Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest.

src kinase activity is elevated in some human tumors, including breast and colon cancers. The precise cellular function of the src family kinases is not clearly understood, but they appear to be involved in numerous signaling pathways. We studied the effects of PD173955, a novel src family-selective tyrosine kinase inhibitor, on cancer cell lines and found that it has significant antiproliferative activity due to a potent arrest of mitotic progression. The mitotic block occurs after chromosome condensation in prophase, before spindle assembly and without loss of cyclin A and B kinase activities. This effect is seen in cancer cell lines of all types with low or high activities of src kinases as well as in untransformed cell lines. In MDA-MB-468 breast cancer cells, this drug produces a rapid inhibition of cellular src and yes kinase activities as well as suppression of the mitotic hyperactivity of these kinases. This compound defines a novel class of antimitotic drugs that work through inhibition of src kinases and possibly other protein kinases that are required for progression through the initial phases of mitosis.

Acute and chronic effects of nicotine on anastomotic patency following ischemia/reperfusion.

The effect of nicotine on anastomotic patency was studied using an isogenic rat-knee transplantation model. Animals were divided into experimental and control groups, with experimental animals exposed to either 40 days of twice-daily nicotine injections (Group 1-chronic exposure) or acute nicotine exposure by graft perfusion (Group 2-acute exposure). Four and 6 hr warm ischemia times were studied. Syngeneic rat knees were transplanted from donor to recipient by microvascular anastomosis of the femoral vessels. There was a statistically significant difference (p < 0.05) in anastomotic patency after 4 hr of ischemia in Group 1 animals exposed to nicotine (33 percent patency) vs. controls (89 percent patency). In addition, there was a statistically significant difference in anastomotic patency after 4 hr of ischemia in Group 2 animals exposed to nicotine (11 percent patency) vs. controls (67 percent patency). No significant differences between controls and Group 1 animals were noted in anastomotic patency after 6 hr of ischemia. Both acute and chronic nicotine exposure reduces anastomotic patency after short intervals of warm ischemia in vascularized composite tissue grafts. This detrimental effect is lost when the ischemic interval is prolonged to periods with poor anastomotic patency rates related to the ischemia/reperfusion itself.

Congenital radial head dislocations.

Congenital radial head dislocation is the most common congenital elbow abnormality. Patients generally remain asymptomatic until adolescence and, at that time, may benefit from radial head resection. Open reduction and ligament reconstruction may offer advantages over late radial head resection if performed before the age of 2 years. Further long-term studies are needed to determine if open reduction and ligament reconstruction are helpful.

Arthroscopic debridement alone for intercarpal ligament tears.

This study examined the role of arthroscopic debridement alone for complete and incomplete intercarpal ligament tears of the wrist. Forty-three wrists underwent arthroscopic evaluation for persistent wrist pain and were identified as having isolated scapholunate or lunotriquetral ligament tears treated by arthroscopic debridement alone of the torn ligament edges. At follow-up examination at an average of 27 months, 29 (66%) wrists having a complete scapholunate ligament tear and 36 (85%) wrists having a limited scapholunate ligament tear had either complete symptom resolution or improved symptomatology. Thirty-three (78%) wrists with a complete lunotriquetral ligament tear and 43 (100%) wrists having a limited lunotriquetral ligament tear had complete symptom resolution or improvement. No wrists were noted to have static intercarpal instability pattern changes on follow-up radiographs. Grip strength improved 23% postoperatively. These findings suggest that intercarpal ligament tears, in a majority of patients, may be treated from a symptomatic standpoint by debridement alone for at least several years. The long-term ability of this approach to maintain a pain-free wrist has yet to be determined. No statistically significant difference was noted in the symptomatic improvement rate of scapholunate compared to lunotriquetral ligament debridement.

Isolated lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma.

OBJECTIVE: Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated. METHODS: TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. PHARMACOKINETICS STUDY: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats received an intravenous injection of 5 x 10(6) methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted. TOXICITY: Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg. PHARMACOKINETICS: Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002). EFFICACY: Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 +/- 10) than in the groups receiving intravenous melphalan (60 +/- 21) or buffered hetastarch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, respectively). CONCLUSION: Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.

Electrodiagnostic testing and carpal tunnel release outcome.

This study examined the correlation of electrodiagnostic test results and symptom outcome after carpal tunnel release. After meeting specific inclusion and exclusion criteria and failing conservative management, 167 patients (227 hands) underwent an open carpal tunnel release. Of 99 hands with a positive electromyographic/nerve conduction velocity study, 93 (93%) had resolved or improved symptoms. This finding compares with a 93% resolution or improvement rate in 27 hands with a negative electromyographic/nerve conduction velocity study and a 93% resolution or improvement in postoperative symptoms in 101 hands on which no electromyographic/nerve conduction velocity study had been performed. Statistical analysis demonstrated no significant differences in final symptom status after carpal tunnel release when comparing patients who had positive, negative, or no electrodiagnostic preoperative testing. Given specific clinical criteria for establishing the diagnosis of carpal tunnel syndrome, electrodiagnostic testing does not appear to correlate with improved final symptomatic outcome after carpal tunnel release.

Treatment of trigger finger in patients with diabetes mellitus.

We present a retrospective study of 54 diabetic patients with 121 trigger digits treated over a 3-year period by one to three injections of corticosteroid mixed with local anesthetic. As a group, diabetic patients responded less favorably to treatment by steroid injection (50% symptom resolution) when compared to reported outcomes of steroid injection treatment for stenosing tenosynovitis in the general population. Insulin-dependent diabetic patients have a higher incidence of multiple digit involvement (59% of patients) and of requiring surgical release for relief of symptoms (56% of digits) when compared to non-insulin-dependent diabetic patients (28% of patients with multiple digit involvement; 28% of digits requiring surgery).

Radioulnar synostosis.

Radioulnar synostosis is a rare condition that exists in two forms: congenital and post-traumatic. Although both may involve either a bony or a fibrous union between the radius and ulna, they differ considerably in their etiologies, treatment, and prognosis. This article explores both of these conditions.

Soft tissue contractures about the elbow.

Hard and soft tissue injury to the elbow may be complicated by progressive secondary joint contracture. Motion-directed therapy often improves or eliminates elbow contracture if it is recognized early in treatment. Progressive soft tissue contracture, with or without the concomitant development of heterotopic ossification, is best treated by surgical release. This article discusses the operative technique and the results of treatment.

Conservative management of carpal tunnel syndrome: a reexamination of steroid injection and splinting.

The awareness of carpal tunnel syndrome by the lay public has increased dramatically in recent years, with an apparent shift in patient-population presentation. We prospectively studied steroid injection and wrist splinting in 76 hands in 57 patients, presenting without advanced disease or associated medical conditions, by standard evaluation and protocol of treatment. The average age of the patients was 38 years; 50 women and 7 men were included. Follow-up examination after simultaneous steroid injection and splinting averaged 11 months. Ten hands were noted to be symptom-free at the final evaluation. Women were noted to have a significant decrease in the rate of symptom resolution when compared to men. Patients, 40 years of age or younger, were also noted to have a significant decrease in the rate of symptom resolution when compared to patients over 40 years of age. No significant differences were noted when comparing symptom duration prior to treatment or workers' compensation insurance status to final symptom resolution. Young women are the least likely to have resolution of carpal tunnel syndrome symptoms when treated conservatively.

Glucocorticoids regulate the transcription of glycerol phosphate dehydrogenase in cultured glial cells.

Utilizing a glycerol phosphate dehydrogenase cDNA clone from the rat glioma C6 cell line, we report that the glucocorticoid regulation of glycerol phosphate dehydrogenase gene expression in glial cells occurs at the transcriptional level. Furthermore, our transcription results in vitro, as well as Northern blot analysis, show that the short-chain fatty acid, sodium butyrate, totally blocks this hydrocortisone-induced transcription of glycerol phosphate dehydrogenase, demonstrating that the site of action of this fatty acid resides in the cell nucleus. The C6 glycerol phosphate dehydrogenase cDNA clone (pGPDH-1,1800 base pairs) used in these studies was selected from a C6 library generated from polysomal poly(A)+ RNA. pGPDH-1 hybridized to a 4.7-kilobase RNA from rat muscle and brain, mouse liver, and C6 cells; this mRNA is at least four times larger than the required coding sequence for glycerol phosphate dehydrogenase. Northern blot analysis of developing rat brain reveals a striking increase in glycerol phosphate dehydrogenase transcripts during the period most associated with peak myelination.

Regulation of mRNAs for three enzymes in the glial cell model C6 cell line.

In the glial cell line C6, regulation of actinomycin D (Act-D)-sensitive translatable polysomal mRNAs of three key enzymes--glycerol phosphate dehydrogenase (GPDH; EC 1.1.1.8) and glutamine synthetase (GS) by glucocorticoids and lactate dehydrogenase (LDH; EC 1.1.1.27) by catecholamines--is described. Though the first two enzymes are hydrocortisone (HC)-inducible, the nature of their response to the hyperacetylating agent sodium butyrate is dramatically different. Furthermore the appearance of GPDH translatable poly(A)+ RNA in HC-induced cells is inhibited by the presence of cycloheximide (CHX), whereas the induction of GS is unaffected by CHX. These observations necessitate further probing into an existing model system to explain the varied mechanisms of induction of these two enzymes by a single inducer. In combination with the third enzyme whose induction by catecholamines is glial specific, we believe that the C6 cell represents the most appropriate cell line for molecular neurobiologists to study the mechanisms of hormone action in glia.