Citations

Background Recent data indicate that the neuroprotective efficacy of isoflurane is not sustained. Delayed neuronal death, mediated in part by apoptosis, contributes to the gradual increase in the size of the infarction. These data suggest that isoflurane may not be able to inhibit delayed neuronal death. The prevention of apoptosis by a caspase inhibitor might provide neuroprotection in addition to that provided by isoflurane. The current study was conducted to determine whether isoflurane-mediated neuroprotection can be made more durable with the administration of z-VAD-fmk, a nonspecific caspase inhibitor. Methods Fasted Wister rats were allocated to awake-zVAD, awake-vehicle, isoflurane-zVAD, or isoflurane-vehicle groups (n = 16/group). Animals were subjected to focal ischemia for 60 min by filament occlusion of the middle cerebral artery. In the awake groups, isoflurane was discontinued after occlusion of the middle cerebral artery. In the isoflurane groups, isoflurane anesthesia was maintained at 1.5 minimum alveolar concentration during occlusion of the middle cerebral artery. Before and after ischemia, daily injections of z-VAD-fmk or vehicle were administered into the lateral cerebral ventricle for 14 days. Neurologic assessment was performed 14 days after ischemia. The volume of cerebral infarction and the number of intact neurons in the periinfarct cortex were determined by image analysis of hematoxylin and eosin-stained coronal brain sections. Results Infarction volume was less in the isoflurane-zVAD group (23 +/- 11 mm, mean +/- SD) than in isoflurane-vehicle, awake-vehicle, and awake-zVAD groups (82 +/- 31, 86 +/- 31, and 59 +/- 25 mm, respectively; P < 0.05). In comparison with the awake-vehicle and isoflurane-vehicle groups, the administration of z-VAD-fmk significantly decreased infarction volume (P < 0.05). The infarction volume between the awake-vehicle and isoflurane-vehicle groups was not different. The number of intact neurons within the periinfarct cortex was significantly less in the awake-vehicle group than in the other three groups (P < 0.05). The isoflurane-zVAD group demonstrated better neurologic function than the awake-vehicle group (P < 0.05). Conclusion These findings are consistent with the premise that ongoing delayed neuronal death, in part mediated by apoptosis, contributes to the progression of cerebral infarction during the recovery period, and its inhibition can provide sustained neuroprotection.

Purpose To compare low-dose (30 Gy) radiotherapy (RT) with observation (OBS) in limited-stage aggressive lymphoma patients achieving complete remission (CR) after chemotherapy, and to measure conversion from partial response (PR) to CR with high-dose (40 Gy) RT. Patients and Methods From 1984 to 1992, stage I (with risk factors) and II adults with diffuse aggressive lymphoma in CR after eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomly assigned to 30 Gy involved-field RT or OBS. PR patients received 40 Gy RT. Results Among 172 CR patients, the 6-year disease-free survival (DFS) was 73% for low-dose RT versus 56% for OBS (two-sided P = .05). Failure-free survival (two-sided P = .06), and time to progression (two-sided P = .06) also favored RT. Intent-to-treat analyses yielded similar results. No survival differences were observed. Three RT versus 15 OBS patients relapsed in initial disease sites. At 6 years, failure-free survival was 63% in PR patients; conversion to CR did not significantly influence clinical outcome. Conclusion For patients in CR after CHOP, low-dose RT prolonged DFS and provided local control, but no survival benefit was observed. The majority of PR patients were event-free at 6 years despite residual radiographic abnormalities. Future efforts should be directed toward improved imaging and more effective systemic therapies.

Rhabdomyosarcomas (RMS) arising at different anatomic sites have distinct clinicopathologic features that affect prognosis and outcome. RMS arising in the extremities generally have a worse prognosis. Case reports and anecdotal experience suggests the possibility that RMS of the hand or foot (RMSHF) may behave even more aggressively than RMS elsewhere in the extremities. This study describes clinicopathologic features and outcome of RMSHF. Charts and pathologic material from RMSHF cases from institutional files over a 32-year interval were reviewed. Additional cases from published reports and series over a 42-year interval were identified by a MEDLINE search. Pertinent clinicopathologic features for each case were compiled. Survival analysis and other data from these patients were compared with previously reported statistics in the literature for RMS at other anatomic sites, including elsewhere in the extremities. Six patients from the institutional files and 46 from published reports were identified. A number of adverse prognostic indicators were observed in the majority of these patients including alveolar morphology (86%) and distant metastasis at presentation (63%). Despite the aggressive nature of these tumors, the majority were smaller than 5 cm (61%). A propensity was observed for metastases to unusual sites such as breast, ovary, testis, pancreas, and kidney. The median survival was 19 months, and the 5-year survival was 27%. While these may reflect a constellation of findings related to site, it is also possible that alveolar histology is the main influence. RMSHF can present as a very small primary tumor with clinically evident or occult metastatic disease. Whether this reflects the location, the predominantly alveolar histologic type, or a molecular genetic subtype will require further analysis. Patients presenting with RMSHF should be thoroughly evaluated for occult metastases at the time of diagnosis and followed closely throughout treatment for subsequent involvement of unusual sites.

ABSTRACT Toll receptors in Drosophila contribute to host defense and establish the body plan. Mammalian homologues of Toll, the Toll‐like receptors (TLRs), are thought to function only in host defense. Here, we report that mice harboring mutations in TLR4 or in CD14, a co‐receptor for TLR4, have an “ideal” body plan consisting of increased bone mineral content, density, and size as well as decreased body fat. These mutant mice live long lives, have normal activity and fertility, and show no evidence of infection. Unlike many strains of caged wild‐type mice, they do not become obese. Although all mice continue to gain body fat, bone content, and overall weight, the difference in bone content and body fat between mutant and wild‐type mice increases with age. Thus, defects in TLR4/CD14 complex generate an “Adonis” phenotype, characterized by this ideal body type, and this function could potentially be exploited for the treatment of osteoporosis and obesity.

In experimental obstructive jaundice in rabbits, thrombosis is definitely delayed in the extracorporeal loop. White thrombi are laid down at the normal rate in many instances; in others there is a delay in deposition of platelets, while in still others cauliflower-like masses of platelets are rapidly deposited and tend to slow or even stop the blood stream before much fibrin is apparent. Fibrin deposits and formation of the red thrombus usually appear late in the experiment and often only at the ends of the collodion tubes. In vigorous animals, the thrombi rarely tend to obstruct and usually cease growing when they have made up the difference between the lumen of the glass tube and of the collodion tube. On the other hand, if the animal's general condition is poor and its circulation depressed, red thrombus forms more rapidly and tends to encroach progressively on the lumen until obstruction takes place. Even in such cases circulation through the loop persists for periods much longer than in the normal animal. Judging from the gross appearance of the thrombus the quantity and quality of fibrin seem deficient. Single injections of bile salts yield pictures similar to those seen in experimental obstructive jaundice. White thrombi are deposited but obstruction of the lumen is delayed because of inadequate formation of fibrin. The continuous intravenous injection of bile salts resulted in a progressive increase of the clotting time and in the level of bile acids of the blood. The state of the extracorporeal loop was likewise similar in many respects to that seen in obstructive jaundice. There was, however, a definite decrease in the size and numbers of white thrombi deposited on the collodion membrane. From the evidence presented it is obvious that the processes of blood coagulation and of thrombosis in the extracorporeal loop are definitely delayed in experimental obstructive jaundice and in animals that have received intravenous injections of bile salts. No attempt is made to explain the changes found in jaundice on the basis of the increased levels of bile acids in the blood although these experiments would indicate that such a possibility has not been ruled out.

The chief points presented in this paper are: 1. Following the ingestion of buckwheat (plant or seed) varicolored guinea pigs, white swine and goats exhibited symptoms of photosensitization, the degree of sensitization being in the order given. 2. Rabbits, dogs, white mice and rats did not manifest symptoms of photosensitization. 3. The symptoms and reactions were: agitation, itching, scratching of the ears, weakness, urticaria with sloughing and symptoms similar to those in anaphylaxis. 4. Microscopic examinations showed the lack of marked pathologic change. The lesions, such as petechial hemorrhage of the lungs, brain, liver, stomach and kidneys, suggest that profound toxemia has been present. 5. Lesions were not found which appeared to be suggestive of malignant neoplasms. 6. Irradiation by a quartz mercury vapor lamp apparently develops a resistance to photosensitization, probably because of increased pigmentation induced by ultra-violet light. 7. From the nature of the physiologic and pathologic reactions produced under various filters and from a consideration of the percentages of transmission of solar energy in the visible spectrum, it would seem that the region of photosensitization lies between 580 millimicrons (yellow) and the red end of the spectrum. This conclusion, moreover, is substantiated by the fact that irradiation by a quartz mercury vapor lamp (which radiates no energy in the visible spectrum at a wave-length greater than 579 millimicrons) produces no symptoms or reactions. 8. Spectrophotometric determinations of alcoholic extracts of grass (non-toxic) and of buckwheat (toxic) show the presence of two additional bands in the absorption spectrum of buckwheat with maxima at about 540 and 600 millimicrons, respectively, together with the common absorption zones at 430 to 490 millimicrons and 630 to 690 millimicrons. 9. Spectrophotometric determinations of blood serums of sensitized animals show, besides the usual absorption bands peculiar to oxyhemoglobin (with maxima at 540 and 580 millimicrons respectively), two zones with maxima at 600 and 660 millimicrons respectively. 10. The fluorescence of chlorophyll per se, as suggested by previous investigators, is not, in all probability, the cause of the sensitization induced by buckwheat. 11. Hematoporphyrine is not the photodynamic substance in all probability. 12. Phylloporphyrine may be the photodynamic substance. In this regard, also, the possibility of cholehematin is not to be ruled out.

1. Distilled water dialyzes through the collodion tube and causes hemolysis. Clotting of the hemolyzed blood in the collodion tube occurs later. 2. Bile salts accelerate the appearance and development of white thrombi in the heparinized animal. The masses of white thrombi are very loose, soft, fragile and easily broken into clumps of platelets. They are poor in fibrin or the fibrin is abnormal, since they have less retractility than those obtained from the use of physiologic sodium chloride solution or calcium chloride or serum. Despite the increase in number and size of white thrombi, normal clotting does not occur. 3. When the collodion tube is surrounded by 1 or 2 per cent d-glucose solution, tiny and numerous white thrombi appear as radiating figures. The masses of white thrombi are rather loose and fragile. The clotting time of the heparinized blood does not appear to be shortened. 4. When a 1 to 2 per cent solution of calcium chloride is used as the dialyzing fluid outside the collodion tube, or when it is injected into the circulation, the formation of white thrombi is accelerated. They grow very rapidly. In spite of the action of heparin, the white thrombi formed are not so fragile as when bile salts are placed outside of the collodion tube. Fibrin seems to form easily. Obstruction of venous cannula takes place speedily and if the clots in the cannula are not removed, the white thrombi in the collodion tube remain small and become red by sedimentation of red cells. 5. Intravenous use of 10 per cent solution of magnesium sulfate without heparin retards the coagulation of circulating blood and permits the blood to flow through the extracorporeal loop from three to four times as long as normal. The formation of white thrombi, as well as red, is retarded. Magnesium sulfate (1 per cent) in physiologic sodium chloride solution placed outside the collodion tube markedly retards the formation of white and red thrombi in the heparinized animal. Magnesium sulfate (10 per cent), 50 mg. for each kilo of body weight each hour, administered intravascularly in the heparinized animal definitely prevents the first stages of thrombosis, and consequently prevents clotting. 6. It is possible by the combined use of adequate amounts of magnesium sulfate and of heparin intravenously to prevent all stages of thrombus formation for from 1 to 3 hours.