Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

The Effect of Anti-Tuftsin Antibody on the Phagocytosis of Bacteria by Human Neutrophils

Tuftsin (Thr-Lys-Pro-Arg) is a naturally occurring tetrapeptide which stimulates most known functions of the polymorphonuclear and mononuclear phagocytic cell lines. Although tuftsin is a well characterized bioactive peptide, the exact physiological role tuftsin plays remains unclear. Specific mouse anti-tuftsin antiserum generated in our laboratory, is now available for phagocytosis inhibition studies. Monolayers of human neutrophils were prepared on glass coverslips from a few drops of finger prick blood obtained from a single healthy donor. The monolayers were treated with and without mouse anti-tuftsin antiserum at dilutions of 1:1000 or 1:2000. Exogenous tuftsin (1 μg/ml) was also added with and without antibody. Treated and untreated neutrophils were subsequently incubated with unopsonized Staphylococcus aureus. The proportion of cells accomplishing phagocytosis (phagocytic index) and the number of bacteria engulfed per cell (avidity index) were recorded. The results showed that exogenous tuftsin increased phagocytosis while the addition of mouse anti-tuftsin antiserum at a 1:1000 dilution inhibited phagocytosis both with and without exogenous tuftsin. This effect was diminished by the antiserum at the 1:2000 dilution. This study reaffirms that tuftsin plays an important physiological role in phagocytosis.     

Japanese encephalitis after a two-week holiday in Bali

Japanese encephalitis is described in a 10-year-old girl after a short holiday in Bali. Four days after returning to Australia the patient presented with a high fever, stupor and rapidly-developing focal neurological signs. Recovery occurred gradually over a period of three months and she has returned to school. Japanese encephalitis viral infection was confirmed by a marked rise in specific haemagglutination-inhibition antibodies and the presence of immunoglobulin M antibodies to the flavivirus group. It is important to be aware of the possibility of arboviral infection in patients with encephalitis. In view of the recent outbreaks of Japanese encephalitis in Asia, travellers to the region should be warned to protect themselves from mosquito-bites.     

CongenitaI Polycystic Disease of the Brain: Report of an Unusual Case

Multiple congenital supratentorial intracerebral cysts occurred in a newborn infant. The cysts, of varying size, content and lining, occupied the cerebral hemispheres. They formed a mosaic pattern on CT scan and left no trace of a recognisable ventricular system. Multiple surgical procedures were performed during the first year of life, and at one year the child was very well and asymptomatic, with two functioning shunts.     

Comparison of local tumor recurrence following excision with the CO2 laser, Nd:YAG laser, and Argon Beam Coagulator

This study compares the incidence of local tumor recurrence following primary excision with the CO2 laser, Nd:YAG laser (contact), Argon Beam Coagulator, or electrocautery. One hundred eight Fisher 344 rats with R3230AC mammary tumors (1.6 +/- 0.04 [SD] cm diameter) were used. All animals were randomized into groups of similar tumor size. In groups C and CS, excision was performed with a Sharplan 1060 CO2 laser (TEMoo, 25 W, continuous wave [CW], 0.2-mm spot size). Wounds in group CS were "sterilized" (0.5-mm spot size, 25 W, CW) by gently heating the wound without causing blanching or charring. In group N, a 0.4-mm contact Laser Blade and a Cooper 8000 Nd:YAG laser at 20 W CW was used. In groups SA1 and SA2, tumors were excised with the scalpel, and hemostasis and wound "sterilization" were accomplished with the Bard System 6000 Argon Beam Coagulator (ABC) at 40 W and 4 liters/min argon gas flow in SA1 and 12 liters/min in SA2. In group E, excision was accomplished at 40 W blend mode, 10 W spray mode. In group EA, excision was accomplished at 60 W cutting current, and hemostasis was achieved with the ABC. The animals were examined for evidence of recurrence for 34 days postoperatively. Mortalities were excluded from analysis. The incidence of recurrence was 11/14 (79%) in C, 6/16 (38%) in CS, 10/14 (71%) in SA1, 6/13 (46%) in SA2, 6/15 (40%) in N, 7/10 (70%) in EA, and 3/15 (20%) in E. Group E is statistically different (P less than .01) from groups EA, C, and SA1. Group C was different (P less than .01) from groups E, CS, and N. These results demonstrate an inverse relationship between tumor recurrence and local thermal effects at the surgical site. The ABC did not increase tumor recurrence. Contact YAG surgery was similar to CO2 laser excision and "sterilization." An attempt to study the influence of gas flow and pressure on local tumor recurrence and metastases should be made.     

Effects of oral stimulation on the cephalic phase of pancreatic exocrine in dogs

In dogs with cannulated gastric and duodenal fistulas, gustatory receptors were stimulated by swab application of taste stimulus solutions. The experiments were performed with fistulas open. A single taste stimulus of either 0.29 M sucrose, 0.1 M critic acid or 0.001 M quinine sulfate produced a large increase in pancreatic secretion of both volume and protein output. Sucrose was a better stimulant than citric acid or quinine sulfate for pancreatic output. After only one or two trials with each stimulant, the secretory response was no longer seen in any of the dogs. Following this extinction of the secretory response, the same dogs were given orally 100 ml of taste stimulus solution mixed with 25 g cellulose. Pancreatic secretory response occurring within 40 min following administration was gradually restored primarily for sucrose-cellulose. Oral administrations of the unpalatable citric or quinine-cellulose mixtures resulted in low pancreatic output, similar to the control water-cellulose. In contrast to oral administrations, intragastric administrations of these taste stimulus-cellulose mixtures resulted in low pancreatic output within 40 min after administration. The results suggest that taste stimulation alone does not affect pancreatic secretion. However, when coupled with swallowing, there is a greater effect by palatable than unpalatable taste stimuli on the cephalic phase of pancreatic secretion.     

Human chondrocytes differentially express matrix modulators during in vitro expansion for tissue engineering

Cartilage tissue engineering plays an important role in the generation of grafts for reconstructive surgery. In cultured chondrocytes, the dedifferentiation of cells seems unavoidable for multiplication. Dedifferentiated cells produce matrix of less quality, and the molecular basis is still not well understood. Therefore, the aim of our study was to investigate the expression of matrix modulators in human chondrocytes during expansion. Human chondrocytes were isolated from septal cartilage (n=32) and held in primary cell culture. Cells were harvested after 1, 6 and 21 days. The differentiation of cells using light microscopy, the expression patterns of various proteins (MMPs, BMPs, and TIMPs) using immunohistochemistry, and the expression of distinct genes using microarray technique, were investigated. The chondrocytes showed strong in vitro proliferation. After 6 and 21 days, BMP-5 and -8 were up-regulated, BMP-2 was down-regulated and BMP-6 was inactivated. Other BMPs were not expressed. The expression of MMP-2, -3 and -13 was up-regulated from day 1 to 21, and MMP-12 and -20 were down-regulated. Other MMPs were not expressed. TIMP-1 was up-regulated and TIMP-3 was down-regulated during expansion. Differential expression of matrix modulators might influence the matrix composition of engineered cartilage. Improving the basic knowledge in this area may ultimately help clinicians to identify and proactively intervene in an attempt to prevent bioartificial cartilage from losing stability.     

Three-dimensional eye-head coordination during gaze saccades in the primate

The purpose of this investigation was to describe the neural constraints on three-dimensional (3-D) orientations of the eye in space (Es), head in space (Hs), and eye in head (Eh) during visual fixations in the monkey and the control strategies used to implement these constraints during head-free gaze saccades. Dual scleral search coil signals were used to compute 3-D orientation quaternions, two-dimensional (2-D) direction vectors, and 3-D angular velocity vectors for both the eye and head in three monkeys during the following visual tasks: radial to/from center, repetitive horizontal, nonrepetitive oblique, random (wide 2-D range), and random with pin-hole goggles. Although 2-D gaze direction (of Es) was controlled more tightly than the contributing 2-D Hs and Eh components, the torsional standard deviation of Es was greater (mean 3.55 degrees ) than Hs (3.10 degrees ), which in turn was greater than Eh (1.87 degrees ) during random fixations. Thus the 3-D Es range appeared to be the byproduct of Hs and Eh constraints, resulting in a pseudoplanar Es range that was twisted (in orthogonal coordinates) like the zero torsion range of Fick coordinates. The Hs fixation range was similarly Fick-like, whereas the Eh fixation range was quasiplanar. The latter Eh range was maintained through exquisite saccade/slow phase coordination, i.e., during each head movement, multiple anticipatory saccades drove the eye torsionally out of the planar range such that subsequent slow phases drove the eye back toward the fixation range. The Fick-like Hs constraint was maintained by the following strategies: first, during purely vertical/horizontal movements, the head rotated about constantly oriented axes that closely resembled physical Fick gimbals, i.e., about head-fixed horizontal axes and space-fixed vertical axes, respectively (although in 1 animal, the latter constraint was relaxed during repetitive horizontal movements, allowing for trajectory optimization). However, during large oblique movements, head orientation made transient but dramatic departures from the zero-torsion Fick surface, taking the shortest path between two torsionally eccentric fixation points on the surface. Moreover, in the pin-hole goggle task, the head-orientation range flattened significantly, suggesting a task-dependent default strategy similar to Listing's law. These and previous observations suggest two quasi-independent brain stem circuits: an oculomotor 2-D to 3-D transformation that coordinates anticipatory saccades with slow phases to uphold Listing's law, and a flexible "Fick operator" that selects head motor error; both nested within a dynamic gaze feedback loop.     

Preliminary assessment of the Con-Bio laser in vivo

A variety of lasers are available for the treatment of pigmented and vascular lesions. This paper presents our preliminary evaluation of the Q-switched 532 nm Con-Bio laser (Continuum Biomedical, Livermore, CA) in a murine model. Mice were anesthetized with intraperitoneal pentobarbital. Laser impacts (10 nsec, 150 mJ max.) were created on the ears at fluences of 1.5, 2, 3, 4, 5, and 6 J/cm 2. Acute study animals were sacrificed 15 min postinjury. Tissues were fixed in formalin and examined via light microscopy. Chronic study animals were allowed to heal for 3 weeks postoperatively. Parameters analyzed included the presence or absence of blistering, hemorrhage, visual assessment of thermal injury, microscopic evidence of vascular coagulation, or disruption and cosmesis. Acute vascular disruption and coagulation were present in all samples. Healing and cosmesis were good at all fluences tested. Tests of the laser in a prefocused mode produced a tissue cavitation effect with a depth of coagulation of 0.73 +/- 0.44 mm and hemorrhage of 0.68 +/- 0.41 mm. A chronic study of the vascular effect on larger vessels (1-2 mm) was conducted on a rabbit ear. Acute disruption was observed, however, all vessels were recanalized when examined grossly and histologically at 3 weeks. These preliminary results suggest that this new laser may be useful for the treatment of cutaneous vascular lesions. Further studies and clinical trials are warranted.