Incorporation of log odds of positive lymph nodes into the AJCC TNM classification improves prediction of survival in oral cancer.

OBJECTIVES: To assess the prognostic performance of a new N classification that incorporates the log odds of positive lymph nodes (LODDS) into the routinely used pathological N classification for oral squamous cell carcinoma (OSCC) patients. DESIGN: Retrospective cohort study utilising LODDS into pN category was performed, and the AJCC TNM stage and T-New N-M stage were compared with respect to 5-year disease-specific survival (DSS) rates. The discriminability was evaluated from the linear trend chi-square test, Akaike information criterion (AIC) and Harrell's c-statistic. SETTING: Medical centrer in Taiwan. PARTICIPANTS: A total of 463 patients received primary surgery and neck dissection between 2004 and 2013 for OSCC. MAIN OUTCOME MEASURES: The discriminability for 5-year DSS rates. RESULTS: The median follow-up period was 54 months, the mean patient age was 54 ± 11 years and 428 patients (92.4%) were male. The patients with higher LODDS had worse 5-year DSS rates. Incorporation of LODDS into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for 5-year DSS with a lower AIC (1883 versus 1897), and higher prediction accuracy (Harrell's c-statistic: 0.768 versus 0.764). CONCLUSIONS: By utilising a merger of the LODDS and pN classifications to create a new N classification has better discriminatory and predictive ability than pathological TNM staging and could help identify high-risk patients for intense adjuvant therapy.

Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance.

Peroxiredoxin (Prx) is a family of bifunctional proteins that exhibit peroxidase and chaperone activities. Prx proteins contain a conserved Cys residue that undergoes a redox change between thiol and disulfide states. 2-Cys Prx enzymes, a subgroup of Prx family, are intrinsically susceptible to reversible hyperoxidation to cysteine sulfinic acid during catalysis. Cysteine hyperoxidation of Prx was shown to result in loss of peroxidase activity and a concomitant gain of chaperone activity. Reduction of sulfinic Prx enzymes, the first known biological example of such a reaction, is catalyzed by sulfiredoxin (Srx) in the presence of ATP. Srx appears to exist solely to support the reversible sulfinic modification of 2-Cys Prx enzymes. Srx specifically binds to 2-Cys Prx enzymes by recognizing several critical surface-exposed residues of the Prxs, and transfer the gamma-phosphate of ATP to their sulfinic moiety, using its conserved cysteine as the phosphate carrier. The resulting sulfinic phosphoryl ester is reduced to cysteine after oxidation of four thiol equivalents.

Soft-copy mammographic readings with different computer-assisted detection cuing environments: preliminary findings.

PURPOSE: To assess the performance of radiologists in the detection of masses and microcalcification clusters on digitized mammograms by using different computer-assisted detection (CAD) cuing environments. MATERIALS AND METHODS: Two hundred nine digitized mammograms depicting 57 verified masses and 38 microcalcification clusters in 85 positive and 35 negative cases were interpreted independently by seven radiologists using five display modes. Except for the first mode, for which no CAD results were provided, suspicious regions identified with a CAD scheme were cued in all the other modes by using a combination of two cuing sensitivities (90% and 50%) and two false-positive rates (0.5 and 2.0 per image). A receiver operating characteristic study was performed by using soft-copy images. RESULTS: CAD cuing at 90% sensitivity and a rate of 0.5 false-positive region per image improved observer performance levels significantly (P < .01). As accuracy of CAD cuing decreased so did observer performances (P < .01). Cuing specificity affected mass detection more significantly, while cuing sensitivity affected detection of microcalcification clusters more significantly (P < .01). Reduction of cuing sensitivity and specificity significantly increased false-negative rates in noncued areas (P < .05). Trends were consistent for all observers. CONCLUSION: CAD systems have the potential to significantly improve diagnostic performance in mammography. However, poorly performing schemes could adversely affect observer performance in both cued and noncued areas.

Knowledge-based computer-aided detection of masses on digitized mammograms: a preliminary assessment.

The purpose of this work was to develop and evaluate a computer-aided detection (CAD) scheme for the improvement of mass identification on digitized mammograms using a knowledge-based approach. Three hundred pathologically verified masses and 300 negative, but suspicious, regions, as initially identified by a rule-based CAD scheme, were randomly selected from a large clinical database for development purposes. In addition, 500 different positive and 500 negative regions were used to test the scheme. This suspicious region pruning scheme includes a learning process to establish a knowledge base that is then used to determine whether a previously identified suspicious region is likely to depict a true mass. This is accomplished by quantitatively characterizing the set of known masses, measuring "similarity" between a suspicious region and a "known" mass, then deriving a composite "likelihood" measure based on all "known" masses to determine the state of the suspicious region. To assess the performance of this method, receiver-operating characteristic (ROC) analyses were employed. Using a leave-one-out validation method with the development set of 600 regions, the knowledge-based CAD scheme achieved an area under the ROC curve of 0.83. Fifty-one percent of the previously identified false-positive regions were eliminated, while maintaining 90% sensitivity. During testing of the 1,000 independent regions, an area under the ROC curve as high as 0.80 was achieved. Knowledge-based approaches can yield a significant reduction in false-positive detections while maintaining reasonable sensitivity. This approach has the potential of improving the performance of other rule-based CAD schemes.

Negative regulation of the SAPK/JNK signaling pathway by presenilin 1.

Presenilin 1 (PS1) plays a pivotal role in Notch signaling and the intracellular metabolism of the amyloid beta-protein. To understand intracellular signaling events downstream of PS1, we investigated in this study the action of PS1 on mitogen-activated protein kinase pathways. Overexpressed PS1 suppressed the stress-induced stimulation of stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK) in human embryonic kidney 293 cells. Interestingly, two functionally inactive PS1 mutants, PS1(D257A) and PS1(D385A), failed to inhibit UV-stimulated SAPK/JNK. Furthermore, H(2)O(2-) or UV-stimulated SAPK activity was higher in mouse embryonic fibroblast (MEF) cells from PS1-null mice than in MEF cells from PS(+/+) mice. MEF(PS1(-/-)) cells were more sensitive to the H(2)O(2)-induced apoptosis than MEF(PS1(+/+)) cells. Ectopic expression of PS1 in MEF(PS1(-/-)) cells suppressed H(2)O(2)-stimulated SAPK/JNK activity and apoptotic cell death. Together, our data suggest that PS1 inhibits the stress-activated signaling by suppressing the SAPK/JNK pathway.

NQ-Y15 inhibits the calcium mobilization by elevation of cyclic AMP in rat platelets.

2-1(4-Cyanophenyl)aminol-3-chloro-1,4-naphthalenedione (NQ-Y15) is a dual action drug which acts as a thromboxane A2 (TXA2) synthase inhibitor and TXA2/PGH2 receptor antagonist. In the present study, we examined the effects of NQ-Y15 on Ca2+ mobilization, which is the common event in various types of platelet activation, in arachidonic acid (AA)-stimulated rat platelets. The elevation of cytosolic Ca2+ concentration ([Ca2+]i) induced by AA was inhibited by NQ-Y15 in a concentration-dependent manner. This inhibition-effect of NQ-Y15 was found to be based on the suppression of the rise in [Ca2+]i by the inhibition of both Ca2+ release from internal stores and Ca2+ influx from the extracellular space. Our successive trial was focused on the role of cyclic AMP (cAMP) in the action of NQ-Y15, because cAMP was reported to be increased by dual action drugs such as picotamide and to inhibit the increase in [Ca2+]i. NQ-Y15 was confirmed to increase cAMP in AA-stimulated rat platelets. These results suggested that NQ-Y15 might inhibit the rise in [Ca2+]i in AA-treated rat platelets by increasing cAMP, which is involved in the inhibition of platelet activation.

Glutathione S-transferase mu modulates the stress-activated signals by suppressing apoptosis signal-regulating kinase 1.

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that can activate the c-Jun N-terminal kinase and the p38 signaling pathways. It plays a critical role in cytokine- and stress-induced apoptosis. To further characterize the mechanism of the regulation of the ASK1 signal, we searched for ASK1-interacting proteins employing the yeast two-hybrid method. The yeast two-hybrid assay indicated that mouse glutathione S-transferase Mu 1-1 (mGSTM1-1), an enzyme involved in the metabolism of drugs and xenobiotics, interacted with ASK1. We subsequently confirmed that mGSTM1-1 physically associated with ASK1 both in vivo and in vitro. The in vitro binding assay indicated that the C-terminal portion of mGSTM1-1 and the N-terminal region of ASK1 were crucial for binding one another. Furthermore, mGSTM1-1 suppressed stress-stimulated ASK1 activity in cultured cells. mGSTM1-1 also blocked ASK1 oligomerization. The ASK1 inhibition by mGSTM1-1 occurred independently of the glutathione-conjugating activity of mGSTM1-1. Moreover, mGSTM1-1 repressed ASK1-dependent apoptotic cell death. Taken together, our findings suggest that mGSTM1-1 functions as an endogenous inhibitor of ASK1. This highlights a novel function for mGSTM1-1 insofar as mGSTM1-1 may modulate stress-mediated signals by repressing ASK1, and this activity occurs independently of its well-known catalytic activity in intracellular glutathione metabolism.

Improvement in macular function after retinal translocation surgery in a patient with age-related macular degeneration.

PURPOSE: To assess focal electroretinographic findings before and after retinal translocation surgery in a patient with age-related macular degeneration. METHOD: Case report. A 79-year-old man with a well-defined subfoveal choroidal neovascular membrane from age-related macular degeneration underwent preoperative and postoperative focal electroretinography. RESULTS: After retinal translocation surgery, best-corrected Snellen visual acuity improved from 9/200 to 20/60. A significant increase in mean foveal amplitude, from 0.08 microV to 0.16 microV (P = 0.008) was recorded. CONCLUSION: Age-related macular degenerative changes in visual acuity and foveal electroretinogram amplitude may be reversible after retinal translocation surgery.

Use of preoperative MR imaging in the management of endometrial carcinoma: cost analysis.

PURPOSE: To compare the cost of magnetic resonance (MR) imaging and its ability to direct the use of lymph node dissection with the cost and ability of conventional surgery for the staging of endometrial carcinoma. MATERIALS AND METHODS: Preoperative MR images of 25 patients who underwent hysterectomy for endometrial carcinoma were retrospectively evaluated. MR imaging results were compared with those of intraoperative gross dissection of the uterus and final histopathologic examination. Medicare reimbursements for two scenarios were compared in each patient. In the MR imaging scenario, the necessity for lymph node dissection was based on MR imaging results and histologic findings at biopsy. In the actual scenario, lymph node dissection was performed at the surgeon's discretion on the basis of findings at gross dissection of the uterus and histologic examination at biopsy. RESULTS: The cost of the MR imaging scenario, as defined by Medicare reimbursements, was 1% ($1, 265/$148,500) less than that of the actual scenario. In the MR imaging scenario, all patients who required lymph node dissection received it, and 86% of the lymph node dissections performed were necessary. In the actual scenario, one necessary lymph node dissection was not performed, and only 31% of the lymph node dissections performed were necessary. CONCLUSION: Staging with MR imaging has costs and accuracy similar to those of the current method of staging with intraoperative gross dissection of the uterus. In addition, MR imaging decreases the number of unnecessary lymph node dissections.

Prophylactic scleral buckle for prevention of retinal detachment following vitrectomy for macular hole.

AIM: To review the rate of retinal detachment after macular hole surgery in patients who received vitrectomy and scleral buckle versus those who had vitrectomy alone. METHODS: All patient charts and hospital records were examined for patients who underwent vitrectomy surgery for macular hole between September 1993 and June 1997. A total of 326 patients were identified and all were followed for a minimum of 6 months. Clinical records were examined for details of the surgical procedure, visual acuity, hole closure status, adjuvant therapies used, and postoperative retinal attachment status. Relative risks (the ratio of the incidence rate in the exposed to that in the unexposed) with 95% confidence intervals and chi(2) tests were calculated to determine which variables were associated with retinal detachment. The primary outcome measure in this review was retinal attachment status. RESULTS: Of 326 eyes which underwent surgery for macular hole during the study period, scleral buckles were utilised in 152 (46.6%) patients. Analysis revealed a detachment rate of 13.2% in patients who did not receive a scleral buckle compared with 5.9% detachment rate in those who did. Analysis of these results indicated a 2.42 times greater risk of developing a retinal detachment in patients without a scleral buckle. Complications related to the use of scleral buckles occurred in two of 152 cases (1.3%) CONCLUSIONS: A reduction in the rate of retinal detachment was noted in patients receiving prophylactic scleral buckles. Those finding suggest a possible beneficial effect of this adjunctive procedure in preventing postoperative retinal detachments. The authors are currently preparing a multicentred, prospective, clinical trial to further study this hypothesis

Effects of Brazilin on the phospholipase A2 activity and changes of intracellular free calcium concentration in rat platelets.

Brazilin (7,11b-dihydrobenz[b]indeno[1,2-d]pyran-3,6a,9,10 (6 H)-tetrol) inhibited thrombin-,collagen- and ADP-induced aggregation of washed rat platelets. Thrombin- and collagen-induced ATP release were also inhibited by brazilin in a concentration-dependent manner. Brazilin inhibited the formation of platelet thromboxane A2 caused by thrombin, whereas it had no effect on the prostaglandin D2 formation. Brazilin inhibited [3H]-arachidonic acid liberation from membrane phospholipids of thrombin-stimulated platelets. Brazilin inhibited the rise of intracellular free calcium caused by thrombin. These results indicate that the inhibition of phospholipase (PLA2) activity and [Ca2+]i elevation might be at least a part of antiplatelet mechanism of brazilin.

A long-term follow-up of choroidal osteoma.

OBJECTIVE: To provide long-term follow-up information on a large series of patients with choroidal osteoma. METHODS: Review of patients with a diagnosis of choroidal osteoma who had been examined at the Bascom Palmer Eye Institute, Miami, Fla, or known to one of us (J.D.M.G.). Information was obtained from hospital medical records or by a questionnaire sent to referring ophthalmologists. Life-table analysis was used to study the loss of vision and development of choroidal neovascularization. RESULTS: We followed up 36 patients, 31 (89%) were female, mean age, 21 years (range, 5-54 years) for a mean of 10 years (range, 2-22 years). Growth was observed for 9 (41%) of 22 well-documented osteomas. The probability of loss of visual acuity to 20/200 or worse was 58% by 10 years and 62% by 20 years. The probability of developing choroidal neovascularization was 47% by 10 years and 56% by 20 years. Successful treatment of the choroidal neovascularization with laser photocoagulation was performed for 5 (25%) of 20 patients. CONCLUSIONS: Most patients with choroidal osteomas maintain good vision in at least 1 eye, but they have a high risk of developing choroidal neovascularization. When this occurs, only a minority can be successfully treated with laser photocoagulation.

Neuronal nitric oxide synthase in the canine prostate: aging, sex steroid, and pathology correlations.

Nitric oxide synthase (NOS) is expressed in the prostate of various species, including humans. NOS catalyzes the production of nitric oxide (NO), which may function in prostatic smooth-muscle relaxation. To investigate further the role of NO in the prostate, we examined neuronal NOS expression in the aging canine prostate, after hormonal perturbation, and correlated these results with histopathologic findings. The study comprised the following treatment groups: intact dogs (treatment group 1, n = 6); dogs who were castrated at 7 days of age and received testosterone and estrogen replacement at 2 years of age (treatment group 2, n = 10); and dogs who were castrated at 2 years of age and received testosterone and estrogen replacement at 2 years of age (treatment group 3, n = 9). Studies were done on prostates removed from dogs after euthanasia at 6 years of age. In treatment group 1, complex benign prostatic hyperplasia (BPH) was observed in all specimens. In treatment group 2, atrophy was observed in 70%, normal prostate with small areas of hyperplasia in 20%, and BPH in 10% of specimens. In treatment group 3, atrophy was observed in 78%, normal histology with small areas of hyperplasia in 11%, and BPH in 11% of specimens. Neuronal NOS localizations were confirmed by western blot analysis and by immunohistochemistry in 0% and 17%, respectively, of specimens in treatment group 1, in 60% and 70%, respectively, of specimens in treatment group 2, and in 67% and 71%, respectively, of specimens in treatment group 3. Neuronal NOS immunoreactivity was localized in histologically normal prostates of four intact, young-adult control dogs (2 years of age). For all treatment groups, neuronal NOS immunoreactivity was confirmed by western blot in 86% of atrophic prostates but in no prostates with BPH (P < 0.001), and it was confirmed by immunohistochemistry in 75% of atrophic prostates but in only 13% of prostates with BPH (P < 0.02). These data suggest that, in the canine prostate, NO release relates to growth and pathology. Low levels of neuronal NOS expression in BPH tissue, compared with higher levels in atrophic tissue, suggest that neuronal NOS expression is down-regulated in the prostate with benign cellular proliferation whereas it is maintained or possibly up-regulated in the prostate with prostatic involution. Whether altered neuronal NOS expression contributes to the pathogeneses of BPH and prostatic involution or whether it occurs as a consequence of these processes requires further investigation.

Computed radiography versus screen-film mammography in detection of simulated microcalcifications: a receiver operating characteristic study based on phantom images.

RATIONALE AND OBJECTIVES: The authors compare a 43-micron computed radiographic system with a mammographic screen-film system for detection of simulated microcalcifications in an observer-performance study. MATERIALS AND METHODS: The task of detecting microcalcifications was simulated by imaging aluminum wire segments (200-500 microns in length; 100, 125, or 150 microns in diameter) that overlapped with tissue background structures produced by beef brisket. A total of 288 such simulations were generated and examined with both computed radiography and conventional screen-film mammography techniques. Computed radiography was performed with high-resolution plates, a 43-micron image reader, and a 43-micron laser film printer. Computed radiographic images were printed with simple contrast enhancement and compared with screen-film images in a receiver operating characteristic study in which experienced readers detected and scored the simulated microcalcifications. Observer performance was quantitated and compared by computing the area under the receiver operating characteristic curve. RESULTS: Although the resolution of the computed radiography system was better than that of commercial systems, it fell short of that of screen-film systems. For the 100-micron microcalcifications, the difference in the average area under the curve was not statistically significant, but it was significant for the larger simulated microcalcifications: the average area under the curve was 0.58 for computed radiography versus 0.76 for screen-film imaging for the 125-micron microcalcifications and 0.83 versus 1.00, respectively, for the 150-micron microcalcifications. CONCLUSION: Observer performance in the detection of small simulated microcalcifications (100-150 microns in diameter) is better with screen-film images than with high-resolution computed radiographic images.

Treatment of capillary vascular malformation (port-wine stains) with photochemotherapy.

One-hundred and thirty patients (85 female, 45 male) with port-wine stains were treated with photodynamic therapy, also called photochemotherapy, which recently has become acknowledged as effective for a variety of malignant tumors. Probably based on the photochemical reaction with the generation of toxic species, photochemotherapy results in endothelial cell injury and death of abnormal capillaries under overlying epidermis. A retrospective review of 118 available patients with port-wine stains reveals that 98.3 percent responded to photochemotherapy with varying degrees of success after one-time treatment. Results were reported under a simple classification system ranging from ordinary to dilated to posttreatment type. In the ordinary group, the results evaluated as excellent, good, fair, and poor were 37.8, 53.7, 8.5, and 0 percent, respectively, before a second treatment; the treated area was an average of 9.8 (range 7 to 13) cm in diameter. In addition, hypertrophic scars, permanent hyperpigmentation, and hypopigmentation were not seen based on proper parameters. Photochemotherapy offers a potentially efficient and promising choice based on a completely different mechanism from that of selected photothermal therapy with the pulsed-dye laser.

Preliminary clinical evaluation of a high-resolution telemammography system.

RATIONALE AND OBJECTIVES: The authors designed, assembled, tested, and clinically evaluated a high-quality, fast, and relatively inexpensive telemammography system. METHODS: The authors designed a telemammography system that uses a high-resolution film digitizer and high data compression (> or = 40:1) to send images over regular telephone lines to a high-resolution laser printer that produces images with the look and feel of the original image and can operate in a hub and spokes mode. The authors then evaluated the system's performance. In a preliminary clinical study, interpretations of the laser-printed system's output of 119 cases were compared with the original interpretations, followed by a review of any clinically significant differences. RESULTS: With the exception of the laser printer, which is a modified off-the-shelf product, all hardware components of the system are commercially available products. The system digitizes (50 microns pixel size), compresses, transmits, receives, decompresses, and prints a 30 MB mammography file in less than 4 minutes. In the clinical study, there were 13 differences (in 13 cases) in the level of concern or recommendations. Seven were found to be clinically insignificant by a third-party review. The remaining six were reviewed by the original interpreter, and three were determined to be significant enough for further action. All were found to result from intra-reader variability rather than differences in visualization of possible abnormalities. CONCLUSIONS: Almost real-time, high-quality telemammography without geographic boundaries is possible with the use of high-level data compression. Telemammography with laser-printed film as the display may make it possible to offer mammographic services in remote locations while using commercially available technology.

Partial sympathetic denervation of the rat epididymis permits fertilization but inhibits embryo development.

The rat cauda epididymidis receives sympathetic innervation from the inferior mesenteric ganglion (IMG). We have previously demonstrated that surgical removal of the IMG and proximal hypogastric nerves (IMG denervation) results in significant and cauda-specific changes in epididymal sperm transport, sperm motility, luminal fluid protein composition, and tissue histology. In the present study we used natural mating trials and intrauterine insemination (IUI) techniques to determine whether or not IMG denervation affects male fertility and reproductive capacity. For the initial studies, adult male Sprague Dawley rats were mated with estrous females 1 and 4 weeks following IMG denervation. Nine days after mating, uterine implantation sites and corpora lutea (CL) were counted. In females mated with sham-operated control males, 85.8% of ovulated oocytes were fertilized and subsequently implanted. In contrast, females mated with IMG-denervated males 1 or 4 weeks following surgery had 0% and 3.5%, respectively, of ovulated oocytes fertilized and implanted. For rats maintained 21 days after mating, an average of 13 +/- 1 pups were delivered by each of nine females mated with sham-operated control male rats; whereas, only seven morphologically normal pups were delivered by one of 14 females mated with IMG-denervated male rats. Additional experiments demonstrated that the decrement in offspring was, in part, due to a significant decrease in the number of spermatozoa in the female uterus following mating with IMG-denervated males. To determine whether IMG denervation exerted an additional effect directly on the fertilizing ability of spermatozoa, IUI experiments were performed. Six million cauda epididymal spermatozoa from 1- or 4-week IMG-denervated males were inseminated into the uterine horns of luteinzing hormone-releasing hormone (LHRH)-synchronized females and 9 days later implantation sites and CL were counted. Implantations were observed for 78%, 28%, and 25% of ovulated oocytes following IUI with spermatozoa from sham-operated controls and from 1- and 4-week IMG-denervated rats, respectively. To determine whether the reduction in implantation sites following IUI with spermatozoa from IMG-denervated rats resulted from impaired oocyte fertilization, studies were performed in which oocytes were retrieved and stained 24 hours after IUI. Comparable fertilization rates of 76.5% and 89.0% were observed using cauda epididymal spermatozoa from IMG-denervated and sham-operated control males, respectively, indicating that oocyte fertilization was not affected by the loss of innervation. These studies establish the importance of innervation from the IMG for ejaculatory competence and sperm reproductive capacity in the male rat. These data further suggest that sympathetic innervation in the epididymis critically influences paternal factors associated with embryonic development.

The use of 5,6 benzo-[alpha]-pyrone (coumarin) and heating by microwaves in the treatment of chronic lymphedema of the legs.

Sixty patients with leg lymphedema from a variety of etiologies were divided into randomized two groups, matched by Grade, duration, age, sex, and cause of lymphedema. Using a double-blind format, one group received 5,6 benzo-[alpha]-pyrone (coumarin 1,2 benzopyrone, 400 mg/day) for six months; the other received a placebo. For the next six months, both groups received a standardized regimen of heat (using microwaves) coupled with compression garments. Benzopyrone produced approximately 20% reduction in the volume (p = 10(-4)) and improvement in circumferences and tonometry (p = 10(-5) and 10(-7)). Symptoms (feelings of swelling, pain, heaviness and loss of mobility) were also significantly improved (p = 0.03 to 10(-7)). During the second six months, when microwave heat therapy was added to drug therapy, the patients who had previously received the placebo showed significant improvement (p = 0.03 to 10(-9)) in signs and symptoms of lymphedema. Some, but not all, of the group that was receiving benzopyrones were also significantly improved by heat therapy (p = 0.8 to 0.002). Taking benzopyrones for 12 months plus heat treatment for six months was significantly better, for some criteria, than the placebo plus heat therapy (p = 0.7 to 0.04). On the other hand, heat plus either placebo or benzopyrone was often significantly better than either the active or inactive drug without heat (p = 0.8 to 10(-9)).