Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.     

The vein of the vestibular aqueduct with potential pathologic perspectives.

HYPOTHESIS: Pathologic changes around the vein of the vestibular aqueduct (VVA) may cause obstruction to the flow of blood toward the sigmoid sinus. Furthermore, a distal obstruction of this vessel may be responsible for a development of a retrograde flow of blood with concomitant drainage of endolymphatic sac (ES) substances to the inner ear. BACKGROUND: The VVA is responsible for the venous drainage of the vestibular apparatus and endolymphatic duct and ES. Previous studies have linked the VVA to Ménière's disease. The aim of the present article was a 3-dimensional perspective study of the VVA with its adjacent anatomic structures. METHODS: In 14 rats, the VVA was examined by 3-dimensional reconstruction of 2-microm serial sections, corrosion cast technique, and scanning electron microscopy. RESULTS: From the external aperture of the vestibular aqueduct, the VVA is interposed between the ES and the operculum. Three to 4 collecting venules from the ES drain into the VVA. The VVA merges at an oblique angle with the sigmoid sinus. CONCLUSION: The VVA courses near the ES, operculum, and sigmoid sinus and is potentially vulnerable to expanding structures in the cranial posterior fossa. The possible role of the VVA for the function of the ES under normal and pathologic conditions is discussed.     

Familial risk of multiple sclerosis: a nationwide cohort study

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.     

Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin

Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin(96-104) epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.     

Prevalence of HTLV-I in arctic regions

Sera of native inhabitants of Arctic regions were assayed for antibodies to HTLV-I by the ELISA technique followed by competition experiments to confirm antibody specificity. Residents of 7 widely separated Alaskan villages exhibited prevalence rates of 0 to 12% for HTLV-I antibodies. Less than 1 % of Greenland Eskimos were HTLV-I antibody-positive. Residents of 3 northern Swedish regions ranged in HTLV-I antibody prevalence from 0 to 5%. Sera of healthy native inhabitants of Alaska and northern Sweden were similarly assayed for antibodies to HTLV-II. No additional sera were shown to be positive for HTLV-II antibodies. While some of the HTLV-I antibody-positive sera exhibited cross-reactivity with HTLV-II antigens, competition experiments using disrupted HTLV-II or purified HTLV-I p24 as test antigens indicated that the primary antibody response in all cases tested was elicited by HTLV-I. Our results show that HTLV-I distribution is not restricted to endemic areas in warm, humid climates, but extends to Arctic regions. Within these regions, HTLV-I exhibits the same restricted distribution seen in other areas where virus infection is prevalent. The Arctic does not seem to be a reservoir for HTLV-II infection. The origin of HTLV-I in Arctic areas is not known. One may speculate that foreign visitors introduced the virus into Aleut and Lapp populations, and that it has been maintained there and restricted in its distribution as a result of close familial relationships.     

Do indomethacin and propofol cause cerebral ischemic damage? Diffusion-weighted magnetic resonance imaging in patients undergoing craniotomy for brain tumors

BACKGROUND: Diffusion-weighted magnetic resonance imaging was used to determine whether indomethacin and propofol induce cerebral ischemic damage in patients undergoing craniotomy for cerebral tumors. As a secondary aim, the authors investigated whether low jugular bulb oxygen saturation values were associated with brain parenchymal damage as evaluated by diffusion-weighted imaging. METHODS: Nine patients subjected to craniotomy for supratentorial brain tumors in propofol-fentanyl anesthesia were studied. Magnetic resonance imaging including diffusion- and perfusion-weighted and structural sequences were performed (1) on the day before surgery, (2) before and (3) 20 min after administration of indomethacin (bolus of 0.2 mg/kg followed by infusion of 0.2 mg.kg.h) in the propofol-fentanyl-anesthetized patient, and (4) 2 days after surgery. Apparent diffusion coefficient maps were calculated. Jugular bulb oxygen saturation, arteriovenous oxygen difference, mean arterial blood pressure, and arterial oxygen and carbon dioxide tensions were measured simultaneously with the magnetic resonance examinations performed during anesthesia. RESULTS: No ischemic lesions were detected in the diffusion-weighted or apparent diffusion coefficient images. A nonsignificant decrease in jugular bulb oxygen saturation from 51% (range, 40-61%) to 43% (range, 37-63%) and increase in arteriovenous oxygen difference from 4.4 mm (range, 2.7-4.6 mm) to 4.7 mm (range, 2.9-5.2 mm) was observed after indomethacin administration. CONCLUSION: Administration of indomethacin during propofol anesthesia is not associated with evidence of ischemic damage in patients with brain tumors, as evaluated by diffusion-weighted imaging.     

Prediction of postoperative pain by preoperative nociceptive responses to heat stimulation

BACKGROUND: Despite major advances in the understanding of the neurobiologic mechanisms of pain, the wide variation in acute pain experience has not been well explained. Therefore, the authors investigated the potential of a preoperatively induced heat injury to predict subsequent postoperative pain ratings in patients undergoing knee surgery. METHODS: Twenty patients were studied. The burn injury was induced 6 days before surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min). The sensory testing, before and 1 h after the injury, included pain score during induction of the burn, secondary hyperalgesia area, thermal and mechanical pain perception, and pain thresholds. Postoperative analgesia consisted of ibuprofen and acetaminophen. Pain ratings (visual analog scale) at rest and during limb movement were followed for 10 days after surgery. RESULTS: The burn injury was associated with development of significant hyperalgesia. There was a significant correlation between preoperative pain ratings during the burn injury and early (0-2 days, area under the curve) and late (3-10 days, area under the curve) postoperative dynamic pain ratings during limb movement. CONCLUSION: The results of this study suggest that the pain response to a preoperative heat injury may be useful in research in predicting the intensity of postoperative pain. These findings may have important implications to identify patients at risk for development of chronic pain and to stratify individuals for investigations of new analgesics.     

Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes

Strength training represents an alternative to endurance training for patients with type 2 diabetes. Little is known about the effect on insulin action and key proteins in skeletal muscle, and the necessary volume of strength training is unknown. A total of 10 type 2 diabetic subjects and 7 healthy men (control subjects) strength-trained one leg three times per week for 6 weeks while the other leg remained untrained. Each session lasted no more than 30 min. After strength training, muscle biopsies were obtained, and an isoglycemic-hyperinsulinemic clamp combined with arterio-femoral venous catheterization of both legs was carried out. In general, qualitatively similar responses were obtained in both groups. During the clamp, leg blood flow was higher (P < 0.05) in trained versus untrained legs, but despite this, arterio-venous extraction glucose did not decrease in trained legs. Thus, leg glucose clearance was increased in trained legs (P < 0.05) and more than explained by increases in muscle mass. Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-alpha/beta, glycogen synthase (GS), and GS total activity. In conclusion, we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups. The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade.     

Craniotomy for supratentorial brain tumors: risk factors for brain swelling after opening the dura mater

OBJECT: Cerebral swelling often occurs during craniotomy for cerebral tumors. The primary aim in this study was to determine risk factors (intracranial pressure [ICP], patient characteristics, histopathological features, neuroimaging characteristics, anesthetic regimen, and perioperative physiological data) predictive of brain swelling through the dural opening. As a secondary aim the authors attempted to define subdural ICP thresholds associated with brain swelling. METHODS: The study population consisted of 692 patients (mean age 50+/-15 years) scheduled for elective craniotomy for supratentorial brain tumors. Brain swelling through the dural opening was estimated according to a four-point scale. The patients were dichotomized as those without cerebral swelling (that is, brain below the dura mater [59 patients] or brain at the level of the dura mater [386 patients]) and those with cerebral swelling (that is, moderate brain swelling [205 patients] or pronounced brain swelling [42 patients]). Logistic regression analysis was used to identify subdural ICP (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.72-2.1, p < 0.0001), midline shift (OR 1.06, 95% CI 1.02-1.11, p = 0.008), a diagnosis of glioblastoma multiforme (OR 2.1, 95% CI 1.01-4.3, p = 0.047), and metastasis (OR 2.9, 95% CI 1.3-6.9, p = 0.01) as independent risk factors of intraoperative brain swelling. Thresholds for ICP associated with brain swelling were defined as follows: at an ICP less than 5 mm Hg, brain swelling rarely occurred (5% probability); at an ICP greater than 13 mm Hg, brain swelling occurred with 95% probability; and at an ICP greater than 26 mm Hg, severe brain swelling occurred with 95% probability. CONCLUSIONS: Subdural ICP is the strongest predictor of intraoperative brain swelling. It is possible to define thresholds of cerebral swelling and the authors recommend subdural ICP measurement as a tool to initiate preventive measures to reduce ICP before opening the dura mater.