Cardiovascular disease risk following a 758 km pilgrimage.

Millions of people participate in pilgrimages around the world such as the Camino de Santiago. However, few studies have examined the effects of this type of activity on cardiovascular disease risk factors. The aim of this study is to evaluate changes in cardiovascular disease risk factors: c-reactive protein, cholesterol, triglycerides, blood pressure, and cardiorespiratory fitness levels following a 758 km, 30-day pilgrimage. 11 healthy male and female subjects between the ages of 18-56 participated in pre and post pilgrimage blood pressure and blood tests, as well as pre, during, and post pilgrimage weight, skin-fold, and aerobic fitness testing. Heart rate monitors and pedometers provided maximum, average, and minimum heart rates as well as distances covered during the exercise. The mean daily walking distance was 25 km at an average intensity of 55.96% (±1.93%) of maximum heart rate. Statistically significant changes were seen in body weight (79.3 kg±3.4 pre vs. 76.4±2.98 post, p<0.05), body fat percentage (24.48%±2.31% pre vs. 23.01%±2.12 post, p<0.05), systolic and diastolic blood pressure (119±3.82/75±2.73 pre vs. 110±5.07/69±3.10 post, p<0.05), as well as cardiorespiratory fitness. These data suggest that some cardiovascular disease risk factors can be improved in healthy subjects participating in a low intensity, long duration, high frequency activity such as a walking pilgrimage.

Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage.

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified ("gene activated") tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

Importance of vitamin D in hospital-based fracture care pathways.

OBJECTIVES: This project was developed to identify ways to support hospital-based improvements for the identification and management of osteoporosis following treatment of a fragility fracture. DESIGN: This is a retrospective review of medical records of sets of consecutive patients who were admitted for surgical treatment of fragility fracture following introduction of several versions of admission and discharge care pathways. Effectiveness of the admission pathway was defined as % subjects with measurement of serum 25- hydroxyvitamin D (25(OH)D) during hospitalization; effectiveness of the discharge pathway was defined as % subjects with documentation of instructions for calcium and/or vitamin D supplementation. SETTING: This study reviewed medical records of patients admitted to hospital for surgical treatment of a fragility fracture. PARTICIPANTS: Medical records were evaluated for 98 patients older than 50-years who were admitted with a fragility fracture of the hip or femur. MEASUREMENTS: Medical records were reviewed for the % subjects with documentation of an in-hospital order for serum 25(OH)D and with documentation of instructions to patients upon discharge concerning calcium and vitamin D intake. Median value of serum 25(OH)D was calculated. RESULTS: In accordance with the admission pathway, serum 25(OH)D was measured in 37% (36/98). The median 25(OH)D level was 19.5 ng/mL; 78% were vitamin D insufficient [serum 25(OH)D < or = 32 ng/mL] and 58% were vitamin D deficient [serum 25(OH)D < or = 20 ng/mL]. In accordance with the discharge pathway, 74% (71/96) were discharged on calcium and/or vitamin D. CONCLUSION: The high prevalence of vitamin D insufficiency (78%) observed in this study affirms the importance of incorporating vitamin D supplementation in hospital-based fracture care pathways. The discharge pathway was more effective than the newer admission pathway, a finding attributable to effects of familiarity, retraining, and introduction of computer-prompts. These evolving pathways represent a much-needed paradigm shift in the care of fragility fracture patients.

Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching.

The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.

Evolution of lung breathing from a lungless primitive vertebrate.

Air breathing was critical to the terrestrial radiation and evolution of tetrapods and arose in fish. The vertebrate lung originated from a progenitor structure present in primitive boney fish. The origin of the neural substrates, which are sensitive to metabolically produced CO2 and which rhythmically activate respiratory muscles to match lung ventilation to metabolic demand, is enigmatic. We have found that a distinct periodic centrally generated rhythm, described as "cough" and occurring in lamprey in vivo and in vitro, is modulated by central sensitivity to CO2. This suggests that elements critical for the evolution of breathing in tetrapods, were present in the most basal vertebrate ancestors prior to the evolution of the lung. We propose that the evolution of breathing in all vertebrates occurred through exaptations derived from these critical basal elements.

Quality of care for patients with a fracture of the hip in major trauma centres: a national observational study.

AIMS: In this study, we aimed to determine whether designation as a major trauma centre (MTC) affects the quality of care for patients with a fracture of the hip. PATIENTS AND METHODS: All patients in the United Kingdom National Hip Fracture Database, between April 2010 and December 2013, were included. The indicators of quality that were recorded included the time to arrival on an orthopaedic ward, to review by a geriatrician, and to operation. The clinical outcomes were the development of a pressure sore, discharge home, length of stay, in-hospital mortality, and re-operation within 30 days. RESULTS: There were 289 466 patients, 49 350 (17%) of whom were treated in hospitals that are now MTCs. Using multivariable logistic and generalised linear regression models, there were no significant differences in any of the indicators of the quality of care or clinical outcomes between MTCs, hospitals awaiting MTC designation and non-MTC hospitals. CONCLUSION: These findings suggest that the regionalisation of major trauma in England did not improve or compromise the overall care of elderly patients with a fracture of the hip. TAKE HOME MESSAGE: There is no evidence that reconfiguring major trauma services in England disrupted the treatment of older adults with a fracture of the hip.

Comparison of two schedules of intermediate-dose methotrexate and cytarabine consolidation therapy for childhood B-precursor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: To compare efficacy and toxicity of two schedules of intermediate-dose methotrexate (IDM) and cytarabine (Ara-C) in remission consolidation of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In 1986, the Pediatric Oncology Group (POG) began a randomized trial to test two schedules of consolidation chemotherapy in children with newly diagnosed B-precursor cell ALL. MTX and Ara-C were given as overlapping 24-hour infusions. The dose and sequence of MTX and Ara-C administration were based on a preclinical model that had demonstrated synergism between these two agents. Two hundred fifteen patients in complete remission were randomized to front-loading consolidation therapy in which six MTX/Ara-C infusions were administered at 3-week intervals from the 7th through the 19th week of therapy. Two hundred thirteen patients in complete remission were randomized to receive standard consolidation therapy in which the six MTX/Ara-C infusions were given every 12 weeks from the 7th through the 67th week of therapy. RESULTS: Both regimens produced similar rates of adverse side effects, except for a higher incidence of CNS toxicity in individuals randomized to the front-loading arm (32 of 215 v 12 of 213 patients, P = .002). Leukoencephalopathy occurred in three patients on the front-loading regimen and was permanent in one. By Kaplan-Meier analysis, the probability of continuing in complete remission for 5 years was 79% (SE = 5%) and 85% (SE = 5%) for good-risk patients, and 66% (SE = 6%) and 61% (SE = 7%) for poor-risk patients randomized to front-loading and standard regimens, respectively. CONCLUSION: Although differences in complete remission durations were not statistically significant by log-rank analysis (P = .62 for good-risk patients, .89 for poor-risk patients, and .99 overall), the results are comparable to those in previous studies using more toxic agents as components of remission consolidation therapy.

Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study.

PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).

Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study.

PURPOSE: To estimate the duration of survival (S) of patients with metastatic osteosarcoma (MOS) at diagnosis treated with a multiagent, ifosfamide-containing chemotherapeutic and surgical regimen and to evaluate the toxicity of this regimen. PATIENTS AND METHODS: Thirty patients aged younger than 30 years received two courses of ifosfamide followed by surgery on the primary tumor and metastatic sites. Patients then received a postsurgical multiagent chemotherapeutic regimen that consisted of high-dose methotrexate (HDMTX), ifosfamide, doxorubicin, and cisplatin. RESULTS: The 5-year event-free survival (EFS) rate was 46.7% (95% confidence interval [CI]; 28.5 to 64.9) and 5-year S rate was 53.3% (95% CI; 35.1 to 71.5). Three patients with bone metastases and one patient with lymph node metastases died. Twenty-six patients presented with pulmonary metastatic nodules only. Eight of these patients had at least eight nodules at diagnosis and had an estimated 5-year EFS rate of 25.0% compared with 66.7% for the 18 patients with less than eight nodules (P=.06). Fourteen patients presented with bilateral lung metastases and had a 5-year EFS rate of 35.7% compared with the 12 patients who presented with unilateral involvement and had a 5-year EFS rate of 75.0% (P=.03). The hematopoietic toxicity experienced by the patients during the entire regimen was relatively mild. Seven patients had renal toxicity characterized by hypophosphatemia and/or hypokalemia. CONCLUSION: This ifosfamide-containing regimen is tolerable and effective in the treatment of patients with osteosarcoma (OS) who present with lung metastases. However, better regimens are required for this group of patients.

Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study.

PURPOSE: To determine the response rate of the combination of cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS: A total of 91 pediatric patients, 83 of whom were fully assessable for response and toxicity, received cyclophosphamide (250 mg/m2/dose) followed by topotecan (0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. All patients received filgrastim (5 mcg/kg) daily until the absolute neutrophil count (ANC) was > or = 1,500 microL after the time of the expected ANC nadir. RESULTS: A total of 307 treatment courses were given to the 83 fully assessable patients. Responses (complete response plus partial response) were seen in rhabdomyosarcoma (10 of 15 patients), Ewing's sarcoma (six of 17 patients), and neuroblastoma (six of 13 patients). Partial responses were seen in two of 18 patients with osteosarcoma and in one patient with a Sertoli-Leydig cell tumor. Twenty-three patients had either minor responses (n = 6) or stable disease (n = 17); the median number of courses administered to patients with partial or complete response was six (range, two to 13 courses), and the median administered to those with stable disease was three (range, one to 11 courses). The toxicity of the combination was limited principally to the hematopoietic system. Of 307 courses, 163 (53%) were associated with grade 3 or 4 neutropenia, 84 (27%) with grade 3 or 4 anemia, and 136 (44%) with grade 3 or 4 thrombocytopenia. Despite the severe myelosuppression, only 34 (11%) of 307 courses were associated with grade 3 or 4 infection. Nonhematopoietic toxicity of grades > or = 3 was rare and consisted of nausea and vomiting (two courses), perirectal mucositis (one course), transaminase elevation (one course), and hematuria (two courses). CONCLUSION: The combination of cyclophosphamide and topotecan is active in rhabdomyosarcoma, neuroblastoma, and Ewing's sarcoma. Stabilization of disease was seen in osteosarcoma, although objective responses were rare in this disease. The therapy can be given with acceptable hematopoietic toxicity with the use of filgrastim support.

Treatment of children with early pre-B and pre-B acute lymphocytic leukemia with antimetabolite-based intensification regimens: a Pediatric Oncology Group Study.

Between May 1987 and January 1991, 1354 patients, 1-21 years old, with standard or poor prognosis B-lineage acute lymphocytic leukemia were treated on the Pediatric Oncology Group Study 8602. One thousand three hundred and twenty-three patients entered remission and 1051 patients were randomized on day 43 to an intensification regimen containing L-asparaginase and intermediate-dose methotrexate (regimen B) or cytarabine and intermediate dose methotrexate (regimen C). After completion of intensification at week 25, all patients received the same maintenance therapy until 3 years from diagnosis. Overall 5-year continuous complete remission (CCR) for regimen B was 72+/-2% (s.e.) and for regimen C, 73+/-2% (P = 0.72 by log-rank analysis). Significant differences between treatments for CCR, testicular, CNS relapses overall or with regard to phenotype (pre-B vs early pre-B), gender, or race were not detected. During intensification, regimen C had significantly more bacterial infections (P = 0.05) and days spent in the hospital (P < 0.001) compared with regimen B, while regimen B had significantly more allergic reactions (P < 0.0001). No significant differences in CCR were noted between patients with pre-B and early pre-B ALL (P = 0.22 stratified by risk group and treatment). This study was unable to detect statistical difference between asparaginase (regimen B) and cytarabine (regimen C) during the intensification phase of therapy in children with B-lineage acute lymphocytic leukemia.

The role of protein synthesis in polymorphonuclear leukocyte phagocytosis II.

Polymorphonuclear leukocytes collected from healthy human volunteers were treated with puromycin which inhibited protein synthesis in the cell. The neutrophils exhibited a marked decrease in phagocytosis after 1 h. The myeloperoxidase mediated conversion of iodide to a protein-bound form was also decreased. Hexosemonophosphate shunt activity remained similar for both puromycin treated PMN and control cells at 1 h. The results suggest that new protein synthesis is necessary to maintain PMN function at full capacity.

Isoflurane causes concentration-dependent inhibition of medullary raphé 5-HT neurons in situ.

BACKGROUND: Anesthetics have a profound influence on a myriad of autonomic processes. Mechanisms of general anesthesia, and how these mechanisms give rise to the multifaceted state of anesthesia, are largely unknown. The ascending and descending serotonin (5-HT) networks are key modulators of autonomic pathways, and are critically involved in homeostatic reflexes across the motor, somatosensory, limbic and autonomic systems. These 5-HT networks are thought to contribute to anesthetic effects, but how anesthetics affect 5-HT neuron function remains a pertinent question. We hypothesized that the volatile anesthetic isoflurane inhibits action potential discharge of medullary raphé 5-HT neurons. METHODS: We conducted extracellular recordings on individual neurons in the medullary raphé region of the unanesthetized in situ perfused brainstem preparation to determine how exposure to isoflurane affects 5-HT neurons. We examined changes in 5-HT neuron baseline firing in response to treatment with either 1, 1.5, or 2% isoflurane. We measured isoflurane concentrations by gas chromatography-mass spectrometry (GC-MS) analysis. RESULTS: Exposure to isoflurane inhibited action potential discharge in raphé 5-HT neurons. We document a concentration-dependent inhibition over a range of concentrations approximating isoflurane MAC (minimum alveolar concentration required for surgical anesthesia). Delivered concentrations of isoflurane were confirmed using GC-MS analysis. CONCLUSIONS: These findings illustrate that halogenated anesthetics greatly affect 5-HT neuron firing and suggest 5-HT neuron contributions to mechanisms of general anesthesia.

Validation of multisociety combined task force definitions of abnormal disk morphology.

BACKGROUND AND PURPOSE: The multisociety task force descriptively defined abnormal lumbar disk morphology. We aimed to use their definitions to provide a higher level of evidence for the validation of MR imaging in the evaluation of this pathology in patients who have undergone diskectomy by retrospectively classifying their preoperative MRI. MATERIALS AND METHODS: This retrospective, institutional review board-approved study included 54 of 86 consecutive patients (47 men; average age, 44 years) enrolled in an ongoing prospective trial of surgically treated lumbar disk herniation who had preoperative MRI and documented intraoperative classification of the abnormal disk as protrusion, extrusion, or sequestration by the treating surgeon. Preoperative MRI was classified by 2 blinded radiologists; discrepancies were resolved by a third reader. Statistical analysis of interobserver agreement and imaging compared with surgical findings was performed. RESULTS: The readers disagreed on only 1 of the 54 cases. The third reader resolved the disagreement. Eight protrusions and 46 extrusions were found on imaging, with no sequestrations. At surgery, there were 13 protrusions and 40 extrusions, with 2 of the extrusions also containing sequestrations; the remaining case had only sequestration. There were 16 discrepancies between imaging and surgery, resulting in 70% agreement. CONCLUSIONS: This study, which was intended to validate the multisociety combined task force definitions of abnormal disk morphology by using MR imaging with a surgical criterion standard, found 70% agreement between imaging diagnosis and surgical findings. Although reasonable, this finding highlights differences that often exist between intraoperative and preoperative imaging findings of lumbar disk herniation.

Transcutaneous leukocyte migration in vivo: cellular kinetics, platelet and C5a dependent activity.

A simple quantitative method for the measurement of leukotaxis in vivo is described. Duplicate skin chambers are placed over tape-stripped skin with 50% autologous serum--50% Hank's balanced salt solution as the attractant. Neutrophils predominate throughout 24 hr in this method with no change to mononuclear cells. A recommended modification of our original method is that chambers are sampled and removed after 8 hr rather than 24 hr since the majority of leukocyte migration occurs within the first 8 hr. Analysis of serum factors showed that heat-inactivation of the serum (56degreesC for 30 min) had no effect. However, depleting platelets or C5 from the serum removed approximately 90% of chemotactic activity for human neutrophils in vivo. Platelets, presumably through activity of their granules, enzymatically cleaves C5a from C5 in plasma. We conclude that C5a, after cleavage from C5, accounts for the majority of chemattractant activity in vivo.

Marrow transplantation for juvenile osteopetrosis.

Two children with the juvenile form of osteopetrosis were treated with marrow transplants from their HLA identical siblings. Following transplantation each child exhibited extensive bone reabsorption with a marked augmentation of osteoclastic function attributable to donor osteoclasts, including remodeling of bone with expansion of intramedullary hematopoiesis and correction of associated abnormalities of thymic factor and natural killer cells. Osteopetrosis ultimately recurred in one patient in whom engraftment of donor hematopoietic elements was not achieved. Our studies indicate that marrow transplantation will correct osteopetrosis but that permanent reconstitution necessitates sustained engraftment of marrow precursors of cells with osteoclastic activity.

Lymphocyte thymidine kinase and treatment response in acute lymphocytic leukemia.

The activity of thymidine kinase (TK) and the proportion of its isozymes (TK1/TK2) were studied in peripheral lymphoid cells of 37 children with acute lymphocytic leukemia (ALL). The high TK in 25 untreated subjects (31.5 +/- 8.9) decreased during chemotherapy-induced remission to uniformly low (5.3 +/- 0.4) normal values, and rose again during relapse to a mean of (24.8 +/- 8.1). The proportion of isozyme 1 followed the same pattern but TK was a more sensitive indicator of disease state. The lymphocyte fractions' TK (per mg protein) correlated with the number (per ml blood) of WBCs, blasts and lymphocytes. Although the higher TK of blasts than of apparently normal lymphocytes was confirmed in cases permitting clean physical separation, the lymphocyte fraction of several untreated subjects with minimal blast counts also exhibited elevated TK. Moreover, this elevation was also seen in relapsed cases even if their blood (unlike bone marrow) was devoid of blasts. The results indicate that quantification of TK can reveal a subpopulation of maldifferentiated lymphocytes which are microscopically normal and that it may provide an objective parameter of prognostic differences between ALL subjects with similar hematological characteristics.

Concurrence of von Willebrand's disease and hemophilia A: implications for carrier detection and prevalence.

Five families with concurrent von Willebrand's disease (VWD) and classic hemophilia (hemophilia A) are described. Three were ascertained through women undergoing hemophilia carrier testing, one through an obligate carrier who also has VWD, and one through the affected father of a hemophiliac. The VWD probands exhibited Type I VWD with reduced Factor VIII-related antigen (VIIIR:Ag) and/or von Willebrand factor on more than one occasion, normal VIIIR:Ag on crossed immunoelectrophoresis, and mild symptoms. No male had both disorders, but two obligate hemophilia carriers also had VWD. Neither was detectable as a carrier by discriminant analysis. Four possible carriers of hemophilia had VWD and would also be classified as noncarriers statistically. These findings suggest that the presence of VWD may invalidate hemophilia carrier testing by conventional methods. The independent entry into the family of the two genes by mating of a hemophilia carrier and a VWD male is documented in two cases and probable in two. The observed frequency of such matings supports the hypothesis that VWD is a common disorder.

Biochemical interactions between methotrexate and 1-beta-D-arabinofuranosylcytosine in hematopoietic cells of children: a Pediatric Oncology Group study.

Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.

Pain sensitivity in patients with temporomandibular disorders: relationship to clinical and psychosocial factors.

OBJECTIVE: We have previously reported that patients with temporomandibular disorders (TMD) exhibit enhanced sensitivity to experimentally evoked pain (1); however, the clinical relevance of this increased pain sensitivity remains unclear. The purpose of this study was to investigate the relationship of experimental pain sensitivity to clinical and psychosocial variables among patients with TMD. DESIGN: Thirty-six TMD patients were studied, half of whom were pain sensitive (PS) and the other half pain tolerant (PT), based on their ability to tolerate an ischemic pain task. Responses to painful thermal and nonpainful visual stimuli as well as clinical/diagnostic symptoms and psychosocial variables were compared for the two groups (i.e., PS vs. PT). RESULTS: Results indicated that, compared with PT patients, the PS group exhibited greater sensitivity to thermal pain and rated innocuous visual stimuli as more intense. PS patients also reported greater clinical pain, but in general the groups did not differ on diagnostic and psychosocial measures. CONCLUSIONS: The results suggest that ischemic pain tolerance is a clinically relevant marker of pain sensitivity in TMD patients. These findings are consistent with the hypothesis that impairments in CNS inhibitory pathways may contribute to the pain associated with TMD.