Matrix metalloproteinases regulate ECM accumulation but not larval heart growth in Drosophila melanogaster.

The Drosophila heart provides a simple model to examine the remodelling of muscle insertions with growth, extracellular matrix (ECM) turnover, and fibrosis. Between hatching and pupation, the Drosophila heart increases in length five-fold. If major cardiac ECM components are secreted remotely, how is ECM "self assembly" regulated? We explored whether ECM proteases were required to maintain the morphology of a growing heart while the cardiac ECM expanded. An increase in expression of Drosophila's single tissue inhibitor of metalloproteinase (TIMP), or reduced function of metalloproteinase MMP2, resulted in fibrosis and ectopic deposition of two ECM Collagens; type-IV and fibrillar Pericardin. Significant accumulations of Collagen-IV (Viking) developed on the pericardium and in the lumen of the heart. Congenital defects in Pericardin deposition misdirected further assembly in the larva. Reduced metalloproteinase activity during growth also increased Pericardin fibre accumulation in ECM suspending the heart. Although MMP2 expression was required to remodel and position cardiomyocyte cell junctions, reduced MMP function did not impair expansion of the heart. A previous study revealed that MMP2 negatively regulates the size of the luminal cell surface in the embryonic heart. Cardiomyocytes align at the midline, but do not adhere to enclose a heart lumen in MMP2 mutant embryos. Nevertheless, these embryos hatch and produce viable larvae with bifurcated hearts, indicating a secondary pathway to lumen formation between ipsilateral cardiomyocytes. MMP-mediated remodelling of the ECM is required for organogenesis, and to prevent assembly of excess or ectopic ECM protein during growth. MMPs are not essential for normal growth of the Drosophila heart.

Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue.

Cyclin D1 and p16INK4A are molecules with pivotal roles in cell cycle control and the development of diverse human cancers, and overexpression of cyclin D1 and loss of p16INK4A expression are common genetic events in head and neck squamous cell carcinoma. The prognostic significance of these molecular events at different sites within the head and neck, however, remains controversial. Thus, we sought to determine the relationship between cyclin D1 and/or p16INK4A expression and disease outcome in squamous cell carcinoma of the anterior tongue. Immunohistochemical detection of nuclear proteins cyclin D1, p53, and p16INK4A, and the Ki-67 labeling index was undertaken in tissue sections from 148 tongue cancers treated by surgical resection. Nuclear antigen status was analyzed in relation to pathological variables, tumor recurrence, and patient survival. Statistical significance was assessed using chi2 analysis for pathological variables and the Kaplan-Meier method, log rank test, and the Cox proportional hazards model for survival parameters. Overexpression of cyclin D1 occurred in 68% of tumors (100 of 147) and was associated with increased lymph node stage (P = 0.014), increased tumor grade (P = 0.003), and reduced disease-free (P = 0.006) and overall (P = 0.01) survival. Loss of p16INK4A expression was demonstrated in 55% of tumors (78 of 143) and was associated with reduced disease-free (P = 0.007) and overall (P = 0.014) survival. Multivariate analysis confirmed that in addition to pathological stage and regional lymph node status, cyclin D1 overexpression and loss of p16INK4A expression are independent predictors of death from tongue cancer. Loss of p16INK4A in the presence of cyclin D1 overexpression conferred a significantly worse disease-free (P = 0.011) and overall (P = 0.002) survival at 5 years. p53 nuclear accumulation and the Ki-67 labeling index were not prognostic. These data indicate that cyclin D1 overexpression and loss of p16INK4A expression predict early relapse and reduced survival in squamous cell carcinoma of the anterior tongue. Simultaneous assessment of cyclin D1 and p16INK4A protein levels define subgroups of patients at increased risk of relapse and may be of clinical utility in optimizing therapy.

Resistance properties of Thera-Band tubing during shoulder abduction exercise.

STUDY DESIGN: Single-group, repeated measures. OBJECTIVES: To investigate the relationship between tubing length and tubing tension for 6 colors of Thera-Band tubing (each color representing a different level of resistance) and to estimate the resistive shoulder torque provided during shoulder abduction exercise. BACKGROUND: Thera-Band tubing is popular for providing resistance in rehabilitation strengthening programs. Unfortunately, it is difficult to compare use of elastic tubing with other resistance training methods because no published data exist on how much resistance is being provided during exercise. METHODS AND MEASURES: Nine male and 6 female subjects (age, 25.9 +/- 3.6 years; height, 173 +/- 10 cm) performed shoulder abduction, using 6 colors of tubing. A strain gauge attached at the fixed end of the tubing directly measured the tension generated during stretch. For each color of tubing, each subject momentarily held a position at 30 degrees, 60 degrees, 90 degrees, 120 degrees, and 150 degrees of abduction. Shoulder joint abduction, limb segment position, and tubing length were analyzed by means of the Peak Motion Measurement System. Simple linear regression equations predicted tubing tension from percent change in tubing length at the joint angle positions. A 2-way (5 x 6) repeated-measures ANOVA determined the mean differences in tubing tension across tubing colors at the shoulder abduction positions. RESULTS: Strong linear relationships were found for each tubing tension when referenced according to changes in tubing length. Significant differences in tension were found for the various colors of tubing. The resistive torque curves for each color tubing were similar to isotonic exercise. CONCLUSIONS: Thera-Band tubing provides linear resistance during shoulder abduction, but the resistive torque provided by the tubing mimics isotonic exercise.

Molecular support for field cancerization in the head and neck.

BACKGROUND: Two competing concepts, field cancerization and micrometastatic lesions, have been postulated to account for the high frequency of second primary tumors and multicentric dysplasia in patients with head and neck carcinoma. METHODS: To provide insight into this process, the authors examined histologically normal mucosa and dysplastic tissue adjacent to invasive tumor for loss of heterozygosity (LOH) at three commonly deleted loci. Tissues from 21 patients with carcinoma of the oral cavity and oropharynx were identified and verified by a pathologist to contain histologically normal mucosa, dysplasia, and adjacent invasive squamous cell carcinoma. Each specimen was analyzed for LOH at D9S171 (9p21), D3S1007 (3p21.3-22), and D3S1228 (3p14). RESULTS: Of the 21 patients, 19 had adequate DNA for analysis. Seventeen patients were heterozygous at one or both of the 3p sites and LOH occurred in 6 of 17 invasive tumor specimens, 1 of 17 dysplasia specimens, and in none of the mucosal specimens. LOH at 9p21 occurred in 11 of 13 informative specimens of invasive tumor, 8 of 13 dysplasia specimens, and 6 of 13 normal mucosa specimens. However, one case that did not have 9p deletion in the tumor demonstrated LOH in the mucosa and two cases had LOH in both the tumor and mucosa but with deletion of the opposite allele. CONCLUSIONS: These data suggest that 9p21 but not 3p14 or 3p21 deletions occur in the absence of histologic changes. In two cases preinvasive and invasive lesions that apparently were an example of histologic progression contained disparate genetic events, calling into question the use of adjacent dysplasia as a model for premalignant lesions.

Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis.

BACKGROUND: Cervical lymph node metastasis in differentiated thyroid carcinoma has mostly been found to have little relationship to prognosis. However, some studies report nodal involvement to be an adverse factor, while others have found it to be favorable. We have undertaken a matched-pair analysis of previously untreated patients, with and without ipsilateral neck metastasis, to examine the significance of nodal spread in patients with otherwise equivalent prognostic factors for differentiated thyroid cancer. METHOD: From a database of 931 patients, treated from 1930 to 1980, we used a computer to match patients with confirmed lateral neck metastasis (N1) to those who were stage NO, and had the following identical prognostic factors: no distant metastasis, age (within 4 years), and tumor size, histology, and intrathyroidal extent. When possible, matches were also made for gender, multifocality, and extent of thyroid surgery. Survival and treatment failures were analyzed, with and without stratification for age. RESULTS: We were able to select 100 N1 patients with corresponding NO patients, sharing the major prognostic risk factors as listed. Overall, there was no difference in survival, although N1 patients more often had recurrence. Mortality increased with age. Analysis at high-risk age (45 years and older) showed significantly more recurrences in N1 patients (p = .008). Twenty-year survival in N1 patients over the age of 45 was lower than that of NO patients. On the other hand, under the age of 45, N1 patients had better survival. These differences, however, did not reach statistical significance. CONCLUSION: Nodal involvement in older patients with thyroid cancer increases the risk of recurrence, although no significant difference in survival is observed in relation to age.

Vocal cord medialization for unilateral paralysis associated with intrathoracic malignancies.

Patients with unilateral vocal cord paralysis from intrathoracic malignancies may have significant dysfunctions of speech, swallowing, ventilation, and effective coughing as a result of inadequate compensation of the nonparalyzed cord. In patients with already compromised pulmonary function, aspiration can be a life-threatening event. Sixty-three patients with intrathoracic malignancies required surgical correction of vocal cord paralysis. Primary pathology included lung cancer (49), esophageal cancer (nine), and miscellaneous tumors (five). Symptoms included hoarseness (62), dyspnea (21), aspiration (26), weight loss (19), dysphagia (14), and pneumonia (14). The surgical procedures included medial displacement of the vocal cord with silicone elastomer (48), temporary Gelfoam injection (seven), and Teflon (polytetrafluoroethylene) injection (eight) to move the affected cord to a medial position. In 11 patients, the operation was performed in the acute postoperative setting to improve pulmonary toilet. Symptomatic improvement was noted in the following proportions of affected patients: hoarseness, 92%; dyspnea, 90%; dysphagia, 93%; aspiration, 92%; pneumonia, 93%; and weight loss, 47%. Overall success rate of the intervention was 57 of 63 patients (90%). All 11 patients treated in the acute setting had immediate improvement. A variety of complications occurred in 17% of patients. Surgical management of vocal cord paralysis in patients with intrathoracic malignancies prevents life-threatening pulmonary complications in the acute postoperative setting. In chronic situations, it provides patients with improved speech, swallowing, and pulmonary function, resulting in improved quality of life, even for patients not cured of their disease.

Increased expression of basic fibroblast growth factor in squamous carcinogenesis of the head and neck is less prevalent following smoking cessation.

Basic fibroblast growth factor (bFGF), a potent angiogenic peptide, is thought to provide a growth advantage to a number of tumors including squamous cancer of the head and neck. The purpose of this study was to demonstrate the in situ expression of bFGF in lesions of the upper aerodigestive tract (UADT) and to correlate that with clinical parameters and known risk factors for carcinoma. On surgical specimens from 52 patients, we used a colorimetric in situ hybridization assay to determine the expression of bFGF mRNA in normal and pathologic conditions commonly seen in squamous mucosa. The extent of reactivity for the bFGF transcript was recorded on a subjective scale from 1+ to 3+, based on the visual intensity of labeling. These findings were subsequently correlated with clinical data. Basic fibroblast growth factor mRNA was detected at low to moderate levels in all sections of normal mucosa, with no distinction between patients with or without squamous cancer. Inflamed mucosa had comparatively strong expression of bFGF mRNA. Among lesions implicated in the stepwise nature of squamous carcinogenesis, we found increases in bFGF expression that were most significant at the level of carcinoma in situ, persisting through the invasive and nodal metastatic stages of the disease (P < 0.005). Interestingly, those increases were significantly less frequent among former smokers (P = 0.02). We have established the expression of bFGF mRNA in normal, inflammatory, and neoplastic tissue within the UADT. Furthermore, we note for the first time that increased expression is associated with the acquisition of more aggressive biologic behavior in squamous carcinogenesis.

Carcinoma of the oropharynx.

Carcinoma of the oropharynx poses particular challenges and problems to head and neck clinicians. These include relative anatomic inaccessibility, field cancerization and the need to minimize speech and swallowing dysfunction. The aim of this review is to bring together an appreciation of the issues involved in the management of this disease and the more recent results of its treatment.

Management of occult neck metastases in oral cavity squamous carcinoma.

A large experience with patients who had radical neck dissection for oral squamous carcinoma has been reviewed in order to compare elective lymphadenectomy results with those achieved when neck dissection was delayed until metastases appeared or was performed initially for limited N1 neck disease. No significant difference in survival rates was observed, but neck failure was a more significant problem when treatment was delayed. This was most obvious in patients treated for tongue cancer. Although the impact of elective neck treatment on "cure" rates will require prospective studies, it seems clear that elective lymphadenectomy can enhance regional control of cancer and improve the quality of the patients' survival.

Modeling and subjective assessment of cell discard in ATM video.

Measurements of subjective picture impairment as a function of network loading in a simulated ATM network are reported. The simulation indicated that cells tend to be discarded in bursts, the frequency and severity of which can be related to the loading by a threshold model. The effect of the discards on broadcast-style video, coded using a single-layer H.261-type method, was found to be a function of scene content and movement at the instant of occurrence. If the visibility of cell discards is maintained at or below threshold in worst-case scenes, the study indicated that network loadings around 55% for a multiplex of 16 video sources and around 70% for a multiplex of 48 video sources are achievable.

Comprehensive treatment strategy for oral and oropharyngeal cancer.

This prospective nonrandomized study analyzes the effectiveness of the following treatment protocol for oral and oropharyngeal cancers: (1) radical initial surgery; (2) elective modified or selective neck dissection for NO necks; (3) jaw preservation unless gross invasion is present; (4) radial forearm freeflap reconstruction; (5) elective tracheotomy; (6) postoperative radiotherapy unless previously given; and (7) active oral rehabilitation. Between 1987 and 1992, 75 patients (55 men and 20 women) with a median age of 58 years had this treatment. Fifteen had been previously treated with radiotherapy. Clinical stages of untreated patients were as follows: 4 patients, stage I; 25 patients, stage II; 12 patients, stage III; and 19 patients, stage IV. Ten patients had segmental jaw resection, 26 had a marginal mandibulectomy, and 26 had a jaw swing. There were no operative deaths, and only one flap (1.2%) failed. Median times for oral feeds and hospital stay were 8 and 17 days, respectively. Forty-four patients had postoperative radiotherapy. Median follow-up time is 30 months, and locoregional control is 95% for previously untreated patients and 54% for previously treated patients. Thirteen patients have died of disease, 8 with locoregional recurrence and 5 with distant metastases alone. We conclude that this treatment strategy is highly effective in previously untreated patients but less effective in salvaging patients in whom radiotherapy has failed.

Biomechanics of wheelchair propulsion as a function of seat position and user-to-chair interface.

This study investigated the biomechanics of lever and hand-rim propulsion and the effects of seat position on propulsion mechanics. Nine able-bodied and six paraplegic spinal cord injured persons participated. Subjects performed hand-rim and lever propulsion on a wheelchair test simulator at a speed and load of 3km/hr and 7.5 watts/side, respectively. A 2 x 3 matrix of randomized seat positions was used. Three-dimensional motion measures of the trunk, shoulder, elbow, and wrist were collected over four-second sample periods for each seat position. Hub torque and stroke arc measurements were determined. Upper extremity motions were significantly different (p less than .05) for the two methods of propulsion. Hand-rim propulsion required less elbow motion, greater shoulder extension, less shoulder rotation and less arm abduction than lever propulsion. Both methods of propulsion required a substantial amount of internal rotation at the shoulder. Seat position changes had a greater effect on joint motion ranges when hand-rim propulsion was performed. No significant differences (p greater than .05) were found for trunk motion for the treatments. The findings provide additional information for development of a model for the optimization of wheelchair propulsion.

Sequential laparotomy and zipper closure in the management of gross peripancreatic sepsis.

Four cases of gross peripancreatic sepsis have been managed with repeated laparotomies and packing of the lesser sac. A zipper was used for abdominal closure in three patients and the abdomen was left open in one. Sequential laparotomy enabled repeated debridement of non-viable pancreatic and peripancreatic tissue and prevented intra-abdominal septic accumulations. An additional benefit of this technique was the frequent detection and correction of clinically unsuspected complications of the septic abdomen.

Percutaneous infraclavicular insertion of long-term central venous Hickman catheters.

Percutaneous infraclavicular subclavian vein insertions of single lumen Hickman right atrial catheters (n = 342) were performed on 308 patients at Royal Prince Alfred Hospital. The indications for insertion were administration of total parenteral nutrition (44.8%), intravenous chemotherapy (40.9%), intravenous therapy in patients with inaccessible peripheral veins (11.7%), and intravenous antibiotic administration (2.6%). Three percutaneous catheter insertions were complicated by pneumothorax (0.88%). There were no other complications of insertion. Catheters remained in situ for a median period of 30 days (range: 2-853 days). The majority of catheters (69.6%) remained functioning and complication-free until the completion of therapy or until the patient died of their original disease. Some catheters became infected (9.9%) and there was a 0.6% incidence of septicaemia due to infected catheters; 8.5% of catheters were removed because of a suspicion of infection that was not subsequently proven. The incidence of infection was highest within the first month after catheter insertion, and decreased thereafter. Percutaneous subclavian insertion of Hickman right atrial catheters appears to be the insertion method of choice in patients requiring long-term central venous access.