MSCT guided sizing of the Edwards Sapien XT TAVI device: impact of different degrees of oversizing on clinical outcome.

AIMS: Prospective data on the usage of 3-dimensional imaging based annulus sizing on the outcome of TAVI is not available yet and there is general uncertainty about the optimal degree of oversizing. In the current study we therefore assessed a 3-D MSCT guided over-sizing approach and evaluated the clinical outcome of different degrees of oversizing. METHODS: TAVI-size-selection was done using systolic MSCT-annulus cross-sectional-area (CSA) measurements in 107 patients with severe aortic stenosis with the goal to oversize the 3rd generation balloon expandable Edwards Sapien XT (ESTV) device in relation to the native aortic annulus CSA. RESULTS: Among different degrees of oversizing there were no differences in the occurrence of stroke, myocardial infarction and death. No aortic injuries were observed. The overall rate of >mild postprocedural aortic regurgitation (PAR) was 7.6%. Increasing oversizing ratios are associated with lower rates of >mild PAR (r = -0.236, p<0.02) with the lowest rate of >mild PAR in patients with area based oversizing ratios >25% and the highest rate in patients with oversizing ratios <15% (0% vs. 15.8%, p<0.02). The rate of postprocedural permanent pacemakers tended to be lower in patients with <15% oversizing compared to those with >25% oversizing (5.3 vs. 16.7%, p<0.23). CONCLUSIONS: MSCT guided ESTV-device sizing is safe and is associated with significantly lower than previously reported rates for PAR. A device/annulus oversizing ratio of 15-25% based on area and 7-12% based on mean diameter appears to provide the best risk-benefit ratio in terms of PAR reduction and conduction disorders.

[Aortic valve stenosis: transcatheter aortic valve implantation (TAVI) ­ transarterial or transapical approach]. / Aortenklappenstenosen: Kathetergestützte Aortenklappenimplantation (TAVI) ­ transarterieller oder transapikaler Zugang.

The calcified aortic stenosis is the dominating valve disease. Patients affected are most common elderly people in the 8 (th) or 9 (th) decade of their life who often show associated comorbidities like reduced left ventricular function, impaired renal function, pulmonary hypertension, and further diseases (Diabetes mellitus, stroke, COPD). In many cases perioperative morbidity and mortality are too high for surgical valve replacement and up to 30 % of patients are rejected. Nevertheless, prognosis of aortic stenosis is worse if the typical symptoms like dyspnea on exertion, syncope, and angina occur. The transcatheter aortic valve implantation is a new method treating this particular group of patients. The aortic valve bioprothesis consists of a balloon-expandable stent or a self-expandable frame, in which a valve of bovine or porcine pericardium is incorporated. The implantation is performed by retrograde access via the femoral or subclavian artery; the balloon-expandable prosthesis can also be implanted by transapical approach. Recently, the PARTNER trial and other studies demonstrate a high implantation success rate and better survival in comparison to standard therapy but exhibit also cerebral vascular and peripheral vascular complications. A further reduction of the available delivery systems and new types of valves which are under experimental tests and clinical evaluation contribute to this development.

Possible importance of increased intra-abdominal pressure for the development of necrotizing enterocolitis.

BACKGROUND/PURPOSE: Despite extensive clinical and laboratory investigations, many aspects of the pathogenesis of necrotizing enterocolitis (NEC) remain unclear. In the present work we describe 5 neonates with NEC in whom intra-abdominal pressure (IAP) was measured to investigate the potential role of abdominal compartment syndrome (ACS) in the development of NEC and to correlate the severity of NEC with the value of IAP. METHODS: IAP pressure was determined in two groups - Group A consisting of five patients without NEC (Control) and Group B consisting of five patients who developed NEC - by measuring the urinary bladder pressure (UBP). The correlation between increased IAP and severity of NEC, complications of NEC and indications for surgery was investigated. RESULTS: In four patients from Group B, the general condition deteriorated despite aggressive supportive treatment, and a laparotomy was performed. These neonates demonstrated a significant increase (compared to Control patients) in UBP (9.0+/-2.5 vs. 4.8+/-1.4 mmHg, p=0.001), which increased progressively with exacerbation of NEC and reached a peak value of 13.3+/-2.4 mmHg before operation. The elevated IAP was accompanied by hemodynamic instability in all patients, respiratory instability in 3 patients and decreased urinary output in one patient. One patient remained unstable and died 6 h after operation. In the fifth patient from Group B, intestinal obstruction developed two weeks after NEC and did not result in increased IAP. CONCLUSIONS: Our results suggest that IAP is associated with an exacerbation of NEC. Thus, this study provides further information which may improve our understanding of the pathogenic process of NEC.

Cardiac surgery for octogenarians--a suitable procedure? Twelve-year operative and post-hospital mortality in 641 patients over 80 years of age.

OBJECTIVES: The increase in life expectancy as a result of therapeutic improvements subsequently leads to a large number of patients with advanced age. The aim of this study was to review the 30-day mortality and mid-term outcome of octogenarians undergoing coronary artery bypass grafting (CABG) or valve replacement (AVR/MVR). METHODS: The data of 641 patients with a mean age of 82.6 years (range 80.0 - 92.6), operated between 9/93 and 12/05, were reviewed. 432 patients underwent CABG, 188 had AVR and 21 had MVR. We analysed peri-/postoperative mortality and clinical outcomes. Follow-up was obtained by phone contact with patients or their physician. Mid-term survival was determined for the whole population by the Kaplan-Meier method; peri- and postoperative risk factor analysis was done using logistic regression. Follow-up ranged from 0.1 to 11.8 years (mean 3.6 +/- 2.6) and was complete for 99%. RESULTS: We observed a perioperative mortality of 8.8% for CABG, 4.8% for AVR and 9.5% for MVR. Perioperative mortality was strongly associated with urgent/emergent operations (P < 0.03), poorer clinical status (P < 0.03), renal dysfunction (P < 0.05) and male gender (P < 0.04). Actuarial survival after 3, 5 and 8 years was as follows: CABG 78%, 66% and 44%; AVR 79%, 68% and 38%; MVR 76%, 61% and 23%. The mean NYHA functional class for survivors improved in the group of patients with CABG from 2.7 to 2.0 (P < 0.03), in the AVR group from 2.8 to 2.0 (P < 0.03), and in the MVR group from 2.9 to 2.3 (P < 0.05). More than 80% of all surviving patients live at home, either alone or with their family. CONCLUSION: In our cohort of octogenarians, cardiac surgery was found to be associated with an acceptable, although increased perioperative mortality. Despite the enhanced perioperative risk, the clinical benefit, as verified by improved functional status and satisfactory mid-term survival rates, justifies surgery in these patients with advanced age.

Hyperbaric oxygen in treatment of neonatal arterial thromboembolism of lower extremities.

Arterial thromboembolism (TE) in the absence of current or recent history of a central catheter is a rare condition in newborn period. We report a case of severe lower extremities arterial TE of unclear etiology in a full-term neonate. By adding hyperbaric oxygenation to thrombolytic and antithrombotic therapy, we achieved improved perfusion of the upper leg tissues, preserving the knee and enabling below-the-knee amputation.

Human endothelial cell septins: SEPT11 is an interaction partner of SEPT5.

The septin SEPT11 is a novel member of the highly conserved septin family. Septins are cytoskeletal GTPases, which form heteropolymeric complexes. They are involved in cytokinesis and other cellular processes, such as vesicle trafficking and exocytosis. SEPT11 has strong homology to SEPT8. Previously, we identified the interaction of SEPT5 and SEPT8. Using the yeast two-hybrid system, we now demonstrate that SEPT11 partners with SEPT5. The molecular interaction of SEPT11 with SEPT5 was verified by coprecipitation of SEPT5 and SEPT11 from lysates of the human T-cell leukaemia cell line JURKAT and by fluorescence resonance energy transfer. The interaction between SEPT5 and SEPT11 requires the GTP-binding domain and the C-terminal extension. Western analysis in various mouse and human tissues revealed that expression of SEPT11 is restricted to the same tissues as those expressing SEPT5, suggesting that SEPT11 and SEPT5 are components of a cell-specific septin complex. SEPT5, which is expressed in human umbilical vein endothelial cells (HUVECs), has been reported to play an important role in exocytosis. We now report that HUVECs also express SEPT11. Given the interactivity between SEPT5 and SEPT11 as shown above and their coexpression in HUVECs, it may be that a complex formed by these two proteins is involved in the exocytosis mechanism in HUVECs.

Intravascular extension of an osteosarcoma of the pubic bone into periprostatic venous plexus.

Pelvic osteosarcomas are uncommon but aggressive tumors that can invade the vascular system. We report a case of a 33-year-old man who presented with groin pain and was found to have a chondroblastic osteosarcoma invading the periprostatic venous plexus. Meticulous intraoperative exploration of the pelvis is necessary in such cases to resect tumor completely, thereby maximizing local control and preventing embolic complications.

Are men treated better than women? Outcome of male versus female patients after CABG using bilateral internal thoracic arteries.

BACKGROUND: Apart from smaller native coronary arteries a lower number of anastomoses and a lower ITA incidence have been suggested as being responsible for the increased mortality in female patients compared to males. The aim of this study was to clarify whether the outcome of females might be a consequence of a different regimen in anastomosis and ITA frequency. METHODS: We evaluated operative data and early outcome of 6906 patients with isolated CABG operated between 1/96 - 7/03 3064 out of 5381 males received bilateral ITA (BITA) vs. 750 of 1525 females. Single ITA (SITA) was performed in 2126 males and 704 females. RESULTS: Demographic and operative data: average age for male patients was 64.0 +/- 9.2 years, for females 68.5 +/- 8.6 years ( p < 0.05). The prevalence of diabetes mellitus was significantly higher in females (34.6 % vs. 27.4 %, p < 0.01). Body mass index (BMI, 26.6 vs. 27.4 mean), incidence of main stem stenosis (23.0 % vs. 23.5 %), ejection fraction < 40 % (7.8 % vs. 10.1 %), urgent or emergent operations (13.1 % vs. 11.3 %) and number of performed anastomoses (3.2 vs. 3.5 mean) showed no significant difference between males and females. Total ITA frequency did not differ (95.3 % vs. 96.5 %), but BITA frequency was significantly higher (56.9 % vs. 49.2 %, p < 0.01) in male patients. Overall 30-day mortality was 2.8 % for males vs. 4.1 % ( p < 0.05) for females. Cardiac-related mortality was significantly higher in female patients (2.6 % vs. 1.1 %, p < 0.01). Non-cardiac-related mortality did not differ significantly. Graft-related mortality for males and females revealed 2.7 % in the BITA, 3.3 % in the SITA group and 6.9 % for patients without ITAs and reached statistical significance ( p < 0.01) for SITA or BITA vs. the no-ITA group, but not for BITA vs. SITA grafting. Nevertheless cardiac-related mortality in male and female patients without an ITA graft was more than two-fold higher compared to these with single ITAs and more than three-fold higher compared to those with BITA grafting. CONCLUSIONS: Female gender, frequently associated with diabetes mellitus, presents a predictor for increased mortality in CABG. A discrimination of women with respect to a restriction of ITA grafting could be confirmed only for bilateral ITAs. The superior results of bilateral ITA grafts are independent of gender.

Temporal lobe volumes in patients with hippocampal sclerosis with or without cortical dysplasia.

BACKGROUND: Recent MRI-based volume reconstruction studies in intractable temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) suggested atrophy that extends to the adjacent neocortical areas. OBJECTIVE: To study the extent of temporal lobe volume (TLV) abnormalities in patients with pathologically confirmed HS (with or without cortical dysplasia [CD]) who underwent anterior temporal lobectomy for the treatment of drug-resistant TLE. METHODS: Fifty patients (right TLE: n = 24; left TLE: n = 26) were found to have HS (hippocampal cell loss of >30%). Associated neocortical CD was seen in 20 patients (43%). MRI-based TLVs and hippocampal and hemispheric volume reconstructions in all patients were compared between pathologic groups and with volumes acquired from 10 age-matched control subjects. RESULTS: TLVs ipsilateral to the epileptogenic zone in patients with TLE were smaller than TLVs in control subjects (p < 0.01). In patients with left TLE, TLVs ipsilateral to the epileptogenic zone were smaller than contralateral TLVs (left: 66.6 +/- 8.3 cm3, right: 74.9 +/- 10.0 cm3; p < 0.001). In patients with right TLE, there were no significant asymmetries. The contralateral TLVs (regardless of the side of surgery) were smaller in the HS + CD group than the HS group (HS + CD group: 74.9 +/- 8.6 cm3, HS group: 79.7 +/- 6.6 cm3; p < 0.05). Patients with HS + CD had a tendency to have less hippocampal atrophy and slightly smaller TLVs ipsilateral to the epileptogenic zone, accounting for significantly smaller TLV/hippocampal volume ratios compared with patients with HS alone. CONCLUSIONS: Drug-resistant TLE due to HS is associated with extrahippocampal temporal lobe atrophy. The presence of bilateral temporal lobe atrophy is suggestive of a more widespread (bilateral) temporal lobe involvement in patients with HS and CD.

[The level of knowledge of general practitioners regarding the early phase of Lyme borreliosis. Survey conducted among 106 general practitioners]. / Niveau de connaissance des médecins généralistes sur la phase précoce de la borréliose de Lyme. Enquête menée chez 106 médecins généralistes.

OBJECTIVE: Determine the level of knowledge of the general practitioners on the early phase of Lyme borreliosis in an endemic area and notably to define the attention paid to the use and interpretation of serologic investigations for the treatment of patients with erythema migrans. METHOD: This was a prospective study conducted from May 15 to June 31, 2001 among 106 randomly selected general practitioners installed in Strasbourg, France. The practitioners were all interviewed in their private practice and by the same person. Three standardized questions were asked, evaluating their level of specific medical training on Lyme borreliosis as well as their practice regarding treatment and diagnosis of erythema migrans. RESULTS: One third of the general practitioners had already accomplished a continued medical education course on Lyme borreliosis. Half of them considered that the diagnosis of erythema migrans was clinical, while the other half believed that serological confirmation was mandatory. However, the answers of those having received specific education on borreliosis were right (p=0.0079) since in this sub-group 72% considered that the diagnosis was exclusively based on clinical examination, versus 41% of the untrained physicians. Eighty-eight percent used the recommended antibiotic regimens to treat erythema migrans. Three practitioners proposed an inefficient treatment that had exposed the patients to the risk of extra-cutaneous complications of the disease. CONCLUSION: Fifty percent of the general practitioners working in endemic areas for Lyme borreliosis still believe that seropositivity against Borrelia burgdorferi is required to diagnose erythema migrans, which is untrue. However, this study shows that a specific education on Lyme borreliosis would significantly improve this score.

Distribution of the Brief Male Sexual Inventory in community men.

The objectives of the study were to characterize male sexual functioning as related to age in community-dwelling older men. In 1989, a random sample of men aged 40-79 y (n=2115) without prior prostate surgery, prostate cancer, or other conditions known to affect voiding function (except benign prostatic hyperplasia) was invited (55% agreed) to participate in the Olmsted County Study of Urinary Symptoms and Health Status Among Men. In 1996, a previously validated male sexual function questionnaire was administered to the cohort. The questionnaire has 11 questions measuring sexual drive (two questions); erectile function (three) and ejaculatory function (two), as well as assessing problems with sex drive, erections, or ejaculation (three); and overall satisfaction with sex life (one). Each question is scored on a scale of 0-4, with higher scores indicating better functioning. Cross-sectional age-specific means (+/-s.d.) for drive, erections, ejaculation, problems, and overall satisfaction declined from 5.2 (+/-1.5), 9.8 (+/-2.5), 7.4 (+/-1.4), 10.7 (+/-2.2), and 2.6 (+/-1.0), respectively, for men in their 40s to 2.4 (+/-1.6), 3.3 (+/-3.4), 3.6 (+/-3.2), 7.7 (+/-3.8), and 2.1 (+/-1.2) for men 70 y and older (all P<0.001). The cross-sectional decline in function with age was not constant, with age-related patterns differing by domain. The percentage of men reporting erections firm enough to have intercourse in the past 30 days declined from 97% (454/468) among those in their 40s to 51% (180/354) among those in their 80s (P&<0.001). In age-adjusted analyses, men reporting regular sexual partners had statistically significantly higher levels of sex drive, erectile function, ejaculatory function, and overall satisfaction than those who did not report regular sexual partners. Sexual drive, erectile functioning, ejaculatory functioning, and overall sexual satisfaction in men show somewhat differing cross-sectional patterns of decline with advancing age. Active sexual functioning is maintained well into the 80s in a substantial minority of community-dwelling men.

Incidence of physician-diagnosed interstitial cystitis in Olmsted County: a community-based study.

OBJECTIVE: To obtain community-based information about the incidence of interstitial cystitis, a chronic disabling condition of the bladder where knowledge is limited because there are no definitive diagnostic criteria. PATIENTS AND METHODS: All residents of Olmsted County, MN, USA who had received a physician-assigned diagnosis of interstitial cystitis between 1976 and 1996 were identified through the resources of the Rochester Epidemiology Project. The clinical findings at diagnosis and during the follow-up were ascertained from the community medical records for each study subject. RESULTS: In all, 16 women and four men received a diagnosis of interstitial cystitis during the study period. The overall age- and sex-adjusted (95% confidence interval) incidence rate was 1.1 (0.6-1.5) per 100 000 population. The age-adjusted incidence rates were 1.6 per 100 000 in women and 0.6 per 100 000 in men (P = 0.04). The median (range) age at initial diagnosis was 44.5 (27-76) years in women and 71.5 (23-79) years in men (P = 0.26). The median number of episodes of care-seeking for symptoms before the diagnosis was one for women and 4.5 for men (P = 0.03). The median duration from the onset of symptoms until the first diagnosis was 0.06 and 2.2 years in women and men, respectively (P = 0.2). CONCLUSIONS: These findings suggest that the incidence of interstitial cystitis in the community is extremely low. Although the gender difference may be real, the trend toward a later diagnosis in men than in women suggests a potential for missed diagnosis in men. This might explain some of the gender difference in the incidence of interstitial cystitis in men and women.

Spiral CT scanning technique in the detection of aspiration of LEGO foreign bodies.

BACKGROUND: Radiolucent foreign bodies (FBs) such as plastic objects and toys remain difficult to identify on conventional radiographs of the neck and chest. Children may present with a variety of respiratory complaints, which may or may not be due to a FB. OBJECTIVE: To determine whether radiolucent FBs such as plastic LEGOs and peanuts can be seen in the tracheobronchial tree or esophagus using low-dose spiral CT, and, if visible, to determine the optimal CT imaging technique. MATERIALS AND METHODS: Multiple spiral sequences were performed while varying the CT parameters and the presence and location of FBs in either the trachea or the esophagus first on a neck phantom and then a cadaver. Sequences were rated by three radiologists blinded to the presence of a FB using a single scoring system. RESULTS: The LEGO was well visualized in the trachea by all three readers (both lung and soft-tissue windowing: combined sensitivity 89 %, combined specificity 89 %) and to a lesser extent in the esophagus (combined sensitivity 31 %, combined specificity 100 %). The peanut was not well visualized (combined sensitivity < 35 %). The optimal technique for visualizing the LEGO was 120 kV, 90 mA, 3-mm collimation, 0.75 s/revolution, and 2.0 pitch. This allowed for coverage of the cadaver tracheobronchial tree (approximately 11 cm) in about 18 s. Although statistical power was low for detecting significant differences, all three readers noted higher average confidence ratings with lung windowing among 18 LEGO-in-trachea scans. CONCLUSION: Rapid, low-dose spiral CT may be used to visualize LEGO FBs in the airway or esophagus. Peanuts were not well visualized.

Natural history of benign prostatic hyperplasia.

Studies in varied settings have provided estimates of the prevalence of surrogate markers of benign prostatic hyperplasia (BPH). In population-based studies, the prevalence of moderate-to-severe lower urinary tract symptoms and depressed peak urinary flow rates increases across successively older age groups. Prostatic volume follows a similar pattern. Unlike clinic-based studies in which correlations are almost nonexistent, the population-based studies demonstrate a modest correlation among lower urinary tract symptoms, peak urinary flow rates, and prostatic volume. These cross-sectional observations extend to serum prostate-specific antigen levels and postvoid residual urine volumes. Data collected during the longitudinal follow-up study of men participating in the Olmsted County Study of Urinary Symptoms and Health Status Among Men provide a more detailed description of the natural history of changes in these surrogate markers of BPH. They also provide insights into their relation with each other and with long-term outcomes of BPH, such as acute urinary retention and treatment of BPH. These data demonstrate the progressive nature of BPH and are useful for the design and interpretation of clinical trials. Furthermore, they suggest that observational studies of etiology and prognosis should take advantage of the spectrum of disease reflected by the full range of values of these quantitative traits, rather than an arbitrary dichotomized outcome.

Prostate volume and prostate-specific antigen in the absence of prostate cancer: a review of the relationship and prediction of long-term outcomes.

BACKGROUND: The risk for long-term outcomes associated with benign prostatic hyperplasia (BPH) has not been well characterized. Untreated, BPH can lead to complications and negative outcomes, such as deterioration of bladder function, urinary tract infection, acute urinary retention (AUR), and surgery. METHODS: A literature review was conducted to summarize the results of studies investigating the relationship of prostate volume and PSA with prediction of long-term outcomes in the absence of prostate cancer. RESULTS: In the studies reviewed, men with moderate to severe symptoms, depressed uroflow, prostatic enlargement and elevated PSA were at greater risk for developing subsequent AUR or surgery. Men with prostatic enlargement had a 3-fold higher risk for acute urinary retention and were 4 times more likely to have had any treatment for BPH. CONCLUSIONS: The results of these studies may assist physicians in discussing treatment options as well as long-term complications with patients.

DNA length-dependent cooperative interactions in the binding of Ku to DNA.

Despite its central role in the nonhomologous DNA end joining process, we still have an incomplete picture of the interaction between Ku and DNA. Here we describe both kinetic (surface plasmon resonance or SPR) and equilibrium (electrophoretic mobility shift assay or EMSA) studies of Ku binding to linear double-stranded DNA. Ku interaction with 1-site DNA is noncooperative, as expected. Electrophoretic mobility shift assays indicate cooperativity in the binding of Ku molecules to DNA long enough for two Ku molecules to bind (2-site DNA). For the kinetic studies, we use surface plasmon resonance in which one end of the DNA molecules is linked to a surface while the other end is free to interact with Ku. We find that one Ku molecule dissociates from 1-site DNA with simple Langmuir (i.e., independent) kinetics. However, two Ku molecules associate and dissociate from 2-site DNA with a time course that cannot be described as a simple Langmuir interaction. On 3- and 4-site DNA, EMSA and SPR studies do not reveal any cooperativity, suggesting that the middle Ku does not exhibit cooperative interaction with the two Ku molecules bound at the DNA ends. These results indicate that Ku molecules can demonstrate cooperative interaction, and this is influenced by their positions along the DNA.

Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies.

PURPOSE: We hypothesized that markedly increasing the number of cores obtained during prostate needle biopsy may improve the cancer detection rate in men with persistent indications for repeat biopsy. MATERIALS AND METHODS: We performed saturation ultrasound guided transrectal prostate needle biopsy in 224 men under anesthesia in an outpatient surgical setting in whom previous negative biopsies had been performed in the office. The mean number of previous sextant biopsy sessions plus or minus standard deviation before saturation biopsy was 1.8 (range 1 to 7). A mean of 23 saturation biopsy cores (range 14 to 45) were distributed throughout the whole prostate, including the peripheral, medial and anterior regions. Indications for repeat biopsy were persistent elevated serum prostate specific antigen (PSA) in 108 cases, persistent elevated PSA and abnormal rectal examination in 27, persistent abnormal rectal examination in 4, high grade prostatic intraepithelial neoplasia in the previous biopsy in 64 and atypia in the previous biopsy in 21. RESULTS: Cancer was detected in 77 of 224 patients (34%). The number of previous negative sextant biopsies was not predictive of subsequent cancer detection by saturation biopsy. Median PSA was 8.7 ng./ml. and median PSA velocity was 0.63 ng./ml. yearly. Of the 77 patients in whom cancer was detected radical prostatectomy was performed in 52. Pathological stage was pT2 in 48 patients and pT3 in 4, while Gleason score was 4 to 5, 6 to 7 and 8 in 5, 46 and 1, respectively. At prostatectomy median cancer volume was 1.04 cc and 85.7% of removed tumors were clinically significant, assuming a 3-year doubling time. The overall complication rate for saturation needle biopsy was 12% and hematuria requiring hospital admission was the most common event. CONCLUSIONS: Saturation needle biopsy of the prostate is a useful diagnostic technique in men at risk for prostate cancer with previous negative office biopsies. This technique allows adequate sampling of the whole prostate gland and has a detection rate of 34% in this cohort of patients.

Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection.

Early after infection, the retroviral RNA genome is reverse transcribed to generate a linear cDNA copy, then that copy is integrated into a chromosome of the host cell. We report that unintegrated viral cDNA is a substrate for the host cell non-homologous DNA end joining (NHEJ) pathway, which normally repairs cellular double-strand breaks by end ligation. NHEJ activity was found to be required for an end-ligation reaction that circularizes a portion of the unintegrated viral cDNA in infected cells. Consistent with this, the NHEJ proteins Ku70 and Ku80 were found to be bound to purified retroviral replication intermediates. Cells defective in NHEJ are known to undergo apoptosis in response to retroviral infection, a response that we show requires reverse transcription to form the cDNA genome but not subsequent integration. We propose that the double-strand ends present in unintegrated cDNA promote apoptosis, as is known to be the case for chromosomal double-strand breaks, and cDNA circularization removes the pro-apoptotic signal.

Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints.

Chromosomal translocations and deletions are among the major events that initiate neoplasia. For lymphoid chromosomal translocations, misrecognition by the RAG (recombination activating gene) complex of V(D)J recombination is one contributing factor that has long been proposed. The chromosomal translocations involving LMO2 (t(11;14)(p13;q11)), Ttg-1 (t(11;14)(p15;q11)), and Hox11 (t(10;14)(q24;q11)) are among the clearest examples in which it appears that a D or J segment has synapsed with an adventitious heptamer/nonamer at a gene outside of one of the antigen receptor loci. The interstitial deletion at 1p32 involving SIL (SCL-interrupting locus)/SCL (stem cell leukemia) is a case involving two non-V(D)J sites that have been suggested to be V(D)J recombination mistakes. Here we have used our human extrachromosomal substrate assay to formally test the hypothesis that these regions are V(D)J recombination misrecognition sites and, more importantly, to quantify their efficiency as V(D)J recombination targets within the cell. We find that the LMO2 fragile site functions as a 12-signal at an efficiency that is only 27-fold lower than that of a consensus 12-signal. The Ttg-1 site functions as a 23-signal at an efficiency 530-fold lower than that of a consensus 23-signal. Hox11 failed to undergo recombination as a 12- or 23-signal and was at least 20,000-fold less efficient than consensus signals. SIL has been predicted to function as a 12-signal and SCL as a 23-signal. However, we find that SIL actually functions as a 23-signal. These results provide a formal demonstration that certain chromosomal fragile sites can serve as RAG complex targets, and they determine whether these sites function as 12- versus 23-signals. These results quantify one of the three major factors that determine the frequency of these translocations in T-cell acute lymphocytic leukemia.

Postictal diffusion-weighted imaging for the localization of focal epileptic areas in temporal lobe epilepsy.

PURPOSE: Diffusion-weighted MR imaging (DWI) is a novel technique to delineate focal areas of cytotoxic edema of various etiologies. We hypothesized that DWI may also detect the epileptogenic region and adjacent areas during the ictal and early postictal periods in patients with temporal lobe epilepsy (TLE). METHODS: We studied patients with intractable TLE (n = 9), due to hippocampal sclerosis (HS, n = 7), left mesial temporal lobe tumor (n = 1), and of unknown etiology (n = 1). Informed consent was obtained before inclusion in the study. All patients with single short seizures were scanned immediately after EEG-documented seizures (between 45 and 150 min); one of two patients in status was scanned 14 h after cessation of seizures. DWI results were analyzed visually and by calculating apparent diffusion coefficient (ADC) maps. RESULTS: We found significant decreases in ADC postictally in one of six patients with TLE due to HS and single short seizures. One patient with an incompletely resected temporal lobe tumor also exhibited ADC abnormalities. One patient in focal status epilepticus revealed a decrease in ADC, and one patient with a continuous aura had no DWI abnormality. CONCLUSIONS: Postictal DWI technique may occasionally help delineate epileptic areas in some patients with TLE. Yield is low in patients with HS and single short seizures: it may be higher in patients with tumor or status epilepticus.