Management of patients with hereditary hemorrhagic telangiectasia undergoing general anesthesia: a cohort from a single academic center’s experience

Purpose

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant disease characterized by capillary malformation leading to multisite cutaneomucosal telangiectasias and multiorgan arteriovenous malformations, which can present challenges to anesthetic care. The primary aim of this report is to present a large cohort of patients with hereditary hemorrhagic telangiectasia undergoing general anesthesia at our institution in regard to comorbid conditions and complications of surgical and anesthetic management.

Methods

A computerized search from January 1, 2002 through December 31, 2011 of the Mayo Clinic medical records database was performed for patients with hereditary hemorrhagic telangiectasia who underwent general anesthesia. Medical records were reviewed. Eligibility criteria included patients with definite or suspected hereditary hemorrhagic telangiectasia based on the Curacao diagnostic criteria who underwent general anesthesia during the study period.

Results

We identified 74 patients with hereditary hemorrhagic telangiectasia who underwent 163 surgeries. The majority had pulmonary arteriovenous malformations (56.7 %) and iron deficiency anemia (64.7 %), and high levels of disease burden with a median American Society of Anesthesiologist Physical Status score of 3. Most surgeries were related to treating conditions associated with hereditary hemorrhagic telangiectasia, with the majority being procedures to the nasal mucosa for recurrent epistaxis (47.2 %). A sizeable proportion of procedures to the nasal mucosa required transfusion of blood (12/77). One case of epistaxis required 11 units of blood until it was successfully controlled. Another notable complication included migration of a coil to pulmonary arteriovenous malformations into the cerebral circulation.

Conclusion

Surgical patients with hereditary hemorrhagic telangiectasia often present with multiorgan involvement. The anesthesia provider needs to be aware of the high prevalence of pulmonary arteriovenous malformations, which may be asymptomatic but can lead to embolic complications. Hemorrhage from epistaxis can be severe, and relatively focal procedures to the nasal mucosa can require blood transfusions.     

A new barium paste for computed tomography of the esophagus

A new 3% barium paste for use in CT of the esophagus was evaluated for its ability to coat the esophageal lumen in 31 patients. The esophagus was divided into proximal, mid, and distal segments to analyze the effectiveness of lumenal opacification. The average percent opacification of these segments was 74.5, 87.7, and 60.8%, respectively, for all patients. These results indicate that this product visibly coats the esophageal lumen in the majority of patients. We found that it is easy to use, is well tolerated, and did not produce scanning artifacts. We conclude that this new oral contrast agent could be used routinely in CT of the esophagus or in selected cases to clarify problem areas.     

Prediction of fetal lung maturity: inaccuracy of study using conventional ultrasound instruments

The ability of three ultrasound (US) parameters--echogenicity, texture, and through transmission--to predict fetal lung maturity was tested in 59 patients using currently available clinical US equipment. The chi square test was used to determine whether there was an association between any single parameter and a "mature" lecithin/sphingomyelin (LS) ratio or specific phosphatidycholine (SPC). Multiple linear regression analysis was used to assess the combined ability of these three parameters and gestational age to predict LS ratio and SPC. There was no correlation between fetal lung maturity, as determined by mature LS and SPC indices, and the US parameters tested using unmodified clinical equipment.     

Disease mapping of Leishmaniasis outbreak in Afghanistan: spatial hierarchical Bayesian analysis

ObjectiveTo analyze the spatial pattern of Leishmaniasis disease in Afghanistan, using provincial level geo-referenced data. The disease is contracted through bites from sand flies and is the third most common vector-borne disease. Leishmaniasis is a serious health concern in Afghanistan with about 250 000 estimated new cases of cutaneous infection nationwide and 67,000 cases in Kabul. This makes Kabul the city with the largest incidence of the disease worldwide.MethodsWe use a Bayesian hierarchical Poisson model to estimate the influence of hypothesized risk factors on the relative risk of the disease. We use random components to take into account the lack of independence of the risk between adjacent areas.ResultsStatistical inference is carried out using Markov Chain Monte Carlo simulation. The final model specification includes altitude, two random components (intercept and slope) and utilizes a conditional autoregressive prior with a deviance information criterion of 247.761. Spatial scan statistics confirm disease clusters in the North-Eastern and South-Eastern regions of Afghanistan with a p-value of less than 0.0001.ConclusionsThe study confirms disease clusters in the North-Eastern and South-Eastern regions of Afghanistan. Our findings are robust with respect to the specification of the prior distribution and give important insights into the spatial dynamics of Leishmaniasis in Afghanistan.     

Pap smear screening among women >/=40 years residing at the United States-Mexico border

Invasive cervical cancer is a preventable disease due to screening for precursor lesions using the Papanicolaou cytological testing (Pap smear). Participants were assessed regarding their access to and utilization of health care services, prevention orientation, history of chronic disease screening, and reproductive health history. Factors independently positively associated with Pap smear screening were age, clinical breast exam (CBE) in the last year, doctor recommendation of a Pap test, living in the United States, and checkup in the past year. Having a regular source of health care, as well as a doctor's recommendation for a Pap smear, appears to have a positive effect on women's Pap smear screening rates in U.S.-Mexico border communities.     

Exposure to Elemental Carbon,Organic Carbon,Nitrate, and Sulfate Fractions of Fine Particulate Matter and Risk of Preterm Birth in New Jersey,Ohio, and Pennsylvania (2000–2005)

Background

Particulate matter ≤ 2.5 μm in aerodynamic diameter (PM_2.5) has been consistently associated with preterm birth (PTB) to varying degrees, but roles of PM_2.5 species have been less studied.

Objective

We estimated risk differences (RD) of PTB (reported per 10⁶ pregnancies) associated with change in ambient concentrations of elemental carbon (EC), organic carbon (OC), nitrates (NO₃), and sulfates (SO₄).

Methods

From live birth certificates from three states, we constructed a cohort of singleton pregnancies at or beyond 20 weeks of gestation from 2000 through 2005 (n = 1,771,225; 8% PTB). We estimated mean species exposures for each week of gestation from monitor-corrected Community Multi-Scale Air Quality modeling data. RDs and 95% confidence intervals (CIs) for four PTB categories were estimated for each exposure using linear regression, adjusted for maternal race/ethnicity, marital status, education, age, smoking, maximum temperature, ozone, and season of conception. We also adjusted for other species in multi-species models.

Results

RDs varied by exposure window and outcome period. EC was positively associated with PTB after 27 and before 35 weeks of gestation. For example, for a 0.25-μg/m³ increase in EC exposure during gestational week 9, RD = 96 (95% CI: –20, 213) and RD = 145 (95% CI: –50, 341) for PTB during weeks 28–31 and 32–34, respectively. Associations with OCs were null or negative. RDs for NO₃ were elevated with exposure in early weeks of gestation, and null in later weeks. RDs for SO₄ exposure were positively associated with PTB, though magnitude varied across gestational weeks. We observed effect measure modification for associations between EC and PTB by race/ethnicity and smoking status.

Conclusion

EC and SO₄ may contribute to associations between PM_2.5 and PTB. Associations varied according to the timing of exposure and the timing of PTB.

Citation

Rappazzo KM, Daniels JL, Messer LC, Poole C, Lobdell DT. 2015. Exposure to elemental carbon, organic carbon, nitrate, and sulfate fractions of fine particulate matter and risk of preterm birth in New Jersey, Ohio, and Pennsylvania (2000–2005). Environ Health Perspect 123:1059–1065; http://dx.doi.org/10.1289/ehp.1408953     

Overriding native cell coordination enhances external programming of collective cell migration

As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, preexisting collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue—electrical stimulation and electrotaxis—to primary mouse skin monolayers where we can tune cell–cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell–cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing preexisting coordination in the tissue by specifically inhibiting E-cadherin–dependent cell–cell adhesion, either by disrupting the formation of cell–cell junctions with E-cadherin–specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control and demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, noncellular systems and confirm that endogenous collectivity should be considered as a key quantitative design variable when optimizing external control of collective migration.

Collective cell migration enables intricate, coordinated processes that are essential to multicellular life, spanning embryonic development, self-healing upon injury, and cancer invasion modes (1). Control of collective cell migration, therefore, would be a powerful tool for biology and bioengineering as such control would enable fundamentally new ways of regulating these key processes, such as enabling accelerated wound healing. Efficient and precise control over cell motility is becoming increasingly feasible with modern biotechnologies. Tunable chemical gradient generators can redirect chemotaxing cells (2, 3), optogenetics can allow dynamic control of cell contractility (4), micropatterned scaffolds can constrain and direct collective growth (5), and recent work in bioelectric interfaces has even demonstrated truly programmable control over directed cell migration in two dimensions (6, 7). However, despite advances in sophisticated tools, applying them to complex cellular collectives raises a fundamental problem: What happens when we command a tissue to perform a collective behavior that competes with its natural collective behaviors?Paradoxically, those endogenous collective cell behaviors already present in tissues are both a boon and bane for attempts to control and program cell behavior. On the one hand, endogenous collective cell migration means the cells already have established mechanisms for coordinated, directional migration that external cues and control can leverage. For instance, cadherin-mediated cell–cell adhesions in tissues mechanically couple cells together and allow for long-range force transmission and coordinated motion. This coupling allows tissues to migrate collectively and directionally over large distances and maintain cohesion and organization far better than individual cells might (8, 9). On the other hand, imposing a new behavior over an existing collective behavior may generate conflicts. Tight cell coupling can create a “jammed state” or solid-like tissue where cells are so strongly attached and confined that they physically lack the fluidity to migrate as a group (10, 11). Strong coordination established via physical coupling can hinder cells from responding to signals for migration, as shown by the need for zebrafish and other embryos to weaken cell–cell junctions prior to gastrulation to ensure cells collectively migrate to necessary locations (12–14). Hence, how “susceptible” a collective system may be to external control likely depends on a tug-of-war between the resilience and strength of the natural collective processes and the potency of the applied stimulus.Here, we specifically investigate the relationship and interplay between an applied, external command attempting to direct collective cell migration and the strength of the underlying collective behaviors already present in the tissue. We address two key questions. 1) How much does the strength of an endogenous collective migration behavior in a tissue limit our ability to control its collective cell migration? 2) How can we circumvent such limitations? To investigate these questions, we needed both a programmable perturbation capable of controlling collective migration and a physiologically relevant model system allowing for tunable “collectivity.” Here, we use collectivity to describe how strongly cells are coordinated with their neighbors during migration—highly collective cells exhibit strong, coordinated motion and vice versa. As a perturbation, we harnessed a bioelectric phenomenon called “electrotaxis”—directed cell migration in direct current (DC) electric fields—using our SCHEEPDOG bioreactor (6). Briefly, electrotaxis arises when endogenous, ionic fields form during healing or development (∼1 V/cm) and apply gentle electrophoretic or electrokinetic forces to receptors and structures in cell membranes, causing them to aggregate or change conformation to produce a front–rear polarity cue (15, 16). Components spanning phosphatidylinositol phosphates (PIPs), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), phosphatase and tensin homolog (PTEN), and small guanosine triphosphate (GTP)ases have been implicated in the transduction process, while gap junctions appear to have an inconclusive role (8, 17–19). Crucially, electrotaxis may be one of the broadest and most conserved migratory cues, having been observed in vitro in over 20 cell types across multiple branches of the tree of life (20–22). As electrotaxis in vitro appears to globally stimulate all cells equally and still induce directional motion, it is distinct from more locally dependent cues such as chemotaxis and haptotaxis. However, as no other reported cue has as much versatility and programmability, electrotaxis is an ideal choice for a broadly applicable cellular control cue in this study.To complement electrotaxis, we chose primary mouse skin for our model system as skin injuries were where the endogenous electrochemical fields that cause electrotaxis were first discovered (in vivo, the wound boundary is negative relative to the surrounding epidermis), and we and others have shown layers of keratinocytes to exhibit strong electrotaxis (6, 23–25). Critically, primary mouse keratinocytes have tunable collectivity in culture as the cadherin-mediated cell–cell adhesion strength in this system can be easily tuned by varying calcium levels in the media—with low-calcium media thought to mimic conditions in the basal layers of the epidermis with weak adhesions and high-calcium media akin to conditions in the uppermost layers of skin with strong adhesions (26–28).Together, these experimental approaches allowed us to precisely explore how the ability to externally “steer” collective migration in a living tissue using a powerful bioelectric cue depends on the native collectivity of the underlying tissue. First, we quantify collective strength in cultured skin layers by measuring neighbor coordination of cellular motion [a standard metric for collective motion adapted from collective theory (29)] and then, validate that the collectivity can be tuned in our model system of mouse keratinocyte monolayers by calibrating junctional E-cadherin levels. Next, we demonstrate how applying the same electrical stimulation conditions to tissues with differing native collectivity results in radically different outputs, with weakly collective tissues precisely responding to our attempts to control their motion, while strongly collective tissues exhibited detrimental supracellular responses resulting in tissue collapse. We then prove that E-cadherin is responsible for these differences, ruling out any effects of calcium signaling per se. Finally, we leverage these findings to develop an approach that allows us to effectively control mature, strongly collective tissues, which we utilize to demonstrate that we can accelerate wound repair in vitro.     

BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway

Chronic lymphocytic leukemia (CLL) B cells express BR3, the specific receptor for the B cell-activating factor of tumor necrosis factor family (BAFF). CLL cells also express 2 other receptors for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI), which also bind a proliferation-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor of kappa B (NF-kappaB) pathway in CLL cells, whereas signaling through BCMA/TACI induced activation of the canonical NF-kappaB pathway. Blocking BR3 did not inhibit the capacity of BAFF to support CLL cell survival in vitro. On the other hand, specifically blocking the canonical NF-kappaB pathway with UTC, an inhibitor of IkappaB kinase beta (IKKbeta), or transfection of CLL cells with the IkappaBalpha super-repressor, blocked the capacity of BAFF and APRIL to promote CLL cell survival in vitro. This contrasts what is found with normal blood B cells, which apparently depend on activation of the alternative NF-kappaB pathway for BAFF-enhanced survival. These findings suggest that inhibitors of protein kinase IKKbeta, which is required for activation of the canonical NF-kappaB pathway, might have a therapeutic role in this disease.