Strain-Dependent Differences in Bone Development, Myeloid Hyperplasia, Morbidity and Mortality in Ptpn2-Deficient Mice

Single nucleotide polymorphisms in the gene encoding the protein tyrosine phosphatase TCPTP (encoded by PTPN2) have been linked with the development of autoimmunity. Here we have used Cre/LoxP recombination to generate Ptpn2ex2−/ex2− mice with a global deficiency in TCPTP on a C57BL/6 background and compared the phenotype of these mice to Ptpn2−/− mice (BALB/c-129SJ) generated previously by homologous recombination and backcrossed onto the BALB/c background. Ptpn2ex2−/ex2− mice exhibited growth retardation and a median survival of 32 days, as compared to 21 days for Ptpn2−/− (BALB/c) mice, but the overt signs of morbidity (hunched posture, piloerection, decreased mobility and diarrhoea) evident in Ptpn2−/− (BALB/c) mice were not detected in Ptpn2ex2−/ex2− mice. At 14 days of age, bone development was delayed in Ptpn2−/− (BALB/c) mice. This was associated with increased trabecular bone mass and decreased bone remodeling, a phenotype that was not evident in Ptpn2ex2−/ex2− mice. Ptpn2ex2−/ex2− mice had defects in erythropoiesis and B cell development as evident in Ptpn2−/− (BALB/c) mice, but not splenomegaly and did not exhibit an accumulation of myeloid cells in the spleen as seen in Ptpn2−/− (BALB/c) mice. Moreover, thymic atrophy, another feature of Ptpn2−/− (BALB/c) mice, was delayed in Ptpn2ex2−/ex2− mice and preceded by an increase in thymocyte positive selection and a concomitant increase in lymph node T cells. Backcrossing Ptpn2−/− (BALB/c) mice onto the C57BL/6 background largely recapitulated the phenotype of Ptpn2ex2−/ex2− mice. Taken together these results reaffirm TCPTP's important role in lymphocyte development and indicate that the effects on morbidity, mortality, bone development and the myeloid compartment are strain-dependent

Malignant hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000–100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%

PI3Kinase signaling in glioblastoma

Glioblastoma (GBM) is the most common primary tumor of the CNS in the adult. It is characterized by exponential growth and diffuse invasiveness. Among many different genetic alterations in GBM, e.g., mutations of PTEN, EGFR, p16/p19 and p53 and their impact on aberrant signaling have been thoroughly characterized. A major barrier to develop a common therapeutic strategy is founded on the fact that each tumor has its individual genetic fingerprint. Nonetheless, the PI3K pathway may represent a common therapeutic target to most GBM due to its central position in the signaling cascade affecting proliferation, apoptosis and migration. The read-out of blocking PI3K alone or in combination with other cancer pathways should mainly focus, besides the cytostatic effect, on cell death induction since sublethal damage may induce selection of more malignant clones. Targeting more than one pathway instead of a single agent approach may be more promising to kill GBM cells

Mathematics and biology: a Kantian view on the history of pattern formation theory

Driesch’s statement, made around 1900, that the physics and chemistry of his day were unable to explain self-regulation during embryogenesis was correct and could be extended until the year 1972. The emergence of theories of self-organisation required progress in several areas including chemistry, physics, computing and cybernetics. Two parallel lines of development can be distinguished which both culminated in the early 1970s. Firstly, physicochemical theories of self-organisation arose from theoretical (Lotka 1910–1920) and experimental work (Bray 1920; Belousov 1951) on chemical oscillations. However, this research area gained broader acceptance only after thermodynamics was extended to systems far from equilibrium (1922–1967) and the mechanism of the prime example for a chemical oscillator, the Belousov–Zhabotinski reaction, was deciphered in the early 1970s. Secondly, biological theories of self-organisation were rooted in the intellectual environment of artificial intelligence and cybernetics. Turing wrote his The chemical basis of morphogenesis (1952) after working on the construction of one of the first electronic computers. Likewise, Gierer and Meinhardt’s theory of local activation and lateral inhibition (1972) was influenced by ideas from cybernetics. The Gierer–Meinhardt theory provided an explanation for the first time of both spontaneous formation of spatial order and of self-regulation that proved to be extremely successful in elucidating a wide range of patterning processes. With the advent of developmental genetics in the 1980s, detailed molecular and functional data became available for complex developmental processes, allowing a new generation of data-driven theoretical approaches. Three examples of such approaches will be discussed. The successes and limitations of mathematical pattern formation theory throughout its history suggest a picture of the organism, which has structural similarity to views of the organic world held by the philosopher Immanuel Kant at the end of the eighteenth century

Radical nephrectomy performed by open, laparoscopy with or without hand-assistance or robotic methods by the same surgeon produces comparable perioperative results

PURPOSE: Radical nephrectomy can be performed using open or laparoscopic (with or without hand assistance) methods, and most recently using the da Vinci Surgical Robotic System. We evaluated the perioperative outcomes using a contemporary cohort of patients undergoing radical nephrectomy by one of the above 4 methods performed by the same surgeon. MATERIALS AND METHODS: The relevant clinical information on 57 consecutive patients undergoing radical nephrectomy from September 2000 until July 2004 by a single surgeon was entered in a Microsoft Access DatabaseTM and queried. Following appropriate statistical analysis, p values < 0.05 were considered significant. RESULTS: Of 57 patients, the open, robotic, laparoscopy with or without hand assistance radical nephrectomy were performed in 18, 6, 21, and 12 patients, respectively. The age, sex, body mass index (BMI), incidence of malignancy, specimen and tumor size, tumor stage, Fuhrman grade, hospital stay, change in postoperative creatinine, drop in hemoglobin, and perioperative complications were not significantly different between the methods. While the estimated median blood loss, postoperative narcotic use for pain control, and hospital stay were significantly higher in the open surgery method (p < 0.05), the median operative time was significantly shorter compared to the robotic method (p = 0.02). Operating room costs were significantly higher in the robotic and laparoscopic groups; however, there was no significant difference in total hospital costs between the 4 groups. CONCLUSIONS: The study demonstrates that radical nephrectomy can be safely performed either by open, robotic, or laparoscopic with or without hand assistance methods without significant difference in perioperative complication rates. A larger cohort and longer follow up are needed to validate our findings and establish oncological outcomes