GALLSTONE CIRRHOSIS: ARE WE ONLY SEEING THE TIP OF THE ICEBERG?

Gallstones are common and their incidence increases with age.¹ Fifty per cent of these stones are in the common bile duct (CBD) in the elderly.² Most of them are silent but with time there is an increasing chance of developing symptoms which are more likely to be serious in the elderly.³ Failure to relieve mechanical obstruction of bile flow may lead to secondary biliary cirrhosis.⁴ It has been estimated that on average secondary biliary cirrhosis develops some seven years after the onset of obstruction from a stricture, four and half years after gallstone obstruction and 10 months after the onset of malignant stricture.⁵ The characteristic features are the pathological findings of portal-portal linkages, with a pattern of monolobular cirrhosis and the preservation of normal vascular relationships.⁶ Secondary biliary cirrhosis may lead to hepatic insufficiency and portal hypertension with the resultant complications, such as bleeding oesophageal varices, hypersplenism with pancytopenia, ascites and encephalopathy. We describe a patient in whom the diagnosis was not suspected until laparotomy and confirmed only at autopsy.     

Diagnostic role of fine-needle aspiration of bone lesions in patients with a previous history of malignancy

At the present time fine-needle aspiration (FNA) is considered a routine diagnostic procedure in evaluating neoplastic vs. nonneoplastic lesions in many organs, with high sensitivity and specificity. The purpose of this study was to assess the utility of FNA in areas of diagnostic difficulty and its limitations in evaluating bone lesions in patients with a previous history of malignancy. From 1989 to 2000, 249 CT-guided FNAs of bone lesion were performed at our institutions; 187/249 (75.1%) patients had a previous history of malignancy. Aspirated material was air-dried for Diff-Quik stain or fixed in ethanol for Papanicolaou staining. Subsequent surgical tissue was available in 69/187 (36.9%) of the cases. There were 114 males and 73 females, ages 14-86 yr (mean, 64 yr). The primary tumor site was lung 49, genitourinary 46, breast 31, gastrointestinal 28, hematopoietic 26, soft tissue/skin 5, and thyroid 2. There were 125 FNAs of the vertebral spine, 19 from the pelvis, 11 from the ribs, 9 from the sternum, 5 from the femur, and 18 from miscellaneous bone sites. Out of 187, 166 (88.7%) were malignant aspirates confirming the patients' primary malignancies. The most common malignancy encountered was adenocarcinoma, 126/187 (67.4%). Surgical tissue was available for review in 69 patients and the results were in agreement with the FNAs diagnosis in all cases. Nine out of 187 (4.8%) cases were diagnosed as marrow elements on cytological material. These patients have been followed for 1-9 yr and have failed to reveal signs or symptoms of clinical recurrence. Three out of 187 (1.6%) cases showed osteomyelitis. Nine out of 187 (4.8%) were unsatisfactory specimens, with biopsy follow-up available in four cases, showing three metastatic tumors and one case of osteomyelitis. FNA of metastatic bone lesions is a major step in pretreatment diagnosis. On satisfactory specimens, the cytological diagnosis viewed in the clinical-radiological context proves to be similar to surgical diagnosis. FNA is an excellent technique with a high accuracy rate in assessing metastatic bone lesions.     

Application of adjunct techniques in cytologic material in the diagnosis of rhabdomyosarcoma: case report and review of the literature

A 4(1/2)-yr-old female presented with right-sided pleural effusion and a retroperitoneal mass. Cytologic analysis of the pleural fluid yielded malignant small round blue cells, which were noncohesive, 3-4 times the size of lymphocytes. The malignant cells had hyperchromatic, pleomorphic nuclei with moderate amounts of vacuolated cytoplasm. A few fiber-shaped cells were also seen. Immunostains for desmin, muscle-specific actin were positive; ultrastructural findings of thick and thin actin-myosin filaments confirmed the diagnosis of embryonal rhabdomyosarcoma. This case illustrates the importance of performing appropriate immunohistochemical stains and ultrastructural studies on cytological material to arrive at a definitive diagnosis.     

Muscle synergies during shifts of the center of pressure by standing persons

Movements by a standing person are commonly associated with adjustments in the activity of postural muscles to cause a desired shift of the center of pressure (COP) and keep balance. We hypothesize that such COP shifts are controlled (stabilized) using a small set of central variables (muscle modes, M-modes), while each M-mode induces changes in the activity of a subgroup of postural muscles. The main purpose of this study has been to explore the possibility of identification of muscle synergies in a postural task using the framework of the uncontrolled manifold (UCM) hypothesis employing the following three steps in data analysis: (i) Identification of M-modes: Subjects were asked to release a load from extended arms through a pulley system, resulting in a COP shift forward prior to load release. Electromyographic (EMG) activity of eleven postural muscles on one side of the body was integrated over a 100 ms interval corresponding to the early stage of the COP shift, and subjected to a principal component (PC) analysis across multiple repetitions of each task. Three PCs were identified and associated with a push-back M-mode, a push-forward M-mode and a mixed M-mode. (ii) Calculation of the Jacobian of the system, which relates changes in the magnitude of M-modes to COP shifts using regression techniques: Subjects performed three different tasks (releasing different loads at the back, voluntarily shifting body weight forward and backward, at different speeds) to verify if the relationship between magnitudes of M-modes and COP shifts is task or direction specific. (iii) UCM analysis: Three tasks were chosen (load release in the front, arm movement forward and backward) which were associated with an early shift in COP. A manifold was identified in the M-mode space corresponding to a certain average (across trials) shift of the COP and variance per degree of freedom within the UCM (V_UCM) and orthogonal (V_ORT) to the UCM was computed. Across subjects, V_UCM was significantly higher than V_ORT when analysis at the third step was performed using a Jacobian computed based on a set of tasks associated with a COP shift in the same direction but not in the opposite direction. This result confirms our hypothesis that the M-modes work together as a synergy to stabilize a desired shift of the COP. Forward and backward COP shifts are associated with different synergies based on the same three M-modes.An erratum to this article can be found at     

The murine NF2 homologue encodes a highly conserved merlin protein with alternative forms

The recently isolated gene for neuroflbromatosls type 2 (NF2)encodes a 595 amlno acid protein, named merlin, which Is relatedto the cytoskeleton-assoclated proteins moesln, ezrin and radlxin.To Identify evolutionarily conserved regions and to providesequence Information necessary for the establishment of a mousemodel for NF2, we have determined the cDNA sequence of the mouseNF2 tumor suppressor gene, and mapped It In the mouse genome.Mouse merlin is a 596 amino acid protein, 98% identical to humanmerlin, but one amlno acid longer due to the Insertion of aproline residue near the C-terminus. Of the nine amlno aciddifferences between mouse and humans, seven occur in the C-termlnal20% of the protein, far from the protein 4. 1 domain that definesthis family. Two of the NF2 cDNA clones reveal evidence of alternativesplicing events that alter the predicted merlin product, oneremoving a 45 amlno acid segment from the middle section ofthe protein and the other changing the C-terminus. The existenceof several different forms of merlin potentially with differentprimary roles will complicate the Identification of the precisefunction that must be disrupted to cause the NF2-assoclatedtumors. The mouse NF2 homologue maps to Chr 11, in a regionhomologous to human Chr 22, but devoid of any mouse mutationswhich could be models of the human disorder.     

Comorbidity of PTSD and depression: associations with trauma exposure, symptom severity and functional impairment in Bosnian refugees resettled in Australia

Background: Posttraumatic stress disorder (PTSD) is common in refugees but its association with longer-term psychosocial dysfunction remains unclear. We examined whether a subgroup of refugees with comorbid PTSD and depression were at particularly high risk of disability. We also investigated whether specific trauma experiences were linked to this comorbid pattern. Methods: Consecutive Bosnians (and one or two compatriots nominated by them) were recruited from a community centre, yielding a total sample of 126 participants (response rate 86%). Measures included a trauma inventory, the Clinician Administered PTSD Scale (CAPS) (Blake et al., 1995) and the depression module of the Structured Clinical Interview (SCID) (First et al., 1997). Results: Three diagnostic groupings emerged: normals (n=39), pure PTSD (n=29), and comorbid PTSD and depression (n=58). Of four trauma dimensions derived from principle components analysis (human rights violations, dispossession and eviction, life threat and traumatic loss), life threat alone was associated with pure PTSD, with life threat and traumatic loss both being associated with comorbidity. Compared to normals and those with pure PTSD, the comorbid group manifested more severe PTSD symptoms as well as higher levels of disability on all indices (global dysfunction: odds RATIO=5.0, P<0.001, distress: odds RATIO=6.0, P<0.001, social impairment: odds ratio 5.9, P<0.001, and occupational disability: odds ratio 5.0, P<0.001). Limitations: Recruitment was not random, the sample size was modest, and trauma event endorsement was based on retrospective accounts. Conclusions: The combination of life threat and traumatic loss may be particularly undermining to the psychological well-being of refugees and consequent comorbidity of PTSD and depression may be associated with longer-term psychosocial dysfunction. The findings raise the question whether the comorbid pattern identified should be given more recognition as a core posttraumatic affective disorder.     

Role of imprint cytology in the diagnosis of gastrointestinal tract malignancies

Endoscopic biopsies obtained from 275 patients (180 from the upper gastrointestinal tract and 95 from the lower gastrointestinal tract) were studied to compare the accuracy of biopsy imprint cytology and histology in the diagnosis of gastrointestinal lesions, and also to establish the degree of reliability of imprint cytology alone for an early diagnosis of malignancy. Biopsy histology results were found to be correct in 100% cases. Imprint cytology had an overall accuracy of 100%, 96.7%, 95.8% and 95.8% for the diagnosis of malignancies of the oesophagus, stomach, duodenum and colorectum respectively. False negative results were obtained with lymphomas. Regenerative cellular atypia was an important cause for false positive results. It was concluded that imprint cytology can serve as a useful and simple tool for an immediate diagnosis of malignancy. This should be subsequently correlated with histopathology which facilitates exact tumour typing and assessment of tumour invasion.     

Fulminant hepatic failure induced oxidative stress in nonsynaptic mitochondria of cerebral cortex in rats

Fulminant hepatic failure (FHF) is a condition with sudden onset of necrosis of hepatocytes and degeneration of liver tissue without any established liver disease. FHF is associated with increased ammonia levels in blood and brain, which is supposed to be neurotoxic, ultimately leading to neuronal death. Evidences from previous studies suggest for mitochondrial dysfunctions under hyperammonemic conditions. In the present investigation, on thioacetamide-induced FHF rat models, studies were undertaken on cerebral nonsynaptic mitochondrial oxidative stress. The results of the present study reveal elevated lipid peroxidation along with reduced total thiol levels in the cerebral cortex mitochondria of experimental animals compared to saline treated control rats. In addition, the enzymatic activities of glutathione peroxidase and glutathione reductase were decreased, with an elevation in Mn-SOD activity. Overall, thioacetamide-induced FHF in rats enhanced the levels of lipid peroxidation coupled with impaired antioxidant defenses in the cerebral nonsynaptic mitochondria.     

Estimation of size of clonal unit for keratinocytes in normal human skin

OBJECTIVE: It has been suggested that keratinocyte (KC) stem cells reside at the epicenter of a clonal population of cells. To estimate the territory or surface area covered by a single stem-cell-derived KC population in human skin, clonal skin maps were created from 3 healthy adult women and from normal skin of a psoriatic patient. DESIGN: Two hundred fifty-eight punch biopsy samples of various sizes (ranging from 2 to 8 mm in diameter) were analyzed for clonality employing X chromosome inactivation patterns at the human androgen receptor gene (HUMARA) locus. DNA was isolated and clonality established by significant decrease of either maternal or paternal X chromosome band patterns following restriction enzyme digestion, polymerase chain reaction amplification, and gel electrophoresis. RESULTS: Fifty-three (41%) of 128 two-mm biopsies were clonal, whereas only 6 (14%) of 43 three-mm, 5 (14%) of 36 four-mm, and 3 (8%) of 35 five-mm biopsies revealed a clonal population of KCs. By contrast, in 5 different biopsies from a psoriatic patient, including 4- or 5-mm sizes, all but 1 were clonal; even an 8-mm biopsy contained a clonal population of KCs. Mantel-Haenszel chi(2) analysis revealed a P value of.001, reflecting a strong trend in probability for presence of a single clone of KCs as related to size of the biopsy sample. By sequentially analyzing 30 contiguous 2-mm biopsy samples within a given strip of skin, 10 clonal domain changes, as reflected in maternal versus paternal switches, were observed. CONCLUSIONS: These results provide direct evidence of a clonal population of KCs in normal and psoriatic lesion-free skin, and indicate that a clonal epidermal unit of KCs frequently can be detected in small biopsies (2 mm), but that in normal skin sampling, overlapping clones are apparently present in larger (ie, 4-5-mm) biopsies, producing nonclonal patterns. The clonal domain of progeny in normal skin has a rather limited territorial boundary (2 mm in diameter). However, in lesion-free skin from a psoriatic patient, there may be clonal expansion of KCs due to perturbation in epidermopoiesis and/or stem cell distribution.     

Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells.

Permeability-glycoprotein (Pgp) positive cells are known to be encoded by the multidrug-resistance gene (MDR1), and characterized by a reduced ability to accumulate drugs. The vinblastin-resistant, Pgp positive CEM-VLB 1000 and its wild type (Pgp-negative and vinblastin-sensitive) counterpart CEM-T4 human leukemia cells, when treated with the alkaloid sanguinarine, were both found to undergo apoptosis at concentrations of 1.5 microg/ml and oncosis/blister cell death (BCD) at concentrations of 12.5 microg/ml. The aim of this study was to assess the ability of sanguinarine to overcome Pgp-mediated multidrug-resistance (MDR), and also to characterize the cell death processes of apoptosis and oncosis (or bimodal cell death) induced by sanguinarine in MDR cells. The cell death processes of apoptosis and oncosis in CEM-VLB 1000 and CEM-T4 cell lines were found to be qualitatively similar when assessed by light microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling, annexin-V-binding, trypan blue exclusion and western blot analysis. Western blotting revealed an increase in the Bax/Bcl-2 ratio and activation of caspase-3 in apoptosis but not oncosis in both cell lines. The Pgp-positive CEM-VLB 1000 cells and their wild type CEM-T4 cells were both equally sensitive to sanguinarine. Thus, sanguinarine may overcome the phenomenon of Pgp-mediated MDR by inducing apoptosis through increasing the Bax/Bcl-2 ratio and activating caspase-3, and oncosis, which involved neither.