Use of autologous fibrin glue in the treatment of splenic trauma: an experimental study.

There is little doubt that preserving the spleen will contribute to a much more favourable outcome in patients undergoing splenic surgery, as a result of avoiding the well known risks of splenectomy. Among many operative methods described for splenic salvage, application of autologous fibrin glue (AFG) is particularly promising because of its unique characteristics. The use of AFG has been evaluated and its efficacy and tissue compatibility assessed in the treatment of splenic trauma in 15 partially splenectomized New Zealand White rabbits. The application of the AFG to the resected splenic surface achieved complete haemostasis in all animals. The animals were divided into four groups and were killed at varying intervals ranging from 24 h to 10 weeks. During re-exploration there was no evidence of recurrent bleeding and histopathological examination revealed progressive absorption of the AFG with a minimal inflammatory response. It is concluded that AFG is an effective haemostatic agent with good systemic and local compatibility and can be used in splenic salvage, which thereby avoids the use of non-autologous products with their risks of disease transmission.     

Evaluation of neurosensory alterations via clinical neurosensory tests following anterior maxillary osteotomy (Bell technique)

Neurosensory deficits are the most common complication following orthognathic surgery. Le Fort I and sagittal split ramus osteotomies have been widely studied but there is a lack of data about the neurosensory alterations resulting from anterior maxillary osteotomy (AMO). This paper evaluates the neurosensory alterations in cutaneous regions including lower eyelid, cheek, nose, upper lip and vestibular and palatal mucosal areas using simple clinical tests following AMO performed with Bell's incision so patients can be properly informed about the extent of sensory loss and its rate of recovery following AMO. Twenty-four sides of 12 patients (eight females; four males) with a mean age of 14.20 ± 1.86 years (range 12–17 years) were examined. Pin prick sensation, light touch sensation, static and dynamic two-point discrimination tests were used. Following AMO, vestibular mucosa, upper lip, nose and cheek were the most commonly affected sites. No alterations were detected in lower eyelid and palatal mucosa. The neurosensory deficits in cheek, nose and upper lip resolved 10 days after surgery. The vestibular mucosa showed normal sensation on day 30. In conclusion, following AMO, neurosensory alterations can occur, but it will resolve spontaneously in 30 days.     

Diversity of γδ T-cell antigens

In the last two decades, it has become clear that γδ T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, γδ antigens as a whole resemble more the antigens recognized by antibodies than those recognized by αβ T cells. Because of this antigenic diversity, no single mechanism—such as the major histocompatibility complex (MHC) restriction of αβ T cells—is likely to provide a basis for all observed T-cell antigen receptor (TCR)-dependent γδ T-cell responses. Furthermore, available evidence suggests that many individual γδ T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of γδ T-cell populations, and thus generate a more efficient immune response.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.