Textbook outcome: A novel metric in heart transplantation outcomes.

OBJECTIVE: Assessing heart transplant program quality using short-term survival is insufficient. We define and validate the composite metric textbook outcome and examine its association with overall survival. METHODS: We identified all primary, isolated adult heart transplants in the United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files from May 1, 2005, to December 31, 2017. Textbook outcome was defined as length of stay 30 days or less; ejection fraction greater than 50% during 1-year follow-up; functional status 80% to 100% at 1 year; freedom from acute rejection, dialysis, and stroke during the index hospitalization; and freedom from graft failure, dialysis, rejection, retransplantation, and mortality during the first year post-transplant. Univariate and multivariate analyses were performed. Factors independently associated with textbook outcome were used to create a predictive nomogram. Conditional survival at 1 year was measured. RESULTS: A total of 24,620 patients were identified with 11,169 (45.4%, 95% confidence interval, 44.7-46.0) experiencing textbook outcome. Patients with textbook outcome were more likely free from preoperative mechanical support (odds ratio, 3.504, 95% confidence interval, 2.766 to 4.439, P < .001), free from preoperative dialysis (odds ratio, 2.295, 95% confidence interval, 1.868-2.819, P < .001), to be not hospitalized (odds ratio, 1.264, 95% confidence interval, 1.183-1.349, P < .001), to be nondiabetic (odds ratio, 1.187, 95% confidence interval, 1.113-1.266, P < .001), and to be nonsmokers (odds ratio, 1.160, 95% confidence interval,1.097-1.228, P < .001). Patients with textbook outcome have improved long-term survival relative to patients without textbook outcome who survive at least 1 year (hazard ratio for death, 0.547, 95% confidence interval, 0.504-0.593, P < .001). CONCLUSIONS: Textbook outcome is an alternative means of examining heart transplant outcomes and is associated with long-term survival. The use of textbook outcome as an adjunctive metric provides a holistic view of patient and center outcomes.

Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20µM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.

[Research in amyotrophic lateral sclerosis: what is new in 2009?]. / La recherche sur la SLA en 2009 : compte rendu du groupe bibliographique de la coordination des centres SLA.

This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published.

The development of a testosterone stimulation test in the Virginia opossum (Didelphis virginiana) and its use in evaluating deslorelin contraception.

The aims of the present study were to examine the variability of testosterone secretion in the Virginia Opossum over a 24 h period and to develop a testosterone stimulation test that would provide an index of the prevailing testosterone biosynthetic capacity of the testes; the latter was used to clinically evaluate the efficacy of a gonadotrophin-releasing hormone agonist contraceptive. Sexually-mature captive opossums (n = 12) located in Africam Safari (Mexico) sampled every 12 h over 24 h consistently showed basal (<0.21 ng mL(-1)) blood testosterone concentrations. Intra-muscular injection of buserelin (2 microg mL(-1)) and human chorionic gonadotrophin (hCG; 1000 IU) resulted in an increase (P < 0.05) of plasma testosterone concentrations with maximal concentrations (3.9 ng mL(-1) and 5.8 ng mL(-1) respectively) occurring 120 min after injection. Plasma testosterone declined relatively rapidly to basal concentrations after 240 min with hCG but remained elevated after the same period of time with buserelin. Male opossums treated with (n = 6) and without (n = 6) a controlled-release deslorelin implant (Suprelorin; 4.7 mg deslorelin) were evaluated over a 10-week period for changes in testosterone secretion (hCG stimulation test) and sperm production (spermatorrhea). At the end of this period, the animals were hemi-castrated and their relative testicular quantitative histology compared. Testosterone concentration decreased over the course of the study in both treated and control animals (P < 0.0001) but there was no apparent effect of deslorelin on testosterone secretion, testicular histology (relative proportions of testicular cell types and seminiferous tubule diameter), or sperm production (presence of sperm in the cauda epididymis or urine).

Parvalbumin-, calbindin-, and calretinin-immunoreactive neurons in the prefrontal cortex of the owl monkey (Aotus trivirgatus): a standardized quantitative comparison with sensory and motor areas.

Recent studies have revealed regional variation in the density and distribution of inhibitory neurons in different cortical areas, which are thought to reflect area-specific specializations in cortical circuitry. However, there are as yet few standardized quantitative data regarding how the inhibitory circuitry in prefrontal cortex (PFC), which is thought to be involved in executive functions such as cognition, emotion and decision making, compares to that in other cortical areas. Here we used immunohistochemical techniques to determine the density and distribution of parvalbumin (PV)-, calbindin (CB)-, and calretinin (CR)-immunoreactive (ir) neurons and axon terminals in the dorsolateral and orbital PFC of the owl monkey (Aotus trivirgatus), and compared them directly with data obtained using the same techniques in 11 different visual, somatosensory and motor areas. We found marked differences in the density of PV-ir, CB-ir, and CR-ir interneurons in several cortical areas. One hundred and twenty eight of all 234 possible between-area pair-wise comparisons were significantly different. The density of specific subpopulations of these cells also varied among cortical areas, as did the density of axon terminals. Comparison of PFC with other cortical areas revealed that 40 of all 66 possible statistical comparisons of the density of PV-ir, CB-ir, and CR-ir cells were significantly different. We also found evidence for heterogeneity in the pattern of labeling of PV-ir, CB-ir, and CR-ir cells and axon terminals between the dorsolateral and orbital subdivisions of PFC. These data are likely to reflect basic differences in interneuron circuitry, which are likely to influence inhibitory function in the cortex.

Brain chimeras for the study of an avian model of genetic epilepsy: structures involved in sound and light-induced seizures.

The epileptic homozygotes of the Fayoumi strain of chickens (Fepi) are affected by photogenic reflex epilepsy with complete penetrance. Here we demonstrate that they are equally affected by audiogenic reflex epilepsy induced by intense sound stimulation. All the Fepi display sound-induced seizures from hatching to adulthood consisting of initial 'ictal arousal' and running fits usually followed by generalized clonico-tonic convulsions. A running fit is the preconvulsive motor symptom specifically induced by auditory stimulation while neck myoclonus is the preconvulsive motor symptom specifically induced by photic stimulation. The EEG interictal spikes and spike and waves are suppressed and replaced by a desynchronized trace during the seizures of both kinds. Viable neural chimeras were obtained by graft of embryonic brain vesicles from Fepi donors into normal chick embryos. Transfer of the complete audiogenic and photogenic phenotypes was obtained in chimeras resulting from embryonic substitution of both the prosencephalon and mesencephalon. The substitution of the prosencephalon alone resulted in transfer of interictal paroxysmal EEG activity accompanied by the sound and light-induced desynchronization and 'ictal arousal' with no motor seizures. Chimeras with embryonic substitution of the mesencephalon alone displayed running fits and convulsions induced by sound stimulation but only neck myoclonus following light stimulation. The conclusions are reached that: (i) the Fepi is a model of audiogenic and photogenic reflex epilepsy; (ii) in both types, the seizure initiator and the convulsion generator are localized in the brainstem, although reinforcement from telencephalic visual structures is needed to trigger photogenic generalized convulsions.

Reflex epilepsy of the fowl and its transfer to normal chickens by brain embryonic grafts.

The genetic photosensitive epilepsy of the Fayoumi chicken was transferred to normal chickens by in situ grafts at 2 days of incubation, of both the prosencephalic and mesencephalic brain vesicles taken from epileptic embryos. However, mesencephalic graft is sufficient to allow convulsions under sound stimulation. Typical EEG patterns are recorded in chimeras having the prosencephalon plus or not the mesencephalon. We conclude that, in this mutant, the whole neural tissue is affected, but the seizure generator is localized inside the mesencephalon, and specific sensory pathways are necessary for seizures to occur.