Group B and F Beta Streptococcus Necrotizing Infection-Surgical Challenges with a Deep Central Plantar Space Abscess A Diabetic Limb Salvage Case Report.

We present the case of a 66-year-old, type II diabetic male with a deep wound to the plantar-lateral aspect of his right hallux. On examination, the central plantar compartment of his right foot was moderately erythematous and tender on palpation. After obtaining a deep wound culture, treatment was complicated by a progression of a group B and F beta streptococcus, necrotizing infection. The patient underwent a right hallux amputation, followed by a plantar medial incision for drainage of an abscess to the medial and central plantar compartments of the foot. Due to the extent and limb threat of the infection, the patient ultimately underwent a transmetatarsal amputation. Advanced healing modalities were also employed to decrease wound healing times, which allowed the patient to achieve early weightbearing and return to activities of daily living. This study depicts how the astute podiatric surgeon needs to make a decision in a timely manner to surgically debride all nonviable and necrotic tissue in order to minimize further amputation and preserve foot function.

Group B and F Beta Streptococcus Necrotizing Infection-Surgical Challenges with a Deep Central Plantar Space Abscess: A Diabetic Limb Salvage Case Report.

We present the case of a 66-year-old, type II diabetic male with a deep wound to the plantar-lateral aspect of his right hallux. On examination, the central plantar compartment of his right foot was moderately erythematous and tender on palpation. After obtaining a deep wound culture, treatment was complicated by a progression of a group B and F beta streptococcus, necrotizing infection. The patient underwent a right hallux amputation, followed by a plantar medial incision for drainage of an abscess to the medial and central plantar compartments of the foot. Due to the extent and limb threat of the infection, the patient ultimately underwent a transmetatarsal amputation. Advanced healing modalities were also employed to decrease wound healing times, which allowed the patient to achieve early weightbearing and return to activities of daily living. This study depicts how the astute podiatric surgeon needs to make a decision in a timely manner to surgically debride all nonviable and necrotic tissue in order to minimize further amputation and preserve foot function.

Angiokeratoma presenting as a melanoma: a case report.

Angiokeratomas are benign skin lesions that can resemble melanomas or verrucae. Although morbidity from these lesions is rare, treatment for angiokeratomas typically consists of simple surgical excision. We aim to describe a case of a painful angiokeratoma that presented with the appearance of melanoma.

Open reduction-internal fixation of a navicular body fracture with dorsal displacement of the first and second cuneiforms: a case report.

Body fractures of the tarsal navicular are relatively uncommon. To date, there is little literature discussing a navicular body fracture with dorsal subluxation of the first and second cuneiforms over the navicular. This case study presents a 30-year-old patient with this injury. He underwent open reduction internal fixation of the navicular body fracture successfully but failed adequate reduction of the navicular cuneiform joint after ligamentous reconstruction. After revisional surgery, he also failed 6 weeks of percutanous pinning with Kirschner-wire fixation. When comparing the literature of a similar injury, the Lisfranc fracture disclocation, the same principles may apply. One should consider rigid open reduction internal fixation or even primary fusion to treat disclocation of the naviculocuneiform joint following a navicular body fracture.

Pilomatrixoma: an infrequently encountered lesion on the lower extremity.

We discuss the clinical presentation and treatment of pilomatrixoma as it occurs in the lower extremity. Although pilomatrixoma is far more common on the head, neck, and upper extremity, it can be found on the lower extremity. Treatment is aimed primarily at excision if the lesion is symptomatic or suspicious for malignancy. The authors present a case of a 73-year-old male who presented to the diabetic foot center with this condition.

A mechanically powered negative pressure device used in conjunction with a bioengineered cell-based product for the treatment of pyoderma gangrenosum: a case report .

Pyoderma gangrenosum (PG), an uncommon inflammatory and ulcerative skin disease, typically is treated medically with a combination of immunosuppression and local wound care, but evidence to guide care is limited. PG wounds can be difficult to heal. A 76-year-old male patient presented with a history of rheumatoid arthritis and recalcitrant PG. After 9 months of treatment with local wound care, steroids, and topical tacrolimus, the wound had increased in size from 1.8 cm x 1.5 cm to 7.2 cm x 5.6 cm. At that time, he was started on a regimen of five applications of a bioengineered cell- based product (one application every 2 weeks for a total of five applications) with twice-weekly mechanically powered negative pressure device changes. The latter was started at 75 mm Hg and changed to 125 mm Hg after 4 weeks. Oral corticosteroid therapy was initially started at 40 mg of prednisone, then slowly tapered to 20 mg, but could not be completely discontinued due to a flare in the patient's rheumatoid symptoms. The wound was completely healed after 16 weeks. Research to ascertain the effectiveness of protocols of PG care, including the combination treatment described, is needed to help clinicians provide evidence-based care for these challenging wounds.

A case of a sural neuroma as a cause of lateral ankle pain.

This article reviews the diagnosis, pathology, and treatment of a lateral ankle (sural) neuroma. Though there have been vague references to neuroma of the sural nerve, no specific case report has been presented. It is felt that mechanical and biomechanical factors may contribute to the formation of this type of painful mass which warrants further discussion as an additional etiology of lateral ankle pain. In this article, we describe a case of neuroma of the sural nerve which was unresponsive to conservative treatments.

HIV neuropathy induced Charcot neuroarthropathy: a case discussion.

Charcot neuroarthropathy is a devastating joint condition that affects persons with neuropathy. With HIV/AIDS treatments prolonging the lives of these persons, it is likely that long-term sequelae of the disease will become more evident in the near future. Patients with this disease frequently develop peripheral neuropathy. A high index of suspicion must be raised in any patient with peripheral neuropathy of any cause and a red, hot, swollen, painful foot for Charcot neuroarthropathy to give these patients proper treatment to help prevent the devastating effects of Charcot neuropathy with its potential consequences including foot ulceration and amputation. We present a case of an individual with HIV peripheral neuropathy and Charcot neuroarthropathy.

Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents.

To develop SAR at both the cannabinoid CB(1) and CB(2) receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB(1) and CB(2) receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure-activity relationships are presented. Although many of these compounds are selective for the CB(2) receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB(1) affinity and good CB(2) affinity.

1-Pentyl-3-phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice.

BACKGROUND: Smoking of synthetic cannabinoid-enhanced "herbal incense" is an emerging substance abuse problem. The indole-derived cannabinoids identified in these products were originally developed as research tools and are structurally distinct from cannabinoids in the cannabis plant. Although abused by humans, most published research on this class of compounds has been performed in vitro. The purpose of this study was to evaluate a novel series of 1-pentyl-3-phenylacetylindoles in mice. METHODS: The potencies of these analogs to produce the cannabinoid agonist effects of antinociception, hypothermia and suppression of locomotion were evaluated in ICR mice. The major structural manipulations in the present series included the type of substituent (i.e., unsubstituted, methyl, methoxy, chloro, bromo, and fluoro) and the position of the substituent on the phenyl ring (i.e., 2-, 3- or 4-position). RESULTS: Potencies of this series of phenylacetylindoles for each cannabinoid effect were highly correlated with CB(1) receptor affinities reported previously. Active compounds produced a profile of effects that resembled that exhibited by Δ(9)-tetrahydrocannabinol (THC). The most critical factor affecting in vivo potency was the position of the substituent. Whereas compounds with 2- and 3-phenylacetyl substituents were efficacious with good potencies, 4-substituents resulted in compounds that had poor potency or were inactive. CONCLUSIONS: These results suggest that phenylacetylindoles with good CB(1) binding affinity share pharmacological properties with THC in mice; however, they also emphasize the complexity of molecular interactions of synthetic cannabinoids with CB(1) receptors and suggest that scheduling efforts based solely upon structural features should proceed with caution.

Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB(1) receptor antagonist.

Rimonabant, the prototypic antagonist of cannabinoid CB(1) receptors, has been reported to have inverse agonist properties at higher concentrations, which may complicate its use as a tool for mechanistic evaluation of cannabinoid pharmacology. Consequently, recent synthesis efforts have concentrated on discovery of a neutral antagonist using a variety of structural templates. The purpose of this study was to evaluate the pharmacological properties of the putative neutral cannabinoid CB(1) receptor antagonist O-2050, a sulfonamide side chain analog of Δ(8)-tetrahydrocannabinol. O-2050 and related sulfonamide cannabinoids exhibited good affinity for both cannabinoid CB(1) and CB(2) receptors. While the other sulfonamide analogs produced cannabinoid agonist effects in vivo (e.g., activity suppression, antinociception, and hypothermia), O-2050 stimulated activity and was inactive in the other two tests. O-2050 also decreased food intake in mice, an effect that was reminiscent of that produced by rimonabant. Unlike rimonabant, however, O-2050 did not block the effects of cannabinoid agonists in vivo, even when administered i.c.v. In contrast, O-2050 antagonized the in vitro effects of cannabinoid agonists in [(35)S]GTPγS and mouse vas deferens assays without having activity on its own in either assay. Further evaluation revealed that O-2050 fully and dose-dependently substituted for Δ(9)-tetrahydrocannabinol in a mouse drug discrimination procedure (a cannabinoid agonist effect) and that it inhibited forskolin-stimulated cyclic AMP signaling with a maximum efficacy of approximately half that of the full agonist CP55,940 [(-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol]. Together, these results suggest that O-2050 is not a viable candidate for classification as a neutral cannabinoid CB(1) receptor antagonist.

1-Bromo-3-(1',1'-dimethylalkyl)-1-deoxy-Δ(8)-tetrahydrocannabinols: New selective ligands for the cannabinoid CB(2) receptor.

Δ(8)-Tetrahydrocannabinol (26), 3-(1',1'-dimethylbutyl)- (12), 3-(1',1'-dimethylpentyl)- (13), 3-(1',1'-dimethylhexyl)- (14) and 3-(1',1'-dimethylheptyl)-Δ(8)-tetrahydrocannabinol (15) have been converted into the corresponding 1-bromo-1-deoxy-Δ(8)-tetrahydrocannabinols (25, 8-11). This was accomplished using a protocol developed in our laboratory in which the trifluoromethanesulfonate of a phenol undergoes palladium mediated coupling with pinacolborane. Reaction of this dioxaborolane with aqueous-methanolic copper(II) bromide provides the aryl bromide. The affinities of these bromo cannabinoids for the cannabinoid CB(1) and CB(2) receptors were determined. All of these compounds showed selectivity for the CB(2) receptor and one of them, 1-bromo-1-deoxy-3-(1',1'-dimethylhexyl)-Δ(8)-tetrahydrocannabinol (10), exhibits 52-fold selectivity for this receptor with good (28nM) affinity.

Synthesis and pharmacology of 1-methoxy analogs of CP-47,497.

Three 1-methoxy analogs of CP-47,497 (7, 8, and 19) have been synthesized and their affinities for the cannabinoid CB(1) and CB(2) receptors have been determined. Although these compounds exhibit selectivity for the CB(2) receptor none have significant affinity for either receptor. Modeling and receptor docking studies were carried out, which provide a rationalization for the weak affinities of these compounds for either receptor.

Synthesis, nicotinic acetylcholine receptor binding, and antinociceptive properties of 3'-(substituted phenyl)epibatidine analogues. Nicotinic partial agonists.

In 1992, John Daly et al. reported the isolation and structure determination of epibatidine. Epibatidine's unique structure and its potent nicotinic agonist activity have had a tremendous impact on nicotine receptor research. This research has led to a better understanding of the nicotinic acetylcholine receptor (nAChR) pharmacophore and to epibatidine analogues with potential as pharmacotherapies for treating various CNS disorders. In this study, we report the synthesis, receptor binding ([(3)H]epibatidine and [(125)I]iodoMLA), and in vivo pharmacological properties (mouse tail flick, hot plate, hypothermia, and spontaneous activity) of a series of 3'-(substituted phenyl)epibatidine analogues (5a-m). Results from these studies have added to the understanding of the nAChR pharmacophore and led to nicotinic partial agonists that may have potential for smoking cessation. All the analogues had affinities for the alpha4beta2 nAChR similar to epibatidine (1). 3'-(3-Dimethylaminophenyl)epibatidine (5m) has a nicotinic partial agonist pharmacological profile similar to the smoking cessation drug varenicline. Other analogues are partial agonists with varying degrees of nicotinic functional agonist and antagonist activity. 3'-(3-Aminophenyl)epibatidine (5j) is a more potent functional agonist and antagonist in all tests than varenicline. 3'-(3-Fluorophenyl)epibatidine and 3'-(3-chlorophenyl)epibatidine (5c and 5e) are more potent than varenicline when tested as agonists in four pharmacological tests and antagonists when evaluated against nicotine in the analgesia hot-plate test.

Characterization of pharmacological and behavioral differences to nicotine in C57Bl/6 and DBA/2 mice.

Approximately 50-70% of the risk for developing nicotine dependence is attributed to genetics; therefore, it is of great significance to characterize the genetic mechanisms involved in nicotine reinforcement and dependence in hopes of generating better smoking cessation therapies. The overall goal of these studies was to characterize behavioral and pharmacological responses to nicotine in C57Bl/6 (B6) and DBA/2 (D2) mice, two inbred strains commonly used for genetic studies on behavioral traits. B6 and D2 mice where subjected to a battery of behavioral tests to measure nicotine's acute effects, calcium-mediated antinociceptive responses, tolerance to chronic treatment with osmotic mini pumps, and following three days of nicotine withdrawal. In general, D2 mice were less sensitive than B6 mice to the acute effects of nicotine, but were more sensitive to blockade of nicotine-induced antinociceptive responses by a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor. B6, but not D2 mice, developed tolerance to nicotine and nicotine conditioned place preference (CPP). While B6 and D2 mice both expressed some physical withdrawal signs, affective withdrawal signs were not evident in D2 mice. These results provide a thorough, simultaneous evaluation of the pharmacological and behavioral differences to experimenter-administered nicotine as measured in several behavioral tests of aspects that contribute to smoking behavior. The B6 and D2 strains show wide phenotypic differences in their responses to acute or chronic nicotine. These results suggest that these strains may be useful progenitors for future genetic studies on nicotine behaviors across batteries of mouse lines such as the BXD recombinant inbred panel.

Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids.

Cannabinoids have long been known to be potent inhibitors of intestinal and colonic propulsion. This effect has generally been attributed to their ability to prejunctionally inhibit release of acetylcholine from excitatory motor neurons that mediate, in part, the ascending contraction phase of the peristaltic reflex. In the present study we examined the effect of cannabinoids on the other transmitters known to participate in the peristaltic reflex using a three-compartment preparation of rat colon that allows separation of ascending contraction, descending relaxation, and the sensory components of the reflex. On addition to the orad motor compartment, anandamide decreased and AM-251, a CB-1 antagonist, increased ascending contraction and the concomitant substance P (SP) release. Similarly, on addition to the caudad motor compartment, anandamide decreased and AM-251 increased descending relaxation and the concomitant vasoactive intestinal peptide (VIP) release. On addition to the central sensory compartment, anandamide decreased and AM-251 increased both ascending contraction and SP release orad, and descending relaxation and VIP release caudad. This suggested a role for CB-1 receptors in modulation of sensory transmission that was confirmed by the demonstration that central addition of anandamide decreased and AM-251 increased release of the sensory transmitter, calcitonin gene-related peptide (CGRP). We conclude that the potent antipropulsive effect of cannabinoids is the result of inhibition of both excitatory cholinergic/tachykininergic and inhibitory VIPergic motor neurons that mediate ascending contraction and descending relaxation, respectively, as well as inhibition of the intrinsic sensory CGRP-containing neurons that initiate the peristaltic reflex underlying propulsive motility.

Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy.

Cannabinoids have been shown to cause CB1-receptor-dependent anticonvulsant activity in both in vivo and in vitro models of status epilepticus (SE) and acquired epilepsy (AE). It has been further demonstrated in these models that the endocannabinoid system functions in a tonic manner to suppress seizure discharges through a CB1-receptor-dependent pathway. Although acute cannabinoid treatment has anticonvulsant activity, little is known concerning the effects of prolonged exposure to CB1 agonists and development of tolerance on the epileptic phenotype. This study was carried out to evaluate the effects of prolonged exposure to the CB1 agonist WIN55,212-2 on seizure activity in a hippocampal neuronal culture model of low-Mg(2+) induced spontaneous recurrent epileptiform discharges (SREDs). Following low-Mg(2+) induced SREDs, cultures were returned to maintenance media containing 10, 100 or 1000 nM WIN55,212-2 from 4 to 24 h. Whole-cell current-clamp analysis of WIN55,212-2 treated cultures revealed a concentration-dependent increase in SRED frequency. Immunocytochemical staining revealed that WIN55,212-2 treatment induced a concentration-dependent downregulation of the CB1 receptor in neuronal processes and at both glutamatergic and GABAergic presynaptic terminals. Prolonged exposure to the inactive enantiomer WIN55,212-3 in low-Mg(2+) treated cultures had no effect on the frequency of SREDs or CB1 receptor staining. The results from this study further substantiate a role for a tonic CB1-receptor-dependent endocannabinoid regulation of seizure discharge and suggest that prolonged exposure to cannabinoids results in the development of tolerance to the anticonvulsant effects of cannabinoids and an exacerbation of seizure activity in the epileptic phenotype.

Discriminative stimulus properties of delta9-tetrahydrocannabinol (THC) in C57Bl/6J mice.

Primarily, rats have served as subjects in Delta(9)-tetrahydrocannabinol's (THC) discrimination studies although other species such as monkeys and pigeons have been used. While the introduction of the knockout and transgenic mice has vastly stimulated the study of the discriminative stimulus effects of drugs there is only a single published report of mice trained to discriminate THC. Thus, this study extended those results by providing a systematic replication that THC serves as an effective discriminative stimulus in mice and by further investigating the mechanisms of action involved in the THC discrimination model in the mouse. Male C57BL/6J mice were trained to discriminate 10 mg/kg THC from vehicle in 2-lever drug discrimination. THC fully and dose dependently substituted for itself. Cannabinoid indoles, except one with low cannabinoid CB(1) receptor affinity, substituted for THC. Anandamide failed to substitute for THC when administered alone but completely substituted when administered with the non-specific fatty acid amide hydrolase inhibitor, phenylmethylsulphonyl fluoride. As expected, nicotine failed to substitute for THC. Lastly, the cannabinoid CB(1) receptor antagonist rimonabant blocked THC's discriminative stimulus effects. Taken together these studies demonstrate THC's ability to produce discriminative stimulus effects as well as demonstrate its pharmacological specificity and mechanism of action in a two-lever drug discrimination mouse model.

Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus.

Several reports have focused on the involvement of the endocannabinoid system in hyperexcitability, particularly in seizure and epilepsy models. Our laboratory recently characterized a novel plasticity change of the cannabinoid type 1 (CB(1)) receptor in hippocampi of epileptic rats following pilocarpine-induced status epilepticus (SE). This long-term redistribution included selective layer-specific changes in CB(1) receptor expression within distinct hippocampal subregions. However, the temporal characteristics of this redistribution during the development of epilepsy had not been examined. Therefore, this study was initiated to evaluate the time course by which pilocarpine-induced SE produced changes in CB(1) receptor expression. Immunohistochemical analysis demonstrated that within 1 week following SE, there was a pronounced loss in CB(1) receptor expression throughout the hippocampus, while staining in many interneurons was preserved. By 1 month post-SE, pilocarpine-treated animals began to display epileptic seizures, and CB(1) receptor expression was characteristic of the redistribution observed in long-term epileptic rats, with decreases in CB(1) receptor immunoreactivity in the stratum pyramidale neuropil and dentate gyrus inner molecular layer, and increases in the strata oriens and radiatum of CA1-3. Observed changes in CB(1) receptor expression were confirmed at multiple time points by western blot analysis. The data indicate that overall decreases in expression following SE preempt a long-lasting CB(1) receptor redistribution, and that differential responses occur within the hippocampus to initial CB(1) receptor losses. This suggests a role for dysregulation of the endocannabinoid system during epileptogenesis and indicates that the CB(1) receptor redistribution temporally correlates with the emergence of epileptic seizures.

Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke.

Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB(2) receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB(2) receptors, by selective CB(2) agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB(2) receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB(1) antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB(2) agonist and a CB(1) antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB(2) receptor agonists and CB(1) receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.