Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward.

BACKGROUND: Hepatitis C treatment is successful in 40-80% of patients in drug sponsored registration trials. However, few studies have examined treatment outcomes in non-trial, routine clinical practice settings. AIM: The aim of this study was to investigate the treatment outcomes and predictors of a sustained virological response in a routine clinical setting. METHODS: Data were collected retrospectively on patients treated for hepatitis C between January 2004 and March 2010 in a tertiary hospital setting. Demographics, treatment outcomes and potential predictors of outcome (viral genotype, viral load, virological response, platelet count, alanine transaminase level, glucose, ferritin, weight, fibrosis and cirrhosis, compliance, dose reductions, adverse events, psychiatric and alcohol history) were recorded. Univariate and multiple logistic regressions were performed. RESULTS: A total of 405 patients was treated during the study period. On an intention to treat basis, sustained virological response rates were 55%, 82% and 72% in genotypes 1, 2 and 3 respectively. Predictors of response were gender, age, genotype, weight, fibrosis, cirrhosis, platelet count and alanine transaminase on univariate analysis. Age, genotype, cirrhosis and platelet count were independently associated with sustained virological response on multiple logistic regression. CONCLUSION: In our cohort, treatment outcomes for genotype 1 and 2 were similar to results from clinical trials but results for genotype 3 were inferior. Clinicians should not assume that results from registration trials are transferable to their own clinical practice. This has particular relevance for the new era of triple therapy regimens containing direct antivirals.

Toxocara canis larval excretory/secretory proteins impair eosinophil-dependent resistance of mice to Nippostrongylus brasiliensis.

Survival of parasitic helminths within a host requires immune evasion and excretory/secretory (ES) proteins may contribute to this process. Eosinophils are important effector cells in immunity of mice to the nematode Nippostrongylus brasiliensis and eosinophilic interleukin-5 transgenic (IL-5 Tg) mice are highly resistant to the earliest stages of primary infections. In contrast, Toxocara canis is largely resistant to eosinophils, with viable larvae encysted in tissues often surrounded by these and other leucocytes. The aim of this study was to investigate whether T. canis ES (TES) proteins inhibit eosinophil-dependent resistance to N. brasiliensis. Mouse serum pre-treated with TES had reduced capacity to mediate the adherence of leucocytes to N. brasiliensis infective-stage larvae (L3) and this correlated with reduced complement C3 deposition on the parasite. TES did not inhibit eosinophil survival or eotaxin-dependent eosinophil migration in vitro. Cellular inflammation and eosinophil degranulation in the skin in response to injection of L3 was also not impaired by TES. However, when TES was included with L3 in an inoculum given to IL-5 Tg mice, a greatly increased number of parasites migrated to the lung. This suggests that the early eosinophil-dependent resistance in these mice was suppressed, by mechanisms yet to be determined.

Creatinine concentrations of accumulated intrauterine fluid to confirm the clinical diagnosis of urometra in mares.

Urine pooling, as a persistent condition, is a cause of infertility in mares due to endometrial inflammation and sperm toxicity. Identification of urometra can be challenging in mares presenting with the condition intermittently, or when urine flows into the uterus but is undetectable in the vagina. Currently, there are no reported objective methods to confirm the clinical diagnosis of urine contamination in intrauterine-fluid accumulations. Since creatinine is present in high concentrations in urine and does not diffuse across cell membranes, creatinine concentration should be increased in mares with urometra, but negligible in normal and mares with intrauterine fluid accumulation (non-urometra cases). To test this hypothesis, creatinine concentrations of intrauterine fluid were measured in mares with a clinical diagnosis of urine accumulation (n=9) or intrauterine fluid containing no urine (n=10). Results showed that creatinine concentrations (mg/dl) were significantly higher in mares that had a clinical diagnosis of urometra (42.8±12.6, range 4.1-109.2) compared with those that did not (0.38±0.1, range 0-0.9). Also, two mares after urethral extension surgery demonstrated a remarkable reduction in creatinine concentrations. This study highlights an undocumented approach to confirm a clinical diagnosis of urometra in mares; the authors anticipate that testing for creatinine in the uterine fluid of mares may become a standard tool for identifying urometra in mares and confirming the success of urogenital surgeries.

Factor H co-purifies with thrombospondin isolated from platelet secretate.

Thrombospondin is a trimeric glycoprotein that has several known functions, including roles in platelet aggregation, phagocytosis and an inhibitor of angiogenesis. Typically the molecule is isolated from platelet secretate by heparin affinity followed by sizing chromatography. In this study, purity is analysed by 7.5% SDS-PAGE under reducing conditions when thrombospondin monomers run as a band at around 180 kDa. Under nonreducing conditions of 7.5% SDS-PAGE, thrombospondin does not penetrate beyond the stacking gel; however, under these conditions a major contaminating band can be seen which, upon reduction, merges into the thrombospondin band. Further purification of this contaminating protein was achieved by DEAE chromatography and it was identified as Factor H by peptide sequencing and immunoblotting. Factor H function was demonstrated by the ability of the protein to function as a cofactor in the Factor-I-mediated cleavage of C3b. Since Factor H has several known functions, such contamination could confound functional studies of thrombospondin thus purified and a pre-elution step of the heparin affinity column is recommended.

Hypothalamic hypopituitarism after pituitary apoplexy in acromegaly.

Pituitary apoplexy in acromegaly is an uncommon event having been recorded approximately 30 times in the English literature. This report records two additional cases that included growth hormone measurements and an assessment of pituitary function. The apoplectic event developed spontaneously in one, and in the other it developed within two weeks of completing a course of radiotherapy to the pituitary gland. Autocure of the acromegaly was apparent. Basal levels of growth hormone were in the normal range but failed to change with provocative stimuli. Luteinizing hormone and follicle-stimulating hormone titers, although detectable, were inappropriately low for the degree of hypogonadism. Pituitary insufficiency was associated with a significant thyroid-stimulating hormone response to protirelin in one patient tested. It is suggested that these experiments of nature lend credence to the proposal that the hypothalamus may play a critical role in the perpetuation of growth hormone hypersecretion in some patients with acromegaly.

Fever in pheochromocytoma.

BACKGROUND: Fever is an infrequently reported finding in patients with pheochromocytoma. Fever in patients with pheochromocytoma may be caused by the tumor, an infection or other factors, each of which will dictate different treatment strategies. METHODS: To determine the incidence, cause, and significance of fever in patients with pheochromocytoma, we reviewed the medical records of 50 hospitalizations of 48 patients. Patients were categorized by the presence or absence of fever. Body temperature elevation, duration of hospitalization in the period prior to surgery or death, age, sex, race, other conditions that could have been responsible for the febrile episode (comorbid events), location, gross and microscopic features of the tumors, and plasma and urine hormone levels were tabulated. The results were compared between the two groups of patients. RESULTS: Fever was present in 14 (28%) of 50 hospitalizations, seven patients (50%) of whom had pheochromocytoma multisystem crisis. Patients with fever and pheochromocytoma were significantly more likely to have a comorbid event, larger tumor, necrosis within the tumor, higher urinary metanephrine levels, longer duration of hospitalization prior to surgery, and to be non-white. Comorbid events included both infectious and noninfectious potential causes of fever. CONCLUSIONS: Fever is common in patients with pheochromocytoma. The causes may be multifactorial and often include an associated illness. A thorough search for coexisting disease is indicated. While fever may prolong hospitalization, it does not portend a disastrous outcome.

Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes.

Complement factor H (fH) is a member of a family of proteins involved in the regulation of complement activation (RCA). These proteins share a common structural motif, the Short Consensus Repeat (SCR), which is structurally conserved among related genes and between phylogenetically divergent species. fH is composed of 20 such SCRs and a variety of biological functions have been localised to specific SCR domains. The majority of individual SCRs identified are encoded by single exons, and processes such as gene conversion, duplication and exon shuffling have been implicated in the evolution and genomic radiation of SCR-encoding genes. We have analysed two GenBank sequence entries relating to two overlapping PAC clones sequenced at the Sanger Centre which contain the entire human fH gene and two adjacent fH-related (fHR) genes, fHR-1 and fHR-3. Here, we report the detailed analysis of the assembled 221 kb of contiguous, ungapped genomic sequence from human chromosome 1q32, in part employing the RUMMAGE-DP automated annotation tool. Genomic duplications involving fH and fHR exons were identified and Alu/L1 repeat dating established that the duplications occurred after the separation of rodent and primate lineages. The analysis indicates that retrotransposition as well as single and multiple exon duplication events are likely to have been involved in SCR radiation and RCA gene evolution, facilitated by conservation of splice-phasing and the single-exon, single-SCR nature of the encoded domains.

Surgical site infection-a population-based study in Australian adults measuring the compliance with and correct timing of appropriate antibiotic prophylaxis.

Prophylaxis for surgical site infection (SSI) is often at variance with guidelines, despite the prevalence of SSI and its associated cost, morbidity, and mortality. The CareTrack Australia study, undertaken by a number of the authors, demonstrated that appropriate care (in line with evidence- or consensus-based guidelines) was provided at 38% of eligible SSI healthcare encounters. Here, we report the indicator-level CareTrack Australia findings for SSI prophylaxis. Indicators were extracted from Australian and international clinical guidelines and ratified by clinical experts. A sample designed to be representative of the Australian population was recruited (n=1154). Participants' medical records were reviewed and analysed for compliance with the five SSI indicators. The main outcome measure was the percentage of eligible healthcare encounters with documented compliance with indicators for appropriate SSI prophylaxis. Of the 35,145 CareTrack Australia encounters, 702 (2%) were eligible for scoring against the SSI indicators. Where antibiotics were recommended, compliance was 49% for contaminated surgery, 57% for clean-contaminated surgery and 85% for surgery involving a prosthesis: these fell to 8%, 10% and 14%, respectively (an average of 11%), when currently recommended timing of antibiotic administration was included. Where antibiotics were not indicated, 72% of patients still received them. SSI prophylaxis in our sample was poor; over two-thirds of patients were given antibiotics, whether indicated or not, mainly at the wrong time. There is a need for national agreement on clinical standards, indicators and tools to guide, document and monitor SSI prophylaxis, with both local and national measures to increase and monitor their uptake.

One-year outcome following biological or mechanical valve replacement for infective endocarditis.

BACKGROUND: Nearly half of patients require cardiac surgery during the acute phase of infective endocarditis (IE). We describe the characteristics of patients according to the type of valve replacement (mechanical or biological), and examine whether the type of prosthesis was associated with in-hospital and 1-year mortality. METHODS AND RESULTS: Among 5591 patients included in the International Collaboration on Endocarditis Prospective Cohort Study, 1467 patients with definite IE were operated on during the active phase and had a biological (37%) or mechanical (63%) valve replacement. Patients who received bioprostheses were older (62 vs 54years), more often had a history of cancer (9% vs 6%), and had moderate or severe renal disease (9% vs 4%); proportion of health care-associated IE was higher (26% vs 17%); intracardiac abscesses were more frequent (30% vs 23%). In-hospital and 1-year death rates were higher in the bioprosthesis group, 20.5% vs 14.0% (p=0.0009) and 25.3% vs 16.6% (p<.0001), respectively. In multivariable analysis, mechanical prostheses were less commonly implanted in older patients (odds ratio: 0.64 for every 10years), and in patients with a history of cancer (0.72), but were more commonly implanted in mitral position (1.60). Bioprosthesis was independently associated with 1-year mortality (hazard ratio: 1.298). CONCLUSIONS: Patients with IE who receive a biological valve replacement have significant differences in clinical characteristics compared to patients who receive a mechanical prosthesis. Biological valve replacement is independently associated with a higher in-hospital and 1-year mortality, a result which is possibly related to patient characteristics rather than valve dysfunction.

Changes in thyroid nodule volume caused by fine-needle aspiration: a factor complicating the interpretation of the effect of thyrotropin suppression on nodule size.

The effectiveness of TSH suppression therapy for thyroid nodules remains controversial. Prior studies have assumed that the fine-needle aspiration biopsy (FNAB), used to confirm a benign condition before the establishment of control and treatment groups, has no effect on nodule volume. Seventeen untreated euthyroid patients with clinical solitary thyroid nodules that were solid (on high-resolution ultrasound) and a colloid goiter (on cytologic examination) had ultrasound measurements of nodule volume before a FNAB, immediately thereafter, and 1 month and 6 months later. Size differences and individual variability at each time period were analyzed. No significant difference in mean thyroid nodule volume was present at any point after the FNAB; however, the changes in nodule volume were quite marked and bidirectional among patients masking the cumulative effect. The variability of the change in individual nodule volume was statistically significant when comparisons were made across time (P = 0.0032). FNAB of thyroid nodules results in significant individual changes in volume after the procedure. Studies, such as the effect of TSH suppression on thyroid nodule volume, that incorporate the FNAB in both control and treatment arms of the experimental design, need to take these changes into account, less erroneous conclusions result.

Circadian variation in onset of acute ischemic stroke.

A circadian pattern for the onset of myocardial and cerebral infarction has been identified. To evaluate this phenomenon further, we analyzed prospectively collected data from 151 patients with acute ischemic stroke. The number of strokes per 6-hour period were the following: midnight to 6 AM, 20 (13%); 6 AM to noon, 86 (57%); noon to 6 PM, 21 (14%); and 6 PM to midnight, 24 (16%). This pattern was not affected by previous use of aspirin. The most frequent time of onset was 6 AM to noon for all subgroups of ischemic stroke: small artery, 71%; cardioembolic, 62%; large artery atherothrombotic, 57%; large artery atheroembolic, 46%; and "other" or unknown cause, 40%. We also investigated the time between awakening and stroke onset in 145 patients and found that 24% of ischemic strokes occurred within the first hour after awakening. Our data demonstrate that an early morning peak exists for all subtypes of stroke. Our data also suggest that the most critical period is the first hour after awakening.

Ischemic stroke in young adults. Experience in 329 patients enrolled in the Iowa Registry of stroke in young adults.

OBJECTIVES: To describe the likely causes of ischemic stroke in a population of young adults and to report the influence of strict algorithms on the diagnosis of the likely cause of stroke in this cohort. DESIGN: Between July 1, 1977, and January 1, 1993, we registered 329 young adults with ischemic stroke in our registry. Diagnostic studies were selected on a case-by-case basis. Presumed causes of stroke were determined using clinical information and the results of diagnostic tests. In each case, a second causative diagnosis was made using the criteria developed for a large clinical trial. SETTING: Patients referred to the Division of Cerebrovascular Diseases in the Department of Neurology at the University of Iowa Hospitals and Clinics, Iowa City, by physicians in Iowa and adjacent states. PATIENTS: Three hundred twenty-nine young adults (182 men and 147 women) aged 15 to 45 years with ischemic stroke; 102 persons, 48 men and 54 women, were aged 30 years or younger. RESULTS: Cerebral arteriography was performed in 227 cases, and the findings were abnormal in 146. Transthoracic echocardiography revealed abnormalities in 82 of 221 patients examined. We identified approximately 60 different disorders that were presumed to be the cause of stroke. There were no major changes in the frequency of subtype diagnoses between the first 144 patients and the subsequent 185. Use of strict diagnostic criteria increased the number of cases of stroke of undetermined etiology (from 45 to 113), and the number attributed to large artery atherosclerosis declined from 71 to 32. CONCLUSIONS: The causes of ischemic stroke in young adults are numerous. Because treatment options in this group are influenced by a presumed cause, an evaluation on a case-by-case basis is warranted. Our experience suggests that a likely cause will be detected in most cases and that a regimented battery of tests may not be required. If strict diagnostic criteria are used, the diagnosis of stroke of undetermined etiology considerably increases. While such strict criteria are important in clinical trials that test new interventions, the value of the application of such methodologies to an unusual population, such as stroke in young adults, needs clarification. In particular, the usefulness of categorizing a stroke as undetermined when two or more possible causes are identified needs to be explored.

Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators.

To test interphysician agreement on the diagnosis of subtype of ischemic stroke, we sent subtype definitions and 18 case summaries (clinical features and pertinent laboratory data) to 24 neurologists who have a special interest in stroke, and asked them to determine the most likely subtype diagnosis. The overall agreement was 0.64 (Kappa [K] = 0.54). Interphysician agreement was highest for the diagnoses of stroke secondary to cardioembolism (K = 0.75) or to large-artery atherosclerosis (K = 0.69). Individual physicians varied widely; four agreed with the consensus diagnosis in all 18 cases, while six others disagreed with the consensus diagnosis in three to five cases. Our level of interphysician agreement is greater than that reported in other studies and was substantial. However, despite using subtype definitions and being given extensive information often not available in the acute setting, physicians still disagree about the etiology of stroke, particularly in regard to stroke due to small-artery occlusion or of undetermined etiology. Physicians seem reluctant not to attribute stroke to a specific etiology. The uncertainty about subtype diagnosis will affect interpretation of the results of clinical trials in patients selected by the subtype of ischemic stroke and also suggests that results of treatment as affected by subtype should be cautiously interpreted unless efforts to assure uniformity are included in the trial's operations. Refinement of algorithms for determining subtype of ischemic stroke do improve interphysician agreement. Such criteria should be applied strictly, and trials should include measures to assure the most uniform diagnosis of stroke subtype possible.

Artifactual elevation of thyroid-stimulating hormone.

A clinically euthyroid patient was found to have a normal serum thyroxine level and an elevated plasma thyrotropin (TSH) level measured by fluoroimmunoassay. Thyroid hormone therapy failed to suppress the TSH level. The TSH level was unresponsive to thyrotropin-releasing hormone (TRH) administration, alpha-subunits of pituitary glycoproteins were undetectable in her plasma, and imaging of the pituitary-hypothalamic region was normal. Measurement of TSH with an assay containing sheep antibody to TSH failed to reveal TSH in the patient's plasma. Addition of mouse IgG to the TSH fluoroimmunoassay reduced the patient's TSH to an undetectable level. These observations are consistent with a spurious elevation of TSH due to the presence of an anti-mouse antibody. Artifactual elevations of TSH have not been identified commonly, but this possibility should be considered when the TSH level is inappropriate for the apparent state of thyroid function.

Human astrocytes express membrane cofactor protein (CD46), a regulator of complement activation.

Expression of membrane cofactor protein (CD46) on cultured human astrocytes was demonstrated by indirect immunofluorescence microscopy and flow cytometry following staining with a monoclonal antibody specific for CD46. Western transfer and immunoblotting detected a doublet of Mr 66,000 and 56,000. Analysis of astrocyte mRNA revealed the presence of multiple alternatively spliced transcripts encoding different extracellular regions or cytoplasmic tails of CD46. Astrocytes were also shown to express decay accelerating factor, but not the type 1 complement receptor. Upregulation of astrocyte CD46 occurred following cytomegalovirus infection. These results indicate that astrocytes express proteins involved in regulation of complement activation and protection against autologous complement.

Expression of CD59, a regulator of the membrane attack complex of complement, on human astrocytes.

The present study demonstrates that human astrocytes synthesize and express CD59, a regulator of the membrane attack complex of complement. This was shown by flow cytometry following staining of astrocytes with MAb to CD59, and Western blotting of astrocyte lysates, which revealed the characteristic 18-23,000 M(r) band of CD59. Synthesis of CD59 by astrocytes was confirmed by detection of CD59 specific mRNA by polymerase chain reaction. A low level of C3 deposition occurred on astrocytes following exposure to autologous serum. CD59 may prevent subsequent damage from C5b-9 and protect astrocytes during inflammatory and infectious disorders of the nervous system.

Simultaneous primary hyperparathyroidism and nodular thyroid disease.

Of 351 patients treated for primary hyperparathyroidism from 1966 to 1981, 70 (20%) had grossly evident nodular thyroid disease at the time of subtotal parathyroidectomy. These patients have been reviewed to determine if prior radiation exposure may play a role in their coexistence and if combined subtotal parathyroidectomy and thyroidectomy are safe and efficacious. Thirty-three of the 70 patients (47%) had received prior radiation therapy for benign conditions of the head and neck. Nine of 15 patients with nonmedullary thyroid carcinoma had received previous irradiation. In addition to subtotal parathyroidectomy, 28 patients underwent total thyroidectomy, 14 underwent bilateral subtotal thyroidectomy, and 28 underwent unilateral lobectomy. There were no deaths and no permanent recurrent laryngeal nerve injury from combined subtotal parathyroidectomy and thyroidectomy. Two patients in whom parathyroid tissue was not autotransplanted required calcium and vitamin D supplementation. This study shows that (1) primary hyperparathyroidism and nodular thyroid disease occur simultaneously with sufficient frequency to warrant careful preoperative and intraoperative evaluation of both glands, (2) radiation probably does play a role in the pathogenesis of coexistent primary hyperparathyroidism and nodular thyroid disease, and (3) in experienced hands combined subtotal parathyroidectomy and thyroidectomy can be safely performed.