Incidental Coronary Artery Calcification Seen on Low-Dose Computed Tomography Is a Risk Factor for Obstructive Coronary Artery Disease in Patients Undergoing Liver Transplant.

Incidental arterial calcification (Ca) on low-dose computed tomography (CT) prior to liver transplant (LT) may help identify those at risk for obstructive coronary artery disease (CAD). A single-center retrospective study of 358 consecutive patients who had undergone LT was performed. Of the 296 patients who met inclusion criteria, 193 patients (65.2%) had CT Ca. Aortic Ca was seen in 116 (39.2%), coronary Ca in 141 (47.6%), and peripheral Ca in 8 patients (2.7%). Patients with coronary Ca were assigned ordinal coronary artery Ca scores and classified as mild, moderate, and severe. All-cause mortality was higher in patients with Ca in any location (14.5% vs 6.8%, P = .05). Of the patients who underwent coronary angiography, those with obstructive CAD were more likely to have aortic and coronary Ca than patients with nonobstructive or no CAD (85.7% vs 50.0%, P = .02 and 92.9% vs 37.9%, P = < .001, respectively). Severe coronary artery Ca scores were more frequent in patients with obstructive CAD (35.7% vs 0%, P < .001). Any severity coronary Ca had an odds ratio of 11.57 (95% CI, 1.61-244.92; P = .04) for obstructive CAD. In conclusion, incidental coronary Ca seen on low-dose CT is a risk factor for obstructive CAD in patients undergoing LT.

Risk of all-type cancer, hepatocellular carcinoma, non-Hodgkin lymphoma and pancreatic cancer in patients infected with hepatitis B virus.

The increased risk of hepatocellular carcinoma (HCC) among patients infected with hepatitis B virus (HBV) is well established; however, long-term risk estimates are needed. Recently, it has been suggested that HBV is associated with non-Hodgkin lymphoma (NHL) and pancreatic cancer (PC). The aim of this Danish nationwide cohort study was to evaluate the association between HBV infection and all-type cancer, HCC, NHL and PC. A cohort of patients infected with HBV (n = 4345) and an age- and sex-matched population-based comparison cohort of individuals (n = 26,070) without a positive test for HBV were linked to The Danish Cancer Registry to compare the risk of all-type cancer, HCC, NHL and PC among the two groups. The median observation period was 8.0 years. Overall, the incidence rate ratio (IRR) for all-type cancer among HBV-infected patients was 1.1 (95% confidence intervals (CI) 0.9-1.3). The IRR of HCC was 17.4 (CI 5.5-54.5), whereas the IRR of PC and NHL was 0.9 (CI 0.3-2.5) and 1.2 (CI 0.4-3.6), respectively. HBV-infected patients had a 10-year risk of 0.24% (Cl 0.12-0.44) for HCC, whereas the comparison cohort had a 10-year risk of 0.03% (Cl 0.02-0.07) for HCC. The risk of all-type cancer, NHL and PC was not higher in the HBV-infected cohort compared to non-HBV infected. We found a 17-fold higher risk of HCC for HBV-infected individuals.

Macrophage-related serum biomarkers soluble CD163 (sCD163) and soluble mannose receptor (sMR) to differentiate mild liver fibrosis from cirrhosis in patients with chronic hepatitis C: a pilot study.

Macrophages regulate the fibrotic process in chronic liver disease. The aim of the present pilot study was to evaluate two new macrophage-specific serum biomarkers [soluble CD163 (sCD163) and soluble mannose receptor (sMR, sCD206)] as potential fibrosis markers in patients chronically infected with hepatitis C virus (HCV). Forty patients with chronic hepatitis C were included from two hospital clinics. On the day of inclusion, transient elastography (TE) was performed to assess the fibrosis stage, and blood samples were collected for the measurement of sCD163 and sMR. The plasma concentrations of both biomarkers were significantly higher in patients infected with HCV and with cirrhosis compared to those with no/mild liver fibrosis (5.77 mg/l vs. 2.49 mg/l and 0.44 mg/l vs. 0.30 mg/l for sCD163 and sMR, respectively). The best separation between groups was obtained by sCD163 [area under the receiver operating characteristic curve (AUC) 0.89 (95 % confidence interval [CI] 0.79-0.99)] as compared to sMR [AUC 0.75 (95 % CI 0.61-0.90)]. sCD163 and sMR correlated significantly (r (2) = 0.53, p < 0.0001). Interestingly, sCD163 also correlated significantly with TNF-α (presented in a previous publication), which is shed to serum by the same mechanism as sCD163 (r (2) = 0.40, p < 0.0001). In conclusion, the macrophage-related markers sCD163 and sMR are significantly higher in patients chronically infected with HCV and with cirrhosis than in those with no/mild fibrosis. sCD163 is a promising new fibrosis marker in patients infected with HCV.

Bladder dose accumulation based on a biomechanical deformable image registration algorithm in volumetric modulated arc therapy for prostate cancer.

Variations in bladder position, shape and volume cause uncertainties in the doses delivered to this organ during a course of radiotherapy for pelvic tumors. The purpose of this study was to evaluate the potential of dose accumulation based on repeat imaging and deformable image registration (DIR) to improve the accuracy of bladder dose assessment. For each of nine prostate cancer patients, the initial treatment plan was re-calculated on eight to nine repeat computed tomography (CT) scans. The planned bladder dose-volume histogram (DVH) parameters were compared to corresponding parameters derived from DIR-based accumulations as well as DVH summation based on dose re-calculations. It was found that the deviations between the DIR-based accumulations and the planned treatment were substantial and ranged (-0.5-2.3) Gy and (-9.4-13.5) Gy for D(2%) and D(mean), respectively, whereas the deviations between DIR-based accumulations and DVH summation were small and well within 1 Gy. For the investigated treatment scenario, DIR-based bladder dose accumulation did not result in substantial improvement of dose estimation as compared to the straightforward DVH summation. Large variations were found in individual patients between the doses from the initial treatment plan and the accumulated bladder doses. Hence, the use of repeat imaging has a potential for improved accuracy in treatment dose reporting.

Previously unrecognized advanced liver disease unveiled by transient elastography in patients with Haemophilia and chronic hepatitis C.

Before the introduction of viral inactivation procedures and viral screening of plasma-products, haemophiliacs were at high risk of infection with HCV. Those who acquired HCV infection in the 1980s, and are still alive today, may have developed significant liver fibrosis or cirrhosis. However, liver biopsy has not routinely been utilized in the evaluation of haemophiliacs with HCV in Denmark. The aim of this study was to investigate the prevalence of significant fibrosis/cirrhosis among haemophiliacs as evaluated by transient elastography (TE). Cross-sectional investigation of adult patients with haemophilia A or B. TE with liver stiffness measurements (LSM) ≥ 8 kPa were repeated after 4-6 weeks. Significant fibrosis and cirrhosis was defined as measurements ≥ 8 kPa or ≥ 12 kPa respectively. Among 307 patients with haemophilia A or B registered at the two Haemophilia centres, 141(46%) participate in this study. Forty (28.4%) had chronic hepatitis C, 33 (23.4%) past hepatitis C and 68 (48.2%) had never been infected, at screening LSM ≥ 8 kPa were found in 45.7%, 24.7% and 4.6% respectively. Among patients with chronic hepatitis C significant fibrosis was confirmed in 17.1% and cirrhosis in 2.9% by repeated LSM ≥ 8 and ≥ 12 kPa respectively. The median TE-value in never HCV-infected haemophiliacs was comparable with what has been found in healthy non-haemophiliacs. In Danish haemophiliacs where liver biopsy has not routinely been used for assessing severity of liver fibrosis, LSM identified advanced liver disease in one-fifth of cases that had not been recognized during clinical follow-up.

Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1.

Information about the stage of liver fibrosis is important for managing patients with chronic hepatitis C (CHC). The aim of this study was to evaluate 12 plasma markers for differentiating no/mild liver fibrosis from cirrhosis among patients with CHC genotype 1. Transient elastography was used to assess the stage of fibrosis for the patients included in the study. Forty patients were included (21 cirrhotic). Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 8 (IL-8), interferon-γ inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), soluble urokinase-type plasminogen activator (suPAR), monokine induced by γ-interferon (MIG), human hepatocyte growth factor (HGF), insulin, interleukin 6 (IL-6), interleukin 1-ß (IL-1ß), leptin, and nerve growth factor (NGF) were analyzed. Concentrations of TNF-α (median 15.0 vs. 25.1 pg/ml, area under the receiver operating characteristic curve [AUC] 0.91), IL-8 (48.7 vs. 103.3 pg/ml, AUC 0.85), IP-10 (176 vs. 566 pg/ml, AUC 0.83), MCP-1 (449 vs. 735 pg/ml, AUC 0.78), suPAR (3.5 vs. 5.2 ng/ml, AUC 0.78), MIG (100 vs. 152 pg/ml, AUC 0.75), and HGF (3.69 vs. 5.58 ng/ml, AUC 0.71) were significantly higher in patients with cirrhosis. In conclusion, several of the investigated markers showed promise for differentiating cirrhosis from no/mild fibrosis among patients with CHC genotype 1.

Improved survival of patients with ovarian cancer in Northern Denmark, 1985-2004.

OBJECTIVE: Ovarian cancer is a serious disease with a high mortality. Our aim was to examine changes in the survival of patients with ovarian cancer in Northern Denmark. STUDY DESIGN AND SETTING: Patients (no. = 3,719) with an incident discharge diagnosis of ovarian cancer (1985-2004) from any hospital in four Danish counties (population, 1.6 million) were included and tracked for mortality through the Danish Civil Registration System. We determined survival and mortality rates stratified by age, and used Cox proportional hazard regression analyses to assess changes over time. RESULTS: Overall survival rate improved between 1985 and 2004. One-year survival increased from 61% to 73%, and five-year survival from 30% to 38%. Compared with the period 1985-1989 the age-adjusted one-year mortality rate ratio (MRR) was 0.65 (2000-2004) and the age-adjusted five-year MRR was 0.80 (1995-1999). The improvement was most pronounced in patients older than 40 years. CONCLUSION: The survival of ovarian cancer patients has improved in Denmark in recent decades. This change may be the result of improved treatment.

Accuracy of ovarian cancer ICD-10 diagnosis in a Danish population-based hospital discharge registry.

OBJECTIVE: We estimated the accuracy of ICD-10 diagnosis of ovarian cancer in a Danish discharge registry (HDR) by comparing it with Cancer Registry data (DCR). STUDY DESIGN AND SETTING: Patients (N=489) living in North Jutland County, Denmark with ovarian cancer or borderline tumour registered in the HDR or the DCR. We estimated the completeness and positive predictive value (PPV) of ovarian cancer discharge diagnosis. Mortality rates were constructed for both registries. RESULTS: The completeness in the HDR for ovarian cancer was 96% (95% confidence interval [CI]: 94%-98%) and PPV was 87% (95% CI: 85%-90%). 87 (18%) of the patients coded with ovarian cancer in the HDR had borderline tumours. When borderline tumours were excluded from the DCR, the PPV declined to 69% and the completeness did not change. The mortality rate ratio for ovarian cancer registered in the HDR compared to the DCR was 1.08 (95% CI: 0.90-1.29). CONCLUSION: The discharge data (ICD-10) had some misclassification, but can be a valuable tool in assessment of the prognosis of ovarian cancer.

Evolutionary rate variation and RNA secondary structure prediction.

Predicting RNA secondary structure using evolutionary history can be carried out by using an alignment of related RNA sequences with conserved structure. Accurately determining evolutionary substitution rates for base pairs and single stranded nucleotides is a concern for methods based on this type of approach. Determining these rates can be hard to do reliably without a large and accurate initial alignment, which ideally also has structural annotation. Hence, one must often apply rates extracted from other RNA families with trusted alignments and structures. Here, we investigate this problem by applying rates derived from tRNA and rRNA to the prediction of the much more rapidly evolving 5'-region of HIV-1. We find that the HIV-1 prediction is in agreement with experimental data, even though the relative evolutionary rate between A and G is significantly increased, both in stem and loop regions. In addition we obtained an alignment of the 5' HIV-1 region that is more consistent with the structure than that currently in the database. We added randomized noise to the original values of the rates to investigate the stability of predictions to rate matrix deviations. We find that changes within a fairly large range still produce reliable predictions and conclude that using rates from a limited set of RNA sequences is valid over a broader range of sequences.

Speech errors in Alzheimer's disease: reevaluating morphosyntactic preservation.

Researchers studying the speech of individuals with probable Alzheimer's disease (PAD) report that morphosyntax is preserved relative to lexical aspects of speech. The current study questions whether dividing all errors into only two categories, morphosyntactic and lexical, is warranted, given the theoretical controversies concerning the production and representation of pronouns and closed-class words in particular. Two experiments compare the speech output of 10 individuals with Alzheimer's disease to that of 15 healthy age- and education-matched speakers. Results of the first experiment indicate that the pattern of errors in the speech of participants with mild PAD reflects an across-the-board increase in the same types of errors made by healthy older speakers, including closed-class and morphosyntactic errors. In the second task, participants produced a grammatical sentence from written stimuli consisting of a transitive verb and two nouns. Only adults with Alzheimer's disease had difficulties with this task, producing many more closed-class word errors than did healthy older adults. Three of the participants with PAD produced nearly agrammatic speech in this task. These 3 people did not differ from the rest of the PAD group in age, education, working memory, or degree of semantic impairment. Further, error rates on the two tasks were highly correlated. We conclude that morphosyntax is not preserved in the speech output of individuals with PAD, but is vulnerable to errors along with all aspects of language that must be generated by the speaker. We suggest that these results best support a model of speech production in which all words are represented by semantic and grammatical features, both of which are vulnerable to failures of activation when there is damage or noise in the system as a result of pathology, trauma, or even divided attention.

Assessing working memory and language comprehension in Alzheimer's disease.

Studies of language impairments in patients with Alzheimer's disease have often assumed that impairments in linguistic working memory underlie comprehension deficits. Assessment of this hypothesis has been hindered both by vagueness of key terms such as "working memory" and by limitations of available working memory tasks, in that many such tasks either seem to have little relationship to language comprehension or are too confusing or difficult for Alzheimer's patients. Four experiments investigated the usefulness of digit ordering, a new task assessing linguistic working memory and/or language processing skill, in normal adults and patients with probable Alzheimer's disease. The digit ordering task was shown to be strongly correlated with the degree of dementia in Alzheimer's patients. The task correlated with measures of language processing on which patients and normal controls performed differently. The results are interpreted as indicating that linguistic representations, linguistic processing, and linguistic working memory are intertwined, such that a deficit of one (e.g., working memory) cannot be said to "cause" a deficit in the other. The implications of this approach are explored in terms of task demands in comprehension and memory measures, and interpretation of previous results in the literature.

Why do Alzheimer patients have difficulty with pronouns? Working memory, semantics, and reference in comprehension and production in Alzheimer's disease.

Three experiments investigated the extent to which semantic and working-memory deficits contribute to Alzheimer patients' impairments in producing and comprehending referring expressions. In Experiment 1, the spontaneous speech of 11 patients with Alzheimer's disease (AD) contained a greater ratio of pronouns to full noun phrases than did the spontaneous speech produced by 9 healthy controls. Experiments 2 and 3 used a cross-modal naming methodology to compare reference comprehension in another group of 10 patients and 10 age-matched controls. In Experiment 2, patients were less sensitive than healthy controls to the grammatical information necessary for processing pronouns. In Experiment 3, patients were better able to remember referent information in short paragraphs when reference was maintained with full noun phrases rather than pronouns, but healthy controls showed the reverse pattern. Performance in all three experiments was linked to working memory performance but not to word finding difficulty. We discuss these findings in terms of a theory of reference processing, the Informational Load Hypothesis, which views referential impairments in AD as the consequence of normal discourse processing in the context of a working memory impairment.

Sentence comprehension deficits in Alzheimer's disease: a comparison of off-line vs. on-line sentence processing.

Two studies explored whether sentence comprehension impairments in Alzheimer's disease (AD) are due to deficits in syntactic processing or memory. Study 1 used a picture-pointing sentence comprehension task to measure the final outcome of comprehension in an off-line fashion. It showed the comprehension of 30 patients with AD to be impaired, but suggested that the deficits could not be attributed solely to syntactic impairments. Study 2 investigated the effects of memory on sentence comprehension by comparing off-line (grammaticality judgment) with on-line (cross-modal naming) language processing in 11 AD and 9 control subjects. The results revealed impaired performance in the off-line task but normal performance in the on-line task using the same sentences. Performance on the off-line task correlated with independent measures of verbal working memory. These data are used to argue that sentence comprehension impairments are related to verbal working memory deficits in AD.

Combination laser conization as treatment of microinvasive carcinoma of the uterine cervix.

During the period June 1985 to August 1992 combination laser conization was considered definite therapy in 41 patients with microinvasive carcinoma of the cervix. Selection criteria for conservative, fertility-saving therapy were: invasion 3 mm or less, no lymphovascular involvement and horizontal spread of 7 mm or less. After treatment patients were followed for 5 to 12 years, mean follow-up 81 months, and mean number of examination was 10. In one cases, adenocarcinoma in situ was diagnosed during follow-up. In all other cases persistent or recurrent disease was not diagnosed during follow-up. By thorough histopathologic evaluation and strict criteria for selection of patients, it was possible to perform conservative treatment with no observed risk of undertreatment. Combination laser conization was a useful treatment modality. A follow-up regimen based on colposcopy and cytology proved sufficient.

Category-specific semantic deficits in focal and widespread brain damage: a computational account.

Category-specific semantic impairments have been explained in terms of preferential damage to different types of features (e.g., perceptual vs. functional). This account is compatible with cases in which the impairments were the result of relatively focal lesions, as in herpes encephalitis. Recently, however, there have been reports of category-specific impairments associated with Alzheimer's disease, in which there is more widespread, patchy damage. We present experiments with a connectionist model that show how "category-specific" impairments can arise in cases of both localized and widespread damage; in this model, types of features are topographically organized, but specific categories are not. These effects mainly depend on differences between categories in the distribution of correlated features. The model's predictions about degree of impairment on natural kinds and artifacts over the course of semantic deterioration are shown to be consistent with existing patient data. The model shows how the probabilistic nature of damage in Alzheimer's disease interacts with the structure of semantic memory to yield different patterns of impairment between patients and categories over time.

Double dissociation of semantic categories in Alzheimer's disease.

Data that demonstrate distinct patterns of semantic impairment in Alzheimer's disease (AD) are presented. Findings suggest that while groups of mild-moderate patients may not display category specific impairments, some individual patients do show selective impairment of either natural kinds or artifacts. We present a model of semantic organization in which category specific impairments arise from damage to distributed features underlying different types of categories. We incorporate the crucial notions of intercorrelations and distinguishing features, allowing us to demonstrate (1) how category specific impairments can result from widespread damage and (2) how selective deficits in AD reflect different points in the progression of impairment. The different patterns of impairment arise from an interaction between the nature of the semantic categories and the progression of damage.

The reliability of preconization diagnostic evaluation in patients with cervical intraepithelial neoplasia and microinvasive carcinoma.

The accuracy of preconization cytology and histology was evaluated in 536 patients undergoing combination laser conization. Exact agreement between cytology and cone diagnosis was observed in 41.8% of the patients. The lowest agreement, 13.6% was demonstrated in cytologic cervical intraepithelial neoplasia (CIN) I, the highest in cytologic CIN III, 64.3%. Concerning microinvasive disease, the positive predictive value of cytology was only 27.3%; the negative predictive value 94.6%. When cytology showed CIN II or worse, the cone biopsy showed CIN or invasive disease in 92.8%. Exact agreement between preconization histology and the cone biopsy was found in 59.5%. Highest agreement was observed in CIN III lesions, 67.1%, and the lowest agreement in CIN II lesions, 42.7%. When preconization showed CIN II, a higher grade of lesion was found in the cone biopsy in 29.1%. Cone biopsy revealed invasive disease in 38 cases. In 24 cases, invasive disease was not demonstrated prior to conization, corresponding totally to 4.7% of patients not suspected to have invasive disease prior to conization. Regarding invasive disease, the sensitivity of preconization histology was 36.8%, the positive predictive value 58.3%, and the negative predictive value 95.3%. Kappa statistics demonstrated rather low agreement between cone diagnoses and preconization diagnoses. These results confirm the potential risk of overlooking invasive disease by conventional preconization evaluation and demonstrate the need for excisional methods in the management of cervical intraepithelial neoplasia to provide a sufficient specimen for diagnostic purposes. Combined with the therapeutic results, combination laser conization was a reliable diagnostic and therapeutic method in the management of patients with CIN and microinvasive cancer of the cervix.

Laser conization: the results of treatment of cervical intraepithelial neoplasia.

Combination laser conization was performed for the treatment of cervical intraepithelial neoplasia (CIN) in 473 patients, who were followed for a mean period of 70 months. In 16 cases (3.4%) CIN was demonstrated during follow up, and in 10 cases (2.1%) within the first year after treatment. The grade of CIN in the cone specimen was of no predictive value to recurrence. When excisional margins were involved recurrence was observed in 8.7% of cases, compared to 2.3% when margins were uninvolved. The risk of recurrence was significantly higher in patients with involvement of the endocervical cone margin. The only case of invasive disease during follow-up was observed more than 2 years after conization; cone biopsy was without involved margins. The results clearly demonstrate the method to be effective and justify an expectant management of all patients after conization by this method.

[Cryotherapy of cervical intraepithelial neoplasia. Long-term prognosis]. / Kryobehandling af cervikal intraepitelial neoplasi. Langtidsprognosen.

Cryotherapy for the treatment of cervical intraepithelial neoplasia (CIN) was performed in 261 patients and the patients were followed for five to 10 years. Cure rate fed significantly with inoeasing grade of CIN and with endocervical involvement. In pure exocervical lesions, 91% and 77.8% of patients with respectively CIN II and CIN III were cured. In patients with endocervical involvement, the grade of lesion was not significant. Life-table calculations showed an over-all risk of persisting CIN during the first year of observation of 8.8%, and a risk of 0.8% during years 6 to 10. Patients age was of no significance. Endocervical involvement should be a contraindication to cryotherapy, and a careful follow-up schedule is mandatory. A careful colposcopic examination especially concerning the lesion area might help to increase the cure rate in patients with exocervical CIN III lesions.

Laser conization for microinvasive carcinoma of the cervix. Short-term results.

Thirty-one patients with microinvasive carcinoma of the uterine cervix (less than 3.0 mm invasion, no lymph vascular involvement), were treated with combination laser conization. The mean follow-up period was 36 months. No cases of invasive disease have been diagnosed during follow-up. Examination during follow-up revealed atypical columnar epithelium in one case, but the hysterectomy specimen was normal. Based on these short-term results, combination laser conization for microinvasive carcinoma of the cervix seemed a sufficient therapy. A precise and careful histopathologic evaluation, and the patient acceptance of a strict follow-up schedule are mandatory to a decision to employ conservative management of microinvasive cervical carcinoma. Only long-term follow-up in patients treated by conservative therapy will be able to finally justify this approach.