JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Successful resuscitation of an ASA 3 patient following ropivacaine-induced cardiac arrest.

A patient with severe myocardial disease and acute-on-chronic renal failure was undergoing a brachial plexus block for formation of an arteriovenous fistula when accidental intravascular injection of ropivacaine resulted in ventricular fibrillation. Cardiopulmonary resuscitation was instituted immediately and the advanced life support algorithm was followed until the return of sinus rhythm. Although, in comparison with bupivacaine, ropivacaine appears to be a safer local anaesthetic agent in the setting of intravenous injection, the emphasis on safety should remain a priority. Awareness of the risk of central nervous system and cardiovascular toxicity and preparation for immediate commencement of resuscitation in the event of toxicity remain of paramount importance.

Kinematic analysis of total knee prosthesis designed for Asian population.

In designing a total knee replacement (TKR) prosthesis catering for the Asian population, 62 sets of femur were harvested and analyzed. The morphometrical data obtained were found to be in good agreement with dimensions typical of the Asian knee and has reaffirmed the fact that Caucasian knees are generally larger than Asian knees. Subsequently, these data when treated using a multivariate statistical technique resulted in the establishment of major design parameters for six different sizes of femoral implants. An extra-small implant size with established dimensions and geometrical shape has surfaced from the study. The differences between the Asian knees and the Caucasian knees are discussed. Employing the established femoral dimensions and motion path of the knee joint, the articulating tibia profile was generated. All the sizes of implants were modeled using a computer-aided software package. Thereupon, these models that accurately fits the local Asian knee were transported into a dynamic and kinematic analysis software package. The tibiofemoral joint was modeled successfully as a slide curve joint to study intuitively the motion of the femur when articulating on the tibia surface. An optimal tibia profile could be synthesized to mimic the natural knee path motion. Details of the analysis are presented and discussed.

Determination of the major dimensions of femoral implants using morphometrical data and principal component analysis.

This paper describes the work that leads to the establishment of a set of major parameters for the design of symmetrical prosthetic implants for the Asian population. In the study, 62 sets of femurs harvested from cadavers were used. The morphometrical data obtained are compared with known results and found to be in good agreement with Asian knees. Subsequently, the data are treated and analysed using the principal component analysis, a statistical technique for analysing multivariate data. The analysis has resulted in the establishment of the major design parameters for six different sizes of femoral implants. Details of the analysis are presented. The major parameters obtained in this work are compared with those of existing implants. Results of the comparison are presented. The relationship between the anterio-posterior and medio-lateral dimensions is also examined and reported.

Parametric modelling of a knee joint prosthesis.

This paper presents an approach for the establishment of a parametric model of knee joint prosthesis. Four different sizes of a commercial prosthesis are used as an example in the study. A reverse engineering technique was employed to reconstruct the prosthesis on CATIA, a CAD (computer aided design) system. Parametric models were established as a result of the analysis. Using the parametric model established and the knee data obtained from a clinical study on 21 pairs of cadaveric Asian knees, the development of a prototype prosthesis that suits a patient with a very small knee joint is presented. However, it was found that modification to certain parameters may be inevitable due to the uniqueness of the Asian knee. An avenue for rapid modelling and eventually economical production of a customized knee joint prosthesis for patients is proposed and discussed.