Neurotoxicity and carcinogenicity of N-methylolacrylamide in F344 rats and B6C3F1 mice

Toxicology and carcinogenicity studies of N-methylolacrylamide were conducted by administering the chemical by gavage in water to both sexes of F344/N rats and B6C3F1 mice 5 times per week for 16 d, 13 wk, or 2 yr. In 16-d studies, rats receiving doses of 200 mg/kg or higher and mice receiving 400 mg/kg died. In 13-wk studies, all rats given 100 mg/kg or higher doses died. Rats receiving 50 mg/kg or higher doses developed hindlimb ataxia progressing to paralysis. In neurobehavioral assessments, decreased forelimb and hindlimb grip strength occurred in rats at doses as low as 12.5 mg/kg. Landing footspread was also increased in dosed rats compared to controls. Axon filament and myelin sheath degeneration in the spinal cord and/or peripheral nerves occurred in rats receiving doses of 25 mg/kg or higher. Necrosis in the granular cell layer of the cerebellum was seen in rats given 200 mg/kg. Mice receiving 200 mg/kg in 13-wk studies died. Decreased grip strength was noted in mice at doses as low as 25 mg/kg, and rotarod performance was also affected by N-methylolacrylamide administration, but no neuropathology was seen microscopically. Testicular weights were decreased at doses as low as 12.5 mg/kg, and hepatocellular necrosis, thymic lymphocyte necrosis, and hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were seen in mice that died (200 mg/kg). In 2-yr studies, survival and weight gains in male and female rats receiving doses of 6 or 12 mg/kg/d were minimally affected. No biologically important clinical signs or neoplastic or nonneoplastic lesions were attributed to N-methylolacrylamide administration to rats, suggesting that higher doses could have been tolerated. In mice, survival was not different between dosed and control groups (0, 25, or 50 mg/kg/d). Body weights were higher by as much as 25% in dosed compared to control groups. No compound-related clinical signs were observed, but increases in neoplasms of the harderian gland, liver, and lung were clearly related to chemical administration in both sexes of mice. Benign granulosa-cell neoplasms of the ovary were also increased in dosed female mice.     

Management und Kontrolle einer Influenzapandemie Konzeptionelle Überlegungen für einen deutschen Influenzapandemieplan

The World Health Organization (WHO) and the majority of the influenza experts assume that an influenza pandemic might reemerge again at any time. Therefore WHO has called upon all member states to set up a national pandemic preparedness plan. For Germany such a plan is long overdue. In order to gain as much time as possible early identification of the pandemic virus is of highest priority. Furthermore progression of a pandemic is influenced by the time needed to develop a subtype specific vaccine as well as by the vaccines availability. However, in case of a pandemic a shortage of vaccines and prophylactic pharmaceuticals cannot be avoided. Therefore, decisions have to be made in order to establish priorities concerning the vaccination and the prophylactic and/or therapeutic antimicrobial treatment of selected sub-populations. There is also a need to lay down measures ensuring the distribution of vaccines and antiviral drugs, adequate health care and ambulance service, and the organization of dignified funerals of the deceased. It is also necessary to enter into an early agreement with vaccine manufacturers on a guaranteed supply of respective batches of vaccine doses. In addition procedures should be established to allow an increase in vaccine production in case of a pandemic. There is also a need for early agreements with the manufacturers of antiviral agents and for a decision concerning the establishment of a national stockpile to guarantee an adequate supply. Some measures must already be taken in the inter-pandemic period. Those are: enhancement of surveillance and research, development of new vaccines and new methods of vaccine production, licensing of new vaccines in case of a pandemic and establishment of a national influenza committee. Problems like the effectiveness of antiepidemic measures, such as immigration control and the closing of schools, must be solved in advance of a pandemic.     

Corticosteroids and Inhaled Salbutamol in Patients with Reversible Airway Obstruction Markedly Decrease the Incidence of Bronchospasm after Tracheal Intubation

Background: In patients with bronchial hyperreactivity, airway instrumentation can evoke life-threatening bronchospasm. However, the best strategy for the prevention of bronchospasm has not been defined. Therefore, in a randomized, prospective, placebo-controlled study, the authors tested whether prophylaxis with either combined salbutamol-methylprednisolone or salbutamol alone (1) improves lung function and (2) prevents wheezing after intubation.

Methods: Thirty-one patients with partially reversible airway obstruction (airway resistance > 180%, forced expiratory volume in 1 s [FEV1] < 70% of predicted value, and FEV1 increase > 10% after two puffs of salbutamol), who were naive to anti-obstructive treatment, were randomized to receive daily for 5 days either 3 x 2 puffs (0.2 mg) of salbutamol alone (n = 16) or salbutamol combined with methylprednisolone (40 mg/day orally) (n = 15). Lung function was evaluated daily. Another 10 patients received two puffs of salbutamol 10 min before anesthesia. In all patients, wheezing was assessed before and 5 min after tracheal intubation.

Results: Within 1 day, both salbutamol and salbutamol-methylprednisolone treatment significantly improved airway resistance (salbutamol, 4.3 +/- 2.0 [SD] to 2.9 +/- 1.3 mmHg [middle dot] s [middle dot] l-1; salbutamol-methylprednisolone, 5.5 +/- 2.9 to 3.4 +/- 1.7 mmHg [middle dot] s [middle dot] l-1) and FEV1 (salbutamol, 1.79 +/- 0.49 to 2.12 +/- 0.61 l; salbutamol-methylprednisolone, 1.58 +/- 0.66 to 2.04 +/- 1.05 l) to a steady state, with no difference between groups. However, regardless of whether single-dose salbutamol preinduction or prolonged salbutamol treatment was used, most patients (8 of 10 and 7 of 9) experienced wheezing after intubation. In contrast, only one patient receiving additional methylprednisolone experienced wheezing (P = 0.0058).     

Cytosolic aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers

Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of 'alcohol flushing' among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10–20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.     

Intraarterial sodium nitroprusside infusion in the treatment of severe ergotism

Treatment of migraine with ergot alkaloids may produce systemic vasospasm in patients, especially as a result of automedication and overconsumption but also due to individual hypersensitivity. Peripheral vasoconstriction may lead to gangrene of the extremities, necessitating amputation. Various treatments have been tried against ischemic complications during ergotism with varied and unpredictable results. We report two recent cases of severe acute peripheral ischemia due to ergotamine abuse successfully treated with continuous systemic sodium nitroprusside infusion. The doses used during intraarterial injection are well below those known to be toxic. Consequently, the adverse effects of cyanide toxicity can be avoided. We think that intraarterial infusion of sodium nitroprusside, associated with forced diuresis and the administration of hydroxycobalamin, constitutes the treatment of choice of extreme peripheral ischemia of ergotism.     

Effects of a monoclonal antibody raised against nerve growth factor on skeletal pain and bone healing after fracture of the C57BL/6J mouse femur.

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis. INTRODUCTION: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. MATERIALS AND METHODS: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. RESULTS: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. CONCLUSIONS: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.     

Treatment of cremaster synkinesias with botulinum toxin A: a video case report.

Synkinesias secondary to nerve lesions and aberrant re-innervation are well-known phenomena especially after lesions of the facial nerve. Synkinesias can successfully be treated with botulinum toxin A (BTx A). Synkinesias of the cremaster muscle have not been described or treated to date. We present the case of a 62-year-old man who developed synkinesias of both cremaster muscles after extensive laparatomy for esophageal cancer. Treatment of synkinesias with various oral medications had been unsuccessful. Electromyography-guided injections of BTx A in both cremaster muscles (15 MU on the right and 10 on the left) led to significant symptom relief for an average of 8 weeks. We present the case including pre- and posttreatment video clips.     

Regulation of serum amyloid a gene expression in Syrian hamsters by cytokines

Amyloid A (AA) protein is derived from serum amyloid A (SAA) and deposited as beta-pleated sheet fibrils in reactive amyloidosis, a disease that occurs spontaneously in golden Syrian hamsters. The precursor SAA is an acute-phase reactant in many species including hamsters, and in this report we have defined the in vivo kinetic and dosage responses for SAA mRNA accumulation in hamsters following administration of various cytokines. Elevations in levels of hepatic SAA mRNA were documented when the doses of interleukin-1, interleukin-6, and tumor necrosis factor were increased. The increase in dosages applied ranged from 2 1/2-fold for interleukin-6 to 10-fold for interleukin-1. SAA transcipt levels were highest 8 h following administration of interleukin-6 or tumor necrosis factor, whereas maximal amounts of SAA-specific mRNA were found 24 h after administration of interleukin-1.