Epidemiology of tuberculosis in Rhode Island. The increase in the reported cases of tuberculosis in Rhode Island from 1985 to 1991 has been striking. This rise has occurred at a faster rate than that for the United States overall. Although the HIV epidemic is largely to blame for the resurgence of tuberculosis nationwide, its impact on tuberculosis locally has been muted. The rise in reported cases in Rhode Island is attributable mainly to increased cases among minority groups, particularly Southeast Asians. Blacks and Hispanics are likewise at an increased risk for developing active disease. Especially alarming is the dramatic rise in the number of tuberculosis cases reported in children in Rhode Island, a reflection of active disease transmission in the community. The Rhode Island Tuberculosis Control Program, already functioning at full capacity, must find ways of curbing the growing tuberculosis problem.


Hepatic, splanchnic and systemic haemodynamic abnormalities in portal hypertension. Portal hypertension is characterized by a pathological increase in portal venous pressure that leads to the formation of portosystemic collaterals that divert portal blood to the systemic circulation, bypassing the liver. Increased vascular resistance to portal blood flow is the initiating factor in portal hypertension. Increased resistance along the hepatic and portocollateral circulation is in part modifiable by pharmacological agents. An additional factor is splanchnic vasodilatation with increased portal blood inflow, which contributes to the maintenance and aggravation of the portal hypertension. Endogenous vasodilators are thought to be responsible for the splanchnic hyperaemia of portal hypertension. Vasodilatation is also prominent in the stomach and lungs, and plays an important role in the pathophysiology of portal hypertensive gastropathy and of the hepatopulmonary syndrome. The systemic circulation is markedly hyperkinetic, with reduced arterial pressure and peripheral resistance and increased cardiac output. The plasma volume is expanded due to renal sodium retention. The expanded plasma volume enables the increase in cardiac output, and represents another mechanism contributing to the increase in portal pressure.


Portal hypertensive gastropathy.

Portal hypertensive gastropathy. There is now substantial clinical evidence to suggest that portal hypertensive gastropathy is an important source of gastrointestinal bleeding in patients with portal hypertension. Although a relatively uncommon presenting feature in such patients, it appears to become progressively more frequent and important the longer such patients with bleeding oesophageal varices survive after treatment by endoscopic sclerotherapy. It is now being increasingly recognized as the most important cause of haemorrhage after oesophageal varices in such patients. The endoscopic and histological characteristics of the condition are now well established but from a clinical point of view it is important to distinguish it from a number of other disorders. The pathogenesis of portal hypertensive gastropathy is poorly understood; venous congestion secondary to portal hypertension undoubtedly plays an important role but this is not thought to account entirely for the condition since abnormalities in the arterial blood supply are also observed. Many abnormalities in gastric mucosal function have been reported but it is unclear whether these are secondary disturbances or whether they play an important primary role in the development of the condition. Animal studies to date have not been helpful due to the lack of a satisfactory experimental model. Portocaval shunt surgery cures portal hypertensive gastropathy but propranolol has been shown to be highly effective in controlling haemorrhage from this condition and should now be considered the treatment of choice. The mechanism of action is unclear, and it remains to be shown whether other beta-blockers, or indeed any other drugs, are useful in treating this disorder.


The role of portosystemic shunting in the management of portal hypertension. In this chapter, we have tried to indicate the role of the portosystemic shunt in the treatment of portal hypertension. The conclusions are evident: in the last 10 years it has lost its role as leader in the treatment of portal hypertension. However, some firm statements can be made. The selective shunt is an operation that provides both good variceal decompression and satisfactory maintenance of liver function. Its results in great part depend on the skill of the surgeon. Only a patient with good liver function (Child's classes A and B) is a candidate for shunt surgery, with, very occasionally, a patient with severe disease (class C). In an emergency, the operation is used only after failure of sclerotherapy, but it must be used at the right time before the patient's condition has deteriorated. In the prevention of variceal rebleeding, the selective shunt or sclerotherapy can be routine measures. The choice between the two treatments depends on the patient's willingness and the ability of the institution to perform both procedures successfully. If sclerotherapy is chosen, the institution must be able to rapidly rescue a sclerotherapy failure by shunt surgery. Liver transplantation is probably the treatment of the future, but it is at present impossible to suggest that the procedure is feasible for all patients with variceal bleeding and severe liver disease.


Management of gastric varices.

Management of gastric varices. Gastric varices (GV) are a common (20%) accompaniment of portal hypertension; they are more often seen in those patients who bleed than in those who do not (27% versus 4%, p < 0.01). They can develop in both segmental and generalized portal hypertension. Depending on their location and relation with oesophageal varices, GVs can be classified as gastrooesophageal varices (GOV) and isolated gastric varices (IGV); each of these can be further subdivided as follows: GOV1 (extension of oesophageal varices along lesser curve) and GOV2 (extension of oesophageal varices towards fundus); and IGV1 (varices in the fundus) and IGV2 (isolated varices anywhere in the stomach). The common presentation of GVs is variceal bleeding and encephalopathy. In comparison with oesophageal varices, GVs bleed significantly less often (64% versus 25%, p < 0.01) but more severely (2.9 +/- 0.3 versus 4.8 +/- 0.6 transfusion units, p < 0.01). Patients with GOV2 and IGV1 bleed more often than patients with other types of GVs. Sclerotherapy for oesophageal varices can significantly influence the natural history of GVs. GOV1, or lesser curve varices, disappear in the majority of cases (59%) after obliteration of oesophageal varices. In those with persisting GOV1, the incidence of bleeding and mortality is high and these patients require gastric variceal sclerotherapy (GVS). During oesophageal variceal sclerotherapy, bleeding can occasionally be induced from GVs. After obliteration of oesophageal varices, recurrence as GVs (secondary GVs) can occur in about 9% of patients. Emergency GVS is quite effective in controlling acute bleeding from GVs, more so than balloon tamponade. Potent sclerosants like tetradecyl sulphate and alcohol and a glue, bucrylate, have been quite effective. Elective GVS can achieve obliteration of GVs in nearly 70% of patients. Rebleeding and ulceration are common complications of GVS; probably related to incomplete obliteration and mucosal injury respectively. Splenectomy is quite effective in treating GVs due to segmental protal hypertension. For GV bleeding due to generalized portal hypertension, a shunt operation is often effective. TIPS procedure appear to be a very promising therapy for GV bleeding. Liver transplantation may be a superior alternative to sclerotherapy and shunt surgery for gastric varices.


Transection and devascularization procedures for bleeding from oesophagogastric varices. Transection and devascularization procedures (Sugiura procedure and transabdominal transection of oesophagus and devascularization) had been the most popular modality of treatment for oesophagogastric varices until the 1970s but the trends of treatment for varices have changed drastically during the last decade. This is partly due to the recent development of endoscopic sclerotherapy and partly due to the patient's increasing demand for less invasive treatment. Recently most patients with oesophagogastric varices are treated initially by endoscopic sclerotherapy and surgical treatment is only called for after sclerotherapy has failed.


Pathophysiology and treatment of ascites and the hepatorenal syndrome. Ascites indicates the accumulation of fluid in the peritoneal cavity, due to a wide range of causes. These causes can be classified according to the presence of portal hypertension, severe blood dyscrasia and peritoneal disease. Cirrhosis is the most frequent cause of ascites. The occurrence of ascites in cirrhosis is due to portal hypertension, which is responsible for the increase in hydrostatic pressure at the sinusoidal level and the alterations of splanchnic and systemic haemodynamics. These latter include increased splanchnic inflow, reduced systemic resistance and increased plasma volume and cardiac output. Portal hypertension also plays a major role in determining sodium retention, which occurs in the setting of increased RAA system and SNS activity. The mechanisms by which portal hypertension leads to the activation of antinatriuretic factors and sodium retention are not completely understood; three main hypotheses have been proposed to explain this relationship, namely the underfilling, the overflow and the peripheral arterial vasodilatation theories. In patients with cirrhosis and ascites, there is an overall activation of the renal prostaglandin system, which probably acts to maintain renal haemodynamics and GFR by counteracting the vasoconstricting effects of AII and noradrenaline on renal circulation. In advanced stages, ascites may become refractory to medical treatment and renal function shows a progressive impairment and eventually acute renal failure, the so-called HRS, due to a marked vasoconstriction of the renal arteries and the opening of the intrarenal-arteriovenous (A-V) shunts. In this condition, the reduced renal synthesis of vasodilating prostaglandins is probably of pathogenic importance. Treatment of ascites is usually based on bed rest, low-sodium diet and administration of aldosterone antagonists and loop diuretics. A sequential treatment of ascites based on the progressive addition of more potent drugs is the best way to relieve ascites while avoiding potentially dangerous side-effects. Patients who fail to respond to the above manoeuvres are said to have refractory ascites. Current treatment of this latter condition is mainly based on therapeutic paracentesis and the application of the LeVeen shunt, but long-term results are unsatisfactory.


Animal implantation results with the Utah-100 total artificial heart. The Utah-100 total artificial heart was designed to have increased reliability over the Jarvik-7 total artificial heart, achieve better fit, and minimize device associated thrombus formation, without decreasing the function. The Utah-100 heart was tested in 28 calves and 3 sheep. The smallest animal at the time of implantation weighted 54 kg. Mean survival duration was 78 days (range, 1-331 days), with 14 animals surviving longer than 60 days. Multiple organ function was maintained satisfactorily with the Utah-100 artificial heart, and mean plasma free hemoglobin values in the calves that survived longer than 100 days were less than 10 mg/dl. Hemorrhage was the main cause of death in animals dying within 30 days after implantation (5/13, 38%); infection was another primary cause of death or termination (4/31, 13%). Deaths due to mechanical failure occurred from valve or diaphragm failure in two cases, yielding a 91% reliability at a 90% confidence level for 60 days' support. No animal died because of driver or other technical failure. Utah-100 hearts showed superior antithrombogenicity in the connector and valve-related areas when compared with the results of the Jarvik-7 heart, which was also fabricated and implanted in our laboratory (p less than 0.01). With these test results, the authors anticipate that the Utah-100 heart will be a safe and effective device for interim use as a bridge to heart transplantation.


Vascular access surgery for maintenance hemodialysis. Variables in hospital stay. Access surgery in support of maintenance hemodialysis is a major factor contributing to prolonged hospitalization in the hemodialysis patient population. In surveying 140 consecutive patients admitted for access surgery, average length of stay was 14 days, independent of race or underlying cause of renal disease. Extended length of stay was most commonly encountered in older patients admitted for thrombosed fistulae or grafts. Postoperative fever, the need for repeated femoral catheterization, delay in access revision or placement due to infection, and the need for adequate social service support resulted in prolonged hospitalization. Understanding and preventing factors that prolong hospitalization may allow the minimization of length of stay in the future and improve quality of life for the end-stage renal disease patient, while also decreasing the cost of care.


Intravascular oxygenation for advanced respiratory failure. Severe acute respiratory failure of varying etiology may require the temporary use of artificial gas exchange devices. So far, extracorporeal membrane oxygenation and extracorporeal carbon dioxide removal have been used successfully for this purpose. A totally implantable intravascular oxygenator (IVOX) recently became available. The authors have used IVOX in three patients who presented with severe respiratory failure secondary to pneumonia (n = 2) and post-traumatic adult respiratory distress syndrome (n = 1). At the time of implantation, all patients had hypoxemia (PaO2 less than 60) despite a 100% inspired oxygen concentration and forced mechanical ventilation. The duration of IVOX therapy ranged from 12 to 71 hr. All patients initially showed improvement in arterial oxygenation, allowing for moderate reduction of ventilator therapy after several hours. In one patient the pulmonary status deteriorated further, and she died from multiple organ failure despite IVOX therapy. One patient could be stabilized but died from other causes. The third patient is a long-term survivor 18 months after IVOX therapy. Gas transfer capabilities of IVOX are limited when compared to extracorporeal membrane oxygenation, and this may restrict its clinical applicability in cases of severe adult respiratory distress syndrome. However, IVOX may be used successfully in selected patients with less severe respiratory failure.


Hybrid artificial cells: microencapsulation of living cells. In 1965, the use of artificial cells for the microencapsulation of living cells was demonstrated. At that time, this technique was also proposed for use in immunoisolation of endocrine cells, islets, and hepatocytes as hybrid artificial organs. Progress in the biotechnology of cell culture in the last 10 years has allowed this approach to be extensively investigated by an increasing number of centers. The author's recent studies concentrated on microencapsulation of hepatocytes as a model system. Such cells were implanted to increase the survival of galactosamine induced fulminant hepatic failure rats, or to decrease the high bilirubin levels in Gunn rats and xenografts of microencapsulated rat hepatocytes into mice provided immunoisolation. Furthermore, hepatocyte secreted hepatic stimulating factors (mw 110,000 D) accumulating in the microcapsules helps to increase the viability of the hepatocytes. In addition to these studies, a novel, two step cell encapsulation method was developed to improve immunoisolation and biocompatibility. Microencapsulation of microorganisms was also carried out using a model microorganism to convert serum cholesterol to carbon dioxide.


Sterilization of a small caliber vascular graft with a polyexpoxy compound. Sterilization of tissue based medical devices via cold sterilization processes has been limited to formaldehyde, glutaraldehyde, and mixtures of the same with alcohols and surfactants. The authors report the sterilization of a small caliber vascular graft with a combination of diglycidyl ether and ethanol. The sterilant contains 1-4% diglycidyl ether and 10-20% ethanol as an aqueous solution. Sterilization is achieved after exposure of the graft to the sterilant solution for a period of 7 days at an elevated temperature (30 degrees - 40 degrees C). The biologic indicator selected for efficacy studies was Bacillus subtilis niger ATCC 9372 (endospores). The grafts were inoculated with a concentrated endospore suspension and immersed in the sterilant solution for increasing time periods. After extensive rinsing over membrane filters to remove any residual sterilant, the grafts and filters were cultured in tryptic soy broth. D10 values were calculated using a fraction-negative, most probable number technique. Additionally, many representative bacteria and fungi were tested and found to be susceptible to the new sterilant developed. The diglycidyl ether/alcohol sterilant developed was found to be efficacious for sterilization of the tissue based vascular grafts tested.


Cardiac pathology following resuscitative circulatory support. Direct mechanical ventricular actuation versus cardiopulmonary bypass. Cardiopulmonary bypass (CPB) is currently advocated for treating refractory cardiac arrest. Direct Mechanical Ventricular Actuation (DMVA) is an alternative method that does not contact the blood and has other unique advantages for providing resuscitative circulatory support, including rapid application and relative technical simplicity. The purpose of this study was to assess pathologic changes in the heart following resuscitation with either CPB or DMVA. Dogs (n = 22) received 1 hr of CPB (n = 11) or DMVA (n = 11) following a 12.5 min cardiac arrest. All deaths [4/11 (CPB) vs. 2/11 (DMVA), p = 0.31] occurred during the initial 24 postoperative hours. At 7 days, survivors had magnetic resonance imaging to determine cardiac ejection fraction [46% (CPB) vs. 51% (DMVA), p = 0.39], as well as the presence of cardiac wall motion abnormalities [50% (CPB) vs. 33% (DMVA), p = 0.57] and gross cardiac lesions [17% (CPB) vs. 17% (DMVA)]. The survivor's hearts were then extirpated, fixed, and examined for gross lesions [2/7 (CPB) vs. 0/9 (DMVA), p = 0.17]. Transmural sections of the anterior and posterior papillary muscles were histologically evaluated. The severity and extent of epicardial fibrosis and focal myocyte necrosis did not differ between groups. These data demonstrate that DMVA does not cause more myocardial trauma than CPB when used to provide resuscitative circulatory support. Therefore, the unique attributes of DMVA may improve resuscitation outcome in patients who suffer refractory cardiac arrest, without additional risk of cardiac injury.


In vitro and in vivo evaluation of microencapsulated porcine islets. To provide a plentiful supply of pancreatic islets for future clinical transplants into diabetic patients, the authors have developed a simple and consistent method of isolation of porcine islets. Both in vitro and in vivo studies demonstrated that the islets were viable and functional. Xenotransplants of 1.5 x 10(3) - 2.5 x 10(3) of microencapsulated porcine islets into diabetic mice resulted in restoration of normoglycemia in 13 of 18 experimental animals for up to 10 months. A xenograft of 50 x 10(3) microencapsulated porcine islets into a spontaneously diabetic monkey normalized hyperglycemia for more than 150 days. This experiment indicated that the transplantation of encapsulated porcine islets has great potential as a clinical treatment in diabetes mellitus.


A cerebrospinal fluid glucose biosensor for diabetes mellitus. A cerebrospinal fluid (CSF) glucose biosensor is introduced. The biosensor is a polarimeter that measures the rotation of plane polarized light proportional to glucose concentration. Preliminary in vitro studies revealed a linear response with good sensitivity over a range of glucose solutions (0-400 mg/dl). Anesthetized, adult dogs underwent intravenous glucose loading, and these preliminary in vivo studies resulted in good correlation (r = 0.98) between CSF polarimeter readings and CSF glucose by laboratory assay. This in vivo correlation suggests that both mutarotation of glucose anomer and changes from other optically active substances present in CSF are either negligible or constant over the range of glucose concentrations studied. The CSF polarimeter showed a significant rise soon after the intravenous loading of glucose (1-30 min) but a longer lag time (45-60 min) between the peak blood glucose and peak CSF polarimeter reading. This preliminary work extends, to the CSF, the concept of measuring optical rotation.


Photodynamic therapy and neoplastic disease. The selective photosensitization of neoplastic lesions is a new modality for eradication of early tumors and palliation of more advanced disease. There is a substantial amount of information relating to modes of photodamage, and the clinical role of this form of therapy is becoming clarified. New sensitizers are being developed with a view toward an enhanced photodynamic effect, utilization of simpler light sources, and elimination of concurrent skin photosensitization. The mechanism whereby efficacious photosensitizers localize in neoplastic, as compared with normal, adjacent tissue remains to be determined, although theories have been proposed. The photosensitizing agent used in most clinical protocols in Photofrin. This product is a complex mixture of porphyrin monomers, dimers, and higher oligomers, and interpretation of biologic and photophysical data is often difficult, although this is not universally appreciated.


Pharmacodynamic and pharmacokinetic aspects of iodo-doxorubicin. Iodo-doxorubicin (I-DOX) is a new doxorubicin (DOX) analog presently in phase II clinical trials in Europe. This drug is similar to DOX in its metabolism but differs in its pharmacokinetics. We describe correlations between pharmacokinetic parameters and toxicity. There is a linear relationship between the dose in mg/m2 and the nadirs of the reduction in white blood cells (WBC), neutrophils (PMN), platelets (PLT), and hemoglobin (HB). Furthermore, a linear correlation exists between the dose in mg/m2 and the area under the curve (AUC) of I-DOX. The relationship between the AUC of I-DOX and the reduction of PMNs plotted on a logarithmic scale shows a sigmoidal curve, whereas no such correlation was found between I-doxorubicinol, the major cytostatic metabolite, and the reduction in PNMs. The variation in the AUC for I-DOX correlated with the relative amount of metabolism of I-DOX. A correlation existed between the relative amount of metabolism of I-DOX and the reduction in PNMs. These results may have an impact on the evaluation of I-DOX in phase II trials, since a sound understanding of the pharmacokinetic/pharmacodynamic relationships can yield important information for minimizing unacceptable toxicity during phase II, as well as phase III, trials.


Relationship between the clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinases-1 (TIMP-1) RNAs. Aberrant expression of secreted proteinases and their specific inhibitors is believed to represent an important factor in the pathogenesis of invasion and metastases of malignant neoplasms. Our previous data indicated a link between elevated expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) and the clinical aggressiveness of malignant non-Hodgkin's lymphomas. Further studies are presented on eighteen cases of high grade, large cell immunoblastic lymphoma in which expression at the RNA level of TIMP-1 and the metalloproteinase, 92 kDa gelatinase, were analyzed. Factors that may influence production of 92 kDa gelatinase, such as necrosis, vascularity, proliferative activity, and extranodal extension, as well as clinical parameters, such as age and sex, stage, location, and survival were assessed. Statistical analysis showed that, although clinical stage was the most important predictor of survival, after controlling for age at diagnosis, levels of 92 kDa gelatinase transcripts added to the ability to predict survival.


Quantitation of comparative thrombogenicity of dog, pig, and human platelets in a hemodialyzer. Comparative platelet thrombogenicity was quantified with In111 labeled platelets. The platelets collected from the blood of Beagle dogs, Yorkshire pigs, and human volunteers were labeled with detergent free In111 tropolone, and sham hemodialysis (SHD) was performed with a hollow fiber dialyzer in a flow loop at 37 degrees C, with flow rates of 7, 150, and 270 ml/min. After SHD, hemodialyzer radioactivity was measured with an ionization chamber, gamma counter, and it was imaged with a gamma camera. The mean values of hemodialyzer-adherent platelet radioactivity were calculated. Canine platelets are more thrombogenic than porcine and human platelets. Quantitation of comparative thrombogenicity with In111 platelets may provide an estimation of prosthesis induced thrombogenicity of human platelets from animal studies.


O6-alkylguanine DNA-alkyltransferase is not a major determinant of sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea in four medulloblastoma cell lines. The protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) has been implicated as a major determinant of resistance of diverse tumors to chloroethylnitrosoureas. To evaluate the contribution of O6-AGT to resistance of medulloblastomas to chloroethylnitrosoureas, we assessed the role of O6-AGT in determining (BCNU). Sensitivity to BCNU cytotoxicity, measured as dose dependent survival of soft agar colony forming ability, varied among the lines. Two lines (UW443 and UW228-3) displayed linear survival curves and comparable BCNU sensitivity (D37 ca. 140 microM). The other lines (UW228-2 and UW228-1) had biphasic survival curves indicating that each line was composed of two sub-populations that differed in BCNU sensitivity. The D37 for these sub-populations ranged from 51 microM to 253 microM. The O6-AGT activities of the cell lines, however, did not reflect their varied susceptibilities to BCNU as evidenced by a 9-fold difference in O6-AGT activity between UW443 and UW228-3. Moreover, elimination of O6-AGT activity by the inhibitor O6-benzylguanine did not appreciably increase sensitivity to BCNU compared with the response of other human tumor cells [Dolan et al. Cancer Res. 51:3367-3372, 1991]. Our results demonstrate that O6-AGT is not a major determinant of BCNU sensitivity in the four medulloblastoma lines.


Fundamental rhythm of sympathetic nerve discharges in animals with total artificial hearts. To evaluate the effect of total artificial heart replacement on the autonomic nervous system, sympathetic neurograms were analyzed by power spectrum and coherence function. Two pneumatically driven, sac type ventricular assist devices were implanted as biventricular bypasses (BVB) in adult, mongrel dogs. After initiation of BVB pumping, the natural heart was electrically fibrillated to form a BVB TAH model. Renal sympathetic nerve activity (RSNA) was recorded using a bipolar electrode attached to the left renal sympathetic nerve. RSNA was amplified and integrated by use of an R-C integrator. Power spectra of the RSNA and values of squared coherence between the arterial pressure wave form and the RSNA were calculated by computer. In animals with total artificial hearts (TAHs), coherence at the cardiac rhythm frequency was decreased, and coherence at the TAH pumping rhythm frequency was increased. These results indicate that the arterial pulse wave observed in TAH animals contributed to the sympathetic neurogram.


Catalysis and ligand binding by thymidylate synthase immobilized on thiopropyl-sepharose 6B. Lactobacillus casei thymidylate synthase, which employs the thiol of cysteine-198 as a covalent catalyst, was reversibly coupled to thiopropyl-Sepharose 6B through the catalytic sulfhydryl group of one of its two subunits, yielding an immobilized heterodimeric form of the enzyme possessing one free active site and one covalently modified active site. Enzyme inactivated by treatment with N-ethylmaleimide, which selectively modifies the active site cysteines but not the remaining cysteines (cys-244), failed to react with the resin. Modified assay procedures were developed and utilized to characterize the activity and ligand binding properties of this unique enzymic species. The immobilized enzyme was found to catalyze thymidylate formation at its free active site but exhibited lowered specific activity (13-fold) and kcat (16-fold) values and an increased Km for dUMP (4-fold) when compared to the native, soluble enzyme. Immobilized enzyme also formed a covalent inhibitory ternary complex with 5-fluoro-2'-deoxyuridylate and 5,10-methylenetetrahydrofolate with a stoichiometry of 0.32 (mol FdUMP: mol enzyme), about half the predicted value of 0.6-0.7. The results of this initial study suggest that the active sites of the native enzyme dimer are asymmetrical in nature, and that the chemical status of the catalytic sulfhydryl groups may play a key role in directing communication between the subunits.


Frequency, therapy, and prevention of infections associated with large bore catheters. Since the introduction of large bore catheters for acute hemodialysis 30 years ago, many problems with handling, material, and contamination of these catheters existed. Nevertheless, the catheterization of the inferior and superior vena cavae with a large bore catheter has proved to be suitable as a rapid connection process for hemodialysis, hemofiltration, hemoperfusion, plasmapheresis, plasmaperfusion, etc. In a retrospective study with 2,626 large bore catheters in 1,627 patients, the frequency of infections, thrombosis, bleeding, and other side effects was investigated. All complications and side effects are presented dependent upon vascular access route. In total, the complication rate was 44.2% higher in subclavian puncture than in internal jugular puncture at 23.9%. The highest complication rates in both vascular access routes were infections or septicemia; infections were observed in 22.8% of subclavian catheters versus 9.5% of internal jugular catheters. Three different catheter materials (Teflon, polyurethane, and polypropylene) were investigated with scanning electron microscopy after removal. The advantages and disadvantages of the different materials are presented.


Carpal tunnel syndrome and systemic sclerosis. Carpal tunnel syndrome (CTS) was observed in 4 cases of a consecutive series of 16 patients admitted for the initial diagnosis or follow-up of systemic scleroderma from 1986 to 1990. We also observed one case of ulnar nerve compression. Neurological involvement was confirmed by electromyogram, and motor and sensory nerve conduction studies. The neurological signs appeared at the beginning of the disease in two cases and preceded the discovery of scleroderma in two. CTS is not rare in scleroderma and must be carefully sought, both clinically and electrophysiologically. Patients with 'idiopathic' CTS might need clinical follow-up for early diagnosis of scleroderma.


The pustule in palmoplantar psoriasis: transformed vesicle or mature microabscess? A three-dimensional study. Psoriasis on the palms and soles is characterized by pustules, vesicles and hyperkeratotic plaques. Several studies have postulated that the pustules and vesicles are round or egg-shaped. This three-dimensional study reveals that neither pustules nor vesicles have a regular spherical morphology. The vesicles are located in the upper and middle layers of the epidermis and may exhibit dumb-bell- or banana-shaped lumina. The pustules consist of different compartments combining characteristics of a dyshidrotic vesicle with those of a microabscess of Munro.


Nonclonal lymphocytic proliferation in cutaneous lymphoid hyperplasia: a flow-cytometric and morphological analysis. Cutaneous lymphoid hyperplasia, follicular B cell pseudolymphoma or lymphadenosis benigna cutis and lymphocytic infiltration of Jessner-Kanof are a group of benign lymphoid hyperplastic disorders which usually involve the skin of the face or head and neck. These lesions may be difficult to differentiate from malignant lymphocytic lymphomas both morphologically and clinically. To evaluate whether quantitative flow-cytometric analysis and DNA ploidy determination of the lymphoid cells in the lesions would provide additional and more precise diagnostic parameters, we have correlatively analyzed a case by morphological, flow-cytometric and immunohistochemical methods. The two latter methods both revealed that the lesions harbored nonclonal heterogeneous subpopulations of lymphoid cells, but 62% of the cells analyzed were of B cell lineage progenies. No pre-B cells, immature B or T determinants were detected. Ploidy analysis of the isolated lymphocytes disclosed predominantly diploid (2 N) cells with about 1% 4 N and a few (less than 5%) hyperdiploid (2.2 N) cells. Cell cycle analysis showed that 97.2% of the cells were in G0-G1 phase. Phenotyping and DNA ploidy study of the lymphocytes of the lesion may provide quantitative diagnostic parameters to distinguish this benign lesion from true lymphocytic lymphoma involvement of skin. The eventual biological behavior of the minor hyperdiploid subpopulation of lymphoid cells found in this lesion is currently uncertain, however.


Wet working conditions increase brittleness of nails, but do not cause it. The incidence of brittle nails is higher in women than in men. Repeatedly a suspected cause for the higher incidence of brittle nails in women is the frequent exposure to water. This study was aimed at clarifying whether wet working conditions increase the incidence of brittle nails in women and men in a similar degree. We determined the incidence of brittle nails in 511 persons in professions that involve frequent hand contact with water. The data were compared to those of a large, non-selected control group. 50% of the female probands showed the sign of brittle nails (control group: 30.4%, p less than 0.05). Only 13.5% of the male test persons of this study had brittle nails; the difference to the control group (13.2%) was not significant. It is discussed that in women the bridges between nail corneocytes are possibly weaker than in males as a constitutional characteristic. Accordingly, frequent alternating periods of hydration and drying increase the incidence of brittle nails particularly in women.


Vitiligo is associated with a significant increase in HLA-A30, Cw6 and DQw3 and a decrease in C4AQ0 in northern Italian patients. HLA polymorphisms of class I (HLA-A, B, C) of class II (HLA-DR, DQ) and of class III (C4A, C4B, BF) were investigated in 93 Northern Italian patients affected with vitiligo and in 388 controls. Vitiligo patients had significant increases in HLA-A30 (corrected p, pc = 0.0144), Cw6 (pc = 0.0189), DQw3 (pc less than 0.0003) and a significant decrease in C4AQ0 (pc = 0.003). Nonfamilial vitiligo is marked by increases in HLA-A30 and DQw3. Extensive vitiligo is marked by increases in HLA-A30 and Cw6. These findings suggest that immunogenetic mechanisms may be responsible for vitiligo and that unique HLA phenotypes may influence the expression of vitiligo in this population.


Quinolones as an alternative treatment of chlamydial, mycoplasma and gonococcal urogenital infections. We report the results of several trials aimed at evaluating the quinolones in urogenital infections. In Chlamydia trachomatis infections, ofloxacin (200 mg b.i.d. for 10 days) gave a cure rate of 98% (n = 66), and fleroxacin (400 mg s.i.d. for 7 days) provided a cure rate of 89% (n = 19). A double-blind study comparing fleroxacin (600 mg s.i.d.) to doxycycline (100 mg b.i.d.) for 7 days showed similar high cure rates for both regimens (100%; n = 23). In Mycoplasma hominis infections, ofloxacin (200 mg b.i.d. for 10 days) yielded a cure rate of 86% (n = 50) for M. hominis and 55% (n = 43) for Ureaplasma urealyticum. Gonococcal infections (n = 122) were all cured by a single dose of 200 mg ofloxacin. Both ofloxacin and fleroxacin were well tolerated and may be recommended for patients with chlamydial or uncomplicated gonococcal infections, although 600 mg fleroxacin showed a higher incidence of adverse events compared to doxycycline.


Acral persistent papular mucinosis and IgA monoclonal gammopathy: report of a case. The case of a 60-year-old man with acral persistent papular mucinosis (APPM), thought to represent a new distinctive form of dermal mucinosis not associated with systemic diseases, is reported. The patient had a 4-year history of multiple small papular lesions on the distal forearms, wrists and back of the hands. Histologically, mucin deposits in the upper and mid dermis sparing a superficial subepidermal grenz zone were observed. In contrast to previously described cases, a monoclonal IgA of kappa light chain isotype was detected. Our findings challenge the view that absence of paraproteinemia is a peculiar characteristic of APPM and raise once more the question of its relationship to the discrete papular form of lichen myxedematosus.


Leukoderma in association with giant congenital nevi: report of two cases. Two patients are presented in whom giant congenital nevi were associated with hypopigmentation. One patient has had no associated melanoma. The second patient developed hypopigmentation years before a melanoma was excised, and increased hypopigmentation was noted years later without evidence of melanoma recurrence. While the mechanism for the development of the hypopigmentation noted in these two patients in uncertain, an immunologically mediated systemic process may be responsible.


Anti-lamin-B autoantibodies in a patient with cold urticaria. Anti-lamin-B autoantibodies at a significant level had been found on two occasions in the serum of a 56-year-old woman who was suffering from an apparently idiopathic chronic cold urticaria. Anti-lamin autoantibodies can be detected in various autoimmune disorders including hepatitis, vasculitis and peripheral blood cytopenia. In our patient, there was no other clinical or biological abnormality. A chance association cannot be ruled out.


Malignant melanoma in a Hispanic male with nevus of Ota. Nevus of Ota is uncommon in the non-Oriental population. We report a case of malignant melanoma with metastasis to the genitourinary tract in a Hispanic male with nevus of Ota. Thirty-six prior cases of nevus of Ota with malignant melanoma reported in the English language are reviewed. Sixty-eight percent were women; 76% were Caucasians. Metastatic disease was reported in 16%. Three patients had liver metastases. Our case was the first involving the genitourinary tract. All but one patient with metastatic disease died within 1 month of presentation. Despite the increased frequency of nevus of Ota in the Japanese, only 4 cases of malignant melanoma have been reported. Nevus of Ota would appear to be a risk factor for developing malignant melanoma in the Caucasian population.


Tripe palms: a significant cutaneous sign of internal malignancy. Tripe palms is a paraneoplastic keratotic skin sign of great predictive value. It is characterized clinically by a curious rugose thickening of the palms with an accentuation of the normal dermatoglyphic ridges and sulci. Histological examination reveals an undulant epidermis with hyperkeratosis, acanthosis and papillomatosis. More than 80 cases have been reported in the literature; 90% of them were associated with an internal malignancy, mostly a carcinoma of the lung or stomach. We herein report a 66-year-old Chinese man with adenocarcinoma of the lung who presented typical tripe palms. Recognition of this distinctive pattern should prompt a meticulous search for an underlying malignancy, particularly lung or gastric carcinoma.


Hair follicle nevus.

Hair follicle nevus. We present a case of hair follicle nevus, a rare hamartoma composed of vellus hair follicles. Hair follicle nevus should be differentiated from accessory auricle, trichofolliculoma and hair nevus.


Annular psoriasiform eruption with lymphocytic infiltration of the epidermis: a variant of acute psoriasis? Disseminated annular psoriasiform lesions developed over a period of 2 months in a 48-year-old man with no preceding psoriatic history of drug intake, being accompanied by general dullness and arthralgia. Etretinate was effective for both skin eruption and arthralgia; only the latter recurred on its cessation 5 months later. However, histologic features examined by serial sections totally lacked those of pustular psoriasis; there were no neutrophils in the epidermis where massive T lymphocyte infiltration existed instead, in a fashion similar to that of early psoriatic lesions. We differentiated this peculiar annular psoriasiform eruption from the annular erythematous lesions noted in pityriasis rosea, erythema annulare centrifugum, subacute cutaneous lupus erythematosus, annular erythema associated with Sjögren's syndrome and erythema chronicum migrans. It is our speculation that this dermatosis represents a variant of acute psoriasis, rather than annular pustular psoriasis. The histopathologic and immunohistologic findings suggest ongoing cellular immune responses in these lesions where some unknown inhibitory mechanisms might be operative against further production of neutrophil chemotactic factors that usually takes place in psoriatic lesions.


Psoriatic alopecia: acute and chronic hair loss in 47 patients with scalp psoriasis. Symptomatic hair loss and alopecia were seen in psoriatic lesions of the scalp in 47 patients. Remarkably, in 66% of the cases it was an inaugural manifestation, and in 36% the scalp was exclusively involved. Therefore 34% of the patients presented with a primary manifestation of isolated scalp psoriasis. Hair loss varied in intensity from protracted to moderate and massive (36% in tufts). It presented as acute (51%), chronic (36%) or chronic recurrent (13%). Thirteen patients (28%) became aware of the hair loss with the beginning of therapy. The alopecia was found to be circumscribed in 75% of the cases and diffuse in 25%. In 2 cases psoriatic alopecia also manifested itself at sites other than the scalp. The telogen count was found to be increased up to 25-86% in the florid stage. Examinations under the light microscope showed a patchy perifollicular lymphohistiocytic infiltrate in the upper and middle dermis with adnexotropia in several cases. This infiltrate can alter the follicle epithelium and may lead to a granulomatous foreign-body reaction with destruction of the hair follicle. After topical antipsoriatic treatment, most of the reexamined patients showed complete hair regrowth, while 5 developed a residual scarring. Therefore, in the patient with circumscribed or diffuse symptomatic alopecia, with or without scarring, psoriatic alopecia should be considered.


Correlation of eosinophils, eosinophil cationic protein and soluble interleukin-2 receptor with the clinical activity of atopic dermatitis. To evaluate the correlation with the clinical activity of atopic dermatitis (AD) we investigated prospectively cellular and serological parameters such as eosinophils, eosinophil cationic protein (ECP), soluble IL-2 receptor (sIL-2R), soluble CD23 (sCD23) and lactate dehydrogenase (LDH) in peripheral blood of 37 AD patients on admission to and discharge from the Department of Dermatology at the University Hospital in Zurich. On admission the actual clinical skin condition as measured by the skin intensity score (SIS) was significantly correlated with eosinophils (p less than 0.005), ECP (p less than 0.05) and sIL-2R (p less than 0.001). During the observation period a significant improvement in the clinical status as measured by the SIS was observed in all AD patients (p less than 0.001). A significant decrease in sIL-2R (p less than 0.005), which was most pronounced in the group of AD patients receiving systemic steroids, together with a decrease in eosinophils and ECP but not in sCD23 and LDH could be demonstrated between admission and discharge. In addition, a slight but significant increase in peripheral blood lymphocytes (p less than 0.005) and monocytes (p less than 0.01) was noted. Comparing the 'extrinsic' (n = 32) and the 'intrinsic' (n = 5) types of AD no significant differences with regard to the above mentioned parameters were found. Our data indicate that cellular and serological parameters such as eosinophils, ECP and sIL-2R reflect the clinical activity of AD and may therefore give further insights into the pathogenesis of this disease.


Relation between urinary albumin excretion and skin involvement in patients with psoriasis. The increase in urinary albumin excretion rate (AER), a hallmark of both diabetic nephropathy and hypertension, has also been described in patients affected with diffuse psoriasis. The aim of this study was to investigate whether such an increase is independent of the coexistence of diabetes or hypertension and whether it may be related to the extension and severity of skin lesions. Median AER, determined by radioimmunoassay, was significantly higher in a group of 32 normotensive nondiabetic psoriatic patients than in 36 age- and sex-matched controls (9.6 vs. 5.3 micrograms/min; p = 0.0006). AER was related with grading of skin involvement (r = 0.65; p = 0.001); patients with the most widespread skin lesions (psoriasis area and severity index: PASI greater than 11) were characterized by a significantly raised median AER (14.9 micrograms/min) compared with those with PASI scores between 4 and 11 (9.8 micrograms/min) or less (5.6 micrograms/min) and controls (F = 10.58; p = 0.0001), independent of other covariates such as age, sex and blood pressure (p = 0.001). This latter finding was confirmed by the prevalence of microalbuminuria (AER greater than 10 micrograms/min) which was present in 2 out of 8 patients with PASI less than 4, 0 out of 12 patients with PASI ranging between 4 and 11 and in 5 out of 12 psoriatics with PASI greater than 11 (p = 0.038 by two-tailed Fisher's exact test).


Plasma lipid changes in psoriatic children. Plasma lipid, lipoprotein and apoprotein concentrations were determined in psoriatic children and in healthy controls. The plasma total cholesterol (TC) was higher than in controls (p = 0.03). The higher cholesterol levels were explained by an almost significant increase in cholesterol associated with high-density lipoproteins and by the tendency towards higher values of cholesterol associated with low-density lipoproteins and very-low-density lipoproteins. No significant changes of plasma triglycerides were observed. Levels of apoproteins (apo) AI and apo B were not significantly different in psoriatic children; however, the levels of apo B were correlated differently with plasma TC in psoriatic children, and the ratio TC/apo B was significantly increased in patients with respect to the controls, suggesting some differences of plasma lipoprotein lipid/apoprotein relationship in psoriasis.


Prediction of glomerular filtration rate using aminoglycoside clearance in critically ill medical patients. The aim of this preliminary investigation was to evaluate the use of aminoglycoside serum concentrations as a surrogate measure of the glomerular filtration rate (GFR) in comparison with other measured and empiric methods against inulin, the criterion standard measure of GFR. A consecutive sample of all eligible patients. An eight-bed medical intensive care unit in a university-affiliated tertiary-care teaching hospital. Ten critically ill medical patients receiving gentamicin or tobramycin for presumed or documented gram-negative bacillary infection were enrolled in the study. The patients were mechanically ventilated and had underlying organ system dysfunction. All ten patients completed the study. Patients underwent renal functional assessment by measured inulin (Cl(in)) and 24-hour urinary creatinine clearance (Clcr). Aminoglycoside serum concentrations were used to estimate GFR and were compared with the two measured methods and a creatinine clearance calculated with the Cockcroft-Gault method (ClCG). All evaluations were performed the same day. Cl(in) averaged 51.6 +/- 35.0 mL/min and serum creatinine ranged from 0.3 to 5.4 mg/dL (26.5 to 477.3 mumol/L). Steady-state peak and trough aminoglycoside concentrations were 6.1 +/- 1.4 and 1.3 +/- 0.9 micrograms/mL, respectively. There were no statistically significant differences between the various methods, although the aminoglycoside-calculated GFR (Cl(amg)) 95 percent confidence intervals were smaller than Clcr and ClCG compared with Cl(in). Mean absolute errors were smaller with Cl(amg) than with Clcr and ClCG. Regression results indicated that only Cl(amg) and ClCG demonstrated agreement with Cl(in) (lines not different from y = x). However, the Cl(amg) showed closer agreement, with a mean square error almost half that of ClCG (9.6 vs. 18.1). Cl(amg) can be used routinely as an estimate of GFR in critically ill patients, with less error than empiric methods.


Heparin and infusion phlebitis: a prospective study. To determine whether heparin sodium, when added to fluids infused through a peripheral catheter, reduces some local catheter-related problems (i.e., phlebitis, catheter obstruction, and extravasation of fluid) and extends the catheter's useful life. Prospective, double-blind, placebo-controlled. Internal medicine ward of a general hospital with 400 beds. Eighty-one consecutive acute collaborating patients who had a venous catheter in the forearm, inserted by nurses with more than one year of professional experience. Heparin sodium 1000 units/mL or NaCl 0.9% was added to compatible infusion fluids just before they were given to the patients. The final concentration of heparin was 1 unit/mL. Length of time until catheters were removed and reasons for their removal. The heparin group had a lower rate of local catheter-related problems than the placebo group (34.3 vs. 61.5 percent, respectively, p less than 0.05; 95 percent confidence interval for the difference 4.3 to 50.1 percent). The catheter's mean life in the heparin group was longer than that of placebo group (98.9 +/- 55.2 vs. 66.2 +/- 47.2 h, respectively, p less than 0.05; 95 percent confidence interval for the difference 9.15 to 56.25 h). This effect was mainly attributable to prevention of noninflammatory catheter-related problems (e.g., obstruction, extravasation) and to a delay in the appearance of phlebitis. Heparin sodium, when added to infusion fluids to a final concentration of 1 unit/mL, diminishes local intravenous catheter-related problems and extends the catheter's life.


Evaluation of glipizide and glyburide in a health maintenance organization. To determine if there was a difference in the long-term glycemic control, average daily dose, and cost of therapy in patients with noninsulin-dependent diabetes mellitus (NIDDM) treated with glyburide and glipizide in a health maintenance organization (HMO). Retrospective evaluation of medical and pharmacy records. Multispecialty group practice HMO. 140 NIDDM patients being treated with either glyburide (n = 70) or glipizide (n = 70) were randomly selected from the populations of patients receiving either drug using computerized pharmacy records. Mean daily doses and blood glucose measurements (fasting blood glucose, random blood glucose, hemoglobin A1C) were stratified in 3-month periods from the time the drug therapy was started or the patient first presented to the clinic for a total of 18 months. Long-term glycemic control was defined as fasting blood glucose less than 8.33 mmol/L (150 mg/dL). The groups were comparable with regard to age (53.4 y glyburide, 56.7 y glipizide), gender (43 M:27 F glyburide, 47 M:23 F glipizide), race (38 W/16 B/16 H glyburide, 45 W/16 B/9 H glipizide), concurrent medical conditions, adverse effects, and compliance. Long-term glycemic control was similar in both groups. Although the number of subjects who were controlled (by definition) tended to be greater in the glyburide group, no clinical or statistical difference was found. There was no statistical difference in mean daily dose between the ethnic groups, but the small numbers preclude further analysis. The glipizide group had a larger percentage increase in dose within the first year than did the glyburide group; however, the percentage increase from the 3-month dose was similar after 18 months (22.7 percent glyburide, 27.5 percent glipizide.) Average daily cost of therapy, based on mean daily dose, was slightly lower for glyburide-treated patients. If glycemic control is similar with glyburide and glipizide, as seen in this study, economic considerations regarding choice of therapy and formulary inclusion may be appropriate.


Compatibility of ceftazidime and aminophylline admixtures for different methods of intravenous infusion. Aminophylline and ceftazidime are sometimes used concurrently in patients with respiratory disorders. Parenteral aminophylline usually is administered as a constant infusion, and ceftazidime is given intermittently or less commonly as a constant infusion. We evaluated the stability and compatibility of the two drugs when aminophylline is given as a constant intravenous infusion and ceftazidime is administered simultaneously either through a y-site (piggyback method) or as a continuous infusion (constant infusion method). The chemical stability of intravenous aminophylline and ceftazidime in dextrose 5% and NaCl 0.9% for both methods was studied. Three different formulations of ceftazidime from the same manufacturer were studied (minibag using reconstituted ceftazidime, premixed minibag, and ceftazidime arginine). For the piggyback and constant infusion methods, samples were collected at 0, 1, and 2 hours; and 0, 6, and 24 hours, respectively. All experiments were conducted in triplicate. Samples were analyzed in duplicate by a stability-indicating HPLC assay method. Ceftazidime and aminophylline were considered stable if concentrations remained above 90 percent of the original concentrations over the time periods studied. Ceftazidime was determined to be compatible with aminophylline in the piggyback method. In contrast, when aminophylline and ceftazidime were admixed in the same intravenous container (constant infusion method), the two drugs were not stable. These data indicate that aminophylline and ceftazidime admixtures are incompatible when prepared in the same intravenous container, which may occur if both are given as a constant infusion. The two drugs are compatible when the ceftazidime is piggybacked into a primary intravenous set in which aminophylline is administered as a constant infusion.


Two cases of suspected immunologic-based hypersensitivity reactions to etoposide therapy. To report two cases of suspected immunologic-based hypersensitivity reactions to etoposide therapy. Two cases are presented that differ from the majority of reported hypersensitivity reactions to etoposide. One patient, who tolerated etoposide during his first three-day chemotherapeutic dosage regimen, developed a hypersensitivity reaction to etoposide upon re-exposure to the drug during the first day of a subsequent three-day cycle. Another patient experienced a hypotensive episode on the first day of an initial three-day regimen, which did not recur on the two subsequent days of the cycle. However, when the patient was re-exposed to etoposide four weeks later, he experienced a severe reaction within minutes of drug infusion. Both patients were premedicated with corticosteroids and neither reported prior drug allergies. Based upon these cases and other literature reports, we believe these reactions primarily represent a type II or immunologic-based hypersensitivity reaction to etoposide.


Cephalexin-induced Stevens-Johnson syndrome. To report a case of cephalexin-induced Stevens-Johnson syndrome (SJS), a devastating adverse drug reaction that involves the entire skin surface and mucosal areas of the body. MEDLINE search (key terms cephalosporins, Stevens-Johnson syndrome, erythema multiforme, and systemic lupus erythematosus) and references identified from bibliographies of pertinent articles. Clinical presentation and manifestations of SJS include the skin, eyes, gastrointestinal tract, and pulmonary system. Infectious complications are the leading cause of mortality. Early intervention is important to prevent progression of SJS. The case described is consistent with the features of this syndrome. The patient presented with fever, arthralgias, and malaise. Skin lesions included a diffuse violet macular rash with erythema and multiple bullous lesions on her neck and abdomen. The skin biopsy was consistent with SJS. Multiple mucocutaneous ulcers were found in her mouth, but no evidence of lower gastrointestinal tract involvement was documented. She remained relatively free of pulmonary complaints except for the presenting bronchitis. Cephalexin should be added to the list of agents to consider as iatrogenic causes of SJS.


Acute renal failure in an elderly woman following intramuscular ketorolac administration. To report a case of ketorolac tromethamine-induced acute renal failure and to discuss the risk factors that make patients more susceptible to the renal effects of nonsteroidal antiinflammatory drugs (NSAIDs). Case reports and review articles identified by MEDLINE. Indexing terms included ketorolac, renal failure, and NSAIDs. Data were abstracted from pertinent published English-language sources and were reviewed by all authors. Ketorolac is an intramuscularly administered NSAID with many of the same adverse effects associated with other oral NSAIDs. Although reversible depression of renal function has been associated with several NSAIDs, to date there have been no published reports of acute renal failure secondary to ketorolac administration. A 71-year-old woman received three doses of ketorolac to control the pain associated with pelvic and T11-T12 compression fractures. Over the next two days, the patient developed signs and symptoms of acute renal failure, including significant increases in blood urea nitrogen, serum creatinine, and peripheral edema. These signs and symptoms resolved over the next three to four days. Certain risk factors, several of which were present in this woman, make individual patients more susceptible to the renal affects of NSAIDs. These risk factors include advanced age, cirrhosis, volume depletion, congestive heart failure, gastrointestinal bleeding, and preexisting mild renal dysfunction. Caution should be taken when initiating ketorolac or any NSAID therapy with specific attention to risk factors that predispose a patient to renal dysfunction.


Anaphylactoid reaction following ketorolac tromethamine administration. To report a case of an anaphylactoid reaction to injectable ketorolac tromethamine in a patient with no prior history of allergies or risk factors associated with nonsteroidal anti-inflammatory drug-induced hypersensitivity reactions. A 37-year-old man without a significant medical history presented to an emergency department with vague, dull, left-sided chest pain. Myocardial infarction was ruled out based on an unremarkable electrocardiogram, chest X-ray, and laboratory data that were within normal limits. Sublingual nitroglycerin 0.4 mg, magnesium/aluminum hydroxide gel 30 mL, and intravenous ranitidine 50 mg were administered without resolution of symptoms. Ketorolac tromethamine 60 mg was administered intramuscularly with resolution of symptoms. The patient was discharged; however, within 30 minutes, he returned to the emergency department with facial swelling, shortness of breath, and chest tightness. Multiple doses of aerosolized albuterol and intravenous methylprednisolone and diphenhydramine were administered, resulting in a slight improvement of symptoms. The patient was admitted for a complete cardiac evaluation that proved negative. The allergic symptoms resolved and the patient was discharged without medication after a three-day hospitalization. Ketorolac tromethamine is the first injectable nonsteroidal antiinflammatory drug approved for short-term pain management. A review of the literature revealed no similar cases of anaphylactoid reaction. Healthcare professionals must be aware of the potential risks of anaphylactoid reactions, especially in light of the increased use of injectable ketorolac in the ambulatory setting and availability of the oral formulation.


Methemoglobinemia in a patient undergoing gastrointestinal endoscopy. To report a case of methemoglobinemia induced by benzocaine in a patient undergoing gastrointestinal endoscopy. Before undergoing an upper gastrointestinal endoscopy, a 15-year-old girl received 20% benzocaine as a spray, to locally anesthetize the pharyngeal mucosa. Thirty minutes after the endoscopy, the patient suddenly became cyanotic, short of breath, and comatose. She was intubated and transferred to the intensive care unit. Her blood methemoglobin concentration was 54 percent. The patient was treated with intravenous methylene blue. Four hours later she was extubated. She was alert, awake, and asymptomatic. This is the fourth reported case of methemoglobinemia induced by benzocaine spray in patients undergoing gastrointestinal endoscopy. Pathways for the formation of methemoglobin in the body are reviewed. Intravenous methylene blue is the drug of choice for this condition, and produces rapid and dramatic reversal of methemoglobinemia. It is common to use benzocaine spray prior to upper gastrointestinal endoscopy. Benzocaine rarely induces methemoglobinemia in these patients. Prompt diagnosis and treatment with intravenous methylene blue is warranted in such cases.


Cloxacillin-induced acute tubulo interstitial nephritis. To report a case of possible cloxacillin-induced acute tubulo interstitial nephritis (AIN). A 15-year-old male patient presented with hypertension, edema, lumbar pain, sterile pyuria, eosinophiluria (ten percent), and severe renal dysfunction three months after the ingestion of cloxacillin. A renal biopsy revealed diffuse edema and inflammatory infiltrate of the interstitium (five percent eosinophils). He received four sessions of peritoneal dialysis with dramatic improvement in urinary output and renal function. His biochemical parameters returned to normal values 21 days after admission, without the use of glucocorticosteroids. Published case reports on AIN induced by penicillin and related drugs are reviewed and compared. The role of interstitial edema in acute renal failure associated with drug-induced AIN is mentioned. AIN is a rare but significant complication of therapy with penicillin and related drugs. The clinical picture is similar for all of these drugs, but skin rash and fever are absent in AIN induced by cloxacillin and cloxacillin-related drugs. Dialysis improved the patient's urinary output and renal function. Beta-lactam antibiotics should be avoided in patients with cloxacillin-induced AIN.


Chlorpropamide-induced hyponatremia in the veteran population. To determine the incidence and possible risk factors associated with chlorpropamide (CPA)-induced hyponatremia in the veteran population. Retrospective cohort study. Federal tertiary care medical center. Veterans receiving CPA from our facility with at least one serum sodium concentration below 135 mmol/L within the past year were eligible. A randomly selected control group consisting of patients taking CPA with normal sodium concentrations was also chosen. One hundred forty-five of 799 patients who had received CPA were included in the study. The average daily dose of CPA was 425 +/- 207 mg (+/- SD). The incidence of hyponatremia associated with CPA was 7.1 percent (57/799 patients). The majority of patients were mildly hyponatremic (48/57 patients, 84 percent) with serum sodium concentrations between 130 and 134 mmol/L. The incidence of CPA-induced syndrome of inappropriate antidiuretic hormone was 2.1 percent. Concurrent angiotensin-converting enzyme (ACE) inhibitor use was identified as a risk factor; thiazide diuretic use was not. The incidence of hyponatremia related to CPA use in elderly veterans is consistent with other reports in the literature. ACE inhibitors may be a predisposing factor for CPA-induced hyponatremia.


Pamidronate.

Pamidronate. The primary objective of this article is to introduce readers to the use of a new agent, pamidronate. The article discusses its use in hypercalcemia of malignancy (HCM), osteolytic lesions, and Paget's disease. Pharmacokinetic data and clinical trials are reviewed, as well as adverse effects and dosage guidelines. A MEDLINE search was used to identify English-language studies involving pamidronate for the period from 1970 to 1992. As comparative trials were few in number, trials using pamidronate as a single agent were also reviewed. Sparse pharmacokinetic data were obtained from clinical trials. All clinical trials available at the time of publication that met the following criteria were reviewed: (1) allowed for adequate rehydration prior to drug therapy; (2) reported standardized and corrected serum calcium concentrations; (3) separated data obtained from patients who received pamidronate alone from those who received pamidronate and concurrent chemotherapy. Pamidronate has a pharmacologic profile similar to that of etidronate, but pamidronate is more potent and has a longer duration of effect. It has been investigated primarily in the treatment of HCM as well as in the treatment of osteolytic bone metastases and Paget's disease. In hypercalcemia of malignancy it appears to be as effective as established agents with the advantage that a single dose of pamidronate 90 mg iv provides a durable response. In Paget's disease chronic oral administration has also been shown to be effective in relieving bone pain. Adverse reactions with intravenous administration are transient and self-limiting and usually occur with the first dose. The most common adverse effect is a transient and self-limiting fever. Chronic oral administration of doses greater than 600 mg/d is associated with gastrointestinal toxicities. Although more well-designed clinical trials comparing pamidronate with standard therapies and other available agents are necessary, initial results indicate that pamidronate is an effective and promising alternative for use in the treatment of HCM.


Adjuvant intravesical therapy for superficial bladder cancer. To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant intravesical therapy for superficial bladder cancer. Information was retrieved from a MEDLINE search, of the English-language literature. Indexing terms included adjuvant pharmaceutics, bladder neoplasms, thiotepa, mitomycin, BCG vaccine, and doxorubicin. Data from several human and in vitro studies were assessed and evaluated, according to the strength of comparative data and therapeutic response. Emphasis was placed on clinical trials that assessed and evaluated dosage, therapeutic regimens, and therapeutic response of adjuvant intravesical therapy for superficial bladder cancer. Adjuvant intravesical therapy and long-term prophylaxis are effective for superficial bladder cancer. Studies have shown that doxorubicin, thiotepa, BCG, and mitomycin, when used as adjuvant therapy, provide better protection than transurethral resection alone against tumor recurrence and prolong the time to when cystectomy is required. Several randomized clinical trials suggest that BCG is superior to thiotepa, doxorubicin, and mitomycin in preventing bladder tumor recurrence and tumor progression. Local cystitis is an adverse effect produced by all four agents; however, BCG vaccine has been reported to cause a higher incidence of adverse reactions (e.g., dysuria, hematuria). BCG may also cause an influenza-like syndrome, arthralgias, and fever, but most of these reactions have resulted in few severe adverse effects when the drug is given in the relatively modest recommended doses.


Lactulose in the management of constipation: a current review. To review the current published clinical studies evaluating the clinical efficacy and safety of lactulose compared with other laxatives or placebo. Adverse effects associated with lactulose are also reported. Information was retrieved by searching the MEDLINE and EMBASE databases for clinical trials, abstracts, conference proceedings, and review articles dealing with lactulose. Emphasis was placed on clinical trials where lactulose was compared with other laxatives or placebo in patient populations where the diagnosis of constipation was reasonably established. The methodology and results from clinical studies were evaluated. Assessment of the studies was made based on diagnosis of constipation, prior management of patients, follow-up of patients, dosage, and adverse effects. Clinical trials in geriatric patients, terminally ill patients, children, and normal and constipated subjects were reviewed. In most instances, lactulose was compared with a placebo, without incorporating the current education on dietary techniques for improving defecation. Generally, clinical trials have demonstrated a beneficial response compared with placebo, although sometimes that response has been only marginally better, from a clinical point of view.


Impact of therapeutic drug monitoring of intravenous theophylline regimens on serum theophylline concentrations in the medical intensive care unit. The primary objective of this study was to determine if a clinical pharmacist ensuring appropriate use and performing careful pharmacokinetic analysis of serum theophylline concentrations (STCs) can result in optimal theophylline regimens for patients in a medical intensive care unit (ICU). In phase 1 of the study, housestaff physicians determined the theophylline dosing regimen. A clinical pharmacist prospectively followed these initial patients, but did not intervene. Patients in phase 2 received intravenous theophylline, with all dosing regimens being based on prospective therapeutic drug monitoring (TDM) by a clinical pharmacist. The first phase enrolled 11 consecutive patients admitted into the medical ICU and requiring intravenous theophylline. This was followed by a second phase of 14 medical ICU patients whose intravenous theophylline regimen was determined by a clinical pharmacist performing pharmacokinetic analysis. Questions were organized into the following sections: (1) number of STC blood samples drawn, (2) number of emergency STCs performed, (3) number of concentrations per infusion-rate changes, (4) number of STC results in the pharmacist-generated regimens that were within the physicians' predetermined acceptable range. In phase 1, 27 theophylline rate changes occurred, with a mean +/- SD of 1.01 +/- 0.3 STCs per day. In phase 2, 44 theophylline infusion rates were changed, with a mean +/- SD of 0.62 +/- 0.3 STCs per day. The TDM group had a significant reduction (p less than 0.001) in inappropriate concentrations (15 vs. 40 percent) as set by predetermined criteria, and fewer emergency theophylline concentration requests (2 vs. 14). Serum theophylline concentrations ordered by the physician were achieved in 85 percent of the pharmacist-generated regimens. Pharmacokinetic analysis when performing TDM in the determination of intravenous theophylline regimens can result in optimal therapy for patients, while significantly reducing the number of STCs required.


Antibiotic use in urban whites and blacks: the Minnesota Heart Survey. To assess racial differences in the use of antibiotics, including penicillins, erythromycins, tetracyclines, sulfas, and cephalosporins. Population-based surveys, conducted from 1985 to 1987. The seven-county metropolitan area of Minneapolis-St. Paul, MN. 3127 whites (response rate 68 percent) and 1047 blacks (response rate 65 percent), aged 35-74 years. White women (26 percent of 1625) were more likely to report having taken an antibiotic in the past year than were white men (18 percent of 1502), black women (18 percent of 590), or black men (15 percent of 457). Reported antibiotic usage decreased with increasing age. Black men were more likely than white men to report the use of tetracyclines or sulfas; otherwise, white men reported higher usage prevalences. White women reported higher usage prevalences of all drug classes than black women. Significant independent predictors of antibiotic use were younger age, white race, and female gender. Potential explanations for these differences include differences in patient access, physician-prescribing behaviors, or both.


Professional self-image among Israeli pharmacists: sectoral differences. To examine sectoral differences in the professional activities and self-images of Israeli pharmacists. Pharmacists from private, community, and hospital sectors (n = 145) completed a survey that assessed the rewards accrued from their professional activities as pharmacists and evaluated their professional and sectoral self-image. Few intersectoral differences were found among Israeli pharmacists. Most agreed that the main rewards in the public sector are secure employment, intellectual challenge, and responsibility. In the private sector, the rewards are high income, responsibility, and opportunity to counsel. The majority of pharmacists in all sectors are satisfied with their profession, and 90.7 percent would choose it again. Nevertheless, they ranked pharmacy eighth among nine professions chosen for comparison, which shows quite a low professional image. The private and hospital pharmacists attributed a higher social status to their own sectors than to the community sector. The inferior professional self-image held by pharmacists, despite the rewards of the profession, should be examined in greater detail.


Aerosolized pentamidine and Pneumocystis carinii pneumonia: patient compliance and outcomes. The study objectives were to compare compliance between every-two-week and every-four-week aerosolized pentamidine regimens, and to determine if patients who were more compliant with the use of aerosolized pentamidine were at decreased risk for developing Pneumocystis carinii pneumonia (PCP). Nonrandomized observational study of patients receiving aerosolized pentamidine for PCP prophylaxis using the hospital pharmacy computer system to document aerosolized pentamidine use and compliance, and the Patient Administration Division's computer to document cases of PCP. Tertiary care, US Army medical center. All patients who were prescribed aerosolized pentamidine (60 mg every two weeks, 300 mg every four weeks, or both) over a 3.5-year period. Mean percent compliance was determined and compared between every-two-week and every-four-week regimens. The relationship between compliance and cases of PCP as determined using nonparametric statistics. Patients (n = 146) who were prescribed aerosolized pentamidine 60 mg every two weeks were more compliant (p = 0.006) than those prescribed 300 mg every four weeks. In addition, those patients who initially received the 60-mg regimen and were switched to the 300-mg regimen were more compliant when taking the 60-mg dose (p = 0.027). There was no association between compliance with either regimen and cases of PCP. Compliance generally was poor with both regimens. Patients on every-two-week regimens of aerosolized pentamidine were more compliant than those on every-four-week regimens. However, regardless of compliance, some patients failed aerosolized pentamidine over the 3.5-year period. Other agents that lend themselves to compliance may be more appropriate for PCP prophylaxis than aerosolized pentamidine.


Setting confidence intervals for drug concentrations from pharmacokinetic parameters. To describe and illustrate a convenient method of forecasting drug concentrations with confidence intervals (CIs) using the means and standard deviations of relevant pharmacokinetic parameters (e.g., clearance and volume of distribution). Using summary statistics from previously published reports, a Monte Carlo technique employing a SAS random number generator creates an arbitrarily large "sample" of each pharmacokinetic parameter. A related "sample" of drug concentrations is provided by inserting the parameters into the appropriate model. A point estimate of the mean drug concentration with a CI is calculated using standard statistical methods. Both the one- and two-compartment body models are illustrated using previous investigations of gentamicin and lidocaine, respectively. One-compartment simulations describe CIs for gentamicin concentrations that vary widely depending on the source of the clearance and volume of distribution parameters. Lidocaine CIs using a two-compartment analysis indicate a range of concentrations quite different from the expected mean. CIs provide a perspective of drug therapy that is considerably more informative than a simple point estimate of the mean concentration.


Lack of in vitro inactivation of tobramycin by imipenem/cilastatin. Inactivation of aminoglycosides by beta-lactam antimicrobials both in vitro and in vivo has been documented. Such an interaction has not previously been documented between carbapenems and aminoglycosides. Examination of serum concentrations of tobramycin in a patient receiving both agents suggested that this interaction might exist. The purpose of this study was to look at this question in an in vitro model. Low concentrations of tobramycin (10 micrograms/mL) were incubated with imipenem/cilastatin (concentrations of 10, 20, and 40 micrograms/mL) in human serum at 37 degrees C. Aliquots of these solutions were withdrawn at 0, 6, 24, 72, and 120 hours and assayed for tobramycin concentrations using a fluorescence polarization immunoassay. Aliquots of tobramycin 10 micrograms/mL and carbenicillin 200 micrograms/mL were analyzed in the same manner, as a positive control. High concentrations of tobramycin (800 micrograms/mL) and imipenem (5000 micrograms/mL)/cilastatin were incubated together at 21 degrees C and sampled at 0, 6, 24, and 72 hours for tobramycin concentrations. The degradation rates for low-concentration tobramycin and the various concentrations of imipenem/cilastatin were not statistically different from those of the controlled incubations. In contrast, carbenicillin significantly enhanced the degradation rate of tobramycin at this concentration (half-life 72 hours and a 34 percent loss at 24 hours, p = 0.0028). Higher in vitro concentrations of imipenem (5000 micrograms/mL)/cilastatin and tobramycin (800 micrograms/mL) resulted in significant, but moderate degradation over controlled incubations (half-life 80 hours and 10 percent loss at 12 hours, p = 0.0031). These results suggest that inactivation of tobramycin is not a problem at common clinically achievable imipenem serum concentrations in patients.


Chemical compatibility of regional anesthetic drug combinations. To define the physical and chemical compatibilities of several classes of drugs that may be used in combination for peridural anesthesia. Morphine, fentanyl, bupivacaine, lidocaine, tetracaine, ketamine, and clonidine were admixed for one hour in five groups of three-drug combinations, plus one group of all seven drugs. The combinations were inspected macroscopically and microscopically to determine physical compatibility. The admixtures were evaluated by gas chromatography/mass spectroscopy (GC/MS) and compared with known standards to determine chemical compatibility. The admixtures showed no physical incompatibility on microscopic or macroscopic evaluation. Chemical compatibility of all mixtures was confirmed by GC/MS. Ion chromatograms of the drugs in admixtures were identical to previously established standards. The agents evaluated demonstrated physical and chemical compatibility under conditions that would be observed during the administration of peridural anesthesia. Combinations of these drugs therefore could be safely admixed for use in anesthesia.


Hypersensitivity and anaphylactoid reactions to ciprofloxacin. To report three cases of life-threatening hypersensitivity reactions to the oral administration of ciprofloxacin. Life-threatening hypersensitivity reactions to oral ciprofloxacin, characterized by diffuse, erythematous, nonpruritic, blanching rash, with fever and hypotension, occurred in two HIV-infected patients. One of these reactions was considered anaphylactoid. A similar hypersensitivity reaction was documented in a non-HIV-infected patient. Premarketing clinical trials described no reports of life-threatening anaphylactoid hypersensitivity reactions to ciprofloxacin. However, postmarketing surveillance studies have documented their occurrence. Seven cases of anaphylactoid reaction to ciprofloxacin have now been documented in HIV-infected patients. As with trimethoprim/sulfamethoxazole, HIV-infected people treated with ciprofloxacin may be at special risk for hypersensitivity reactions.


Enhanced anticoagulant effect of coumarin derivatives induced by doxycycline coadministration. To report two cases of enhanced oral anticoagulant effect induced by doxycycline coadministration. Case report. University teaching hospital. Two patients on chronic oral anticoagulation therapy who presented with severe bleeding and marked impairment in blood coagulation tests shortly after the initiation of doxycycline therapy. The literature concerning the possible effects of tetracyclines on hemostasis with or without antecedent anticoagulation therapy is reviewed and the speculated mechanisms for such an interaction are discussed. The administration of tetracyclines such as doxycycline to patients on chronic oral anticoagulation therapy may be associated with a marked enhancement in anticoagulant effect. In such patients the prothrombin ratio should be closely monitored and the anticoagulant dosage adjusted accordingly.


Nonthrombocytopenic purpura associated sequentially with nifedipine and diltiazem. To report the case of a patient who developed nonthrombocytopenic purpura sequentially following the administration of nifedipine and diltiazem. Case reports, MEDLINE review of pertinent literature, and review of relevant studies. Data were extracted from direct patient observation and review of laboratory studies and published reports. Nonthrombocytopenic purpura secondary to cutaneous vasculitis is a known, although rare, adverse effect of nifedipine. It has not been reported in association with diltiazem. We report the case of a 75-year-old woman in whom a purpuric rash demonstrated by biopsy to be attributable to cutaneous vasculitis developed in the course of nifedipine therapy. The rash disappeared after discontinuation of the drug; however, it recurred when diltiazem therapy was initiated. Nonthrombocytopenic purpura may be associated with diltiazem as well as with nifedipine. When this adverse effect occurs following administration of a calcium-channel blocker, caution is advised in using other agents of the same class.


Case report of a syncopal episode associated with fluoxetine. To report a syncopal episode associated with fluoxetine in a young, relatively healthy man. Single case report. 585-bed private hospital. A 30-year-old man with hypertension, esophageal ulcers, and syncope of recent onset. Fluoxetine was started six weeks prior to the syncopal episode in this patient, and is the medication most temporally associated with the event. Because the patient had a normal neurologic examination and electroencephalogram, but an abnormal electrocardiogram on admission and one month after discharge, the syncopal episode was most likely caused by cardiovascular effects of fluoxetine. Fluoxetine has been reported to cause cardiac conduction abnormalities in otherwise normal individuals. Bradycardia secondary to a direct effect of fluoxetine, or to a drug interaction among fluoxetine, ranitidine, and enalapril is the most likely explanation for this patient's syncopal episode.


Profuse diarrhea after misoprostol use in a patient with a history of Crohn's disease. To report a case of profuse diarrhea after misoprostol use in a patient with a history of Crohn's disease and to discuss the role of eicosanoids in Crohn's disease. Patient medical records, case reports, review articles identified by MEDLINE, and personal communication with the physician, patient, and manufacturer. From interviews, the manufacturer, and pertinent published sources by one author and reviewed by the others. A 55-year-old woman presented to clinic complaining of multiple joint pains. Her medical history was significant for peptic ulcer disease, hypertension, and Crohn's disease in remission since May 1989. Her joint pains were treated with ibuprofen 600 mg po qid and misoprostol 200 micrograms po qid (after meals and at bedtime). Following the administration of three doses of ibuprofen and misoprostol, the patient experienced abdominal cramps, pain, and voluminous, watery diarrhea for two days. Upon discontinuation of the ibuprofen and misoprostol, all of her gastrointestinal symptoms resolved within 12 hours. Rechallenge with ibuprofen alone failed to produce a recurrence of symptoms. Enhanced synthesis of intestinal eicosanoids has been demonstrated in Crohn's disease. Misoprostol, a synthetic analog of one of the eicosanoids, could induce a flare-up of Crohn's disease as suggested in this patient. Misoprostol should be used with caution in patients with known inflammatory bowel disease.


Clarithromycin: review of a new macrolide antibiotic with improved microbiologic spectrum and favorable pharmacokinetic and adverse effect profiles. To compare the new macrolide antibiotic clarithromycin with erythromycin in terms of in vitro activity, pharmacokinetics, pharmacodynamics, clinical efficacy, and toxicity. An English-language literature search employing MEDLINE (1987-91), Index Medicus (1987-91), Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy (1990), Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (1991), and bibliographic reviews of related textbooks and review articles. Eighty-five articles were selected. Clinical trials with clarithromycin have been limited, and emphasis was placed on trials reported in the Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy and Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Articles were assessed for study quality and specific information addressing the stated purpose. In articles reporting the results of clinical trials, emphasis was placed on comparative efficacy and toxicity. A review of 24 human trials suggests that clarithromycin is equally effective as erythromycin, penicillin VK, ampicillin, or amoxicillin for treatment of a variety of upper and lower respiratory tract or skin infections. Clarithromycin also appears to be better tolerated than these agents, with a lower incidence of gastrointestinal adverse effects. Limited clinical studies in patients with Mycobacterium leprae or Mycobacterium avium-intracellulare complex (MAI) suggest that clarithromycin may prove to be efficacious and well tolerated in the treatment of these infections. Clarithromycin is as effective in vivo as erythromycin, with less gastrointestinal irritation. Additionally, clarithromycin appears to expand the traditional spectrum of macrolide antibiotics, with promising activity against M. leprae and MAI.


The triglyceride connection in atherosclerosis. To examine the proposed mechanism of triglyceride-induced atherogenesis, to address the controversy surrounding serum triglycerides as a coronary heart disease (CHD) risk factor, and to recommend an appropriate therapeutic approach to hypertriglyceridemia. Studies, review articles, and editorials published since 1976. A MEDLINE search of English-language literature was conducted using the terms triglyceride and hypertriglyceridemia. Studies, review articles, and editorials were selected for detailed review if they addressed the pathogenesis of triglyceride-induced atherosclerosis, the controversy associated with elevated serum triglyceride as a CHD risk factor, and hypertriglyceridemia treatment options. Data were reviewed that described the atherogenicity of chylomicron and very low-density lipoprotein (VLDL) remnants, the inverse relationship that exists between high-density lipoprotein (HDL) and serum triglyceride, the hypertriglyceridemia treatment controversy, and the treatment options of diet, exercise, weight control, alcohol restriction, and medication. Hypertriglyceridemia is a well-known risk factor for pancreatitis. However, its role in atherogenesis is less well defined. Several proposed connections appear to exist between hypertriglyceridemia and atherosclerosis, including the inverse correlation between triglycerides and HDL, the presumed atherogenicity of triglyceride-rich lipoprotein remnant particles, the potential resultant increase in the serum concentration and atherogenicity of low-density lipoprotein (LDL), and the proposed interaction between serum triglyceride and the fibrinolytic/coagulation system. Clinical trials addressing this issue offer mixed results that are subject to interpretation. Diet, exercise, weight control, alcohol restriction, and certain lipid-lowering medications are effective at reducing serum triglyceride. Hypertriglyceridemia is a theoretical risk factor for CHD because of the increased production of atherogenic chylomicron and VLDL remnants, the inverse relationship present between serum triglyceride and HDL, the possible resultant increase in LDL attributable to remnant-reduced hepatic LDL-receptors as well as the formation of more dense and, therefore, more atherogenic LDL, and to the interaction between serum triglyceride and the fibrinolytic/coagulation system. However, most clinical trials that have found hypertriglyceridemia to be a risk factor for CHD do not include other CHD risk factors in their analyses. Therapeutic intervention to lower serum triglyceride with diet, exercise, and/or drugs is definitely recommended in the treatment and/or prevention of pancreatitis; however, the role of triglyceride-lowering to reduce CHD risk remains controversial.


Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer's disease. Velnacrine testing for tolerance and safety in both normal elderly subjects and patients with Alzheimer's disease (AD) is reviewed to illustrate the importance of Phase I trials in the target group as more predictive of safety and tolerance for subsequent multicenter trials than those conducted in healthy elderly subjects. Both a single-dose and a randomized, double-blind, placebo-controlled, ascending, multiple-dose study were performed with healthy, elderly men. In the multiple-dose study, the subjects were randomized to four groups of 14, with 10 subjects receiving velnacrine and 4 receiving placebo. The doses were velnacrine 25 (group 1), 50 (group 2), and 100 mg (group 3), respectively, administered twice daily; group 4 received 100 mg three times daily for 28 days. Blood and urine were collected serially for the pharmacokinetic assessment. With AD patients, 24 subjects were randomly assigned to receive either placebo or velnacrine for 10 days in a double-blind, sequential escalation study in a hospital setting. There were three groups of 8 subjects. Six patients in each group received velnacrine and 2 placebo. The three groups received respective dosages of 450, 300, and 225 mg/d three times daily. Adverse events were closely monitored and recorded. The multiple-dose test in healthy elderly men included 56 men, aged 60-74 years. Rigorous screening for any potential complications that could affect absorption, distribution, metabolism, or excretion preceded patient entry in the AD patient study. Patients with a history of major psychiatric, neurologic, and cardiovascular disorders were excluded. The patients ranged in age from 56 to 89 years, and were equally distributed between gender. Velnacrine was administered in various doses. We emphasize the extreme adverse effects encountered in the AD patient group compared with the healthy group. Plasma concentrations of velnacrine over time in both groups are given, as well as the drug's half-life and excretion rates. The tolerable dosage predicted by studies performed in healthy elderly subjects was 300 mg/d. This dosage was not tolerable among the AD patients. A dosage as high as 450 mg/d resulted in a tonic seizure in one patient. The predicted dosage of 300 mg/d produced an adverse effect profile in AD patients that included dizziness, nausea and/or vomiting, headaches, and severe diarrhea. AD patients tolerated a dosage of 225 mg/d. A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.


Adjuvant corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS patients. To review published abstracts, case reports, and journal articles and evaluate data examining the use of systemic corticosteroids as adjuvant treatment for Pneumocystis carinii pneumonia (PCP) in patients with AIDS. Computerized online databases, peer-reviewed journals from January 1986 through September 1991, and personal communication with a National Institutes of Health correspondent. The authors identified 13 reports pertinent to this review. By author consensus, five studies were selected for analysis based on sample size, controlled study design, and clinical outcome measures. Recommendations of an expert panel from the National Institutes of Health and the University of California also are discussed. Data are presented based on the methodologic strength of the studies reviewed. Studies are assessed on sample size, inclusion criteria, comparative cohort populations, specific patient outcome measures, and statistical analysis. Results of the study analysis support the use of systemic corticosteroids as early adjunctive therapy for AIDS patients with moderate-to-severe PCP who have an initial arterial oxygen partial pressure of less than 70 mm Hg or an alveolar-arterial gradient greater than 35 mm Hg on room air. Improved outcomes included decreased mortality, respiratory failure, and deterioration of oxygenation. Data evaluated have shown that adjuvant corticosteroid therapy is most effective when initiated within 72 hours of beginning specific antipneumocystis therapy. A small, but sometimes significant, increased rate of infection in steroid-treated patients was noted. Based on the literature reviewed, early systemic adjuvant corticosteroid therapy can benefit patients with moderate-to-severe AIDS-related PCP. The steroid regimen used in the largest controlled trial and recommended by the expert panel is prednisone 40 mg bid (days 1-5), then 40 mg/d (days 6-10), then 20 mg/d (days 1-21).


Serum albumin concentrations: who needs them? To examine the multiple factors that influence serum albumin concentrations and to discuss settings in which the monitoring of such concentrations provides clinically useful information. Original investigations, review articles, books, and abstracts published in English. Studies pertaining to factors affecting serum albumin concentration were chosen based on general applicability. Recommendations related to the appropriate monitoring of albumin concentrations were based on studies performed in the clinical setting with direct applicability to patient care. Data on factors affecting serum albumin concentration were extracted from studies that resulted in similar conclusions regardless of assay technique. Appropriate indications for albumin monitoring were derived from studies demonstrating direct clinical relevance. A number of factors may influence serum albumin concentration and ultimately affect interpretation of the concentration. Serum albumin concentrations generally are useful in the institutional setting shortly after admission or preoperatively to determine patient prognosis. Albumin concentrations have limited merit for predicting the free fractions of various hormones, electrolytes, and drugs. When used as an indicator of nutritional support, albumin concentrations are most helpful when measured over longer periods in relatively stable patients. Serum albumin determinations should be limited to those situations in which the concentrations are likely to provide clinically useful information. Such situations are limited.


Home total parenteral nutrition in a "no-bowel" patient in Spain. To report a case of a patient with no functional bowel who was receiving home total parenteral nutrition in a country that has had a few professional experiences in this area of therapy. A woman with a history of scattered colonic polyposis developed a mesenteric tumor that caused intestinal obstruction. Tumor withdrawal required the excision of 1.5 m of jejunum-ileum. Postoperative complications required further surgical intervention and subtotal intestinal resection. Duodenocolic anastomosis was not possible and a high output and permanent fistula remained. The complications of home parenteral nutrition addressed in the literature are reviewed. The problems encountered in our patient have been resolved. After three years of postoperative survival, we believe the quality of life of our patient has increased and the parenteral nutrition team members are much better prepared to manage patients with similar problems.