Surgical strategies in esophageal carcinoma with emphasis on radical lymphadenectomy.

From 1975 through 1988, 257 patients with carcinoma of the thoracic esophagus have been treated in our department. Operability was 90% (232/257); overall resectability, 77% (198/257), and for the operated group, 85% (198/232). Hospital mortality rate was 9.6% but decreased to 3% over the period 1986 to 1988. There were 65% squamous cell epitheliomas and 35% adenocarcinomas. Tumor, nodes, and metastases (pTNM) staging was as follows: stage I, 11.6%; stage II, 23.2%; stage III, 37.9%; stage IV, 27.3%. Overall survival rate was 62.5% at 1 year, 42.4% at 2 years, and 30% at 5 years. According to the pTNM staging, 5-year survival was 90% for stage I, 56% for stage II, 15.3% for stage III, and 0 for stage IV. There were no statistically significant differences according to tumor localization, pathologic type, sex, or age. Introducing extensive resection and extended lymphadenectomy seems to improve significantly survival in patients in whom an operation with curative intention was performed, the 1 year survival rate being 90.8% versus 72%; 2-year survival, 81% versus 46%; and 5-year survival, 48.5% versus 41% for radical and nonradical resections, respectively. Based on multivariate Cox regression analysis, only TNM stage and presence or absence of lymph nodes are important factors in predicting survival: stage 1 tumors have lower risk, and involvement of lymph nodes creates higher risk. Using this analysis, there was only for the patients with involved lymph nodes (N1) a significantly better prognosis when a radical lymph node dissection was performed (p = 0.0055). Barrett adenocarcinomas have no worse prognosis than other esophageal carcinomas, with a 5-year survival rate of 91.5% if lymph nodes are negative, and a 54% overall 5-year survival rate. Functional results after restoration of continuity with gastric tubulation were judged excellent to very good in 86.5% at 1 year, but infra-aortic anastomoses have a much higher incidence of peptic esophagitis: 53% versus 8% for cervical anastomoses. From this study it can be concluded that in experienced hands surgery today offers the best chances for optimal staging, potential cure, and prolonged high-quality palliation.


Vascularized tissue transfer for closure of irradiated wounds after soft tissue sarcoma resection.

During the years 1985 to 1989, 82 patients were included in the soft tissue sarcoma protocol. Preoperative irradiation (50-54 Gy) was performed in all patients before tumor extirpation. Microwave hyperthermia was performed in conjunction with radiation in patients who had gross tumor remaining after initial biopsy. Primary closure with vascularized tissue (flaps) in lieu of conventional wound closure by skin approximation led to less complications (19% versus 51%), fewer secondary procedures for wound closure (10% versus 35%), shorter average hospitalization (15 versus 48 days) and greater limb salvage rate (97% versus 91%). The authors conclude that vascularized tissue (flaps) for primary wound closure in irradiated tissue leads to improved wound healing, and should be considered the procedure of choice for heavily irradiated soft tissue sarcoma defects.


A prospective evaluation of plasma-TFE and expanded PTFE grafts for routine and early use as vascular access during hemodialysis.

The use of prosthetic grafts as vascular access for chronic hemodialysis is frequently necessary in patients with end-stage renal disease. Most commonly, expanded polytetrafluoroethylene (e-PTFE) has been employed because of ease of handling, tissue inertness, and acceptable long-term patency. Delay in use to allow for tissue ingrowth, however, has often required placement of temporary access devices. The authors have undertaken evaluation of a new material, plasma polymerized woven dacron Plasma-TFE, in a prospective randomized trial (Plasma-TFE VA) to compare clinical behavior against e-PTFE grafts, and we have used the Plasma-TFE grafts in an additional group of patients (Plasma-TFE AVA) as early access (within 1 week of implantation). Twenty-one Plasma-TFE grafts were implanted in 19 patients and 19 e-PTFE grafts were implanted in 17 patients in a prospective randomized fashion. Additionally, 31 Plasma-TFE grafts were implanted in 31 nonrandomized patients for early access. Primary patency rates in Plasma-TFE VA and e-PTFE grafts were equivalent at 12 months (0.471 and 0.556). When Plasma-TFE AVA primary patency was included (0.621), comparisons were not statistically significant (p = 0.50). Similarly, secondary patency rates among the three groups did not differ (cumulative proportion patent at 12 months: Plasma-TFE VA 0.403, e-PTFE 0.658, Plasma-TFE AVA 0.510). In considering after-revision patency after graft thrombosis, however, the Plasma-TFE grafts (both VA and AVA) performed significantly more poorly (p = 0.027) than e-PTFE grafts. Incidence of graft infection, wound infection, arm edema, hematoma from use, and occurrence of distal limb ischemia between Plasma-TFE (VA and AVA) and e-PTFE did not differ statistically. The authors conclude that Plasma-TFE compares favorably to e-PTFE with respect to primary and secondary patency and nonthrombotic complications, even with early use. Plasma-TFE does not perform as well as e-PTFE, however, after graft thrombosis.


Logistics and technique for combined hepatic-intestinal retrieval.

During a 13-month period, en bloc liver-small bowel cadaveric grafts were procured for seven children and one adult. All liver grafts functioned immediately, and all but one of the recipient patients recovered. Return of absorptive small bowel function was slow, but the integrity of the bacterial intestinal barrier was not disrupted. The described technique allows the procurement of other abdominothoracic organs, with the exception of the whole pancreas.


[The efficacy of Augmentin in suppurative complications in neurosurgery].

The results of clinical and laboratory studies on the use of augmentin in severe purulent complications after neurosurgical operations are presented. The laboratory studies carried out with the use of an automatic system Cobas Bact (Roch) showed that the numbers of the augmentin resistant strains of Staphylococcus and Enterobacteriaceae among the pathogens were 47 and an average of 64.5%, respectively. Gram-negative bacteria resistant to augmentin were 1.5 to 2 times less frequent than those resistant to amoxycillin. Still, they were much more frequent than those resistant to cefotaxime and ceftriaxone. Clinical efficacy of augmentin was studied in treatment of 39 patients with various affections of the brain such as tumors, trauma, vascular malformations and inflammatory processes. The postoperative complications were represented by meningitis, pneumonia, sepsis and their associations. The use of augmentin in the severe intra- and extracranial complications was favourable in 82.1% of the cases.


[Augmentin in the clinical picture of infectious diseases].

Augmentin is a new combination manufactured by Smith Kline Beecham (Great Britain). It is composed of amoxycillin and clavulanic acid and has antibacterial activity. Augmentin was used in clinical trials in the therapy of 50 adult patients with suppurations after surgical operations on the organs of the abdominal cavity, general staphylococcal infections, pneumonia and prophylactically during the preoperative period. It was also used in the treatment of 30 children patients with bronchopulmonary affections and inflammatory otorhinolaryngological diseases. The clinical trials were performed in the Clinic of Infectious Diseases of the N. G. Gabrichevskiĭ Moscow Research Institute of Epidemiology and Microbiology. For comparison ampicillin was used in the trials. Augmentin was shown to be an efficient formulation with antibacterial activity which could be successfully used in the parenteral therapy of severe affections due to organisms sensitive to it. In the treatment of the children patients with pneumonia augmentin by its therapeutic efficacy proved to be superior to ampicillin. The tolerance of augmentin was good.


[Augmentin in the combined therapy of puerperal diseases].

Augmentin was used in treatment of mild forms of postnatal endometritis and serous mastitis. Augmentin tablets proved to be efficient in endometritis due to enterobacteria and obligate nonsporulating anaerobes and mastitis due to Staphylococcus aureus strains sensitive to the preparation. No adverse events were recorded. It was shown that in the treatment of mild postnatal infections the augmentin tablets were not inferior by their activity of combinations of antibiotics against aerobic and anaerobic microflora.


[A clinico-laboratory assessment of the efficacy of an Augmentin suspension in treating children with suppurative-inflammatory diseases caused by opportunistic bacteria].

Augmentin suspension (amoxycillin+clavulanic acid) was estimated in clinico-laboratory studies with respect to children suffering from pyoinflammatory diseases of various localization and its high efficacy was shown. Good and satisfactory results were recorded in 96.3 per cent of the cases in the treatment (monotherapy) and afterwards in the patients, adverse reactions such as nausea and vomiting being recorded only in 1 patient. The therapy with augmentin led to normalization of the microflora of the upper respiratory tract mucosa and a 1.5-fold increase in the neutrophil engulfment index.


[The antimicrobial activity of Augmentin (amoxicillin/clavulanic acid) compared to other antibacterial agents].

Sensitivity of clinical strains of gram-positive and gram-negative bacteria to Augmentin was studied in comparison to other antibiotics. Augmentin was shown to be advantageous in the level and spectrum of its antibacterial activity over ampicillin and other broad-spectrum antibiotics.


[A comparative analysis of the immunochemical determination of gentamycin by fluorescence polarization and quenching].

A polarization fluorescence immunoassay (PFIA) for gentamicin with using a set of reagents made in this country was developed. One ml of fluorescein-labeled gentamicin (50 nM) and 100 microliters of antiserum are added to 50 microliters of the sample and the fluorescence polarization is measured. The time of the assay is 10 to 15 minutes, the range of the measurable concentrations is 0 to 800 ng/ml, the sensitivity of the method is 5 ng/ml and the accuracy is 5.8-10.3 per cent. A fluorescence quenching immunoassay (FQIA) for gentamicin was also developed. Determination of gentamicin by the FQIA does not require the use of a specific polarization fluorimeter. Its linear calibrating dependence is more convenient. However, its accuracy and sensitivity are 3 times lower than those of the PFIA.


Blue toe syndrome. Causes and management.

The sudden development of cyanotic lesions on the feet may be a result of atheroembolic disease or a number of medical conditions. A careful history and physical examination, basic laboratory tests, and noninvasive vascular assessment usually distinguish between medical and surgical causes and direct the choice of further investigations. Specific therapy is often available for medical conditions causing this syndrome. The management of atheroembolic disease is more controversial. In particular, further research is necessary to determine which patients need surgical intervention and which patients can be managed safely by medical therapy.


Physical restraints in the practice of medicine. Current concepts.

This article reviews the current status of the utilization of physical restraints in the practice of medicine. Based on current data from the reference sources, appropriate guidelines for the utilization of physical restraints in the practice of medicine are presented. A review of the current literature as referenced in the article. Only English-language references were used. Articles were selected based on a review of articles from Index Medicus, English-language only. Articles were reviewed by the author for validity and appropriateness. The guidelines of data quality, validity, and appropriateness were applied to all articles by the author. Restraints are frequently used in the practice of medicine. As many as 85% of nursing home patients will be restrained at some time and up to 17% of hospitalized medical patients will be restrained. This treatment is not always appropriate but there are no current guidelines available for the practicing physician to assist him or her in these decisions. The current use of physical restraints is discussed. The risks of restraints are reviewed and the reasons for restraint use are cited. The question regarding the efficacy of restraints is directly addressed for each of the situations in which restraints are most commonly used. The ethical and legal considerations concerning the use of restraints are reviewed, current concepts are summarized, and guidelines for improved usage of restraints are suggested. Despite their extensive use, there is virtually no evidence to support the efficacy of restraints. The risks of using mechanical restraints are numerous and well documented. The detrimental psychologic impact of restraints needs to be emphasized. Restraints are inappropriately used if employed because of fear of liability should a patient fall. The proper approach to the patient at risk of falling is to address the contributing factors that place the patient at risk and, where possible, correct them. Restraints are overused in medicine. Guidelines are given to help improve the employment of this potentially harmful practice.


Resource utilization among intensive care patients. Managed care vs traditional insurance.

There is considerable evidence that members of managed care organizations use fewer hospital resources than patients covered by traditional health insurance. While intensive care might seem to be an unlikely setting for such differences to exist, the relationship between health coverage and use of intensive care has not been examined. We conducted a cross-sectional analysis of consecutive intensive care unit admissions at a regional tertiary care teaching hospital. Patients in managed care plans (n = 159) and with traditional insurance (n = 389) were compared with respect to length of stay, hospital charges, charges for specific services, and use of mechanical ventilation. The analysis controlled for severity of illness, as measured by the Mortality Probability Model, case mix, and mortality. The whole sample as well as subsamples representing medical, emergency surgery, and elective surgery patients were examined. The managed care group, on average, had short stays (both hospital and intensive care unit), lower charges, and less use of mechanical ventilation than the traditionally insured group. Average differences of about 30% to 40% were observed. The finding held for the whole sample as well as the medical and emergency surgery subsamples. The differences were more pronounced in the patients with lowest severity of illness. Even in a setting where there would appear to be relatively little room for discretion in treatment decisions, incentives associated with type of health insurance seemed to affect resource use.


From data to policy ... to politics. The Minnesotans health care plan for universal access to care.

Calls for major reform of the health care delivery system have been sounded at both the state and federal level. However, given the lack of consensus on health care reform at a federal level, more than half of the states are developing initiatives for universal access to care. In 1989, the Minnesota legislature created the Health Care Access Commission to develop a blueprint for universal access in Minnesota. To assist this effort, we studied the extent and nature of uninsurance and underinsurance within the state. In this article we report the findings of that study and discuss how the findings were first used to develop recommendations for universal access legislation. We then describe the fate of the legislation. Finally, we describe the veto and the creation of HealthRight, the recently enacted plan for health care reform bill in Minnesota. This plan simultaneously expands access to care and aims to contain health care costs.


Screening women of childbearing age for human immunodeficiency virus. A cost-benefit analysis.

In light of the increasing problem of perinatal human immunodeficiency virus (HIV) transmission, the issue of screening women for HIV is receiving considerable attention. We analyzed the costs and benefits of screening women of childbearing age for HIV. The analysis was based on a dynamic model of the HIV epidemic that incorporated disease transmission and progression, behavioral changes, and effects of screening and counseling. We found that the primary benefit of screening programs targeted to women of childbearing age lies not in the prevention of HIV infection in their newborns but in the prevention of infection in their adult contacts. Because of this benefit, screening medium- and high-risk women is likely to be cost-beneficial over a wide range of assumptions about program cost and behavioral changes in response to screening.


Physicians' attitudes toward mandatory workplace urine drug testing.

Workplace drug testing programs are being increasingly implemented in both the public and private sectors, and health care workers are unlikely to be excluded from such testing. A survey of attending physicians' attitudes toward mandatory hospital-based urine drug testing was undertaken in a medium-sized, midwestern county. Seventy-four percent (272/368) of the sample responded. Seventy-two percent of the subjects believed physician drug use to be a minor or nonexistent problem, 38% lacked confidence in the testing procedure, and 60% believed that testing infringed on the physician's right to privacy; yet 87% would submit to testing if required by a hospital. Forty-five percent of respondents agreed with the policy of mandatory testing for physicians with hospital privileges, 34% disagreed, and 21% were uncertain. Respondents were more supportive of mandatory testing of other health care and non-health care occupations than for themselves. Support for testing was greatest for illicit drugs. If implemented, physicians preferred mandatory testing to be performed by hospital medical staff independent of hospital administration. Further education and discussion within the physician community appears to be necessary before widespread mandatory workplace urine drug testing of physicians is implemented.


Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients.

The study assessed dialysis support in patients with primary systemic amyloidosis without associated multiple myeloma in whom renal insufficiency developed. The study group consisted of 211 patients with biopsy-proved primary systemic amyloidosis examined at the Mayo Clinic, Rochester, Minn. No patient was lost to follow-up. Thirty-seven (18%) of the patients received dialysis therapy. Of those presenting with renal amyloid, one third received dialysis. The median time from diagnosis to initiation of dialysis was 13.8 months. The median survival for patients from the start of dialysis was 8.2 months. There was no survival difference between hemodialysis (n = 27) and peritoneal dialysis (n = 10). The most important predictors of which patients would ultimately require dialysis were the 24-hour urinary protein loss and serum creatinine values at the time amyloidosis was diagnosed. None of the patients seen at diagnosis with a normal serum creatinine value and proteinuria of less than 2 g/d required dialysis during follow-up. Of the 37 patients who received dialysis, 31 died, and 21 of the 31 died as a result of extrarenal progression of their systemic amyloidosis. Fifteen of the 31 deaths were a result of cardiac amyloidosis. All long-term survivors had normal echocardiograms without evidence of amyloid. Eighteen percent of patients with primary amyloidosis undergo dialysis. The 24-hour urinary protein loss and creatinine values are helpful in predicting which patients eventually will require dialysis. The median survival for patients starting dialysis is less than 1 year. Patients whose two-dimensional echocardiograms are normal are most likely to derive long-term benefit from dialysis.


Occupation and risk of nonfatal myocardial infarction.

While some analytic studies have suggested that individuals in occupations representing higher compared with lower socioeconomic status have a decreased risk of coronary heart disease, it is unclear whether occupation itself has an etiologic role in the development of coronary heart disease or whether differences in as yet uncontrolled coronary risk factors may account for these differences in risk. White-collar vs blue-collar occupation and risk of coronary heart disease was evaluated among 230 male patients hospitalized for a first myocardial infarction and 222 control subjects of the same age, sex, and neighborhood of residence. Information on coronary risk factors was obtained from home interviews, and blood specimens were drawn to test lipid and lipoprotein levels. Usual occupation was dichotomized into white-collar and blue-collar occupation according to the Edwards' classification. The relative risk of myocardial infarction of white-collar compared with blue-collar workers was 0.74 (95% confidence interval, 0.46 to 1.19) after controlling for age, cigarette smoking, family history of premature myocardial infarction, history of treatment for high blood pressure, body mass index, history of diabetes, alcohol consumption, type A personality, leisure-time physical activity, total calories, and percentage of calories consumed as saturated fat. However, there was no residual association after control for high-density lipoprotein cholesterol yielding a relative risk of 0.98 (95% confidence interval, 0.59 to 1.63). These results suggest that white-collar occupation per se does not appear to protect from coronary heart disease. Any apparent protective effect on myocardial infarction that has been previously observed in white-collar compared with blue-collar workers may be attributable to differences in high-density lipoprotein cholesterol levels.


Lack of age-related differences in the clinical presentation of digoxin toxicity.

Digoxin toxicity occurs most commonly among the elderly. While the clinical syndrome of digoxin toxicity is well understood, how toxic manifestations change with age is not known. We performed secondary analysis of data from a postmarketing surveillance study of patients with life-threatening digoxin toxicity treated with digoxin antibody therapy. Patients receiving long-term maintenance digoxin therapy and aged 55 years or older were divided into four age groups: 55 to 64, 65 to 74, 75 to 84, and 85 years and older (n = 45, 167, 183, and 83, respectively) and compared with regard to presenting manifestations, digoxin dosing, serum potassium and digoxin levels, and renal function. The prevalence of high-degree atrioventricular block showed an increasing but nonsignificant trend with age (40%, 40%, 42%, and 47%, respectively). Age-related trends in high-degree atrioventricular block were stronger among men than women and even stronger among men with underlying cardiac ischemia. The proportion of subjects with nausea/vomiting as a toxic manifestation did not consistently change with age (42%, 48%, 48%, and 46%, respectively). There were no age-related differences in degree of renal impairment or maintenance dose, but maintenance dose decreased with increasing renal impairment. Among patients with life-threatening digoxin toxicity, there is no age-related difference in clinical presentation.


Risk of age-related fractures in patients with primary hyperparathyroidism.

Bone mass is reduced, but the influence of primary hyperparathyroidism (HPT) on fracture risk is controversial. We addressed this issue in a population-based retrospective cohort study. Ninety residents of Rochester, Minn, were first diagnosed with HPT in 1965 through 1976 and an equal number of age- and sex-matched control subjects from the community were identified. Fractures were assessed through review of each subject's complete (inpatient and outpatient) medical records in the community. Prior to the date of diagnosis, Rochester residents with HPT were more likely to have a history of fractures than were matched control subjects from the same population (30% vs 18%). Subsequently, 36% of cases and 31% of control subjects experienced one or more new fractures during 1072 person-years of follow-up; survival free of a new fracture was almost the same in the two groups. Women had more fractures than men, and fracture rates increased with age. Fractures appeared to be somewhat more frequent in those with baseline serum calcium levels of 2.74 mmol/L or more, in those with comorbid conditions possibly due to HPT and in those who did not undergo parathyroidectomy, but these differences were not statistically significant. In a multivariate analysis, only age at diagnosis was an independent predictor of fracture risk, with a 36% increase in risk per 10-year increase in age. Overall fracture risk was increased prior to diagnosis of HPT but not afterward. Because the numbers involved were small, however, we cannot exclude an increased likelihood of fractures in certain subgroups of HPT patients.


High incidence rates of invasive pneumococcal disease in the White Mountain Apache population.

In this article we determine the incidence and clinical spectrum of invasive pneumococcal disease in the White Mountain Apache population, a group known to have a high incidence of invasive disease due to Haemophilus influenzae type b. Patients from whom cultures of normally sterile body sites yielded Streptococcus pneumoniae were identified retrospectively through review of hospital laboratory records from a 6.8-year period. Clinical data were reviewed and incidence rates were computed. The Whiteriver Indian Health Service Hospital is located on the 1.7-million-acre White Mountain Apache Reservation in eastern Arizona. Approximately 10,000 members of the White Mountain Apache Tribe reside on or near the reservation and receive health care through the Whiteriver Indian Health Service Hospital. The average annual incidence rates of invasive pneumococcal disease were calculated and clinical characteristics were reviewed. One hundred thirty-eight cases of invasive pneumococcal disease were identified. The average annual incidence rate was 207 per 100,000 population, and 156 per 100,000 population when adjusted for age by direct standardization to the 1988 US population. The incidence rate was highest in children between 1 and 2 years--2396 per 100,000. The overall case-fatality rate was 5%. Pneumococcal pneumonia was the diagnosis in 79% of the patients 5 years of age or older. Alcohol abuse, identified in 66% of the cases in adults, was the most common underlying medical condition. The incidence rates in White Mountain Apaches are the highest reported for any population. A vaccine effective in children would greatly benefit this population.


Acquired immunodeficiency syndrome/human immunodeficiency virus risk behavior among gay men in small cities. Findings of a 16-city national sample.

Most research on acquired immunodeficiency syndrome has been conducted in several of the country's largest cities, and little is known about the current level of human immunodeficiency virus risk taking among gay men in other geographical areas. The purpose of this study was to determine the frequency of risk behavior practices among gay men in smaller communities. A large sample of men who patronized gay bars in 16 small and moderate-size cities drawn from six states in four different regions of the country was surveyed to determine the frequency of high-risk behavior and factors influencing risk taking. Eighty-five percent of men in all cities' bars completed all survey measures. The community samples were 1991 men; mean age, 31.3 years; mean education, 10.6 years; 90% were white and 10% were of other ethnicities. All participants provided detailed information on their sexual behavior practices over the preceding 2 months and completed measures assessing their perceived peer norms concerning safer sex practices and risk avoidance, intentions to avoid risk, personal risk estimation, acquired immunodeficiency syndrome risk knowledge, perceived threat of acquired immunodeficiency syndrome/human immunodeficiency virus, and serostatus testing history. High-risk patterns were still common among gay men in these smaller cities; nearly one third of all men had engaged in unprotected anal intercourse an average of eight times in the past 2 months, usually outside monogamous relationships. High-risk behavior was most strongly associated with beliefs that safer sex practices would not be well accepted by peers, weak intentions to use condoms, underestimation of personal vulnerability to the acquired immunodeficiency syndrome, younger age, and higher levels of overall sexual activity. Nine percent of men tested said they were seropositive. Growing human immunodeficiency virus prevalence and continued high rates of risk behavior indicate that a new "front line" for human immunodeficiency virus prevention among homosexually active men has shifted to the country's smaller cities. Community prevention efforts in these areas are urgently needed to avert sharp increases in future human immunodeficiency virus infections in this population.


Purulent otitis media in adults.

While the bacterial origin of otitis media has been studied extensively in children, there are few data regarding adults with this disease. We undertook this study to identify the incidence, prevalence, and bacteriologic origin of purulent otitis media in adults. This was accomplished through a review of the English-language literature on adult otitis media and a retrospective review of adult patients with this disease who were hospitalized at our institution. Results of literature review indicate that Streptococcus pneumoniae and Haemophilus influenzae are the most common causes of otitis media in ambulatory adults, but this illness is uncommon, with an incidence of only 0.25%. Hospitalized patients in whom this diagnosis was established suffered a variety of serious suppurative complications such as mastoiditis, meningitis, or brain abscess. Otalgia and fever were the most common symptoms noted in this patient population. Further studies of adult otitis media need to be performed to determine bacteriologic, symptomatic, and high-risk patient groups.


Outcome of cardiopulmonary resuscitation in the intensive care setting.

Although cardiopulmonary resuscitation (CPR) has been shown to be most effective in a monitored setting, previous studies have focused primarily on patients with acute cardiac events rather than chronic progressive disease. This study examined the outcome of CPR in the medical and surgical intensive care units where patients often have acute illness superimposed on chronic underlying conditions. We present a retrospective chart review of all patients undergoing CPR in medical and surgical intensive care units during a 2-year period. One hundred fourteen charts were reviewed. Patient mean age was 59 years. The primary underlying disease was malignancy in 29 (25%), vascular disease in 20 (18%), chronic liver disease in eight (7%), end-stage renal disease in six (5%), chronic obstructive pulmonary disease in five (5%), and other conditions in 46 (40%) patients. Although 50 (44%) of the patients were initially resuscitated, only six (5%) ultimately survived to hospital discharge. Only one of 29 patients with malignancy and one of 39 septic patients survived. Age, sex, and Acute Physiology and Chronic Health Evaluation II scores were similar among survivors and nonsurvivors. Furthermore, four of the six survivors died within 1 year of discharge, and the two others had severe disabilities. Patients with chronic medical conditions undergoing CPR even in an intensive care unit setting seldom survive to hospital discharge. Even among the few survivors, the near term prognosis is poor. Therefore, the decision to perform CPR should take into account underlying chronic medical conditions and not merely the setting of the arrest.


Life-sustaining interventions in frail elderly persons. Talking about choices.

Engaging older persons in consideration of use of life-sustaining measures, such as cardiopulmonary resuscitation, tube feeding, and urgent intubation, is widely recommended, yet uncommon. We studied the short-term impact of a physician-initiated discussion, geared toward guiding informed decision-making, with 20 frail elderly homebound patients. A battery of psychologic rating scales was administered in a pre-post design. Eighteen subjects completed the protocol. Fifteen of the mentally capable surviving subjects were reinterviewed 18 months following the initial discussion to evaluate durability of their decisions. Most welcomed the discussion and clear choices regarding future care usually emerged. Depression rating scales decreased slightly for the entire sample. For the subgroup having relatively internal locus of control, there was an increase in life satisfaction scores. No patient demonstrated signs of emotional trauma consequent to the discussion. On follow-up, several patients were indecisive about their choices. Involvement of these patients in decision-making appeared to have no adverse effects, and, for some, it was therapeutic, possibly through enhancement of personal control. Durability of their decisions was not a consistent finding, however.


Ranitidine pharmacokinetics and adverse central nervous system reactions.

Treatment with histamine2-receptor antagonists has been associated with adverse central nervous system reactions (CNS-ADRs). Previous studies of cimetidine have shown an association between CNS-ADRs and high cimetidine drug levels. While case reports of ranitidine CNS-ADRs have appeared, we wanted to study a series of patients, some of whom were critically ill, for the presence of CNS-ADRs and to correlate these with ranitidine pharmacokinetics. A prospective, observational, open study included 163 consecutive patients, of whom 41 met entry criteria. A nonlinear least-squares regression analysis was used to establish a ranitidine pharmacokinetic dosing model. Ranitidine levels were determined by a high-performance liquid chromatographic assay. Individual ranitidine pharmacokinetics were determined by means of a bayesian model. Observations on 13 possible CNS-ADRs were recorded. The CNS-ADRs were evaluated by the Naranjo rating system. Ranitidine-associated CNS-ADRs, particularly lethargy, confusion, somnolence, and disorientation, occurred more frequently in patients with renal function impairment, and these were associated with higher peak concentrations, average plasma concentrations, and area under the curve. Ranitidine, when given in conventional doses, can cause CNS-ADRs, particularly in older patients who have substantial renal function impairment. These CNS-ADRs occur as a consequence of altered ranitidine disposition. Ranitidine doses should be reduced when renal function impairment is present, and patients should be carefully observed for CNS-ADRs.


Biguanide-associated lactic acidosis. Case report and review of the literature.

The biguanides are a class of oral hypoglycemic agents that are commonly used in the treatment of diabetes mellitus. Such agents include metformin, phenformin, and buformin. The use of phenformin was discontinued in the United States in 1976 because of probable association with lactic acidosis. However, metformin is currently in common use in many parts of the world. In this report, we describe a patient with severe lactic acidosis secondary to metformin administration, and review the literature relevant to biguanide-associated lactic acidosis. We describe a diabetic man with end-stage renal failure and diabetes mellitus who was hospitalized with life-threatening lactic acidosis (lactate, 10.9 mmol/L). Unbeknownst to the hospital staff, he was being treated with metformin, which had been prescribed in Indonesia. Arterial blood gas analysis revealed a pH of 6.76 and a bicarbonate level of 1.6 mmol/L prior to treatment. Following therapy, which included oxygen, volume expansion, other supportive therapy, and hemodialysis, the patient completely recovered and was discharged from the hospital. Lactic acidosis can complicate biguanide therapy in diabetic patients with renal insufficiency. We review the literature relevant to the pathogenesis and therapy of biguanide-associated lactic acidosis. Physicians who have completed their training after 1976 may not be familiar with metformin and other biguanides, but with the increasing numbers of immigrants to the United States, physicians should be aware of the potential complications of these medications.


'Diaphragmlike' stricture and ulcer of the colon during diclofenac treatment.

Diclofenac sodium is a widely used enteric-coated nonsteroidal anti-inflammatory drug. We describe a woman with Hemoccult-positive stools and iron deficiency anemia who developed both a colonic ulcer and a "diaphragm-like" colonic stricture while taking enteric-coated diclofenac. These lesions were evident on colonoscopy but not on barium studies. Biopsy specimens of the ulcer and stricture revealed particulate matter that was indistinguishable from diclofenac pill fragments by electron microscopy. Discontinuation of diclofenac therapy resulted in resolution of anemia and Hemoccult-positive stools. We conclude that (1) enteric-coated diclofenac is associated with both colonic ulcers and diaphragm-like colonic strictures; (2) the pathophysiologic mechanism for the development of both ulcers and strictures may involve a direct action of diclofenac within these lesions; (3) colonoscopy may be superior to barium studies in evaluating patients receiving diclofenac who have iron deficiency anemia and/or Hemoccult-positive stools.


Improved survival in mice with diet-induced pancreatitis treated with new potent protease inhibitor, E-3123 and a broad spectrum antibiotic, cefmetazole.

This study was designed to evaluate the infectious factor in the pathogenesis of acute pancreatitis and the effects of a combination therapy with a new potent protease inhibitor, E-3123, and a broad spectrum antibiotic cefmetazole (CMZ) in mice with CDE diet-induced severe acute pancreatitis. Combination therapy with E-3123 and CMZ showed significant protective effects against the high mortality rate, increased serum amylase and ascitic fluid amylase levels, pancreatic amylase and lysosomal enzyme content, plasma endotoxin levels, redistribution of lysosomal enzyme from the lysosomal to the zymogen fraction, lysosomal and mitochondrial fragility, and also improved the histological findings when compared with the E-3123 alone. These results suggest that infections factors play an important role in the development of severe acute pancreatitis and that protease inhibitors in combination with antibiotics may be clinically beneficial.


Protective effects of combined therapy with a protease inhibitor, ONO 3307, and a xanthine oxidase inhibitor, allopurinol on temporary ischaemic model of pancreatitis in rats.

The protective effect of a new potent protease inhibitor, ONO 3307, in combination with a xanthine oxidase inhibitor, allopurinol, was tested in pancreatico-biliary duct obstruction (PBDO) with temporary pancreatic ischemia in rats. After PBDO with ischemia, we observed hyperamylasemia, pancreatic edema, congestion of amylase and lysosomal enzyme cathepsin B as well as impaired output of amylase and cathepsin B into the pancreatic juice and a redistribution of lysosomal enzyme from the lysosomal fraction to the zymogen fraction. The administration of ONO 3307 plus allopurinol almost completely prevented the pancreatic injuries induced by PBDO with ischemia. These results indicate the important roles of temporary pancreatic ischemia in the pathogenesis of pancreatic damage and the usefulness of combination therapy with a new potent protease inhibitor and xanthine oxidase inhibitor in the protection against clinical acute pancreatitis.


[Protective effect of prostaglandin E2 on cerulein-induced rat pancreatitis].

In order to clarify the effect of prostaglandin E2 (PGE2) on cerulein-induced rat pancreatitis, we investigated the interaction of PGE2 with cerulein or secretin. Intravenous infusion of 10 micrograms/kg.h cerulein inhibited external secretion of the pancreas from one hour and caused macroscopic edema at 3 hours. Administration of PGE2 relieved the inhibitory effect of supramaximal dose of cerulein and decreased the pancreatic edema. The 100 micrograms/kg.hr PGE2 had no significant effect on the pancreatic juice volume and amylase secretion stimulated with 0.2 micrograms/kg.hr of cerulein. Intravenous injection of 100 micrograms/kg PGE2 inhibited both the volume and amylase secretion of pancreatic juice stimulated with 1 U/kg.h of secretin. The protective effect of PGE2 on cerulein-induced pancreatitis was not the stimulation on secretion but caused the cytoprotective effect of PG such as stabilization of cytoplasmic and lysosomal membrane.


[Cystic falx meningioma: report of a case with difficulty in radiologic diagnosis].

A case of cystic falx meningioma in the frontal region in which preoperative neuroradiologic diagnosis was difficult is reported. This 33-year-old man had suffered from epileptic seizures three times in one month. Physical and neurological examinations on admission were normal. A cystic mass with a small nodule was found on CT in the frontal region. Thin wall was enhanced smoothly and the nodule attached to the falx was enhanced heterogeneously. The mass was considered to be an extra-axial lesion on MRI. The right anterior falcine artery seemed to feed the mass. Bifrontal craniotomy was performed. Cyst was evacuated, and a soft reddish mass was subtotally removed. Cyst fluid was yellowish and protein content was 3.5 g/dl. Histopathological diagnosis was a meningotheliomatous meningioma and tumor cells were present also in the thin cyst wall. At the second operation the mass was completely removed, cyst wall inclusive. When we encounter a cystic mass in the sites of predilection of meningiomas, we have to consider the possibility of a cystic meningioma. If the mass has meningeal vascularization, a correct diagnosis is not difficult. Taking the location of the mass into consideration, an accurate interpretation of CT and MRI findings indicating extra-axial nature of the mass is indispensable.


[Possibilities for using bedside cards as secondary comparison in trace element studies with the PCR technique].

When fresh blood is not available as a control in stain investigations extracted teeth, hair, preserved tissue samples, histological slides, cigarette butts or used stamps can also be used. This paper reports on a stain investigation performed 7 months after the death of the victim, where a bedside card from the medical records was successfully employed as a control blood sample. In a series of 10 bedside cards up to 9 years old, the investigation with the PCR method showed recognizable patterns in the STR systems SE 33 and TC 11. Matching patterns could be found from the 4 sections of each card (anti A, anti B, anti AB and anti D). A comparison of the oldest card with a fresh blood sample of the patient also showed matching patterns. AMPFLPs were successful with more recent cards. Using the PCR method typing of bedside cards from medical records up to 10 years old can be used in stain investigations.


Emodin O-methyltransferase from Aspergillus terreus.

Emodin O-methyltransferase, an enzyme catalyzing methylation of the 8-hydroxy group of emodin, was identified in the mould Aspergillus terreus IMI 16043, a (+)-geodin producing strain. The enzyme catalyzed the formation of questin from emodin and S-adenosyl-L-methionine. By chromatography on DEAE-cellulose, Phenyl Sepharose, Q-Sepharose, Hydroxyapatite, and CM-cellulose, emodin O-methyltransferase was purified to apparent homogeneity. The purified protein had a molecular weight of 322 kDa as estimated by gel filtration and 53.6 kDa as estimated by gel electrophoresis under denaturing conditions, suggesting that the active enzyme was a homohexamer. The enzyme showed pI 4.4 and optimum pH 7-8. Magnesium ion or manganese ion was not an absolute requirement, nor increased the enzyme activity. The enzyme had strict substrate specificity and very low Km values for both emodin (3.4 x 10(-7) M) and S-adenosyl-L-methionine (4.1 x 10(-6) M).


[Morphologic patterns in suicidal stab injuries of the neck].

Stabs into the neck are seen very seldom in connection with suicide. If there are features typical of suicide, the medico-legal analysis of the pathomorphological findings essentially may contribute to the differentiation from homicidal injuries. On the basis of the observations already published and three own cases an attempt is made to derive criteria of self-infliction for differential diagnosis from the autopsy findings. Concomitant injuries and combination with another method of suicide have turned out to be important indications of self-infliction.


A strictly anaerobic nitrate-reducing bacterium growing with resorcinol and other aromatic compounds.

With resorcinol as sole source of energy and organic carbon, two stains of gram-negative, nitrate-reducing bacteria were isolated under strictly anaerobic conditions. Strain LuBRes1 was facultatively anaerobic and catalase- and superoxide dismutase-positive. This strain was affiliated with Alcaligenes denitrificans on the basis of substrate utilization spectrum and peritrichous flagellation. Strain LuFRes1 could grow only under anaerobic conditions with oxidized nitrogen compounds as electron acceptor. Cells were catalase-negative but superoxide dismutase-positive. Since this strain was apparently an obligate nitrate reducer, it could not be grouped with any existing genus. Resorcinol was completely oxidized to CO2 by both strains. Neither an enzyme activity reducing or hydrolyzing the resorcinol molecule, nor an acyl-CoA-synthetase activating resorcylic acids or benzoate was detected in cell-free extracts of cells grown with resorcinol. In dense cell suspensions, both strains produced a compound which was identified as 5-oxo-2-hexenoic acid by mass spectrometric analysis. This would indicate a direct, hydrolytic cleavage of the resorcinol nucleus without initial reduction.


Light and the recovery from heat shock induce the synthesis of 38 kDa mitochondrial proteins in Neurospora crassa.

The effect of light on the protein synthesis pattern in the mitochondria of Neurospora crassa was examined by in vivo labelling with [35S]-methionine and two-dimensional gel electrophoresis. A brief 5-min illumination induced the rapid and transient synthesis of a 38-kDa protein. White collar-mutants were not stimulated to synthesize this protein by light. A protein of a similar molecular weight and isoelectrical point was synthesized during recovery from heat shock.


[Suicide with chloroquine combined with maprotiline and trimipramine].

Report on suicide with chloroquine in combination with maprotiline and trimipramine. Chloroquine and his metabolite monodesethylchloroquine could be determined in organs and body fluids. The highest organ-concentrations of chloroquine were found in liver and kidney. The survival time and dose are discussed.


The effect of pH on the heat production and membrane resistance of Streptococcus bovis.

Non-growing cultures of Streptococcus bovis JB1 which were incubated in 2-[N-moropholino] ethane-sulfonic acid (MES)-phosphate buffer (pH 6.8) and glucose (2 g/l) produced heat at a rate of 0.17 mW/mg protein, and this rate was proportional to the enthalpy change of the homolactic fermentation. Since the growth-independent heat production could be eliminated by dicyclohexylcarbodiimide (DCCD), an inhibitor of F1F0 ATPases, it appeared that virtually all of the energy was being used to counteract proton flux through the cell membrane. When the pH was decreased from 6.8 to 5.8, heat production and glucose consumption increased, the electrical potential (delta psi) declined, the chemical gradient of protons (Z delta pH) increased, and there was a small increase in total protonmotive force (delta p). Further decreases in pH (5.8 to 4.5) caused a marked decrease in heat production and glucose consumption even though there was only a small decline in membrane voltage. Based on the enthalpy of ATP (4 kcal or 16.8 kJ/mol), it appeared that 38% of the wattage was passing through the cell membrane. The relationship between membrane voltage and membrane wattage or glucose consumption was non-linear (non-ohmic), and it appeared that the resistance of the membrane to current flow was not constant. Based on the electrical formula, resistance = voltage2/wattage and resistance = voltage/amperage, there was a marked increase in membrane resistance when the pH was less than 6.0. The increase in membrane resistance at low pH allowed S. bovis to maintain its membrane potential and expend less energy when its ability to ferment glucose was impaired.


[Gunshot injury caused by a training bullet].

In the course of a scuffle a 50-year old man has been shot by a revolver. The culprit and witnesses state, there has been only one shot, whereas the victim declared having been shot twice. The medico-legal investigation revealed a gunshot wound that passed through the left thigh, a grazing shot of the right hand and a superficial lesion of the skin at the forehead with sprinkled gunshot residue in the epidermis. The investigation confirmed the statement of the victim: the first shot to the forehead was caused by a plastic training cartridge, the second to the right hand and thigh by a cartridge loaded with an ordinary bullet.


An Escherichia coli mutant containing only demethylmenaquinone, but no menaquinone: effects on fumarate, dimethylsulfoxide, trimethylamine N-oxide and nitrate respiration.

The mutant strain AN70 (ubiE) of Escherichia coli which is known to lack ubiquinone (Young IG et al. 1971), was analyzed for menaquinone (MK) and demethylmenaquinone (DMK) contents. In contrast to the wild-type, strain AN70 contained only DMK, but no MK. The mutant strain was able to grow with fumarate, trimethylamine N-oxide (TMAO) and dimethylsulfoxide (DMSO), but not with nitrate as electron acceptor. The membranes catalyzed anaerobic respiration with fumarate and TMAO at 69 and 74% of wild-type rates. DMSO respiration was reduced to 38% of wild-type activities and nitrate respiration was missing (less than or equal to 8% of wild-type), although the respective enzymes were present in wild-type rates. The results complement earlier findings which demonstrated a role for DMK only in TMAO respiration (Wissenbach et al. 1990). It is concluded, that DMK (in addition to MK) can serve as a redox mediator in fumarate, TMAO and to some extent in DMSO respiration, but not in nitrate respiration. In strain AN70 (ubiE) the lack of ubiquinone (Q) is due to a defect in a specific methylation step of Q biosynthesis. Synthesis of MK from DMK appears to depend on the same gene (ubiE).


[Aspiration of gastric contents in hanging with typical position of the strangulation cord and free suspension].

Among 193 cases of hanging from the years 1978 to 1991 examined in the institute of Forensic Medicine of the Freie Universität Berlin 8 cases with an aspiration of stomach contents had been reported. Herefrom 3 cases were hanging in a "typical" position (suspension point at the back of the head, free suspension of the hanging body) and did not undergo resuscitation. By free suspension of the hanging body the observed massive aspiration of gastric contents only can be explained by an at least partly open connecting passage between the laryngeal entry and the entrance of the oesophagus. The post mortem flowing in of stomach contents as well as a post mortem gastro-oesophageal peristalsis seem not to be able for explicating the findings. Differences in important parameters (e.g. gastric contents, alcoholization) to the cases of hanging without aspiration were not found. Even by free suspension of the body, running noose and point of suspension in the back of the neck sometimes the connection between larynx and oesophagus may stay open, especially when by emesis a high pressure is produced by the stomach.


Isopropylbenzene (cumene)--a new substrate for the isolation of trichloroethene-degrading bacteria.

Various bacterial isolates from enrichments with isopropylbenzene (cumene), toluene or phenol as carbon and energy sources were tested as to their potential to oxidize trichloroethene (TCE). In contrast to toluene and phenol, all isolates enriched on isopropylbenzene were able to oxidize TCE. Two isolates, strain JR1 and strain BD1, were identified as Pseudomonas spec. and as Rhodococcus erythropolis, respectively. TCE oxidation was accompanied by the liberation of stoichiometric amounts of chloride. Initial TCE oxidation rate increased proportional to the substrate concentration from 25 to 200 microM TCE. Maximal initial TCE-degradation rates found here were 4 to 5 nmol.min-1.mg protein-1. The TCE degradation rate decreased with time. The two isolates showed a temperature optimum for TCE degradation between 10 and 20 degrees C. In addition to TCE, R. erythropolis BD1 degraded only cis- and trans-dichloroethene whereas Pseudomonas spec. JR1 was able to oxidize also 1,1-dichloroethene, vinyl chloride, trichloroethane, and 1,2-dichloroethane.


N5-methyltetrahydromethanopterin: coenzyme M methyltransferase in methanogenic archaebacteria is a membrane protein.

An assay is described that allows the direct measurement of the enzyme activity catalyzing the transfer of the methyl group from N5-methyltetrahydromethanopterin (CH3-H4MPT) to coenzyme M (H-S-CoM) in methanogenic archaebacteria. With this method the topology, the partial purification, and the catalytic properties of the methyltransferase in methanol- and acetate-grown Methanosarcina barkeri and in H2/CO(2)-grown Methanobacterium thermoautotrophicum were studied. The enzyme activity was found to be associated almost completely with the membrane fraction and to require detergents for solubilization. The transferase activity in methanol-grown M. barkeri was studied in detail. The membrane fraction exhibited a specific activity of CH3-S-CoM formation from CH3-H4MPT (apparent Km = 50 microM) and H-S-CoM (apparent Km = 250 microM) of approximately 0.6 mumol.min-1.mg protein-1. For activity the presence of Ti(III) citrate (apparent Km = 15 microM) and of ATP (apparent Km = 30 microM) were required in catalytic amounts. Ti(III) could be substituted by reduced ferredoxin. ATP could not be substituted by AMP, CTP, GTP, S-adenosylmethionine, or by ATP analogues. The membrane fraction was methylated by CH3-H4MPT in the absence of H-S-CoM. This methylation was dependent on Ti(III) and ATP. The methylated membrane fraction catalyzed the methyltransfer from CH3-H4MPT to H-S-CoM in the absence of ATP and Ti(III). Demethylation in the presence of H-S-CoM also did not require Ti(III) or ATP. Based on these findings a mechanism for the methyltransfer reaction and for the activation of the enzyme is proposed.


Genes for a second terminal oxidase in Bradyrhizobium japonicum.

Bradyrhizobium japonicum possesses a mitochondria-like respiratory chain terminating with an aa3-type cytochrome c oxidase. The gene for subunit I of this enzyme (coxA) had been identified and cloned previously via heterologous hybridization using a Paracoccus denitrificans DNA probe. In the course of these studies, another B. japonicum DNA region was discovered which apparently encoded a second terminal oxidase that was different from cytochrome aa3 but also belonged to the superfamily of heme/copper oxidases. Nucleotide sequence analysis revealed a cluster of at least four genes, coxMNOP, organized most probably in an operon. The predicted coxM gene product shared significant similarity with subunit II of cytochrome c oxidases from other organisms: in particular, all of the proposed CuA ligands were conserved as well as three of the four acidic amino acid residues that might be involved in the binding of cytochrome c. The coxN gene encoded a polypeptide with about 40% sequence identity with subunit I representatives including the previously found CoxA protein: the six presumed histidine ligands of the prosthetic groups (two hemes and CuB) were strictly conserved. A remarkable feature of the DNA sequence was the presence of two genes, coxO and coxP, whose products were both homologous to subunit III proteins. A B. japonicum coxN mutant strain was created by marker exchange mutagenesis which, however, exhibited no obvious defects in free-living, aerobic growth or in root nodule symbiosis with soybean. This shows that the coxMNOP genes are not essential for respiration in the N2 fixing bacteroid.


Purification and characterization of a methanol-induced cobamide-containing protein from Sporomusa ovata.

The major cobamide-containing protein from methanol-utilizing Sporomusa ovata was 8-fold enriched to apparent homogeneity. The protein exhibited a molecular mass of 40 kDa and of 38 kDa determined by gel filtration and by SDS-polyacrylamide gel electrophoresis, respectively. This finding indicates a monomeric protein structure. Monospecific polyclonal antisera raised against the protein did not cross react with another cobamide-containing protein from Sporomusa cells. Only the 40 kDa cobamide-containing protein was induced by methanol, since proteins from cells grown on 3,4-dimethoxybenzoate, betaine H2/CO2, or fructose showed faint or no cross reaction. Hence, the 40 kDa cobamide-containing protein is presumably involved in the methyl-transfer reaction of the methanol metabolism. The purified enzyme revealed 1.1 mol of p-cresolyl cobamide per mol of protein, but it lacked of iron-sulfur centers. Remarkably, the cofactor was firmly bound to its protein.


Neuroendocrine response to L-5-hydroxytryptophan challenge in prepubertal major depression. Depressed vs normal children.

The neuroendocrine response to L-5-hydroxytryptophan was compared in 37 prepubertal children who met the Research Diagnostic Criteria for major depressive disorder with that in 23 normal children with no lifetime history of any psychiatric disorder and very low rates of depression in both first- and second-degree relatives. Intravenous L-5-hydroxytryptophan (0.8 mg/kg) was given over a 1-hour interval after preloading with oral carbidopa, an inhibitor of peripheral but not central L-5-hydroxytryptophan metabolism. L-5-Hydroxytryptophan, a precursor of serotonin, increases serotonin turnover in the central nervous system when given after carbidopa. Seven (19%) of the 37 children with major depressive disorder and two (9%) of the 23 normal children had nausea or vomiting and therefore did not complete the full infusion. They were subsequently excluded from data analysis. After this stimulation, prolactin, cortisol, and growth hormone secretion were compared between diagnostic groups. The depressed children secreted significantly less cortisol (effect size, 0.70) and significantly more prolactin (effect size, 0.83). There was a sex-by-diagnosis interaction in prolactin response to L-5-hydroxytryptophan and, on examination, the prolactin hypersecretion was seen in depressed girls but not in depressed boys compared with same-sex controls. There was no significant stimulation of growth hormone in either group. These findings are consistent with dysregulation of central serotonergic systems in childhood major depression.


Neuroendocrine responses to m-chlorophenylpiperazine and L-tryptophan in bulimia.

Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitary-adrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.


Effect of axis II diagnoses on treatment outcome with clomipramine in 55 patients with obsessive-compulsive disorder.

We used the Structured Interview for DSM-III Personality Disorders to diagnose DSM-III personality disorders systematically in 55 patients with obsessive-compulsive disorder in the active-treatment cell of a controlled trial of clomipramine hydrochloride. Patients with a cluster A personality disorder had significantly higher obsessive-compulsive disorder severity scores at baseline, and the number of personality disorders was strongly related to baseline severity of obsessive-compulsive disorder symptoms. At the conclusion of the 12-week study, we found no significant difference in treatment outcome with clomipramine between those patients with at least one personality disorder and those with no personality disorders. However, the presence of schizotypal, borderline, and avoidant personality disorders, along with total number of personality disorders, did predict poorer treatment outcome. These variables were strongly related to having at least one cluster A personality disorder diagnosis, which was also a strong predictor of poorer outcome. Implications of these findings are discussed.


Anxiogenic effects of caffeine in patients with anxiety disorders.

The effects on measures of anxiety from two doses of oral caffeine (250 and 500 mg) and placebo were compared in 12 patients with generalized anxiety disorder (GAD), 12 patients with panic disorder, and 12 normal subjects. Caffeine produced significantly less decrease in electroencephalographic alpha wave activity, greater decrease in N1-P2 auditory evoked potential amplitude, and greater increased in skin conductance level, systolic and diastolic blood pressure, critical fusion flicker frequency, and self-ratings of anxiety and sweating in patients with GAD than in normal patients. Patients with panic disorder showed different reactivity than normal patients did with respect to electroencephalographic alpha waves, N2 latency, N2-P2 auditory evoked potential amplitude, and physical tiredness but were less reactive than patients with GAD on several variables. It is concluded that patients with GAD are abnormally sensitive to caffeine and that the data support the view that panic disorder is a separable disorder from GAD.


Physiologic responses to loud tones in Israeli patients with posttraumatic stress disorder.

Orbicularis oculi (eye blink) electromyogram, skin conductance, and heart rate responses to 15 consecutive 95-dB, 500-millisecond, 1000-Hz tones with 0-millisecond rise and fall times were measured in 14 patients with posttraumatic stress disorder, 14 patients with other anxiety disorders, 15 mentally healthy subjects with past traumatic experiences, and 19 mentally healthy subjects with no trauma history. The patients with posttraumatic stress disorder showed significantly larger skin conductance and heart rate responses and a trend toward larger electromyogram responses to the tones than every other group. These effects were not explained by subjective anxiety, resting physiologic arousal, physiologic arousal preceding the tone trials, or initial physiologic responsivity. The group with posttraumatic stress disorder was the only one that failed to show habituation of skin conductance responses.


Naltrexone and coping skills therapy for alcohol dependence. A controlled study.

Ninety-seven alcohol-dependent patients were treated for 12 weeks in a double-blind, placebo-controlled study evaluating naltrexone and two manual guided psychotherapies in the treatment of alcohol dependence. Patients were randomized to receive either naltrexone or placebo and either coping skills/relapse prevention therapy or a supportive therapy designed to support the patient's own efforts at abstinence without teaching specific coping skills. Naltrexone proved superior to placebo in measures of drinking and alcohol-related problems, including abstention rates, number of drinking days, relapse, and severity of alcohol-related problems. Medication interacted with the type of psychotherapy received. The cumulative rate of abstinence was highest for patients treated with naltrexone and supportive therapy. For those patients who initiated drinking, however, patients who received naltrexone and coping skills therapy were the least likely to relapse.


Desipramine treatment of cocaine dependence in methadone-maintained patients.

We performed a double-blind, placebo-controlled, randomized 12-week trial of desipramine hydrochloride treatment of cocaine dependence among methadone-maintained patients. Fifty-nine patients completed the 12-week medication trial (36 received desipramine and 23 received placebo), and 94% were recontacted 1, 3, and 6 months after treatment. There were significantly more dropouts in the desipramine than in the placebo group. Baseline to 12-week comparisons of Addiction Severity Index interview data indicated that both groups showed improvements. At 12 weeks, the desipramine group showed significantly better psychiatric status than the placebo group but did not differ from the placebo group on any of 21 other outcome measures, including cocaine use. During the 12-week medication phase and at the 1-month follow-up evaluation, urine toxicology screenings showed no significant difference between groups, but the placebo group had significantly less cocaine use at both the 3- and 6-month follow-up points. We conclude that desipramine has few benefits with regard to control of cocaine use in this population.


Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine.

In a double-blind, placebo-controlled 12-week randomized clinical trial, we compared amantadine hydrochloride (300 mg/d; n = 33), desipramine hydrochloride (150 mg/d; n = 30), and placebo (n = 31) in the treatment of cocaine-abusing methadone-maintained patients. Treatment retention and medication compliance were excellent, with more than 75% of the patients completing the full 12-week trial. Although reported cocaine abuse was significantly lower in the medicated groups compared with the placebo group at week 4, this difference became nonsignificant at week 8, and no difference was found in cocaine-free urine samples. Future studies of amantadine and desipramine treatment in these patients should consider alternatives to methadone hydrochloride, such as buprenorphine hydrochloride, and the selection of more homogeneous patient subgroups, such as depressed cocaine abusers.


Interinstitutional assessment of colorectal carcinoma surgical pathology report adequacy. A College of American Pathologists Q-Probes study of practice patterns from 532 laboratories and 15,940 reports.

In 1991, the College of American Pathologist's Q-Probes Quality Improvement Program evaluated practices in 532 institutions for pathologic information provided in surgical pathology reports of 15,940 resected primary colorectal carcinomas. Participating institutions studied their last 30 completed cases and were from the United States (98%), Canada (1.5%), and Australia (0.4%). The influence of various institutional differences and other practice patterns were analyzed to determine factors associated with an increased institutional likelihood of providing information on pathology reports. The one practice significantly associated with increased likelihood of providing complete oncologic pathology information on eight of 11 gross and microscopic information items surveyed was the use of a standard report form or checklist. Other institutional differences bearing inconsistent associations included teaching institution status, presence of pathology residency, use of microscopic descriptions, institution bedsize category, and performance of DNA ploidy analysis. The development and adoption of a standardized report form or checklist for each case is a simple but effective means to assure report adequacy and consistent communication of oncologic pathology information. In conjunction with accompanying criteria for its accurate use, this process can be considered a practice guideline or practice parameter that can be extended to the surgical pathology examination of all resected malignant neoplasms.


Confidentiality of human immunodeficiency virus status on autopsy reports. Council on Ethical and Judicial Affairs, American Medical Association.

The medical profession has long recognized the need to maintain the confidentiality of a patient's medical condition, particularly when stigmatizing conditions, like human immunodeficiency virus infections, are involved. The obligation to maintain confidentiality continues after the death of the patient. At the same time, there may be public health concerns that justify limited disclosure of a deceased person's human immunodeficiency virus status. This report provides guidelines that balance the need for confidentiality with public health concerns when a deceased person infected with the human immunodeficiency virus undergoes an autopsy.


Postmortem recovery of human immunodeficiency virus type 1 from plasma and mononuclear cells. Implications for occupational exposure.

To determine the ability to recover human immunodeficiency virus type 1 (HIV-1) from the plasma and mononuclear cell (MNC) fractions of postmortem blood samples from patients with the acquired immunodeficiency syndrome. Blood was randomly cultured post mortem from 41 patients with the acquired immunodeficiency syndrome. Plasma and MNC cultures were performed as well as serum antigen assays. Evaluation parameters included MNC recovery, MNC viability, time of sample collection after death, time of inoculation of coculture following sample acquisition, and storage conditions of the body (ie, refrigeration vs nonrefrigeration). Blood samples were obtained from patients with the acquired immunodeficiency syndrome being prepared for burial at metropolitan area funeral homes. Postmortem samples were obtained from 41 patients with the acquired immunodeficiency syndrome. Virus recovery from either cells or plasma. Human immunodeficiency virus type 1 was recovered from 21 (51%) of 41 patients at 0.5 to 21.25 hours postmortem. Recovery of HIV-1 from plasma and/or MNC fractions was variable with 6 (15%) of 41 plasma+/MNC+, 12 (29%) of 41 plasma-/MNC+, three (7%) of 41 plasma+/MNC-, and 20 (49%) of 41 plasma-/MNC-. Plasma p24 levels (> 30 pg/mL) were detectable in 14 (48%) of 37 samples tested. Of those culture-positive patients, seven (33%) of 21 were refrigerated compared with the culture-negative group in which 10 (50%) of 20 were refrigerated. Time from death until specimen acquisition was the only factor significantly associated with recovery of HIV-1. These results should be useful for health care workers and others exposed to postmortem blood from HIV-infected individuals and should lead to changes in the processing practices of morticians and/or pathologists for HIV-1-infected cadavers.


A decade of acceptable autopsy rates. Does concordance of clinician and pathologist views explain relative success?

In an attempt to better understand the basis and significance of an annual autopsy rate consistently over 45% for the past decade, we recently investigated the attitudes and practices of 36 pathologists and 176 clinicians in our institution with respect to the function of the autopsy service and the utility of the autopsy. The autopsy report was "not used in a consistent manner" by 57% of clinical respondents. Several clinicians thought that autopsy reports were too long (20%) and too slow (38%), but not with the frequency that pathologists did, 73% and 58%, respectively. Significantly more pathologists than clinicians believed autopsy rates have fallen over the past 20 years because (1) people think that everything about the deceased is already known, (2) medical students are poorly educated about the autopsy, (3) pathologists have diminished interest, (4) physicians fear litigation, (5) physicians fear "being wrong," (6) pathologists lack financial incentives, and (7) Joint Commission on Accreditation of Healthcare Organizations requirement is not in place. Perceptions regarding the frequency of major discrepancies between clinical and autopsy findings were comparable, 17% and 13%, for pathologists and clinicians, respectively. Our "high" institutional autopsy rate does not reflect concordance of perceptions expressed by clinicians and pathologists and, thus, other factors may be important in the maintenance of an acceptable rate.


Autopsy-determined causes of death following cardiac transplantation. A study of 81 patients and literature review.

The principal and contributory causes of death in 81 autopsied heart transplant patients who died at Groote Schuur Hospital, Cape Town, South Africa, were investigated and subdivided according to the immunosuppressive regimen used as well as the postoperative survival period. Mean graft survival was 488 days. Chronic rejection (30%), infection (23%), and acute rejection (20%) were the most common principal causes of death. Both fatal and nonfatal infections involved the lung predominantly. A review of the literature revealed 198 other autopsied heart transplant patients whose principal cause of death could be analyzed; infection accounted for almost half of these latter deaths, followed by acute and chronic rejection. Contributory causes of death in the 81 patients were as follows: infection (17%), acute rejection (16%), chronic rejection (14%), miscellaneous conditions (14%), embolism (14%), pancreatitis (11%), peptic ulcer (9%), inadequate donor heart (3%), and malignancy (1%). We conclude that infection, together with acute and/or chronic rejection, are still the major causes of death in heart transplant patients.


Attitudes of funeral directors and embalmers toward autopsy.

Although physician and family attitudes toward autopsy have been suggested as factors leading to declining autopsy rates, attitudes of funeral directors and embalmers toward autopsy have not been studied. We surveyed members of the Illinois Funeral Directors Association concerning beliefs about the purposes of autopsy, problems they experienced with autopsied cases, and the advice they gave to family members about permitting autopsy. Three hundred eight (42.2%) of 730 funeral directors and embalmers responded to the questionnaire. Although 80.3% believed that autopsy served a purpose, 46.4% had counseled families not to permit autopsy, and 16.6% did so more than half the time. Perceived difficulty in embalming autopsied cases (odds ratio, 2.3), family concern about the risk of disfigurement (odds ratio, 1.9 to 2.2), having attempted to talk to a pathologist or hospital administrator about a poorly performed autopsy (odds ratio, 2.0), and belief in the purpose of autopsy (odds ratio, 0.38), were significant independent predictors of counseling against autopsy. Of funeral directors who counseled against autopsy, 28.3% reported that families never permitted autopsy, and 39.4% reported that families only occasionally permitted autopsy, in cases where they had counseled against it. Funeral directors from Illinois counties with 1989 medical certificate case autopsy rates of less than 5% counseled against autopsy more frequently than funeral directors from counties with higher autopsy rates. We conclude that although most funeral directors and embalmers believe in the purposes of the autopsy, difficulties in embalming autopsied cases, and family concern about the risk of disfigurement, may lead members of the funeral profession to counsel against autopsy, and that such advice may influence families not to permit an autopsy.


Accumulation of brown adipose tissue and nutritional status. A prospective study of 366 consecutive autopsies.

Increased amounts of brown adipose tissue have been reported to occur in association with several diseases. The objective of the present study was to determine whether brown adipose tissue accumulation is related to nutritional status. Histologic sections of periadrenal tissue prospectively obtained at consecutive autopsies from 366 adults were examined. The cases were separated into three groups: malnourished (101 autopsies), normotrophic (128 autopsies), and obese (137 autopsies), according to the Quetelet index. Of these patients, 89 had brown adipose tissue accumulation, 35 were malnourished, 32 were normotrophic, and 22 were obese. The results showed a correlation between brown adipose tissue and patient nutritional status and a higher brown adipose tissue accumulation in malnourished patients. Cardiovascular disease was the most common type of illness present in the cases with brown adipose tissue accumulation.


The Bethesda System. A proposal for reporting abnormal cervical smears based on the reproducibility of cytopathologic diagnoses.

In the Bethesda System, noninvasive squamous abnormalities are classified as atypical squamous cells of undetermined significance (ASQUS), low-grade squamous intraepithelial lesions, and high-grade squamous intraepithelial lesions. The Bethesda System eliminates two diagnostic distinctions that are made in the dysplasia/carcinoma in situ and cervical intraepithelial neoplasia (CIN) classifications, CIN1 vs koilocytotic atypia and CIN2 vs CIN3, and maintains three others, negative vs ASQUS, ASQUS vs koilocytotic atypia, and CIN1 vs CIN2. To determine whether the diagnostic distinctions preserved in the Bethesda System are made more consistently than those eliminated, we analyzed the interobserver reproducibility of two cytopathologists in classifying 257 smears. The findings indicate that the distinctions retained in the Bethesda System are more reproducible than those eliminated. Specifically, cases classified as koilocytotic atypia were distinguished from CIN1 no more reproducibly than predicted by chance, whereas CIN2 and CIN3 were distinguished as consistently as any other pair of diagnoses examined. In 13 cases in which there was interobserver discordance, one reviewer classified the smear as ASQUS and the other reviewer diagnosed CIN2 or CIN3. The findings in this study suggest that smears showing koilocytotic atypia and/or CIN1 may be reported as low-grade squamous intraepithelial lesions without further specification. In contrast, smears showing high-grade squamous intraepithelial lesions may be further classified as CIN2 or CIN3 in accordance with the Bethesda guidelines. Since the diagnosis of ASQUS is applied to smears showing a wide spectrum of changes, management of patients with the diagnosis of ASQUS will be facilitated by providing an explanatory note and/or recommendations when appropriate.


The effectiveness of cytologic evaluation of products of conception.

In therapeutic abortions, the major issue of concern to physicians and patients is the documentation of an intrauterine pregnancy and its successful termination. We describe an inexpensive cytologic approach by which results can be obtained in a few hours and a permanent method of documentation provided. Three hundred cases of therapeutic abortion were evaluated by the cytologic method, and 93.7% of cases were positive, ie, they demonstrated the presence of nucleated red blood cells and/or placental villi. By routine histologic examination, 96.3% of the cases were positive. In only 2% of cases was the cytologic finding negative and the histologic finding positive. If the histologic finding is also negative, we recommend, based on our data, that the patient be reevaluated.


Sudden death associated with aortitis and fibrosclerosing disease of the conduction system.

Aortitis is known to complicate a number of autoimmune diseases and syphilis. In most patients with autoimmune disease, arthritis is the initial presentation followed by aortic insufficiency. We report two cases of ostensibly healthy, middle-aged men in whom the initial manifestation of aortitis was sudden death. In each patient, there was extension of inflammation from the aorta into the atrioventricular node. These cases emphasize the importance of examining the conducting system in cases of sudden death associated with aortitis and no grossly evident cause of death. To our knowledge, this is the first report of aortitis presenting as sudden death.


Architectural remodeling of lung allografts in acute and chronic rejection.

The mesenchymal and extracellular matrix alterations that occur in acute and chronic rejection of the lung allograft were studied immunohistochemically, utilizing a wide panel of antibodies. In early rejection, perivascular and peribronchiolar mononuclear infiltrates were associated with basement membrane disruption of the vessels and airways and an ingrowth of muscle-specific actin-, vimentin-positive, desmin-negative spindle cells accompanied by type IV collagenase-positive histiocytes. Subsequent fibrous scarring was manifested by perforation and reduplication of the basement membrane of airways and vessels and dense collagen deposition, primarily type III. As has been suggested in idiopathic pulmonary fibrosis, the fragmentation of basement membranes and the deposition of collagen IV and laminin by mesenchymal cells in vessels and airways may reflect the irreversible fibrosis responsible for allograft dysfunction.


Mammary origin of metastases. Immunohistochemical determination.

Zinc-alpha 2-glycoprotein, gross cystic disease fluid protein 15, and estrogen receptors are expressed in a great proportion of breast carcinomas. These markers were investigated by immunohistochemistry in 28 metastases from breast carcinomas and for comparison on 24 metastases from other carcinomas. A group of 83 primary nonmammary tumors was also studied. Most (> 96%) breast carcinoma metastases expressed one or several markers, while all metastases of other origins were negative. This sensitive and apparently specific immunostaining proved to be of great utility in cases in which the mammary origin of metastases was difficult to establish. In four axillary lymph node metastases, it even led to the discovery of an occult homolateral breast carcinoma that was not detectable by clinical and mammographic investigations. This study indicates that the combined use of zinc-alpha 2-glycoprotein, gross cystic disease fluid protein 15, and estrogenic receptors represents a useful immunostaining technique that can help the pathologist in determining the origin of breast carcinoma metastases.


Uterine leiomyoblastoma (epithelioid leiomyoma) neoplasm of low-grade malignancy. A histopathologic study.

Uterine leiomyoblastomas are neoplasms of smooth muscle origin, which despite their benign histopathologic characteristics, have been shown to invade locally, metastasize, and recur, resulting in the patient's death. In an effort to define possible cellular changes that could explain the disparity between histopathologic features and biologic behavior, we have studied a series of three uterine leiomyoblastomas that, in routine sections, exhibited benign morphological characteristics. A detailed histopathologic study revealed, in all three cases, randomly distributed clusters of neoplastic cells with overt malignant features, such as cellular and nuclear atypia, abnormal mitoses, local infiltrating tendencies, and vascular invasion. These findings suggest that uterine leiomyoblastomas should be viewed as neoplasms of low-grade malignancy of a distinct clinicopathologic entity.


Primary malignant melanoma of the urinary bladder.

Primary malignant melanoma is an unusual neoplasm in the urinary bladder that is infrequently found in association with melanosis. We report a case of bladder-invasive malignant melanoma with melanosis in which the melanosis exhibited melanocytic atypia extending through to melanoma in situ and was diagnosed by immunohistochemical techniques using a monoclonal antibody, HMB-45. To our knowledge, such findings have not been reported previously.


Primary carcinoid tumor of the urinary bladder.

A 62-year-old woman who presented with urinary frequency and microscopic hematuria was found to have a 1.2 x 1.0 x 0.6-cm polypoid carcinoid tumor of the urinary bladder. The tissue resected from the base after removal of the polypoid lesion disclosed a small focus of residual carcinoid tumor, associated with Brunn's epithelial nests, cystitis cystica, and cystitis glandularis. Tumor cells exhibited strong argyrophilia and weak argentaffinity. Immunohistochemical staining reactions were strongly positive for chromogranin and serotonin, and electron microscopy revealed characteristic dense-core granules. Flow cytometric evaluation revealed an aneuploid cell population with a DNA index of 1.20.


Epidermal growth factor receptor expression in Barrett's esophagus.

Six cases of known Barrett's esophagus were examined immunohistochemically for the presence of epidermal growth factor receptor. All cases showed expression of epidermal growth factor receptor in intestinal metaplastic Barrett's epithelium, the most common form of Barrett's change. Expression of epidermal growth factor receptor may be important in neoplastic transformation in Barrett's esophagus, possibly by an autocrine mechanism. Alternatively, epidermal growth factor receptor expression in intestinal metaplastic Barrett's epithelium may represent a nonneoplastic regenerative phenomenon as seen at other sites within the gastrointestinal tract. Further larger studies are required to assess the clinical significance of these findings.


Dissection of the aorta and coronary arteries associated with acute cocaine intoxication.

Acute myocardial ischemia, cardiac arrhythmias, and conduction disturbances are the most common cardiovascular complications of cocaine and its alkaloidal freebase "crack." Cocaine abuse-related acute aortic dissection has been reported only rarely: three cases in the last 5 years. Described herein, to our knowledge, is the first case of cocaine intoxication-associated acute aortic dissection that also involved the coronary arteries, causing sudden death.


Eosinophil-mediated bile duct stricture. A case studied by immunohistochemistry.

Major basic protein accounts for the majority of the protein within the eosinophilic granule. Utilizing immunohistochemical staining for major basic protein, we have demonstrated the dominant role of the eosinophil in a reversible bile duct stricture.


Nitroimidazoles, XIV: Synthesis of 4-nitroimidazoles with 1-substituents containing acid, ester or phenol functions, and radiosensitizing efficiency of some of these compounds.

1,4-Dinitroimidazole and 1,4-dinitro-2-methylimidazole were reacted with aminocarboxylic acids and their esters, aminosulfonic acids, and aminophenol to obtain the corresponding 1-substituted-4-nitroimidazoles. The radiosensitizing efficiency of some esters of 2-(4-nitro-1-imidazolyl)alkanecarboxylic acids was tested.


[Synthesis and cytostatic effect of 2-phenyl-3-alkyl(aryl)-2,3-dihydro-1,3,2(lambda-5)- benzoxazaphosphorine-4-one derivatives].

Preparation of 2,3-dihydro-1,3,2-benzoxazaphosphorin-4-one derivatives and their 2-oxo derivatives is described. Compounds 1 and 12 have anticancer activity.


[2-Amino-3-cyano-dihydroindol-5-ones. 2. The biological activity of a new class of compounds].

2-Amino-3-cyano-dihydroindol-5-ones 2 and 3 are formed by reaction of 2-Aminopyrrole-3-carbonitriles 1 with acetylenic acid esters. In various biological test systems they behave as cytotoxic agents.


[2-Amino-3-cyano-dihydroindol-5-ones. 3. The chemical reactivity of a new class of compounds].

The chemical reactivity of cytotoxic 5-indolone derivatives is examined in order to get ideas about their behaviour in biological systems. Dienone-phenol-rearrangement preserving the indole ring system could not be achieved, aromatization of 1b gives the phenol derivative 3 alpha. In diluted NaOH ester hydrolysis occurs (1a,b----4a,b). Hydrolysis in conc. H2SO4 yields the amides 5a,b,d. In ethanolic HCl the ammonium salts 6a,b,d are formed. Acylation of 1a to 8 reveals the endocyclic N-atom as the nucleophilic center. Benzaldehyde being a strong electrophile adds to 1b in position 4. Weaker electrophiles such as dimethyl acetylenedicarboxylate (ADC) only react with the amides 5b,d to give 11 and 12. Nucleophiles (water, ethanol, n-propylamine) add to the delta 6-double bond yielding 14-16.


Assessment of anti-HIV activity of some benzimidazolylthiazoles.

Benzimidazolylthiazoles 2 were synthesized by condensing 1H-benzimidazole-2-acetonitrile (1) with sulphur and isothiocyanates. The syntheses of the Schiff bases 3, thioureas 4, and thiazolopyrimido[1,6-a]benzimidazoles 5 and 6 are also described. Seven compounds were evaluated in vitro against human HIV, however, no significant activity was observed with any of these compounds.


Studies on annelated [1,4]benzothiazines and [1,5]benzothiazepines, V. Synthesis and biological activity of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine.

The synthesis of a new series of N-2 alkylamino derivatives of 4,5-dihydro-s-triazolo[3,4-d]-1,5-benzothiazepine has been accomplished starting from 2,3-dihydro-1,5-benzothiazepin-4(5H)ones and their 2-methyl and 2-aryl derivatives. All the compounds were tested in vitro for their antimicrobial activity, but none of them showed remarkable activity. The tricyclic compounds 7a-j, 8a-j, 9a-j, 10a-j, and 11a-j were also screened for their CNS activity in mice and several of them showed interesting activity.


Biotransformation of the sympathomimetic tetraminol in vitro.

On incubation with the postmitochondrial fraction of the liver homogenate of rabbits, guinea-pigs, rats, and mice in the presence of NADPH and oxygen, the alpha-sympathomimetic trans-3-(2-hydroxyethylamino)-5,8-dimethoxy-1,2,3,4-tetrahydro-2-n aphthol (Tetraminol, 1) is preferentially O-demethylated in position 8, yielding metabolite 3. In male rats O-demethylation is stronger than in females.


[Enantioselective biotransformation of a new theophylline derivative].

Reductive amination of 4 with (RS)-2 is an improved method to obtain 7-((RS)2-((RS)-1-Methyl-2-phenyl-ethylamino)propyl)-theophylline (3) (ratio of diastereomers 1:1) compared with SN-displacement of proxyphyllintosylate with (RS)-2 (ratio of diastereomers 9:1). Due to steric hindrance 3 is no noteworthy prodrug for the intermediate formation of (RS)-2 in rats. The enantioselectivity of 2 after a single oral dose of 3 is determined in 24-h urine by HPLC on a Cyclobond-column using the isoindole derivatives, formed from o-phthalaldehyde, thioglycolic acid, and 2. The R(-)-amphetamine isomer is formed to a lesser amount (34.8%, range 32-37%) than the S(+)-isomer (65.2%, range 63-68%).


Benzo[b]thiophenes, II: Novel benzo[b]thienylhydrazine and 1,3,4-oxadiazole derivatives as potential antidepressant agents.

Three novel series of benzo[b]thiophene derivatives bearing various hydrazone, hydrazine and 1,3,4-oxadiazole moieties were synthesized as potential antidepressant agents. 22 Compounds were evaluated for their in vitro inhibitory effect on monoamine oxidase enzyme (MAO) type A. Several compounds inhibited MAO stronger than pargyline hydrochloride. Maximum inhibitions of 83% and 90% were observed with 1-benzyl-2-(3-chlorobenzo[b]thienyl-2-carbonyl)hydrazine (24) and 1-[2-(4-chlorophenyl)ethyl]-2-(3-chlorobenzo[b]thienyl-2- carbonyl)hydrazine (35), respectively.


Urological long-term follow-up in women with spinal cord injuries.

One hundred eight women and 434 men admitted with spinal cord injuries between 1973 and 1987 were observed prospectively to determine the effects of age, sex, neurological classification, and method of bladder management method on renal function and urological complications. The primary method of bladder management for women throughout the study period was indwelling urethral catheterization as compared to condom drainage for their male counterparts. Renal function was determined by effective renal plasma flow and urological complications were determined by clinical symptoms and/or objective findings on intravenous pyelography (IVP). Analysis reveals that as in the general population advancing age and being female were significantly associated with lower ERPF (p < .05). Only in men were neurological classification (quadriplegia) and bladder management (ileoconduit) associated with significant decreases in ERPF (p < .05). Furthermore, women and men showed no significant differences in urological complication rates. From the data it can be concluded that there is no particular method of bladder management for women that necessarily leads to impaired renal function.


Subscapular nerve block in the painful hemiplegic shoulder.

Shoulder pain frequently superimposes substantial disability on a limb already limited by hemiplegia. The subscapularis muscle is a major internal rotator of the shoulder and, therefore, plays a role in the flexor synergy pattern commonly seen in spastic hemiplegia. Thirteen patients with spastic hemiplegia, limited range of motion, and painful shoulders underwent percutaneous phenol blocks to the nerves to the subscapularis. Patients' ages ranged from 22 to 76 (x 46 years) and the duration of hemiplegia from two to 13 months. Immediate and significant (p < 0.01) improvements in range of motion were observed in abduction (21 degrees), flexion (40 degrees), and external rotation (38 degrees). Relief of pain was also noted with the previously painful movement. Subscapularis nerve block is a new and potentially useful technique in the management of the painful hemiplegic shoulder.


Phenol block for hip flexor muscle spasticity under ultrasonic monitoring.

Hip flexor spasticity, which is often associated with central nervous system (CNS) diseases, is a major impediment in rehabilitation. In order to cope with this problem, lumbar nerve blocking techniques developed by Meelhuysen and major and minor psoas muscle blocking techniques developed by Awad have been used in combination with physical therapies. Based on these techniques, we conducted major and minor psoas muscle phenol block (motor point block or intramuscular nerve block) under ultrasonic monitoring. Phenol block was conducted in nine patients with cerebral infarction (13 blocking procedures) and three with spinal cord injuries (six blocking procedures) while keeping them in a lateral position with the operation side upside. The beginning of the femoral nerves and part of the lumbar artery were visualized by ultrasound in some patients. As a result of the improvement of hip flexor spasticity, the range of hip joint motion (determined by the Mundale technique, prone hip extension and Thomas test) improved shortly after blocking. When physical therapy was conducted after blocking, improvement of skin care management was observed in eight cases, ability to keep in a stable sitting position in nine, improvement of a standing posture in three, increases in the ability to walk in two and alleviation of pain in three. Although nerve block is reported to result in hematoma, decreases in muscle force, pain, cystic/rectal disorders and hypogonadism, we have observed no such complication in our patients.


Associated movement in hemiplegia: the effects of force exerted, limb usage and inhibitory training.

The intensity of associated movement or motor overflow in the contralateral limb during a unimanual task was evaluated in postacute traumatic brain injured (TBI) young adults with left side hemiplegia and age-matched controls. Both groups demonstrated increased overflow with increasing active limb force, although the trend was for greater overflow to occur in the TBI group, particularly when the spastic limb was active. Following three successive days of inhibitory training with electromyographic feedback, TBI subjects were able to significantly reduce the amount of overflow in the contralateral limb, greater inhibition occurring in the noninvolved limb during spastic limb movement. The results are discussed in terms of a dual model of inhibitory control and the role of such processes in uncoupling the limbs for independent limb usage.