Diuretics, arrhythmias and silent myocardial ischaemia in hypertensive patients. Patients with high blood pressure have an increased risk of sudden death compared to the normotensive population. In the highest quintile of patients with systolic blood pressure above 155 mmHg, the risk of sudden death is 3.2 greater than those in the lowest quintile. Ventricular premature contractions without known coronary artery disease also increase the risk of sudden death. Other known risk factors in this regard are age, smoking, obesity and left ventricular hypertrophy. Hypertensive patients have an increased prevalence of ventricular arrhythmias which is most pronounced in those with left ventricular hypertrophy. However, a causal relationship between ventricular arrhythmias and sudden death is uncertain. Existing data do not allow any firm conclusion as to the effects of antihypertensive treatment on such arrhythmias or on the risk of sudden death. Silent ischaemia is not uncommon in patients with hypertension but, so far, no consistent relation with coronary artery disease, left ventricular hypertrophy or neurohormonal abnormalities has been demonstrated. Silent ischaemia is an independent predictor for the development of cardiac events in patients with hypertension and may be a predictor for sudden death in these patients. Ninety-two percent of patients with ventricular tachycardia (VT) and silent myocardial ischaemia can be expected to develop morbid cardiac events compared with only 37% of those who have neither VT or silent ischaemia. At present, there is no information on the influence of diuretics on silent ischaemia in hypertensive patients. It can be concluded that both ventricular arrhythmias and silent ischaemia are important and independent risk factors for cardiac events in hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Diuretics in hypertension: clinical experiences. Diuretics have long been used in the treatment of hypertension and are outstandingly efficacious when used either alone or in combination with other antihypertensive compounds. Blood pressure is controlled with diuretics alone in over 50% of patients and in over 80% in combination with other drugs. Thiazide diuretics were used singly and in combination in the early VA Co-operative studies that demonstrated decrease in cardiovascular morbidity with blood pressure control. Subsequent studies have confirmed these early findings and clearly demonstrated that the thiazide diuretics are as effective in lowering blood pressure as other currently available antihypertensive compounds. Diuretics, like all other antihypertensives, have side effects, of which the most important ones are hypokalaemia, alterations of the plasma lipid profile, hyperuricaemia and glucose intolerance. Diuretic-induced hypokalaemia may be hazardous in the presence of digitalis, but does not appear to have any inherent propensity to induce life-threatening arrhythmias. Diuretics remain amongst first-line drugs in the treatment of high blood pressure due to their efficacy, especially in blacks and the elderly, the potentiation of the antihypertensive efficacy of other compounds, their low side effect profile and their low cost.


Comparative efficacy of diuretics: benefit versus risk: results of clinical trials. Although several large trials have been conducted with the aim of establishing the need for, and the best approach to, the treatment of hypertension, none have specifically addressed the question of the best use of diuretics. Analysing the trials to obtain specific answers about diuretics is therefore difficult, and particularly so because of differences in trial design and in the medications used. Comparisons between active treatment and no therapy have tended to show that active treatment is associated with a significant reduction in the incidence of strokes and a small reduction in myocardial infarction and death. Comparisons of treatment strategies, as opposed to comparisons of particular drugs, are hard to interpret and some conclusions that have been drawn about a harmful effect of diuretics are probably misleading. Trials comparing diuretics and beta-blockers suggest that these types of drug have similar effects on clinical events although the most recently published study suggests that diuretics are more effective than beta-blockers in preventing myocardial infarction. Therefore, it seems that what matters is blood pressure reduction, not the means by which this is achieved. The biochemical effects of diuretics are probably not important, but only one trial has investigated the use of a low dose of diuretics.


Adverse reactions to diuretics.

Adverse reactions to diuretics. Diuretics can result in various undesired biochemical changes, such as impotence, skin rashes, nausea, dizziness and lethargy as well as subjective side effects. The side effects are mostly predictable, their effects depending on both the circulatory blood volume and on the transport of water and solute in the renal tubules. Two of the commonest side effects are mild hypovolaemia, when any diuretic is used, and mild hypokalaemia when the non-potassium-sparing diuretics, such as thiazides and frusemide are used. Its occurrence is dose dependent and can be corrected by potassium supplements, but potassium-retaining diuretics, which also correct the often associated fall in serum magnesium, are preferable. Many reports link hypokalaemia with cardiac arrhythmias, but some dispute this association in the absence of the concomitant use of digoxin. Hyponatraemia rarely occurs, but can be life threatening. Calcium excretion is markedly reduced, but unlike other electrolyte disturbances from diuretics, this may be valuable: some suggest diuretics have an anti-osteoporotic action. Diuretics increase glucose and insulin resistance and should be used sparingly in diabetics. They rarely cause a non-ketotic hyperosmolar coma. Urate is raised, but clinical gout is not common. Cholesterol elevation has been reported in some studies, but long-term studies indicate that lipid changes are minor. Other rare side effects are not predictable from their pharmacological actions and these include the occurrence of skin rashes, thrombocytopenia, pancreatitis and interstitial nephritis; and ototoxicity from frusemide.


Tropisetron, a new 5-HT3 receptor antagonist, in the prevention of irradiation-induced nausea, vomiting and diarrhoea. Tropisetron, a 5-HT3 receptor antagonist, was evaluated as antiemetic prophylaxis during postoperative abdominal irradiation of ovarian carcinoma patients. Twenty consecutive women with Stages I-III (FIGO) epithelial ovarian carcinomas were included. At the start of radiotherapy all patients were clinically tumor-free. Twelve women received irradiation on whole-abdominal fields, 1.0 Gy per fraction, during 6 weeks. Eight women were irradiated on the lower abdomino-pelvic fields, 1.7 Gy per fraction, during 5 weeks. Efficacy and adverse events were recorded by the patients in diary-form booklets using visual analog scales (VAS). All patients completed the treatment series and none was lost to follow-up. Nausea, generally mild (mean 20 mm VAS) and of short duration, increased from start (30%) to end of radiotherapy (54%). Episodes of vomiting were few in number and occurred in less than 10% of the cases. Diarrhoea was common towards the end of the radiotherapy courses, especially when the dose per fraction was 1.7 Gy and the need for extra antidiarrhoeal medication (loperamide) increased from 38% at the start to 100% at the end. The mean weight loss was only 1.2 kg during 5-6 weeks. The overall ratings for quality of life were excellent or good in 75-85% of the cases. The efficacy of tropisetron was rated excellent or good in 80% of the cases and the tolerability likewise in 85% in the overall evaluation of the drug made by the investigator. Tropisetron therefore seems to be a promising and well-tolerated drug in conjunction with extended radiotherapy on the whole- or lower-abdominal fields.(ABSTRACT TRUNCATED AT 250 WORDS)


Benign granular cell tumor mimicking carcinoma of the breast. Report of a case. A case of granular cell tumor of the breast in a 59 year-old woman is presented. Clinical evaluation suggested carcinoma with infiltration of the skin. The granular cell tumor was diagnosed on frozen section and the lesion was treated by wide local excision including the overlying skin. Granular cell tumors of the breast, which are usually benign, may closely mimic breast carcinoma, both clinically and on frozen section. The possibility of granular cell tumor of the breast with its potential for a false-positive diagnosis on frozen section supports a two-step procedure for the treatment of breast cancer, especially in young women, to prevent inappropriate radical surgery.


Influence of metastases on the prognosis of adenocarcinoma of uterine cervix. 95 cases of adenocarcinoma of the uterine cervix were analysed for the influence of metastasis on the prognosis. When there was penetration of cervical stroma, < 10 mm or > 10 mm, spread of the tumour to the uterine corpus, metastasis in the ovaries and no detection of metastasis in patients the differences in survival rates were not statistically significant. Local spread of adenocarcinoma to the uterine corpus, penetration of cervical stroma > 10 mm and metastasis to ovaries may not adversely influence the patients survival.


Serum values of CA72.4 in patients with gastrointestinal system tumors comparison with CEA and CA 19.9. Serum CA 72.4 levels of patients with malignant gastrointestinal disorders (n = 77) were determined in parallel with the CEA and CA 19.9 levels. The values related to healthy individuals were 1.7 U/ml, with a median of 1.7 U/ml, whereas an average of 12.1 U/l (median 2 U/ml) was measured in malignancy. Among all three markers CEA showed the highest positive rate while the values for CA 19.9 and CA 72.4 were lower. Although positive rates among the healthy group were observed with CEA and CA 19.9, no false positives were found with CA 72.4. Elevated CA 72.4 levels were found in 17.6% of patients with gastric carcinoma and 56.3% with colorectal carcinoma. All markers showed significant sensitivity for the malignant state when used alone. However, the regression analysis revealed that only the combination of CA 72.4 and CEA may contribute significantly to the diagnostic potential. Our results indicate that complementation of CEA with CA 72.4 can significantly increase the sensitivity in the serodiagnosis of gastrointestinal system cancers. Combination of positive information from these two sources is likely to lead to a more accurate diagnosis and may therefore improve the efficiency of the follow-up and therapeutic response.


Hysteroscopy as an elective tool in abnormal uterine bleeding in perimenopausal women. Abnormal Uterine Bleeding is a very frequent pathology particularly in perimenopausal age (> or = 45 years). The Authors report the experience of the 2nd Department of Ob/Gyn. of Rome University "La Sapienza" from January 1985 up to September 1991. The hysteroscopic evaluation of 789 patients in perimenopausal age is reviewed. The Authors analyze in detail the main cause of metrorrhagia describing the hysteroscopic aspect and relative incidence. Finally, some considerations concerning the great usefulness that a simple and accurate diagnostic investigation such as hysteroscopy represents in a routine diagnostic procedure, are reported.


Squamous cell carcinoma antigen in cervical cancer. Squamous cell carcinoma (SCC) antigen was described as being associated with malignant disease of the uterine cervix, and was determined by a radioimmunoassay technique. We studied squamous cell carcinoma serum levels in 72 patients from our gynecological clinic. Forty-three were diagnosed as having gynecological malignancies, and 29 as having benign diseases. The malignant disease group included 35 carcinomas of the uterine cervix, 7 endometrial cancers, and 3 vulvar cancers. Gynecological cancers were classified according to the FIGO system. We also determined SCC levels among 69 healthy subjects. Results showed that 97.1% of healthy subjects were below the cut-off point, 2.5 micrograms/l. Patients with benign gynecological diseases had increased SCC levels in 5.9% of cases. Among gynecological cancers, 56% of 23 cases of cervical cancer and one of three vulvar cancer, all of them in the active phase, had increased levels. The nine squamous carcinomas of the cervix with no evidence of disease, as well as seven endometrial adenocarcinomas with active disease were negative. Thirty-three percent of 12 cervical cancers in Stages I and II were high levels, compared to 81% of 11 advanced stages; none of the 2 early stage carcinoma of the vulva, but 1 advanced stage were increased. SCC is clinically applicable to monitor size and tumor volume of carcinomas of the uterine cervix derived from squamous epithelium.


Surgical management of intestinal complications of radiotherapy for gynecological malignancies. Sixty patients treated for gynecological malignancies with radiation therapy and operated upon because of late intestinal complications of the treatment were studied. Among patients irradiated for cervical carcinoma an incidence of 3.2% of operated intestinal lesions was encountered. Fifty-nine per cent of the women had a history of previous pelvic inflammatory disease on pelvic surgery. The most common symptoms leading to surgery were mechanical subileus/ileus, pain and fistulas. The majority of patients (53%) were operated upon within 2 years after irradiation, but an interval up to 20 years was recorded. 50% were operated upon within 2 years after irradiation, but an interval up to 20 years was recorded. 50% were reoperated during follow-up. Intestinal resections (38%) and by-passes (15%) were the most frequent surgical procedures at first operation. 57% of the patients were operated upon due to acute conditions and 31% were due to chronic problems, 12% due to tumour suspicion. An operation mortality rate of 5% was found. No obvious correlation could be seen between accumulated irradiation dose and severity of complications. The results of surgical intervention and complications are analysed and different strategies in handling these patients discussed.


Proposal for an organic future in gynecologic oncology all over the world. This is a proposal for an educational program and training all over the world, with the basic requirements for the objective. The author reviews the qualifications for becoming a Gynecologic Oncology (G.O.) specialist. To define what a G.O. specialist is, the aptitudes, abilities and the time for the training. To get a good learning, elementary facilities are furnished at an appropriate Institution. Ways of control at National level and problems and difficulties that may issue from starting the program are pointed out.


Variations of lymphocyte sub-populations in vulvar condylomata during therapy with beta-interferon. Several experiences induced us to consider genital HPV infection as an expression of a local immunodeficiency. The aim of our study was to research the effect of immunotherapy on the lymphocyte subpopulations and Langerhans cells in vulvar condyloma. Twenty women with persistent vulvar condylomata, treated with 2,000,000 IU/die of beta-interferon for 15 days, were submitted to vulvar biopsy before and 2-5 months after medical treatment. The frozen sections obtained were assayed with the following monoclonal antibodies: OKT 4 (T helper lymphocytes), OKT 8 (T suppressor lymphocytes), OKB 7 (B lymphocytes) and S-100 protein (Langerhans cells). Using a morphometric evaluation, the average number of both intraepithelial and stromal lymphocyte subsets and of the intraepithelial Langerhans cells was assessed. In all the biopsies preceeding the medical treatment we found a low number of T helper lymphocytes both in the epithelium and stroma, with inversion of T4/T8 lymphocyte ratio and rare presence of Langerhans cells. In patients with a good therapeutic response (50-100% of condyloma reduction) we observed an increase in intraepithelial T4 lymphocytes and a decrease in both intraepithelial and stromal T8 lymphocytes. In cases with persistent disease after therapy, the histological pattern was similar to that observed in the first biopsy, with the exception of a significant increase in the average number of Langerhans cells. Our data correlate the clinical response to the immunotherapy with the histology of lymphocyte subsets in the vulvar condylomata. The increase in Langerhans cells observed in patients with negative response may be interpreted with a probable inability of these cells to promote the immune reaction.


The quality of the Pap smear.

The quality of the Pap smear. Three methods of cervical Pap smear have been studied: the classical spatula, the combination of spatula and cytobrush, and the Cervex-Brush. Thirty-two percent of the spatula smears did not provide endocervical cylinder cells. Significantly better results can be achieved by performing the smear with a combination of spatula and cytobrush (11% without cylinder cells), or with Cervex-Brush (15% without cylinder cells). Cervical smears using a spatula alone are therefore discouraged.


Postnatal width changes in the internal structures of the human mandible: a longitudinal three-dimensional cephalometric study using implants. This paper presents case-specific quantitative evidence of the systematic lateral displacement of metallic implants in the mandibles of treated and untreated human subjects between the ages of 8.5 and 15.5 years. This evidence appears to be consistent with the inference of small, but systematic increases in distance between the internal structures of the two sides of the osseous mandible during growth. Such a conclusion, however, is inconsistent with traditional beliefs that the internal structures of the mandibular symphysis fuse at the midline during the first post-natal year and remain dimensionally constant thereafter. We recently published evidence of statistically significant transverse displacement of metallic implants in the mandibular body region for 12 of 28 subjects for whom longitudinal data were available. Of the twelve subjects for whom statistically significant changes were observed, widening occurred in eleven cases and narrowing in one. Matching data are now available on concurrent ramus changes for 22 of the same 28 subjects, including 11 of the 12 for whom statistically significant width changes had previously been noted in the body region. In eight of these 11 subjects, statistically significant widening in the ramus region was also observed. No subject had statistically significant widening in the ramus region without also having statistically significant widening in the body region. No subject had statistically significant trans-ramus narrowing.


Long-term effect of rapid maxillary expansion studied in one patient with the aid of metallic implants and roentgen stereometry. The articulatory displacement of maxillary bones during and after rapid maxillary expansion (RME) was studied with metallic implants and roentgen stereometry (RSA) for 3653 days in a girl aged 12 at start of treatment. She had a narrow upper dental arch with anterior crowding and a normal incisor relationship, and a normal sagittal molar relationship with bilateral cross-bite. Three implants were inserted in each maxillary bone and they remained stable in the bones during the 10-year observation period. In the 3-D analysis of the articulatory displacement, the left maxillary bone was studied in relation to the right bone in three periods: RME (23 days), retention (108 days) and follow-up (3522 days). Extensive relapse of rotations as well as translations was found and the long-term effect of RME was limited. In our opinion the relapse was caused mainly by the resistance to deformation from circum-maxillary sutures and surrounding soft tissue matrix, and inadequate bone formation in the involved sutures. As is generally known in clinical oral orthopaedics, changes obtained by short-term simple mechanical interference with a complex biological system tend to reverse spontaneously. Thus, the rationale for RME treatment may be seriously questioned.


A TEM analysis of tissue channels in normal and orthodontically tensioned rat molar periodontal ligament. This investigation tested the hypotheses that (1) tissue channels (TC) exist in normal periodontal ligament (PDL) between the cervical and apical zones, and (2) orthodontic tooth tension alters their number and distribution within this region. A continuous 1.0 N tension was applied to the maxillary first molar for 30 minutes and ionic tracer precipitate used to analyse TC in unstained TEM sections. In normal PDL, the mean number of tissue channels (MNTC) was 0.10 +/- 0.01/micron 2 in the 0-2-microns PDL zone extending from the vessel wall, 0.09 +/- 0.02/micron 2 in the 2-4-microns zone, and 0.06 +/- 0.02/micron 2 in the 4-6 microns zone. Differences were not statistically significant. Extrusion increased the MNTC to 0.28 +/- 0.01/micron 2, 0.20 +/- 0.02/micron 2, and 0.16 +/- 0.02/micron 2, in the 0-2-, 2-4- and 4-6-microns zones, respectively (P < 0.001). For normal PDL in the tooth, middle and bone circumferential thirds the TC distribution were even. In the tensioned PDL, TC in the circumferential tooth third (0.20 +/- 0.02/micron 2), middle third (0.19 +/- 0.01/micron 2), and bone third (0.23 +/- 0.02/micron 2) increased significantly (P < 0.001) from normal ligament. The total increase in experimental MNTC was associated mainly with the post-capillary-sized venules, venous capillaries, and arterial capillaries. With progression from the cervical to apical regions the MNTC in control PDL failed to significantly fit a quadratic regression pattern. By contrast, tensioned PDL showed a marked regression pattern (P < 0.001) indicating a reduction in MNTC with vertical depth.(ABSTRACT TRUNCATED AT 250 WORDS)


Periodontal conditions around tipped and upright molars in adults. An intra-individual retrospective study. In 69 individuals from a randomized epidemiological material comprising 450 adults, an intra-individual comparison of the periodontal condition of 73 mesially tipped molars (30 degrees or more to a line perpendicular to the occlusal plane) and contralateral upright molars was made. The alveolar bone level mesially and distally of each tooth was registered in periapical radiographs. The occurrence of plaque, gingivitis and probeable pocket depths of 4 mm or more mesially and distally of each tooth was registered. No significant differences between tipped and upright molars could be found, regardless of the variable tested. The clinical implications of the findings are discussed from an orthodontic as well as a periodontal and prosthetic point of view.


The analysis of profiles using curvature analysis. The difficulties of localizing landmarks using standardized lateral skull radiographs has been acknowledged. A method is described for producing an objective way of identifying landmarks on the facial profile leading to a useful segmentation and quantitative description of the contours and features of the face. The method uses scale space filtering techniques and curvature analysis, first employed in pattern recognition. The method has been used on two groups: a random sample of twelve-year-old females and a sample of 10 patients with a normal facial morphology who had cephalometric X-rays taken at 5, 9, 13, 16, and 20 years. It demonstrated that the shape of each of the curves is similar in the first group except in the mouth region. The growth study produced meaningful data on the growth of the face.


On the prediction of dentist-evaluated patient compliance in orthodontics. The aim of the present study was to determine to what degree social and psychological patient variables can predict orthodontic co-operation evaluated by dentists 3 and 6 months after the beginning of treatment. The subjects were 94 patients from seven orthodontic practices. They received a questionnaire with four subscales: impulsiveness, dominance, anxiety, and orthodontic attitudes. Compliance was assessed by an 11-item instrument based on the studies of Slakter et al. (1980). None of the social indices could predict co-operation, but the psychological scales for orthodontic attitudes, impulsiveness and dominance showed a significant relationship to later co-operation. The combination of all psychological variables (regression equation) could explain co-operation 3 months later to 12.1 per cent and to 16.8 per cent 6 months later. The implications for psychological guidance in orthodontics and future research are discussed.


The ranking of facial attractiveness.

The ranking of facial attractiveness. A method of assessing facial attractiveness is described in which facial photographs were ranked by adults in order from the most to the least attractive. The rankings of a group of normal 10-year-old children were compared to those given to a group of similarly aged patients with repaired clefts. Most previous methods have grouped patients into categories, but this tends to obscure individual differences in facial attractiveness: patients with small differences in appearance are generally placed in the same group. In the ranking technique described in this paper these individual differences were not obscured. Those individuals with repaired clefts were consistently judged as being less attractive than those in the normal group. It is suggested that this method could be further developed to assess the cosmetic benefit produced by treatment of facial deformity.


The effect of treatment of skeletal open bite with two types of bite-blocks. The treatment of anterior skeletal open bite was studied in two groups of children. The children of one group wore a removable spring-loaded bite-block in the lower jaw for one year. The bite-block exerted an intrusive force on the upper and lower posterior teeth. The children of the other group were treated for 3 months with bite-blocks with repelling magnets. These bite-blocks were cemented on the posterior teeth of both jaws. The effects of treatment were monitored by measurement of the bite-force (group with spring bite-blocks only), by electromyographic recording of the activity of the temporal and masseter muscles, and by X-ray cephalometry. Recordings were made before, during, and at the end of the treatment, and at a follow-up observation. The bite-force increased during the first months of treatment, but was then unchanged. The activity of the masseter muscle during maximal bite also increased in the first part of the period of treatment with a spring bite-block. In the group treated with magnetic bite-blocks, there was an increase in the resting activity of the masseter muscle and in the chewing activity of the anterior temporal muscle. The effects of the treatment on bite and facial morphology were less marked in the group with spring bite-blocks than in the group with magnetic bite-blocks, with an average improvement of the overbite of 1.3 mm with the spring bite-block therapy. In the group with magnetic bite-blocks, the average improvement in overbite was 3 mm. This was thought to be due to anterior rotation of the mandible and increased eruption of the incisors. The mandibular rotation was a result of intrusion of the upper and lower posterior teeth and possibly also increased mandibular growth. A follow-up of the cases treated with magnetic bite-blocks revealed a tendency for the beneficial effects of the treatment to relapse which possibly could be counteracted by a long phase of active retention.


Studies on the solubilization of the water-insoluble fraction from human lens and cataract. Studies were carried out comparing the ability of urea extraction and sonication to solubilize the water-insoluble (WI) protein fraction from human lens tissue. Sonication and urea extraction were able to solubilize greater than 80% of the insoluble protein whether whole lenses or lens nuclei were used. This was true for normal lens and +1 cataracts; however, only 60% solubilization was obtained with the WI fraction from more advanced cataracts. Equal aliquots of a WI fraction from both pooled normal and pooled cataract lens nuclei were solubilized with and without reducing agents. The addition of dithiothreitol (DTT) had no significant effect on solubilization of the normal lens WI fraction. DTT did increase the protein solubilized from the cataract WI fraction by 30% with urea extraction; however, no increase was seen with sonication. When sodium borohydride was used as the reducing agent, essentially the same results were obtained. The solubilized protein populations were identical by SDS-PAGE and amino acid analysis. The addition of reducing agents had no effect on the amino acid content of the solubilized proteins with the single exception of lysine. This amino acid was markedly decreased in the proteins extracted in the presence of 40 mM sodium borohydride, but not with DTT. These data suggest that the borohydride not only increased the amount of protein solubilized, but likely also stabilized glycated lysine residues during the acid hydrolysis. Therefore, sonication readily provides a soluble preparation of the WI proteins from normal and cataract lens nuclei without the need for denaturing agents, however, disulfide-linked and lysine modified crystallins were best solubilized with urea.


Thrombin stimulates inositol phosphate formation, intracellular calcium fluxes and DNA synthesis in cultured fetal human non-pigmented ciliary epithelial cells. Thrombin at concentrations as low as 20 pM (0.002 U ml-1) was found to stimulate inositol phosphate levels in cultured human non-pigmented ciliary epithelial cells. Several other proteases, including trypsin and plasmin, had little or no effect, of several protease inhibitors tested, only those with specificity for thrombin blocked the effect. Studies with active site-blocked thrombin suggested that the esterolytic active site of thrombin is required for inositol phosphate stimulation, while gamma-thrombin, which has reduced binding affinity to fibrinogen also showed reduced effectiveness in stimulating inositol phosphates. In the presence of 10 mM LiCl, thrombin stimulated inositol monophosphate, inositol bisphosphate and inositol trisphosphate formation, with a prolonged rise of the first and transient early rises in the latter two species. Thrombin also elevated intracellular Ca2+ levels as measured with the fluorescent calcium probe, indo-1-AM. This elevation could be blocked by prior addition to cells of the thrombin inhibitor, hirudin, and was dependent upon extracellular Ca2+ for the maintenance of an elevated level in the presence of thrombin. Incorporation of thymidine into DNA in confluent cultures was also stimulated by thrombin, with a four-fold increase in incorporation at 35 hr in thrombin-treated cells compared to controls. The half-maximal concentration for this process was 0.25 U ml-1. Pretreatment with 100 ng ml-1 pertussis toxin greatly reduced the thrombin effect, which is consistent with a role for a G-protein in stimulation of DNA synthesis by thrombin.


Ca2+/Na+ exchanger and Na+,K+ 2Cl- cotransporter in lens fiber plasma membrane vesicles. When the Ca(2+)-sensitive fluorescent probe, Fura-2, or the Na(+)-sensitive probe, SBFI, in their cell permeable forms or the Cl(-)-specific probe, SPQ, were incubated with plasma membrane vesicles prepared from dogfish and bovine lenses fibers, there was a selective accumulation of the ion-specific probes within the vesicles. The SBFI and Fura-2 fluorescent excitation ratios of 340 nm to 380 nm (em: 505 nm) in the presence of an outwardly-directed Na+ gradient across the vesicles membrane, indicate that the influx of Ca2+ is increased by 152.5% and 147.4% for dogfish and bovine vesicles, respectively. The Na+ influx into the vesicles is also enhanced by 154.1% for dogfish and 149.1% for bovine lens when an outwardly-directed Ca2+ was present. This stimulation is not affected when either 50 microM valinomycin, or 50 mM K+ is present. The activity of this bidirectional Ca2+/Na+ exchanger could be inhibited by 100 microM bepridil or 200 microM La3+. The entrance behaviour of Cl- as monitored by the SPQ fluorescent signal indicates that, the Cl- influx is Na(+)-dependent. The Cl- influx is stimulated 152.8% and 187.6% for dogfish and bovine lens, respectively, when an inwardly-directed Na+ gradient is present, and is further enhanced when a K+ gradient is also present. The stoichiometry of Na+ to Cl- entering the vesicles was 1:2. This Na+,K+ 2Cl- cotransporter is not affected by 20 microM valinomycin or 50 mM K+. However, the transporter is completely inhibited by 50 microM furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)


Ultrastructural changes of the retina and the retinal pigment epithelium in Briard dogs with hereditary congenital night blindness and partial day blindness. The offspring of two Briard dogs (brother and sister) with congenital, clinically stationary night blindness showed an aggravation of the disease with severe impairment of day vision in addition to night blindness. This ultrastructural study was performed on four such second generation puppies at the age of 4 months. The neuroretina and retinal pigment epithelium (RPE) from four locations were studied: the central area (immediately temporal to the optic disc); the centre of the tapetal area; the upper periphery (border of tapetal area); and the lower periphery (non-tapetal area). The RPE showed large inclusions, seemingly lipid in nature, mainly in the central and tapetal areas of the retina. Small, membrane bound, electron-dense inclusions were scattered in the RPE cytoplasm in all areas examined. The small inclusions were found to be less numerous in normal than in affected dogs and may be lysosomal in nature. Forty to fifty percent of the rod outer segments in the tapetal area showed disorientation of the disc membranes, whereas the corresponding figures were 20-40% in the central and lower peripheral areas and 6-25% in the upper peripheral area. No structural abnormalities were found in the rod inner segments or synaptic bodies. The cones were better preserved. The inner retina appeared normal. These electron microscopic findings seem to correspond to a previously published electrophysiologic evaluation, indicating a defective and delayed rod function (virtually no scotopic a- and b-waves), a better preserved cone function (photopic flicker responses present, although reduced) and impaired RPE activity (a prominent, slow negative potential of long latency at the site of the c-wave). It appears that these Briard dogs, showing structural changes of the rod outer segments in addition to pigment epithelial inclusions, mainly located in the posterior pole, comprise a pigment epitheliopathy and retinopathy morphologically different from other hereditary canine retinopathies that have been described earlier in the literature and different from animal models of congenital night blindness.


Experimental autoimmune posterior uveitis accompanied by epitheloid cell accumulations (EAPU). A new type of experimental ocular disease induced by immunization with PEP-65, a pigment epithelial polypeptide preparation. Purified retinal pigment epithelial cells of bovine eyes have been fractionated by a series of buffer and detergent extractions. The electropherogram of the buffer-insoluble, Triton X-100-soluble fraction (RPE-TS) exhibits a major polypeptide band of M(r) 65 kDa and a variety of minor components. Electrophoretically purified 65 kDa-band protein (PEP-65) is immunologically unrelated to the known uveitogenic photoreceptor proteins, to other neural retina proteins, and to PEP-X, the RPE-melanin-bound uveitogenic antigen. An immunocytochemical study of eye tissues suggests that it is exclusively located in the RPE. Immunization of Lewis rats with PEP-65 or affinity-purified RPE-TS induces a new type of ocular disease: experimental autoimmune posterior uveitis accompanied by epitheloid cell accumulations (monocytes) adjacent to the RPE (EAPU). The disease starts 9 days after immunization, provided that pertussis toxin is used as co-adjuvant. The first clinical signs are transient flare and cells in the anterior chamber. Choroiditis develops, and epitheloid cells accumulate focally along one or both sides of the Bruch's membrane-RPE layer. Such foci resemble, in some respects, Dálen-Fuchs nodules which occur in human sympathetic ophthalmia. Areas of inflammation are frequently localized in the chorioretinal periphery adjacent to the pars plana. Vitreous cell infiltration is the most prominent clinical feature of EAPU. During at least 2 months, extending chorioretinal areas containing epitheloid cell collections remain while the adjacent photoreceptor cells sometimes disappear without being invaded by these cells. Retinal vasculitis is seldomly observed and pinealitis is absent. EAPU has the latter feature in common with PEP-X-induced experimental autoimmune anterior uveitis (EAAU). The two diseases differ from the various photoreceptor antigen-induced forms of EAU where pinealitis and inflammation of the neural retina are prominent features. However, just as in EAU and EAAU, EAPU can be adoptively transferred, and is inhibited by cyclosporin treatment suggesting T-cell dependency.


Photomembrane turnover in frog retina: light intensity and spectral correlates. Light regulates membrane turnover in vertebrate rod photoreceptor cells. Rods shed membrane-filled tips immediately after light onset, with light inhibiting the dark priming phase but initiating the light induction phase. This study examines the intensities and wavelengths of light that control these two shedding requirements, and demonstrates unexpected situations where red or dim lights are simultaneously dark to the dark priming mechanism and light to the light induction process. Since shedding takes place immediately following darkness we asked if dim or red light could substitute for true darkness and dark prime the retinas: our results confirm this. White light, less than 0.7 microE m m-2 sec-1 (0.15 W m2 or 40 lx), allows dark priming, and even 15 microE m-2 sec-1 of red fluorescent light dark primes as effectively as true darkness. Conversely, bright white light and wavelengths from 480 to 560 nm inhibit dark priming, implying that dark priming inhibition is a photopic mechanism transduced by photopigment in the 502-cone. We also asked if dim or red light could induce shedding, substituting for the bright light usually employed: again, the results confirm thus. White light as dim as 0.15 microE m-2 sec-1 induces shedding and red light is an effective light trigger. This light induction is initiated at all wavelengths tested (420-640 nm), with a maximum effect between 540 and 600 nm. Finally, we find that retinas shed continuously in red or dim white light. These lights substitute both for the darkness necessary for dark priming and for the light of light induction, extending shedding from the 20 min dark-light transition period to hours or days. We also find that the dim, red light of natural dawn is as effective a shedding stimulus as the sudden onset of bright laboratory light.


Potassium currents from isolated frog lens epithelial cells. Using the perforated patch version of whole-cell recording, we have measured currents from isolated frog lens epithelial cells. Three types of currents were seen. A time-independent outwardly rectifying potassium current was identified that sets the resting voltage. This potassium current differs significantly from any of the potassium currents recorded with the whole-cell technique in mammalian lens epithelial cells. In addition to the potassium current, the two other currents present were both outwardly rectifying: one was time-independent while the other showed distinct activation.


Protein-thiol mixed disulfides in human lens. Protein-thiol mixed disulfide formation has been implicated as a possible mechanism for the protein-protein aggregation in cataractogenesis. Previously we have found that two species of thiols are bound to proteins: GSH (PSSG) and cysteine (PSSC). In this study we found these molecules are ubiquitous in animal lenses with the highest levels in human, dog and rat, and lowest in monkey. However, the relative amount of PSSG to PSSC is quite different in each animal species. The ratio of PSSG/PSSC was 1/10 in rat lens, 4/1 in human and dog lenses and 2/1 in monkey lens. We also studied the effect of aging on the protein-thiol mixed disulfide levels in human donor lenses between 3 months and 88 years. Lens GSH levels were inversely related to age, similar to earlier reports, but PSSC levels increased linearly with age. PSSG levels showed a triphasic pattern with an initial sharp and linear increase from a low content in infants to a highest level at age 20; fell back about 50% to a new steady state level that was maintained for four more decades; finally, above 60 years, the levels in some lenses were two to three-fold higher while some lenses remained at the same low value. PSSC in human lens appeared to concentrate in the nuclear region and in the water insoluble proteins while PSSG was more evenly distributed. Besides the aging effect on the protein-thiol mixed disulfides, oxidative stress also potentiated protein modification in the human lens.(ABSTRACT TRUNCATED AT 250 WORDS)


C57BL/6J-vit/vit mouse model of retinal degeneration: light microscopic analysis and evaluation of rhodopsin levels. The C57BL/6J-vit/vit mouse is a newly described model of retinal degeneration in which photoreceptor cells die over the course of a year and the retinal pigment epithelium is unevenly pigmented. The present study utilized histological and biochemical techniques to assess the progression of the retinal degeneration in the vit/vit mouse ages 2 weeks to 8 months. Results of systematic morphometric evaluation indicated that the inner nuclear and plexiform layers of the retina are similar in thickness to age-matched C57BL/6J controls, but the outer plexiform layer is significantly thinner by 4 months. Rows of photoreceptor cells are lost at a rate of about one per month beginning at 2 months of age. By 8 months, the photoreceptor cell nuclei have diminished to only two to three rows. Inner segments of the vit/vit retina are similar in length to controls. Outer segments separate from the RPE during the first 2 months, they seem to be elongated at 2-3 months, but become severely disrupted past 4 months. Beginning at about 5 months, numerous darkly-staining cells resembling photoreceptor cell nuclei are observed in the area of the inner and outer segments and the subretinal space. Spectrophotometric analysis of rhodopsin indicated similar levels in vit/vit and controls at 6 weeks but a 50% reduction by 22 weeks. At 46 weeks, the level of rhodopsin in the mutant animal was less than 0.1 nmol per retina. The loss of rhodopsin in the vit/vit retinas correlated strongly with the decreasing number of rows of photoreceptor cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantitative analysis of neurons and glial cells in the rat somatosensory cortex, with special reference to GABAergic neurons and parvalbumin-containing neurons. The number of neuronal and glial cells in the rat somatosensory cortex (barrel area) has been estimated by a stereological method, the disector, using pairs of toluidine blue-stained, plastic-embedded 0.5-microns-thick sections, 1.5 microns distant from each other. Chemical properties of those disector-counted cells were further analyzed by postembedding immunocytochemical methods on adjacent semithin sections. Thus we were able to analyze quantitatively number, distribution, and proportion of five cell types: (1) gamma-aminobutyric acid-(GABA)-negative neurons; (2) GABA-like immunoreactive (GABA-LIR) neurons; (3) a specific calcium-binding protein parvalbumin-immunoreactive (PV-IR) neurons, a subpopulation of GABA-LIR neurons; (4) S-100 beta-LIR glial cells (astrocytes); and (5) S-100 beta-negative glial cells (oligodendrocytes and microglia). The densities of total cells, glial cells, and neurons in the rat somatosensory cortex were 85.4 +/- 10(3)/mm3, 30.5 x 10(3)/mm3, and 54.9 x 10(3)/mm3, respectively. Of all neurons 25% and 14% were GABA-LIR and PV-IR, respectively; all PV-IR neurons are GABA-LIR, and thus about 54% of GABA-LIR neurons are PV-positive. The number of total cells under a unit surface area of 1 mm2 through the thickness of the somatosensory cortex was 171.6 x 10(3); the number of neurons and glial cells were 110.2 x 10(3) and 61.4 x 10(3), respectively. There were 27.7 x 10(3) GABA-LIR neurons and 15.0 x 10(3) and 12.7 x 10(3) PV-IR neurons and PV-negative GABA-LIR neurons, respectively. The laminar distribution of each group of cells shows prominent differences, indicating that the cellular composition was different from layer to layer. The density of GABA-LIR neurons was highest in layer IV. The numerical density of PV-IR neurons was 2-4 times higher in layer IV than in layers II/III, V, and VI, whereas that of PV-negative GABA-LIR neurons was almost constant throughout the layers.


Functional topography of cat primary auditory cortex: representation of tone intensity. The neuronal response to tones as a function of intensity was topographically studied with multiple-unit recordings in the primary auditory cortex (AI) of barbiturate-anesthetized cats. The spatial distribution of the characteristics of rate/level functions was determined in each of three intensely studied cases and their relationship to the distribution of spectral parameters (sharpness of tuning and responses to broadband transients) in the same animals was determined. The growth of the high-intensity portion of rate/level functions was estimated by linear regression. Locations with monotonically growing high-intensity portions were spatially segregated from locations with nonmonotonic rate/level functions. Two noncontiguous areas with a high degree of nonmonotonicity were observed. One was located at the dorsoventral center of AI, and a second in the dorsal third of AI. The more ventral aggregate of high nonmonotonicity coincided with the region of sharp frequency tuning. The stimulus levels that produced the highest firing rate (strongest response level, SRL) at any sampled location ranged from 10 to 80 dB sound pressure level (SPL). Several spatial aggregates with either high or low SRLs were observed in AI. The region of sharpest tuning was always associated with a region of low SRLs. The response threshold to contralateral tones at the characteristic frequency (CF) ranged from -10 dB SPL to 85 dB SPL with the majority between 0 and 40 dB SPL. The spatial distribution of response thresholds indicated several segregated areas containing clusters with either higher or lower response thresholds. The correlation of response threshold with integrated bandwidth and transient responses was only weak. Low- and high-intensity tones of the same frequency are represented at different locations in AI as judged by the amount of evoked neuronal activity and are largely independent of the frequency organization. The spatial distribution of locations with high monotonicity and low strongest response levels were aligned with the organization of the integrated excitatory bandwidth and covaried with the response strength to broadband stimuli.


Nystagmus induced by electrical stimulation of the vestibular and prepositus hypoglossi nuclei in the monkey: evidence for site of induction of velocity storage. Electrical stimulation of the vestibular nuclei (VN) and prepositus hypoglossi nuclei (PPH) of alert cynomolgus monkeys evoked nystagmus and eye deviation while they were in darkness. At some sites in VN, nystagmus and after-nystagmus were induced with characteristics suggesting that velocity storage had been excited. We analyzed these responses and compared them to the slow component of optokinetic nystagmus (OKN) and to optokinetic after-nystagmus (OKAN). We then recorded unit activity in VN and determined which types of nystagmus would be evoked from the sites of recording. Nystagmus and eye deviations were also elicited by electrical stimulation of PPH, and we characterized the responses where unit activity was recorded in PPH. Horizontal slow phase velocity of the VN "storage" responses was contralateral to the side of stimulation. The rising time constants and peak steady-state velocities were similar to those of OKN, and the falling time constants of the after-nystagmus and of OKAN were approximately equal. Both the induced after-nystagmus and OKAN were habituated by stimulation of the VN. When horizontal after-nystagmus was evoked with animals on their sides, it developed yaw and pitch components that tended to shift the vector of the slow phase velocity toward the spatial vertical. Similar "cross-coupling" occurs for horizontal OKAN or for vestibular post-rotatory nystagmus elicited in tilted positions. Thus, the storage component of nystagmus induced by VN stimulation had the same characteristics as the slow component of OKN and the VOR. Positive stimulus sites for inducing nystagmus with typical storage components were located in rostral portions of VN. They lay in caudal ventral superior vestibular nucleus (SVN), dorsal portions of central medial vestibular nucleus (MVN) caudal to the abducens nuclei and in adjacent lateral vestibular nucleus (LVN). More complex stimulus responses, but with contralateral after-nystagmus, were induced from surrounding regions of ventral MVN and LVN, rostral descending vestibular nucleus and the marginal zone between MVN and PPH. Vestibular-only (VO), vestibular plus saccade (VPS) and tonic vestibular pause (TVP) units were identified by extracellular recording. Stimulation near type I lateral and vertical canal-related VO units elicited typical "storage" responses with after-nystagmus in 23 of 29 tracks (79%). Stimulus responses were more complex from the region of neurons with oculomotor-related signals, i.e., TVP or VPS cells, although after-nystagmus was also elicited from these sites. Effects of vestibular nerve and nucleus stimulation were compared.(ABSTRACT TRUNCATED AT 400 WORDS)


Motor cortical activity in a memorized delay task. Two rhesus monkeys were trained to move a handle on a two-dimensional (2D) working surface in directions specified by a light at the plane. They first captured with the handle a light on the center of the plane and then moved the handle in the direction indicated by a peripheral light (cue signal). The signal to move (go signal) was given by turning off the center light. The following tasks were used: (a) In the non-delay task the peripheral light was turned on at the same time as the center light went off. (b) In the memorized delay task the peripheral light stayed on for 300 ms and the center light was turned off 450-750 ms later. Finally, (c) in the non-memorized delay task the peripheral light stayed on continuously whereas the center light went off 750-1050 ms after the peripheral light came on. Recordings in the arm area of the motor cortex (N = 171 cells) showed changes in single cell activity in all tasks. In both delay tasks, the neuronal population vector calculated every 20 ms after the onset of the peripheral light pointed in the direction of the upcoming movement, which was instructed by the cue light. Moreover, the strength of the population signal showed an initial peak shortly after the cue onset in both the memorized and non-memorized delay tasks but it maintained a higher level during the memorized delay period, as compared to the non-memorized task.(ABSTRACT TRUNCATED AT 250 WORDS)


Striatal neuronal activity during the initiation and execution of hand movements made in response to visual and vibratory cues. Recordings were obtained from 146 neurons in the neostriatum of rhesus monkeys while they performed wrist movements in response to visual and vibratory cues. Of these, 75 putamena nd 29 caudate neurons exhibited changes in firing rate that were temporally related to the onset of the wrist movements and that began prior to movement onset. This premovement activity (PMA) usually was directionally specific, in that the magnitude or direction of change in firing rates was different during flexion trials as compared to trials involving wrist extension. PMA onset usually preceded movement onset by more than 100 ms and in most instances preceded the average onset of task-related changes in electromyographic (EMG) activity in muscles of the wrist and forelimb. For most neurons, the changes in neuronal activity that began prior to movement were maintained during movement execution. However, approximately one-third of the neurons that exhibited PMA changed their firing rate in the opposite direction, relative to their PMA and to their baseline rate of activity, once the movement began. Several other neurons either exhibited PMA only or they altered their discharge rates during movement execution but did not exhibit PMA. These observations suggest that, despite the close temporal relationship between the onset of PMA and the onset of wrist movement, the neuronal mechanisms mediating the PMA may differ from those that occur during movement execution. The PMA onset of neostriatal neurons occurred earlier in visually cued than in vibratory cued trials. These differences were statistically significant only for flexion trials, however, in which movements were made against a load and in the same direction as the palmar vibratory stimulus. For trials involving wrist extension, PMA onsets for visually cued as compared with vibratory cued trials were not statistically different. These findings contrast with data obtained previously from somatosensory cortical neurons during performance of the same behavioral task. On average, PMA in the putamen began earlier, relative to movement onset, than it did in the somatosensory cortex. Moreover, in the somatosensory cortex, PMA onset occurred earlier in vibratory cued than in visually cued trials, irrespective of movement direction (Nelson 1988; Nelson and Douglas 1989). For putamen neurons, but not for caudate or cortical neurons, the onset of PMA also occurred significantly earlier during extension trials than flexion trials, irrespective of the modality of the "go-cue".(ABSTRACT TRUNCATED AT 400 WORDS)


Head movement propensity.

Head movement propensity. In studies of human eye-head coordinated saccadic gaze shifts, different laboratories have found greatly different magnitudes of head movements for a given amplitude of gaze shift (head movement gain). The present study was conducted to examine why, and to quantify volitional head movements. Fixation/target lights were located at 20 degrees and 40 degrees on either side of a central light. There were two tasks or modes. In the non-aligned mode, gaze fixation (first light) was followed by a gaze step to the target (second light) accurately and quickly. In the head-aligned mode, the head was aligned within 3 degrees of the first fixation light (i.e., initial starting position) before the step sequence began. In both non-aligned and head-aligned modes, subject instructions pertaining to the second target light concerned only gaze; there was no requisite head position. The head movement propensity of nine subjects was ranked according to the mean gain (head/target amplitude) of two 40 degree jumps (0-40 degrees and -20 to +20 degrees) in the non-aligned mode. This ranking method clearly identified extreme head-movers and non-movers. The moderate movers were further characterized by three additional criteria, derived by comparing the gains in different jumps, which varied in starting position and amplitude. First, when the two 40 degree jumps were compared, typically the gain of non-movers was less in the symmetric jump (-20 to +20 degrees) with the gain of the head-movers was greater in the symmetric jump. Second, in the head-aligned mode the gain of non-movers progressively increased when the starting position was progressively moved eccentrically, whereas the gain of head-movers increased only slightly, if at all. Third, when the gains of two symmetric (40 degrees and 80 degrees) jumps were compared, the head-movers consistently had opposite trends from non-movers. These three comparative criteria and the initial criterion together define head movement propensity. To explain the above observations, three effects are proposed. First, a "midline-attraction" effect causes resistance to movement away from the midline in non-movers and an increase in movement amplitude if the jump starts eccentrically. Second, a "resetting" effect occurs when the eccentricity of the jump is varied; the stopping position is reset closer to the target. Third, an "awareness/arousal" effect increases the gain in the head-aligned mode due to the intrinsic nature of the alignment procedure.(ABSTRACT TRUNCATED AT 400 WORDS)


Metabolic brain pattern of sustained auditory discrimination. Positron emission tomography of [18F]-2-fluorodeoxyglucose was used to assess the functional brain activity of normal subjects while performing auditory discrimination (CPT), while receiving an identical set of tones as in CPT, but with the instructions that they were background noise, or while at rest. The present study: (1) confirms earlier findings of an association between the functional activity of the right midprefrontal cortex and the performance of auditory discrimination, (2) localizes this increase in right prefrontal cortex activity to the middle prefrontal gyrus; and (3) provides a framework of specific testable hypotheses for the evaluation of the importance of certain limbic and paralimbic areas in the biological determination of sustained attention to be addressed in future studies. The framework accounts for the now confirmed finding that the middle cingulate has lower metabolic activity in CPT than at rest, and new findings of alterations in temporal lobe processing of tones in response to attention.


Feedforward postural stabilization in a distal bimanual unloading task. The aim of the present study was to investigate postural adjustments and positional stability in a bimanual unloading task, involving essentially the index finger, in order to test whether proactive adjustments are also observed in distal body segments. A second goal of the study was to evaluate the concept of a central command that would be responsible for coupling movement and posture. The positional disturbance of the right load-bearing index finger of healthy human subjects was studied under two types of manipulations: passive, i.e., imposed, unloading and active unloading, by the subject's left index finger. It was found that, in such a distal task, positional stabilization of the load-bearing finger was much better (by a factor of 6) in the active situation than the passive situation. This improvement was greater than previously reported for a proximal task. An electromyogram (EMG) analysis of the mostly implicated dorsal interosseous muscles revealed a typical unloading reflex in the passive situation (reactive mode) and a suppression of EMG before unloading onset in the active situation (proactive mode). Averaged records showed an almost perfect synchronization between the EMG suppression in the load-bearing interosseous muscle and the onset of the EMG burst of the unloading index finger. A trial-by-trial analysis, however, revealed a considerable scatter in intervals of the two EMG events, with a tendency of the activity burst in the left finger to occur slightly before the suppression of EMG in the load-bearing muscle. No positive correlation was found between the precision of synchronization (intervals near zero time) and the accuracy of performance, i.e., positional stability of the unloaded finger. Although the trial-by-trial variability was large, it is suggested that at least some of this variability is caused by a nonsteady state of motoneuronal excitability. In view of the low-pass property of the muscle, the observed variability in synchronization may be sufficiently precise to maintain the hypothesis of a central temporal coupling of the events in the two hands through a common command. However, the lack of a correlation between the degree of synchronization and the performance in stability argues rather in favor of separate commands to the two hands that select the parameters in the spatial domain. Finally, an intermanual EMG or torque analysis is proposed that might be useful in assessing the accuracy in goal achievement, i.e., the maintenance of a stable finger position in spite of the "internal" perturbation.


Translational head movements of pigeons in response to a rotating pattern: characteristics and tool to analyse mechanisms underlying detection of rotational and translational optical flow. Pigeons freely standing in the centre of a two-dimensionally textured cylinder not only rotate but also laterally translate their head in response to the pattern sinusoidally oscillating or unidirectionally rotating around their vertical axis. The translational head movement dominates the response at high oscillation frequencies, whereas in a unidirectionally rotating drum head translation declines at about the same rate as the rotational response increases. It is suggested that this is a consequence of charging the 'velocity storage' in the vestibulo-ocular system. Similar to the rotational head movement (opto-collic reflex), the translational head movement is elicited via a wide-field motion sensitive system. The underlying mechanism can be described as vector integration of movement vectors tangential to the pattern rotation. Stimulation of the frontal visual field elicits largest translational responses while rotational responses can be elicited equally well from any azimuthal position of a moving pattern. Experiments where most of the pattern is occluded by a screen and the pigeon is allowed to view the stimulus through one or two windows demonstrate a short-range inhibition and long-range excitation between movement detectors that feed into the rotational system. Furthermore, the results obtained from such types of experiments suggest that the rotational system inhibits the translational system. These mechanisms may help the pigeon to decompose image flow into its translational and rotational components. Because of their translational response to a rotational stimulus, it is concluded, however, that pigeons either generally cannot perfectly perform the task or they need further visual information, like differential image motion, that was not available to them in the paradigms.


Reticulospinal and reticuloreticular pathways for activating the lumbar back muscles in the rat. These experiments tested hypotheses about the logic of reticulospinal and reticuloreticular controls over deep back muscles by examining descending efferent and contralateral projections of the sites within the medullary reticular formation (MRF) that evoke EMG responses in lumbar axial muscles upon electrical stimulation. In the first series of experiments, retrograde tracers were deposited at gigantocellular reticular nucleus (Gi) sites that excited the back muscles and in the contralateral lumbar spinal cord. The medullary reticular formation contralateral to the Gi stimulation/deposition site was examined for the presence of single- and double-labeled cells from these injections. Tracer depositions into Gi produced labeled cells in the contralateral Gi and Parvocellular reticular nucleus (PCRt) whereas the lumbar injections retrogradely labeled cells only in the ventral MRF, indicating that separate populations of medullary reticular cells project to the opposite MRF and the lumbar cord. In the second series of experiments the precise relationships between the location of neurons retrogradely labeled from lumbar spinal cord depositions of the retrograde trace, Fluoro-Gold (FG) and effective stimulation tracks through the MRF were examined. The results indicate that the Gi sites that are most effective for activation of the back muscles are dorsal to the location of retrogradely labeled lumbar reticulospinal cells. To verify that cell bodies and not fibers of passage were stimulated, crystals of the excitatory amino acid agonist, N-methyl-D-aspartate (NMDA) were deposited at effective stimulation sites in the Gi. NMDA decreased the ability of electrical stimulation to activate back muscles at 5 min postdeposition, indicating a local interaction of NMDA with cell bodies at the stimulation site. In the third series of experiments, electrical thresholds for EMG activation along a track through the MRF were compared to cells retrogradely labeled from FG deposited into the cervical spinal cord. In some experiments, Fast Blue was also deposited into the contralateral lumbar cord. Neurons at low threshold points on the electrode track were labeled following cervical depositions, indicating a direct projection to the cervical spinal cord. The lumbar depositions, again, labeled cells in MRF areas that were ventral to the locations of effective stimulation sites, primarily on the opposite side of the medulla. In addition, the lumbar depositions back-filled cells in the same cervical segments to which the Gi neurons project. These results suggest that one efferent projection from effective stimulation sites for back muscle activation is onto propriospinal neurons in the cervical cord, which in turn project to lumbar cord levels.(ABSTRACT TRUNCATED AT 400 WORDS)


Spinothalamic and propriospinal neurones in the upper cervical cord of the rat: terminations of primary afferent fibres on soma and primary dendrites. Experiments were performed on rats to determine whether primary afferents from the upper cervical region terminate directly on spinothalamic and propriospinal neurones. The central terminations of primary afferents from the upper cervical region were identified by diffusely filling their axons with horseradish peroxidase. Spinothalamic neurones or propriospinal neurones were identified in the same experimental animals by using retrograde transport of wheat germ agglutinin conjugated to horseradish peroxidase. Approximately 3-11% of spinothalamic cells in laminae 4-6 of spinal segments C2-4 received apparent synaptic contacts from primary afferents on the soma or primary dendrites. Approximately 18-36% of propriospinal neurones with axons descending to lower thoracic or lumbar levels received apparent synaptic contacts on the soma or primary dendrites. These data provide anatomical evidence that spinothalamic and long propriospinal neurones in the upper cervical cord are excited directly by primary afferents. The data also help to clarify the neural circuitry underlying somatic sensation and reflex movements evoked by neck receptors.


Kindling is associated with the formation of novel mossy fibre synapses in the CA3 region. A Golgi and electron microscopy study of the hippocampal CA3 region was performed on control and kindled Wistar rats. The observations provide evidence that, in epileptic rats, mossy fibres sprout and establish novel synapses with the basilar dendrites of CA3 pyramidal neurons. These newly-developed synapses showed the typical features of mossy synapses observed in the stratum lucidum, including the appearance of complex giant spines. The morphological changes reported here may represent a histopathological substrate for the epilepsy in the absence of overt signs of a hippocampal lesion.


Decreasing the cortical response to monocular deprivation need not decrease cell shrinkage in cat lateral geniculate nucleus. Monocular deprivation (MD) of young kittens decreases the response of visual cortex cells to the deprived eye. In addition, it causes cell shrinkage in the layers of the lateral geniculate nucleus (LGN) innervated by the deprived eye. To determine whether the shrinkage of LGN cells is dependent upon changes in the response of cortical cells, we compared LGN cell shrinkage in three groups of MD animals. Two were controls; the third received lesions of fibers bringing norepinephrine and acetylcholine to the visual cortex. This procedure greatly attenuated the effect of MD on the visual cortex. The amount of LGN cell shrinkage did not differ among the three groups. We conclude that LGN shrinkage after MD does not require a dramatic loss of cortical cell responses to the deprived eye.


Responses from outside classical receptive fields of dorsal lateral geniculate cells in rabbits. The effects of stimuli at locations remote from classic receptive fields (CRF) of lateral geniculate cells were examined in rabbits. In anesthetized rabbits, small targets positioned well outside the CRF either facilitated or decreased responses evoked by a stimulus positioned within the most active area of the CRF in 51% of the cells tested, in spite of the fact that when presented in isolation the remote target failed to modify the spontaneous activity of the recorded cell. Late components of the discharge pattern evoked by the central stimulus were mostly influenced by the peripheral target. Focal or ectopic areas surrounding the CRF are thus identified. These areas were not a direct extension of the CRF, since the normal evoked response was unchanged when the remote stimulus moved closer to the CRF. Cells whose CRF were centrally located reacted with an augmented response in the presence of the additional stimulus, whereas units whose CRF was more eccentric exhibited a weaker response when the peripheral target was introduced in the visual field. We also investigated whether superior colliculus afferents to the lateral geniculate nucleus could be associated with these ectopic areas (EA). Depressing superior colliculus activity produced two types of results: (a) often the late component of the response pattern was modified; and (b) the influence of the remote stimulus disappeared with collicular blockade in 80% of tested neurons. These results provide evidence that the CRF of geniculate cells may be surrounded by satellite zones, which modify the responses to the central target when invaded by circumscribed stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)


Pulmonary gas exchange response following allergen challenge in patients with allergic asthma. Pulmonary gas exchange was studied in 8 patients with allergic asthma before and after allergen challenge. Ventilation-perfusion relationships were assessed by the multiple inert gas elimination technique and forced expiratory flow by conventional spirometry. Measurements were made before, 7-8 minutes, and 0.5, 2.5 and 5 hours after challenge. During baseline conditions all patients showed normal forced expiratory flow (FEV1 3.9 +/- 0.77 (SD) l) and gas exchange expressed as the dispersion of pulmonary blood flow, log SDQ (0.35 +/- 0.08), (one of the common descriptors of ventilation-perfusion (VA/Q) inequality). Immediately after challenge there were significant decreases in FEV1 (to 2.3 +/- 0.75 l) and arterial PO2 (from 13.1 +/- 0.9 to 9.5 +/- 1.2 kPa). The developed ventilation-perfusion inequalities were similar to those found in other asthma studies, i.e. mainly a broad (log SDQ increased to 0.73 +/- 0.30) and sometimes bimodal distribution of the perfusion. Thirty minutes after challenge FEV1 significantly improved to 3.2 +/- 1.18 l while log SDQ remained high (0.71 +/- 0.32). Two and a half hours after challenge log SDQ was reduced and almost normalized to 0.38 +/- 0.07. Five patients developed a late phase reaction with decreasing flow rates after 5 hours. Three of these patients also showed increased log SDQ. There was no clear relationship between gas exchange mismatch and reduced forced expiratory flow. The results support the hypothesis that reduced expiratory flow and gas exchange impairment are caused by different pathophysiological mechanisms.


Protective effect of loop diuretics, piretanide and frusemide, against sodium metabisulphite-induced bronchoconstriction in asthma. We determined whether the loop diuretic, piretanide, had a similar inhibitory action against sodium metabisulphite (MBS)-induced bronchoconstriction in asthmatic subjects as frusemide and, if so, its duration of action. In the first study, we compared the effect of inhaled placebo, piretanide (24 mg), or frusemide (40 mg), on the provocative concentration of MBS needed to cause a 20% fall in baseline forced expiratory volume in one second (FEV1) (PC20MBS) in 12 mild asthmatic subjects before, immediately after, and at 1.5, 3, 6, and 24 h, after inhalation. Both piretanide and frusemide induced a significant diuresis lasting at least 24 h. Frusemide caused a mean 3.8 fold (95% confidence interval: 2.3-6.3 fold), piretanide a 2.5 fold (1.8-3.4 fold) and placebo a 1.7 fold (1.5-1.9 fold) increase in PC20MBS. The effects of frusemide and piretanide were significantly greater than that of placebo. At later time points, tachyphylaxis to the bronchoconstrictor effects of MBS was observed during the placebo limb. In the second study, we measured PC20MBS at 90 min after inhalation of either placebo, piretanide (24 mg), or frusemide (40 mg). No significant difference in PC20MBS was observed. We conclude that piretanide in addition to frusemide significantly inhibits MBS-induced bronchoconstriction and that this action is short-lived over less than 90 min. Frusemide was more potent in inhibiting MBS-induced bronchoconstriction despite causing a smaller diuretic effect than piretanide. The basic mechanism of action of the loop diuretics in the airways remains unclear.


The effect of amiloride on the airway response to metabisulphite in asthma: a negative report. Frusemide, a loop diuretic, has been shown to potently inhibit several indirect bronchoconstrictor challenges in asthma. The mechanism by which nebulized frusemide protects against indirect bronchoconstrictor stimuli in asthma is not known. One mechanism could be related to inhibition of sodium transport. If this is the case, then amiloride, another inhibitor of sodium transport, should also protect against indirect bronchoconstrictor challenges. Ten subjects with mild asthma were administered either 10(-2) M amiloride or placebo, by nebulizer, in a double-blind crossover fashion. After each inhalation, forced expiratory volume in one second (FEV1) was recorded at 10 min intervals for 30 min, after which a metabisulphite challenge was performed. No significant difference in the response to metabisulphite was seen between placebo and amiloride treatment. The mean difference in provocative dose of metabisulphite producing a 20% fall in FEV1 (PD20) between placebo and amiloride was 1.015 doubling doses, 95% confidence interval (95% CI) -0.201 to 2.231, (p = 0.09). This result does not support the hypothesis that frusemide is acting to protect against bronchoconstrictor challenges in asthma by an effect on sodium transport.


Salmeterol versus slow-release theophylline combined with ketotifen in nocturnal asthma: a multicentre trial. French Multicentre Study Group. We wished to assess the efficacy of inhaled salmeterol (SML; 50 micrograms b.i.d.) compared to a combination of slow-release theophylline and ketotifen p.o. (TK; T 300 mg+K 1 mg b.i.d.) for the treatment of nocturnal asthma. Ninety six patients with nocturnal asthma, (forced expiratory volume in one second (FEV1) 60-90% of predicted value, reversibility > or = 15%, at least two nocturnal awakenings per week) were eligible for a multicentre, double-blind, double-dummy cross-over study (14-day run-in, two successive 28-day treatment periods). Efficacy was assessed as success/failure, success being defined as the complete disappearance of nocturnal symptoms/awakening during the last week of each treatment period. There was a statistically significant difference between SML and TK for this criterion: 46% and 39% success with SML during periods I (first 28-day period) and II (following the cross-over), compared to only 15% and 26% with TK, respectively (p < 0.01). SML was also significantly better for the other criteria (lung function, rescue salbutamol intake during day and night). Side-effects were five times less frequent in SML-treated patients (p < 0.004). Efficacy and tolerance of SML were obviously far better than those of TK in patients with nocturnal asthma.


Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi. The mechanism of action of xanthines in asthma remains controversial. Since sensory innervation may play a role in the pathogenesis of asthma, we investigated whether xanthines were capable of reducing the contractile response of the bronchi to nerve stimulation. In guinea-pig bronchi in vitro, electrical field stimulation (EFS: 40 V, 16 Hz, 0.2 ms during 10 s) induces a rapid cholinergic contraction followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. We measured isometric neuronally-mediated contractions of bronchial smooth muscle and studied the effects of increasing concentrations of two xanthine derivatives, theophylline, an antagonist of adenosine receptors, and enprofylline, which has no effect on adenosine receptors. Both enprofylline (1-50 microM) and theophylline (10-100 microM) inhibited, in a concentration-dependent manner, the peptidergic contraction, an effect which was more marked with enprofylline than theophylline (EC50 = 9.6 +/- 0.7 microM and 62.0 +/- 4.7 microM, respectively). Conversely, the cholinergic response was unaffected. Contractions induced by exogenous substance P (0.03-3 microM) were also unaffected by theophylline and enprofylline at the above mentioned EC50s. Our results suggest that concentrations of theophylline, similar to those used therapeutically, reduce the release of sensory neuropeptides from C-fibre endings. This effect is unrelated to adenosine receptor blockade, since enprofylline had a similar inhibitory effect.


Effects of inspiratory resistance, inhaled beta-agonists and histamine on canine tracheal blood flow. Tracheobronchial blood flow is potentially important in asthma as it could either influence the clearance of mediators from the airways, thus affecting the duration and severity of bronchospasm, or enhance oedema formation with a resultant increase in airflow obstruction. In anaesthetized dogs, spontaneously breathing via a tracheostomy, we investigated the effects of three interventions which are relevant to acute asthma attacks and could potentially influence blood flow and its distribution to the mucosa and remaining tissues of the trachea: 1) increased negative intrathoracic pressure swings (-25 +/- 1 cmH2O) induced by an inspiratory resistance; 2) variable inhaled doses of a beta-adrenoceptor-agonist (terbutaline); and 3) aerosolized histamine sufficient to produce a threefold increase in pulmonary resistance. Microspheres labelled with different radioisotopes were used to measure blood flow. Resistive breathing did not influence tracheobronchial blood flow. Following a large dose of terbutaline, mucosal blood flow (Qmb) increased by 50%. After inhaled histamine, Qmb reached 265% of the baseline value. We conclude that, whereas increased negative pressure swings do not influence tracheobronchial blood flow or its distribution, inhalation of aerosolized terbutaline, corresponding to a conventionally nebulized dose, increases mucosal blood flow. Our results also confirm that inhaled histamine, in a dose sufficient to produce moderate bronchoconstriction, increases tracheal mucosal blood flow in the area of deposition.


Gas exchange during simulated airway secretion in the anaesthetized rabbit. We wished to study the effect of airways secretion on gas exchange. Peripheral airway secretion was simulated in 9 rabbits by the continuous inhalation of nebulized isotonic saline, at a droplet size of about 3 microns. Intrapulmonary deposition of saline in the peripheral airways (83% in airways smaller than 0.5 mm) did not alter total inspiratory resistance (mean 5.4 kPa.l-1.s), but led to a decrease in compliance of the total respiratory system from 45.9 to 21.8 ml.kPa-1 after one hour of nebulization. Arterial oxygen tension decreased from 17.8 kPa to 12.1 and 6.9 kPa after 5 and 60 min of nebulization, respectively. PaCO2 was unaffected after 5 min (4.5 kPa) but increased to 7.0 kPa after 60 min of nebulization. Ventilation-perfusion relationships (VA/Q) showed a significant increase in perfusion of areas with low VA/Q ratios (from 0.7 to 6.3% of cardiac output) and in shunt (from 1.4 to 4.3%) after 5 min of nebulization. At the end of the experiment shunt was increased markedly to 29.7% of cardiac output whereas perfusion of low VA/Q regions remained at the same level (7.3%). The results from this animal model indicate that all gas exchange abnormalities known to occur in asthma can be reproduced without measurably increasing the resistance of the respiratory system.


Protective effect of pulmonary surfactant on elastase-induced emphysema in mice. The aim of this study was to obtain some evidence of a protective role for pulmonary surfactant in the pathogenesis of emphysema. Firstly, we developed a quick and easy method to treat mice with a series of intratracheal instillations. Subsequently, three groups of mice were treated as follows: two groups received intratracheal instillations with pancreatic elastase (1.8 mg.kg-1 BW) followed after 3, 48 and 96 h in one group (El/Surf group) by intratracheal administration of surfactant (100 mg phospholipid.kg-1 BW), and in the other group by instillations with saline (El/s group). The third group of control mice was treated with saline followed by three doses of surfactant (s/Surf group). After eight weeks, the mice were killed and emphysema was measured by calculating the mean linear intercepts (Lm) of airspaces. The Lm values in the different groups were statistically tested for differences by the Mann-Whitney test. Instillation of pancreatic elastase (El/s group) resulted in an evenly distributed increase in Lm compared with the control group. Administration of surfactant in elastase-treated mice (El/Surf group) resulted in a statistically significant inhibition of airspace enlargement. Although the Lm in the El/Surf group was still higher than in the control group, analysis of histograms of Lm values per field of examination revealed that the Lm distribution in the former group was similar to that of the s/Surf group. The El/s group, on the contrary, showed the presence of many fields with enlarged air spaces. Repeated instillations with saline and/or surfactant had no effect on the Lm.(ABSTRACT TRUNCATED AT 250 WORDS)


Clara cell protein in serum and bronchoalveolar lavage. The 10 kDa Clara cell protein was measured in serum and bronchoalveolar lavage (BAL) from 39 healthy subjects (14 smokers, 25 nonsmokers) and from 41 patients with respiratory disease (chronic obstructive pulmonary disease (COPD), sarcoidosis, lung cancer). Clara cell protein appears as one of the most abundant respiratory tract derived proteins, with values averaging 7% of the total protein content of lung lavages from healthy nonsmokers. A significant reduction of Clara cell protein was found in BAL from smokers and patients with COPD or lung cancer. The same pattern of change was found in the concentrations of Clara cell protein in serum. Pulmonary sarcoidosis did not affect absolute values of Clara cell protein in lung lavages but was associated with elevated levels in serum. Changes in lung lavage Clara cell protein differed from that of albumin, beta 2-microglobulin or the secretory component, since the latter were unaffected by smoking or COPD but increased in sarcoidosis and lung cancer. These results indicate that Clara cell protein in BAL or serum might serve as a sensitive indicator of nonciliated bronchial cell dysfunction.


Nasal and paranasal disease in adult cystic fibrosis patients. Children with cystic fibrosis frequently have nasal polyps and sinusitis. This study addresses (para-) nasal disease in 39 adult cystic fibrosis patients. Fifteen patients (39%) had recently had serious nasal symptoms and 26% sinusitis. Seventeen (44%) had nasal polyposis. Almost all sinus radiographs taken showed opacification, which was unrelated to symptoms. Polypectomies and antral irrigations were usually ineffective, whilst more extensive surgery generally gave better results. It is concluded that a substantial number of adult cystic fibrosis patients frequently have upper airway symptoms. Sinus radiographs have little or no diagnostic value. Treatment of (para-) nasal disease in cystic fibrosis patients can be difficult; a guideline for treatment is suggested, calling for simple interventions coupled with intranasal steroids and nasal irrigation in early disease and for endoscopic to radical sinus surgery in recurrent advanced disease.


Outcome of respiratory distress syndrome at 28 days: a prospective longitudinal study. Fifty eight newborn infants with respiratory distress syndrome (RDS) were prospectively studied, in order to determine clinical variables prognostic of poor outcome at 28 days. Twenty six infants survived without bronchopulmonary dysplasia (BPD), 13 had Type 1 BPD, 4 had Type 2 BPD and 15 infants died before 28 days. Survivors without BPD had higher birthweights and gestational ages. Among the other infants, severity of initial lung disease was the best discriminator between outcome groups: Type 1 BPD infants had the best lungs at onset, and the nonsurvivors had the worst lungs. Stepwise multiple logistic regression identified gestational age and the ventilatory index number 1 (VI1) (= respirator frequency x maximal inspiratory pressure) at day 3 as the most useful variables to predict "poor outcome" (nonsurvival or Type 2 BPD). Ninety five percent of the infants were correctly classified using a cut-off probability of 0.5. We conclude that RDS outcome at 28 days is determined at a very early stage and that poor outcome can be predicted with reasonable accuracy at three days of age.


Nosocomial pneumonia in critically ill comatose patients: need for a differential therapeutic approach. The purpose of this prospective clinical study was to determine the incidence, bacteriology and outcome of lower respiratory tract infections developed among 208 consecutive, critically ill comatose patients, hospitalized in a university hospital, medical-surgical intensive care unit, over a three year period. Nosocomial pneumonia developed in 53 (25%) patients after a mean of 8.1 days (range 3-31 days). Furthermore, there were five superinfections, raising the mean incidence to 28%. One patient developed secondary bacteraemia, and another two had septic shock. Fifteen (28%) patients from the pneumonia group died, and six of these deaths were considered to be directly related to nosocomial pneumonia. Identification of the causative agent, using the protected specimen brush technique, was possible in 42 episodes; in 10 (24%) of these cases more than one microorganism was isolated. Gram-positive cocci represented 53% of isolates, and Staphylococcus aureus accounted for 78% of all Gram-positive cocci, being the most frequent microorganism in this population. In conclusion, nosocomial pneumonia is a common complication of critically ill comatose patients. Its characteristic aetiological spectrum in this population should affect antibiotic prescription. Consequently, we suggest including antimicrobial drugs which are active against S. aureus in the empirical regimen until aetiological diagnosis is established.


European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): hypothesis and design. Chronic obstructive pulmonary disease (COPD) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality. Cigarette smoking is the most important aetiological factor. The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers. In cigarette smokers with poorly reversible airflow obstruction, the effect over 3 yrs of an inhaled glucocorticosteroid, budesonide 400 micrograms b.i.d., on the decline of lung function, measured as postbronchodilator forced expiratory volume in one second (FEV1), will be compared with that of placebo. The trial has been designed to detect a difference in yearly decline of at least 30 ml.year-1. The study is a parallel group, randomised, double-blind, multicentre study. Patients will be recruited from 47 centres in 12 countries in Europe. It will start with a run-in consisting of two 3 month periods. During the first 3 months, the patients will be offered a smoking cessation programme. All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested. After these two periods, patients will be randomised to receive either inhaled budesonide, 400 micrograms b.i.d., or placebo for a period of 3 yrs.


Lung allograft transplantation: indications, preoperative assessment and postoperative management. In spite of a shortage of available donors, an increasing number of heart-lung transplantations have been performed within the last decade. This procedure, first limited to patients with pulmonary vascular disease, has been successfully extended to patients with end stage lung disease, including cystic fibrosis. More recently, single lung, double-lung and bilateral single lung transplantation have become other therapeutic options. Better selection of patients and donors as well as improvements in surgical techniques and immunosuppression regimens have contributed to the reduction in the high perioperative mortality experienced in the early stages. Moreover, the introduction of daily spirometry and transbronchial lung biopsies have permitted early and reliable diagnosis of opportunistic infection and rejection. The most serious late complication of lung transplantation is obliterative bronchiolitis and further research is urgently required to improve diagnosis and management of this condition.


Calibration of aerosol output from the Mefar dosimeter: implications for epidemiological studies. Standardized methods for the measurement of airway responsiveness may use the Mefar MB3 inhalation dosimeter to generate standard doses of methacholine aerosol. The manufacturer provides calibrated output data for every nebulizer, so that a standard output may be achieved by varying nebulization time. This output is, however, measured by weight loss (WL), which may over-estimate true aerosol output (AO) because of concomitant evaporation. We have used a chemical (fluoride) tracer method to measure AO directly from two batches of Mefar nebulizers (batch 1 n = 5, batch 2 n = 10) and compared results with manufacturer's quoted WL. Mean AO from batch 1 was 10.56 mg.s-1 (range 9.50-11.63, SD = 0.92 mg.s-1), and mean AO from batch 2 was 5.66 mg.s-1 (range 4.92-6.58, SD = 0.57 mg.s-1), implying that AO varied little within, but substantially between, the two nebulizer batches. Manufacturer's quoted WL does not reflect this near two fold difference: mean WL batch 1 = 14.0 mg.s-1 (range 13-15 mg.s-1); mean WL batch 2 = 11.1 mg.s-1 (range 11-12 mg.s-1). The median aerosol fractions (AO/WL) for batches 1 and 2 were 76% (range 65-83%) and 50% (range 43-60%), respectively. Similar results were obtained with our own measurement of weight loss. This implies that if the median nebulizers of batches 1 and 2 were calibrated (as recommended) by the manufacture's WL to deliver a presumed 100 micrograms methacholine dose, the actual doses delivered would be 76 micrograms and 50 micrograms, the range for all 15 nebulizers being 43-83 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)


Pulmonary alveolar microlithiasis and lymphocytic interstitial pneumonitis in a ten year old girl. Pulmonary alveolar microlithiasis (PAM) is a rare lung disease, characterized by progressive formation of intra-alveolar calculi in response to an unknown stimulus. We report an unusual presentation of PAM in a 10 year old girl with clinically significant interstitial lung disease and histological evidence of both PAM and lymphocytic interstitial pneumonitis. A rapid improvement of pulmonary function and exercise tolerance was seen in response to glucosteroid therapy.


Tumour-like presentation of pulmonary sarcoidosis. We report a case of pulmonary sarcoidosis, which initially presented as a left apical infiltrate. The later course mimicked a pulmonary neoplasm, with left upper lobe atelectasis secondary to bronchial stenosis, resulting from both endobronchial sarcoidosis and extrinsic compression by enlarged lymph nodes. Extrinsic pressure from sarcoid nodes on the left main pulmonary artery and recurrent laryngeal nerve, also caused a reduction in pulmonary parenchymal perfusion and left vocal cord paresis.


Systemic to pulmonary vascular malformation. A case is reported of life-threatening haemoptysis as a result of an anomalous communication between a bronchial artery and pulmonary vein, demonstrated by angiography. The patient recovered following bilobectomy of the right lower and middle lobes. When a systemic artery is involved in an arteriovenous malformation of the lung, haemodynamics are different compared with those present in malformations fed by the pulmonary artery. This implicates other clinical features, options for surgical intervention and prognosis. In reviewing the literature, a relationship with Rendu-Osler-Weber disease is absent in these specific malformations.


Molecular basis for red cell membrane viscoelastic properties. An unusual combination of membrane properties allows the red cell to undergo extensive deformation without cell fragmentation, enabling it to effectively perform its function of oxygen delivery during its long life span in the circulation. These material properties are the consequence of a composite structure in which a plasma membrane envelope made up of amphiphilic surfactant molecules is anchored to a network of skeletal proteins through tethering sites (transmembrane proteins) in the bilayer. Explosive growth in our understanding of the primary structure of the various red cell membrane proteins, definition of specific mutations in various red phenotypes, and detailed biophysical characterization of membrane properties of normal and mutant red cells has enabled development of models of molecular and structural basis for red cell properties.


Oral capture and grasping of an artificial nipple by rat fetuses. Although born blind and deaf, newborn rats exhibit a remarkable capacity to recognize and gain access to the nipples of the lactating mother. However, it is well-known that full-term rat neonates will not attach to an artificial nipple. In the present study, an artificial nipple fashioned from soft vinyl was presented to rat fetuses from E17-E21 of gestation. Fetuses showed side-to-side head movements that resulted in oral capture of the nipple on E18 and exhibited a direct nipple-grasping response from E19 through term. Frame-by-frame analysis of videotape records of E21 rat fetuses revealed that tactile contact with the artificial nipple elicited mouthing, licking directed at the nipple, forelimb treadling, and grasping of the nipple. Fetuses also exhibited components of aversive behavior, including facial wiping and head turning, that appeared to terminate oral contact with the nipple. Morphine pretreatment reduced the expression of aversive responses and promoted licking and grasping of the artificial nipple. In addition to documenting the prenatal ontogeny of this important neonatal behavior, these findings imply a role for endogenous opioids in the newborn rat's first suckling episode.


Response of bonnet macaque dyads to an acute foraging task under different motivational conditions. To explore behavioral patterns in bonnet macaque mother-infant dyads under environmental challenge, the motivation of infants to contact their mothers during a 1-hr foraging period was manipulated in two ways. First, sessions were given in which the infants were separated from their mothers for 3 hr prior to the foraging period. Second, sessions were given in which the infants were allowed access to food prior to the foraging period, thereby presumably reducing their motivation to separate from mother to seek food for themselves during the foraging period. Neither manipulation resulted in heightened conflict within the dyads. Separation of the infants prior to the foraging period did result, in general, in mothers forfeiting foraging task engagement to attend to their infants. The extent to which a mother exhibited this pattern correlated with her level of foraging effectiveness.


Long-Evans and Sprague-Dawley rats differ in their spatial navigation performance during ontogeny and at maturity. The Morris maze has become a popular method for the assessment of spatial navigation. However, its use to study the development of spatial abilities has been limited to pigmented rats. Thus, the aim of the present study was to compare albino Sprague-Dawley and pigmented Long-Evans rats using this test during postnatal Days 20 through 27, and Day 90. It was found that Long-Evans rats showed significantly shorter escape latencies and swim distances than the Sprague-Dawley rats on Days 20-25 but not on Days 26-27. However, when tested at Day 90, the Long-Evans rats again showed more rapid location of the escape platform and shorter swim distances than the Sprague-Dawley rats. Probe trial analysis (platform removed) indicated that Long-Evans rats were generally more accurate in their localization of the former platform location than Sprague-Dawley rats. In a second experiment in which 21-day-old rats of both strains were tested in a proximal-cue version of the maze, the question of whether this performance difference might have related to visuo-perceptual differences was considered. Since no dissimilarity in performance was observed, a spatial-learning difference between the two strains would seem best able to explain the preceding data.