A rationale and framework for addressing physician cognitive impairment.

Medical error is costly, in terms of the health and wellbeing of the patient, their family, and the financial burden placed on the medical system. Reducing medical error is paramount to minimizing harm and improving outcomes. One potential source of medical error is physician cognitive impairment. Determining how to effectively assess and mange physician cognitive impairment is an important, albeit difficult problem to address. There have been calls and attempts to implement age-based cognitive screening, but this approach is not optimal. Instead, we propose that neuropsychological assessment is the gold standard for fitness-for-duty evaluations and that there is a need for the development of physician-based, normative data to improve these evaluations. Here, we outline the framework of our research protocol in a large, academic medical center, in partnership with hospital leadership and legal counsel, which can be modeled by other medical centers. With high rates of physician burnout and an aging physician population, the United States is facing a looming public health crisis that requires proactive management.

Children as hematopoietic cell donors in research: when is it approvable?

With increasing frequency, allogeneic hematopoietic cell transplantation involving children is being performed in the research setting. Allogeneic hematopoietic cell transplantation, however, cannot be performed without a hematopoietic stem cell (HSC) donor. This donor is often a sibling of the recipient and may also be a child. In such circumstances, it is unclear whether or how the federal regulations for pediatric research apply to the minor donors. This introductory paper reviews the issues to be considered while evaluating studies that use HSCs obtained from minor donors and identifies areas where further research is needed. In the era of increasing applicability for donor-derived cellular therapies, we provide a suggested framework for determining when minor donors qualify as human research subjects and when their participation can be approved under the federal regulations.

Insufficient evidence to support separate BMI definitions for obesity in children and adolescents from south Asian ethnic groups in the UK.

Re-evaluation of adult obesity thresholds in some ethnic groups has led to the questioning of childhood obesity thresholds. An expert group was convened to examine the representativeness of childhood obesity definitions, evidence for ethnic differences in body composition in UK children and the extent of misclassification of adiposity by current body mass index (BMI) thresholds in south Asian and black groups. The group concluded that the current International Obesity Task Force (IOTF) definitions remained the most appropriate for use in the United Kingdom, but further research was needed on the relationship of body shape, fat mass, metabolic markers and ethnicity in children and adolescents.

Body fat reference curves for children.

OBJECTIVE: To refine the diagnosis of childhood obesity by creating new sex-specific centile curves for body fat and to base these references on a simple and affordable method that could be widely adopted in clinical practice and surveys. DESIGN: Body fat was measured by bio-impedance in 1985 Caucasian children aged 5-18 years from schools in Southern England. Smoothed centile charts were derived using the LMS method. RESULTS: The new body fat curves reflect the known differences in the development of adiposity between boys and girls. The curves are similar by sex until puberty but then diverge markedly, with males proportionately decreasing body fat and females continuing to gain. These sex differences are not revealed by existing curves based on body mass index. We present charts in which cutoffs to define regions of 'underfat', 'normal', 'overfat' and 'obese' are set at the 2nd, 85th and 95th centiles. These have been designed to yield similar proportions of overweight/overfat and obese children to the IOTF body mass index cutoffs. CONCLUSIONS: Direct assessment of adiposity, the component of overweight that leads to pathology, represents a significant advance over body mass index. Our new charts will be published by the Child Growth Foundation for clinical monitoring of body fat, along with the software to convert individual measurements to Z-scores.

Immune reconstitution following hematopoietic progenitor cell transplantation: challenges for the future.

Successful hematopoietic progenitor cell transplantation requires rapid and complete transfer of the donor hematopoietic and immune systems to the host. Whereas the uncontrolled transfer of a nontolerant donor immune system results in GVHD in many cases, strategies which diminish GVHD also diminish immune reconstitution. Thus, the reliable, rapid and safe transfer of immunity from donor to host remains a major challenge for the field. Advances in the understanding of the biology of immune reconstitution have elucidated that thymic-dependent immune reconstitution can restore global immunity, but is especially vulnerable to toxicities associated with transplant. Alternatively, homeostatic peripheral expansion can be exploited for targeted immunity toward pathogens and tumors, but is difficult to manipulate without exacerbating GVHD risk. New translatable strategies are needed to safely augment one or both of these pathways in the setting of allogeneic hematopoietic progenitor cell transplantation.

Highly efficient blue-light generation from a compact, diode-pumped femtosecond laser by use of a periodically poled KTP waveguide crystal.

We present a simplified, potentially portable, and highly efficient blue-light source from a periodically poled KTP waveguide crystal with a compact femtosecond Cr:LiSAF laser. This light source generates 5.6 mW of blue average output power at 424 nm with 27 mW of incident fundamental in a single-pass extracavity arrangement at room temperature. The overall system efficiency of electrical power to blue light is 0.5%, and the internal second-harmonic generation conversion efficiency is as high as 37%. The slope efficiency of 5.5% pJ(-1) at low pulse energies is, to our knowledge, the highest slope efficiency yet reported for frequency conversion into the blue spectral region.

Interleukin-7: master regulator of peripheral T-cell homeostasis?

Recent evidence has implicated interleukin-7 (IL-7) as a master regulator of T-cell homeostasis, based upon its essential role in the homeostatic expansion of naive T-cell populations in response to low-affinity antigens (Ags) and its capacity to enhance dramatically the expansion of peripheral T-cell populations in response to high-affinity Ags. Furthermore, T-cell-depleted humans have a unique inverse relationship between the peripheral CD4(+) T-cell count and the level of circulating IL-7. Together, these data suggest that increased amounts of IL-7 become available following T-cell depletion, thus, enhancing the high- and low-affinity Ag-driven expansion of the population of residual, mature T cells and boosting thymic regenerative capacity, as a means to restore T-cell homeostasis.

A potential role for interleukin-7 in T-cell homeostasis.

Interleukin (IL)-7 is known to up-regulate thymopoietic pathways of T-cell regeneration. Recent work also has shown it to potently enhance thymic-independent peripheral expansion and to restore immunocompetence in athymic T-cell-depleted hosts. We hypothesized that endogenous IL-7 could contribute to the restoration of T-cell homeostasis following T-cell depletion. To analyze this, we evaluated circulating IL-7 levels and lymphocyte subsets in multiple clinical cohorts with T-cell depletion of varying etiologies. In pediatric (n = 41) and adult (n = 51) human immunodeficiency virus-infected CD4-depleted patients, there were strong inverse correlations between IL-7 levels and CD4 counts (r = -0.77, P <.0001, and r = -0.68, P <.0001). Declines in IL-7 were temporally correlated with recovery of CD4 counts. Similar patterns were observed in CD4-depleted patients receiving cancer chemotherapy (r = -0.65, P =.009). Therefore, in 2 disparate clinical scenarios involving CD4 depletion, IL-7 levels dynamically respond to changes in CD4 T-cell number, making this cytokine uniquely suited as a candidate regulator of T-cell homeostasis. Furthermore, in patients with idiopathic CD4 lymphopenia, a much weaker relationship between IL-7 levels and peripheral blood CD4 counts was observed, suggesting that an impaired IL-7 response to CD4 depletion may contribute to the impaired lymphocyte homeostasis observed in this population. In light of the known effects of IL-7 on T-cell regeneration, we postulate that increased availability of IL-7 could play a critical role in restoring T-cell homeostasis following T-cell depletion.

Interleukin-7 restores immunity in athymic T-cell-depleted hosts.

Thymic-deficient hosts rely primarily on antigen-driven expansion to restore the peripheral T-cell compartment following T-cell depletion (TCD). The degree to which this thymic-independent pathway can restore immune competence remains poorly understood but has important implications for a number of clinical conditions including stem cell transplantation and human immunodeficiency virus (HIV) infection. A model of HY-mediated skin graft rejection by athymic, TCD mice was used to show that restoration of naive and recall responses via peripheral expansion requires transfer of only 25 x 10(6) lymph node (LN) cells representing approximately 10% of the T-cell repertoire. Constitutive expression of bcl-2 in the expanding inocula restored recall responses to HY at a substantially lower LN cell dose (1 x 10(6)), which is normally insufficient to induce HY-mediated graft rejection in athymic hosts. Interestingly, bcl-2 had no effect on primary responses. Interleukin-7 (IL-7) potently enhanced thymic-independent peripheral expansion and led to HY graft rejection using an LN cell dose of 1 x 10(6) in both primary and recall models. The restoration of immune competence by IL-7 appeared to be mediated through a combination of programmed cell death inhibition, improved costimulation, and modulation of antigen-presenting cell (APC) function. These results show that immune competence for even stringent antigens such as HY can be restored in the absence of thymic function and identify IL-7 as a potent modulator of thymic-independent T-cell regeneration.

Propagation of intercellular calcium waves in C6 glioma cells transfected with connexins 43 or 32.

In this study, gap junction-deficient C6 glioma cells, transfected with either connexin 43 (Cx43) or 32 (Cx32), have been used to evaluate the ability of these connexins to pass intercellular Ca2+ waves. Ca2+ waves, observed with fluorescence imaging using fura-2 or fluo-3, were initiated by mechanical stimulation in the presence of a supra-perfusion of the extracellular fluid or by the non-contact technique of flash photolysis of intracellular caged-IP3. Following manual mechanical stimulation, the parental C6 glioma cells and cells expressing Cx43 and Cx32 gap junctions all propagated intercellular Ca2+ waves. Ca2+ waves in cells expressing Cx43 traveled approximately twice the distance as compared to waves in cells expressing Cx32 or parental cells. The cells expressing Cx43 were also about twice as sensitive to ATP as cells expressing Cx32. In the presence of a supra-perfusion of extracellular fluid, the Ca2+ waves in parental cells were almost abolished while the mechanically induced Ca2+ waves in the cells expressing Cx43 and Cx32 propagate similar but limited distances of several cells in a direction opposite to the fluid flow. The photolytic release of IP3, but not Ca2+, in cells expressing Cx43 or Cx32 resulted in the propagation of Ca2+ waves that traveled distances similar to those observed in the presence of supra-perfusion. Parental C6 glioma cells did not initiate intercellular Ca2+ waves when stimulated by photolysis. From these studies we conclude that (1) both Cx43 and Cx32 based gap junctions are permeable to IP3 and can serve to communicate Ca2+ waves, (2) that Ca2+ wave propagation via gap junctions was dependent on the diffusion of IP3 but not Ca2+, (3) that an extracellular messenger capable of communicating waves is released from only the stimulated cell, and (4) that simultaneous intracellular and extracellular signaling can occur to enhance the propagation of intercellular Ca2+ waves.

IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation.

Thymic-dependent differentiation of bone marrow (BM)-derived progenitors and thymic-independent antigen-driven peripheral expansion of mature T cells represent the 2 primary pathways for T-cell regeneration. These pathways are interregulated such that peripheral T-cell expansion is increased in thymectomized versus thymus-bearing hosts after bone marrow transplantation (BMT). This study shows that this interregulation is due to competition between progeny of these 2 pathways because depletion of thymic progeny leads to increased peripheral expansion in thymus-bearing hosts. To test the hypothesis that competition for growth factors modulates the magnitude of antigen-driven peripheral expansion during immune reconstitution in vivo, a variety of T-cell active cytokines were administered after BMT. Of the cytokines (interleukins) tested (IL-3, IL-12, IL-6, IL-2, and IL-7), IL-2 modestly increased peripheral expansion in the face of increasing numbers of thymic emigrants, whereas IL-7 potently accomplished this. This report also demonstrates that the beneficial effect of IL-7 on immune reconstitution is related to both increases in thymopoiesis as well as a direct increase in the magnitude of antigen-driven peripheral expansion. Therefore, the administration of exogenous IL-7, and to a lesser extent IL-2, abrogates the down-regulation in antigen-driven peripheral expansion that occurs in thymus-bearing hosts after BMT. These results suggest that one mechanism by which T-cell-depleted hosts may support antigen-driven T-cell expansion in vivo is via an increased availability of T-cell-active cytokines to support clonal expansion.

Efficient frequency doubling of a pulsed laser diode by use of a periodically poled KTP waveguide crystal with Bragg gratings.

Blue light with an average power of as much as 7.5 mW in picosecond pulses has been generated at 486, 488, and 491 nm from a frequency-doubled, nonresonant injection seeded, gain-switched InGaAs/GaAs diode laser by use of a periodically poled KTP waveguide crystal that incorporates a Bragg grating section.

Impact of CDMA wireless phone power output and puncture rate on hearing aid interference levels.

Interference between digital wireless phones and hearing aids occurs when the radiofrequency bursts from the phone transmission are demodulated by the hearing aid amplifier. The amplified interference signal is heard as a "buzz" or "static" by the hearing aid wearer. Most research and standards development activity has focused on worst-case scenarios with the phone operating at its maximum power. Since this power level is often not typical in urban and suburban settings, it is of value to determine the impact of lower power levels on the overall level of audible interference. Using a frequency analyzer, and several hearings aids and code division multiple access (CDMA) phones, the audio frequency spectrum of interference was recorded for each phone-aid combination and for a range of power levels producing from no interference to maximum interference. As phone power is increased, the interference signal becomes distinguishable from the ambient noise level and a linear response region is observed in which a specified increase in power output results in a proportional increase in the overall input referenced interference level (OIRIL). As power is increased beyond the linear region, the hearing aid enters a saturation region where an additional power increase results in a reduction or no increase in the OIRIL. The numeric differences in interference documented in this study were used in conjunction with the results of a previous study by the authors to determine the impact of reduced power on speech intelligibility and annoyance. The amount of improvement for a given power reduction depends on the radiofrequency immunity of the hearing aid and is substantial for hearing aids with poor immunity. For high-immunity aids, the level of audible interference remains low even at high phone power levels.

Monitoring children's growth: how are we doing?

This month the Chief Medical Officer's National Screening Committee held its first conference on systematic reviews of screening in child health. It was managed by the Child Growth Foundation, included an interim report on growth screening and posed the question whether children needed more of the same. Tam Fry, Honorary Chairman of the Foundation, believes that, as far as growth is concerned, they do despite the improvements that have been made since the "new" centile charts were introduced four years ago and reported in Professional Care of Mother & Child.