[Absence of the musculocutaneous nerve and its distribution from median nerve: About two cases and literature review]. / Absence du nerf musculocutané et distribution à partir du nerf médian : à propos de deux cas et revue de la littérature.

Musculocutaneous nerve arises mostly from the lateral cord of brachial plexus. Nevertheless, variations have been reported and, among them: the total absence of musculocutaneous nerve (from 1.4 to 15%), the absence of its passage through the coracobrachial muscle, its variable level of penetration as measured from the tip of the coracoid process, and its communicating branches with the median nerve. We report two cases of unilateral musculocutaneous nerve absence in a 66-year-old male and a 95-year-old female cadavers, on the right and the left side, respectively. The nerve fibers normally coming from musculocutaneous nerve emerged from the median nerve. The knowledge of this anatomical variation is important specially when performing plexus bloc or Latarjet's procedure.

[Necrotizing fasciitis and cellulitis of the upper limb resulting from centipede bite: two case reports]. / Dermohypodermite bactérienne et phlegmon du membre supérieur par morsure de scolopendre: à propos de deux cas.

Centipede bites occurring in tropical countries are rare, however vigilance must be exercised during activities in the open air and dwellings should be checked in the event of rain. The bite is very painful and can be accompanied by generalised signs. An initial wound disinfection and a check of antitetanus vaccination status is all that is usually needed to ensure an uneventful outcome. There are however, rare cases where local toxicity and a bacterial super-infection, often with Gram+ cocci, can lead to a cellulitis or even necrotizing fasciitis of the hand. The diagnosis of a centipede bite can be made by the double marks made by the fangs. Wound debridement and antibiotics led to a good outcome in both our cases.

Thigh compartment syndrome after intramedullary femoral nailing: possible femoral nerve block influence on diagnosis timing.

We report a case of anterior thigh compartment syndrome (TCS), which occurred after a closed femoral fracture internal fixation using an intramedullary rod. A 20 ml ropivacaine hydrochloride single-injection femoral block had preceded general anaesthesia to conduct the surgical procedure. The compartment syndrome diagnosis was made the morning after surgery when the level of pain was interpreted as disproportionate to the treated lesion; in addition, compartment pressure measure had increased to 54 mmHg. A compartment fasciotomy was performed. Diagnostic delays have previously been observed and attributed to nerve blocks in cases of tibial fracture. This patient's report raises the question of whether a femoral block may be responsible for delays in diagnosing compartment syndrome, although no series have been published of such occurrences in large numbers. When nerve blocks are used, they should be more analgesic than anaesthetic. Careful patient monitoring remains important.

Liposuction and extravasation injuries in ICU.

Liposuction is a minimally invasive surgical technique, occasionally used to minimize the risk of devastating soft tissue necrosis following extravasation of noxious substances. Anaesthetists and intensive care physicians frequently use agents that may cause serious tissue injury if extravasated. Therefore, knowledge on how to manage this complication is important. We present two cases of percutaneous extravasation of noxious agents in intensive care patients and discuss their subsequent management.

[Anaesthetic management of the patient with acute intracranial hypertension]. / Réunion de neuroanesthésie-réanimation. Prise en charge anesthésique du patient en hypertension intracrânienne aiguë.

Transcranial Doppler and, if possible, measurement of intracranial pressure (ICP) allow preoperative diagnosis of acute intracranial hypertension (ICH) after brain trauma. The main goal of the anaesthesiologist is to prevent the occurrence of secondary brain injuries and to avoid cerebral ischaemia. Treatment of high ICP is mainly achieved with osmotherapy. High-dose mannitol administration (1.4 to 2 g/kg given in bolus doses) may be considered a better option than conventional doses, especially before emergency evacuation of a cerebral mass lesion. Hypertonic saline seems as effective as mannitol without rebound effect and without diuresis increase. Haemostasis should be normalized before neurosurgery and invasive blood pressure monitoring is mandatory. For anaesthesia induction, thiopental or etomidate may be used. In case of ICH, halogenated and nitrous oxide should be avoided. Until the dura is open, mean arterial pressure should be maintained around 90 mmHg (or cerebral perfusion pressure around 70 mmHg). If a long-lasting (several hours) extracranial surgery is necessary, ICP should be monitored and treatment of ICH should have been instituted before.

Inhibition of leukotriene B4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritis.

BACKGROUND: Leukotriene B4 (LTB(4)) has a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To investigate the inhibition of ex vivo LTB(4)-induced Mac-1 (CD11b/CD18) expression in leucocytes of patients with RA by the new oral LTB(4) receptor antagonist BIIL 284. METHODS: The pharmacokinetics and inhibition of LTB(4)-induced Mac-1 expression of BIIL 284 were characterised in 26 adult patients with RA who were treated with BIIL 284 25 mg, 150 mg, or placebo given once a day for 14 days according to a double blind, randomised, parallel group design. RESULTS: T(max) of BIIL 315 in plasma (main metabolite and active principle of BIIL 284 in plasma) was achieved about four hours after drug administration, and C(max,ss) and AUC(0-6h,ss) increased in proportion to the dosage. 100% inhibition of LTB(4)-induced MAC-1 expression was reached after two hours (150 mg) or four hours (25 mg), showing a statistically significant difference in comparison with placebo (p<0.005). A longlasting dynamic effect was seen consistently even when plasma concentrations declined to very low values 24 hours after administration. Secondary clinical efficacy end points remained unchanged probably owing to the short duration of treatment. Adverse events (AEs) were reported in 12 patients during the study. No serious AEs or laboratory AEs were seen. CONCLUSIONS: Both the 25 mg and 150 mg doses of BIIL 284 safely and effectively inhibit Mac-1 expression on neutrophils; thus longer treatment with BIIL 284 may result in clinical benefit for patients with RA.

Adult presentation of MCAD deficiency revealed by coma and severe arrythmias.

We report the case of a 33-year-old man who presented with headaches and vomiting. Soon after admission he became drowsy and agitated, developed ventricular tachycardia and his neurological state worsened (Glasgow coma score 6). Blood analysis showed respiratory alkalosis, hyperlactacidemia (8 mmol/l), hyperammonemia (390 micro mol/l) and hypoglycaemia (2.4 mmol/l). Subsequently, he developed supraventricular tachycardia, ventricular tachycardia and ultimately ventricular fibrillation resulting in cardiac arrest, which was successfully treated. A CT scan of the head revealed cerebral oedema. Whilst in the intensive care unit, he developed renal failure and rhabdomyolysis. The metabolic abnormalities seen at the time of admission normalised within 48 h with IV glucose infusion. Biological investigations, including urinary organic acids and plasma acylcarnitines, showed results compatible with MCAD deficiency. Mutation analysis revealed the patient was homozygous for the classical mutation A985G. This is one of only a few reports of severe cardiac arrhythmia in an adult due to MCAD deficiency. This condition is probably under-diagnosed in adult patients with acute neurological and/or cardiac presentations.

Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn's disease.

BACKGROUND & AIMS: ISIS-2302, an antisense oligonucleotide directed against intercellular adhesion molecule 1, was effective in steroid refractory Crohn's disease in a pilot trial. The aim of this study was to investigate safety and efficacy of ISIS-2302 in chronic active Crohn's disease (CACD). METHODS: A dose-interval, multicenter, placebo-controlled trial was conducted in 75 patients with steroid-refractory CACD (Crohn's Disease Activity Index [CDAI], 200-400). The primary endpoint was steroid-free remission (CDAI <150) at week 14. RESULTS: Only 2 of 60 (3.3%) ISIS-2302-treated and no placebo patients reached the primary endpoint. Steroid-free remission at week 26 (secondary endpoint) was reached in 8 of 60 (13.3%) active treatment and 1 of 15 (6.7%) placebo patients. A greater proportion of ISIS-2302-treated than placebo patients achieved a steroid dose <10 mg/day at weeks 14 and 26 (48.3% vs. 33.3% and 55.0% vs. 40.0%, respectively, and a glucocorticoid dose of 0 mg [prednisone equivalent] at week 26 [23.3% vs. 6.7%, respectively]). Treatment with ISIS-2302 was safe. The most common side effects were injection site reactions in the active treatment group (23% in ISIS-2302-treated patients vs. none in placebo patients). No statistically significant differences in the frequency of side effects were detected between dose groups. CONCLUSIONS: The trial did not prove clinical efficacy of ISIS-2302 based on the primary endpoint. Positive trends were observed in some of the secondary endpoints.

Immunopharmacological in vitro effects of Eleutherococcus senticosus extracts.

The objective of these investigations was to further elucidate the immunopharmacological profile of fluid extracts of Eleutherococcus senticosus and to identify the specific role of its characteristic eleutherosides B and E. An ethanolic dry extract of Eleutherococcus senticosus was used as starting material for the isolation of the eleutherosides B and E. Immunopharmacological studies included expression of major histocompatibility complex class I and II molecules by rat bone marrow-derived mononuclear phagocytes, human lymphocyte marker flow cytometry, and in vitro testing of human lymphocyte functions. In contrast to the isolated eleutherosides B and eleutherosides E and the re-mixed eleutherosides B and E, the whole ethanolic fluid extract of Eleutherococcus senticosus was able to induce and enhance interleukin-1 and interleukin-6 but not interleukin-2 production in vitro. The effective concentration of the whole ethanolic extract ranged from 1.0-0.1 mg/ml for the enhancement of interleuking-1 alpha production and 1.0-0.03 mg/ml for the enhancement of interleukin-6 production. It is concluded that the observed enhancing immunopharmacological activities on acute phase response mediators are best exhibited by the induction with whole ethanolic extracts whereas the species-specific and characteristic eleutherosides B and E are not associated with these activities.

Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study.

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.

Interferon-gamma in the prevention of severe burn-related infections: a European phase III multicenter trial. The Severe Burns Study Group.

OBJECTIVES: To determine the efficacy and tolerance of interferon-gamma-1b (IFN-gamma) for the prevention of death related to infection in patients with burn injury who were at risk for infection. The positive anti-infective effects of IFN-gamma observed in animal models and in clinical studies provided the rationale for this study. DESIGN: Randomized, double-blind, placebo-controlled, phase III multicenter trial, with a group sequential design, conducted at 23 European burn centers. PATIENTS: Two hundred sixteen patients with major critical burn (Abbreviated Burn Severity Index score of > or = 7). INTERVENTION: Patients were randomized to receive IFN-gamma (100 microg) or placebo daily by subcutaneous injection for up to 90 days. MEASUREMENT AND MAIN RESULTS: The primary end point (the incidence of death related to infection within 90 days from the start of treatment) was similar in the two treatment groups. There were no significant differences between the two treatments in any of the secondary end points (all causes of mortality at 90 days, incidence of infectious complications, duration of intensive care unit or hospital stay, and scar formation at 90 days). CONCLUSION: IFN-gamma did not protect burn patients from infections or decrease the mortality from infections.

A model on the escape from the Malthusian trap.

"We propose a model to capture the escape from the Malthusian trap in the longrun. Our aim is to emphasize the key role of endogenous technological progress--as initiated by population growth and education--for longrun economic development. In addition we stress the importance to consider the level of fertility and mortality as the determinants of economic development and not only the rate of population growth. In particular, we may observe different economic growth rates in countries with the same rate of population growth, but differing levels of birth and death rates."

Rationale, design and performance of a clinical trial to investigate interferon-gamma (Imukin) in the prophylactic treatment of severe burns-related infections.

Recent advances in resuscitation therapy have increased the survival rate of patients with severe burns in the burn shock phase. Infectious complications represent the major cause of death in patients with extensive burns, however, in spite of the application of early and aggressive interventions. Extensive burn injury causes profound alterations in various essential elements of the normal host immune response and the main aim of treatment after resuscitation is to maintain or even improve host resistance. The positive anti-infective effects of interferon (IFN)-gamma observed in animal models and in clinical studies, for example in chronic granulomatous disease, provided the rationale for a study to investigate its use in patients with severe burns. A study was therefore designed to determine the efficacy and tolerance of IFN-gamma in preventing death related to infection in patients with severe burn injury who are at risk of infection. In order to avoid unnecessary risk for patients and reduce the cost, a sequential design was chosen. The primary end-point was reviewed in a group sequential manner after every 60 patients through an independent monitoring board. The study was a randomised, double-blind, Phase III multi-centre trial, conducted at 23 European Burn Centres. An interval censored survival time approach was taken, using information collected at days 8, 15, 30, 60, and 90. The trial is still blinded, but the rationale for conducting the study and its design are discussed.

On a causal mechanism of chronic thymic involution in man.

The age-associated chronic thymus involution is interpreted to occur due to cytolytic depletion of thymic stromal tissue whose cells present altered self-peptides. Using simplified assumptions and based on morphometric data on thymic involution in man, the chance for a single protein to be altered is estimated to be in the range of 2-4 x 10(-6) per year. The corresponding mutation rate is compatible with that derived from both evolutionary and direct studies, thus supporting the proposed model.

Low incidence of antibody formation due to long-term interferon-alpha 2c treatment of cancer patients.

In order to study the long-term immunogenicity of interferon-alpha 2c (Berofor) in cancer patients, serum was collected starting in 1983 from study patients with various proliferative diseases who received interferon-alpha 2c at different doses, according to different schedules, and via different routes. A total of 1992 samples were tested for the presence of anti-interferon-alpha 2c antibodies. Due to long-term interferon-alpha 2c treatment, 346 patients were eligible for induction of neutralizing anti-interferon antibodies over a treatment period of 2-52 months. Most patients were treated for longer than 6 months. Of the 346 patients, three patients (0.87%) exhibited measurable titers of neutralizing antibodies following therapy with interferon-alpha 2c. One hundred and sixty-three patients suffered from non-Hodgkin lymphomas, leukemias, and preleukemias. One patient with chronic myeloid leukemia experienced antibody induction under therapy. The other 183 patients had solid tumors. Two of them reacted with antibody production. All titers were very low (1:12, 1:8, and 1:64). Compared with figures reported for other interferon-alpha preparations, the propensity of interferon-alpha 2c to induce neutralizing antibodies seems to be very low. This property might be related to arginines occurring as critical residues in positions 23 and 34 of the interferon-alpha 2c molecule.

Population growth, farmland, and the long-run standard of living.

"This paper studies the natural-resources element in the theory of population growth over the very long run. In the context of the stock of land and Malthusian crises in earlier times, the model shows how resources have become more available rather than more scarce, even as population and income have increased. The paper sketches a mechanism which added to the Malthusian system, leads to entirely different conclusions than does the Malthusian system.... That is, population growth creates new problems which in the short run constitute additional burdens which, in the longer run, lead to new developments that leave people better off than if the problems had never arisen." This is a revised version of a paper originally presented at the 1989 Annual Meeting of the Population Association of America (see Population Index, Vol. 55, No. 3, Fall 1989, p. 382).

A rapid in vitro method for the evaluation of potential antitumor drugs requiring metabolic activation by hepatic S9 enzymes.

Metabolic activation is a prerequisite for the antitumor activity of certain drugs such as cyclophosphamide. In vitro assays require systems for metabolic activation to reveal the toxicity of such compounds for tumor cells. Although a number of methods utilizing systems for the in vitro metabolic activation of drugs have been published, practical assays applicable to large scale screening for such agents have been lacking. We, therefore, now report that incorporation of a liver subcellular fraction (S9) into a recently established cell growth inhibition assay (microculture tetrazolium assay) significantly increased the cytotoxicity of cyclophosphamide. Under optimal conditions, the 50% growth inhibitory concentration was decreased in the presence of S9 from more than 600 micrograms/ml to less than 4 micrograms/ml, depending upon the cell line. The method also proved suitable for studies investigating metabolic detoxification (enzymatically or non-enzymatically) by conjugation reactions. For example, glutathione (5 mM) markedly reduced the cytotoxicity of activated cyclophosphamide. In contrast, the addition of UDP glucuronate (10 mM) in the presence of the UDP-glucuronosyltransferase activator UDP-N-acetylglucosamine (10 mM) had little effect on cyclophosphamide toxicity.

Population growth and economic development in the very long run: a simulation model of three revolutions.

The authors propose an economic model capable of simulating the 4 main historical stages of civilization: hunting, agricultural, industrial, and postindustrial. An output-maximizing society to respond to changes in factor endowments by switching technologies. Changes in factor proportions arise through population growth and capital accumulation. A slow rate of exogenous technical process is assumed. The model synthesizes Malthusian and Boserupian notions of the effect of population growth on per capita output. Initially the capital-diluting effect of population growth dominates. As population density increases, however, and a threshold is reached, the Boserupian effect becomes crucial, and a technological revolution occurs. The cycle is thereafter repeated. After the second economic revolution, however, the Malthusian constraint dissolves permanently, as population growth can continue without being constrained by diminishing returns to labor. By synthesizing Malthusian and Boserupian notions, the model is able to capture the salient features of economic development in the very long run.