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Humoral and cell-mediated immunity in peripheral blood following introduction of antigen into the middle ear.

Serum levels of specific IgG and the sensitization of peripheral blood T-lymphocytes were measured in guinea pigs after single-dose antigenic sensitization by two routes: intratympanic and intradermal injection. Keyhole limpet hemocyanin (KLH) served as the antigen. Intratympanic injection of antigen resulted in much lower levels of circulating anti-KLH IgG than intradermal injection. When KLH was conjugated with alum to produce nonspecific inflammation and serve as adjuvant, the intratympanic route was considerably enhanced, but remained much less effective than the intradermal route. Development of an IgG response was also somewhat less rapid following intratympanic than following intradermal administration. Marked sensitization of circulating T-lymphocytes was seen after intradermal injection of alum-precipitated KLH. A much weaker, though still positive, response was seen after intradermal injection of KLH alone and with the intratympanic injection of alum-precipitated KLH. No T-lymphocyte sensitization could be detected after intratympanic injection of KLH alone. It was concluded that the afferent limb of both humoral (IgG) and cell-mediated immunity was operative in the middle ear. Therefore, the middle ear does not represent an immunologically "privileged" site. On the other hand, the afferent limb from the middle ear appears to operate less effectively and rapidly than that from the dermis. This observation is consistent with observations in other mucosal systems.

Animals↗

Mechanistic analysis of high antitumor effect of intradermal administration of lipopolysaccharide from Pantoea Agglomerans.

Lipopolysaccharide from Pantoea Agglomerans (LPSp) has a remarkably high antitumor activity even against poorly immunogeneic tumors when given by intradermal injection combined with cyclophosphamide (CY). We have extended this study to gain an insight into the mechanism of this antitumor effect, and especially into the induction of cell mediated immunity. In immunohistological studies, extensive necrosis and marked infiltration of the inflammatory cells at the tumor were observed after intradermal injection of LPSp combined with CY, but not after CY alone or after no treatment. The cells around the tumors were mostly neutrophils and macro phages (Mac 1+); T cells (CD4+, CD8+) were also present. The serum levels of cytokines, induced after intradermal injection of LPSp, were determined and compared with intravenous administration of LPSp or recombinant TNF-SAM2. TNF-alpha, IL-1, IL-6 and GM-CSF were measured by ELISA as a marker of cytokine induction. The peak level of TNF-alpha induced by intradermal injection of LPSp was about 5000 pg ml-1, which was considered relatively small since this level was observed even in clinical trial. There seems to be a longer period of release of TNF-alpha after an intradermal injection than after an intravenous injection. This may produce the remarkably high antitumor effect of the intradermal injection. The antitumor effect of intradermal administration combined with CY was evaluated in nude mice to clarify the role of T cells in high antitumor activity. In this experiment, antitumor activity was found to be much less in BALB/c nu/nu mice without regression, while complete regression was frequently observed in syngeneic mice, showing the crucial role of T cells in this treatment. These observations suggest that intradermal administration of LPSp in combination with CY continuously releases and induces not only extensive necrosis of the tumor but also cell mediated antitumor immunity, which may be indispensable for complete regression of the tumor. Clinical application of this treatment for advanced cancer patients is in progress.

Animals↗

Low-volume jet injection for intradermal immunization in rabbits.

BACKGROUND: This study tested a low-volume (20-30 microl/20-30 microg DNA) jet injection method for intradermal delivery of a DNA vaccine. Jet injection offers the advantages of a needle-less system, low-cost, rapid preparation of the injected DNA solution, and a simple delivery system. More than one construct can be injected simultaneously and the method may be combined with adjuvants. RESULTS: Low-volume jet injection targeted delivery of a DNA solution exclusively to the dermis and epidermis of rabbits. A three injection series of plasmid DNA, encoding the Hepatitis B Surface Antigen stimulated a humoral immune response in 2/5 rabbits. One rabbit developed a significant rise in antibody titer after 1 injection and one following 2 injections. There were no significant differences between jet injection and particle bombardment in the maximal antibody titers or number of injections before response. A three injection series of the same plasmid DNA by particle bombardment elicited a significant rise in antibody titer in 3/5 rabbits. One rabbit developed antibody after 1 injection and two after 3 injections. In contrast, 0/5 rabbits receiving DNA by needle and syringe injection responded. In the jet injection and particle bombardment groups, gene expression levels in the skin did not predict response. While immune responses were similar, luciferase gene expression levels in the skin following particle bombardment were 10-100 times higher than jet injection. CONCLUSION: Low-volume jet injection is a simple, effective methodology for intradermal DNA immunization.

Animals↗

Experimental skin necrosis produced by adriamycin.

Skin ulceration caused by extravasation of Adriamycin follows a severely protracted course accompanied by considerable morbidity. To develop an animal model of Adriamycin ulceration, we compared intradermal injection of Adriamycin to injection beneath the panniculus carnosus with varying drug volumes and concentrations. Injections beneath the rat panniculus carnosus caused only irregular ulcerative lesions. Intradermal injection produced predictable, uniform skin necrosis and ulceration. Both increasing volume and increasing concentration of Adriamycin caused proportionate increases in skin ulcer size and in time required for healing. A critical concentration range for Adriamycin necrosis is 0.010--0.020 mg/ml, suggesting that the drug would have to be greatly diluted to reduce clinical skin ulceration. Adriamycin-induced skin necrosis heals at a slower rate than surgically created skin defects of similar size, indicating a reduced rate of wound contraction. Removal of the necrotic skin allows faster healing, although still slower than normal, due to removal of splinting effect. Histology shows early skin necrosis, with acute inflammation developing after 1 week. Epidermal hypertrophy is present at the edges of the necrosis. The small vessels remain patent. Multiple small vesicles of unknown etiology are seen in the necrotic dermis.

Animals↗

Spantide II, a novel tachykinin antagonist, and galanin inhibit plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw.

The effect of intradermal injection of Spantide II, a novel tachykinin antagonist, and the neuropeptide galanin on neurogenic plasma extravasation induced by antidromic stimulation of C-fibers in the sciatic nerve was examined in the hindpaws of rats. Activation of C-fibers by antidromic sciatic nerve stimulation (2 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans Blue in the skin area of the hindpaw innervated by the sciatic nerve. Intradermal injection of 3 nmol Spantide II significantly inhibited this response. The plasma extravasation was nearly totally abolished when the concentration of Spantide II was increased to 9 nmol. Intradermal injection of 1.5 and 15 nmol galanin also inhibited plasma extravasation. Intradermal injection of 9 nmol Spantide II effectively blocked the plasma extravasion in the hindpaw induced by 8 nmol intravenous substance P. Plasma extravasation induced by intravenous substance P was also inhibited by the higher, but not by the lower, dose of galanin injected intradermally. The present results indicate that Spantide II, a potent non-toxic tachykinin antagonist, effectively blocks the neurogenic plasma extravasation induced by antidromic C-fiber stimulation, thus supporting the view that tachykinins play an important role in this neurogenic inflammatory process. It is further shown that galanin, a naturally occurring neuropeptide present in primary afferents, also inhibits C-fiber activation-evoked plasma extravasation, indicating an interaction between galanin and tachykinins in the peripheral terminals of primary afferents, possibly through both pre- and postsynaptic mechanisms.

Amino Acid Sequence↗

Effects of growth factors on doxorubicin-induced skin necrosis: documentation of histomorphological alterations and early treatment by GM-CSF and G-CSF.

Extravasation of vesicant antineoplastic agents such as doxorubicin into the skin or subcutaneous tissues may result in loss of the full thickness of the skin or underlying structures. Several treatment methods have been advocated but none has demonstrated any superiority to the others. The authors designed a controlled animal study in 88 rats to test three methods of early treatment of extravasation of the vesicant antineoplastic agent doxorubicin. The first step of the study included 48 Sprague-Dawley rats. All animals received intradermal injections of 1 mg doxorubicin superficially to the panniculus carnosus in the dorsum. The rats were then divided into four groups of 12 rats each, as follows: group 1, no treatment; group 2, immediate intradermal injection of 0.1 ml saline to the same site; group 3, immediate intradermal injection of 10 microg granulocyte macrophage-colony stimulating factor (GM-CSF) in 0.1 ml saline to the same site; group 4, immediate intradermal injection of 10 microg granulocyte-colony stimulating factor (G-CSF) in 0.1 ml saline to the same site. During the next 6 weeks the rats were observed for the development of necrosis. Ulcers developed and reached maximum size two weeks after the injections. The largest ulcers according to area were observed in group 1 and the mean value was 21.25 mm (p < 0.05). Although wound areas were significantly smaller in the saline group than in the control group and the mean value was 7.58 mm (p < 0.05), the smallest lesions were observed in groups 3 and 4, and the mean values were 1.08 mm and 0.83 mm respectively (p < 0.05). There was statistically no difference with regard to mean ulcer area between groups 3 and 4. During the second step of the experiment, the remaining 40 Sprague-Dawley rats were used. Groups containing 10 rats each were designed similarly after all animals received intradermal injections of 1 mg doxorubicin into the back. On the 10th day after the injection, the entire area of the ulcer together with the underlying panniculus carnosus was excised for pathological examination and for determination of glucose 6-phosphate dehydrogenase (G6PD) activity. On microscopic examination, the extravasated ulcer consisted of a large area of ischemic necrosis. There was marked damage to small blood vessels in the form of fibrinoid necrosis and vasculitis. Injured vessel counts were higher in the control group (group 1; p < 0.05). No difference was observed in G6PD activity between the groups. The authors conclude that both saline and tissue growth factors (GM-CSF and G-CSF) are useful for the early treatment of doxorubicin extravasation; however, GM-CSF and G-CSF are more beneficial.

Analysis of Variance↗

NK-1, but not NK-2, tachykinin receptors mediate plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw: demonstrated with the NK-1 antagonist CP-96,345 and the NK-2 antagonist Men 10207.

The effects of intradermal injection of CP-96,345 and Men 10207, selective antagonists for NK-1 and NK-2 tachykinin receptors, respectively, on the extravasation of plasma protein induced by antidromic stimulation of unmyelinated sensory fibers in the sciatic nerve was studied in rat hindpaw. Activation of unmyelinated fibers by antidromic sciatic nerve stimulation (1 Hz, 5 min) consistently evoked a localized plasma extravasation of Evans blue on the skin area of the hindpaw innervated by the sciatic nerve, which was not inhibited by intradermal injection of saline or Men 10207 (9 and 35 nmol). In contrast, CP-96,345 (3 and 9 nmol, but not 1 nmol), injected intradermally 15 min prior to nerve stimulation dose-dependently inhibited this response. Plasma extravasation induced by intravenously injected substance P was also inhibited by CP-96,345. Since CP-96,345 is a highly selective antagonist for NK-1 tachykinin receptors, it is suggested that the plasma extravasation induced by antidromic C-fiber stimulation and by systemically applied tachykinins is mediated by NK-1 tachykinin receptors.

Animals↗

Antagonism of Paf-induced oedema formation in rabbit skin: a comparison of different antagonists.

1. Eight platelet activating factor (Paf) antagonists were evaluated as inhibitors of oedema formation in rabbit skin induced by intradermal injection of Paf plus prostaglandin E2 (PGE2). Antagonists were tested by both intradermal (i.d.) and intravenous (i.v.) routes. 2. Intradermal injection of two antagonists structurally-related to Paf (SRI 63-675 and CV-3988) resulted in a partial inhibition of Paf-induced oedema formation but at high doses of antagonist, marked agonist activities were detected. CV-3988 administered i.v. inhibited Paf-induced plasma leakage by 73-80%; however, oedema responses to a range of other inflammatory mediators were also reduced, albeit to a lesser extent (40-60%). SRI 63-675 administered i.v. did not significantly inhibit Paf-induced oedema. 3. The antagonist 48740 RP administered either i.d. or i.v. showed partial, but selective, inhibition of Paf-induced oedema formation, although the doses required were high when compared with other antagonists. 4. BN 52021 was a weak Paf antagonist when injected i.d., but following i.v. administration the responses to Paf were inhibited by 63-71%. Responses to all other mediators tested were unaffected. 5. Kadsurenone and its synthetic derivatives, L-652,731 and L-659,989 all blocked responses to Paf in the skin. L-659,989 was the most potent, achieving almost total inhibition when injected i.d. and i.v.; moreover, it was selective for Paf. L-652,731 was more potent than kadsurenone. 6. WEB 2086 given i.d. and i.v. showed similar activity to L-659,989 and it was also selective for Paf-induced oedema formation. 7. These results illustrate that in rabbit skin not all Paf antagonists are selective for Paf, some showing agonist-like activity which can mask antagonist properties. It is suggested that before ascribing a role for endogenous Paf in an inflammatory reaction based on results with antagonists, the activity of the antagonists in the model under investigation should be rigorously established.

Animals↗

Sentinel node localization in breast cancer using intradermal dye injection: results, influencing factors and learning curve.

To evaluate the identification rate, false negative rate, concordance, negative predictive value of sentinel node localization in breast cancer using intradermal isosulfan blue injection whether this is accurate enough for surgical approach in breast cancer surgery and whether there is a significant learning curve for this technique. Factors affecting the outcomes of the procedure are also determined. From August 2002 to September 2003, 66 cases of stage 0-IIIB operable breast cancer patients underwent sentinel lymph node biopsy before standard breast cancer operation. Overall, identification rate was 80.3%, false negative rate was 10.6%, concordance was 86.8%, negative predictive value was 83.3%, sentinel node was the only node that was positive in 45.5%, and mean operative time was 55.1 minutes. Factors found to lower sentinel node identification rate are neoadjuvant chemotherapy and large tumor (T3-4) while previous excision was not found to affect the identification rate. There is significant learning curve in this technique and this should be performed at least 40-45 cases in the learning phase to accomplish a high identification rate and lower false negative rate before implicating into clinical practice.

Adolescent↗

AMPA/kainate antagonist LY293558 reduces capsaicin-evoked hyperalgesia but not pain in normal skin in humans.

BACKGROUND: Animal studies suggest that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-kainate (AMPA-KA) receptors are involved in pain processing. The effects of the competitive AMPA-KA antagonist LY293558 in two types of experimental pain in human volunteers, brief pain sensations in normal skin, and mechanical allodynia-pinprick hyperalgesia were studied after the injection of intradermal capsaicin. METHODS: Brief intravenous infusions of the competitive AMPA-KA antagonist LY293558 were given to 25 healthy volunteers to examine acute toxicity and analgesic effects. Fifteen volunteers then entered a double-blinded, three-period crossover study. In a Phase II study, LY293558 infusions (100% maximally tolerated dose vs. 33% maximally tolerated dose vs. placebo) began 10 min after intradermal injection of 250 microg capsaicin in volar forearm. Spontaneous pain, areas of mechanical allodynia and pinprick hyperalgesia, and side effects were determined every 5 min for 60 min. RESULTS: The median maximally tolerated dose was 1.3 +/- 0.4 (range, 0.9-2.0) mg/kg. Tests of cognitive and neurological function were unchanged. Dose-limiting side effects were hazy vision in 95% of volunteers and sedation in 40%. There were no significant changes in electrical or warm-cool detection and pain thresholds or heat pain thresholds. LY293558 had little effect on brief pain sensations in normal skin. Both high and low doses of LY293558 significantly reduced pain intensity, pain unpleasantness, and the area in which light brush evoked pain after intradermal capsaicin. There was a trend toward a dose-response effect of LY293558 on the area in which pinprick evoked pain after intradermal capsaicin, which did not reach statistical significance. CONCLUSIONS: The authors infer that AMPA-KA receptor blockade reduces the spinal neuron sensitization that mediates capsaicin-evoked pain and allodynia. The low incidence of side effects at effective doses of LY293558 suggests that this class of drugs may prove to be useful in clinical pain states.

Adult↗

Esthetic refinements in forehead flap nasal reconstruction.

OBJECTIVE: To identify refinements in forehead flap nasal reconstruction that consistently provide better esthetic and functional results. DESIGN: Case series of patients undergoing forehead flap nasal reconstruction from July 1, 1987, to May 31, 1994. SETTING: University hospital ambulatory surgery department. PATIENTS: Thirty-two patients with various nasal defects. INTERVENTIONS: Modifications of currently accepted techniques of paramedian forehead flap nasal reconstruction, namely, flap harvest and contouring, W-plasty closure of the superior forehead donor site, and creation of soft-tissue triangles. The principles of open-structure rhinoplasty are incorporated into cartilaginous reconstruction of the nasal tip and columella. The alar rim is reconstructed with cartilage grafts placed at the nasal rim. MAIN OUTCOME MEASURES: Esthetic and functional results of nasal reconstruction were subjectively graded by three otolaryngologists (V.C.Q., D.A.S., and M.F.R.) and the patients. RESULTS: Improved esthetic and functional nasal reconstruction. The most common nasal subunits reconstructed were as follows: ala, 27 patients (84%); side-wall, 22 patients (69%); dorsum, 18 patients (56%), and tip, 15 patients (47%). The esthetic results ranged from average to excellent (3 to 5 on a scale of 5), the functional results ranged from improved to much improved over preoperative breathing (4 to 5). Two patients required unplanned surgical revisions. Forty-seven percent of patients chose to undergo dermabrasion. Five patients required postoperative intradermal injection of triamcinolone acetonide (Kenalog). Three patients required preoperative tissue expansion. Flap or graft loss, infection, or hematoma did not occur. CONCLUSIONS: The predictability of the techniques in providing excellent results in patients undergoing nasal reconstruction decreases the need for revision procedures and helps the patient and the surgeon achieve the desired outcome.

Aged↗

A stratified randomized study of intradermal BCG in patients with carcinoma of the bronchus: prolongation of quality but not length of life in inoperable patients.

This paper reports the results of a stratified, randomized trial of monthly intradermal injections of Glaxo BCG in addition to conventional therapy (surgery, radiotherapy or no treatment) in a consecutive series of 75 men with confirmed bronchial carcinoma. BCG treatment did not significantly prolong survival but had consistenly more effect in prolonging the period in good general condition and in "acceptable" clinical condition. These were significantly prolonged among the BCG patients (all histopathologies) treated with a full course of radiotherapy (p = 0.01, p = 0.005) and among the 43 patients with squamous carcinoma after adjustment for treatment and general prognostic factors (ratio of observed to expected deaths (O/E) for BCG 0.65, P = 0.025). There was a tendency for BCG patients with oat cell carcinoma to survive less well than controls (O/E for BCG 1.40 not significant). Within comparable groups of patients with squamous carcinoma the delay in decline of general condition was accompanied by reduced weight loss.

Aged↗

Treatment of skin injuries induced by sulfur mustard with calmodulin antagonists, using the pig model.

Sulfur mustard (HD) is a potent cutaneous vesicant that penetrates rapidly through the skin, causing prolonged injuries and leading to severe incapacitation. Although there has been long and intensive efforts to find a treatment for HD skin lesions, no effective treatment is available for HD-induced skin injuries. Recently, ointments containing calmodulin antagonists were found to be effective in preventing skin injuries induced by HD in hairless mice. The present study was designed to investigate the beneficial effects of topical treatments with calmodulin antagonists against HD skin lesions in the pig model. The pig is used as a preferred animal model for human skin in many studies, including vesicants. Neat HD, either in liquid form (0.2-1 microl droplets) or as vapour, was applied to the back skin of female pigs (a cross Large White & Landrace, 10-12 kg) for various exposure durations. Evaluation was based on quantitative analysis of the degree of erythema and area of the lesions, as well as histological evaluation. Calmodulin antagonists (10% pentamide, 1% trifluoperazine, 2% thioridazine) and anaesthetics (20% lidocaine and 3% benoxinate) were dissolved in pluronic F-127 base according to Kim et al. (Eur. J. Pharmacol. 1996; 313: 107-114) or in saline, and were applied either topically as ointments or by intradermal injection, as early as 5 min post-exposure (twice a day for at least 3 days). The results demonstrated that topically applied pluronic base ointments containing lidocaine or pentamide produce beneficial effects when applied immediately after short-term HD exposure to pig skin.

Administration, Topical↗

Cross-presentation of virus-like particles by skin-derived CD8(-) dendritic cells: a dispensable role for TAP.

Virus-like particles (VLP) induce efficient CTL responses although they do not carry any genetic information. Here, we analyzed MHC class I associated presentation of VLP-derived CTL-epitopes in vivo. After intradermal injection of VLP containing the immunodominant epitope (p33) of lymphocytic choriomeningitis virus (p33-VLP), presentation of peptide p33 in draining lymph nodes was largely restricted to CD8(-) skin-derived dendritic cells (DC). Surprisingly, and in contrast to findings with tumor cells, TAP1-deficient DC and macrophages mediated efficient cross-presentation of VLP-derived p33 in vivo and in vitro. However, the ability of TAP1-deficient DC to cross-present p33-VLP was reduced compared to wild-type DC, indicating that in DC, both TAP-dependent and TAP-independent pathways were operative. In contrast, macrophages cross-presented p33-VLP normally in the absence of TAP. The TAP-dependent pathway of cross-presentation is therefore confined to DC while both macrophages and DC harbor the TAP-independent pathway. In summary, the results show that VLP-derived epitopes are cross-presented by CD8(-) DC in vivo in a partial TAP-independent fashion and highlight important differences in the processing machinery of DC versus macrophages.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma.

BACKGROUND: The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL). METHODS: The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted. RESULTS: Twenty patients were enrolled in this trial. The median patient age was 59 years. Ten patients had been treated previously (median, 2 regimens; range, 1 to 7). Eighteen (90%) patients had stage III or IV disease. Autologous vaccines were successfully prepared for 17 (85%) patients and all received at least 1 dose. The treatment was very well tolerated. One patient experienced a response with biopsy-proven clearance of the lymphoma cells in 2 of the skin nodules at 3.0 months that lasted for 7.0 months. Eight patients had stable disease for 6.0 to 19.8 months. The median failure-free survival duration in patients who received vaccine therapy was 5.2 months. CONCLUSIONS: HSPPC-96 can be prepared from tumor specimens for the majority of lymphoma patients, but it had limited efficacy in inducing responses in patients with active diseases. Further studies of HSPPCs, therefore, should be considered in adjuvant settings or in combination with other immunomodulatory agents to assess survival benefit.

Aged↗

Tumor necrosis factor (TNF) receptor type 1 (p55) is a main mediator for TNF-alpha-induced skin inflammation.

Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic proinflammatory cytokine that elicits a large number of biological effects, including inflammatory and immunoregulatory responses. Biological activities of TNF-alpha are mediated by two distinct TNF receptors, p55 type 1 receptor (TNFR1) and p75 type 2 receptor (TNFR2). To determine the role of TNF-alpha in the induction of inflammatory responses in the skin, gene-targeted mutant mice lacking either TNFR1 or TNFR2 were painted with irritant chemicals. Both phenol and croton oil painting onto the ears induced less inflammation in TNFR1(-) mice than normal and TNFR2(-) mice. Intradermal injection of TNF-alpha (0.2-200 ng for 3 days) into the ear induced less inflammation in TNFR1(-) mice than in normal mice. TNFR2(-) mice developed a normal inflammatory reaction to high doses of TNF-alpha (20-200 ng for 3 days), while they showed minimal reactivity to low doses of TNF-alpha (0.2-2 ng for 3 days). TNF-alpha is known to trigger the release of a series of other cytokines and to induce the expression of cell adhesion molecules, thus contributing to the development of inflammation. The levels of protein and mRNA for interleukin (IL)-6 were elevated in keratinocytes from normal as well as TNFR2(-) mice after treatment with TNF-alpha, while keratinocytes from TNFR1(-) mice did not show any up-regulation of IL-6. TNF-alpha induced intercellular adhesion molecule (ICAM)-1 expression in the keratinocytes from normal and TNFR2(-) mice, but not in those from TNFR1(-) mice. These results indicate that TNFR1 is critical for induction of skin inflammation by TNF-alpha.

Administration, Topical↗

Effects of vasodilators guanethidine, nicardipine, nitroglycerin, and prostaglandin E1 on primary afferent nociceptors in humans.

Although vasodilator agents have been used to alleviate the pain of complex regional pain syndromes, the precise mechanism of pain relief is not well known. In this study the effects of various kinds of vasodilators on primary afferent nociceptors were investigated by measuring the thermal pain threshold. Evaluated in the study were the effects of guanethidine (2 mg/mL), nicardipine (0.2 mg/mL). Nitroglycerin (0.3 mg/mL), and prostaglandin E1 (1 microgram/mL) on the cutaneous pain threshold and blood flow at 7-day intervals in six healthy volunteers. Each aliquot of 0.5 mL of the test vasodilator or lidocaine (10 mg/mL) and saline (control) were intradermally injected at three sites each on both forearms. The pricking-pain threshold and skin tissue blood flow were determined using a radiant heat-stimulating system and a laser-Doppler tissue-blood flowmeter, respectively. The pain threshold increased with lidocaine, guanethidine, and nicardipine; remained unchanged with Nitroglycerin; but decreased with prostaglandin E1. In contrast, the skin tissue blood flow increased by four to nine times with all vasodilators. These results indicate that the effect of vasodilators on primary afferent nociceptors is not related to the vasodilating effect and may not involve a common mechanism of action for pain relief in complex regional pain syndromes.

Adult↗

Basic fibroblast growth factor promotes apoptosis and suppresses granulation tissue formation in acute incisional wounds.

Cytokines are thought to play an important role in cellular loss and apoptosis during the repair of granulation tissue. In order to investigate the role of apoptosis following the administration of basic fibroblast growth factor (bFGF) to a wound, the present study examined the relationship between the degree of granulation tissue formation and the level of apoptosis in rat skin incisional wounds, following treatment with an intradermal injection of bFGF (0.1 microg and 1 microg per cm of wound). Histological assessment of the width of the wound tissue showed that the degree of granulation tissue in the 1 microg-bFGF-treated group had increased by day 7, but then subsequently diminished by days 14 and 28. The TUNEL index increased rapidly from day 1, peaking on day 7, with the index being higher in the 1 microg-bFGF-treated group on days 4, 7, and 14, when compared with a control group. In parallel with a marked increase in the TUNEL index over the first 14 days, the number of cells positive for vimentin and CD3 in the 1 microg-bFGF-treated wounds had decreased by day 14. The number of PCNA-positive cells, an indicator of cell proliferation, peaked on day 4 in the bFGF-treated wounds and then declined rapidly. On the basis of these results, it is suggested that the suppression of granulation tissue formation in bFGF-treated wounds is mainly due to an early and persistent increase in apoptosis in the granulation tissue cells. The expression of both transforming growth factor (TGF)-beta1 and bFGF was also elevated in the bFGF-treated wounds on days 4 and 7, suggesting that fibroblast apoptosis was induced by bFGF treatment. Unexpectedly, on day 28, the wound breaking strength was not reduced in the bFGF-treated wounds. These results indicate that apoptosis regulation following bFGF administration to an incisional wound may lead effectively to granulation tissue formation and promote a scar-less repair process.

Acute Disease↗