Three different pathogenic mechanisms for paraparesis in association with bacterial infections

Three different pathogenic mechanisms are apparent for paraparesis in association with a bacterial infection: a spinal cord compression caused by either an epidural abscess or a vertebral collapse due to spondylitis, an ischaemic spinal cord lesion as a result of septic thromboembolus in abdominal aorta, and a nonspecific, probably immunological, cause in association with reactive polyarthritis. An example of each of these mechanisms is described by means of case histories.     

Nuclear morphometry and DNA flow cytometry as prognostic factors in female breast cancer.

OBJECTIVE--To evaluate the predictive value of traditional prognostic factors, nuclear morphometry, and flow cytometric data in invasive breast cancer. DESIGN--Open study. SETTING--One university hospital in Finland. SUBJECTS--248 women with invasive breast cancer followed up for more than 11 years. MAIN OUTCOME MEASURES--Univariate and multivariate analysis of factors thought to indicate prognosis. RESULTS--Diameter of the tumour, lymph node status, S phase fraction. DNA index, the age of the patient, and the SD of nuclear perimeter were significant independent predictors in the whole series in a multivariate analysis. In node negative patients the SED of the nuclear perimeter and diameter of the tumour had independent prognostic value, whereas in node positive patients diameter of the tumour and the S phase fraction were independently related to survival. CONCLUSIONS--Diameter of the tumour is an important prognostic factor in breast carcinomas. Histoquantitative methods are superior to conventional histological techniques for the prediction of outcome in women with breast cancer.     

Tumor size, nuclear morphometry, mitotic indices as prognostic factors in axillary-lymph-node-positive breast cancer.

The biopsy specimens from the primary tumors of 234 women with axillary-lymph-node-positive breast carcinomas (followed up for a mean of 10.9 years) were subjected to interactive morphometric analysis of nine nuclear factors. The proliferative activity of the tumors was estimated by determining two different mitotic indices. Morphometrically determined nuclear factors and mitotic indices showed a significant correlation to the histological grading (p less than 0.0001). Mitotic activity index (MAI; p = 0.018) and volume-corrected mitotic index (M/V index; p = 0.005) accurately predicted the tumor recurrence. Recurrence-free survival was related to the M/V index (p = 0.0003), MAI (p = 0.0024) and tumor size (p = 0.0144). Disease-related survival was determined by the tumor size (p less than 0.0001), M/V index (p = 0.0142) and MAI (p = 0.0492) in that order. On the other hand, the nuclear factors analyzed and the histological grading used had no predictive value (i.e. tumor recurrence, recurrence-free survival or tumor-related survival) in these women. The results indicate that mitotic indices can be successfully applied in place for subjective grading and nuclear morphometry in predicting the disease outcome in patients with axillary-lymph-node-positive breast carcinomas. The mitotic indices provide independent prognostic information in addition to tumor size. The major clinical implications of these results would be to accurately disclose among these women the high-risk patients (i.e. those with high mitotic indices), who might benefit from more agressive adjuvant therapies.     

Alcohol-related mortality, drinking behavior, and business cycles

This paper explores the connection between alcohol-related mortality, drinking behavior, and macroeconomic conditions in Finland using both aggregate and microlevel data from recent decades. The aggregate data reveal that an improvement in economic conditions produces a decrease in alcohol-related mortality. Microlevel data show that alcohol consumption increases during economic expansion while the probability of being a drinker remains unchanged. This demonstrates that alcohol-related mortality and self-reported alcohol consumption may be delinked in the short-run business cycle context. One explanation for this paradox is that most harmful forms of drinking are not captured in survey-based data used to study the effect of macroeconomic conditions on alcohol consumption. Our evidence does not overwhelmingly support the conclusions reported for the United States that temporary economic downturns are good for health.     

Immune response against P815X2 mastocytoma growing in syngeneic DBA/2 mice. V. Spleen immunoreactivity and cell mediated cytotoxicity

The in vitro cytotoxicity assay and the histological in vivo analysis were used to study cell-mediated immunity in the spleen of DBA/2 mice bearing subcutaneously developing P815X2 mastocytoma. Mononuclear cells separated from the spleen showed P815X2 specific cytotoxic activity between days 10 (12) and 16 following tumor inoculation. Maximal cytotoxicity was detected on days 13 and 14. In the T cell area of the spleen white pulp (C-PALS), an increase in the proportions of T lymphocytes and mononuclear phagocytes was observed on days 10 and 12 after the injection of P815X2 cells. On day 14, the T cell level in C-PALS dropped below control values, and the cellular density in the T cell area was reduced. Tumor metastases were seen in the spleen from day 14 onwards. The results indicate, that the T cell reaction in vivo was detectable in C-PALS one to two days earlier than the in vitro cytotoxicity of the spleen cells. By the time of maximal cytotoxic activity, the in vivo reaction had disappeared.     

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.     

Search for large genomic alterations of the BRCA1 gene in a Finnish population

Mutations in the BRCA1 and BRCA2 genes are known to predispose to breast cancer. In Finland, however, only 21% of all breast cancer families have mutations in these genes. Recent studies have shown that large genomic alterations of BRCA1 are common in many countries. Because such alterations will be missed in conventional mutation screening strategies, we decided to screen Finnish breast and ovarian cancer families for genomic alterations by using a multiplex polymerase chain reaction method. The most characteristic features of BRCA1-related breast cancer were used to select patients, namely (1) both breast and ovarian cancer in the family (48 patients), (2) four or more breast cancers in family (22 patients), or (3) young age (< or =40 years) of onset (58 patients). A total of 128 patients were included in the study. All exons of BRCA1 were analyzed but no alterations were found. This study excludes the frequent occurrence of large genomic alterations in the BRCA1 gene in Finland. Here, again, Finland differs from other countries with a mixed population structure. Our results are in agreement with the common hypothesis that there are still unknown breast cancer susceptibility gene(s) that are responsible for breast cancer predisposition.     

Human papillomavirus testing with the hybrid capture 2 assay and PCR as screening tools

The recognition of high-risk human papillomaviruses (HPVs) as etiological agents of cervical cancer has increased the demands to use testing for HPV for the detection of abnormal cervical smears and for cervical cancer screening. The present study compared the performance of the Hybrid Capture 2 (HC2) assay with that of PCR for the detection of significant cervical lesions in 1,511 women with different risks for HPV infections in three New Independent States of the former Soviet Union. The results showed that the level of agreement between the HC2 assay and PCR was substantial, with a kappa (Cohen) value of 0.669 (95% confidence interval [CI], 0.629 to 0.709). Of the 228 samples with discrepant results, 92 were positive by the HC2 assay but negative by PCR, whereas 136 samples were PCR positive but HC2 assay negative. The positive predictive values (PPVs) of the HC2 assay and PCR in detecting high-grade intraepithelial lesions (HSILs) were 4.5% (95% CI, 3.5 to 5.5%) and 3.6% (95% CI, 2.7 to 4.5%), respectively, and the negative predictive values (NPVs) were 99.6% (95% CI, 99.3 to 99.9%) and 99.3% (95% CI, 98.9 to 99.7%), respectively. The sensitivities of the HC2 assay and PCR for the detection of HSILs were 85.2 and 74.0%, respectively, and the specificities were 67.2 and 64.1%, respectively. In receiver operating characteristic (ROC) analysis, the performance of the HC2 assay for the detection of HSILs was excellent (P = 0.0001); the area under the ROC analysis curve was 0.858 (95% CI, 0.811 to 0.905), and the optimal balance between sensitivity (86.5%) and specificity (80%) was obtained with an HC2 assay cutoff level of 15.6 relative light units/positive control. Use of this cutoff would increase the specificity of the HC2 assay to 80.0% without compromising sensitivity. In conclusion, the results of PCR and the HC2 assay were concordant for 85% of samples, resulting in substantial reproducibility. Both tests had low PPVs, equal specificities, and equal (almost 100%) NPVs for the detection of HSILs; but the sensitivity of the HC2 assay was slightly better.     

HPV infections and tonsillar carcinoma

Since human papillomavirus (HPV) was first linked to laryngeal/oral carcinomas in 1983, several studies have confirmed its causal role in a subgroup of upper aerodigestive tract tumours. Of the non-genital cancers, tonsillar carcinomas (TCs) have the strongest association with HPV. By the end of 2002, 432 TCs had been analysed for HPV DNA. Overall detection rate was 51%, with HPV-16 being the most prevalent (84%). The original proposal that HPV-33 would be the most frequent HPV in TCs has not been confirmed, being present in only 4.6% of cases. HPV copy numbers are similar to those found in genital carcinomas (10-300 copies/cell), although HPV is mainly episomal in TC. The importance of this observation is unclear, although a role for subepithelial proliferative lymphatic tissue has been speculated. Patients with HPV-16 positive tumours have better overall and disease specific survival than HPV negative patients. They are also younger and the association with conventional risk factors-smoking and drinking-is less significant than in HPV negative patients. Thus, recent data suggest a distinct pattern for HPV-16 positive TCs.     

Natural history of oral papillomavirus infections in spouses: a prospective Finnish HPV Family Study.

BACKGROUND: The natural history of genital human papillomavirus infection is well known, but nearly nothing is known about the outcome of oral HPV-infection. OBJECTIVES AND STUDY DESIGN: To study natural history of oral HPV in spouses during the follow-up 331 women (mean 25.5+/-3.4 years) and 131 men (mean 28.8+/-5.0 years) were recruited from maternity unit. Scrapings from healthy oral mucosa of spouses at baseline, 2, 6, 12 and 24 months and genital samples were taken for HPV testing. HPV DNA was detected by nested PCR and confirmed by hybridization using a cocktail of 12 high-risk (HR) oligoprobes. RESULTS: The detection rate of HR HPVs varied from 15% to 27%. Baseline oral HPV status between the spouses was closely related (odds ratio 4.3; 95% confidence interval 1.6-12.0; P=0.006). Persistent oral infection in one spouse was a significant risk factor (odds ratio 10.0; 95% confidence interval 1.5-68.7; P=0.005) for oral HR HPV persistence in the other partner. Cumulative incidence of new HR HPV infections was identical in both spouses, while men seemed to clear their infection more rapidly. In univariate survival analysis, the partner's oral or genital HPV status, oral sex habits or age did not predict clearance or acquisition of oral HR HPV. CONCLUSION: Natural history of HPV infection in oral mucosa mimics that of genital HPV infection. Oral sex had no association to oral HPV infection, but a persistent oral HPV infection of the spouse increased the risk of persistent oral HPV infection 10-fold in the other spouse.