Tankyrases Promote Homologous Recombination and Check Point Activation in Response to DSBs.

DNA lesions are sensed by a network of proteins that trigger the DNA damage response (DDR), a signaling cascade that acts to delay cell cycle progression and initiate DNA repair. The Mediator of DNA damage Checkpoint protein 1 (MDC1) is essential for spreading of the DDR signaling on chromatin surrounding Double Strand Breaks (DSBs) by acting as a scaffold for PI3K kinases and for ubiquitin ligases. MDC1 also plays a role both in Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) repair pathways. Here we identify two novel binding partners of MDC1, the poly (ADP-ribose) Polymerases (PARPs) TNKS1 and 2. We find that TNKSs are recruited to DNA lesions by MDC1 and regulate DNA end resection and BRCA1A complex stabilization at lesions leading to efficient DSB repair by HR and proper checkpoint activation.

Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy.

Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca(2+) sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca(2+)-binding EF hands. Ca(2+) stores are refilled through a process called store-operated Ca(2+) entry (SOCE). Upon Ca(2+)-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca(2+) entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca(2+) sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca(2+) level in TAM cells and a dysregulation of intracellular Ca(2+) homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function.

4 decisions that can affect your anesthesia subsidy.

Four key considerations can affect the size of an anesthesia subsidy: Staffing models. The fair market value compensation for clinicians. The type of provider the organization needs. The payment approach for management of anesthesia services.

Microcirculatory alterations in cardiac surgery: effects of cardiopulmonary bypass and anesthesia.

BACKGROUND: Heterogeneity in microvascular perfusion is associated with impaired tissue oxygenation. We hypothesized that cardiac surgery with or without cardiopulmonary bypass (CPB) could induce microvascular alterations. METHODS: We used an orthogonal polarization spectral imaging technique to evaluate the sublingual microcirculation in patients undergoing cardiac surgery with (n = 9) or without (n = 6) CPB. We also included, as a control group, 7 patients undergoing thyroidectomy with the same anesthetic procedure. Hemodynamic and microcirculatory variables were obtained the day before surgery, after induction of anesthesia, during CPB, on admission to the intensive care unit or the recovery room, and 6 and 24 hours after the end of the surgical procedure. Data are presented as median (25th to 75th percentile). RESULTS: No differences in hemodynamic variables were observed between the two cardiac surgery groups. The proportion of perfused vessels was similar in all three groups at baseline (89% [87% to 90%]), and decreased similarly after induction of anesthesia to 71% (69% to 74%). It decreased further during CPB to 53% (50% to 56%). On admission to the intensive care unit or recovery room, alterations were more severe in CPB than in off-pump patients (60% [59% to 62%] versus 64% [61% to 65%]; p = 0.03), whereas they had already normalized in thyroidectomy patients (89% [86% to 90%]; p = 0.0005 versus cardiac surgery). In both cardiac surgery groups these microcirculatory alterations decreased with time, but persisted at 24 hours. The severity of microvascular alterations correlated with peak lactate levels after cardiac surgery (y = 11.5 - 0.15x; r(2) = 0.65; p < 0.05). CONCLUSIONS: Microcirculatory alterations are observed in cardiac surgery patients whether or not CPB is used. Anesthesia contributes to these alterations, but its effects are transient.

Assessment of thoracic epidural analgesia during general anesthesia using pupillary reflex dilation: a preliminary study.

OBJECTIVE: Pupillary reflex dilation (PRD) secondary to noxious stimulation accurately predicts sensory block during combined lumbar epidural/general anesthesia. Therefore, the adequacy of PRD-guided thoracic epidural infusion during general anesthesia for thoracotomy was studied. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Thirteen patients undergoing thoracotomy. INTERVENTIONS: An epidural catheter was placed at the T3-T4 level with initial infusion rate of 5 mL/h of ropivacaine 0.5%. Propofol/remifentanil target-controlled infusion was used for induction and maintenance of general anesthesia. Remifentanil effect site concentration was maintained constant at 0.5 ng/mL during surgery. By using a portable pupillometer, PRD secondary to tetanic stimulation of the C8, T2, and T4 segments were evaluated. Ropivacaine flow rate was adapted half hourly, according to PRD testing and a predefined algorithm. At the end of surgery, PRD was tested in the 3 investigated segments, and general anesthesia was stopped. After emergence, these zones were tested for their sensitivity to cold. Pain was evaluated by using the visual analog scale. RESULTS: Pain scores were <3 of 10 in 84.6% of the patients. Mean PRD was 0.9 +/- 0.6 mm in unblocked levels versus 0.2 +/- 0.5 mm in blocked segments (p = 0.02). PRD >or= 0.5 mm was predictive of incomplete block (sensitivity 76%, specificity 79%, and positive predictive value 86%). PRD >or= 1 mm was highly predictive of inadequate block (sensitivity 73%, specificity 91%, and positive predictive value 94%). CONCLUSION: PRD-guided continuous thoracic epidural analgesia under low-dose remifentanil/propofol anesthesia is feasible and ensures good postoperative analgesia.

Duration of anesthesia as an indicator of morbidity and mortality in office-based facial plastic surgery: a review of 1200 consecutive cases.

OBJECTIVE: To define whether duration of anesthesia is an indicator of patient morbidity and mortality in facial plastic surgery performed in an accredited office-based surgical facility. DESIGN: A prospective and retrospective outcomes analysis of 1200 consecutive patients who underwent facial plastic surgery from July 1995 to February 2005. Outcomes of patients who underwent surgery with anesthesia for less than 240 minutes were compared with those of patients who underwent surgery with anesthesia for more than 240 minutes. RESULTS: Of the 1200 cases analyzed, in 1032 (86%), duration of anesthesia was longer than 240 minutes. There were no deaths and no cases of myocardial infarction or pulmonary embolism in this study group. Morbidity in the 1200 cases was reported as follows: 1 case of respiratory failure, 1 case of central nervous system deficit, 1 case of adverse reaction to medication, and 1 case that required transfer to a hospital. There were 6 cases of prolonged recovery from anesthesia. Incidences of major morbidity in the group of 168 patients (14%) whose anesthesia lasted less than 240 minutes were the same as in the group whose anesthesia lasted more than 240 minutes. CONCLUSIONS: In an accredited office-based facial plastic surgery facility, anesthesia duration is not an indicator of patient morbidity and mortality. Combined facial plastic surgery procedures, using general anesthesia, can be accomplished safely in the office-based environment, and inpatient care would not have altered morbidity in this study group.

Office-based anesthesia: an overview.

Office-based anesthesia, like other specific forms of anesthesia practice, has many unique attributes. Better work hours and a closer working relationship with surgeons and patients can provide the forum for a considerable amount of professional resonance. Moreover, the itinerant nature of the practice, the limited resources, and the need to innovate on the spur of the moment can make for variety and excitement. The gamut of anesthesia techniques, patient comorbidities, and surgeon expectations does not necessarily produce a facile experience, of course. But no specific anesthesia specialty or venue is devoid of challenge. While OBA is different from other types of anesthesia practice, this distinction does not necessarily make it superior or inferior. The political climate has improved, with more states acknowledging the status of OBS and OBA. This may force those OBA providers who routinely practice without regard to practical and appropriate industry standards out of business. AAAHC accreditation of an OBA practice may serve as a confidence-inspiring indication to patients that nationwide peer-reviewed standards are being met. However, everyone involved must recognize that accreditation is not a substitute for the sound application of clinical knowledge and expertise, as well as the collection and assessment of quality assurance data. It is inappropriate to view each OBS client as a minihospital. Although this may seem a simpler business model, the business and legal issues can be far more complex than those found in more traditional locales. A meld between business-person and clinician is becoming more a rule than an exception, and efforts to maintain and promote professional sovereignty will help forge continued growth of this unique form of anesthesiology practice.