Centrosomes in the DNA damage response—the hub outside the centre

Here, we review how DNA damage affects the centrosome and how centrosomes communicate with the DNA damage response (DDR) apparatus. We discuss how several proteins of the DDR are found at centrosomes, including the ATM, ATR, CHK1 and CHK2 kinases, the BRCA1 ubiquitin ligase complex and several members of the poly(ADP-ribose) polymerase family. Stereotypical centrosome organisation, in which two centriole barrels are orthogonally arranged in a roughly toroidal pericentriolar material (PCM), is strongly affected by exposure to DNA-damaging agents. We describe the genetic dependencies and mechanisms for how the centrioles lose their close association, and the PCM both expands and distorts after DNA damage. Another consequence of genotoxic stress is that centrosomes undergo duplication outside the normal cell cycle stage, meaning that centrosome amplification is commonly seen after DNA damage. We discuss several potential mechanisms for how centrosome numbers become dysregulated after DNA damage and explore the links between the DDR and the PLK1- and separase-dependent mechanisms that drive centriole separation and reduplication. We also describe how centrosome components, such as centrin2, are directly involved in responding to DNA damage. This review outlines current questions on the involvement of centrosomes in the DDR.     

Differences in neonatal mortality among whites and Asian American subgroups: evidence from California

OBJECTIVE: To obtain information about health outcomes in neonates in 9 subgroups of the Asian population in the United States. DESIGN: Cross-sectional comparison of outcomes for births to mothers of Cambodian, Chinese, Filipino, Indian, Japanese, Korean, Laotian, Thai, and Vietnamese origin and for births to non-Hispanic white mothers. Regression models were used to compare neonatal mortality across groups before and after controlling for various risk factors. SETTING: All California births between January 1,1991, and December 31, 2001. PARTICIPANTS: More than 2.3 million newborn infants. MAIN EXPOSURE: Racial and ethnic groups. MAIN OUTCOME MEASURE: Neonatal mortality (death within 28 days of birth). RESULTS: The unadjusted mortality rate for births to non-Hispanic white mothers was 2.0 per 1000. The unadjusted mortality rate for births to Chinese and Japanese mothers was significantly lower (Chinese: 1.2 per 1000, P<.001; Japanese: 1.2 per 1000, P=.004), and for births to Korean mothers the rate was significantly higher (2.7 per 1000, P=.003). For infants of Chinese mothers, observed risk factors explain the differences observed in unadjusted data. For infants of Cambodian, Japanese, Korean, and Thai mothers, differences persist or widen after risk factors are considered. After risk adjustment, infants of Cambodian, Japanese, and Korean mothers have significantly lower neonatal mortality rates compared with infants born to non-Hispanic white mothers (adjusted odds ratios, 0.58 for infants of Cambodian mothers, 0.67 for infants of Japanese mothers, and 0.69 for infants of Korean mothers; all P<.05); infants of Thai mothers have higher neonatal mortality rates (adjusted odds ratio, 1.89; P<.05). CONCLUSIONS: There are significant variations in neonatal mortality between subgroups of the Asian American population that are not entirely explained by differences in observable risk factors. Efforts to improve clinical care that treat Asian Americans as a homogeneous group may miss important opportunities for improving infant health in specific subgroups.     

Volume Dependence of High-Frequency Respiratory Mechanics in Healthy Adults

Respiratory system input impedance (Zrs) at low to medium frequencies below 100 Hz, and study of its volume dependence, have been used extensively to quantify airway and tissue mechanics. Zrs at high oscillation frequencies including the first antiresonant frequency (far,1) may contain important information about airway mechanics. Changes in high-frequency Zrs with lung volume have not been studied. The volume-dependent behavior of high-frequency Zrs, specifically far,1 and respiratory system resistance at first antiresonance (Rrs(far,1)), was characterized in 16 healthy adults. Zrs was measured with a forced oscillation signal (5–302.5 Hz) through a wavetube setup. To track Zrs, subjects performed slow deep inspiratory and expiratory maneuvers over 30-s measurements, during which average impedance was calculated over 0.4-s intervals, with successive overlapping estimates every 0.156 s. Flow was measured using a pneumotachometer and integrated to obtain volume. Transpulmonary pressure dependence (Ptp) of Zrs was separately determined in five subjects. Both far,1 and Rrs(far,1) decreased with increasing lung volume and Ptp, consistent with an increase in airway caliber and decreased airway wall compliance as volume increased. These characterizations provide insight into airway mechanics, and are furthermore a necessary first step toward determining whether volume dependence of the first antiresonance is altered in disease.     

The outcome of CPR initiated in nursing homes

To determine outcomes following attempted cardiopulmonary resuscitation initiated in nursing homes, we retrospectively reviewed ambulance and hospital records for all 705 people aged 65 or over who underwent attempted resuscitation by ambulance crews in 1987 in Baltimore City and Baltimore County. From medic unit encounter forms we noted whether or not the address of origin was a nursing home and to what hospital the person was taken. Hospital records were then examined to determine outcomes: death in the emergency room, death during consequent hospitalization, or live discharge. Complete information was obtained for all 117 nursing-home residents and for 580 of 588 nonresidents. When attempted resuscitation was begun in a nursing home, only two patients survived to hospital discharge, whereas 61 nonresidents (11%) survived after a mean stay of 14 days. Of the 115 nursing-home residents who did not survive to hospital discharge, 102 (89%) were pronounced dead in the emergency room, two (2%) more died within 24 hours of admission, and the remaining 11 (9%) died after an average stay of five days. Of the 519 nonresidents who died before discharge, 433 (83%) were pronounced dead in the emergency room, 16 (3%) died in the first 24 hours, and 70 (14%) lived an average of nine days. One of the two nursing-home residents who survived was an 87-year-old woman who spent 30 days in the hospital and died eight months after returning to the nursing home, demented, cachectic, with a large sacral pressure sore.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuroimaging features of heroin inhalation toxicity: "chasing the dragon"

OBJECTIVE: Our objective was to illustrate the dramatic neuroimaging findings of toxic leukoencephalopathy caused by heroin vapor inhalation. CONCLUSION: Symmetric abnormality involving the cerebellar white matter and posterior limb of the internal capsule is characteristic of heroin vapor inhalation toxicity, although involvement may be more extensive, depending on the severity of the condition. MR imaging and CT appear to be essential for making this diagnosis because clinical history is often unreliable and findings at physical examination are nonspecific.     

Laparoscopic bile duct exploration via choledochotomy followed by primary duct closure is feasible and safe for the treatment of choledocholithiasis

Background

The common bile duct traditionally is managed with T-tube drainage after choledochotomy and removal of common bile duct (CBD) stones, but this approach carries an associated tube-related morbidity rate, including bile leak, of 10.5–20 %. This study examined the safety and effectiveness of laparoscopic CBD exploration (LCBDE) followed by primary duct closure.

Methods

This is a retrospective analysis of 120 consecutive patients (81 female) who underwent LCBDE between October 2002 and October 2012. The duct primarily was closed in all patients. The results are given as median (range).

Results

Trans-CBD exploration was performed in 120 patients and all cases were successfully completed laparoscopically. The maximum diameter of the CBD was 9.4 (3–30) mm and the number of CBD stones detected was 3 (0–20). The biliary tree was clear at the end of exploration in 116 patients (96.7 %). The operating time was 122 (70–360) min. The mortality rate, morbidity rate, postoperative bile leak rate, rate of retained CBD stones after the primary procedure, and CBD stricture rate at a follow-up of 39.2 (2–82) months were 0, 8.3, 2.5, 3.3, and 0.8 %, respectively. The postoperative hospital stay was 2.1 (1–29) days.

Conclusion

Primary duct closure following LCBDE is safe, can be employed routinely as an alternative to T-tube insertion, and has a short hospital stay and low morbidity rate.     

A technique for frameless stereotaxy and placement of transarticular screws for atlanto-axial instability in rheumatoid arthritis

The aim of the present study was to outline a new surgical technique and describe how, in a clinical setting, computer-generated image-guidance can assist in the planning and accurate placement of transarticular C1/C2 screws inserted using a minimally invasive exposure. Forty-six patients with atlanto-axial instability due to rheumatoid arthritis underwent posterior stabilisation with transarticular screws. This was achieved with a minimal posterior exposure limited to C1 and C2 and percutaneous screw insertions via minor stab incisions. The Stealth Station (Medtronic Sofamor Danek, Memphis, Tenn., USA) was used for image guidance to navigate safely through C2. Reconstructed computed tomographic (CT) scans of the atlanto-axial complex were used for image guidance. It was possible to perform preoperative planning of the screw trajectory taking into account the position of the intraosseous portion of the vertebral arteries, the size of the pars interarticularis and the quality of bone in C2. Screws could be inserted percutaneously over K-wires using a drill guide linked to the image-guidance system. Preoperative planning was performed in all 46 patients and accurate registration allowed proposed screw trajectories to be identified. Thirty-eight patients had bilateral screws inserted and eight had a unilateral screw. A total of 84 screws were inserted using the Stealth Station. There were no neurovascular injuries. This technique for placing transarticular screws is accurate and safe. It allows a minimally invasive approach to be followed. Image guidance is a useful adjunct for the surgeon undertaking complex spinal procedures.     

Case management for substance abusers with HIV/AIDS: a randomized clinical trial

In a random assignment study, substance-abusing patients with HIV/AIDS in a public general hospital received a brief contact condition or received 12 months of case management delivered by paraprofessionals. Patient outcomes included substance use, HIV transmission risk, physical health, psychological status, and quality of living situation. In both conditions, a significant decrease occurred in a range of problems from Intake to the 6-month interview, followed by no significant pattern of change at 12- and 18-month interviews. On major outcome variables, there were no significant differences between the brief contact and case management conditions. Sixteen percent had died by the 18-month interview. Process data indicated wide variation in the amount of case management received by participants, and the amount of case management was not related to improvement in the outcome measures. The study has limitations yet does not support the hypothesis that case management improves outcomes better than brief contact for this population.