Heterogeneity in chronic fatigue syndrome - empirically defined subgroups from the PACE trial.

BACKGROUND: Chronic fatigue syndrome is likely to be a heterogeneous condition. Previous studies have empirically defined subgroups using combinations of clinical and biological variables. We aimed to explore the heterogeneity of chronic fatigue syndrome. METHOD: We used baseline data from the PACE trial, which included 640 participants with chronic fatigue syndrome. Variable reduction, using a combination of clinical knowledge and principal component analyses, produced a final dataset of 26 variables for 541 patients. Latent class analysis was then used to empirically define subgroups. RESULTS: The most statistically significant and clinically recognizable model comprised five subgroups. The largest, 'core' subgroup (33% of participants), had relatively low scores across all domains and good self-efficacy. A further three subgroups were defined by: the presence of mood disorders (21%); the presence of features of other functional somatic syndromes (such as fibromyalgia or irritable bowel syndrome) (21%); or by many symptoms - a group which combined features of both of the above (14%). The smallest 'avoidant-inactive' subgroup was characterized by physical inactivity, belief that symptoms were entirely physical in nature, and fear that they indicated harm (11%). Differences in the severity of fatigue and disability provided some discriminative validation of the subgroups. CONCLUSIONS: In addition to providing further evidence for the heterogeneity of chronic fatigue syndrome, the subgroups identified may aid future research into the important aetiological factors of specific subtypes of chronic fatigue syndrome and the development of more personalized treatment approaches.

Fetal dose during radiotherapy: clinical implementation and review of the literature.

Two pregnant patients received radiation therapy, one for the treatment of mediastinal Hodgkin's lymphoma and the other for a head and neck squamous cell carcinoma. The fetuses were both protected by additional shielding which reduced the unshielded exposure of the first fetus by 20-40%, and that of the second by 20-60%. The first child received an estimated maximum dose of 42 cGy, the second a maximum dose of 9 cGy. Treatment details are reported and a review of the literature that addresses the possible irradiation-induced side effects at low doses is included.

Quantifying the impact of membrane microtopology on effective two-dimensional affinity.

Just as interactions of soluble proteins are affected by the solvent, membrane protein binding is influenced by the surface environment. This is particularly true for adhesion receptors because their function requires tightly apposed membranes. We sought to demonstrate, and further, to quantify the possible scale of this phenomenon by comparing the effective affinity and kinetic rates of an adhesion receptor (CD16b) placed in three distinct environments: red blood cells (RBCs), detached Chinese hamster ovary (CHO) cells, and K562 cells. Effective affinity reflects both the intrinsic receptor-ligand kinetics and the effectiveness of their presentation by the host membranes. Expression of CD16b, a low affinity Fcgamma receptor, was established by either transfection or spontaneous insertion via its glycosylphosphatidylinositol anchor. Binding to IgG-coated RBCs, measured using a micropipette method, indicated a 50-fold increase in effective affinity for receptors on RBCs over CHO and K562 cells, whereas the off rates were similar for all three. Electron microscopy confirmed that specific tight contacts were broad in RBC-RBC conjugates but sparse in CHO-RBC conjugates. We suggest that through modulation of surface roughness the cytoskeleton can greatly impact the effectiveness of adhesion molecules, even those with no cytoplasmic structures. Implications for locomotion and static adhesion are discussed.

Current indications for left thoracotomy in coronary revascularization and valvular procedures.

BACKGROUND: Left thoracotomy is infrequently used for cardiac procedures, but its application in reoperative and minimally invasive coronary revascularization and in valvular procedures has been reported recently. METHODS: Three case reports and a review of the current literature illustrate the unique benefits of this approach for myocardial revascularization and valve replacement. RESULTS: Reoperative coronary revascularization of the left anterior descending and circumflex coronary arteries was performed off-pump via a left posterolateral thoracotomy. For the second case, this approach was used for coronary artery bypass grafting of the right coronary and left anterior descending arteries with femoral-femoral cardiopulmonary bypass in a patient with congestive heart failure and coronary artery disease who also required closure of a patent ductus arteriosus. In the third case, mitral valve replacement using femoral venous and aortic cannulation for cardiopulmonary bypass was performed via a left thoracotomy to avoid a retrosternal gastric conduit in a patient with severe mitral stenosis and congestive heart failure. All patients returned to normal activity and are asymptomatic. CONCLUSIONS: These case reports and a comprehensive review of the literature demonstrate the utility of left thoracotomy as an alternative approach to standard median sternotomy in selected cases of revascularization and valvular procedures.

Modeling concurrent binding of multiple molecular species in cell adhesion.

Cell adhesion provides not only physical linkage but also communication between the cell and its environment. As such, it is important to many cellular functions. Recently, the probability distribution of forming a low number of specific adhesive bonds in a short-duration contact has been described (Chesla et al., Biophys. J. , 1998, 75:1553-1572). This model assumes that binding occurs between a single receptor species and a single ligand species. However, cell adhesion molecules rarely work alone in physiological settings. To account for these in vivo situations, we extended the previous model to include concurrent interactions of multiple receptor-ligand species, introducing the concept of independent binding. Closed-form solutions have been obtained for cases where competition is absent or can be neglected. In two companion papers (Williams et al., Biophys. J., 2000, 79:1858-1866; 2000, 79:1867-1875), the model developed herein has been applied to analyze two sets of experiments designed such that the validity of the theory was also tested.

Concurrent binding to multiple ligands: kinetic rates of CD16b for membrane-bound IgG1 and IgG2.

CD16b (FcgammaRIIIb) is the most common receptor for the Fc domain of IgG on leukocytes. The binding of Fc receptors to immunoglobulin triggers a wide array of immune responses. In published assays measuring the reaction of CD16b with isotypes of soluble IgG, the affinity for IgG1 was low and that for IgG2 was undetectable. Here we report the first measurement of kinetic rates of CD16b binding to membrane-bound IgG isotypes-a physically distinct and physiologically more relevant presentation-using a recently developed micropipette method. In contrast to the soluble data, we found clearly measurable IgG2 binding, with a forward kinetic rate six-fold lower than that of IgG1 but with an equilibrium affinity only threefold lower. This suggests a nonnegligible role for IgG2 in Fc-mediated immune responses, particularly in longer duration contacts. The binding constants were measured from two sets of experiments. Single-isotype experiments were analyzed by an existing model (, Biophys. J. 75:1553-1572). The resulting kinetic rates were used as input to an extended model (, Biophys. J. 79:1850-1857.) to predict the results of mixed-isotype experiments. This design enabled rigorous validation of the concurrent binding model through a test of its predictive ability.

Concurrent and independent binding of Fcgamma receptors IIa and IIIb to surface-bound IgG.

Fc receptor-antibody interactions are key mechanisms through which antibody effector functions are mediated. Neutrophils coexpress two low-affinity Fcgamma receptors, CD16b (FcgammaRIIIb) and CD32a (FcgammaRIIa), possessing overlapping ligand binding specificities but distinct membrane anchor and signaling capacities. Using K562 cell transfectants as a model, the kinetics of both separate and concurrent binding of CD16b and CD32a to surface-bound IgG ligands were studied. CD16b bound human IgG with 2-3 times higher affinity than did CD32a (A(c)K(a) = 4.1 and 1.6 x 10(-7) microm(4), respectively) and both FcgammaRs had similar reverse kinetic rates (k(r) = 0.5 and 0.4 s(-1), respectively). Because CD16b is expressed on neutrophils at a 4-5 times higher density than CD32a, our results suggest that CD16b plays the dominant role in binding of neutrophils to immobilized IgG. The question of possible cross-regulation of binding affinity between CD16b and CD32a was investigated using our multispecies concurrent binding model (Zhu and Williams, Biophys. J. 79:1850-1857, 2000). Because the model assumes independent binding (no cooperation among different species), the excellent agreement between the model predictions and the experimental data suggests that, when coexpressed on K562 cells, these two FcgammaRs do not interact in a manner that alters the kinetic rates of either molecule.

Counterpoint: better radiation treatment of non-small cell lung cancer using new techniques without elective nodal irradiation.

The treatment of non-small cell lung cancer has continued to evolve with the advent of improved staging technologies, chemotherapeutic agents, and methods of radiation delivery. Treatment of clinically uninvolved, regional lymph nodes historically has been delivered in the attempt to cover unseen disease, reduce regional failure, and improve survival. None of these suppositions has been tested nor are they supported by data. With enhanced staging using modalities like positron emission tomography and esophageal ultrasonography, treatment portals can be designed to encompass known disease with greater accuracy and confidence. Data for early-stage non-small cell lung cancer is now increasing and strongly suggest that eliminating elective nodal irradiation does not result in a high incidence of nodal relapse and does not compromise survival. Three-dimensional conformal radiotherapy incorporates better targeting and beam directions to effect smaller treatment volumes that include only clinically evident disease. It provides treatment techniques that maximize tumor dose and minimize normal tissue toxicity. Using smaller fields that do not incorporate elective nodal regions may allow higher doses, and these may help improve local control and survival in a disease where current results are unacceptable.

Clinical implementation of the AAPM Task Group 36 recommendations on fetal dose from radiotherapy with photon beams: a head and neck irradiation case report.

We present the results of our efforts in estimating and diminishing the fetal dose expected when a 29-year-old patient, 22 weeks pregnant, received external beam radiation therapy for a squamous cell carcinoma of the tongue. We explain our use of the information contained, and recommendations made, in the Report of the American Association of Physicists in Medicine Radiation Therapy Committee Task Group 36 [Med. Phys. 22, 63-82 (1995)]. We also explain our dose estimation, describe our validation measurements, and demonstrate the effectiveness of supplemental shielding. Consequently, this case report will serve as a guide to radiation oncologists and medical physicists who may encounter similar cases.

Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group.

Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

Evolution of a cardiovascular information system.

The competitive nature of our evolving health care system mandates a concomitant increase in the level of sophistication of the cardiovascular information system. The new paradigms in health care also mandate a re-engineering of the process of data collection and analysis. This paper deals with a variety of hardware, software, and human issues encountered at our institution. Topics covered include implementation of service line management, utilization of an interdisciplinary medical informatics model, database conversion, and application development. Special attention will be paid to the development of a system which is a comprehensive information system for clinical and financial management of the cardiovascular patient, not just a quality-of-care database.

What is the marginal cost for marginal risk in cardiac surgery?

BACKGROUND: It has been shown that postoperative length of stay (LOS) correlates highly with mortality risk for cardiac surgical procedures. Similar correlations have been found for charges with LOS and costs with risk. METHODS: Postoperative LOS and risk scores were obtained, tabulated, and compiled into the five original Parsonnet risk groups for 2,589 patients who underwent cardiac operations from 1992 through 1996 at one hospital. The correlation of the group mean LOS with the group mean risk was tested. RESULTS: The correlation coefficient was 0.9827; 96.58% of the variance was removed using risk to predict LOS. A calculation of the difference in cost for difference in risk for cohorts of patients is developed. CONCLUSIONS: The high correlation of mean LOS with mean risk permits calculation of marginal cost for marginal risk based on clinical data. The marginal cost is equal to the difference in variable costs for cohorts.

Onlay patch repair of tracheobronchial rupture.

Two cases are reported of tracheobronchial repair in which a posteriorly based intercostal muscle flap was incorporated into the membranous portion of the airway to increase the diameter of the reconstruction or to relieve tension in the suture lines. This technique permits repair of a small left main bronchus without compromise to the lumen and tension-free repair of the membranous trachea.

Inducible macrophage apoptosis following sepsis is mediated by cysteine protease activation and nitric oxide release.

Recent studies indicate that polymicrobial sepsis can markedly increase inducible macrophage Ao (nonnecrotic cellular suicide) and that this is associated with decreased M phi function. In vitro studies suggest that M phi Ao can be induced by IL-1 beta via interleukin-1 beta-converting enzyme (ICE, a cysteine protease), prostanoids, or reactive oxygen/nitrogen. However, the mechanism(s) underlying this process in septic M phi remains unknown. To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-operation. Twenty-four hours thereafter, M phi were isolated from the peritoneum (PM phi) and liver (LM phi). Macrophage monolayers were treated with LPS (10 micrograms/ml) alone (Cont) or in the presence of iodoacetamide (Iodo, 5 mM), N-methylmalamide (meth, 5 mM), ibuprophen (Ibu, 40 micrograms/ml), N-methyl-L-arginine (LNMA, 0.4 mM), or superoxide dismutase (SOD, 60,000 U/ml) for 24 hr. The extent of Ao was determined using an enzyme-linked immunosorbent cell-death assay, which detects the presence of cytoplasmic oligonucleosomes measured as optical density. The results indicate that both PM phi and LM phi from septic animals exhibit increased Ao over cells from sham animals. However, only the nonspecific cysteine protease inhibitors (Iodo and meth) and the NO inhibitor LNMA blocked septic mouse M phi Ao. Furthermore, only PM phi from CLP mice treated with Iodo, but not LNMA or IBU, showed an improved capacity to release IL-6. We conclude that increased M phi Ao seen during sepsis appears to be mediated by both ICE-like cysteine protease activation and NO release but the level/mechanism of action of these inhibitors differs.

Role of radiotherapy in the treatment of small cell lung carcinoma.

Radiotherapy is an important component in the treatment of limited stage small cell carcinoma of the lung. It improves both local control and survival. This article reviews the scientific and clinical data that have led to combined therapy being considered the current standard for care of limited stage disease. Questions of radiation dose, treatment volume, fractionation, and integration with chemotherapy are discussed. New avenues of investigation to reduce toxicity and optimize treatment efficacy are also discussed.

Photodynamic therapy for endobronchial malignant disease: a prospective fourteen-year study.

BACKGROUND: After intravenous injection, the photosensitizer dihematoporphyrin either is selectively retained in tumor cells. This photosensitizer absorbs 630 nm wavelength light energy and produces a singlet oxygen that destroys the tumor. Photodynamic therapy was performed on endobronchial tumors with the use of light generated by an argon dye laser system delivered through cylinder diffusing tip quartz fibers passed through the biopsy channel of a flexible endoscope. OBJECTIVES: Our objectives were to determine factors affecting survivals, benefits, and complications. METHODS: From 1982 to May 1996, photodynamic therapy was performed on 175 patients with endobronchial tumors. Sixteen had stage I disease, 9 stage II, 42 stage IIIA, 64 stage IIIB, and 44 stage IV. All were followed up until death or November 1996. RESULTS: Multivariate analysis of survival of the effects of age, sex, race, histologic features, Karnofsky Performance Status, and clinical stage showed the clinical stage (p < 0.0001) to be the most statistically significant factor. Sixteen patients with stage I disease had a 93% 5-year disease-related estimated survival. Median (months) survivals were as follows: stage I = not reached; stage II = 22.5; stage IIIA = 5.7; stage IIIB = 55; and stage IV = 5.0. Performance status does become significant when it reaches 50 but was not significant for stages I or II. CONCLUSIONS: Photodynamic therapy may be considered as an alternative treatment for patients under consideration for surgical treatment for stage I carcinoma in whom the risk of surgery is high. The length of palliation for patients with noncurative disease was equal to or better than that reported historically for most other treatment regimens.

Kinesthetic perceptions of intrinsic anterior-posterior axes.

The purpose of this research was to investigate whether kinesthetic and proprioceptive perceptions of "straight ahead" were defined by a head- or trunk-fixed axis. Subjects were instructed to align the forearm with the head or trunk anterior-posterior (a/p) axis by elbow flexion or extension in the horizontal plane in five different conditions. In each condition the experimenter varied initial elbow and shoulder horizontal flexion or extension angles and head and/or trunk orientation (by rotation about a vertical axis) on each trial before the subject moved the forearm to align it with the head or trunk axis. The upper limb motion was voluntarily constrained to the horizontal plane through the shoulder. Variable errors were significantly lower when subjects aligned the forearm to the trunk-fixed a/p axis. Furthermore, the perceptual errors showed a greater dependence on body segment orientations when the forearm was aligned to the head axis than to the trunk axis. We conclude that the trunk a/p axis is preferred to the head a/p axis for specifying upper limb segment orientations in the horizontal plane at the kinesthetic perceptual level.

Visual perceptions of head-fixed and trunk-fixed anterior/posterior axes.

The purpose of the present experiment was to determine the preferred visual "straight ahead" or anterior/posterior (a/p) axis at the perceptual level. The ability of 12 neurologically normal, young adult subjects to position a rod parallel to the head and trunk a/p axes while viewing eccentrically located visual targets were studied under six conditions: 1. fixed-subjects stood erect with the head aligned to the trunk and viewed a central target while visually aligning a hand-held rod to the head and trunk a/p axis. 2. eyes-subjects moved only their eyes to view eccentric targets and aligned the rod to the head and trunk a/p axis. 3. head-trunk-subjects viewed the eccentric targets by rotating the head about a vertical axis and aligned the rod to the trunk a/p axis. 4. head-head-subjects viewed the targets as in 3 and positioned the rod parallel to the head a/p axis. 5. trunk-head-subjects viewed the targets by rotating the trunk and head as a unit about the vertical axis and aligned the rod parallel to the head a/p axis (note that the head and trunk a/p axes were misaligned by the experimenter prior to target viewing). 6. trunk-trunk-subjects viewed targets as in 5 and positioned the rod parallel to the trunk a/p axis. Subjects performed 25-35 consecutive trials within each condition. Perceptual errors were similar for aligning the rod to the trunk and head a/p axes; however, moving the trunk produced much larger constant and variable perceptual errors than moving the head. In a second experiment, four subjects controlled the position of a lighted rod held by a robot arm in complete darkness. They were instructed to align the rod to either the head or trunk a/p axis under conditions similar to the fixed, head-trunk, and head-head tasks described above. Perceptual errors were much larger when aligning the rod to the head a/p axis than to trunk a/p axis when the head was moved. This shows that the trunk a/p axis is clearly preferred at the perceptual level when visual background cues are not present. These data strongly suggest that the visual coordinate system uses a trunk-fixed a/p axis to define the subjective straight-ahead direction and right/left position of a target. Implications of these findings for sensorimotor transformations in control of upper limb movements to visual targets are discussed.