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Biomedical subjects

M J Jacobs

Publications and source records attributed to M J Jacobs.

At least 91 records · Page 5Linked to original sources
PubMed1994

Cathepsin D, but not cathepsin B, releases T cell stimulatory fragments from lysozyme that are functional in the context of multiple murine class II MHC molecules.

In this study, the major endosomal/lysosomal proteases cathepsin D and cathepsin B were tested on their ability to release T cell stimulatory peptides from hen egg white lysozyme (HEL) in vitro. Whereas neither enzyme could cleave unreduced HEL under mild conditions, reduced HEL was readily cleaved by cathepsin D but not by cathepsin B. Instead, cathepsin B was found to be very active in the trimming of HEL peptides after their release by cathepsin D. Following high-performance liquid chromatography (HPLC) fractionation, cathepsin D-released HEL fragments were screened for recognition by HEL-specific T cells from three strains of mice, i.e. B10.A (H-2a), C57BL/6 (H-2b) and BALB/c (H-2d). Peptides in a large number of different HPLC fractions triggered significant T cell responses in all three strains. Interestingly, the response profiles of T cells from the three different strains showed marked similarities. Also, several individual synthetic HEL sequences corresponding to selected cathepsin D-released fragments were recognized by murine T cells in the context of all three major histocompatibility complex (MHC) haplotypes tested. Our data suggest that cathepsin D rather than cathepsin B may play a central role in the initial release of HEL fragments during endosomal/lysosomal processing. The relatively long HEL fragments released by cathepsin D, containing about 20-30 amino acid residues, are significantly more promiscuous in murine class II MHC binding than the shorter synthetic HEL sequences previously employed by others for the delineation of HEL epitopes. Extensive documentation of HEL epitopes in previous investigations indicate that this promiscuity cannot be explained by simply assuming that longer peptides contain additional epitopes. Rather, an increased peptide length by itself appears to promote promiscuous MHC binding.

Animals↗
PubMed1994

Percutaneous intentional extraluminal recanalisation of the femoropopliteal artery.

Percutaneous intentional extraluminal recanalisation (PIER) of the femoropopliteal artery is a new catheter technique to overcome long chronic occlusions. This technique was applied to 40 long chronic occlusions of the femoropopliteal segment. The mean length of the superficial femoral artery (SEA) occlusions was 16.9 cm, the mean length of the popliteal occlusions was 11.8 cm and the mean length of the femoropopliteal occlusions was 27.6 cm. Primary recanalisation success was 85%. Patency showed a significant correlation with poor initial angiographic result (p < 0.05). Life-time table analysis of the successful group demonstrated a primary clinical patency of 59% at 1 and 2 years and a secondary clinical patency of 71% at 1 year and 65% at 2 years. There were no serious complications related to this technique. PIER technique is simple and cost-effective, and shows a good initial success-rate with a promising 2 years clinical patency. This technique might be of importance for patients with a critical lower leg ischaemia, when there are contraindications for primary bypass surgery either from a technical or a general point of view.

Aged↗
PubMed1994

Reflex sympathetic dystrophy: result of autonomic denervation?

1. To investigate the nature of sympathetic dysfunction in the pathogenesis of reflex sympathetic dystrophy, the microcirculatory vasoconstrictive responses to dependency were investigated in the skin of the hand of 76 reflex sympathetic dystrophy patients with unilateral disease by means of laser Doppler flowmetry (in perfusion units) and capillary microscopy. The patients were divided into three stages according to their perception of skin temperature (stage I in the case of a stationary warmth sensation, stage II in the case of an intermittent warmth and cold sensation, and stage III in the case of a stationary cold sensation). The vasoconstrictive responses were induced by lowering of the affected hand. 2. As compared to controls, the mainly sympathetically mediated vasoconstrictive response at thermoregulatory level of the skin microcirculation, as measured by laser Doppler flowmetry, was attenuated at stage I (1.82 versus 1.41, P < 0.05), stage II (1.82 versus 1.09, P < 0.0001) and stage III (1.82 versus 1.14, P < 0.01), suggesting the involvement of sympathetic denervation at all stages of the reflex sympathetic dystrophy syndrome. This sympathetic denervation may also account for the observed increase in thermoregulatory skin blood flow at stage I as compared to controls (152 versus 81, P < 0.01). 3. Since sympathetic denervation has been reported to cause increased sensitivity of vascular structures to catecholamines, the decrease in thermoregulatory skin blood flow at stages II (54 versus 81, P < 0.05) and III (31 versus 81, P < 0.05), both as compared to controls, may result from hypersensitivity to catecholamines of skin microvessels. 4. The sympathetically independent vasoconstrictive response at the nutritive level of skin microcirculation, as measured by capillary microscopy, was impaired only at stage III as compared to controls (1.04 versus 2.06, P < 0.05). This divergence in microvascular reactivity upon dependency of the nutritive and thermoregulatory subsystems also supports the hypothesis of sympathetic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Suppression of hen egg lysozyme-induced arthritis by intravenous antigen administration: no role in this for antigen-driven bystander suppression.

The induction of tolerance, particularly by intervention before established immunity, is widely accepted. We studied the effects of intravenous (i.v.) administration of hen egg lysozyme (HEL), before as well as after immunization, on a HEL-induced arthritis. Arthritis and also cartilage destruction were almost completely suppressed when 100 micrograms HEL was injected before immunization. Antigen-specific proliferative T cell responses and IL-2 production in vitro were inhibited. Antigen-specific immunoglobulin and IgG1 titres were equal in control and tolerized mice, in contrast to lowered IgG2a titres in tolerized animals. Detailed histological studies showed that the immune complex-dependent polymorphonuclear cell phase (< 24 h after arthritis induction) was equal for control and HEL-injected mice. Only in the T cell-dependent phase of the arthritis (> 24 h), did suppression become pronounced in tolerized mice. I.v. administration of 100 micrograms HEL after immunization could only marginally reduce infiltrate and exudate, and no reduction of cartilage destruction was seen. An elegant way to interfere in an established immunity can be offered by creation of bystander suppression. We show that i.v. administration of HEL followed by triggering with HEL, at the moment either of immunization or of arthritis induction, does not reduce a methylated bovine serum albumin (BSA)-arthritis. We conclude that arthritis can be suppressed almost totally when HEL is injected intravenously before immunization. Treatment after immunization is less effective. The i.v. induced suppression is T cell-mediated and and antigen-specific: no bystander suppression circuit can be generated.

Animals↗
PubMed1994

Anergy of antigen-specific T lymphocytes is a potent mechanism of intravenously induced tolerance.

Intravenous (i.v.) injection of an antigen before immunization has been shown to be a potent way to induce suppression at the T-cell level. In this study we demonstrate an almost complete suppression of arthritis (using antigen-induced arthritis as a model) by i.v. injection of 100 micrograms hen egg lysozyme (HEL) 7 days before immunization. Underlying mechanisms, including suppression by CD8+ T lymphocytes, suppression by T-helper 2 (Th2) or anergy of antigen-specific T lymphocytes, were studied. In vivo treatment with either anti-CD8 or anti-interleukin-4 (IL-4) could not abrogate i.v.-induced tolerance. Lymphocyte stimulation assays showed reduced antigen-specific proliferative responses and IL-2 production in tolerized mice. The possible role of soluble suppressive cytokines was examined in vitro by adding anti-IL-4, anti-IL-10 or anti-transforming growth factor-beta (TGF-beta). Neutralization of these factors could not diminish suppression. Finally, anergy of antigen-specific T lymphocytes was tested as a possible mechanism for i.v.-induced tolerance. Results demonstrated that reduced proliferative T-cell responses were reversible: incubation of tolerized lymph node cells for 5 days in added recombinant (r)IL-2 fully restored proliferative capacity back to normal. We therefore conclude that the main mechanism of i.v.-induced tolerance in our model is anergy of antigen-specific T lymphocytes.

Animals↗
PubMed1994

Role of IL-2 and IL-4 in exacerbations of murine antigen-induced arthritis.

In this study the roles of different T-cell subsets, and produced cytokines, were investigated in an animal model for acute exacerbations. Flare-up reactions are inducible in the chronic phase of a smouldering antigen-induced inflammation by injection of a small amount of an antigen into a hyper-reactive knee joint. In vivo treatment with anti-CD4 monoclonal antibodies (mAb) almost totally blocked the flare reaction, whereas anti-CD8 treatment did not exert any effect. The role of T-helper 1 (Th1) cells in delayed-type hypersensitivity-resembling diseases is generally entitled proinflammatory, whereas Th2 cells act in an anti-inflammatory manner. To investigate the role of these T-cell subsets in flare-up reactions, anti-interleukin-2 (IL-2) and anti-IL-4 mAb treatments were performed. Anti-IL-2 treatment partly blocked the flare reaction, and anti-IL-4 treatment, although the result was unexpected, blocked the flare more efficiently. Furthermore, when human recombinant IL-2 (hrIL-2) and murine recombinant IL-4 (mrIL-4) were co-injected with the antigen to test their ability respectively to potentiate or down-regulate the flare reaction, both cytokines demonstrated additional pro-inflammatory effects, although hrIL-2 was more potent than mrIL-4. The mere effect of hrIL-2 and mrIL-4 was studied by direct injection into a hyperreactive joint. No flare-up reaction or cell-influx could be induced, suggesting that other mediators are needed to exert pro-inflammatory effects of IL-2 or IL-4. We conclude that not only Th1 cells, but also Th2 lymphocytes (at least regarding IL-4 production) may play a pro-inflammatory role in flare-up reactions of chronic arthritis. Considering therapeutic application of Th2 cell-derived cytokines, one should be aware of the possible pro-inflammatory potential of IL-4.

Acute Disease↗
PubMed1994

[New aspects of post-traumatic dystrophy syndrome?].

Posttraumatic dystrophy (PTD) is a syndrome that involves both neurological symptoms and microvascular abnormalities. A total of 44 consecutive patients seen for the first time with PTD were investigated. In 42 patients X-rays were taken: of the cervical spine in the case of PTD of the hand, and of the cervical, thoracic, and lumbar spine in the case of PTD of the foot. Two patients refused this investigation. In all 44 patients microvascular functions were investigated by means of transcutaneous oximetry, laser Doppler flow metering and capillary microscopy. In 34 of 42 patients radiographical disturbances of the vertebral column were noted, 19 of them on the same side as the affected extremity. Patients with a sensation of warmth in the affected extremity during the investigations exhibited a different microvascular behaviour than patients with a cold feeling. Both groups had different microvascular outcomes from healthy volunteers.

Adolescent↗
PubMed1993

Isolated profundaplasty in critical limb ischaemia--still of any use?

Because of the improved quality of peripheral bypass surgery, the role of isolated profundaplasty in revascularisation of the critically ischaemic limb has become very limited. This retrospective study of 72 isolated profundaplasties performed for critical limb ischaemia revealed a clinical improvement 1 year postoperatively of 39% in the period 1978-1983 and of only 9% between 1984-1990. In the total period, patient survival after 1 year was 81% and limb salvage 60%. Clinical, haemodynamic and arteriographic parameters were analysed for their predictive value of clinical success. The presence of tissue necrosis or ulceration (clinical stage IV) affected clinical outcome negatively (p < 0.05). Risk factors and indicators for arteriosclerotic disease, age of the patient and ankle-brachial systolic pressure index (ABI) had no significant predictive value. Evaluation of the preoperative arteriographies revealed that only the aspect of the profunda femoris artery beyond its orifice was of significance: there was a strong relationship between the absence of obstructive disease in this part of the artery and clinical improvement (p < 0.005). These two significant parameters may be guidelines when considering an isolated profundaplasty as an alternative in the treatment of critical limb ischaemia. However, in the presence of other treatment possibilities nowadays, especially bypass surgery, the procedure appears to offer a very poor success rate.

Aged↗
PubMed1993

Factors determining the outcome of crural and pedal revascularisation for critical limb ischaemia.

The influences of clinical factors, site of distal anastomosis, type of graft and angiographic run-off, on graft patency and limb salvage following 141 femorocrural and pedal bypasses in 121 patients were investigated retrospectively. The grafts consisted of 111 femorocrural and 30 pedal bypasses; 49% of the patients had diabetes mellitus. Venous grafts were implanted in 116 limbs, using either in situ vein (65), reversed vein (38) or composite vein (13) graft. Twenty-five prosthetic grafts (14 PTFE and 11 umbilical veins) were inserted. After 1, 2, 3 and 4 years of follow-up, the primary cumulative patency rates for all grafts were respectively 67, 61, 55 and 55%, and the secondary patency rates were 75, 70, 64 and 64%. The site of distal anastomosis had no influence on graft patency rate; neither was there any significant effect of clinical risk factors and run-off on graft patency. Prosthetic grafts showed significantly lower patencies compared to venous grafts and appeared to be the only independent prognostic risk factor for graft failure (multivariate analysis; p = 0.03). Overall limb salvage rate was 84% at 3 years. There were four amputations with patent grafts. The limb salvage rates for in situ vein, reversed/composite vein and prosthetic grafts were 89, 79 and 66% at 3 years, respectively. Various bypass grafts to the crural and pedal arteries are successful and durable. The use of prosthetic grafts results in significantly lower patency rates, but appears to be effective for limb salvage.

Adult↗
PubMed1993

Skin microcirculation in diabetic and non-diabetic patients at different stages of lower limb ischaemia.

One hundred and one non-diabetic and 54 diabetic patients suffering from lower limb ischaemia were divided into (i) asymptomatic subjects, (ii) claudicants, (iii) critically ischaemic patients, i.e. Fontaine III or IV patients with either an ankle pressure < 51 mmHg or a toe pressure < 31 mmHg, and (iv) Fontaine III or IV patients in whom ankle and toe pressures could not be assessed due to vessel wall sclerosis or skin ulceration. Skin microcirculation was investigated to assess (a) the compounding effect of diabetes in leg ischaemia and (b) the additive value of microcirculatory investigation in the appreciation of the severity of the ischaemic disease. The techniques used included capillary microscopy, transcutaneous oximetry and laser Doppler fluxmetry. The severity of ischaemia was readily discernable using microcirculatory techniques. The presence of diabetes appeared to change skin microcirculatory perfusion, but especially in critically ischaemic patients, the microcirculation was no more compromised than non-diabetics. Using skin oxygen tension measurements, a positive predictive value of 77% was obtained in the detection of critical ischaemia, when a cut-off value of 30 mmHg was applied. Seventy per cent of patients, in whom the severity of ischaemia could not be classified using blood pressure measurements, could be classified as critically ischaemic on the basis of microcirculatory investigation. In conclusion, the influence of diabetes on the microcirculation is outweighed by the effects of atherosclerosis when vascular disease becomes severe. Techniques to investigate skin microcirculation are a useful way of assessing the severity of lower limb ischaemia in the presence of diabetes mellitus or if peripheral blood pressures cannot be obtained.

Aged↗
PubMed1993

Creation of a distal arteriovenous fistula improves microcirculatory hemodynamics of prosthetic graft bypass in secondary limb salvage procedures.

PURPOSE: In patients with critical limb ischemia, poor distal arterial runoff, and absence of autogenous veins, the use of an artificial graft and an arteriovenous fistula might be a valuable option. However, in these patients little information is available regarding preoperative and postoperative microcirculatory hemodynamics after this type of intervention. METHODS: With the use of intravital capillary microscopy, we studied the effect of distal revascularization on the microcirculation in 26 patients with critical limb ischemia. All patients had had failed vascular reconstructive operations, and artificial grafts were required because of the absence of autogenous veins. Patients were prospectively investigated and divided into two groups: 12 patients received a femorocrural bypass with polytetrafluoroethylene grafts, and 14 patients underwent the same procedure with the creation of an arteriovenous fistula at the site of the distal anastomosis and ligation of the proximal vein. Red blood cell velocity was measured before and after arterial occlusion to determine microcirculatory hemodynamic alterations. RESULTS: Immediate postoperative graft patency was achieved in all 26 patients. The 1-year cumulative graft patency rate was 64% in the group that had creation of an arteriovenous fistula, which was significantly higher (p < 0.01) compared with that in the group in which a fistula was not created (21%). The 1-year cumulative foot salvage rate was 72% in the patients with an arteriovenous fistula and 43% in the patients without a fistula (p < 0.05). Red blood cell velocity increased similarly in both groups after the bypass procedure. Peak and time to peak red blood cell velocity also improved significantly in both groups; however, comparing both groups, peak and time to peak red blood cell velocity were significantly better (p < 0.05) in the patients with an arteriovenous fistula and remained significantly higher during the follow-up period. CONCLUSIONS: In conclusion, creation of an adjunctive arteriovenous fistula at the distal anastomosis of a prosthetic graft appears to improve microcirculatory hemodynamics in the nutritional capillary vascular bed. Improved graft patency and foot salvage rates suggest that this procedure benefits patients with critical limb ischemia who have no usable veins.

Adult↗
PubMed1993

Aberrant tolerance induction with cationic antigens.

We studied the induction of tolerance in female C57B1/6 mice by oral and intravenous (i.v.) administration of protein antigens before immunization. Native proteins [chicken egg albumin (OVA), bovine serum albumin (BSA)] and their cationic derivatives [amidated (a)OVA, aBSA, methylated (m)BSA] were compared in their capacity to suppress cell-mediated immunity (CMI), as measured by a delayed type hypersensitivity test (DTH). Oral feeding of 0.5 mg negative proteins gave a clear suppression. By contrast, cationic derivatives (50 micrograms to 50 mg) did not suppress CMI. Data from cross-experiments, where aOVA was fed in OVA-immune mice, showed no suppression at all. When OVA was fed in aOVA-immune mice, only a partial suppression was achieved. The potency to induce tolerance differed also when the antigens were administered i.v.: 25 micrograms OVA was sufficient to induce a clear suppression, whereas a much higher amount of aOVA (500 micrograms) caused marginal suppression in OVA- and aOVA-immune mice, respectively. Nevertheless, when concentrations of aOVA up to 2.5 mg were tested in a chronic model of arthritis, a significant suppression was achieved. The differences in inducing a CMI suppression may have implications for the feasibility of immunointervention. Successful modulation of human arthritis may be highly dependent on the nature of the antigen involved.

Administration, Oral↗
PubMed1993

Induction of tolerance by T-cell vaccination is possible beyond the area of autoimmunity: down-regulation of immunity directed to foreign protein antigens.

T-cell vaccination using antigen-specific lines or clones has been shown to be effective in down-regulating immunity in various experimental autoimmune models. Anti-idiotypic networks developing during differentiation of the immune system are considered to be a safeguard against autoimmunity and these pre-existing networks are supposed to be a prerequisite for successful vaccination. However, the interesting question of feasibility of T-cell vaccination beyond the area of autoimmunity remains to be answered. The present study is the first one providing evidence of successful T-cell vaccination in mice immunized against foreign protein antigens (in this system supposedly no pre-existing network exists). Intraperitoneal (i.p.) administration of hen egg lysozyme (HEL)- and chicken egg albumin (OVA)-specific lymph node cells (LNC) were shown to effectively down-regulate immunity (as measured in a delayed type of hypersensitivity) to HEL and OVA, respectively. In contrast, vaccination was unsuccessful with methylated bovine serum albumin (mBSA)-specific LNC in mBSA immunity. Suppression induced by HEL- and OVA-specific LNC was antigen specific. Unlike the greater part of other studies, in which antigen-specific lines or clones were used, we used draining LNC of immunized mice, which after activation were fixed with glutardialdehyde and injected i.p. 10 days before immunization. Finally, effects of T-cell vaccination were studied in a chronic HEL-induced arthritis. Joint swelling, cell influx and cartilage matrix depletion were significantly less in mice treated with antigen-specific cells. We conclude that successful vaccination is feasible in mice rendered immune to foreign protein antigens using a pool of LNC as source of vaccine, suggesting no necessity of a strong pre-existing network.

Animals↗
PubMed1992

Health USA.

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Health Policy↗
PubMed1992

Assessment of the microcirculation provides additional information in critical limb ischaemia.

Systolic ankle and toe pressure measurements are considered to be the best way of documenting arterial occlusive disease. In the European consensus, chronic critical limb ischaemia is defined as persistent pain with an ankle pressure lower than 50 mmHg. To investigate the possible adjunct value of microcirculatory assessment, capillary microscopy and transcutaneous oximetry were performed in 21 asymptomatic persons (F1), 89 claudicants (F2) and 54 patients with critical limb ischaemia (F3/4). Capillary morphology (diameter, density) and dynamics [red blood cell velocity (RBCV), peak RBCV and time to peak RBCV], as well as transcutaneous oximetry parameters were determined for each Fontaine group and compared with ankle and toe pressure measurements. Despite considerable overlap, ankle and toe pressures were significantly (p less than 0.001) different between F1, F2 and F3/4 patients. Capillary density (p less than 0.05), diameter (p less than 0.05), peak RBCV (p less than 0.05) and time to peak RBCV (p less than 0.01), as well as transcutaneous oximetry parameters (p less than 0.001) were significantly different between all groups and impaired with progression of ischaemia. However, a similar overlap between all groups was observed, except the supine TcpO2 parameter which separated F3/4 patients completely from the other groups. In all patients with critical limb ischaemia, dynamic parameters, such as peak RBCV (p less than 0.01) and time to peak RBCV (p less than 0.001), were significantly lower as compared to non-critically ischaemic patients, irrespective of an ankle pressure below or above a value of 50 mmHg, illustrating the additional value of microcirculatory assessment in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Microvascular reactivity differences between the two legs of patients with unilateral lower limb ischaemia.

Posturally induced microvascular constriction in the skin of the leg is disturbed in severe ischaemia. It is unknown whether this disturbance is of local or central origin and whether the stage of ischaemia at which this disturbance occurs differs when the nutritive and thermoregulatory flow levels are compared. We investigated the effect of posture on the skin microcirculation in 21 patients with unilateral severe ischaemia. The results were compared with those from the contralateral, asymptomatic leg and with results from 11 age-matched controls. Patients were investigated in supine and sitting positions, using capillary microscopy to measure nutritive flow, and laser Doppler fluxmetry (LDF) to measure thermoregulatory flow, of the big toes. In the supine position, capillary flow and LDF were lower in the diseased than in the asymptomatic and control legs. After changing from the supine to the sitting position, capillary perfusion decreased in all three groups, but was most pronounced in the controls. Laser Doppler flux decreased in the controls, but increased in the diseased legs, suggesting disturbed vasoconstriction mechanisms in the deeper skin microvessels. These findings indicate that in severe limb ischaemia, posturally induced microvascular reactivity is sustained at the nutritive level but not at the thermoregulatory level. This disturbed reactivity is considered a local phenomenon, as it is not observed in the contralateral leg.

Adult↗
PubMed1992

The relevance of posturally induced microvascular constriction after revascularisation in patients with chronic leg ischaemia.

In patients with severe chronic lower limb ischaemia, postural vasoconstriction is disturbed, resulting in enhanced skin microcirculatory perfusion on leg dependency. After vascular reconstructive surgery, postoperative oedema formation is frequently seen. In 31 patients with leg ischaemia undergoing revascularisation we investigated whether and, if so, for how long after surgery postural vasoconstriction would take to recover, and whether disturbed vasoconstriction correlates with the occurrence of postoperative oedema. Capillary microscopy and laser Doppler fluxmetry were used to assess nutritional and total skin perfusion, respectively. The measurements were performed before and up to 37 days after surgery. After revascularisation, the mean ankle blood pressure index rose from 40 to 82%. All patients, except those with persistently disturbed vasoconstriction showed improved microcirculatory parameters. Postural vasoconstriction was restored in 24 patients, occurring approximately on the eighth postoperative day. All patients who failed to recover vasoconstriction developed postoperative oedema. This study shows that the disturbance in postural vasoconstriction can be reversible, probably due to recovery of arteriolar smooth muscle tone, and that patients with persistently disturbed postural vasoconstriction, are prone to develop postoperative oedema.

Adult↗