Development of KVO treatment strategies for chronic pain in a rat model of Gulf War Illness.

We examined whether combinations of Kv7 channel openers could be effective modifiers of deep tissue nociceptor activity; and whether such combinations could then be optimized for use as safe analgesics for pain-like signs that developed in a rat model of GWI (Gulf War Illness) pain. Voltage clamp experiments were performed on subclassified nociceptors isolated from rat DRG (dorsal root ganglion). A stepped voltage protocol was applied (-55 to -40 mV; Vh = -60 mV; 1500 ms) and Kv7 evoked currents were subsequently isolated by linopirdine subtraction. Directly activated and voltage activated K+ currents were characterized in the presence and absence of Retigabine (5-100 µM) and/or Diclofenac (50-140 µM). Retigabine produced substantial voltage dependent effects and a maximal sustained current of 1.14 pA/pF ± 0.15 (ED50: 62.7 ± 3.18 µM). Diclofenac produced weak voltage dependent effects but a similar maximum sustained current of 1.01 ± 0.26 pA/pF (ED50: 93.2 ± 8.99 µM). Combinations of Retigabine and Diclofenac substantially amplified resting currents but had little effect on voltage dependence. Using a cholinergic challenge test (Oxotremorine, 10 µM) associated with our GWI rat model, combinations of Retigabine (5 uM) and Diclofenac (2.5, 20 and 50 µM) substantially reduced or totally abrogated action potential discharge to the cholinergic challenge. When combinations of Retigabine and Diclofenac were used to relieve pain-signs in our rat model of GWI, only those combinations associated with serious subacute side effects could relieve pain-like behaviors.

Combinations of classical and non-classical voltage dependent potassium channel openers suppress nociceptor discharge and reverse chronic pain signs in a rat model of Gulf War illness.

In a companion paper we examined whether combinations of Kv7 channel openers (Retigabine and Diclofenac; RET, DIC) could be effective modifiers of deep tissue nociceptor activity; and whether such combinations could then be optimized for use as safe analgesics for pain-like signs that developed in a rat model of GWI (Gulf War Illness) pain. In the present report, we examined the combinations of Retigabine/Meclofenamate (RET/MEC) and Meclofenamate/Diclofenac (MEC/DIC). Voltage clamp experiments were performed on deep tissue nociceptors isolated from rat DRG (dorsal root ganglion). In voltage clamp studies, a stepped voltage protocol was applied (-55 to -40 mV; Vh=-60 mV; 1500 msec) and Kv7 evoked currents were subsequently isolated by Linopirdine subtraction. MEC greatly enhanced voltage dependent conductance and produced exceptional maximum sustained currents of 6.01 ± 0.26 pA/pF (EC50: 62.2 ± 8.99 µM). Combinations of RET/MEC, and MEC/DIC substantially amplified resting currents at low concentrations. MEC/DIC also greatly improved voltage dependent conductance. In current clamp experiments, a cholinergic challenge test (Oxotremorine-M, 10 µM; OXO), associated with our GWI rat model, produced powerful action potential (AP) bursts (85 APs). Optimized combinations of RET/MEC (5 and 0.5 µM) and MEC/DIC (0.5 and 2.5 µM) significantly reduced AP discharges to 3 and 7 Aps, respectively. Treatment of pain-like ambulatory behavior in our rat model with a RET/MEC combination (5 and 0.5 mg/kg) successfully rescued ambulation deficits, but could not be fully separated from the effect of RET alone. Further development of this approach is recommended.

Projection structures of three photosynthetic complexes from Rhodobacter sphaeroides: LH2 at 6 A, LH1 and RC-LH1 at 25 A.

Three photosynthetic complexes, light-harvesting complex 2 (LH2), light-harvesting complex 1 (LH1), and the reaction centre-light-harvesting complex 1 photounit (RC-LH1), were purified from a single species of a purple bacterium, Rhodobacter sphaeroides, and reconstituted into two-dimensional (2-D) crystals. Vesicular 2-D crystals of LH1 and RC-LH1 were imaged in negative stain and projection maps at 25 A resolution were produced. The rings formed by LH1 have approximately the same mean diameter as the LH1 rings from Rhodospirillum rubrum ( approximately 90 A) and therefore are likely to be composed of 15 to 17 alphabeta subunits. In the projection map calculated from the RC-LH1 2-D crystals, the reaction centre is represented by an additional density in the centre of the ring formed by the LH1 subunits. The marked improvement of shape and fine structure after a rotational pre-alignment of the RC-LH1 unit cells before averaging strongly suggests that the RC is not in a unique orientation within the LH1 rings. Tubular crystals of LH2 showed a high degree of order and allowed calculation of a projection map at 6 A resolution from glucose-embedded specimens. The projection structure shows a ring of nine alphabeta subunits. Variation of the alpha-helical projection densities suggests that the 9-fold symmetry axis is tilted with respect to the membrane normal.

Acute and chronic morbidity differences between muscle-sparing and standard lateral thoracotomies.

INTRODUCTION: Opinions differ regarding differences between totally muscle-sparing thoracotomy and standard lateral thoracotomy approaches to pulmonary resection with respect to operative time, postoperative pain and morbidity, and occurrence of chronic postthoracotomy pain syndromes and subjective shoulder dysfunction. METHODS: Three hundred thirty-five consecutive patients undergoing muscle-sparing thoracotomy (n = 148) or lateral thoracotomy (n = 187) to accomplish lobectomy for stage I lung cancer during a 40-month period were evaluated. Local rib resection was not employed, and two chest tubes were routinely used after operation in both thoracotomy groups. Epidural analgesia use was similar after operation in the two groups (muscle-sparing thoracotomy 38%, lateral thoracotomy 38%). The postoperative hospital courses and patient functional statuses at 1 year were examined. RESULTS: Demographic analyses demonstrated no differences between groups in age, sex, or association of significant comorbid medical illness. Although the operative time required for muscle-sparing thoracotomy was shorter, there were no differences between thoracotomy approaches in any of the other primary acute postoperative variables analyzed (chest tube duration, length of hospital stay, postoperative narcotic requirements, and postoperative mortality). The frequencies of chronic pain and shoulder dysfunction assessed 1 year after operation were also similar between thoracotomy groups. CONCLUSIONS: The relative efficacies and rates of occurrence of acute or chronic morbidity are equivalent after muscle-sparing thoracotomy and standard lateral thoracotomy. Although muscle-sparing thoracotomy may possibly be performed more expediently, it appears that the singular advantage of muscle-sparing thoracotomy over standard lateral thoracotomy involves the preservation of chest wall musculature in case rotational muscle flaps should be needed later.

Unilateral thoracoscopic surgical approach for diffuse emphysema.

We evaluated the use of a lateral thoracoscopic approach for lung reduction surgery in patients with diffuse emphysema. Sixty-seven patients with a mean age of 61.9 years underwent operation. Operative side was determined by preoperative imaging. The procedures were laser ablation in 10 patients and stapler resection in 57 patients. Ten patients, including six of the 10 patients in the laser-only group had poor outcome (death or hospitalization longer than 30 days), leading us to abandon the laser technique. Of the remaining 57 patients undergoing primary stapled resection, duration of chest tube placement averaged 13 days (range 3 to 53 days) with a mean hospital stay of 17 days (range 6 to 99 days). Seven patients required ventilation for longer than 72 hours, six patients underwent conversion of the procedure to open thoracotomy, four patients acquired arrhythmias, and three patients were treated for empyema. There was one early death (1.7%), from cardiopulmonary failure. Forty patients returned for 3-month evaluation. Significant (p < 0.0001) improvements were seen in forced vital capacity (2.69 L after vs 2.26 L before) and forced expiration volume in 1 second (1.04 L after vs 0.82 L before), with 25 of 40 patients (63%) showing an improvement of more than 20%. Lung volume measures, in particular residual volume, fell significantly. Arterial blood gas analysis revealed that carbon dioxide tension fell significantly in patients with preoperative hypercapnia (carbon dioxide tension > 45 mm Hg, p = 0.018). Six-minute walk test results improved (894 feet after vs 784 feet before, p = 0.002), and symptomatic benefit was confirmed by significant improvement in the dyspnea index. The combination of both hypercapnia and reduced single-breath diffusing capacity for carbon monoxide was significantly more frequent (p = 0.0026) and was 86% specific (5 of 6 patients) in predicting serious postoperative risk. We conclude that the lateral thoracoscopic surgical approach to diffuse emphysema offers significant improvement in pulmonary mechanics and functional impairment. Patients with a combination of hypercapnia and reduced single-breath diffusing capacity for carbon monoxide should not be considered for this procedure because of significant perioperative risk.

Comparison of open versus thoracoscopic lung biopsy for diffuse infiltrative pulmonary disease.

BACKGROUND: Patients with diffuse pulmonary infiltrates often require biopsy for a diagnosis. Standard operative therapy, open wedge resection via thoracotomy, is associated with known morbidity. We hypothesized that closed thoracoscopic wedge resection may result in reduced morbidity and decreased duration of hospital stay. This retrospective study compares open resection with thoracoscopic wedge resection in patients with diffuse pulmonary infiltrates. METHODS: Seventy-five patients with diffuse pulmonary infiltrates underwent diagnostic lung biopsy. Patients requiring mechanical ventilation and high levels of pressure support before biopsy were excluded from the study. Between March 1987 and September 1991, a total of 28 patients underwent open wedge resection via lateral thoracotomy. Since April 1991, a total of 47 patients underwent thoracoscopic resection. RESULTS: There was no difference between the groups in age, sex, presence of immunosuppression, or final pathologic diagnosis. Adequate tissue was obtained for pathologic diagnosis in all patients of both groups. All surgeons believed that thoracoscopic biopsy provided better visualization of the entire lung than did a limited thoracotomy. Mean operative time was 69 minutes for open biopsies and 93 minutes for thoracoscopic biopsies [p = 0.038]. Mean duration of chest tube drainage was not significantly different between the two groups. Duration of hospital stay was significantly less for thoracoscopic biopsy (4.9 days) than for open biopsy (12.2 days) (p = 0.018). Fourteen of 28 open biopsies resulted in complications compared with 9 of 47 closed biopsies (p = 0.009). There were 6 deaths among patients having open biopsies and 3 deaths among those having closed biopsies (p = not significant). CONCLUSION: A significant decrease in hospital stay was noted with thoracoscopic biopsy when compared with lung biopsy via the standard open approaches. Thoracoscopy provided excellent visualization and allowed for wedge resection that provided adequate tissue for diagnosis in patients with diffuse pulmonary interstitial disease.

Diagnosing the indeterminate pulmonary nodule: percutaneous biopsy versus thoracoscopy.

BACKGROUND: The malignant potential of indeterminate solitary pulmonary nodules (SPN) mandates accurate diagnostic management. METHODS: 613 patients undergoing either computed tomographic lung biopsy (CT-Bx) (n = 312) or thoracoscopic excisional biopsy (Thor-Bx) (n = 301) for the diagnosis of SPN were evaluated for relative accuracy, complications, and effect on clinical treatment. RESULTS: CT-Bx identified a malignant diagnosis (Dx) in 201 (64%) of 312 patients; 85 (42%) underwent operations. A total of 116 patients (58%) with synchronous cancer (n = 16), impaired physiologic condition, or unresectable lesions (n = 100) were not operated. Surgical treatment was deferred for 20 patients (6%) with a "specific benign" Dx and 44 physiologically impaired patients with "nonspecific benign" CT-Bx. Forty-seven patients with "nonspecific benign" Dx underwent operation. Thirty-two (68%) lesions were malignant (4 metastatic, 28 primary cancer). CT-Bx accuracy was 86% for malignant and 79 (71%) of 111) for benign lesions. Surgery was still required for 132 (82%) of 163 patients with resectable lesions. Complications occurred in 24% of patients. A specific benign or malignant Dx was obtained in 292 (96%) of 301 patients undergoing Thor-Bx. Conversion to thoracotomy for lobectomy occurred in 38 (21%) of 179 patients with lung cancer. One hundred forty-one patients with lung cancer and impaired physiologic condition and all patients with metastatic (n = 44) and benign lesions (n = 78) had thoracoscopic resection alone. Complications occurred in 22% of patients. CONCLUSIONS: Limited accuracy for benign Dx with CT-Bx requires surgical biopsy for patients with SPN with adequate physiologic reserve. Thor-Bx is a safe and accurate minimally invasive surgical approach to resectable peripheral SPN.

Thoracoscopic resection of 85 pulmonary lesions.

Advances in endoscopic surgical equipment and laser technology have expanded the role of thoracoscopy to include thoracoscopic pulmonary resection. Eighty-five thoracoscopic pulmonary resections were performed on 61 consecutive patients with small lesions (less than 3 cm) in the outer third of the lung. Patients with preoperative histologic evidence of bronchogenic carcinoma were excluded unless there was impairment of cardiopulmonary function, advanced age, or concomitant extrathoracic malignancy. These thoracoscopic pulmonary resections were accomplished with the neodymium:yttrium-aluminum garnet laser (31), endoscopic stapler (29), or both (25). The mean diameter of the lesions was 1.3 cm (range, 0.4 to 2.7 cm). There has been one late death (38th postoperative day) unrelated to the operation. Morbidity consisted of postoperative atelectasis (2), pneumonia (2), bleeding requiring transfusion (1), and bronchopleural fistula of greater than 7 days duration (3). There were no wound problems. The mean period of chest tube drainage was 3.3 +/- 3.0 days. Mean postoperative stay was 5.7 +/- 4.9 days. The pathologic diagnosis was benign disease in 28 patients (interstitial fibrosis/pneumonitis, 15; radiation fibrosis, 1; sclerosing hemangioma, 1; rheumatoid nodules, 1; granuloma, 2; nocardia, 1; infarct, 1; hamartoma, 4; scar, 1; cytomegalovirus pneumonia, 1), metastatic malignancy in 20 patients, and bronchogenic carcinoma in 13 patients. Five patients found at thoracoscopic pulmonary resection to have bronchogenic cancer had adequate pulmonary function and therefore underwent formal segmentectomy (3) or lobectomy (2). Thoracoscopic pulmonary resection was the only operation performed on patients with benign disease, patients with metastatic lesions, and selected patients with limited stage bronchogenic carcinoma at increased risk for thoracotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative pain-related morbidity: video-assisted thoracic surgery versus thoracotomy.

One hundred thirty-eight consecutive, nonrandomized patients, with equivalent demographic and preoperative physiologic parameters, underwent either a video-assisted thoracic surgical (VATS) approach (n = 81) or a limited lateral thoracotomy (LLT) approach (n = 57) to accomplish pulmonary resection for peripheral lung lesions (< or = 3 cm in diameter). Wedge resection was done in 74 VATS patients and 19 LLT patients. Seven patients underwent VATS lobectomy and 38 patients had lobectomy performed through an LLT. Pain was quantitated by postoperative narcotic requirements, the need for intercostal/epidural analgesia, and patient perception of pain index scoring. Shoulder and pulmonary function (forced expiratory volume in 1 second) were measured preoperatively, 3 days postoperatively, and at 3 weeks of follow-up. Patients undergoing VATS experienced significantly less postoperative pain. No patients undergoing VATS required intercostal block/epidural analgesia; 31 LLT patients (54%) required this treatment for breakthrough pain (p = 0.001). Narcotic requirements were less (p = 0.05) among VATS patients, which correlated with lower perception of pain index after operation for VATS patients. Shoulder girdle strength was equally impaired at day 3, but function was more improved in VATS patients at 3 weeks (p = 0.01). Patients undergoing wedge resection alone by LLT had greater impairment in early (day 3) pulmonary function (forced expiratory volume in 1 second) (p = 0.002); this difference from VATS was not sustained at 3 weeks. Video-assisted thoracic surgery is associated with reduced pain, shoulder dysfunction, and early pulmonary impairment compared with LLT for select patients requiring pulmonary resection.

Aging of bitemarks: a literature review.

The aging of bitemarks through the subjective interpretation of visual signs has created an area of controversy in the forensic science community. The healing dynamics of these bite wounds has been insufficiently studied and is poorly understood. A review of the literature related to bitemark aging was undertaken in an effort to summarize the currently published information on this misunderstood subject.

Accuracy of bite mark overlays: a comparison of five common methods to produce exemplars from a suspect's dentition.

Physical comparison of a suspect's teeth to a bite mark injury using hollow volume comparison overlays is a common forensic odontology technique. Several methods are used to record characteristics of the size, shape and position of the teeth and to generate overlays. These include computer-based, radiographic, xerographic and hand-traced methods. Five common overlay production methods were compared using digital images of dental study casts as a reference standard. Area of the biting edges of the anterior teeth and relative rotation of each anterior tooth were measured and compared. The computer-based production method was determined to be the most accurate of those studied. It produced accurate representations of the biting edges of the teeth in an objective manner. The radiographic method was determined to be more accurate than the xerographic method with respect to tooth area measurement. The opposite is true with respect to tooth rotation. Hand-traced methods, from either wax impressions of teeth or directly from study casts, were determined to be inaccurate and subjective. It is recommended that forensic odontologists discontinue the use of hand-traced overlays in bite mark comparison cases.

Radiographic reconstruction of root morphology in skeletonized remains: a case study.

This is a case study in the application of a laboratory technique first described by Dr. Brion C. Smith in the Journal of Forensic Sciences in January 1992. Our study evaluated a human skull that showed perimortem and/or postmortem tooth loss. It was discovered in 1991 and deemed to have no usable dental information due to severe alveolar bone destruction. In 1994, using minor modifications of Dr. Smith's technique, we sealed off the open tooth sockets and injected a radiopaque material which, after radiographic analysis, revealed previously unobserved dental information. This report demonstrates that root morphology can be reconstructed. This yields radiographic information that may be useful in the identification of unknown human remains.

Jurisprudence issues in forensic odontology.

This article exposes the dental profession in the legal environment and the rules that control the acceptance or rejection of expert witness testimony. Written by a practicing dentist and attorney, the author believes that the new forensic dentistry aspirant should develop mentoring relationships with more experienced medico-legal professionals to supplement traditional dental education.

Digital analysis of bite marks and human identification.

This article introduces the dental investigator to the basic concepts of digital imaging techniques as they apply to crime scene photographic evidence. In all aspects of forensic dentistry, analytical comparison methods demand rigorous attention to scale dimensions and the detection of photographic distortion in images of forensic interest. Dental radiographs, photographic slides, negatives, prints, and digital images are all amenable to digital techniques that are useful in controlling quality and expanding the abilities of the forensic dentist to compare known and questioned evidence. The intent of this article is to show accurate means of measuring physical parameters of dental evidence, correction of common photographic distortion and size discrepancies, elimination of examiner subjectivity, better control of image visualization, and standardization of comparison procedures.