[Limitations and perspectives of teaching and research in basic sciences at the Portuguese Faculties of Medicine]. Well known difficulties of teaching and research lived by basic sciences of the medical school curriculum in Portugal are becoming desperate. Two main problems deserve major concern and urgent solutions: firstly, the recruitment and continuing formation of motivated candidates for teaching and/or research in those areas; secondly, the establishment of adequate economic support that makes those careers in basic teaching and research attractive, along with the provision or creation of the necessary support for both activities. Specific administrative and financial solutions are required from the government, in order to foster a realistic future in the preclinical areas of the medical curricula.


Change in bone mass immediately before menopause. A group of 75 healthy women nearing menopause were entered into a longitudinal study of bone mass and bone cell function. All were at least 46 years, were still menstruating, and had premenopausal levels of follicle stimulating hormone (FSH) and estradiol (E2). Bone density measurements of the spine (dual-photon absorptiometry, DPA) and total-body (DPA) and forearm (single-photon absorptiometry, SPA) were made at 6 month intervals along with measurements of FSH and E2 over an average of 2.04 +/- 0.45 years. The annual rate of change in bone mass was determined for each individual by regressing the bone mass measurement at each site at the time of observation. The slopes were pooled, and the percentage annual change was calculated as the mean slope divided by the initial mean bone mass value. The mean rates of change in bone mass were calculated with and without weighting by length of observation. No meaningful differences in the results were seen in the weighted values compared to the unweighted values, and none of the sites showed a slope significantly different from zero. Demonstrated reproducibility and sample size provided sufficient power to detect annual weighted rates of change of 0.81% for spine BMC, 0.69% for spine BMD, 1.31% for forearm BMC, 1.55% for forearm BMC/BW, and 1.09% for total body bone mineral. We conclude that if changes in bone mineral are occurring in women at this age, they are substantially less than 1%/year for spine and not much more for the forearm or total skeleton.


Enhancement of osteoinduction by vitamin D metabolites in rachitic host rats. Diaphyseal bone from normal Sprague-Dawley rats was delipidated in chloroform-methanol and demineralized in 0.6 N HCl at 4 degrees C. The bones were then implanted for 7-28 days into rats made rachitic by a low-phosphate, vitamin D-deficient diet (VDP-) for 3 weeks. Bones from VDP- and normal rats were also implanted into normal hosts. When normal rats were used as the host environment, a consistent sequence of cartilage induction and bone formation was observed. Demineralized rachitic bone (RB) implanted into normal host rats resulted in cartilage and bone induction similar to that seen for normal bone (NB) implants. Transmission electron microscopy of RB in normal hosts revealed morphologically normal chondrocytes and cartilage matrix with normal mineralization. In contrast, implantation of NB in VDP- hosts resulted in delayed chondrogenesis and lack of calcification. Furthermore, similar results were observed when RB was implanted into VDP- hosts. Treatment of VDP- hosts with either 1 alpha-hydroxyvitamin D3 or 24,25-dihydroxyvitamin D3 did not accelerate the sequential appearance of precartilage or cartilage. However, 24,25-(OH)2D3 administered alone or in combination with 1 alpha-OHD3 significantly increased the amount of calcified cartilage observed at 2 weeks postimplantation compared to implants from either untreated VDP-hosts or those treated only with 1 alpha-OHD3. New bone formation was observed at 4 weeks postimplantation in all vitamin D-treated groups as determined by von Kossa staining or direct electron microscope examination. There was no apparent difference in the quantitative or qualitative bone formed within the various vitamin D-treated groups. Serum calcium and phosphorus levels were lower and alkaline phosphatase levels were higher in VDP- hosts compared with normal animals or those treated with vitamin D metabolites. The results of this study show a reduction in the capacity of progenitor cells in VDP- rat hosts to respond to osteoinductive factor(s). This impaired response appears to be corrected by vitamin D metabolites.


Evidence for the formation of a complex between osteopontin and osteocalcin. We hypothesize that the mechanisms governing bone formation and remodeling involve the assembly of some of the components of the extracellular matrix into supramolecular complexes. We have examined the associations of osteopontin (OPN) with other proteins isolated from demineralized rat long bones. Three ligand binding techniques were used to demonstrate the formation of complexes between osteopontin and osteocalcin (OCN). Using gel overlay assays, the binding between soluble 125I-OPN and OCN immobilized in acrylamide gels was visualized. Competition for 125I-OPN-OCN complexes was demonstrated when unlabeled OCN-enriched bone extract was included in gel overlay solutions. Also, gel overlay assays showed 125I-OCN binding to OPN. Saturable binding was shown in solid-phase filter binding assays, which yielded an equilibrium binding constant of moderately high affinity (approximately 10(-8) M). Specificity of OPN-OCN complex formation was confirmed by measuring binding in the presence of unlabeled OPN and OCN versus a bone-localized serum protein, alpha 2HS-glycoprotein. Finally, the formation of soluble complexes were demonstrated in a modified Hummel-Dreyer gel filtration assay. These results indicate that OPN and OCN form complexes in vitro. The possible functions of OPN-OCN complexes in osteoclast recruitment and attachment are discussed.


Advantages of peripheral radiogrametry over dual-photon absorptiometry of the spine in the assessment of prevalence of osteoporotic vertebral fractures in women. Since osteoporosis develops in most postmenopausal women and is probably the most important single factor in the pathogenesis of osteoporotic fractures of the spine, hip, and wrist (and at other sites), methods suitable for mass screening should be developed. In this study of 97 women aged 24-79, measurements of the lumbar spine mineral content by dual-photon absorptiometry (DPA) were compared with the summed combined cortical thickness measurements from radiographs of the radius and metacarpal II (MR). There was good correlation between the two methods (r = 0.90). The correlation of age with MR was higher than with DPA. The correlation of years postmenopause was significant with MR but not with DPA. Taking the -2 SD level of the premenopausal means to be previously established vertebral fracture thresholds, 24% of the DPA measurements, but no MR measurements in patients with vertebral compressions, were above the fracture threshold. Since MR measurement requires taking only two small plain radiographs using ordinary x-ray equipment, it is concluded that this less expensive method is better suited to screening for osteoporotic vertebral fracture risk in postmenopausal women than DPA.


Relationship between the location of osteoblastic alkaline phosphatase activity and bone formation in human iliac crest bone. It is not feasible to use in vivo tetracycline double labeling to study bone formation in biopsies taken during the emergency fixation of fractures. We therefore compared the trabecular localization and extent of osteoblastic alkaline phosphatase (AP) perimeters with tetracycline and osteoid perimeters in iliac crest biopsies from 7 women with postmenopausal osteoporosis and 13 women without metabolic bone disease. Fresh biopsies were chilled to -70 degrees C, and triplicate serial unfixed undecalcified cryostat sections were cut and reacted for AP, stained for osteoid, or mounted unstained. At individual remodeling sites, the mineralizing perimeter (M.Pm) was measured as the extent of a double or single label accompanied by greater than or equal to 1 lamella of osteoid and greater than or equal to 1 lamella of mineralized matrix between the mineralization front and the adjacent label. Osteoid perimeters (O.Pm) and AP perimeters (AP.Pm) were also measured. In each biopsy there was good agreement between the location of AP and bone formation (kappa statistic, range 0.71-1.0). The overall sensitivity and specificity of AP as an indicator of the location of bone formation were 0.963 and 0.902, respectively. At the level of the basic multicellular unit, in those samples in which greater than 3 active BMUs were found, there was (1) significant positive correlation between the M.Pm and both AP.Pm and AP-positive O.Pm (except 1 patient) and (2) no significant difference between the M.Pm and AP-positive O.Pm (17 of 18 patients and 18 of 18 patients at the tissue level).(ABSTRACT TRUNCATED AT 250 WORDS)


Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis. We previously demonstrated an increase in cancellous bone volume and trabecular number in patients with mild primary hyperparathyroidism (PHPT). To test the hypothesis that this increase is due to preservation of cancellous bone architecture, we conducted a trabecular strut analysis using a new method that measures trabecular connectivity. Iliac crest biopsies from 37 patients with PHPT, 14 men (28-68 years) and 23 women (26-68 years), were examined histomorphometrically and compared to cadaveric samples from 24 age-matched subjects, 17 men and 7 women. Two-dimensional indices of cancellous structure--node number (N.Nd), terminus number (N.Tm), node to node (Nd.Nd), node to terminus (Nd.Tm), and terminus to terminus (Tm.Tm) strut lengths, and total strut length (TSL)--were measured and the ratio of node number to terminus number (N.Nd/N.Tm) calculated. TSL, N.Nd, and Nd.Nd were significantly higher in patients than in controls. TSL and Nd.Nd, but not N.Nd or Nd/Tm, decreased significantly with age in PHPT, indicating that age-related bone loss in PHPT occurs without significant loss of trabecular connectivity. Two-dimensional indices reflecting connectivity or the amount of bone, that is, N.Nd, Nd.Nd, N.Nd/N.Tm, and TSL, correlated positively with cancellous bone volume (BV/TV) and trabecular number (Tb.N) and negatively with trabecular spacing (Tb.Sp) in both PHPT and controls. Trabecular thickness (Tb.Th) correlated positively with Nd.Nd and Tb.N and negatively with Tm.Tm in PHPT but not in controls. The present data show that in PHPT there is not only greater cancellous bone volume and trabecular number but preserved trabecular connectivity as well. The data further support the hypothesis that in PHPT cancellous bone architecture is maintained.


Extracellular matrix formation by osteoblasts from patients with osteogenesis imperfecta. Extracellular matrix proteins synthesized by bone cells isolated from 16 patients with different forms of osteogenesis imperfecta (OI) were analyzed in vitro. Specific components of the extracellular matrix by OI and age-matched cultures were investigated by steady-state radiolabeling followed by quantitation of label into specific proteins and comparison of OI cultures to those of age-matched controls. The in vitro proliferation of OI bone cells was found to be lower than that of control cells. In seven patients, abnormalities of the alpha 1(I) and/or alpha 2(I) chains of type I collagen were detected by gel electrophoresis. In two of these patients, the mutations in the COLIA1 and COLIA2 genes have been previously identified. Although the amount of total protein synthesized by the cells in culture was the same for OI bone cells and age-matched control cells, OI bone cells showed a significantly reduced synthesis of not only collagen but also other bone matrix glycoproteins. The synthesis of osteonectin (SPARC/BM40) and three proteoglycans [a large chondroitin sulfate proteoglycan, biglycan (PGI), and decorin (PGII)] was found to be decreased in OI cells. The reduction was most pronounced at the developmental age at which these macromolecules reach maximal levels during normal development.


Nitroblue tetrazolium reduction and bone resorption by osteoclasts in vitro inhibited by a manganese-based superoxide dismutase mimic. Oxygen-derived free radicals are produced by osteoclasts. Oxygen radical formation occurs at the osteoclast/bone surface interface. This location next to bone implies that oxygen radicals, including but not limited to superoxide, are needed for bone resorption. Compounds that scavenge superoxide are being developed as pharmaceutical agents to inhibit the damaging effects of oxygen radical formation on tissues. One such scavenger is the Desferal-manganese complex (DMnC). DMnC reduced the amount of formazan staining produced by the interaction of oxygen radicals with nitroblue tetrazolium (NBT) in both individual mouse calvarial osteoclasts in tissue explants and isolated osteoclasts. As a result of the reduced concentrations of oxygen radicals, DMnC inhibited bone resorption by calvarial explants and isolated osteoclasts. Superoxide dismutase (SOD) inhibited NBT reduction and bone resorption by isolated osteoclasts but to a lesser degree than DMnC. Inhibition of bone resorption in the isolated osteoclast system increased in parallel to the concentration of DMnC in cultures. Desferal without Mn had no effect on bone resorption by isolated osteoclasts. These results support the hypothesis that osteoclasts produce oxygen radicals as part of the process of bone resorption.


Qualitative defects in natural killer cell function in ia osteopetrotic rats. Recent studies have provided evidence that cells of the immune system and their associated cytokines function in the regulation of bone turnover. The incisors absent (ia) osteopetrotic rat represents a model in which a defect in the immune system and bone resorption can be studied. Osteopetrosis in the ia rat is characterized by a generalized excess accumulation of bone as a result of reduced bone resorption by defective osteoclasts that lack a ruffled border and the ability to exocytose their osteolytic enzymes. Previous attempts to identify associated defects in the ia immune system have proven unsuccessful; ia rats demonstrate normal delayed hypersensitivity, mitogenic activity, and macrophage function. Inasmuch as the skeletal manifestations of the ia mutation may be the result of a defect in exocytosis, related defects may be evident in immune cells utilizing exocytosis of granules or enzymes for their cytolytic function. Natural killer (NK) cells function by such a mechanism. Therefore, these studies were undertaken to evaluate the natural immune system in ia rats. NK activity assessed by 51Cr release assays was significantly reduced in ia animals compared to normal littermates. Mononuclear cells isolated from the peripheral blood of ia rats revealed a significantly greater percentage of large granular lymphocytes than normal littermates. Comparison of NK cell phenotypes using two phenotypic parameters for NK cells (OX8+, OX19- cells and 3.2.3+ cells) revealed that the mononuclear isolates of spleen and peripheral blood of mutant animals had significantly greater percentages of OX8+, OX19- and 3.2.3+ cells than normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)


The bisphosphonate, alendronate, prevents bone loss in ovariectomized baboons. We examined the effect of the amino bisphosphonate alendronate, administered IV every 2 weeks at 0.05 and 0.25 mg/kg for 1 year, on bone loss and parameters related to bone metabolism in ovariectomized baboons. Relative to non-OVX animals, the OVX baboons experienced increased bone turnover, reflected in biochemical and histomorphometric measurements, and bone loss assessed by dual-beam absorptiometry in the lumbar spine, which was similar to changes observed in ovariectomized women. Alendronate treatment maintained all parameters of bone turnover at control (nonovariectomized) levels and prevented the bone loss in a dose-dependent manner. We concluded that ovariectomized baboons offer a suitable model for the bone changes observed in ovariectomized women and that these changes can be prevented by sustained administration of an appropriate dose of this aminobisphosphonate.


Effect of fluoride on bone and bone cells in ovariectomized rats. To evaluate whether treatment with a mitogenic agent may increase bone formation and bone mass in osteopenia induced by estrogen deficiency, we determined the effect of oral fluoride treatment on bone and bone cells in ovariectomized rats. Sodium fluoride (NaF) was administered to 3-month-old ovariectomized rats 1 day after ovariectomy (OVX) for 1, 3, and 6 months. NaF was given in drinking water at the dose of 1 mg/kg body weight per day. Fluoride administration led to a partial prevention of the bone loss induced by OVX as shown by histologic analysis of tibial metaphysis and by evaluation of femoral calcium content. These beneficial effects of fluoride were more striking at early time points (1 and 3 months postovariectomy) than after 6 months of treatment. The increase in trabecular bone volume in OVX rats treated with fluoride was associated with a rise in the osteoblast surface, which was increased by 60, 72, and 235% at 1, 3, and 6 months postovariectomy compared to untreated OVX rats. In OVX rats and in sham-operated rats plasma osteocalcin was increased in correlation with the osteoblast surface. However, these two parameters were not correlated in OVX rats treated with fluoride. The heat-labile bone-specific alkaline phosphatase in plasma was decreased in OVX rats treated with fluoride compared to OVX rats, suggesting that both the number and the activity of osteoblasts were affected by NaF treatment. To examine the effect of fluoride on the osteocalcin production and the proliferative capacity of bone cells, osteoblastic cells were isolated by collagenase digestion from the bone surface of tibia in treated and untreated OVX rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization. Parathyroid hormone-related protein (PTHrP) has been identified immunohistochemically in 60% of breast carcinoma and in 92% of breast cancer metastases in bone. To establish whether the localization of the PTHrP antigen reflects protein synthesis and also to investigate the role of PTHrP in metastatic disease, as part of an ongoing study, we used in situ hybridization to study the localization of PTHrP mRNA in a retrospective series of primary breast tumors and their metastatic lesions. Paraffin sections of 17 primary and 26 metastatic lesions, 11 of which were in bone, were available for the study: 10 of the 17 (59%) primary lesions, 8 of 11 (73%) breast cancer metastases to bone, and 3 of 15 (20%) metastases to non-bone sites showed specific localization of PTHrP mRNA. These findings establish that PTHrP is commonly synthesized by primary breast cancers and support previous immunohistochemical studies reporting a higher incidence of PTHrP-positive tumor cells in skeletal metastases than in nonskeletal metastases.


Disodium 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonate (EB-1053) is a potent inhibitor of bone resorption in vitro and in vivo. The ability of the new nitrogen-containing bisphosphonate disodium-1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphona te (EB-1053) to inhibit osteoclastic resorption was examined in vitro and in vivo. Results were compared to those obtained with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (pamidronate or APD). In vitro, when tested in osteoclast precursor-dependent systems (fetal mouse metacarpals and a coculture system), EB-1053 suppressed 45Ca release effectively and was found to be about 10 times more potent than pamidronate (ED50 = 2.5 x 10(-7) versus 2.5 x 10(-6) M, respectively). The EB-1053-inhibited osteoclastic resorption could be reversed by treatment with parathyroid hormone (PTH). In vivo, daily subcutaneous injections of EB-1053 to young growing rats for 7 days increased metaphyseal bone mass in tibiae dose dependently. In these experiments EB-1053 was about 50 times more potent than pamidronate. These studies show that EB-1053 is a very potent bisphosphonate that has potential use in the treatment of skeletal disorders.


Development expression of bone sialoprotein mRNA in rat mineralized connective tissues. Bone sialoprotein (BSP) is a phosphorylated and sulfated glycoprotein that is a major noncollagenous protein of bone and other mineralizing connective tissues. BSP is characterized by the presence of several polyglutamic acid segments and an RGD motif that mediates cell attachment through a vitronectin-like receptor. Although the precise function of BSP is unknown, the expression of BSP in conjunction with bone formation in vitro indicates a role for this protein in the biomineralization of connective tissues. In this study we used Northern hybridization and in situ hybridization to determine the tissue-specific and developmental expression of BSP during embryogenesis and growth of rat tissues. Analysis of tissues obtained from 13, 17, and 21 day fetuses, and from 4-, 14-, and 100-day-old animals indicates that BSP mRNA expression is restricted to cells actively forming the mineralizing tissues of bone, dentin and cementum. BSP mRNA transcripts were first evident in fully differentiated osteoblasts of 17 day fetal tissues at sites of de novo intramembranous and endochondral bone formation, with maximal expression observed at 21 days of gestation. Thereafter, BSP mRNA levels decreased markedly, and in adult bone hybridization was detected only in the primary spongiosa of long bones. In comparison, mRNAs for osteopontin (OPN), alkaline phosphatase (ALP), and osteocalcin (OC) peaked at 4-14 days postpartum before declining. In the tibiae, Northern hybridization revealed a second peak of mRNA for BSP, ALP, and OPN at 14 days, reflecting an increased osteogenic activity due to the formation of the secondary centers of ossification in the epiphyseal cartilage. In situ hybridization also revealed BSP mRNA in hypertrophic chondrocytes at sites of bone formation, in odontoblasts of the incisor during dentinogenesis, and in cementoblasts during cementogenesis. In view of the restricted distribution and temporal changes in the expression of BSP mRNA that we observed together with the chemical properties of BSP, we believe that this protein has a specific role in mediating the initial stages of connective tissue mineralization.


Brainstem auditory evoked potentials in patients with mitochondrial encephalomyopathy. Brainstem auditory evoked potentials (BAEPs) were evaluated in three patients with mitochondrial encephalomyopathy belonging to the same family. This study showed marked alterations of BAEPs in all patients: reduction of wave amplitude, poor repeatability of responses in test-retest and abnormalities in wave form and latency. The neuroradiological examinations (CT-scan, MRI) did not show significant structural brain abnormalities. Abnormal BAEPs in our patients may be related to central metabolic disorder rather than hearing loss.


Study of the P300 event-related potential through brain mapping in phonological dyslexics. The auditory P300 was studied through brain mapping in 10 phonological dyslexics (7 M and 3 F), who were found to differ significantly from normals in presenting a longer P300 latency and smaller amplitude on the N2-P3 wave. Interesting too was the asymmetry of the P300 distribution between the two hemispheres, with less amplitude on the right. These findings confirm the hypothesis of reduced right hemisphere functioning during the process of information analysis in phonological dyslexics.


Indication, efficiency and complications of intrathecal pump supported baclofen treatment in spinal spasticity. In 19 patients, who suffered from severe spinal spasticity of different etiologies and did not respond sufficiently to oral antispastic therapy, intrathecal Baclofen test boli were administered. In 11 patients a DAD (Drug Administration Device) [SynchroMedR Model 8611 H, Medtronic Inc. Minneapolis, USA] was implanted. Catheter dislocation or torsion was the most common complication to be observed in these 11 patients. Long term intrathecal Baclofen application was effective in all patients, as reducing spasticity, flexor spasms and spasm induced pain. In some cases the motor performance ameliorated.


Long-term intrathecal baclofen treatment in supraspinal spasticity. Baclofen, a derivate of gamma-amino butyric acid (GABA), is known to be a useful drug in spasticity treatment. To achieve a good therapeutic response higher oral dosages have to be administered related with central side effects. Intrathecal application of Baclofen in microgram range dosages is proved to be effective in spinal spasticity. The efficiency of intrathecal Baclofen in patients suffering from supraspinal spasticity is discussed controversially. We report on 9 patients with long-term intrathecal Baclofen treatment, all of them responding well presenting a marked reduced muscle tone. In most cases an improvement of motor performance and in two cases improved bladder function was observed. The therapeutical dosages administered to patients with supraspinal spasticity exceed those administered to patients with spinal spasticity by approximately 100% without provoking central side effects. Despite the risks connected with this method it has to be considered as treatment of choice in cases of severe supraspinal spasticity.


"Premorbid" personality of patients with Parkinson's disease. To elucidate the possible existence of a so called "premorbid parkinsonian personality" we studied 33 patients with Parkinson's disease (PD) and 66 controls who did not differ in age, sex, geographic origin, and cultural level, with the Spanish version of the Minnesota Multiphasic Personality Inventory (MMPI). Females of the PD group obtained significantly higher scores than females of the control group for the scales of hypochondria (p less than 0.01), depression (p less than 0.01), hysteria (p less than 0.05), and social introversion (p less than 0.01). The scores of the males with PD in all of the clinical scales of MMPI did not differ significantly from those of the male controls. These results, despite the difficulty of interpretation of a test done in a retrospective way, would agree with the hypothesis previously suggested of the possible existence of a "premorbid" parkinsonian personality, at least in females.


Amoebae free-living. Report of the first Italian case of myelitis. The AA. refer on the first Italian case of amoebae "Limax" primitive myelitis in a 25-year-old man. Microscopical observation showed amoebae free-living, but their cultivation and identification were not possible. The patient recovered because of the propriety of diagnosis and therapy with amphotericin B.


Dementia of Alzheimer type (DAT) in a man chronically exposed to pesticides. A patient chronically exposed to pesticides with dementia of Alzheimer type (DAT) is presented. We evaluate the pathogenic role of these substances in the disease and suggest the usefulness of an epidemiological attention on the environmental factors in certain neurodegenerative diseases.


[Therapeutic options in metastatic renal carcinoma]. Within the scope of urogenital tract tumoral diseases, renal adenocarcinoma is the third most frequent neoplasia diagnosed in the adult population. The limited clinical presentations in early analysis and their anarchical behaviour are the cause for 50% to 60% of patients having already developed distant disease at the time of diagnosis. The only curative procedure so far is radical surgery, which is possible when there is a single metastatic site and sometimes even, depending on various factors which will be analyzed, several sites. In these occasions, the traditional therapeutic choices (Hormonotherapy, Chemotherapy, Radiotherapy) have proven to have limited or no efficacy in managing the disease. This fact, together with the successful results obtained in other tumoral processes, have allowed the clinical development of different modalities of Immunotherapy for the management of metastatic renal carcinoma, with results clearly hopeful. This work is a review of the results reported for each of the mentioned therapeutic choices, basically analyzing the role currently played by surgery and immunotherapy in the management of advanced renal carcinoma.


[Laparoscopic nephrectomy: a case report]. Presentation and clinical picture outline of a patient who underwent transperitoneal laparoscopy-assisted nephrectomy. The procedure lasted 4 hours and the patient was discharged 72 hours later without incidence or complications. The paper describes the technique (presently unique and for selective indications), as well as the resources that the extensive laparoscopic experience of our group put into practice to perform the first successful laparoscopic nephrectomy in humans in our country.


[Current validity of urethroplasty in two stages]. Review of 18 patients with complex urethral stenosis, who underwent a two-stage urethroplasty in our Unit over the last three years. Clinical results have been favourable in all patients and, from the radiological point of view, there has been only one re-stenosis. Complications rate has been low and can be superimposed to that of any urethroplasty procedure. The paper emphasizes the enormous relevance of the care taken between both surgical stages on the procedure's final result.


[Ultrasonic retrograde urethrography. Technique. Comparison with radiologic retrograde urethrography]. Using ultrasound scan urethrography (U.S.U.) and radiological retrograde urethrography (R.U.), the anterior urethra has been studied in 61 males in an attempt to establish the best technique to perform U.S.U. and to compare it, from the technical point of view, with R.U. U.S.U. should be made retrogradely filling the urethra with a saline solution, under direct ultrasound guidance, which allows to see the anterior urethra, from the syringe come introduced into the glandular urethra up to the urogenital diaphragm and the beginning of the membranous urethra. Overall, U.S.U. is faster to perform than R.U., nine times cheaper, more comfortable for the patient, and there is no risk of exposure to irradiation or radiological markers.


[Endourologic treatment of calyceal diverticulum complicated with lithiasis]. Presentation of 9 cases of calyceal diverticulum symptomatic lithiasis, 6 of which have been treated up to the present time. Of the remaining 3, one patients, in spite of its evolutive character (increased cavity) and moderate pain, prefers to abstain from therapeutic therapy, but undergoes follow-up controls every 6 months; the other 2 cases are waiting endourological treatment. Out of 6 patients who underwent surgery, two cases, who had previously experienced shockwave extracorporeal lithotripsy (SWEL), were advised to have endourological procedures due to persistence of pain and gallstones debris.


[Renal carcinoma and non-Hodgkin's lymphoma. A clinical report]. Presentation of one case of a 61-year old male with a non-Hodgkin lymphoma, where a renal cell adenocarcinoma was unexpectedly discovered during and extension study. Review of the pathogenic significance of such association in the light of the various explicative hypothesis of this concurrence.


[Renal adenocarcinomas associated with other malignant neoplasms]. The renal adenocarcinoma is not a frequent tumour within the scope of multiple neoplasias, at least in the clinical series. Conversely, it appears at a higher relative rate in the post-mortem series. This paper submits a review of renal adenocarcinoma associated in life to other malignant neoplasias, enumerating their major clinical and epidemiological data. Also, it reviews the literature with regard to frequency and etiology, applying the data to our series. The paper concludes that hypernephroma is not a tumour frequently associated with others in life, given its tendency to be secondary to other primary ones, therefore its development depending on survival to the initial tumour. It also emphasizes the need for adequate anamnesis aimed to detect multi-cancer syndromes and the etiology of multiple neoplasias. Further studies are needed to understand the scope of multiple neoplasias and their relative risk.


[Acquired cystic renal disease associated with renal carcinoma: report of 3 cases]. Presentation of three cases of haemodialysis patients with acquired cystic renal disease (ACRD) who, over the course of their illness, developed clear cells renal carcinoma. The paper emphasizes the common association of these two entities and the need to consider ACRD cases as patients at high risk of developing renal neoplasia.


[Dermatomyositis as paraneoplastic syndrome of bladder tumor]. The dermatomyositis is a connective tissue disease characterized by changes affecting both the skin and the muscle, appearing most frequently around the fifth and sixth decades and which association to a vesical tumour is very rare. This paper contributes one case of paraneoplastic dermatomyositis associated to infiltrant vesical tumour, presenting erythematous damage in face, nape of the neck and upper thorax, as well as periorbital heliotrope erythema and fingernails base and sides telangiectasia, all of which are typical signs of dermatomyositis.


[Bladder amyloidosis].

[Bladder amyloidosis]. We present a case of Vesical Amyloidosis (V.A.) in a woman with Rheumatoid Arthritis. Clinical data, other locations and Histochemical findings are consistent with Secondary Amyloidosis. After T.U.R., she was treated with Dimethylsulfoxide (DMSO) and Colchicine. Her severe hematuria disappeared.


[Emphysematous cystitis caused by Klebsiella pneumoniae]. Emphysematous cystitis is a very uncommon clinical activity as compared to the high incidence of urinary infections in diabetic patients. The paper explains the pathophysiological mechanisms and updates its clinical and therapeutic diagnostic choices regarding one case of favourable evolution following medical treatment.


[Laparoscopic cystoprostatovesiculectomy and ureterosigmoidostomy. Experimental surgical model]. The authors have performed 26 experimental laparoscopic cystoprostatovesiculectomies in pigs, 17 of which were followed by ureterosigmoidostomies, also laparoscopically. Using a 10 mm trocar at the umbilical level (optics), another 10 mm at the hypogastric level (pliers and titanium staple applicator), a third 5 mm in left iliac fossa (pliers) and another 5 mm in right iliac fossa (electric shears), cystectomy is performed with a routine technique: stapling and section of deferents, umbilical arteries, vesical lateral pedicles and prostate-seminal pedicles. A double ligature precedes the section of the urethra in the pelvian fundus. A plier passed within an Amplatz jacket (previously introduced through the anus) assists the laparoscopic ureterosigmoidostomy "in elephant trunk" which is performed by sero-muscle suture using 3-zero reabsorbable single-strand material. Overcoming the anatomical differences existing with humans, the illustrated experimental model confirms the possibility of performing this type of procedures in human beings, which would considerably curtail the morbidity associated with this type of surgery.


Personality traits and behaviors of alcohol-impaired drivers: a comparison of first and multiple offenders. Using an interview and questionnaire format, 358 driving under the influence of alcohol (DUI) first offenders and 141 DUI multiple offenders were compared on measures of personality traits, drinking behavior and problems, and driving behavior and history. In addition, official driving records for the two groups were compared. Results indicated that multiple offenders were significantly higher in hostility, sensation seeking, psychopathic deviance, mania, and depression than first offenders. Multiple offenders were significantly lower in emotional adjustment and assertiveness. Multiple offenders had significantly more nontraffic arrests, accidents, and traffic tickets than first offenders. They also consumed significantly more alcohol, evidenced more alcohol problems, and had higher BACs at the time of arrest than first offenders. Results are discussed in terms of general problem behavior and implications for intervention and treatment.


Readiness for smoking change among middle-aged Finnish men. According to the transtheoretical model of change, smoking cessation attempts are preceded by three stages: precontemplation, contemplation, and preparation. These stages have shown great utility in predicting and impacting on behavior change. This cross-cultural study examined the distribution of the stages within a 33% random sample of middle-aged Finnish men. Of 490 regular smokers, 57.6% were in precontemplation, 29.4% in contemplation, and 13.0% in preparation. Five conceptual clusters were used to predict the stage membership. The number of lifetime quit attempts and the number of 24-h quit attempts in the past 12 months were found to be the best discriminators among the stages. The overall correct classification rate into stages using stepwise discriminant function analysis was 64.0%, substantially better than the chance rate. However, the analysis was successful for precontemplators only. Results showed that most smokers were precontemplators. Previous attempts to reduce smoking provided some predictive information concerning stage membership. Demographics, addiction to smoking, current smoking, smoking environment, and quit history were incomplete predictors of stage membership, as theoretically predicted.


Personal and parental alcohol abuse, and victimization in obese binge eaters and nonbingeing obese. Current obesity research has begun to emphasize the importance of pretreatment assessment and more individually tailored treatment protocols. Obese binge eaters have been identified as a subgroup of the obese who do not respond well to standard behavioral treatment programs. We were interested in identifying variables that are important to consider when assessing and treating obese binge eaters. The present study assessed the prevalence of personal alcohol abuse, parental alcohol abuse, and victimization in 62 males and 274 females seeking treatment for obesity. Obese binge eaters (OBE) had significantly greater rates of personal alcohol abuse, parental alcohol abuse, and victimization than the nonbingeing obese (NBO) in our sample. Further studies of the OBE population are recommended.


Compliance of genetic code with base-composition deflecting pressure. Gene DNAs of different organisms show a wide variation in their G+C content as much as 20% to 80%. This variation has been regarded as the result of the compliance of the genetic code with the base-composition-deflecting mutational pressure. To make possible a quantitative discussion of this genetic code's elasticity, we made a statistical study of the G+C frequency at the 1st, 2nd, and 3rd positions of codons: 4.5 x 10(6) codons in 11,981 protein coding regions in the DNA data base were analyzed. The data were examined quantitatively by using a species-independent universal equation which describes the base frequencies at the three codon sites in terms of the constraint parameters characteristic of the sites and an intersite interaction. By a best fitting procedure between theoretical curves and data points, the constraint parameters and the characteristic G+C contents to which the 1st and the 2nd site base compositions are bound were determined. The base substituting mutation of the coding sequence under the base-composition-deflecting pressure is divided into following three stages of the different compliance from the elastic one to the rigid: 1) the 3rd position of codons change by synonymous substitution; 2) the 1st and then 2nd positions change accompanying amino acid replacement; and 3) in the organisms exposed under an extremely high base composition deflecting pressure, the codon table is forced to be altered. The compliance parameters were derived quantitatively for the first two stages. In conclusion, a simultaneous analysis of data from organisms as divers as virus and man discovered that there is a set of constraints common to species, which governs the frequency of codon bases, and it can be described by a universal equation.


The effects of caffeine and nicotine consumption on mood and somatic variables in a penitentiary inmate population. A sample of 144 inmates from a maximum security penitentiary responded to a request for information regarding their average daily intake of nicotine and caffeine. They also rated the quality of their appetite and sleep, their level of concentration, their mood and specific feelings of anger, anxiety, frustration, and irritability. Factor analysis generated a two-factor solution of these variables, namely general mood state (mood, anxiety, anger, frustration, and irritability) and a somatic state (appetite, concentration, and sleep). Analysis of variance showed an interaction between level of smoking (nonsmokers, low and high cigarette smokers) and caffeine use (moderate vs. high) on the general mood factor. Nonsmokers who consumed high levels of caffeine experienced poorer general mood than any other group. There was a main effect of cigarette smoking status on the somatic factor, such that greater dissatisfaction was associated with greater consumption. Caffeine consumption was generally high, averaging 800 mg of caffeine per day, per inmate, well above the amount considered to be potentially damaging to health.


The interaction of sociological and biological factors in adolescent cigarette smoking. This article considers the interaction of social and biological factors in the context of adolescent cigarette smoking. Parent and peer smoking are the sociological variables and testosterone is the biological indicator. The subjects are 212 males and females 12-14 years of age. The findings support the interaction model, suggesting that both sociological and biological factors are necessary for understanding adolescent smoking.


Selenium and arsenic in biology: their chemical forms and biological functions. Based on the recent development of analytical methods, sensitive systems for the analysis and speciation of selenium and arsenic have been established. A palladium addition technique was developed for the accurate determination of selenium in biological samples using graphite furnace atomic absorption analysis. For the speciation of the elements, combined methods of HPLC either with ICP-AES or with ICP-MS were found to work well. These systems were applied to the elucidation of the chemical form of the elements in natural samples. Some chemical properties of the selenium-mercury complex in dolphin liver were elucidated: i.e., it was a cationic, water-soluble, low molecular weight compound containing selenium and mercury in a 1:1 molar ratio, and was shown to be different from a known selenium-mercury complex, bis(methylmercuric)selenide. The major selenium compound excreted in human urine was revealed to be other than any of those previously identified (TMSe, selenate, and selenite). TMSe, a suspected major metabolite in urine, was found, if at all, in low levels. The major water-soluble, and lipid-soluble arsenic compounds in a brown seaweed, U. pinnatifida (WAKAME), were rigorously identified, and the results were compared with other data on marine algae and animals. The major organic arsenic compounds (termed "arseno-sugars") in marine algae commonly contain 5-deoxy-5-dimethylarsinyl-ribofuranoside moiety. There are various kinds of arseno-sugar derivatives containing different side-chains attached to the anomeric position of the sugar, and the distribution of each arsenic species seems to be related to algal species. The arseno-sugar (A-XI) is present in every alga so far examined, is metabolized to lipids, and possibly may play some specific role in the algal cells. On the other hand, the major arsenic compound in fish, crustacea and molluscs has been identified as arsenobetaine, which is an arseno-analog of glycinebetaine, a very common osmo-regulator in living organisms. Arsenobetaine is not detected in marine algae while arseno-sugars are not present in marine animals except for some molluscs which contain both compounds in considerable amounts. Arsenobetaine is present in the urine of human beings who have eaten foods derived from marine animals.


Long-term maintenance following attainment of goal weight: a preliminary investigation. The present study sought to determine whether the high relapse rates observed among subjects in fixed length behavioral-based weight loss programs would be lowered if subjects were allowed to continue in treatment until they had reached their desired weights. Five hundred seventeen (517) clients at a commercial weight-loss program were surveyed approximately 1 year posttreatment regarding their current weight status. Of the 267 subjects who responded to the mailed survey, it was found that 82% remained within 10% of their posttreatment weights at the time of the follow-up. Of particular interest was the fact that weight trends during the intervening year suggested subjects were actively and effectively calibrating their weight. It was concluded that the high relapse rates typical for this mode of treatment may be an artifact of premature treatment cessation and further investigation is indeed merited.


Mechanisms for gene conversion and homologous recombination: the double-strand break repair model and the successive half crossing-over model. Two mechanisms for gene conversion and homologous recombination were discussed. (1) The double-strand break repair model. A double-strand break is expanded to a gap, which is then repaired by copying a homologous sequence. The gene conversion is often accompanied by crossing-over of the flanking sequences. We obtained evidence for this model in Red pathway of bacteriophage lambda and RecE pathway of E. coli. (2) The successive half crossing-over model. Half crossing-over leaves one recombinant duplex and one or two end(s) out of two parental duplexes. The resulting ends are, in turn, recombinogenic. Successive rounds of the half crossing-over mechanism explains why apparent plasmid gene conversion in RecF pathway of E. coli is not accompanied by crossing-over. This model can explain chromosomal gene conversion if we assume that the donor is first replicated. Gene conversion during mating-type switching in yeast, antigenic variation in unicellular microorganisms, and chromosomal gene conversion in mammalian somatic cells are explained by this model. Distinguishing between these two mechanisms is important in understanding recombination in yeast and mammalian cells and also in its application to gene targeting.


Oral contraception noncompliance: the extent of the problem. Compliance has been defined as the extent to which a patient's behavior coincides with the clinical prescription. The lowest expected failure rate of oral contraceptive (OC) use has been suggested to be 0.1%; however, in typical users, the failure rate varies by age, race, and marital status. In some populations in the United States (eg, unmarried black adolescents), the failure rate is 18%; rates that factor in the occurrence of abortions suggest an overall failure rate of 6.2% during the first year of use. If the annual failure rate of 6.2% is assumed, long-term failure rates rapidly approach 25% to 50% (ie, the proportion of users who will experience an unintended pregnancy) over 10 years of use. The gap between the lowest expected failure rate and the failure rates seen in typical users is related in large part to problems of compliance. Compliance with OC use includes both correct daily use and continuing use. Factors that contribute to OC discontinuation include the experience of side effects, fears and misinformation about OC side effects fueled by negative media reports, and intermittent use. There are relatively few data regarding the issue of missed pills and correct use, but studies suggest that adolescents may miss an average of 3 pills a month, and at least 20% to 30% of individuals miss a pill every month. Patients may have difficulty in the transition from one packet of pills to the next, and missed pills that extend the hormone-free interval may contribute to the failure rate.(ABSTRACT TRUNCATED AT 250 WORDS)


Developmental level as a predictor of alcoholism treatment response: an attempted replication. Over 12 years ago, a developmental level (DL) cognitive measure derived from the Rorschach was found to be a powerful predictor of alcohol-related outcomes following behaviorally oriented inpatient alcoholism treatment. These findings represent the strongest evidence of a relationship between cognitive functioning and treatment response. The current pilot study attempted to determine whether the large effects previously obtained with the DL measure could be replicated. The Rorschach was administered during the first week of treatment to 20 male alcoholic patients attending 1-month day hospital rehabilitation program. The Addiction Severity Index (ASI) was administered upon entry into treatment and a follow-up ASI was also administered 7 months after treatment entry. A higher DL was found to be significantly related to less recent drinking and intoxication at baseline as well as to lower alcohol-related problem levels in general. However, all of the relationships between DL and alcohol-related behaviors at follow-up were found to be either small or in a direction opposite to that hypothesized. Some of the reasons for the discrepancy between the findings of the current study and the earlier study are discussed.


Medical aspects of oral contraceptive discontinuation. Oral contraceptive (OC) compliance is adversely affected by three medical factors: side effects, poor cycle control, and patients' fears of serious diseases. Most physicians recognize these factors but fail to understand their true impact on continuation rates. In one study, half of current OC users who changed brands and half of former OC users cited unwanted side effects as their reason for discontinuation. Moreover, a substantial number of women discontinue OCs without consulting their physicians. Among the so-called nuisance side effects cited by patients, the most prominent are bleeding irregularities. In new patients just beginning OC therapy, bleeding irregularities such as breakthrough bleeding and amenorrhea can lead to a very high discontinuation rate; as many as 50% of new users discontinue OCs before the end of the first year because of such side effects. OC discontinuation rates among other patient populations vary. The problem has not been studied extensively, but existing data show the problem is a large one. One study involving 550 women of various ages and years of OC use confirmed that cycle control problems led many women to discontinue OC use--often resulting in an unplanned pregnancy. Six percent of the women in this study discontinued OC use because of poor cycle control, and 23% of this group experienced subsequent unwanted pregnancies. In contrast, clinical tolerance with the new progestins such as gestodene is good; in one study 86% of patients had normal bleeding patterns. The principal consequences of poor cycle control are loss of confidence in the OC and the physician, increased anxiety, disruption of sexual relations, additional physician calls and visits, pregnancy tests, discontinuation, and noncompliance. The perception that European women have regarding the pill is that it is a reliable method that does not interfere with sexual activities. However, doubts about the safety of OCs influence compliance with the method. While concerns regarding blood clots have diminished, the fear of cancer is still a concern for many women. The androgenic side effects of weight gain, acne,and breast tenderness are particularly troubling for adolescents, who are sensitive to changes in body image. In one recent study, 20% to 25% of women stopped taking OCs because of weight gain or acne, and another 25% stopped because of fear of cancer. The medical component of improving compliance is the physician's choice of OC. Formulations with low, effective doses of hormones and the fewest side effects should be selected. Cycle control and the side-effect profile are improved with the new progestins.(ABSTRACT TRUNCATED AT 400 WORDS)


Alcohol abusers' perceptions of the accuracy of their self-reports of drinking: implications for treatment. Several major literature reviews have concluded that alcohol abusers generally give valid self-reports when interviewed under certain conditions. Nevertheless, across all studies a small proportion of alcohol abusers' self-reports continue to be suspect. Sources of invalidity may relate to subject factors or to circumstances under which data are collected. One novel way of gaining information about conditions possibly affecting the accuracy of alcohol abusers' self-reports is to ask the subjects themselves. In the present study, 208 alcohol abusers were asked about (a) how accurately different people they knew or lived with would report their (i.e., the subjects') drinking at different levels (e.g., abstinent, 1-4 drinks) compared to the subjects' own reports; (b) how accurate their own reports would be at different levels of ethanol consumption; and (c) how accurate their own reports would be when interviewed under different conditions (e.g., by phone, their therapist, a researcher, their employer). The results are largely consistent with studies that have empirically examined the validity of alcohol abusers' self-reports. Suggestions for future research and evaluation are offered.


Oral contraceptives and cycle control: a critical review of the literature. Control of spotting and breakthrough bleeding and absence of withdrawal bleeding, collectively termed cycle control, is the single most important determinant of whether a new user of oral contraceptives (OCs) will continue this method. However, information about different OC preparations and how they affect such problems, including the effects of progestogen and estrogen phasing and the components of these hormones, is scant and confusing. Studies cited in this report reveal highly variable rates of bleeding problems in women taking OCs: after 6 months of OC use, the prevalence of spotting varied between 0% and 8.5%; of breakthrough bleeding, 0% and 12.2%; and of amenorrhea, 0% and 5.8%. At least some of this variation is attributable to differing study populations and cultures, study designs, and the manner in which data were collected and reported. However, methodologic weaknesses were common, often involving lack of randomization and blinding, and attrition rates were high. Despite these limitations, it is clear that the frequency of bleeding problems decreases with continuing use of OCs, emphasizing the need for patient reassurance about the transient nature of these problems. In addition, gestodene-containing preparations appear to offer better cycle control than do desogestrel-containing preparations and levonorgestrel-containing preparations better control than norethindrone-containing preparations. However, the strongest lesson to emerge is the need for more rigorous studies to adequately address questions of comparative bleeding problems, particularly with newer triphasic formulations. These conclusions underscore the importance of counseling new OC users about the possibility of bleeding problems, reassuring them that most such problems are temporary, and, that if compliance is maintained, these will not impair contraceptive efficacy.


Noncontraceptive benefits of modern low-dose oral contraceptives. Most oral contraceptive formulations in current use contain 50 micrograms or less of ethinyl estradiol and 1 mg or less of the various progestins: norethindrone (0.5-1 mg), norgestrel (0.3-0.5 mg), or levonorgestrel (0.05-0.25 mg) [1]. The new generation of progestins--norgestimate, desogestrel and gestodene--are derived from levonorgestrel, the biologically active enantiomer of norgestrel. These steroids have specific metabolic and pharmacologic activity that allow oral contraception at lower doses than previous progestins. Desogestrel and norgestimate are both prodrugs and must undergo hepatic and gastrointestinal metabolism to become biologically active compounds. Gestodene is immediately and completely bioavailable [2]. For the new formulations containing less than 50 micrograms of ethinyl estradiol, the incidence of complications has decreased. With most of the early medical problems identified, current research can now focus on other aspects of oral contraception such as compliance and OC use failure. Prominent noncontraceptive health benefits have been observed in OC users and represent new directions for future research. When the risk-benefit ratio of OC use is evaluated in healthy women today, it clearly favors the benefits. However, these will not be fully realized without an increase in method compliance.


Patient education and understanding: a critical review. In the United Kingdom, family planning services are readily available to all women, regardless of economic status. Oral contraceptives play an important role in this effort, yet studies suggest that many patients still do not understand how to use these agents appropriately. Specifically, poor patient compliance is much more prevalent than initially thought. Factors influencing compliance in UK populations include age, socioeconomic group, education, side effects, packaging, and health care delivery. In order for these medications to be effective among various female populations, there is a need for greater emphasis on patient education about oral contraception. Several possible approaches are discussed.


Patient counseling.

Patient counseling. The success or failure of oral contraceptive (OC) use depends very heavily on the type and extent of the counseling a woman is given both before and during pill administration. If she selects the OC as her method of choice after considering all the options, a clear, detailed, and accurate discussion should ensue about its proper use; any fears that she may have should be explored; and great emphasis should be placed on the advantages and effectiveness of our current pills and, above all, on their numerous health benefits. All her questions should be answered in a thorough and emphatic fashion, and she should be encouraged to ask for additional answers at any time in the future. Finally, if her history reveals that she is at risk for sexually transmitted diseases (STDs), she must be informed that the pill, while highly protective against unplanned pregnancy, will not provide protection against most STDs or HIV infections, and that she should also use condoms and/or a female barrier contraceptive with each act of intercourse.


The interaction of glycosaminoglycans with heparin cofactor II: structure and activity of a high-affinity dermatan sulfate hexasaccharide. The binding sites for dermatan sulfate and heparin in HCII overlap but are not identical. This may explain the observation that HCII binds non-specifically to heparin oligosaccharides but preferentially binds to a minor hexasaccharide isolated from dermatan sulfate having the structure shown in Fig. 4B. The tissue distribution of dermatan sulfate molecules containing the high-affinity HCII binding site may regulate HCII activity in vivo. Finally, in the presence of dermatan sulfate or heparin, the N-terminal acidic domain of HCII may interact with the hirudin-binding site of thrombin to produce maximal stimulation of the thrombin-HCII reaction.


New approaches for defining sequence specific synthesis of heparan sulfate chains. Mammalian cells synthesize heparan sulfate proteoglycans (HSPG) which consist of core proteins with covalently linked glycosaminoglycans (GAGs) of 50-150 disaccharide units. The GAGs exhibit great structural diversity which arise from differing arrangements of alternate disaccharide units. It has been hypothesized that HSPG may be involved in regulating the most basic aspects of cell biologic systems such as adhesion, proliferation and differentiation. However, considerable doubt exists about the specific nature of the above interactions because of a failure to isolate GAGs of unique monosaccharide sequence with appropriate biologic activities. We have demonstrated that mouse LTA cells synthesize cell surface heparan sulfate proteoglycans with regions of defined monosaccharide sequence that specifically interact with antithrombin (HSPGact). However, it remains unclear how HSPGact can be generated by a biosynthetic pathway with no simple template for directing the ordered assembly of monosaccharide units. To examine this issue, we treated LTA cells with ethylmethane sulfonate and then identified mutants that exhibit decreased antithrombin binding to heparan sulfate chains but possess no gross defects in glycosaminoglycan biosynthesis. After screening 40,000 colonies, we isolated 7 stable mutants which synthesize 8-27% of the wild type HSPGact but produce normal amounts of other HSPG. These mutants are recessive in nature, and fall into at least two different complementation groups. The delineation of the molecular basis of these defects should greatly improve our understanding of how cells synthesize HSPG with regions of defined monosaccharide sequence.


Participant enrollment, participation, and compliance in chemoprevention trials. Chemoprevention trials offer exciting opportunities for decreasing the risk for cancer. Close attention to the recruitment, enrollment, and compliance of participants will aid greatly in both the cooperation of participants and the long-term adherence that are essential for the success of these trials.


A model system for studying nutritional interventions on colon tumor growth: effects of marine oil. Lipid nutrition effects were evaluated on the growth of a transplantable colon tumor (CT-26) at various sites in the BALB/c mouse. CT-26 implanted into the back or flank of these mice grew well independent of the quality or quantity of fat in the diet. However, when implanted in the mid-portion of the descending colon, tumor growth was related to the level of dietary saturated (coconut oil) or n-6 unsaturated (safflower oil) fat in the diet. Similar findings were obtained when the tumor was utilized in a pulmonary colonization assay. Dietary marine oil (mainly EPA, and DHA n-3 polyunsaturated oils) was found to markedly impair the growth of CT-26 implanted in the bowel and lung, but not in the back. Thus, CT-26 exhibits nutrition responsiveness at certain sites, but not at others. This may help to explain contradictory findings concerning dietary lipids in certain studies. Inhibition of tumor growth by marine oils may afford preventive or chemotherapeutic implications as its mode of action unfolds. Histologic findings in bowel tumors from mice fed marine oil but not other oils revealed focal areas of necrosis. It is appreciated that arachidonate metabolism is competitively interfered with by EPA in both cyclooxygenase and lipoxygenase pathways. The possibility is raised that the metabolism of marine oils in this model system may generate lipid peroxidation products to a greater extent than n-6 lipids and in turn is associated with focal areas of necrosis. A model system of nutritionally non-responsive and nutritionally responsive sites for the post-promotional growth of a bowel tumor affords the opportunity to explore lipid effects with control and test tumors in hosts fed identical lipid nutriture.


Breast cancer--the optimal diet.

Breast cancer--the optimal diet. In summary, the evidence based upon global and metabolic epidemiology, and animal studies supported by biologic understanding of the various mechanisms in which dietary fat can affect promotion and progression of breast cancer supports the concept that dietary fat, in particular, certain types of fat, and dietary fiber affect the causation, promotion, and progression of breast cancer. The epidemiologic evidence of the link between breast cancer and dietary fat is still controversial due to methodological problems in designing a valid test. Also a number of studies dealt with the question of fat intake in pre-menopausal women, where admittedly the association is weak. What now needs to be done is to verify the effect of a low-fat diet in post-menopausal breast cancer patients. We suggest that a similar trial on pre-menopausal breast cancer patients in conjunction with ovarian ablation should be conducted. The question to be considered is what in terms of dose, type, and duration of fat and fiber will be required to obtain a measureable effect on the recurrence rate and survival of breast cancer patients.


Effects of voluntary exercise and/or food restriction on pancreatic tumorigenesis in male rats. Studies were undertaken to evaluate the effects of caloric restriction on voluntary exercise in a rat model of pancreatic cancer. Suckling male Lewis rats were initiated with 3 doses (30 mg/kg body weight) of the pancreatic carcinogen azaserine. At 28 days of age they were weaned to one of four experimental protocols; namely, sedentary/ad libitum fed, voluntary exercise/ad libitum fed, sedentary/food restricted, and voluntary exercise/food restricted. Voluntary exercise was provided by free access to running wheels fitted with odometers. Food restriction was intended to be mild, at less than 10% reduction of ad libitum intake. Putative pre-neoplastic pancreatic foci were identified microscopically at 4 months post-azaserine treatment. As previously shown, food restriction led to increased wheel activity, but the increased activity could not be maintained beyond the first half of the post-initiation treatment phase. Additionally, the extensive wheel running occurred only when available food was restricted by greater than 10%. Exercise per se had a lesser effect compared to food restriction on pancreatic tumorigenesis.


Dietary fat, calories, and mammary gland tumorigenesis. In this communication, a vast array of studies designed to examine the relationship between dietary fat and experimental mammary gland tumorigenesis was reviewed and critiqued. It is clear, as reported by many laboratories, that as the fat content of the diet is increased from a low or standard level to a high level, a consistent and substantial increase in the development of rodent mammary gland tumors is observed. The longer the duration the high-fat diet is fed, the greater the enhancing effect on tumorigenesis. Furthermore, the stimulatory effect of a high-fat diet is observed even when fed commencing late in an animal's life. A multitude of studies also have provided evidence that the type of fat can markedly influence the development of rodent mammary gland tumors. In general, high dietary levels of unsaturated fats (e.g., corn oil, sunflower-seed oil) stimulate this tumorigenic process more than high levels of saturated fats (e.g., beef tallow, coconut oil); diets rich in certain fish oils (e.g., Menhaden oil, Max EPA) are often the most inhibitory to this tumorigenic process. Importantly, however, supplementation of saturated fat or fish oil diets with modest amounts of unsaturated fats, e.g., corn oil, often negates the mammary tumor inhibitory activities of these fats. Thus, rather extreme differences in the types of fat are required for a differential in mammary gland tumorigenesis; common proportionate blends of different fats of animal, plant, and/or fish origin are often unable to differentially influence this tumorigenic process. Diets rich in monoenoic fatty acids, e.g., those containing high levels of olive oil, have been examined in a number of studies; results from these studies have been inconsistent. A number of reports suggest that the increase in development of mammary tumors in rodents fed a high-fat diet, compared with those fed a low-fat diet, is due to specific metabolic activities of the fat per se, activities independent of a caloric mechanism. Careful analysis of these reports suggest that such a conclusion may not be totally warranted. Indeed, persuasive evidence is accumulating indicating that the major mammary tumor development enhancing activities of a high-fat diet may be via a caloric (energy) mechanism. Caloric restriction, even in animals fed a high-fat diet, significantly suppresses mammary tumor development. Even mild caloric restriction (e.g., 12%) can significantly suppress development of mammary tumors in rodents.(ABSTRACT TRUNCATED AT 400 WORDS)


Voluntary exercise and experimental mammary cancer. The results of these studies indicate that voluntary activity suppresses the development of chemically and virally induced primary mammary tumors in rats and mice fed high-fat diets. These diets were chosen to mimic the current U.S. fat consumption of approximately 40% of calories as fat. It remains to be seen if activity exerts a similar suppressive effect on animals fed their customary low-fat diet (10% calories as fat). In general, the activity profiles of the female Fischer F-344 and Sprague-Dawley rat and the C3H/o mu j mouse exhibited a similar pattern with an early peak followed by a gradual plateau over time. The effects of activity on body fat composition showed a trend toward a decreased percent of body fat when compared to sedentary animals but a statistically significant decrease was found only in the F-344 female rat. In the DMBA model, carcinogen dose did alter outcome parameters. For example, time to first tumor was extended under low- but not high-DMBA conditions, and, conversely, tumor multiplicity was significantly decreased in the high- but not low-DMBA group. In the NMU model, an inverse association was found between the amount of activity and tumor incidence. A similar association was not found with the DMBA model. The reason for this is uncertain, but further analysis in terms of other parameters such as total tumor number may shed more light on this discrepancy. The suppressive effect of activity on the MMTV-induced mouse mammary tumor is of particular interest since it raises the possibility that activity may exert effects on the process of provirus insertion, and/or oncogene activation--an area of great potential promise in cancer prevention. Activity appeared to enhance the volume and to a lesser degree the number of metastatic foci in the lungs of F-344 retired breeders under high-fat but not medium-fat conditions. In addition, the most active animals in the high-fat group exhibited the greatest volume of metastases. These results, together with those in the NMU model, point to the critical importance of the quantity of voluntary activity an animal engages in and its relation to both primary and secondary cancer prevention. They imply that beyond a certain point of either frequency or intensity, the beneficial effect of exercise may be nullified by competing deleterious effects. The metastases study has also brought to light the importance of dietary fat as a potential intervening variable.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of amount and type of exercise on experimentally induced breast cancer. It appears that exercise derived by treadmill running can enhance or inhibit the development of mammary cancer depending on the intensity and duration of the activity. The effects of timing of exercise relative to the phases of carcinogenesis and the frequency of exercise on the tumorigenic response in the mammary gland have yet to be studied. What is needed are further investigations of a spectrum of exercise conditions that exert differential effects on measures of physical fitness, energy intake, body composition, and/or the efficiency of utilization of carbohydrate, fat, and protein as energy substrates. This should facilitate identification of critical relationships between physical activity and the risk for cancer. This goal can best be achieved initially through carefully controlled laboratory studies using appropriate experimental systems. There are several mechanisms by which exercise could alter the course of tumor development. A goal in this field should be to first characterize the influence on tumorigenesis of amount and type of exercise that have differential effects on metabolism and thereafter proceed to investigate the basis for the effects observed. Experiments should be designed to dissociate effects of exercise related to local and/or systemic changes induced by skeletal muscle contraction from those attributable to changes in energy expenditure. Ultimately, investigations of the type proposed should allow for determination of whether the quantity and quality of exercise needed to attain health-related benefits for chronic diseases such as cancer differs from what is recommended for fitness benefits. This should also permit formulation of a specific set of recommendations about the amount and type of physical activity that in concert with appropriate dietary practices can significantly reduce the risk for cancer.


Modulation of chemical toxicity by modification of caloric intake. Caloric restriction increases maximum achievable lifespan and offsets the time to development of degenerative disease. Part of these desirable effects may result from positive modulation of toxic events. We have shown that when rodents are placed on a diet that is reduced in total calories by 40%, several beneficial changes on biochemical systems which impact on toxicologic processes are positively enhanced. Lipid metabolism is reduced and, therefore, the potential for lipoperoxidation is reduced. Additionally, activity of enzymes that produce free radicals as byproducts (cytochrome P4502C11) are also reduced. Concurrently, we have shown that the "effective" activity of catalase and the activity of superoxide dismutase (which are required for the detoxification of toxic oxygen radicals) are significantly increased by caloric restriction. The activities of enzymes of drug and xenobiotic metabolism are also altered by caloric restriction. The effect upon activity may be to either decrease or increase activity, dependent upon whether the enzyme activates compounds to intermediates which may be more toxic or whether the enzyme acts to reduce toxicity. We have also shown that caloric restriction may affect the initiation stage of carcinogenesis. Aflatoxin B1 binding to hepatic nuclear DNA was reduced by caloric restriction (caloric restriction reduced both major adducts that are formed upon exposure to aflatoxin B1). caloric restriction also reduced cytochrome P4502C11 which converts aflatoxin B1 to its toxic epoxide, and may partly explain the reduction in binding. These results suggest that caloric restriction may, in part, extend the time to development of degenerative disease by altering basic biochemical mechanisms of toxicity.


Cellular and molecular mechanisms of B lymphocyte tolerance. A paradox of immunology is that the immune system is distributed so widely in the body, as a large number of cells that discharge most of their effector functions as single cells; but, at the same time, the elements of the system are so very interdependent, not only via specialized cell clusters and microenvironments, but also by mobile feedback loops, cellular and molecular. The end result is that one cannot really understand one element of the system without understanding every other, at least to a degree. Certainly, tolerance cannot be isolated from immune activation, nor B cell from T cell tolerance, rendering the task of the reviewer somewhat thankless. This being said, the last few years have seen wonderful progress in our grasp of B cell tolerance, to which the transgenic revolution has contributed a great deal. The fact that B cell tolerance exists as an important component of self-tolerance has been firmly established, as have the limits of the process in terms of both the survival of low-affinity antiself clonotypes and the question of location and concentration of antigen required for tolerance induction. Two processes have been identified as key alternatives: clonal abortion/maturation arrest/deletion and induction of clonal anergy. The latter requires a less strong Ig receptor crosslinking signal, may be partial, and is reversible. Recognition of these facts has prompted both experimentation and speculation on possible functions of the anergic cell. One unsatisfactory area, which we have not addressed because nothing like a consensus has been reached, is T cell-mediated suppression and its possible effects on tolerant states, including anergy induction in B cells. The phenomenology of suppression is too striking to sweep under the carpet, and suppressor T cell memory in particular (Adelstein et al., 1990) requires much more investigation; however, suppression has not been shown to play a major role in any of the best-studied transgenic models. These can readily be explained on the basis of direct interactions between the B cell target for abortion or anergy and the self antigen in question. The biochemical basis of discrimination between immunity and tolerance has also progressed, but not as fast. This is understandable, as so many signaling pathways have to come together for full immune induction, and as immaturity of the signal transduction pathway plays a profound role that must be studied in normal cells, with all the attendant difficulties of cell separation.(ABSTRACT TRUNCATED AT 400 WORDS)


The evaluation of ear canal, middle ear, temporal bone, and cerebellopontine angle masses in infants, children, and adolescents. Ear canal, middle ear, temporal bone, and CPA angle masses (except for cholesteatomas) are rare in the pediatric population. The physician needs to have a high degree of suspicion for such lesions if a child presents with ear pain unrelated to infection or otorrhea that fails to improve after treatment. A precise diagnosis needs to be made in these children and also in those with hearing loss, vertigo, and facial paralysis. The most useful imaging procedures for ear, temporal bone, and CPA masses are CT and MR imaging. With a suspected vascular lesion, a definitive diagnosis usually can be made by an imaging procedure or angiography. In all cases of mass lesions, except for some aneurysms and infections, a tissue diagnosis must be secured.


Helicobacter pylori, gastritis, and ulcers in pediatrics. Hp now appears to be more than a simple commensal organism in patients with gastritis or peptic ulcer disease. Microbiologic, serologic, and epidemiologic studies all confirm that Hp has an important role in children with abdominal pain. Hp is found in the gastric mucosa of children with histologically proven gastritis or peptic ulcer. The organism can be transmitted from human to human with evidence of colonization, appearance of gastritis, and serum antibody response. Antimicrobial therapy directed at Hp eradicates colonization and resolves symptoms. Hp antibodies appear more frequently in familial clusters and the frequency of antibody positivity increases with age. Children are more likely to have symptomatic disease associated with elevated antibody titers. Recurrence of disease is associated with reappearance of the organism. At the present time, colonization can be detected only by gastric biopsy; however, it may be possible eventually to diagnose or follow infections by obtaining serum antibody titers or urea breath-testing. The natural history of Hp infection is unclear. Although it can cause an acute gastritis, it generally is found in association with chronic gastritis. The increase in seropositivity with age may mean that slow changes evolve over decades or that age cohorts have been infected differentially. How does antral colonization with Hp cause duodenal ulceration? The organism is not found in the duodenum and most patients with gastritis do not develop ulcers. This may be related to changes in acid production and mucosal protection associated with Hp colonization, but few studies have been done. What factors initiate Hp infection? Both volunteers who became colonized first suppressed acid secretion with H2-antagonists. Hypochlorhydria also seems to follow Hp infection in these same studies. The role of diet and drugs, or other environmental and genetic factors, in initiating infection is largely unexplored. An effective means of therapy needs to be developed. Although Hp appears sensitive in vitro to many compounds, it is difficult to eradicate in vivo, especially with monotherapy. Single-drug therapy suppresses the organism, but recurrence rates are high. It is difficult to deliver effective doses of drugs to the mucous niche the organism has selected and concerns about long-term therapy and its side effects persist. Current data suggest no ready solution to the initial case presentation. A child with primary gastritis or duodenal ulcer should be treated first with standard antacid and H2-receptor antagonist therapy. If endoscopy is performed, biopsies of normal-appearing areas of gastric antrum should be stained for Hp and a biopsy urease test should be performed.(ABSTRACT TRUNCATED AT 400 WORDS)


Newborn screening for cystic fibrosis. The Cystic Fibrosis Neonatal Screening Study Group. Many questions remain regarding the efficacy, risks, and costs of CF neonatal screening. The major gap in knowledge that must be closed before CF neonatal screening can be recommended generally in the United States concerns the potential long-term medical benefits of initiating treatment in early infancy. It would be premature, in our opinion, to implement mass population screening of newborns for CF until the benefits and risks have been fully defined, and an adequate and logistically feasible testing system developed and/or highly effective therapy for CF lung disease becomes available. It is for this reason we designed a randomized, controlled investigation of CF neonatal screening and implemented this project in Wisconsin during 1985. The fact that 5 years of randomized screening and systematic evaluation of outcome measures have not yet revealed any pulmonary benefits underscores the importance of rigorous investigation to resolve the efficacy issue. In addition to the medical uncertainties, we believe that the ethical issues described herein need to be resolved; this concern pertains not only to the CF patient but also the heterozygote carrier. On the other hand, financial factors and uncertainty about the cost effectiveness of CF neonatal screening do not appear to be dominant issues according to our assessment of current data. Despite the reservations related to the benefit/risk relationship, we expect that the discovery of the CF gene should have a favorable impact on neonatal screening for the disease, as well as for management.


Intravenous immunoglobulin in the prevention and treatment of neonatal bacterial sepsis. IVIG has been shown in vitro to enhance many antibody-dependent immunologic functions. In animal models, IVIG enhanced the survival of septic neonates. In humans, preliminary data indicate that prophylactic IVIG may diminish the incidence of bacterial sepsis in VLBW neonates if sufficient doses of the immunoglobulin are administered repeatedly. IVIG administered after the onset of clinical symptoms may improve the survival of septic human neonates. However, the studies designed to assess the efficacy of IVIG to treat established sepsis have employed a small number of subjects and have, overall, provided inconclusive data. IVIG has been tolerated well by neonates, but the safety and long-term consequences of administering IVIG to newborn infants are not yet defined. IVIG will likely serve as a useful adjunct to enhance the antibacterial defenses of newborn infants. Use of IVIG in human neonates remains experimental at this time; therefore, the clinical application of IVIG for the prevention or treatment of neonatal bacterial sepsis should await the development of guidelines to be derived from ongoing multicentered, placebo-controlled clinical trials.


Dietary manipulation in experimental inflammatory bowel disease. Eicosanoids are major mediators of defensive and inflammatory processes of the gut mucosa. The activity of the eicosanoid system is modulated by neural and hormonal pathways, but local factors acting within the gastrointestinal lumen may also be involved. We have studied the influence of dietary fatty acids on eicosanoid synthesis by the gastrointestinal mucosa. Since omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower or cod liver oil as sources of omega-6 or omega-3 fatty acids, respectively. Rats fed with the cod-liver-oil-supplemented diet for four weeks showed high omega-3 and low omega-6 plasma fatty acid levels compared to rats fed with the sunflower oil diet. Synthesis of arachidonic-acid-derived eicosanoids (6-keto-PGF1 alpha, PGE2, TXB2, LTB4, and LTC4) by gastric and intestinal mucosa was found to be lower in the cod liver group as compared to the sunflower group. However, significant generation of eicosapentaenoic-acid-derived eicosanoids (PGE3 and LTC5) was observed only in the cod liver group. We used the (trinitrobenzenesulphonic acid) TNBS model of inflammatory colitis to test the effect of the dietary fat on the development of inflammatory lesions of the bowel. A single intracolonic instillation of the hapten TNBS dissolved in 10% ethanol induces chronic granulomatous lesions of the colonic mucosa that persist for up to 8 weeks. Luminal release of eicosanoid mediators, as measured by intracolonic dialysis, was lower in the cod liver group than in the sunflower group, particularly during the chronic stage of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of non-steroidal anti-inflammatory drugs on glutathione levels in various organs of rat. Since glutathione (GSH) depletion (about 20% of total GSH content) can impair the cell's defence against the toxic actions of drugs and may lead to cell injury and death, we examined the effect of piroxicam, naproxen and ketoprofen on GSH levels in various organs of the rat (brain, eye, liver, stomach, heart, leg adductor muscle). Ketoprofen in brain and leg adductor muscle dramatically decreases the GSH levels, giving rise to potential cellular toxicity.


Use of the rat air pouch model of inflammation to evaluate regional drug delivery. We have used the rat inflammatory air pouch model to investigate some of the pharmacokinetic and pharmacodynamic issues relating to regional drug delivery. S(+)Ibuprofen was administered either intravenously or directly into the air pouch at the same time as the irritant (carrageenan). Serial samples of exudate and plasma were then taken and assayed for drug concentrations and various efficacy markers. Ibuprofen given intrapouch, was found to inhibit in a dose-dependent manner the concentration of prostaglandin E2 and the number of white cells in the exudate. Plasma and pouch concentration-time profiles are described for s(+)Ibuprofen: there is evidence for greater drug retention in the pouch than in plasma following regional and systemic delivery.


Desferrioxamine potentiated SOD antiinflammatory activity in rat adjuvant arthritis: role of iron and bacterial toxins. In this paper we studied the modulating inflammatory activity of iron in the adjuvant arthritis, taking indomethacin as a standard antiinflammatory drug and a superoxide dismutase derivative (MPEG-SOD) as a scavenger of free radicals. Moreover, we evaluated the changes in potential intestinal pathogens requiring iron for growth, in order to study the role of bacteria in the altered gastrointestinal functions observed during arthritis. We observed a 50% arthritis inhibition on the 14th day with MPEG-SOD plus desferrioxamine, a significant decrease in serum iron in arthritic rats compared to controls, and a significant Cl. perfringens increase on the 28th day in the presence of MPEG-SOD. Our data demonstrate that hypoferremia, in arthritis, is a protective mechanism overall in the early phase and could protect the intestinal tract by inhibiting the development of potential pathogens.


Anti-inflammatory effect of tuftsin and its retro-inverso analogue in rat adjuvant arthritis. Tuftsin, an immunostimulating tetrapeptide derived from immunoglobulin heavy chain, and its retro-inverso analogue have been tested in rat adjuvant arthritis. The secondary lesion of rats injected with Freund's adjuvant was significantly inhibited by both the natural and retro-inverso tuftsin administered orally. The retro-inverso analogue was at least tenfold more potent than the parent molecule, suggesting an increased stability to degradation, because of its molecular modification. The anti-inflammatory effect of tuftsin may be due to its ability to modulate macrophage function.


Copper supplementation in the rat: preliminary observations on the clinical, hematological and histopathological profile. Complete toxicological examinations in female rats fed an "anti-inflammatory" 200 ppm copper-containing diet for 30 and 58 days were performed. Copper was found to accumulate in liver, kidneys and paws; however, at the hematological, clinical chemical and histopathological levels, this treatment did not seem able to induce any toxic accumulation phenomenon in the examined rats.


Time- and dose-related influence of dexamethasone on morphine-induced hypermotility in mice. The effect of interaction between dexamethasone (DEX) and morphine on locomotor activity in mice was investigated. DEX alone (1.0 and 10 mg/kg i.p.) did not affect the locomotor activity of mice when injected immediately before the beginning of the session. DEX (1.0 mg) injected two hours before the session did not modify the activity of mice whereas the higher dose (10 mg) increased it. Morphine alone (30 mg/kp i.p.) induced a consistent increase in the locomotor activity. DEX (1.0 mg) injected at the same time as morphine reduced the morphine hypermotility, whereas that injected two hours before morphine had no influence on morphine hypermotility. DEX (10 mg) consistently potentiated the morphine hypermotility both when administered together and two hours before morphine. We conclude that DEX exerts an important time- and dose-related influence on morphine-induced hyperactivity in mice.


Indomethacin-induced enteropathy: effect of the drug regimen on intestinal permeability in rats. To set up and characterize reproducible, long-standing small intestinal inflammation in rats, animals were given three different oral regimens of indomethacin (Ind): a bolus of 10 mg/kg in water and three daily doses of 2, 4, and 8 mg/kg Ind in (a) the drinking water or (b) the standard diet. The effect of Ind on the small intestine was monitored by measuring intestinal permeability (IP). The three-day regimen seemed more suitable than a bolus dose to induce long-standing inflammatory modifications in the rat small intestine and Ind administered in the drinking water gave more consistent modifications of IP and more reproducible results than Ind in food. IP seemed a suitable tool for detecting these inflammatory changes in the small-intestinal physiology. This model could be used to assess the effect of new drugs on inflammation.


Immunological aspects of inflammatory bowel diseases of the human gut. The gut has a highly specialized immune apparatus, particularly involving the production of protective secretory immunoglobulin A (IgA), but also involving T-cell immunity. Secretory IgA plays a major role in preventing antigen uptake, both of infectious and non-infectious types. IgA immune responses are initiated by antigen uptake into specialized lymphoid aggregates such as Peyer's patches, and IgA plasma cell precursors are subsequently distributed throughout the gut and also over other mucosal surfaces. The clinical consequences of perturbation of the local immune system of the gut are surveyed in this article, including the consequences of immunodeficiency and the conditions reflecting an enhanced expression of immunity in the gut mucosa. The potential impact of non-steroidal anti-inflammatory drugs on the local immune system is discussed.


Role of Helicobacter pylori in gastritis and duodenitis in man. Although Helicobacter pylori is now accepted as the major aetiological factor in chronic gastritis in man, many of the factors which determine its pathogenicity are unknown. The organism has adapted to survive in the low-pH environment of the stomach, partly through its ability to buffer hydrogen ion by the hydrolysis of urea and by the presence of lectins on its surface, which bind to gastric mucosa and epithelial cells. After attachment, harmful toxins and enzymes have access to the gastric cells and cellular damage and an immune response ensues. In patients with duodenal ulceration, Helicobacter pylori-related gastritis predominantly affects the gastric antrum and has a high prevalence. Excessive gastrin production has been suggested as a potential aetiological factor linking infection with duodenal ulcer development. Perhaps more important is the association between gastric metaplasia of the duodenal epithelium, which is correlated with acid load and is more extreme in H. pylori positive patients with duodenitis. Organisms may subsequently spread from the gastric antrum into areas of gastric metaplasia in the duodenal bulb, leading to areas of chronic duodenitis and ultimately frank ulceration. It should not be overlooked, however, that other factors such as genetic predisposition, blood group, stress, drugs and smoking all have a role to play in the outcome, given the comparatively small number of patients in the general population infected with H. pylori who develop ulcer disease.


Interleukin 1 beta (IL-1 beta) release from fresh and cultured colonic mucosa in patients with ulcerative colitis (UC). Interleukin-1, a cytokine produced by macrophages and other tissue cells, has a major role in inflammatory and immunological responses. Increased levels of IL-1 activity have been reported in experimental colitis and in patients with active Crohn's disease (CD) and ulcerative colitis (UC). IL-1 beta release from fresh and cultured colonic biopsies and IL-1 beta plasma concentrations was determined in 15 patients with active UC, 16 with UC in remission and 10 normal control subjects. Biopsies, taken at colonoscopy were weighed, washed in 1 ml of 0.9% sodium chloride solution and then cultured for 24 h in 10% fetal calf serum/RPMI. IL-1 beta activity was determined by ELISA KIT (Cystron Biotechnology) in plasma samples, washing solution and the incubation medium. Very low levels of IL-1 beta were detected only in 3 plasma samples, all from active patients. Significantly more IL-1 beta was released from fresh and cultured colonic mucosa obtained from patients with UC in remission compared to normal mucosa (p less than 0.01). Furthermore, specimens from active UC released significantly more IL-1 beta than those from patients in remission (p less than 0.01). In conclusion, IL-1 may play an important role in mediating the inflammatory response in UC.


15-HETE is the main eicosanoid formed by human colonic mucosa. Eicosanoids were measured in colonic biopsies from eleven patients with active ulcerative colitis and from thirteen controls. Eicosanoid formation was measured after the addition of arachidonic acid and stimulation with calcium ionophore A23187. The 15-lipoxygenase derivative 15-hydroxy-eicosatetraenoic acid (15-HETE) was the predominant product formed in all biopsies. The amount of 15-HETE formed was dependent on the site of biopsy and decreased in the controls in biopsies taken in an aboral direction in the colon. The formation of 15-HETE and that of prostaglandin E2 (PGE2) and PGF2 alpha was proportional to the histologically obtained inflammation score. The role of 15-H(P)ETE as a mediator in ulcerative colitis should, therefore, be considered in addition to the effects of known modulators such as leukotriene B4 (LTB4) and PGE2.


Treatment of the mucosa with local anaesthetics in ulcerative colitis. A new paradigm for the treatment of ulcerative colitis has recently been presented: Treatment of the mucosa with lidocaine (2%) enemas for prolonged periods. This therapy was introduced based on the hypothesis that hyperreactive autonomic nerves may play a pathogenetic role in the disease. One hundred consecutive patients have now been treated and the results presented. The proctitis patients all responded to the treatment, despite previous therapeutic failures in more than two-thirds of the cases. They were treated for 3-12 weeks, but 68% had a relapse (observation period 20 months). Of the 49 patients with proctosigmoiditis, two-thirds had chronic symptoms resistant to previous therapy. One of these patients did not respond to lidocaine, but developed fulminant total colitis. The other patient had therapeutic failure with lidocaine but responded well to subsequent cortisone enemas. The patients were treated until the subsets of T-lymphocytes (OKT4+ and OKT8+) disappeared from the mucosa. This occurred in parallel with symptomatic relief and eventual healing in 83% of the patients after treatment for 6-34 weeks. Of all the patients with proctosigmoiditis, 42% presented with recurrent symptoms (observation period 16 months). Of the 17 patients with left-sided colitis, all went primarily into remission within 2-4 months, but 23% had a relapse (observation period 13 months). The 6 patients with total colitis had symptomatic relief and improvement of histology when treated over 3-8 months. One patient had recurrence after 12 months. Treatment with a local anaesthetic in ulcerative colitis is a new approach to mucosal inflammation. The beneficial effects may be due to blockade of certain neural effects, such as epithelial proliferation and shedding and congestion of the mucosal vasculature, with actions on cells of the immune system.


Species differences in the pattern of eicosanoids produced by inflamed and non-inflamed tissue. The synthesis of 14C labelled arachidonic acid metabolites was measured in colonic tissues obtained from mice, rats, guinea pigs, rabbits, piglets and in colonic biopsies from humans during colonoscopy. The main eicosanoids formed after stimulation with calcium ionophore A23187 were: in humans, 15-hydroxy-eicosatetraenoic acid (15-HETE); in mice, 12-HETE; in rats, 12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandin F1 alpha (6kPGF1 alpha); in guinea pigs, PGD2; in rabbits, 6kPGF1 alpha, PGE2 and 15-HETE; and in pigs PGE2 and 12-HETE. In inflamed 15-HETE production was increased in man, HHT and 12-HETE production in rats and overall eicosanoid production in mice.