[The concentration of carbon dioxide at the end of expiration as an index of hemodynamic status in open-heart operations]. The interrelationship of the cardiac index (CI) and carbon dioxide concentration measured at the end of respiration (CO2ER) was studied in 258 patients, aged from 5 to 71 years, during operations on the open heart. Statistical analysis of the stage of revision of the left ventricular posterior wall showed that CO2ER decreases from 29.9 +/- 0.7 mm Hg to 24.9 +/- 1.4 mm Hg in parallel with reduction of CI from 2.81 +/- 0.19 l/min/m2 to 1.62 +/- 0.13 l/min/m2. At the end of this manipulation the CI and CO2ER were restored to the initial level. Marked parallel dynamics of CO and CO2ER was revealed in continuous appraisal of the cardiac output (CO), determined by the method of catheter flow measurement, at the stage of parallel circulation and blood pumping from the extracorporeal circulation apparatus before CO2ER stabilization. The correlation coefficient of these parameters varied in this stage in various patients from +0.73 to +0.96. Analysis of the mass of data (n = 161) collected in 14 patients showed that the CI--CO2ER relation was exponential in character and could be expressed by the equation CI (l/min/m2) = e (-0.99 + 0.065 x CO2ER); standard determination error +/- 0.42 l/min/m2. Analysis of the "CO2ER-venous pressure" relation in these 14 patients showed it to be similar to the "cardiac index-venous pressure" relation. The coefficients of correlation between CVD and CO2ER at this stage ranged in various patients from +0.74 to +0.96 and those between VP and CI from +0.58 to +0.97. Transition of the relations to the plateau occurred at equal CVP values.


[The diagnosis and surgical treatment of ischemic heart disease in patients with occlusive arterial lesions of the lower extremities]. Concomitant ischemic heart disease was encountered in every 5 patients among 840 patients who underwent operation for occlusive lesions of the arteries of the lower limbs. Coronary cardiosclerosis increases the incidence of fatal myocardial infarction in the early and late-term postoperative periods. The presence of a clinical picture of ischemic heart disease and ECG changes require the performance of loading tests and, if their results are positive, the accomplishment of coronary ventriculography so as to solve the question of preventive revascularization of the myocardium. Preventive aortocoronary shunting excludes the risk of the development of cardiogenic complications in reconstruction of the great arteries of the lower limbs.


[The diagnosis and treatment of pulmonary artery thromboembolisms]. The article discusses experience in the diagnosis and methods of treatment of thromboembolism of the pulmonary arteries at the Department of Surgery of the Vessels of the Scientific Research Institute of Experimental Surgery. There were 238 patients under observation. A complex of modern diagnostic methods were applied, including, besides the routine methods of examination, angiopulmonography with measurement of blood pressure in the pulmonary trunk and right heart chamber and scanning of the lungs. Thus, comparison of the modern antipulmonological and isotope examinations allow a correct intravital diagnosis of thromboembolism of the pulmonary artery to be established. Administration of thrombolytics into the focus of affection by catheterization of the pulmonary artery is the most effective method of nonoperative treatment.


[Balloon catheter mitral valvuloplasty in pregnant women]. Catheter balloon mitral valvulotomy was performed in two patients with rheumatic mitral stenosis on the 28th and 24th weeks of pregnancy. The operation in the first patient was carried out at the onset of pulmonary edema. The results of treatment were good in both cases. The area of the mitral orifice in the patients increased from 1.5 and 1.6 to 3.2 and 3.5 cm2, the pressure gradient between the left atrium and the left ventricle reduced from 40 and 30 to 6 and 4 mm Hg. This was attended by disappearance of diastolic murmur and clinical manifestations of pulmonary congestion in both patients. Mitral regurgitation did not develop after the operation. Roentgenoscopy lasted 20 and 33 minutes. Screens were used to protect the fetus from the direct effect of X-rays. Pregnancy terminated in both patients by spontaneous at term delivery. They gave birth to two healthy girls. Catheter balloon mitral valvuloplasty does not yield to closed mitral commissurotomy in efficacy. Due to its low traumatizing property and no need for general anesthesia this intervention is preferable for pregnant females suffering from mitral stenosis.


[The accelerated training of skin-fascia flaps]. The suggested method for training cutaneofascial flaps is based on the results of histological studies, it can be applied in the early postoperative period, and reduces the intervals between the stages of plastic surgery with flaps. Training is possible in any localization of the cutaneofascial flap.


[The complications of puncture catheterization of the subclavian vein and their diagnosis]. The authors describe 21 complications which occurred in puncture catheterization of the subclavian vein in 1,276 (1.65%) patients. They varied widely in character--hemothorax, pneumothorax, thrombosis of the subclavian vein, etc. The case record of one patient with traumatic pneumothorax after puncture catheterization of the subclavian vein is discussed in detail.


[Special methods of examination and their role in the selection of the extent and type of surgical intervention in patients with pelvic osteomyelitis]. The article analyses the results of radiological and computer methods of examination applied in 117 patients with chronic osteomyelitis of the pelvis to determine the site and activity of the process and choose the most rational surgical approach. The localization of the process is determined by radiography, fistulography (if a fistula exists), scanning of the skeleton, and computer tomography. Scanning of the skeleton makes it possible to determine the activity of the process. The optimal operative approach and volume of operation are chosen by comparing the radiological findings (radio- and fistulography) and the results of computer tomography. The success of surgical treatment of patients with chronic osteomyelitis of the pelvis is determined to a great measure by the informativeness of the results of preoperative examination of the patient. With this in view, the most optimal combinations of the range of modern diagnostic measures should be used more widely.


[Wound healing after vacuum drainage].

[Wound healing after vacuum drainage]. Vacuum therapy was applied in the management of 63 patients with postoperative ventral hernias, 101 patients with a similar pathological conditions were treated by the traditional method for wound healing. From analysis of the results of treatment and with due consideration for the results of additional methods of examination it was established that vacuum prevents accumulation of exudate and blood clots in the wound cavity and removes the risk medium for the development of pyo-inflammatory complications. Moreover, by promoting the coming together of the wound edges and liquidation of the wound cavity, vacuum therapy affects the metabolic reorganizations in the tissues and leads to stabilization of the regeneration mechanisms. The use of vacuum therapy in the postoperative period creates the possibility of regulating the reparative reactions through an active effect on the healing of the wound in the phase of inflammation, protecting in this manner the biology of the wound process and preventing infectious complications.


[Effective forms of surgical dressing materials produced by the Paul Hartman firm]. From study of gauze dressings produced by the Paul Hartman firm the authors analyse the approaches to their elaboration. It is shown that the use of industrially sterilized gauze dressing-material creates the condition for fruitful work of the surgeon and ensures economy of the gauze. Concrete problems of the production of modern gauze dressing material by Soviet industry are defined.


[Prognosis and prevention of infection in emergency surgery]. The results of treatment of 176 patients with sepsis at the department of urgent surgery in 1985-1990 are discussed. The authors suggest a stage complex program of acute surgical sepsis prevention, which consists of purposeful measures applied in the pre-, intra-, and postoperative period and includes the following recommendations: conduction of skin tests, preoperative injection of antibiotics, preoperative immunization of patients, immunological methods for the choice of antibiotics, methods for rational immunologic correction, phagotherapy. Besides, the authors developed and introduced into practice an individual method for prognosticating the course and outcome of acute surgical sepsis based on E. V. Gubler's (1978) mathematical method. It is concluded that the suggested methods are very effective, with their application the sepsis mortality rate reduced from 75% to 37.5%, i.e. by half.


[Sulfhydryl groups and succinate dehydrogenase of blood lymphocytes in patients with inflammatory processes]. Patients with pyo-inflammatory processes were found to have a reduced SH-group content and SDH activity of peripheral blood lymphocytes. A clear dependence between the severity and extent of the pyo-inflammatory process and the SH-group and SDH values. Lymphocyte SDH is more sensitive than the SH-groups to the pyo-inflammatory process and responds by reduced activity. Study of SDH activity and SH-group content of lymphocytes in dynamics are sensitive tests for the severity of the pyo-inflammatory process, unspecific reactivity of the organism, and the efficacy of the applied treatment.


[Surgical treatment of extensive defects of the tissues and trophic ulcers in the area of the heel tendon using an L-shaped flap]. Operations were conducted on 22 patients with defects in soft tissues and trophic ulcers of cicatrix in the region of the calcaneal tendon. In 16 patients with extensive cicatricial lesions occupying two distal thirds or the whole region, an L-shaped flap of skin and fat was used, it was formed on the postero-lateral distal third of the leg, in the zone of the lateral malleolus and the lateral surface of the foot. The flap measured 20-22 cm in length and 6-7 cm in width. The ratio of the vertical part of the flap to the horizontal part was 3:1, 2:1, or 1:1 depending on the level of the defect and the area of the wound. The flap is mobilized strictly along the fascia so as not to injure the subcutaneous fat. The sural nerve is included in the flap to preserve its sensitivity, the rich venous network of the small saphenous vein provides for drainage, while the perforating arteries of the anterior tibial and fibular arteries, entering the base of the flap, ensure a sufficiently stable collateral circulation. Necrosis of the end of the flap occurred in 2 among 16 patients, in obliteration of the leg arteries (1) and cutting of tissues in the zone of the flap base (1) during previous surgical intervention. Complete healing was achieved in all cases; there were no recurrences in follow-up periods of 6 months to 8 years. The L-shaped flap retained its normal properties, the deformity of the donor site was negligible.


[Treatment of suppurative wounds in patients with diabetes mellitus by magnetic field and laser irradiation]. The efficacy of including a magnetic field, low-intensity laser beam, and their combination in the complex of therapeutic measures was studied in 119 patients with suppurative wounds and diabetes mellitus. With the use of magnetic field or laser beam intoxication diminished, the organism's immunological status was stabilized within a shorter time, the wound process followed a quicker course, and treatment took less time. The magnetic-laser effect has advantages over separate use of these factors.


[Plastic surgery of combined cutaneo-osseous defects of the hand]. The article analyses modern methods for the restoration of of defects in the metacarpal bones, based on microsurgical techniques. A case is described in which a new method for one-stage reconstruction of the hand in combined traumatic defect in the first and second metacarpal bones and an extensive defect in the soft tissues on the back of the hand was used. The hand was reconstructed by means of a vascularized complex autograft on a common vascular pedicle which included two separate fragments of the scapula and a fascial flap of the scapular region. With the application of the described method successful functional rehabilitation of the injured hand was achieved in a short period. A good cosmetic effect of the plastic repair was also noted.


[Diagnosis and treatment of septicemia]. There were 52 patients with sepsis, 61.6% were over 60 years of age (63.3% of patients had septicemia, 36.7% had septicopyemia). The disease was caused by ++pyo-inflammatory diseases of the vessels in 34.6% and the urinary system in 17.3% of cases. Microbial causative agents were isolated from the blood in 83.3% of patients (monoculture in 46.6%, associations of microorganisms in 36.6%; staphylococcus in 59.7%, gram-negative microflora in 46.7%). The most frequently encountered disorders of the immunological status were reduction of the number of lymphocytes and their T- (85%) and B-population (62.9%), increase of the level of immunoglobulins M (81.5%) and A (55.6%), decrease of the number of accessory T-cells (73.6%) and the ratio of accessory and suppressant T-cells (52.6%). Along with the application of antibacterial therapy, which relieved the microcirculatory blockage, and detoxication measures in the treatment of the purulent foci, much attention was paid to immunologic correction for the removal of primary and secondary insufficiency (endobulin, ++T-activin, isoprinosin). Blocking of the immunological reaction was relieved in 65.5% of patients by discrete plasmapheresis with compensation for the deficiency with endobulin, quick-frozen plasma, and rheopreparations. In the group of 52 patients 12 died (mortality 23.1%).


[Stable extraosseous compression osteosynthesis in fractures of the crural bones]. The article deals with the main principles of the conception of stable extraosseous compression osteosynthesis, the necessary conditions for its successful application. Operations were conducted on 87 patients for diaphyseal fractures of the leg bones by means of methods, instruments, and fixators suggested by the Osteosynthesis Association (OA, Switzerland). The late-term results of treatment were followed-up in 80 patients, 8 of them had complications (fracture and migration of the plate, nonunion of the fragments, osteomyelitis, recurrent fractures).


[Treatment of femoral neck fractures using carbon implants]. The article generalizes the experience in the use of endoprostheses of carbon materials in fractures of the femoral neck in elderly individuals. Twenty-seven cases are discussed, the average age of the patients was 76 years. Owing to the possibility of forming from carbon materials a device which meets the functional demands of the organs and tissues, such widely encountered complications in endoprosthesis as stretching of the implant's pedicle and destruction of the device were avoided.


[Zonography in solitary bone cysts].

[Zonography in solitary bone cysts]. The zonography method is gaining more and more users today and arouses a definite interest of specialists in medicine. This is due to the peculiarities of the method and the tremendous clinical possibilities which make it possible to improve and accelerate the diagnosis not only of diseases of the lungs and kidneys, but also of some segments of the bone system. The availability of zonography allows it to be used successfully in the diagnosis of various, pathological among others, types of bone fractures, tumors of the skeleton and, therefore, makes it possible to watch the reparative manifestations and the development of the process. Radio-sonographic comparisons of long tubular bones and large joints in 2,500 cases made it possible to reveal in 15 patients, aged from 17 to 80 years, solitary rarely encountered bone cysts not complicated by fractures. Their existence was suspected due to scrupulous collection of the medical history with consideration for the localization of the pain syndrome, in the absence of abnormalities in the blood and urinary tests. A fine, ++non-ectatic, regularly sclerosed capsule was seen in the 15 cases, the septa between the cavities were clearly contrasted and demonstrated better than on ordinary radiographs, and there were no infractions or pathological fractures.


[A surgical method in the complex treatment of metastatic bone tumors]. The article deals with the results of operations applied in the system of complex treatment of 83 patients (86 operations) with metastases of malignant tumours in the skeletal bones. Fourteen patient had carcinoma of the lung, 23--carcinoma of the breast, 28--carcinoma of the kidney, 8--carcinoma of the thyroid gland, and 10 patients had other malignant tumors. Operative interventions in the form of resection of the articular end or total removal of a tubular bone with endoprosthesis in affection of a long tubular bone and its pathological fracture or the threat of such fracture were substantiated. In the presence of special indications, osteosynthesis of the pathological fracture or amputation (exarticulation) of the limb may be undertaken. Laminectomy is indicated in metastatic lesion of the spine with the development of neurological disorders. Four (5%) patients died in the postoperative period. Average survival in the group of patients was 35 months, in the separate groups it was as follows: lung carcinoma metastases--9 months, kidney carcinoma metastases--31 months, thyroid carcinoma metastases--37 months, breast carcinoma metastases--40 months, metastases of other forms of malignant tumors--30 months. Longest survival--7.5 years. Average value of life quality according to Karnovsky was 30% before operation and 67% after it.


[Organization of surgical services for disaster victims]. The principal problems of the organization of surgical aid to the injured were considered from the analysis of the elimination of the consequences of large catastrophes which happened in the country in the recent years. The role and significance of rendering mutual and self-assistance are shown and methods for their study and mastering are suggested. At the stages of qualified and specialized aid priority is given to the work of medical service teams. Variants of their formation, financing, and working regimen are discussed. The author also discusses questions dealing with the organizational structures of the base medical institutions rendering qualified and specialized surgical service.


[Treatment of fractures of long bones associated with extensive skin avulsion]. The work analyses the experience in the treatment of 46 patients with fractures of long tubular bones and extensive wounds with avulsion of the skin at the department of emergency traumatology from 1983 to 1988. The method of choice in the treatment of fractures of the long tubular bones in this category of patients is functionally-stable osteosynthesis mainly with external fixation apparatuses on a nail or rod basis. A rational succession of the manipulations for surgical debridement of the extensive wound was determined, which made the surgeon's work much easier and reduced the time needed for the operation. The skin defects in extensive wounds were repaired by Krasovitov's method in 16 patients, in 30 patients reimplantation of the skin was carried out by means of a split avulsed graft measuring 0.3-0.5 mm in thickness. A complex approach to the treatment of patients of bot groups was applied in the postoperative period, which improved the outcome of the treatment considerably. From comparative analysis of the immediate and late-term results of healing of the reimplanted grafts the authors conclude that dermatomic (0.4-0.5 mm) plastics with a split avulsed graft is preferable.


[Key problems of the pathogenesis of infection]. The authors analyse the results of clinico-immunological studies in 452 patients with various forms of pyogenic surgical infection; 292 of the patients had surgical sepsis. It is proved that the condition of the primary and secondary purulent foci determines the course of the wound process and the occurrence and progress of sepsis. Radical surgical debridement of the wound leads to early optimization of the condition of the immune system and creates conditions for effective immunologic correction and intensive therapy.


[Microbial contamination of wounds and prevention of suppurative complications]. A specially elaborated punch card was used to study 1,784 case records of patients with pyogenic complications of wounds of various origin: pyogenic complications after cavitary operations, purulent surgical diseases; pyogenic complications of injuries, injections, and trophic ulcers. It was established that each type of wound is characterized by its own microflora. A follow-up showed that surgical intervention in combination with various antiseptics differ in their effect on microbial dissemination. Nontraditional methods (physiotherapy combined with volumetrically charged by an electrochemical method activated water with a pH of 2.5) have the best effect on the wound infection. Such an approach to the problem made it possible to reduce the expenditures on antiseptics considerably and improve the results of treatment and gain an economical effect.


[Surgical treatment of post-burn cicatricial deformities of the anterior surface of the thorax]. Operations were carried out on 11 patients with postburn keloidal cicatrix of the anterior chest wall the area of which ranged from 27 to 240 cm2. To, correct the deformity, extensive mobilization of the skin-fat layers of the axillae, subclavicular, region' anterior surface of the shoulder joints, and lateral surfaces of the chest is conducted. After excision of the cicatrix the layers are transposed to the wound and the skin covering is restored. Peripheral necrosis occurred in two patients but did not influence the outcome of the plastic procedures. Tailoring flaps from the mobilized layers causes a poorer cosmetic effect. Study of the results in follow-up periods of 2 to 18 months showed a good esthetic outcome in all patients, which allows the method to be recommended for the management of cicatricial deformities of the anterior chest surface.


[Classification of complications of combined injuries of abdominal organs and long tubular bones in traffic accidents]. The outcomes of treatment of 386 victims with abdominal trauma and fractures of the long tubular bones were studied. The authors systematized the typical complications developing after the trauma, both on the part of the injured organs of the abdominal cavity and true pelvis and the fractures of the long tubular bones. This allowed the developed complications to be divided according to time into early, late, and sequelae of trauma. The early complications of injuries to the organs of the abdomen and true pelvis are as follows: suppuration of postoperative wounds, postoperative wound dehiscence with or without eventration, recurrent intracavitary hemorrhage, progressing local peritonitis, incompetence of anastomoses, intestinal obstruction, abdominal abscesses and infiltrates, abscesses and infiltrates in the true pelvis, intestinal paresis, large hematomas, phlegmons of the anterior abdominal wall. The late complications are: sluggish wounds of the anterior abdominal wall, formation of ligature fistulas, postoperative ventral hernias, suppuration of intraorganic and interstitial hematomas, subclinical forms of sepsis and sepsis, thrombophlebitic complications, chronic venous insufficiency, persistent wounds, and other complications. The sequelae of injury to the organs of the abdominal cavity and true pelvis are: intestinal fistulas, functional intestinal disorders, gastric disease, the dumping syndrome, cicatricial changes of the anterior abdominal wall, posttraumatic disease, venous insufficiency, pneumosclerosis, chronic pneumonia, pulmonary emphysema, chronic vascular insufficiency, etc. The early complications in fractures of long tubular bones in the group of studied patients: suppuration of osteomuscular wounds, recurrent displacement of bone fragments, bone necrosis in open type IIIC, IIID fractures, gangrene of the limb consequent upon crushing of skin and subcutaneous tissue, subluxations, secondary subluxations of limbs.(ABSTRACT TRUNCATED AT 250 WORDS)


Serum bile acid monitoring as an early indicator of allograft function in canine orthotopic liver transplantation. This study was undertaken to elucidate the correlation between early graft function and serum bile acids profile in canine orthotopic liver transplantation (OLT). The recipient dogs were categorized into four groups: group A (n = 5); bile output over 10 ml during initial 6 hours, group B (n = 4); bile output less than 1 ml during the same period, group C (n = 5); transplanted immediately after graft harvesting, and group D (n = 5); transplanted after 7-hour ice-cold preservation in lactated Ringer's solution. In all cases serum total bile acid (TBA) was markedly elevated during anhepatic phase, the value being 49.4 +/- 48.5 mumol/L. However, in group A, TBA decreased promptly after revascularization, the value at 4-hour being 14.7 +/- 12.7 mumol/L. In contrast, the corresponding TBA level in group B was 62.3 +/- 27.5 mumol/L 4 hours later (p < 0.01 vs group A). In group C, TBA also decreased immediately after reperfusion. Furthermore, in comparison between groups C and D, TBA level was significantly different 4 and 6 hours after reperfusion (p < 0.01). In the reduction rate of TBA (value at each time point after reperfusion the value immediately before reperfusion), the significant difference was observed after 2 hours between groups A and B (p < 0.05). In addition, significant difference was recognized at 30 minutes between groups C and D (p < 0.05). Although the changes of most bile acid fractions were proportional to the changes of TBA in all four groups, the detection of lithocolic acid at 6 hours was characteristic of both groups B and D. In conclusion, there was strong correlation between the TBA level and the graft function during early postoperative period. Therefore, TBA will be a specific and early indicator to differentiate the quality of the transplanted grafts in OLT.


The computed tomographic evaluation of patellofemoral joint in patellar fractures treated with open reduction and internal fixation. In this study, we examined 97 patella fractures in which open reduction and internal fixation had been performed at the 1st Orthopaedics and Trauma Clinic of Social Security Ankara Hospital between January 1983 and December 1988. After 24 to 96 months, on an average of 48.4 months follow-up period, the cases were evaluated clinically for knee function complaints and by CT and roentgenography for patellofemoral articulation. In 11 of the patients (11.5) there was patellar displacement, 2 of the patients had patellar tilt (2.1%) and in 14 patients (14.5%) there was malalignment in which 1 patient (1.1%) had both patellar tilt and displacement. This data was obtained by measuring femoral trochlear angle (FTA) and patellar tilt angle (PTA) by CT at various degrees of knee flexion. Thirty-three patients (34%) had slight and 19 patients (19.6%) had severe degenerative changes in the patellofemoral articulation. It is found that there is close relation between the variability of the pain complaints of the patients and the type of the fracture and the time of management and the postoperative rehabilitation.


[Osteosynthesis of crural bone fractures using bone plates with pegs]. A metal plate with pegs for osteosynthesis was designed and introduced into practice for the treatment of diaphyseal fractures of the leg bones. Studies for appraising the tension-deformity condition proved that installation of 20 cone-shaped pegs on the inner surface of the plate increases the stability of fixation 3.6-fold. Besides, the cone-shaped pegs facilitate maintenance of intactness of the vessels of the periosteum and soft tissues as a result of which the conditions for healing of the fractures improve. Operations were carried out on 43 patients, in 41 with good outcomes. External immobilization was not applied in the postoperative period, early restorative treatment was conducted.


A [14C]2-deoxy-D-glucose study of brain structures related to conditioned emotional response in the rat. We used [14C]2-deoxy-D-glucose (2-DG) to determine activated brain structures related to conditioned emotional response (CER) in rats. The experimental groups were conditioned with paired conditioned-stimulus (CS; flickering light and clicking sound) and unconditioned-stimulus (US; foot-shock) for either 25 or 50 trials. The control groups were also exposed to the same stimuli but in unpaired or random sequence. Two days after conditioning, rats were intravenously injected with [14C]2-DG and then exposed to the CS alone (CER test) in a shock box. Mean optical densities of 44 brain structures were measured with an autoradiogram, and their optical density ratios were compared by 2-by-2 (paired vs unpaired and 25 vs 50 trials) analysis of variance. Those brain structures were of 2 types; the first type showed similar changes of 2-DG uptake in both paired and unpaired groups (Areas 7 and 40 of the cerebral cortex, the habenula and the colliculus inferior), while the second type showed that 2-DG uptake increased in the paired groups but decreased in the unpaired groups (Areas 24, 10, 6, 4 and 3 of the cerebral cortex), as a function of number of trials. Because changes of 2-DG uptake in the first type structures and in Areas 3, 4 and 6 of the second type structures are regarded to reflect learning-nonspecific effects and task- or stimuli-related symmetrical activation, respectively, we concluded that Areas 24 (anterior cingulate cortex) and 10 (prefrontal cortex) were specifically related to conditioned emotional response.


Gastrointestinal cancer: pathogenesis, risk factors and the development of intermediate biomarkers for chemoprevention studies. Dietary, environmental and genetic factors contribute to the etiology, pathogenesis and risk for gastrointestinal cancers. Measurements of cell proliferation and differentiation further identify abnormal cellular properties associated with increased susceptibility to gastrointestinal cancer. In precancerous esophagus, the proliferative compartment increases in size, increased ploidy and dysplasia develop, and epithelial cells express abnormal cytokeratins and ectopic tumor-associated antigens. In precancerous stomach, increased proliferative activity and metaplasia develop. Intestinal enzymes and mucins are expressed and normal gastric antigens are replaced by intestinal or embryonic antigens. In flat colonic mucosa and in colonic adenomas, expansions of the proliferative compartment occur. Gene expression is modified, gene deletions occur and blood group-related antigens are modified as the cells undergo abnormal differentiation and develop into adenomas and carcinomas. Chemopreventive regimens are now being tested to determine whether they modify such intermediate biomarkers toward normal levels characteristic of lower risk for neoplasia. It is anticipated that the utilization of intermediate biomarkers in chemoprevention studies may permit more novel chemopreventive regimens to be tested in human subjects than heretofore was possible.


Lectin reactivities as intermediate biomarkers in premalignant colorectal epithelium. Normal colonic epithelial cells undergo maturation as they traverse the crypt to the lumenal surface. The binding of lectins to goblet cell mucins and other glycoconjugates changes as the cells migrate and differentiate. Additional stepwise modifications in glycoconjugate expression occur in premalignant and malignant neoplasms that may be detected by lectin binding studies. The lectins Dolichos biflorus agglutinin (DBA) and soybean agglutinin (SBA) have been developed as markers of differentiation in normal-appearing colonic epithelium. Using a quantitative biometric system to score tissues, reduced levels of lectin binding have been found in rectal tissue from patients with familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer. The lectin Amaranthus caudatus agglutinin (ACA) binds to a cytoplasmic glycoconjugate expressed at the base of the colonic crypt and serves as a possible proliferation marker in the distal, but not proximal, colon. ACA binding increases in tandem with increased levels of proliferation (using BrdU incorporation) in neoplastic tissues. Binding by the peanut lectin (PNA) occurs late in the adenoma-to-carcinoma sequence--in larger adenomas and in cancers--and serves as a marker of advancing neoplasia. Lectins identify the stepwise changes that occur during normal differentiation, proliferation and in advancing neoplasia. By selecting the appropriate probe, biomarkers may be developed for early, intermediate, and late events in colorectal cancer.


Oncogenes as markers for early detection of cancer. Oncogenes are formed in human tumors as a result of mutations or DNA rearrangements leading to the abnormal expression or function of proto-oncogenes. Approximately 20 different oncogenes are reproducibly activated in malignancies of several types, including breast, colon, lung, pancreatic, and thyroid carcinomas, leukemias, and lymphomas. The potential utility of these oncogenes as markers for early detection of cancer is dependent on the stage of tumor development at which they are activated, and on whether the mutated oncogenes are readily distinguished from the corresponding proto-oncogenes by assays that are sufficiently sensitive to detect precancerous lesions.


Suppressor gene alterations in the colorectal adenoma-carcinoma sequence. Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate to bring about the neoplastic phenotype. Colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the inactivation of several tumor suppressor genes. We have found frequent allelic deletions of specific portions of chromosomes 5, 17, and 18 which presumably harbor suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is frequently mutated not only in colon cancer but in several other tumor types as well. Candidate suppressor genes have also recently been identified on chromosomes 18 and 5. The DCC gene on chromosome 18q encodes a protein with significant sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. Alterations of this gene may interfere with normal cell growth and differentiation by disrupting cell-cell or cell-substrate interactions. Two genes (MCC and APC) on chromosome 5q have also recently been identified and partially cloned. These genes are located in a region tightly linked to familial adenomatous polyposis (FAP). While MCC mutations have been found only in sporadic colon tumors, APC mutations have been identified in sporadic tumors as well as the germline of patients with FAP. Studies are currently in progress to increase our understanding of how alterations of these genes affect colorectal tumor cell growth.


Abnormal DNA content as a biomarker of large bowel cancer risk and prognosis. Aneuploid cell populations can be defined as those that contain an abnormal number of chromosomes or an abnormal amount of DNA. Aneuploidy can be reliably detected by flow cytometric analysis of DNA content. This technique not only identifies aneuploid cell populations but can also quantify the percent of cells in various phases of the cell cycle, thus giving an indication of the proliferative activity of a tissue. Aneuploidy occurs in approximately 60% of established colorectal cancers, and many studies have demonstrated that patients with aneuploid tumors have a poorer prognosis than patients with diploid colon cancers. Some studies have suggested that the proliferative rate of tumors, as assessed by the percent of cells in S phase, also has prognostic significance. Until recently, aneuploidy was thought to occur only in malignant tissues, but it has been clearly shown that aneuploid cell populations can be identified in benign adenomatous polyps as well as in non-neoplastic-appearing mucosa of patients with chronic ulcerative colitis and Barrett's esophagus. In chronic ulcerative colitis, aneuploidy occurs more frequently in patients with dysplasia or cancer than in those with no evidence of neoplasia. Similarly, dysplastic and malignant biopsies are more commonly aneuploid than non-neoplastic biopsies. Patients who have undergone colectomy for cancer or dysplasia in the setting of chronic ulcerative colitis frequently have multiple areas of aneuploidy throughout the remainder of their colon. Whether aneuploidy can be useful as a marker of cancer risk in patients with chronic ulcerative colitis deserves further investigation.


Intermediate biomarkers of precancer and their application in chemoprevention. The Chemoprevention Branch of the National Cancer Institute has established a program for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacy in vitro and in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase III trials in which cancer reduction is the endpoint require large subject groups (tens of thousands) and follow-up duration of more than five years. Because of these requirements, the cost of such trials are high. The Chemoprevention Branch is addressing this challenge by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints. The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non-invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence.


Molecular and endocrine biomarkers in non-involved breast: relevance to cancer chemoprevention. The animal models for chemoprevention of breast cancer have provided important experimental systems to evaluate the efficacy of tumor suppression by dietary macro- and micronutrients. In the initiation/promotion cascade, early occurring premalignant changes constitute less extensively examined aspects of disease progression. Molecular, endocrine and cellular biomarkers may provide clinically relevant endpoints for prevention of breast cancer that focus on downregulation of preneoplastic transformation. In vitro models derived from non-involved murine and human mammary tissues are utilized to identify molecular, endocrine and cellular markers that are perturbed in response to such diverse initiators as viruses and chemical carcinogens. This upregulation was manifested as persistent Ras p21-GTP binding, altered C16 alpha/C2 hydroxylation of estradiol, and hyperplasia preceding tumorigenesis. Prototypic chemopreventive agents such as n-3 polyunsaturated fatty acids, retinoids, and indole-3-carbinol were capable of downregulating all of the preneoplastic markers perturbed by initiators. Experimental modulation of these biomarkers in murine and human mammary tissue prior to the expression of a fully transformed tumorigenic phenotype is suggestive of their potential clinical application in chemopreventive intervention for breast cancer.


Prostatic intraepithelial neoplasia: a premalignant lesion. Putative premalignant changes in the prostate have been recognized for a number of years. A variety of synonyms have been given to the most commonly described lesion, characterized by proliferation and dysplasia of the normal two cell layers lining prostatic acini and ductules; prostatic intraepithelial neoplasia (PIN) is the term most often used. A premalignant prostatic lesion should have morphologic features similar to invasive carcinoma (CA), a spatial association with microinvasive cancer arising from the lesion, and should occur at a greater frequency, severity and extent in organs harboring CA. Most definitively, progression from the premalignant lesion into CA should be observed over time. PIN fulfills all but the last of these requirements. High grade PIN is cytologically indistinguishable from prostate carcinoma (CAP). The major differentiating feature between PIN and CAP is the presence, although frequently disrupted, of the basal cell layer in the former. We have studied the basal cell layer in PIN using antibodies to high molecular weight cytokeratins and have found a correlation between PIN grade and the percent disruption of the basal cell layer. The cells making up PIN are phenotypically similar to those of CAP. We have used a variety of markers including cytokeratins, vimentin and the lectin Ulex euroapaeus to demonstrate this similarity. Additionally, we and others have noted decreased PIN immunoreactivity with antibodies directed against prostate specific antigen (PSA) and prostatic acid phosphatase. Other investigators have noted additional phenotypic similarities between PIN and CAP, including the ABH and Lewis antigens. PIN incidence and grade correlate well with the presence of CAP elsewhere in the prostate.(ABSTRACT TRUNCATED AT 250 WORDS)


Indicators of increased breast cancer risk in humans. Specific atypical histological patterns of epithelial hyperplasia (AH) indicate a medically relevant risk of breast cancer development in 5-10% of women with otherwise benign biopsies. This risk is about four times that of similar women, i.e., of the same age and at risk for the same length of time. These relative risks are not stable with time and fall 10-15 years after detection. Absolute risk for invasive breast cancer after AH is about 10% in 10-15 years after biopsy and is most certain for perimenopausal women. Proliferative disease without atypia predicts only a slight elevation of risk with a relative risk (RR) of 1.5 to 2 times that of the general population. There is such a strong interaction between family history and AH that it is relevant to consider women with atypical hyperplasia who have a positive family history (FH) of breast cancer separately from those who do not. The absolute risk of breast cancer development in women with AH without a FH was 8% in 10 years (RR about 4), whereas those with a positive family history experienced a risk of about 20% at 15 years (RR of about 10). This interaction of AH and FH has also been observed in other recent studies. Low replacement doses of conjugated estrogen after menopause do not further elevate risk beyond that identified by histology.(ABSTRACT TRUNCATED AT 250 WORDS)


Candidate biomarkers for application as intermediate end points of lung carcinogenesis. The need for validated intermediate end point markers to facilitate lung cancer chemointervention research is compelling. Three major classes of lung markers are relevant for this application. Since lung cancer includes four distinct histologies, markers that map degrees of histologic differentiation are important. Many of the markers for squamous differentiation overlap with the candidates for application in the study of head and neck cancer. Production of tissue-specific cell products especially for surfactant or CEA is of interest, because the gene structure is known and many differentiation-related polymorphisms exist. This strategy would be useful for adenomatous type tissue. A second type of marker is the broad group of differentiation markers. The carbohydrate or blood group-like antigens comprise a representative example. Carbohydrate structures are expressed in a specific sequence during fetal processes, and this sequence appears to reverse with the development of a cancer. Retrodifferentiation of specific differentiation markers is the basis of a major effort to effect earlier lung cancer detection using sputum immunocytochemistry. The final class includes markers which affect either positive or negative aspects of growth. Candidates in this area include growth factors or their receptors, or genes that regulate growth. If the intermediate end point marker reflects tumor biology and that biology is in the causal path of tumor progression, serial observation of that parameter should indicate the success of the intervention. In all three of these examples, the clinical material to be analyzed could be sputum specimens, bronchial biopsies or resected lung tissue. Systematic analysis of these markers in context of intervention trials is required to validate their utility.(ABSTRACT TRUNCATED AT 250 WORDS)


Precancerous lesions of the human esophagus: multiparametric study of esophageal biopsies from a high-risk population in Linxian, China. Histopathology, morphometry, tritiated thymidine incorporation and immunohistochemistry were studied in 221 esophageal biopsies from subjects with cytologica hyperplasia in Linxian, China. A spectrum of 7 morphologic entities were found: (1) normal/near normal (NN); (2) basal cell hyperplasia 0 (BHO); (3) simple hyperplasia (SH); (4) mixed basal and spinous cell hyperplasia (MBS); (5) basal cell hyperplasia 1 (BH1); (6) dysplasia (D); and (7) non-proliferative lesion (NP). Forty percent of the biopsies had combinations of histologic types. The thickness of the epithelium was increased in SH, MBS, and BH1, but not in BHO and NP. Elongation of papillae was frequently seen in SH, MBS, BH1, and D. Papillary bleeding was very prevalent in the esophageal specimens studied. A variety of cellular changes were found in peripapillary areas especially when bleeding occurred. [3H]-thymidine labeling index was dramatically increased in the entire epithelium in dysplasia, and also increased in cell layer 3 of MBS, BH1 and D. Blood group antigen LeY and lectin WGA showed consistent positivity in cellular membranes of the squamous cells, and these changes occurred before gross morphologic alterations. These findings provide a hypothesis for the sequence of pathogenetic events leading to esophageal carcinoma, and define each step with corresponding biomarkers for cancer prevention studies.


The natural history of intraepithelial neoplasia: relevance to the search for intermediate endpoint biomarkers. The development of carcinomas, defined as invasive epithelial neoplasms, is preceded by a preinvasive stage termed intraepithelial neoplasia that typically lasts for years. Intraepithelial neoplasia is the target tissue for the action of chemopreventive agents and the site where biomarkers frequently develop. The term "dysplasia" refers to the morphological alterations that characterize intraepithelial neoplasia and, according to many authors, consists of seven basic changes that are the same for the majority of epithelia. These are increased nuclear size, abnormal nuclear shape, increased nuclear stain uptake, nuclear pleomorphism (increased variation in size, shape, and stain uptake), increased mitoses, abnormal mitoses, and disordered or absent differentiation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. The use of intraepithelial neoplasia as an intermediate endpoint biomarker requires that effective chemopreventive agents cause it to regress. Two examples are the regression of dysplastic oral leukoplakia produced by beta-carotene and the regression of colonic polyps in familial polyposis patients following treatment with the nonsteroidal antiinflammatory drug sulindac. There is a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.


Statistical validation of intermediate markers of precancer for use as endpoints in chemoprevention trials. Using an intermediate marker of precancer as an endpoint for evaluating agents that may prevent cancer involves a presumption that the modification of the marker will be accompanied by a modification of cancer incidence. This presumption can hold only if the marker is on or very closely linked to a causal pathway. Epidemiologists have discussed the nature of evidence required to infer causal relationships, and we briefly survey their work. Studies relating exposure (E) to marker (M) provide only indirect evidence for causality. Those relating marker (M) to disease (D) are more relevant. We propose a new validation criterion based on an analysis of the three-way relationship of exposure (E), marker (M) and disease (D). We discuss the level of evidence required for using intermediate markers as endpoints for Phase II and Phase III trials, and propose very stringent criteria for Phase III trials. For Phase II trials, we propose less stringent criteria, but still recommend that the marker (M) should have been shown to have a strong association with disease (D).


Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials. Chemoprevention trials in lung and upper aerodigestive tract (UADT) cancer are guided by the field cancerization hypothesis. Inhaled carcinogens place the entire epithelial lining at risk for the development of cancer. The hypothesis is supported by the occurrence of premalignant lesions, such as leukoplakia or squamous metaplasia, and multiple primary tumors within the field. The concept of carcinogenesis as a multistep process suggests the possibility of blocking or reversing the progression to invasive cancer with systemic treatment. A series of ongoing clinical trials will determine the efficacy of retinoid chemoprevention and will attempt to develop intermediate biomarkers. Biomarkers which reliably reflect progression towards cancer could be used to dramatically improve the efficiency of chemoprevention trials and also would aid in screening potential chemoprevention agents. Genomic biomarkers include non-specific estimates of ongoing DNA injury, such as micronuclei, as well as development of aneuploidy and alterations in oncogenes. A class of biomarkers of increasing importance assess proliferation and growth regulation, and include proliferating cell nuclear antigen (PCNA), TGF-beta, EGFR and retinoid receptors. Other markers, such as the blood group antigens, reflect differentiation and may be associated with the development of premalignant lesions. Preliminary data from several of these markers has suggested an association with carcinogenic exposures and premalignant lesions, but none of these markers either alone or in panels have yet been validated as a reliable surrogate for the development of invasive cancer.


Ulcerative colitis and colon cancer: biology and surveillance. The risk of colorectal carcinoma is increased among patients with longstanding ulcerative colitis and Crohn's disease. The development of cancer in inflammatory bowel disease is hypothesized to evolve by a multistep process involving genetic instability, clonal expansion and the development of a malignant phenotype. The contribution of nutritional factors such as folate deficiency is of great interest; molecular genetic mechanisms are under study. In contrast to sporadic colorectal carcinoma, carcinomas in ulcerative colitis are associated with a long prior history of chronic inflammation and the subsequent development of epithelial dysplasia. Dysplasia is defined as an unequivocal neoplastic alteration of the colonic mucosa. The object of surveillance is prevention of death from cancer by detection at a premalignant or early curable stage. Patients at greatest risk of cancer who customarily undergo endoscopic surveillance are those with extensive colitis of more than 8 years duration. Dysplastic epithelium may occur in flat mucosa, and may produce a plaque or a nodular/villiform appearance. Dysplasia is not present in all patients with cancer in colitis. It is important to develop more sensitive and specific markers for the presence of precancer or cancer in colitis. Under study are proliferation-associated markers detected by immunohistochemistry, lectin binding, flow cytometry and laser-induced fluorescence coupled with endoscopy.


Growth kinetics and chemoprevention of aberrant crypts in the rat colon. Single and multiple colonic crypts exhibiting dysplasia that are detectable in situ by staining of rat colon with methylene blue are called aberrant crypts (AC) and may serve as an intermediate marker for colon cancer. In a characterization study, we have established the kinetics of AC growth and development over a period of 20 d following injection of rats with the carcinogen azoxymethane (AOM). AC are not present at 5 d post-injection, but are a constant feature at 10 d and thereafter. Multiple AC, presumably clonal, begin to evolve at 10 d and are consistent by 20 d, forming incipient microadenomata. We have examined 20 candidate chemopreventive agents for inhibition of AC. All agents were given in AIN-76 diet, at two dose levels, with injections of AOM. AC were measured after 5 weeks of growth. Among the most active AC-inhibiting agents were BHA, DFMO, quercetin, diallyl sulfide, 18 beta-glycyrrhetinic acid, and ascorbyl palmitate. In a post-initiation study, the differentiating agent sodium butyrate was ineffective, but piroxicam was highly effective in modulating AC growth. Further, piroxicam inhibited AC development at all stages of growth from single to polycryptal clusters of AC. The AC assay shows marked sensitivity and specificity for screening agents for chemoprevention of colon cancer.


Intermediate biomarkers of increased risk for colorectal cancer: comparison of different methods of analysis and modifications by chemopreventive interventions. Intermediate biomarkers of abnormal cell growth and development have recently been used in chemoprevention trials in attempts to identify the efficacy of chemopreventive agents in human subjects. Measurements carried out include those related to cell proliferation, differentiation, and gene structure and expression in the colon. Among modified patterns of cell proliferation identified by microautoradiographic or immunoperoxidase assays, a characteristic expansion in the size of the proliferative compartment has been observed in normal-appearing colorectal mucosa of human subjects with disease increasing cancer risk; the same patterns have been induced by chemical carcinogens in rodents. Moreover, this intermediate biomarker has been modulated by chemopreventive agents in both rodents and humans. Newer intermediate biomarkers being studied for application to human chemopreventive programs include normal and abnormal patterns of expression of mucins, intermediate filaments and cytoskeletal proteins, and the structure and expression of a variety of genes associated with normal and abnormal cell development. The application of these various intermediate biomarkers to chemoprevention studies is increasing the ability of investigators to analyze the effects of novel chemopreventive agents in the colon and in other organs.


Cell proliferation biomarkers in the gastrointestinal tract. Measurements of epithelial cell proliferation in the mucosa of the gastrointestinal tract pointed out the existence of cell kinetic abnormalities which can be involved in the first steps of carcinogenesis. In particular, an increase in the cell proliferation rate and an abnormal distribution of proliferating cells were found both in animals exposed to carcinogens and in human subjects at high risk of gastrointestinal cancer. In some diseases which predispose to cancer (i.e., chronic atropic gastritis, hereditary gastrointestinal cancer, sporadic colorectal neoplasia, chronic ulcerative colitis) we observed an expansion of the proliferative compartment even when the mucosa was not affected by morphological abnormalities. This proliferative feature seems to be associated with the presence of defects in cell differentiation. The abnormality is well detected by the histological examination of the proliferative pattern using microautoradiography after incorporation of tritiated thymidine, or using immunohistochemistry after bromodeoxyuridine uptake. The literature, and our own results, indicate that the search for abnormalities of epithelial cell proliferation can be useful in studying the earliest mechanisms leading to gastrointestinal cancer, in detecting subjects at high cancer risk, and for pilot chemoprevention studies using these abnormalities as intermediate biomarkers of gastrointestinal cancer risk.


Cell proliferation in colorectal tumor progression: an immunohistochemical approach to intermediate biomarkers. Cell renewal in the large intestine mucosa is normally tied to a rigidly compartmentalized model. Immunohistochemical identification of cells in S phase through uptake of bromodeoxyuridine is the method of choice for detailed compartmental mapping of proliferation, while immunohistochemical detection of proliferation-associated antigens (Ki-67, PCNA, DNA polymerase alpha) provides information in advanced tumor cases. Mucosal hyperproliferation due to inflammation may be transient (self-limited colitis, Crohn's disease, acute radiation damage) or lasting (ulcerative colitis). Progressive shifting of the proliferation zone to the crypt surface (Stage II abnormality) is a late feature of irradiated rectal mucosa and subgroups of ulcerative colitis patients at high risk for cancer. Hyperproliferation and Stage II abnormality coexist in the mucosa of patients with colorectal neoplasia, but are mutually independent and correlated to different clinical and pathological features of the disease. These cytokinetic abnormalities are highly predictive markers of the adenoma-carcinoma sequence, but are not associated with de novo adenocarcinoma. Proliferation increases progressively in the subsequent steps of this sequence, except in early cancer.


Altered glycosylation of mucin glycoproteins in colonic neoplasia. Considerable alteration of cellular carbohydrates such as glycolipids and glycoproteins occurs in colonic neoplasia. Some of these changes are also observed at certain embryonic stages of differentiation and are, therefore, considered onco-developmental changes. In colon cancer cells, many of the phenotypic markers for malignancy have been found on carbohydrate moieties, and some have been found on the peptide portion of mucin glycoproteins. The changes in carbohydrate antigens include altered expression of core region carbohydrates, extension of backbone structures and modification of peripheral carbohydrate structures that may arise due to abnormal glycosylation processes. Altered glycosylation may also result in the exposure of the peptide moiety of the mucin glycoprotein. Therefore, these altered mucin glycoprotein structures may serve as tumor markers. However, it remains to be determined whether they will be useful as intermediate endpoint markers.


Blood group-related carbohydrate antigen expression in malignant and premalignant colonic neoplasms. Cell surface glycoconjugates of colonic epithelial cells carry certain carbohydrate antigens related to blood group substances. During the progression to malignancy, these oligosaccharide immunodeterminants undergo specific types of alterations. In colon cancers, the blood group antigens A, B, H, and Le(b), which are normally expressed only in the proximal colon, can be re-expressed in distal colon cancers or deleted in proximal colon cancers. Also, an antigen which is incompatible with the individual's blood type can be expressed. Similar alterations occur in adenomatous polyps, but with reduced frequency. The simple form of blood group-related Le(x) and Le(y) antigens found in normal mucosa can undergo modification by oligosaccharide elongation, internal fucosylation, and sialylation into novel structures found in carcinomas as well as in adenomas with greatest malignant potential. Finally, antigens representing the first steps of glycosylation, Tn, T, sialosyl-Tn (STn), which are normally cryptic in the colon, can be unmasked due to incomplete glycosylation in adenomatous polyps and cancers. Several of these antigens, such as extended Le(x), extended Le(y), T, and sialosyl-Tn, are quite cancer-specific in that they are rarely expressed in normal mucosa or hyperplastic polyps, but preferentially occur in adenomas of greatest malignant potential. As such, these antigens might be useful as candidate intermediate endpoint biomarkers.


The Seventh K Prathap Memorial Lecture. The pathogenesis of autoimmune immune complex disease. It has been proposed that autoimmune immune complex disease, of which SLE is the type example, is caused essentially by a failure to properly metabolise immune complexes and that this allows the establishment of feedback cycles which cause more immune complexes to be formed. The essential genetic predisposition to this disease is complement deficiency of the components of the early classical pathway and some degree of genetic complement deficiency, particularly of C4a, is found in more than half the patients. It seems likely that acquired complement deficiencies, possibly present at the time of initiation of the disease, may be important in many of the other cases.


In-house microcomputer software package for management of histopathology reports. A system for computerising histopathology records developed in-house using dBASE IV on IBM-compatible microcomputers in a local area network is described. The software package uses a horizontal main menu bar with associated pull-down submenus as interface between the machine and the user. It is very easy to use. The package provides options for selecting databases by years, entering/editing records, browsing data, making multi-characteristics searches/retrievals, printing data, and maintaining databases that includes backing-up and repairing corrupted databases.


Oesophagostomiasis in man: report of the first Malaysian case with emphasis on its pathology. This paper describes the first Malaysian case of oesophagostomiasis. The patient was an 8-year-old Malay boy who presented to Ipoh General Hospital, Perak with abdominal pain and weight loss. Examination revealed multiple cavitated pseudotumours of the colon. A hemicolectomy was performed. Examination of the lesions revealed Oesophagostomum worms in the necrotic centres. The differential diagnoses and the pathology caused by Oesophagostomum are discussed. A brief review of the available literature is presented.


Biphenotypic hybrid acute leukaemia detected by two colour flow cytometry. Immunophenotypic studies using immunofluorescent flow cytometry were performed on the blast cells of 36 patients with acute leukaemia using a panel of eight monoclonal antibodies. Six patients had blasts which co-expressed markers for lymphoid and myeloid differentiation, and which were therefore defined as biphenotypic hybrid acute leukaemia. Of the six, three patients were in the paediatric age group (below 12 years old) while the other three were more than 12 years old. Peripheral blood counts were variable; however, bone marrow infiltration was extensive (blasts > or = 75% in all). At the time of study, remission was achieved in only two patients. The authors' data show that biphenotypic hybrid acute leukaemia is not rare in Malaysia. This represents a subgroup of acute leukaemia identifiable by immunophenotyping but not by the French-American-British classification based on morphological and basic cytochemical studies alone. The recognition of this subgroup is important for both practical and theoretical reasons. There are implications for treatment of the individual patient because treatment directed at a single lineage may not be effective. The two colour flow cytometry proved to be a useful tool for diagnosis and classification of acute leukaemia.


Immunolabelling of prolactin at ultrastructural level using the protein A-gold technique on Epon-embedded tissue. The use of the colloidal-gold technique in electron microscopy immunocytochemistry has provided important information on the in situ localisation of intracellular antigens. We have developed a post-embedding technique for prolactin localisation on resin-embedded human pituitary tissue sections by the use of the protein-A gold conjugate. Human pituitary tissue obtained at autopsy was processed for electron microscopical study without post-osmication and then embedded in Epon. The indirect immunoperoxidase method was used for light microscopical targetting of lactotroph cells for subsequent electron microscopical antigen localisation. Ultra-thin sections were labelled with human anti-human prolactin followed by protein-A gold conjugate. Specific labelling was observed over secretory granules with a density of 15-30 particles per granule, as determined by the Quantimet 570 image analysis system. This technique provides a means of studying the pathophysiology of hormonal secretion at ultrastructural level and can be a useful tool in diagnostic and research investigations.


Strychnine poisoning: a case report.

Strychnine poisoning: a case report. A teenage male was admitted to a hospital in the United Kingdom following the ingestion of strychnine. The typical spasms of strychnine poisoning were observed and he died during the fourth convulsion. The post mortem findings are presented, and strychnine poisoning is discussed.


Bacteriology turnaround time in seven Malaysian general hospitals. A turnaround time study was conducted for bacteriological culture tests in seven Malaysian general hospitals. The turnaround times were determined using a specially designed form that was completed by the ward staff. Doctors at these hospitals were also polled to find out whether they were satisfied with the promptness of bacteriological test reporting in their hospitals. The turnaround times obtained from this survey were found to be satisfactory taking into account the constraints of laboratory methods employed. Nevertheless only about a third of doctors expressed satisfaction with the timeliness of the bacteriological test reporting. Doctors and microbiologists should get together and agree on acceptable standards of turnaround times that are practical and reasonable.


A morphological and immunohistochemical study of plasma cell proliferative lesions. Monoclonal plasma cell proliferative diseases such as multiple myeloma and plasmacytoma can involve extramedullary sites at the time of first presentation, or subsequently in the course of the disease. Under such circumstances, they can mimic primary or metastatic carcinomas, neuroendocrine or neuroectodermal tumours and lymphomas, and the pathologist often has to resort to immunohistochemistry as an aid to diagnosis. We studied the morphology and immunohistochemical properties of 10 cases of previously confirmed monoclonal plasma cell proliferative lesions retrieved from the files of the Department of Pathology, University of Malaya. Serial 4u thick paraffin sections were stained with H&E, the Unna-Pappenheim technique for nucleic acid and a panel of antibodies using a standard immunoperoxidase technique. Light chain restriction was demonstrable in most of the cases. Seven (70%) showed kappa and 2 (20%) lambda light chain restriction. The remaining case was not stainable with most of the antibodies in the panel. The majority (80%) of cases showed accompanying IgG heavy chain in the cytoplasm, while 1 case had IgA. Seven (70%) showed membrane positivity with antibody to epithelial membrane antigen (EMA) and 7 (70%) cytoplasmic positivity with antibody to vimentin. This study enhances our awareness that neoplastic plasma cells can be positive for EMA and vimentin, and cautions us from misinterpreting these lesions as carcinomas or sarcomas. Notwithstanding that, immunohistochemical staining for kappa and lambda light chains can be helpful in differentiating monoclonal plasma cell proliferations from polyclonal ones.


Sudden death in a young adult due to coronary artery aneurysm secondary to suspected Kawasaki disease. A healthy 17-year-old Chinese male suddenly collapsed and died during a game of badminton. The autopsy examination revealed a solitary calcified aneurysm of the left common coronary artery with marked stenosis of the orifices of the anterior descending and circumflex branches. Histology of the aneurysm was non-specific with hyalinised scar tissue and foci of calcification. The only illness of significance in the past was an episode of 'pyrexia of unknown origin' at the age of 8 months. A review of the notes of that hospital admission revealed that the illness was most probably Kawasaki disease.


Assessing the validity of the dimensions of prenatal attachment. Prenatal attachment has been considered a multidimensional construct. The Maternal-Fetal Attachment Scale (MFAS) was developed to measure prenatal attachment. Five subscales were incorporated into the MFAS to represent the dimensions. The purpose of this study was to examine the validity of the dimensions of prenatal attachment as represented by the MFAS subscales. A content analysis of parental remarks about the fetus was conducted. The categories generated from this analysis did not correspond to the MFAS subscales. Therefore, while the results support prenatal attachment as multidimensional, they did not support the specific dimensions represented by the MFAS.


A comparison between adolescent and adult women on prenatal anxiety and self-confidence. The purpose of this study was to investigate anxiety and self-confidence in adolescent and adult pregnant women. Thirty-five adolescents, ages 13 to 16, and 58 adult women, ages 21 to 33, participated in this study. The majority of the sample was black and unmarried, and all attended a low-risk prenatal clinic for a first pregnancy. Spielberger's State-Trait Anxiety Inventory (STAI) and Pharis' Self-Confidence Scale were administered during the women's second trimester of pregnancy. Results indicated significant negative correlations for both state and trait anxiety during pregnancy and self-confidence for all women, but no significant differences in anxiety and self-confidence between the two groups. Results indicate the need for nurses to develop and implement plans for decreasing anxiety and enhancing self-confidence of all pregnant women.


Women's views of postpartum sibling visitation. The purpose of this study was to identify women's views of postpartum sibling visitation. Fifty-eight Lamaze-prepared, married multigravidae expressed their views on sibling visitation in a semistructured interview conducted during their postpartum hospitalization. The majority of women (84%) chose to have their children visit. Women identified positive and negative aspects of sibling visitation, explained reasons for not having siblings visit, and discussed reactions to separation from their children. The women believed both siblings and mothers benefitted emotionally from the visit. Negative aspects of sibling visitation included emotional reactions of mothers and siblings, lack of control between siblings and infants, and inconvenient location for the visit.


3-(Phenylamino)alanine, a novel aniline-derived amino acid associated with the eosinophilia-myalgia syndrome: a link to the toxic oil syndrome? The eosinophilia-myalgia syndrome (EMS) is an inflammatory disease that occurred in epidemic proportions in the United States during 1989. Cases of EMS were also reported in Europe and elsewhere. Clinically, EMS resembles the Spanish toxic oil syndrome. EMS has been associated with ingestion of manufactured L-tryptophan and, more specifically, with lots of tryptophan that contained the trace contaminant 1,1'-ethylidenebis(tryptophan) (EBT). Another trace contaminant ("peak UV-5") has been reported, but the strength of its association with EMS has not been demonstrated. Herein we report independently that peak UV-5 is 3-(phenylamino)alanine (PAA). Patients with EMS ingested significantly greater amounts of both PAA and EBT than did control tryptophan users. PAA is chemically similar to 3-phenylamino-1,2-propanediol, an aniline derivative isolated from samples of oil that were consumed by persons in whom the toxic oil syndrome developed. The discovery of an aniline-derived contaminant in tryptophan raises the possibility that EMS and toxic oil syndrome may have a common etiologic trigger.


Contribution of a measure of disease complexity (COMPLEX) to prediction of outcome and charges among hospitalized patients. Attention has been focused on the need to adjust hospital reimbursement and outcomes of hospital care for level of illness. Extant measures of disease severity, however, fail to consider the contribution of disease complexity. We developed an easily retrievable measure of disease complexity (COMPLEX) by modifying an existing severity system, computerized Disease Staging. The contribution of COMPLEX (the number of body systems affected with a Disease Staging score of 2 or more) to the prediction of outcome was assessed in two studies: (1) a population-based analysis of readmission and mortality after hospitalization and (2) an analysis of hospital charges among patients who were in an intensive-care unit. The amount of variation in mortality explained by factors included in the Health Care Financing Administration model was significantly improved when COMPLEX was added to the model (adjusted odds ratio per body system, 1.83; 95% confidence interval, 1.61 to 2.08). A significant association was also observed between COMPLEX score and hospital readmission after adjustment for age, sex, case-mix, and disease severity (adjusted odds ratio, 1.31; 95% confidence interval, 1.20 to 1.44). When COMPLEX was added to case-mix and disease severity in a model for predicting hospital charges, the percentage of variation in hospital charges explained by the model increased from 25% to 38%. These findings demonstrate the important contribution of disease complexity to the analysis of outcome of medical care and utilization of resources. Outcome or reimbursement models that do not incorporate disease complexity may negatively affect institutions with a high proportion of patients who have complex conditions.


Effect of megestrol acetate on the human pituitary-adrenal axis. A few previous reports have suggested that megestrol acetate, a synthetic progestational agent frequently used as an antineoplastic drug, suppresses serum cortisol concentrations in humans. To explore this concept further, we prospectively performed several measurements of the pituitary-adrenal axis in patients receiving megestrol acetate (160 or 800 mg/day). The data from these evaluations demonstrate that megestrol acetate reversibly decreases serum cortisol concentrations in humans and that this effect seems to originate from a suppression of the pituitary-adrenal axis. Additional studies should be conducted to determine the implications of the low levels of serum cortisol.


Ciprofloxacin versus trimethoprim-sulfamethoxazole: treatment of community-acquired urinary tract infections in a prospective, controlled, double-blind comparison. In this study, we determined the safety and efficacy of the treatment of adults with urinary tract infection with ciprofloxacin hydrochloride (250 mg twice daily for 10 days) in comparison with trimethoprim-sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily for 10 days). Patients with signs and symptoms of urinary tract infection were randomized to receive ciprofloxacin (98 women and 5 men) or trimethoprim-sulfamethoxazole (92 women and 8 men). The success rate of therapy was 91% for both treatment arms of the study. Among seven failures after ciprofloxacin therapy, three were due to relapse of infection and two to side effects that necessitated a change in medication; in addition, two patients had persistent symptoms and required hospitalization. Among the six failures associated with trimethoprim-sulfamethoxazole therapy, four were due to relapse, one to persistence of infection, and one to a side effect that necessitated a change in medication. Among the patients treated with trimethoprim-sulfamethoxazole, 32% had mild or moderate adverse reactions; in comparison, 17% of the ciprofloxacin-treated patients had adverse reactions (P = 0.026). For the treatment of urinary tract infection in adult patients in this study, ciprofloxacin and trimethoprim-sulfamethoxazole were equally effective, but ciprofloxacin was associated with fewer adverse reactions.


Measurement of small bowel and colonic transit: indications and methods. In this article, we review the currently available techniques for measuring small intestinal and colonic transit. In addition, we describe the characteristics of an ideal test that provided the rationale for the development and validation of a gastrointestinal and colonic transit test at the Mayo Clinic. This new technique assesses regional transit of solid radiolabeled particles of the same size through the entire digestive tract and provides further insights into motor physiologic processes of the gut. By means of a delayed-release methacrylate-coated capsule, isotopically labeled pellets are delivered to the colon as a single bolus; thereby, dispersion of isotope throughout the small bowel is avoided because of the gradual emptying of chyme from the stomach. Similar pellets labeled with a different isotope can be used to assess gastric and small bowel transit. These new methods for measuring transit have also led to insights into the pathogenesis of unexplained gastrointestinal symptoms and disease states. Thus, we demonstrated that in healthy subjects, ileocolonic transfer of chyme occurs in boluses; this transfer is impaired in patients with myopathic pseudo-obstruction. The emptying rate of the proximal colon is an important determinant of the pathophysiologic features of colonic disease; thus, colonic transit is delayed in cases of severe idiopathic constipation. In contrast, rapid emptying of the proximal colon influences stool weight in diarrhea-predominant irritable bowel syndrome. An integrated approach for studying gastric, small bowel, and colonic transit by using the same radiolabeled particle provides a useful, clinically applicable method for evaluating gastrointestinal symptoms and for measuring motor function of the entire digestive tract without need for intubation; cost and radiation exposure are acceptable.


Colonic cancer during pregnancy: case report and review of the literature. Colonic cancer during pregnancy is rare. Herein we describe a case of adenocarcinoma of the transverse colon in a 29-year-old pregnant patient. Early diagnosis is difficult because the initial symptoms of colorectal cancer, such as abdominal pain, nausea and vomiting, constipation, and abdominal distention, are often attributed to a normal pregnancy. Management of colonic cancer during pregnancy depends on gestational age and operability of the tumor. Medical and surgical management considerations are discussed.


Understanding vascular ultrasonography.

Understanding vascular ultrasonography. The technology of imaging has progressed rapidly; thus, physicians must stay abreast of the principles of utilization and the interpretation of these new tests. Most of the information about this technology is presented in subspecialty literature that is not readily accessible or easily interpretable by nonspecialists. Herein we review the current literature on vascular ultrasonography and present the information in a simple, practical manner. The safety, utility, and accuracy of the ultrasound devices are delineated for the study of various vascular conditions.


[Infection caused by the human immunodeficiency virus type 1 in prostitutes and risk factors]. Women dedicated to prostitution constitute a group at risk of acquiring the human immunodeficiency virus-1 (HIV-1). This study was designed with the aim of knowing the frequency of this infection in prostitutes and the factors associated to the same. A descriptive transversal study with analytic components including 444 women who voluntarily attended an AIDS prevention center from 1986-1991 was carried out. The HIV-1 antibody test was performed in 440 of the subjects. All the subjects were interrogated on sociodemographic variables and risk of infection. Of the 440 women studied, 24 had HIV-1 antibodies with a global prevalence (1986-1991) of 5.5% with confidence intervals of 3.4, and 7.6% at 95% (CI 95%). During the study period the prevalence remained stable: 6.8% (1986-87), 5.5% (1988), 4.3% (1989) and 4.3% (1990-91). No positive association was found between HIV-1 infection and education, time in prostitution and the use of condoms. HIV-1 infection was strongly associated to the use of drugs, adjusted odds ratio by logistic regression OR = 26.9 (CI 95%: 8.9; 9/1). Positive associations were also observed with greater number of sexual partners and syphilis but these did not reach statistical significance. The percentage of prostitutes who used condoms with more than 33% of their clients increased from 44.5% in 1986-87 to 85.9% in 1990-91. In this study no considerable changes were found with respect to the prevalence of infection by the human immunodeficiency virus-1 in prostitutes in Spain. Similarly, this collective has increased its use of preventive measures although they remain insufficient, indicating that more energetic preventive strategies are necessary. These measures should be particularly active with the group of young prostitutes.


[Incidence of cancer of the breast and the female genital system in the province of Zaragoza, 1975-1984]. Cancer of the breast and female genital organs represents 40% of the tumors found in women. Registers of cancer on a population base constitutes a basic source of information for measuring the incidence of these tumors in the population. The magnitude of cancer of the breast and female genital organs was analyzed in the province of Zaragoza during the period 1975-1984 according to the different geographic areas in the province. The rate of incidence, accumulated incidence and the rate of incidence adjusted by age were calculated. The source of information used was the Register of Cancer of Zaragoza. The rate of incidence observed for these tumors was found to be 84 per 100,000 women/year with breast cancer representing 58% of the cases. The truncated rates were higher than the rates of incidence except for the localization of other genital organs indicating a greater frequency of these tumors at intermediate ages. In Zaragoza, the capital city, an excess of incidence was found for most of the localizations studied. This may be explained by the existence of greater frequency of these tumors in urban areas. In the capital this excess was not observed for unspecified cancer of the uterus. This may be due to the greater precision of diagnosis in the capital than in the rest of the province because of the availability of health care centers. In the province of Zaragoza, cancer of the breast is most frequent than cancer of any of the other female genital organs. The greatest frequency of these neoplasms was found at an intermediate age. In Zaragoza city, a greater frequency of cancer was registered than in the rest of the province. These results are of interest for the proposal of programs for prevention and control.


[Self care of common health disorders: results of a telephone survey of the general population]. Self-care of health problems including self-medication, constitutes the most frequent response to the most common acute symptoms in several studies carried out in other countries. Indeed there are few data concerning the scope of self-care in Spain. A telephone survey was carried out by a questionnaire of response limited to a sample of 660 homes in the city of Barcelona. In each home response was required by only one person between the ages of 15 and 80 on the common symptoms experienced within the previous 30 days and their behavior in response to the same. In 448 homes response was obtained from adults on the habits of self-care or medical consultation in episodes of headache, lumbalgia, colds, diarrhea, fever or dysmenorrhea registered the previous month. The global rate of response was 70% with a higher number of refusals among men. Headache (42.8%), lumbalgia (41.7%) and colds (34.4%) were the most frequent symptoms with self-medication including physical and home remedies being the most common response. Self-care for minor health problems is frequent in the population studied. The type of symptom in addition to age and sex appear to be the most important determining factors in this behavior.


Experimental conditions determine effects of ascorbic acid on reperfusion injury: comparison of tissue damage with hemodynamic parameters in rat isolated hearts. Restoration of coronary blood flow after myocardial ischemia is always a matter of urgency, but the resulting surgical or drug-induced reperfusion of ischemic tissue is often associated with myocardial functional disturbances and tissue injury. The present study was carried out to select experimental conditions under which optimal effects of antioxidants can be observed on the adverse effects of reperfusion of ischemic myocardium. The release of lactate dehydrogenase (LDH) and changes in hemodynamic parameters were compared in two models of cardiac reperfusion injury in rat isolated hearts. LDH release from electrically-stimulated hearts perfused under constant flow and with initial (5 min) reperfusion in calcium-free buffer was greater than that from hearts perfused under constant pressure in which ischemia was induced by reduced flow. Combined SOD+catalase was a weak inhibitor of LDH release in both models, ascorbic acid being more potent under constant pressure than under constant flow conditions. A longer ischemic period enhanced the inhibitory effect of ascorbate. Contractility and ventricular end-diastolic pressure recovered slowly during perfusion under constant flow and brief calcium removal, but remained unphysiological under constant pressure. SOD+catalase had no effect on hemodynamic parameters. Ascorbic acid exacerbated ischemia+reperfusion-induced changes in contractility, ventricular pressure, heart rate and coronary flow under constant pressure, but facilitated recovery of contractility on reperfusion under constant flow and brief calcium removal. In studies on antioxidants, different experimental conditions appear to be necessary to observe beneficial effects on tissue damage on the one hand and on hemodynamics on the other. Mild to moderate ischemia, with sustained pacemaker activity, appears to be the condition under which antioxidants provide hemodynamic improvement. In isolated rat hearts, biochemical parameters of tissue damage may be misleading for the effects of antioxidants.


In vitro inhibition of adenosine deaminase by flavonoids and related compounds. New insight into the mechanism of action of plant phenolics. The effects of 20 flavonoids, anthocyanes and other phenolic compounds of plant origin have been tested in vitro for their inhibitory effect on the enzyme adenosine deaminase (ADA). Significant effects were obtained with most compounds at concentrations between 0.0001 and 0.1 mg/mI. Thus, plant phenolics can be considered as natural ADA enzyme inhibitors. It is assumed that they also increase the actual adenosine (Ado) concentration in vivo. This may explain many of the pharmacological activities of these compounds on a molecular basis.


Comparison of vasodilator effects on human middle cerebral artery constriction induced by vasoconstrictors or activated platelets. Experiments were performed on de-endothelized perfused human middle cerebral artery constricted with noradrenaline, serotonin, prostaglandin F2 alpha and collagen-aggregated platelets, all of which provoked similar vasoconstriction; however, the ability of dipyridamole, prostacyclin and nifedipine to reduce the constriction was significantly less marked when induced by activated platelets. The decrease in drug antispasmatic effects was less marked for nifedipine than for other vasodilators. It was suggested that the resistance of platelet-induced vasoconstriction to vasodilator action depends on platelets ability to release several vasoactive substances simultaneously.


Dehalogenation and N-dealkylation of chlorpromazine as revealed by plasma concentrations of metabolites in a population of chronically medicated schizophrenics. Dehalogenaton and N-demethylation of chlorpromazine (CPZ) were studied in twelve psychotic inpatients orally treated for four weeks with a daily CPZ dose of 6.4 +/- 1.1 (S.E.) mg/kg body weight (1.5-14.1, range). Weekly drug and metabolite plasma concentrations were measured by a gas liquid chromatography-nitrogen/phosphorus detector method (GLC/NPD). Plasma concentrations of the parent compound CPZ, of the dehalogenated metabolite promazine (PZ) and of the N-dealkylated metabolites N-monodemethylated chlorpromazine (CPZ-nor1) and N-didemethylated chlorpromazine (CPZ-nor2) had already reached a steady state by the end of the first week of treatment. During the entire treatment period the major plasma component was found to be PZ. Patients (N = 6) on a low dose regimen (3.7 +/- 0.2 mg/kg body weight) showed significantly lower mean plasma concentrations of CPZ and nor metabolites than patients (N = 6) on a higher dose regimen (8.6 +/- 0.7 mg/kg body weight). PZ mean plasma concentrations, however, were not significantly different in the two groups of patients, indicating that the yield of the CPZ dechlorination pathway, as opposed to that of the N-demethylation pathway, was already maximal at the CPZ concentrations attained under the low dose regimen. Male patients (N = 5) exhibited significantly higher mean PZ plasma concentrations over the 4 week period of the study than female patients (N = 7).


Pethidine pharmacokinetics after intramuscular dose: a comparison in Caucasian, Chinese and Nepalese patients. The pharmacokinetics of pethidine after a single intramuscular injection were studied in 30 male patients of Caucasian, Chinese and Nepalese extraction. There were no significant differences between the three ethnic groups in the mean time for maximum absorption (tmax) and peak plasma concentration (Cmax) of pethidine. The mean (+/- S.D.) elimination half life (t1/2) of pethidine was shorter in Caucasians (4.5 +/- 1.3 h) compared with Nepalese (6.3 +/- 1.6 h) and Chinese (8.1 +/- 3.1 h) (p < 0.01). The plasma clearance of pethidine was greater in Caucasians (14.2 +/- 4.8 ml.min-1.kg-1) than in Nepalese (12.6 +/- 2.9 ml.min-1.kg-1) and Chinese (10.0 +/- 2.9 ml.min-1.kg-1) (p < 0.05); yet the apparent renal clearance was similar (64.1 +/- 22.9, 86.7 +/- 44.5 and 61.4 +/- 30.1 ml.min-1.kg-1, respectively, for the Chinese (n = 6), Caucasian (n = 6) and Nepalese (n = 9) patients). No apparent ethnic differences were found in the tmax and Cmax of norpethidine which emerged as the major metabolite in the plasma in the three races. An apparently higher area under plasma concentration-time curve (AUC infinity [symbol: see text]) and longer elimination t1/2 of the metabolite were observed in the two Asian patient groups. It appears that both the Chinese and Indian groups did not eliminate pethidine as effectively as the Caucasians after a single intramuscular injection, which may be the result of interethnic variability in the metabolism of pethidine. Caution may be required on multiple dosing of pethidine in Asian patients due to the possible accumulation of the parent drug and its toxic metabolite, norpethidine.


Functional and non-functional liver blood flow in patients with liver cirrhosis measured by indocyanine green. Indocyanine green administration was used in a group of ten patients with liver cirrhosis with portal hypertension to estimate hepatic extraction, liver blood flow and the degree of blood shunting. Extraction coefficients obtained by the hepatic catheterization were well correlated with the pharmacokinetic method. Values of the total liver blood flow measured by the classical method based on Fick's principle were always higher than those evaluated by the pharmacokinetic analysis estimating the functional liver blood flow only. Estimates of the degree of shunting varied between 32.0-78.9% of the total liver blood flow. A statistically significant correlation (r = 0.79) was found between the percentage of the functional fraction of the total liver blood flow and albuminemia. It is suggested that in liver cirrhosis with portal hypertension the reduction of the functional fraction of total liver blood flow is combined with partial impairment of hepatic cell metabolism in the remaining functional areas of the liver. In such a case neither the "intact" nor the "sick hepatocyte" hypotheses are appropriate in their strict sense for the interpretation of the findings.


Calcium modulators and the gut: an update. Calcium is critical for stimulus-secretion coupling at the cellular level in the gut. Recent experimental evidence suggests a role for calcium modulating compounds in vivo. Specifically, calcium channel blocking drugs of the dihydropyridine class exert potent anti-secretory and anti-stress ulcer effects. However, these same compounds exacerbate ethanol-induced gastric mucosal injury. Calcium chelating compounds, including EDTA and EGTA, reduce both forms of experimental ulcer as well as gastric secretion. Mechanisms underlying the gastroprotective effects of calcium modulating agents include neural, hormonal, peptide and enzymatic activity and these compounds represent a viable avenue of research for future therapeutic development.


Hepatic endoplasmic reticulum storage diseases. Endoplasmic Reticulum Storage Diseases (ERSD) represent a novel group of inborn errors of metabolism affecting secretory proteins and resulting in hepatocytic storage and plasma deficiency of the corresponding protein. The hepatocellular storage is due to a molecular abnormality hindering the translocation of the abnormal protein from the rough (RER) to the smooth endoplasmic reticulum (SER). The molecular abnormality is genetically determined; hence it is hereditary, congenital, familial and permanent. The storage is selective and exclusive for the mutant protein and predisposes to the development of chronic cryptogenic liver disease. ERSD include alpha-1-antitrypsin deficiency, fibrinogen storage and alpha-1-antichymotrypsin deficiency. Basically, the diagnosis of ERSD is a morphological one: immunohistochemistry and electron microscopy are essential tools for their identification.


Liver changes in reactive haemophagocytic syndrome. Hepatomegaly and deranged liver functions are common findings in reactive haemophagocytic syndrome (RHS). We report the findings of 12 fatal cases of RHS in which histological materials of the liver are available for study. The underlying diseases of these patients included lymphoma/leukaemia (6 cases), disseminated undifferentiated carcinoma of the ovary (1 case), disseminated nasopharyngeal carcinoma complicated by tuberculosis (1 case), adenovirus pneumonia (1 case), pneumococcal pneumonia (1 case), typhoid fever (1 case), and possible drug intoxication (1 case). Ten patients had involvement of the liver by the underlying disease process which contributed to the marked hepatic derangement. Non-specific reactive hepatitis, sinusoidal dilatation and steatosis resulting from systemic or local effects of the associated diseases and the haemophagocytosis also added to the high incidence of liver abnormalities. A diffuse Kupffer cell hyperplasia with haemophagocytosis is characteristic of the syndrome, as all the cases showed increased numbers of bland-looking histiocytes within the hepatic sinusoids and haemophagocytosis which was moderate to marked in 8 cases and mild in 4. Thus the finding of Kupffer cell hyperplasia with prominent haemophagocytosis in liver biopsy is indicative of an element of RHS and warrants clinical monitoring. Differential diagnoses of haemophagocytosis in liver are also discussed.


Vitamin A abuse: development of cirrhosis despite cessation of vitamin A. A six-year clinical and histopathologic follow-up. We report the case of a 35-year-old man who contracted vitamin A-induced liver cirrhosis. Five years before, he had been investigated for vitamin A-induced non-cirrhotic portal hypertension. In this case, the clinical and histopathologic evolution from non-cirrhotic portal hypertension to cirrhosis was documented. In spite of the cessation of pharmaceutical vitamin A intake, the disease progressed. Therapy with colchicine and phenobarbital apparently did not influence evolution to cirrhosis. This suggests that vitamin A can trigger largely unknown mechanisms of liver fibrosis which seem to be self-perpetuating.


Analysis of lymphoid follicles in liver of patients with chronic hepatitis C. Using immunohistological methods, we studied the lymphoid follicles in liver biopsy specimens obtained from patients with chronic hepatitis C(CH-C) to determine whether they represented an autoimmune manifestation. In 84 specimens obtained by liver biopsy from 76 patients positive for C-100 antibody, we assessed the presence or absence of lymphoid follicles within the portal areas, and then compared the clinical and immunohistological profiles of the two groups defined on this basis. There were no significant differences in the serological and clinical profiles of the two groups, but the T4:T8 cell ratio within the portal areas differed significantly. A T4:T8 cell ratio > 1.0 was more common in the specimens containing lymphoid follicles. This finding resembled the distribution of T cell subpopulations in the portal areas of patients with autoimmune hepatitis, and suggested that lymphoid follicles may be worth investigating to elucidate the relationship between chronic hepatitis C and autoimmune hepatitis.