Spectrum and subcellular determinants of fluorinated anesthetic-mediated proximal tubular injury.

Currently used fluorinated anesthetics are chemically related to methoxyflurane (MF), a drug that caused many cases of clinical acute renal failure during previous widespread use. To determine whether newer fluorinated anesthetics might also have nephrotoxic effects, three currently used agents (isoflurane (IF), sevoflurane (SF), and desflurane) or MF were added to rat proximal tubular segments, followed by assessments of cell integrity (ATP levels and percent lactic dehydrogenase release). Ether served as a negative control. MF, IF, and SF each induced lethal proximal tubular segment injury (up to 92, 71, and 30% lactic dehydrogenase release, respectively) and massive ATP depletion. ATP losses were observed at or near clinically relevant drug levels, they preceded lethal injury, and they correlated with approximately 50% and approximately 100% reductions in total and Na,K-ATPase-driven respiration, respectively. Clinically relevant inorganic fluoride levels simulated fluorinated anesthetic toxicity. However, fluoride release from the anesthetics (a cytochrome P450 process) did not appear to be required for toxicity (no protection with P450 inhibitors and no detectable inorganic fluoride release). As IF was judged to be one-third as toxic as MF, subclinical tubular injury (increased urine N-acetyl-beta-D-glucosaminidase (NAG) levels) after its use was sought in 19 surgical patients. Fifteen patients undergoing comparable operations with SF (approximately one-half as toxic as IF in vitro) and nine patients undergoing regional/ local anesthesia were controls. The IF group doubled its urinary NAG levels by the end of surgery (P < 0.005). Conversely, NAG levels remained stable in both control groups. The conclusions are that 1) currently used fluorinated anesthetics, particularly IF, share (but to a lesser degree) MFs tubulotoxic effects, 2) ATP depletion (probably due to decreased production) and Na,K-ATPase inhibition are likely contributing mechanisms, 3) fluoride is a prime determinant of this toxicity, and 4) tubular injury can be expressed at or near clinically relevant anesthetic/inorganic fluoride levels. That increased enzymuria can develop in patients after IF anesthesia suggests that the above in vitro data could have potential clinical relevance in selected patients.     

Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase

BACKGROUND: Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity. METHODS: This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the gamma(1)34.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model. RESULTS: We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR. CONCLUSIONS: These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy.     

Rapid cognitive decline following lumbar puncture in a patient with a dural arteriovenous fistula

BACKGROUND: Dural arteriovenous fistulas (DAVFs) are frequently accompanied with raised intracranial pressure and clinical findings suggestive of pseudotumor cerebri. However, unlike pseudotumor cerebri, the clinical response to lumbar cerebrospinal fluid (CSF) removal can vary from beneficial to acute clinical deterioration leading to death. The criteria for the safe use of lumbar puncture (LP) in patients with a DAVF are not well established. METHODS: A 61-year-old man presented with visual difficulty. Magnetic resonance imaging (MRI) and angiography revealed a left transverse sinus DAVF. He underwent multiple embolizations of arterial feeders over 3 years. He was then noted to have cognitive deficits in short term memory, listening, and concentrating. Over several days after an LP he became increasingly lethargic but arousable. Within hours after a repeat LP there was a rapid deterioration in the patient's level of consciousness and he became unarousable. RESULTS: A brain MRI revealed extensive dilated cortical veins and left temporal lobe venous ischemia without tonsillar herniation. A cerebral angiogram showed an extensive left transverse sinus DAVF with an occluded lateral transverse sinus and increased retrograde venous drainage. Embolization of the arterial feeders in combination with trans-venous coil embolization of the left transverse sinus reversed the patient's neurologic decline. He was discharged neurologically intact except for his chronic visual acuity problems. CONCLUSION: We speculate that when a DAVF manifests retrograde venous flow sufficient to cause cognitive deficits, lumbar CSF drainage must be undertaken with extreme caution.     

Parenteral iron therapy exacerbates experimental sepsis

BACKGROUND: Catalytic iron can potentiate systemic inflammation via its pro-oxidant effects. This raises the possibility that parenteral iron administration might exacerbate a concomitant septic state. This study sought to experimentally test this hypothesis. METHODS: Male CD-1 mice were subjected to experimental sepsis via intraperitoneal injection of heat-killed Escherichia coli +/- concomitant intravenous iron sucrose (Venofer; 2 mg). Nonseptic mice +/- iron therapy served as controls. Plasma tumor necrosis factor-alpha (TNF-alpha) levels were assessed 2 hours postinjections (serving as an inflammatory marker). Oxidative stress was gauged in heart or kidney tissue (at either 4 or 24 hours) by heme oxygenase-1 (HO-1) mRNA or protein levels. Overall sepsis severity was assessed by morbidity/mortality rates (at 24 hours). RESULTS: Iron alone or sepsis alone each induced oxidant stress in heart and kidney (HO-1 mRNA/protein increases). When iron and E. coli were coadministered, additive or synergistic HO-1 mRNA/protein increments resulted. Iron injection alone only slightly raised TNF-alpha levels (from 0 to 2.3 pg/mL; P= 0.01). However, iron approximately doubled the TNF-alpha increments which arose from the septic state (1400 --> 2600 pg/mL). Neither sepsis alone, nor iron alone, induced any mortality and no mice became moribund (0/24 mice). However, when iron + sepsis were combined, approximately 60% of mice either died (5/12) or developed a moribund (2/12) state (P= 0.005). CONCLUSION: Parenteral iron administration can induce systemic oxidative stress and modest TNF-alpha release. However, when iron is given during experimental sepsis, profound increases in both processes, and approximately 60% mortality, result. Given that renal failure patients have decreased antioxidant defenses and intermittently develop bacteremia, the potential for parenteral iron therapy to exacerbate clinical sepsis needs to be addressed.     

Case studies for illustration and discussion: peripheral nerve tumors

This article gives a presentation of a variety of surgical cases of peripheral nerve tumors for illustration and discussion. The first three cases include a schwannoma, a neurofibroma, and a desmoid tumor of the brachial plexus region. Case 4 is that of a patient with a common peroneal ganglion cyst, and case 5 is that of a patient with an angiolipoma of the forearm. Cases 6 through 8 illustrate a plexiform neurofibroma, a malignant peripheral nerve sheath tumor, and a metastatic carcinoma to the brachial plexus region. In case 9, a patient with schwannomatosis was treated for multiple spinal schwannomas.     

Concentrations of surface-dust metals in Native American jewelry-making homes in Zuni Pueblo, New Mexico

This pilot study was conducted to identify the metals used by home-based Native American jewelry makers, to quantify the metals in dust samples taken from jewelers' homes, and to compare these concentrations with background levels from control homes in which jewelry was not made. Participants were recruited from Zuni Pueblo, New Mexico. Surface dust samples were collected from the work and living areas of 20 jewelers' homes, and from the living areas of 20 control homes. Silver, copper, tin, boron, nickel, zinc, lead, and cadmium were significantly higher in work areas than in living areas of jewelry-making homes (p < or = 0.02). Silver, copper, nickel, and antimony were significantly higher in living areas of jewelers' homes compared with control homes (p < or = 0.04). Ventilation measures did not effectively reduce metal concentrations in jewelers' homes; concentrations in nonwork areas remained elevated.     

Use of radiolabelled iododeoxyuridine as adjuvant treatment for experimental tumours of the liver

BACKGROUND: The aim of the study was to determine whether hepatic regeneration stimulates growth of tumour residing within the liver, and whether a difference in the rate of DNA synthesis in liver and tumour may be used to target cancer using the radiolabelled thymidine analogue 5-iodo-2'-deoxyuridine (IUdR). METHODS: Partial hepatectomy was performed on Buffalo rats bearing solitary nodules of syngeneic Morris hepatoma. Liver and tumour DNA synthesis was measured by incorporation of radioactive IUdR. [(125)I]IUdR was tested as an adjuvant therapy after hepatectomy in Buffalo rats bearing diffuse microscopic Morris hepatomas to simulate the clinical situation. RESULTS: Liver regeneration enhanced liver and tumour DNA synthesis as measured by incorporation of radioactive IUdR. Liver DNA synthesis returned to baseline by 7 days, whereas tumour DNA synthesis remained above baseline level. Hepatectomy enhanced the growth of microscopic liver tumours. [(125)I]IUdR (250 micro Ci or 1 mCi/kg) administered 4 days after hepatectomy significantly reduced tumour growth without signs of systemic toxicity or liver dysfunction. CONCLUSION: The local environment of the regenerating liver stimulates tumour growth. The thymidine analogue [(125)I]IUdR may be used preferentially to target tumour DNA synthesis in the regenerating liver, and may prove useful as an adjuvant therapy for hepatic tumours after surgical resection.