Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat

Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.     

Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity.

Stage I and II squamous cell cancers of the oral cavity have a high recurrence rate given their size and relative amenability to surgical resection. It has been suggested that one way to decrease this recurrence rate is to augment the surgical resection of these tumors with either elective neck dissection or radiation therapy. However, this would expose a significant number of patients to the unnecessary morbidity associated with either of these modalities. In an attempt to identify those patients most at risk for recurrence, we retrospectively determined the clinical and histologic factors that were associated with recurrence in 49 patients with stage I and II oral cavity cancer. Multiple regression analysis revealed that when various interactions between variables were controlled for, only the presence of a positive surgical margin or a tumor depth greater than 5 mm was significantly associated with recurrence. Each individually increased the likelihood of recurrence almost threefold.     

Antileishmanial activity of harmaline and other tryptamine derivatives

Tryptamine derivatives harmaline and α-ethyltryptamine were found to possess a novel antiparasitic action against human pathogen Leishmania mexicana amazonensis both in vitro and in vivo. In vitro, harmaline was the most potent compound tested, with an ED₅₀ of 99μ, whilst α-ethyltryptamine (ED₅₀ 149 μ) had the best therapeutic index (2). In vivo, α-ethyltryptamine was most effective when given orally (ED₅₀ 47 mg/kg), but was also effective when given topically. We suggest that further investigation of traditional plant drugs containing derivatives of β-carbolines and alkyltryptamines would provide a number of novel antiparasitic drugs.     

Discovery and inclusion of SOFA score episodes in mortality prediction

Predicting the survival status of Intensive Care patients at the end of their hospital stay is useful for various clinical and organizational tasks. Current models for predicting mortality use logistic regression models that rely solely on data collected during the first 24 h of patient admission. These models do not exploit information contained in daily organ failure scores which nowadays are being routinely collected in many Intensive Care Units. We propose a novel method for mortality prediction that, in addition to admission-related data, takes advantage of daily data as well. The method is characterized by the data-driven discovery of temporal patterns, called episodes, of the organ failure scores and by embedding them in the familiar logistic regression framework for prediction. Our method results in a set of D logistic regression models, one for each of the first D days of Intensive Care Unit stay. A model for day d  D is trained on the patient subpopulation that stayed at least d days in the Intensive Care Unit and predicts the probability of death at the end of hospital stay for such patients. We implemented our method, with a specific form of episodes, called aligned episodes, on a large dataset of Intensive Care Unit patients for the first 5 days of stay (D = 5) in the unit. We compared our models with ones that were developed on the same patient subpopulations but which did not use the episodes. The new models show improved performance on each of the five days. They also provide insight in the effect of the various selected episodes on mortality.     

Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content

Amyotrophic lateral sclerosis (ALS) is a late-onset neurological disorder characterized by death of motoneurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the mechanisms whereby they induce disease are not fully understood. Here, we use time-lapse microscopy to monitor for the first time the effect of mutant SOD1 on fast axonal transport (FAT) of bona fide cargoes in living neurons. We analyzed FAT of mitochondria that are a known target for damage by mutant SOD1 and also of membrane-bound organelles (MBOs) using EGFP-tagged amyloid precursor protein as a marker. We studied FAT in motor neurons derived from SOD1G93A transgenic mice that are a model of ALS and also in cortical neurons transfected with SOD1G93A and three further ALS-associated SOD1 mutants. We find that mutant SOD1 damages transport of both mitochondria and MBOs, and that the precise details of this damage are cargo-specific. Thus, mutant SOD1 reduces transport of MBOs in both anterograde and retrograde directions, whereas mitochondrial transport is selectively reduced in the anterograde direction. Analyses of the characteristics of mitochondrial FAT revealed that reduced anterograde movement involved defects in anterograde motor function. The selective inhibition of anterograde mitochondrial FAT enhanced their net retrograde movement to deplete mitochondria in axons. Mitochondria in mutant SOD1 expressing cells also displayed features of damage. Together, such changes to mitochondrial function and distribution are likely to compromise axonal function. These alterations represent some of the earliest pathological features so far reported in neurons of mutant SOD1 transgenic mice.