The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism--or inverse agonism--as potential obesity treatment and other therapeutic use.

There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.

[Infectious complications of mandibular osteotomy]. / Complications infectieuses des ostéotomies mandibulaires.

BACKGROUND: Infection is a rare complication after orthognathic surgery. A rate of 1% to 15% has been reported in the literature. We reviewed our experience. MATERIAL AND METHODS: We reviewed retrospectively 60 mandibular osteotomies performed between 1998 and 1999. There were 41 women and 19 men, mean age 24 years. All were given antibiotic therapy using cefamandol 1500 mg preoperatively then 750 mg every 6 hours peroperatively and cefixime 400 mg/d postoperatively for 7 days. Patients were followed for at least 6 months after surgery. RESULTS: There were 10 infections (16% of the cases) involving a hematoma in 2 cases, adenitis in 1, osteitis on a cortical fragment in 2 and osteitis on implanted material in 5. DISCUSSION: We defined infection following orthognathic surgery as a collection or purulent fistula with either a high polynuclear count in the discharge fluid or a positive culture. Both soft tissue (for example infection of a perimandibular hematoma) or bone infections were equally considered. We found two types of risk factors: patient-related or procedure-related. Patient-related factors included smoking, paradontal status, and dental hygiene. The main procedure-related factor was duration of surgery. Measures of prevention include extraction of the wisdom teeth, interruption of smoking, preoperative scaling and careful dental care, rigorous operative technique, antibiotic therapy.

[Complications of genioplasty]. / Complications des génioplasties.

Genioplasty is one of the safest interventions in orthognathic surgery. We reviewed a series of 200 cases of genioplasty with or without other osteotomies and found 6 complications. We compared our findings with the rare data reported in the literature. We were able to distinguish: peroperative complications: atypical osteotomy, hemorrhage, soft tissue damage, injury to the mental nerve; postoperative complications: neurosensory deficits, hematoma, infection, secondary displacement, bone necrosis, mental ptosis, defective ossification, dental lesions, paradontal lesions, irregular mandibular contours. We present a discussion on means of prevention and treatment of these complications following genioplasty.

Modulation of microvascular permeability by 21-aminosteroids after burn injuries.

Burn injuries initiate lipid peroxidation in capillary endothelial cells and cause alterations in microvascular permeability, with subsequent leakage of fluid and protein from the plasma into the interstitium. We evaluated the effects of two lazaroid compounds (U74389F and U75412E) on alterations in microvascular permeability that resulted from burn injuries. A canine model was used for the evaluation of microvascular permeability at the site of the burn injury with the use of a measure of the reflection coefficient (sigma(d)). Hindpaw lymph flow, lymph and plasma total protein concentrations, and arterial, venous, and capillary pressures were measured before burn injuries and for 6 hours in 6 different groups. Footpaw weight gain was then calculated as the percentage of increase of experimental hindpaw relative to the contralateral paw. The damage was attenuated by 20 mg/kg of lazaroid U75412E given before the injuries, but a lower dose was not effective. This agent was also effective in limiting edema formation, as evidenced by changes in footpaw weight gain. However, the administration of either lazaroid compound produced no significant effect on the burn-induced changes in capillary permeability. We conclude that these lazaroids do not prevent burn-induced changes in permeability at the site of injury when administered after an injury. U75412E administered before the injury was effective in limiting the alterations in microvascular permeability.

A critical assessment of endpoints of shock resuscitation.

Modern hemodynamic therapy is not only the recognition and treatment of hypotension but also the avoidance and treatment of shock in its broadest sense. The major issues include the recognition of hypoperfusion of the body as a whole or its individual tissues and organ systems and the determination of the best endpoints for the treatment of shock. Even if all of the commonly used clinical indicators of shock are "normal," shock on a cellular, tissue, or organ basis may still be present. Whether "organ-specific" assessments, such as gastric tonometry or tissue oxygen tension measurement, are the ultimate answer to this problem remains to be seen. The determination of adequate intravascular volume (preload) continues to present major difficulties in the care of critically ill or injured patients. Although PCWP is frequently helpful, it is not a gold standard. A bedside ultrasonic technique, such as esophageal Doppler sonography, may replace the Swan-Ganz catheter technique in many patients.

Variation in axillary node dissection influences the degree of nodal involvement in breast cancer patients.

BACKGROUND AND OBJECTIVES: The number of positive axillary lymph nodes predicts prognosis and is often important in determining adjuvant chemotherapy in breast cancer patients. This study was undertaken to determine if differences in the extent of axillary node dissection would alter the number of reported positive nodes. METHODS: The study population consisted of 302 patients with invasive breast cancer who underwent complete (level I/II/III) axillary lymph node dissection. Assuming that all patients had undergone a level I/II dissection, it was determined how frequently a patient's nodal category (0, 1-3, 4-9, >10 positive nodes) would have been altered if a level I or level I/II/III dissection were performed. RESULTS: Assuming that all 302 patients had undergone a level I/II dissection, performing only level I dissection would have resulted in a change in nodal category in 15.9% of all patients and 36.1% of patients with positive nodes. The corresponding changes for a level I/II/III dissection would have been 4.3% and 9.5%, respectively. CONCLUSIONS: Variations in the level of axillary node dissection for breast cancer can result in significant changes in the number of positive axillary nodes. This can potentially bias adjuvant chemotherapy recommendations if treatment decisions are based on this prognostic factor.

[Maxillary pre-implant rehabilitation: a study of 55 cases using autologous bone graft augmentation]. / Réhabilitation maxillaire pré implantaire: étude de 55 cas avec greffe de comblement par os autologue.

Preprosthetic rehabilitation of the maxillary bone is sometimes difficult due to severe bone resorption in the posterolateral regions. The sinus lift with autogenous bony graft has given us satisfactory results since 1990 but requires a rigorous protocol before and during surgery to assure a lasting anchorage to the prosthesis. We describe morbidity and technical choices of this intervention in a series of 55 patients.

Gender and cancer support group participation.

PURPOSE: Although support groups are offered to many patients who have received a diagnosis of cancer, a majority of patients choose not to participate. This article reports the results of a study comparing the behavior of men diagnosed with prostate cancer and women diagnosed with breast cancer in their responses to invitations to participate in support groups. DESCRIPTION OF STUDY: One hundred thirty women with breast cancer and 87 men with prostate cancer completed a structured telephone interview. The interview included questions about the patients' choices about support group participation. RESULTS: Interview findings showed that men are less likely to join a support group, but those men who do join attend meetings for about 1 year, as do the women who join. Men and women cite essentially the same reasons for participation: to learn more about their diagnosis, to share their, concerns to compare their physical and emotional progress with other individuals. CLINICAL IMPLICATIONS: These results indicate the need for further exploration of effective interventions for men and women who have been diagnosed with prostate and breast cancer, respectively, in an effort to offer support for the difficult psychological and emotional issues associated with their diagnoses. Although more women than men join support groups, the majority of both populations (67% for women, 87% for men) do not attend any support group meetings. Innovative approaches are needed to encourage participation in existing support groups or to design alternative interventions.

Post-treatment dopexamine infusions partially reverse reductions in cranial mesenteric blood flow and mucosal oxygenation induced by hypoxia in newborn piglets.

A severe hypoxic insult is known to induce dramatic reductions in newborn intestinal blood flow and is, thus, considered a vector for the development of neonatal intestinal ischemic diseases. Dopexamine (DPX) is a novel synthetic agent that has potent B2-adrenoceptor and dopaminergic activity, the clinical effects of which include an increase in cardiac output and in mesenteric blood flow. Having previously shown that infusion of DPX before hypoxia (HYP) mitigated the reduction in newborn mesenteric blood flow, we sought to define its efficacy when given after an established hypoxic insult. Ultrasonic transit time blood flow probes were placed around the ascending aorta and cranial mesenteric artery of anesthetized, mechanically ventilated 0 to 2-day-old piglets. Small bowel mucosal oxygenation was observed with a tissue oxygen monitoring system. After stabilization, animals were subjected to one of the following: HYP (FIO2 = 0.12) for 60 minutes (n = 12); DPX (5 microg/kg/min) infusion begun 10 minutes after induction of HYP/DPX (n = 11). Almost no alterations in any of the monitored variables were shown in a group (n = 5) of similarly instrumented, untreated animals. In contrast, although both hypoxic piglet groups experienced significant (P < 0.05, analysis of variance) declines from baseline cardiac output, mesenteric blood flow, and mucosal oxygenation, each of these deleterious effects was significantly (P < 0.05) blunted in the DPX-treated animals. During periods of systemic hypoxemia, the reductions in neonatal mesenteric blood flow and oxygenation can be somewhat blunted by DPX. As such, this agent may prove of clinical benefit when an infant is threatened by a hypoxic episode.

Laparoscopic retroperitoneal repair of recurrent postoperative lumbar hernia.

A patient who previously underwent an attempt at open mesh repair of a lumbar hernia that occurred following iliac crest bone harvesting was managed successfully by laparoscopic retroperitoneal fixation of the prosthetic material to the iliac crest using bone screws. A review of the literature supports the use of such a novel approach to manage this often vexing problem.

Comparison of mammographically guided breast biopsy techniques.

OBJECTIVE: To determine which mammographically guided breast biopsy technique is the most efficient in making a diagnosis in women with suspicious mammograms. SUMMARY BACKGROUND DATA: Mammographically guided biopsy techniques include stereotactic 14-gauge core-needle biopsy (SC bx), stereotactic 11-gauge suction-assisted core biopsy (Mammotome [Mbx]), stereotactic coring excisional biopsy (Advanced Breast Biopsy Instrument [ABBI]), and wire-localized biopsy (WL bx). Controversy exists over which technique is best. METHODS: All patients undergoing any one of these biopsy methods over a 15-month period were reviewed, totaling 245 SC bx, 107 Mbx, 104 ABBI, and 520 WL bx. Information obtained included technical success, pathology, discordant pathology, and need for open biopsy. RESULTS: Technical success was achieved in 94.3% of SC bx, 96.4% of Mbx, 92.5% of ABBI, and 98.7% of WL bx. The sensitivity and specificity were 87.5% and 98.6% for SC bx, 87.5% and 100% for Mbx, and 100% and 100% for ABBI. Discordant results or need for a repeat biopsy occurred in 25.7% of SC bx, 23.2% of Mbx, and 7.5% of ABBI biopsies. In 63.6% of ABBI and 50.9% of WL bx, positive margins required reexcision; of the cases with positive margins, 71.4% of ABBI and 70.4% of WL bx had residual tumor in the definitive treatment specimen. CONCLUSION: Although sensitivities and specificities of SC bx and Mbx are good, 20% to 25% of patients will require an open biopsy because a definitive diagnosis could not be reached. This does not occur with the ABBI excisional biopsy specimen. The positive margin rates and residual tumor rates are comparable between the ABBI and WL bx. The ABBI avoids operating room and reexcision costs; therefore, in appropriately selected patients, this appears to be the most efficient method of biopsy.

Initial experience with laparoscopic repair of incisional hernias.

BACKGROUND: Development of a safe, unobtrusive means to repair the large incisional hernia continues to represent a challenge to surgeons. METHODS: A retrospective analysis of the first 12 patients who underwent an attempt at laparoscopic repair of an incisional hernia at a single institution was carried out. RESULTS: Of the 12 attempts at laparoscopic repair, 11 were completed. No serious perioperative morbidity was encountered. During a mean follow-up of 12.5 months, one recurrence (due to a technical shortcoming that has since been overcome) was identified. CONCLUSIONS: The laparoscopic approach to incisional hernia repair is a safe alternative to open repair of abdominal wall defects.

Postburn vitamin C infusions do not alter early postburn edema formation.

To determine whether vitamin C would alter burn induced edema accumulation, hind paw venous pressure, lymph flow (QL), and lymph-to-plasma protein ratio (CL/CP) were monitored in groups of 5 dogs before and 4 hours after 1) a 5 sec 100 degrees C or 90 degrees C foot paw scald; 2) intravenous vitamin C given 30 min before or after a 100 degrees C scald; and 3) vitamin C given 30 min after a 90 degrees C scald. Throughout the experiments, hind paw venous pressure was elevated and maintained by outflow restriction until steady state QL and (CL/CP)min were reached. Changes in protein permeability (CL/CP), fluid conductance properties (Kf) of the capillary membrane, and paw weight gain were determined. Compared with preburn values, scald uniformly produced significant (P < .05, ANOVA) increases in QL, CL/CP and Kf. Although preburn infusion of vitamin C significantly (P < .01) attenuated burn-induced increases in paw weight gain (36 +/- 3% vs 19 +/- 4%), neither of the groups that received vitamin C postburn experienced significant modulations in paw weight gain (28 +/- 4% vs 36 +/- 3% in 100 degrees C burn only; 23 +/- 4% vs 28 +/- 3% in 90 degrees C burn only) or in any of the variables used to monitor capillary membrane integrity. Vitamin C infusions initiated after graded scald produced no changes in the burn-induced increases in microvascular permeability or in edema formation measured at the injury site.

Regional blood flow response to hypothermia in premature, newborn, and neonatal piglets.

BACKGROUND/PURPOSE: Hypothermia (HT) remains a significant stress to the newborn and has been implicated in the pathogenesis of necrotizing enterocolitis (NEC). The authors assessed the effect of transient HT (32 degrees C) on regional organ blood flow in anesthetized piglets at age 7 to 10 days preterm (PREM), 1 to 2 days (NB), and 1 to 2 weeks (NEO). METHODS: Radiolabeled microspheres were used to determine organ blood flows (mL/min/g) at baseline, 15, and 60 minutes after HT and 60 minutes after rewarming to baseline core temperature. RESULTS: Heart rate and cardiac output decreased significantly in all groups. Cardiac flow decreased significantly in the NEO group, and central nervous system (CNS) flow decreased significantly in the NB and NEO groups. Both returned to baseline levels after rewarming. The PREM group experienced decreased cardiac, CNS, and intestinal blood flows but not to significant levels. NB and NEO intestinal blood flow showed significant decreases, which remained so after rewarming (a response not seen in hypoxia or hypovolemia). Cardiac output did not return to baseline levels in any group. CONCLUSIONS: HT causes derangements in organ blood flows that differ from other deleterious stimuli such as hypoxia and hypovolemia. The prolonged intestinal ischemia supports HT as a factor in the development of NEC. This delay may offer opportunity to intervene in an attempt to lessen ischemia-reperfusion injury.

Laparoscopic incisional hernia repair after transverse rectus abdominis myocutaneous flap reconstruction.

Abdominal wall herniation is a relatively rare but well recognized complication that is known to occur following TRAM flap mobilization. Herein is presented a novel means to approach such a hernia, using the minimally invasive surgical approach to repair the defect with a piece of prosthetic material.

Comparison of novel synthetic materials with traditional methods to repair exposed abdominal wall fascial defects.

Repair of large abdominal wall defects is a challenge, particularly when full-thickness tissue loss prohibits coverage of the fascial repair. Two novel synthetic materials (TMS-1 and TMS-2) have been shown to be better accepted than expanded polytetrafluoroethylene (Gore-Tex), and polypropylene (Marlex) in the closure of clean and contaminated fascial wounds that are immediately covered by skin/soft tissue. Therefore, 1-cm2 abdominal wall defects were created in each of the four quadrants of rat groups. Gore-Tex, Marlex, and TMS-1 or TMS-2 were used to repair three defects, the fourth being primarily closed. To ensure that each repair remained exposed, skin edges were sutured to underlying muscle. Additional animal groups underwent the same protocol; however, peritonitis was induced at surgery using a fecal inoculum technique. Animals were sacrificed 2 weeks later, at which time a blinded observer assessed the surface area and severity of adhesions. In clean wounds, the surface area of formed adhesions was less (p < .004) after primary closure than each synthetic material; among the synthetics, TMS-2 caused significantly (p < .01) less extensive adhesions than Marlex. In addition, the severity of adhesions to TMS-2 was comparable to that of defects closed primarily, and less severe (p < .02) than those formed to Gore-Tex and Marlex. In animals with peritonitis, primary closure caused less extensive (p < .03) adhesions than Marlex and Gore-Tex and significantly (p < .002) less severe adhesions than Marlex, Gore-Tex, and TMS-2. However, the severity of adhesions formed to TMS-1 repairs proved comparable to primarily closed wounds. These experiments reaffirm the tenet that, whenever possible, abdominal wounds should undergo primary fascial closure. When soft tissue coverage over the repair cannot be achieved, TMS-2 is well tolerated in clean wounds. However, the superiority of TMS-1 over the other synthetic materials in contaminated wounds suggests it may also ultimately prove to be of clinical utility.

Lymph isolated from a regional scald injury produces a negative inotropic effect in dogs.

Large surface-area burns in patients have been associated with a severe impairment in cardiac performance, as evidenced by a decline in cardiac output. The mechanisms responsible for this profound myocardial dysfunction are largely unknown. We investigated the effects of lymph isolated from the scalded hind limb of dogs on regional myocardial blood flow, coronary vascular reactivity, and contractile performance. Dogs were instrumented with ultrasonic dimension crystals in the myocardium supplied by the left anterior descending (LAD) and by the left circumflex (LCx) coronary arteries. After cannulating a hind limb lymphatic, lymph was infused directly into the LAD before and after a 10-second 100 degrees C hind limb scald. Scalding alone did not alter myocardial contractile performance in the LAD or LCx regions, coronary artery blood flow, or systemic hemodynamics. Interestingly, postburn lymph infused into the LAD resulted in a 38% decline in LAD zone segment shortening (p < 0.01 vs baseline) that lasted throughout the 5-hour observation period. In contrast, segment shortening in the (control) LCx region was unaffected by postburn lymph injections into the LAD. Regional myocardial blood flow (radiolabeled microspheres) in the LAD and LCx regions was unchanged after scald injury or intracoronary injection of postburn lymph. In addition, LAD coronary artery vascular reactivity to acetylcholine and nitroglycerin was also unaffected by the regional thermal injury or by injection of lymph into the LAD. These data suggest that a regional scald injury results in the production and release of a potent myocardial depressant factor(s) that produces a direct negative inotropic effect on the canine myocardium.

Efficacy of a novel synthetic material to close exposed fascial defects.

BACKGROUND: After developing a synthetic composite material (TMS-1) made from a porous polypropylene mesh (placed in apposition to fascia) coated on the "visceral" side with solid polyurethane, we compared its efficacy with that of porous polytetrafluoroethylene, polypropylene, and primary fascial closure when the repairs were left exposed to the environment. METHODS: We created 1 cm2 abdominal wall defects in each of the four abdominal quadrants of rats (n = 12). We used porous polytetrafluoroethylene, polypropylene, and TMS-1 to repair three defects; the fourth we primarily closed. The skin was left open in all cases, leaving the fascial closures exposed. A second group of rats (n = 24) had the same operation, except that peritonitis was induced using a standard fecal inoculation technique. When the rats were killed 2 weeks later, a "blinded" observer using a standard scale assessed the surface area and severity of adhesions formed. RESULTS: When compared with the other synthetic materials, the surface area of adhesions formed was significantly less after primary closure in clean conditions; in contaminated conditions, it was less than porous polytetrafluoroethylene, polypropylene, and the same as TMS-1. Furthermore, in contaminated conditions, the severity of adhesions beneath TMS-1 was the same as primary closure and significantly less than those beneath the polypropylene. CONCLUSION: The overall superiority of TMS-1 over porous polytetrafluoroethylene and polypropylene in septic conditions justifies further experiments to define its long-term efficacy in the repair of large defects.