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.

Pediatric phase I trial and pharmacokinetic study of piritrexim administered orally on a five-day schedule.

Piritrexim, a new nonclassical antifolate, was evaluated in a multiinstitutional phase I trial in children. The starting dose was 290 mg/m2/day, administered p.o. every 12 h for 5 consecutive days, with courses repeated every 21 days. Dose reduction, initially to 200 mg/m2/day and subsequently to 140 mg/m2/day, was required because dose limiting myelosuppression and mucositis were encountered at the 290- and 200-mg/m2/day dose levels. Non-dose limiting toxicities included transient elevations in liver function tests, mild nausea, and skin rashes. The maximum tolerated dose was 140 mg/m2/day for 5 days. Pharmacokinetic monitoring was performed at steady state during the first course. For the 140-, 200-, and 290-mg/m2/day dose groups, the mean +/- SE peak plasma concentrations were 5.3 +/- 0.84, 9.3 +/- 1.7, and 10.2 +/- 2.3 microM, respectively, and occurred at a median of 1.5 h following the p.o. dose. The mean area under the plasma concentration-time curves were 18.1 +/- 2.3, 45.4 +/- 8.9, and 56.9 +/- 16.3 microM.h, respectively. Absolute bioavailability in two patients who were also monitored following a single i.v. dose of 140 and 200 mg/m2/day of piritrexim was 35 and 93%, respectively. Dose limiting toxicities were observed in 9 of 10 patients with 12-h trough piritrexim concentrations greater than 0.5 microM, whereas only 2 of 7 patients with trough concentrations less than 0.5 microM experienced dose limiting toxicities. A limited pharmacokinetic sampling strategy that allowed the area under the plasma concentration-time curve to be accurately predicted from the 3- and 6-h plasma drug concentration was developed. The recommended dose for future phase II trials is 140 mg/m2/day administered p.o. every 12 h for 5 consecutive days. Pharmacokinetic monitoring at 3, 6, and 12 h postdose may be useful for estimating bioavailability and for predicting which patients are at greatest risk for developing toxicity.

Characterization and distribution of basic fibroblast growth factor-containing cells in the rat hippocampus.

Basic fibroblast growth factor (bFGF), a member of the heparin-binding growth factor family, is present in relatively high levels in the brain where it may play an important role in the maintenance, repair, and reorganization of the tissue. Although bFGF is associated mainly with astrocytes throughout most of the central nervous system (CNS), a narrow but prominent band of pyramidal neurons, which coincides with the CA2 subregion of Ammon's horn in the hippocampus, stains intensely for bFGF. In order to gain an understanding of which cells express bFGF and whether or not BFGF is a good marker for CA2 neurons, we have used a mouse monoclonal antibody directed against recombinant human bFGF to characterize the distribution and localization of bFGF expression in the hippocampus. We find that about one-quarter of the neurons in CA2 are bFGF positive, and they appear smaller and have more irregular-shaped nuclei than their unstained counterparts. In addition, all glial fibrilary acidic protein (GFAP)-positive astrocytes in the hippocampus stain for bFGF, and the distribution of these astrocytes is heterogeneous in the hippocampus. Finally, in both astrocytes and CA2 pyramidal neurons, bFGF immunoreactivity is localized primarily in the nucleus and to a lesser extent in the cytoplasm and processes of stained cells.

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.

Persistence of antibody after the administration of influenza vaccine to children with cancer.

Children with cancer who received an intramuscular injection of inactivated split or whole bivalent (A/New Jersey/76-A/Victoria/75) influenza virus vaccine during the fall of 1976 were tested up to 18 months later for the persistence of antibody. Titers of antibody greater than of equal to 10 to influenza A/New Jersey/76 virus were present in the sera of 34 children two weeks after immunization. The geometric mean titer was 40.0. Eighteen months later a titer greater than or equal to 10 was present in 13 (38%) children; the geometric mean titer was 8.5. Of 36 children with a titer of antibody greater than or equal to 10 to A/Victoria/75 virus two weeks after immunization, 34 still had a detectable titer in the later examination. The geometric mean titer declined from 65.3 to 25.6. Titers of antibody to B/Hong Kong/72 virus (not included in the vaccine) remained relatively stable. In 11 children the usual chemotherapy was discontinued during the study. The shorter persistence of antibody to A/New Jersey/76 virus, in contrast to that of the other two influenza viruses tested, was associated with a lack of prior exposure to the virus and the absence of subsequent natural infection with this virus or an antigenically related subtype. The potential effect of cancer chemotherapy on the persistence of antibody levels is unclear.

Differences in response in vivo to amphotericin B among Candida albicans strains.

A group of ten Candida albicans strains previously determined to be resistant or susceptible to topical amphotericin B in vivo and in vitro were exposed to treatment with different concentrations of the drug in a quantitative model of candidal keratitis in Dutch-belted rabbits. After 5 days of topical treatment with amphotericin B eye drops in concentrations of 0.3%, 0.03%, or 0.003%, quantitative isolate recovery in treated animals was compared with that of untreated controls. A dose response was observed for all five susceptible strains. The two strains that were most sensitive to amphotericin B in vitro also were the most susceptible in vivo. At each dose level there was a two- to eightfold reduction in isolate recovery among highly susceptible strains compared with less susceptible strains (P less than 0.05). The five resistant strains remained so even when the 0.3% concentration was used. Among strains of C. albicans susceptible to amphotericin B, there appeared to be a variation in degree of susceptibility in vivo that correlated with the minimum inhibitory concentration.

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.

Electrocardiographic voltage in pericardial effusion.

The usefulness of the electrocardiographic sign of "low voltage" in the diagnosis of pericardial effusion was investigated in 122 patients comprising three study groups. Sixty-four patients (group 1) had a pericardial effusion detected and measured by echocardiographic studies. The volume of the effusion showed no correlation with electrocardiographic voltage. A second group of 36 patients was identified as having low voltage on routine electrocardiograms. Only 13 (36 percent) had echocardiographically demonstrable pericardial effusion. Group 3 consisted of 22 patients who required pericardiocentesis. The ECGs obtained immediately after pericardiocentesis showed an increase in average voltage of 0.48 mm in the limb leads and 0.83 mm in the precordial leads for each 100 ml of fluid removed. This study demonstrates that a single ECG with "low voltage" is not useful in the diagnosis of pericardial effusion but that a reduction in the voltage of serial ECGs may suggest the development of pericardial effusion.

Open lung biopsy. Its effects on therapy in the pediatric patient.

The records of 35 pediatric patients who had open lung biopsies at Columbus Children's Hospital, Columbus, Ohio, were analyzed to determine the results and the effects on therapy. Twenty-two (63 percent) of these patients were immunocompromised, and they are compared to the non-compromised group. A diagnosis was obtained in all cases. An infectious agent was identified in 13 (37 percent) of the patients. Ten of these were immunocompromised. In 43 percent (15 patients) of the total group and 55 percent (12 patients) of the immunocompromised group, the results of the biopsy effected a change in therapy. Five patients died, all of whom were immunosuppressed. None died as a direct result of the open lung biopsy. The total morbidity rate was 23 percent (eight patients). We concluded that open lung biopsy can be accomplished safely in the pediatric patient and that the results affect the therapeutic decision-making process a significant portion of the time.

Postoperative pericarditis following thymectomy for myasthenia gravis. A prospective study.

Eight consecutive patients who underwent thymectomy for the treatment of myasthenia gravis were evaluated prospectively for the development of postoperative pericarditis. In four of the eight patients (50 percent) pericarditis developed within 48 hours after thymectomy. All four had a three-component pericardial friction rub, two of the four patients had a new postoperative pericardial effusion by echocardiography, and in two typical ECG diffuse concave ST segment elevation and evolutionary ST and T wave changes developed. In the four patients with postoperative pericarditis, a malignant thymoma adherent to the pericardium was found in two, while two patients had a normal thymus histology with no adherence to the pericardium. Thus, postoperative pericarditis was found in both of the patients with a thymoma and in two of six patients without a thymoma. This study demonstrates that a high incidence of pericarditis occurs following thymectomy for the treatment of myasthenia gravis.

Reasonable surgery for thoracic neuroblastoma in infants and children.

Neuroblastoma is the most commonly encountered soft tissue malignant tumor of childhood. Over the past 30 years we have treated 180 patients with neuroblastoma. Sixty-five percent had primary abdominal tumors and 20 percent (41 patients) had primary chest tumors. For the 22 patients under the age of 2 years, the 2 year survival rate was 87 percent. There were 19 patients who were 2 years of age or older, and of these only seven patients have survived 2 years after the diagnosis was made. The vast majority of these patients were treated with surgery (debulking type procedure) and postoperative radiation and chemotherapy. Patients with the most differentiated tumors had a remarkably good survival rate, with no deaths. However, the tumors with lesser differentiation did not stratify enough focus to draw conclusions as to survival. Staging correlated the least with survival when compared to age or grading. The 2 year survival rates for patients with Stage I, II, III, IV, and IV-S disease were 75, 82, 100, 17, and 80 percent, respectively. In conclusion, 41 cases of documented primary thoracic neuroblastoma are reviewed, with follow-up from 2 to 27 years (average 9.3 years). We have concluded from this experience that age is the main determining factor influencing survival. Heroic and/or radical surgery is contraindicated in this disease.

Ocular pharmacokinetics of saperconazole in rabbits. A potential agent against keratomycoses.

The ocular pharmacokinetics of saperconazole, an experimental lipophilic triazole with activity against filamentous fungi, including Aspergillus and Candida species, were evaluated in rabbits by radioassay. The drug was administered by topical, subconjunctival, and oral routes. Following a single 20-microL drop of 0.25% saperconazole in normal corneas, a mean (+/- SEM) peak level of 2.32 +/- 0.06 micrograms/g was achieved in 10 minutes. In débrided corneas, a peak level of 13.09 +/- 2.87 micrograms/g was achieved in 2 minutes. The drug was rapidly cleared from the cornea within 2 hours. The administration of 13 drops during 1 hour resulted in a threefold increase in normal corneal levels and in a sixfold increase in débrided cornea levels. Peak levels following subconjunctival injection in normal corneas (12.91 +/- 2.02 micrograms/g) were approximately twofold greater than those following sustained topical administration (6.19 +/- 0.16 micrograms/g) and, in débrided corneas, were a third higher than those following topical therapy in débrided corneas. Clearance was virtually complete by 8 hours. Levels following oral administration were low and probably subtherapeutic in all ocular tissues that were evaluated. Bioassay studies revealed that 44.17% of the drug in the cornea following topical administration was bioactive.

Influence of corticosteroid on experimentally induced keratomycosis.

To assess the effect of corticosteroid on the establishment of experimentally induced keratomycoses, rabbits were injected subconjunctivally with triamcinolone acetonide on two successive days before inoculation with Candida albicans, Aspergillus fumigatus, or Fusarium solanae. Whereas isolate recovery rates declined steadily in normal control corneas, they remained stable over 15 days in corticosteroid-treated corneas. Clinically, inflammation was equivalent (A fumigatus and F solanae) or significantly less (C albicans; P = .001) until the 10th day. At 15 days, inflammation in corticosteroid-treated corneas was significantly worse in animals infected with A fumigatus (P = .003) or F solanae (P = .02). Inflammatory signs correlated inconsistently with isolate recovery. Pathogenicity of the infecting organism appears to be important in determining the degree to which corticosteroid is able to mask clinical signs of infection while enhancing fungal replication.

Ocular uptake of fluconazole following oral administration.

The ocular penetration and distribution of oral fluconazole was studied in Dutch-belted rabbits. Measured by high-pressure liquid chromatography, fluconazole readily penetrated all ocular tissues and fluids. No difference was observed between the levels obtained in phakic and aphakic eyes. Four hours after a single oral dose of 20 mg/kg, the mean levels and SEs were as follows: cornea, 13.3 +/- 1.4 micrograms/g; aqueous, 7.4 +/- 0.3 mg/L; vitreous, 9.8 +/- 0.9 mg/L; and choroid/retina, 5.2 +/- 0.4 micrograms/g. These levels were approximately twice those obtained with a 10-mg/kg dose. The corneal concentrations correlated highly with serum levels (r = .89). A steady accumulation in both normal corneas and corneas infected with Candida albicans was noted when 17.5 mg/kg of fluconazole was administered twice daily over a 5-day period. Drug levels did not increase in the cornea when fluconazole was administered as a single daily dose of 35 mg/kg. In view of its excellent ocular pharmacokinetic profile, fluconazole merits further attention as an orally administered agent for ocular fungal infections.

Independent preclerkship study: a five year experience.

An independent study program (ISP) was instituted in 1970 for a group of 32 preclerkship medical students picked randomly from a group of 64 volunteers. The academic achievements of these classes, as measured by mean National Board scores, is compared with their classmates in the lecture discussion (LD) program where possible. The significant differences noted obtain even when the ISP students are compared only with LD students matched for premedical point-hour ratios and Medical College Admissions Test scores. These data attest to the overall success of the ISP program. The differences appear to us to be due mainly to factors related to motivation and maturity. The ease of preparations, convenience, and economy of the associated computer-assisted instruction make these methods attractive for use in residency training and continuing medical education where maturity and motivation may well be presumed.

Effects of pharmacological myocardial depression on coronary artery collateral formation.

Treatment of angina pectoris falls within two spheres: (1) increasing myocardial blood flow (direct bypass, vasodilators), or (2) reducing oxygen demand (beta blockade, propranolol). If the latter depresses the stimulus for collateralization without improving input, its use in certain forms of coronary disease may require reconsideration. To examine this hypothesis, 25 dogs (four groups) were evaluated by surface mapping, angiographic collateral mapping, and hemodynamic studies including cardiac output, systemic and coronary pressures, coronary flow, and left ventricular end-diastolic pressure, pressure to time (LVdp/dt). Collateralization was induced with ameroid constrictor placement in Groups I, III, and IV. Groups II and III received immediate propranolol treatment (3 to 5 mg. per kilogram per day for 6 weeks); Group IV received delayed treatment (4 weeks after constriction); and Group I received no propranolol (constrictor alone). Collateral formation was depressed significantly in the acutely beta-blockaded dogs (Group III) by surface and angiographic mapping and by hemodynamic evidence of depressed coronary flow and altered coronary retrograde pressures. Alterations in established collaterals (Group IV) were not consistent. These data suggest that pharmacological reduction of myocardial oxygen demand reduces coronary collateralization experimentally, requiring further evaluation of its usage in multivessel coronary disease to the exclusion of direct bypass.

Nonpenetrating trauma to the thoracic aorta.

Twenty-seven patients underwent surgical repair for nonpenetrating injuries of the thoracic aorta. Emergency operation was performed in 19 patients with acute aortic injury and there were 12 survivors. Left heart bypass (LHB), external shunts, and simple aortic cross-clamping were methods employed during repair. All operative deaths occurred in the left heart bypass group. Morbidity, hospital stay, operative time, and blood loss all were markedly less in patients repaired with an external shunt or simple cross-clamping. Systemic heparinization related adversely to mortality and morbidity. Eight patients had repair of chronic post-traumatic descending aortic aneurysms. One of these had previous repair elsewhere with paraplegia and subsequent mycotic aneurysm at the graft repair site. He presented to us with massive hemoptysis. Surgical correction in the chronic group was performed using either left heart bypass, external shunt, or simple aortic cross-clamp with graft interposition. The only death occurred in a patient repaired on left heart bypass.

Pulmonary resections in children: problems and precautions.

Forty-eight pulmonary resections were performed in 45 children. The principal indications for operation were bronchiectasis, congenital cysts, and lobar emphysema. Nine complications occurred in five children. There were three deaths, a mortality of 6.7%. While resection can be performed safely in most children, a high-risk group is identified as those with severe congenital cardiopulmonary disease complicated by chronic or recurrent infection.

Photodynamic therapy for esophageal tumors.

Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.

Combined median sternotomy and posterior lateral thoracotomy: a method for proximal and distal thoracic aortic exposure.

A method for exposure of the heart, ascending aorta, aortic arch vessels, and descending thoracic aorta in a single surgical field is presented. Five illustrative cases are reviewed. Indications for use include trauma to the aorta and arch vessels, aneurysms or dissections, ductus aneurysms, or complex or secondary coarctations of the aorta.