Diagnosing liver fibrosis: a narrative review of current literature for dermatologists.

Chronic liver disease is a growing problem worldwide due to obesity, alcohol-related liver disease and viral hepatitis. Liver fibrosis is generally asymptomatic and patients may not present until they have advanced cirrhosis, when the scope for reversibility is limited. Identification of asymptomatic individuals at an early stage is fundamental to reversing the rising toll of liver-related morbidity and mortality. Awareness of liver disease and the techniques for diagnosis is important for dermatologists, not only due to the burden of disease in the general population but also because some dermatology cohorts may have an elevated risk. For example, there is an increased prevalence of metabolic syndrome and excess alcohol use in those with psoriasis and hidradenitis suppurativa. In isolation, standard liver function tests lack sensitivity to detect advanced fibrosis and cirrhosis and are of limited value. Traditionally diagnosis has relied on liver biopsy, which remains the gold standard but is both costly and invasive. There have been several recent advances in the development of noninvasive alternatives. These include scoring systems combining clinical and conventional laboratory parameters for use as screening tools, direct serum biomarkers of fibrogenesis and tissue elastography using both ultrasound (Fibroscan) and magnetic resonance. This review summarizes current and future noninvasive diagnostic techniques for evaluation of liver fibrosis.

Determinants of long-term outcome in severe alcoholic hepatitis.

BACKGROUND: Although short-term outcome in severe alcoholic hepatitis (SAH) is well described, its long-term course remains uncharacterised. AIM: To assess determinants of long-term outcome in SAH. METHODS: Data were recorded from a cohort with SAH (admission Discriminant Function (DF) ≥32). Kaplan-Meier (KM) and Cox proportional hazards survival analyses were performed to determine predictors of outcome. RESULTS: One hundred and nine patients were included; 63.3% male, aged 49.6 ± 9.4 years with median follow-up of 40.7 months (95% CI 37.2-44.3). Median DF was 58, 86.2% had cirrhosis and 65.1% received corticosteroids and/or pentoxifylline. Overall mortality was 57.8%, 96.8% of deaths being liver-related and 65.1% occurring after the index hospitalisation. Estimated 5-year survival was 31.8%. Hepatorenal syndrome was the only baseline factor independently associated with mortality (HR 3.78, 95% CI 1.98-7.19, P < 0.0001), although it predicted short-term, rather than long-term outcome (median survival 0.52 months, 95% CI 0.43-0.61). Of the 87 patients (79.8%) who survived index hospitalisation, 65.1% experienced recidivism. Abstinence at last follow-up remained the only independent predictor of survival in multivariate analysis (HR 0.370, 95% CI 0.168-0.818, P = 0.014). Five-year survival was higher in abstainers (75.3%) compared with relapsed and continued drinkers (26.8% and 21.0%, respectively, P = 0.005). However, the survival benefit from abstinence only became statistically significant at 18 months postdischarge (HR 2.714, 95% CI 0.995-7.404, P = 0.051). CONCLUSIONS: Estimated 5-year survival after index hospitalisation with SAH is 31.8% with alcohol relapse occurring in two-thirds of patients. Abstinence remains the only independent predictor of long-term survival. Novel strategies to improve abstinence after admission with SAH are urgently needed.

De novo Cryoglobulinaemic Mononeuritis Multiplex during Treatment of Chronic Hepatitis C Infection: A Viral Effect or Induced by Pegylated Interferon Alpha?

Cryoglobulinaemic mononeuritis multiplex (MNM) is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection for which interferon-based antiviral therapy is currently the treatment of choice. Rarely MNM can be associated with HCV treatment though generally in the setting of pre-existing cryoglobulinaemia and detectable HCV viraemia. We report an unusual case of de novo MNM occurring late during the course of pegylated interferon and ribavirin therapy for chronic HCV infection, following a prolonged period of viral suppression. The patient had no evidence of cryoglobulinaemia prior to HCV treatment and undetectable HCV RNA levels at the time of presentation with MNM. The case raises the possibility that MNM could develop as an adverse immunomodulatory effect of pegylated interferon therapy.

Predicting oscillatory dynamics in the movement of territorial animals.

Understanding ecological processes relies upon the knowledge of the dynamics of each individual component. In the context of animal population ecology, the way animals move and interact is of fundamental importance in explaining a variety of observed patterns. Here, we present a theoretical investigation on the movement dynamics of interacting scent-marking animals. We study how the movement statistics of territorial animals is responsible for the appearance of damped oscillations in the mean square displacement (MSD) of the animals. This non-monotonicity is shown to depend on one dimensionless parameter, given by the ratio of the correlation distance between successive steps to the size of the territory. As that parameter increases, the time dependence of the animal's MSD displays a transition from monotonic, characteristic of Brownian walks, to non-monotonic, characteristic of highly correlated walks. The results presented here represent a novel way of determining the degree of persistence in animal movement processes within confined regions.

Brownian walkers within subdiffusing territorial boundaries.

Inspired by the collective phenomenon of territorial emergence, whereby animals move and interact through the scent marks they deposit, we study the dynamics of a 1D Brownian walker in a random environment consisting of confining boundaries that are themselves diffusing anomalously. We show how to reduce, in certain parameter regimes, the non-Markovian, many-body problem of territoriality to the analytically tractable one-body problem studied here. The mean square displacement (MSD) of the 1D Brownian walker within subdiffusing boundaries is calculated exactly and generalizes well known results when the boundaries are immobile. Furthermore, under certain conditions, if the boundary dynamics are strongly subdiffusive, we show the appearance of an interesting nonmonotonicity in the time dependence of the MSD, giving rise to transient negative diffusion.

Binding of a peptide from a Streptococcus dysgalactiae MSCRAMM to the N-terminal F1 module pair of human fibronectin involves both modules.

Host invasion by a number of pathogenic bacteria such as staphylococci and streptococci involves binding to fibronectin, a ubiquitous extracellular matrix protein. On the bacterial side, host extracellular matrix adherence is mediated by MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) which, in some cases, have been identified to be important virulence factors. In this study we used nuclear magnetic resonance spectroscopy to characterize the interaction of B3, a synthetic peptide derived from an adhesin of Streptococcus dysgalactiae, with the N-terminal module pair 1F12F1 of human fibronectin. 1F12F1 chemical shift changes occurring on formation of the 1F12F1/B3 complex indicate that both modules bind to the peptide and that a similar region of each module is involved. A similar surface of the 4F15F1 module pair had previously been identified as the binding site for a fibronectin-binding peptide from Staphylococcus aureus.

Is the quality of surgical residency applicants deteriorating?

BACKGROUND: Among directors of general surgery residencies, there is a concern that the quality of medical students applying to surgical residencies is declining. METHODS: Quality of surgical applicants was assessed by several methods including subjective opinions determined by survey and by objective data including student United States Medical Licensing Examination (USMLE) scores of matched candidates. The number of applicants interviewed, total interviews granted, proportion of Alpha Omega Alpha (AOA) students, and the rank order of the candidates matched was obtained by survey. The survey included data on postgraduate year 1 (PGY-1) residents from July 1996 to July 1999. Three mailings were made to 226 US surgical residency programs. RESULTS: Data were obtained from 90 programs. Surgery program directors disagreed with a survey statement that overall quality of applicants had declined (P <0.01), but agreed with a statement that activities of medical schools to enroll graduating students into primary care had hurt recruitment (P <0.001). Objective data revealed no change in mean USMLE part I scores of PGY-1 residents over the 4 years (P = 0.265, power = 0.81). There was no change in proportion of matched residents who were AOA over time. The mean score of all new PGY-1 residents, the rank of the first matched resident, the rank of the last ranked resident, and proportion of AOA students was higher in programs with five or more categorical spots when compared with programs of at most four (P <0.001). Across all programs, there was a trend to go lower on the rank list to fill categorical positions over time (P <0.001). CONCLUSIONS: There is a perception that medical school policies act to discourage recruitment of quality medical students into general surgery programs, and surgery programs are going deeper into their rank lists to fill categorical positions. However, the average USMLE part I score of applicants to surgical residencies and proportion of AOA applicants has not decreased.

Identification of residues involved in the interaction of Staphylococcus aureus fibronectin-binding protein with the (4)F1(5)F1 module pair of human fibronectin using heteronuclear NMR spectroscopy.

Many pathogenic Gram-positive bacteria express cell surface proteins that bind to components of the extracellular matrix. This paper describes studies of the interaction between ligand binding repeats (D3 and D1-D4) of a fibronectin-binding protein from Staphylococcus aureus with a module pair ((4)F1(5)F1) from the N-terminal region of fibronectin. When D3 was added to isotope-labeled (4)F1(5)F1, (1)H, (15)N, and (13)C NMR chemical shift changes indicate that binding is primarily via residues in (4)F1, although a few residues in (5)F1 are also affected. Both hydrophobic and electrostatic interactions appear to be involved. The NMR data indicate that part of the D3 repeat converts from a disordered to a more ordered, extended conformation on binding to (4)F1(5)F1. In further NMR experiments, selective reduction of the intensity of D1-D4 resonances was observed on binding to (4)F1(5)F1, consistent with previous suggestions that in each of D1, D2, and D3 repeats, the main fibronectin binding site is in the C-terminal region of the repeat. In D1-D4, these regions also appear to go from a disordered to a more ordered conformation of fibronectin binding. Although the regions of the two proteins which interact had been previously identified, the findings presented here identify, for the first time, the specific residues in both proteins that are likely to be involved in the interaction.

Upper arm arteriovenous fistulas as a reliable access alternative for patients requiring chronic hemodialysis.

The wrist fistula is the access procedure of choice in the hemodialysis patient. However, unavailable or unusable anatomy in this aging population has made them difficult to establish. This study retrospectively compares patency, occlusion, and complication rates of upper arm arteriovenous fistulas (AVFs) as a reliable alternative. Fifty-eight upper arm AVFs were created in 52 patients between February 1995 and August 1997 at Hermann Hospital, affiliated with the University of Texas Health Science Center in Houston, Texas. Fistulas were constructed using the brachial artery (BA) side-to-end (n = 56) or side-to-side (n = 1) with either the cephalic vein (CV; n = 39), transposed basilic vein (TBV; n = 16), or other vein [basilic vein (BV; n = 1), transposed cephalic vein (TCV; n = 1), median cubital vein (MCV; n = 1)]. One-year primary patency rates for upper arm AVFs were 66 per cent, and secondary patency rates were 22 per cent. Flow rates averaged 354.6 mL/minute. Primary and secondary patency rates for fistulas created are: BA-CV (67% and 20%), BA-TBV (63% and 25%), and other upper arm AVFs 66 per cent without revisions. Primary patencies for both BA-CV and BA-TBV fistulas were similar to previously reported studies. Secondary patencies proved to be less effective. Upper arm AVFs should be considered before graft placement when wrist and forearm anatomy does not lend itself to fistula creation.

Solution structure of the N-terminal F1 module pair from human fibronectin.

Multiple sites within the N-terminal domain (1-5F1) of fibronectin have been implicated previously in fibronectin matrix assembly, heparin binding, and binding to cell surface proteins of pathogenic bacteria. The solution structure of 1F1(2)F1, the N-terminal F1 module pair from human fibronectin, has been determined using NMR spectroscopy. Both modules in the pair conform to the F1 consensus fold. In 4F1(5)F1, the only other F1 module pair structure available, there is a well-defined intermodule interface; in 1F1(2)F1, however, there is no detectable interface between the modules. Comparison of the backbone 15N-{1H} NOE values for both module pairs confirms that the longer intermodule sequence in 1F1(2)F1 is flexible and that the stabilization of the 4F1 C-D loop observed in 4F1(5)F1, as a result of the intermodule interface, is not observed in 1F1(2)F1.

Ceiling fan injuries: the Townsville experience.

From 1 April 1995 to 31 March 1997, 50 people presented to Townsville General Hospital with injuries caused by ceiling fans. Injuries ranged from grazes to compound skull fractures, and seven patients required admission to hospital for ongoing treatment. Most of these injuries could have been avoided. Current safety guidelines for the use of ceiling fans are inadequate.

Solution structure of a pair of modules from the gelatin-binding domain of fibronectin.

BACKGROUND: Fibronectin has a role in vital physiological processes such as cell migration during embryogenesis and wound healing. It mediates the attachment of cells to extracellular matrices that contain fibrous collagens. The affinity of fibronectin for native collagen and denatured collagen (gelatin) is located within a 42 kDa domain that contains four type 1 (F1) and two type 2 (F2) modules. A putative ligand-binding site has been located on an isolated F2 module, but the accessibility of this site in the intact domain is unknown. Thus, structural studies of module pairs and larger fragments are required for a better understanding of the interaction between fibronectin and collagen. RESULTS: The solution structure of the 101-residue 6F1 1F2 module pair, which has a weak affinity for gelatin, has been determined by multidimensional NMR spectroscopy. The tertiary structures determined for each module conform to the F1 and F2 consensus folds established previously. The experimental data suggest that the two modules interact via a small hydrophobic interface but may not be tightly associated. Near-random-coil 1H NMR chemical shifts and fast dynamics for backbone atoms in the linker indicate that this region is unlikely to be involved in the overall stabilisation of the module pair. CONCLUSIONS: The modules in the 6F1 1F2 module pair interact with each other via a flexible linker and a hydrophobic patch, which lies on the opposite side of the 1F2 module to the putative collagen-binding site. The intermodule interaction is relatively weak and transient.

Solution structure of the glycosylated second type 2 module of fibronectin.

Fibronectin is an extracellular matrix glycoprotein that plays a role in a number of physiological processes involving cell adhesion and migration. The modules of the fibronectin monomer are organized into proteolytically resistant domains that in isolation retain their affinity for various ligands. The tertiary structure of the glycosylated second type 2 module (2F2) from the gelatin-binding domain of fibronectin was determined by two-dimensional nuclear magnetic resonance spectroscopy and simulated annealing. The structure is well defined with an overall fold typical of F2 modules, showing two double-stranded antiparallel beta-sheets and a partially solvent-exposed hydrophobic cluster. An N-terminal beta-sheet, that was not present in previously determined F2 module structures, may be important for defining the relative orientation of adjacent F2 modules in fibronectin. This is the first three-dimensional structure of a glycosylated module of fibronectin, and provides insight into the possible role of the glycosylation in protein stability, protease resistance and modulation of collagen binding. Based on the structures of the isolated modules, models for the 1F22F2 pair were generated by randomly changing the orientation of the linker peptide between the modules. The models suggest that the two putative collagen binding sites in the pair form discrete binding sites, rather than combining to form a single binding site.

Solution structure of a type 2 module from fibronectin: implications for the structure and function of the gelatin-binding domain.

BACKGROUND: Fibronectin is an extracellular matrix glycoprotein involved in cell adhesion and migration events in a range of important physiological processes. Aberrant adhesion of cells to the matrix may contribute to the breakdown of normal tissue function associated with various diseases. The adhesive properties of fibronectin may be mediated by its interaction with collagen, the most abundant extracellular matrix protein. The collagen-binding activity of fibronectin has been localized to a 42 kDa proteolytic fragment on the basis of this fragment's affinity for denatured collagen (gelatin). This gelatin-binding domain contains the only type 2 (F2) modules found in the protein. The F2 modules of the matrix metalloproteinases MMP2 and MMP9 are responsible for the affinity of these proteins for gelatin. Knowledge of the structure of fibronectin will provide insights into its interactions with other proteins, and will contribute to our understanding of the structure and function of the extracellular matrix, in both normal and disease-altered tissues. RESULTS: We have determined the solution structure of the first F2 (1F2) module from human fibronectin by two-dimensional NMR spectroscopy. The tertiary structure of the 1F2 module is similar to that of a shorter F2 module, PDC-109b, from the bovine seminal plasma protein PDC-109. The 1F2 module has two double-stranded antiparallel beta sheets oriented approximately perpendicular to each other, and enclosing a cluster of highly conserved aromatic residues, five of which form a solvent-exposed hydrophobic surface. The N-terminal extension in 1F2 brings the N and C termini of the module into close proximity. CONCLUSIONS: The close proximity of the N and C termini in 1F2 allows for interactions between non-contiguous modules in the gelatin-binding domain. Thus, instead of forming an extended, linear chain of modules, the domain may have a more compact, globular structure. A pocket in the module's solvent-exposed hydrophobic surface may bind nonpolar residues in the putative fibronectin-binding site of the extracellular matrix component type I collagen.

Structure and function of fibronectin modules.

Fibronectin is an important component of the extracellular matrix and is involved in a diverse range of physiological processes. It is a mosaic protein composed almost entirely of three types of module, F1, F2 and F3. Although the structures of single F1, F2 and F3 modules have been available for a number of years, in many cases the key to understanding the structure-function relationships in fibronectin and other proteins containing these modules lies in studies of module pairs and larger domains. This review focuses on recent advances in the understanding of the structure and function of fibronectin modules.

Anion channel blockers inhibit swelling-activated anion, cation, and nonelectrolyte transport in HeLa cells.

The effect of osmotic cell swelling on the permeability of HeLa cells to a range of structurally unrelated solutes including taurine, sorbitol, thymidine, choline, and K+ (96Rb+) was investigated. For each solute tested, reduction in the osmolality of the medium from 300 to 200 mosmol/kgH2O caused a significant increase in the unidirectional influx rate. In each case, the osmotically activated transport component was nonsaturable up to external substrate concentrations of 50 mM. Inhibitors of the swelling-activated anion channel of HeLa cells [quinine, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, niflumate, 1,9-dideoxyforskolin, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and tamoxifen] blocked the osmotically activated influx of each of the different substrates tested, as well as the osmotically activated efflux of taurine and I-. Tamoxifen and NPPB were similarly effective at blocking the osmotically activated efflux of 96Rb+. The simplest of several hypotheses consistent with the data is that the osmotically activated transport of the different solutes tested here is via a swelling-activated anion-selective channel that has a significant cation permeability and a minimum pore diameter of 8-9 A.

Omental transposition in chronic spinal cord injury.

The results of omental transposition in chronic spinal cord injury have been reported in 160 patients operated upon in the United States, Great Britain, China, Japan, India and Mexico, with detailed outcomes reported in few studies. Recovery of function to a greater degree than expected by natural history has been reported. In this series, 15 patients with chronic traumatic spinal cord injury (> 1.5 years from injury) underwent transposition of pedicled omentum to the area of the spinal cord injury. Of the first series of four patients who were operated upon in 1988, one died, one was lost to follow-up and two were followed with sequential neurological examinations and Magnetic Resonance Imaging (MRI) scans preoperatively, at 1 year post injury and 4 1/2 years post injury. Another 11 patients were operated in 1992 and underwent detailed neurological and neurophysiological examinations and had MRI scans preoperatively and every 4 months for at least 1 year after surgery. All patients completed a detailed self-report form. Of the total of 13 operated patients in both series followed for 1-4 1/2 years, six reported some enhanced function at 1 year and five of these felt the changes justified surgery primarily because of improved truncal control and decreased spasticity. MRI scans showed enlargement of the spinal cord as compared to preoperative scans in seven patients. Increased T2 signal intensity of the spinal cord was found by 1 year after surgery in eight of 13 operated patients. Neurophysiological examinations of 11 patients in the second series agreed with self-reports of increases or decreases in spasticity (r = 0.65, P < 0.03). Somatosensory evoked potentials and motor evoked potentials at 4 month intervals up to 1 year in these patients showed no change after surgery. Neurological testing, using the American Spinal Injury Association (ASIA) and International Medical Society of Paraplegia (IMSOP) international scoring standards, failed to show any significant changes when the 1-year post operative examination was compared to the first preoperative examination except for decreased sensory function after surgery which approached statistical significance. When the 11 patients in the second series were compared to eight non-operated matched patients, followed for a similar length of time, no significant differences were found. Complications encountered in the operated patients from both series included one postoperative death from a pulmonary embolus, one postoperative pneumonia, three chronic subcutaneous cerebrospinal fluid (CSF) fistulae requiring wound revision, and one patient who developed biceps and wrist extensor weakness bilaterally requiring graft removal. We conclude that the omental graft remains viable over time and this operation can induce anatomical changes in the spinal cord as judged by MRI. Some patients reported subjective improvement but this was not supported by objective testing. We, therefore, find no justification for further clinical trials of this procedure in patients who have complete or sensory incomplete lesions. Further testing in motor incomplete patients would seem appropriate only with compelling supportive data.

High-resolution structural studies of the factor XIIIa crosslinking site and the first type 1 module of fibronectin.

The N-terminal domain of fibronectin undergoes factor XIIIa-catalysed crosslinking to fibrin, bacteria and collagen. The reactive glutamine residue is in an extended, random coil 'tail' of about 18 residues that would be accessible for crosslinking.