Batroxobin-induced clots exhibit delayed and reduced platelet contractile force in some patients with clotting factor deficiencies.

Thrombin causes platelet activation via multiple pathways, and deficient thrombin generation reduces platelet contractile force (PCF) during clot retraction. We hypothesized that PCF in blood samples from clotting factor-deficient patients would be diminished due to delayed or deficient thrombin generation. Blood samples from patients with fibrinogen, and factor V, VII, VIII, IX, X, XI and XIII deficiencies were compared to samples from normal controls. PCF in patient blood clotted with thrombin (1 NIH UmL(-1)) was compared to PCF in clots formed with batroxobin (0.25 micro g mL(-1)). PCF in the former should be normal, but PCF in the latter is dependent on thrombin generation within the sample and might be deficient. In factor VII-(n = 2, P < 0.05), factor VIII-(n = 6, P < 0.005) and factor XI-(n = 2, P < 0.05) deficient platelet-rich plasmas, PCF in batroxobin-induced clots was significantly lower than in thrombin-induced clots. In factor IX deficiency (n = 2), one patient had a dramatic reduction in PCF while a second patient had increased PCF. PCF was insignificantly (P = 0.346) reduced in two patients with factor X deficiency, and was normal in one patient with factor V deficiency. The factor X result is consistent with work in model systems, which indicates that as little as 1-3% factor X activity is sufficient to restore thrombin generation to normal. The factor V result probably indicates that the deficiency is incomplete. PCF in thrombin-induced clots was normal in all of these patients. Low fibrinogen and factor XIII deficiency reduced PCF in both thrombin- and batroxobin-induced clots. These results indicate that PCF is reduced, probably due to delayed thrombin generation, in some factor-deficient platelet-rich plasma samples.

Delayed, reduced or inhibited thrombin production reduces platelet contractile force and results in weaker clot formation.

Clot retraction is a thrombin-dependent, platelet-mediated contraction of the cellular clot mass. In this study, the effects of delayed, deficient and inhibited thrombin generation on the development of platelet contractile force (PCF) and clot elastic modulus (CEM) were measured. When normal citrated whole blood is clotted by the addition of exogenous thrombin (1 U/ml) and calcium (10 mmol/l), PCF and CEM start to develop within the first minute and begin to level off by 1200 s. If identical samples are clotted with batroxobin (0.21 microg/ml) and calcium (10 mmol/l), both PCF and CEM development are delayed approximately 5 min. After 1200 s of clotting, however, values in the batroxobin system approach those seen with exogenous thrombin. If the added calcium concentration is held constant at 10 mmol/l, increasing the exogenous thrombin concentration from 0 to 0.5 U/ml results in increased PCF and CEM values. Above 0.5 U thrombin, the effect plateaus. At exogenous calcium of 10 mmol/l, increasing batroxobin concentrations (0-0.210 microg/ml) caused a 75% increase in PCF and a 55% increase in CEM. The increase in CEM reached a plateau above 0.05 microg batroxobin/ml. The effects of varying calcium concentrations were evaluated at constant batroxobin (0.21 microg/ml) and thrombin (1 U/ml) concentrations. With thrombin, PCF and CEM increased by > 700% as CaCl2 increased from 0 to 5 mmol/l. Above 5 mmol/l, no additional increases occurred. With batroxobin, PCF did not develop at CaCl2 concentrations < or = 2.5 mmol/l. Above 2.5 mmol/l CaCl2, PCF values increased and at 10 mmol/l CaCl2 were equal to those seen with thrombin. CEM in batroxobin-mediated clots peaked at 10 mmol/l CaCl2 but were 40% less than the values found in thrombin-mediated clots. When the thrombin inhibitor P-PACK was added to the batroxobin system, dose-dependent decreases in PCF and CEM were noted. At 120 micromol/l, P-PACK totally suppressed PCF. PCF in blood from a factor VIII-deficient patient varied significantly when clotted with batroxobin versus thrombin. PCF development in factor VIII-deficient blood was normal with thrombin but is delayed and depressed with batroxobin. PCF values in factor VIII-deficient blood did not reach the thrombin value after 1200 s of clotting, and CEM was significantly less. These results confirm that PCF development is thrombin dependent and that delay or reduction of PCF development results in structurally weaker clots.

Alterations of platelet aggregation kinetics with ultraviolet laser emission: the "stunned platelet" phenomenon.

Platelets, a major constituent of thrombus, play a crucial role in the pathogenesis of acute ischemic coronary syndromes. The effect of ultraviolet laser emission on platelets within thrombi is unknown. The effects of increasing levels of laser energy on platelets in whole blood were investigated. Blood samples were obtained by aseptic venipuncture and anticoagulated with 3.8% sodium citrate. Samples were exposed to increased levels (0, 30, 45, 60 mJ/mm2; 25 Hz) of ultraviolet excimer laser fluence (308 nm wave-length) and then tested for ADP and collagen induced platelet aggregation, platelet concentration, and for platelet contractile force (PCF) development. Scanning electron microscopy was used to detect laser induced morphologic changes of platelets and by flow cytometric analysis to detect changes in expression of platelet surface antigens p-selectin (CD 62) and glycoprotein IIb/IIIa (CD 43). Exposure to excimer laser energy produced dose dependent suppression of platelet aggregation and force development ("stunned platelets"). ADP aggregation decreased from 8.0+/-1.1 Ohms (mean+/-SEM) to 3.7+/-0.8 Ohms (p<0.001) to 2.7+/-0.6 Ohms (p <0.001) and to 1.8+/-0.5 Ohms (p <0.001) as the laser energy increased from 0 to 30 to 45 to 60 mJ/mm2, respectively. Collagen induced aggregation decreased from 21.4+/-1.4 Ohms to 15.7+/-1.2 Ohms (p <0.001) to 11.7+/-1.1 Ohms (p <0.001) and to 9.9+/-1.0 Ohms (p <0.001), in response to the same incremental range of laser energy. Platelet contractile forces declined from 34,500+/-3700 to 27.800+/-2700 dynes as laser energy increased from 0 to 60 mJ/mm2 (p <0.03). Platelet concentration did not change with increasing laser energy. The expression of platelet surface antigen p-selectin (CD 62) remained stable through increasing levels of laser energy exposures while the percentage of CD 43 positive platelets significantly increased with exposure to laser energy, yet the level of expression did not exceed 0.5% of cells. Thus, aggregation kinetics are altered in platelets exposed to ultraviolet laser energy as manifested by decreased platelet aggregation and reduction in platelet force development capability. The response is dose dependent and most pronounced at higher energy levels such as 60 mJ/mm2.

Rapid clot formation and abnormal fibrin structure in a symptomatic patient taking fenfluramine--a case report.

A 35-year-old woman experienced symptomatic calf pain while taking a combination of fenfluramine and phentermine. All symptoms resolved when the medications were stopped, but pain returned when fenfluramine was restarted. Laboratory evaluation revealed mild elevations of aspartate aminotransferase and lactate dehydrogenase and a remarkably shortened prothrombin time (6.3 seconds). Additional studies revealed that the clots were composed of very thin fibrin fibers. All laboratory abnormalities, including the abnormal fibrin structure, completely resolved when fenfluramin was stopped. Direct addition of fenfluramine or phentermine to normal plasma did not alter either coagulation kinetics or fibrin structure, supporting the concept that the induced changes may have originated at the hepatic level. Clots composed of thin fibers are much more resistant to fibrinolysis, and could potentially put such patients at risk for thrombotic complications. This is the first report of clotting abnormalities associated with fenfluramine use. Subsequent to its use in this patient, fenfluramine was removed from clinical use due to reports of acquired valvular heart disease.

Storage pool disease in chronic lymphocytic leukemia: abnormal aggregation and secretion without bleeding.

Although bleeding complications are relatively common in patients with chronic lymphocytic leukemia, they tend to be related to thrombocytopenia or an acquired clotting factor inhibitor. Chronic lymphocytic leukemia-associated thrombocytopenia, which may also contribute to the hemorrhagic risk, is generally caused by decreased production and immune-mediated destruction. This is the case of a 56-year-old man with longstanding chronic lymphocytic leukemia who developed thrombocytopenia (platelet counts of approximately 50,000/microL) with an associated abnormal platelet morphology. Although the patient did not suffer clinically significant bleeding, several tests of platelet function were grossly abnormal. Electron microscopic examination of the platelets revealed virtually complete absence of dense granules. Platelet aggregation did not occur with adenosine diphosphate (10 microM), collagen (2 micrograms/mL), or ristocetin (1 mg/mL). Doubling the agonist concentrations produced only minimal agglutination with ristocetin. The bleeding time was mildly prolonged at 9.0 and 10.5 minutes. Von Willebrand antigen and ristocetin cofactor levels were normal. Collagen-induced adenosine triphosphate secretion was less than 10% that of a matched normal control. In contrast, platelet force development was virtually normal, reaching 4,800 dynes at 1,200 seconds compared with 5,800 dynes for the healthy control. The patient's clots demonstrated enhanced clot modulus 44,000 dynes/cm2 versus 22,400 dynes/cm2 for the healthy control. The latter finding was primarily because of high fibrinogen concentration. This third report of storage pool disease in a patient with chronic lymphocytic leukemia demonstrates that dense granule release is not required for normal platelet-mediated force development.

Use of TPA-induced clot lysis time (TCLOT) to diagnose abnormal clot structure and fibrinolysis in a patient with spontaneous bleeding into his leg.

Diagnosis and treatment of patients with bleeding due to enhanced fibrinolysis is hampered by the absence of a rapid screen of fibrinolytic potential. The authors have developed a simple assay to assess clot structure and fibrinolysis in patient samples exposed to tissue plasminogen activator (TPA). They present the case of a forty-one-year-old man who presented with spontaneous bleeding despite normal results from coagulation screening tests, platelet count, platelet aggregation studies, platelet force development, and bleeding time. Evaluation of the patient's clot structure revealed a very weak, low-modulus, clot that rapidly dissolved in the presence of TPA. Identification of the abnormality allowed treatment with epsilon-aminocaproic acid with prompt resolution of bleeding.

Abnormal fibrin structure and inhibition of fibrinolysis in patients with multiple myeloma.

Abnormal clot structures have been reported in patients with multiple myeloma, and purified immunoglobulin G (IgG) has been shown to influence fibrin assembly in purified systems. Recently fibrin structure has been demonstrated to be a major determinant of fibrinolytic rates. This study examined the effects of purified polyclonal and monoclonal myeloma IgG on fibrin structure and fibrinolysis in plasma clots. Clotting was initiated by the addition of thrombin (1.0 NIH units/ml) and calcium (10 mmol/L). Gelation was monitored as a time-dependent increase in optical density (633 nm). Fibrin fiber size (mu = mass-length ratio) was measured by scanning the gel from 800 to 400 nm. Two preparations of polyclonal IgG and plasma samples from 10 patients with myeloma were studied. Both Sandoglobulin (Sandoz Pharmaceuticals Corp.) and Gamimmune (Miles Inc., Cutter Biological) decreased final gel turbidity as the IgG concentration increased from 0 to 15 mg/ml. Because of its high maltose content, Gamimmune produced more-pronounced effects. Over a concentration range of 0 to 15 mg IgG per milliliter, mu decreased from 1.25 to 0.59 x 10(13) daltons/cm for Sandoglobulin and from 1.30 to 0.18 x 10(13) daltons/cm for Gamimmune. Polyclonal IgG at 15 mg/ml prolonged clot lysis induced by tissue-type plasminogen activator (tPA) from 800 seconds to > 12 hours. Similar effects were noted in myeloma clots. mu values in myeloma clots were significantly smaller than mu values in comparable normal clots. mu became smaller and lysis times became increasingly prolonged as the IgG level increased. High IgG concentrations induce thin fiber formation and impair fibrinolysis in plasma gels. These results demonstrate that fibrinolysis is inhibited in myeloma clots and that the degree of inhibition is correlated with IgG-mediated alterations in fibrin structure. Thin fibrin fibers may contribute to thrombotic risk in myeloma.

Buyouts & ventures. Selling ... or selling out.

Charity begins at home, yet across the country hometown not-for-profit hospitals are forming joint partnerships with investor-owned systems. In some of these cases no foundation is created to continue the hospital's good deeds. In this special report, Hospitals & Health Networks looks at the issues and asks, "Do these joint ventures need more public scrutiny?"

Heparin ablates force development during platelet mediated clot retraction.

Although snake venom enzymes such as reptilase do not cause viscous metamorphosis, platelet secretion or clot retraction; when batroxobin and calcium are added to citrated blood significant platelet force development occurs. When this batroxobin-calcium system was applied to the study of platelet function during cardiopulmonary bypass (CPB), force development was found to be completely inhibited. After heparin reversal by protamine sulfate, significant recovery of force occurred. The present investigation was performed to evaluate the role of heparin in reducing force development during CPB. At concentrations above 0.10 U/ml, heparin totally suppressed force development in normal plasma. Addition of protamine sulfate to heparinized plasma caused complete recovery of force development. These concentrations of heparin had little effect on platelet aggregation by ADP or collagen. Possible direct effects of heparin on fibrin assembly and structure were studied by adding varying amounts of heparin to plasma and then inducing clot formation with batroxobin. At 1 U/ml, heparin reduced the size of fibrin fibers by 33%. Higher heparin concentrations had no additional effect. These results indicate that heparin may be responsible for a significant component of the decreased platelet force noted during cardiopulmonary bypass. To test whether heparin's effect could be due to suppression of thrombin activity, the effects of the antithrombin hirudin on force development were measured. Hirudin also inhibited force development in a concentration dependent manner. Thus, heparin's reduction of platelet force development may be due, at least in part, to suppression of thrombin activity.

Effects of poloxamer 407 on the assembly, structure and dissolution of fibrin clots.

Poloxamer 407 has shown clinical promise in suppressing surgically related adhesion formation. The mechanisms by which this occurs are not well understood. Since poloxamer 188 has rather dramatic fibrin altering properties, the present study was performed to evaluate the effects of poloxamer 407 on fibrin assembly, structure and dissolution. Studies were performed in platelet-rich plasma (PRP), platelet-poor plasma (PPP) and a purified protein system. Poloxamer 407 enhanced the rate of fibrin assembly, and increased final gel turbidity. As poloxamer 407 concentration rose from 0 to 20 mg/ml in the purified protein system, the final gel optical density (OD) increased from 0.30 to 0.95, and fiber size (mass/length ratio [mu]) increased from 2.4 to 13.4 x 10(13) daltons/cm. Precipitation was noted in the purified system at poloxamer 407 concentrations > or = 20 mg/ml. Over a poloxamer 407 range of 0-20 mg/ml, mu increased from 2.64 to 13.2 x 10(13) daltons/cm in PRP. In PPP, mu increased from 2.95 to 9.25 x 10(13) daltons/cm. In contrast to results with poloxamer 188, clot lysis with tPA (43 IU/ml) was prolonged in the presence of poloxamer 407. At 20 mg of poloxamer 407 per ml, clot lysis was less than 18% complete after 3000 s. For the control, lysis was 50% complete after 1350 s. Poloxamer 407 inhibition of fibrinolysis was due to inhibition of plasminogen activation or plasmin activity. The fibrin altering properties of poloxamer 407 may partially explain some of this agent's interesting clinical properties.

Effects of ionic and nonionic contrast media on clot structure, platelet function and thrombolysis mediated by tissue plasminogen activator in plasma clots.

Various radiographic contrast agents have anticoagulant or prothrombotic properties. Ionic agents are reported to have greater antithrombotic potential while nonionic agents are considered more thrombogenic. Some agents after fibrin structure and bind to platelets in purified systems. This study compared the effects of iohexol, a nonionic agent, and iothalamate, an ionic agent, on fibrin assembly, clot structure, platelet function and clot dissolution in plasma. Plasma gels containing increasing concentrations of iothalamate were composed of thinner fibers with decreased fiber mass/length ratios (mu) and reduced gel turbidity. Such clots were more rigid and more resistant to fibrinolysis induced by tissue plasminogen activator (tPA). Gel elastic modula increased from 10,000 to 27,000 dyn/cm2 as iothalamate concentration increased from 0 to 20 mM. 50% lysis time increased from 800 to 1,250 s with the addition of 10 mM iothalamate. At 20 mM, iothalamate had no effect on ADP-induced platelet aggregation but prolonged the lag phase seen with collagen-induced aggregation. Platelet force development increased from 15,300 to 20,400 dyn with 20 mM iothalamate. The effect of iohexol were similar. Gel optical density dropped from 0.50 to 0.32, mu fell from 3.3 to 2.2 x 10(13) D/cm, and elastic modulus rose from 11,000 to 24,000 dyn/cm2 as iohexol concentration was increased from 0 to 20 mM. Clots formed in the presence of 60 mM iohexol and tPA did not dissolve in 72 h while control clot 50% lysis time was 450 s. At concentrations > or = 40 mM, iohexol completely blocked collagen-induced platelet aggregation. Platelet force development increased from 7,660 to 19,600 with 40 mM iohexol. Contrast media possess profound fibrin-altering activities in plasma. Fibrin formed in the presence of some agents may be significantly more resistant to fibrinolysis.

A sensitive platelet activation-based functional assay for the antileukemic agent bryostatin 1.

Bryostatin 1, a macrocyclic lactone activator of protein kinase C (PKC) currently in phase I evaluation, is a biologic response modifier which exhibits significant antitumor activity in several experimental systems. Clinical trials have been hampered by the absence of a sensitive assay for bryostatin 1 blood levels. The purpose of these studies was to exploit the exquisite sensitity of human platelets to bryostatin 1-induced aggregation in order to develop an assay capable of detecting plasma bryostatin 1 levels in the nanomolar range. Addition of bryostatin 1 (5-100 nM) to platelet-rich plasma resulted in complete platelet aggregation. A highly linear relationship was observed between low bryostatin 1 concentrations (i.e. 2-25 nM) and (i) reduction in the lag phase prior to aggregation and (ii) maximal rate of aggregation (R = 0.976). At higher bryostatin 1 concentrations (i.e. 10-100 nM), platelet aggregation was accompanied by detectable ATP release; both the extent and maximal rate of ATP secretion were highly linear functions of bryostatin 1 levels (R = 0.992). Bryostatin 1 concentrations in anticoagulated human blood samples could also be determined by mixing platelet poor plasma obtained from such samples with normal platelet-rich plasma. Notably, measurement of the delay in the aggregation lag phase permitted quantitation of bryostatin 1 concentrations of 5 nM or below. The capacity to detect bryostatin 1 plasma levels of 10 nM or lower should facilitate the conduct of pharmacokinetic and pharmacodynamic studies in conjunction with ongoing phase 1 trials.

Reductions in platelet force development by cardiopulmonary bypass are associated with hemorrhage.

Quantitative assessment of platelet dysfunction after cardiopulmonary bypass (CPB) and prediction of excessive microvascular bleeding remain elusive goals. We used a sensitive instrument capable of simultaneously measuring the force generated by platelets during plasma clot retraction and global clot strength. We hypothesized that CPB would significantly reduce these two variables. Platelet-rich plasma was obtained from eight patients undergoing aortocoronary revascularization prior to induction, after 90 min of CPB, and after protamine administration. Platelet force development was measured using a standardized technique that controlled for platelet number and permitted clot formation in the presence of heparin. Despite the presence of a measurable elastic modulus, platelet force development during bypass was abolished. Peak platelet force development after CPB was significantly lower than before CPB (5255 +/- 955 dynes vs 11,600 +/- 780 dynes, P = 0.01). The percent recovery (after/before bypass) of peak platelet force development inversely correlated with tube thoracostomy drainage during the first 24 h after placement (rs = -0.71, P = 0.048). This study demonstrates that CPB has dramatic effects on platelet force development. The correlation between the percent recovery of peak platelet force development and blood loss supports the clinical relevance of this measurement.

Glycoprotein IIb/IIIa blockade inhibits platelet-mediated force development and reduces gel elastic modulus.

The effects of GPIIb/IIIa blockade on clot retraction were studied utilizing an instrument which directly measures force produced by platelets. GPIIb/IIIa disruption by calcium chelation, and GPIIb/IIIa blockade by peptides and anti-GPIIb/IIIa antibodies were investigated. One mM EDTA suppressed ADP-induced platelet aggregation by 72% and reduced force developed at 1200 s by 33%. At 234 microM, the tetrapeptide Arg-Gly-Asp-Ser (RGDS) suppressed platelet aggregation by 74%, reduced force at 1200 s by 45% and reduced gel elastic modulus by 19%. At 10 microM, the peptide D-Arg-Gly-L-Asp-L-Try (D-RGDW) completely suppressed platelet aggregation, reduced force development by 38% and reduced gel elastic modulus by 29%. At 0.133 microM, monoclonal anti-GPIIIa antibody (AP-3) reduced force development by 74% and reduced gel modulus by 60%. Murine antiGPIIb/IIIa antibodies 10E5 and 7E3 markedly suppressed force development. At 0.133 microM, 10E5 reduced force by 89% and reduced gel modulus by 67%. At 0.053 microM, 7E3 completely stopped force development and reduced gel modulus by 46%. Platelet aggregation was blocked by 0.027 microM 7E3. Selective GPIIb blockade by antibodies did not affect force development. None of the agents studied altered fibrin structure as monitored by effects of fibrin mass/length ratios. Suppression of platelet aggregation occurred at inhibitor concentrations substantially lower than those required to suppress force development. Complete suppression of platelet aggregation did not assure inhibition of clot retraction probably due to profound platelet activation by thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrin structure and concentration alter clot elastic modulus but do not alter platelet mediated force development.

During clot retraction, platelets interact with fibrin resulting in marked reduction of clot volume. Altered fibrin structure has been reported to affect clot retraction as measured by serum expression. This study was performed to test whether such altered retraction was the result of increased resistance to network collapse or due to decreased force development by platelets. Altered fibrin structure was documented as variation of fibre mass/length ratios (mu) and shifts in clot elastic modulus. The force developed by platelets during clotting was measured directly. Increasing the fibrinogen concentration led to thinner fibre formation (decreased mu), and a linear increase in gel elastic modulus. Over a fibrinogen concentration range of 100 to 400 mg/dl, force development was minimally affected. Force development and clot elastic modulus increased in a linear fashion with increasing platelet concentration. Increasing the calcium concentration from 5 to 20 mM caused a 160% increase in fibrin fibre size (mu), and a 52% decline in clot modulus. Force developed at 1200 s declined by 17%. At 15 mg/ml, dextran and hydroxyethyl starch (HES) also increased mu, and decreased clot modulus; however, both agents markedly reduced force development. Increasing ionic strength or the addition of IgG decreased mu and increased gel elastic modulus. Force development increased modestly with increased ionic strength, did not change with addition of IgG in saline and declined with addition of IgG in maltose. This study indicates that force development is primarily dependent on platelet function while clot modulus depends on both fibrin structure and platelet function.(ABSTRACT TRUNCATED AT 250 WORDS)

At high heparin concentrations, protamine concentrations which reverse heparin anticoagulant effects are insufficient to reverse heparin anti-platelet effects.

Combined effects of heparin and protamine on plasma clot structure and platelet function were studied. Anticoagulant effects were monitored as changes in aPTT. Clot structure was defined in terms of fibrin fiber mass/length ratio (mu) and clot elastic modulus (EM). Platelet function was studied utilizing platelet aggregation and platelet force development (PFD) measurements. Heparin (1 U/ml) prolonged the aPTT from 30 to > 300 seconds, reduced PFD from 5,100 to 0 dynes, decreased mu (in batroxobin-induced gels) from 1.36 to 1.08 x 10(13) daltons/cm and decreased clot EM from 9,600 to 2000 dynes/cm2. Varying amounts of protamine reversed these effects: 16 micrograms/ml normalized the aPTT, 20 micrograms/ml normalized PFD, 32 micrograms/ml corrected mu, and 20 micrograms/ml returned EM to baseline. At high heparin concentrations (4 U/ml), protamine concentrations which corrected anticoagulant effects were inadequate to reverse antiplatelet effects. A protamine concentration of 40 micrograms/ml normalized the aPTT and mu, but 140 micrograms/ml of protamine was required to reverse heparin suppression of force development and clot elastic modulus. Excess protamine inhibited clotting and platelet function. In plasma containing 1 u heparin/ml, 140 micrograms protamine/ml reduced PFD by 83%, prolonged the aPTT by 63%, and reduced clot EM by 75%. In heparin free plasma, > 75 micrograms protamine/ml prolonged the aPTT. Thus, platelet function and clot structure are sensitive to protamine during heparin neutralization, and anti-platelet effects of heparin may persist when the aPTT is completely corrected. Excess protamine inhibits platelet function and compromises clot structure.

Duplication of the colon: varied presentations of a rare congenital anomaly.

Duplication of the colon is a rare congenital anomaly which may produce diagnostic difficulties for both clinician and radiologist. We report three patients who illustrate the spectrum of clinical and radiographic features which may be encountered. Radiology is essential in assessing the full extent of this condition including its various presentations, associated congenital anomalies, and anticipated complications.

Intramuscular thiothixene in acute psychotic states.

Seventy-four patients treated with intramuscular thiothixene and other major tranquillisers were analysed retrospectively. Thiothixene proved to be more effective than the other drugs in controlling acute psychosis.