantly lower than in serum PCR-positive biopsies (1.9 ± 1.5/0.15 ± 0.4 vs. 4.2 ± 1.4/1.1 ± 1.3, respectively). Finally, HCV RNA was not detectable in serum PCR-negative liver biopsies but was detectable in all serum PCR-positive control biopsies. In conclusion, serum PCR-negative individuals may have mild histological abnormalities more suggestive of nonspecific reactive changes, steatosis or nonalcoholic steatohepatitis rather than chronic HCV, even when significant antibody responses are present in serum. Negative serum PCR status appears to reflect cleared past–exposure in liver.
Biliary Cholesterol Hypersecretion in Gallstone–Susceptible Mice Is Associated With Hepatic Up–Regulation of the High–Density Lipoprotein Receptor Srbi
Authors: Fuchs Michael , Ivandic Boris , Müller Oliver , Schalla Carmen , Scheibner Jürgen , Bartsch Petra , Stange Eduard F.
Published: August 2002

Enhanced hepatocellular trafficking of cholesterol to the bile canaliculus and cholesterol hypersecretion appears critical for gallstone formation. Therefore, we studied in more detail the hepatic cholesterol transport pathways in a mouse model of cholesterol gallstone disease. Biliary lipid secretion rates, plasma lipoprotein levels, hepatic expression of lipoprotein receptors, lipid regulatory enzymes, and putative cholesterol transporting proteins were analyzed in gallstone–susceptible C57L/J and gallstone–resistant AKR/J mice, which were fed a lithogenic diet. Biliary cholesterol hypersecretion in C57L mice was associated with decreased plasma high–density lipoprotein (HDL) cholesterol levels and significant hepatic induction of the HDL receptor (SRBI) and cholesteryl ester hydrolase. In response to the lithogenic diet, fatty–acid binding protein of liver (FABPL) was markedly induced in both mouse strains. Caveolin 1 was elevated only in plasma membranes of gallstone–susceptible C57L mice, which also failed to down–regulate cholesterol synthesis. These data suggest a role of the reverse cholesterol transport pathway for genetically determined gallstone susceptibility in the mouse.
Caspase Inhibition Reduces Apoptotic Death of Cryopreserved Porcine Hepatocytes
Authors: Yagi Toshikazu , Hardin Joseph A. , Valenzuela Yunuen M. , Miyoshi Hideyuki , Gores Gregory J. , Nyberg Scott L.
Published: August 2002

Cryopreserved porcine hepatocytes are a ready source of metabolic function for use in a bioartificial liver (BAL). However, cryopreservation is associated with a loss of hepatocyte viability. The mechanism of cell death during cryopreservation is incompletely understood, but may involve apoptosis through caspase activation. This study evaluates the cytoprotective effect of a global caspase inhibitor, benzyloxycarbonyl–Val–Ala–DL–Asp–fluoromethylketone (ZVAD–fmk) during cryopreservation of porcine hepatocytes. Freshly isolated porcine hepatocytes (viability, 97.4% ± 0.9%) were cryopreserved in 60 μmol/L ZVAD–fmk (+ZVAD group) or without ZVAD–fmk (-ZVAD group) for 24 to 72 hours. Apoptotic and necrotic death were both observed after thawing and after 24 hours of culture. Caspase 3-like activity was significantly reduced by ZVAD–fmk, and was associated with improved viability and reduced apoptotic death of porcine hepatocytes after cryopreservation. Mitochondrial membrane potential (MMP) was increased in cultures of porcine hepatocytes that were cryopreserved in ZVAD–fmk. These results demonstrate the following: 1) Caspase 3-like protease activation and apoptosis occurs in porcine hepatocytes during cryopreservation; and 2) mitochondrial injury in this process is reduced by caspase inhibition.
Role of Hepatitis B, C, and D Viruses in Dual and Triple Infection: Influence of Viral Genotypes and Hepatitis B Precore and Basal Core Promoter Mutations on Viral Replicative Interference
Authors: Jardi Rosendo , Rodriguez Francisco , Buti Maria , Costa Xose , Cotrina Montserrat , Galimany Roman , Esteban Rafael , Guardia Jaime
Published: August 2002

The interactions among hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) were studied by measuring HBV–DNA and HCV–RNA levels and by determining the influence of viral genotypes and mutations in HBV basal core promoter (BCP) and precore regions. We included 65 consecutive patients, 25 HBV/HCV, 18 HBV/HDV, and 22 HBV/HCV/HDV. Controls consisted of 55 patients with chronic HBV and 55 with chronic HCV infection. HBV–DNA and HCV–RNA levels were lower in coinfections than in single infections (P < .05). HBV/HCV coinfection was associated with lower HBV viremia (8.2 × 104 copies/mL) and lower HCV–RNA levels (7 × 105 IU/mL), than the corresponding control group (P < .05), with more marked decrease in HBV replication (P < .05). Moreover, in HBV/HCV coinfection and in triple coinfection we observed an inverse relationship between HBV–DNA and HCV–RNA levels (P < .05). HBV/HDV coinfection was associated with lower HBV viremia (2.5 × 104 copies/mL) than that found in HBV infection (P < .05). Patients with triple coinfection showed lower HBV–DNA and HCV–RNA levels than control groups (P < .05). Prevalence of precore mutations was lower in HCV coinfections (P < .05). No significant association was observed between HCV–RNA levels and HBV precore mutations, BCP mutations or HBV genotypes, or between HBV–DNA levels and HCV genotypes (P < .05). In conclusion, HCV exhibited stronger inhibitory action in the reciprocal inhibition seen in HBV/HCV coinfection. HDV was the dominant virus in HBV/HDV coinfection and in triple coinfection, and had a greater unfavorable influence on HCV than on HBV replication. The reciprocal inhibition of viral replication seemed to be little influenced by the inherent genomic factors studied.
Effects of a long-acting formulation of octreotide on renal function and renal sodium handling in cirrhotic patients with portal hypertension: A randomized, double-blind, controlled trial
Authors: Ottesen Lone Harild , Aagaard Niels Kristian , Kiszka-Kanowitz Marianne , Rehling Michael , Henriksen Jens Henrik , Pedersen Erling Bjerregaard , Flyvbjerg Allan , Bendtsen Flemming
Published: August 2002

Octreotide seems to have a beneficial effect on variceal bleeding, and long-term administration for the prevention of rebleeding is currently being evaluated. Experimental studies have suggested a beneficial effect of chronic octreotide treatment on renal function, while clinical studies have shown variable effects. Twenty-five cirrhotic patients with portal hypertension were randomized in a double-blind design to placebo or a single subcutaneous dose of a long-acting formulation of octreotide (octreotide-LAR) (20 mg). Renal function tests were performed before dosing and repeated after 30 days. The patients were in sodium steady state at the time of study. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by a constant infusion clearance technique. Renal sodium handling was determined by lithium and sodium clearance measurements. Therapeutic serum levels of octreotide along with a reduction of insulin-like growth factor I (IGF-I) (P < .01) and an increase of IGF binding protein 1 (P < .05) were demonstrated. No effect of octreotide was observed on GFR, ERPF, or filtration fraction (GFR/ERPF). Changes in clearance and extraction fraction of sodium and lithium during octreotide treatment were not significantly different from those of placebo. In addition, no changes in free water clearance, urinary flow rate, or 24-hour Na excretion were demonstrated. A significant increase of mean arterial pressure (+5 mm Hg; P < .01) was observed after treatment with octreotide-LAR. It is concluded that in spite of increased arterial pressure, octreotide-LAR has no significant effect on renal hemodynamics and tubular function in clinically stable cirrhotic patients with portal hypertension. (Hepatology 2001;34:471-477.)
High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity
Authors: Donato Maria Francesca , Arosio Eliana , Del Ninno Ersilio , Ronchi Guido , Lampertico Pietro , Morabito Alberto , Balestrieri Maria Rita , Colombo Massimo
Published: August 2002

The prevalence, risk factors, and clinical significance of high liver cell proliferative activity were investigated in 208 well-compensated cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis C) who had been under prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum α-fetoprotein (AFP) determination. Immunostaining for proliferating cell nuclear antigen (PCNA) was employed to assess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a computer-assisted image analysis system. The overall PCNA labeling index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly higher in the 50 patients who developed HCC during 88 ± 42 months of follow-up than in the 158 patients who remained cancer-free (3.6% ± 2.4% vs. 1.6% ± 1.5%; P < .0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI discriminated between patients at high and low risk for developing cancer. By multivariate analysis, high histologic grading scores and gender were associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was the strongest independent predictor of cancer (hazard ratio, 5.49; 95% CI, 2.90-10.37). Overall, survival was significantly lower in patients with high liver cell proliferative activity rates than in those with low proliferative rates (10% vs. 75%; P < .0001). In conclusion, development of HCC in patients with compensated cirrhosis seems to be reliably predicted by liver cell proliferation status. (Hepatology 2001;34:523-528.)