N,N'-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents.
Oral N-acetyl-L-cysteine (NAC) is used clinically for treatment of chronic obstructive pulmonary disease. NAC is easily oxidized to its disulfide. We show here that N,N'-diacetyl-L-cystine (DiNAC) is a potent modulator of contact sensitivity (CS)/delayed type hypersensitivity (DTH) reactions in rodents. Oral treatment of BALB/c mice with 0.003 to 30 micromol/kg DiNAC leads to enhancement of a CS reaction to oxazolone; DiNAC is 100 to 1000 times more potent than NAC in this respect, indicating that it does not act as a prodrug of NAC. Structure-activity studies suggest that a stereochemically-defined disulfide element is needed for activity. The DiNAC-induced enhancement of the CS reaction is counteracted by simultaneous NAC-treatment; in contrast, the CS reaction is even more enhanced in animals treated with DiNAC together with the glutathione-depleting agent buthionine sulfoximine. These data suggest that DiNAC acts via redox processes. Immunohistochemically, ear specimens from oxazolone-sensitized and -challenged BALB/c mice treated with DiNAC display increased numbers of CD8(+) cells. DiNAC treatment augments the CS reaction also when fluorescein isothiocyanate is used as a sensitizer in BALB/c mice; this is a purported TH2 type of response. However, when dinitrofluorobenzene is used as a sensitizer, inducing a purported TH1 type of response, DiNAC treatment reduces the reaction. Treatment with DiNAC also reduces a DTH footpad-swelling reaction to methylated BSA. Collectively, these data indicate that DiNAC in vivo acts as a potent and effective immunomodulator that can either enhance or reduce the CS or DTH response depending on the experimental conditions. (+info)
Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey.
We investigated whether uninjured cutaneous C-fiber nociceptors in primates develop abnormal responses after partial denervation of the skin. Partial denervation was induced by tightly ligating spinal nerve L6 that innervates the dorsum of the foot. Using an in vitro skin-nerve preparation, we recorded from uninjured single afferent nerve fibers in the superficial peroneal nerve. Recordings were made from 32 C-fiber nociceptors 2-3 wk after ligation and from 29 C-fiber nociceptors in control animals. Phenylephrine, a selective alpha1-adrenergic agonist, and UK14304 (UK), a selective alpha2-adrenergic agonist, were applied to the receptive field for 5 min in increasing concentrations from 0.1 to 100 microM. Nociceptors from in vitro control experiments were not significantly different from nociceptors recorded by us previously in in vivo experiments. In comparison to in vitro control animals, the afferents found in lesioned animals had 1) a significantly higher incidence of spontaneous activity, 2) a significantly higher incidence of response to phenylephrine, and 3) a higher incidence of response to UK. In lesioned animals, the peak response to phenylephrine was significantly greater than to UK, and the mechanical threshold of phenylephrine-sensitive afferents was significantly lower than for phenylephrine-insensitive afferents. Staining with protein gene product 9.5 revealed an approximately 55% reduction in the number of unmyelinated terminals in the epidermis of the lesioned limb compared with the contralateral limb. Thus uninjured cutaneous C-fiber nociceptors that innervate skin partially denervated by ligation of a spinal nerve acquire two abnormal properties: spontaneous activity and alpha-adrenergic sensitivity. These abnormalities in nociceptor function may contribute to neuropathic pain. (+info)
Cytokine-mediated inflammatory hyperalgesia limited by interleukin-4.
1. The effect of IL-4 on responses to intraplantar (i.pl.) carrageenin, bradykinin, TNFalpha, IL-1beta, IL-8 and PGE2 was investigated in a model of mechanical hyperalgesia in rats. Also, the cellular source of the IL-4 was investigated. 2. IL-4, 30 min before the stimulus, inhibited responses to carrageenin, bradykinin, and TNFalpha, but not responses to IL-1beta, IL-8 and PGE2. 3. IL-4, 2 h before the injection of IL-1beta, did not affect the response to IL-1beta, whereas IL-4, 12 or 12+2 h before the IL-1beta, inhibited the hyperalgesia (-30%, -74%, respectively). 4. In murine peritoneal macrophages, murine IL-4 for 2 h before stimulation with LPS, inhibited (-40%) the production of IL-1beta but not PGE2. Murine IL-4 (for 16 h before stimulation with LPS) inhibited LPS-stimulated PGE2 but not IL-1beta. 5. Anti-murine IL-4 antibodies potentiated responses to carrageenin, bradykinin and TNFalpha, but not IL-1beta and IL-8, as well as responses to bradykinin in athymic rats but not in rats depleted of mast cells with compound 40/80. 6. These data suggest that IL-4 released by mast cells limits inflammatory hyperalgesia. During the early phase of the inflammatory response the mode of action of the IL-4 appears to be inhibition of the production TNFalpha, IL-1beta and IL-8. In the later phase of the response, in addition to inhibiting the production of pro-inflammatory cytokines, IL-4 also may inhibit the release of PGs. (+info)
Isolated femoropopliteal bypass graft for limb salvage after failed tibial reconstruction: a viable alternative to amputation.
PURPOSE: Femoropopliteal bypass grafting procedures performed to isolated popliteal arteries after failure of a previous tibial reconstruction were studied. The results were compared with those of a study of primary isolated femoropopliteal bypass grafts (IFPBs). METHODS: IFPBs were only constructed if the uninvolved or patent popliteal segment measured at least 7 cm in length and had at least one major collateral supplying the calf. When IFPB was performed for ischemic lesions, these lesions were usually limited to the digits or small portions of the foot. Forty-seven polytetrafluoroethylene grafts and three autogenous reversed saphenous vein grafts were used. RESULTS: Ankle brachial pressure index (ABI) increased after bypass grafting by a mean of 0.46. Three-year primary life table patency and limb-salvage rates for primary IFPBs were 73% and 86%, respectively. All eight IFPBs performed after failed tibial bypass grafts remained patent for 2 to 44 months, with patients having viable, healed feet. CONCLUSION: In the presence of a suitable popliteal artery and limited tissue necrosis, IFPB can have acceptable patency and limb-salvage rates, even when a polytetrafluoroethylene graft is used. Secondary IFPB can be used to achieve limb salvage after failed tibial bypass grafting. (+info)
Superficial femoral eversion endarterectomy combined with a vein segment as a composite artery-vein bypass graft for infrainguinal arterial reconstruction.
OBJECTIVE: The purpose of this study was to determine the results of composite artery-vein bypass grafting for infrainguinal arterial reconstruction. METHODS: This study was designed as a retrospective case series in two tertiary referral centers. Forty-eight of 51 patients underwent the procedure of interest for the treatment of ischemic skin lesions (n = 42), rest pain (n = 3), disabling claudication (n = 1), and infected prosthesis (n = 2). The intervention used was infrainguinal composite artery-vein bypass grafting to popliteal (n = 18) and infrapopliteal (n = 30) arteries, with an occluded segment of the superficial femoral artery prepared with eversion endarterectomy and an autogenous vein conduit harvested from greater saphenous veins (n = 43), arm veins (n = 3), and lesser saphenous veins (n = 2). The main outcome measures, primary graft patency rates, foot salvage rates, and patient survival rates, were described by means of the life-table method for a mean follow-up time of 15.5 months. RESULTS: The cumulative loss during the follow-up period was 6% and 24% at 6 and 12 months, respectively. The primary graft patency rates, the foot salvage rates, and the patient survival rates for patients with popliteal grafts were 60.0% +/- 9.07%, 75.7% +/- 9.18%, and 93.5% +/- 6.03%, respectively, at 1 month; 53.7% +/- 11.85%, 68.9% +/- 12.47%, and 85. 0% +/- 9.92% at 1 year; and 46.7% +/- 18.19%, 68.9% +/- 20.54%, and 53.1% +/- 17.15% at 5 years. For infrapopliteal grafts, the corresponding estimates were 72.4% +/- 7.06%, 72.9% +/- 6.99%, and 92.7% +/- 4.79% at 1 month; 55.6% +/- 10.70%, 55.4% +/- 10.07%, and 77.9% +/- 9.02% at 1 year; and 33.6% +/- 22.36%, 55.4% +/- 30.20%, and 20.8% +/- 9.89% at 5 years. CONCLUSION: The composite artery-vein bypass graft is a useful autogenous alternative for infrainguinal arterial reconstruction when a vein of the required quality is not available or when the procedure needs to be confined to the affected limb. (+info)
Brain activation during maintenance of standing postures in humans.
The regulatory mechanism of bipedal standing in humans remains to be elucidated. We investigated neural substrates for maintaining standing postures in humans using PET with our mobile gantry PET system. Normal volunteers were instructed to adopt several postures: supine with eyes open toward a target; standing with feet together and eyes open or eyes closed; and standing on one foot or with two feet in a tandem relationship with eyes open toward the target. Compared with the supine posture, standing with feet together activated the cerebellar anterior lobe and the right visual cortex (Brodmann area 18/19), and standing on one foot increased cerebral blood flow in the cerebellar anterior vermis and the posterior lobe lateral cortex ipsilateral to the weight-bearing side. Standing in tandem was accompanied by activation within the visual association cortex, the anterior and posterior vermis as well as within the midbrain. Standing with eyes closed activated the prefrontal cortex (Brodmann area 8/9). Our findings confirmed that the cerebellar vermis efferent system plays an important role in maintenance of standing posture and suggested that the visual association cortex may subserve regulating postural equilibrium while standing. (+info)
Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity.
In spite of recent breakthroughs in understanding limb patterning, the genetic factors determining the differences between the forelimb and the hindlimb have not been understood. The genes Pitx1 and Tbx4 encode transcription factors that are expressed throughout the developing hindlimb but not forelimb buds. Misexpression of Pitx1 in the chick wing bud induced distal expression of Tbx4, as well as HoxC10 and HoxC11, which are normally restricted to hindlimb expression domains. Wing buds in which Pitx1 was misexpressed developed into limbs with some morphological characteristics of hindlimbs: the flexure was altered to that normally observed in legs, the digits were more toe-like in their relative size and shape, and the muscle pattern was transformed to that of a leg. (+info)
Insertion of the abductor hallucis muscle in feet with and without hallux valgus.
Textbooks of human anatomy present different opinions on the insertion of the abductor hallucis muscle which is concerned in etiology as well as in therapy of hallux valgus. In plastic and reconstructive surgery the muscle is taken as a graft for flap-surgery. In this study 109 feet (58 right, 51 left) were examined, 18 of these with clinical hallux valgus. The tendon of the muscle may attach to the tendon of the medial head of the short flexor hallucis muscle where a subtendineous bursa can be found. At the head of the first metatarsal bone the joint capsule is reinforced by fibres arising from the medial sesamoid bone which may be called "medial sesamoidal ligament." The tendon passes the first metatarsophalangeal joint plantarily to its transverse axis. Three types of insertion could be distinguished: type A, insertion at the proximal phalanx (N = 42); type B, insertion at the medial sesamoid ligament and at the medial sesamoid bone (N = 65); type C, insertion at the medial sesamoid bone (N = 2). In all types superficial fibres of the tendon extended to the medial and plantar sides of the base of the proximal phalanx, running in a plantar to dorsal direction. Statistical analysis exposed neither significant differences between both sides nor significant difference between normal feet and feet with hallux valgus. Therefore, a specific pattern of insertion of the abductor hallucis muscle in hallux valgus cannot be stated. (+info)