ABSTRACT
Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.
Subject(s)
Cation Transport Proteins/genetics , Homeostasis/genetics , Hyperostosis/genetics , Mutation , Osteosclerosis/genetics , Skull Base/abnormalities , Animals , Cell Line , Cells, Cultured , Disease Models, Animal , HEK293 Cells , Humans , Hyperostosis/metabolism , Mice, Inbred C57BL , Mice, Knockout , Osteoblasts/cytology , Osteoblasts/metabolism , Osteosclerosis/metabolism , Signal Transduction/genetics , Skull Base/metabolism , Zinc/metabolismABSTRACT
OBJECTIVE: Failed back surgery syndrome (FBSS) is a term embracing a constellation of conditions that describes persistent or recurring low back pain, with or without sciatica following one or more spine surgeries. It has been shown in animals that electrical stimulation of the high cervical C2 area can suppress pain stimuli derived from the L5-S1 dermatome. It is unknown whether C2 electrical stimulation in humans can be used to treat pain derived from the L5-S1 area, and a case is reported in which subcutaneous C2 is applied to treat FBSS. CASE: A patient presents to the neuromodulation clinic because of FBSS (after three lumbar diskectomies) and noninvasive neuromodulation is performed consisting of transcutaneous electrical nerve stimulation (TENS) at C2. The C2 TENS stimulation is successful in improving pain. It induces paresthesias in the C2 dermatome above a certain amplitude threshold, but does not generate paresthesias in the pain area. However, the patient becomes allergic to the skin-applied TENS electrodes and therefore a new treatment strategy is discussed with the patient. A subcutaneous C2 electrode is inserted under local anesthesia, and attached to an external pulse generator. METHODS: Three stimulation designs are tested: a classical tonic stimulation, consisting of 40 Hz stimulation, a placebo, and a burst stimulation, consisting of 40 Hz burst mode, with five spikes delivered at 500 Hz at 1000 µsec pulse width and 1000 µsec interspike interval. RESULTS: The patient's stimulation results demonstrate that burst mode is superior to placebo and tonic mode, and she receives a fully implanted C2 electrode connected to an internal pulse generator via an extension wire. CONCLUSION: The burst design is capable of both suppressing the least and worst pain effectively, and she has remained almost pain-free for over three years.
Subject(s)
Electric Stimulation Therapy , Failed Back Surgery Syndrome/therapy , Implantable Neurostimulators , Adult , Cervical Vertebrae , Contraindications , Diskectomy , Electric Stimulation Therapy/instrumentation , Electric Stimulation Therapy/methods , Failed Back Surgery Syndrome/etiology , Female , Follow-Up Studies , Humans , Hypersensitivity/etiology , Lumbar Vertebrae/surgery , Pain Measurement , Transcutaneous Electric Nerve Stimulation/adverse effects , Transcutaneous Electric Nerve Stimulation/instrumentation , Treatment OutcomeABSTRACT
BACKGROUND: We describe a patient who developed delayed blindness of the left eye at 5 weeks after endovascular coiling of a large ophthalmic aneurysm. CASE DESCRIPTION: A 44-year-old male was admitted with visual decline due to compression of the optic nerve by a large ophthalmic aneurysm. The aneurysm was treated by endovascular coiling, but visual function was unchanged. One month and 7 days later, the patient developed sudden blindness of the affected eye, despite complete angiographical occlusion of the aneurysm. Surgical exploration in an attempt to restore vision showed a fully thrombosed aneurysm but, surprisingly, complete transection of the optic nerve just proximal to its entry into the optic canal. CONCLUSIONS: This report describes a rare complication of a sudden increase in size of a large ophthalmic aneurysm despite successful endovascular occlusion.
Subject(s)
Blindness/etiology , Embolization, Therapeutic , Endovascular Procedures , Intracranial Aneurysm/therapy , Ophthalmic Artery , Optic Nerve Injuries/complications , Adult , Cerebral Angiography , Humans , Imaging, Three-Dimensional , Male , Optic Nerve Injuries/diagnosisABSTRACT
OBJECTIVE: To study the rate of superficial temporal artery (STA) preservation and the effectiveness of STA reconstruction in patients undergoing a pterional craniotomy. METHODS: Included patients (n = 136) underwent either an emergency or an elective pterional craniotomy. In case of deliberate transection or accidental damage of the STA, it was repaired microsurgically at the end of the procedure. Postoperatively, the patency of the STA was assessed on CT angiography, MR angiography, or conventional angiography and complications related to wound healing were recorded. RESULTS: Of the 136 operated patients, the STA could be identified in 120 cases (88%). Of these 120 cases, the STA could be dissected and left undamaged in 60 patients (44%). In 52 patients (38%), 1 of the 2 branches of the STA had to be transsected to elevate the muscle-skin flap. Forty-six of the transected arteries could be anastomosed at the end of the procedure. All of these arteries were patent directly after repair. In the remaining 16 patients (12%), the STA was not identified during approach. All anastomosed arteries (n = 46) were patent. Two patients developed a postoperative infection. CONCLUSIONS: Preserving or reconstructing of the STA during pterional craniotomy is feasible in the majority of the patients with very high rate of anastomosis patency. STA hinders elevation of the skin/muscle flap in approximately 38% of the pterional approaches and without reconstruction afterwards, the STA would been occluded.
Subject(s)
Cerebral Revascularization/methods , Craniotomy/methods , Temporal Arteries/injuries , Temporal Arteries/surgery , Brain Neoplasms/surgery , Cerebral Angiography , Cerebral Revascularization/adverse effects , Craniotomy/adverse effects , Humans , Intracranial Aneurysm/etiology , Intracranial Aneurysm/surgery , Magnetic Resonance Angiography , Postoperative Complications , Surgical Instruments , Temporal Arteries/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
OBJECT: Ischemia-induced tissue depolarizations probably play an important role in the pathophysiology of cerebral ischemia caused by parent vessel occlusion. Their role in ischemia caused by subarachnoid hemorrhage (SAH) remains to be investigated. The authors determined whether ischemic depolarizations (IDs) or cortical spreading depressions (CSDs) occur after SAH, and how these relate to the extent of tissue injury measured on magnetic resonance (MR) images. In addition, they assessed whether administration of MgSO4 reduces depolarization time and lesion volume. METHODS: By means of the endovascular suture model, experimental SAH was induced in 52 rats, of which 37 were appropriate for analysis, including four animals that underwent sham operations. Before induction of SAH, serum Mg++ levels were measured and 90 mg/kg intravascular MgSO4 or saline was given. Extracellular direct current potentials were continuously recorded from six Ag/AgCl electrodes, before and up to 90 minutes following SAH, after which serum Mg++ levels were again measured. Next, animals were transferred to the MR imaging magnet for diffusion-weighted (DW) MR imaging. Depolarization times per electrode were averaged to determine a mean depolarization time per animal. No depolarizations occurred in sham-operated animals. Ischemic depolarizations occurred at all electrodes in all animals after SAH. Only two animals displayed a single spreading depression-like depolarization. The mean duration of the ID time was 41 +/- 25 minutes in the saline-treated controls and 31 +/- 30 minutes in the Mg++-treated animals (difference 10 minutes: p = 0.31). Apparent diffusion coefficient (ADC) maps of tissue H2O, obtained using DW images approximately 2.5 hours after SAH induction, demonstrated hypointensities in both hemispheres, but predominantly in the ipsilateral cortex. No ADC abnormalities were found in sham-operated animals. The mean lesion volume, as defined on the basis of a significant ADC reduction, was 0.32 +/- 0.42 ml in saline-treated controls and 0.11 +/- 0.06 ml in Mg++-treated animals (difference 0.21 ml; p = 0.045). Serum Mg++ levels were significantly elevated in the Mg++-treated group. CONCLUSIONS: On the basis of their data, the authors suggest that CSDs play a minor role, if any, in the acute pathophysiology of SAH. Administration of Mg++ reduces the cerebral lesion volume that is present during the acute period after SAH. The neuroprotective value of Mg++ after SAH may, in part, be explained by a reduction in the duration of the ID of brain cells.
Subject(s)
Brain Infarction/drug therapy , Brain Infarction/etiology , Brain Ischemia/drug therapy , Brain Ischemia/etiology , Calcium Channel Blockers/therapeutic use , Cortical Spreading Depression/drug effects , Magnesium Sulfate/therapeutic use , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Animals , Brain Infarction/pathology , Brain Ischemia/physiopathology , Cortical Spreading Depression/physiology , Disease Models, Animal , Electrophysiology , Magnetic Resonance Imaging , Male , Rats , Rats, Wistar , Subarachnoid Hemorrhage/physiopathology , Time FactorsABSTRACT
OBJECTIVE: Spinal cord stimulation via epidurally implanted electrodes is a common treatment for medically intractable neuropathic pain of different origins. Because tonic electrical stimulation evokes paresthesias over the painful area, this method has never been proven scientifically to be superior to placebo. Recently, burst stimulation (in which closely spaced, high-frequency stimuli are delivered to the spinal cord) has been developed, which does not generate paresthesias. METHODS: A randomized placebo controlled trail in which we compared three stimulation paradigms (burst, tonic, and placebo) was performed on 15 consecutive pain patients. In contrast to tonic stimulation, burst stimulation was able to provide pain relief without the generation of paresthesias, permitting us to use a double-blinded placebo controlled approach. Primary outcome measures were visual analog scale pain scores for back pain, limb pain, and general pain. Secondary outcome measures included the pain vigilance and awareness questionnaire, which is used to measure attention to pain and pain changes, and visual analog scale of the worst, least, and momentary pain. In a subgroup of five patients, a source-localized electroencephalogram was performed under four conditions: baseline, tonic, burst, and placebo stimulation. RESULTS: Burst stimulation was able to improve back, limb, and general pain by 51%, 53%, and 55% and tonic stimulation by 30%, 52%, and 31%, respectively. Pain now, least, and worst pain were improved by 50%, 73%, and 36% by burst stimulation, respectively, and 26%, 46%, and 13% by tonic stimulation. In comparison with placebo, burst, corrected for multiple comparisons, was significantly better for all measurements. However, the greatest differences were obtained in the pain vigilance and awareness questionnaire measurements: burst improved the attention to pain and pain changes, whereas tonic and placebo worsened these measurements. The analysis via encephalogram demonstrates burst stimulation activates the dorsal anterior cingulate and right dorsolateral prefrontal cortex more than tonic stimulation. CONCLUSIONS: The differences between tonic and burst stimulation are likely attributable to a more-selective modulation of the medial pain pathways by burst stimulation, as shown by the activation of the dorsal anterior cingulate cortex.