Bromodeoxyuridine tablet methodology for in vivo

5-Bromodeoxyuridine (BrdU) tablets with different physical characteristics are useful in a wide variety of studies requiring detection of DNA replication in vivo. These tablets can effect a high substitution of BrdU in DNA, thereby permitting sister chromatid differentiation in chromosomes stained with 33258 Hoechst alone or in conjunction with Giemsa. Baseline and cyclophosphamide-induced in vivo sister chromatid exchange frequencies in mouse spleen, marrow, and thymus were measured and found to be significantly greater than those in spermatogonia. Sister chromatid exchange analysis was also extended to mouse liver and to Chinese hamster and Armenian hamster marrow cells. Sister chromatid differentiation was observed in Armenian hamster meiotic tissue, and evidence for interhomolog chromatid exchange obtained.     

Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy

Ongoing clinical trials designed to explore the use of extracranial stereotactic radiosurgery (ESR) for different tumour sites use large doses per fraction (15, 20, 30 Gy or even larger). The question of whether the linear-quadratic (LQ) model is appropriate to describe radiation response for such large fraction doses has been raised and has not been answered definitively. It has been proposed that mechanism-based models, such as the lethal-potentially lethal (LPL) model, could be more appropriate for such large fraction/acute doses. However, such models are not well characterized with clinical data and they are generally not easy to use. The purpose of this work is to modify the LQ model to more accurately describe radiation response for high fraction/acute doses. A new parameter is introduced in the modified LQ (MLQ) model. The new parameter introduced is characterized based both on in vitro cell survival data of several human tumour cell lines and in vivo animal iso-effect curves. The MLQ model produces a better fit to the iso-effect data than the LQ model. For a high single dose irradiation, the prediction of the MLQ is consistent with that from the LPL model. Unlike the LPL model, the MLQ model retains the simplicity of the LQ model and uses the well-characterized alpha and beta parameters. This work indicates that the standard LQ model can lead to erroneous results when used to calculate iso-effects with large fraction doses, such as those used for ESR. We present a solution to this problem.     

Effects of muscle conditioning on position sense at the human forearm during loading or fatigue of elbow flexors and the role of the sense of effort

In a forearm position-matching task in the horizontal plane, when one (reference) arm is conditioned by contraction and length changes, subjects make systematic errors in the placement of their other, indicator arm. Here we describe experiments that demonstrate the importance not just of conditioning the reference arm, but of the indicator arm as well. Total errors from muscle conditioning represented up to a quarter of the angular range available to subjects. The sizes of the observed effects have led us to repeat other, previously reported experiments. In a matching task in the vertical plane, when muscles of both arms were conditioned identically, if the subject supported their arms themselves, or when the arms were loaded by the addition of weights, the loading did not introduce new position errors. To test the effect of exercise, subjects' elbow flexors were exercised eccentrically or concentrically by asking them to lower or raise a set of weights using forearm muscles. The exercise produced 25–30% decreases in maximum voluntary contraction strength of elbow flexors and this led to significant position-matching errors. The directions and magnitudes of the errors were similar after the two forms of exercise and indicated that subjects perceived their exercised muscles to be longer than they actually were. To conclude, the new data from loading the arm are not consistent with the idea that the sense of effort accompanying support of a load, provides positional information in any simple way. Our current working hypothesis is that when muscles are active, position-sense involves operation of a forward internal model. Loading the arm produces predictable changes in motor output and afferent feedback whereas changes after exercise are unpredictable. This difference leads to exercise-dependent errors.     

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY)

Maturity-onset diabetes of the young (MODY) resulting from mutations in the glucokinase (GCK) gene accounts for approximately 20% of MODY in the UK. We have performed fluorescent single stranded conformation polymorphism (F-SSCP) analysis or direct sequencing of the GCK gene in 212 patients referred as part of a research cohort or for diagnostic molecular genetic testing. Mutation screening has identified 43 different mutations in 61 individuals, of which 21 are novel. This report details the mutations identified and their associated clinical features.     

Synaptic actions of peripheral nerve impulses upon Deiters neurones via the mossy fibre afferents

1. The cerebellar integration of sensory inputs to Deiters neurones was investigated in decerebrate cats. In some preparations decerebration was combined with transection of the olivocerebellar fibres.2. In the latter preparations peripheral nerve impulses generally produced a response consisting of a sequence of the following post-synaptic potentials: (i) an initial e.p.s.p. (d(1)), (ii) early i.p.s.p. (h(1)), (iii) later i.p.s.p. (h(2)).3. The mean latencies of d(1), h(1) and h(2) were 5.7, 7.3 and 9.8 msec from the forelimb nerves, and 7.5, 9.0 and 13.4 msec from the hind limb nerves, respectively.4. The stimulus intensity-response relation indicates that the Group I muscle afferents as well as the low threshold cutaneous afferents contribute to the response.5. In the preparations with the intact inferior olive there were additional components of the post-synaptic potentials: a later e.p.s.p. (d(2)) and another later i.p.s.p. (h(3)), their mean latencies being 15.3 and 19.7 msec from the forelimb nerves, and 18.0 and 21.3 msec from the hind limb nerves, respectively.6. The d(1) and h(2) components were attributed to the mossy fibre afferents and d(2) and h(3) to the climbing fibres; d(1) and d(2) were due to excitation through the collaterals of the mossy and climbing fibres, and h(2) and h(3) to inhibition from Purkyne cells activated by the mossy and climbing fibres, respectively. h(1) was too early to be produced through the cerebellum, and was probably mediated by inhibitory neurones in the reticular formation.     

The Turner syndrome research registry: Creating equipoise between investigators and participants

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient‐powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33‐item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side‐by‐side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.     

Comparison of in vitro and in vivo alpha/beta ratios for prostate cancer

Parallel in vitro and in vivo studies provide insight into the relationship between clinical response and intrinsic cellular radiosensitivity and may aid in the development of predictive assays. Compilations of radiosensitivity parameters from in vitro experiments can also be used to examine the potential effectiveness of alternative or new treatment plan designs until enough clinical data become available to directly estimate the requisite radiosensitivity parameters. In this work, survival data for six prostate cancer cell lines (ten datasets total) have been extracted from the literature and re-analysed using the linear-quadratic (LQ) survival model. The paired bootstrap technique for regression is used to compute 95% confidence intervals for the estimated radiosensitivity parameters. LQ radiosensitivity parameters derived from the in vitro data are then compared to radiosensitivity parameters derived from clinical data for prostate cancer. Estimates of alpha range from 0.09 to 0.35 Gy(-1) (all cell lines), and the alpha/beta ratio ranges from 1.09 to 6.29 Gy (all cell lines). Point estimates of the repair half-time (PPC-1, TSU-Pr1, PC-3 and DU-145 cell lines) range from 5.7 to 8.9 h (95% confidence interval from 0.26 h to 10.7 h). Differences in the radiosensitivity parameters determined from the data reported by different laboratories are as large as or larger than the differences in radiosensitivity parameters observed among the various prostate cell lines. The reported studies demonstrate that even seemingly small corrections for dose rate effects, such as those expected in high dose rate (HDR) experiments, can sometimes have a significant impact on estimates of alpha and alpha/beta. By neglecting dose rate effects in the analysis of HDR experiments, estimates of the alpha/beta, ratio may be too high by factors as large as 1.3 to 6.2. The half-time for repair derived from the in vitro experiments appears significantly larger (slower repair rate) than estimates derived from the clinical data. However, the prostate radiosensitivity parameters alpha and alpha/beta may be approximately the same in vitro and in vivo. Most of the in vitro data are consistent with an alpha/beta ratio for prostate cancer less than 3 or 4 Gy.     

Teaching systems-based practice to residents by using independent study projects.

The changing health care marketplace requires new graduates to be familiar with complex health systems. Since 1999 the Oregon Health & Science University internal medicine residency program has offered a seminar-based health systems curriculum, but residents lacked an opportunity to actively apply learned concepts. To achieve this goal, the authors developed a second curricular component, the Health Systems Independent Study Project (HSISP). The HSISP is a self-directed assessment of a health care system or delivery issue residents complete in their third year. The curriculum was implemented in 2001 with goals of gaining a focused understanding of a health systems concept and building related skills. Residents present their study projects to all curriculum participants. Topics addressed so far include adherence to coronary artery disease guidelines in a defined population, screening strategies for lung cancer, resident burnout, and many others. Residents have found that these projects enhance their systems knowledge, help them link systems-based-practice concepts to clinical practice, and foster opportunities for networking and early career development.     

The 4p- syndrome—An autopsy study

The autopsy of an infant with the 4p- or Wolf-Hirschhorn syndrome revealed visceral abnormalities not previously described, i.e., agenesis of the gallbladder and spleen. The parent's chromosomes were normal.