Microbiology, infection control, immunizations, and infectious disease exposure: education and practices in United States nursing schools.

Previous data suggest that nursing students in the United States are inadequately protected against hepatitis B. This survey focused on the immunization and education practices, infection control knowledge, and follow-up to infectious disease exposure by U.S. nursing schools. To ascertain education requirements, immunization practices, and infectious disease postexposure follow up, a survey was sent to the director or dean of 1164 U.S. nursing schools. Seven hundred sixty-five schools (65.7%) responded to the survey. A microbiology course was required before clinical experience by 49% of schools. Clinical experience in the operating room was given by 16%, 65% of schools offered infectious and communicable disease courses, and 98% offered universal precaution instructions. The hepatitis B vaccine was required by 11%; 2% required yearly influenza vaccination. In a comparison of programs, the diploma schools were more likely to have written policies for infectious disease exposure follow-up and to use appropriate agencies for exposure follow-up (p = 0.0001). A microbiology course before clinical experience should be encouraged. Immunization policies and infectious disease exposure follow-up are currently inadequate in U.S. associate degree and baccalaureate nursing programs.


Neuropathologic features of Parkinson's, Huntington's, and Alzheimer's diseases.

Some of the similarities and differences between the neuropathology of Parkinson's disease, Huntington's disease, and Alzheimer's disease have been reviewed, and the relationship between the three diseases has been discussed. Although interconnected and reciprocally innervated structures are affected in PD and HD, they appear less closely related than in PD and AD. Different neurotoxins may play a part in their pathogenesis, as also suggested from other evidence. Neuropathologic features of PD, HD and AD are entirely compatible with a role for neurotoxins in their pathogenesis, but do not by themselves make a strong case for a neurotoxic hypothesis. However, additional neuropathologic studies of experimental neurotoxins may further strengthen arguments in favor of a neurotoxic etiology, as the MPTP animal model is doing for Parkinson's disease. Such experimental studies along with further molecular biological and other sophisticated new methods may open the way for exciting new developments in the near future.


A follow-up study of isolated cases of suspected Huntington's disease.

We reviewed 49 patients in whom a diagnosis of Huntington's disease (HD) seemed possible on clinical grounds, but who gave no history of definitely affected relatives. In 32 with the typical clinical features of HD (progressive chorea and dementia, postural instability, abnormal initiation of saccadic eye movements), the diagnosis was confirmed in 7 patients who had had autopsies, affected relatives were found in 5 others, and HD remained probable in a further 13 who were reexamined. In the 17 with a less typical clinical picture, a diagnosis of HD appeared most likely in 2; other causes for chorea such as cerebrovascular disease, neuroacanthocytosis, recrudescence of Sydenham's chorea, and drug-induced tardive dyskinesia could be invoked in the remainder. We conclude that the likelihood of HD in a patient with the typical clinical features of this disorder but no history of affected relatives is at least 75%, which for practical purposes implies a risk to their children hardly less than in familial HD. The most plausible explanations for seemingly sporadic patients with HD are nonpaternity and mild, late-onset disease that is overlooked by other family members.


Electroconvulsive therapy treatment of depression in a patient with adult GM2 gangliosidosis.

Adult GM2 gangliosidosis is a rare disorder that often presents with both neurological and psychiatric syndromes. Effective treatment of the psychotic and affective symptoms associated with this disorder has been complicated by poor treatment response and the concern that many psychotropic agents may worsen the underlying gangliosidosis. We report the successful use of electroconvulsive therapy for treatment of severe depression in a young man with adult GM2 gangliosidosis.


Comparative acid tolerances and inhibitor sensitivities of isolated F-ATPases of oral lactic acid bacteria.

pH activity profiles and inhibitor sensitivities were compared for membrane ATPases isolated from three oral lactic acid bacteria, Lactobacillus casei ATCC 4646, Streptococcus mutans GS-5, and Streptococcus sanguis NCTC 10904, with, respectively, high, moderate, and low levels of acid tolerance. Membranes containing F1F0 ATPases were isolated by means of salt lysis of cells treated with muralytic enzymes. Membrane-free F1F0 complexes were then isolated from membranes by detergent extraction with Triton X-100 or octylglucoside. Finally, F1 complexes free of the proton-conducting F0 sector were obtained by washing membranes with buffers of low ionic strength. The pH activity profiles of the membrane-associated enzymes reflected the general acid tolerances of the organisms from which they were isolated; for example, pH optima were approximately 5.5, 6.0, and 7.0, respectively, for enzymes from L. casei, S. mutans, and S. sanguis. Roughly similar profiles were found for membrane-free F1F0 complexes, which were stabilized by phospholipids against loss of activity during storage. However, profiles for F1 enzymes were distinctly narrower, indicating that association with F0 and possibly other membrane components enhanced tolerance to both acid and alkaline media. All of the enzymes were found to have similar sensitivities to Al-F complexes, but only F1F0 enzymes were highly sensitive to dicyclohexylcarbodiimide. The procedures described for isolation of membrane-free F1F0 forms of the enzymes from oral lactic acid bacteria will be of use in future studies of the characteristics of the enzymes, especially in studies with liposomes.


Rapid method for separation of bacterial DNA from humic substances in sediments for polymerase chain reaction.

The polymerase chain reaction (PCR) was used to amplify an Escherichia coli 16S ribosomal gene fragment from sediments with high contents of humic substances. Total DNA was extracted from 1 g of E. coli seeded or unseeded samples by a rapid freeze-and-thaw method. Several approaches (use of Bio-Gel P-6 and P-30 and Sephadex G-50 and G-200 columns, as well as use of the Stoffel fragment) were used to reduce interference with the PCR. The best results were obtained when crude DNA extracts containing humic substances were purified by using Sephadex G-200 spun columns saturated with Tris-EDTA buffer (pH 8.0). Eluted fractions were collected for PCR analyses. The amplified DNA fragment was obtained from seeded sediments containing fewer than 70 E. coli cells per g. Because only 1/100 of the eluted fractions containing DNA extracts from 70 cells per g was used for the PCR, the sensitivity of detection was determined to be less than 1 E. coli cell. Thus, DNA direct extraction coupled with this technique to remove interference by humic substances and followed by the PCR can be a powerful tool to detect low numbers of bacterial cells in environmental samples containing humic substances.


Identification of a 14-kDa laminin binding protein (HLBP14) in human melanoma cells that is identical to the 14-kDa galactoside binding lectin.

The carbohydrate moieties present on laminin play a crucial role in the multiple biological activities of this basement membrane glycoprotein. We report the identification of a human laminin binding protein with an apparent molecular mass of 14 kDa on sodium dodecyl sulfate-polyacrylamide gels that was found, after purification and amino acid microsequencing, to be identical to the previously described 14-kDa galactoside binding soluble L-14 lectin. We have designated this human laminin binding protein as HLBP14. HLBP14 was purified from human melanoma cells in culture by laminin affinity chromatography and gel electroelution. We demonstrate that HLBP14 binds specifically to the poly-N-acetyllactosamine residues of murine laminin and does not bind to other glycoproteins that do not contain such structures, such as fibronectin. HLBP14 was eluted from a murine laminin column by lactose, N-acetyllactosamine, and galactose but not by other control saccharides, including glucose, fucose, mannose, and melibiose. It did not bind to laminin treated with endo-beta-galactosidase. Lactose also eluted HLBP14 off a human laminin affinity column, implying that human laminin also contains poly-N-acetyllactosamine residues. On immunoblots, polyclonal antibodies raised against HLBP14 recognized HLBP14 as well as 31- and 67-kDa molecules that are also laminin binding proteins, indicating that these proteins share common epitopes. L-14, a dimeric lactose binding lectin, is expressed in a wide variety of tissues. Although the expression of this molecule has been linked to a variety of biological events, the elucidation of its specific functions has been elusive. The observation that HLBP14, a human cancer cell laminin binding protein, is identical to L-14 strongly suggests that the functions attributed to this lectin could be mediated, at least in part, through its ability to interact with the poly-N-acetyllactosamine residues of laminin. HLBP14 could potentially play a role during tumor invasion and metastasis by modulating the interactions between cancer cells and laminin.


Differential scanning calorimetric investigation of pea chloroplast thylakoids and thylakoid fractions.

High sensitivity differential scanning calorimetry (DSC) was employed to study the thermal denaturation of components of pea chloroplast thylakoid membranes. In contrast to previous reports utilizing spinach thylakoids, several transitions are reversible, and deconvolution of the calorimetric curves indicates nine transitions in both first and second heating scans, but overlapping transitions obscure at least three transitions in the first heating scans of control thylakoids. Glutaraldehyde fixation increases the denaturation temperature of several transitions which is consistent with a reported increase in thermal stability of thylakoid function due to fixation. Acidic pH treatment has little effect on the DSC curves, although it has been reported to have a significant effect on membrane structure. Separation of grana from stroma thylakoids indicates that components responsible for transitions centered at approximately 56, 73, 77, and 91 degrees C are predominantly or exclusively associated with grana thylakoids, whereas components responsible for transitions centered at approximately 63 and 81 degrees C are predominantly associated with stroma thylakoids. A broad transition centered at 66 degrees C is associated with grana thylakoids, whereas a sharp transition at the same temperature is due to a component associated with stroma thylakoids. Evidence obtained by washing treatments suggests the latter transition originates from the denaturation of the thylakoid ATPase (CF1). Analysis of the calorimetric enthalpy values indicates most components of the grana thylakoids denature irreversibly at high temperature, whereas components associated with the stroma thylakoids have a considerable degree of thermal reversibility.


Sleep and psychiatric disorders. A meta-analysis.

We reviewed the literature on sleep in psychiatric disorders and evaluated the data by meta-analysis, a statistical method designed to combine data from different studies. A total of 177 studies with data from 7151 patients and controls were reviewed. Most psychiatric groups showed significantly reduced sleep efficiency and total sleep time, accounted for by decrements in non-rapid eye movement sleep. Rapid eye movement sleep time was relatively preserved in all groups, and percentage of rapid eye movement sleep was increased in affective disorders. Reduction in rapid eye movement sleep latency was seen in affective disorders but occurred in other categories as well. Although no single sleep variable appeared to have absolute specificity for any particular psychiatric disorder, patterns of sleep disturbances associated with categories of psychiatric illnesses were observed. Overall, findings for patients with affective disorders differed most frequently and significantly from those for normal controls.


Lipid analysis of the major salivary glands in streptozotocin-diabetic rats and the effects of insulin treatment.

Two separate sets of experiments were performed on female Wistar rats made diabetic with streptozotocin: (1) a time-course study where groups of three animals were removed at weekly intervals, up to 4 weeks after induction of diabetes, with an age-matched group of control (normal) animals kept for 4 weeks; (2) six further animals were made diabetic and kept for 7 weeks; three of these were given insulin in the final week. At the required time the animals were anaesthetized and the salivary glands removed and preserved by fixation or freezing. The frozen tissues were later homogenized and the protein and lipid content analysed. Histologically, intracellular lipid droplets had accumulated in the majority of the diabetic salivary glands. In the time-course experiment, the visible amount of intracellular lipid reached a maximum after 2 weeks and then decreased, with a concomitant disappearance of interstitial lipid. The increased lipid content was not attributable to any one class. The fatty acid profiles of the glands showed an increase in the percentages of C18:0 (stearic acid) and C18:2w6 (linoleic acid) and a decrease in the percentages of C18:1w9 (oleic acid) and C20:4w6 (arachidonic acid). After 1 week of insulin treatment the lipid content and the fatty acid profiles returned to normal. Thus the effect of insulin on salivary gland lipid metabolism is rapid both in its occurrence and reversibility. The effects seen in the diabetic rats are considered to be due to a lack of insulin and not to the presence of streptozotocin.


Inactivation of sarcoplasmic-reticulum Ca(2+)-ATPase in low-frequency-stimulated muscle results from a modification of the active site.

Molecular changes underlying the partial inactivation of the sarcoplasmic-reticulum (SR) Ca(2+-) ATPase in low-frequency-stimulated fast-twitch muscle were investigated in the present study. The specific Ca(2+)-ATPase activity, as well as the ATP- and acetyl phosphate-driven Ca2+ uptakes by the SR, were reduced by approx. 30% in 4-day-stimulated muscle. Phosphoprotein formation of the enzyme in the presence of ATP or Pi was also decreased to the same extent. Measurements of ATP binding revealed a 30% decrease in binding to the enzyme. These changes were accompanied by similar decreases in the ligand-induced (ATP, ADP, Pi) intrinsic tryptophan fluorescence. A decreased binding of fluorescein isothiocyanate (FITC) corresponded to the lower ATP binding and phosphorylation of the enzyme. Moreover, Pi-induced changes in fluorescence of the FITC-labelled enzyme did not differ between SR from stimulated and contralateral muscles, indicating that Ca(2+)- ATPase molecules which did not bind FITC were responsible for the decreased Pi-dependent phosphorylation, and therefore represented the inactive form of the enzyme. No differences existed between the Ca(2+)-induced changes in the intrinsic fluorescence of SR from stimulated and contralateral muscles which fit their similar Ca(2+)-binding characteristics. Taking the proposed architecture of the Ca2(+)-ATPase into consideration, our results suggest that the inactivation relates to a circumscribed structural alteration of the enzyme in sections of the active site consisting of the nucleotide-binding and phosphorylation domains.


Telecommunications for the disabled.

Scientific and technological advances should be used to give the disabled every possible opportunity for personal development. There is great scope for improving the lot of disabled people by providing access to modern telecommunications systems. In the Third World, such progress could be encouraged if donor agencies stipulated that a certain proportion of funding should serve this purpose.


Protein kinase C enhances myosin light-chain kinase effects on force development and ATPase activity in rat single skinned cardiac cells.

Many neurohormones alter the force of cardiac contraction by variations in the intracellular Ca2+ concentration. alpha 1-Adrenergic and muscarinic stimulations, rather, modify the sensitivity of contractile proteins to Ca(2+)-calmodulin-myosin light-chain kinase (MLCK) complex induces a large increase in Ca2+ sensitivity (0.14 pCa unit) of these easily accessible myofilaments. This increase is further enhanced by up to 0.19 pCa unit when protein kinase C (PKC) is added together with MLCK. Similarly, the Ca2+ ATPase activity of skinned cells in suspension is increased in the presence of MLCK and further in the presence of both kinases. 32P-labelling and SDS/PAGE show that these changes are associated with light-chain 2 (LC2) phosphorylation together with phosphorylation of troponin I and troponin T when PKC is added. Although to a smaller extent than in smooth muscle, phosphorylation of cardiac myosin LC2 may be involved in the modulation of heart contractility.


Atrial natriuretic peptide and the baroreflex control of circulation.

An emerging role for atrial natriuretic peptide (ANP) as a modulator of baroreflex function is suggested by a number of experimental observations. In several animal species and in humans, ANP appears to reset the baroreflex control of heart rate in a way that favors bradycardia and opposes cardioacceleration. In addition, ANP interferes with the reflexes originating from cardiopulmonary receptors in the control of vascular tone. The modulation of baroreflexes by ANP seems to be related, at least in part, to the interaction of the atrial peptide with the effects of angiotensin II. This influence of ANP on the baroreflex control of circulation may be important in short-term cardiovascular adaptations, and may have particular relevance to conditions characterized by volume overload and impaired baroreflex function, such as certain forms of hypertension and congestive heart failure.


Comparison of atracurium-induced neuromuscular block in rectus abdominis and hand muscles of man.

We have compared neuromuscular block in the rectus abdominis and the hand muscles in 11 adult patients. Atracurium 0.5 mg kg-1 was administered by single bolus and anaesthesia maintained with isoflurane and nitrous oxide in oxygen. Train-of-four (TOF) stimulation was applied to the 10th intercostal space in the anterior axillary line and to the ulnar nerve at the wrist. Electromyographic (EMG) responses were recorded over the rectus abdominis and hypothenar muscles. Neuromuscular block had a significantly faster onset in the rectus abdominis (mean 1.6 (SEM 0.2) min) than in the hand (2.4 (0.3) min) (P less than 0.001). Recovery occurred more rapidly in the rectus abdominis: time to 25% TOF recovery was 39 (3) min at rectus abdominis and 51 (4) min at the hand (P less than 0.001). Time to 75% TOF recovery was 56 (4) min at rectus abdominis and 72 (6) min at the hand (P less than 0.001).


The role of enoximone in cardiac surgery.

After cardiopulmonary bypass (CPB), some patients may require circulatory support. This study examined the role of the phosphodiesterase-III inhibitor, enoximone, in cardiac surgery. Eighty patients selected by chance were allocated randomly to two groups: 40 patients received enoximone 1.0 mg kg-1 approximately 10 min before weaning from CPB and 40 served as a control group. Additional pharmacological therapy (adrenaline, noradrenaline, nitroglycerin) was given, when necessary, by anaesthetists who were not involved in the study. In addition to standard monitoring, skin capillary blood flow was assessed using a laser Doppler technique before, during and after CPB until 2 h after the end of the operation. In the period after bypass, cardiac index was always significantly greater in the enoximone than in the control group. Systemic and pulmonary vascular resistance were less in the enoximone-treated patients, indicating a reduction in right and left ventricular wall stress. Oxygen consumption in the enoximone patients was significantly greater after CPB, whereas intrapulmonary shunting was comparable in the two groups. In comparison with baseline values, skin capillary blood flow in the enoximone patients was always greater than that in the control group. In comparison with the control patients, significantly fewer enoximone patients needed adrenaline, and in a smaller dose, even 2 h after operation, whereas more enoximone patients required noradrenaline therapy for a short period. We conclude that the use of enoximone before weaning from CPB improved overall cardiac function, reduced the need of catecholaminergic inotropic support, and provided increased organ perfusion up to 2 h after operation.


Comparison of extradural administration of sufentanil, morphine and sufentanil-morphine combination after caesarean section.

We have studied postoperative analgesia and unwanted side effects of a single dose of a mixture of morphine and sufentanil administered extradurally with the effects produced by extradural injection of each opioid alone in 64 patients after Caesarean delivery. The patients were allocated randomly to receive morphine 4 mg (n = 21), sufentanil 50 micrograms (n = 22) or morphine 2 mg with sufentanil 25 micrograms (n = 21) via an extradural catheter in a double-blind design. Intensity of pain was measured using a linear visual analogue scale. Compared with the effect produced by morphine alone, the morphine-sufentanil combination produced more rapid onset of pain relief (19 (SD 5) min vs 79 (23) min for a 75% reduction of pain; P less than 0.01), whereas the duration and quality of analgesia assessed during 12 h was similar for these two groups. In contrast, patients receiving sufentanil alone required significantly more supplementary analgesia 4 h after administration than with morphine alone or morphine combined with sufentanil. There were no significant changes in cardiorespiratory variables in any group. Side effects consisted mainly of pruritus and nausea and did not differ between groups, with the exception of early and transient dizziness which was observed only in patients given sufentanil either alone or in combination with morphine. We conclude that a single extradural injection of morphine and sufentanil combines the short onset time produced by sufentanil and the long duration of analgesia attributable to morphine, thus providing excellent and prolonged analgesia after Caesarean delivery.


[Left side approach in laparoscopic cholecystectomy: first-year experience].

Laparoscopic cholecystectomy can be performed following two main approaches: the french technique, used by the majority of surgeons, and the anglo-saxon technique. The Authors describe the basic concept of the "left side" approach according to the Anglo-american method, underlining some of the advantages. Their one-year results (November 1990-November 1991) confirm the data already available in the Literature.


Effects of 5-HT-1A receptor agonists on ethanol preference in the rat.

Pharmacological manipulation of brain serotonin (5-HT) neurons has recently become recognized as an important approach in the treatment of ethanol (ET-OH) dependence. In the present study, we observed the effects of three agonists of 5-HT-1A receptor subtype, 8-OHDPAT, buspirone, and NDO-008, on ET-OH preference in Wistar male rats. Animals received ET-OH intragastrically during the first week of the experiment, and then during 2 consecutive weeks, the only source of fluid (23 h/d) was 5% and 8% wt/vol ET-OH solution, respectively. Then the animals were presented with a free-choice between water and 8% ET-OH solution for a 1-week period. Based on the baseline recordings, two groups of rats were formed: a high preference group (ET-OH intake greater than 50% of total daily fluid intake) and a low preference group of rats (ET-OH intake less than 20%). During week 5 of the experiment, animals were treated with 5-HT receptor agonists (subcutaneous injections twice daily for 4 days). The treatment caused a significant reduction of ET-OH intake in the high preference group, but caused no change in the remaining groups. The effect of highly selective 5-HT-1A receptor agonist, 8-OHDPAT, on ET-OH consumption in the high preference group was antagonized by cyanopindolol, a nonselective antagonist of 5-HT-1 receptor subtype. Our results support the hypothesis that activation of 5-HT-1A receptors reduces ET-OH preference.


[Laparoscopic cholecystectomy: analysis of first 203 cases].

Laparoscopic cholecystectomy is a valid alternative to open cholecystectomy. The Authors present their experience in the management of 208 consecutive patients. The low incidence of complications, the short hospital stay as well as earlier return to work, and lower medical expenses are the advantages of laparoscopic surgery. The latter is, therefore, more suitable for the treatment of benign gallbladder diseases.


[Anatomo-surgical considerations in laparoscopic cholecystectomy].

The Authors emphasize the importance of a perfect anatomo-surgical knowledge for laparoscopic cholecystectomy. Therefore, the anatomic structures of the region are taken into account from a "laparoscopic" point of view, with great care to accessory bile duct, hepatic artery, and cystic artery. Knowledge and confidence with the anatomy of the region are essential to identify abnormal structures and subsequently switch from a laparoscopic to a laparotomic approach.


[Laparoscopic cholecystectomy in acute cholecystitis].

In a 18 month period 19 patients (4.7%) out of 400 affected by acute cholecystitis underwent laparoscopic cholecystectomy. In 18 cases the diagnosis was preoperative on clinical signs or ultrasound scan basis. Intraoperative and histologic confirm was obtained in all cases. Mean age was 44.9, 11 were males and 8 females. The procedure resulted longer and more difficult compared to the global series of the same period: 90 min. versus 56 min. respectively, with a difficulty score higher than 4 in 89% of cases versus 40% of the global series. Furthermore, in 56% of cases versus 23.3% of the global series an intraoperative contamination from gallbladder content was recorded. Nevertheless, only 1 (5%) minor complication was observed, in the form of omphalitis, which recovered in 2 days. Therefore, discharge was possible in average within 4 days, excluding the first two cases operated, respectively discharged in 5th and 7th p.o. day as a precautionary measure. Early coelioscopic cholecystectomy is safe and effective, if carried out by well trained surgeons, even in acute cholecystitis.


[Laparoscopic cholecystectomy using argon bistoury].

A total of 92 patients were submitted to laparoscopic cholecystectomy during the period Autumn 1990-Spring 1991. The dissection of the gallbladder from the hepatic bed was performed in 40 patients using the Argon beam coagulator, in 25 using the monopolar electrocoagulator and in 27 using the Holmio laser beam. In average, with the Argon beam coagulator time procedure was respectively 2.7 and 5.4 minutes shorter than monopolar electrocoagulator and Holmio laser. Only one complication (pneumomediastinum) was correlated with the use of the Argon beam coagulator.


[Laparoscopic cholecystectomy: considerations on the technique].

The Authors analyze the single steps of laparoscopic cholecystectomy and describe the technique usually preferred. On the basis of the experience acquired, advantages and disadvantages of each manoeuver and instrument available are pointed out.


[Mini-invasive surgical treatment of gallstones and common bile duct calculi].

Between June 1st 1990 and December 31st 1991, 449 patients with cholelithiasis were operated on. All patients with isolated cholecystolithiasis (400) were offered video-laparoscopic (VLC) treatment. Forty-nine patients had both cholecystolithiasis and choledocholithiasis. They all underwent further evaluation by ERCP, on the basis of which 30 patients were selected for sequential endoscopic and laparoscopic treatment with endoscopic papillosphincterotomy (EPST) followed by VLC. Three patients were selected for VLC and ideal laparoscopic choledocholithotomy. No complications were observed. At present, sequential ERCP-PST and VLC treatment seems to be the ideal approach to combined cholecystic and choledochal lithiasis in terms of safety, efficacy and tolerability. The increasing surgical skill in the field of minimally invasive surgery and the availability of sophisticated laparoscopic instrumentation allow to consider VLC and laparoscopic choledocholithotomy a valid alternative in terms of reduced surgical trauma and patient discomfort.


[Aseptic resection of the intraluminal colon in laparoscopy].

Laparoscopic surgery is an "old" technique extending to new applications including colon surgery. Basically, even though surgical technique and indications do not differ from traditional surgery, it has the advantage to eliminate most of the complications associated with an abdominal incision. In order to improve also the outcome of intestinal anastomoses, an aseptic technique by intestinal intussusception previously described (3) has been modified and carried out laparoscopically in 3 pigs and 3 dogs successfully. The animals were sacrificed after 2 months. Anastomoses were evaluated endoscopically by barium enema and by gross and microscopic examination. Results indicated no mortality or complications except for a small area of mucosal peri-anastomotic necrosis in one dog, which spontaneously healed. Therefore, it seems that the aseptic resection of the colon is possible with laparoscopy obtaining at the same time a decreased morbidity related to the abdominal incision and colonic anastomosis.


Recommendations regarding estrogen replacement therapy after treatment of endometrial cancer.

A history of endometrial cancer has long been considered a contraindication to estrogen replacement therapy. Yet women with such a history, like other women when postmenopausal, often suffer vasomotor symptoms that could easily be relieved with estrogen. In fact there is no good evidence that estrogen significantly increases the risk of recurrence after treatment for endometrial cancer. Some studies now suggest that estrogen plus a progestin may actually decrease the risk of cancer recurrence in these patients. The benefits of estrogen in preventing osteoporosis and cardiovascular disease in postmenopausal women is substantial.


Tamoxifen prophylaxis in breast cancer.

An increasing body of data suggests that tamoxifen can suppress development of preclinical breast cancer. Newer data in postmenopausal women also demonstrate major biologic effects of tamoxifen on risk factors for cardiovascular disease and osteoporosis. Taken together, this information supports the hypotheses that use of tamoxifen will provide overall health benefits and lower the incidence of breast cancer in selected women, particularly postmenopausal women, who are willing to take a daily hormone pill indefinitely and who do not develop significant symptomatic side effects. Clinical trials addressing these hypotheses are beginning in the United States, Great Britain, and Italy, but the design and completion of such trials present significant challenges. Until clear data are available from the clinical trials just being launched, tamoxifen should not be given to healthy women who do not have breast cancer.


Endoscopic ultrasonography: an effective new tool for diagnosing gastrointestinal tumors.

Endoscopic ultrasonography is a new technique used to evaluate the gastrointestinal tract and contiguous organs. High resolution endoscopic ultrasound dramatically improves tumor characterization, and enables more precise TNM staging. The earlier diagnosis achieved with this technique combined with more precise staging, permits the most effective timing and selection of chemotherapy, radiation therapy, and surgery. This new technology will almost certainly have great impact on the clinical outcome of patients with gastrointestinal tumors.


A prospective study into the value of patch and intradermal tests in identifying topical corticosteroid allergy.

We have prospectively performed patch and intradermal tests on 105 consecutive patients, attending for patch testing, to determine the optimum method of screening for corticosteroid hypersensitivity. Patch tests with Pivalone and a corticosteroid series (all 1% in ethanol) detected all the patients with steroid sensitivity. However, intradermal tests were essential to exclude false positive reactions and detect all relevant steroid allergies in any individual patient.


Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicentre, double-blind, randomised, parallel group study. Ondansetron Study Group.

A total of 535 chemotherapy naive, hospitalised patients (263 male/272 female) scheduled to receive cisplatin (50-120 mg m-2)-containing regimens participated in a randomised, double-blind, parallel group study to evaluate the efficacy and safety of three intravenous dose schedules of ondansetron in the prophylaxis of acute nausea and emesis. One hundred and eighty two patients received a loading dose of 8 mg of ondansetron followed by a 24 h infusion of 1 mg h-1 (group 1); 180 and 173 patients received single doses of 32 mg (group II) and 8 mg (group III) respectively, followed by a 24 h placebo infusion. Complete and major control (less than or equal to 2 emetic episodes) of acute emesis was achieved in 74% of patients in group I, 78% in group II and 74% in group III. Seventy seven per cent of the patients in group I, and 75% of patients in groups II and III respectively experienced no or mild nausea during the 24 h observation period. A retrospective stratification of the efficacy data on the basis of patient gender showed the response rate in females to be significant lower (43% vs 67%; less than 0.001). Ondanestron was well tolerated; mild headache was the most commonly reported adverse event (11% of patients) with a similar incidence in the three groups of patients. In conclusion, a single intravenous dose of 8 mg of ondansetron given prior to chemotherapy is as effective as a 32 mg daily dose given as either a single dose of a continuous infusion in the prophylaxis of acute cisplatin-induced emesis.


Dehydroepiandrosterone sulfate and other possible influencing factors that modulate sex hormone-binding globulin levels in the hirsute patient.

This study was designed to investigate the most important factors affecting serum concentrations of sex hormone-binding globulin (SHBG) in women with hirsutism. We compared endocrine profiles based on biochemical measurements of LH, FSH, oestradiol, testosterone (T), prolactin, 17-hydroxy-progesterone, dehydroepiandrosterone sulphate (DHEAS), SHBG, cortisol and insulin in the follicular phase in 32 healthy women and 52 patients. The study group was subdivided according to SHBG levels into Group A (low level) and Group B (high level). Significant differences between Groups A and B were found in DHEAS and T levels, but not in body mass index or insulinaemia. There was a relationship between DHEAS and SHBG levels (r = 0.51) and between T and SHBG (r = 0.31). We conclude that DHEAS may be a significant modulator of SHBG in the female hirsute patient, an observation seldom mentioned in previous reports.


A theoretical study concerning the mode of interaction of the histamine H2-agonist dimaprit.

A theoretical study was performed to elucidate the mode of interaction of the histamine H2-agonist dimaprit with the histamine H2-receptor. For this purpose receptor mapping techniques, including ab initio energy calculations, geometry optimizations and molecular electrostatic potential calculations (MEPs), have been used. The characteristics of dimaprit were compared to those of histamine for which the points of interaction with the H2-receptor are known, as well as its bioactive conformation. In this comparative study two possible models for the interaction of dimaprit with the H2-receptor were considered. In one model the two nitrogen atoms of the isothiourea moiety of dimaprit play an essential role in the recognition of the ligand by the receptor and have the same function as the nitrogen atoms of the imidazole ring of histamine; in the second model this role is fulfilled by a sulphur and a nitrogen atom of the same isothiourea moiety. The comparison to histamine was based on geometrical resemblance as well as on similarity in MEPs. Also the conformational energy of dimaprit in the two interaction models was considered. Results of the investigations reveal that the isothiourea moiety of dimaprit most probably interacts with the histamine H2-receptor through the sulphur and nitrogen atom, the first atom acting as a proton acceptor and the second one as a proton donor. Subsequently, three analogues of dimaprit, namely SK&F 91487, SK&F 91488 and SK&F 92054, were studied. It was possible to explain their pharmacological behavior within the proposed model.(ABSTRACT TRUNCATED AT 250 WORDS)


Activation of CD8+ murine T cells from tumor-draining lymph nodes by phorbol dibutyrate plus calcium ionophore.

When lymphocytes from the lymph nodes draining the site of a progressively growing MCA-105 sarcoma are stimulated in vitro with autologous tumor and low-dose interleukin-2 (IL-2), they will grow and develop the ability to lyse autologous tumor cells in vitro; these lymphocytes can also eradicate tumor metastases in vivo. Phorbol esters and calcium ionophores activate signal transduction pathways in T cells and mimic the events triggered by antigen binding. We therefore sought to determine whether large numbers of MCA-105 tumor-specific, therapeutically active T cells could be obtained from MCA-105 draining lymph nodes (DLNs) following a brief exposure to phorbol dibutyrate (PDBu) and ionomycin (Io). DLN cells primarily stimulated with autologous tumor, followed by a secondary stimulation with PDBu-Io and cultured in 20 U/ml IL-2, demonstrated marked expansion of cell numbers during 3 weeks in culture, had moderate cytolytic activity [37% at effector:target ratio (E:T) = 80:1], and were all CD8+ T cells. In contrast, DLN cells stimulated primarily with PDBu-Io and cultured in 20 U/ml IL-2 demonstrated at least 8-10-fold greater growth than antigen-stimulated DLN cells during 3 weeks, were moderately cytolytic (31% at E:T = 80:1), and were a mixed population of CD8+ and CD4+ T lymphocytes. DLN cells that were expanded by either protocol, like cells stimulated repeatedly in vitro with tumor cells, could eliminate MCA-105 pulmonary metastases when given with IL-2 in an adoptive immunotherapy model. DLN cells stimulated primarily with PDBu-Io completely eradicated MCA-105 metastases but had no in vivo antitumor activity against the syngeneic B16 melanoma or MCA-203 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials.

To calculate the effect of changes in carbohydrate and fatty acid intake on serum lipid and lipoprotein levels, we reviewed 27 controlled trials published between 1970 and 1991 that met specific inclusion criteria. These studies yielded 65 data points, which were analyzed by multiple regression analysis using isocaloric exchanges of saturated (sat), monounsaturated (mono), and polyunsaturated (poly) fatty acids versus carbohydrates (carb) as the independent variables. For high density lipoprotein (HDL) we found the following equation: delta HDL cholesterol (mmol/l) = 0.012 x (carb----sat) + 0.009 x (carb----mono) + 0.007 x (carb---- poly) or, in milligrams per deciliter, 0.47 x (carb----sat) + 0.34 x (carb----mono) + 0.28 x (carb----poly). Expressions in parentheses denote the percentage of daily energy intake from carbohydrates that is replaced by saturated, cis-monounsaturated, or polyunsaturated fatty acids. All fatty acids elevated HDL cholesterol when substituted for carbohydrates, but the effect diminished with increasing unsaturation of the fatty acids. For low density lipoprotein (LDL) the equation was delta LDL cholesterol (mmol/l) = 0.033 x (carb----sat) - 0.006 x (carb----mono) - 0.014 x (carb----poly) or, in milligrams per deciliter, 1.28 x (carb----sat) - 0.24 x (carb----mono) - 0.55 x (carb---- poly). The coefficient for polyunsaturates was significantly different from zero, but that for monounsaturates was not. For triglycerides the equation was delta triglycerides (mmol/l) = -0.025 x (carb----sat) - 0.022 x (carb----mono) - 0.028 x (carb---- poly) or, in milligrams per deciliter, -2.22 x (carb----sat) - 1.99 x (carb----mono) - 2.47 x (carb----poly).(ABSTRACT TRUNCATED AT 250 WORDS)


Multiple amino acid substitutions suggest a structural basis for the separation of biological activity and receptor binding in a mutant interleukin-1 beta protein.

Receptor binding and biological activity properties of human interleukin-1 beta can be dissociated by mutating a single amino acid, arginine 127, to glycine (IL-1 beta R----G) [Gehrke et al. (1990) J. Biol. Chem. 265, 5922-5925]. The mechanism underlying the reduced biological activity has been examined by replacing arginine 127 with several other amino acids, followed by determination of biological activity using a T-helper cell proliferation assay. Mutant IL-1 beta proteins containing lysine, glutamic acid, tryptophan, or alanine in place of arginine 127 maintain biological activity. These data strongly suggest that IL-1 beta biological activity is not directly dependent upon the specific properties of charge, hydrophobicity/hydrophilicity, or side-chain group presented by the residue at position 127. Molecular modeling analyses indicate that the structural integrity of the antiparallel beta-strand 1/12 pair is disturbed in the glycine 127 mutant protein. Collapse of beta-strand 1 into a hydrated space between strands 1, 2, and 4 could structurally alter a cleft in IL-1 beta that contains a cluster of highly conserved amino acids, including a key aspartic acid residue [Ju et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 2658-2662]. Mutagenesis data and the differential activities of the IL-1 beta R----G and IL-1 receptor antagonist proteins in stimulating early and late gene expression [Conca et al. (1991) J. Biol. Chem. 266, 16265-16268] suggest that multiple receptor-ligand contacts, exclusive of those required for receptor binding, are required for the stimulation of full IL-1 biological activity.


Minimum length of a sequence-specific DNA binding peptide.

NMR experiments show that a stable complex can be formed between a 14-base-pair oligonucleotide and a disulfide-bonded dimer of a peptide containing 27 residues of the basic region of the yeast transcriptional activator GCN4; the complex is in slow exchange on the NMR time scale. In contrast, a nonspecific complex is in fast exchange on the NMR time scale. DNase I footprinting experiments show that dimers of peptides containing as few as 20 residues of GCN4 bind DNA with sequence specificity similar to that of the intact protein. Circular dichroism experiments suggest that specific binding involves only 15 residues, corresponding to residues 231-245 of GCN4, in an alpha-helical conformation. These results limit substantially the region of GCN4 involved in sequence-specific DNA contacts and provide a uniquely simple model for studying protein-DNA interactions in detail.


Cytoplasmic location of amino acids 359-440 of the Neurospora crassa plasma membrane H(+)-ATPase.

The topographic location of the region comprising amino acids 359-440 of the Neurospora crassa plasma membrane H(+)-ATPase has been elucidated using reconstituted proteoliposomes and protein chemical techniques. Proteoliposomes containing H(+)-ATPase molecules oriented predominantly with their cytoplasmic surface facing outward were cleaved with trypsin and the resulting digest was subjected to centrifugation on a glycerol step gradient to separate the released and liposome-bound peptides. The released peptides were recovered in the upper regions of the step gradient, whereas the liposome-bound peptides were recovered near the 40% glycerol interface. The released peptides present in the upper fractions were reduced, 14C-carboxy-methylated, and then separated by high performance liquid chromatography. Two radioactive cysteine-containing peptides with retention times of about 162 and 182 min were identified as H(+)-ATPase peptides comprising residues Leu363-Lys379 and Leu388-Arg414, respectively, by comparison to standards prepared from the purified ATPase. This information thus establishes a cytoplasmic location for residues 359-418 in the H(+)-ATPase polypeptide chain. It also infers a cytoplasmic location for residues 419-440, since this stretch of amino acids is too short to cross the membrane and return between regions known to be cytoplasmically located. These results and the results of other recent experiments establish the topographical location of nearly all of the 919 residues in the H(+)-ATPase molecule.


Purification of a phosphatidylinositol/phosphatidylcholine transfer protein from Neurospora crassa.

This paper reports, for the first time, the purification of a phospholipid transfer protein (PLTP) from a fungus, Neurospora crassa. The protein was purified from the post-microsomal supernatant of N. crassa by successive chromatography on DEAE-cellulose, Sephadex-G75 and PBE 94 (pH 4-7). The purified protein (M(r) 38,000) was found to transfer phosphatidylinositol preferentially over phosphatidylcholine, like the PLTP from the yeast, Saccharomyces cerevisiae. PC transfer was completely inhibited by inactivation of free amino groups or tryptophan residues. Surprisingly, the protein did not cross-react with antibodies against the bovine brain PITP. The cellular content of the protein was maximal during the logarithmic phase of growth. However, no direct correlation between the content of the protein and PC transfer activity could be demonstrated.


Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.


The expression of thromboxane A2 synthase and thromboxane A2 receptor gene in human uterus.

The expression of thromboxane (TX) A2 synthase and thromboxane A2 receptor gene in human uterus was investigated by immunoblotting, immunocytochemistry, Northern blot, in situ hybridization, and autoradiographic analyses. Human uterus contains a single immunoreactive protein of 55 kDa that corresponds to the molecular size of human TXA2 synthase. Human uterus also contains a single 2.8-kb TXA2 receptor mRNA transcript and a receptor protein that can bind TXA2 antagonist, 125I-PTA-OH. The immunoreactive TXA2 synthase, TXA2 receptor mRNA, and protein are present in endometrial glands, stromal cells, myometrial smooth muscle, and uterine blood vessels. The TXA2 synthase and TXA2 receptors in different uterine cells varied within as well as between various reproductive states. There were differences in the binding site numbers even between elongated and circular myometrial smooth muscle in all reproductive states except postmenopause. In summary, the data presented demonstrate for the first time that different human endometrial and myometrial cells and uterine blood vessels express TXA2 synthase as well as TXA2 receptor gene. The expression, as well as changes during various reproductive states, suggests that TXA2 could be an autocrine/paracrine regulator of human myometrial contractions, endometrial secretory functions, and intrauterine blood flow and could play a role in the initiation and/or progression of labor in women.


[Renal stent implantation. The current indications, 2-year results and the possibilities for percutaneous stent recovery].

Use of the Strecker flexible balloon-expandable tantalum stent for treatment of renal artery stenosis after failed angioplasty or transaortic thrombendarterectomy was evaluated in 18 patients (17 hypertensive, 1 normotensive). Right (n = 10) and left (n = 6) renal arteries were involved; in 2 patients renal artery stenosis had developed after kidney transplantation. Indications for stent placement were inadequate immediate postangioplasty response (n = 16), and obstructing intimal flaps following transaortic endarterectomy (n = 2). Stent placement was technically successful (less than 20% residual stenosis) and patency was preserved in 14 patients. Mid-term results (mean, 12-13 months) of 11 patients showed restenoses (greater than 50%) in 2 patients, and improvement of hypertension in 8 patients. The Strecker stent may be helpful in treating residual stenosis after failed revascularization procedures of the renal arteries, although long-term efficacy of stent placement will not be known until trials with more subjects and longer follow-up periods are completed.


Plasma crosslinked fibrin polymers: quantitation based on tissue plasminogen activator conversion to D-dimer and measurement in normal and patients with acute thrombotic disorders.

Plasma crosslinked fibrin polymers (XLFP) are formed as a result of in vivo hemostatic activation and are elevated in thrombotic disease. We have investigated the plasmic degradation of plasma XLFP in vitro to provide information regarding the pattern of crosslinking and the composition of degradation products. Plasma XLFP were identified by sodium dodecyl sulfate (SDS)-agarose electrophoresis and Western blotting and quantitated by gel scanning. D-dimer was measured by enzyme-linked immunosorbent assay and the results were verified by SDS-polyacrylamide gel electrophoresis and Western blotting of the digests. Complete degradation of XLFP occurred only after supplementation of plasma with plasminogen (5 U/mL) and incubation with recombinant tissue plasminogen activator (rt-PA), indicating that the normal plasma plasminogen concentration limits plasmic degradation in vitro. Gel electrophoresis showed that the principal terminal degradation products of XLDP were fragments D, DD, and E, indicating that crosslinking occurred primarily through gamma chain dimers. After adding a low concentration of thrombin to plasma in vitro, XLFP increased progressively before clotting, and the concentration correlated with the increase in the D-dimer concentration after degradation (r = .98). Plasma XLFP and D-dimer concentrations in plasmic digests were significantly elevated in patients with stroke (150 +/- 83 micrograms/mL and 88 +/- 32 micrograms/mL), myocardial infarction (217 +/- 110 micrograms/mL and 84 +/- 30 micrograms/mL), and venous thrombosis (187 +/- 80 micrograms/mL and 86 +/- 19 micrograms/mL) compared with normals (28 +/- 12 micrograms/mL and 25 +/- 7 micrograms/mL). There was a strong correlation between the plasma concentration of XLFP and the D-dimer immunoreactivity of plasma after plasmic degradation (r = .87). The results indicate that XLFP in plasma are crosslinked primarily through gamma chains and degrade to fragment DD with plasminogen activation. Also, the immunoreactivity of in vitro plasmic digests of plasma reflects the concentration of XLFP and may provide a useful indirect measure of in vivo hemostatic activation in patients with thrombotic disease.


Correlation between interferon (IFN) alpha resistance and deletion of the IFN alpha/beta genes in acute leukemia cell lines suggests selection against the IFN system.

Homozygous and hemizygous deletions of the interferon A (IFNA) and IFNB genes have been frequently observed in acute leukemia cell lines, primary acute leukemia cases, and gliomas. Because IFNs have an antiproliferative effect, selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype. Although the deletion of the IFNA/B genes could interrupt an autocrine loop that controls cell proliferation, cells would still respond to exogenous IFN alpha/beta and, thus, lesions at the receptor or signal transduction level should also be present to render cells resistant to exogenous IFN alpha/beta. To test if selection against the IFN system was operating in acute leukemias, the sensitivity to the antiproliferative effect of IFN alpha 2 was studied in acute leukemia cell lines with and without alterations of the IFNA/B genes. We found that 10 of 11 acute leukemia cell lines with alterations of the IFNA/B genes were resistant to the antiproliferative effect of IFN alpha 2, whereas only two of eight cell lines with normal IFNA/B genes were IFN-resistant. We then examined the possibility that an alteration of the receptor expression could account for the lack of response to IFN alpha 2. No significant alteration in the expression or structure of the IFN alpha receptor was observed. We also studied the downmodulation of the alpha subunit of the IFN alpha receptor upon IFN alpha 2 binding. One cell line with deletion of the IFNA/B genes showed impaired downmodulation of the IFN alpha receptor. The data presented here suggest that selection against the IFN alpha/beta system could play a role or accompany the development of the malignant phenotype.


A prospective study of skeletal changes during short-term acitretin therapy.

We prospectively analyzed skeletal changes of 16 patients who were treated with acitretin for various disorders of keratinization at doses of 10-50 mg/day (overall mean 0.4 mg/kg/day) for 7-12 months (mean 11.4 months). Skeletal changes from pretherapy findings were observed in 5 patients. In 4 of 5 patients they appeared to be linked to a preexisting degenerative pathology and could not be attributed to acitretin therapy. However, in 1 patient a spinal osseous side effect could not be excluded. No retinoid-induced extraspinal tendon or ligament calcifications were observed.


Ultrastructural changes in onychomycosis during the treatment with bifonazole/urea ointment.

In the present study, we investigated the effects of bifonazole/urea ointment, a novel topical drug for the treatment of onychomycosis, on the ultrastructure of normal and fungus-infected human toenails by scanning electron microscopy. Nails were treated with the drug ex vivo and compared to untreated controls. During treatment, the corneocyte layers disintegrated, and the structure markedly loosened. After 5 days of treatment, the morphology of fungal cells, found at the undersurface of infected nails, was changed due to the antifungal drug action. The present data demonstrate that by the use of this drug, the agent effectively penetrates the nail plate and affects the fungal cells.


Inhibition of neutrophil chemotactic factor production in comedonal bacteria by subminimal inhibitory concentrations of erythromycin.

The effect of 1/10 minimal inhibitory concentrations (sub-MIC) of erythromycin (EM) on human neutrophil chemotactic factor production in comedonal bacteria, Propionibacterium acnes strains, Propionibacterium granulosum strains and coagulase-negative staphylococcus (CNS) strains was assayed using the Boyden chamber method. Sub-MIC of EM significantly suppressed neutrophil chemotactic factor production in all strains of P. acnes, P. granulosum and CNS. Our results suggest that sub-MIC of EM may have an anti-inflammatory action by reducing the inflammatory capacity of comedonal bacteria in inflammatory acne.


Murine erythrocyte ankyrin cDNA: highly conserved regions of the regulatory domain.

Ankyrin is an essential link between cytoskeletal proteins, such as spectrin, and membrane bound proteins, such as protein 3, the erythrocyte anion exchanger. Although the amino acid structure of human ankyrin is known, the functional regions have been only partially defined. Sequence comparisons between mouse and human ankyrin offer one mechanism of identifying highly conserved regions that probably have functional significance. We report the isolation and sequencing of a series of overlapping murine erythroid ankyrin (Ank-1) cDNAs from spleen and reticulocyte libraries (total span 6238 bp) and identify potentially important regions of murine-human reticulocyte ankyrin homology. Comparison of the predicted peptide sequences of mouse and human erythroid ankyrins shows that these ankyrins are highly conserved in both the N-terminal, protein 3 binding domain (96% amino acid identity) and in the central spectrin-binding domain (97% identity), but differ in the C-terminal regulatory domain (79% identity). However, the C-terminal regulatory domain contains two regions of peptide sequence that are perfectly conserved. We postulate these regions are important in the regulatory functions of this domain.


The circadian rhythm of atrial natriuretic peptide, vasoactive intestinal peptide, beta-endorphin and cortisol in healthy young and elderly subjects.

Atrial natriuretic peptide, vasoactive intestinal peptide, beta-endorphin and cortisol are humoral variables characterized by a 24-h periodicity. We evaluated the circadian rhythm of these peptides and hormones in healthy subjects who were young (between 20-25 years) or elderly (between 65-75 years). All were on controlled diets. Blood samples were collected six times during a 24-h period (at 06.00, 08.00, 12.00, 18.00, 20.00 and 24.00 h) beginning 8-h after start of recumbency. The time-related data were analysed by the Cosinor method in order to validate the circadian rhythm and to quantify rhythmometric parameters which included the midline estimate of rhythm (mesor). In contrast to the young subjects, Cosinor analysis failed to reveal a significant circadian rhythm in elderly subjects, for plasma cortisol. In elderly subjects oscillation (mesor) of atrial nutriuretic peptide was higher, while that of vasoactive intestinal peptide and beta-endorphins was lower. The results suggest changes in the physiological secretion of these three peptides in healthy elderly subjects.


The CREB family of transcription activators.

A diverse family of transcription factors bind to the cAMP-response elements found in a variety of mammalian and viral gene promoters. One of the members of this family, CREB, is being intensively studied so as to elucidate the mechanisms by which second messenger signal transduction pathways act to positively and negatively regulate transcription.


The inhibitory ankyrin and activator Rel proteins.

The gene families encoding the proteins NF-kappa B, c-Rel and Dorsal, in conjunction with their respective inhibitors l kappa B, pp40, and Cactus, achieve specificity in gene regulation by means of common principles. The related activities of NF-kappa B and Dorsal are mediated by heterodimeric or homodimeric complexes of proteins containing the conserved dimerization and DNA-binding domain termed Rel. The l kappa Bs and Cactus, which share a core series of structural repeats termed ankyrin, inhibit cognate activators through differential interactions with the Rel-homology domain. Together, the inhibitory ankyrin proteins and their cognate Rel dimers probably define specific signalling pathways able to activate specific gene expression. Both gene families include proto-oncogenes, thus broadly implicating Rel/l kappa B in the control of both normal gene expression and the aberrant gene expression that makes cells cancerous.


The emerging neuropoietic cytokine family: first CDF/LIF, CNTF and IL-6; next ONC, MGF, GCSF?

CDF/LIF is a polyfunctional cytokine that shares a remarkable overlap with ciliary neurotrophic factor in its actions on neurons, and with interleukin-6 in its actions on other tissues. Moreover, the receptors for this cytokine, as well as those for ciliary neurotrophic factor, share homology with the subunits of the interleukin-6 receptor. The predicted structural similarity of these proteins with oncostatin M, myelomonocytic growth factor and granulocyte colony-stimulating factor, as well as at least a partial overlap in biological activities, is now prompting further examination of their roles in neuronal gene expression.


Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer.

An open randomised Phase III trial was conducted of the depot GnRH analogue goserelin (Zoladex) versus stilboestrol (3 mg/day) in patients with advanced or metastatic prostate cancer. The study included 250 patients and the median follow-up was 43 months. In the Zoladex arm the time to first response was achieved earlier and more patients reported an improvement in symptoms. There was no statistically significant difference between the Zoladex and the stilboestrol arms with regard to survival and time to treatment failure. A major reason for treatment failure was the preponderance of adverse events in patients receiving stilboestrol. It is suggested that stilboestrol should no longer be used for prostate cancer when equally effective alternative treatments are available.


The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke.

The non-competitive N-methyl-D-aspartate receptor/channel antagonist dizocilipine maleate (MK-801) has been reported to reduce infarct volume in a variety of focal stroke models. We examined the effect of MK-801 on infarct volume and cerebral blood flow in temporary and permanent focal ischemia in rats. In Wistar rats exposed to permanent right common carotid artery and 2 h of transient right middle cerebral and left common carotid artery occlusion followed by 22 h of reperfusion, MK-801 reduced infarct volume by 73% (P less than 0.05) and significantly increased cerebral blood flow to the ischemic core throughout the 2-h period of ischemia. In spontaneously hypertensive rats (SHRs) exposed to permanent right common carotid artery occlusion and 2 h of transient right middle cerebral artery occlusion followed by 22 h of reperfusion, MK-801 decreased infarct volume by 13% (P greater than 0.05) and increased cerebral blood flow to the penumbral region. In SHRs subjected to permanent right common carotid and middle cerebral artery occlusion MK-801 reduced infarct volume by 18% at 3 h (P greater than 0.05), by 25% at 6 h (P less than 0.01) and by 18% at 24 h (P less than 0.05). MK-801-treated SHRs had no difference in cerebral blood flow to the ischemic core, but increased cerebral blood flow to penumbral zones as compared with untreated SHRs. These results suggest that the protective effect of MK-801, at least in part, relates to improved cerebral blood flow.


Localization of amyloid precursor protein in GAP43-immunoreactive aberrant sprouting neurites in Alzheimer's disease.

Previous in vitro studies have suggested that amyloid precursor protein (APP) could be involved in cell surface adhesion, neuritic growth and survival of hippocampal neurons. In the present study, involvement of APP in aberrant sprouting in Alzheimer's disease (AD) was studied by comparing immunolabeling patterns of anti-APP and anti-growth-associated protein 43 (anti-GAP43). Confocal laser imaging of frontal cortex sections double-immunolabeled for APP and GAP43 showed an increase, in AD, of presynaptic boutons immunostained with anti-GAP43 that contained anti-APP immunoreactivity. The neuritic plaques in AD cases presented intense anti-GAP43 immunoreactive abnormal neurites colocalized with anti-APP. Three-dimensional reconstruction of the plaques showed that anti-APP was colocalized with anti-GAP43 in 57.5% of the aberrant sprouting neurites. We conclude that co-expression of APP with GAP43 in the plaque might be involved in the aberrant sprouting response observed in AD.


Differential effects of excitotoxic basolateral and corticomedial lesions of the amygdala on the behavioural and endocrine responses to either sexual or aggression-promoting stimuli in the male rat.

The effects of discrete excitotoxic lesions of the basolateral (BL) and corticomedial (CM) amygdaloid areas on both male rat sexual behaviour and inter-male agonistic behaviour were investigated. The effects of the same lesions on the hormonal responses (luteinising hormone (LH) following sexual behaviour, corticosterone following aggressive interactions) which accompany these behavioural responses were measured. Basolateral lesions had no effect on male sexual behaviour but significantly reduced the level of aggressive inter-male behaviour. However, the increase in plasma corticosterone concentration which occurs after such an interaction was not affected by basolateral lesions. In contrast, corticomedial lesions did not affect inter-male offence but severely affected copulatory behaviour, including a significant decrease in the males' investigation of the receptive female. However, the increase in plasma LH concentrations induced by the presence of a receptive female was not affected by the CM lesion. These results demonstrate a dissociation between the two amygdaloid regions with respect to the contributions made to the two social behaviours under study. This anatomical division may reflect differential amygdaloid sensory control of these behaviours. A further dissociation between amygdaloid contribution to behavioural and hormonal responses was also revealed. Neither hormonal response showed a parallel decline with the relevant behavioural response, suggesting that neither the basolateral nor corticomedial amygdaloid complex is responsible for coordinating behavioural and endocrine responses to a specific stimulus.


Role of 5-hydroxytryptamine receptors on luteinizing-hormone-releasing hormone release in the ovariectomized, estradiol-treated rat.

The present experiments examined the effect of ketanserin [5-hydroxytryptamine-2 (5-HT2) antagonist] and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (5-HT1 agonist) on the in vitro release of luteinizing-hormone-releasing hormone (LHRH) from the medial basal hypothalamus-preoptic area-suprachiasmatic nucleus region (MBH-POA-SCN) of ovariectomized (OVX), estradiol-(E2) treated rats using in vitro superfusion techniques. Regularly cycling female Holtzman rats (250-300 g) were maintained on a photoperiod of 0500-1900 h light at 22 +/- 2 degrees C. Rats were ovariectomized (25-30 days) and received Silastic E2 implants (150 micrograms E2/ml sesame oil) SC 48 h prior to the in vitro superfusion. Following a control period of Krebs-Ringer Phosphate (KRP) superfusion, ketanserin (5-HT2 receptor antagonist, 1 x 10(-6) M) significantly increased LHRH release (p less than 0.05). Subsequent superfusion of 5-HT (1 x 10(-8) M) significantly decreased (p less than 0.05) the effect of ketanserin on LHRH release. The 5-HT2 antagonist Lilly 53857 (1 x 10(-6) M or 1 x 10(-5) M) did not increase LHRH release above control levels. Neither 5-HT nor quipazine had a significant effect on LHRH release at 1 x 10(-6) M. Superfusion of 8-OH-DPAT (5-HT1 receptor agonist 1 x 10(-5) M) significantly (p less than 0.01) increased LHRH release but subsequent superfusion of 8-OH-DPAT + pindolol (mixed 5-HT1a,1b and a beta-adrenergic receptor antagonist, 1 x 10(-6) M) or pindolol alone had no effect on LHRH release. These results suggest that the 5-HT1 receptor plays a role in LHRH release and this effect may be related to the opposing effects of postsynaptic and autoreceptors. However, the failure of Lilly 53857 to reproduce the stimulatory effect of ketanserin on LHRH release suggests that 5-HT2 receptors in the MBH-POA-SCN may not modify LH release during the estrous cycle.


Effects of early postnatal sex steroids on acquisition and extinction of a continuously reinforced lever-pressing response.

The effects of early postnatal dihydrotestosterone (DHT) and estradiol on the sexually dimorphic continuously reinforced lever-pressing response were investigated. 90-day-old male rats postnatally treated (during the first eight days of postnatal life) with cyproterone acetate (CA), tamoxifen (TX) or vehicle, and 90-day-old females treated with estradiol benzoate (EB), DHT or vehicle in the same postnatal period, were studied during the acquisition and extinction of the continuously reinforced lever-pressing response using a free-operant procedure. During acquisition, the control males made more responses per minute than the control females, and also reached the extinction criterion significantly sooner than the females. CA treatment impaired the male's performance at the levels of that shown by females, whereas TX treatment affected neither acquisition nor extinction. Inversely, in both experimental phases females treated with DHT performed like control females, whereas the acquisition and extinction performances of the EB-females were similar to those obtained in the control or TX male groups.


Attenuation of drinking sweetened water following calcium channel blockade.

Recent reports cite results that both cocaine-induced conditioned place preference and activity stimulation are attenuated by pretreatment with the calcium channel blocker isradipine (ISR) in rats. By blocking voltage-dependent L-type calcium channels, ISR may regulate neural dopamine release that, in turn, decreases the putative rewarding effects mediated by dopaminergic mechanisms. It is known that nonfluid deprived rats avidly consume sweetened fluids; this suggests that the sweet taste is rewarding. Three experiments were conducted to determine the effects of ISR on drinking sweetened and nonflavored water. Experiment 1 was designed to test whether ISR would attenuate the intake of a palatable solution in a dose-dependent manner. To this end, ISR was administered both peripherally (3.0-30 mg/kg) and centrally (0.3-30 micrograms/rat) prior to a solution of saccharin and d-glucose (S + G) being made available to rats (15 min/day) and intake was recorded. ISR produced dose-dependent decreases (38%-81%) in S + G intake dependent on the route of administration. In Experiment 2, water intake was measured in 18 h water-deprived rats following ISR (10 mg/kg) administration as well as comparing S + G drinking. The effect of two ISR vehicles, dimethyl sulfoxide and Tween 80, upon fluid intake was also determined. ISR injection did not attenuate water intake in 18 h water-deprived rats and the choice of vehicle did not affect the ISR-induced attenuation of S + G drinking. In Experiment 3, a single dose (30 micrograms) of ICV administered ISR, that attenuated S + G intake by approximately 44%, did not attenuate water intake in 18 h water-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)


New agents labelled with technetium 99m for myocardial perfusion imaging.

New agents labelled with technetium 99m (99mTc) are now available for myocardial perfusion imaging. In this article the author reviews the biologic characteristics, the imaging protocols and the clinical usefulness of thallous chloride Tl 201, 99mTc-sestamibi and 99mTc-teboroxime (not yet available in Canada), as well as their complementary roles in the detection of coronary artery disease.


Oral ondansetron for the control of delayed emesis after cisplatin. Report of a phase II study and a review of completed trials to manage delayed emesis.

Despite excellent control of vomiting during the initial 24 hours after chemotherapy with combination antiemetics, most patients who receive cisplatin at doses of 120 mg/m2 experience delayed emesis 24-120 hours after chemotherapy. Twenty patients receiving cisplatin (greater than or equal to 100 mg/m2) as initial chemotherapy were entered into this Phase II trial to test the effectiveness of oral ondansetron, a specific serotonin receptor (5-HT3) antagonist, in controlling delayed emesis. All patients received intravenous metoclopramide, dexamethasone, and lorazepam for the control of acute emesis 0-24 hours after receiving cisplatin. They then received ondansetron 16 mg orally three times a day for 4 days. Fifteen percent of those who were treated with oral ondansetron had complete control of delayed emesis during the entire 4-day period (95% confidence interval, 3-38%). No serious adverse events occurred. At the dose and schedule tested, oral ondansetron did not appear to control delayed emesis. Previous trials of programs to lessen this complication suggest that both metoclopramide and dexamethasone are effective in lessening delayed vomiting and that the combination of these drugs is more effective than placebo. Although in one trial ondansetron appeared to control delayed emesis in patients who received cisplatin at doses of 50-120 mg/m2, it was not superior to either placebo or metoclopramide in two randomized studies. Additional testing of the 5-HT3 antagonists, both alone and in combination, will be needed to establish their role in the management of this condition.


Recent developments in endocrine treatment of prostate cancer.

Cancer of the prostate gland is the most frequently occurring malignant lesion in men. Because most prostate cells depend on androgen for growth, removal of testosterone by either orchiectomy or medical castration using diethylstilbestrol or a luteinizing hormone-releasing hormone (LHRH) analogue is first-line treatment for patients with symptomatic Stage D2 disease. The trend in hormonal therapy has been toward long-acting minimal-dosing high-compliance regimens, capitalizing on the recent availability of the long-acting LHRH analogues, which require only monthly injections to maintain castration levels of testosterone, and the nonsteroidal antiandrogen ICI 176,334, which (in early clinical trials) appears to block intracellular testosterone activity with a once-a-day oral regimen. To eliminate the rapid LH increase that can occur during early agonist therapy, combinations of LHRH analogues and antiandrogens (total androgen blockade) have been tested and appear promising. The effects of hormonal treatment in patients with symptomatic Stage D2 prostate cancer have been studied extensively and are relatively well understood. By contrast, hormonal treatment has not been explored in contemporary randomized Phase III trials of asymptomatic Stage D2, D1, or C disease, localized Stage B or A disease, or before prostate surgery or radiation treatment. Research must continue to determine the optimal regimen that suppresses testosterone activity with the least amount of toxicity.


Impact of polydonor mixed lymphocyte culture media on quantity and quality of myeloid metaphases.

A novel mitotic stimulator of myeloid hematopoietic cells was prospectively evaluated to detect enhanced quantity and quality of metaphases from bone marrow (BM) cultures for cytogenetic analysis. This polydonor mixed lymphocyte conditioned (PMLC) media decreased the culture failure rate, improved detection of chromosomal aberrations, and reduced technologists' analysis time. The conditioned media is recommended as a highly effective culture system for normal and neoplastic cells of myeloid lineage.


Interactions between p21ras proteins and their GTPase activating proteins.

Two proteins that regulate p21ras GTPase activity have been identified. These proteins interact with a region of ras p21 that is necessary for p21ras function and may themselves be components of signalling complexes. The first of these proteins to be identified, GAP, contains domains that interact with receptor tyrosine kinases and other tyrosine phosphoproteins, providing a direct link between signalling pathways involving these proteins and p21ras. The second, the product of the NF1 gene, is less well characterized but seems to connect p21ras to other signalling pathways which are perturbed in the NF1 disease. The ability of p21ras to interact with GAP may be compromised by competitive binding to the product of the Ki-rev1 gene, p21rap1. This competition for binding to GAP, or other proteins that interact with the effector site of ras p21, may explain the ability of Ki-rev1 to suppress cellular transformation by ras oncogenes.


Lymphokine production by human melanoma tumor-infiltrating lymphocytes.

Lymphokine production by human melanoma tumor-infiltrating lymphocytes (TIL) was studied. Uncultured TIL produced interferon gamma (IFN gamma), but not interleukin-2 (IL-2) or IL-4, in response to anti-CD3 mAb or IL-2. In bulk cultures, IL-2-activated TIL displaying autologous tumor-specific cytotoxicity (CTL-TIL) produced IFN gamma in culture with medium alone, whereas IL-2-activated noncytotoxic TIL did not. Addition of anti-CD3 mAb or autologous tumor cells up-regulated IFN gamma production in IL-2-activated TIL from 10 of 12 or 6 of 12 cases respectively. Those from 4 of 12 cases (2 CTL-TIL and 2 noncytotoxic TIL) produced IL-2 in culture with medium alone. At the clonal level, 5 (4 CD4+ and 1 CD8+) of 7 autologous tumor-specific CTL clones derived from TIL and 3 (2 CD4+ and 1 CD8+) of 7 noncytotoxic TIL clones produced IFN gamma in culture with medium alone, which was up-regulated by adding anti-CD3 mAb. Two IFN gamma-producing CTL clones tested produced IL-2 in 4x-concentrated supernatants from a 3.5-h culture with medium alone. Furthermore, 2 IFN gamma-producing CTL clones tested expressed mRNA for both IFN gamma and IL-2. IL-2 production and its mRNA expression were up- or down-regulated, respectively, by adding anti-CD3 mAb or autologous tumor cells. IL-4 production was not observed in culture either with medium alone or with IL-2 in any of the cells described above. Anti-CD3 mAb was required for IL-4 production in 3 of 12 IL-2-activated TIL, 2 of 6 CTL clones, and none of 5 noncytotoxic TIL clones. In summary, IFN gamma production was characteristic of melanoma TIL. Some autologous tumor-specific CTL in TIL are suggested to be productive of IL-2 and IFN gamma under unstimulated conditions, both being required for self-activation in an autocrine loop.


Annexin VI is required for budding of clathrin-coated pits.

Isolated plasma membranes attached to a solid substratum at 4 degrees C have numerous clathrin-coated pits. These pits initially are flat but become deeply invaginated after warming to 37 degrees C. The pits remain tethered to the membrane in this rounded condition unless supplied with ATP, Ca2+, and cytosol. We now show that when cytosol is treated to remove the Ca(2+)-dependent, phospholipid-binding protein annexin VI, coated pit budding no longer takes place. Addition of purified annexin VI back to the annexin VI-depleted cytosol restores budding activity to normal. Purified annexin VI alone shows only a modest budding activity, suggesting that the cytosol contains a factor(s) in addition to annexin VI that is required for full activity. Cytosol-dependent activation of annexin VI requires both ATP and Ca2+. Annexin VI appears to be not only an active component in the detachment of coated pits from the membrane but also a site for regulating the formation of coated vesicles.


Pharmacologic treatment of osteoarthritis.

Current pharmacotherapy for osteoarthritis (OA) is aimed at relief of pain and functional disability. Although an inflammatory component may be found in some cases, there is little evidence that anti-inflammatory drugs commonly used in the treatment of OA provide more relief than simple analgesics. A growing body of knowledge about the pathophysiology of OA now offers opportunities to develop interventions aimed at retarding the progressive degeneration of articular cartilage. This is a function of an imbalance between cartilage matrix synthesis and breakdown. New and experimental treatments include oral, parenteral, and intra-articular agents, some of which are chemicals and others biological products. Their modes of action have generally not been established in humans, but may be inferred from in vitro culture systems and animal models. These mechanisms include inhibition of synovial cell-derived cytokines and chondrocyte-derived degradative enzymes, inactivation of superoxide free radicals, stimulation of matrix synthesis, and enhancement of synovial fluid lubrication. Many of these treatments have been shown to provide short- or long-term symptomatic improvement in clinical trials. Protection of cartilage or promotion of repair has been demonstrated in animal studies, but not convincingly in human OA studies.


A protein tyrosine kinase in the interferon alpha/beta signaling pathway.

The mutant human cell line 11.1 is unresponsive to interferon alpha. Here we describe the genetic complementation of this mutant and the identification and cloning of the wild-type gene that corrects the defect. Using transfection with genomic DNA in conjunction with a powerful back-selection, we isolated a cosmid that reverts the mutant phenotype of 11.1 cells. The cosmid encodes a single message whose level is greatly reduced in mutant cells. Complementary DNAs were cloned and found to be virtually identical to tyk2, a human mRNA encoding a non-receptor protein tyrosine kinase of previously unknown function. This finding shows that tyk2 links the interferon alpha/beta receptor to the cytoplasmic transcription factor that mediates activation of interferon-responsive genes.


Disease, illness and health: theoretical models of the disablement process.

Handicap is the result of a process of disablement whose origin is a pathological condition (disease). According to some definitions of health (e.g., a state of complete physical, mental and social well-being), the classical biomedical concept is too restrictive to cover all the consequences of disease. New models have been proposed: the impairment-disability-handicap model presented by WHO, the situational handicap model, and the quality-of-life model. A unifying schema of the disablement process includes these concepts and provides a useful way of analysing the consequences of disease. Factors that modify the disablement process can be identified by their respective impacts, and provide operational guidelines for public health interventions.


Plasma atrial natriuretic peptide is unstable under most storage conditions.

Atrial natriuretic peptide (ANP) is a hormonal regulator of cardiovascular fluid volume. More than 1,000 scientific articles were written about ANP between 1987 and 1991. Because some articles hinted at problems with storing ANP, this study examined the effect of numerous techniques for storing and processing human ANP samples. Samples were obtained repeatedly from three patients, treated, and stored under a variety of conditions. Experiment 1 evaluated the effects of different preservatives at 35, 21, 14, 10, and 7 days before assay. Experiment 2 evaluated nonspecific binding of ANP to different storage tubes during 28 days of storage. Experiment 3 evaluated the effect of storage at -20 degrees C, -80 degrees C, and -196 degrees C for 1 month. ANP was very unstable, degrading as much as 30% after 3 days of storage and by more than 50% in 1 month even when stored at -80 degrees C. Only storage at -196 degrees C (in liquid nitrogen) kept ANP stable for 1 month. Extraction and lyophilization of the samples before freezing and assay within 7 days of freezing only partially minimized the amount of degradation. All other processing techniques had little effect on slowing the degradation of ANP. These findings raise disturbing questions about the interpretation of the substantial literature on ANP.


Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients.

Although serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis in the general population and Lp(a) levels are increased in hemodialysis patients, an association of Lp(a) with the risk of clinical events attributed to atherosclerosis has not been established in the chronic hemodialysis patient population. We therefore determined the association between Lp(a) levels and the risk of clinical events of presumed atherosclerotic etiology in a prospective study of an outpatient hemodialysis population. Lp(a) was measured by radioimmunoassay in a baseline cardiovascular disease risk assessment in a consecutive series of 129 hemodialysis patients. The relation between baseline Lp(a) and clinical events of presumed atherosclerotic etiology was determined during 48 months of follow-up. Hemodialysis patients had a median Lp(a) concentration that was approximately four times as high as the median Lp(a) concentration in normal controls and twice as high as the levels in controls with angiographic evidence of coronary artery disease [median Lp(a), 38.4 versus 16.9 mg/dl; p less than 0.001]. Baseline Lp(a) levels were no different in participants with or with no history of a previous clinical event at the time of the baseline examination. However, baseline Lp(a) concentration (p less than 0.001) and a history of atherosclerotic clinical events (p = 0.001) were associated with clinical events during the period of follow-up. In contrast, baseline serum total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, age, gender, race, or duration of hemodialysis were unrelated to this risk in the prospective study. Stepwise multiple logistic regression analysis demonstrated that serum Lp(a) concentration (p = 0.001) and the presence of a previous clinical event (p = 0.004) were the only independent contributors to the risk of a clinical event during the period of follow-up. Lp(a) is an independent risk factor for clinical events attributed to atherosclerotic cardiovascular disease in patients receiving chronic hemodialysis treatment of end-stage renal disease.


Effect of balloon angioplasty on femoral artery evaluated with intravascular ultrasound imaging.

Intravascular ultrasound was used to assess the immediate effect of balloon angioplasty on the superficial femoral artery. In 16 consecutive patients, corresponding ultrasonic cross sections (n = 72) before and after balloon angioplasty were qualitatively and quantitatively analyzed. The qualitative data were compared with angiographic findings. Before intervention, the angiographically demonstrated obstructive lesions were confirmed by intravascular ultrasound. Ultrasound enabled discrimination between soft (n = 43) and hard (n = 29) lesions, as well as between eccentric (n = 57) and concentric (n = 15) lesions. After balloon angioplasty, the presence of a dissection assessed angiographically in 14 patients was confirmed by intravascular ultrasound. Additional morphological information provided by ultrasound included plaque rupture in 14 patients and internal lamina rupture in six patients. Quantitative ultrasound data revealed an increase in free lumen area from 9.7 +/- 4.7 to 18.3 +/- 7.0 mm2 (p less than or equal to 0.01), an increase in minimal lumen diameter from 2.8 +/- 0.7 to 3.6 +/- 1.2 mm (p less than or equal to 0.01), and an increase in media-bounded area from 21.7 +/- 5.4 to 28.3 +/- 5.8 mm2 (p less than or equal to 0.01). The lesion area for the majority of cases (n = 32) remained unchanged (13.0 +/- 4.9 mm2 versus 12.9 +/- 4.6 mm2), or the lesion disappeared partially (from 9.1 +/- 0.9 to 4.3 +/- 1.4 mm2, n = 4, p less than or equal to 0.01) or totally (from 10.1 +/- 4.2 to 0 mm2, n = 6). Stretching of the arterial wall was further evidenced by medial thinning from 0.55 +/- 0.19 to 0.34 +/- 0.11 mm (p less than or equal to 0.01). Luminal enlargement by balloon dilatation is achieved primarily by overstretching the arterial wall, with the lesion volume remaining practically unchanged. Overstretching is accompanied almost always by dissection and plaque rupture and occasionally by an internal lamina rupture.


The expression of GAP43 mRNA during the late embryonic and early postnatal development of the CNS of the rat: an in situ hybridization study.

GAP43 is a developmentally regulated phosphoprotein which is almost exclusively found in neurons. Numerous correlative studies have shown that GAP43 is expressed at high levels during neurite extension, axonal elongation and synaptogenesis. In this study we used in situ hybridization to examine GAP43 expression during late embryonic and early postnatal development. The highest relative levels of GAP43 at all stages were present in the neocortex. Levels in this and other regions peaked between postnatal days 5 and 10. These results indicate that high levels of GAP43 mRNA correlate most highly with the latter stages of axon outgrowth and with the early stages of synapse formation.


Cyclophosphamide treatment antagonizes the in vitro development of Mycobacterium lepraemurium-induced suppressor cell precursors.

The in vitro-inducible maturation of splenic suppressor cell precursors detected during the early phase of Mycobacterium lepraemurium infection can be abrogated when a high dose of cyclophosphamide (Cy) is inoculated to infected mice 2 days before assay. The drug does not act directly on adherent suppressor cell precursors, but rather inhibits their activation by a non-adherent cell subset whose phenotype has not yet been elucidated. It was established by flow cytometry analyses, that despite a marked increase in the total number of splenic non-adherent cells following M. lepraemurium infection, the effect of Cy on Ia+, Thy-1+, CD4+ and CD8+ cells in infected mice was comparable to that observed in normal controls. It was not possible to determine the duration of the inhibiting effect of Cy on non-adherent regulatory cells, because the drug was itself inducing suppressor cells from 7 days after inoculation. By the time spleen cell suspensions were totally free of Cy-induced suppressor cells, infection-dependent suppressor cell precursors were once again detected, indicating that Cy treatment did not prevent their in vivo accumulation. Therefore, even though M. lepraemurium-induced adherent suppressor cell precursors are themselves fully resistant to Cy, their development is transiently abrogated by the drug, most probably through the impairment of a non-adherent cell subset regulating their maturation.


Analysis of T cell receptors in rheumatoid arthritis: the increased expression of HLA-DR antigen on circulating gamma delta+ T cells is correlated with disease activity.

The phenotypic characteristics of peripheral blood T cells, isolated from 37 rheumatoid arthritis (RA) patients and 17 healthy controls were determined with special emphasis on gamma delta+ T cells and CD4-CD8- alpha beta+ T cells. Two- and three-colour automated flow cytometry analyses were performed using a panel of MoAbs directed against differentiation antigens and T cell receptor molecules. The results demonstrated: (i) no significant difference between the percentages of CD4-CD8- alpha beta+ T cells in patients and controls; (ii) a significant decrease of the gamma delta+ T cell level in the peripheral blood of RA patients relative to controls; (iii) phenotypic abnormalities of circulating gamma delta+ T cells in RA patients suggestive of an activation status in vivo. These abnormalities included a significant reduction in the density of the T cell differentiation antigen CD3 and an increase in the expression of HLA-DR antigen. The level of circulating HLA-DR+/gamma delta+ T cells was significantly higher in patients with active disease. HLA-DR+/gamma delta+ T cells were also present in the synovial fluid obtained from three patients with an active disease. In addition, preliminary experiments showed that the activated gamma delta+ T cells were predominantly V delta 1. Taken together, these data support the involvement of gamma delta+ T cells in the pathogenesis of RA.


A persistent T cell expansion in the peripheral blood of a normal adult male: a new clinical entity?

A dramatic and persistent T cell expansion in a healthy adult male was initially identified, using anti-T cell receptor for antigen (TCR)-specific MoAbs. The expanded T cells were found to be expressing TCR containing V alpha 12.1 and V beta 5.2, and they composed approximately one third of all the CD8+ T cells. The cells were shown to be not only non-activated (HLA-DR-, IL-2R-) but also of 'virgin' cell type (CD45RA+/CD45RO-) and they persisted over the observation period of more than one and a half years. Various T and B cell markers, and all other laboratory and physical parameters analysed, were normal. The expanded CD8+ T cells were further characterized by polymerase chain reaction (PCR) amplification, using V beta- and C beta-specific primers, followed by hybridization with J beta-specific probes. Close to 90% of the V alpha 12.1+ V beta 5.2+ T cells were found to utilize the J beta 2.5 gene segment, thus strongly suggesting the expanded T cells to be monoclonal. The condition may constitute a T cell counterpart to 'monoclonal gammopathy of undetermined significance' (MGUS), and by analogy we suggest it should be designated 'monoclonal T cell expansion of undetermined significance' (MTUS).


Preferential activation of peripheral blood V gamma 9+ gamma/delta T cells by group A, B and C but not group D or F streptococci.

Previous studies have established that inactivated mycobacteria are potent and selective activators of V gamma 9+/V delta 2+ human gamma/delta T cells. Here we have analysed the proliferative response of human gamma/delta T cells to five serologically distinct groups of streptococci. While heat-inactivated streptococci of all five serogroups tested (A, B, C, D and F) induced a strong proliferative response in peripheral blood mononuclear cells (PBMC), only groups A, B and C elicited a selective activation of V gamma 9+ gamma/delta T cells in 10 (serogroup B) or 11 (serogroups A and C) of 11 tested healthy individuals. In striking contrast, groups D and F streptococci failed to activate gamma/delta T cells in nine of 11 donors and induced only a weak gamma/delta T cell response in two additional individuals. Depletion of V gamma 9+ T cells before culture completely eliminated all gamma/delta T cell responses to streptococci. These data indicate that groups A, B and C (but not D or F) streptococci can be included in the growing list of selective ligands for V gamma 9+/V delta 2+ human gamma/delta T cells.


Bispecific anti-human red blood Rhesus-D antigen x anti Fc gamma RI targeted antibody-dependent cell-mediated cytotoxicity and phagocytosis by mononuclear leucocytes.

The Fc receptor mediated antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis induced by bispecific antibody (BsAb) to the high-affinity Fc receptor for IgG (Fc gamma RI) and to human red blood group antigen RhD were studied in vitro, using human mononuclear leucocytes as effector cells. The results were compared with those obtained by using a human monoclonal IgG1 anti-RhD used alone and a reference human polyclonal anti-RhD antibody. The effect of non-specific human IgG on FcR-mediated functions by mononuclear leucocytes was checked. The results demonstrate that BsAb presents a high resistance of Fc-mediated function to blockade by non-specific human IgG compared with that of both polyclonal and monoclonal anti-RhD antibodies. These results further encourage possible clinical application of bispecific antibody in passive immunotherapy.


Dynamic simultaneous anterior and posterior imaging of transplant and native renal function using dual-headed gamma camera.

The authors describe the nonvisualization of a renal transplant on DTPA scan with late visualization of activity within the bladder in a 27-year-old patient with diabetes. Origin of bladder activity was later clarified by dynamic anterior and posterior imaging using MAG 3 and an extra large field-of-view, dual-headed gamma camera.


Does increased life expectancy imply active life expectancy?

From Danish results, it is argued that longer life need not imply worse health. If we as individuals and society will prevent the "pawnbroker-diseases," increase access to geriatric rehabilitation, and supply necessary services in an individualised way, most added years can be active years. The following conclusions are drawn: In the first decades after the year 2000, morbidity, disability and mortality will be postponed, but treatment will be more important for prolongation of life than prevention. Therefore, the net result will be extension of morbidity. The next question is how severe disability will be among the increased number of people who have a disease, but are not dying from it. The elderly will be more healthy in the future, but the prevalence of chronic disabling diseases may not change, or may even increase. That is because healthy men and women can postpone disability and death until higher ages (successful aging), but some elderly persons live with premature disabling diseases, which might have killed them some decades ago. When elderly people make the transition from autonomy to dependence in the course of a disease, it is possible by early geriatric intervention and rehabilitation to restore them to functional levels and provide them with more active years. It is possible to disseminate geriatric rehabilitation to a much wider population of elderly with multipathology and social problems. In this way, disability can be overcome in a higher fraction of diseased elderly.(ABSTRACT TRUNCATED AT 250 WORDS)