Mitochondrial dysfunction can lead to diverse cellular and organismal responses. We used DNA microarrays to characterize the transcriptional responses to different mitochondrial perturbations in Saccharomyces cerevisiae. We examined respiratory-deficient petite cells and respiratory-competent wild-type cells treated with the inhibitors of oxidative phosphorylation antimycin, carbonyl cyanide m-chlorophenylhydrazone, or oligomycin. We show that respiratory deficiency, but not inhibition of mitochondrial ATP synthesis per se, induces a suite of genes associated with both peroxisomal activities and metabolite-restoration (anaplerotic) pathways that would mitigate the loss of a complete tricarboxylic acid cycle. The array data suggested, and direct microscopic observation of cells expressing a derivative of green fluorescent protein with a peroxisomal matrix-targeting signal confirmed, that respiratory deficiency dramatically induces peroxisome biogenesis. Transcript profiling of cells harboring null alleles of RTG1, RTG2, or RTG3, genes known to control signaling from mitochondria to the nucleus, suggests that there are multiple pathways of cross-talk between these organelles in yeast.

Antimycin A↗

PubMed2001

Results of immediate breast reconstruction after skin-sparing mastectomy.

Skin sparing mastectomy (SSM) removes the breast, nipple-areolar complex, previous biopsy incisions, and skin overlying superficial tumors. Preservation of the native skin envelope facilitates immediate breast reconstruction. The procedure has been adopted for the treatment of breast cancer. All cases of SSM and immediate breast reconstruction performed by the senior author (G.W.C.) from January 1, 1993, through December 12, 1997, were reviewed. Patient demographics, cancer staging, treatment, types of surgery performed, and postoperative outcomes were examined. Aesthetic outcomes were measured using four 3-point subscales. A total of 100 patients underwent 118 SSMs during the study period. The American Joint Committee on Cancer staging was as follows: stage 0, 27 patients; stage I, 25 patients; stage II, 39 patients; stage III, 7 patients; stage IV, 3 patients; recurrent, 2 patients; and cystosarcoma phylloides, 1 patient. The mean follow-up was 42.7 months. Local recurrence occurred in 2 patients (2.7%). Reconstructive methods included the transverse rectus abdominis musculocutaneous flap (N = 82; pedicled, 73; free, 9), the latissimus flap (N = 18), and tissue expansion (N = 20). Two patients underwent contralateral delayed reconstruction. The aesthetic results achievable with the three methods were similar. The failure rate was higher for expander reconstruction (10%) than those observed for transverse rectus abdominis musculocutaneous (4.9%) and latissimus (5.6%) flaps. SSM can be used in the treatment of invasive breast cancer without compromising local control. The aesthetic results of the three methods were similar, but tissue expander reconstruction had a higher failure rate.

Adult↗

PubMed2001

Near-fatal gamma-butyrolactone intoxication--first report in the UK.

Gamma-hydroxybutyrate (GHB) is a compound used in the treatment of alcohol withdrawal, narcolepsy, and for induction of anaesthesia. It is also contained in many products illegally marketed as "dietary supplements" and is increasingly being recognised as a potential drug of abuse. We report the case of a 44-year-old man who suffered coma and life-threatening respiratory depression following an accidental overdose of the GHB prodrug, gamma-butyrolactone (GBL), contained in a "health drink". He made a full recovery following appropriate supportive treatment. GHB toxicity should be included in the differential diagnosis of patients with altered mental state, particularly where there is a history of recreational drug abuse.

4-Butyrolactone↗

PubMed2000

Intracranial percutaneous transluminal angioplasty for arteriosclerotic stenosis.

BACKGROUND: Patients with intracranial arteriosclerotic disease have significant morbidity and mortality rates, and some are unresponsive to medical treatment and have unacceptable surgical risks. Percutaneous transluminal angioplasty of the intracranial vessels is a possible alternative to surgery. OBJECTIVES: To present our experience with percutaneous transluminal angioplasty and to summarize our data. PATIENTS AND METHODS: Sixteen patients underwent intracranial percutaneous transluminal angioplasty for high-grade arteriosclerotic stenosis based on strict inclusion and exclusion criteria. All patients had symptoms referable to the stenosis except one. Angioplasty was performed in 6 intracranial vertebral arteries, 3 basilar arteries, 5 middle cerebral arteries, and 3 distal internal carotid arteries. One patient had concomitant stent placement. RESULTS: There was 1 treatment failure secondary to tortuous vascular anatomy. Vessel caliber was increased to more than 80% of normal in 6 patients and to 50% to 70% of normal in 6 patients, with a reduction of symptoms. Three intimal dissections occurred during angioplasty; one of these, in a precavernous segment of the internal carotid artery, was stented. One patient restenosed within 1 month of treatment. The remaining treated arteries remained patent during follow-up of 3 months to 2 years. Stroke as a complication occurred in 2 patients, 1 mild and 1 severe. There was no mortality. CONCLUSIONS: Occlusive arteriosclerotic disease involving the intracranial cerebral vessels can be managed medically with antiplatelet and anticoagulant drug therapy or surgically. However, in patients who are unresponsive to medical therapy or who have unacceptable surgical risks, percutaneous transluminal angioplasty is an attractive alternative that can be performed in selected patients with relatively low risk and good clinical outcome.

Adult↗

PubMed2000

Voltammetry of a flavocytochrome c(3): the lowest potential heme modulates fumarate reduction rates.

Iron-induced flavocytochrome c(3), Ifc(3), from Shewanella frigidimarina NCIMB400, derivatized with a 2-pyridyl disulfide label, self-assembles on gold electrodes as a functional array whose fumarate reductase activity as viewed by direct electrochemistry is indistinguishable from that of Ifc(3) adsorbed on gold or graphite electrodes. The enhanced stability of the labeled protein's array permits analysis at a rotating electrode and limiting catalytic currents fit well to a Michaelis-Menten description of enzyme kinetics with K(M) = 56 +/- 20 microM, pH 7.5, comparable to that obtained in solution assays. At fumarate concentrations above 145 microM cyclic voltammetry shows the catalytic response to contain two features. The position and width of the lower potential component centered on -290 mV and corresponding to a one-electron wave implicates the oxidation state of the lowest potential heme of Ifc(3) as a defining feature in the mechanism of fumarate reduction at high turnover rates. We propose the operation of dual pathways for electron transfer to the active site of Ifc(3) with the lowest potential heme acting as an electron relay on one of these pathways.

Binding Sites↗

PubMed2000

Endovascular treatment of paraclinoid aneurysms.

BACKGROUND: Paraclinoid aneurysms include those that are distal to the cavernous segment of the internal carotid artery and proximal to the posterior communicating artery. The purpose of this study was to review our experience with the endovascular treatment of this group of aneurysms, which are difficult to treat surgically. METHODS: Between June 1994 and April 1999, 66 patients (56 female, 10 male) with a mean age of 50.1 years (range 13-75, median 51) underwent endovascular treatment for 71 paraclinoid aneurysms. The mean size of the dome was 8.9 mm (range 3-25 mm, median 7) and the of neck was 3.8 mm (range 1.4-8 mm, median 4). Thirteen patients presented with acute subarachnoid hemorrhage, and 4 with previous subarachnoid hemorrhage. Six aneurysms produced mass effect with visual symptoms, 4 presented with transient ischemic attacks, and 44 were incidental. Nine patients had had previous unsuccessful surgery. All procedures were performed under general anesthesia and with systemic heparinization. RESULTS: Ninety endovascular procedures were performed on 71 aneurysms: GDC coiling in 78 (including 45 with the remodeling technique), permanent balloon occlusion in 9, and 3 had both GDC coiling and permanent balloon occlusion. In ten aneurysms it was not possible to place coils in the lumen of the aneurysm with the available technology and balloon occlusion was not indicated. Five of these were treated surgically and 5 remain untreated. All patients had immediate post procedure angiography. Of the 61 aneurysms that were treated, 46 (75%) have angiographic follow-up of 6 months or more. Morphological outcome following endovascular therapy for 61 aneurysms at last available follow-up showed > 95% occlusion in 52/61 (85.2%) and <95% in 9/61 (14.8%). Eight patients required surgery, 2 for partial coiling, 2 for refilling of a neck remnant, 2 for persistent mass effect and 2 for coil protrusion. In the 90 procedures performed, 2 (2.2%) patients had major permanent deficits (1 monocular blindness, 1 hemiparesis), 1 (1.1%) had a minor visual field cut, and 2 (2.2%) patients died from major embolic events. CONCLUSION: Properly selected paraclinoid aneurysms can be successfully treated by endovascular technology. The morbidity and mortality rate of the endovascular approach in our experience is equal to or better than the published surgical series of similar aneurysms. We recommend that the endovascular approach be given primary consideration in the treatment of paraclinoid aneurysms.

Adolescent↗

PubMed2000

Surgery following endovascular coiling of intracranial aneurysms.

BACKGROUND: Surgery for intracranial aneurysms that have been treated by endovascular coiling is a new challenge for neurosurgeons and the need for it will undoubtedly continue to increase. The indications for, timing, and technique of surgery in our experience are described. METHODS: We have reviewed our experience with 11 patients who underwent surgery following endovascular coiling with Guglielmi detachable coils (GDCs) of an aneurysm. We analyzed the indications for surgery, surgical techniques used, and patient outcome. RESULTS: There were nine female and two male patients. The mean age was 49 years (range 13 to 67 years). The intervals between coiling and surgery were 1, 2, 3, 4, 7, 7, 10, and 14 days, 6 weeks, 2, 18, and 25 months. The indications for surgery were partial treatment (3), growth of residual neck (2), persistent mass effect of a giant aneurysm (1), mass effect from the coil ball (2), coil migration (2), and coil protrusion with embolic event (1). The coils were removed at the time of surgery from 9 of 11 aneurysms before clipping. In two cases it was possible to place a clip across the neck of the aneurysm without removing the coils, as the coils no longer occupied the neck. There were two permanent deficits directly related to the endovascular procedures. Two other patients who presented with subarachnoid hemorrhage had residual neurological deficits post surgery and one patient with a giant aneurysm had persistent visual loss. CONCLUSION: Surgery remains a viable option at any time for treating aneurysms that have been previously treated by GDC placement. The operative approach is determined by the need for coil removal and the duration since coiling.

Adolescent↗

PubMed2000

Techniques of coiling cerebral aneurysms.

BACKGROUND: More than 200 aneurysms have been coiled at the UIC Medical Center within the last 5 years. We describe in detail the technical factors that increase the chance of complete occlusion of a cerebral aneurysm with coils. Aneurysms selected for coiling have good geometry or are in a location that is difficult to reach surgically. Patients with medical conditions that preclude surgical treatment may also undergo coiling. METHODS: Patients with aneurysms, either ruptured or unruptured, are treated under general anesthesia, fully anticoagulated and deeply paralyzed. Coiling is done under simultaneous biplane roadmapping. After the first coil has created a mesh, the aneurysm is densely packed with soft coils of decreasing diameter, until no more coils can be deployed into the aneurysm. RESULTS: The morbidity and mortality rates associated with the coiling procedure have continuously decreased over the last 5 years. The morphological outcomes have improved, due to extensive use of the remodeling technique and to advancements in materials, such as refinements in the coils themselves or the availability of over-the-wire balloon catheters in different sizes and hydrophilic wires with complex tip configurations. Twenty-one percent of the aneurysms were considered to be incompletely occluded immediately after coiling. Of this group, one-third of the aneurysms were found to be completely occluded on follow-up angiograms by 6 months; these have remained occluded. One-third were more than 95% occluded after the coiling procedure; in these patients, the dome was completely occluded, but there was a small neck remnant, which has remained stable in all patients on control angiograms obtained at 6 months and 1, 2, and 4 years; none have rebled. These patients are followed medically. The remaining one-third of the aneurysms in this subgroup were less than 95% occluded, although the dome was completely thrombosed. None of them have rebled, but the neck remnant in most has regrown over a period ranging from 6 months to 2 years. These patients have undergone a second treatment-either surgical clipping, permanent occlusion of the parent vessel, or repeat coiling using the remodeling technique. The overall rebleeding rate of incompletely occluded aneurysms is extremely low (less than 1%). CONCLUSION: The low morbidity and mortality rates and the good morphological outcome obtained in most cases make coiling a reasonable alternative to surgical clipping in properly selected cases.

Embolization, Therapeutic↗

PubMed2000

Mitochondria-to-nuclear signaling is regulated by the subcellular localization of the transcription factors Rtg1p and Rtg3p.

Cells modulate the expression of nuclear genes in response to changes in the functional state of mitochondria, an interorganelle communication pathway called retrograde regulation. In yeast, expression of the CIT2 gene shows a typical retrograde response in that its expression is dramatically increased in cells with dysfunctional mitochondria, such as in rho(o) petites. Three genes control this signaling pathway: RTG1 and RTG3, which encode basic helix-loop-helix leucine zipper transcription factors that bind as heterodimer to the CIT2 upstream activation site, and RTG2, which encodes a protein of unknown function. We show that in respiratory-competent (rho(+)) cells in which CIT2 expression is low, Rtg1p and Rtg3p exist as a complex largely in the cytoplasm, and in rho(o) petites in which CIT2 expression is high, they exist as a complex predominantly localized in the nucleus. Cytoplasmic Rtg3p is multiply phosphorylated and becomes partially dephosphorylated when localized in the nucleus. Rtg2p, which is cytoplasmic in both rho(+) and rho(o) cells, is required for the dephosphorylation and nuclear localization of Rtg3p. Interaction of Rtg3p with Rtg1p is required to retain Rtg3p in the cytoplasm of rho(+) cells; in the absence of such interaction, nuclear localization and dephosphorylation of Rtg3p is independent of Rtg2p. Our data show that Rtg1p acts as both a positive and negative regulator of the retrograde response and that Rtg2p acts to transduce mitochondrial signals affecting the phosphorylation state and subcellular localization of Rtg3p.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗

PubMed2000

Spinal cord infarction and tetraplegia--rare complications of meningococcal meningitis.

A previously healthy 25-yr-old female developed flaccid areflexic tetraplegia, with intact cranial nerve function, 36 h after the diagnosis of bacterial meningitis. Polymerase chain reaction studies of cerebrospinal fluid and blood were positive for Neisseria meningitidis, serogroup B. Magnetic resonance of the cervicothoracic spine revealed increased signal intensity and expansion in the lower medulla, upper cervical cord and cerebellar tonsils. Neurosurgical consultation recommended hyperventilation, dexamethasone and regular mannitol therapy rather than decompressive intervention. The clinical course over the following 12 days was complicated by the development of progressive central nervous and multisystem organ failure with disseminated intravascular coagulopathy. Autopsy revealed cerebral oedema with cystic infarction extending from the medulla to the upper cervical cord and cerebellar tonsils. Flaccid areflexic tetraplegia with spinal cord infarction has not been reported following bacterial infection in an adult. The clinical implications would suggest complete central nervous system evaluation of patients recovering from meningococcal meningitis, since spinal cord lesions, although uncommon, do occur. In those very rare situations where a patient develops significant peripheral neurological deficits, urgent magnetic resonance imaging is warranted, to rule out an infective focus or an underlying anatomical anomaly.

Adult↗

PubMed2000

Role of magnetic resonance imaging and diagnostic and interventional angiography in vascular and neoplastic diseases of the skull base associated with vestibulocochlear symptoms.

There are many vascular and neoplastic diseases as well as normal variants that produce the vestibulocochlear symptoms of pulsatile tinnitus, hearing loss, dizziness, and ataxia. Magnetic resonance imaging may be diagnostic, and magnetic resonance angiography/magnetic resonance venography have added to the ability of magnetic resonance to image vascular abnormalities. The extent of neoplasms is accurately assessed and complication of vascular lesions are clearly seen. However, detailed vascular anatomy requires high-quality selective angiography. This enables optimal treatment planning. Endovascular therapeutic intervention has a major role to play in conjunction with surgery of skull base lesions and may be curative in certain conditions, avoiding major surgical procedures. The interventionalist, however, must have an excellent knowledge of the external carotid circulation and all of its potential communications with the internal circulation to avoid serious embolic complications.

Angiography↗

PubMed2000

What percentage of surgically clipped intracranial aneurysms have residual necks?

OBJECTIVE: To determine the angiographically proven rate and persistence of occlusion of intracranial aneurysms after surgical clipping as reported in the literature. This should establish a basis for comparing surgery with new endovascular methods of treatment. METHODS: We reviewed the literature published during the period from 1979 through 1999, dividing the articles into two groups. The first group of articles reported patients undergoing surgical treatment with immediate postoperative angiography. The second group of articles documented symptomatic recurrence or regrowth of aneurysms that were surgically treated previously. The data from these articles are presented for analysis. RESULTS: During the period 1979 to 1999, six series of patients undergoing surgical treatment of aneurysms with immediate postoperative angiography were reported. These reported series comprised a total of 1,397 patients, of whom 1,370 underwent postoperative angiography demonstrating 1,569 clipped aneurysms. Residual filling was found in 82 aneurysms (5.2%) on postoperative angiography. Of the 1,370 patients, only 124 patients with 169 aneurysms were reported to have had any long-term angiographic follow-up. The second group consisted of 226 patients representing six reported groups of patients, who either presented up to 24 years after aneurysm clipping with recurrent symptoms of hemorrhage or mass effect, or had important findings on intraoperative and postoperative angiograms. CONCLUSION: The lack of information regarding both the frequency of residual filling or regrowth and long-term angiographic follow-up of patients with surgically treated aneurysms makes meaningful comparison between surgical treatments and new treatment methods for intracranial aneurysms difficult or impossible. Detailed analysis with high-quality angiography should be performed to determine the success of surgical treatment.

Cerebral Angiography↗

PubMed2000

Giant anterior communicating artery aneurysm infiltrated with a primary cerebral lymphoma: case report.

OBJECTIVE AND IMPORTANCE: Central nervous system lymphomas exhibit angiotropic characteristics. Nevertheless, direct association with an intracranial aneurysm is very rarely reported. We present a case of a giant aneurysm infiltrated with a large cell non-Hodgkin's lymphoma. The incidence of primary central nervous system lymphoma is increasing, and similar cases may become more frequent in the future. CLINICAL PRESENTATION: A 65-year-old man had presented with a giant anterior cerebral artery aneurysm, new onset of seizures, aphasia, and hemiparesis. The aneurysm was treated with Guglielmi detachable coils. Six months later, the patient exhibited fever and neurological deterioration. Magnetic resonance images suggested an enhancing lesion posterior to the neck of the aneurysm. Antibiotic treatment given elsewhere was unsuccessful. INTERVENTION: A craniotomy for a suspected abscess was performed, with removal of the aneurysm and clipping of the neck. The aneurysm sac appeared to be filled with thrombus and pus. The results of aerobic, anaerobic, and fungal cultures were negative. Postoperative magnetic resonance images demonstrated a residual mass, posterior to the aneurysm within the striatum and the internal capsule. Histological examination of the aneurysm wall revealed a large B-cell lymphoma. The diagnosis was confirmed by a stereotactic biopsy. Radiation therapy resulted in a transient decrease in the size of the lesion. CONCLUSION: Although the tumor was not apparent on the initial imaging studies, it may have been the cause of the patient's presenting symptoms. Infiltration of the aneurysm wall by the lymphoma also raises the possibility of a causal relationship. As the incidence of primary central nervous system lymphoma is reported to be on the increase, awareness this uncommon association of an aneurysm and malignant lymphoma is of value.

Aged↗