Ric-8A gene deletion or phorbol ester suppresses tumorigenesis in a mouse model of GNAQ(Q209L)-driven melanoma.

The heterotrimeric G protein α subunit oncogenes GNAQ or GNA11 carry Q209X or R183X activating mutations and are present with ~90% frequency in human uveal melanomas. Forced expression of GNAQ/11(Q209L) in melanocytes is sufficient to drive metastatic melanoma in immune-compromised mice. No known drugs directly target these oncogenic G proteins. Ric-8A is the molecular chaperone that selectively folds Gαq/i/13 subunits. Targeting Ric-8A serves as a rational, yet unexplored approach to reduce the functional abundance of oncogenic Gαq/11 in order to blunt cancer signaling. Here, using mouse melanocyte cell graft tumorigenesis models, we determined that Ric-8A genetic ablation attenuated the abundance and melanoma-driving potential of Gαq-Q209L. A new conditional Ric-8A(Flox/Flox); Rosa-CreER(+/)(-) mouse strain was derived and used as a tissue source to culture an immortalized, tamoxifen-inducible Ric-8A knockout melanocyte cell line that required 12-O-tetradecanoylphorbol-13-acetate (TPA, phorbol ester) for growth. The cell line failed to grow tumors when grafted into immune-compromised mice regardless of Ric-8A expression. Stable expression of human GNAQ(Q209L), but not GNAQ(WT) in the cell line promoted TPA-independent cell proliferation, and upon cell grafting in mice, the initiation and robust growth of darkly-pigmented melanoma tumors. Deletion of Ric-8A in GNAQ(Q209L) cells restored TPA-dependent growth, reduced Gαq-Q209L below detectable levels and completely mitigated tumorigenesis from primary or secondary cell line grafts. Interestingly, TPA treatment of cultured GNAQ(Q209L) cells or host animals grafted with GNAQ(Q209L) cells also sharply reduced Gαq-Q209L abundance and tumorigenic capacity. Finally, tumorigenesis initiated from GNAQ(Q209L) cell grafts, followed by host mouse systemic tamoxifen treatment to delete Ric-8A in the grafted cells completely abrogated GNAQ(Q209L)-driven tumor progression unless a stable human RIC-8A transgene was used to rescue the floxed Ric-8A alleles. Our work defines two new rational targets that may be developed as potential uveal melanoma therapies through reduction of Gαq/11-Q209L oncoprotein abundance: (1) Ric-8A inhibition and (2) phorbol ester treatment.

Acute toxicity and antihyperlipidemic activity of rhizome of Tectaria coadunata (Kukkutnakhi): A folklore herb.

BACKGROUND: Tectaria coadunata (Wall. Ex Hook and Grev.) C. Chr (Kukkutnakhi) is a pteridophyte fern which is found in Western Ghats, Kerala Ghats, and Mahendragiri forest region. It is used by many Vaidyas in hyperlipidemic conditions and obesity. AIM: This study aimed to evaluate the acute toxicity and antihyperlipidemic activity of T. coadunata in experimental animals. MATERIALS AND METHODS: Oral acute toxicity study was carried out in female Wistar rats as per OECD 425 guideline. Antihyperlipidemic activity of powder of T. coadunata (540 mg/kg) was carried out in high-fat diet-induced hyperlipidemia in Wistar albino rats. RESULTS: T. coadunata rhizome powder at the dose of 2000 mg/kg did not produce any mortality and toxic effects during acute toxicity study in female rats. Test drug produced highly significant (P < 0.001) reversal in the triglycerides and very-low-density lipoprotein (VLDL)-cholesterol along with nonsignificant decrease in the cholesterol level in rats fed with hyperlipidemic diet. Further, T. coadunata has shown nonsignificant decrease in serum urea, serum glutamic pyruvic transaminase, alkaline phosphatase, and bilirubin direct while statistically significant decrease in bilirubin total in comparison to cholesterol control group. Histopathological study has shown reversal of adverse changes induced by hyperlipidemic diet in heart, liver, and kidney. CONCLUSION: It is concluded that drug is safe up to the dose level of 2000 mg/kg in rats. Rhizome of T. coadunata has shown antihyperlipidemic activity in rats, which suggest its potential role in hyperlipidemia and associated conditions.

Behçet's syndrome complicated by cutaneous leukocytoclastic vasculitis. Response to prednisone and chlorambucil.

Traditionally described as a triad consisting of recurrent aphthous stomatitis, genital ulcerations, and uveitis, Behçet's syndrome is now recognized as a multisystem disease with protean manifestations. We studied a patient with chronic recurrent migratory superficial thrombophlebitis and marked cutaneous hyperreactivity (pathergy) who developed leukocytoclastic vasculitis with recalcitrant leg ulcerations nine years after the onset of his illness. Although he was treated with topical and systemic antibiotics for presumed bacterial superinfection, cutaneous ulcerations continued to develop and enlarge; only after prednisone therapy was begun was there a dramatic response with complete resolution. Despite high-dose prednisone therapy, the pathergy test remained markedly positive; however, no new skin ulcerations appeared.

Dural sarcoidosis presenting with transient neurologic symptoms.

Despite the propensity of sarcoid granulomas to be clustered around blood vessels, transient ischemic attacks and strokes are rare. A 43-year-old man had recurrent transient dysarthria and right hemiparesis; a biopsy specimen showed neurosarcoidosis. There was complete resolution of both symptomatology and the subdural sarcoid mass lesion with the administration of corticosteroid therapy.

Delayed renal localization of Ga-67: concise communication.

Five hundred Ga-67 images, requested for detection or follow-up of inflammatory or neoplastic diseases, were reviewed to evaluate the incidence of delayed renal localization and the clinical significance of different degrees of uptake. Renal uptake in 48- or 72-hr images was graded as follows: 0 = background activity; 1+ = greater than background but less than spine; 2+ = close to spine but less than liver; 3+ = same as liver; 4+ = greater than liver. On the 500 images, 996 kidneys were evaluated and among them 600 (60%) had 0 uptake and 340 (34%) had 1+. These 940 kidneys were all considered to be normal. Fifty-six (6%) had 2+ or more uptake, with possible causes for uptake being: infection 27, drug-induced renal damage ten, urinary stasis or slow excretion seven, collagen vascular disease six, renal failure four, acute tubular necrosis one (ATN), and indeterminate one. Cases of renal infection or failure tended to show more or less 4+ uptake, while drug damage, ATN, or urinary stasis tended to have 2+ uptake.

Abnormal technetium-99m pyrophosphate images in unstable angina: ischemia versus infarction?

There is controversy concerning the specificity of myocardial infarct imaging with technetium-99m pyrophosphate due to the high frequency of false positive images, especially in patients with unstable angina. In this study technetium-99m pyrophosphate images were compared with frequent determinations of plasma creatine kinase, MB isoenzyme (MB CK) activity in 116 patients admitted with the diagnosis of unstable angina. It was hypothesized that frequent measurement of MB CK activity, a sensitive and specific marker for myocardial necrosis, using sensitive assay techniques would detect small amounts of myocardial necrosis which might have been unrecognized by conventional clinical methods. The scintigraphic results and isoenzyme determinations agreed in 88 percent of patients; both tests were normal in 69 percent and both were abnormal, indicating acute myocardial infarcation, in 19 percent of patients. In the remaining 14 patients (12 percent), the scans were abnormal, but MB CK activity was normal. In five of these patients (4 percent), abnormal scintigrams presumably reflected persistent scan positivity after previous myocardial infarction. Only the remaining nine patients (8 percent) could be classified as having unexplained false positive scans, a frequency substantially less than that reported by other investigators who based the diagnosis of myocardial infarction on conventional clinical criteria. These results suggest that abnormal technetium-99m pyrophosphate images in patients with unstable angina generally indicate myocardial necrosis.

Actinobacillus actinomycetemcomitans endocarditis in hypertrophic obstructive cardiomyopathy.

We report a case of bacterial endocarditis due to Actinobacillus actinomycetemcomitans in a man with hypertrophic obstructive cardiomyopathy complicated by a mycotic aneurysm and thrombosis of the right common iliac artery. The patient was successfully treated with a combination of ampicillin and gentamicin, but was left with residual mitral incompetence.

High-pressure liquid chromatography of nadolol and other beta-adrenergic blocking drugs.

A high-pressure liquid chromatographic assay was developed for the analysis of the beta-adrenergic blocking agent nadolol as a bulk material or formulated in a tablet. Other beta-adrenergic blocking drugs such as acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, practolol, propranolol, sotalol, and timolol can be chromatographed in this system. An ethylsilane column and a mobile phase consisting of 35% methanol-65% aqueous 0.0005 M hydrochloric acid-0.05 M sodium chloride are used. Detection is either at 254 nm with a variable-wavelength detector. As exemplified by nadolol, the drug content can be quantitated with or without atenolol as an internal standard.

Inhibition of mucopolysaccharide sulfation.

A method of measuring the inhibition of sulfation in mucopolysaccharides employed the coupled enzyme system of Wortman. This procedure utilized the phenol and mucopolysaccharide sulfotransferases of beef cornea extract. Compounds tested against this system included amino acids, salicylates, 2-mercaptoethylamine and a derivative, heterocyclic ethanethiosulfuric acids, arylsulfonamidoethanethiosulfates, and several other compounds. In general, the salicylates and thiosulfates were inhibitory, with sodiumm 2-(4-acetamidobenzenesulfonamido)-ethanethiosulfate being the most inhibitory and 2-mercaptoethylguanidine trithiocarbonic acid the second most inhibitory. Salicylamide and allopurinol, which have been employed in kidney stone therapy, were inhibitors. Kidney stones have a mucopolysaccharide sulfate matrix, which is involved in their growth.

Fracture-dislocation at the thoracolumbar junction in an infant with locked vertebrae. A case report.

STUDY DESIGN: A retrospective, single-patient case report. OBJECTIVES: To report on a 9-month-old infant with fracture-dislocation at the thoracolumbar junction with locking of vertebral bodies, probably with incomplete neurologic injury and partial postoperative recovery. SUMMARY OF BACKGROUND DATA: Fracture-dislocation at the thoracolumbar junction is rare in infants, the upper cervical spine being the level usually affected. Incomplete neurologic injury is uncommon after such a severe shear injury. METHODS: The patient was followed through personal examination and chart review from initial presentation to 6 months after the injury. RESULTS: Open reduction with posterior spinal fusion was followed by partial neurologic recovery and a stable spine over 6-month follow-up. CONCLUSIONS: Fracture-dislocation at the thoracolumbar junction is rare in infancy. This is probably due to unique anatomic and biomechanical features of the spine in infancy.

The effect of fundoplication with or without proximal gastric vagotomy on gastric emptying and serum gastrin.

Jordan and Herrington have both advocated the addition of a proximal gastric vagotomy [PGV] to fundoplication to improve exposure and decrease the likelihood of vagal entrapment which might lead to delayed gastric emptying. This study documents the effect of fundoplication with or without PGV on gastric emptying and postprandial gastrin values. Twelve dogs had measurement of gastric emptying of an isotopically labeled solid meal. Plasma gastrin was also measured at 15-min intervals for 1 hr postprandially following a 60 g beef meal. Six of the animals then had a standard fundoplication with incorporation of vagi in the wrap; the other six underwent fundoplication combined with PGV, excluding the vagi. All studies were repeated after 8 weeks. Gastric emptying was unchanged by fundoplication alone. PGV resulted in a slight but significant slowing of gastric emptying (P = 0.04), values by paired t test. Fundoplication alone had no effect on serum gastrin levels, but there was a slight, statistically insignificant increase in serum gastrin when PGV was added (P greater than 0.1). This delay could aggravate pre-existing emptying problems in patients with esophagitis. These data do not support inclusion of proximal gastric vagotomy as a routine part of the fundoplication.

Reverse discordant behavior in microfollicular adenoma of thyroid. Case report.

A patient with reverse discordant behavior between Tc-99m pertechnetate and I-123 in a solitary microfollicular adenoma is presented and possible mechanism is discussed.

Interstitial lymphoscintigraphy for diagnosis of lymphocele.

A patient with the development of a post-surgical mass in the thigh, at the site of surgery, is described. Lymphoscintigraphy was important in solving the clinical dilemma.

Accumulation of technetium-99m MDP in a cavernous hemangioma of the liver.

A cavernous hemangioma of the liver presented as an area of increased activity on an isotope bone scan. A review of the literature fails to reveal any previous reports of this phenomenon.

Unusual scintiscan appearance of Meckel's diverticulum. A case report.

The case reported demonstrates an unusual appearance of a Meckel's diverticulum on preoperative Tc-99m pertechnetate abdominal scintiscan. Precise pathologic correlation with histopathologic findings in the resected specimen elucidated the unusual findings on the scintiscan.

Anti-inflammatory activity of root bark and stem bark of Shyonaka.

BACKGROUND: Shyonaka (Oroxylum indicum Vent.; Bignoniaceae) root bark is one of the ingredients of dashamoola (a group of 10 roots), and is used for its anti-inflammatory and analgesic action in a number of compound formulations in Ayurveda. AIM: Ayurvedic Pharmacopoeia of India (API) recommends using the stem bark instead of root bark. MATERIAL AND METHODS: An attempt has been made to study the anti-inflammatory activity of both root bark and stem bark kashaya (decoction) experimentally. CONCLUSION: Results showed significant anti-inflammatory activity of root bark and stem bark decoction.