[Development and importance of combined organ transplantation]. In 1966, Kelly and Lillehei transplanted a pancreas together with a kidney in a young patient suffering from end-stage diabetic nephropathy. Since this first combined organ transplantation, various organs have been transplanted together: heart-lung (Cooley 1969), liver-kidney (Margreiter 1983), liver-pancreas-stomach-small bowel (Starzl 1983), heart-liver (Starzl, Bahnson 1984), heart-lung-liver (Wallwork, Calne 1986), and liver-small bowel (Grant 1990). Although some of these combined organ transplants will only occasionally be necessary, some others such as kidney-pancreas, heart-lung, or liver-kidney have already gained clinical relevance.


[Developments in the field of transplantation of bones and cartilage]. Experience with more than 2000 allogenic bone and cartilage transplantations between 1975 and 1990 confirms the indication for implanting this material in a wide range of applications. Especially in reconstructive surgery and after tumor resection the use of this procedure is increasing. The main advantage is the almost unlimited availability and the possibility of en bloc and orthotopic administration. Even with extensive defects, we saw satisfying results. An overall complication rate of 4.5% is low, and infection is the complication most frequently seen. Primary consolidation was seen in over 80% on average after 17 weeks.


[Organ transplantation, development and perspectives of the legal status]. The FRG has no transplantation law as most other European countries do. A model of agreement is practised which is derived from fundamental principles, i.e., a personal right outlasting death and the agreement of the next of kin for organ removal. The paper favours a legal regulation that resolves the difference between a model of presumed consent on the hand and a model of agreement on the other hand, and advocates informing the next of kin, who can then object as representatives of the deceased.


[Organ donation to hospitals not specializing in transplantation]. The necessary and possible rate of transplantations is limited by the insufficient availability of donor organs. In the FRG, only 36% of all hospitals (transplantation centers excluded) are active in postmortem organ donation. In only 57% are other organs than the kidneys (liver, pancreas, heart, lung) explanted. The main problems do not derive primarily from structural difficulties (no intensive care unit, limited capacity of operation room or staff), but from an insufficient degree of cooperation with the transplantation center and an uncertain legal position. Possible solutions to the problem (transplantation coordinator, legal regulation) are discussed.


[Anatomic-functional viewpoints in treatment of injuries of the spine]. The ligaments of the lumbar motion segment acting together constitute primarily a holistic system responsible for every static and dynamic phase of segmental control. Taking into account the elastic tension produced by the intervertebral disks and the partial constraint imposed by the vertebral joints, the lumbar motion segment may be regarded as a particular form of ligamentous mechanism. Its fiber bundles, which are for the most part nonelastic, usually make a contribution to segmental movement, although the extent of their involvement depends upon how far that movement has progressed.


[Classification and surgical indications in spinal injuries]. A simple and precise classification of vertebral injuries is the key to correct treatment, depending on the differentiation of temporary or permanent instability. This aim is met by a classification presented by Magerl, Harms, Gertzbein et al. It is based on three main types according to the pathomechanics consisting of several subgroups with morphological aspects. In the neurological field, indications for surgical treatment are absolute after a free interval or rapid rising of the level of lesion. In vertebral injuries operative indications are found in possibly permanent instabilities or kyphotic deformities. Some indications depend on the patient himself, especially age and psychosis.


[Neurologic disorders after injuries of the spine]. The most frequent result of a cervical or dorsal spinal cord injury is a transverse lesion with quadriplegia or paraplegia, total loss of bladder and bowel control, breakdown of sympathetic function, and complete loss of sensory function. Partial cord lesion leading to central/anterior/posterior or Brown-Séquard syndromes are rare. Progressive clinical signs of cord damage are only rarely due to sub- or epidural hematoma or edema; in nearly all cases, they point to a persistent instability of the spine.


[Indications, choice of procedure and results of conservative therapy of spinal injuries]. For conservative treatment of injuries of the cervical spine, two different methods are available: The HALO fixator and the collar. The choice depends on the kind and extension of the injury. Stable thoracic and lumbar vertebral fractures are treated in a conservative functional way in order to strengthen the muscular apparatus. Three-point-fixation with a brace is not necessary. Functional therapeutic methods can also be applied in the case of instable fractures if they are not operable. During a rigid confinement to bed, the postural reduction by increasing lordosis has turned out to be the treatment of choice. As an essential measure the patient has to take part in a "backschool" with postural exercises for the daily life.


[Surgical treatment of injuries of the upper cervical spine]. The surgical treatment of instabilities of the upper cervical spine requires the use of differentiated procedures if physiological anatomy is to be largely restored. Successful procedures are diagonal screw fixation of the axis from the anterolateral aspect in the case of odontoid fractures Anderson type II and III (high type), transpedicular screw osteosynthesis of C2 in hangman's fractures, and transarticular screw fixation of C1/2 with posterior fusion for atlantoaxial instabilities. In occipito-atlantal trauma occipitoatlantoaxial fusion is required.


[Surgical treatment of injuries of the lower cervical spine]. Fractures at the C3-C7 level present primarily diagnostic problems. If instability is certain, therapy is simple: using an image intensifier, dislocation is reduced under general anesthesia and relaxation, and later secured by anterior interbody fusion. Compound fractures demand total resection of the vertebral body and its (autologous) replacement. Plating of the adjacent segments is mandatory. Neurological function after a dysfunction free interval may be fully restored if primary reduction and stabilization are achieved. Postponed treatment is less useful, but may also improve neurological deficits.


[Dorsal stabilization of thoracic and lumbar vertebral injuries]. The concept of angle-stable transpedicular screw-rod instrumentation, realized in the different models of internal spine fixators with intrinsic stability, allows secure stabilization of the most unstable fracture patterns, limited-segment fixation and three-dimensional reduction of the fragments. The canal diameter is improved by ligamentotaxis and, if necessary, by hemilaminectomy and fragment impaction. Late collapse of the upper disk space must be anticipated and may lead to some increase in kyphotic deformity. The situations are identified where an additional formal interbody fusion is recommended.


[Ventral stabilization of thoracic and lumbar spinal injuries]. An isolated ventral approach to the thoracal or lumbar spine seems sufficient in special burst fractures (type A2/3) or older compression fractures. The most effective ventral decompression of the spinal cord is followed by the fusion of the ventral body. Ventral plate instrumentation avoid dislocations of the interposed bone transplants. Our own clinical results are demonstrated.


[Indications and technique of combined dorso-ventral stabilization of the spine]. In delayed treatment of fracture dislocations or luxation of the cervical spine, combined dorsoventral operative treatment is necessary. After anatomical reduction from dorsal, stabilization is performed from ventral using autologous bone grafting and a plate. The injured intervertebral disk is removed to avoid protrusion. At the thoracolumbar spine this technique includes ventral bone grafting with a corticocancellous sandwich block and dorsal transpedicular fixation using an internal fixator system. This simplifies removal of the implant.


[Complications in surgical management of spinal injuries]. Operative treatment of spinal injuries requires an accurate surgical technique and biochemical know-how to avoid complications due to mistakes in device handling, operative technique, and indication. Device failures are caused by loosening of locking clamps or fracture of Schanz screws, followed by loss of angle stability and early loss of reduction. Maldisplacement of pedicle screws may involve irritation of neurovascular structures or loss of correction as well as insufficient transpedicular bone reduction and bone grafting. In burst fractures with destruction of the vertebral body and loose canal fragments, the posterior approach is less efficient than a combined procedure.


[Spinal injuries in polytrauma patients]. In about 30% of all multiple trauma patients, spinal injuries are found. The diagnostic and therapeutic procedure follows the five-step program for acute multiple trauma patients. Only in cases of open lesions or secondary deterioration of neurologic symptoms do we indicate an urgent operative treatment in step 3. All other patients should only be operated on after normalization of vital functions in step 5. The high risk for further complications is represented by the combination of thoracic spine lesions and lung contusion.


[New classification of practical surgical performance]. The commission was founded in April 1990 by the Professional Association of German Surgeons to devise a new evaluation of surgical practice, especially operative procedures. The catalogue uses time as its first approach, but also gives other qualities for surgical work. The given time values for some standard operations are backed up by statistical calculation of well-documented times in three different surgical units.


[Performance structure and performance documentation in ambulatory surgery]. Between January and September 1991, the average turnover of outpatient surgical centers in the Palatinate medical district was DM 100,000. A total 14.5% of this amount was costs of operation. Hourly charges are DM 300-600. For economical reasons, operations which do not cover these costs cannot be done.


[Test procedures and social welfare regulation--an assessment of the performance of surgery?]. Test and appeal proceedings in the self-administrating health insurance companies, according to the reform of the public health law of 1.1.1989 (SGB V) Welfare tribunal, namely, state welfare tribunal, and Federal welfare tribunal and its composition and functions. The responsibilities and rights of honorary medical judges in the welfare jurisdiction. A discussion of a possible discrepancy between the demand for economic behavior of the doctor involved in the health-care and the keeping of an up-to-date scientific standard (evaluation). Possibilities of putting medical-scientific arguments into the process of searching a verdict. Perspectives.


[Assessing performance in surgical research and teaching]. The clinical registration of performance mainly serves to ascertain the staff plan. The measure of teaching and research is not quality but quantity in hours. For teaching, the time of lectures is taken with an added factor of 1.5 for lectures and 0.5 for practical training for preparation. For research it is customary to take an index of 10% of yearly working hours of all physicians working in medical care. Therefore, in an university hospital approximately 25% of the staff plan accounts for research and teaching.


[Assessing performance and reimbursement in "emergency ambulatory surgery" from the viewpoint of hospital administration]. 1) Definition of emergency and its payment is given, as well as the legal background of charging by the hospital. 2) The total work on outpatient departments of a central hospital is shown, especially that of surgical emergency cases. 3) The reasons for documentation of actual work are discussed, by whom and how, and the problems arising. 4) The payment for patients with social insurance is considered in respect of the official fees and the cost-averaging of the hospital as a nonprofit organisation.


[Assessing performance in new German states]. With the disbandment of the G.D.R., the following also ended: a) the central registration of all inpatients, which allowed statements to be made about hospital morbidity; b) the central tumor documentation, in which all tumor patients were registered up to 5 years after first treatment. Data relating to the clinic are being set up. We present a proven program of operating statistics set up by the working group for quality assurance.


[What is the value of anorectal manometry today?]. Since it was first introduced into clinical investigations in 1960 by M. Schuster, anorectal electromanometry has become one of the most-important methods to evaluate anorectal continence. Electromanometry now is a wide-spread, safe and simple screening method to analyze chronic constipation and to control the results of proctologic surgery. Its most important parameters are the anorectal pressure profile, the squeezing pressure profile, the adaptation reaction, the internal sphincter relaxation, and the rectal sphincteric reflex to the external anal sphincter. Wherever proctology is performed, electromanometry and electromyography of the external sphincter muscle should be done.


[Three-dimensional evaluation of computerized tomography images of pediatric fractures]. Three-dimensional reconstruction from CT was performed in pediatric patients after joint, facial, or spinal injury. Three-dimensional reconstruction proved particularly helpful in children with reduced post-trauma joint mobility. Free fragments, joint dislocations, and articulate surface defects were demonstrated. Here, as well as in facial and spinal injury, three-dimensional CT may facilitate and augment the understanding of two-dimensional displays.


[Surgical indications of funnel chest].

[Surgical indications of funnel chest]. Pathological findings in ECG represent indications for operation only if they are accompanied by subjective complaints and psychogenic problems. The extent of the abnormality usually does not correlate with the patient's complaints. Disappearance of such complaints after surgery does not be considered as a sign of successful surgery. Even a deep funnel chest is not necessarily an indication for operation if the patient has no complaints and can manage the situation. A flat funnel chest should not be operated on. The operation can be performed in patients between 4 and 24 years of age. If severe associated anomalies require operation as well, the choice is not for correction of the funnel chest first.


[1992 tumor classification/developments]. Surgical oncology must consider some new international and national publications: 1. New fascicles of the 2nd edition of the WHO International Histological Classification of Tumors. 2. The 1992 revision of the 4th edition of the UICC TNM Classification and of the UICC TNM Atlas. 3. The TNM Supplement 1992/93 (UICC), which includes, among other things, explanatory notes for uniform use, proposals for further development, and a compilation of prognostic factors other than TNM and R to be considered in clinical studies. 4. The fully revised and enlarged tumor documentation system of the Working Group of German Cancer Centers (Arbeitsgemeinschaft Deutscher Tumorzentren).


[Techniques and experiences in funnel chest operations]. Hegemann's technique of funnel chest correction using transsternal metal bar stabilization was adapted from the method published by Sulamaa and coworkers in 1958. Until the end of 1991, about 2400 chest wall corrections were performed in our department, more than 2000 of them using modifications of the original method. The principles of external chest wall measurement, our classification method, and the current operative modifications are described. In long-term follow-up examinations less than 3% recurrences should be possible.


[Experiences with funnel and pigeon chest correction with the modified Ravitch method]. We present 843 operations of chest wall deformities performed from 1971 to 1991 using the modified technique of Ravitch. We discuss the indication for operation, the perioperative management, and the early and late complications. In 54% we found a good result, and in up to 91% an acceptable one. In 9%, the result was poor. Furthermore we report our interview of 184 patients about their opinion on the perioperative situation and the result.


[Skin culture--keratinocytes].

[Skin culture--keratinocytes]. Our efforts to cultivate keratinocytes and to use cultivated epidermal grafts which are then transplanted onto deep second- and third-degree burns and donor sites date back in 1987. Our laboratory is now able to provide our intensive care unit with cultured epidermografts as a routine procedure. Furthermore, we have developed a simple method for cryopreservation of cultured human epidermal keratinocytes. So in 1980, a skin bank was set up which provides us with cryopreserved allogenic cultured epidermis. Indications, operative management, and results are presented and accompanied by typical clinical cases.


[Myocutaneous flaps for reconstruction of large tissue defects of the trunk]. Large defects in the thorax and abdominal wall require a stable reconstruction. The use of muscle flaps offers many advantages: 1. Anatomically constant vascular patterns with a good blood circulation of the overlying fascia and skin. 2. Stable reconstruction of the whole wall as well as effective substitution of infected or irradiated tissue. Clinical cases and technical details are presented.


[Progress in the use of tissue expanders for defect closure of the body surface--experimental principles]. The principle of soft tissue expansion has been applied in widespread techniques in the field of plastic and reconstructive surgery since Radovan (1976) presented a method in which silicone expanders were subcutaneously implanted. Many experimental and clinical reports have been published since then, dealing particularly with the histomorphology, vascularization, and pathophysiology of expanded skin as well as with surgical techniques. Our own study intends to identify the effects of tissue expanders on the biomechanical, biochemical, and morphological qualities of expanded skin, and to determine the influence of pharmacological therapy during expansion.


[Progress in the use of tissue expanders for defect closure of the body surface--clinical aspects]. The time-honored principle of tissue expansion has only gained clinical relevance in the past 10 years. Its advantages are that sound tissue of equal texture, color, and quality adjacent to a defect or scarred area can be transposed to treat defects without producing further scars. Especially in the hair covered part of the head, but also in reconstruction of the female breast after mastectomy, in large scars from burns, or in large pigmented nevi, tissue expansion has to be reliable. Only when used in extremities does a higher rate of complication demand a certain restriction.


[Anatomy of the flexor and extensor tendons]. The flexor and extensor tendons of the hand are equipped with special gliding mechanisms. Blood supply is provided via paratenon and in the fibro-osseous tunnel via mesotenon. The tendons show different amplitudes of active excursion which decrease distally. The function of flexors and extensors is coordinated and supplemented by reflexes and by the correlating relay system of lumbricals. Activation of extensor aponeurosis results via the so-called extrinsic and intrinsic system, where the IP joints are additionally linked functionally by the oblique retinacular ligaments of Landsmeer. At the level of the MP joint, the dorsal aponeuroses are furthermore linked by oblique fibrous structures, which lead to functional impairment of the neighboring MP joints in maximal flexion and extension of a finger due to an effect of tenodesis (so-called quadriga phenomenon).


[Progress in primary management of the extensor tendon]. Extensor tendon injuries are conventionally treated by immobilizing the involved digit in an extended position for 4-6 weeks, followed by active mobilization. This regimen is compared with early controlled active mobilization with dynamic splintage. The improved results are demonstrated.


[Surgical indications--who determines the limits?]. The indication for revascularization in claudicants is determined by the complaints of the patients and the risk of the procedure. Instead of good long-term results, a possible more rapid progression of arteriosclerosis should be considered after a vascular procedure. In limb-threatening ischemia, a vascular intervention is possible in up to 95% of cases. In the case of poor prognosis, the patient himself decides whether or not amputation is the primary treatment. The consent of the patient is valid only when there is no possibility of revascularization as determined by objective criteria, or when the patient chooses amputation primarily. Therefore, the indication for amputation is not limited by the competence of a single surgeon.


[Progress in arterial reconstruction of the upper and lower leg--percutaneous transluminal procedures]. Conventional PTA represents the state of the art method for treating arterial occlusive disease of the leg arteries. Rotational angioplasty is an improvement over conventional PTA in treating long proximal occlusions of the SFA. It can also be used as a second treatment in cases that were primarily unsuccessful with PTA, with an initial success of 59%. Stent implantation is mainly indicated in limb-threatening ischemia. It also permits successful management of an aneurysm as a late and rare complication correlated to PTA. Atherectomy produces better initial success in eccentric stenotic lesions than PTA. It also permits the successful management of obstructive intimal flaps after angioplasty. The new techniques only improve on PTA, if they are used in the differential therapeutic strategy mentioned above.


[17 years experience with saphenous vein in situ bypass]. Long-term results of femorodistal in situ vein bypasses depend on the quality of the outflow tract. The cumulative patency of in situ bypasses to the third popliteal segment with a three-vessel runoff is 82.2% at 5 years, compared to 56% for bypasses to a single tibial artery. Immediate occlusions during the first 3 postoperative days are fatal for long-term permeability. After successful revision, the cumulative patency is only 39.5% at 5 years, compared to 64.9% for the whole group. A prospective randomized trial could show that an adjunct intra-arterial treatment with PGE 1 over 10 days can statistically significantly reduce the rate of fatal immediate occlusions.


[Surgery of perforant veins].

[Surgery of perforant veins]. The eradication of incompetent perforating veins combined with fasciotomy is a successful concept in the therapy of leg ulcers. Both can be achieved by endoscopy. Under endoscopic control, the medial, anterior, and posterior groups of perforating veins can be prepared at different levels and dissected after bipolar coagulation. Under endoscopic control the superficial fasciae of the leg are split.


[Para-tibial fasciotomy].

[Para-tibial fasciotomy]. Fifty patients with large venous ulcers have been surgically treated by paratibial fasciotomy plus dissection of incompetent perforating veins since January 1990. The operative mortality rate was 0.0%. A single significant complication (hematoma) required a secondary operation. Forty-eight ulcers healed within 8 weeks completely. In two cases, the venous ulcers recurred. Healing could be obtained under conservative treatment. Our results suggest that paratibial fasciotomy is the method of choice for the treatment of chronic deep venous insufficiency stage III after unsuccessful conservative treatment.


[Extended resection in tumor surgery of the lung]. Out of 3823 prospectively followed patients with bronchial carcinoma, 1404 were operated upon. After radical resection, prognoses for 5-year survival in T3 and T4 tumors was 22% and 10%, respectively. Resection was carried out in 190 T3 tumors and 202 T4 tumors. Indications are based on existing or imminent complications in advanced locoregional tumor growth. Surgery must be decided on as palliative treatment in a high number of cases. This kind of surgical tumor management requires sophisticated techniques.


[Complications in surgery of varicose veins]. Complications after varicose vein operations are rare. Minor complications such as lesions of cutaneous nerves, e.g. saphenus or sural nerve, hematomas, lymphogenic fistulas or postoperative edemas are reported and can be treated conservatively. Major complications like injuries to the femoral vein must be considered in about 1% and injuries to the femoral arteries in 0.02%. This means, for example, for the FRG 50 serious venous and 10 serious arterial injuries with the possibility of limb loss/year. Deep vein thrombosis and pulmonal infarction occurred in 3300 of our varicose vein operations, in 0.15% and 0.06% respectively. Knowledge of vascular surgery and anatomy with all variations of the venous systems are mandatory for varicose vein surgery.


[Esthetic aspects of varicose vein surgery]. In addition to relieving variceal pain and preventing potential ulcer formation, the goal of variceal surgery is also a cosmetic one. The problems faced at surgery include scars, hematomas, and residual and recurrent varicose veins. Intraoperative interventions and surgical techniques to prevent these are presented here.


[Thoracic injuries--when is use of the heart-lung machine necessary?]. Most patients with severe blunt or penetrating thoracic injuries die early after the accident (approximately 50%). The majority of those who reach an emergency department (approximately 80-85%) can therefore be treated initially with intensive observation (following drainage and/or intubation). If clinical deterioration due to continuous bleeding or progressive hemodynamic and respiratory problems occurs, however, urgent surgical intervention is indicated. Transfer of those critical patients to specialized hospitals often becomes dangerous because of time loss, and it is unnecessary as major equipment (e.g., extracorporeal circulation) is demanded only in the minority of operations.


[Surgery of infiltrating tumors of the pericardium and myocardium]. Tumors arising from different organs may infiltrate the peri- and myocardium. Complete resections and defect repairs are possible using a variety of operating techniques. Although longterm survival rates of those patients with advanced tumor stages are unfavorable, individuals can be cured. Almost always, the patient's condition can symptomatically be improved by reduction of cardiac tamponade, venous congestion, and dyspnoe.


[Constrictive pericarditis--surgery with or without heart-lung machine?]. In patients suffering from constrictive pericarditis, the best hemodynamic results can be achieved by total mobilization of the heart and complete resection of the pericardium. Among 72 patients operated upon from 1969 to 1991, the use of extracorporeal circulation became necessary only twice. Therefore, we suggest the use of heart lung machine only in patients with bad myocardial function or in patients who need correction of additional diseases. Routine use of extracorporeal circulation is not mandatory.


[Regional hyperthermic perfusion--therapeutic concept and long term results]. Isolation perfusion was introduced in 1957 by Creech and Krementz for treatment of malignancies of the limbs. The isolation of the extremity from the body circulation allows a high concentration of cytostatics without systemic side effects. Regionally metastasizing malignant melanomas with satellites, intransit or lymph node metastases are generally accepted indications for isolation perfusion. There is still controversy about elective adjuvant perfusion in stage I melanoma. Prospective randomized studies must clarify this situation. Krementz demonstrated long-term survival rates between 29% and 52%. Our group of patients with satellites and intransit metastases shows a 10-year survival rate of 48%. Considering the historical data of our patients without perfusion and with a 10-year survival of 11%, there is a highly significant statistical difference. In conclusion, isolation perfusion is the therapy of choice in patients with locally metastasized malignant melanoma of the limbs.


[Multivisceral and extended resection in tumor surgery--esophageal cancer]. Extended resections are strategies in the surgical treatment of cancer which provide large oncological safety margins: these are of particular relevance in the neck in view of the close anatomical relation of the major cervical organs. In the region of the distal esophagus, extended resections may be a reasonable alternative to conservative approaches even when only intended as a palliative treatment. The removal of metastases does not influence the outcome in patients with esophageal carcinoma, in contrast to simultaneous surgery of other malignancies.


[Non-cardiac complications after open heart surgery]. The most important complications after open heart surgery are neurological, gastrointestinal (GI), and renal complications. New neurological deficits may occur in 1%, and neuropsychiatric alterations may be observed in 40%. In 6% peripheral neurological damage occurs. Endoscopy in all patients whose clinical history suggests signs of gastric ulcer disease, and perioperative H2-blocking therapy are effective in reducing severe GI bleeding to 1%. Small-bowel ischemia is a rare but high risk complication. Hepatitis due to homologous blood transfusion is as low as 2%-3%. Postoperative renal insufficiency occurs in 1% needing hemodialysis. Good hemodynamic condition during and after surgery reduces the frequency of extracardiac complications as well as the reduction of use of homologous blood transfusions for open heart surgery.


[Priority of interventions: myocardial revascularization--heart valve replacement--carotid endarterectomy--tumor surgery]. The simultaneous treatment of heart and concomitant disease is now possible in many cases, and is usual in heart-valve disease with coexistent coronary artery disease. If in addition to the heart disease, a carotid artery stenosis exists, a simultaneous operation is preferred in our clinic using the aid of extracorporeal circulation (with hypothermia, hemodilution, and full heparinization). When both heart disease that is in need of operation and a malignant tumor are present, the clinical strategy can be dependent only on the prognosis of the malignant illness.


[Acute pulmonary embolism--are vena cava interruption procedures and extracorporeal circulation always necessary?]. Between 1983 und 1991, emergency pulmonary embolectomy with the aid of extracorporeal circulation was performed in 13 patients. Ten patients were in class IV according to Greenfield, seven came into the operating theater with external cardiac massage. The 30-day mortality was 46%. In the same period, 15 venous interruption procedures were performed (three Adams de Weese Clip, ten Greenfield-Filter, and two femoral vein ligations). Eight times the venous interruption procedure was done prophylactically. The acute pulmonary embolism of class III and IV according to Greenfield is an indication for lytic therapy. We operate only if there is a contraindication to lytic therapy or if there is deterioration of the clinical state.


[Reconstruction of atrioventricular valves in partial and total atrioventricular canal]. Among the anomalies of endocardial cushion defects, the partial (PCAVC) and common (CCAVC) AV canal present a special challenge to the cardiac surgeon. In particular, reconstruction of the AV valve can be difficult in CCAVC because of morphologic variations. Within 17 years, 383 patients with this disease were operated on. Early mortality of PCAVC is below 1%, and of CCAVC below 5%. A total of 90% of the survivors are in NYHA class I. In general, plastic reconstruction of the mitral valve is performed. The risk of reoperation for recurrent mitral incompetence in both groups is between 7% and 10%. Mitral valve replacement is a rare event (1.5%).


[Reconstruction of the subvalvular mitral valve tissue in mechanical mitral valve replacement]. Since it was demonstrated in experimental studies that preservation of the subvalvular mitral apparatus is of significance for left ventricular function, it was concluded that in mitral valve replacement complete excision of the mitral valve is disadvantageous for the patient. Clinical experience showed that in patients with mitral regurgitation and large mitral annulus, most of the valvular apparatus can be preserved. In stenotic mitral valve disease, it may be possible to decalcify and mobilize the mitral apparatus and to preserve it. If it is necessary to excise the mitral valve completely, one should think of replacing the chordae tendineae and thus improving postoperative left ventricular function.


[Preservation of the posterior mitral valve leaflet and effect on follow-up results after additional mitral valve implantation]. As early as 1964, Lillehei et al. published the technique of preservation of the posterior mitral leaflet (PML) and chordae tendineae in combination with mitral prosthesis implantation (MPI). In a limited randomized number of 95 patients with MPI the influence of preservation of PML on hemodynamics and physical capacity at least 46 months after surgery without (group A) and with preservation of PML (group B) was investigated. Statistically significant differences in favor of group B were found for cardiac index, pulmonary artery pressure after stress, end-diastolic volume index (EDVI), physical capacity and survival rate after a complication-free course. Basing on these results at rest and after exertion (30 W), patients with preservation of PML and MPI are long-term in a better clinical condition.


[The severely injured patient in the emergency center--new diagnostic, therapeutic and organizational concepts]. Recent advances in clinical intensive care medicine and legal aspects of quality assurance require new concepts and methods in preclinical emergency medicine. Different new methods of emergency medicine are presented and evaluated as to their economy, practicability, and medical efficacy, points which have to be considered in order to make general recommendations.


[Infection management in surgical intensive care patients]. Achieving significant reductions in the rate of infections contracted in hospital requires an integrated approach. Such an approach is comprised of standardized procedures in the areas of prevention, diagnosis, therapy, and tracking. Prevention must begin by differentiating between exogeneous and primary or secondary endogenous infections. For infections already contracted, diagnosis and therapy must be standardized to the greatest possible extent, thereby discouraging recourse to a polypragmatic approach. Finally, tracking provides important information about the type, number, and origin of infections, as well as about the resistance of pathogens and the success of infection-control techniques. Standardization should not be limited to a single ward or hospital, but should extend to the national and even international level.


[Multivisceral and extended resection in tumor surgery: stomach cancer]. The aim of curative surgery in gastric cancer is the complete removal of all tumour bulk both macroscopically and microscopically (R0 resection). The operative strategy should consider the location of tumor, its histological character (Laurén classification), and the stage of disease according to the TNM-classification. Lymphadenectomy of compartments I and II does not increase operative morbidity and mortality if performed routinely, but seems to increase long-term survival in patients with stages II and IIIa disease. Routine removal of the spleen does not lead to better results. Gastrectomy in locally advanced gastric cancer with combined resection of adjacent organs can prolong survival in absence of peritoneal disseminating or distant metastases if R0 resection is achieved. The indication for gastrectomy of patients with an incurable stage of disease (peritoneal dissemination, distant metastases) should be determined after considering the individual status of the patient and surgical risk and can be performed as a so-called ultima ratio resection with the aim of palliation.


[Synchronous resection of liver metastases of colorectal cancers]. From 1981 to 1991, 161 patients underwent liver resection for colorectal secondaries with curative intent. In 57 patients metastases were synchronous to the primary tumor and were resected in 29 cases simultaneously and in 28 patients after a 2-week delay. Median survival of 28 months is similar to the treatment result for metachronous metastases. However, the recurrence-free interval was significantly shorter (7.5 months vs 11.8 months; p = 0.05). Radical resection of the primary tumor contributes to the treatment result; segmental resections of colorectum without lymphadenectomy should be avoided. Indication for liver resection should be made in the case of solitary lesions and in patients without extrahepatic disease. The type of resection for the primary tumor or for liver metastases does not influence survival, morbidity, or operative mortality.


[Multivisceral and extended resection in tumor surgery. Bone and peripheral soft tissue tumors]. Out of 92 patients with bone sarcoma and 640 patients with sarcomas of soft tissue 45 thoracic girdle amputations and 23 hemipelvectomies were performed. Radical surgery is the most effective prognostic factor. Recurrences stem from unradical operations which fail to include a compartment resection with a mantle of normal tissue in the case of soft tissue sarcomas or a resection of the sarcoma-bearing bone with normal surrounding tissue. Although multimodal therapies often cause tumour regression and necrosis, they do not stop recurrences if even minimal macroscopic parts of tumour have been left in situ.


[Abdominal multivisceral resection of colonic cancer]. Multivisceral resection in combination with extended lymph node dissection is used in the surgical treatment of locally advanced colon carcinoma without distant metastases. This also applies to tumours with marked peritumorous inflammation in contact with neighbouring organs where an intraoperative diagnostic attempt could result in tumour seeding. The low mortality and complication rate following multivisceral resection justifies this concept. The 5-year survival rate following multivisceral resection in advanced colon carcinoma is over 80%.


[Pelvic multivisceral resection from the viewpoint of surgery]. Even rectal carcinomas, carcinomas of the female genital tract, and retroperitoneal sarcomas of the pelvis with invasion of adjacent organs are potentially curable by extending the operation to the relevant structures. In the Surgical Department of the University of Erlangen, 1535 patients with a first diagnosis of rectal carcinoma were treated from 1978 to 1988. Among these patients, 97 multivisceral pelvic resections (patients with distant metastases excluded) were performed. True tumor invasion had occurred in 48%, the others were operated on for inflammatory adhesion. In 54 patients, the anal sphincter was preserved. Postoperative mortality was 7%. The 5-year survival of those patients with tumor invasion of adjacent organs and R0-resection (n = 26) was 32%. Excluding the five patients with a tear or incision of the tumor (n = 5), the 5-year survival of the remaining patients was 44%. One patient who was operated on for a leiomyosarcoma of the rectum with a multivisceral resection of the rectum, prostate, and urine bladder is still alive 9 years after the operation without recurrence. The history of this patient argues for pelvic exenteration also in males, if a R0 resection can be performed.


[Multivisceral resection of colorectal cancer--experiences of the Colorectal Cancer Study Group]. Between 1984 and 1986, 2341 patients with colorectal carcinoma from 7 German institutions entered the colorectal carcinoma study group (SGCRC). In 197 of 2053 patients with radical resections, the operation was extended by multivisceral resection. The two groups of patients were comparable in age, preoperative risk factors, postoperative morbidity, and mortality. Long-term results showed no statistically significant difference in survival according to the 5-year survival rates, calculated by the actuarial method when curative resections in UICC stage II and III were compared. After curative resection (R0), the presence or absence of intraoperative tumor-cell dissemination could be identified as a significant prognostic factor. The analysis of T4 tumors without distant metastases or serosal penetration showed a significant correlation between the percentage of patients treated by R0 resection and long-term survival in the different participating institutions.


I kappa B/MAD-3 masks the nuclear localization signal of NF-kappa B p65 and requires the transactivation domain to inhibit NF-kappa B p65 DNA binding. The active nuclear form of the NF-kappa B transcription factor complex is composed of two DNA binding subunits, NF-kappa B p65 and NF-kappa B p50, both of which share extensive N-terminal sequence homology with the v-rel oncogene product. The NF-kappa B p65 subunit provides the transactivation activity in this complex and serves as an intracellular receptor for a cytoplasmic inhibitor of NF-kappa B, termed I kappa B. In contrast, NF-kappa B p50 alone fails to stimulate kappa B-directed transcription, and based on prior in vitro studies, is not directly regulated by I kappa B. To investigate the molecular basis for the critical regulatory interaction between NF-kappa B and I kappa B/MAD-3, a series of human NF-kappa B p65 mutants was identified that functionally segregated DNA binding, I kappa B-mediated inhibition, and I kappa B-induced nuclear exclusion of this transcription factor. Results from in vivo expression studies performed with these NF-kappa B p65 mutants revealed the following: 1) I kappa B/MAD-3 completely inhibits NF-kappa B p65-dependent transcriptional activation mediated through the human immunodeficiency virus type 1 kappa B enhancer in human T lymphocytes, 2) the binding of I kappa B/MAD-3 to NF-kappa B p65 is sufficient to retarget NF-kappa B p65 from the nucleus to the cytoplasm, 3) selective deletion of the functional nuclear localization signal present in the Rel homology domain of NF-kappa B p65 disrupts its ability to engage I kappa B/MAD-3, and 4) the unique C-terminus of NF-kappa B p65 attenuates its own nuclear localization and contains sequences that are required for I kappa B-mediated inhibition of NF-kappa B p65 DNA binding activity. Together, these findings suggest that the nuclear localization signal and transactivation domain of NF-kappa B p65 constitute a bipartite system that is critically involved in the inhibitory function of I kappa B/MAD-3. Unexpectedly, our in vivo studies also demonstrate that I kappa B/MAD-3 binds directly to NF-kappa B p50. This interaction is functional as it leads to retargeting of NF-kappa B p50 from the nucleus to the cytoplasm. However, no loss of DNA binding activity is observed, presumably reflecting the unique C-terminal domain that is distinct from that present in NF-kappa B p65.


Mutation of a tyrosine localization signal in the cytosolic tail of yeast Kex2 protease disrupts Golgi retention and results in default transport to the vacuole. Kex2 protease processes pro-alpha-factor in a late Golgi compartment in Saccharomyces cerevisiae. The first approximately 30 residues of the 115 amino acid CO2H-terminal cytosolic tail (C-tail) of the Kex2 protein (Kex2p) contain a Golgi retention signal that resembles coated-pit localization signals in mammalian cell surface receptors. Mutation of one (Tyr713) of two tyrosine residues in the C-tail or deletion of sequences adjacent to Tyr713 results in loss of normal Golgi localization. Surprisingly, loss of the Golgi retention signal resulted in transport of C-tail mutant Kex2p to the vacuole (yeast lysosome), as judged by kinetics of degradation and by indirect immunofluorescence. Analysis of the loss of Kex2 function in vivo after shutting off expression of wild-type or mutant forms proved that mutations that cause rapid vacuolar turnover do so by increasing the rate of exit of the enzyme from the pro-alpha-factor processing compartment. The most likely explanation for these results is that mutation of the Golgi retention signal in the C-tail results in transport of Kex2p to the vacuole by default. Wild-type Kex2p also was transported to the vacuole at an increased rate when overproduced, although apparently not due to saturation of a Golgi-retention mechanism. Instead, the wild-type and C-tail mutant forms of Kex2p may follow distinct paths to the vacuole.


Morphological classification of the yeast vacuolar protein sorting mutants: evidence for a prevacuolar compartment in class E vps mutants. The collection of vacuolar protein sorting mutants (vps mutants) in Saccharomyces cerevisiae comprises of 41 complementation groups. The vacuoles in these mutant strains were examined using immunofluorescence microscopy. Most of the vps mutants were found to possess vacuolar morphologies that differed significantly from wild-type vacuoles. Furthermore, mutants representing independent vps complementation groups were found to share aberrant morphological features. Six distinct classes of vacuolar morphology were observed. Mutants from eight vps complementation groups were defective both for vacuolar segregation from mother cells into developing buds and for acidification of the vacuole. Another group of mutants, represented by 13 complementation groups, accumulated a novel organelle distinct from the vacuole that contained a late-Golgi protein, active vacuolar H(+)-ATPase complex, and soluble vacuolar hydrolases. We suggest that this organelle may represent an exaggerated endosome-like compartment. None of the vps mutants appeared to mislocalize significant amounts of the vacuolar membrane protein alkaline phosphatase. Quantitative immunoprecipitations of the soluble vacuolar hydrolase carboxypeptidase Y (CPY) were performed to determine the extent of the sorting defect in each vps mutant. A good correlation between morphological phenotype and the extent of the CPY sorting defect was observed.


Inducible expression of calmodulin antisense RNA in Dictyostelium cells inhibits the completion of cytokinesis. The single gene encoding calmodulin in the eukaryotic microorganism Dictyostelium discoideum was cloned and sequenced. The gene was found to contain three introns, one lying immediately after the translation initiation codon. The deduced amino acid sequence indicated that Dictyostelium calmodulin contains 19 amino acid differences from vertebrate calmodulin, including extensions at both termini. Northern blot analysis showed that similar levels of calmodulin mRNA are present throughout growth and development of wild-type cells. A complete copy of the calmodulin cDNA was prepared, and an 87-base pair fragment complementary to the 5'-end of the calmodulin mRNA was subcloned into the Dictyostelium transformation vector pVEII, such that expression of the antisense transcript was driven by the discoidin I gamma promoter. Transformed cells were selected and maintained at low cell density, a condition resulting in minimal activity of the discoidin I promoter. High level expression was induced by allowing the transformants to reach high cell density or by growing them in the presence of medium conditioned by high density cells. Under these conditions, in which calmodulin mRNA and protein levels were reduced about twofold, the calmodulin antisense transformants lost the ability to complete cytokinesis. A contractile ring formed and constricted, but the midbody linking daughter cells failed to break. The resulting cell population contained multinucleated cells and networks of cells connected by cytoplasmic bridges. Normal cell division was restored when the cells were diluted to low density. These observations have identified a new point at which calmodulin may regulate cell cleavage.


Requirement for ESP1 in the nuclear division of Saccharomyces cerevisiae. Mutations in the ESP1 gene of Saccharomyces cerevisiae disrupt normal cell-cycle control and cause many cells in a mutant population to accumulate extra spindle pole bodies. To determine the stage at which the esp1 gene product becomes essential for normal cell-cycle progression, synchronous cultures of ESP1 mutant cells were exposed to the nonpermissive temperature for various periods of time. The mutant cells retained viability until the onset of mitosis, when their viability dropped markedly. Examination of these cells by fluorescence and electron microscopy showed the first detectable defect to be a structural failure in the spindle. Additionally, flow cytometric analysis of DNA content demonstrated that massive chromosome missegregation accompanied this failure of spindle function. Cytokinesis occurred despite the aberrant nuclear division, which often resulted in segregation of both spindle poles to the same cell. At later times, the missegregated spindle pole bodies entered a new cycle of duplication, thereby leading to the accumulation of extra spindle pole bodies within a single nucleus. The DNA sequence predicts a protein product similar to those of two other genes that are also required for nuclear division: the cut1 gene of Schizosaccharomyces pombe and the bimB gene of Aspergillus nidulans.


A Dictyostelium myosin II lacking a proximal 58-kDa portion of the tail is functional in vitro and in vivo. We used molecular genetic approaches to delete 521 amino acid residues from the proximal portion of the Dictyostelium myosin II tail. The deletion encompasses approximately 40% of the tail, including the S2-LMM junction, a region that in muscle myosin II has been proposed to be important for contraction. The functions of the mutant myosin II are indistinguishable from the wild-type myosin II in our in vitro assays. It binds to actin in a typical rigor configuration in the absence of ATP and it forms filaments in a normal salt-dependent manner. In an in vitro motility assay, both monomeric and filamentous forms of the mutant myosin II translocate actin filaments at 2.4 microns/s at 30 degrees C, similar to that of wild-type myosin II. The mutant myosin II is also functional in vivo. Cells expressing the mutant myosin II in place of the native myosin II perform myosin II-dependent activities such as cytokinesis and formation of fruiting bodies, albeit inefficiently. Growth of the mutant cells in suspension gives rise to many large multinucleated cells, demonstrating that cytokinesis often fails. The majority of the fruiting bodies are also morphologically abnormal. These results demonstrate that this region of the myosin II tail is not required for motile activities but its presence is necessary for optimum function in vivo.


Predisposing psychological factors in the development of reflex sympathetic dystrophy. A review of the empirical evidence. To examine the literature for evidence that psychological factors predispose certain individuals to development of reflex sympathetic dystrophy (RSD). English-language journal articles that described psychological data on patients diagnosed with RSD, identified through Medline search and bibliography reviews. All studies reporting data on psychological factors in adult, adolescent, or child patients with RSD were included. We extracted data regarding psychological factors in patients with RSD and assessed validity of these studies through evaluation against seven basic research criteria. Of the 20 articles reviewed, 15 reported the presence of depression, anxiety, and/or life stress in patients with RSD. However, the methodological quality of these studies was generally poor, with most meeting three or less of the seven validity criteria. In particular, the absence of prospective designs restricts conclusions concerning whether psychological factors are etiologically related to RSD. The data reviewed are consistent with a theoretical model in which depression, anxiety, or life stressors may influence development of RSD through their effects on alpha-adrenergic activity. However, conclusions regarding etiological significance of these factors are not possible due to the dearth of high-quality studies. Suggestions for prospective research are described.


Etiopathogenesis of reflex sympathetic dystrophy: a review and biopsychosocial hypothesis. Reflex sympathetic dystrophy (RSD) is an enigmatic condition. Many clinicians, however, believe that psychological factors could contribute to the onset and persistence of the syndrome. In this article we critically review the evidence from psychometric and psychodynamic/biographical studies that suggests a role for such factors. An etiopathogenetic hypothesis based on the authors' clinical experience and the foregoing literature also encompasses elements of stress-coping theory, cognitive-behavioral views on chronic pain, and the psychobiological approach to sympathetic nervous system dysfunction. Implications of this model for future psychological research and the therapeutic treatment of RSD are discussed.


Chronic low back pain patients around the world: cross-cultural similarities and differences. The current study sought to determine whether there were any significant cross-cultural differences in medical-physical findings, or in psychosocial, behavioral, vocational, and avocational functioning, for chronic low back pain patients. Partially double-blind controlled comparison of six different culture groups. Subjects were selected from primarily ambulatory care facilities specializing in treating chronic pain patients. PATIENTS-SUBJECTS: Subjects consisted of 63 chronic low back pain patients and 63 healthy controls. Low back pain patients were randomly selected from six different culture groups (American, Japanese, Mexican, Colombian, Italian, and New Zealander). Ten to 11 were gathered per culture from a pool of patients treated at various pain treatment programs. Likewise, 10 or 11 control group subjects were obtained from each culture from a pool of healthy support staff. The Sickness Impact Profile and the Medical Examination and Diagnostic Information Coding System were used as primary outcome measures. Findings showed that (a) low back pain subjects across all cultures had significantly more medical-physical findings and more impairment on psychosocial, behavioral, vocational, and avocational measures than controls did; (b) Mexican and New Zealander low back pain subjects had significantly fewer physical findings than other low back pain groups did; (c) the American, New Zealander, and Italian low back pain patients reported significantly more impairment in psychosocial, recreational, and/or work areas, with the Americans the most dysfunctional; and (d) findings were not a function of working class, age, sex, pain intensity, pain duration, previous surgeries, or differences in medical-physical findings. It was concluded that there were important cross-cultural differences in chronic low back pain patients' self-perceived level of dysfunction, with the American patients clearly the most dysfunctional. Possible explanations included cross-cultural differences in social expectation; attention; legal-administrative requirements; financial gains; attitudes-expectations about usage, type, and availability of health care; and self-perceived ability and willingness to cope.


Bacteriology, drug stability and exchange of percutaneous delivery systems and antibacterial filters in long-term intrathecal infusion of opioid drugs and bupivacaine in "refractory" pain. To provide a basis for recommendations on the exchange of containers (syringes and cassettes) and antibacterial filters, and for choice of administration device in patients with "refractory" pain treated with long-term percutaneous intrathecal (IT) infusions of opioid (morphine or buprenorphine) and bupivacaine mixtures. Prospective, cohort, nonrandomized control trial-case series, with consecutive sample, no standard criterion, and cost-benefit analysis. Tertiary care center, institutional practice as well as hospitalized and ambulatory care. Eighty-nine (51 women and 38 men); 81 with malignant pain and 8 with benign "refractory" pain. (a) The chemical stability of the drugs in the containers during 30 days. (b) The results of bacteriologic culture of the residual volumes of the analgesic mixtures from used and reused (1-16 times) syringes (n = 135) and cassettes (n = 258), and of 5 ml of sterile isotonic saline filtered through the used Millipore filters (n = 149). The bacteriologic samples from the 89 patients were taken after 1-40 (median = 7), 1-86 (median = 20), and 5-78 (median = 31) days of IT treatment, respectively. Chemical stability: buprenorphine and bupivacaine concentrations-liquid chromatography; morphine concentrations--gas chromatography. Bacteriologic cultures: standard laboratory procedures. The hypothesis (repeated use of the infusion systems and their exchange once a month does not significantly affect drug concentrations or increase the infection risk) was elaborated before data collection began. The bupivacaine-opioid mixtures were found to be chemically stable within 3-10% of the original doses up to 30 days. Seventeen cultures (from five syringes, six cassettes, and six filters) in 13 patients (having no signs of meningeal infection) were found to be colonized with Staphylococcus aureus (n = 4), coagulase negative staphylococci (n = 7), viridans streptococci (n = 3), Neisseria sp (n = 4), Corynebacterium sp (n = 4), Enterobacter sp (n = 2), Klebsiella sp (n = 3), gram-negative bacilli (n = 1), and yeasts (n = 2). The place of IT treatment, its duration, and patient-related infection risk factors (age; malignancy; diabetes; presence of a colostomy, pyelostomy, or indwelling urinary catheter; and the presence and location of infection foci) were not related to the results of the cultures. However, 9 of the 17 positive cultures came from patients with skin ulcers, a notable incidence. The positive cultures had no connection with the cultured item, its in-use duration, the number of times of reuse, the analgesic drugs used, their concentrations or the presence of preservatives (sodium metabisulfite and sodium edetate), or the antiseptic agent (70% ethanol or 0.5% chlorhexidine gluconate) used during bacteriologic sampling. The bacterial growth was sparse in 14 and massive in 3 of the 17 positive cultures. One item (filter) from one patient with meningitis was sterile. In our population, exchange of the infusion systems when they are empty (within 1 month) and of the antibacterial filters once a month does not appear to affect the concentrations of, or increase the infection risk from, the opioid-bupivacaine mixtures. The risk of bacterial contamination/colonization of the syringes from syringe drivers does not seem to be higher than that of cassettes from external portable pumps.


Intrathecal baclofen suppresses central pain in patients with spinal lesions. A pilot study. To assess the efficacy of acute intrathecal (i.t.) baclofen on chronic, dysesthetic, and spasm-related pain (SRP) among patients with spinal spasticity [i.e., multiple sclerosis (MS), spinal cord injury (SCI), transverse myelitis (TMy)]. Double-blind, randomized, and placebo (vehicle) controlled trials (n = 7), and nonrandomized, nonblinded trials (n = 2). In-patient program at Samaritan Rehabilitation Institute, Phoenix, Arizona, U.S.A. MS (n = 4), spinal cord compression (n = 1), and TMy (n = 2) in the double-blind trial, and SCI (n = 2) in the nonblinded trial; all had chronic spinal lesions and function-limiting spasticity refractory to oral medications, including baclofen (p.o.). i.t. baclofen (50 micrograms) in 1 ml preservative-free normal saline into the L1-2 interspace. Electromyographic (EMG) activity; intravesical and intraurethral pressures; Ashworth Scale and tendon response values; visual analog scales for describing dysesthetic pain intensity; and threshold/EMG relationships after controlled pinch as an indication of nociceptive pain. i.t. baclofen (a) caused marked reduction of segmental reflexes before suppression of intersegmental reflexes; (b) significantly suppressed dysesthetic pain and SRP with temporal dissociation; and (3) did not influence pinch-induced and musculoskeletal (low back) pain. The suppressive action of i.t. baclofen on spontaneous and evoked (allodynia) dysesthetic pain suggests that a dysfunctional spinal gamma-aminobutyric acidB receptor system, including functional supersensitivity, is associated with the phenomenon of central pain among patients with spinal lesions. Temporal dissociation regarding the action on dysesthetic pain and SRP suggests that disparate central mechanisms subserve the two clinical states.


Long-term phantom breast syndrome after mastectomy. Phantom breast syndrome after mastectomy has already been reported by us and other authors. The temporal course, character, and extent of these phenomena, however, have not yet been elucidated. To investigate in a prospective study the incidence, clinical picture, and temporal course of phantom breast syndrome during a 6-year period. One-hundred twenty women who embarked on consecutive postoperative control or treatment at our department during a 1-year period were interviewed by a standard questionnaire 3 weeks after the operation. Of these, 110 patients were interviewed 1 year later and 69 were interviewed again 6 years later. The median age at the first interview was 54 years (Quartile (Q)1 = 45 years; Q3 = 62 years) and at the third interview 6 years later, 60 years (Q1 = 51 years; Q3 = 68 years). The incidence of phantom pain and nonpainful phantom sensations was 13.3% and 15.0%, respectively, 3 weeks after mastectomy, 12.7% and 11.8%, respectively, after a year, and 17.4% and 11.8%, respectively, after 6 years. We found significant relationships between preoperative pain and phantom breast syndrome, but no significant relationship between age and the occurrence of this syndrome. Neither postoperative sequelae nor cancer treatment including radiotherapy seemed to affect the occurrence of phantom breast syndrome. Pain in the scar, which was clearly distinguishable from phantom pain, was present in 35.0% of the patients 3 weeks postoperatively, in 22.7% after 1 year, and persisted in 30.9% 6 years later. The present incidence of phantom-related phenomena is close to the incidence reported by others. However, persistent phantom pain after mastectomy may be more common than usually expected. Also, the persistence of pain in the scar seems to be more common than generally expected.


A comparison of psychosocial functioning and personality in amputee and chronic pain populations. To compare two populations with disabling conditions, amputation and chronic pain, in terms of psychosocial functioning and personality factors. We hypothesized that the degree of disability of amputees would resemble that of patients with chronic musculoskeletal pain. We also examined the prevalence of personality characteristics stereotypic of chronic pain in the two samples. Survey. Outpatients at the pain and amputee clinics of a teaching hospital. Ninety-four patients (47.7% of the number approached) were selected in consecutive samples taken from records and clinics. Sickness Impact Profile (SIP) and the Millon Clinical Multiaxial Inventory (MCMI). The two groups did not differ on the SIP total score. Sixteen of 47 amputees reported significant pain, and this group showed higher levels of overall disability than did patients with chronic musculoskeletal pain (n = 47) and significantly greater disability than the 31 amputees reporting low levels of pain. Contrary to common perceptions of chronic pain patients, 25% showed no significant evidence of psychopathology. Only anxiety and dysthymia levels were clinically elevated in more than 50% of chronic pain patients. Results are discussed in terms of the dual disability of amputees with chronic pain and of the hazards of attributing common characteristics to heterogenous patient groups.


Predictors of outcome in the treatment of chronic "psychogenic" pain with amitriptyline and brief psychotherapy. Baseline measures associated with outcome are described for amitriptyline and brief psychotherapy used in the outpatient treatment of chronic "psychogenic" pain. The results delineate patient profiles associated with suitability for these treatments. These may serve as guidelines for choice in the treatment of heterogeneous pain clinic patients.


Ocular diclofenac. A review of its pharmacology and clinical use in cataract surgery, and potential in other inflammatory ocular conditions. Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug with analgesic activity. When instilled as a topical 0.1% solution in a limited number of patients undergoing cataract surgery, diclofenac limits surgically induced miosis, reduces signs of ocular inflammation, does not cause elevations in intraocular pressure, and reduces the occurrence and severity of cystoid macular oedema. Preliminary findings suggest a niche for topical diclofenac in other ocular inflammatory conditions such as iritis, episcleritis and conjunctivitis, although its efficacy in these areas awaits confirmation. The drug appears well tolerated, apart from a transient burning sensation after instillation in some patients. Ocular diclofenac thus appears well suited as a local anti-inflammatory adjunct to cataract surgery, and may be useful in some other inflammatory ocular conditions.


Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis. The estradiol transdermal therapeutic system is a percutaneous delivery device which, when affixed to the skin, delivers estradiol (the major estrogen in premenopausal women) into the systemic circulation at a constant rate for up to 4 days. Because this method of delivery avoids first-pass hepatic metabolism, premenopausal levels of estradiol can be maintained in postmenopausal women using very low dosages. Bone density decreases at an accelerated rate after the menopause, which can lead to development of osteoporosis and increased fracture risk. In common with other estrogen therapies, transdermal estradiol provides protection against osteoporosis following spontaneous or surgical menopause, as evidenced by both biochemical markers of bone resorption and, in a small number of studies, measurement of bone mineral density. Protection against further vertebral fractures was also demonstrated in women with established osteoporosis in one study. Transdermal estradiol also has beneficial effects on vaginal cytology and menopausal symptoms similar to those of oral estrogens. The tolerability of transdermal estradiol appears to be very good, the most common adverse effect being local irritation at the application site. As with other estrogens, transdermal estradiol can be given continuously or in 4-week (3 weeks on/1 week off) cycles, and concomitant progestogen therapy is recommended in women with intact uteri, in order to minimise the risk of endometrial hyperplasia. Available evidence thus suggests that transdermal estradiol may represent an attractive alternative to other forms of estrogen therapy for the prevention, and possibly treatment, of postmenopausal osteoporosis.


Prevention of osteoporosis. Current recommendations. Osteoporosis and its treatment have attracted much attention in recent years, especially since the widespread recognition of its association with the menopause. The resulting fractures are a cause of considerable morbidity and mortality in the elderly, and current costs of treating these patients has been estimated to be in excess of pounds 500 million per annum in the UK. As the causes of osteoporosis are now recognised the condition may be largely preventable, especially in women, and significant savings in health expenditure could be made if preventive methods are applied to those most at risk. The most well researched preventive treatment for osteoporosis is hormone replacement therapy (HRT) which offers additional benefits to those who choose it. Alternative methods currently under investigation for those who cannot or will not use HRT include those agents which inhibit the resorption of bone and those that stimulate the production of new bone. Treatment of established disease, i.e. attempts at increasing bone density in those with significant loss, is more difficult and methods so far investigated are not without risks and adverse effects. Furthermore, whether an increase in bone mineral density results in a reduced rate of fracture incidence has yet to be confirmed.


HMG-CoA reductase inhibitor use in the aged. A review of clinical experience. While the benefit of cholesterol-lowering in the elderly has yet to be proven in clinical trials, individuals at high risk of coronary events who otherwise enjoy a good quality of life, should not be denied cholesterol-lowering therapy on the basis of age alone. Moreover, hypolipidaemic drugs are already extensively used in the aged. The HMG-CoA reductase inhibitors lovastatin, simvastatin and pravastatin are potent well tolerated hypolipidaemic therapies in young subjects. Although there have been few studies on their use in elderly subjects, the available data suggest the efficacy and safety of HMG-CoA reductase inhibitors in similar to that established for younger age groups.


The epidemiology and therapy of airflow limitation in the elderly. Airways disease is a frequent problem poorly recognised in older people. Many have reversible airway limitation and do not receive appropriate therapy. As in younger patients, pulmonary function tests are essential as a baseline and in relation to formal trials of treatment in both the diagnosis and management. Preferably, the assessment of all patients with airflow limitation should include a corticosteroid trial to correctly identify all patients who need long term prophylactic therapy. Many older patients have difficulty using the metered dose inhalers and the addition of volume spacer devices, though cumbersome, has many further advantages. In some patients, airflow limitation may be complicated by the presence of cardiac failure, arrhythmias and arterial hypoxia, and these problems also need to be reviewed.


Aromatase inhibitors in malignant diseases of aging. Aromatase inhibition is an established endocrine treatment modality in postmenopausal breast cancer and is currently considered as an interesting experimental treatment approach in other malignant conditions such as endometrial carcinomas and prostatic cancer. While the 'classic' aromatase inhibitor aminoglutethimide causes many adverse effects that makes it unfit for use in elderly patients, several novel aromatase inhibitors with minimal adverse effects are currently being investigated. These drugs may provide important new tools in the endocrine treatment of malignant diseases in aging patients.


DNA reactive and epigenetic carcinogens. Animal and human carcinogens exert their effects through diverse mechanisms which include DNA reaction and epigenetic effects. This review covers the basis for distinguishing between carcinogens that have either DNA reactivity or epigenetic activity as their primary effect.


Overview of genotoxic carcinogens and non-genotoxic carcinogens. It is known that carcinogens designated on the basis of longterm animal test results are extremely diverse in character, both in terms of potencies and the mechanism of action, which leads to complexity in their assessment for cancer risk to humans. The classification of carcin0ogens into two categories, namely, genotoxic and non-genotoxic varieties has been proposed to give a longical foundation on which cancer risk assessment can be reasonably based. The term "genotoxic carcinogen" indicates a chemical capable of producing cancer by directly altering the genetic material of target cells, while "non-genotoxic carcinogen" represents a chemical capable of producing cancer by some secondary mechanism not related to direct gene damage. This classification has contributed to the exclusion of various rodent-specific carcinogens from the group of chemicals with potential cancer risk to humans. However, the term, "nongenotoxic carcinogen" tends to give the mistaken impression that carcinogens shown to be negative for mutagenicity in a series of test systems might be harmless to humans. It should be realized that clear-cut criteria for this classification have not been established because of insufficiencies in the available information concerning mechanisms of action of non-genotoxic carcinogens. Future scientific advances leading to elucidation of the subcellular mechanisms of carcinogenesis are necessary for establishment of the unified, more realistic and mechanism-based approach to cancer risk estimation form exposure to chemicals.


Search for the mechanism of toxicity of dioxins. A lesson in toxicology. The development of modern toxicology was strongly influenced by parallel evolutions of sister disciplines as well as regulatory requirements. This led to an overemphasis of some areas of toxicology while other aspects of it experienced at least a temporary benign neglect. The author of this paper believes that the few and far between successes in elucidating the mechanism of toxicity of chemicals are related to this uneven approach to a very complex problem. Based on one of the most important and controversial contemporary issues in toxicology, viz. that of dioxins, it is argued that by a systematic step-wise use of methodologies borrowed from sister disciplines, our capabilities of elucidating the mechanism of action of toxicants can be considerably improved.


Tissue repair by thrombin-derived peptides in the rat. An ordered sequence of events occurs following tissue damage to bring about healing. One molecule involved in this process is thrombin. Utilizing rat linear incision and full dermal excision models, we have investigated the ability of two thrombin-derived RGD-containing peptides, p517 and p508, to enhance tissue repair under normal and healing-impaired conditions. p508, at 0.5 micrograms peptide per wound, produced a significant .23% improvement in wound strength in a dose-dependent manner. Similarly, a single application of 0.5 micrograms p517 per 6-cm linear incision would significantly increased wound-breaking strength approximately 18% at nine days postsurgery (control: 3.95 +/- 0.13 Newtons, vs. p517: 4.68 +/- 0.13 Newtons; P < 0.001). However, in glucocorticoid-stressed rats, the application of 0.5 micrograms per wound p508 or 517 did not significantly influence steroid-impaired healing. In the full dermal skin excision wound model, a single application of 0.5 micrograms p508 per wound at the time of surgery significantly reduced average wound area at days 3 and 5, when healing was impaired by glucocorticoid administration. Wound area was also reduced by p508 treatment at day 3 in the normal animal, but this effect was not statistically significant. We suggest wound-healing benefits of p508 and p517 may activate wound fibroblast proliferation or stimulate other cell types in the wound site through an RGD-mediated interaction.


Construction of affinity sorbents utilizing glutathione analogs. Solution-phase N-fluorenylmethoxycarbonyl (Fmoc) mediated peptide synthesis has been adapted to the synthesis of glutathione (gamma-glutamyl-cysteinyl-glycine) analogs. A protecting group strategy has been devised in which all of the masking groups are removed with mild base. This allows for the synthesis of acid-sensitive materials and lessens concerns about the alkylation at sulfur by carbocations known to be present in the trifluoroacetic acid mixtures usually employed for deprotection of peptides made by the Fmoc methodology. A series of structurally varied glutathione analogs were prepared by modifying the peptide in two ways. The first involved C-terminal substitution for glycine by one of several different amino acids. The second involved substitution of one of five alkyl or aryl groups onto the cysteine sulfhydryl. The complete set of all combinations would yield 48 reagents, of which 25 have actually been synthesized. Following confirmation of the structures by FAB mass spectrometry, the peptides were immobilize by conjugation to epoxyfunctionalized Sepharose at pH 11-12. The amount and identity of immobilized peptide was assayed by amino acid analysis of acid-hydrolyzed resin. One of the tripeptides was purified by ion-exchange and preparative HPLC.


Conformational studies on beta-amino acid-containing peptides. I. Modified amino acids (such as beta-amino acids) are becoming increasingly popular research tools in the development of orally active and metabolically stable peptidomimetics. We present conformational energy calculations using molecular mechanics (MM2) on two model compounds containing beta-amino acids. The low-energy models are characterized by a lack of intramolecular hydrogen-bonding interactions, qualitatively consistent with the results of the IR studies. The structures obtained from the limited amount of x-ray crystal data on compounds with beta-amino acid incorporated lie within 3 kcal/mol of the global minimum obtained from the present calculations. Preliminary stereochemical guidelines for the incorporation of beta-amino acid residues have been proposed.


Outcome of thyroid function in newborns from mothers treated with amiodarone. Amiodarone, a drug extensively used as an antiarrhythmic agent, contains 37% iodine and causes several thyroid abnormalities. The transplacental passage of amiodarone occurs with chronic therapy; we describe in this report the outcome of 9 pregnant women who used amiodarone (200 mg/day) for treatment of resistant tachycardia and the follow-up of their newborns. All women were clinically euthyroid at the 3rd trimester and showed expected values of thyroid hormones (mean +/- SD: total T4, 228 +/- 45 nmol/L; total T3, 4.0 +/- 0.65 nmol/L; TSH, 4.0 +/- 1.8 mU/L; negative thyroid antibodies). At birth all newborns were normal on routine examination with no goiter or corneal changes. T4 and TSH, measured on dried umbilical blood spots were normal or borderline-normal in 8 of 9 babies. Only 1 neonate presented clearly abnormal values of T4 and TSH (96 mU/L); on clinical grounds the baby was normal, without signs of hypothyroidism. At 1 month of life, T4 and TSH were normal. Follow-ups at 3, 6, and 12 months were normal. We conclude that is not necessary to discontinue treatment with amiodarone in pregnant women with resistant tachycardia, but it is imperative to evaluate the thyroid function of the newborn, since transient hypothyroidism may occur.


C-terminal amidation of calcitonin by carboxypeptidase Y catalyzed transpeptidation with a photocleavable nucleophile. The C-terminal amidation of calcitonin represents an important technological problem. A method using a serine carboxypeptidase-catalyzed transpeptidation reaction in combination with photochemical cleavage to give the warranted peptide amide is described. The overall yield is higher than 95%.


Clinical picture of endemic cretinism in central Apennines (Montefeltro). Endemic cretinism is still present in an endemic goiter area of the central Apennines (Montefeltro) (goiter prevalence 55%; mean urinary iodine level 39 micrograms/g creatinine). Clinical and biochemical features of patients with myxedematous, neurologic, and mixed cretinism were studied. Also, in this area, as in most other, neurologic cretinism is more prevalent than myxedematous and mixed forms. The hormonal profiles of the three types of cretinism were clearly different. Nevertheless, all myxedematous cretins had some neurologic disorders (hyperreflexia, increased muscle tone, disorder of gait, Babinski sign, hypoacusia) that were similar to those present in neurologic cretins. These findings suggest that neurologic damage is very similar in all forms of endemic cretinism, reflecting a diffuse insult to the developing fetal nervous system. Furthermore, these data support the hypothesis that the primary pathophysiologic event in the different types of endemic cretinism is represented by maternal and fetal hypothyroidism, while differences may be explained by the extent and duration of postnatal hypothyroidism. All the cretins were over 35 of age, suggesting a severe iodine deficiency in the past decades, and a progressive improvement of nutritional status resulted in "silent iodine prophylaxis." However, recent studies have revealed the persistence of a moderate iodine deficiency, a high prevalence of neurologic hypoacusia, and reduction of mental performance in normal schoolchildren of this area. These findings constitute strong evidence in favor of adequate iodine prophylaxis.


Conformation of aminosuccinyl dipeptides Ac-L-X-L-Asu-NMe from empirical energy calculations. The aminosuccinyl (Asu) residue is formed as intermediate in some peptide and protein reactions. Potential energy calculations, using the parameters of the empirical conformational energy program for peptides (ECEPP), were performed on blocked X-Asu dipeptides, where X = Gly, Ala, Ser, Val and Pro. Results indicate that intra-residue interactions are dominant, and the low-energy dipeptide conformations correspond to the low-energy single-residue minima. Comparisons were made with previous results from energy calculations on blocked Asu-X dipeptides (X = Gly, Ala, Ser and Val).


Surrogate thyroglobulin receptors and T cell proliferation in Hashimoto's thyroiditis. Immunoglobulin molecules on the surface of a B lymphocyte are the endogenous "receptors" to which specific antigens bind. Studies in mice have shown that a monoclonal antibody, conjugated with palmitate to provide a lipid tail, can be inserted into the cell membrane to provide a "surrogate" antigen receptor. We have investigated whether a palmitate conjugate of a human monoclonal antibody specific for thyroglobulin (TG) could function as a surrogate TG receptor on blood mononuclear cells separated into fractions enriched for T cells or depleted of T cells (non-T cells). Using flow cytometry, we detected surrogate TG receptors on non-T (but not on T) cells from 11 of 11 individuals studied (5 Hashimoto patients and 6 control donors). In contrast, endogenous TG receptors could only be detected on non-T cells from 1 of 3 Hashimoto patients and from 0 of 4 control donors. Because of the efficient binding of TG by surrogate receptors on non-T cells, we assessed the ability of such cells to present TG to T cells. Proliferation in response to TG was observed in T cells from only 1 of 5 Hashimoto patients. This low frequency of response was no different from that previously detected using cultures of T cells and autologous dendritic cells. Therefore, the successful generation of surrogate receptors on non-T cells is not associated with more efficient TG presentation of T cells. Furthermore, the significance of the present study is that the T cells, not the antigen-presenting cells, are likely to be the limiting element in the T cell proliferative response to TG and other thyroid autoantigens.


Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy. To investigate the efficacy of magnetic resonance imaging (MRI) in the assessment of thyroid-associated ophthalmopathy (TAO), 51 patients with TAO were evaluated by ophthalmologic examinations and MRI at 0.5 T. Thickness of extraocular muscles (EM) was measured by T1-weighted image. Signal intensities of EM and orbital connective tissue (OCT) were measured by short inversion time inversion recovery (STIR) image and expressed as a ratio by comparison to the signal intensity of cerebral substantia alba (SI, signal intensity ratio). Significant enlargement of one or more EM was observed in 86% of patients with TAO, and SI of EM (2.15 +/- 0.63, mean +/- SD) was significantly increased compared with control values (n = 16; 1.35 +/- 0.33; t test, p < 0.01). SI of OCT tended to be greater than that in the control group, although the difference was not significant. There was a significant positive correlation between thickness of EM and severity of ophthalmopathy, assessed as an ophthalmopathy index (p < 0.05). SI of neither EM nor OCT correlated with the severity of the eye disease. To investigate whether MRI findings could predict the outcome of methylprednisolone pulse therapy, we studied 23 patients with TAO who received this treatment. SI of EM and OCT in the 12 patients giving favorable responses were significantly greater than those in the 11 patients without good response (t test, p < 0.01). On the other hand, the thickness of eye muscles did not correlate with the outcome of treatment except for that of medial rectus muscle. There was a significant correlation between SI of EM and that of OCT (r = 0.78, p < 0.01), suggesting possible similar pathologic processes in these tissues in TAO.(ABSTRACT TRUNCATED AT 250 WORDS)


Expression of the thyroid hormone receptor, the oncogenes c-myc and H-ras, and the 90 kD heat shock protein in normal, hyperplastic, and neoplastic human thyroid tissue. Expression of the thyroid hormone receptor (TR beta), the 90 KD heat shock protein (HSP 90), and the oncogenes H-ras and c-myc mRNA in normal hyperplastic, and neoplastic human thyroid tissue was investigated by Northern blot and slot blot analyses. The TR beta mRNA was present in all normal and neoplastic thyroid tissue samples. The levels were significantly higher in normal and hyperplastic tissues (7.91 +/- 0.48 and 7.60 +/- 0.68 arbitrary units, respectively) than in neoplastic tissues (3.82 +/- 0.67) (p < 0.001). H-ras and c-myc mRNA were also detected in glandular tissue specimens, but no significant difference was observed in their expression levels. Furthermore, there was a tendency to a negative correlation between the level of TR beta and c-myc mRNA (p = 0.06). In normal thyroid tissue, HSP 90 mRNA levels were significantly higher than in hyperplastic and papillary carcinoma tissue specimens (p < 0.001). These results indicate that mRNA of TR beta and HSP 90 (the latter only in papillary thyroid carcinoma) are expressed in relation to the degree of cellular differentiation. Furthermore, the presence of TR beta in normal thyroid tissue implies that T3 and T4 may be involved in the regulation of their own production via TR beta activated feedback mechanism(s).


The 5' region of the human thyroglobulin gene contains members of the Alu family. Repeated sequences were identified in the 5' region of the human Tg gene in introns 4, 5, 10, and 11. Another repeated cluster was located in the 5' flanking sequences, approximately 6 Kb upstream from the first exon. The nucleotide sequence analysis indicated that these repeated sequences are members of the Alu family. The homology between the sequences of the intron 4 and the Alu consensus was 86%. The Alu member studied was oriented in the direction of transcription of the Tg.


Human chorionic gonadotropin induces c-myc mRNA expression via TSH receptor in FRTL-5 rat thyroid cells. To elucidate the gene regulation of the thyroid-cell growth-promoting activity by human chorionic gonadotropin (hCG), we investigated the effect of hCG on c-myc proto-oncogene expression in cultured rat FRTL-5 cells by the Northern blot method. hCG induced c-myc mRNA expression, which peaked at 60-120 min. A dose-dependent increase in c-myc mRNA levels was also ascertained. In the presence of crude immunoglobulin G (IgG) from 2 patients with primary hypothyroidism who had blocking type TSH-receptor antibody, c-myc mRNA expressions induced by hCG were decreased to 82% and 62%, compared with that in the presence of normal IgG. The present results suggest that the expression of c-myc mRNA is a part of the molecular mechanism through which hCG regulates the proliferation of thyroid cells, and that hCG-induced c-myc mRNA expression is presumed to be mediated in part by TSH receptors.


Dual-site thyroid ectopy in a mother and son. We found familial thyroid ectopy in a mother and son, each of whom had an anterior neck mass corresponding to a perihyoid ectopic thyroid. In addition, technetium scintigraphy revealed another focus of aberrant uptake at their tongue roots. Neither patient showed hypothyroid symptoms or abnormal biochemical data other than a mildly elevated TSH level in the son. No other member of the family had a thyroid disorder. To our knowledge this is the first documented instance of familial thyroid ectopy in multiple sites. The observed similarity in distribution of ectopic tissue suggests a hereditary pathogenic factor.


Low-molecular-weight iodoproteins in the congenital goiters of cog/cog mice. Previously we described sedimentation and immunologic abnormalities of thyroglobulin (Tg) in a strain of mice with inherited congenital goiter and hypothyroidism (cog/cog). The goals of the present study were to determine the extent to which thyroid gland stimulation by TSH accounts for the abnormal properties of cog/cog Tg and to characterize further the abnormally small iodoproteins found in cog/cog mice. Cog/cog and control +/cog and BALB/c mice were fed with either normal or thyroid-hormone-containing diets and were injected with Na125I. Sucrose density gradient centrifugation of labeled thyroid extracts from cog/cog mice on normal diet showed that 82% of the iodine was in iodoproteins smaller than Tg, with sedimentation rates of 3-8S. No 12S and 19S peaks, characteristic of normal Tg, were present, but distinct and stable 12S and 19S peaks emerged after recentrifugation of the 12S and 19S areas. In contrast, in cog/cog mice treated with T4, a smaller (55%) amount of 3-8S iodoproteins and distinct 12S and 19S peaks were present. In both groups of mice, the labeled 3-8S iodoproteins were composed of three fractions: 15% precipitated by antirat Tg serum, 38% precipitated by antimouse albumin serum, and 47% not precipitated by either serum. The 3-8S iodoproteins contained labeled MIT and DIT and no T4. On sodium dodecyl sulfate polyacrylamide gel electrophoresis the 3-8S iodoprotein fraction that reacted with anti-Tg serum contained a distinct electrophoretic band at 49K. The 3-8S nonreactive iodoproteins resolved into several bands of lower molecular weight. We conclude that the 3-8S iodoproteins in cog/cog mice are heterogeneous and that TSH stimulation contributes to the production of these low-molecular-weight iodoproteins.


Fucosylation of glycoproteins begins in the rough endoplasmic reticulum of mouse active thyrotrophs. Our aim was to determine whether fucosylation of glycoproteins begins in the rough endoplasmic reticulum (RER) of active thyrotrophs. This would contrast with most cells studied, in which fucosylation generally is associated with the Golgi apparatus. Mouse thyrotropic tumor tissue was incubated with [35S]methionine for 2, 5, 7, 10, 30, and 90 minutes. TSH and free alpha-subunits were immunoprecipitated from cell lysates, and they displayed a time-dependent increase in affinity for lentil lectin (which binds oligosaccharides having core fucose), even at short times. Since no 20-30 minute lag in onset of TSH- and free alpha-subunit-lentil binding was appreciated, as might have been expected had fucosylation begun only in the Golgi, it appeared that fucosylation was beginning in the RER of thyrotrophs. Pituitary tissue from euthyroid and hypothyroid mice was incubated with [3H]fucose, then subjected to electron microscopic autoradiography. The pituitaries of hypothyroid mice had numerous "thyroidectomy cells," which had 40% of silver grains over dilated cisternae of RER. "Nonthyroidectomy" cells had few silver grains over RER; most were over secretory granules and Golgi areas. Thus, active mouse thyrotrophs appear to shift the subcellular site of fucosylation partially from Golgi to RER, and this phenomenon may represent one cellular mechanism whereby the endocrine regulation of the structure of TSH oligosaccharides is accomplished.


Effects of epidermal growth factor, phorbol ester, and retinoic acid on hormone synthesis and morphology in porcine thyroid follicles cultured in collagen gel. Epidermal growth factor (EGF), phorbol esters (PEs), and retinoic acid (RA) inhibit differentiated functions of thyrocytes. In the present study the inhibitory effects of these growth-promoting factors on hormone synthesis were studied in thyroid follicles cultured in type-I collagen gel, and morphologic alteration by these factors was examined by light and electron microscopy (EM). Porcine open thyroid follicles obtained by treatment with 0.1% collagenase were embedded in collagen gel and cultured in Ham's F12 medium supplemented with 6H (insulin, hydrocortisone, somatostatin, transferrin, glycyl-his-lys, and thyrotropin) + 0.5% fetal bovine serum (FBS). After 1 week these open follicles developed to closed follicles, and the medium was changed to one containing 6H + 0.5% FBS + 0.1 microM sodium iodide (NaI). Some media were supplemented with either EGF, phorbol 12-myristate 13-acetate (PMA), or all-trans RA. The closed follicles retained ability for hormone synthesis for 2 weeks after the medium change in the presence of 6H + FBS + NaI. The amounts of T4 and T3 secreted into the culture medium from day 9 to day 12 after the medium change were 60% and 45% of those from day 0 to day 4, respectively. EGF reduced production of T4 and T3 by 61% and 69%, respectively; PMA, by 87% and 99%; and RA, by 55% and 44%. In the medium supplemented with 6H + 0.5% FBS, the follicles exhibited intact polarity. Apical surfaces with microvilli were oriented to the follicular lumen and tight junctions were on the apical side of cell-to-cell contacts. Desmosomes were found on both the apical and basal halves of the cell contacts.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of dexamethasone, calcium and 1,25-dihydroxycholecalciferol on calcitonin and calcitonin gene-related peptide mRNA levels from the CA-77 C cell line. We used the CA-77 cell, a murine C-cell line derived from a medullary thyroid carcinoma, to study the effects of glucocorticoids, calcium, and vitamin D metabolites on calcitonin (CT) gene expression. Total RNA was isolated, and CT and CT gene-related peptide (CGRP) mRNAs were measured by Northern hybridizations using specific probes. A control mRNA probe (cyclophilin) was used to quantitate the specificity of the changes in CT and CGRP mRNAs. The CA-77 C cell line cultured in basal conditions with a medium deprived of fetal calf serum, but was supplemented by insulin, expressed mainly the CGRP mRNA. Dexamethasone was found to increase both CT and CGRP mRNAs in a time- and dose-dependent way without changing the alternative splicing. A slight but significant increase in the steady-state CT mRNA level was found 3 days after addition of 10(-10) M dexamethasone; the same dose slightly decreased the CGRP mRNA level; concentrations of dexamethasone > or = 10(-9) M elevated both mRNAs. A twelve-fold increase for CT mRNA, and an eightfold increase in CGRP mRNA occurred 3 days after administration of 10(-6) M dexamethasone. Kinetic data revealed inductions of both mRNAs 24 hours after exposure to 10(-7) M dexamethasone, and highest CT and CGRP mRNAs levels were observed after 72 hours of treatment. Calcium from 1-4 mM in short-term (1 hour and 4 hour) or long-term stimulations (1 day and 4 days), with or without dexamethasone cotreatment was ineffective. CT and CGRP mRNAs levels were both half-reduced 48 hours after addition of 10(-7) M 1,25-dihydroxycholecalciferol; this effect was transient, as it disappeared 2 days later.


The best asthma care. A case problem in continuous quality improvement. In the future, health care delivery systems may need to respond to requests from payers to demonstrate the quality of care they provide for types of patients or diseases. Here, asthma is used as an example of what such a response might look like in the context of continuous quality improvement.


Determining medical necessity of outpatient physical therapy services. A patient referred for physical therapy may attend one or several therapy visits or may continue to receive ongoing therapy services several times weekly for several months. The question of the continued medical necessity of those services arises often. Determination of medical necessity for continued therapy services requires knowledge of the natural history of diseases that may require therapy services, familiarity with the effectiveness of treatment alternatives for those diseases, and awareness of community practice patterns. Accurate and complete documentation from the therapist or referring physician is required for the physician advisor or utilization review consultant to make an accurate determination of medical necessity. A structured format for providing this documentation is suggested.